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 .
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 78-104 are pending. Claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, 76, and 78-104 are under examination. Claims 76 and 78-84 are canceled.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 6/10/2026 and 8/6/206 were filed after the mailing date of the non-final office action on 3/10/2026. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are 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
Response to Arguments
Applicant’s arguments, see Applicant Reply page 9, para. 3, filed 6/10/2026, with respect to defective/missing sequences under 37 CFR 1.831(a) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new source of defective sequence issues is described below.
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 DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.831-1.834 because the “Sequence Listing XML,” as a separate part of the disclosure, is defective, damaged or unreadable.
Refer to document “Sequence Listing in Computer Readable Format is Defective” dated 6/15/2026.
Required response - Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above submitted in accordance with either item 1. or 2.; together with
o A statement that identifies the location of all additions, deletions or replacements of sequence information relative to the replaced “Sequence Listing XML” as required by 37 CFR 1.835(b)(3);
o A statement that indicates support for the replacement “Sequence Listing XML” in the application, as filed, as required by 37 CFR 1.835(b)(4); and
o A statement that the replacement “Sequence Listing XML” includes no new matter as required by 37 CFR 1.835(b)(5).
AND
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125, inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
Regarding claim 1, claim 1 was analyzed under 35 U.S.C. 112(f) and it is the opinion of the Examiner that claim 1 does not invoke 112(f) because a structure is provided in the same claim.
Previous 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 were previously 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.
Response to Arguments
Applicant’s arguments, see Applicant Reply page 9, para. 3, filed 6/10/2026, with respect to claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, and 58 have been fully considered and are persuasive. The rejection of claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, and 58 has been withdrawn. Claims 76 and 78-89 have been canceled, making the rejection of these claims moot.
Claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, 76, and 78-89 were previously 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.
Response to Arguments
Applicant’s arguments, see Applicant Reply page 10, para. 2, filed 6/10/2026, with respect to claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, and 58 have been fully considered and are persuasive. The rejection of claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, and 58 has been withdrawn. Claims 76 and 78-89 have been canceled, making the rejection of these claims moot.
Claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, 76, and 78-89 were previously 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.
Response to Arguments
Applicant’s arguments, see Applicant Reply page 11, para. 5, filed 6/10/2026, with respect to claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, and 58 have been fully considered and are persuasive. The rejection of claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, and 58 has been withdrawn. Claims 76 and 78-89 have been canceled, making the rejection of these claims moot.
Previous Claim Rejections - 35 USC § 103
Claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, 76, and 78-89 were previously rejected under 35 U.S.C. 103. Claims 76 and 78-84 have been canceled, rendering those rejections moot.
Response to Arguments
Applicant’s arguments, see Applicant Reply page 13, para. 2, filed 6/10/2026, with respect to the rejection of claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, 85-89 under U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, new grounds of rejection are made below.
New 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.
Claims 1, 2, 17, 23, 31, 58, 92, and 93 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schneider et al. WO2010/017369, published 2/11/2010.
Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27).
This peptide reads on the formula Y[XY]4(d)PPT[XY]4 when X=arginine and Y=valine.
This amphiphile is provided in a physiologically compatible solution: “The hydrogels are physiologically compatible, having a pH of 7.4 and containing 150 mM NaCl. Unless referring to a specific experiment, where the pH values and concentrations of ingredients are exact within experimental uncertainty, a pH value of 7.4 should be understood to encompass physiologically acceptable variations around that value and an NaCl concentration of 150 mM NaCl should be understood to encompass physiologically acceptable variations around that value, provided that the desired gel properties are maintained. Thus, the pH value may vary at least within a range of 7.35 to 7.45 and the NaCl concentration may vary at least within in a range of 140 to 160 mM, provided that the desired gel properties are maintained. The pH is maintained with a suitable buffer, typically a nonionic buffer such as bis-tris propane (BTP). As used herein, the term "physiological buffer" will be used to designate an aqueous solution buffered to pH=7.4, containing 50 mM BTP and 150 mM NaCl. The MAX peptide content of hydrogels according to the invention may be at least 0.1 wt%, or at least 0.3 wt%, or at least 0.5 wt%.” (Schneider et al., page 4, para. 3).
The peptide of Schneider may be injected: “The hydrogels of this invention may be of particular value for treating an animal for a medical condition. If the anionic macromolecule is a therapeutic agent, for example an anionic protein, the hydrogel may conveniently be applied by injection through a syringe needle, allowing minimally invasive deposition of the therapeutic agent at a desired localized site. Such treatment may be used for a mammal, a bird, a reptile, or any animal. Treatment of humans may be of particular value. In an animal, final release of all of the anionic macromolecule may depend upon destruction of the hydrogel structure due to enzymatic degradation of the MAX molecules, a process that may take several months to complete.” (Schneider et al., page 9, para 2).
The peptide of Schneider is purified: “Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. Peptide is injected onto the column under isocratic conditions.” (Schneider et al., page 10, para. 1).
The peptide of Schneider may be sterilized: “For the bulk release studies, MAXl and HPL8 peptide stock solutions were first prepared in glass vials by dissolving 1.5 mg or 6 mg of each peptide in 150 μL of sterile, chilled water resulting in two stock solutions for each peptide” (Schneider page 23, para. 2).
Finally Schneider discloses a method of treating a subject with said peptide in claims 16-18:
“16. A method of treating an animal, comprising the step of introducing the hydrogel of any one of claims 1-12 into the body of an animal.
17. The method of claim 16, further comprising a step of shearing the hydrogel prior to introducing it into the body of the animal.
18. The method of claim 17, wherein the shearing results from injection into the animal through a syringe needle.”
Consequently, claim 1 is anticipated by Schneider et al. and rejected.
Regarding claim 2, claim 1 is anticipated as described above. The peptide of Schneider has a net charge of +8, which falls between +2 and +11.
Consequently, claim 2 is anticipated by Schneider et al. and rejected.
Regarding claim 17, claim 1 is anticipated as described above. Schneider discloses combining the hydrogel peptide with a buffer in order to induce self-assembly: “ Proteins of varying size and charge (Table 3) were incorporated in the high salt buffered solution and then added to the aqueous HPL8 solution to trigger self-assembly.” (Schneider et al., page 24, para. 3).
Consequently, claim 17 is anticipated by Schneider et al. and rejected.
Regarding claim 23, claim 17 is anticipated as described above. Schneider discloses the following buffer:
“The pH is maintained with a suitable buffer, typically a nonionic buffer such as bis-tris propane (BTP). As used herein, the term "physiological buffer" will be used to designate an aqueous solution buffered to pH=7.4, containing 50 mM BTP and 150 mM NaCl.” (Schneider et al., page 4, para. 3)
Consequently, claim 23 is anticipated by Schneider et al. and rejected.
Regarding claim 31, claim 1 is anticipated as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 31 is anticipated by Schneider et al. and rejected.
Regarding claim 58, claim 1 is anticipated as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
MPEP 2131.03 states: “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
Consequently, claim 58 is anticipated by Schneider et al. and rejected.
Regarding claim 92, claim 31 is anticipated as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 92 is anticipated by Schneider et al. and rejected.
Regarding claim 93, claim 93 is anticipated as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 93 is anticipated by Schneider et al. and rejected.
New 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 3, 4, 12, 13, 86, 89, 90, 91, and 94-98 are rejected under 35 U.S.C. 103 as being unpatentable over Schneider et al. WO2010/017369, published 2/11/2010 as applied to claim 1, further in view of Butterick et al. WO2009117497, published 9/24/2009.
Regarding claim 3, claim 1 is anticipated as described above. Schneider does not explicitly disclose topical application of the hydrogel comprising the claimed peptide amphiphile.
However, Butterick discloses the topical usage of the exact same peptide:
“The hydrogel can also comprise a therapeutic agent and be utilized to deliver the therapeutic agent to a target site, such as to a tissue in vivo or in vitro. For example, the hydrogel may contain agents that stimulate cell proliferation or differentiation, stimulate wound healing, or inhibit bacterial growth. Such agents may include, but are not limited to analgesics, antibiotics, antineoplastics, hemostatic agents, anticoagulants, cytokines, growth factors, anti-inflammatories, small molecules, proteins, peptides, nucleotides, or cells. Spray delivery for β-sheet peptide hydrogels has broad medical application in, for example, tissue and bone engineering, regenerative and cosmetic treatment for hair and skin, cell-based diagnostics, surgery, wound-healing and wound-sealing”. (Butterick et al., page 3, para. 2).
Butterick discloses the same peptide as SEQ ID NO: 46, also called MAX28.
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 hydrogel of Schneider topically as disclosed by Butterick to arrive at the claimed invention because Butterick is applying the same peptide to skin.
A person of ordinary skill in the art would be motivated to do this to avoid injection and to distribute the hydrogel over a wider area of skin than injection provides. A person of ordinary skill in the art would have a reasonable expectation of success because Butterick is using the same peptide on skin.
Consequently, claim 3 is obvious over Schneider et al. over Butterick et al. and rejected.
Regarding claim 4, claim 3 is obvious as described above. The peptide disclosed by Schneider (and Butterick) has a charge of +8.
Consequently, claim 4 is obvious over Schneider et al. over Butterick et al. and rejected.
Regarding claim 12, claim 3 is obvious as described above. Butterick discloses delivery by spray: “A method for delivering β-sheet peptide hydrogels to a target surface by shear- thinning and spraying the peptide hydrogel onto the surface is provided. The peptide hydrogels can be applied over a range of thicknesses and can cover broad surface areas. The β-sheet peptide hydrogels may also include a therapeutic agent.” (Butterick et al., Abstract).
Consequently, claim 12 is obvious over Schneider et al. over Butterick et al. and rejected.
Regarding claim 13, claim 3 is obvious as described above. Butterick discloses that the target tissue may be soft tissue: “Hydrogels are a class of materials that have significant promise for use in soft tissue and bone engineering and wound sealing, in part because of their well-hydrated, porous structure.” (Butterick et al., page 1, para. 3).
Consequently, claim 13 is obvious over Schneider et al. over Butterick et al. and rejected.
Regarding claim 86, claim 3 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 86 is obvious over Schneider et al. in view of Butterick et al. and rejected.
Regarding claim 89, claim 3 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
MPEP 2131.03 states: “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
Consequently, claim 89 is obvious over Schneider et al. in view of Butterick et al. and rejected.
Regarding claim 90, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 90 is obvious over Schneider et al. in view of Butterick et al. and rejected.
Regarding claim 90, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 90 is obvious over Schneider et al. in view of Butterick et al. and rejected.
Regarding claim 91, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 91 is obvious over Schneider et al. in view of Butterick et al. and rejected.
Regarding claim 94, claim 3 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 94 is obvious over Schneider et al. in view of Butterick et al. and rejected.
Regarding claim 95, claim 94 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 95 is obvious over Schneider et al. in view of Butterick et al. and rejected.
Regarding claim 96, claim 95 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 96 is obvious over Schneider et al. in view of Butterick et al. and rejected.
Regarding claim 97, claim 96 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 97 is obvious over Schneider et al. in view of Butterick et al. and rejected.
Regarding claim 98, claim 86 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4). The charged amino acids are all lysine in this case.
Consequently, claim 98 is obvious over Schneider et al. in view of Butterick et al. and rejected.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Schneider et al. WO2010/017369, published 2/11/2010, 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 anticipated as described above.
Schneider does 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 Schneider.
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 Schneider et al. in view of Jin et al. and rejected.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Schneider et al. WO2010/017369, published 2/11/2010 in view of Butterick et al. WO2009117497, published 9/24/2009, 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.
Schneider and Butterick 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 Schneider and Butterick 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 Schneider et al. in view of Butterick 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 Schneider et al. WO2010/017369, published 2/11/2010 in view of Butterick et al. WO2009117497, published 9/24/2009, 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.
Schneider and Butterick 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 Schneider and Butterick 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 Schneider et al. in view of Butterick et al. as applied to claim 3 above, further in view of Nunez et al. and rejected.
Claims 18 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Schneider et al. WO2010/017369, as applied to claim 1, further in view of Mehta et al. ((US 20170072008, published 3/16/2017)).
Regarding claim 18, claim 17 is anticipated as described above. Schneider does not specifically disclose combining the preparation and buffer less than 10 minutes before administration.
However, 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 of the method of Schneider using the timing 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 Schneider et al. in view of Mehta et al. and rejected.
Regarding claim 20, claim 1 is anticipated 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 and chloride ions are not present.
Schneider does not specifically disclose this buffer condition.
However, 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 disclosed by Mehta with the method of Schneider. Such a buffer optimization is also a matter of routine optimization.
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 and both Schneider and Mehta disclose self-assembling hydrogels. 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 and both Schneider and Mehta disclose self-assembling hydrogels.
Consequently, claim 20 is obvious over Schneider et al. in view of Mehta et al. and rejected.
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Schneider et al. WO2010/017369, as applied to claim 1, further in view of Mant et al. (Mant, et al. Peptide characterization and application protocols. Totowa, NJ: Humana Press, 3-55 (2007)).
Regarding claim 40, claim 1 is anticipated as described above. Schneider does not disclose a specific purity. Schneider does disclose purification by RP-HPLC: “ Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. “ (Schneider et al., page 10, para. 1).
Mant discloses that RP-HPLC has purity yields of 95%: “As shown in Fig. 18, the purified product had a purity of <95% and a yield of <90% recovery.” (Mant et al., page 45, para. 3).
Consequently, claim 40 is obvious over Schneider et al. in view of Mant et al. and rejected.
Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Schneider et al. WO2010/017369, 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.
Schneider does 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 Schneider 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 Schneider et al. as applied to claim 1 above, further in view of Mauri et al. and rejected.
Claim 85 is rejected under 35 U.S.C. 103 as being unpatentable over Schneider et al. WO2010/017369, published 2/11/2010 in view of Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Mehta et al. ((US 20170072008, published 3/16/2017)).
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 and chloride ions are not present.
Schneider and Butterick do not specifically disclose this buffer condition.
However, 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 disclosed by Mehta with the method of Schneider and Butterick. Such a buffer optimization is also a matter of routine optimization.
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 and both Schneider and Mehta disclose self-assembling hydrogels. 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 and both Schneider and Mehta disclose self-assembling hydrogels.
Consequently, claim 85 is obvious over Schneider et al. in view of Butterick et al. as applied to claim 3, in view of Mehta et al. and rejected.
