DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of the species in the reply filed on 9/30/2025 is acknowledged.
Priority
Priority to US 63/063,782, filed 8/10/2020, is acknowledged.
Claim Status
Claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, 76, and 78-89 are pending. Claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, 76, and 78-89 are under examination.
Information Disclosure Statement
The information disclosure statements (IDS) were submitted on 7/18/2023, 10/6/2023, 9/3/2024, 7/1/2025, and 10/15/2025, before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Specifically, the specification recites amino acids sequences that require a SEQ ID NO on page 6 lines 9 and 10; page 22 lines 2, 5, 11, 14, 21; page 25 lines 24, 29, 30; page 26 lines 5, 11, 12, 23, 24; page 31 lines 30, 31, 34; page 44 line 25; page 45 Table 3, Table 4, Table 5.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, 76, and 78-89 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “substantially alternating pattern” in claim 1 is a relative term which renders the claim indefinite. The term “substantially alternating pattern” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Regarding claim 1, a question exists as to how many residues are required to create the claimed “substantially alternating pattern”. Applicant provides example sequences, but given the complex mathematical nature of protein residue combinatorics, a potentially infinite number of alternating patterns are possible given the limitations of claim 1 and it is not clear which of these possibilities would be considered “substantially alternating” are which ones would not.
Claim 1 is rejected.
Regarding claims 2-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, 76, and 78-89, these claims also include “substantially alternating pattern” directly or by way of dependency. Consequently, these claims are rejected.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, 76, and 78-89 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites the function “…configured to self-assemble into the hydrogel…”. However, the recited peptide constraints of “…comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence..” has no length boundaries and broad amino acid identities. Therefore, this sequence space is enormous, potentially infinite.
In this case, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. (MPEP § 2163 (II.A.3.a.ii.))
According to MPEP § 2163 (II.A.3.a.ii.), a "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
As described above, claim 1 recites an extremely large genus of peptides.
MPEP § 2163 (II.A.3.a.ii.) states that “for inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’”
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus.
Applicant does not disclose discrete examples. Applicant discloses peptide data without sequences in Table 1 (Specification, page 42, Table 1). Applicant discloses that different peptides have different numbers of arginines: “The peptide hydrogel may additionally exhibit antimicrobial properties. In general, the antimicrobial properties may be provided by including an antimicrobial functional group. In some embodiments, the antimicrobial functional group may include a cation-rich peptide sequence. In exemplary embodiments, the antimicrobial functional group may include varying ratios of lysine (K) and arginine (R) (FIG. 4). The antimicrobial peptide hydrogel may provide antimicrobial effects against gram-positive and negative bacteria, including, for example, E. coli (FIG. 4), S. aureus, and P. aeruginosa. FIG. 4 is a graph showing
antimicrobial activity (as percent non-viable E. coli remaining after 24 hours of administration) of varying concentrations of peptides having 8 arginine residues (PEP8R), 6 arginine residues (PEP6R), 4 arginine residues (PEP4R), and 2 arginine residues (PEP2R).” (Specification, page 48, line 9). However, it is not clear which sequences are tested in the Example section of the specification.
At the time the invention was made, the level of skill for preparing peptides with desired functional properties was high. However, even if a synthesis and selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify peptides that yield polypeptides with the recited properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure (length) provided by the provided species, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what peptide with a particular set of properties would look like structurally.
No definitive examples are provided. Even if the peptides disclosed in the sequence listing were all tested, this would only be twenty-three sequences of a potentially infinite sequence space. Therefore, the provided examples only represent a limited structural diversity.
Since only a limited number of species of peptides are taught within the claimed genus above, the instant claim above fails the written description requirement. A representative number of species has not been taught to describe this genus. Regarding the peptides, a single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3).
Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates.
Given this unpredictability of protein design, the skilled artisan would not have been in possession of the substantial repertoire of peptide species encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every polynucleotide molecule recited by claim 10.
Regarding claim 2, claim 2 recites the method of claim 1, further A method of treating a subject, comprising: administering the preparation in an amount effective to promote deactivation of a target microorganism at the target tissue, wherein the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11.
This claim does put a charge constraint on the peptides, but does not otherwise reduced the genus size which is still incredibly large. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claim 2 is rejected.
Regarding claims 3-5, 9, 11-13, 17-18, 20, and 23, these claims all have the same genus size as claim 1 or claim 2 and one of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claims 3-5, 9, 11-13, 17-18, 20, and 23 are rejected.
Regarding claim 31, this claim recites the following constraints on the genus:
“The method of claim 1, wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10; the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.”
In a rough approximation, this claim encompasses (10^3)((3^3)(10^3))^10(8)((10^3)(3^3)(10^3) combinations, which is in excess of 1 X 10^30 sequences. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claim 31 is rejected.
Regarding claims 40, 44, 58, 76, and 78-79, these claims all have the same genus size as claim 1 or claim 2 and one of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claims 40, 44, 58, 76, and 78-79 are rejected.
Regarding claim 80, this claim has the same sequence space as claim 31. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claim 80 is rejected.
Regarding claims 81-89, these claims all have the same genus size as claim 1 or claim 2 and one of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claims 81-89 are rejected.
Claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, 76, and 78-89 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the peptides PEP2R, PEP4R, PEP6R, and PEP8R to form into hydrogels that exhibit deactivation of bacteria and treating bacterial biofilms, does not reasonably provide enablement for all claimed peptides to deactivate any possible microorganism nor prevent any biofilms nor treat non-bacterial biofilms. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
The breadth of the claims;
The breadth of claim 1 encompasses any peptide with a folding group having a plurality of charged amino acids residues and hydrophobic residues arranged is a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel. Claim 2 encompasses the same peptide with a charge restriction, but this peptide can deactivate microorganisms.
The nature of the invention;
The invention is a self-assembling peptide that assembles into a hydrogel.
The state of the prior art;
Li et al. (Li, Jieling, et al. Soft matter 15.8:1704-1715. (2019)) discloses that the design of self-assembling peptides has many factors to considers: “They designed four octapeptides with alternating charged and noncharged residues (AEAEAKAK, AEAKAEAK, FEFEFKFK, and FEFKFEFK, where E and K represent glutamic acid and lysine, respectively) and found that sequences containing phenylalanine were more likely to form self-supporting hydrogels, while peptides with alanine residues could form only viscous solutions even at higher concentrations. Peptides (AEAEAKAK and AEAKAEAK) with high contents of alanine and glutamic acid residues showed a greater tendency to form α-helical structures than those with low alanine and glutamic acid contents, while the other two peptides with sequences of FEFEFKFK and FEFKFEFK were reported to form β-sheet structures. These studies on charge-induced structure differentiation should shed light on the mechanism of secondary structure formation and transformation in supramolecular organization.” (Li et al, page 1706, col. 1, para. 1).
Li discloses that ions as well as charge can influence the design of such peptides:
“Not only charges but also ions can affect the self-assembly and hydrogelation behavior of peptides. Ulijn's group reported the copper ion-induced gelation of GHK (G represents glycine and H represents histidine) and FFD (D represents aspartic acid).54 Generally, GHK itself was not a gelator, and FFD has been reported to form a hydrogel only at pH 5. In the work by Ulijn's group, they found that the addition of copper ions to a GHK and FFD mixture at pH 7.4 could trigger the spontaneous hydrogel formation of the mixture. Xu and coworkers reported Ca2+ ion-induced gelation of peptides.55 They designed three small-molecule hydrogelators consisting of multiple carboxylate groups that could form calcium bridges through the coordination of COO− groups and Ca2+ ions. They found that at near-neutral pH, in the absence of Ca2+, the three hydrogelators could form only viscous solutions. Interestingly, upon the addition of Ca2+, the viscous solution could be turned into hydrogels. Moreover, the storage moduli of the hydrogel could be easily tuned by changing the Ca2+ ion concentration. A small increase in Ca2+ concentration could drastically increase the storage modulus of the hydrogel, and the highest storage moduli could reach up to 1.6 × 105 Pa at a quite low concentration of the hydrogelators (0.8 wt%). Increasing the concentration of Ca2+ enhanced not only the storage modulus but also the cross-linking density due to the intrafiber and interfiber coordination of Ca2+ in the hydrogel. Their work offers an alternative approach to control the mechanical properties of soft nanomaterials.” (Li et al, page 1706, col. 1, para. 2).
Regarding the microorganisms, Segal et al. (Segal, et al. Journal of Fungi 4.4: 135. Segal, Esther, and Daniel Elad. "Treatments for fungal infections." Journal of Fungi 4.4 (2018): 135.) discloses that different microorganisms, such as fungi, respond to treatments differently than bacteria: “Antifungal therapy is complicated compared to antibacterial treatments by the fact that fungi and their hosts are both eukaryotic organisms, resulting in fewer targets for selective activity. Thus, the variety of early antimycotics was limited and aimed primarily at the topical treatment of superficial mycoses until the 1980s. The few drugs that could be used systemically for invasive fungal infections were often hampered by toxic effects. The subsequent increase in systemic mycoses, resulting mostly from pathological and iatrogenic states of immunosuppression, necessitated the development of new drugs for systemic administration having a broader spectrum, lower toxicity and better pharmacodynamic/pharmacokinetic characteristics. This led to the production of new and improved azoles and polyene formulations, as well as a new family of drugs—the echinocandins. Several antimycotic drugs currently in various phases of development have novel molecular targets and they are unlikely to be subject to cross resistance with existing drugs [1–4]. It is noteworthy that since immunosuppression is the predisposing factor, to a large part, for invasive fungal infections, the restoration of a functional immune system as soon as possible is of essence in achieving therapeutic success [5], keeping in mind the possible complications derived from the immune reconstitution inflammatory syndrome (IRIS).” (Segal, et al., page 1, para. 1).
(D) The level of one of ordinary skill;
A person of ordinary skill in the art in the field of fusion proteins is usually at least a Master’s level education.
(E) The level of predictability in the art;
Protein-protein interactions are generally unpredictable. A single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3).
Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang 2 (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates.
(F) The amount of direction provided by the inventor and the existence of working examples and the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Applicant provides four examples, PEP2R, PEP4R, PEP6R, and PEP8R, the sequences of which are not fully clear from the specification.
Regarding claim 1, claim 1 encompasses a huge number of peptide sequences as described above. Only PEP2R, PEP4R, PEP6R, and PEP8R, which lack sequences, are shown to self-assemble into hydrogels. It would require undue experimentation for a person of ordinary skill in the art to test all the claimed sequences to see if they properly self-assemble. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and therefore claim 1 is rejected.
Regarding claim 2, claim 2 encompasses a necessarily smaller genus of peptides than claim 1, but still an enormous genus. Claim 2 requires the ability to deactivate microorganisms, which may include fungi. As described above, the treatment for fungi is not the same as for bacteria. The same logic would apply to other microorganisms that are not bacteria. It would require undue experimentation for a person of ordinary skill in the art to test all the claimed sequences to see if they properly self-assemble and see if they are capable of deactivating any possible microorganism. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and therefore claim 1 is rejected.
Regarding claim 3, claim 3 encompasses a huge number of peptide sequences as described above. Only PEP2R, PEP4R, PEP6R, and PEP8R, which lack sequences, are shown to self-assemble into hydrogels. It would require undue experimentation for a person of ordinary skill in the art to test all the claimed sequences to see if they properly self-assemble. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and therefore claim 3 is rejected.
Regarding claim 4, claim 3 encompasses a necessarily smaller genus of peptides than claim 3, but still an enormous genus. Claim 2 requires the ability to deactivate microorganisms, which may include fungi. As described above, the treatment for fungi is not the same as for bacteria. The same logic would apply to other microorganisms that are not bacteria. It would require undue experimentation for a person of ordinary skill in the art to test all the claimed sequences to see if they properly self-assemble and see if they are capable of deactivating any possible microorganism. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and therefore claim 1 is rejected.
Regarding claims 5, 9, 11-13, 17-18, 20, and 23, these claims require the same amount of experimentation as claims 1-4. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and therefore claims 5, 9, 11-13, 17-18, 20, and 23 are rejected.
Regarding claim 31, claim 31 encompasses a necessarily smaller genus of peptides than claim 1, but still an enormous genus. It would require undue experimentation for a person of ordinary skill in the art to test all the claimed sequences to see if they properly self-assemble. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and therefore claim 31 is rejected.
Regarding claims 31, 40, 44, and 58, these claims require the same amount of experimentation as claims 1-4. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and therefore claims 31, 40, 44, and 58 are rejected.
Regarding claim 76, claim 76 encompasses a necessarily smaller genus of peptides than claim 1, but still an enormous genus. Claim 76 requires the ability to treat biofilms. As described above, the treatment for fungi is not the same as for bacteria. Therefore, claim 76 is enabled for bacterial biofilms only. The same logic would apply to other microorganisms that are not bacteria. Regarding prevention, no data is provided that shows prevention of biofilms, bacterial or otherwise.
It would require undue experimentation for a person of ordinary skill in the art to test all the claimed sequences to see if they properly self-assemble and see if they are capable of deactivating any possible microorganism, treat non-bacterial biofilms, or prevent any biofilm. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and therefore claim 76 is rejected.
Regarding claims 78-84, these claims require the same amount of experimentation as claim 76. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and therefore claims 78-84 are rejected.
Regarding claims 85-89, these claims require the same amount of experimentation as claim 3. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and therefore claims 85-89 are rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3, 17, 18, 20, 58, 85, and 89 are rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017.
.
Regarding claim 1, claim 1 recites a method of introducing a hydrogel into a subject, comprising: administering a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution into a target tissue of the subject by injection, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into the hydrogel, the hydrogel being sterilized.
Mehta discloses administering a solution comprising an amphiphilic self-assembling peptide: “…administering, through the delivery device, a solution comprising an amphiphilic self-assembling peptide comprising between about 7 amino acids and 32 amino acids in an effective amount and in an effective concentration to the target area to form a hydrogel barrier under physiological conditions of the target area to treat the pulmonary bulla;…” (Mehta et al., Claim 1).
Mehta also discloses a hydrogel-forming peptide sequence (RADA)4 which is arranged in a substantially alternating pattern of charged and hydrophobic amino acids and a turn sequence (aspartic acid). (Mehta et al., Claim 6).
Mehta also discloses the peptide being in an aqueous solution: “The method of claim 35, wherein preparing the solution comprising the self-assembling peptide comprises:
adding water to a peptide powder of the self-assembling peptide to provide an aqueous peptide solution;…” (Mehta et al., Claim 40).
Mehta discloses injecting the peptide solution: “The method of claim 1, wherein administering the solution comprises injecting the solution into the target area, with overflow solution..” (Mehta et al., Claim 7).
Mehta does not explicitly disclose purification or sterilization of the peptide preparation. However, Gil discloses the filtration and sterilization of very similar peptides: “Among other things, the present disclosure demonstrates that certain peptide compositions (e.g., compositions of particular peptides, at particular concentrations, and/or having particular rheological properties) have certain characteristics and/or may not be amenable to certain handling and/or processing steps such as, for example, filtration (e.g., sterilizing filtration).” (Gil et al., para. [0005]).
“Specifically, solutions of RADA16, IEIK13, and KLD12 per prepared at concentrations indicated below in Table 1. As can be seen, in general, higher concentration solutions showed higher max viscosity.” (Gil et al., para. [0103] and para. [0104], Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of Mehta with the purification scheme of Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to purify the peptide preparation to avoid contaminants being injected into the subject to be treated. A person of ordinary skill in the art would have a reasonable expectation of success because (RADA)4 is synonymous with RADA16 and that was one of the peptides purified by Gil.
Consequently, claim 1 is obvious over Mehta et al. in view of Gil et al. and rejected.
Regarding claim 3, claim 3 recites method of applying a hydrogel to a subject, comprising: topically administering a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution to a target tissue of the subject, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, the hydrogel being sterilized; and topically administering to the target tissue a buffer comprising an effective amount of an ionic salt and a biological buffering agent to form the hydrogel.
Mehta discloses administering a solution comprising an amphiphilic self-assembling peptide: “…administering, through the delivery device, a solution comprising an amphiphilic self-assembling peptide comprising between about 7 amino acids and 32 amino acids in an effective amount and in an effective concentration to the target area to form a hydrogel barrier under physiological conditions of the target area to treat the pulmonary bulla;…” (Mehta et al., Claim 1).
Mehta also discloses a hydrogel-forming peptide sequence (RADA)4 which is arranged in a substantially alternating pattern of charged and hydrophobic amino acids and a turn sequence (aspartic acid). (Mehta et al., Claim 6).
Mehta discloses topical administration of the solution: “Administering the solution may comprise applying the solution topically to the target area.” (Mehta et al., para [0070]).
Mehta discloses usage of buffers: “In some embodiments, a buffer, such as a buffer solution may be added to the self-assembling peptide solution or the self-assembling peptide.” (Mehta et al., para [0142]) and the usage of ionic salts: “To adjust the salt ionic strength of the peptide solutions by way of example, various salt buffer solutions including NaCl, KCl, MgCl2, CaCl2 and DPBS (10×) were added to 2 mL of 1.5% peptide solutions.” (Mehta et al., para. [0177]).
Mehta does not explicitly disclose purification or sterilization of the peptide preparation. However, Gil discloses the filtration and sterilization of very similar peptides: “Among other things, the present disclosure demonstrates that certain peptide compositions (e.g., compositions of particular peptides, at particular concentrations, and/or having particular rheological properties) have certain characteristics and/or may not be amenable to certain handling and/or processing steps such as, for example, filtration (e.g., sterilizing filtration).” (Gil et al., para. [0005]).
“Specifically, solutions of RADA16, IEIK13, and KLD12 per prepared at concentrations indicated below in Table 1. As can be seen, in general, higher concentration solutions showed higher max viscosity.” (Gil et al., para. [0103] and para. [0104], Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of Mehta with the purification scheme of Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to purify the peptide preparation to avoid contaminants being injected into the subject to be treated. A person of ordinary skill in the art would have a reasonable expectation of success because (RADA)4 is synonymous with RADA16 and that was one of the peptides purified by Gil.
Consequently, claim 3 is obvious over Mehta et al. in view of Gil et al. and rejected.
Regarding claim 17, claim 1 is obvious as described above. Claim 17 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 17 is obvious over Mehta et al. in view of Gil et al. and rejected.
Regarding claim 18, claim 17 is obvious as described above. Claim 18 further recites the case wherein the combining of the buffer and preparation takes places less than about 10 minutes prior to administration.
Mehta discloses: “It may also be desired to provide a hydrogel barrier that is quick to gel, i.e., the gelation kinetics are such that, upon administration, the hydrogel barrier is formed within a short amount of time to treat the pulmonary bulla and/or leakage. The short amount of time may be instantaneous or, for example, less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds, or other times disclosed herein.” (Mehta et al., para. [0064]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to trigger hydrogel assembly this way as disclosed by Mehta. The time frame of less than 5 minutes overlaps substantially with less than 10 minutes as claimed. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the art would do this if they wanted to inject a partially formed hydrogel or fully formed hydrogel. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes that the hydrogel barrier forms , less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds.
Consequently, claim 18 is obvious over Mehta et al. in view of Gil et al. and rejected.
Regarding claim 20, claim 1 is obvious as described above. Claim 20 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Mehta discloses: “The salt solution may comprise at least one anion selected from the group consisting of chloride, sulfate, acetate, carbonate, chloride, citrate, cyanide, fluoride, sulfate, nitrate, nitrite, and phosphate.” (Mehta et al., para. [0129]).
Furthermore, Mehta discloses the following example: “A peptide hydrogel mixed with a cation/anion solution which affected mechanical properties and another with a very low concentration of a contrast agent which did not affect the mechanical properties were both designed. The two gels were: (1) a combination of the self-assembling peptide with a well-known cation/anion solution, Ringer's Solution (pH 5.3), used in the medical field and (2) a combination of the self-assembling peptide with a well-known contrast agent, indigo carmine, which is a dye solution containing sulfate (anion) and sodium (cation) ions. Indigo carmine contains indigoindisulfonate sodium (C16H8N2Na2O8S2), water, and sodium citrate (C6H8O7) for pH adjustment.” (Mehta et al., para. [0190]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use acetate or citrate counterions with the claimed peptide.
A person of ordinary skill in the art would be motivated to try counterions from the finite list provided by Mehta and be further motivated by the example provided by Mehta that utilizes citrate in the buffer. A person or ordinary skill in the art would have a reasonable expectation of success because acetate and citrate are listed by Mehta as buffer ions.
Consequently, claim 20 is obvious over Mehta et al. in view of Gil et al. and rejected.
Regarding claim 58, claim 1 is obvious as described above. Claim 58 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Mehta discloses the following peptide concentrations:
“The effective concentration may include peptide concentrations in the solution in a range of about 0.1 weight per volume (w/v) percent to about 10 w/v percent. The effective concentration may include peptide concentrations in the solution in a range of about 0.1 w/v percent to about 3.5 w/v percent. In certain embodiments, the effective concentration may be about 1 w/v percent. In certain other embodiments, the effective concentration may be about 1.5 w/v percent. In other embodiments, the effective concentration may be about 2.5 w/v percent.” (Mehta et al., para. [0107]).
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Consequently, claim 58 is obvious over Mehta et al. in view of Gil et al. and rejected.
Regarding claim 85, claim 3 is obvious as described above. Claim 85 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Mehta discloses: “The salt solution may comprise at least one anion selected from the group consisting of chloride, sulfate, acetate, carbonate, chloride, citrate, cyanide, fluoride, sulfate, nitrate, nitrite, and phosphate.” (Mehta et al., para. [0129]).
Furthermore, Mehta discloses the following example: “A peptide hydrogel mixed with a cation/anion solution which affected mechanical properties and another with a very low concentration of a contrast agent which did not affect the mechanical properties were both designed. The two gels were: (1) a combination of the self-assembling peptide with a well-known cation/anion solution, Ringer's Solution (pH 5.3), used in the medical field and (2) a combination of the self-assembling peptide with a well-known contrast agent, indigo carmine, which is a dye solution containing sulfate (anion) and sodium (cation) ions. Indigo carmine contains indigoindisulfonate sodium (C16H8N2Na2O8S2), water, and sodium citrate (C6H8O7) for pH adjustment.” (Mehta et al., para. [0190]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use acetate or citrate counterions with the claimed peptide.
A person of ordinary skill in the art would be motivated to try counterions from the finite list provided by Mehta and be further motivated by the example provided by Mehta that utilizes citrate in the buffer. A person or ordinary skill in the art would have a reasonable expectation of success because acetate and citrate are listed by Mehta as buffer ions.
Consequently, claim 85 is obvious over Mehta et al. in view of Gil et al. and rejected.
Regarding claim 89, claim 3 is obvious as described above. Claim 89 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Mehta discloses the following peptide concentrations:
“The effective concentration may include peptide concentrations in the solution in a range of about 0.1 weight per volume (w/v) percent to about 10 w/v percent. The effective concentration may include peptide concentrations in the solution in a range of about 0.1 w/v percent to about 3.5 w/v percent. In certain embodiments, the effective concentration may be about 1 w/v percent. In certain other embodiments, the effective concentration may be about 1.5 w/v percent. In other embodiments, the effective concentration may be about 2.5 w/v percent.” (Mehta et al., para. [0107]).
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Consequently, claim 89 is obvious over Mehta et al. in view of Gil et al. and rejected.
Claims 2 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017 as applied to claim 1, further in view of Salick et al. (US20110171304, published 7/14/2011).
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites administering in an amount effective to promote deactivation of a target microorganism at the target tissue, wherein the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11.
Mehta and Gil do not specifically disclose a peptide meeting these limitations. However, Salick et al. discloses an hydrogel-forming antimicrobial peptide sequence that does meet these limitations: “A peptide comprising the sequence VKVKVRVKVDPPTKVKVRVKV-NH2 forms a hydrogel which has the ability to shear-thin and recover. The hydrogel, both before and after shear-thinning, is capable of killing bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).” (Salick et al., Abstract).
This peptide has a net charge of +8 and possesses turn sequence residues D-proline and proline. Furthermore, it kills MRSA bacteria which qualifies as “deactivation” under the broadest reasonable interpretation of “deactivation”.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of Mehta and Gil with the peptide disclosed by Salick to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination to create a hydrogel that is active against harmful MRSA bacteria. A person of ordinary skill in the art would have a reasonable expectation of success because Salick discloses that VKVKVRVKVDPPTKVKVRVKV-NH2 is capable of killing MRSA and forms a hydrogel. Also, this peptide is similar in size and has alternating hydrophobic and charged residues so a person of ordinary skill in the art would expect the purification methods of Gil to work on this peptide as well.
Consequently, claim 2 is obvious over Mehta et al. in view of Gil et al. as applied to claim 1 above, further in view of Salick et al. and rejected.
Regarding claim 4, claim 3 is obvious as described above. Claim 4 further recites administering in an amount effective to promote deactivation of a target microorganism at the target tissue, wherein the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11.
Mehta and Gil do not specifically disclose a peptide meeting these limitations. However, Salick et al. discloses an hydrogel-forming antimicrobial peptide sequence that does meet these limitations: “A peptide comprising the sequence VKVKVRVKVDPPTKVKVRVKV-NH2 forms a hydrogel which has the ability to shear-thin and recover. The hydrogel, both before and after shear-thinning, is capable of killing bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).” (Salick et al., Abstract).
