DETAILED ACTION
Examiner acknowledges receipt of the reply filed 4/30/2026, in response to the restriction requirement mailed 04/03/2026.
Claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, and 64-73 are pending. Claims 2, 12, 13, 35, 67, and 70-73 are withdrawn from further consideration for the reasons set forth below.
Claims 1, 3, 4, 7-10, 14, 19, 31, 49, 53-56, 61, 64-66, 68, and 69 are being examined on the merits in this office 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 .
Priority
The filing receipt dated 07/16/2024 provides the following:
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Election/Restrictions
Applicant's election of Group I (claims 1, 3, 4, 7-10, 14, 19, 31, 35, 49, 53-56, 61, 64-66, 68, and 69) with traverse in the reply filed on 4/30/2026 is acknowledged. The traversal is on the ground(s) that the hydrogel is “administered in methods of treating, eliminating, or inhibiting difficult microorganism communities, such as biofilm”. Applicant asserts that the peptides of cited reference Mehta lack a turn sequence and dot not possess any intrinsic antimicrobial properties. Applicant asserts that the cited reference Schneider is silent regarding any antimicrobial treatment (reply filed 4/30/2026 at p. 4).
This is not found persuasive.
Regarding “administered in methods of treating, eliminating, or inhibiting difficult microorganism communities”, this was not regarded as the special technical feature. Consequently, disclosure of this element is not required.
Additionally, Schneider discloses self-assembling peptides that form therapeutic hydrogels comprising a turn sequence to aid in peptide folding for controlled self-assembly (e.g., para [0033]-[0036). The hydrogel further comprises an aqueous medium (e.g., abstract, claim 1, para [0026]. [0033]). The hydrogels can be administered/delivered, egg, by injection (para [0039], [0025], [0081]). Schneider discloses e.g., MAX28
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(para [0030]), which has 100% identity with PEP8R (instant Fig 5A). MPEP § 2112.01 recites, “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established.” In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "Products of identical chemical composition can not have mutually exclusive properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.” See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Thus, Schneider alone is sufficient to split unity of invention between groups 1-3.
It is further noted that identified groups of inventions I-III, as set forth in the restriction mailed 4/3/2026, do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons:
As noted, 37 CFR 1.475 (b)- see restriction mailed 4/3/2026 at pp. 2-3, limits unity of invention to a single method of use group. Applicants have three method of use groups, thus, unity is lacking and restriction is proper.
The requirement is still deemed proper and is therefore made FINAL.
Claims 2, 12, 13, 67, and 70-73 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 4/30/2026.
Applicant’s election of the following species without traverse in the reply filed on 4/30/2026 is acknowledged.
Target microorganism- Staphylococcus aureus
peptide- SEQ ID NO:2
functional group- none
target site- dermal tissue
Claims 1, 3, 4, 7-10, 14, 19, 31, 49, 53-56, 61, 64-66, 68, and 69 read on the elected species.
Applicant did not provide any separate arguments for traversal with respect to the elected species. See Applicant’s traversal arguments and Examiner’s rebuttal arguments that apply to the elected species and are incorporated herein as well.
Claim 35 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 4/30/2026.
Drawings
The drawings are objected to for the following reasons.
Figures 3-6, 10, 13-15, 17, 19-20, 23, 25, and 30 each contain multiple parts that should be separately identified and described in the respective figure legends.
Figure 13 has “F” in the upper left part of the figure. Examiner notes that this does not correlate with a Fig 13F. The “F” should be identified or deleted from the figure.
Fig 5A includes peptide sequences comprising four or more amino acids that are not associated with SEQ ID NOs. All sequences longer than ten nucleotides or four amino acids referenced in the specification must include a SEQ ID NO and must be included in the Sequence Listing. See MPEP § 2421-2422.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
Specification - Sequence Compliance
This application is objected to because the sequences are not associated with a sequence identifier (a SEQ ID NO). Examiner notes that additional sequences in the specification may also need a SEQ ID NO: as this is not a comprehensive list of the entire specification. All sequences longer than ten nucleotides or four amino acids referenced in the specification must include a SEQ ID NO and must be included in the Sequence Listing. See MPEP § 2421-2422. Applicant must amend the specification in response to this office action and must confirm that all sequences in the specification are included in the sequence listing.
See specification filed 10/10/2026 at e.g., pp. 5 and 24-27. See also Fig 5.
Examiner requests that Applicants review the specification to confirm that all sequences, as required, comply with MPEP § 2421-2422.
Claim Objections
Claims 1, 3, 7, 8, 10, 19, 31, 49, 53, 55, 56, and 65 are objected to because of the following informalities:
Claim 1 should be amended to recite “comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the purified amphiphilic 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 purified amphiphilic peptide being configured to self-assemble into a hydrogel”.
Claims 3, 7, 8, 19, 31, 35, 49, 53, 55, 56, and 65 should be amended to recite “claim 1[[ ]],” to remove the extra space before the comma.
Claim 3 should be amended to recite “ a local site of the microbial contamination in the subject”.
Claim 10 should be amended to recite “hard tissue;[[,]] or a biological fluid”.
Claim 19 should be amended to recite a SEQ ID NO after the peptide. Claim 19 should further be amended to recite “wherein.
Appropriate correction is required.
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, 3, 4, 7-10, 14, 31, 49, 53-56, 64-66, 68, and 69 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.
Claim 1 recites the limitation "the peptide" at lines 4 and 6. There is insufficient antecedent basis for this limitation in the claim. The claim should be amended to recite “the amphiphilic peptide” for proper antecedent basis.