Claim 87 is rejected under 35 U.S.C. 103 as being unpatentable over Schneider et al. WO2010/017369, published 2/11/2010 in view of Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Mant et al. (Mant, et al. Peptide characterization and application protocols. Totowa, NJ: Humana Press, 3-55 (2007)).
Regarding claim 87, claim 3 is obvious as described above. Schneider and Butterick do not disclose a specific purity. Schneider does disclose purification by RP-HPLC: “ Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. “ (Schneider et al., page 10, para. 1).
Mant discloses that RP-HPLC has purity yields of 95%: “As shown in Fig. 18, the purified product had a purity of <95% and a yield of <90% recovery.” (Mant et al., page 45, para. 3).
Consequently, claim 87 is obvious Schneider et al. in view of Butterick et al. as applied to claim 3, further in view of Mant et al. and rejected.
Claim 88 is rejected under 35 U.S.C. 103 as being unpatentable over Schneider et al. WO2010/017369, published 2/11/2010 in view of Butterick et al. WO2009117497, published 9/24/2009, 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.
Schneider and Butterick 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 Schneider and Butterick 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 Schneider et al. and Butterick et al. as applied to claim 3 above, further in view of Mauri et al. and rejected.
Claims 99 and 100 are rejected under 35 U.S.C. 103 as being unpatentable over Schneider et al. WO2010/017369, published 2/11/2010 as applied to claim 1, further in view of Henikoff et al. (Henikoff, et al. Proceedings of the national academy of sciences 89.22: 10915-10919 (1992)) and Salick et al. US20110171304, published 7/14/2011.
Regarding claim 99, claim 1 is anticipated as described above. Schneider et al. does not explicitly discloses these amino acid sequences.
However, Schneider et al. discloses : VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27) and VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4).
Furthermore, Salick discloses the peptide MARG1:VKVKVRVKVDPPTKVKVRVKV-NH2, which also forms a hydrogel: “MARG1 forms a hydrogel that shear-thins and rapidly re-forms upon cessation of shearing, so that the peptide hydrogel can be applied by injection via a syringe or other similar device to a contaminated surface where it kills MRSA on contact. The hydrogel can also be used as a coating to inhibit MRSA infection.” (Salick et al., para. [0019]).
Henikoff teaches that arginine and lysine are conservative substitutions for each other in Fig. 2, the Blosum62 substitution matrix (Henikoff, et al., page 10917, Fig. 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 make the conservative mutations disclosed by Henikoff to the positively charged residues of the sequences of Schneider to arrive at the claimed invention, for example, VKVRVRVRVDPPTRVRVRVKV-NH2 (Applicant SEQ ID NO: 2) because Salick teaches that mixing lysine and arginine residues in a MAX peptide results in a functional product and because Schneider discloses one peptide with all lysine residues and one with all arginine residues.
A person of ordinary skill in the art would be motivated to make these substitutions to modulate the exact activity of the hairpin peptide and would have a reasonable expectation of success because of the peptide of Salick shows that mixing these residues can result in a functional peptide. Furthermore, a finite group of possible conservative substitutions are possible with this peptide.
Consequently, claim 99 is obvious over Schneider et al. as applied to claim 1, further in view of Henikoff et al. Salick et al. and rejected.
Regarding claim 100, claim 99 is obvious as described above. The analysis of claim 99 shows how a person of ordinary skill in the art would arrive at Applicant SEQ ID NO: 2.
Consequently, claim 100 is obvious over Schneider et al. as applied to claim 1, further in view of Henikoff et al. Salick et al. and rejected.
Claims 101 and 102 are rejected under 35 U.S.C. 103 as being unpatentable over Schneider et al. WO2010/017369, published 2/11/2010 in view of Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Henikoff et al. (Henikoff, et al. Proceedings of the national academy of sciences 89.22: 10915-10919 (1992)) and Salick et al. US20110171304, published 7/14/2011.
Regarding claim 101, claim 3 is obvious as described above. Schneider and Butterick do not explicitly discloses these amino acid sequences.
However, Schneider et al. discloses : VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27) and VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4).
Furthermore, Salick discloses the peptide MARG1:VKVKVRVKVDPPTKVKVRVKV-NH2, which also forms a hydrogel: “MARG1 forms a hydrogel that shear-thins and rapidly re-forms upon cessation of shearing, so that the peptide hydrogel can be applied by injection via a syringe or other similar device to a contaminated surface where it kills MRSA on contact. The hydrogel can also be used as a coating to inhibit MRSA infection.” (Salick et al., para. [0019]).
Henikoff teaches that arginine and lysine are conservative substitutions for each other in Fig. 2, the Blosum62 substitution matrix (Henikoff, et al., page 10917, Fig. 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 make the conservative mutations disclosed by Henikoff to the positively charged residues of the sequences of Schneider and Butterick to arrive at the claimed invention, for example, VKVRVRVRVDPPTRVRVRVKV-NH2 (Applicant SEQ ID NO: 2) because Salick teaches that mixing lysine and arginine residues in a MAX peptide results in a functional product and because Schneider discloses one peptide with all lysine residues and one with all arginine residues.
A person of ordinary skill in the art would be motivated to make these substitutions to modulate the exact activity of the hairpin peptide and would have a reasonable expectation of success because of the peptide of Salick shows that mixing these residues can result in a functional peptide. Furthermore, a finite group of possible conservative substitutions are possible with this peptide.
Consequently, claim 101 is obvious over Schneider et al. and Butterick et al. as applied to claim 3, further in view of Henikoff et al. Salick et al. and rejected.
Regarding claim 102, claim 101 is obvious as described above. The analysis of claim 101 shows how a person of ordinary skill in the art would arrive at Applicant SEQ ID NO: 2.
Consequently, claim 102 is obvious over Schneider et al. and Butterick et al. as applied to claim 3, further in view of Henikoff et al. Salick et al. and rejected.
Claim 103 is rejected under 35 U.S.C. 103 as being unpatentable over Schneider et al. WO2010/017369, published 2/11/2010 as applied to claim 1, further in view of Roux et al. (Roux, et al. Journal of peptide science: an official publication of the European Peptide Society 14.3: 354-359 (2008)).
Regarding claim 103, claim 1 is anticipated as described above. Schneider does not disclose the case wherein the peptide is free of TFA.
However, Roux discloses removal of TFA from synthesized peptides:
“Even though the excess TFA is easy to remove by a classic freeze-drying method, it is more challenging to remove the TF-acetate counter-ion, which strongly interacts with the positive charges of cationic peptides. Hitherto, the most convenient procedure to replace the TF-acetate counter-ion by another counter-ion has been mixing the peptide with an excess of a stronger acid than TFA, followed by a freeze-drying step [12]. A stronger acid than TFA is able to reprotonate the TF-acetate into its free acid form, which is then easily removed by freeze-drying [13]. However, this approach has essentially two drawbacks: (i) the very acidic solution can chemically damage the peptides, and (ii) the very restrictive choice of possible counterions, i.e. the counter-ions that are associated with strong acids (e.g. HCl, H2SO4, HF, HNO3).
The TF-acetate exchange was tested on the dicationic octapeptide lanreotide [14] synthesized in our laboratory by SPPS using an Fmoc strategy. Three different approaches were investigated: (i) RP-HPLC using acetic acid in the mobile phase, (ii) ionexchange
resin loaded with diluted acetic acid, and (iii) deprotonation/reprotonation cycle of lanreotide
positive charges (–NH3 +). The removal of TF-acetate counter-ions and its exchange by acetate were followed by quantitative 19F-NMR and 1H-NMR, respectively. Finally, we compared the ATR FT-IR spectra of lanreotide before and after the counter-ion exchange procedures.” (Roux et al., page 354, 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 remove TFA as disclosed by Roux from the peptide of Schneider to arrive at the claimed invention because Roux describes this as a routine procedure: “In all cases, TFA needs to be removed due to its drawbacks related to several physicochemical characterizations and biological studies. The presence of TFA can change the behavior of the peptide [3] or modify its conformation.” (Roux et al., page 354, col. 1, para. 2).
A person of ordinary skill in the art would be motivated to remove the TFA due to the problems disclosed by Roux above and would have a reasonable expectation of success because Roux discloses multiple procedures for this process as described above.
Consequently, claim 103 is obvious over Schneider et al. as applied to claim 1, further in view of Roux et al. and rejected.
Claim 104 is rejected under 35 U.S.C. 103 as being unpatentable over Schneider et al. WO2010/017369, published 2/11/2010 in view of Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Roux et al. (Roux, et al. Journal of peptide science: an official publication of the European Peptide Society 14.3: 354-359 (2008)).
Regarding claim 104, claim 3 is obvious as described above. Schneider and Butterick do not disclose the case wherein the peptide is free of TFA.
However, Roux discloses removal of TFA from synthesized peptides:
“Even though the excess TFA is easy to remove by a classic freeze-drying method, it is more challenging to remove the TF-acetate counter-ion, which strongly interacts with the positive charges of cationic peptides. Hitherto, the most convenient procedure to replace the TF-acetate counter-ion by another counter-ion has been mixing the peptide with an excess of a stronger acid than TFA, followed by a freeze-drying step [12]. A stronger acid than TFA is able to reprotonate the TF-acetate into its free acid form, which is then easily removed by freeze-drying [13]. However, this approach has essentially two drawbacks: (i) the very acidic solution can chemically damage the peptides, and (ii) the very restrictive choice of possible counterions, i.e. the counter-ions that are associated with strong acids (e.g. HCl, H2SO4, HF, HNO3).
The TF-acetate exchange was tested on the dicationic octapeptide lanreotide [14] synthesized in our laboratory by SPPS using an Fmoc strategy. Three different approaches were investigated: (i) RP-HPLC using acetic acid in the mobile phase, (ii) ionexchange
resin loaded with diluted acetic acid, and (iii) deprotonation/reprotonation cycle of lanreotide
positive charges (–NH3 +). The removal of TF-acetate counter-ions and its exchange by acetate were followed by quantitative 19F-NMR and 1H-NMR, respectively. Finally, we compared the ATR FT-IR spectra of lanreotide before and after the counter-ion exchange procedures.” (Roux et al., page 354, 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 remove TFA as disclosed by Roux from the peptide of Schneider and Butterick to arrive at the claimed invention because Roux describes this as a routine procedure: “In all cases, TFA needs to be removed due to its drawbacks related to several physicochemical characterizations and biological studies. The presence of TFA can change the behavior of the peptide [3] or modify its conformation.” (Roux et al., page 354, col. 1, para. 2).
A person of ordinary skill in the art would be motivated to remove the TFA due to the problems disclosed by Roux above and would have a reasonable expectation of success because Roux discloses multiple procedures for this process as described above.
Consequently, claim 104 is obvious over Schneider et al. and Butterick et al. as applied to claim 3, further in view of Roux et al. and rejected.
Previous Double Patenting
Claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, 76, and 78-89 were previously rejected on the grounds of nonstatutory double patenting.
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 15, para. 3, filed 6/10/2026, with respect to the rejections of claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, and 84-89 under nonstatutory double patenting have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, new grounds of rejection are made below.
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, 2, 17, 23, 31, 58, 92, and 93 are rejected on the ground of nonstatutory double patenting over claims 1-8 of U.S. Patent No. 10,245,299 in view of Schneider et al. WO2010/017369, published 2/11/2010.
Claim 1 of the ‘299 patent discloses:
“ A method of treating a pulmonary bulla in a subject, comprising:
introducing a delivery device to a target area of the pulmonary bulla of the subject;
positioning an end of the delivery device in the target area in which a treatment of the pulmonary bulla is desired;
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;
removing the delivery device from the target area; and
collapsing the pulmonary bulla prior or subsequent to administering the solution.”
The ‘299 patent does not specifically disclose a peptide comprising a sequence of Y[XY]N(d)PPT[XY]M wherein N and M are 4.
However, claim 1 of the ‘299 patent allows for a peptide that does fit that formula, i.e. 20 amino acids in length. Furthermore, Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27).
This peptide reads on the formula Y[XY]4(d)PPT[XY]4 when X=arginine and Y=valine.
This amphiphile is provided in an physiologically compatible solution: “The hydrogels are physiologically compatible, having a pH of 7.4 and containing 150 mM NaCl. Unless referring to a specific experiment, where the pH values and concentrations of ingredients are exact within experimental uncertainty, a pH value of 7.4 should be understood to encompass physiologically acceptable variations around that value and an NaCl concentration of 150 mM NaCl should be understood to encompass physiologically acceptable variations around that value, provided that the desired gel properties are maintained. Thus, the pH value may vary at least within a range of 7.35 to 7.45 and the NaCl concentration may vary at least within in a range of 140 to 160 mM, provided that the desired gel properties are maintained. The pH is maintained with a suitable buffer, typically a nonionic buffer such as bis-tris propane (BTP). As used herein, the term "physiological buffer" will be used to designate an aqueous solution buffered to pH=7.4, containing 50 mM BTP and 150 mM NaCl. The MAX peptide content of hydrogels according to the invention may be at least 0.1 wt%, or at least 0.3 wt%, or at least 0.5 wt%.” (Schneider et al., page 4, para. 3).
The peptide of Schneider may be injected: “The hydrogels of this invention may be of particular value for treating an animal for a medical condition. If the anionic macromolecule is a therapeutic agent, for example an anionic protein, the hydrogel may conveniently be applied by injection through a syringe needle, allowing minimally invasive deposition of the therapeutic agent at a desired localized site. Such treatment may be used for a mammal, a bird, a reptile, or any animal. Treatment of humans may be of particular value. In an animal, final release of all of the anionic macromolecule may depend upon destruction of the hydrogel structure due to enzymatic degradation of the MAX molecules, a process that may take several months to complete.” (Schneider et al., page 9, para 2).
The peptide of Schneider is purified: “Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. Peptide is injected onto the column under isocratic conditions.” (Schneider et al., page 10, para. 1).
The peptide of Schneider may be sterilized: “For the bulk release studies, MAXl and HPL8 peptide stock solutions were first prepared in glass vials by dissolving 1.5 mg or 6 mg of each peptide in 150 μL of sterile, chilled water resulting in two stock solutions for each peptide” (Schneider page 23, para. 2).
Finally Schneider discloses a method of treating a subject with said peptide in claims 16-18:
“16. A method of treating an animal, comprising the step of introducing the hydrogel of any one of claims 1-12 into the body of an animal.
17. The method of claim 16, further comprising a step of shearing the hydrogel prior to introducing it into the body of the animal.