This peptide has a net charge of +8 and possesses turn sequence residues D-proline and proline. Furthermore, it kills MRSA bacteria which qualifies as “deactivation” under the broadest reasonable interpretation of “deactivation”.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of Mehta and Gil with the peptide disclosed by Salick to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination to create a hydrogel that is active against harmful MRSA bacteria. A person of ordinary skill in the art would have a reasonable expectation of success because Salick discloses that VKVKVRVKVDPPTKVKVRVKV-NH2 is capable of killing MRSA and forms a hydrogel. Also, this peptide is similar in size and has alternating hydrophobic and charged residues so a person of ordinary skill in the art would expect the purification methods of Gil to work on this peptide as well.
Consequently, claim 4 is obvious over Mehta et al. in view of Gil et al. as applied to claim 3 above, further in view of Salick et al. and rejected.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017 as applied to claim 1, further in view of Jin et al. (Jin, Jing-fen, et al. Patient preference and adherence:923-942 (2015)).
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein injecting the preparation into the subject comprises infusing the preparation into the subject, or the preparation is injected via intravenous, intrasecal, intramuscular, subcutaneous, intradermal, intramedullary, intravascular, intraventricular, intrabiliary, intrathecal, or epidural administration.
Mehta and Gil do not specifically disclose these modes of injection. However, Jin et al. discloses that intravenous, intramuscular, and subcutaneous modes of injections are frequently used: “Intravenous (IV), intramuscular (IM), and subcutaneous (SC) are the three most frequently used injection routes in medication administration. Comparative studies of SC versus IV, IM versus IV, or IM versus SC have been sporadically conducted, and some new findings are completely different from the dosage recommendation as described in prescribing information.” (Jin et al., Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use one of the injection methods disclosed by Jin with the method of Mehta and Gil.
A person of ordinary skill in the art would be motivated to use such methods for the following reasons: “ IV injection is the introduction of a medication into the veins using a needle, and it is used when rapid absorption is called for, when fluid cannot be taken by mouth, or when the medication to be administered is too irritating to be injected into the skin or muscles. SC injection is administered as a bolus into the subcutis. IM injection is the technique used to deliver a medication deep into the muscles, allowing the medication to be absorbed into the bloodstream quickly. Prescribing information for some medications notes that they can be injected via one or more routes (eg, epinephrine can be delivered by IV, IM, or SC route), while prescribing information for the majority of injectable medications only describes one injection route.” (Jin et al., page 924, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because these are the three most frequently used injection methods in this field as disclosed above.
Consequently, claim 5 is obvious over Mehta et al. in view of Gil et al. as applied to claim 1, further in view of Jin et al. and rejected.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017 as applied to claim 3, further in view of Harding et al. (Harding, K. G., V. Jones, and P. Price. "Topical treatment: which dressing to choose." Diabetes/metabolism research and reviews 16.S1: S47-S50. (2000)).
Regarding claim 9, claim 3 is obvious as described above. Claim 9 further recites the case wherein the method further comprises applying a topical dressing after administration of the preparation.
Mehta and Gil do not specifically disclose the usage of a wound dressing. However, Harding et al. discloses the usage of wound dressings: “Wounds have existed since prehistoric times and many famous physicians through the ages have contributed to an understanding of healing. Around 1000 BC Homer provided a detailed description of 147 wounds in the Iliad. Hippocrates in 400 BC wrote 70 essays, many of which describe wounds and how we recognise the value of cleansing and the use of wine and vinegar as topical treatment for wounds. Celsus (20–50 AD) described the cardinal features of inflammation and Galen then dominated medical thinking until the Middle Ages when Paracelsus made the observation that although he dressed the wound God healed it. Subsequently absorbent cotton and gauze materials came into widespread use, and in 1916 Vaseline-coated gauze was first developed.” (Harding et al., page S47, para. 1). Furthermore, Harding discloses various advantages to different types of dressings (Harding et al., page S50, Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use wound dressings as disclosed by Harding after the method of Mehta and Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use wound dressings to avoid post-treatment infection and have a reasonable expectation of success because Harding discloses that dressings have been used for thousands of years and there are new modern dressings that have more specialized roles.
Consequently, claim 9 is obvious over Mehta et al. in view of Gil et al. as applied to claim 3 above, further in view of Harding et al. and rejected.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017 as applied to claim 3, further in view of Nunez (https://www.healthline.com/health/debridement, accessed 3/4/2026, published 2/13/2019).
Regarding claim 11, claim 3 is obvious as described above. Claim 11 further recites the case wherein target tissue is debrided before administration of the preparation.
Mehta and Gil do not specifically disclose debridement. However, Nunez discloses that: “Debridement is the removal of dead (necrotic) or infected skin tissue to help a wound heal. It’s also done to remove foreign material from tissue.” (Nunez, page 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to debride the target tissue as disclosed by Nunez before the method of Mehta and Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to debride the tissue to gain the benefits disclosed by Nunez: “Wound debridement can:
help healthy tissue grow
minimize scarring
reduce complications of infections” (Nunez, page 1, para. 3).
A person of ordinary skill in the art would have a reasonable expectation of success because Nunez discloses that this procedure is essential for wounds stuck in the first healing stage: “The procedure is essential for wounds that aren’t getting better. Usually, these wounds are trapped in the first stage of healing. When bad tissue is removed, the wound can restart the healing process.” (Nunez, page 1, para. 2).
Consequently, claim 11 is obvious over Mehta et al. in view of Gil et al. as applied to claim 3 above, further in view of Nunez and rejected.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017 as applied to claim 3, further in view of Ibrahim (Ibrahim, Sarah A. "Spray-on transdermal drug delivery systems." Expert opinion on drug delivery 12.2:195-205 (2015)).
Regarding claim 12, claim 3 is obvious as described above. Claim 12 further recites the case wherein administration is by spray, dropper, film, squeeze tube, or syringe.
Mehta and Gil do not specifically disclose administration by spray, dropper, film, squeeze tube, or syringe. However, Ibrahim discloses that: “A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug–solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin.” (Ibrahim, page 195, para. 2).
Ibrahim also discloses that: “Spray-on products have been successfully used on skin for local and topical indications, with recent advancements allowing systemic delivery of drugs.” (Ibrahim, page 196, col. 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to deliver the preparation topically with a spray.
A person of ordinary skill in the art would be motivated to use spray application because Ibrahim discloses that spray on drug delivery can increase drug loading into skin as described by Ibrahim above.
A person of ordinary skill in the art would have a reasonable expectation of success because Ibrahim discloses that spray has been successfully used for the delivery of drug products as described above.
Consequently, claim 12 is obvious over Mehta et al. in view of Gil et al. as applied to claim 3 above, further in view of Ibrahim and rejected.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017 as applied to claim 1, further in view of Salick et al. (US20110171304, published 7/14/2011) and Broekhuizen et al. (Broekhuizen, et al. "Tissue around catheters is a niche for bacteria associated with medical device infection." Critical care medicine 36.8: 2395-2402 (2008)).
Regarding claim 13, claim 1 is obvious as described above. Claim 13 further recites the case wherein 13 the target tissue is a tissue selected from mesenchymal tissue, connective tissue, muscle tissue, nervous tissue, embryonic tissue, dermal tissue, bone tissue, dental tissue, corneal tissue, cutaneous tissue, integumental tissue, soft tissue, and hard tissue, or administration to the target tissue comprises administration to a biological fluid selected from tears, mucus, urine, menses, blood, wound exudates, and mixtures thereof.
Mehta and Gil do not specifically disclose these target tissues.
However, Broekhuizen discloses that skin tissue becomes susceptible to bacterial infection when medical devices such as catheters are used:
“The skin biopsies of patients 1, 2, 3, 5, 7, and 8 contained large numbers of bacteria (≥103 cfu) of the same species as cultured from the subcutaneous tissue, predominantly S. epidermidis and E. faecalis (Table 1). The subcutaneous tissue swabs yielded no bacteria (patient 4 and 6) or only relatively low numbers of bacteria (patients 2, 3, 5, and 8). In patient 7, the subcutaneous swab yielded >103 bacteria, but the subcutaneous tissue samples, including those from the deeper tissue (3rd level biopsy, Table 1, Fig. 1), contained very high numbers of bacteria. Apparently, in this patient both the skin and the subcutaneous tissue were highly colonized.” (Broekhuizen et al., page 2398, col. 2, para. 2).
Salick discloses that MRSA infections can occur with medical devices: “In general, infection at a wound site prolongs healing, and with respect to medical implants, infection at the implant-tissue interface can result in implant failure. Thus, the ability to control and prevent infections is of critical importance in the medical field. One common infectious bacterium, Staphylococcus aureus, has traditionally been treated with standard antibiotics. However, drug resistant bacterial strains have evolved. Methicillin-resistant Staphylococcus aureus (MRSA) infections have become common and account for about 55% of all nosocomial infections acquired in intensive care units in the United States.” (Salick et al., para. [0003]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the method of Mehta and Gil with the antimicrobial peptide of Salick to a dermal area because of the risk of bacterial infection described by Broekhuizen.
A person of ordinary skill in the art would be motivated to do this to avoid infection in a patient with a medical device that interfaces with skin and have a reasonable expectation of success because Salick discloses the antimicrobial activity of their disclosed peptide, particularly against MRSA.
Consequently, claim 13 is obvious over Mehta et al. in view of Gil et al. as applied to claim 1, further in view of Salick et al. and Broekhuizen et al. and rejected.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017 as applied to claim 1, further in view of Branco et al. (Branco, Monica C., et al. "Fast dynamics of semiflexible chain networks of self-assembled peptides." Biomacromolecules 10.6: 1374-1380.) (2009)).
Regarding claim 23, claim 17 is obvious as described above. Claim 23 further recites the case wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bris-tris propane (BTP).
Mehta et al. discloses: “In some embodiments, a solution or composition of the self-assembling peptide may be buffered with about 0.15 M of at least one of sodium chloride, potassium chloride, and calcium chloride.”
Furthermore, Branco discloses the mechanism of hydrogel induction for a peptide MAX1: VKVKVKVKVDPPTKVKVKVKV which is very similar to Applicant SEQ ID NO: 2. Branco discloses:
“The primary sequence of MAX1 consists of a total of 20 amino acids with alternating valine (V) and lysine (K) residues on two β-strands. (13-16) These strands are centrally connected by a tetrapeptide (-VDPPT-) sequence that has a high propensity to adopt a type II′ β-turn configuration (Figure 1A). In pH 7.4 aqueous solutions at low ionic strength, these peptides are designed to remain freely soluble and unfolded due to electrostatic repulsions between the positively charged lysine side chains (Figure 1B). When a physiologically relevant salt concentration is introduced (150 mM NaCl), the electrostatic repulsions between the lysine side chains are screened and the peptide folds into a β-hairpin structure, stabilized by intramolecular hydrogen bonds. (13, 14) When folded, the hairpin exhibits facial amphiphilicity with one face containing hydrophilic lysine residues and the other face comprised of hydrophobic valines. The valine-rich face undergoes hydrophobic collapse, driving the self-assembly of the folded hairpins into fibrils, which are further stabilized by intermolecular hydrogen bonding. (17) These two events, folding and self-assembly, although discussed as separate events, are most likely occurring concurrently. (44) The resultant fibrils are essentially irreversibly assembled such that their structure is path dependent. Transmission electron microscopy (TEM), small angle neutron scattering (SANS), and rheology demonstrate that the resultant, rigid networks of the semiflexible fibrils are composed of a bilayer of hairpins with a cross-sectional diameter of 3 nm, corresponding to the width of a folded peptide (Figure 1C). The fibrils are connected by noncovalent, interfibrillar junctions and entanglements. (13, 14, 16) Imperfections in the self-assembly mechanism, in which one hairpin is rotated relative to another hairpin in the bilayer, gives rise to interfibril branching (Figure 1B).” (Branco et al., page 1374, col. 2., para. 1).
Branco also discloses the buffer composition of “MAX1 and MAX8 hydrogels of 1.0 and 1.5 wt % were prepared using a pH 7.4, 50 mM BTP buffer with a salt concentration of 150 mM NaCl.” (Branco et al., page 1375, col. 2., para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the buffer composition disclosed by Branco to induce hydrogel formation as disclosed by Mehta and Gil.
A person of ordinary skill in the art would be motivated to induce hydrogel formation before injection if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow.
A person of ordinary skill in the art would have a reasonable expectation of success because the peptide of Branco is charge identical to Applicant SEQ ID NO: 2 and possesses a turn sequence just like Applicant SEQ ID NO: 2. A person of ordinary skill in the art would reasonably expect a peptide so similar to react in a similar manner to the same buffer conditions. Also, the Branco paper is about hydrogel crosslink formation in general and Branco uses this buffer to induce hydrogel formation.
Consequently, claim 23 is obvious over Mehta et al. in view of Gil et al. as applied to claim 17 above, further in view of Branco et al. and rejected.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017 as applied to claim 1, further in view of Veiga et al. (Veiga, Ana Salomé, et al. "Arginine-rich self-assembling peptides as potent antibacterial gels." Biomaterials 33.35: 8907-8916 (2012)).
Regarding claim 31, claim 1 is obvious as described above. Claim 31 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Veiga discloses an arginine-rich self-assembling peptide, aligned against Applicant SEQ ID NO: 2:
VKVRVRVRVDPPTRVRVRVKV
VKVRVRVRVDPPTRVRVRVKV
For these peptides, Y=V, X=R and K, N=4, M=4, and T is a D-proline and a proline.
Consequently, claim 31 is obvious over Mehta et al. in view of Gil et al. as applied to claim 1 above, further in view of Veiga et al. and rejected.
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017 as applied to claim 1, further in view of Kumar et al. (Kumar, et al. Protein Expression and Purification 95: 129-135 (2014)).
Regarding claim 40, claim 1 is obvious as described above. Claim 40 further recites the case wherein the peptide is at least 80% purified.
Mehta and Gil do not disclose a specific protein purity.
However, Mehta discloses that the peptides may be purified: “The peptides can be chemically synthesized or they can be purified from natural and recombinant sources.” (Mehta et al., para. [0116]).
Furthermore, Kumar discloses methods of protein purification that result in proteins that are at least 80%: “Subsequently, GST–APJ C-ter was purified to ∼90% purity by GSH affinity in cleavage buffer with 2 M urea (Fig. 1c and d). GST-apelin23* and GST-apelin proteins were over-expressed at 24 °C and purified to ∼95–99% purity (Supplementary Figs. 3 and 4 respectively) by GSH affinity chromatography.” (Kumar et al., page 132, col. 2, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to purify the peptide of claim 1 to at least 80% purity.
A person of ordinary skill in the art would be motivated to purify the peptide because impurities are unwanted in therapeutic compositions so they don’t interfere with the activity of the therapeutic or crate toxic side effects. A person of ordinary skill in the art would have a reasonable expectation of success because Mehta discloses that peptide may be purified and Kumar discloses specific protocols and percentage purities that result from said protocols.
Consequently, claim 40 is obvious over Mehta et al. in view of Gil et al. as applied to claim 1 above, further in view of Kumar et al. and rejected.
Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017 as applied to claim 1, further in view of Mauri et al. (Mauri, et al. Journal of visualized experiments: JoVE 116: 54445.(2016)).
Regarding claim 44, claim 1 is obvious as described above. Claim 44 further recites the case wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.
Mehta and Gil et al. do not specifically disclose an additional functional group added to the peptide. However, Mauri discloses the usage of RGD functionalization to improve the cell adhesion capabilities of a hydrogel:
“The combination of click chemistry and the microwave-assisted method is suitable to produce biocompatible hydrogels with desired functionalities and improved performances in biomedical applications. This work aims to synthesize RGD-functionalized hydrogels. RGD (arginylglycylaspartic acid) is a tripeptide that can mimic cell adhesion proteins and bind to cell-surface receptors, creating a hospitable microenvironment for cells within the 3D polymeric network of the hydrogels. RGD functionalization occurs through Huisgen 1,3-dipolar cycloaddition. Some PAA carboxyl groups are modified with an alkyne moiety, whereas RGD is functionalized with azido acid as the terminal residue of the peptide sequence. Finally, both products are used in a copper catalyzed click reaction to permanently link the peptide to PAA. This modified polymer is used with carbomer, agarose and polyethylene glycol (PEG) to synthesize a hydrogel matrix. The 3D structure is formed due to an esterification reaction involving carboxyl groups from PAA and carbomer and hydroxyl groups from agarose and PEG through microwave-assisted polycondensation. The efficiency of the gelation mechanism ensures a high degree of RGD functionalization. In addition, the procedure to load therapeutic compounds or biological tools within this functionalized network is very simple and reproducible.” (Mauri et al., Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add the RGD functionality of Mauri to the peptide of Mehta and Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination in order to increase the cell adhesion potential of the hydrogel in question. A person of ordinary skill in the art would have a reasonable expectation of success because Mauri describes in detail how this RGD functionalization performs this task and Mauri is specifically discussing hydrogels.
Consequently, claim 44 is obvious over Mehta et al. in view of Gil et al. as applied to claim 1 above, further in view of Mauri et al. and rejected.
Claims 76, 78-84, and 86-88 are rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017), Salick et al. (US20110171304, published 7/14/2011) and Zapotoczna et al. (Zapotoczna, et al. PLoS pathogens 12.7: e1005671 (2016)).
Regarding claim 76, claim 76 recites a method of treating or preventing a biofilm comprising a microbial, fungal, or viral colonization, the method comprising: topically or by injection administering to a target site of the biofilm a thermally stable preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11,the peptide being configured to self-assemble into a hydrogel, the hydrogel being sterilized, in an amount effective to treat or prevent the biofilm.
Mehta discloses administering a solution comprising an amphiphilic self-assembling peptide: “…administering, through the delivery device, a solution comprising an amphiphilic self-assembling peptide comprising between about 7 amino acids and 32 amino acids in an effective amount and in an effective concentration to the target area to form a hydrogel barrier under physiological conditions of the target area to treat the pulmonary bulla;…” (Mehta et al., Claim 1).
Mehta discloses injecting the peptide solution: “The materials and methods may include administration, application, or injection of a self-assembling peptide, or a solution comprising a self-assembling peptide, or a composition comprising a self-assembling peptide, to a predetermined or desired target area.” (Mehta et al., para. [0051]) and ” Administering the solution may comprise injecting the solution into the target area, with overflow to, for example, cover the target area topically.” (Mehta et al. para. [0070]).
Mehta does not explicitly disclose purification or sterilization of the peptide preparation. However, Gil discloses the filtration and sterilization of very similar peptides: “Among other things, the present disclosure demonstrates that certain peptide compositions (e.g., compositions of particular peptides, at particular concentrations, and/or having particular rheological properties) have certain characteristics and/or may not be amenable to certain handling and/or processing steps such as, for example, filtration (e.g., sterilizing filtration).” (Gil et al., para. [0005]).
“Specifically, solutions of RADA16, IEIK13, and KLD12 per prepared at concentrations indicated below in Table 1. As can be seen, in general, higher concentration solutions showed higher max viscosity.” (Gil et al., para. [0103] and para. [0104], Table 1).
Salick et al. discloses an hydrogel-forming antimicrobial peptide sequence that does meet these limitations: “A peptide comprising the sequence VKVKVRVKVDPPTKVKVRVKV-NH2 forms a hydrogel which has the ability to shear-thin and recover. The hydrogel, both before and after shear-thinning, is capable of killing bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).” (Salick et al., Abstract).
This peptide has a net charge of +8 and possesses turn sequence residues D-proline and proline.
Lastly, Zapotoczna discloses that MRSA creates biofilms: “From the earliest identification of poly-N-acetylglucosamine (PNAG)/polysaccharide intercellular adhesin (PIA) as a first known mediator of Staphylococcus epidermidis biofilm formation (reviewed in [1]), interest in this important virulence determinant has led to the discovery of multiple biofilm mechanisms in S. epidermidis and S. aureus.” (Zapotoczna et al., page 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the purification scheme of Gil and the peptide of Salick to treat the biofilm as disclosed by Zapotoczna to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to purify the peptide preparation to avoid contaminants being injected into the subject to be treated. A person of ordinary skill in the art would be motivated to use the peptide of Salick to create a hydrogel that is active against harmful MRSA bacteria.
A person of ordinary skill in the art would have a reasonable expectation of success because (RADA)4 is synonymous with RADA16 and that was one of the peptides purified by Gil.
A person of ordinary skill in the art would have a reasonable expectation of success because Salick discloses that VKVKVRVKVDPPTKVKVRVKV-NH2 is capable of killing MRSA and forms a hydrogel. Also, this peptide is similar in size and has alternating hydrophobic and charged residues so a person of ordinary skill in the art would expect the purification methods of Gil to work on this peptide as well.
Finally, Zapotoczna discloses that MRSA can create biofilms and therefore this method treats biofilms by killing MRSA.
Consequently, claim 76 is obvious over Mehta et al. in view of Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 78, claim 76 is obvious as described above. Claim 78 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 78 is obvious over Mehta et al. in view of Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 79, claim 76 is obvious as described above. Claim 79 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Mehta discloses: “The salt solution may comprise at least one anion selected from the group consisting of chloride, sulfate, acetate, carbonate, chloride, citrate, cyanide, fluoride, sulfate, nitrate, nitrite, and phosphate.” (Mehta et al., para. [0129]).
Furthermore, Mehta discloses the following example: “A peptide hydrogel mixed with a cation/anion solution which affected mechanical properties and another with a very low concentration of a contrast agent which did not affect the mechanical properties were both designed. The two gels were: (1) a combination of the self-assembling peptide with a well-known cation/anion solution, Ringer's Solution (pH 5.3), used in the medical field and (2) a combination of the self-assembling peptide with a well-known contrast agent, indigo carmine, which is a dye solution containing sulfate (anion) and sodium (cation) ions. Indigo carmine contains indigoindisulfonate sodium (C16H8N2Na2O8S2), water, and sodium citrate (C6H8O7) for pH adjustment.” (Mehta et al., para. [0190]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use acetate or citrate counterions with the claimed peptide.
A person of ordinary skill in the art would be motivated to try counterions from the finite list provided by Mehta and be further motivated by the example provided by Mehta that utilizes citrate in the buffer. A person or ordinary skill in the art would have a reasonable expectation of success because acetate and citrate are listed by Mehta as buffer ions.
Consequently, claim 79 is obvious over Mehta et al. in view of Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 80, claim 76 is obvious as described above. Claim 80 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Salick discloses this peptide: VKVKVRVKVDPPTKVKVRVKV-NH2 (Salick et al., Abstract).
For this peptide, Y=V, X=R and K, N=4, M=4, and T is a D-proline and a proline.
Consequently, claim 80 is obvious over Mehta et al. in view of Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 81, claim 76 is obvious as described above. Claim 81 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Mehta discloses the following peptide concentrations:
“The effective concentration may include peptide concentrations in the solution in a range of about 0.1 weight per volume (w/v) percent to about 10 w/v percent. The effective concentration may include peptide concentrations in the solution in a range of about 0.1 w/v percent to about 3.5 w/v percent. In certain embodiments, the effective concentration may be about 1 w/v percent. In certain other embodiments, the effective concentration may be about 1.5 w/v percent. In other embodiments, the effective concentration may be about 2.5 w/v percent.” (Mehta et al., para. [0107]).
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Consequently, claim 81 is obvious over Mehta et al. in view of Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 82, claim 76 is obvious as described above. Claim 82 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 82 is obvious over Mehta et al. in view of Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 83, claim 82 is obvious as described above. Claim 83 further recites the case wherein the combining of the buffer and preparation takes places less than about 10 minutes prior to administration.
Mehta discloses: “It may also be desired to provide a hydrogel barrier that is quick to gel, i.e., the gelation kinetics are such that, upon administration, the hydrogel barrier is formed within a short amount of time to treat the pulmonary bulla and/or leakage. The short amount of time may be instantaneous or, for example, less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds, or other times disclosed herein.” (Mehta et al., para. [0064]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to trigger hydrogel assembly this way as disclosed by Mehta. The time frame of less than 5 minutes overlaps substantially with less than 10 minutes as claimed. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the art would do this if they wanted to inject a partially formed hydrogel or fully formed hydrogel. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes that the hydrogel barrier forms , less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds.
Consequently, claim 83 is obvious over Mehta et al. in view of Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Claim 84 is rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017), Salick et al. (US20110171304, published 7/14/2011) and Zapotoczna et al. (Zapotoczna, et al. PLoS pathogens 12.7: e1005671 (2016)) as applied to claim 76 above, further in view of Branco et al. (Branco, Monica C., et al. "Fast dynamics of semiflexible chain networks of self-assembled peptides." Biomacromolecules 10.6: 1374-1380.) (2009)).
Regarding claim 84, claim 82 is obvious as described above. Claim 84 further recites the case wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bris-tris propane (BTP).
Mehta et al. discloses: “In some embodiments, a solution or composition of the self-assembling peptide may be buffered with about 0.15 M of at least one of sodium chloride, potassium chloride, and calcium chloride.”