The terms "substantially alternating pattern" and “turn sequence” in claim 1 are relative terms which renders the claim indefinite. The terms "substantially alternating pattern" and “turn sequence” are 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" and which ones would not.
Additionally, the metes and bounds of the term “turn sequence” are not set forth. The skilled artisan is not provided any guidance to distinguish the boundaries of the “folding group” from the “turn sequence” within the claimed amphiphilic peptide.
Because claims 3, 4, 7-10, 14, 31, 49, 53-56, 64-66, 68, and 69 depend from indefinite claim 1 and do not clarify the point of confusion, they must also be rejected under 35 U.S.C. 112(b).
Claim 4 recites the limitation "the peptide". There is insufficient antecedent basis for this limitation in the claim. The claim should be amended to recite “the amphiphilic peptide”.
Claims 31, 49, and 53-55 recite the limitation "the peptide". There is insufficient antecedent basis for this limitation in the claims. The claims should be amended to recite “the amphiphilic peptide”.
Claim 53 recites the limitation "the cationic peptide". There is insufficient antecedent basis for this limitation in the claim. To overcome this rejection, examiner recommends that claim 19 be amended to recite “wherein the peptide is an anionic peptide or a cationic peptide;[,]] the cationic peptide having a net charge of from +2 to +11”.
Claim 61 recites the limitation "the target tissue". There is insufficient antecedent basis for this limitation in the claim.
Regarding claim 66, the use of parenthetical phrases render the claims indefinite because it is unclear whether the limitations following the phrases or in parentheses are part of the claimed invention. The phrase "e.g." renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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, 3, 4, 7-10, 14, 19, 31, 49, 53-56, 61, 64-66, 68, and 69 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 functions “…configured to self-assemble into the hydrogel…” and “effective to promote deactivation of the microbial contamination”. 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, peptides encompassed within the instant claim scope is potentially infinite.
The specification states at p. 63, ll. 1-9 that the microorganism/microbe may be bacteria, archaea, fungi, algae, protozoa, and/or virus. The microbial contamination may be associated with a single pathogenic species or genus. The microbial contamination may be associated with a community of pathogens.
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 amphiphilic peptides and microbes.
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.
The specification is limited to disclosing four peptides of the instant claim scope: PEP2R, PEP4R, PEP6R, and PEP8R (Ex 1, Fig 5A).
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As set forth in the table, the disclosed peptides are similar in sequence and represent a limited structural diversity.
The examples further disclosed antibacterial activity to gram positive and gram negative bacteria. There are no examples of treating/prevention by a virus, protozoa, algae, etc.
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.
Since only a limited number of species of amphiphilic peptides are taught within the claimed genus above, the instant claims fail 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- cited in IDS filed 5/06/2026) 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- cited in IDS filed 5/06/2026).
Another example of the unpredictable effects of mutations on protein function, Drumm et al (Annu. Rev. Pathol. Mech. Dis., 2012, 7, pages 267-282) teach cystic fibrosis is an autosomal recessive disorder caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, for example, page 268, Section "CYSTIC FIBROSIS". Drumm et al further teach several mutations can cause cystic fibrosis, including two mutations G551D and G551S; and clinical consequences are quite different for these two changes, as the G551D variant has virtually no detectable activity, and consequently a classic, severe phenotype is associated; G551S, however, has reduced but clearly detectable function and is associated with a much milder presentation of CF, for example page 269, left column, the last paragraph. Drumm et al also teach that in the most common cystic fibrosis mutation AF508 (the absence of amino acid 508 of the normally 1,480-amino acid protein) gives rise to the cystic fibrosis phenotype, for example, page 268, right column, the 2ⁿᵈ paragraph. Thus, even the substitution or deletion of a single amino acid can have dramatic and unpredictable effects on the function of the protein. The unpredictability of the effect of amino acid substitution on the function and/or property of peptide/protein is further confirmed and discussed in Yampolsky et al (Genetics, 2005, 170, pages 1459-1472). Yampolsky et al teach even conservative substitution can significantly affect the function of the protein/peptide, for example, page 1465, Table 3. The references illustrate the inherent unpredictability with respect to the biological activity of a given protein/peptide after even minor changes to the primary amino acid sequence.
Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang et al (MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)- cited in IDS filed 5/06/2026) 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 peptide encompassed within the instant claims.
Considering the scope of the genus of instant claimed peptides and microorganisms, instant specification fails to provide sufficient examples to describe the entire genus as claimed.
Taken all these together, considering the state of the art and the disclosure in the instant specification, it is deemed that the instant specification fails to provide adequate written description for the claimed genus of amphiphilic peptides other than the limited examples, and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed, had possession of the entire scope of the claimed invention.
Claims 1, 3, 4, 7-10, 14, 19, 31, 49, 53-56, 61, 64-66, 68, and 69 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 peptides PEP2R, PEP4R, PEP6R, and PEP8R that can form into hydrogels for use in treating a subject with a bacterial infection, does not reasonably provide enablement for all iterations of amphiphilic peptides and treatment/prevention of microbes that fall within the instant claim scope. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to:
(1) The breadth of the claims; (2) The nature of the invention; (3) The state of the prior art; (4) The level of one of ordinary skill; (5) The level of predictability in the art; (6) The amount of direction provided by the inventor; (7) The existence of working examples; and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Regarding factors (2) The nature of the invention and (1) The breadth of the claims. The claims are drawn to 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 the microbial contamination.