18. The method of claim 17, wherein the shearing results from injection into the animal through a syringe needle.”
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 peptide of Schneider to perform the method of the ‘299 patent to arrive at the claimed invention because Schneider discloses a self-assembling peptide that creates a hydrogel that is the appropriate length required by the ‘299 patent.
A person of ordinary skill in the art would be motivated to use the peptide of Schneider because it meets all the physical requirements of the ‘299 patent and the ‘299 patent discloses introducing the peptide with a device, such as a syringe for injection.
A person of ordinary skill in the art would have a reasonable expectation of success because the peptide of Schneider also forms self-assembling hydrogels.
Consequently, claim 1 is obvious over the ‘299 patent in view of Schneider et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. The peptide of Schneider has a net charge of +8, which falls between +2 and +11.
Consequently, claim 2 is obvious over the ‘299 patent in view of Schneider et al. and rejected.
Regarding claim 17, claim 1 is obvious as described above. Schneider discloses combining the hydrogel peptide with a buffer in order to induce self-assembly: “ Proteins of varying size and charge (Table 3) were incorporated in the high salt buffered solution and then added to the aqueous HPL8 solution to trigger self-assembly.” (Schneider et al., page 24, para. 3).
Consequently, claim 17 is obvious over the ‘299 patent in view of Schneider et al. and rejected.
Regarding claim 23, claim 17 is obvious as described above. Schneider discloses the following buffer:
“The pH is maintained with a suitable buffer, typically a nonionic buffer such as bis-tris propane (BTP). As used herein, the term "physiological buffer" will be used to designate an aqueous solution buffered to pH=7.4, containing 50 mM BTP and 150 mM NaCl.” (Schneider et al., page 4, para. 3)
Consequently, claim 23 is obvious over the ‘299 patent in view of Schneider et al. and rejected.
Regarding claim 31, claim 1 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 31 is obvious over the ‘299 patent in view of Schneider et al. and rejected.
Regarding claim 58, claim 1 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
MPEP 2131.03 states: “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘obvious’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
Consequently, claim 58 is obvious over the ‘299 patent in view of Schneider et al. and rejected.
Regarding claim 92, claim 31 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 92 is obvious over the ‘299 patent in view of Schneider et al. and rejected.
Regarding claim 93, claim 93 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 93 is obvious over the ‘299 patent in view of Schneider et al. and rejected.
Claims 3, 4, 12, 13, 86, 89, 90, 91, and 94-98 are rejected on the ground of nonstatutory double patenting over claims 1-8 of U.S. Patent No. 10,245,299 in view of Schneider et al. WO2010/017369, published 2/11/2010 as applied to claim 1, further in view of Butterick et al. WO2009117497, published 9/24/2009.
Regarding claim 3, claim 1 is obvious as described above. The ‘299 patent and Schneider do not explicitly disclose topical application of the hydrogel comprising the claimed peptide amphiphile.
However, Butterick discloses the topical usage of the exact same peptide:
“The hydrogel can also comprise a therapeutic agent and be utilized to deliver the therapeutic agent to a target site, such as to a tissue in vivo or in vitro. For example, the hydrogel may contain agents that stimulate cell proliferation or differentiation, stimulate wound healing, or inhibit bacterial growth. Such agents may include, but are not limited to analgesics, antibiotics, antineoplastics, hemostatic agents, anticoagulants, cytokines, growth factors, anti-inflammatories, small molecules, proteins, peptides, nucleotides, or cells. Spray delivery for β-sheet peptide hydrogels has broad medical application in, for example, tissue and bone engineering, regenerative and cosmetic treatment for hair and skin, cell-based diagnostics, surgery, wound-healing and wound-sealing”. (Butterick et al., page 3, para. 2).
Butterick discloses the same peptide as SEQ ID NO: 46, also called MAX28.
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 hydrogel of the ‘299 and Schneider topically as disclosed by Butterick to arrive at the claimed invention because Butterick is applying the same peptide to skin.
A person of ordinary skill in the art would be motivated to do this to avoid injection and to distribute the hydrogel over a wider area of skin than injection provides. A person of ordinary skill in the art would have a reasonable expectation of success because Butterick is using the same peptide on skin.
Consequently, claim 3 is obvious over the ‘299 patent and Schneider et al. as applied to claim 1, further in view of Butterick et al. and rejected.
Regarding claim 4, claim 3 is obvious as described above. The peptide disclosed by Schneider (and Butterick) has a charge of +8.
Consequently, claim 4 is obvious over the ‘299 patent and Schneider et al. as applied to claim 1, further in view of Butterick et al. and rejected.
Regarding claim 12, claim 3 is obvious as described above. Butterick discloses delivery by spray: “A method for delivering β-sheet peptide hydrogels to a target surface by shear- thinning and spraying the peptide hydrogel onto the surface is provided. The peptide hydrogels can be applied over a range of thicknesses and can cover broad surface areas. The β-sheet peptide hydrogels may also include a therapeutic agent.” (Butterick et al., Abstract).
Consequently, claim 12 is obvious over the ‘299 patent and Schneider et al. as applied to claim 1, further in view of Butterick et al. and rejected.
Regarding claim 13, claim 3 is obvious as described above. Butterick discloses that the target tissue may be soft tissue: “Hydrogels are a class of materials that have significant promise for use in soft tissue and bone engineering and wound sealing, in part because of their well-hydrated, porous structure.” (Butterick et al., page 1, para. 3).
Consequently, claim 13 is obvious over the ‘299 patent and Schneider et al. as applied to claim 1, further in view of Butterick et al. and rejected.
Regarding claim 86, claim 3 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 86 is obvious over the ‘299 patent and Schneider et al. as applied to claim 1, further in view of Butterick et al. and rejected.
Regarding claim 89, claim 3 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
MPEP 2131.03 states: “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘obvious’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
Consequently, claim 89 is obvious over the ‘299 patent and Schneider et al. as applied to claim 1, further in view of Butterick et al. and rejected.
Regarding claim 90, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 90 is obvious over the ‘299 patent and Schneider et al. as applied to claim 1, further in view of Butterick et al. and rejected.
Regarding claim 90, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 90 is obvious over the ‘299 patent and Schneider et al. as applied to claim 1, further in view of Butterick et al. and rejected.
Regarding claim 91, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 91 is obvious over the ‘299 patent and Schneider et al. as applied to claim 1, further in view of Butterick et al. and rejected.
Regarding claim 94, claim 3 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 94 is obvious over the ‘299 patent and Schneider et al. as applied to claim 1, further in view of Butterick et al. and rejected.
Regarding claim 95, claim 94 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 95 is obvious over the ‘299 patent and Schneider et al. as applied to claim 1, further in view of Butterick et al. and rejected.
Regarding claim 96, claim 95 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 96 is obvious over the ‘299 patent and Schneider et al. as applied to claim 1, further in view of Butterick et al. and rejected.
Regarding claim 97, claim 96 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 97 is obvious over the ‘299 patent and Schneider et al. as applied to claim 1, further in view of Butterick et al. and rejected.
Regarding claim 98, claim 86 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4). The charged amino acids are all lysine in this case.
Consequently, claim 98 is obvious over the ‘299 patent and Schneider et al. as applied to claim 1, further in view of Butterick et al. and rejected.
Claim 5 is rejected on the ground of nonstatutory double patenting over claims 1-8 of U.S. Patent No. 10,245,299 in view of Schneider et al. WO2010/017369, published 2/11/2010 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.
The ‘299 patent and Schneider 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 the ‘299 patent and Schneider.
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 and Schneider et al. as applied in claim 1, further in view of Jin et al. and rejected.
Claim 9 on the ground of nonstatutory double patenting over claims 1-8 of U.S. Patent No. 10,245,299 in view of Schneider et al. WO2010/017369, published 2/11/2010 in view of Butterick et al. WO2009117497, published 9/24/2009 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, Schneider, and Butterick 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 the ‘299 patent, Schneider, and Butterick 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, Schneider et al., and Butterick 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 over claims 1-8 of U.S. Patent No. 10,245,299 in view of Schneider et al. WO2010/017369, published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009 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, Schneider, and Butterick 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 Schneider and Butterick 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, Schneider et al., and Butterick et al. as applied to claim 3 above, further in view of Nunez et al. and rejected.
Claims 18 and 20 are rejected on the ground of nonstatutory double patenting over claims 1-8 of U.S. Patent No. 10,245,299 in view of Schneider et al. WO2010/017369, published 2/11/2010 as applied to claim 1, further in view of Mehta et al. ((US 20170072008, published 3/16/2017)).
Regarding claim 18, claim 17 is obvious as described above. The ‘299 patent and Schneider do not specifically disclose combining the preparation and buffer less than 10 minutes before administration.
However, 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 of the method of the ‘299 patent and Schneider using the timing 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 Schneider et al. as applied to claim 1, further in view of Mehta 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 and chloride ions are not present.
The ‘299 patent Schneider do not specifically disclose this buffer condition.
However, 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 disclosed by Mehta with the method of the ‘299 patent and Schneider. Such a buffer optimization is also a matter of routine optimization.
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 and both Schneider and Mehta disclose self-assembling hydrogels. 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 and both Schneider and Mehta disclose self-assembling hydrogels.
Consequently, claim 20 is obvious over the ‘299 patent in view of Schneider et al. as applied to claim 1, further in view of Mehta et al. and rejected.
Claim 40 is rejected on the ground of nonstatutory double patenting over the ‘299 patent in view of Schneider et al. as applied to claim 1, further in view of Mehta et al. and rejected., further in view of Mant et al. (Mant, et al. Peptide characterization and application protocols. Totowa, NJ: Humana Press, 3-55 (2007)).
Regarding claim 40, claim 1 is obvious as described above. The ‘299 patent and Schneider do not disclose a specific purity. Schneider does disclose purification by RP-HPLC: “ Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. “ (Schneider et al., page 10, para. 1).
Mant discloses that RP-HPLC has purity yields of 95%: “As shown in Fig. 18, the purified product had a purity of <95% and a yield of <90% recovery.” (Mant et al., page 45, para. 3).
Consequently, claim 40 is obvious over the ‘299 patent in view of Schneider et al. as applied to claim 1, further in view of Mant et al. and rejected.
Claim 44 is rejected on the ground of nonstatutory double patenting over the ‘299 patent in view of Schneider et al. 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 and Schneider 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 ‘299 patent and Schneider 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 Schneider et al. as applied to claim 1 above, further in view of Mauri et al. and rejected.
Claim 85 is rejected on the ground of nonstatutory double patenting over the ‘299 patent in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Mehta et al. ((US 20170072008, published 3/16/2017)).
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 and chloride ions are not present.
The ‘299 patent, Schneider, and Butterick do not specifically disclose this buffer condition.
However, 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 disclosed by Mehta with the method of the ‘299 patent, Schneider, and Butterick. Such a buffer optimization is also a matter of routine optimization.
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 and both Schneider and Mehta disclose self-assembling hydrogels. 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 and both Schneider and Mehta disclose self-assembling hydrogels.
Consequently, claim 85 is obvious over the ‘299 patent, Schneider et al., and Butterick et al. as applied to claim 3, in view of Mehta et al. and rejected.
Claim 87 is rejected on the ground of nonstatutory double patenting over the ‘299 patent in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Mant et al. (Mant, et al. Peptide characterization and application protocols. Totowa, NJ: Humana Press, 3-55 (2007)).
Regarding claim 87, claim 3 is obvious as described above. The ‘299 patent, Schneider, and Butterick do not disclose a specific purity. Schneider does disclose purification by RP-HPLC: “ Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. “ (Schneider et al., page 10, para. 1).
Mant discloses that RP-HPLC has purity yields of 95%: “As shown in Fig. 18, the purified product had a purity of <95% and a yield of <90% recovery.” (Mant et al., page 45, para. 3).
Consequently, claim 87 is obvious over the ‘299 patent, Schneider et al., and Butterick et al. as applied to claim 3, further in view of Mant et al. and rejected.
Claim 88 is rejected on the ground of nonstatutory double patenting over the ‘299 patent in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, 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.
The ‘299 patent, Schneider, and Butterick 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 ‘299 patent, Schneider, and Butterick 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, Schneider et al. and Butterick et al. as applied to claim 3 above, further in view of Mauri et al. and rejected.
Claims 99 and 100 are rejected on the ground of nonstatutory double patenting over the ‘299 patent in view of Schneider et al. published 2/11/2010, as applied to claim1, further in view of Henikoff et al. (Henikoff, et al. Proceedings of the national academy of sciences 89.22: 10915-10919 (1992)) and Salick et al. US20110171304, published 7/14/2011.
Regarding claim 99, claim 1 is obvious as described above. The ‘299 patent and Schneider et al. do not explicitly discloses these amino acid sequences.
However, Schneider et al. discloses : VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27) and VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4).
Furthermore, Salick discloses the peptide MARG1:VKVKVRVKVDPPTKVKVRVKV-NH2, which also forms a hydrogel: “MARG1 forms a hydrogel that shear-thins and rapidly re-forms upon cessation of shearing, so that the peptide hydrogel can be applied by injection via a syringe or other similar device to a contaminated surface where it kills MRSA on contact. The hydrogel can also be used as a coating to inhibit MRSA infection.” (Salick et al., para. [0019]).
Henikoff teaches that arginine and lysine are conservative substitutions for each other in Fig. 2, the Blosum62 substitution matrix (Henikoff, et al., page 10917, Fig. 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 make the conservative mutations disclosed by Henikoff to the positively charged residues of the sequences of the ‘299 patent and Schneider to arrive at the claimed invention, for example, VKVRVRVRVDPPTRVRVRVKV-NH2 (Applicant SEQ ID NO: 2) because Salick teaches that mixing lysine and arginine residues in a MAX peptide results in a functional product and because Schneider discloses one peptide with all lysine residues and one with all arginine residues.
A person of ordinary skill in the art would be motivated to make these substitutions to modulate the exact activity of the hairpin peptide and would have a reasonable expectation of success because of the peptide of Salick shows that mixing these residues can result in a functional peptide. Furthermore, a finite group of possible conservative substitutions are possible with this peptide.
Consequently, claim 99 is obvious over the ‘299 patent in view of Schneider et al. as applied to claim 1, further in view of Henikoff et al. Salick et al. and rejected.
Regarding claim 100, claim 99 is obvious as described above. The analysis of claim 99 shows how a person of ordinary skill in the art would arrive at Applicant SEQ ID NO: 2.