Furthermore, Branco discloses the mechanism of hydrogel induction for a peptide MAX1: VKVKVKVKVDPPTKVKVKVKV which is very similar to Applicant SEQ ID NO: 2. Branco discloses:
“The primary sequence of MAX1 consists of a total of 20 amino acids with alternating valine (V) and lysine (K) residues on two β-strands. (13-16) These strands are centrally connected by a tetrapeptide (-VDPPT-) sequence that has a high propensity to adopt a type II′ β-turn configuration (Figure 1A). In pH 7.4 aqueous solutions at low ionic strength, these peptides are designed to remain freely soluble and unfolded due to electrostatic repulsions between the positively charged lysine side chains (Figure 1B). When a physiologically relevant salt concentration is introduced (150 mM NaCl), the electrostatic repulsions between the lysine side chains are screened and the peptide folds into a β-hairpin structure, stabilized by intramolecular hydrogen bonds. (13, 14) When folded, the hairpin exhibits facial amphiphilicity with one face containing hydrophilic lysine residues and the other face comprised of hydrophobic valines. The valine-rich face undergoes hydrophobic collapse, driving the self-assembly of the folded hairpins into fibrils, which are further stabilized by intermolecular hydrogen bonding. (17) These two events, folding and self-assembly, although discussed as separate events, are most likely occurring concurrently. (44) The resultant fibrils are essentially irreversibly assembled such that their structure is path dependent. Transmission electron microscopy (TEM), small angle neutron scattering (SANS), and rheology demonstrate that the resultant, rigid networks of the semiflexible fibrils are composed of a bilayer of hairpins with a cross-sectional diameter of 3 nm, corresponding to the width of a folded peptide (Figure 1C). The fibrils are connected by noncovalent, interfibrillar junctions and entanglements. (13, 14, 16) Imperfections in the self-assembly mechanism, in which one hairpin is rotated relative to another hairpin in the bilayer, gives rise to interfibril branching (Figure 1B).” (Branco et al., page 1374, col. 2., para. 1).
Branco also discloses the buffer composition of “MAX1 and MAX8 hydrogels of 1.0 and 1.5 wt % were prepared using a pH 7.4, 50 mM BTP buffer with a salt concentration of 150 mM NaCl.” (Branco et al., page 1375, col. 2., para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the buffer composition disclosed by Branco to induce hydrogel formation as disclosed by Mehta, Gil, Salick, and Zapotoczna.
A person of ordinary skill in the art would be motivated to induce hydrogel formation before injection if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow.
A person of ordinary skill in the art would have a reasonable expectation of success because the peptide of Branco is charge identical to Applicant SEQ ID NO: 2 and possesses a turn sequence just like Applicant SEQ ID NO: 2. A person of ordinary skill in the art would reasonably expect a peptide so similar to react in a similar manner to the same buffer conditions. Also, the Branco paper is about hydrogel crosslink formation in general and Branco uses this buffer to induce hydrogel formation.
Consequently, claim 84 is obvious over Mehta et al. in view of Gil et al., Salick et al., and Zapotoczna et al. as applied to claim 82 above, further in view of Branco et al. and rejected.
Claim 86 is rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017 as applied to claim 3, further in view of Veiga et al. (Veiga, Ana Salomé, et al. "Arginine-rich self-assembling peptides as potent antibacterial gels." Biomaterials 33.35: 8907-8916 (2012)).
Regarding claim 86, claim 3 is obvious as described above. Claim 86 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Veiga discloses an arginine-rich self-assembling peptide, aligned against Applicant SEQ ID NO: 2:
VKVRVRVRVDPPTRVRVRVKV
VKVRVRVRVDPPTRVRVRVKV
For these peptides, Y=V, X=R and K, N=4, M=4, and T is a D-proline and a proline.
Consequently, claim 86 is obvious over Mehta et al. in view of Gil et al. as applied to claim 3 above, further in view of Veiga et al. and rejected.
Claim 87 is rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017 as applied to claim 3, further in view of Kumar et al. (Kumar, et al. Protein Expression and Purification 95: 129-135 (2014)).
Regarding claim 87, claim 3 is obvious as described above. Claim 87 further recites the case wherein the peptide is at least 80% purified.
Mehta and Gil do not disclose a specific protein purity.
However, Mehta discloses that the peptides may be purified: “The peptides can be chemically synthesized or they can be purified from natural and recombinant sources.” (Mehta et al., para. [0116]).
Furthermore, Kumar discloses methods of protein purification that result in proteins that are at least 80%: “Subsequently, GST–APJ C-ter was purified to ∼90% purity by GSH affinity in cleavage buffer with 2 M urea (Fig. 1c and d). GST-apelin23* and GST-apelin proteins were over-expressed at 24 °C and purified to ∼95–99% purity (Supplementary Figs. 3 and 4 respectively) by GSH affinity chromatography.” (Kumar et al., page 132, col. 2, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to purify the peptide of claim 1 to at least 80% purity.
A person of ordinary skill in the art would be motivated to purify the peptide because impurities are unwanted in therapeutic compositions so they don’t interfere with the activity of the therapeutic or crate toxic side effects. A person of ordinary skill in the art would have a reasonable expectation of success because Mehta discloses that peptide may be purified and Kumar discloses specific protocols and percentage purities that result from said protocols.
Consequently, claim 87 is obvious over Mehta et al. in view of Gil et al. as applied to claim 1 above, further in view of Kumar et al. and rejected.
Claim 88 is rejected under 35 U.S.C. 103 as being unpatentable over Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017 as applied to claim 3, further in view of Mauri et al. (Mauri, et al. Journal of visualized experiments: JoVE 116: 54445.(2016)).
Regarding claim 88, claim 3 is obvious as described above. Claim 88 further recites the case wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.
Mehta and Gil et al. do not specifically disclose an additional functional group added to the peptide. However, Mauri discloses the usage of RGD functionalization to improve the cell adhesion capabilities of a hydrogel:
“The combination of click chemistry and the microwave-assisted method is suitable to produce biocompatible hydrogels with desired functionalities and improved performances in biomedical applications. This work aims to synthesize RGD-functionalized hydrogels. RGD (arginylglycylaspartic acid) is a tripeptide that can mimic cell adhesion proteins and bind to cell-surface receptors, creating a hospitable microenvironment for cells within the 3D polymeric network of the hydrogels. RGD functionalization occurs through Huisgen 1,3-dipolar cycloaddition. Some PAA carboxyl groups are modified with an alkyne moiety, whereas RGD is functionalized with azido acid as the terminal residue of the peptide sequence. Finally, both products are used in a copper catalyzed click reaction to permanently link the peptide to PAA. This modified polymer is used with carbomer, agarose and polyethylene glycol (PEG) to synthesize a hydrogel matrix. The 3D structure is formed due to an esterification reaction involving carboxyl groups from PAA and carbomer and hydroxyl groups from agarose and PEG through microwave-assisted polycondensation. The efficiency of the gelation mechanism ensures a high degree of RGD functionalization. In addition, the procedure to load therapeutic compounds or biological tools within this functionalized network is very simple and reproducible.” (Mauri et al., Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add the RGD functionality of Mauri to the peptide of Mehta and Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination in order to increase the cell adhesion potential of the hydrogel in question. A person of ordinary skill in the art would have a reasonable expectation of success because Mauri describes in detail how this RGD functionalization performs this task and Mauri is specifically discussing hydrogels.
Consequently, claim 88 is obvious over Mehta et al. in view of Gil et al. as applied to claim 1 above, further in view of Mauri et al. and rejected.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 3, 17, 18, 20, 58, 85, 89 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017).
Regarding claim 1, claim 1 recites a method of introducing a hydrogel into a subject, comprising: administering a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution into a target tissue of the subject by injection, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into the hydrogel, the hydrogel being sterilized.
Claim 1, 3, of the ’299 patent discloses: “…administering, through the delivery device, a solution comprising an amphiphilic self-assembling peptide comprising between about 7 amino acids and 32 amino acids in an effective amount and in an effective concentration to the target area to form a hydrogel barrier under physiological conditions of the target area to treat the pulmonary bulla…”
Mehta discloses administering a solution comprising an amphiphilic self-assembling peptide: “…administering, through the delivery device, a solution comprising an amphiphilic self-assembling peptide comprising between about 7 amino acids and 32 amino acids in an effective amount and in an effective concentration to the target area to form a hydrogel barrier under physiological conditions of the target area to treat the pulmonary bulla;…” (Mehta et al., Claim 1).
Mehta also discloses a hydrogel-forming peptide sequence (RADA)4 which is arranged in a substantially alternating pattern of charged and hydrophobic amino acids and a turn sequence (aspartic acid). (Mehta et al., Claim 6).
Mehta also discloses the peptide being in an aqueous solution: “The method of claim 35, wherein preparing the solution comprising the self-assembling peptide comprises:
adding water to a peptide powder of the self-assembling peptide to provide an aqueous peptide solution;…” (Mehta et al., Claim 40).
Mehta discloses injecting the peptide solution: “The method of claim 1, wherein administering the solution comprises injecting the solution into the target area, with overflow solution..” (Mehta et al., Claim 7).
The ‘299 patent and Mehta do not explicitly disclose purification or sterilization of the peptide preparation. However, Gil discloses the filtration and sterilization of very similar peptides: “Among other things, the present disclosure demonstrates that certain peptide compositions (e.g., compositions of particular peptides, at particular concentrations, and/or having particular rheological properties) have certain characteristics and/or may not be amenable to certain handling and/or processing steps such as, for example, filtration (e.g., sterilizing filtration).” (Gil et al., para. [0005]).
“Specifically, solutions of RADA16, IEIK13, and KLD12 per prepared at concentrations indicated below in Table 1. As can be seen, in general, higher concentration solutions showed higher max viscosity.” (Gil et al., para. [0103] and para. [0104], Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘299 patent and Mehta with the purification scheme of Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to purify the peptide preparation to avoid contaminants being injected into the subject to be treated. A person of ordinary skill in the art would have a reasonable expectation of success because (RADA)4 is synonymous with RADA16 and that was one of the peptides purified by Gil.
Consequently, claim 1 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. and rejected.
Regarding claim 3, claim 3 recites method of applying a hydrogel to a subject, comprising: topically administering a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution to a target tissue of the subject, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, the hydrogel being sterilized; and topically administering to the target tissue a buffer comprising an effective amount of an ionic salt and a biological buffering agent to form the hydrogel.
Claim 1 of the ’299 patent discloses: “…administering, through the delivery device, a solution comprising an amphiphilic self-assembling peptide comprising between about 7 amino acids and 32 amino acids in an effective amount and in an effective concentration to the target area to form a hydrogel barrier under physiological conditions of the target area to treat the pulmonary bulla…”
Mehta discloses administering a solution comprising an amphiphilic self-assembling peptide: “…administering, through the delivery device, a solution comprising an amphiphilic self-assembling peptide comprising between about 7 amino acids and 32 amino acids in an effective amount and in an effective concentration to the target area to form a hydrogel barrier under physiological conditions of the target area to treat the pulmonary bulla;…” (Mehta et al., Claim 1).
Mehta also discloses a hydrogel-forming peptide sequence (RADA)4 which is arranged in a substantially alternating pattern of charged and hydrophobic amino acids and a turn sequence (aspartic acid). (Mehta et al., Claim 6).
Mehta discloses topical administration of the solution: “Administering the solution may comprise applying the solution topically to the target area.” (Mehta et al., para [0070]).
Mehta discloses usage of buffers: “In some embodiments, a buffer, such as a buffer solution may be added to the self-assembling peptide solution or the self-assembling peptide.” (Mehta et al., para [0142]) and the usage of ionic salts: “To adjust the salt ionic strength of the peptide solutions by way of example, various salt buffer solutions including NaCl, KCl, MgCl2, CaCl2 and DPBS (10×) were added to 2 mL of 1.5% peptide solutions.” (Mehta et al., para. [0177]).
The ’299 patent and Mehta do not explicitly disclose purification or sterilization of the peptide preparation. However, Gil discloses the filtration and sterilization of very similar peptides: “Among other things, the present disclosure demonstrates that certain peptide compositions (e.g., compositions of particular peptides, at particular concentrations, and/or having particular rheological properties) have certain characteristics and/or may not be amenable to certain handling and/or processing steps such as, for example, filtration (e.g., sterilizing filtration).” (Gil et al., para. [0005]).
“Specifically, solutions of RADA16, IEIK13, and KLD12 per prepared at concentrations indicated below in Table 1. As can be seen, in general, higher concentration solutions showed higher max viscosity.” (Gil et al., para. [0103] and para. [0104], Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘299 patent and Mehta with the purification scheme of Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to purify the peptide preparation to avoid contaminants being injected into the subject to be treated. A person of ordinary skill in the art would have a reasonable expectation of success because (RADA)4 is synonymous with RADA16 and that was one of the peptides purified by Gil.
Consequently, claim 3 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. and rejected.
Regarding claim 17, claim 1 is obvious as described above. Claim 17 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by the ‘299 patent Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 17 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. and rejected.
Regarding claim 18, claim 17 is obvious as described above. Claim 18 further recites the case wherein the combining of the buffer and preparation takes places less than about 10 minutes prior to administration.
Mehta discloses: “It may also be desired to provide a hydrogel barrier that is quick to gel, i.e., the gelation kinetics are such that, upon administration, the hydrogel barrier is formed within a short amount of time to treat the pulmonary bulla and/or leakage. The short amount of time may be instantaneous or, for example, less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds, or other times disclosed herein.” (Mehta et al., para. [0064]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to trigger hydrogel assembly this way as disclosed by Mehta. The time frame of less than 5 minutes overlaps substantially with less than 10 minutes as claimed. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the art would do this if they wanted to inject a partially formed hydrogel or fully formed hydrogel. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes that the hydrogel barrier forms , less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds.
Consequently, claim 18 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. and rejected.
Regarding claim 20, claim 1 is obvious as described above. Claim 20 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Mehta discloses: “The salt solution may comprise at least one anion selected from the group consisting of chloride, sulfate, acetate, carbonate, chloride, citrate, cyanide, fluoride, sulfate, nitrate, nitrite, and phosphate.” (Mehta et al., para. [0129]).
Furthermore, Mehta discloses the following example: “A peptide hydrogel mixed with a cation/anion solution which affected mechanical properties and another with a very low concentration of a contrast agent which did not affect the mechanical properties were both designed. The two gels were: (1) a combination of the self-assembling peptide with a well-known cation/anion solution, Ringer's Solution (pH 5.3), used in the medical field and (2) a combination of the self-assembling peptide with a well-known contrast agent, indigo carmine, which is a dye solution containing sulfate (anion) and sodium (cation) ions. Indigo carmine contains indigoindisulfonate sodium (C16H8N2Na2O8S2), water, and sodium citrate (C6H8O7) for pH adjustment.” (Mehta et al., para. [0190]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use acetate or citrate counterions with the claimed peptide.
A person of ordinary skill in the art would be motivated to try counterions from the finite list provided by Mehta and be further motivated by the example provided by Mehta that utilizes citrate in the buffer. A person or ordinary skill in the art would have a reasonable expectation of success because acetate and citrate are listed by Mehta as buffer ions.
Consequently, claim 20 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. and rejected.
Regarding claim 58, claim 1 is obvious as described above. Claim 58 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Mehta discloses the following peptide concentrations:
“The effective concentration may include peptide concentrations in the solution in a range of about 0.1 weight per volume (w/v) percent to about 10 w/v percent. The effective concentration may include peptide concentrations in the solution in a range of about 0.1 w/v percent to about 3.5 w/v percent. In certain embodiments, the effective concentration may be about 1 w/v percent. In certain other embodiments, the effective concentration may be about 1.5 w/v percent. In other embodiments, the effective concentration may be about 2.5 w/v percent.” (Mehta et al., para. [0107]).
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Consequently, claim 58 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. and rejected.
Regarding claim 85, claim 3 is obvious as described above. Claim 85 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Mehta discloses: “The salt solution may comprise at least one anion selected from the group consisting of chloride, sulfate, acetate, carbonate, chloride, citrate, cyanide, fluoride, sulfate, nitrate, nitrite, and phosphate.” (Mehta et al., para. [0129]).
Furthermore, Mehta discloses the following example: “A peptide hydrogel mixed with a cation/anion solution which affected mechanical properties and another with a very low concentration of a contrast agent which did not affect the mechanical properties were both designed. The two gels were: (1) a combination of the self-assembling peptide with a well-known cation/anion solution, Ringer's Solution (pH 5.3), used in the medical field and (2) a combination of the self-assembling peptide with a well-known contrast agent, indigo carmine, which is a dye solution containing sulfate (anion) and sodium (cation) ions. Indigo carmine contains indigoindisulfonate sodium (C16H8N2Na2O8S2), water, and sodium citrate (C6H8O7) for pH adjustment.” (Mehta et al., para. [0190]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use acetate or citrate counterions with the claimed peptide.
A person of ordinary skill in the art would be motivated to try counterions from the finite list provided by Mehta and be further motivated by the example provided by Mehta that utilizes citrate in the buffer. A person or ordinary skill in the art would have a reasonable expectation of success because acetate and citrate are listed by Mehta as buffer ions.
Consequently, claim 85 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. and rejected.
Regarding claim 89, claim 3 is obvious as described above. Claim 89 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Mehta discloses the following peptide concentrations:
“The effective concentration may include peptide concentrations in the solution in a range of about 0.1 weight per volume (w/v) percent to about 10 w/v percent. The effective concentration may include peptide concentrations in the solution in a range of about 0.1 w/v percent to about 3.5 w/v percent. In certain embodiments, the effective concentration may be about 1 w/v percent. In certain other embodiments, the effective concentration may be about 1.5 w/v percent. In other embodiments, the effective concentration may be about 2.5 w/v percent.” (Mehta et al., para. [0107]).
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Consequently, claim 89 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. and rejected.
Claims 2 and 4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 1, further in view of Salick et al. (US20110171304, published 7/14/2011).
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites administering in an amount effective to promote deactivation of a target microorganism at the target tissue, wherein the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11.
The ‘299 patent, Mehta, and Gil do not specifically disclose a peptide meeting these limitations. However, Salick et al. discloses an hydrogel-forming antimicrobial peptide sequence that does meet these limitations: “A peptide comprising the sequence VKVKVRVKVDPPTKVKVRVKV-NH2 forms a hydrogel which has the ability to shear-thin and recover. The hydrogel, both before and after shear-thinning, is capable of killing bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).” (Salick et al., Abstract).
This peptide has a net charge of +8 and possesses turn sequence residues D-proline and proline. Furthermore, it kills MRSA bacteria which qualifies as “deactivation” under the broadest reasonable interpretation of “deactivation”.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘966 patent, Mehta, and Gil with the peptide disclosed by Salick to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination to create a hydrogel that is active against harmful MRSA bacteria. A person of ordinary skill in the art would have a reasonable expectation of success because Salick discloses that VKVKVRVKVDPPTKVKVRVKV-NH2 is capable of killing MRSA and forms a hydrogel. Also, this peptide is similar in size and has alternating hydrophobic and charged residues so a person of ordinary skill in the art would expect the purification methods of Gil to work on this peptide as well.
Consequently, claim 2 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. as applied to claim 1 above, further in view of Salick et al. and rejected.
Regarding claim 4, claim 3 is obvious as described above. Claim 4 further recites administering in an amount effective to promote deactivation of a target microorganism at the target tissue, wherein the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11.
The ‘299 patent, Mehta, and Gil do not specifically disclose a peptide meeting these limitations. However, Salick et al. discloses an hydrogel-forming antimicrobial peptide sequence that does meet these limitations: “A peptide comprising the sequence VKVKVRVKVDPPTKVKVRVKV-NH2 forms a hydrogel which has the ability to shear-thin and recover. The hydrogel, both before and after shear-thinning, is capable of killing bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).” (Salick et al., Abstract).
This peptide has a net charge of +8 and possesses turn sequence residues D-proline and proline. Furthermore, it kills MRSA bacteria which qualifies as “deactivation” under the broadest reasonable interpretation of “deactivation”.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘299 patent, Mehta, and Gil with the peptide disclosed by Salick to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination to create a hydrogel that is active against harmful MRSA bacteria. A person of ordinary skill in the art would have a reasonable expectation of success because Salick discloses that VKVKVRVKVDPPTKVKVRVKV-NH2 is capable of killing MRSA and forms a hydrogel. Also, this peptide is similar in size and has alternating hydrophobic and charged residues so a person of ordinary skill in the art would expect the purification methods of Gil to work on this peptide as well.
Consequently, claim 4 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. as applied to claim 1 above, further in view of Salick et al. and rejected.
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 1, further in view of Jin et al. (Jin, Jing-fen, et al. Patient preference and adherence:923-942 (2015)).
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein injecting the preparation into the subject comprises infusing the preparation into the subject, or the preparation is injected via intravenous, intrasecal, intramuscular, subcutaneous, intradermal, intramedullary, intravascular, intraventricular, intrabiliary, intrathecal, or epidural administration.
The ’299 patent, Mehta, and Gil do not specifically disclose these modes of injection. However, Jin et al. discloses that intravenous, intramuscular, and subcutaneous modes of injections are frequently used: “Intravenous (IV), intramuscular (IM), and subcutaneous (SC) are the three most frequently used injection routes in medication administration. Comparative studies of SC versus IV, IM versus IV, or IM versus SC have been sporadically conducted, and some new findings are completely different from the dosage recommendation as described in prescribing information.” (Jin et al., Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use one of the injection methods disclosed by Jin with the method of Mehta and Gil.
A person of ordinary skill in the art would be motivated to use such methods for the following reasons: “ IV injection is the introduction of a medication into the veins using a needle, and it is used when rapid absorption is called for, when fluid cannot be taken by mouth, or when the medication to be administered is too irritating to be injected into the skin or muscles. SC injection is administered as a bolus into the subcutis. IM injection is the technique used to deliver a medication deep into the muscles, allowing the medication to be absorbed into the bloodstream quickly. Prescribing information for some medications notes that they can be injected via one or more routes (eg, epinephrine can be delivered by IV, IM, or SC route), while prescribing information for the majority of injectable medications only describes one injection route.” (Jin et al., page 924, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because these are the three most frequently used injection methods in this field as disclosed above.
Consequently, claim 5 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. as applied to claim 1 above, further in view of Jin et al. and rejected.
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 3, further in view of Harding et al. (Harding, K. G., V. Jones, and P. Price. "Topical treatment: which dressing to choose." Diabetes/metabolism research and reviews 16.S1: S47-S50. (2000)).
Regarding claim 9, claim 3 is obvious as described above. Claim 9 further recites the case wherein the method further comprises applying a topical dressing after administration of the preparation.
The ‘299 patent, Mehta, and Gil do not specifically disclose the usage of a wound dressing. However, Harding et al. discloses the usage of wound dressings: “Wounds have existed since prehistoric times and many famous physicians through the ages have contributed to an understanding of healing. Around 1000 BC Homer provided a detailed description of 147 wounds in the Iliad. Hippocrates in 400 BC wrote 70 essays, many of which describe wounds and how we recognise the value of cleansing and the use of wine and vinegar as topical treatment for wounds. Celsus (20–50 AD) described the cardinal features of inflammation and Galen then dominated medical thinking until the Middle Ages when Paracelsus made the observation that although he dressed the wound God healed it. Subsequently absorbent cotton and gauze materials came into widespread use, and in 1916 Vaseline-coated gauze was first developed.” (Harding et al., page S47, para. 1). Furthermore, Harding discloses various advantages to different types of dressings (Harding et al., page S50, Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use wound dressings as disclosed by Harding after the method of ‘299 patent, Mehta, and Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use wound dressings to avoid post-treatment infection and have a reasonable expectation of success because Harding discloses that dressings have been used for thousands of years and there are new modern dressings that have more specialized roles.
Consequently, claim 9 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. as applied to claim 3 above, further in view of Harding et al. and rejected.
Claim 11 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 3, further in view of Nunez (https://www.healthline.com/health/debridement, accessed 3/4/2026, published 2/13/2019).
Regarding claim 11, claim 3 is obvious as described above. Claim 11 further recites the case wherein target tissue is debrided before administration of the preparation.
The ‘299 patent, Mehta, and Gil do not specifically disclose debridement. However, Nunez discloses that: “Debridement is the removal of dead (necrotic) or infected skin tissue to help a wound heal. It’s also done to remove foreign material from tissue.” (Nunez, page 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to debride the target tissue as disclosed by Nunez before the method of the ‘299 patent, Mehta, and Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to debride the tissue to gain the benefits disclosed by Nunez: “Wound debridement can:
help healthy tissue grow
minimize scarring
reduce complications of infections” (Nunez, page 1, para. 3).
A person of ordinary skill in the art would have a reasonable expectation of success because Nunez discloses that this procedure is essential for wounds stuck in the first healing stage: “The procedure is essential for wounds that aren’t getting better. Usually, these wounds are trapped in the first stage of healing. When bad tissue is removed, the wound can restart the healing process.” (Nunez, page 1, para. 2).
Consequently, claim 11 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. as applied to claim 3 above, further in view of Nunez and rejected.
Claim 12 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 3, further in view of Ibrahim (Ibrahim, Sarah A. "Spray-on transdermal drug delivery systems." Expert opinion on drug delivery 12.2:195-205 (2015)).
Regarding claim 12, claim 3 is obvious as described above. Claim 12 further recites the case wherein administration is by spray, dropper, film, squeeze tube, or syringe.
The ‘299 patent, Mehta, and Gil do not specifically disclose administration by spray, dropper, film, squeeze tube, or syringe. However, Ibrahim discloses that: “A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug–solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin.” (Ibrahim, page 195, para. 2).
Ibrahim also discloses that: “Spray-on products have been successfully used on skin for local and topical indications, with recent advancements allowing systemic delivery of drugs.” (Ibrahim, page 196, col. 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to deliver the preparation topically with a spray.