The specification discloses that the term “treatment” of an injury, condition, or disease refers to reducing the severity or frequency of at least one symptom of that injury, condition, or disease, compared to a similar but untreated subject. Treatment can also refer to halting, slowing, or reversing the progression of an injury, condition, or disease, compared to a similar but untreated subject. Treatment may comprise addressing the root cause of the injury, condition, or disease and/or one or more symptoms (specification at p. 19, ll. 3-8).
The specification states at p. 63, ll. 1-9:
In general, the microbial contamination, colonization, or infection may be induced by proliferation of a pathogenic microorganism (disease-causing microorganism). Thus, the methods may generally comprise administering the preparation in an amount effective to promote deactivation of a pathogenic microorganism. Administration may provide broad-spectrum antimicrobial treatment. In certain embodiments, administration may promote deactivation of multi-drug resistant organisms (MDRO). The pathogenic microorganism may be bacteria, archaea, fungi, algae, protozoa, and/or virus. The microbial contamination may be associated with a single pathogenic species or genus. The microbial contamination may be associated with a community of pathogens.
Microbial contamination can be caused by any number of organisms including but not limited to, bacteria, viruses, fungi, parasites (such as flukes and Plasmodium), and protozoa (such as trypanosomes and Giardia).
(3) The state of the prior art: Examiner notes that the following references are a brief selection of several of the recited forms of microbial contamination but is not comprehensive of the full claim scope.
A search of the art did not uncover a single agent that was able to treat/prevent all forms of microbial contamination (i.e. bacterial, viral, fungal, and parasitic) that fall within the instant claim scope.
There is a great number of bacteria, protozoa and fungal infections. For example, the CDC lists a large number of fungal diseases that cause disease (https://www.cdc.gov/fungal/diseases/index.html accessed 5/21/21). The Merck Manual (https://www.merckmanuals.com/home/skin-disorders/fungal-skin-infections/overview-of-fungal-skin-infections accessed 2/19/19) teaches antifungal drugs for treatment of fungal infections. There was no disclosure of treatment for other microorganisms with the antifungal agents. The Merck Manual (https://www.merckmanuals.com/professional/infectious-diseases/fungi/overview-of-fungal-infections accessed 10/21/2020) teaches that fungal infections are often classified as either opportunistic or primary. Opportunistic infections are those that develop mainly in immunocompromised hosts; primary infections can develop in immunocompetent hosts. It would be highly unlikely and require undue experimentation to test whether a claimed amphiphilic peptide would be able to treat and prevent all fungal infections.
With respect to bacterial infections, bacterial infections can take on many forms and be caused by Gram-positive and gram-negative bacterium. Doron (“Bacterial infections: Overview”; International Encyclopedia of Public Health, 2008:273-282) teaches that bacteria are ubiquitous and bacterial resistance to antimicrobials is a rapidly growing problem with potentially devastating consequences (Introduction). Doron teaches that new species and new variants of familiar species continue to be discovered, particularly as we intrude into new ecosystems (Introduction). Doron also teaches that host factors are critical in determining whether disease will develop following transmission of a bacteria agent, such as genetic makeup, nutritional status, age, duration of exposure to the organism and coexisting illness (last para of Introduction). Importantly the National Institute of Health (https://www.niaid.nih.gov/research/antimicrobial-resistance-threats 2/11/20) teaches that a number of pathogen are increasingly resistant to existing antibiotics and antifungals. For example, the NIH states that N. gonorrheae has developed resistance to nearly all antibiotics used for treatment, making it harder to treat much less prevent.
The Merck Manual (https://www.merckmanuals.com/professional/infectious-diseases/viruses/overview-of-viruses accessed 2/19/19) teaches antiviral drugs and states that the drug interfere with viral particle attachment, inhibit cellular receptor, factor required for viral replication or block specific virus coded enzymes. The Merck Manual also teaches that some drugs may be effective against other viruses (i.e. HIV drugs are used for Hepatitis B), however the Merck Manual, nor does the prior art teach that a single drug or drug combination could treat all viruses.
The Merck Manual (https://www.merckmanuals.com/professional/infectious-diseases/approach-to-parasitic-infections/approach-to-parasitic-infections?query=protozoa accessed 10/22/2020) teaches that human parasites encompass three different forms: Single-cell organisms (protozoa, microsporidia), multicellular helminths (worms), and ectoparasites such as scabies and lice. Treatments vary depending on the specific form of infection.
Therefore, if one considers all of the bacteria, protozoa, viral, and fungal species known in the art and the fact that some pathogens are resistant to treatment, it would be highly unpredictable and require undue experimentation to test whether or not a claimed amphiphilic peptide could all bacteria, protozoa, viral, and fungal infections. Importantly, the prior art is silent regarding a single agent for treating/preventing of ALL the different microbes that fall within the instant claim scope.
Therefore, the state of the art at the time of the application is that the etiology and treatment/prevention of all forms of microbial contamination (e.g., including but not limited tom bacterial, fungal, viral, and protozoan infections) is challenging and complex. Adding to the complexity are the many different pathogens and subjects encompassed within the instant claims. The specification states: The term “subject” is intended to include human and non-human animals, for example, vertebrates, large animals, and primates.
It is noted that pharmaceutical and biological art is generally unpredictable, requiring each embodiment to be individually assessed for physiological activity. Given this fact, historically the development of new drugs has been difficult and time-consuming. Adding to the unpredictability is that many treatment options may show promise in animal models, but may fail to show therapeutic improvement in clinical trials. There is no absolute predictability, even in view of the high level of skill in the art.