Consequently, claim 100 is obvious over the ‘299 patent in view of Schneider et al. as applied to claim 1, further in view of Henikoff et al. Salick et al. and rejected.
Claims 101 and 102 are rejected on the ground of nonstatutory double patenting over the ‘299 patent in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Henikoff et al. (Henikoff, et al. Proceedings of the national academy of sciences 89.22: 10915-10919 (1992)) and Salick et al. US20110171304, published 7/14/2011.
Regarding claim 101, claim 3 is obvious as described above. The ‘299 patent, Schneider, and Butterick do not explicitly discloses these amino acid sequences.
However, Schneider et al. discloses : VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27) and VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4).
Furthermore, Salick discloses the peptide MARG1:VKVKVRVKVDPPTKVKVRVKV-NH2, which also forms a hydrogel: “MARG1 forms a hydrogel that shear-thins and rapidly re-forms upon cessation of shearing, so that the peptide hydrogel can be applied by injection via a syringe or other similar device to a contaminated surface where it kills MRSA on contact. The hydrogel can also be used as a coating to inhibit MRSA infection.” (Salick et al., para. [0019]).
Henikoff teaches that arginine and lysine are conservative substitutions for each other in Fig. 2, the Blosum62 substitution matrix (Henikoff, et al., page 10917, Fig. 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 make the conservative mutations disclosed by Henikoff to the positively charged residues of the sequences of the ‘299 patent, Schneider, and Butterick to arrive at the claimed invention, for example, VKVRVRVRVDPPTRVRVRVKV-NH2 (Applicant SEQ ID NO: 2) because Salick teaches that mixing lysine and arginine residues in a MAX peptide results in a functional product and because Schneider discloses one peptide with all lysine residues and one with all arginine residues.
A person of ordinary skill in the art would be motivated to make these substitutions to modulate the exact activity of the hairpin peptide and would have a reasonable expectation of success because of the peptide of Salick shows that mixing these residues can result in a functional peptide. Furthermore, a finite group of possible conservative substitutions are possible with this peptide.
Consequently, claim 101 is obvious over the ‘299 patent in view of Schneider et al. and Butterick et al. as applied to claim 3, further in view of Henikoff et al. Salick et al. and rejected.
Regarding claim 102, claim 101 is obvious as described above. The analysis of claim 101 shows how a person of ordinary skill in the art would arrive at Applicant SEQ ID NO: 2.
Consequently, claim 102 is obvious over the ‘299 patent in view of Schneider et al. and Butterick et al. as applied to claim 3, further in view of Henikoff et al. Salick et al. and rejected.
Claim 103 is rejected on the ground of nonstatutory double patenting over the ‘299 patent in view of Schneider et al. published 2/11/2010 as applied to claim 1, further in view of Roux et al. (Roux, et al. Journal of peptide science: an official publication of the European Peptide Society 14.3: 354-359 (2008)).
Regarding claim 103, claim 1 is obvious as described above. The ‘299 patent and Schneider do not disclose the case wherein the peptide is free of TFA.
However, Roux discloses removal of TFA from synthesized peptides:
“Even though the excess TFA is easy to remove by a classic freeze-drying method, it is more challenging to remove the TF-acetate counter-ion, which strongly interacts with the positive charges of cationic peptides. Hitherto, the most convenient procedure to replace the TF-acetate counter-ion by another counter-ion has been mixing the peptide with an excess of a stronger acid than TFA, followed by a freeze-drying step [12]. A stronger acid than TFA is able to reprotonate the TF-acetate into its free acid form, which is then easily removed by freeze-drying [13]. However, this approach has essentially two drawbacks: (i) the very acidic solution can chemically damage the peptides, and (ii) the very restrictive choice of possible counterions, i.e. the counter-ions that are associated with strong acids (e.g. HCl, H2SO4, HF, HNO3).
The TF-acetate exchange was tested on the dicationic octapeptide lanreotide [14] synthesized in our laboratory by SPPS using an Fmoc strategy. Three different approaches were investigated: (i) RP-HPLC using acetic acid in the mobile phase, (ii) ionexchange
resin loaded with diluted acetic acid, and (iii) deprotonation/reprotonation cycle of lanreotide
positive charges (–NH3 +). The removal of TF-acetate counter-ions and its exchange by acetate were followed by quantitative 19F-NMR and 1H-NMR, respectively. Finally, we compared the ATR FT-IR spectra of lanreotide before and after the counter-ion exchange procedures.” (Roux et al., page 354, 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 remove TFA as disclosed by Roux from the peptide of the ‘299 patent and Schneider to arrive at the claimed invention because Roux describes this as a routine procedure: “In all cases, TFA needs to be removed due to its drawbacks related to several physicochemical characterizations and biological studies. The presence of TFA can change the behavior of the peptide [3] or modify its conformation.” (Roux et al., page 354, col. 1, para. 2).
A person of ordinary skill in the art would be motivated to remove the TFA due to the problems disclosed by Roux above and would have a reasonable expectation of success because Roux discloses multiple procedures for this process as described above.
Consequently, claim 103 is obvious over the ‘299 patent in view of Schneider et al. as applied to claim 1, further in view of Roux et al. and rejected.
Claim 104 is rejected on the ground of nonstatutory double patenting over the ‘299 patent in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Roux et al. (Roux, et al. Journal of peptide science: an official publication of the European Peptide Society 14.3: 354-359 (2008)).
Regarding claim 104, claim 3 is obvious as described above. The ‘299 patent, Schneider, and Butterick do not disclose the case wherein the peptide is free of TFA.
However, Roux discloses removal of TFA from synthesized peptides:
“Even though the excess TFA is easy to remove by a classic freeze-drying method, it is more challenging to remove the TF-acetate counter-ion, which strongly interacts with the positive charges of cationic peptides. Hitherto, the most convenient procedure to replace the TF-acetate counter-ion by another counter-ion has been mixing the peptide with an excess of a stronger acid than TFA, followed by a freeze-drying step [12]. A stronger acid than TFA is able to reprotonate the TF-acetate into its free acid form, which is then easily removed by freeze-drying [13]. However, this approach has essentially two drawbacks: (i) the very acidic solution can chemically damage the peptides, and (ii) the very restrictive choice of possible counterions, i.e. the counter-ions that are associated with strong acids (e.g. HCl, H2SO4, HF, HNO3).
The TF-acetate exchange was tested on the dicationic octapeptide lanreotide [14] synthesized in our laboratory by SPPS using an Fmoc strategy. Three different approaches were investigated: (i) RP-HPLC using acetic acid in the mobile phase, (ii) ionexchange
resin loaded with diluted acetic acid, and (iii) deprotonation/reprotonation cycle of lanreotide
positive charges (–NH3 +). The removal of TF-acetate counter-ions and its exchange by acetate were followed by quantitative 19F-NMR and 1H-NMR, respectively. Finally, we compared the ATR FT-IR spectra of lanreotide before and after the counter-ion exchange procedures.” (Roux et al., page 354, 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 remove TFA as disclosed by Roux from the peptide of the ‘299 patent, Schneider, and Butterick to arrive at the claimed invention because Roux describes this as a routine procedure: “In all cases, TFA needs to be removed due to its drawbacks related to several physicochemical characterizations and biological studies. The presence of TFA can change the behavior of the peptide [3] or modify its conformation.” (Roux et al., page 354, col. 1, para. 2).
A person of ordinary skill in the art would be motivated to remove the TFA due to the problems disclosed by Roux above and would have a reasonable expectation of success because Roux discloses multiple procedures for this process as described above.
Consequently, claim 104 is obvious over the ‘299 patent, Schneider et al., and Butterick et al. as applied to claim 3, further in view of Roux et al. and rejected.
Claims 1, 2, 17, 23, 31, 58, 92, and 93 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-11, 13-15, 20, 32, 36, 50, 54-57, 62, and 65-74 of U.S. Patent Application 18/040,380 in view of Schneider et al. WO2010/017369, published 2/11/2010.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1 of the ‘380 application discloses:
“ A method of treating a fungal contamination 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 target fungal organism associated with the fungal contamination.”
The ‘380 application does not specifically disclose a peptide comprising a sequence of Y[XY]N(d)PPT[XY]M wherein N and M are 4.
However, claim 1 of the ’380 application allows for a peptide that does fit that formula, i.e. 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. Furthermore, Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27).
This peptide reads on the formula Y[XY]4(d)PPT[XY]4 when X=arginine and Y=valine.
This amphiphile is provided in an physiologically compatible solution: “The hydrogels are physiologically compatible, having a pH of 7.4 and containing 150 mM NaCl. Unless referring to a specific experiment, where the pH values and concentrations of ingredients are exact within experimental uncertainty, a pH value of 7.4 should be understood to encompass physiologically acceptable variations around that value and an NaCl concentration of 150 mM NaCl should be understood to encompass physiologically acceptable variations around that value, provided that the desired gel properties are maintained. Thus, the pH value may vary at least within a range of 7.35 to 7.45 and the NaCl concentration may vary at least within in a range of 140 to 160 mM, provided that the desired gel properties are maintained. The pH is maintained with a suitable buffer, typically a nonionic buffer such as bis-tris propane (BTP). As used herein, the term "physiological buffer" will be used to designate an aqueous solution buffered to pH=7.4, containing 50 mM BTP and 150 mM NaCl. The MAX peptide content of hydrogels according to the invention may be at least 0.1 wt%, or at least 0.3 wt%, or at least 0.5 wt%.” (Schneider et al., page 4, para. 3).
The peptide of Schneider may be injected: “The hydrogels of this invention may be of particular value for treating an animal for a medical condition. If the anionic macromolecule is a therapeutic agent, for example an anionic protein, the hydrogel may conveniently be applied by injection through a syringe needle, allowing minimally invasive deposition of the therapeutic agent at a desired localized site. Such treatment may be used for a mammal, a bird, a reptile, or any animal. Treatment of humans may be of particular value. In an animal, final release of all of the anionic macromolecule may depend upon destruction of the hydrogel structure due to enzymatic degradation of the MAX molecules, a process that may take several months to complete.” (Schneider et al., page 9, para 2).
The peptide of Schneider is purified: “Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. Peptide is injected onto the column under isocratic conditions.” (Schneider et al., page 10, para. 1).
The peptide of Schneider may be sterilized: “For the bulk release studies, MAXl and HPL8 peptide stock solutions were first prepared in glass vials by dissolving 1.5 mg or 6 mg of each peptide in 150 μL of sterile, chilled water resulting in two stock solutions for each peptide” (Schneider page 23, para. 2).
Finally Schneider discloses a method of treating a subject with said peptide in claims 16-18:
“16. A method of treating an animal, comprising the step of introducing the hydrogel of any one of claims 1-12 into the body of an animal.
17. The method of claim 16, further comprising a step of shearing the hydrogel prior to introducing it into the body of the animal.
18. The method of claim 17, wherein the shearing results from injection into the animal through a syringe needle.”
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 peptide of Schneider to perform the method of the ‘380 application to arrive at the claimed invention because Schneider discloses a self-assembling peptide that creates a hydrogel that is the appropriate length required by the ‘380 application.
A person of ordinary skill in the art would be motivated to use the peptide of Schneider because it meets all the physical requirements of the ‘380 application.
A person of ordinary skill in the art would have a reasonable expectation of success because the peptide of the ‘380 application and Schneider also forms self-assembling hydrogels.
Consequently, claim 1 is obvious over the ‘380 application in view of Schneider et al. and provisionally rejected.
Regarding claim 2, claim 1 is obvious as described above. The peptide of Schneider has a net charge of +8, which falls between +2 and +11.
Consequently, claim 2 is obvious over the ‘380 application in view of Schneider et al. and provisionally rejected.
Regarding claim 17, claim 1 is obvious as described above. Schneider discloses combining the hydrogel peptide with a buffer in order to induce self-assembly: “ Proteins of varying size and charge (Table 3) were incorporated in the high salt buffered solution and then added to the aqueous HPL8 solution to trigger self-assembly.” (Schneider et al., page 24, para. 3).
Consequently, claim 17 is obvious over the ‘380 application in view of Schneider et al. and provisionally rejected.
Regarding claim 23, claim 17 is obvious as described above. Schneider discloses the following buffer:
“The pH is maintained with a suitable buffer, typically a nonionic buffer such as bis-tris propane (BTP). As used herein, the term "physiological buffer" will be used to designate an aqueous solution buffered to pH=7.4, containing 50 mM BTP and 150 mM NaCl.” (Schneider et al., page 4, para. 3)
Consequently, claim 23 is obvious over the ‘380 application in view of Schneider et al. and provisionally rejected.
Regarding claim 31, claim 1 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 31 is obvious over the ‘380 application in view of Schneider et al. and provisionally rejected.
Regarding claim 58, claim 1 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
MPEP 2131.03 states: “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘obvious’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
Consequently, claim 58 is obvious over the ‘380 application in view of Schneider et al. and provisionally rejected.
Regarding claim 92, claim 31 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 92 is obvious over the ‘380 application in view of Schneider et al. and provisionally rejected.
Regarding claim 93, claim 93 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 93 is obvious over the ‘380 application in view of Schneider et al. and provisionally rejected.
Claims 3, 4, 12, 13, 86, 89, 90, 91, and 94-98 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-11, 13-15, 20, 32, 36, 50, 54-57, 62, and 65-74 of U.S. Patent Application 18/040,380 view of Schneider et al. WO2010/017369, published 2/11/2010 as applied to claim 1, further in view of Butterick et al. WO2009117497, published 9/24/2009.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 3, claim 1 is obvious as described above. The ‘380 application and Schneider do not explicitly disclose topical application of the hydrogel comprising the claimed peptide amphiphile.
However, Butterick discloses the topical usage of the exact same peptide:
“The hydrogel can also comprise a therapeutic agent and be utilized to deliver the therapeutic agent to a target site, such as to a tissue in vivo or in vitro. For example, the hydrogel may contain agents that stimulate cell proliferation or differentiation, stimulate wound healing, or inhibit bacterial growth. Such agents may include, but are not limited to analgesics, antibiotics, antineoplastics, hemostatic agents, anticoagulants, cytokines, growth factors, anti-inflammatories, small molecules, proteins, peptides, nucleotides, or cells. Spray delivery for β-sheet peptide hydrogels has broad medical application in, for example, tissue and bone engineering, regenerative and cosmetic treatment for hair and skin, cell-based diagnostics, surgery, wound-healing and wound-sealing”. (Butterick et al., page 3, para. 2).