A person of ordinary skill in the art would be motivated to use spray application because Ibrahim discloses that spray on drug delivery can increase drug loading into skin as described by Ibrahim above.
A person of ordinary skill in the art would have a reasonable expectation of success because Ibrahim discloses that spray has been successfully used for the delivery of drug products as described above.
Consequently, claim 12 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. as applied to claim 3 above, further in view of Ibrahim et al. and rejected.
Claim 13 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 1, further in view of Salick et al. (US20110171304, published 7/14/2011) and Broekhuizen et al. (Broekhuizen, et al. "Tissue around catheters is a niche for bacteria associated with medical device infection." Critical care medicine 36.8: 2395-2402 (2008)).
Regarding claim 13, claim 1 is obvious as described above. Claim 13 further recites the case wherein 13 the target tissue is a tissue selected from mesenchymal tissue, connective tissue, muscle tissue, nervous tissue, embryonic tissue, dermal tissue, bone tissue, dental tissue, corneal tissue, cutaneous tissue, integumental tissue, soft tissue, and hard tissue, or administration to the target tissue comprises administration to a biological fluid selected from tears, mucus, urine, menses, blood, wound exudates, and mixtures thereof.
The ’299 patent, Mehta, and Gil do not specifically disclose these target tissues.
However, Broekhuizen discloses that skin tissue becomes susceptible to bacterial infection when medical devices such as catheters are used:
“The skin biopsies of patients 1, 2, 3, 5, 7, and 8 contained large numbers of bacteria (≥103 cfu) of the same species as cultured from the subcutaneous tissue, predominantly S. epidermidis and E. faecalis (Table 1). The subcutaneous tissue swabs yielded no bacteria (patient 4 and 6) or only relatively low numbers of bacteria (patients 2, 3, 5, and 8). In patient 7, the subcutaneous swab yielded >103 bacteria, but the subcutaneous tissue samples, including those from the deeper tissue (3rd level biopsy, Table 1, Fig. 1), contained very high numbers of bacteria. Apparently, in this patient both the skin and the subcutaneous tissue were highly colonized.” (Broekhuizen et al., page 2398, col. 2, para. 2).
Salick discloses that MRSA infections can occur with medical devices: “In general, infection at a wound site prolongs healing, and with respect to medical implants, infection at the implant-tissue interface can result in implant failure. Thus, the ability to control and prevent infections is of critical importance in the medical field. One common infectious bacterium, Staphylococcus aureus, has traditionally been treated with standard antibiotics. However, drug resistant bacterial strains have evolved. Methicillin-resistant Staphylococcus aureus (MRSA) infections have become common and account for about 55% of all nosocomial infections acquired in intensive care units in the United States.” (Salick et al., para. [0003]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the method of the ‘299 patent, Mehta, and Gil with the antimicrobial peptide of Salick to a dermal area because of the risk of bacterial infection described by Broekhuizen.
A person of ordinary skill in the art would be motivated to do this to avoid infection in a patient with a medical device that interfaces with skin and have a reasonable expectation of success because Salick discloses the antimicrobial activity of their disclosed peptide, particularly against MRSA.
Consequently, claim 13 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. as applied to claim 1 above, further in view of Salick et al. and Broekhuizen et al. and rejected.
Claim 23 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 17, further in view of Branco et al. (Branco, Monica C., et al. "Fast dynamics of semiflexible chain networks of self-assembled peptides." Biomacromolecules 10.6: 1374-1380.) (2009)).
Regarding claim 23, claim 17 is obvious as described above. Claim 23 further recites the case wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bris-tris propane (BTP).
Mehta et al. discloses: “In some embodiments, a solution or composition of the self-assembling peptide may be buffered with about 0.15 M of at least one of sodium chloride, potassium chloride, and calcium chloride.”
Furthermore, Branco discloses the mechanism of hydrogel induction for a peptide MAX1: VKVKVKVKVDPPTKVKVKVKV which is very similar to Applicant SEQ ID NO: 2. Branco discloses:
“The primary sequence of MAX1 consists of a total of 20 amino acids with alternating valine (V) and lysine (K) residues on two β-strands. (13-16) These strands are centrally connected by a tetrapeptide (-VDPPT-) sequence that has a high propensity to adopt a type II′ β-turn configuration (Figure 1A). In pH 7.4 aqueous solutions at low ionic strength, these peptides are designed to remain freely soluble and unfolded due to electrostatic repulsions between the positively charged lysine side chains (Figure 1B). When a physiologically relevant salt concentration is introduced (150 mM NaCl), the electrostatic repulsions between the lysine side chains are screened and the peptide folds into a β-hairpin structure, stabilized by intramolecular hydrogen bonds. (13, 14) When folded, the hairpin exhibits facial amphiphilicity with one face containing hydrophilic lysine residues and the other face comprised of hydrophobic valines. The valine-rich face undergoes hydrophobic collapse, driving the self-assembly of the folded hairpins into fibrils, which are further stabilized by intermolecular hydrogen bonding. (17) These two events, folding and self-assembly, although discussed as separate events, are most likely occurring concurrently. (44) The resultant fibrils are essentially irreversibly assembled such that their structure is path dependent. Transmission electron microscopy (TEM), small angle neutron scattering (SANS), and rheology demonstrate that the resultant, rigid networks of the semiflexible fibrils are composed of a bilayer of hairpins with a cross-sectional diameter of 3 nm, corresponding to the width of a folded peptide (Figure 1C). The fibrils are connected by noncovalent, interfibrillar junctions and entanglements. (13, 14, 16) Imperfections in the self-assembly mechanism, in which one hairpin is rotated relative to another hairpin in the bilayer, gives rise to interfibril branching (Figure 1B).” (Branco et al., page 1374, col. 2., para. 1).
Branco also discloses the buffer composition of “MAX1 and MAX8 hydrogels of 1.0 and 1.5 wt % were prepared using a pH 7.4, 50 mM BTP buffer with a salt concentration of 150 mM NaCl.” (Branco et al., page 1375, col. 2., para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the buffer composition disclosed by Branco to induce hydrogel formation as disclosed by the ‘299 patent, Mehta, and Gil.
A person of ordinary skill in the art would be motivated to induce hydrogel formation before injection if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow.
A person of ordinary skill in the art would have a reasonable expectation of success because the peptide of Branco is charge identical to Applicant SEQ ID NO: 2 and possesses a turn sequence just like Applicant SEQ ID NO: 2. A person of ordinary skill in the art would reasonably expect a peptide so similar to react in a similar manner to the same buffer conditions. Also, the Branco paper is about hydrogel crosslink formation in general and Branco uses this buffer to induce hydrogel formation.
Consequently, claim 23 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. as applied to claim 17 above, further in view of Branco et al. and rejected.
Claim 31 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 1, further in view of Veiga et al. (Veiga, Ana Salomé, et al. "Arginine-rich self-assembling peptides as potent antibacterial gels." Biomaterials 33.35: 8907-8916 (2012)).
Regarding claim 31, claim 1 is obvious as described above. Claim 31 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Veiga discloses an arginine-rich self-assembling peptide, aligned against Applicant SEQ ID NO: 2:
VKVRVRVRVDPPTRVRVRVKV
VKVRVRVRVDPPTRVRVRVKV
For these peptides, Y=V, X=R and K, N=4, M=4, and T is a D-proline and a proline.
Consequently, claim 31 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. as applied to claim 1 above, further in view of Veiga et al. and rejected.
Claim 40 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 1, further in view of Kumar et al. (Kumar, et al. Protein Expression and Purification 95: 129-135 (2014)).
Regarding claim 40, claim 1 is obvious as described above. Claim 40 further recites the case wherein the peptide is at least 80% purified.
The ‘299 patent, Mehta, and Gil do not disclose a specific protein purity.
However, Mehta discloses that the peptides may be purified: “The peptides can be chemically synthesized or they can be purified from natural and recombinant sources.” (Mehta et al., para. [0116]).
Furthermore, Kumar discloses methods of protein purification that result in proteins that are at least 80%: “Subsequently, GST–APJ C-ter was purified to ∼90% purity by GSH affinity in cleavage buffer with 2 M urea (Fig. 1c and d). GST-apelin23* and GST-apelin proteins were over-expressed at 24 °C and purified to ∼95–99% purity (Supplementary Figs. 3 and 4 respectively) by GSH affinity chromatography.” (Kumar et al., page 132, col. 2, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to purify the peptide of claim 1 to at least 80% purity.
A person of ordinary skill in the art would be motivated to purify the peptide because impurities are unwanted in therapeutic compositions so they don’t interfere with the activity of the therapeutic or crate toxic side effects. A person of ordinary skill in the art would have a reasonable expectation of success because Mehta discloses that peptide may be purified and Kumar discloses specific protocols and percentage purities that result from said protocols.
Consequently, claim 40 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. as applied to claim 1 above, further in view of Kumar et al. and rejected.
Claim 44 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 1, further in view of Mauri et al. (Mauri, et al. Journal of visualized experiments: JoVE 116: 54445.(2016)).
Regarding claim 44, claim 1 is obvious as described above. Claim 44 further recites the case wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.
The ‘299 patent, Mehta, and Gil et al. do not specifically disclose an additional functional group added to the peptide. However, Mauri discloses the usage of RGD functionalization to improve the cell adhesion capabilities of a hydrogel:
“The combination of click chemistry and the microwave-assisted method is suitable to produce biocompatible hydrogels with desired functionalities and improved performances in biomedical applications. This work aims to synthesize RGD-functionalized hydrogels. RGD (arginylglycylaspartic acid) is a tripeptide that can mimic cell adhesion proteins and bind to cell-surface receptors, creating a hospitable microenvironment for cells within the 3D polymeric network of the hydrogels. RGD functionalization occurs through Huisgen 1,3-dipolar cycloaddition. Some PAA carboxyl groups are modified with an alkyne moiety, whereas RGD is functionalized with azido acid as the terminal residue of the peptide sequence. Finally, both products are used in a copper catalyzed click reaction to permanently link the peptide to PAA. This modified polymer is used with carbomer, agarose and polyethylene glycol (PEG) to synthesize a hydrogel matrix. The 3D structure is formed due to an esterification reaction involving carboxyl groups from PAA and carbomer and hydroxyl groups from agarose and PEG through microwave-assisted polycondensation. The efficiency of the gelation mechanism ensures a high degree of RGD functionalization. In addition, the procedure to load therapeutic compounds or biological tools within this functionalized network is very simple and reproducible.” (Mauri et al., Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add the RGD functionality of Mauri to the peptide of Mehta and Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination in order to increase the cell adhesion potential of the hydrogel in question. A person of ordinary skill in the art would have a reasonable expectation of success because Mauri describes in detail how this RGD functionalization performs this task and Mauri is specifically discussing hydrogels.
Consequently, claim 44 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al. as applied to claim 1 above, further in view of Mauri et al. and rejected.
Claims 76, 78-84, and 86-88 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017), Gil et al. (US20170202986, published 7/20/2017), Salick et al. (US20110171304, published 7/14/2011) and Zapotoczna et al. (Zapotoczna, et al. PLoS pathogens 12.7: e1005671 (2016)).
Regarding claim 76, claim 76 recites a method of treating or preventing a biofilm comprising a microbial, fungal, or viral colonization, the method comprising: topically or by injection administering to a target site of the biofilm a thermally stable preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11,the peptide being configured to self-assemble into a hydrogel, the hydrogel being sterilized, in an amount effective to treat or prevent the biofilm.
Claim 1 of the ’299 patent discloses: “…administering, through the delivery device, a solution comprising an amphiphilic self-assembling peptide comprising between about 7 amino acids and 32 amino acids in an effective amount and in an effective concentration to the target area to form a hydrogel barrier under physiological conditions of the target area to treat the pulmonary bulla…”
Mehta discloses administering a solution comprising an amphiphilic self-assembling peptide: “…administering, through the delivery device, a solution comprising an amphiphilic self-assembling peptide comprising between about 7 amino acids and 32 amino acids in an effective amount and in an effective concentration to the target area to form a hydrogel barrier under physiological conditions of the target area to treat the pulmonary bulla;…” (Mehta et al., Claim 1).
Mehta discloses injecting the peptide solution: “The materials and methods may include administration, application, or injection of a self-assembling peptide, or a solution comprising a self-assembling peptide, or a composition comprising a self-assembling peptide, to a predetermined or desired target area.” (Mehta et al., para. [0051]) and ” Administering the solution may comprise injecting the solution into the target area, with overflow to, for example, cover the target area topically.” (Mehta et al. para. [0070]).
Mehta does not explicitly disclose purification or sterilization of the peptide preparation. However, Gil discloses the filtration and sterilization of very similar peptides: “Among other things, the present disclosure demonstrates that certain peptide compositions (e.g., compositions of particular peptides, at particular concentrations, and/or having particular rheological properties) have certain characteristics and/or may not be amenable to certain handling and/or processing steps such as, for example, filtration (e.g., sterilizing filtration).” (Gil et al., para. [0005]).
“Specifically, solutions of RADA16, IEIK13, and KLD12 per prepared at concentrations indicated below in Table 1. As can be seen, in general, higher concentration solutions showed higher max viscosity.” (Gil et al., para. [0103] and para. [0104], Table 1).
Salick et al. discloses an hydrogel-forming antimicrobial peptide sequence that does meet these limitations: “A peptide comprising the sequence VKVKVRVKVDPPTKVKVRVKV-NH2 forms a hydrogel which has the ability to shear-thin and recover. The hydrogel, both before and after shear-thinning, is capable of killing bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).” (Salick et al., Abstract).
This peptide has a net charge of +8 and possesses turn sequence residues D-proline and proline.
Lastly, Zapotoczna discloses that MRSA creates biofilms: “From the earliest identification of poly-N-acetylglucosamine (PNAG)/polysaccharide intercellular adhesin (PIA) as a first known mediator of Staphylococcus epidermidis biofilm formation (reviewed in [1]), interest in this important virulence determinant has led to the discovery of multiple biofilm mechanisms in S. epidermidis and S. aureus.” (Zapotoczna et al., page 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the purification scheme of Gil and the peptide of Salick to treat the biofilm as disclosed by Zapotoczna to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to purify the peptide preparation to avoid contaminants being injected into the subject to be treated. A person of ordinary skill in the art would be motivated to use the peptide of Salick to create a hydrogel that is active against harmful MRSA bacteria.
A person of ordinary skill in the art would have a reasonable expectation of success because (RADA)4 is synonymous with RADA16 and that was one of the peptides purified by Gil.
A person of ordinary skill in the art would have a reasonable expectation of success because Salick discloses that VKVKVRVKVDPPTKVKVRVKV-NH2 is capable of killing MRSA and forms a hydrogel. Also, this peptide is similar in size and has alternating hydrophobic and charged residues so a person of ordinary skill in the art would expect the purification methods of Gil to work on this peptide as well.
Finally, Zapotoczna discloses that MRSA can create biofilms and therefore this method treats biofilms by killing MRSA.
Consequently, claim 76 is obvious over the ‘299 patent in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 78, claim 76 is obvious as described above. Claim 78 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 78 is obvious over the ‘299 patent in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 79, claim 76 is obvious as described above. Claim 79 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Mehta discloses: “The salt solution may comprise at least one anion selected from the group consisting of chloride, sulfate, acetate, carbonate, chloride, citrate, cyanide, fluoride, sulfate, nitrate, nitrite, and phosphate.” (Mehta et al., para. [0129]).
Furthermore, Mehta discloses the following example: “A peptide hydrogel mixed with a cation/anion solution which affected mechanical properties and another with a very low concentration of a contrast agent which did not affect the mechanical properties were both designed. The two gels were: (1) a combination of the self-assembling peptide with a well-known cation/anion solution, Ringer's Solution (pH 5.3), used in the medical field and (2) a combination of the self-assembling peptide with a well-known contrast agent, indigo carmine, which is a dye solution containing sulfate (anion) and sodium (cation) ions. Indigo carmine contains indigoindisulfonate sodium (C16H8N2Na2O8S2), water, and sodium citrate (C6H8O7) for pH adjustment.” (Mehta et al., para. [0190]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use acetate or citrate counterions with the claimed peptide.
A person of ordinary skill in the art would be motivated to try counterions from the finite list provided by Mehta and be further motivated by the example provided by Mehta that utilizes citrate in the buffer. A person or ordinary skill in the art would have a reasonable expectation of success because acetate and citrate are listed by Mehta as buffer ions.
Consequently, claim 79 is obvious over the ‘299 patent in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 80, claim 76 is obvious as described above. Claim 80 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Salick discloses this peptide: VKVKVRVKVDPPTKVKVRVKV-NH2 (Salick et al., Abstract).
For this peptide, Y=V, X=R and K, N=4, M=4, and T is a D-proline and a proline.
Consequently, claim 80 is obvious over the ‘299 patent in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 81, claim 76 is obvious as described above. Claim 81 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Mehta discloses the following peptide concentrations:
“The effective concentration may include peptide concentrations in the solution in a range of about 0.1 weight per volume (w/v) percent to about 10 w/v percent. The effective concentration may include peptide concentrations in the solution in a range of about 0.1 w/v percent to about 3.5 w/v percent. In certain embodiments, the effective concentration may be about 1 w/v percent. In certain other embodiments, the effective concentration may be about 1.5 w/v percent. In other embodiments, the effective concentration may be about 2.5 w/v percent.” (Mehta et al., para. [0107]).
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Consequently, claim 81 is obvious over the ‘299 patent in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 82, claim 76 is obvious as described above. Claim 82 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 82 is obvious over the ‘299 patent in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 83, claim 82 is obvious as described above. Claim 83 further recites the case wherein the combining of the buffer and preparation takes places less than about 10 minutes prior to administration.
Mehta discloses: “It may also be desired to provide a hydrogel barrier that is quick to gel, i.e., the gelation kinetics are such that, upon administration, the hydrogel barrier is formed within a short amount of time to treat the pulmonary bulla and/or leakage. The short amount of time may be instantaneous or, for example, less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds, or other times disclosed herein.” (Mehta et al., para. [0064]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to trigger hydrogel assembly this way as disclosed by Mehta. The time frame of less than 5 minutes overlaps substantially with less than 10 minutes as claimed. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the art would do this if they wanted to inject a partially formed hydrogel or fully formed hydrogel. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes that the hydrogel barrier forms , less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds.
Consequently, claim 83 is obvious over the ‘299 patent in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Claim 84 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017), Gil et al. (US20170202986, published 7/20/2017), Salick et al. (US20110171304, published 7/14/2011) and Zapotoczna et al. (Zapotoczna, et al. PLoS pathogens 12.7: e1005671 (2016)) as applied to claim 76 above, further in view of Branco et al. (Branco, Monica C., et al. "Fast dynamics of semiflexible chain networks of self-assembled peptides." Biomacromolecules 10.6: 1374-1380.) (2009)).
Regarding claim 84, claim 82 is obvious as described above. Claim 84 further recites the case wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bris-tris propane (BTP).
Mehta et al. discloses: “In some embodiments, a solution or composition of the self-assembling peptide may be buffered with about 0.15 M of at least one of sodium chloride, potassium chloride, and calcium chloride.”
Furthermore, Branco discloses the mechanism of hydrogel induction for a peptide MAX1: VKVKVKVKVDPPTKVKVKVKV which is very similar to Applicant SEQ ID NO: 2. Branco discloses:
“The primary sequence of MAX1 consists of a total of 20 amino acids with alternating valine (V) and lysine (K) residues on two β-strands. (13-16) These strands are centrally connected by a tetrapeptide (-VDPPT-) sequence that has a high propensity to adopt a type II′ β-turn configuration (Figure 1A). In pH 7.4 aqueous solutions at low ionic strength, these peptides are designed to remain freely soluble and unfolded due to electrostatic repulsions between the positively charged lysine side chains (Figure 1B). When a physiologically relevant salt concentration is introduced (150 mM NaCl), the electrostatic repulsions between the lysine side chains are screened and the peptide folds into a β-hairpin structure, stabilized by intramolecular hydrogen bonds. (13, 14) When folded, the hairpin exhibits facial amphiphilicity with one face containing hydrophilic lysine residues and the other face comprised of hydrophobic valines. The valine-rich face undergoes hydrophobic collapse, driving the self-assembly of the folded hairpins into fibrils, which are further stabilized by intermolecular hydrogen bonding. (17) These two events, folding and self-assembly, although discussed as separate events, are most likely occurring concurrently. (44) The resultant fibrils are essentially irreversibly assembled such that their structure is path dependent. Transmission electron microscopy (TEM), small angle neutron scattering (SANS), and rheology demonstrate that the resultant, rigid networks of the semiflexible fibrils are composed of a bilayer of hairpins with a cross-sectional diameter of 3 nm, corresponding to the width of a folded peptide (Figure 1C). The fibrils are connected by noncovalent, interfibrillar junctions and entanglements. (13, 14, 16) Imperfections in the self-assembly mechanism, in which one hairpin is rotated relative to another hairpin in the bilayer, gives rise to interfibril branching (Figure 1B).” (Branco et al., page 1374, col. 2., para. 1).
Branco also discloses the buffer composition of “MAX1 and MAX8 hydrogels of 1.0 and 1.5 wt % were prepared using a pH 7.4, 50 mM BTP buffer with a salt concentration of 150 mM NaCl.” (Branco et al., page 1375, col. 2., para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the buffer composition disclosed by Branco to induce hydrogel formation as disclosed by the ‘299 patent, Mehta, Gil, Salick, and Zapotoczna.
A person of ordinary skill in the art would be motivated to induce hydrogel formation before injection if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow.
A person of ordinary skill in the art would have a reasonable expectation of success because the peptide of Branco is charge identical to Applicant SEQ ID NO: 2 and possesses a turn sequence just like Applicant SEQ ID NO: 2. A person of ordinary skill in the art would reasonably expect a peptide so similar to react in a similar manner to the same buffer conditions. Also, the Branco paper is about hydrogel crosslink formation in general and Branco uses this buffer to induce hydrogel formation.
Consequently, claim 84 is obvious over the ‘299 patent in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. as applied to claim 82 above, further in view of Branco et al. and rejected.
Claim 86 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017), Gil et al. (US20170202986, published 7/20/2017) as applied to claim 3, further in view of Veiga et al. (Veiga, Ana Salomé, et al. "Arginine-rich self-assembling peptides as potent antibacterial gels." Biomaterials 33.35: 8907-8916 (2012)).
Regarding claim 86, claim 3 is obvious as described above. Claim 86 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Veiga discloses an arginine-rich self-assembling peptide, aligned against Applicant SEQ ID NO: 2:
VKVRVRVRVDPPTRVRVRVKV
VKVRVRVRVDPPTRVRVRVKV
For these peptides, Y=V, X=R and K, N=4, M=4, and T is a D-proline and a proline.
Consequently, claim 86 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al., as applied to claim 3 above, further in view of Branco et al. and rejected.
Claim 87 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017 as applied to claim 3, further in view of Kumar et al. (Kumar, et al. Protein Expression and Purification 95: 129-135 (2014)).
Regarding claim 87, claim 3 is obvious as described above. Claim 87 further recites the case wherein the peptide is at least 80% purified.
Mehta and Gil do not disclose a specific protein purity.
However, Mehta discloses that the peptides may be purified: “The peptides can be chemically synthesized or they can be purified from natural and recombinant sources.” (Mehta et al., para. [0116]).
Furthermore, Kumar discloses methods of protein purification that result in proteins that are at least 80%: “Subsequently, GST–APJ C-ter was purified to ∼90% purity by GSH affinity in cleavage buffer with 2 M urea (Fig. 1c and d). GST-apelin23* and GST-apelin proteins were over-expressed at 24 °C and purified to ∼95–99% purity (Supplementary Figs. 3 and 4 respectively) by GSH affinity chromatography.” (Kumar et al., page 132, col. 2, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to purify the peptide of claim 1 to at least 80% purity.
A person of ordinary skill in the art would be motivated to purify the peptide because impurities are unwanted in therapeutic compositions so they don’t interfere with the activity of the therapeutic or crate toxic side effects. A person of ordinary skill in the art would have a reasonable expectation of success because Mehta discloses that peptide may be purified and Kumar discloses specific protocols and percentage purities that result from said protocols.
Consequently, claim 87 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al., as applied to claim 3 above, further in view of Branco et al. and rejected.
Claim 88 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017) in view of Gil et al. (US20170202986, published 7/20/2017 as applied to claim 3, further in view of Mauri et al. (Mauri, et al. Journal of visualized experiments: JoVE 116: 54445.(2016)).
Regarding claim 88, claim 3 is obvious as described above. Claim 88 further recites the case wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.