Thus, treating all microbial contaminations of variable origin, e.g., bacterial, protozoal, viral, and fungal, or combinations thereof- the possibilities are vast. Each microbe is distinct and it would be highly unpredictable given the art and the breadth of the claims to determine if the claimed amphiphilic peptide can treat all microbial contaminations.
Li et al. (Soft matter 15.8:1704-1715 (2019)- cited in IDS filed 5/06/2026) is a review article disclosing 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 at p. 1706, para. 1. Li further discloses that ions as well as charge can influence the design of such peptides. Li et al states at p. 1706, para 2:
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). 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. 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.
(4) The relative skill of those in the art:
MPEP 2141.03 states (in part)” A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At 1396, 82 USPQ2d at 1396. The “hypothetical person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988) (disagreeing with the examiner’s definition of one of ordinary skill in the art (i.e. a doctorate level engineer or scientist working at least 40 hours per week in semiconductor research or development), and finding that the hypothetical person is not definable by way of credentials, and that the evidence in the application did not support the conclusion that such a person would require a doctorate or equivalent knowledge in science or engineering). In the instant case, the skill in the art high with respect to physicians and scientists. The level of skill in the art (physicians and scientists) would be high.
(5) The predictability or unpredictability of the art: The invention is directed toward the treatment of disease and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
Therefore, the state of the art at the time of the application there is no single agent that can treat/prevent all microbes that fall within the instant claim scope. Adding to the complexity are the vast number of amphiphilic peptides that fall within the instant claim scope. It is further noted that subject encompasses numerous species. Pharmaceutical and biological art is generally unpredictable, requiring each embodiment to be individually assessed for physiological activity. Given this fact, historically the development of new drugs has been difficult and time-consuming. Adding to the unpredictability is that many treatment options may show promise in animal models, but may fail to show therapeutic improvement in clinical trials. There is no absolute predictability, even in view of the high level of skill in the art.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification discloses PEP2R, PEP4R, PEP6R, and PEP8R and antibacterial activity against Gram positive (S. aureus) and Gram negative (E. coli and P. aeruginosa) bacteria (Ex 1, Fig 5A).
Example 2, 3 and 16 are prophetic examples that were not reduced to practice.
Examples 4-11, 13 and 14 disclose antimicrobial activity against Gram-positive (E. faecium, S. epidermidis, S. heamolyticus, and MRSA) and gram negative bacteria ( P. aeruginosa, E. coli, K. pneumonia, and A. baumanii).
Example 12 indicates that the peptides are selective for bacteria, while maintaining mammalian cell viability.
Example 15 discloses antimicrobial activity against Gram negative bacteria (P. aeruginosa).
There was no disclosure of treatment or prevention of any infection other than bacterial infections; e.g., no viruses, protozoa, or fungal microorganisms were reduced to practice.
(8) The quantity of experimentation necessary: MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” Because of the sheer scope of the claim language, numerous unrelated infectious diseases will have to be tested, and the effective amount of a compound for each disease, one of ordinary skill in the art would be burdened with undue “painstaking experimentation study” to practice the instant claims.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3, 4, 7-10, 14, 19, 49, 53, 54, 56, 64-66, 68, and 69 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Veiga et al. (Biomaterials 3:8907-8916 (2012)- cited in IDS filed 10/05/2023).
Veiga et al. teach a method of treating bacterial infections [reads on microbial contamination associated with a community of microorganisms] comprising administering a purified amphiphilic peptide in an aqueous compatible solution, the peptide comprising alternating charged and hydrophobic amino and a turn sequence, wherein the peptide self-assembles into a hydrogel (see e.g., Abstract, pp. 8907-
8912). Veiga teaches self-assembling ß-hairpin peptides, including SEQ ID NO: 2 of the instant application, VKVRVRVRVDPPTRVRVRVKV (PEP6R), an amphiphilic peptide (see e.g., Abstract, p. 8910). In antibacterial assays, they further teach using the peptides in an aqueous buffer, BTP, with water and sodium chloride (pp. 8908-8910), and the reference teaches that all peptides were purified as a part of the peptide synthesis (p. 8908). Antibacterial hydrogels can be used to directly treat accessible
wounds to prevent or kill existing infection (e.g., p. 18907). Accordingly, the limitations of claim 1 are satisfied.
Regarding claims 3, 8, 9, and 64, Veiga teach that the peptide is effective at killing both gram-positive and gram-negative bacteria, including multi-drug resistant P. aeruginosa [pathogenic microorganism] (abstract, p. 8913-8915, Fig 4). “P. aeruginosa is an especially bad actor, being the fourth most common nosocomial pathogen accounting for 10% of all hospital infections” (p. 8907). Antibacterial hydrogels can be used to directly treat accessible wounds to prevent or kill existing infection (e.g., p. 8907, abstract).
Regarding claim 4, Veiga et al. teach the use of an acetate counterion, TFA, in the peptide synthesis, and they do not teach the use of chloride in any form in the synthesis of the peptide (e.g., p. 8908).
Regarding claim 7, Veiga et al. teach that the peptide is effective at killing at least 90% of bacteria (e.g., Figs. 4, 6, 8, 10, and 11).
Regarding claim 10, wounds include dermal wounds [reads on dermal tissue; cutaneous tissue] (e.g., p. 8907).
Regarding claim 14, the preparation can be administered by injection [reads on parenterally] (e.g., p. 8908, 8914-8915).