Butterick discloses the same peptide as SEQ ID NO: 46, also called MAX28.
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 hydrogel of the ‘299 and Schneider topically as disclosed by Butterick to arrive at the claimed invention because Butterick is applying the same peptide to skin.
A person of ordinary skill in the art would be motivated to do this to avoid injection and to distribute the hydrogel over a wider area of skin than injection provides. A person of ordinary skill in the art would have a reasonable expectation of success because Butterick is using the same peptide on skin.
Consequently, claim 3 is obvious over the ‘380 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 4, claim 3 is obvious as described above. The peptide disclosed by Schneider (and Butterick) has a charge of +8.
Consequently, claim 4 is obvious over the ‘380 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 12, claim 3 is obvious as described above. Butterick discloses delivery by spray: “A method for delivering β-sheet peptide hydrogels to a target surface by shear- thinning and spraying the peptide hydrogel onto the surface is provided. The peptide hydrogels can be applied over a range of thicknesses and can cover broad surface areas. The β-sheet peptide hydrogels may also include a therapeutic agent.” (Butterick et al., Abstract).
Consequently, claim 12 is obvious over the ‘380 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 13, claim 3 is obvious as described above. Butterick discloses that the target tissue may be soft tissue: “Hydrogels are a class of materials that have significant promise for use in soft tissue and bone engineering and wound sealing, in part because of their well-hydrated, porous structure.” (Butterick et al., page 1, para. 3).
Consequently, claim 13 is obvious over the ‘380 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 86, claim 3 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 86 is obvious over the ‘380 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 89, claim 3 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
MPEP 2131.03 states: “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘obvious’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
Consequently, claim 89 is obvious over the ‘380 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 90, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 90 is obvious over the ‘380 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 91, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 91 is obvious over the ‘380 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 94, claim 3 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 94 is obvious over the ‘380 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 95, claim 94 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 95 is obvious over the ‘380 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 96, claim 95 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 96 is obvious over the ‘380 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 97, claim 96 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 97 is obvious over the ‘380 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 98, claim 86 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4). The charged amino acids are all lysine in this case.
Consequently, claim 98 is obvious over the ‘380 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-11, 13-15, 20, 32, 36, 50, 54-57, 62, and 65-74 of U.S. Patent Application 18/040,380 in view of Schneider et al. WO2010/017369, published 2/11/2010 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 because the patentably indistinct claims have not in fact been patented.
Regarding claim 5, claim 1 is obvious as described above.
The ‘380 application and Schneider 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 the ‘380 application and Schneider.
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 ‘380 application and Schneider et al. as applied in claim 1, further in view of Jin et al. and provisionally rejected.
Claim 9 on the ground of nonstatutory double patenting over claims 1-4, 7-11, 13-15, 20, 32, 36, 50, 54-57, 62, and 65-74 of U.S. Patent Application 18/040,380 in view of Schneider et al. WO2010/017369, published 2/11/2010 in view of Butterick et al. WO2009117497, published 9/24/2009 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 because the patentably indistinct claims have not in fact been patented.
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 ‘380 application, Schneider, and Butterick 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 the ‘380 application, Schneider, and Butterick 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, Schneider et al., and Butterick et al. 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 over claims 1-8 of U.S. Patent No. 10,245,299 in view of Schneider et al. WO2010/017369, published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009 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 because the patentably indistinct claims have not in fact been patented.
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 ‘380 application, Schneider, and Butterick 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 Schneider and Butterick 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 ‘380 application, Schneider et al., and Butterick et al. as applied to claim 3 above, further in view of Nunez et al. and provisionally rejected.
Claims 18 and 20 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-11, 13-15, 20, 32, 36, 50, 54-57, 62, and 65-74 of U.S. Patent Application 18/040,380 in view of Schneider et al. WO2010/017369, published 2/11/2010 as applied to claim 1, further in view of Mehta et al. ((US 20170072008, published 3/16/2017)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 18, claim 17 is obvious as described above. The ‘380 application and Schneider do not specifically disclose combining the preparation and buffer less than 10 minutes before administration.
However, 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 of the method of the ‘380 application and Schneider using the timing 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 Schneider et al. as applied to claim 1, further in view of Mehta et 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 and chloride ions are not present.
The ‘380 application Schneider do not specifically disclose this buffer condition.
However, 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 disclosed by Mehta with the method of the ‘380 application and Schneider. Such a buffer optimization is also a matter of routine optimization.
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 and both Schneider and Mehta disclose self-assembling hydrogels. 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 and both Schneider and Mehta disclose self-assembling hydrogels.
Consequently, claim 20 is obvious over the ‘380 application in view of Schneider et al. as applied to claim 1, further in view of Mehta et al. and provisionally rejected.
Claim 40 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-11, 13-15, 20, 32, 36, 50, 54-57, 62, and 65-74 of U.S. Patent Application 18/040,380 in view of Schneider et al. as applied to claim 1, further in view of Mehta et al. and rejected., further in view of Mant et al. (Mant, et al. Peptide characterization and application protocols. Totowa, NJ: Humana Press, 3-55 (2007)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 40, claim 1 is obvious as described above. The ‘380 application and Schneider do not disclose a specific purity. Schneider does disclose purification by RP-HPLC: “ Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. “ (Schneider et al., page 10, para. 1).
Mant discloses that RP-HPLC has purity yields of 95%: “As shown in Fig. 18, the purified product had a purity of <95% and a yield of <90% recovery.” (Mant et al., page 45, para. 3).
Consequently, claim 40 is obvious over the ‘380 application in view of Schneider et al. as applied to claim 1, further in view of Mant et al. and provisionally rejected.
Claim 44 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-11, 13-15, 20, 32, 36, 50, 54-57, 62, and 65-74 of U.S. Patent Application 18/040,380 in view of Schneider et al. 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 because the patentably indistinct claims have not in fact been patented.
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 ‘380 application and Schneider 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 ‘380 application and Schneider 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 ‘380 application in view of Schneider et al. as applied to claim 1 above, further in view of Mauri et al. and provisionally rejected.
Claim 85 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-11, 13-15, 20, 32, 36, 50, 54-57, 62, and 65-74 of U.S. Patent Application 18/040,380 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Mehta et al. ((US 20170072008, published 3/16/2017)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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 and chloride ions are not present.
The ‘380 application, Schneider, and Butterick do not specifically disclose this buffer condition.
However, 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 disclosed by Mehta with the method of the ‘380 application, Schneider, and Butterick. Such a buffer optimization is also a matter of routine optimization.
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 and both Schneider and Mehta disclose self-assembling hydrogels. 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 and both Schneider and Mehta disclose self-assembling hydrogels.
Consequently, claim 85 is obvious over the ‘380 application, Schneider et al., and Butterick et al. as applied to claim 3, in view of Mehta et al. and provisionally rejected.
Claim 87 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-11, 13-15, 20, 32, 36, 50, 54-57, 62, and 65-74 of U.S. Patent Application 18/040,380 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Mant et al. (Mant, et al. Peptide characterization and application protocols. Totowa, NJ: Humana Press, 3-55 (2007)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 87, claim 3 is obvious as described above. The ‘380 application, Schneider, and Butterick do not disclose a specific purity. Schneider does disclose purification by RP-HPLC: “ Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. “ (Schneider et al., page 10, para. 1).
Mant discloses that RP-HPLC has purity yields of 95%: “As shown in Fig. 18, the purified product had a purity of <95% and a yield of <90% recovery.” (Mant et al., page 45, para. 3).
Consequently, claim 87 is obvious over the ‘380 application, Schneider et al., and Butterick et al. as applied to claim 3, further in view of Mant et al. and provisionally rejected.
Claim 88 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-11, 13-15, 20, 32, 36, 50, 54-57, 62, and 65-74 of U.S. Patent Application 18/040,380 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, 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 because the patentably indistinct claims have not in fact been patented.
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.
The ‘380 application, Schneider, and Butterick 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 ‘380 application, Schneider, and Butterick 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 ‘380 application, Schneider et al. and Butterick et al. as applied to claim 3 above, further in view of Mauri et al. and provisionally rejected.
Claims 99 and 100 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-11, 13-15, 20, 32, 36, 50, 54-57, 62, and 65-74 of U.S. Patent Application 18/040,380 in view of Schneider et al. published 2/11/2010, as applied to claim1, further in view of Henikoff et al. (Henikoff, et al. Proceedings of the national academy of sciences 89.22: 10915-10919 (1992)) and Salick et al. US20110171304, published 7/14/2011.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 99, claim 1 is obvious as described above. The ‘380 application and Schneider et al. do not explicitly discloses these amino acid sequences.
However, Schneider et al. discloses : VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27) and VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4).
Furthermore, Salick discloses the peptide MARG1:VKVKVRVKVDPPTKVKVRVKV-NH2, which also forms a hydrogel: “MARG1 forms a hydrogel that shear-thins and rapidly re-forms upon cessation of shearing, so that the peptide hydrogel can be applied by injection via a syringe or other similar device to a contaminated surface where it kills MRSA on contact. The hydrogel can also be used as a coating to inhibit MRSA infection.” (Salick et al., para. [0019]).
Henikoff teaches that arginine and lysine are conservative substitutions for each other in Fig. 2, the Blosum62 substitution matrix (Henikoff, et al., page 10917, Fig. 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 make the conservative mutations disclosed by Henikoff to the positively charged residues of the sequences of the ‘380 application and Schneider to arrive at the claimed invention, for example, VKVRVRVRVDPPTRVRVRVKV-NH2 (Applicant SEQ ID NO: 2) because Salick teaches that mixing lysine and arginine residues in a MAX peptide results in a functional product and because Schneider discloses one peptide with all lysine residues and one with all arginine residues.
A person of ordinary skill in the art would be motivated to make these substitutions to modulate the exact activity of the hairpin peptide and would have a reasonable expectation of success because of the peptide of Salick shows that mixing these residues can result in a functional peptide. Furthermore, a finite group of possible conservative substitutions are possible with this peptide.
Consequently, claim 99 is obvious over the ‘380 application in view of Schneider et al. as applied to claim 1, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Regarding claim 100, claim 99 is obvious as described above. The analysis of claim 99 shows how a person of ordinary skill in the art would arrive at Applicant SEQ ID NO: 2.
Consequently, claim 100 is obvious over the ‘380 application in view of Schneider et al. as applied to claim 1, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Claims 101 and 102 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-11, 13-15, 20, 32, 36, 50, 54-57, 62, and 65-74 of U.S. Patent Application 18/040,380 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Henikoff et al. (Henikoff, et al. Proceedings of the national academy of sciences 89.22: 10915-10919 (1992)) and Salick et al. US20110171304, published 7/14/2011.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 101, claim 3 is obvious as described above. The ‘380 application, Schneider, and Butterick do not explicitly discloses these amino acid sequences.
However, Schneider et al. discloses : VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27) and VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4).
Furthermore, Salick discloses the peptide MARG1:VKVKVRVKVDPPTKVKVRVKV-NH2, which also forms a hydrogel: “MARG1 forms a hydrogel that shear-thins and rapidly re-forms upon cessation of shearing, so that the peptide hydrogel can be applied by injection via a syringe or other similar device to a contaminated surface where it kills MRSA on contact. The hydrogel can also be used as a coating to inhibit MRSA infection.” (Salick et al., para. [0019]).
Henikoff teaches that arginine and lysine are conservative substitutions for each other in Fig. 2, the Blosum62 substitution matrix (Henikoff, et al., page 10917, Fig. 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 make the conservative mutations disclosed by Henikoff to the positively charged residues of the sequences of the ‘380 application, Schneider, and Butterick to arrive at the claimed invention, for example, VKVRVRVRVDPPTRVRVRVKV-NH2 (Applicant SEQ ID NO: 2) because Salick teaches that mixing lysine and arginine residues in a MAX peptide results in a functional product and because Schneider discloses one peptide with all lysine residues and one with all arginine residues.
A person of ordinary skill in the art would be motivated to make these substitutions to modulate the exact activity of the hairpin peptide and would have a reasonable expectation of success because of the peptide of Salick shows that mixing these residues can result in a functional peptide. Furthermore, a finite group of possible conservative substitutions are possible with this peptide.
Consequently, claim 101 is obvious over the ‘380 application in view of Schneider et al. and Butterick et al. as applied to claim 3, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Regarding claim 102, claim 101 is obvious as described above. The analysis of claim 101 shows how a person of ordinary skill in the art would arrive at Applicant SEQ ID NO: 2.
Consequently, claim 102 is obvious over the ‘380 application in view of Schneider et al. and Butterick et al. as applied to claim 3, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Claim 103 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-11, 13-15, 20, 32, 36, 50, 54-57, 62, and 65-74 of U.S. Patent Application 18/040,380 in view of Schneider et al. published 2/11/2010 as applied to claim 1, further in view of Roux et al. (Roux, et al. Journal of peptide science: an official publication of the European Peptide Society 14.3: 354-359 (2008)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 103, claim 1 is obvious as described above. The ‘380 application and Schneider do not disclose the case wherein the peptide is free of TFA.
However, Roux discloses removal of TFA from synthesized peptides:
“Even though the excess TFA is easy to remove by a classic freeze-drying method, it is more challenging to remove the TF-acetate counter-ion, which strongly interacts with the positive charges of cationic peptides. Hitherto, the most convenient procedure to replace the TF-acetate counter-ion by another counter-ion has been mixing the peptide with an excess of a stronger acid than TFA, followed by a freeze-drying step [12]. A stronger acid than TFA is able to reprotonate the TF-acetate into its free acid form, which is then easily removed by freeze-drying [13]. However, this approach has essentially two drawbacks: (i) the very acidic solution can chemically damage the peptides, and (ii) the very restrictive choice of possible counterions, i.e. the counter-ions that are associated with strong acids (e.g. HCl, H2SO4, HF, HNO3).
The TF-acetate exchange was tested on the dicationic octapeptide lanreotide [14] synthesized in our laboratory by SPPS using an Fmoc strategy. Three different approaches were investigated: (i) RP-HPLC using acetic acid in the mobile phase, (ii) ionexchange
resin loaded with diluted acetic acid, and (iii) deprotonation/reprotonation cycle of lanreotide
positive charges (–NH3 +). The removal of TF-acetate counter-ions and its exchange by acetate were followed by quantitative 19F-NMR and 1H-NMR, respectively. Finally, we compared the ATR FT-IR spectra of lanreotide before and after the counter-ion exchange procedures.” (Roux et al., page 354, 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 remove TFA as disclosed by Roux from the peptide of the ‘380 application and Schneider to arrive at the claimed invention because Roux describes this as a routine procedure: “In all cases, TFA needs to be removed due to its drawbacks related to several physicochemical characterizations and biological studies. The presence of TFA can change the behavior of the peptide [3] or modify its conformation.” (Roux et al., page 354, col. 1, para. 2).