Mehta and Gil et al. do not specifically disclose an additional functional group added to the peptide. However, Mauri discloses the usage of RGD functionalization to improve the cell adhesion capabilities of a hydrogel:
“The combination of click chemistry and the microwave-assisted method is suitable to produce biocompatible hydrogels with desired functionalities and improved performances in biomedical applications. This work aims to synthesize RGD-functionalized hydrogels. RGD (arginylglycylaspartic acid) is a tripeptide that can mimic cell adhesion proteins and bind to cell-surface receptors, creating a hospitable microenvironment for cells within the 3D polymeric network of the hydrogels. RGD functionalization occurs through Huisgen 1,3-dipolar cycloaddition. Some PAA carboxyl groups are modified with an alkyne moiety, whereas RGD is functionalized with azido acid as the terminal residue of the peptide sequence. Finally, both products are used in a copper catalyzed click reaction to permanently link the peptide to PAA. This modified polymer is used with carbomer, agarose and polyethylene glycol (PEG) to synthesize a hydrogel matrix. The 3D structure is formed due to an esterification reaction involving carboxyl groups from PAA and carbomer and hydroxyl groups from agarose and PEG through microwave-assisted polycondensation. The efficiency of the gelation mechanism ensures a high degree of RGD functionalization. In addition, the procedure to load therapeutic compounds or biological tools within this functionalized network is very simple and reproducible.” (Mauri et al., Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add the RGD functionality of Mauri to the peptide of Mehta and Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination in order to increase the cell adhesion potential of the hydrogel in question. A person of ordinary skill in the art would have a reasonable expectation of success because Mauri describes in detail how this RGD functionalization performs this task and Mauri is specifically discussing hydrogels.
Consequently, claim 88 is obvious over the ‘299 patent in view of Mehta et al. and Gil et al., as applied to claim 3 above, further in view of Branco et al. and rejected.
Claims 1, 2, 5, 17, 18, 20, 23, 31, 40, 44, and 58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 20, 32, 54, 57, 74 of copending Application No. 18/040,380 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Jain et al. (Jain, Kewal K Drug delivery systems : 1-54. (2019)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 1, claim 1 recites a method of introducing a hydrogel into a subject, comprising: administering a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution into a target tissue of the subject by injection, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into the hydrogel, the hydrogel being sterilized.
The ’380 application discloses a method of introducing a hydrogel into a subject in claim 1:
“A method of treating a fungal contamination of a subject in need thereof, comprising: administering to a target site of the subject a thermally stable preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, in an amount effective to promote deactivation of a target fungal organism associated with the fungal contamination.”
Claim 57 of the ‘380 application discloses: “The method of claim 1 or claim 2, wherein the preparation is sterile.”
Mehta discloses injecting the peptide solution: “The method of claim 1, wherein administering the solution comprises injecting the solution into the target area, with overflow solution..” (Mehta et al., Claim 7).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘380 application with the injection delivery of Mehta to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to inject the preparation because of the advantages recited by Jain:
“ Advantages of parenteral administration are:
Rapid onset of action
Predictable and almost complete bioavailability
Avoidance of the gastrointestinal tract with problems of oral drug administration
Provides a reliable route for drug administration in very ill and comatose patients, who are not able to ingest anything orally: (Jain et al., page 4, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because Mehta is injected the same kind of composition as the ‘380 application.
Consequently, claim 1 is obvious over the ‘380 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites administering in an amount effective to promote deactivation of a target microorganism at the target tissue, wherein the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11.
Claim 54 of the ‘380 application discloses: “The method of claim 1, wherein the peptide is anionic or cationic, the cationic peptide having has a net charge of from +2 to +11.”
Consequently, claim 2 is obvious over the ‘380 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein injecting the preparation into the subject comprises infusing the preparation into the subject, or the preparation is injected via intravenous, intrasecal, intramuscular, subcutaneous, intradermal, intramedullary, intravascular, intraventricular, intrabiliary, intrathecal, or epidural administration.
Jain discloses that: “Parenteral literally means introduction of substances into the body by routes other than the gastrointestinal tract, but practically the term is applied to injection of substances by subcutaneous, intramuscular, intravenous, and intra-arterial routes. Injections made into specific organs of the body for targeted drug delivery will be described under various therapeutic areas.” (Jain et al., page 3, para. 2)
Consequently, claim 5 is obvious over the ‘380 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 17, claim 1 is obvious as described above. Claim 17 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 17 is obvious over the ‘380 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 18, claim 17 is obvious as described above. Claim 18 further recites the case wherein the combining of the buffer and preparation takes places less than about 10 minutes prior to administration.
Mehta discloses: “It may also be desired to provide a hydrogel barrier that is quick to gel, i.e., the gelation kinetics are such that, upon administration, the hydrogel barrier is formed within a short amount of time to treat the pulmonary bulla and/or leakage. The short amount of time may be instantaneous or, for example, less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds, or other times disclosed herein.” (Mehta et al., para. [0064]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to trigger hydrogel assembly this way as disclosed by Mehta. The time frame of less than 5 minutes overlaps substantially with less than 10 minutes as claimed. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the art would do this if they wanted to inject a partially formed hydrogel or fully formed hydrogel. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes that the hydrogel barrier forms , less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds.
Consequently, claim 18 is obvious over the ‘380 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 20, claim 1 is obvious as described above. Claim 20 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Claim 4 of the ‘380 application discloses: “The method of claim 1, wherein the peptide comprises an effective amount of counterions, to form the hydrogel, the peptide being free of chloride counterions and the counterions selected from acetate and citrate counterions.”
Consequently, claim 20 is obvious over the ‘380 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 23, claim 17 is obvious as described above. Claim 23 further recites the case wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bris-tris propane (BTP).
Claim 74 of the ‘380 application discloses: “The method of claim 73, wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bis-tris propane (BTP).”
Consequently, claim 23 is obvious over the ‘380 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 31, claim 1 is obvious as described above. Claim 31 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Claim 20 of the ‘380 application discloses: “The method of claim 1, wherein:the folding group has a sequence comprising Y[XYlN[T][YXMY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10:the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.”
Consequently, claim 31 is obvious over the ‘380 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 40, claim 1 is obvious as described above. Claim 40 further recites the case wherein the peptide is at least 80% purified.
Claim 32 of the ‘380 application discloses: “The method of claim 1, wherein the peptide is at least 80% purified. “
Consequently, claim 40 is obvious over the ‘380 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 44, claim 1 is obvious as described above. Claim 44 further recites the case wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.
Claim 36 of the ‘380 application discloses: “The method of claim 1, wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.”
Consequently, claim 44 is obvious over the ‘380 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 58, claim 1 is obvious as described above. Claim 58 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Mehta discloses the following peptide concentrations:
Claim 50 of the ‘380 application discloses: “The method of claim 1 or claim 2, wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.”
Consequently, claim 58 is obvious over the ‘380 application in view of Mehta et al. and Jain al. and provisionally rejected.
Claims 3, 4, 11, 13, and 85-89 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 15, 50, 54, 57, 62 of copending Application No. 18/040,380.
This is a provisional nonstatutory double patenting rejection.
Regarding claim 3, claim 3 recites method of applying a hydrogel to a subject, comprising: topically administering a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution to a target tissue of the subject, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, the hydrogel being sterilized; and topically administering to the target tissue a buffer comprising an effective amount of an ionic salt and a biological buffering agent to form the hydrogel.
The ’380 application discloses a method of introducing a hydrogel into a subject in claim 1:
“A method of treating a fungal contamination of a subject in need thereof, comprising: administering to a target site of the subject a thermally stable preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, in an amount effective to promote deactivation of a target fungal organism associated with the fungal contamination.”
Claim 57 of the ‘380 application discloses: “The method of claim 1 or claim 2, wherein the preparation is sterile.”
Claim 15 of the ‘380 application discloses: “The method of claim 1 or claim 2, comprising administering the preparation to a target site of a subject topically, enterally, or parenterally”.
Consequently, claim 3 is anticipated by the ‘380 application and provisionally rejected.
Regarding claim 4, claim 3 is obvious as described above. Claim 4 further recites administering in an amount effective to promote deactivation of a target microorganism at the target tissue, wherein the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11.
Claim 54 of the ‘380 application discloses: “The method of claim 1, wherein the peptide is anionic or cationic, the cationic peptide having has a net charge of from +2 to +11.”
Consequently, claim 4 is anticipated by the ‘380 application and provisionally rejected.
Regarding claim 11, claim 3 is obvious as described above. Claim 11 further recites the case wherein target tissue is debrided before administration of the preparation.
Claim 62 of the ‘380 application discloses: “The method of claim 1 or claim 2, further comprising debridement of the target tissue prior to administration of the preparation.”
Consequently, claim 11 is anticipated by the ‘380 application and provisionally rejected.
Regarding claim 13, claim 1 is obvious as described above. Claim 13 further recites the case wherein 13 the target tissue is a tissue selected from mesenchymal tissue, connective tissue, muscle tissue, nervous tissue, embryonic tissue, dermal tissue, bone tissue, dental tissue, corneal tissue, cutaneous tissue, integumental tissue, soft tissue, and hard tissue, or administration to the target tissue comprises administration to a biological fluid selected from tears, mucus, urine, menses, blood, wound exudates, and mixtures thereof.
Claim 11 of the ‘380 application discloses: “The method of claim 1 or claim 2, wherein administration to the target tissue or target site comprises administration to a tissue selected from mesenchymal tissue, connective tissue, muscle tissue, nervous tissue, embryonic tissue, dermal tissue, bone tissue, dental tissue, corneal tissue, cutaneous tissue, integumental tissue, soft tissue, and hard tissue, or a biological fluid selected from tears, mucus, urine, menses, blood, wound exudates, and mixtures thereof.”
Consequently, claim 13 is anticipated by the ‘380 application and provisionally rejected.
Regarding claim 85, claim 3 is anticipated as described above. Claim 85 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Claim 4 of the ‘380 application discloses: “The method of claim 1 or claim 2, wherein the peptide comprises an effective amount of counterions, to form the hydrogel, the peptide being free of chloride counterions and the counterions selected from acetate and citrate counterions.”
Consequently, claim 85 is anticipated by the ‘380 application and provisionally rejected.
Regarding claim 86, claim 3 is anticipated as described above. Claim 86 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Claim 20 of the ‘380 application discloses: “The method of claim 1, wherein: the folding group has a sequence comprising Y[XYlN[T][YXMY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10:the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Consequently, claim 86 is anticipated by the ‘380 application and provisionally rejected.
Regarding claim 87, claim 3 is anticipated as described above. Claim 87 further recites the case wherein the peptide is at least 80% purified.
Claim 32 of the ‘380 application discloses: “The method of claim 1 or claim 2, wherein the peptide is at least 80% purified.”
Consequently, claim 87 is anticipated by the ‘380 application and provisionally rejected.
Regarding claim 88, claim 3 is anticipated as described above. Claim 88 further recites the case wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.
Claim 36 of the ‘380 application discloses: “The method of claim 1, wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.”
Consequently, claim 88 is anticipated by the ‘380 application and provisionally rejected.
Regarding claim 89, claim 3 is obvious as described above. Claim 89 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Claim 50 of the ‘380 application discloses: “The method of claim 1 or claim 2, wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.”
Consequently, claim 89 is anticipated by the ‘380 application and provisionally rejected.
Claim 9 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 15, 50, 54, 57 of copending Application No. 18/040,380, applied to claim 3 above, further in view of Harding et al. (Harding, K. G., V. Jones, and P. Price. "Topical treatment: which dressing to choose." Diabetes/metabolism research and reviews 16.S1: S47-S50. (2000)).
Regarding claim 9, claim 3 is anticipated as described above. Claim 9 further recites the case wherein the method further comprises applying a topical dressing after administration of the preparation.
The ‘380 application does not specifically disclose the usage of a wound dressing. However, Harding et al. discloses the usage of wound dressings: “Wounds have existed since prehistoric times and many famous physicians through the ages have contributed to an understanding of healing. Around 1000 BC Homer provided a detailed description of 147 wounds in the Iliad. Hippocrates in 400 BC wrote 70 essays, many of which describe wounds and how we recognise the value of cleansing and the use of wine and vinegar as topical treatment for wounds. Celsus (20–50 AD) described the cardinal features of inflammation and Galen then dominated medical thinking until the Middle Ages when Paracelsus made the observation that although he dressed the wound God healed it. Subsequently absorbent cotton and gauze materials came into widespread use, and in 1916 Vaseline-coated gauze was first developed.” (Harding et al., page S47, para. 1). Furthermore, Harding discloses various advantages to different types of dressings (Harding et al., page S50, Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use wound dressings as disclosed by Harding after the method of the ‘380 application to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use wound dressings to avoid post-treatment infection and have a reasonable expectation of success because Harding discloses that dressings have been used for thousands of years and there are new modern dressings that have more specialized roles.
Consequently, claim 9 is obvious over the ‘380 application as applied to claim 3 above, further in view of Harding et al. and provisionally rejected.
Claim 12 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 15, 50, 54, 57 of copending Application No. 18/040,380, applied to claim 3 above, further in view of Ibrahim (Ibrahim, Sarah A. "Spray-on transdermal drug delivery systems." Expert opinion on drug delivery 12.2:195-205 (2015)).
Regarding claim 12, claim 3 is anticipated as described above. Claim 12 further recites the case wherein administration is by spray, dropper, film, squeeze tube, or syringe.
The ‘380 application does not specifically disclose administration by spray, dropper, film, squeeze tube, or syringe. However, Ibrahim discloses that: “A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug–solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin.” (Ibrahim, page 195, para. 2).
Ibrahim also discloses that: “Spray-on products have been successfully used on skin for local and topical indications, with recent advancements allowing systemic delivery of drugs.” (Ibrahim, page 196, col. 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to deliver the preparation topically with a spray.
A person of ordinary skill in the art would be motivated to use spray application because Ibrahim discloses that spray on drug delivery can increase drug loading into skin as described by Ibrahim above.
A person of ordinary skill in the art would have a reasonable expectation of success because Ibrahim discloses that spray has been successfully used for the delivery of drug products as described above.
Consequently, claim 12 is obvious over the ‘380 application as applied to claim 3 above, further in view of Ibrahim and provisionally rejected.
Claims 76 and 79-81 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 15, 20, 54, 57 of copending Application No. 18/040,380 in view of Ramage et al. (Ramage, et al. International journal of microbiology 2012.1: 528521 (2012)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 76, claim 76 recites a method of treating or preventing a biofilm comprising a microbial, fungal, or viral colonization, the method comprising: topically or by injection administering to a target site of the biofilm a thermally stable preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11,the peptide being configured to self-assemble into a hydrogel, the hydrogel being sterilized, in an amount effective to treat or prevent the biofilm.
The ’380 application discloses a method of introducing a hydrogel into a subject in claim 1:
“A method of treating a fungal contamination of a subject in need thereof, comprising: administering to a target site of the subject a thermally stable preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, in an amount effective to promote deactivation of a target fungal organism associated with the fungal contamination.”
Claim 57 of the ‘380 application discloses: “The method of claim 1 or claim 2, wherein the preparation is sterile.”
Claim 54 of the ‘380 application discloses: “The method of claim 1 or claim 2, wherein the peptide is anionic or cationic, the cationic peptide having has a net charge of from +2 to +11.”
Claim 15 of the ‘380 application discloses: “The method of claim 1 or claim 2, comprising administering the preparation to a target site of a subject topically, enterally, or parenterally. “
Ramage et al. discloses:
“Yeasts and filamentous fungi biofilm-related infections have also been increasingly described [6], including Pneu-mocystis [7], Coccidioides [8], Aspergillus [9], Zygomycetes[10], Blastoschizomyces [11], Saccharomyces [12], Malassezia[13], Trichosporon [14], and Cryptococcus [15]. Cryptococcusneoformans has been shown to colonize and subsequently form biofilms on ventricular shunts [15], peritoneal dialysisfistulas [16], prosthetic hip joints [17], and cardiac valves[18].” (Ramage et al, page 1, col. 2, para. 2)
Therefore, fungi can form biofilms.
Consequently, claim 76 is obvious over the ‘380 application in view of Ramage et al. and provisionally rejected.
Regarding claim 79, claim 76 is obvious as described above. Claim 79 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Claim 4 of the ‘380 application discloses: “The method of claim 1, wherein the peptide comprises an effective amount of counterions, to form the hydrogel, the peptide being free of chloride counterions and the counterions selected from acetate and citrate counterions.”
Consequently, claim 79 is obvious over the ‘380 application in view of Ramage et al. and provisionally rejected.
Regarding claim 80, claim 76 is obvious as described above. Claim 80 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Claim 20 of the ‘380 application discloses: “method of claim 1, wherein: the folding group has a sequence comprising Y[XYlN[T][YXMY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10:the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.”
Consequently, claim 80 is obvious over the ‘380 application in view of Ramage et al. and provisionally rejected.
Regarding claim 81, claim 76 is obvious as described above. Claim 81 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Claim 50 of the ‘380 application discloses: “The method of claim 1 or claim 2, wherein the preparation comprises between 0.1%0.5% w/v and 8.0% 3.0% w/v of the peptide.”
Consequently, claim 80 is obvious over the ‘380 application in view of Ramage et al. and provisionally rejected.
Claim 78 and 82-84 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 15, 54, 57, of copending Application No. 18/040,380 in view of Ramage et al. (Ramage, et al. International journal of microbiology 2012.1: 528521 (2012)) as applied to claim 76 above, further in view of Mehta et al. (US 20170072008, published 3/16/2017).
Regarding claim 78, claim 76 is obvious as described above. Claim 78 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 78 is obvious over the ‘380 application in view of Ramage et al. as applied to claim 76 above, further in view of Mehta et al. and provisionally rejected.
Regarding claim 82, claim 76 is obvious as described above. Claim 82 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 82 is obvious over the ‘380 application in view of Ramage et al. as applied to claim 76 above, further in view of Mehta et al. and provisionally rejected.
Regarding claim 83, claim 82 is obvious as described above. Claim 83 further recites the case wherein the combining of the buffer and preparation takes places less than about 10 minutes prior to administration.
Mehta discloses: “It may also be desired to provide a hydrogel barrier that is quick to gel, i.e., the gelation kinetics are such that, upon administration, the hydrogel barrier is formed within a short amount of time to treat the pulmonary bulla and/or leakage. The short amount of time may be instantaneous or, for example, less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds, or other times disclosed herein.” (Mehta et al., para. [0064]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to trigger hydrogel assembly this way as disclosed by Mehta. The time frame of less than 5 minutes overlaps substantially with less than 10 minutes as claimed. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the art would do this if they wanted to inject a partially formed hydrogel or fully formed hydrogel. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes that the hydrogel barrier forms , less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds.
Consequently, claim 83 is obvious over the ‘380 application in view of Ramage et al. as applied to claim 76 above, further in view of Mehta et al. and provisionally rejected.
Regarding claim 84, claim 82 is obvious as described above. Claim 84 further recites the case wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bris-tris propane (BTP).
Claim 74 of the ‘380 application discloses: “wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bis-tris propane (BTP).”
Consequently, claim 84 is obvious over the ‘380 application in view of Ramage et al. as applied to claim 76 above, further in view of Mehta et al. and provisionally rejected.
Claims 1, 2, 5, 17, 18, 20, 23, 31, 40, 44, and 58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 19, 31, 49, 53, 56, 73 of copending Application No. 18/040,388 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Jain et al. (Jain, Kewal K Drug delivery systems : 1-54. (2019)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 1, claim 1 recites a method of introducing a hydrogel into a subject, comprising: administering a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution into a target tissue of the subject by injection, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into the hydrogel, the hydrogel being sterilized.
The ‘388 application discloses a method of introducing a hydrogel into a subject in claim 1:
“A method of treating a microbial contamination associated with a community of microorganisms of a subject in need thereof, comprising: administering to a target site of the subject a thermally stable preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, in an amount effective to promote deactivation of a target microorganism associated with the microbial contamination;
Claim 56 of the ‘388 application discloses: “The method of claim 1, wherein the preparation is sterile.”
Mehta discloses injecting the peptide solution: “The method of claim 1, wherein administering the solution comprises injecting the solution into the target area, with overflow solution..” (Mehta et al., Claim 7).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘388 application with the injection delivery of Mehta to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to inject the preparation because of the advantages recited by Jain:
“ Advantages of parenteral administration are:
Rapid onset of action
Predictable and almost complete bioavailability
Avoidance of the gastrointestinal tract with problems of oral drug administration
Provides a reliable route for drug administration in very ill and comatose patients, who are not able to ingest anything orally: (Jain et al., page 4, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because Mehta is injected the same kind of composition as the ‘388 application.
Consequently, claim 1 is obvious over the ‘388 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites administering in an amount effective to promote deactivation of a target microorganism at the target tissue, wherein the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11.
Claim 53 of the ‘388 application discloses: “The method of claim 1, wherein the peptide is anionic or cationic, the cationic peptide having has a net charge of from +2 to +11.”
Consequently, claim 2 is obvious over the ‘388 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein injecting the preparation into the subject comprises infusing the preparation into the subject, or the preparation is injected via intravenous, intrasecal, intramuscular, subcutaneous, intradermal, intramedullary, intravascular, intraventricular, intrabiliary, intrathecal, or epidural administration.
Jain discloses that: “Parenteral literally means introduction of substances into the body by routes other than the gastrointestinal tract, but practically the term is applied to injection of substances by subcutaneous, intramuscular, intravenous, and intra-arterial routes. Injections made into specific organs of the body for targeted drug delivery will be described under various therapeutic areas.” (Jain et al., page 3, para. 2)
Consequently, claim 5 is obvious over the ‘388 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 17, claim 1 is obvious as described above. Claim 17 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 17 is obvious over the ‘388 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 18, claim 17 is obvious as described above. Claim 18 further recites the case wherein the combining of the buffer and preparation takes places less than about 10 minutes prior to administration.
Mehta discloses: “It may also be desired to provide a hydrogel barrier that is quick to gel, i.e., the gelation kinetics are such that, upon administration, the hydrogel barrier is formed within a short amount of time to treat the pulmonary bulla and/or leakage. The short amount of time may be instantaneous or, for example, less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds, or other times disclosed herein.” (Mehta et al., para. [0064]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to trigger hydrogel assembly this way as disclosed by Mehta. The time frame of less than 5 minutes overlaps substantially with less than 10 minutes as claimed. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the art would do this if they wanted to inject a partially formed hydrogel or fully formed hydrogel. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes that the hydrogel barrier forms , less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds.
Consequently, claim 18 is obvious over the ‘388 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 20, claim 1 is obvious as described above. Claim 20 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Claim 4 of the ‘388 application discloses: “The method of claim 1, wherein the peptide comprises an effective amount of counterions, to form the hydrogel, the peptide being free of chloride counterions and the counterions selected from acetate and citrate counterions.”
Consequently, claim 20 is obvious over the ‘388 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 23, claim 17 is obvious as described above. Claim 23 further recites the case wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bris-tris propane (BTP).
Claim 73 of the ‘388 application discloses: “The method of claim 72, wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bis-tris propane (BTP).”
Consequently, claim 23 is obvious over the ‘388 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 31, claim 1 is obvious as described above. Claim 31 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Claim 19 of the ‘388 application discloses: “The method of claim 1, wherein:the folding group has a sequence comprising Y[XYlN[T][YXMY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10:the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.”
Consequently, claim 31 is obvious over the ‘388 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 40, claim 1 is obvious as described above. Claim 40 further recites the case wherein the peptide is at least 80% purified.
Claim 31 of the ‘388 application discloses: “The method of claim 1 or claim 2, wherein the peptide is at least 80% purified. “
Consequently, claim 40 is obvious over the ‘388 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 44, claim 1 is obvious as described above. Claim 44 further recites the case wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.
Claim 35 of the ‘388 application discloses: “The method of claim 1, wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.”
Consequently, claim 44 is obvious over the ‘388 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 58, claim 1 is obvious as described above. Claim 58 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Mehta discloses the following peptide concentrations:
Claim 49 of the ‘388 application discloses: “The method of claim 1 or claim 2, wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.”
Consequently, claim 58 is obvious over the ‘388 application in view of Mehta et al. and Jain al. and provisionally rejected.
Claims 3, 4, 11, 13, and 85-89 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 10, 14, 19, 31, 35, 49, 53, 56, 62 of copending Application No. 18/040,388.
This is a provisional nonstatutory double patenting rejection.
Regarding claim 3, claim 3 recites method of applying a hydrogel to a subject, comprising: topically administering a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution to a target tissue of the subject, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, the hydrogel being sterilized; and topically administering to the target tissue a buffer comprising an effective amount of an ionic salt and a biological buffering agent to form the hydrogel.
The ‘388 application discloses a method of introducing a hydrogel into a subject in claim 1:
“A method of treating a microbial contamination associated with a community of microorganisms of a subject in need thereof, comprising: administering to a target site of the subject a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, in an amount effective to promote deactivation of a the microbial contamination.”
Claim 56 of the ‘388 application discloses: “The method of claim 1 or claim 2, wherein the preparation is sterile.”
Claim 14 of the ‘388 application discloses: “The method of claim 1 or claim 2, comprising administering the preparation to a target site of a subject topically, enterally, or parenterally”.
Consequently, claim 3 is anticipated by the ‘388 application and provisionally rejected.
Regarding claim 4, claim 3 is obvious as described above. Claim 4 further recites administering in an amount effective to promote deactivation of a target microorganism at the target tissue, wherein the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11.
Claim 53 of the ‘388 application discloses: “The method of claim 1, wherein the peptide is anionic or cationic, the cationic peptide having has a net charge of from +2 to +11.”
Consequently, claim 4 is anticipated by the ‘388 application and provisionally rejected.
Regarding claim 11, claim 3 is obvious as described above. Claim 11 further recites the case wherein target tissue is debrided before administration of the preparation.
Claim 62 of the ‘388 application discloses: “The method of claim 1 or claim 2, further comprising debridement of the target tissue prior to administration of the preparation.”
Consequently, claim 11 is anticipated by the ‘388 application and provisionally rejected.