Regarding claim 19, Veiga et al. teach the peptide VKVRVRVRVDPPTRVRVRVKV (PEP6R, instant SEQ ID NO:2) (abstract, Fig 3B). In this peptide, X is Arg or Lys; X is Arg or Lys; turn sequence is DPro-Pro-Thr; n=4; and m=3 . The reference further teaches PEP8R, PEP4R, and PEP2R (e.g., p. 8909, Figs 1 and 3B).
With regard to claim 49, Veiga et al. teach PEP6R hydrogels comprised 0.5%, 1, 1.5, or 2% weight of a peptide (e.g., pp. 8908, 8910-8914).
Regarding claims 53 and 54, the peptide PEP6R has a net charge of +9 (p. 8912).
Regarding claim 56, Veiga teaches that the peptide is sterile filtered (p. 8908).
Regarding claim 65, Veiga teaches that bacterial infections are a common problem associated with dermal wounds. These infections can prolong or impair wound healing, contributing to tissue morbidity and in extreme cases, result in sepsis (p. 8907). Antibacterial hydrogels can be used to directly treat accessible wounds to prevent or kill existing infection. Id.
Regarding claim 66, Veiga et al. teach that hydrogel materials that display inherent activity against bacteria can be used to directly treat accessible wounds to prevent or kill existing infection, that hydrogels composed of self-assembling ß-hairpin peptides, having a high content of arginine, are extremely effective antimicrobials (see Abstract). They also teach that microbial infections are a common problem associated with dermal wounds, within which P. aeruginosa accounts for 10% of all hospital infections, and this is particularly relevant for patients with burns [reads on trauma wounds, e.g. burns) (p. 8907).
Regarding claim 68, Veiga et al. teach the use of a buffer comprising 150 mM sodium chloride and 50 mM BTP (e.g., p. 8910). They explicitly teach using this buffer along with the peptides directly in wells of tissue-culture treated plates to test its antimicrobial ability e.g., p. 8910). Here, the buffer is therefore used at the target site . Moreover, Veiga et al. teach that the addition of buffer triggers peptide folding, self-assembly. Id.
Regarding claim 69, Veiga et al. teach the use of a buffer comprising 150 mM sodium chloride and 50 mM BTP (e.g., pp. 8908-8910).
Claim Rejections - 35 USC § 103
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.
Claim(s) 1, 3, 4, 7-10, 14, 19, 31, 49, 53-56, 64-66, 68, and 69 is/are rejected under 35 U.S.C. 103 as being unpatentable over Veiga et al. (Biomaterials 3:8907-8916 (2012)- cited in IDS filed 10/05/2023), and further in view of Spirio et al (U.S. 2006/0084607).
Veiga et al. teach a method of treating bacterial infections [reads on microbial contamination associated with a community of microorganisms] comprising administering a purified amphiphilic peptide in an aqueous compatible solution, the peptide comprising alternating charged and hydrophobic amino and a turn sequence, wherein the peptide self-assembles into a hydrogel (see e.g., Abstract, pp. 8907-
8912). Veiga teaches self-assembling ß-hairpin peptides, including SEQ ID NO: 2 of the instant application, VKVRVRVRVDPPTRVRVRVKV (PEP6R), an amphiphilic peptide (see e.g., Abstract, p. 8910). The reference further teaches PEP8R, PEP4R, and PEP2R (e.g., p. 8909, Figs 1 and 3B). In antibacterial assays, they further teach using the peptides in an aqueous buffer, BTP, with water and sodium chloride (pp. 8908-8910), and the reference teaches that all peptides were purified as a part of the peptide synthesis (p. 8908). Antibacterial hydrogels can be used to directly treat accessible wounds to prevent or kill existing infection (e.g., p. 18907). Veiga teach that the peptide is effective at killing both gram-positive and gram-negative bacteria, including multi-drug resistant P. aeruginosa [pathogenic microorganism] (abstract, p. 8913-8915, Fig 4). Wounds include dermal wounds [reads on dermal tissue; cutaneous tissue] (e.g., p. 8907).
Veiga et al. do not explicitly teach the purity of the claimed amphiphilic peptides.
Spirio et al teach a plurality of amphiphilic peptides having alternating hydrophilic and hydrophobic amino acids that self-assemble into a beta-sheet macroscopic scaffold (abstract, claim 1). The peptides can form a hydrogel (claims 12, 76). Spirio et al teach that the high purity hydrogels comprising the amphiphilic peptide can be directly applied to a wound site and used to treat/facilitate wound healing (e.g., paras. [0072]-[0083]). Spirio et al further teach methods of preparation and purifying the amphiphilic peptides, e.g., using standard peptide purification techniques, including gel filtration and ion exchange high pressure liquid chromatography (HPLC). The peptides can be purified using reverse phase HPLC (paras [0045]-[0046]). The final product may be at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% pure. In some embodiments at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the individual peptide chains in a final peptide product are identical in length and sequence (para [0047]).
It would have been obvious to one of ordinary skill in the art to prepare a purified amphiphilic peptide, e.g., purified PEP6R that is at least 80% purified. Veiga et al teaches preparation and purification of the peptide by RP-HPLC (e.g., p. 8908).
Spirio et al. further taught that RP-HPLC was a standard technique for purifying amphiphilic peptides that could self assemble into macroscopic scaffolds/hydrogels. The skilled artisan would have been motivated to increase the purity of the peptide because Spirio et al taught that purification (e.g., RP-HPLC) separates peptide having the desired sequence from several types of byproducts. The first is excess reagents, from which the desired peptide sequence is easily separated because it has a different chemical structure and higher molecular weight. The second includes deletion adducts, peptide chains similar in sequence to the desired peptide but which have one or more missing amino acids. Enhanced removal of deletion adducts increases the solubility of the desired peptides in aqueous media and changes various properties of the self-assembled scaffolds (para [0047]).