A person of ordinary skill in the art would be motivated to remove the TFA due to the problems disclosed by Roux above and would have a reasonable expectation of success because Roux discloses multiple procedures for this process as described above.
Consequently, claim 103 is obvious over the ‘380 application in view of Schneider et al. as applied to claim 1, further in view of Roux et al. and provisionally rejected.
Claim 104 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-11, 13-15, 20, 32, 36, 50, 54-57, 62, and 65-74 of U.S. Patent Application 18/040,380 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Roux et al. (Roux, et al. Journal of peptide science: an official publication of the European Peptide Society 14.3: 354-359 (2008)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 104, claim 3 is obvious as described above. The ‘380 application, Schneider, and Butterick do not disclose the case wherein the peptide is free of TFA.
However, Roux discloses removal of TFA from synthesized peptides:
“Even though the excess TFA is easy to remove by a classic freeze-drying method, it is more challenging to remove the TF-acetate counter-ion, which strongly interacts with the positive charges of cationic peptides. Hitherto, the most convenient procedure to replace the TF-acetate counter-ion by another counter-ion has been mixing the peptide with an excess of a stronger acid than TFA, followed by a freeze-drying step [12]. A stronger acid than TFA is able to reprotonate the TF-acetate into its free acid form, which is then easily removed by freeze-drying [13]. However, this approach has essentially two drawbacks: (i) the very acidic solution can chemically damage the peptides, and (ii) the very restrictive choice of possible counterions, i.e. the counter-ions that are associated with strong acids (e.g. HCl, H2SO4, HF, HNO3).
The TF-acetate exchange was tested on the dicationic octapeptide lanreotide [14] synthesized in our laboratory by SPPS using an Fmoc strategy. Three different approaches were investigated: (i) RP-HPLC using acetic acid in the mobile phase, (ii) ionexchange
resin loaded with diluted acetic acid, and (iii) deprotonation/reprotonation cycle of lanreotide
positive charges (–NH3 +). The removal of TF-acetate counter-ions and its exchange by acetate were followed by quantitative 19F-NMR and 1H-NMR, respectively. Finally, we compared the ATR FT-IR spectra of lanreotide before and after the counter-ion exchange procedures.” (Roux et al., page 354, 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 remove TFA as disclosed by Roux from the peptide of the ‘380 application, Schneider, and Butterick to arrive at the claimed invention because Roux describes this as a routine procedure: “In all cases, TFA needs to be removed due to its drawbacks related to several physicochemical characterizations and biological studies. The presence of TFA can change the behavior of the peptide [3] or modify its conformation.” (Roux et al., page 354, col. 1, para. 2).
A person of ordinary skill in the art would be motivated to remove the TFA due to the problems disclosed by Roux above and would have a reasonable expectation of success because Roux discloses multiple procedures for this process as described above.
Consequently, claim 104 is obvious over the ‘380 application, Schneider et al., and Butterick et al. as applied to claim 3, further in view of Roux et al. and provisionally rejected.
Claims 1, 2, 17, 23, 31, 58, 92, and 93 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. WO2010/017369, published 2/11/2010.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1 of the ‘388 application discloses:
“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 ‘388 application does not specifically disclose a peptide comprising a sequence of Y[XY]N(d)PPT[XY]M wherein N and M are 4.
However, claim 1 of the ‘388 application allows for a peptide that does fit that formula, i.e. 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. Furthermore, Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27).
This peptide reads on the formula Y[XY]4(d)PPT[XY]4 when X=arginine and Y=valine.
This amphiphile is provided in an physiologically compatible solution: “The hydrogels are physiologically compatible, having a pH of 7.4 and containing 150 mM NaCl. Unless referring to a specific experiment, where the pH values and concentrations of ingredients are exact within experimental uncertainty, a pH value of 7.4 should be understood to encompass physiologically acceptable variations around that value and an NaCl concentration of 150 mM NaCl should be understood to encompass physiologically acceptable variations around that value, provided that the desired gel properties are maintained. Thus, the pH value may vary at least within a range of 7.35 to 7.45 and the NaCl concentration may vary at least within in a range of 140 to 160 mM, provided that the desired gel properties are maintained. The pH is maintained with a suitable buffer, typically a nonionic buffer such as bis-tris propane (BTP). As used herein, the term "physiological buffer" will be used to designate an aqueous solution buffered to pH=7.4, containing 50 mM BTP and 150 mM NaCl. The MAX peptide content of hydrogels according to the invention may be at least 0.1 wt%, or at least 0.3 wt%, or at least 0.5 wt%.” (Schneider et al., page 4, para. 3).
The peptide of Schneider may be injected: “The hydrogels of this invention may be of particular value for treating an animal for a medical condition. If the anionic macromolecule is a therapeutic agent, for example an anionic protein, the hydrogel may conveniently be applied by injection through a syringe needle, allowing minimally invasive deposition of the therapeutic agent at a desired localized site. Such treatment may be used for a mammal, a bird, a reptile, or any animal. Treatment of humans may be of particular value. In an animal, final release of all of the anionic macromolecule may depend upon destruction of the hydrogel structure due to enzymatic degradation of the MAX molecules, a process that may take several months to complete.” (Schneider et al., page 9, para 2).
The peptide of Schneider is purified: “Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. Peptide is injected onto the column under isocratic conditions.” (Schneider et al., page 10, para. 1).
The peptide of Schneider may be sterilized: “For the bulk release studies, MAXl and HPL8 peptide stock solutions were first prepared in glass vials by dissolving 1.5 mg or 6 mg of each peptide in 150 μL of sterile, chilled water resulting in two stock solutions for each peptide” (Schneider page 23, para. 2).
Finally Schneider discloses a method of treating a subject with said peptide in claims 16-18:
“16. A method of treating an animal, comprising the step of introducing the hydrogel of any one of claims 1-12 into the body of an animal.
17. The method of claim 16, further comprising a step of shearing the hydrogel prior to introducing it into the body of the animal.
18. The method of claim 17, wherein the shearing results from injection into the animal through a syringe needle.”
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 peptide of Schneider to perform the method of the ‘388 application to arrive at the claimed invention because Schneider discloses a self-assembling peptide that creates a hydrogel that is the appropriate length required by the ‘388 application.
A person of ordinary skill in the art would be motivated to use the peptide of Schneider because it meets all the physical requirements of the ‘388 application.
A person of ordinary skill in the art would have a reasonable expectation of success because the peptide of the ‘388 application and Schneider also forms self-assembling hydrogels.
Consequently, claim 1 is obvious over the ‘388 application in view of Schneider et al. and provisionally rejected.
Regarding claim 2, claim 1 is obvious as described above. The peptide of Schneider has a net charge of +8, which falls between +2 and +11.
Consequently, claim 2 is obvious over the ‘388 application in view of Schneider et al. and provisionally rejected.
Regarding claim 17, claim 1 is obvious as described above. Schneider discloses combining the hydrogel peptide with a buffer in order to induce self-assembly: “ Proteins of varying size and charge (Table 3) were incorporated in the high salt buffered solution and then added to the aqueous HPL8 solution to trigger self-assembly.” (Schneider et al., page 24, para. 3).
Consequently, claim 17 is obvious over the ‘388 application in view of Schneider et al. and provisionally rejected.
Regarding claim 23, claim 17 is obvious as described above. Schneider discloses the following buffer:
“The pH is maintained with a suitable buffer, typically a nonionic buffer such as bis-tris propane (BTP). As used herein, the term "physiological buffer" will be used to designate an aqueous solution buffered to pH=7.4, containing 50 mM BTP and 150 mM NaCl.” (Schneider et al., page 4, para. 3)
Consequently, claim 23 is obvious over the ‘388 application in view of Schneider et al. and provisionally rejected.
Regarding claim 31, claim 1 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 31 is obvious over the ‘388 application in view of Schneider et al. and provisionally rejected.
Regarding claim 58, claim 1 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
MPEP 2131.03 states: “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘obvious’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
Consequently, claim 58 is obvious over the ‘388 application in view of Schneider et al. and provisionally rejected.
Regarding claim 92, claim 31 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 92 is obvious over the ‘388 application in view of Schneider et al. and provisionally rejected.
Regarding claim 93, claim 93 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 93 is obvious over the ‘388 application in view of Schneider et al. and provisionally rejected.
Claims 3, 4, 12, 13, 86, 89, 90, 91, and 94-98 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. WO2010/017369, published 2/11/2010 as applied to claim 1, further in view of Butterick et al. WO2009117497, published 9/24/2009.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 3, claim 1 is obvious as described above. The ‘388 application and Schneider do not explicitly disclose topical application of the hydrogel comprising the claimed peptide amphiphile.
However, Butterick discloses the topical usage of the exact same peptide:
“The hydrogel can also comprise a therapeutic agent and be utilized to deliver the therapeutic agent to a target site, such as to a tissue in vivo or in vitro. For example, the hydrogel may contain agents that stimulate cell proliferation or differentiation, stimulate wound healing, or inhibit bacterial growth. Such agents may include, but are not limited to analgesics, antibiotics, antineoplastics, hemostatic agents, anticoagulants, cytokines, growth factors, anti-inflammatories, small molecules, proteins, peptides, nucleotides, or cells. Spray delivery for β-sheet peptide hydrogels has broad medical application in, for example, tissue and bone engineering, regenerative and cosmetic treatment for hair and skin, cell-based diagnostics, surgery, wound-healing and wound-sealing”. (Butterick et al., page 3, para. 2).
Butterick discloses the same peptide as SEQ ID NO: 46, also called MAX28.
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 hydrogel of the ‘299 and Schneider topically as disclosed by Butterick to arrive at the claimed invention because Butterick is applying the same peptide to skin.
A person of ordinary skill in the art would be motivated to do this to avoid injection and to distribute the hydrogel over a wider area of skin than injection provides. A person of ordinary skill in the art would have a reasonable expectation of success because Butterick is using the same peptide on skin.
Consequently, claim 3 is obvious over the ‘388 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 4, claim 3 is obvious as described above. The peptide disclosed by Schneider (and Butterick) has a charge of +8.
Consequently, claim 4 is obvious over the ‘388 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 12, claim 3 is obvious as described above. Butterick discloses delivery by spray: “A method for delivering β-sheet peptide hydrogels to a target surface by shear- thinning and spraying the peptide hydrogel onto the surface is provided. The peptide hydrogels can be applied over a range of thicknesses and can cover broad surface areas. The β-sheet peptide hydrogels may also include a therapeutic agent.” (Butterick et al., Abstract).
Consequently, claim 12 is obvious over the ‘388 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 13, claim 3 is obvious as described above. Butterick discloses that the target tissue may be soft tissue: “Hydrogels are a class of materials that have significant promise for use in soft tissue and bone engineering and wound sealing, in part because of their well-hydrated, porous structure.” (Butterick et al., page 1, para. 3).
Consequently, claim 13 is obvious over the ‘388 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 86, claim 3 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 86 is obvious over the ‘388 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 89, claim 3 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
MPEP 2131.03 states: “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘obvious’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
Consequently, claim 89 is obvious over the ‘388 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 90, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 90 is obvious over the ‘388 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 90, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 90 is obvious over the ‘388 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 91, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 91 is obvious over the ‘388 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 94, claim 3 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 94 is obvious over the ‘388 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 95, claim 94 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 95 is obvious over the ‘388 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 96, claim 95 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 96 is obvious over the ‘388 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 97, claim 96 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 97 is obvious over the ‘388 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 98, claim 86 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4). The charged amino acids are all lysine in this case.
Consequently, claim 98 is obvious over the ‘388 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. WO2010/017369, published 2/11/2010 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 because the patentably indistinct claims have not in fact been patented.
Regarding claim 5, claim 1 is obvious as described above.
The ‘388 application and Schneider 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 the ‘388 application and Schneider.
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 ‘388 application and Schneider et al. as applied in claim 1, further in view of Jin et al. and provisionally rejected.
Claim 9 on the ground of nonstatutory double patenting over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. WO2010/017369, published 2/11/2010 in view of Butterick et al. WO2009117497, published 9/24/2009 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 ‘388 application, Schneider, and Butterick 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 the ‘388 application, Schneider, and Butterick 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, Schneider et al., and Butterick et al. 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 over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. WO2010/017369, published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009 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 ‘388 application, Schneider, and Butterick 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 Schneider and Butterick 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 ‘388 application, Schneider et al., and Butterick et al. as applied to claim 3 above, further in view of Nunez et al. and provisionally rejected.
Claims 18 and 20 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. WO2010/017369, published 2/11/2010 as applied to claim 1, further in view of Mehta et al. ((US 20170072008, published 3/16/2017)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 18, claim 17 is obvious as described above. The ‘388 application and Schneider do not specifically disclose combining the preparation and buffer less than 10 minutes before administration.
However, 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 of the method of the ‘388 application and Schneider using the timing 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 Schneider et al. as applied to claim 1, further in view of Mehta et 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 and chloride ions are not present.
The ‘388 application Schneider do not specifically disclose this buffer condition.
However, 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 disclosed by Mehta with the method of the ‘388 application and Schneider. Such a buffer optimization is also a matter of routine optimization.
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 and both Schneider and Mehta disclose self-assembling hydrogels. 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 and both Schneider and Mehta disclose self-assembling hydrogels.
Consequently, claim 20 is obvious over the ‘388 application in view of Schneider et al. as applied to claim 1, further in view of Mehta et al. and provisionally rejected.
Claim 40 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. as applied to claim 1, further in view of Mehta et al. and provisionally rejected., further in view of Mant et al. (Mant, et al. Peptide characterization and application protocols. Totowa, NJ: Humana Press, 3-55 (2007)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 40, claim 1 is obvious as described above. The ‘388 application and Schneider do not disclose a specific purity. Schneider does disclose purification by RP-HPLC: “ Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. “ (Schneider et al., page 10, para. 1).
Mant discloses that RP-HPLC has purity yields of 95%: “As shown in Fig. 18, the purified product had a purity of <95% and a yield of <90% recovery.” (Mant et al., page 45, para. 3).