Regarding claim 13, claim 1 is obvious as described above. Claim 13 further recites the case wherein 13 the target tissue is a tissue selected from mesenchymal tissue, connective tissue, muscle tissue, nervous tissue, embryonic tissue, dermal tissue, bone tissue, dental tissue, corneal tissue, cutaneous tissue, integumental tissue, soft tissue, and hard tissue, or administration to the target tissue comprises administration to a biological fluid selected from tears, mucus, urine, menses, blood, wound exudates, and mixtures thereof.
Claim 10 of the ‘388 application discloses: “The method of claim 1 or claim 2, wherein administration to the target tissue or target site comprises administration to a tissue selected from mesenchymal tissue, connective tissue, muscle tissue, nervous tissue, embryonic tissue, dermal tissue, bone tissue, dental tissue, corneal tissue, cutaneous tissue, integumental tissue, soft tissue, and hard tissue, or a biological fluid selected from tears, mucus, urine, menses, blood, wound exudates, and mixtures thereof.”
Consequently, claim 13 is anticipated by the ‘388 application and provisionally rejected.
Regarding claim 85, claim 3 is anticipated as described above. Claim 85 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Claim 4 of the ‘388 application discloses: “The method of claim 1 or claim 2, wherein the peptide comprises an effective amount of counterions, to form the hydrogel, the peptide being free of chloride counterions and the counterions selected from acetate and citrate counterions.”
Consequently, claim 85 is anticipated by the ‘388 application and provisionally rejected.
Regarding claim 86, claim 3 is anticipated as described above. Claim 86 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Claim 19 of the ‘388 application discloses: “The method of claim 1, wherein: the folding group has a sequence comprising Y[XYlN[T][YXMY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10:the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Consequently, claim 86 is anticipated by the ‘388 application and provisionally rejected.
Regarding claim 87, claim 3 is anticipated as described above. Claim 87 further recites the case wherein the peptide is at least 80% purified.
Claim 31 of the ‘388 application discloses: “The method of claim 1 or claim 2, wherein the peptide is at least 80% purified.”
Consequently, claim 87 is anticipated by the ‘388 application and provisionally rejected.
Regarding claim 88, claim 3 is anticipated as described above. Claim 88 further recites the case wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.
Claim 35 of the ‘388 application discloses: “The method of claim 1, wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.”
Consequently, claim 88 is anticipated by the ‘388 application and provisionally rejected.
Regarding claim 89, claim 3 is obvious as described above. Claim 89 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Claim 49 of the ‘388 application discloses: “The method of claim 1 or claim 2, wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.”
Consequently, claim 89 is anticipated by the ‘388 application and provisionally rejected.
Claim 9 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 10, 14, 19, 31, 35, 49, 53, 56, 62 of copending Application No. 18/040,388, applied to claim 3 above, further in view of Harding et al. (Harding, K. G., V. Jones, and P. Price. "Topical treatment: which dressing to choose." Diabetes/metabolism research and reviews 16.S1: S47-S50. (2000)).
Regarding claim 9, claim 3 is anticipated as described above. Claim 9 further recites the case wherein the method further comprises applying a topical dressing after administration of the preparation.
The ‘388 application does not specifically disclose the usage of a wound dressing. However, Harding et al. discloses the usage of wound dressings: “Wounds have existed since prehistoric times and many famous physicians through the ages have contributed to an understanding of healing. Around 1000 BC Homer provided a detailed description of 147 wounds in the Iliad. Hippocrates in 400 BC wrote 70 essays, many of which describe wounds and how we recognise the value of cleansing and the use of wine and vinegar as topical treatment for wounds. Celsus (20–50 AD) described the cardinal features of inflammation and Galen then dominated medical thinking until the Middle Ages when Paracelsus made the observation that although he dressed the wound God healed it. Subsequently absorbent cotton and gauze materials came into widespread use, and in 1916 Vaseline-coated gauze was first developed.” (Harding et al., page S47, para. 1). Furthermore, Harding discloses various advantages to different types of dressings (Harding et al., page S50, Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use wound dressings as disclosed by Harding after the method of the ‘388 application to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use wound dressings to avoid post-treatment infection and have a reasonable expectation of success because Harding discloses that dressings have been used for thousands of years and there are new modern dressings that have more specialized roles.
Consequently, claim 9 is obvious over the ‘388 application as applied to claim 3 above, further in view of Harding et al. and provisionally rejected.
Claim 12 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 10, 14, 19, 31, 35, 49, 53, 56, 62 of copending Application No. 18/040,388, applied to claim 3 above, further in view of Ibrahim (Ibrahim, Sarah A. "Spray-on transdermal drug delivery systems." Expert opinion on drug delivery 12.2:195-205 (2015)).
Regarding claim 12, claim 3 is anticipated as described above. Claim 12 further recites the case wherein administration is by spray, dropper, film, squeeze tube, or syringe.
The ‘388 application does not specifically disclose administration by spray, dropper, film, squeeze tube, or syringe. However, Ibrahim discloses that: “A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug–solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin.” (Ibrahim, page 195, para. 2).
Ibrahim also discloses that: “Spray-on products have been successfully used on skin for local and topical indications, with recent advancements allowing systemic delivery of drugs.” (Ibrahim, page 196, col. 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to deliver the preparation topically with a spray.
A person of ordinary skill in the art would be motivated to use spray application because Ibrahim discloses that spray on drug delivery can increase drug loading into skin as described by Ibrahim above.
A person of ordinary skill in the art would have a reasonable expectation of success because Ibrahim discloses that spray has been successfully used for the delivery of drug products as described above.
Consequently, claim 12 is obvious over the ‘388 application as applied to claim 3 above, further in view of Ibrahim and provisionally rejected.
Claims 76 and 79-81 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 10, 14, 19, 31, 35, 49, 53, 56, 62 of copending Application No. 18/040,388 in view of Salick et al. (US20110171304, published 7/14/2011) and Zapotoczna et al. (Zapotoczna, et al. PLoS pathogens 12.7: e1005671 (2016)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 76, claim 76 recites a method of treating or preventing a biofilm comprising a microbial, fungal, or viral colonization, the method comprising: topically or by injection administering to a target site of the biofilm a thermally stable preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11,the peptide being configured to self-assemble into a hydrogel, the hydrogel being sterilized, in an amount effective to treat or prevent the biofilm.
The ‘388 application discloses a method of introducing a hydrogel into a subject in claim 1:
“A method of treating a microbial contamination associated with a community of microorganisms of a subject in need thereof, comprising: administering to a target site of the subject a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, in an amount effective to promote deactivation of a microbial contamination.”
Claim 56 of the ‘388 application discloses: “The method of claim 1 or claim 2, wherein the preparation is sterile.”
Claim 53 of the ‘388 application discloses: “The method of claim 1 or claim 2, wherein the peptide is anionic or cationic, the cationic peptide having has a net charge of from +2 to +11.”
Claim 14 of the ‘388 application discloses: “The method of claim 1 or claim 2, comprising administering the preparation to a target site of a subject topically, enterally, or parenterally. “
Salick et al. discloses an hydrogel-forming antimicrobial peptide sequence that does meet these limitations: “A peptide comprising the sequence VKVKVRVKVDPPTKVKVRVKV-NH2 forms a hydrogel which has the ability to shear-thin and recover. The hydrogel, both before and after shear-thinning, is capable of killing bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).” (Salick et al., Abstract).
This peptide has a net charge of +8 and possesses turn sequence residues D-proline and proline.
Lastly, Zapotoczna discloses that MRSA creates biofilms: “From the earliest identification of poly-N-acetylglucosamine (PNAG)/polysaccharide intercellular adhesin (PIA) as a first known mediator of Staphylococcus epidermidis biofilm formation (reviewed in [1]), interest in this important virulence determinant has led to the discovery of multiple biofilm mechanisms in S. epidermidis and S. aureus.” (Zapotoczna et al., page 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the purification scheme of Gil and the peptide of Salick to treat the biofilm as disclosed by Zapotoczna to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to purify the peptide preparation to avoid contaminants being injected into the subject to be treated. A person of ordinary skill in the art would be motivated to use the peptide of Salick to create a hydrogel that is active against harmful MRSA bacteria.
A person of ordinary skill in the art would have a reasonable expectation of success because Salick discloses that VKVKVRVKVDPPTKVKVRVKV-NH2 is capable of killing MRSA and forms a hydrogel. Also, this peptide is similar in size and has alternating hydrophobic and charged residues so a person of ordinary skill in the art would expect the purification methods of Gil to work on this peptide as well.
Finally, Zapotoczna discloses that MRSA can create biofilms and therefore this method treats biofilms by killing MRSA.
Consequently, claim 76 is obvious over the ‘388 application in view of Salick et al., and Zapotoczna et al. and rejected and provisionally rejected.
Regarding claim 79, claim 76 is obvious as described above. Claim 79 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Claim 4 of the ‘388 application discloses: “The method of claim 1, wherein the peptide comprises an effective amount of counterions, to form the hydrogel, the peptide being free of chloride counterions and the counterions selected from acetate and citrate counterions.”
Consequently, claim 79 is obvious over the ‘388 application in view of Salick et al., and Zapotoczna et al. and rejected and provisionally rejected.
Regarding claim 80, claim 76 is obvious as described above. Claim 80 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Claim 19 of the ‘388 application discloses: “method of claim 1, wherein: the folding group has a sequence comprising Y[XYlN[T][YXMY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10:the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.”
Consequently, claim 80 is obvious over the ‘388 application in view of Salick et al., and Zapotoczna et al. and rejected and provisionally rejected.
Regarding claim 81, claim 76 is obvious as described above. Claim 81 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Claim 49 of the ‘388 application discloses: “The method of claim 1 or claim 2, wherein the preparation comprises between 0.1%0.5% w/v and 8.0% 3.0% w/v of the peptide.”
Consequently, claim 80 is obvious over the ‘388 application in view of Salick et al., and Zapotoczna et al. and rejected and provisionally rejected.
Claim 78 and 82-84 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 15, 54, 57, of copending Application No. 18/040,380 in view of Salick et al., and Zapotoczna et al. as applied to claim 76 above, further in view of Mehta et al. (US 20170072008, published 3/16/2017).
Regarding claim 78, claim 76 is obvious as described above. Claim 78 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 78 is obvious over the ‘388 application in view of Salick et al. and Zapotoczna et al. as applied to claim 76 above, further in view of Mehta et al. and provisionally rejected.
Regarding claim 82, claim 76 is obvious as described above. Claim 82 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 82 is obvious over the ‘388 application in view of Salick et al. and Zapotoczna et al. as applied to claim 76 above, further in view of Mehta et al. and provisionally rejected.
Regarding claim 83, claim 82 is obvious as described above. Claim 83 further recites the case wherein the combining of the buffer and preparation takes places less than about 10 minutes prior to administration.
Mehta discloses: “It may also be desired to provide a hydrogel barrier that is quick to gel, i.e., the gelation kinetics are such that, upon administration, the hydrogel barrier is formed within a short amount of time to treat the pulmonary bulla and/or leakage. The short amount of time may be instantaneous or, for example, less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds, or other times disclosed herein.” (Mehta et al., para. [0064]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to trigger hydrogel assembly this way as disclosed by Mehta. The time frame of less than 5 minutes overlaps substantially with less than 10 minutes as claimed. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the art would do this if they wanted to inject a partially formed hydrogel or fully formed hydrogel. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes that the hydrogel barrier forms , less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds.
Consequently, claim 83 is obvious over the ‘388 application in view of Salick et al. and Zapotoczna et al. as applied to claim 76 above, further in view of Mehta et al. and provisionally rejected.
Regarding claim 84, claim 82 is obvious as described above. Claim 84 further recites the case wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bris-tris propane (BTP).
Claim 74 of the ‘388 application discloses: “wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bis-tris propane (BTP).”
Consequently, claim 84 is obvious over the ‘388 application in view of Salick et al. and Zapotoczna et al. as applied to claim 76 above, further in view of Mehta et al. and provisionally rejected.
Claims 1, 2, 5, 17, 18, 20, 23, 31, 40, and 58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 39, 42, 47, 55, 77, 83 of copending Application No. 18/682,493 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Jain et al. (Jain, Kewal K Drug delivery systems : 1-54. (2019)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 1, claim 1 recites a method of introducing a hydrogel into a subject, comprising: administering a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution into a target tissue of the subject by injection, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into the hydrogel, the hydrogel being sterilized.
The ‘493 application discloses a method of introducing a hydrogel into a subject in claim 1:
“A method of treating a nerve injury, comprising: administering to a target site of a nerve injury a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, in an amount effective to treat the nerve injury.”
Claim 83 of the ‘493 application discloses: “The method of claim 82, wherein the preparation is sterilized by autoclave sterilization.”
Mehta discloses injecting the peptide solution: “The method of claim 1, wherein administering the solution comprises injecting the solution into the target area, with overflow solution..” (Mehta et al., Claim 7).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘493 application with the injection delivery of Mehta to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to inject the preparation because of the advantages recited by Jain:
“ Advantages of parenteral administration are:
Rapid onset of action
Predictable and almost complete bioavailability
Avoidance of the gastrointestinal tract with problems of oral drug administration
Provides a reliable route for drug administration in very ill and comatose patients, who are not able to ingest anything orally: (Jain et al., page 4, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because Mehta is injected the same kind of composition as the ‘493 application.
Consequently, claim 1 is obvious over the ‘493 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites administering in an amount effective to promote deactivation of a target microorganism at the target tissue, wherein the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11.
Claim 77 of the ‘493 application discloses: “The method of claim 1, wherein the peptide is anionic or cationic, the cationic peptide having has a net charge of from +2 to +11.”
Consequently, claim 2 is obvious over the ‘493 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein injecting the preparation into the subject comprises infusing the preparation into the subject, or the preparation is injected via intravenous, intrasecal, intramuscular, subcutaneous, intradermal, intramedullary, intravascular, intraventricular, intrabiliary, intrathecal, or epidural administration.
Jain discloses that: “Parenteral literally means introduction of substances into the body by routes other than the gastrointestinal tract, but practically the term is applied to injection of substances by subcutaneous, intramuscular, intravenous, and intra-arterial routes. Injections made into specific organs of the body for targeted drug delivery will be described under various therapeutic areas.” (Jain et al., page 3, para. 2)
Consequently, claim 5 is obvious over the ‘493 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 17, claim 1 is obvious as described above. Claim 17 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 17 is obvious over the ‘493 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 18, claim 17 is obvious as described above. Claim 18 further recites the case wherein the combining of the buffer and preparation takes places less than about 10 minutes prior to administration.
Mehta discloses: “It may also be desired to provide a hydrogel barrier that is quick to gel, i.e., the gelation kinetics are such that, upon administration, the hydrogel barrier is formed within a short amount of time to treat the pulmonary bulla and/or leakage. The short amount of time may be instantaneous or, for example, less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds, or other times disclosed herein.” (Mehta et al., para. [0064]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to trigger hydrogel assembly this way as disclosed by Mehta. The time frame of less than 5 minutes overlaps substantially with less than 10 minutes as claimed. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the art would do this if they wanted to inject a partially formed hydrogel or fully formed hydrogel. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes that the hydrogel barrier forms , less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds.
Consequently, claim 18 is obvious over the ‘493 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 20, claim 1 is obvious as described above. Claim 20 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Claim 39 of the ‘493 application discloses: “The method of claim 1, wherein the peptide comprises an effective amount of counterions, to form the hydrogel, the peptide being free of chloride counterions and the counterions selected from acetate and citrate counterions.”
Consequently, claim 20 is obvious over the ‘493 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 23, claim 17 is obvious as described above. Claim 23 further recites the case wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bris-tris propane (BTP).
Claim 42 of the ‘493 application discloses: “The method of claim 1, further comprising administering to the target site a buffer comprising an effective amount of an ionic salt and a biological buffering agent to form the hydrogel, wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bis-tris propane (BTP).”
Consequently, claim 23 is obvious over the ‘493 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 31, claim 1 is obvious as described above. Claim 31 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Claim 47 of the ‘493 application discloses: “The method of claim 46, wherein the folding group has a sequence comprising Y[XYlN[T][YXMY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10:the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.”
Consequently, claim 31 is obvious over the ‘493 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 40, claim 1 is obvious as described above. Claim 40 further recites the case wherein the peptide is at least 80% purified.
Claim 55 of the ‘493 application discloses: “The method of claim 1, wherein the peptide is at least 80% purified. “
Consequently, claim 40 is obvious over the ‘493 application in view of Mehta et al. and Jain al. and provisionally rejected.
Regarding claim 58, claim 1 is obvious as described above. Claim 58 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Mehta discloses the following peptide concentrations:
Claim 73 of the ‘493 application discloses: “The method of claim 1, wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.”
Consequently, claim 58 is obvious over the ‘493 application in view of Mehta et al. and Jain al. and provisionally rejected.
Claims 3, 4, 13, and 85-89 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 28, 39, 47, 55, 73, 77, 83 of copending Application No. 18/682,493.
This is a provisional nonstatutory double patenting rejection.
Regarding claim 3, claim 3 recites method of applying a hydrogel to a subject, comprising: topically administering a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution to a target tissue of the subject, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, the hydrogel being sterilized; and topically administering to the target tissue a buffer comprising an effective amount of an ionic salt and a biological buffering agent to form the hydrogel.
The ‘493 application discloses a method of introducing a hydrogel into a subject in claim 1:
“A method of treating a nerve injury, comprising: administering to a target site of a nerve injury a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, in an amount effective to treat the nerve injury.”
Claim 83 of the ‘493 application discloses: “The method of claim 82, wherein the preparation is sterilized by autoclave sterilization.”
Claim 28 of the ‘493 application discloses: “The method of claim 2, comprising administering the preparation to a target site of a subject topically, enterally, or parenterally”.
Consequently, claim 3 is anticipated by the ‘493 application and provisionally rejected.
Regarding claim 4, claim 3 is obvious as described above. Claim 4 further recites administering in an amount effective to promote deactivation of a target microorganism at the target tissue, wherein the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11.
Claim 77 of the ‘493 application discloses: “The method of claim 1, wherein the peptide is anionic or cationic, the cationic peptide having has a net charge of from +2 to +11.”
Consequently, claim 4 is anticipated by the ‘493 application and provisionally rejected.
Regarding claim 13, claim 1 is obvious as described above. Claim 13 further recites the case wherein 13 the target tissue is a tissue selected from mesenchymal tissue, connective tissue, muscle tissue, nervous tissue, embryonic tissue, dermal tissue, bone tissue, dental tissue, corneal tissue, cutaneous tissue, integumental tissue, soft tissue, and hard tissue, or administration to the target tissue comprises administration to a biological fluid selected from tears, mucus, urine, menses, blood, wound exudates, and mixtures thereof.
Claim 3 of the ‘493 application discloses: “The method of claim 1, wherein the target site of the nerve injury is associated with a central nervous system (CNS) tissue or a peripheral nervous system (PNS) tissue.”
Consequently, claim 13 is anticipated by the ‘493 application and provisionally rejected.
Regarding claim 85, claim 3 is anticipated as described above. Claim 85 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Claim 39 of the ‘493 application discloses: “The method of claim 1, wherein the peptide comprises an effective amount of counterions, to form the hydrogel, the peptide being free of chloride counterions and the counterions selected from acetate and citrate counterions.”
Consequently, claim 85 is anticipated by the ‘493 application and provisionally rejected.
Regarding claim 86, claim 3 is anticipated as described above. Claim 86 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Claim 47 of the ‘493 application discloses: “The method of claim 46, wherein: the folding group has a sequence comprising Y[XYlN[T][YXMY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10:the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Consequently, claim 86 is anticipated by the ‘493 application and provisionally rejected.
Regarding claim 87, claim 3 is anticipated as described above. Claim 87 further recites the case wherein the peptide is at least 80% purified.
Claim 55 of the ‘493 application discloses: “The method of claim 1, wherein the peptide is at least 80% purified.”
Consequently, claim 87 is anticipated by the ‘493 application and provisionally rejected.
Regarding claim 89, claim 3 is obvious as described above. Claim 89 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Claim 73 of the ‘493 application discloses: “The method of claim 1, wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.”
Consequently, claim 89 is anticipated by the ‘493 application and provisionally rejected.
Claim 9 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 28, 39, 47, 55, 73, 77, 83 of copending Application No. 18/682,493, applied to claim 3 above, further in view of Harding et al. (Harding, K. G., V. Jones, and P. Price. "Topical treatment: which dressing to choose." Diabetes/metabolism research and reviews 16.S1: S47-S50. (2000)).
Regarding claim 9, claim 3 is anticipated as described above. Claim 9 further recites the case wherein the method further comprises applying a topical dressing after administration of the preparation.
The ‘493 application does not specifically disclose the usage of a wound dressing. However, Harding et al. discloses the usage of wound dressings: “Wounds have existed since prehistoric times and many famous physicians through the ages have contributed to an understanding of healing. Around 1000 BC Homer provided a detailed description of 147 wounds in the Iliad. Hippocrates in 400 BC wrote 70 essays, many of which describe wounds and how we recognise the value of cleansing and the use of wine and vinegar as topical treatment for wounds. Celsus (20–50 AD) described the cardinal features of inflammation and Galen then dominated medical thinking until the Middle Ages when Paracelsus made the observation that although he dressed the wound God healed it. Subsequently absorbent cotton and gauze materials came into widespread use, and in 1916 Vaseline-coated gauze was first developed.” (Harding et al., page S47, para. 1). Furthermore, Harding discloses various advantages to different types of dressings (Harding et al., page S50, Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use wound dressings as disclosed by Harding after the method of the ‘493 application to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use wound dressings to avoid post-treatment infection and have a reasonable expectation of success because Harding discloses that dressings have been used for thousands of years and there are new modern dressings that have more specialized roles.
Consequently, claim 9 is obvious over the ‘493 application as applied to claim 3 above, further in view of Harding et al. and provisionally rejected.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 28, 39, 47, 55, 73, 77, 83 of copending Application No. 18/682,493, applied to claim 3 above, further in view of Nunez (https://www.healthline.com/health/debridement, accessed 3/4/2026, published 2/13/2019).
Regarding claim 11, claim 3 is anticipated as described above. Claim 11 further recites the case wherein target tissue is debrided before administration of the preparation.
The ‘493 application does not specifically disclose debridement. However, Nunez discloses that: “Debridement is the removal of dead (necrotic) or infected skin tissue to help a wound heal. It’s also done to remove foreign material from tissue.” (Nunez, page 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to debride the target tissue as disclosed by Nunez before the method of Mehta and Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to debride the tissue to gain the benefits disclosed by Nunez: “Wound debridement can:
help healthy tissue grow
minimize scarring
reduce complications of infections” (Nunez, page 1, para. 3).
A person of ordinary skill in the art would have a reasonable expectation of success because Nunez discloses that this procedure is essential for wounds stuck in the first healing stage: “The procedure is essential for wounds that aren’t getting better. Usually, these wounds are trapped in the first stage of healing. When bad tissue is removed, the wound can restart the healing process.” (Nunez, page 1, para. 2).
Consequently, claim 11 is obvious over the ‘493 application as applied to claim 3 above, further in view of Nunez and rejected.
Claim 12 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 28, 39, 47, 55, 73, 77, 83 of copending Application No. 18/040,388, applied to claim 3 above, further in view of Ibrahim (Ibrahim, Sarah A. "Spray-on transdermal drug delivery systems." Expert opinion on drug delivery 12.2:195-205 (2015)).
Regarding claim 12, claim 3 is anticipated as described above. Claim 12 further recites the case wherein administration is by spray, dropper, film, squeeze tube, or syringe.
The ‘493 application does not specifically disclose administration by spray, dropper, film, squeeze tube, or syringe. However, Ibrahim discloses that: “A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug–solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin.” (Ibrahim, page 195, para. 2).
Ibrahim also discloses that: “Spray-on products have been successfully used on skin for local and topical indications, with recent advancements allowing systemic delivery of drugs.” (Ibrahim, page 196, col. 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to deliver the preparation topically with a spray.
A person of ordinary skill in the art would be motivated to use spray application because Ibrahim discloses that spray on drug delivery can increase drug loading into skin as described by Ibrahim above.
A person of ordinary skill in the art would have a reasonable expectation of success because Ibrahim discloses that spray has been successfully used for the delivery of drug products as described above.
Consequently, claim 12 is obvious over the ‘493 application as applied to claim 3 above, further in view of Ibrahim and provisionally rejected.
Claim 44 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 39, 42, 47, 55, 77, 83 of copending Application No. 18/682,493 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Jain et al. (Jain, Kewal K Drug delivery systems : 1-54. (2019)) as applied to claim 1, further in view of Mauri et al. (Mauri, et al. Journal of visualized experiments: JoVE 116: 54445.(2016)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 44, claim 1 is obvious as described above. Claim 44 further recites the case wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.