Accordingly, claim 31 is rendered obvious.
Regarding claim 55, the peptide can be lyophilized (e.g., para [0046], [0087]).
Claims 1, 3, 4, 7-10, 14, 19, 31, 49, 53-56, 64-66, 68, and 69 are rendered obvious in view of the teachings of Veiga et al and Spirio et al.
Claim(s) 1, 3, 4, 7-10, 14, 19, 31, 49, 53-56, 61, 64-66, 68, and 69 is/are rejected under 35 U.S.C. 103 as being unpatentable Veiga et al. (Biomaterials 3:8907-8916 (2012)- cited in IDS filed 10/05/2023) and Spirio et al (U.S. 2006/0084607), as applied to claims 1, 3, 4, 7-10, 14, 19, 31, 49, 53-56, 64-66, 68, and 69 above, and further in view of Falabella (Dermatologic Therapy 19:317-325 (2006)).
The teachings of Veiga et al and Spirio et al. are set forth above. The references do not teach debridement of the target tissue prior to administration of the preparation.
Falabella teaches that debridement can play a vital role in wound preparation and the removal of barriers that impair wound healing. In accordance with the TIME principles, department can help remove nonviable tissue, control inflammation or infection, decrease excess moisture, and stimulate a non-advancing wound edge (abstract). The review article discusses various methods of debridement, e.g., analytic, chemical, mechanical, surgical, and biological (Table 1).
It would have been obvious to one of ordinary skill in the art to perform debridement of wounded/infected tissue before applying the preparation comprising the claimed amphiphilic peptide to improve therapeutic outcome and reduce/eliminate microbial contamination of the tissue. The skilled artisan would have had a reasonable expectation of success, as taught by Falabella, debridement was well-known and common technique in medical care.
Accordingly, claim 61 is rendered obvious.
Claims 1, 3, 4, 7-10, 14, 19, 31, 49, 53-56, 61, 64-66, 68, and 69 are rendered obvious in view of the teachings of the cited references.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 10, 14, 19, 49, 53, 54, 64-66, 68, and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-37 of copending Application No. 19/637983 (hereinafter referred to as “the ‘983 application”). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons. The ‘983 application is a CIP of the instant application.
Regarding claims 1, 3, and 64, claim 1 of the ‘983 recites a method of treating a fistula in a subject, comprising administering to a target site within a cavity of the fistula 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, the peptide being configured to self-assemble into a hydrogel, in an amount effective to treat the fistula; and administering to the target site a buffer configured to induce self-assembly of the peptide into the hydrogel. Claims 12 and 17 recite that the fistula is an anal fistula associated with an infection [reads on microbial contamination].
Regarding claim 10, claim 1 of the ‘983 application recites that the fistula is an anal fistula, arteriovenous fistula, vaginal fistula , or sinus tract fistula (reads on soft tissue, terminal tissue).
Regarding claim 14, claim 3 of the ‘983 application recites topical administration. Claim 5 recites administering by injection [reads on parenteral administration].
Regarding claim 19, claims 26 and 27 of the ‘983 application recite 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 0-8 turn sequence amino acids, and N and M are each independently between 2 and 10, and wherein the turn sequence amino acids are independently selected from a D-proline, an L-proline, aspartic acid, threonine, asparagine, and combinations thereof.
Regarding claim 49, claim 3 of the ‘983 application recites wherein the preparation comprises between 0.1% w/v and 8.0% w/v of the peptide. Regarding claims 53 and 54, claim 28 of the ‘983 application recites that the peptide has a net charge of from -9 to +11. It would be obvious to one of ordinary skill in the art to optimize result effective variables such as amounts of peptides within the preparation, and net charge of the peptide. The MPEP states the following: Generally, differences in result effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages. "); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. V. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Regarding claim 65, claims 11 and 19 of the ‘983 application recites that the fistula is a tunneling wound or undermining wound; the preparation is used to treat a gastrointestinal.
Regarding claim 66, claims 1, 11, 18, and 19 of the ‘983 application recite tunneling wounds, undermining wounds, and gastrointestinal wounds e.g., anal fistula.
Regarding claim 68, the method further comprises administering a buffer to the target site to induce self-assembly of the peptide into the hydrogel (claims 1-5 of the ‘983 application).
Regarding claim 69, claims 30-32 of the ‘983 application recite administering between 1 mM and 300 mM of an ionic salts, e.g. sodium chloride. Claims 1, 2, 33 and 34 recite administering a buffer (1-300 mM). Buffers include bis-tris propane (BTP). It would be obvious to one of ordinary skill in the art to optimize result effective variables such as concentrations of sodium chloride and BTP. The MPEP states the following: Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages").
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 4, 10, 14, 19, 31, 49, 53, 54, 56, 64-66, 68, and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 12-14, 17, 20-22, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, and 89-92 of copending Application No. 18/040364 (hereinafter referred to as “the ‘364 application”). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
Regarding claims 1, 3, and 64, claim 1 of the ‘364 recites 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 the hydrogel; and administering the hydrogel comprising the biological material to a target tissue of the subject. Claim 3 recites a method of grafting biological material in a subject, comprising: combining administering to a target site of the subject a hydrogel formed from 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 the hydrogel, the hydrogel being sterile, and administering to the target site an effective amount of the biological material to graft the biological material. Claim 12 recites administering to the target site and effective amounts of the biological material to treat a wound, biofilm, microbial contamination, fungal contamination, or viral contamination.