Consequently, claim 40 is obvious over the ‘388 application in view of Schneider et al. as applied to claim 1, further in view of Mant et al. and provisionally rejected.
Claim 44 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. 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 because the patentably indistinct claims have not in fact been patented.
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 ‘388 application and Schneider 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 ‘388 application and Schneider 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 ‘388 application in view of Schneider et al. as applied to claim 1 above, further in view of Mauri et al. and provisionally rejected.
Claim 85 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Mehta et al. ((US 20170072008, published 3/16/2017)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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 and chloride ions are not present.
The ‘388 application, Schneider, and Butterick do not specifically disclose this buffer condition.
However, 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 disclosed by Mehta with the method of the ‘388 application, Schneider, and Butterick. Such a buffer optimization is also a matter of routine optimization.
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 and both Schneider and Mehta disclose self-assembling hydrogels. 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 and both Schneider and Mehta disclose self-assembling hydrogels.
Consequently, claim 85 is obvious over the ‘388 application, Schneider et al., and Butterick et al. as applied to claim 3, in view of Mehta et al. and provisionally rejected.
Claim 87 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Mant et al. (Mant, et al. Peptide characterization and application protocols. Totowa, NJ: Humana Press, 3-55 (2007)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 87, claim 3 is obvious as described above. The ‘388 application, Schneider, and Butterick do not disclose a specific purity. Schneider does disclose purification by RP-HPLC: “ Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. “ (Schneider et al., page 10, para. 1).
Mant discloses that RP-HPLC has purity yields of 95%: “As shown in Fig. 18, the purified product had a purity of <95% and a yield of <90% recovery.” (Mant et al., page 45, para. 3).
Consequently, claim 87 is obvious over the ‘388 application, Schneider et al., and Butterick et al. as applied to claim 3, further in view of Mant et al. and provisionally rejected.
Claim 88 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, 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 because the patentably indistinct claims have not in fact been patented.
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.
The ‘388 application, Schneider, and Butterick 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 ‘388 application, Schneider, and Butterick 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 ‘388 application, Schneider et al. and Butterick et al. as applied to claim 3 above, further in view of Mauri et al. and provisionally rejected.
Claims 99 and 100 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. published 2/11/2010, as applied to claim1, further in view of Henikoff et al. (Henikoff, et al. Proceedings of the national academy of sciences 89.22: 10915-10919 (1992)) and Salick et al. US20110171304, published 7/14/2011.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 99, claim 1 is obvious as described above. The ‘388 application and Schneider et al. do not explicitly discloses these amino acid sequences.
However, Schneider et al. discloses : VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27) and VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4).
Furthermore, Salick discloses the peptide MARG1:VKVKVRVKVDPPTKVKVRVKV-NH2, which also forms a hydrogel: “MARG1 forms a hydrogel that shear-thins and rapidly re-forms upon cessation of shearing, so that the peptide hydrogel can be applied by injection via a syringe or other similar device to a contaminated surface where it kills MRSA on contact. The hydrogel can also be used as a coating to inhibit MRSA infection.” (Salick et al., para. [0019]).
Henikoff teaches that arginine and lysine are conservative substitutions for each other in Fig. 2, the Blosum62 substitution matrix (Henikoff, et al., page 10917, Fig. 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 make the conservative mutations disclosed by Henikoff to the positively charged residues of the sequences of the ‘388 application and Schneider to arrive at the claimed invention, for example, VKVRVRVRVDPPTRVRVRVKV-NH2 (Applicant SEQ ID NO: 2) because Salick teaches that mixing lysine and arginine residues in a MAX peptide results in a functional product and because Schneider discloses one peptide with all lysine residues and one with all arginine residues.
A person of ordinary skill in the art would be motivated to make these substitutions to modulate the exact activity of the hairpin peptide and would have a reasonable expectation of success because of the peptide of Salick shows that mixing these residues can result in a functional peptide. Furthermore, a finite group of possible conservative substitutions are possible with this peptide.
Consequently, claim 99 is obvious over the ‘388 application in view of Schneider et al. as applied to claim 1, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Regarding claim 100, claim 99 is obvious as described above. The analysis of claim 99 shows how a person of ordinary skill in the art would arrive at Applicant SEQ ID NO: 2.
Consequently, claim 100 is obvious over the ‘388 application in view of Schneider et al. as applied to claim 1, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Claims 101 and 102 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Henikoff et al. (Henikoff, et al. Proceedings of the national academy of sciences 89.22: 10915-10919 (1992)) and Salick et al. US20110171304, published 7/14/2011.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 101, claim 3 is obvious as described above. The ‘388 application, Schneider, and Butterick do not explicitly discloses these amino acid sequences.
However, Schneider et al. discloses : VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27) and VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4).
Furthermore, Salick discloses the peptide MARG1:VKVKVRVKVDPPTKVKVRVKV-NH2, which also forms a hydrogel: “MARG1 forms a hydrogel that shear-thins and rapidly re-forms upon cessation of shearing, so that the peptide hydrogel can be applied by injection via a syringe or other similar device to a contaminated surface where it kills MRSA on contact. The hydrogel can also be used as a coating to inhibit MRSA infection.” (Salick et al., para. [0019]).
Henikoff teaches that arginine and lysine are conservative substitutions for each other in Fig. 2, the Blosum62 substitution matrix (Henikoff, et al., page 10917, Fig. 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 make the conservative mutations disclosed by Henikoff to the positively charged residues of the sequences of the ‘388 application, Schneider, and Butterick to arrive at the claimed invention, for example, VKVRVRVRVDPPTRVRVRVKV-NH2 (Applicant SEQ ID NO: 2) because Salick teaches that mixing lysine and arginine residues in a MAX peptide results in a functional product and because Schneider discloses one peptide with all lysine residues and one with all arginine residues.
A person of ordinary skill in the art would be motivated to make these substitutions to modulate the exact activity of the hairpin peptide and would have a reasonable expectation of success because of the peptide of Salick shows that mixing these residues can result in a functional peptide. Furthermore, a finite group of possible conservative substitutions are possible with this peptide.
Consequently, claim 101 is obvious over the ‘388 application in view of Schneider et al. and Butterick et al. as applied to claim 3, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Regarding claim 102, claim 101 is obvious as described above. The analysis of claim 101 shows how a person of ordinary skill in the art would arrive at Applicant SEQ ID NO: 2.
Consequently, claim 102 is obvious over the ‘388 application in view of Schneider et al. and Butterick et al. as applied to claim 3, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Claim 103 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. published 2/11/2010 as applied to claim 1, further in view of Roux et al. (Roux, et al. Journal of peptide science: an official publication of the European Peptide Society 14.3: 354-359 (2008)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 103, claim 1 is obvious as described above. The ‘388 application and Schneider do not disclose the case wherein the peptide is free of TFA.
However, Roux discloses removal of TFA from synthesized peptides:
“Even though the excess TFA is easy to remove by a classic freeze-drying method, it is more challenging to remove the TF-acetate counter-ion, which strongly interacts with the positive charges of cationic peptides. Hitherto, the most convenient procedure to replace the TF-acetate counter-ion by another counter-ion has been mixing the peptide with an excess of a stronger acid than TFA, followed by a freeze-drying step [12]. A stronger acid than TFA is able to reprotonate the TF-acetate into its free acid form, which is then easily removed by freeze-drying [13]. However, this approach has essentially two drawbacks: (i) the very acidic solution can chemically damage the peptides, and (ii) the very restrictive choice of possible counterions, i.e. the counter-ions that are associated with strong acids (e.g. HCl, H2SO4, HF, HNO3).
The TF-acetate exchange was tested on the dicationic octapeptide lanreotide [14] synthesized in our laboratory by SPPS using an Fmoc strategy. Three different approaches were investigated: (i) RP-HPLC using acetic acid in the mobile phase, (ii) ionexchange
resin loaded with diluted acetic acid, and (iii) deprotonation/reprotonation cycle of lanreotide
positive charges (–NH3 +). The removal of TF-acetate counter-ions and its exchange by acetate were followed by quantitative 19F-NMR and 1H-NMR, respectively. Finally, we compared the ATR FT-IR spectra of lanreotide before and after the counter-ion exchange procedures.” (Roux et al., page 354, 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 remove TFA as disclosed by Roux from the peptide of the ‘388 application and Schneider to arrive at the claimed invention because Roux describes this as a routine procedure: “In all cases, TFA needs to be removed due to its drawbacks related to several physicochemical characterizations and biological studies. The presence of TFA can change the behavior of the peptide [3] or modify its conformation.” (Roux et al., page 354, col. 1, para. 2).
A person of ordinary skill in the art would be motivated to remove the TFA due to the problems disclosed by Roux above and would have a reasonable expectation of success because Roux discloses multiple procedures for this process as described above.
Consequently, claim 103 is obvious over the ‘388 application in view of Schneider et al. as applied to claim 1, further in view of Roux et al. and provisionally rejected.
Claim 104 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-4, 7-10, 12-14, 19, 31, 35, 49, 53-56, 61, 64-73 of U.S. Patent Application 18/040,388 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Roux et al. (Roux, et al. Journal of peptide science: an official publication of the European Peptide Society 14.3: 354-359 (2008)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 104, claim 3 is obvious as described above. The ‘388 application, Schneider, and Butterick do not disclose the case wherein the peptide is free of TFA.
However, Roux discloses removal of TFA from synthesized peptides:
“Even though the excess TFA is easy to remove by a classic freeze-drying method, it is more challenging to remove the TF-acetate counter-ion, which strongly interacts with the positive charges of cationic peptides. Hitherto, the most convenient procedure to replace the TF-acetate counter-ion by another counter-ion has been mixing the peptide with an excess of a stronger acid than TFA, followed by a freeze-drying step [12]. A stronger acid than TFA is able to reprotonate the TF-acetate into its free acid form, which is then easily removed by freeze-drying [13]. However, this approach has essentially two drawbacks: (i) the very acidic solution can chemically damage the peptides, and (ii) the very restrictive choice of possible counterions, i.e. the counter-ions that are associated with strong acids (e.g. HCl, H2SO4, HF, HNO3).
The TF-acetate exchange was tested on the dicationic octapeptide lanreotide [14] synthesized in our laboratory by SPPS using an Fmoc strategy. Three different approaches were investigated: (i) RP-HPLC using acetic acid in the mobile phase, (ii) ionexchange
resin loaded with diluted acetic acid, and (iii) deprotonation/reprotonation cycle of lanreotide
positive charges (–NH3 +). The removal of TF-acetate counter-ions and its exchange by acetate were followed by quantitative 19F-NMR and 1H-NMR, respectively. Finally, we compared the ATR FT-IR spectra of lanreotide before and after the counter-ion exchange procedures.” (Roux et al., page 354, 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 remove TFA as disclosed by Roux from the peptide of the ‘388 application, Schneider, and Butterick to arrive at the claimed invention because Roux describes this as a routine procedure: “In all cases, TFA needs to be removed due to its drawbacks related to several physicochemical characterizations and biological studies. The presence of TFA can change the behavior of the peptide [3] or modify its conformation.” (Roux et al., page 354, col. 1, para. 2).
A person of ordinary skill in the art would be motivated to remove the TFA due to the problems disclosed by Roux above and would have a reasonable expectation of success because Roux discloses multiple procedures for this process as described above.
Consequently, claim 104 is obvious over the ‘388 application, Schneider et al., and Butterick et al. as applied to claim 3, further in view of Roux et al. and provisionally rejected.
Claims 1, 2, 17, 23, 31, 58, 92, and 93 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. WO2010/017369, published 2/11/2010.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1 of the ‘493 application discloses:
“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.”
The ‘493 application does not specifically disclose a peptide comprising a sequence of Y[XY]N(d)PPT[XY]M wherein N and M are 4.
However, claim 1 of the ‘493 application allows for a peptide that does fit that formula, i.e. 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. Furthermore, Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27).
This peptide reads on the formula Y[XY]4(d)PPT[XY]4 when X=arginine and Y=valine.
This amphiphile is provided in an physiologically compatible solution: “The hydrogels are physiologically compatible, having a pH of 7.4 and containing 150 mM NaCl. Unless referring to a specific experiment, where the pH values and concentrations of ingredients are exact within experimental uncertainty, a pH value of 7.4 should be understood to encompass physiologically acceptable variations around that value and an NaCl concentration of 150 mM NaCl should be understood to encompass physiologically acceptable variations around that value, provided that the desired gel properties are maintained. Thus, the pH value may vary at least within a range of 7.35 to 7.45 and the NaCl concentration may vary at least within in a range of 140 to 160 mM, provided that the desired gel properties are maintained. The pH is maintained with a suitable buffer, typically a nonionic buffer such as bis-tris propane (BTP). As used herein, the term "physiological buffer" will be used to designate an aqueous solution buffered to pH=7.4, containing 50 mM BTP and 150 mM NaCl. The MAX peptide content of hydrogels according to the invention may be at least 0.1 wt%, or at least 0.3 wt%, or at least 0.5 wt%.” (Schneider et al., page 4, para. 3).
The peptide of Schneider may be injected: “The hydrogels of this invention may be of particular value for treating an animal for a medical condition. If the anionic macromolecule is a therapeutic agent, for example an anionic protein, the hydrogel may conveniently be applied by injection through a syringe needle, allowing minimally invasive deposition of the therapeutic agent at a desired localized site. Such treatment may be used for a mammal, a bird, a reptile, or any animal. Treatment of humans may be of particular value. In an animal, final release of all of the anionic macromolecule may depend upon destruction of the hydrogel structure due to enzymatic degradation of the MAX molecules, a process that may take several months to complete.” (Schneider et al., page 9, para 2).
The peptide of Schneider is purified: “Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. Peptide is injected onto the column under isocratic conditions.” (Schneider et al., page 10, para. 1).
The peptide of Schneider may be sterilized: “For the bulk release studies, MAXl and HPL8 peptide stock solutions were first prepared in glass vials by dissolving 1.5 mg or 6 mg of each peptide in 150 μL of sterile, chilled water resulting in two stock solutions for each peptide” (Schneider page 23, para. 2).
Finally Schneider discloses a method of treating a subject with said peptide in claims 16-18:
“16. A method of treating an animal, comprising the step of introducing the hydrogel of any one of claims 1-12 into the body of an animal.
17. The method of claim 16, further comprising a step of shearing the hydrogel prior to introducing it into the body of the animal.