The ‘493 application, Mehta, and Jain do not specifically disclose an additional functional group added to the peptide. However, Mauri discloses the usage of RGD functionalization to improve the cell adhesion capabilities of a hydrogel:
“The combination of click chemistry and the microwave-assisted method is suitable to produce biocompatible hydrogels with desired functionalities and improved performances in biomedical applications. This work aims to synthesize RGD-functionalized hydrogels. RGD (arginylglycylaspartic acid) is a tripeptide that can mimic cell adhesion proteins and bind to cell-surface receptors, creating a hospitable microenvironment for cells within the 3D polymeric network of the hydrogels. RGD functionalization occurs through Huisgen 1,3-dipolar cycloaddition. Some PAA carboxyl groups are modified with an alkyne moiety, whereas RGD is functionalized with azido acid as the terminal residue of the peptide sequence. Finally, both products are used in a copper catalyzed click reaction to permanently link the peptide to PAA. This modified polymer is used with carbomer, agarose and polyethylene glycol (PEG) to synthesize a hydrogel matrix. The 3D structure is formed due to an esterification reaction involving carboxyl groups from PAA and carbomer and hydroxyl groups from agarose and PEG through microwave-assisted polycondensation. The efficiency of the gelation mechanism ensures a high degree of RGD functionalization. In addition, the procedure to load therapeutic compounds or biological tools within this functionalized network is very simple and reproducible.” (Mauri et al., Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add the RGD functionality of Mauri to the peptide of the ‘493 application, Mehta, and Jain to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination in order to increase the cell adhesion potential of the hydrogel in question. A person of ordinary skill in the art would have a reasonable expectation of success because Mauri describes in detail how this RGD functionalization performs this task and Mauri is specifically discussing hydrogels.
Consequently, claim 44 is obvious over the ‘493 application in view of Mehta et al. and Jain al. as applied to claim 1 above, further in view of Mauri et al and provisionally rejected.
Claim 88 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 28, 39, 47, 55, 73, 77, 83 of copending Application No. 18/682,493 as applied to claim 3, further in view of Mauri et al. (Mauri, et al. Journal of visualized experiments: JoVE 116: 54445.(2016)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 88, claim 3 is anticipated as described above. Claim 88 further recites the case wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.
The ‘493 application, Mehta, and Jain do not specifically disclose an additional functional group added to the peptide. However, Mauri discloses the usage of RGD functionalization to improve the cell adhesion capabilities of a hydrogel:
“The combination of click chemistry and the microwave-assisted method is suitable to produce biocompatible hydrogels with desired functionalities and improved performances in biomedical applications. This work aims to synthesize RGD-functionalized hydrogels. RGD (arginylglycylaspartic acid) is a tripeptide that can mimic cell adhesion proteins and bind to cell-surface receptors, creating a hospitable microenvironment for cells within the 3D polymeric network of the hydrogels. RGD functionalization occurs through Huisgen 1,3-dipolar cycloaddition. Some PAA carboxyl groups are modified with an alkyne moiety, whereas RGD is functionalized with azido acid as the terminal residue of the peptide sequence. Finally, both products are used in a copper catalyzed click reaction to permanently link the peptide to PAA. This modified polymer is used with carbomer, agarose and polyethylene glycol (PEG) to synthesize a hydrogel matrix. The 3D structure is formed due to an esterification reaction involving carboxyl groups from PAA and carbomer and hydroxyl groups from agarose and PEG through microwave-assisted polycondensation. The efficiency of the gelation mechanism ensures a high degree of RGD functionalization. In addition, the procedure to load therapeutic compounds or biological tools within this functionalized network is very simple and reproducible.” (Mauri et al., Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add the RGD functionality of Mauri to the peptide of the ‘493 application, Mehta, and Jain to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination in order to increase the cell adhesion potential of the hydrogel in question. A person of ordinary skill in the art would have a reasonable expectation of success because Mauri describes in detail how this RGD functionalization performs this task and Mauri is specifically discussing hydrogels.
Consequently, claim 88 is obvious over the ‘493 application as applied to claim 3 above, further in view of Mauri et al and provisionally rejected.
Claims 1, 3, 17, 18, 20, 58, 85, 89 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 18/040,364 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 1, claim 1 recites a method of introducing a hydrogel into a subject, comprising: administering a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution into a target tissue of the subject by injection, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into the hydrogel, the hydrogel being sterilized.
Claim 1 of the ‘364 application discloses: “A method of administering biological material to a subject, comprising: combining the biological material with: a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, the hydrogel being sterile, and a buffer configured to induce self-assembly of; and administering the hydrogel comprising the biological material to a target tissue of the subject.”
Mehta discloses administering a solution comprising an amphiphilic self-assembling peptide: “…administering, through the delivery device, a solution comprising an amphiphilic self-assembling peptide comprising between about 7 amino acids and 32 amino acids in an effective amount and in an effective concentration to the target area to form a hydrogel barrier under physiological conditions of the target area to treat the pulmonary bulla;…” (Mehta et al., Claim 1).
Mehta also discloses a hydrogel-forming peptide sequence (RADA)4 which is arranged in a substantially alternating pattern of charged and hydrophobic amino acids and a turn sequence (aspartic acid). (Mehta et al., Claim 6).
Mehta also discloses the peptide being in an aqueous solution: “The method of claim 35, wherein preparing the solution comprising the self-assembling peptide comprises:
adding water to a peptide powder of the self-assembling peptide to provide an aqueous peptide solution;…” (Mehta et al., Claim 40).
Mehta discloses injecting the peptide solution: “The method of claim 1, wherein administering the solution comprises injecting the solution into the target area, with overflow solution..” (Mehta et al., Claim 7).
The ‘364 application and Mehta do not explicitly disclose purification or sterilization of the peptide preparation. However, Gil discloses the filtration and sterilization of very similar peptides: “Among other things, the present disclosure demonstrates that certain peptide compositions (e.g., compositions of particular peptides, at particular concentrations, and/or having particular rheological properties) have certain characteristics and/or may not be amenable to certain handling and/or processing steps such as, for example, filtration (e.g., sterilizing filtration).” (Gil et al., para. [0005]).
“Specifically, solutions of RADA16, IEIK13, and KLD12 per prepared at concentrations indicated below in Table 1. As can be seen, in general, higher concentration solutions showed higher max viscosity.” (Gil et al., para. [0103] and para. [0104], Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘364 application and Mehta with the purification scheme of Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to purify the peptide preparation to avoid contaminants being injected into the subject to be treated. A person of ordinary skill in the art would have a reasonable expectation of success because (RADA)4 is synonymous with RADA16 and that was one of the peptides purified by Gil.
Consequently, claim 1 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. and rejected.
Regarding claim 3, claim 3 recites method of applying a hydrogel to a subject, comprising: topically administering a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution to a target tissue of the subject, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, the hydrogel being sterilized; and topically administering to the target tissue a buffer comprising an effective amount of an ionic salt and a biological buffering agent to form the hydrogel.
Mehta discloses administering a solution comprising an amphiphilic self-assembling peptide: “…administering, through the delivery device, a solution comprising an amphiphilic self-assembling peptide comprising between about 7 amino acids and 32 amino acids in an effective amount and in an effective concentration to the target area to form a hydrogel barrier under physiological conditions of the target area to treat the pulmonary bulla;…” (Mehta et al., Claim 1).
Mehta also discloses a hydrogel-forming peptide sequence (RADA)4 which is arranged in a substantially alternating pattern of charged and hydrophobic amino acids and a turn sequence (aspartic acid). (Mehta et al., Claim 6).
Mehta discloses topical administration of the solution: “Administering the solution may comprise applying the solution topically to the target area.” (Mehta et al., para [0070]).
Mehta discloses usage of buffers: “In some embodiments, a buffer, such as a buffer solution may be added to the self-assembling peptide solution or the self-assembling peptide.” (Mehta et al., para [0142]) and the usage of ionic salts: “To adjust the salt ionic strength of the peptide solutions by way of example, various salt buffer solutions including NaCl, KCl, MgCl2, CaCl2 and DPBS (10×) were added to 2 mL of 1.5% peptide solutions.” (Mehta et al., para. [0177]).
The ‘364 application and Mehta do not explicitly disclose purification or sterilization of the peptide preparation. However, Gil discloses the filtration and sterilization of very similar peptides: “Among other things, the present disclosure demonstrates that certain peptide compositions (e.g., compositions of particular peptides, at particular concentrations, and/or having particular rheological properties) have certain characteristics and/or may not be amenable to certain handling and/or processing steps such as, for example, filtration (e.g., sterilizing filtration).” (Gil et al., para. [0005]).
“Specifically, solutions of RADA16, IEIK13, and KLD12 per prepared at concentrations indicated below in Table 1. As can be seen, in general, higher concentration solutions showed higher max viscosity.” (Gil et al., para. [0103] and para. [0104], Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘364 application and Mehta with the purification scheme of Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to purify the peptide preparation to avoid contaminants being injected into the subject to be treated. A person of ordinary skill in the art would have a reasonable expectation of success because (RADA)4 is synonymous with RADA16 and that was one of the peptides purified by Gil.
Consequently, claim 3 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. and rejected.
Regarding claim 17, claim 1 is obvious as described above. Claim 17 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by the ‘364 application Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 17 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. and rejected.
Regarding claim 18, claim 17 is obvious as described above. Claim 18 further recites the case wherein the combining of the buffer and preparation takes places less than about 10 minutes prior to administration.
Mehta discloses: “It may also be desired to provide a hydrogel barrier that is quick to gel, i.e., the gelation kinetics are such that, upon administration, the hydrogel barrier is formed within a short amount of time to treat the pulmonary bulla and/or leakage. The short amount of time may be instantaneous or, for example, less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds, or other times disclosed herein.” (Mehta et al., para. [0064]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to trigger hydrogel assembly this way as disclosed by Mehta. The time frame of less than 5 minutes overlaps substantially with less than 10 minutes as claimed. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the art would do this if they wanted to inject a partially formed hydrogel or fully formed hydrogel. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes that the hydrogel barrier forms , less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds.
Consequently, claim 18 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. and rejected.
Regarding claim 20, claim 1 is obvious as described above. Claim 20 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Mehta discloses: “The salt solution may comprise at least one anion selected from the group consisting of chloride, sulfate, acetate, carbonate, chloride, citrate, cyanide, fluoride, sulfate, nitrate, nitrite, and phosphate.” (Mehta et al., para. [0129]).
Furthermore, Mehta discloses the following example: “A peptide hydrogel mixed with a cation/anion solution which affected mechanical properties and another with a very low concentration of a contrast agent which did not affect the mechanical properties were both designed. The two gels were: (1) a combination of the self-assembling peptide with a well-known cation/anion solution, Ringer's Solution (pH 5.3), used in the medical field and (2) a combination of the self-assembling peptide with a well-known contrast agent, indigo carmine, which is a dye solution containing sulfate (anion) and sodium (cation) ions. Indigo carmine contains indigoindisulfonate sodium (C16H8N2Na2O8S2), water, and sodium citrate (C6H8O7) for pH adjustment.” (Mehta et al., para. [0190]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use acetate or citrate counterions with the claimed peptide.
A person of ordinary skill in the art would be motivated to try counterions from the finite list provided by Mehta and be further motivated by the example provided by Mehta that utilizes citrate in the buffer. A person or ordinary skill in the art would have a reasonable expectation of success because acetate and citrate are listed by Mehta as buffer ions.
Consequently, claim 20 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. and rejected.
Regarding claim 58, claim 1 is obvious as described above. Claim 58 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Mehta discloses the following peptide concentrations:
“The effective concentration may include peptide concentrations in the solution in a range of about 0.1 weight per volume (w/v) percent to about 10 w/v percent. The effective concentration may include peptide concentrations in the solution in a range of about 0.1 w/v percent to about 3.5 w/v percent. In certain embodiments, the effective concentration may be about 1 w/v percent. In certain other embodiments, the effective concentration may be about 1.5 w/v percent. In other embodiments, the effective concentration may be about 2.5 w/v percent.” (Mehta et al., para. [0107]).
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Consequently, claim 58 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. and rejected.
Regarding claim 85, claim 3 is obvious as described above. Claim 85 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Mehta discloses: “The salt solution may comprise at least one anion selected from the group consisting of chloride, sulfate, acetate, carbonate, chloride, citrate, cyanide, fluoride, sulfate, nitrate, nitrite, and phosphate.” (Mehta et al., para. [0129]).
Furthermore, Mehta discloses the following example: “A peptide hydrogel mixed with a cation/anion solution which affected mechanical properties and another with a very low concentration of a contrast agent which did not affect the mechanical properties were both designed. The two gels were: (1) a combination of the self-assembling peptide with a well-known cation/anion solution, Ringer's Solution (pH 5.3), used in the medical field and (2) a combination of the self-assembling peptide with a well-known contrast agent, indigo carmine, which is a dye solution containing sulfate (anion) and sodium (cation) ions. Indigo carmine contains indigoindisulfonate sodium (C16H8N2Na2O8S2), water, and sodium citrate (C6H8O7) for pH adjustment.” (Mehta et al., para. [0190]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use acetate or citrate counterions with the claimed peptide.
A person of ordinary skill in the art would be motivated to try counterions from the finite list provided by Mehta and be further motivated by the example provided by Mehta that utilizes citrate in the buffer. A person or ordinary skill in the art would have a reasonable expectation of success because acetate and citrate are listed by Mehta as buffer ions.
Consequently, claim 85 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. and rejected.
Regarding claim 89, claim 3 is obvious as described above. Claim 89 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Mehta discloses the following peptide concentrations:
“The effective concentration may include peptide concentrations in the solution in a range of about 0.1 weight per volume (w/v) percent to about 10 w/v percent. The effective concentration may include peptide concentrations in the solution in a range of about 0.1 w/v percent to about 3.5 w/v percent. In certain embodiments, the effective concentration may be about 1 w/v percent. In certain other embodiments, the effective concentration may be about 1.5 w/v percent. In other embodiments, the effective concentration may be about 2.5 w/v percent.” (Mehta et al., para. [0107]).
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Consequently, claim 89 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. and rejected.
Claims 2 and 4 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application 18/040,364 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 1, further in view of Salick et al. (US20110171304, published 7/14/2011).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites administering in an amount effective to promote deactivation of a target microorganism at the target tissue, wherein the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11.
The ‘364 application, Mehta, and Gil do not specifically disclose a peptide meeting these limitations. However, Salick et al. discloses an hydrogel-forming antimicrobial peptide sequence that does meet these limitations: “A peptide comprising the sequence VKVKVRVKVDPPTKVKVRVKV-NH2 forms a hydrogel which has the ability to shear-thin and recover. The hydrogel, both before and after shear-thinning, is capable of killing bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).” (Salick et al., Abstract).
This peptide has a net charge of +8 and possesses turn sequence residues D-proline and proline. Furthermore, it kills MRSA bacteria which qualifies as “deactivation” under the broadest reasonable interpretation of “deactivation”.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘966 patent, Mehta, and Gil with the peptide disclosed by Salick to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination to create a hydrogel that is active against harmful MRSA bacteria. A person of ordinary skill in the art would have a reasonable expectation of success because Salick discloses that VKVKVRVKVDPPTKVKVRVKV-NH2 is capable of killing MRSA and forms a hydrogel. Also, this peptide is similar in size and has alternating hydrophobic and charged residues so a person of ordinary skill in the art would expect the purification methods of Gil to work on this peptide as well.
Consequently, claim 2 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. as applied to claim 1 above, further in view of Salick et al. and rejected.
Regarding claim 4, claim 3 is obvious as described above. Claim 4 further recites administering in an amount effective to promote deactivation of a target microorganism at the target tissue, wherein the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11.
The ‘364 application, Mehta, and Gil do not specifically disclose a peptide meeting these limitations. However, Salick et al. discloses an hydrogel-forming antimicrobial peptide sequence that does meet these limitations: “A peptide comprising the sequence VKVKVRVKVDPPTKVKVRVKV-NH2 forms a hydrogel which has the ability to shear-thin and recover. The hydrogel, both before and after shear-thinning, is capable of killing bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).” (Salick et al., Abstract).
This peptide has a net charge of +8 and possesses turn sequence residues D-proline and proline. Furthermore, it kills MRSA bacteria which qualifies as “deactivation” under the broadest reasonable interpretation of “deactivation”.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘364 application, Mehta, and Gil with the peptide disclosed by Salick to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination to create a hydrogel that is active against harmful MRSA bacteria. A person of ordinary skill in the art would have a reasonable expectation of success because Salick discloses that VKVKVRVKVDPPTKVKVRVKV-NH2 is capable of killing MRSA and forms a hydrogel. Also, this peptide is similar in size and has alternating hydrophobic and charged residues so a person of ordinary skill in the art would expect the purification methods of Gil to work on this peptide as well.
Consequently, claim 4 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. as applied to claim 1 above, further in view of Salick et al. and rejected.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application 18/040,364 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 1, further in view of Jin et al. (Jin, Jing-fen, et al. Patient preference and adherence:923-942 (2015)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein injecting the preparation into the subject comprises infusing the preparation into the subject, or the preparation is injected via intravenous, intrasecal, intramuscular, subcutaneous, intradermal, intramedullary, intravascular, intraventricular, intrabiliary, intrathecal, or epidural administration.
The ‘364 application, Mehta, and Gil do not specifically disclose these modes of injection. However, Jin et al. discloses that intravenous, intramuscular, and subcutaneous modes of injections are frequently used: “Intravenous (IV), intramuscular (IM), and subcutaneous (SC) are the three most frequently used injection routes in medication administration. Comparative studies of SC versus IV, IM versus IV, or IM versus SC have been sporadically conducted, and some new findings are completely different from the dosage recommendation as described in prescribing information.” (Jin et al., Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use one of the injection methods disclosed by Jin with the method of Mehta and Gil.
A person of ordinary skill in the art would be motivated to use such methods for the following reasons: “ IV injection is the introduction of a medication into the veins using a needle, and it is used when rapid absorption is called for, when fluid cannot be taken by mouth, or when the medication to be administered is too irritating to be injected into the skin or muscles. SC injection is administered as a bolus into the subcutis. IM injection is the technique used to deliver a medication deep into the muscles, allowing the medication to be absorbed into the bloodstream quickly. Prescribing information for some medications notes that they can be injected via one or more routes (eg, epinephrine can be delivered by IV, IM, or SC route), while prescribing information for the majority of injectable medications only describes one injection route.” (Jin et al., page 924, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because these are the three most frequently used injection methods in this field as disclosed above.
Consequently, claim 5 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. as applied to claim 1 above, further in view of Jin et al. and rejected.
Claim 9 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application 18/040,364 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 3, further in view of Harding et al. (Harding, K. G., V. Jones, and P. Price. "Topical treatment: which dressing to choose." Diabetes/metabolism research and reviews 16.S1: S47-S50. (2000)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 9, claim 3 is obvious as described above. Claim 9 further recites the case wherein the method further comprises applying a topical dressing after administration of the preparation.
The ‘364 application, Mehta, and Gil do not specifically disclose the usage of a wound dressing. However, Harding et al. discloses the usage of wound dressings: “Wounds have existed since prehistoric times and many famous physicians through the ages have contributed to an understanding of healing. Around 1000 BC Homer provided a detailed description of 147 wounds in the Iliad. Hippocrates in 400 BC wrote 70 essays, many of which describe wounds and how we recognise the value of cleansing and the use of wine and vinegar as topical treatment for wounds. Celsus (20–50 AD) described the cardinal features of inflammation and Galen then dominated medical thinking until the Middle Ages when Paracelsus made the observation that although he dressed the wound God healed it. Subsequently absorbent cotton and gauze materials came into widespread use, and in 1916 Vaseline-coated gauze was first developed.” (Harding et al., page S47, para. 1). Furthermore, Harding discloses various advantages to different types of dressings (Harding et al., page S50, Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use wound dressings as disclosed by Harding after the method of ‘364 application, Mehta, and Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use wound dressings to avoid post-treatment infection and have a reasonable expectation of success because Harding discloses that dressings have been used for thousands of years and there are new modern dressings that have more specialized roles.
Consequently, claim 9 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. as applied to claim 3 above, further in view of Harding et al. and rejected.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 3, further in view of Nunez (https://www.healthline.com/health/debridement, accessed 3/4/2026, published 2/13/2019).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 11, claim 3 is obvious as described above. Claim 11 further recites the case wherein target tissue is debrided before administration of the preparation.
The ‘364 application, Mehta, and Gil do not specifically disclose debridement. However, Nunez discloses that: “Debridement is the removal of dead (necrotic) or infected skin tissue to help a wound heal. It’s also done to remove foreign material from tissue.” (Nunez, page 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to debride the target tissue as disclosed by Nunez before the method of the ‘364 application, Mehta, and Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to debride the tissue to gain the benefits disclosed by Nunez: “Wound debridement can:
help healthy tissue grow
minimize scarring
reduce complications of infections” (Nunez, page 1, para. 3).
A person of ordinary skill in the art would have a reasonable expectation of success because Nunez discloses that this procedure is essential for wounds stuck in the first healing stage: “The procedure is essential for wounds that aren’t getting better. Usually, these wounds are trapped in the first stage of healing. When bad tissue is removed, the wound can restart the healing process.” (Nunez, page 1, para. 2).
Consequently, claim 11 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. as applied to claim 3 above, further in view of Nunez and rejected.
Claim 12 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application 18/040,364 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 3, further in view of Ibrahim (Ibrahim, Sarah A. "Spray-on transdermal drug delivery systems." Expert opinion on drug delivery 12.2:195-205 (2015)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 12, claim 3 is obvious as described above. Claim 12 further recites the case wherein administration is by spray, dropper, film, squeeze tube, or syringe.
The ‘364 application, Mehta, and Gil do not specifically disclose administration by spray, dropper, film, squeeze tube, or syringe. However, Ibrahim discloses that: “A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug–solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin.” (Ibrahim, page 195, para. 2).
Ibrahim also discloses that: “Spray-on products have been successfully used on skin for local and topical indications, with recent advancements allowing systemic delivery of drugs.” (Ibrahim, page 196, col. 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to deliver the preparation topically with a spray.
A person of ordinary skill in the art would be motivated to use spray application because Ibrahim discloses that spray on drug delivery can increase drug loading into skin as described by Ibrahim above.
A person of ordinary skill in the art would have a reasonable expectation of success because Ibrahim discloses that spray has been successfully used for the delivery of drug products as described above.
Consequently, claim 12 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. as applied to claim 3 above, further in view of Ibrahim et al. and rejected.
Claim 13 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application 18/040,364 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 1, further in view of Salick et al. (US20110171304, published 7/14/2011) and Broekhuizen et al. (Broekhuizen, et al. "Tissue around catheters is a niche for bacteria associated with medical device infection." Critical care medicine 36.8: 2395-2402 (2008)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 13, claim 1 is obvious as described above. Claim 13 further recites the case wherein 13 the target tissue is a tissue selected from mesenchymal tissue, connective tissue, muscle tissue, nervous tissue, embryonic tissue, dermal tissue, bone tissue, dental tissue, corneal tissue, cutaneous tissue, integumental tissue, soft tissue, and hard tissue, or administration to the target tissue comprises administration to a biological fluid selected from tears, mucus, urine, menses, blood, wound exudates, and mixtures thereof.
The ‘364 application, Mehta, and Gil do not specifically disclose these target tissues.
However, Broekhuizen discloses that skin tissue becomes susceptible to bacterial infection when medical devices such as catheters are used:
“The skin biopsies of patients 1, 2, 3, 5, 7, and 8 contained large numbers of bacteria (≥103 cfu) of the same species as cultured from the subcutaneous tissue, predominantly S. epidermidis and E. faecalis (Table 1). The subcutaneous tissue swabs yielded no bacteria (patient 4 and 6) or only relatively low numbers of bacteria (patients 2, 3, 5, and 8). In patient 7, the subcutaneous swab yielded >103 bacteria, but the subcutaneous tissue samples, including those from the deeper tissue (3rd level biopsy, Table 1, Fig. 1), contained very high numbers of bacteria. Apparently, in this patient both the skin and the subcutaneous tissue were highly colonized.” (Broekhuizen et al., page 2398, col. 2, para. 2).
Salick discloses that MRSA infections can occur with medical devices: “In general, infection at a wound site prolongs healing, and with respect to medical implants, infection at the implant-tissue interface can result in implant failure. Thus, the ability to control and prevent infections is of critical importance in the medical field. One common infectious bacterium, Staphylococcus aureus, has traditionally been treated with standard antibiotics. However, drug resistant bacterial strains have evolved. Methicillin-resistant Staphylococcus aureus (MRSA) infections have become common and account for about 55% of all nosocomial infections acquired in intensive care units in the United States.” (Salick et al., para. [0003]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the method of the ‘364 application, Mehta, and Gil with the antimicrobial peptide of Salick to a dermal area because of the risk of bacterial infection described by Broekhuizen.
A person of ordinary skill in the art would be motivated to do this to avoid infection in a patient with a medical device that interfaces with skin and have a reasonable expectation of success because Salick discloses the antimicrobial activity of their disclosed peptide, particularly against MRSA.
Consequently, claim 13 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. as applied to claim 1 above, further in view of Salick et al. and Broekhuizen et al. and rejected.
Claim 23 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application 18/040,364 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 17, further in view of Branco et al. (Branco, Monica C., et al. "Fast dynamics of semiflexible chain networks of self-assembled peptides." Biomacromolecules 10.6: 1374-1380.) (2009)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 23, claim 17 is obvious as described above. Claim 23 further recites the case wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bris-tris propane (BTP).
Mehta et al. discloses: “In some embodiments, a solution or composition of the self-assembling peptide may be buffered with about 0.15 M of at least one of sodium chloride, potassium chloride, and calcium chloride.”