Regarding claim 4, claim 29 of the ‘364 application recites herein 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.
Regarding claim 10, claim 34 of the ‘364 application recites 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.
Regarding claim 14, claim 26 of the ‘364 application administering the hydrogel or the biological material topically or parenterally to the subject.
Regarding claim 19, claim 39 of the ‘364 application recites herein: 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, wand 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.
Regarding claim 31, claim 45 of the ‘364 application recites that the peptide is at least 80% purified.
Regarding claim 49, claim 63 of the ‘364 application recites he preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Regarding claims 53 and 54, claim 28 of the ‘983 application recites that the peptide has a net charge of from +2 to +11. It would be obvious to one of ordinary skill in the art to optimize result effective variables such as amounts of peptides within the preparation, and net charge of the peptide. The MPEP states the following: Generally, differences in result effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages. "); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. V. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Regarding claim 56, claims 1, 3, and 70 of the ‘364 application teach that the preparation comprising the peptide is sterile.
Regarding claim 65, claims 12 and 78 of the ‘364 application teach that the target site is associated with a wound.
Regarding claim 66, claims 12 and 78 of the ‘364 application teach administering an effective amount of the biological material [hydrogel comprising the claimed peptide] to treat the wound, tissue injury.
Regarding claim 68, claims 1 and 3 of the ‘364 application recite administering a buffer configured to induce self-assembly of the hydrogel.
Regarding claim 69, claim 32 recites 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).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 4, 8, 10, 14, 19, 31, 49, 53-56, 61, 64-66, 68, and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 8-11, 13, 14, 20, 32, 36, 50, 55-57, 62, and 65-84 of copending Application No. 18/040380 (hereinafter referred to as “the ‘380 application”). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
Regarding claims 1 and 3, claim 1 of the ‘380 recites a method of treating a fungal contamination of a subject in need thereof, comprising: topically administering to a target site of the subject associated with the fungal contamination a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptide being configured to self-assemble into a hydrogel and comprising a sequence of Y[XY]N(d)PPT[XY]M where X is a charged amino acid, Y is a hydrophobic amino acid, and N and M are each 4, the peptide being cationic and having a net charge between +2 and +11, in an amount effective to eliminate or reduce a target fungal organism associated with the fungal contamination.
Regarding claim 4, claim 4 of the ‘380 application recites herein 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.
Regarding claim 8, claim 9 recites wherein the target fungal organism is a pathogenic fungal organism [reads on pathogenic microorganism].
Regarding claim 10, claim 11 of the ‘380 application recites 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.
Regarding claim 14, claim 1 of the ‘380 application recites topically administering the claimed peptide.
Regarding claim 19, claim 1 of the ‘380 application recites a sequence comprising Y[XY]N(d)PPT[XY]M, where X is a charged amino acids, Y is a hydrophobic amino acid, T is 2-8 turn sequence amino acids, and N and M are each 4.
Regarding claim 31, claim 32 of the ‘380 application recites that the peptide is at least 80% purified.
Regarding claim 49, claim 50 of the ‘380 application recites he preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Regarding claim 53, claim 1 of the ‘380 application recites that the peptide has a net charge of from +2 to +11.
Regarding claim 54, claim 55 of the ‘380 application recites that the peptide has a net charge of from +5 to +9.
Regarding claim 55, claim 56 recites that the peptide is lyophilized.
Regarding claim 56, claim 57 of the ‘380 application teach that the preparation comprising the peptide is sterile.
Regarding claim 61, claim 62 recites further comprising debridement of the target tissue prior to administration of the preparation.
Regarding claim 64, claim 65 of the ‘380 application recites wherein the fungal contamination is a fungal colonization or infection. Microbial is not expressly defined in the specification. Given the broadest reasonable claim interpretation, microbial colonization or infection encompasses a fungal infection.
Regarding claim 65, claim 66 of the ‘380 application teach that the target site is associated with a wound.
Regarding claim 66, claim 67 of the ‘380 application recites comprising administering the preparation in an amount effective to treat at least one of partial and full thickness wounds, first and second degree burns, tunneled/undermined wounds, surgical wounds, probably, gastrointestinal wounds, and draining wounds.
Regarding claim 68, claims 69, 71, and 73 of the ‘380 application recite administering a buffer configured to induce self-assembly of the hydrogel.
Regarding claim 69, claims 70, 72, and 74 of the ‘380 application recite 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).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4, 14, 19, 31, 49, 53-56, 65, 68, and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, 9, 11-17, 22, 23, 27, 29, 30, 39, 41, 42, 46, 50-52, 54, 56, 57, 59-61, 65, 68, 91, 112, 113, 119, 130, 134, 136, 138, and 147-157 of copending Application No. 18/040374 (hereinafter referred to as “the ‘374 application”). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
Regarding claim 1, claim 1 of the ‘374 application recites a preparation comprising a purified amphiphilic 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 peptide being anionic or cationic, the cationic peptide having a net charge between +2 and +11; and a buffer comprising from 5 mM to 200 mM ionic salts and from 1 mM to 150 mM of a biological buffering agent. Claim 3 of the ‘374 application recites a preparation comprising: a purified amphiphilic 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 peptide comprising an effective amount of counterions comprising at least one of acetate and citrate counterions. Claim 4 of the ‘374 application recites a hydrogel formed of a preparation comprising: a purified amphiphilic 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; and a buffer configured to induce self-assembly of the peptide to form the hydrogel, the hydrogel being sterile. Claim 112 of the ‘374 application recites that the preparation can be formulated for management of wounds or tissues.