Furthermore, Branco discloses the mechanism of hydrogel induction for a peptide MAX1: VKVKVKVKVDPPTKVKVKVKV which is very similar to Applicant SEQ ID NO: 2. Branco discloses:
“The primary sequence of MAX1 consists of a total of 20 amino acids with alternating valine (V) and lysine (K) residues on two β-strands. (13-16) These strands are centrally connected by a tetrapeptide (-VDPPT-) sequence that has a high propensity to adopt a type II′ β-turn configuration (Figure 1A). In pH 7.4 aqueous solutions at low ionic strength, these peptides are designed to remain freely soluble and unfolded due to electrostatic repulsions between the positively charged lysine side chains (Figure 1B). When a physiologically relevant salt concentration is introduced (150 mM NaCl), the electrostatic repulsions between the lysine side chains are screened and the peptide folds into a β-hairpin structure, stabilized by intramolecular hydrogen bonds. (13, 14) When folded, the hairpin exhibits facial amphiphilicity with one face containing hydrophilic lysine residues and the other face comprised of hydrophobic valines. The valine-rich face undergoes hydrophobic collapse, driving the self-assembly of the folded hairpins into fibrils, which are further stabilized by intermolecular hydrogen bonding. (17) These two events, folding and self-assembly, although discussed as separate events, are most likely occurring concurrently. (44) The resultant fibrils are essentially irreversibly assembled such that their structure is path dependent. Transmission electron microscopy (TEM), small angle neutron scattering (SANS), and rheology demonstrate that the resultant, rigid networks of the semiflexible fibrils are composed of a bilayer of hairpins with a cross-sectional diameter of 3 nm, corresponding to the width of a folded peptide (Figure 1C). The fibrils are connected by noncovalent, interfibrillar junctions and entanglements. (13, 14, 16) Imperfections in the self-assembly mechanism, in which one hairpin is rotated relative to another hairpin in the bilayer, gives rise to interfibril branching (Figure 1B).” (Branco et al., page 1374, col. 2., para. 1).
Branco also discloses the buffer composition of “MAX1 and MAX8 hydrogels of 1.0 and 1.5 wt % were prepared using a pH 7.4, 50 mM BTP buffer with a salt concentration of 150 mM NaCl.” (Branco et al., page 1375, col. 2., para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the buffer composition disclosed by Branco to induce hydrogel formation as disclosed by the ‘364 application, Mehta, and Gil.
A person of ordinary skill in the art would be motivated to induce hydrogel formation before injection if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow.
A person of ordinary skill in the art would have a reasonable expectation of success because the peptide of Branco is charge identical to Applicant SEQ ID NO: 2 and possesses a turn sequence just like Applicant SEQ ID NO: 2. A person of ordinary skill in the art would reasonably expect a peptide so similar to react in a similar manner to the same buffer conditions. Also, the Branco paper is about hydrogel crosslink formation in general and Branco uses this buffer to induce hydrogel formation.
Consequently, claim 23 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. as applied to claim 17 above, further in view of Branco et al. and rejected.
Claim 31 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application 18/040,364 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 1, further in view of Veiga et al. (Veiga, Ana Salomé, et al. "Arginine-rich self-assembling peptides as potent antibacterial gels." Biomaterials 33.35: 8907-8916 (2012)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 31, claim 1 is obvious as described above. Claim 31 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Veiga discloses an arginine-rich self-assembling peptide, aligned against Applicant SEQ ID NO: 2:
VKVRVRVRVDPPTRVRVRVKV
VKVRVRVRVDPPTRVRVRVKV
For these peptides, Y=V, X=R and K, N=4, M=4, and T is a D-proline and a proline.
Consequently, claim 31 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. as applied to claim 1 above, further in view of Veiga et al. and rejected.
Claim 40 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application 18/040,364 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 1, further in view of Kumar et al. (Kumar, et al. Protein Expression and Purification 95: 129-135 (2014)).
Regarding claim 40, claim 1 is obvious as described above. Claim 40 further recites the case wherein the peptide is at least 80% purified.
The ‘364 application, Mehta, and Gil do not disclose a specific protein purity.
However, Mehta discloses that the peptides may be purified: “The peptides can be chemically synthesized or they can be purified from natural and recombinant sources.” (Mehta et al., para. [0116]).
Furthermore, Kumar discloses methods of protein purification that result in proteins that are at least 80%: “Subsequently, GST–APJ C-ter was purified to ∼90% purity by GSH affinity in cleavage buffer with 2 M urea (Fig. 1c and d). GST-apelin23* and GST-apelin proteins were over-expressed at 24 °C and purified to ∼95–99% purity (Supplementary Figs. 3 and 4 respectively) by GSH affinity chromatography.” (Kumar et al., page 132, col. 2, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to purify the peptide of claim 1 to at least 80% purity.
A person of ordinary skill in the art would be motivated to purify the peptide because impurities are unwanted in therapeutic compositions so they don’t interfere with the activity of the therapeutic or crate toxic side effects. A person of ordinary skill in the art would have a reasonable expectation of success because Mehta discloses that peptide may be purified and Kumar discloses specific protocols and percentage purities that result from said protocols.
Consequently, claim 40 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. as applied to claim 1 above, further in view of Kumar et al. and rejected.
Claim 44 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application 18/040,364 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017) as applied to claim 1, further in view of Mauri et al. (Mauri, et al. Journal of visualized experiments: JoVE 116: 54445.(2016)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 44, claim 1 is obvious as described above. Claim 44 further recites the case wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.
The ‘364 application, Mehta, and Gil et al. do not specifically disclose an additional functional group added to the peptide. However, Mauri discloses the usage of RGD functionalization to improve the cell adhesion capabilities of a hydrogel:
“The combination of click chemistry and the microwave-assisted method is suitable to produce biocompatible hydrogels with desired functionalities and improved performances in biomedical applications. This work aims to synthesize RGD-functionalized hydrogels. RGD (arginylglycylaspartic acid) is a tripeptide that can mimic cell adhesion proteins and bind to cell-surface receptors, creating a hospitable microenvironment for cells within the 3D polymeric network of the hydrogels. RGD functionalization occurs through Huisgen 1,3-dipolar cycloaddition. Some PAA carboxyl groups are modified with an alkyne moiety, whereas RGD is functionalized with azido acid as the terminal residue of the peptide sequence. Finally, both products are used in a copper catalyzed click reaction to permanently link the peptide to PAA. This modified polymer is used with carbomer, agarose and polyethylene glycol (PEG) to synthesize a hydrogel matrix. The 3D structure is formed due to an esterification reaction involving carboxyl groups from PAA and carbomer and hydroxyl groups from agarose and PEG through microwave-assisted polycondensation. The efficiency of the gelation mechanism ensures a high degree of RGD functionalization. In addition, the procedure to load therapeutic compounds or biological tools within this functionalized network is very simple and reproducible.” (Mauri et al., Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add the RGD functionality of Mauri to the peptide of Mehta and Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination in order to increase the cell adhesion potential of the hydrogel in question. A person of ordinary skill in the art would have a reasonable expectation of success because Mauri describes in detail how this RGD functionalization performs this task and Mauri is specifically discussing hydrogels.
Consequently, claim 44 is obvious over the ‘364 application in view of Mehta et al. and Gil et al. as applied to claim 1 above, further in view of Mauri et al. and rejected.
Claims 76, 78-84, and 86-88 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application 18/040,364 in view of Mehta et al. (US 20170072008, published 3/16/2017), Gil et al. (US20170202986, published 7/20/2017), Salick et al. (US20110171304, published 7/14/2011) and Zapotoczna et al. (Zapotoczna, et al. PLoS pathogens 12.7: e1005671 (2016)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 76, claim 76 recites a method of treating or preventing a biofilm comprising a microbial, fungal, or viral colonization, the method comprising: topically or by injection administering to a target site of the biofilm a thermally stable preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide is anionic or cationic, the cationic peptide having a net charge between +2 and +11,the peptide being configured to self-assemble into a hydrogel, the hydrogel being sterilized, in an amount effective to treat or prevent the biofilm.
Claim 1 of the ‘364 application discloses: “A method of administering biological material to a subject, comprising: combining the biological material with: a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide comprising a folding group having a plurality of charged amino acid residues and hydrophobic amino acid residues arranged in a substantially alternating pattern and a turn sequence, the peptide being configured to self-assemble into a hydrogel, the hydrogel being sterile, and a buffer configured to induce self-assembly of; and administering the hydrogel comprising the biological material to a target tissue of the subject.”
Mehta discloses administering a solution comprising an amphiphilic self-assembling peptide: “…administering, through the delivery device, a solution comprising an amphiphilic self-assembling peptide comprising between about 7 amino acids and 32 amino acids in an effective amount and in an effective concentration to the target area to form a hydrogel barrier under physiological conditions of the target area to treat the pulmonary bulla;…” (Mehta et al., Claim 1).
Mehta discloses injecting the peptide solution: “The materials and methods may include administration, application, or injection of a self-assembling peptide, or a solution comprising a self-assembling peptide, or a composition comprising a self-assembling peptide, to a predetermined or desired target area.” (Mehta et al., para. [0051]) and ” Administering the solution may comprise injecting the solution into the target area, with overflow to, for example, cover the target area topically.” (Mehta et al. para. [0070]).
Mehta does not explicitly disclose purification or sterilization of the peptide preparation. However, Gil discloses the filtration and sterilization of very similar peptides: “Among other things, the present disclosure demonstrates that certain peptide compositions (e.g., compositions of particular peptides, at particular concentrations, and/or having particular rheological properties) have certain characteristics and/or may not be amenable to certain handling and/or processing steps such as, for example, filtration (e.g., sterilizing filtration).” (Gil et al., para. [0005]).
“Specifically, solutions of RADA16, IEIK13, and KLD12 per prepared at concentrations indicated below in Table 1. As can be seen, in general, higher concentration solutions showed higher max viscosity.” (Gil et al., para. [0103] and para. [0104], Table 1).
Salick et al. discloses an hydrogel-forming antimicrobial peptide sequence that does meet these limitations: “A peptide comprising the sequence VKVKVRVKVDPPTKVKVRVKV-NH2 forms a hydrogel which has the ability to shear-thin and recover. The hydrogel, both before and after shear-thinning, is capable of killing bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).” (Salick et al., Abstract).
This peptide has a net charge of +8 and possesses turn sequence residues D-proline and proline.
Lastly, Zapotoczna discloses that MRSA creates biofilms: “From the earliest identification of poly-N-acetylglucosamine (PNAG)/polysaccharide intercellular adhesin (PIA) as a first known mediator of Staphylococcus epidermidis biofilm formation (reviewed in [1]), interest in this important virulence determinant has led to the discovery of multiple biofilm mechanisms in S. epidermidis and S. aureus.” (Zapotoczna et al., page 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the purification scheme of Gil and the peptide of Salick to treat the biofilm as disclosed by Zapotoczna to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to purify the peptide preparation to avoid contaminants being injected into the subject to be treated. A person of ordinary skill in the art would be motivated to use the peptide of Salick to create a hydrogel that is active against harmful MRSA bacteria.
A person of ordinary skill in the art would have a reasonable expectation of success because (RADA)4 is synonymous with RADA16 and that was one of the peptides purified by Gil.
A person of ordinary skill in the art would have a reasonable expectation of success because Salick discloses that VKVKVRVKVDPPTKVKVRVKV-NH2 is capable of killing MRSA and forms a hydrogel. Also, this peptide is similar in size and has alternating hydrophobic and charged residues so a person of ordinary skill in the art would expect the purification methods of Gil to work on this peptide as well.
Finally, Zapotoczna discloses that MRSA can create biofilms and therefore this method treats biofilms by killing MRSA.
Consequently, claim 76 is obvious over the ‘364 application in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 78, claim 76 is obvious as described above. Claim 78 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 78 is obvious over the ‘364 application in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 79, claim 76 is obvious as described above. Claim 79 further recites the case wherein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being free of chloride ions and the counterions are selected from acetate and citrate counterions.
Mehta discloses: “The salt solution may comprise at least one anion selected from the group consisting of chloride, sulfate, acetate, carbonate, chloride, citrate, cyanide, fluoride, sulfate, nitrate, nitrite, and phosphate.” (Mehta et al., para. [0129]).
Furthermore, Mehta discloses the following example: “A peptide hydrogel mixed with a cation/anion solution which affected mechanical properties and another with a very low concentration of a contrast agent which did not affect the mechanical properties were both designed. The two gels were: (1) a combination of the self-assembling peptide with a well-known cation/anion solution, Ringer's Solution (pH 5.3), used in the medical field and (2) a combination of the self-assembling peptide with a well-known contrast agent, indigo carmine, which is a dye solution containing sulfate (anion) and sodium (cation) ions. Indigo carmine contains indigoindisulfonate sodium (C16H8N2Na2O8S2), water, and sodium citrate (C6H8O7) for pH adjustment.” (Mehta et al., para. [0190]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use acetate or citrate counterions with the claimed peptide.
A person of ordinary skill in the art would be motivated to try counterions from the finite list provided by Mehta and be further motivated by the example provided by Mehta that utilizes citrate in the buffer. A person or ordinary skill in the art would have a reasonable expectation of success because acetate and citrate are listed by Mehta as buffer ions.
Consequently, claim 79 is obvious over the ‘364 application in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 80, claim 76 is obvious as described above. Claim 80 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Salick discloses this peptide: VKVKVRVKVDPPTKVKVRVKV-NH2 (Salick et al., Abstract).
For this peptide, Y=V, X=R and K, N=4, M=4, and T is a D-proline and a proline.
Consequently, claim 80 is obvious over the ‘364 application in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 81, claim 76 is obvious as described above. Claim 81 further recites the case wherein the preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Mehta discloses the following peptide concentrations:
“The effective concentration may include peptide concentrations in the solution in a range of about 0.1 weight per volume (w/v) percent to about 10 w/v percent. The effective concentration may include peptide concentrations in the solution in a range of about 0.1 w/v percent to about 3.5 w/v percent. In certain embodiments, the effective concentration may be about 1 w/v percent. In certain other embodiments, the effective concentration may be about 1.5 w/v percent. In other embodiments, the effective concentration may be about 2.5 w/v percent.” (Mehta et al., para. [0107]).
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Consequently, claim 81 is obvious over the ‘364 application in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 82, claim 76 is obvious as described above. Claim 82 further recites the case wherein a buffer is combined with the preparation before administration as to induce hydrogel formation.
Mehta discloses: “The term “self-assembling peptide” may refer to a peptide that may exhibit a beta-sheet structure in aqueous solution in the presence of specific conditions to induce the beta-sheet structure. These specific conditions may include adjusting the pH of a self-assembling peptide solution. The adjustment may be an increase or a decrease in the pH of the self-assembling peptide solution. The increase in pH may be an increase in pH to a physiological pH. The specific conditions may also include adding a cation, such as a monovalent cation or a divalent cation, to a self-assembling peptide solution. The specific conditions may also include adding an anion, such as a monovalent anion or a divalent anion, to a self-assembling peptide solution. (Mehta et al., para. [0055]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a buffer to modify the pH as disclosed by Mehta to induce self-assembly of the hydrogel before administration.
A person of ordinary skill in the art would be motivated to do this if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes how pH manipulation can induce hydrogel formation.
Consequently, claim 82 is obvious over the ‘364 application in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Regarding claim 83, claim 82 is obvious as described above. Claim 83 further recites the case wherein the combining of the buffer and preparation takes places less than about 10 minutes prior to administration.
Mehta discloses: “It may also be desired to provide a hydrogel barrier that is quick to gel, i.e., the gelation kinetics are such that, upon administration, the hydrogel barrier is formed within a short amount of time to treat the pulmonary bulla and/or leakage. The short amount of time may be instantaneous or, for example, less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds, or other times disclosed herein.” (Mehta et al., para. [0064]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to trigger hydrogel assembly this way as disclosed by Mehta. The time frame of less than 5 minutes overlaps substantially with less than 10 minutes as claimed. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the art would do this if they wanted to inject a partially formed hydrogel or fully formed hydrogel. A person of ordinary skill in the art would have a reasonable expectation of success because as described above, Mehta describes that the hydrogel barrier forms , less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, or less than 30 seconds.
Consequently, claim 83 is obvious over the ‘364 application in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. and rejected.
Claim 84 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,245,299 in view of Mehta et al. (US 20170072008, published 3/16/2017), Gil et al. (US20170202986, published 7/20/2017), Salick et al. (US20110171304, published 7/14/2011) and Zapotoczna et al. (Zapotoczna, et al. PLoS pathogens 12.7: e1005671 (2016)) as applied to claim 76 above, further in view of Branco et al. (Branco, Monica C., et al. "Fast dynamics of semiflexible chain networks of self-assembled peptides." Biomacromolecules 10.6: 1374-1380.) (2009)).
Regarding claim 84, claim 82 is obvious as described above. Claim 84 further recites the case wherein the buffer comprises between about 10 mM and 150 mM sodium chloride and between about 10 mM and 100 mM Bris-tris propane (BTP).
Mehta et al. discloses: “In some embodiments, a solution or composition of the self-assembling peptide may be buffered with about 0.15 M of at least one of sodium chloride, potassium chloride, and calcium chloride.”
Furthermore, Branco discloses the mechanism of hydrogel induction for a peptide MAX1: VKVKVKVKVDPPTKVKVKVKV which is very similar to Applicant SEQ ID NO: 2. Branco discloses:
“The primary sequence of MAX1 consists of a total of 20 amino acids with alternating valine (V) and lysine (K) residues on two β-strands. (13-16) These strands are centrally connected by a tetrapeptide (-VDPPT-) sequence that has a high propensity to adopt a type II′ β-turn configuration (Figure 1A). In pH 7.4 aqueous solutions at low ionic strength, these peptides are designed to remain freely soluble and unfolded due to electrostatic repulsions between the positively charged lysine side chains (Figure 1B). When a physiologically relevant salt concentration is introduced (150 mM NaCl), the electrostatic repulsions between the lysine side chains are screened and the peptide folds into a β-hairpin structure, stabilized by intramolecular hydrogen bonds. (13, 14) When folded, the hairpin exhibits facial amphiphilicity with one face containing hydrophilic lysine residues and the other face comprised of hydrophobic valines. The valine-rich face undergoes hydrophobic collapse, driving the self-assembly of the folded hairpins into fibrils, which are further stabilized by intermolecular hydrogen bonding. (17) These two events, folding and self-assembly, although discussed as separate events, are most likely occurring concurrently. (44) The resultant fibrils are essentially irreversibly assembled such that their structure is path dependent. Transmission electron microscopy (TEM), small angle neutron scattering (SANS), and rheology demonstrate that the resultant, rigid networks of the semiflexible fibrils are composed of a bilayer of hairpins with a cross-sectional diameter of 3 nm, corresponding to the width of a folded peptide (Figure 1C). The fibrils are connected by noncovalent, interfibrillar junctions and entanglements. (13, 14, 16) Imperfections in the self-assembly mechanism, in which one hairpin is rotated relative to another hairpin in the bilayer, gives rise to interfibril branching (Figure 1B).” (Branco et al., page 1374, col. 2., para. 1).
Branco also discloses the buffer composition of “MAX1 and MAX8 hydrogels of 1.0 and 1.5 wt % were prepared using a pH 7.4, 50 mM BTP buffer with a salt concentration of 150 mM NaCl.” (Branco et al., page 1375, col. 2., para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the buffer composition disclosed by Branco to induce hydrogel formation as disclosed by the ‘364 application, Mehta, Gil, Salick, and Zapotoczna.
A person of ordinary skill in the art would be motivated to induce hydrogel formation before injection if they wanted to inject a partially formed hydrogel or if hydrogel formation for a given peptide was very slow.
A person of ordinary skill in the art would have a reasonable expectation of success because the peptide of Branco is charge identical to Applicant SEQ ID NO: 2 and possesses a turn sequence just like Applicant SEQ ID NO: 2. A person of ordinary skill in the art would reasonably expect a peptide so similar to react in a similar manner to the same buffer conditions. Also, the Branco paper is about hydrogel crosslink formation in general and Branco uses this buffer to induce hydrogel formation.
Consequently, claim 84 is obvious over the ‘364 application in view of Mehta et al., Gil et al., Salick et al., and Zapotoczna et al. as applied to claim 82 above, further in view of Branco et al. and rejected.
Claim 86 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application 18/040,364 in view of Mehta et al. (US 20170072008, published 3/16/2017), Gil et al. (US20170202986, published 7/20/2017) as applied to claim 3, further in view of Veiga et al. (Veiga, Ana Salomé, et al. "Arginine-rich self-assembling peptides as potent antibacterial gels." Biomaterials 33.35: 8907-8916 (2012)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 86, claim 3 is obvious as described above. Claim 86 further recites the case wherein: the folding group has a sequence comprising Y[XY]N[T][YX]MY, where X is 1-3 charged amino acids, Y is 1-3 hydrophobic amino acids, T is 2-8 turn sequence amino acids, and N and M are each independently between 2 and 10;
the hydrophobic amino acid residues are independently selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, threonine, tryptophan, and combinations thereof; and the charged amino acid residues are independently selected from arginine, lysine, histidine, and combinations thereof; and the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Veiga discloses an arginine-rich self-assembling peptide, aligned against Applicant SEQ ID NO: 2:
VKVRVRVRVDPPTRVRVRVKV
VKVRVRVRVDPPTRVRVRVKV
For these peptides, Y=V, X=R and K, N=4, M=4, and T is a D-proline and a proline.
Consequently, claim 86 is obvious over the ‘364 application in view of Mehta et al. and Gil et al., as applied to claim 3 above, further in view of Branco et al. and rejected.
Claim 87 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application 18/040,364 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017 as applied to claim 3, further in view of Kumar et al. (Kumar, et al. Protein Expression and Purification 95: 129-135 (2014)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 87, claim 3 is obvious as described above. Claim 87 further recites the case wherein the peptide is at least 80% purified.
Mehta and Gil do not disclose a specific protein purity.
However, Mehta discloses that the peptides may be purified: “The peptides can be chemically synthesized or they can be purified from natural and recombinant sources.” (Mehta et al., para. [0116]).
Furthermore, Kumar discloses methods of protein purification that result in proteins that are at least 80%: “Subsequently, GST–APJ C-ter was purified to ∼90% purity by GSH affinity in cleavage buffer with 2 M urea (Fig. 1c and d). GST-apelin23* and GST-apelin proteins were over-expressed at 24 °C and purified to ∼95–99% purity (Supplementary Figs. 3 and 4 respectively) by GSH affinity chromatography.” (Kumar et al., page 132, col. 2, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to purify the peptide of claim 1 to at least 80% purity.
A person of ordinary skill in the art would be motivated to purify the peptide because impurities are unwanted in therapeutic compositions so they don’t interfere with the activity of the therapeutic or crate toxic side effects. A person of ordinary skill in the art would have a reasonable expectation of success because Mehta discloses that peptide may be purified and Kumar discloses specific protocols and percentage purities that result from said protocols.
Consequently, claim 87 is obvious over the ‘364 application in view of Mehta et al. and Gil et al., as applied to claim 3 above, further in view of Branco et al. and rejected.
Claim 88 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application 18/040,364 in view of Mehta et al. (US 20170072008, published 3/16/2017) and Gil et al. (US20170202986, published 7/20/2017 as applied to claim 3, further in view of Mauri et al. (Mauri, et al. Journal of visualized experiments: JoVE 116: 54445.(2016)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 88, claim 3 is obvious as described above. Claim 88 further recites the case wherein the peptide includes a functional group having between 3 and 30 amino acids, the functional group being engineered to express a bioactive property.
Mehta and Gil et al. do not specifically disclose an additional functional group added to the peptide. However, Mauri discloses the usage of RGD functionalization to improve the cell adhesion capabilities of a hydrogel:
“The combination of click chemistry and the microwave-assisted method is suitable to produce biocompatible hydrogels with desired functionalities and improved performances in biomedical applications. This work aims to synthesize RGD-functionalized hydrogels. RGD (arginylglycylaspartic acid) is a tripeptide that can mimic cell adhesion proteins and bind to cell-surface receptors, creating a hospitable microenvironment for cells within the 3D polymeric network of the hydrogels. RGD functionalization occurs through Huisgen 1,3-dipolar cycloaddition. Some PAA carboxyl groups are modified with an alkyne moiety, whereas RGD is functionalized with azido acid as the terminal residue of the peptide sequence. Finally, both products are used in a copper catalyzed click reaction to permanently link the peptide to PAA. This modified polymer is used with carbomer, agarose and polyethylene glycol (PEG) to synthesize a hydrogel matrix. The 3D structure is formed due to an esterification reaction involving carboxyl groups from PAA and carbomer and hydroxyl groups from agarose and PEG through microwave-assisted polycondensation. The efficiency of the gelation mechanism ensures a high degree of RGD functionalization. In addition, the procedure to load therapeutic compounds or biological tools within this functionalized network is very simple and reproducible.” (Mauri et al., Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add the RGD functionality of Mauri to the peptide of Mehta and Gil to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination in order to increase the cell adhesion potential of the hydrogel in question. A person of ordinary skill in the art would have a reasonable expectation of success because Mauri describes in detail how this RGD functionalization performs this task and Mauri is specifically discussing hydrogels.
Consequently, claim 88 is obvious over the ‘364 application in view of Mehta et al. and Gil et al., as applied to claim 3 above, further in view of Branco et al. and rejected.
Conclusion
No claim is allowed.
Claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, 76, and 78-89 are rejected.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654