The instant claims are drawn to a method of treating a microbial contamination of a subject comprising the compositions claimed in the ‘374 application.
Instant claim 1 is drawn to method of treating a microbial contamination associated with a community of microorganisms of a subject in the thereof, comprising administering to a target site of the subject a preparation comprising a purified amphiphilic peptide in an aqueous biocompatible solution, the peptides 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 the microbial contamination.
It would have been obvious to one of ordinary skill in the art at the time the invention was made that the compositions of the ‘374 application could be used for treating a microbial contamination because the compositions comprised a purified amphiphilic 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 and a buffer [aqueous biocompatible solution]. Furthermore, the ‘374 claims teach that the preparation can be formulated to manage wounds or tissue. The ‘374 specification indicates that the wounds can be caused by/associated with an infection (e.g., pp. 8, 13, 58-59). “[The specification] may be used to learn the meaning of terms and interpreting the coverage of a claim." In re Basell Poliolefine Italia S.P.A., 89 USPQ2d 1030, 1036 (Fed. Cir. 2008). Thus, even though the instant claims recite specificities not explicitly recited by the claims of the ‘374 application, species of the instant claims are encompassed by the claims of the ‘374 application. Accordingly, the skilled artisan would have had a reasonable expectation of success in administering the claimed amphiphilic peptide hydrogel preparation of the ‘374 application in a method of treating a microbial contamination in a subject. Thus, claim 1 is rendered obvious.
Regarding claim 4, claims 27 and 29 of the ‘374 application recites herein the peptide comprises an effective amount of counterions to form the hydrogel, the peptide being substantially free of chloride counterions and the counterions selected from acetate and citrate counterions.
Regarding claim 14, claim 136, 150, and 52, and 154, recite that delivery of the device comprising the claimed peptide hydrogel is in a syringe [reads on parenteral].
Regarding claim 19, claims 22 and 23 of the ‘374 application recites 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; and wherein the turn sequence has 2-8 amino acid residues independently selected from a D-proline, an L-proline, aspartic acid, threonine, and asparagine.
Regarding claim 31, claim 30 of the ‘374 application recites that the peptide is at least 80% purified.
Regarding claim 49, claim 46 of the ‘374 application recites he preparation comprises between 0.5% w/v and 3.0% w/v of the peptide.
Regarding claim 53, claims 1 and 40 of the ‘374 application recites that the peptide has a net charge of from +2 to +11.
Regarding claim 54, claim 42 of the ‘374 application recites that the peptide has a net charge of from +5 to +9.
Regarding claim 55, claim 39 recites that the peptide is lyophilized.
Regarding claim 56, claims 4, 11, and 119 of the ‘374 application teach that the preparation comprising the peptide is sterile.
Regarding claim 65, claim 112 of the ‘374 application teach that preparation is formulated for management of wounds or tissues [reads on target site associated with a wound].
Regarding claim 68, claims 4 and 134 of the ‘374 application recite administering a buffer configured to induce self-assembly of the hydrogel.
Regarding claim 69, claims 56, 57, 60, 61 of the ‘374 application recite 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).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Relevant Art Not Relied Upon
Rodriguez et al (Chem Soc Rev 45:47974824 (2016)) is a review article teaching that peptide based hydrogels have received much attention due to their potential biomedical applications. The majority of the gel forming peptides present a b-sheet motif that is composed of alternating hydrophobic/hydrophilic amino acids (abstract). Rodriguez et al discloses that four peptide hydrogels having antibacterial properties, PEP2R, PEP4R, PEP6R and PEP8R (pp. 4808-4809, Table 1). The peptide design is based on the known fact that cationic peptides are active against a broad spectrum of bacteria, via a membrane disruption mechanism. All the Arg containing peptides seemed to have larger G0 than MAX1 at physiological pH. This can be attributed to the higher propensity to form b-sheets for Arg than Lys and the higher energetic stability of interaction between arginines than between lysines. Interestingly, the peptides G0 increased with the number of Arg residues but then slightly decreased when all Lys where substituted with Arg: PEP2R (650 Pa) < PEP4R (920 Pa) < PEP8R (1180 Pa) < PEP6R (1620 Pa) (Table 1). It is known that Arg–Arg interactions are highly regulated by solvation effects (up to 6 or more water molecules can participate in stabilizing guanidinium–guanidinium interactions). Therefore, it is possible that in PEP8R this water stabilization network cannot be successfully accommodated during peptide assembly. Additionally, it has been observed that intramolecular interactions between charged residues in b-hairpin systems are stronger when the residues are located closer to the turn than when located closer to the termini, which is most likely due to end fraying. This could also explain the smaller G0 for PEP8R relative to PEP6R. All peptides showed antimicrobial activity and some degree of haemolysis, which correlates with the substitution of Lys by Arg residues.
Conclusion
No claims are allowed.
Claims 1-4, 7-10, 12-14, 19, 31, 49, 53-56, 61, and 64-73 are pending. Claims 2, 12, 13, 35, 67, and 70-73 are withdrawn.
Claims 1, 3, 4, 7-10, 14, 19, 31, 49, 53-56, 61, 64-66, 68, and 69 are rejected.
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/KRISTINA M HELLMAN/Examiner, Art Unit 1654
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