18. The method of claim 17, wherein the shearing results from injection into the animal through a syringe needle.”
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 peptide of Schneider to perform the method of the ‘493 application to arrive at the claimed invention because Schneider discloses a self-assembling peptide that creates a hydrogel that is the appropriate length required by the ‘493 application.
A person of ordinary skill in the art would be motivated to use the peptide of Schneider because it meets all the physical requirements of the ‘493 application.
A person of ordinary skill in the art would have a reasonable expectation of success because the peptide of the ‘493 application and Schneider also forms self-assembling hydrogels.
Consequently, claim 1 is obvious over the ‘493 application in view of Schneider et al. and provisionally rejected.
Regarding claim 2, claim 1 is obvious as described above. The peptide of Schneider has a net charge of +8, which falls between +2 and +11.
Consequently, claim 2 is obvious over the ‘493 application in view of Schneider et al. and provisionally rejected.
Regarding claim 17, claim 1 is obvious as described above. Schneider discloses combining the hydrogel peptide with a buffer in order to induce self-assembly: “ Proteins of varying size and charge (Table 3) were incorporated in the high salt buffered solution and then added to the aqueous HPL8 solution to trigger self-assembly.” (Schneider et al., page 24, para. 3).
Consequently, claim 17 is obvious over the ‘493 application in view of Schneider et al. and provisionally rejected.
Regarding claim 23, claim 17 is obvious as described above. Schneider discloses the following buffer:
“The pH is maintained with a suitable buffer, typically a nonionic buffer such as bis-tris propane (BTP). As used herein, the term "physiological buffer" will be used to designate an aqueous solution buffered to pH=7.4, containing 50 mM BTP and 150 mM NaCl.” (Schneider et al., page 4, para. 3)
Consequently, claim 23 is obvious over the ‘493 application in view of Schneider et al. and provisionally rejected.
Regarding claim 31, claim 1 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 31 is obvious over the ‘493 application in view of Schneider et al. and provisionally rejected.
Regarding claim 58, claim 1 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
MPEP 2131.03 states: “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘obvious’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
Consequently, claim 58 is obvious over the ‘493 application in view of Schneider et al. and provisionally rejected.
Regarding claim 92, claim 31 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 92 is obvious over the ‘493 application in view of Schneider et al. and provisionally rejected.
Regarding claim 93, claim 93 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 93 is obvious over the ‘493 application in view of Schneider et al. and provisionally rejected.
Claims 3, 4, 12, 13, 86, 89, 90, 91, and 94-98 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. WO2010/017369, published 2/11/2010 as applied to claim 1, further in view of Butterick et al. WO2009117497, published 9/24/2009.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 3, claim 1 is obvious as described above. The ‘493 application and Schneider do not explicitly disclose topical application of the hydrogel comprising the claimed peptide amphiphile.
However, Butterick discloses the topical usage of the exact same peptide:
“The hydrogel can also comprise a therapeutic agent and be utilized to deliver the therapeutic agent to a target site, such as to a tissue in vivo or in vitro. For example, the hydrogel may contain agents that stimulate cell proliferation or differentiation, stimulate wound healing, or inhibit bacterial growth. Such agents may include, but are not limited to analgesics, antibiotics, antineoplastics, hemostatic agents, anticoagulants, cytokines, growth factors, anti-inflammatories, small molecules, proteins, peptides, nucleotides, or cells. Spray delivery for β-sheet peptide hydrogels has broad medical application in, for example, tissue and bone engineering, regenerative and cosmetic treatment for hair and skin, cell-based diagnostics, surgery, wound-healing and wound-sealing”. (Butterick et al., page 3, para. 2).
Butterick discloses the same peptide as SEQ ID NO: 46, also called MAX28.
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 hydrogel of the ‘299 and Schneider topically as disclosed by Butterick to arrive at the claimed invention because Butterick is applying the same peptide to skin.
A person of ordinary skill in the art would be motivated to do this to avoid injection and to distribute the hydrogel over a wider area of skin than injection provides. A person of ordinary skill in the art would have a reasonable expectation of success because Butterick is using the same peptide on skin.
Consequently, claim 3 is obvious over the ‘493 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 4, claim 3 is obvious as described above. The peptide disclosed by Schneider (and Butterick) has a charge of +8.
Consequently, claim 4 is obvious over the ‘493 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 12, claim 3 is obvious as described above. Butterick discloses delivery by spray: “A method for delivering β-sheet peptide hydrogels to a target surface by shear- thinning and spraying the peptide hydrogel onto the surface is provided. The peptide hydrogels can be applied over a range of thicknesses and can cover broad surface areas. The β-sheet peptide hydrogels may also include a therapeutic agent.” (Butterick et al., Abstract).
Consequently, claim 12 is obvious over the ‘493 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 13, claim 3 is obvious as described above. Butterick discloses that the target tissue may be soft tissue: “Hydrogels are a class of materials that have significant promise for use in soft tissue and bone engineering and wound sealing, in part because of their well-hydrated, porous structure.” (Butterick et al., page 1, para. 3).
Consequently, claim 13 is obvious over the ‘493 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 86, claim 3 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 86 is obvious over the ‘493 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 89, claim 3 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
MPEP 2131.03 states: “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘obvious’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
Consequently, claim 89 is obvious over the ‘493 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 90, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 90 is obvious over the ‘493 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 90, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 90 is obvious over the ‘493 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 91, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 91 is obvious over the ‘493 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 94, claim 3 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 94 is obvious over the ‘493 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 95, claim 94 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 95 is obvious over the ‘493 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 96, claim 95 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 96 is obvious over the ‘493 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 97, claim 96 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 97 is obvious over the ‘493 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 98, claim 86 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4). The charged amino acids are all lysine in this case.
Consequently, claim 98 is obvious over the ‘493 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. WO2010/017369, published 2/11/2010 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 because the patentably indistinct claims have not in fact been patented.
Regarding claim 5, claim 1 is obvious as described above.
The ‘493 application and Schneider 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 the ‘493 application and Schneider.
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 ‘493 application and Schneider et al. as applied in claim 1, further in view of Jin et al. and provisionally rejected.
Claim 9 on the ground of nonstatutory double patenting over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. WO2010/017369, published 2/11/2010 in view of Butterick et al. WO2009117497, published 9/24/2009 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 ‘493 application, Schneider, and Butterick 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 the ‘493 application, Schneider, and Butterick 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, Schneider et al., and Butterick et al. 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 over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. WO2010/017369, published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009 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 ‘493 application, Schneider, and Butterick 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 Schneider and Butterick 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, Schneider et al., and Butterick et al. as applied to claim 3 above, further in view of Nunez et al. and provisionally rejected.
Claims 18 and 20 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. WO2010/017369, published 2/11/2010 as applied to claim 1, further in view of Mehta et al. ((US 20170072008, published 3/16/2017)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 18, claim 17 is obvious as described above. The ‘493 application and Schneider do not specifically disclose combining the preparation and buffer less than 10 minutes before administration.
However, 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 of the method of the ‘493 application and Schneider using the timing 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 Schneider et al. as applied to claim 1, further in view of Mehta et 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 and chloride ions are not present.
The ‘493 application Schneider do not specifically disclose this buffer condition.
However, 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 disclosed by Mehta with the method of the ‘493 application and Schneider. Such a buffer optimization is also a matter of routine optimization.
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 and both Schneider and Mehta disclose self-assembling hydrogels. 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 and both Schneider and Mehta disclose self-assembling hydrogels.
Consequently, claim 20 is obvious over the ‘493 application in view of Schneider et al. as applied to claim 1, further in view of Mehta et al. and provisionally rejected.
Claim 40 is provisionally rejected on the ground of nonstatutory double over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. as applied to claim 1, further in view of Mehta et al. and provisionally rejected., further in view of Mant et al. (Mant, et al. Peptide characterization and application protocols. Totowa, NJ: Humana Press, 3-55 (2007)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 40, claim 1 is obvious as described above. The ‘493 application and Schneider do not disclose a specific purity. Schneider does disclose purification by RP-HPLC: “ Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. “ (Schneider et al., page 10, para. 1).
Mant discloses that RP-HPLC has purity yields of 95%: “As shown in Fig. 18, the purified product had a purity of <95% and a yield of <90% recovery.” (Mant et al., page 45, para. 3).
Consequently, claim 40 is obvious over the ‘493 application in view of Schneider et al. as applied to claim 1, further in view of Mant et al. and provisionally rejected.
Claim 44 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. 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 because the patentably indistinct claims have not in fact been patented.
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 and Schneider 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 and Schneider 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 Schneider et al. as applied to claim 1 above, further in view of Mauri et al. and provisionally rejected.
Claim 85 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Mehta et al. ((US 20170072008, published 3/16/2017)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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 and chloride ions are not present.
The ‘493 application, Schneider, and Butterick do not specifically disclose this buffer condition.
However, 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 disclosed by Mehta with the method of the ‘493 application, Schneider, and Butterick. Such a buffer optimization is also a matter of routine optimization.
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 and both Schneider and Mehta disclose self-assembling hydrogels. 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 and both Schneider and Mehta disclose self-assembling hydrogels.
Consequently, claim 85 is obvious over the ‘493 application, Schneider et al., and Butterick et al. as applied to claim 3, in view of Mehta et al. and provisionally rejected.
Claim 87 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Mant et al. (Mant, et al. Peptide characterization and application protocols. Totowa, NJ: Humana Press, 3-55 (2007)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 87, claim 3 is obvious as described above. The ‘493 application, Schneider, and Butterick do not disclose a specific purity. Schneider does disclose purification by RP-HPLC: “ Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. “ (Schneider et al., page 10, para. 1).
Mant discloses that RP-HPLC has purity yields of 95%: “As shown in Fig. 18, the purified product had a purity of <95% and a yield of <90% recovery.” (Mant et al., page 45, para. 3).
Consequently, claim 87 is obvious over the ‘493 application, Schneider et al., and Butterick et al. as applied to claim 3, further in view of Mant et al. and provisionally rejected.
Claim 88 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, 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 because the patentably indistinct claims have not in fact been patented.
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.
The ‘493 application, Schneider, and Butterick 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, Schneider, and Butterick 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, Schneider et al. and Butterick et al. as applied to claim 3 above, further in view of Mauri et al. and provisionally rejected.
Claims 99 and 100 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. published 2/11/2010, as applied to claim1, further in view of Henikoff et al. (Henikoff, et al. Proceedings of the national academy of sciences 89.22: 10915-10919 (1992)) and Salick et al. US20110171304, published 7/14/2011.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 99, claim 1 is obvious as described above. The ‘493 application and Schneider et al. do not explicitly discloses these amino acid sequences.
However, Schneider et al. discloses : VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27) and VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4).
Furthermore, Salick discloses the peptide MARG1:VKVKVRVKVDPPTKVKVRVKV-NH2, which also forms a hydrogel: “MARG1 forms a hydrogel that shear-thins and rapidly re-forms upon cessation of shearing, so that the peptide hydrogel can be applied by injection via a syringe or other similar device to a contaminated surface where it kills MRSA on contact. The hydrogel can also be used as a coating to inhibit MRSA infection.” (Salick et al., para. [0019]).
Henikoff teaches that arginine and lysine are conservative substitutions for each other in Fig. 2, the Blosum62 substitution matrix (Henikoff, et al., page 10917, Fig. 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 make the conservative mutations disclosed by Henikoff to the positively charged residues of the sequences of the ‘493 application and Schneider to arrive at the claimed invention, for example, VKVRVRVRVDPPTRVRVRVKV-NH2 (Applicant SEQ ID NO: 2) because Salick teaches that mixing lysine and arginine residues in a MAX peptide results in a functional product and because Schneider discloses one peptide with all lysine residues and one with all arginine residues.
A person of ordinary skill in the art would be motivated to make these substitutions to modulate the exact activity of the hairpin peptide and would have a reasonable expectation of success because of the peptide of Salick shows that mixing these residues can result in a functional peptide. Furthermore, a finite group of possible conservative substitutions are possible with this peptide.
Consequently, claim 99 is obvious over the ‘493 application in view of Schneider et al. as applied to claim 1, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Regarding claim 100, claim 99 is obvious as described above. The analysis of claim 99 shows how a person of ordinary skill in the art would arrive at Applicant SEQ ID NO: 2.
Consequently, claim 100 is obvious over the ‘493 application in view of Schneider et al. as applied to claim 1, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Claims 101 and 102 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Henikoff et al. (Henikoff, et al. Proceedings of the national academy of sciences 89.22: 10915-10919 (1992)) and Salick et al. US20110171304, published 7/14/2011.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 101, claim 3 is obvious as described above. The ‘493 application, Schneider, and Butterick do not explicitly discloses these amino acid sequences.
However, Schneider et al. discloses : VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27) and VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4).
Furthermore, Salick discloses the peptide MARG1:VKVKVRVKVDPPTKVKVRVKV-NH2, which also forms a hydrogel: “MARG1 forms a hydrogel that shear-thins and rapidly re-forms upon cessation of shearing, so that the peptide hydrogel can be applied by injection via a syringe or other similar device to a contaminated surface where it kills MRSA on contact. The hydrogel can also be used as a coating to inhibit MRSA infection.” (Salick et al., para. [0019]).
Henikoff teaches that arginine and lysine are conservative substitutions for each other in Fig. 2, the Blosum62 substitution matrix (Henikoff, et al., page 10917, Fig. 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 make the conservative mutations disclosed by Henikoff to the positively charged residues of the sequences of the ‘493 application, Schneider, and Butterick to arrive at the claimed invention, for example, VKVRVRVRVDPPTRVRVRVKV-NH2 (Applicant SEQ ID NO: 2) because Salick teaches that mixing lysine and arginine residues in a MAX peptide results in a functional product and because Schneider discloses one peptide with all lysine residues and one with all arginine residues.
A person of ordinary skill in the art would be motivated to make these substitutions to modulate the exact activity of the hairpin peptide and would have a reasonable expectation of success because of the peptide of Salick shows that mixing these residues can result in a functional peptide. Furthermore, a finite group of possible conservative substitutions are possible with this peptide.
Consequently, claim 101 is obvious over the ‘493 application in view of Schneider et al. and Butterick et al. as applied to claim 3, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Regarding claim 102, claim 101 is obvious as described above. The analysis of claim 101 shows how a person of ordinary skill in the art would arrive at Applicant SEQ ID NO: 2.
Consequently, claim 102 is obvious over the ‘493 application in view of Schneider et al. and Butterick et al. as applied to claim 3, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Claim 103 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. published 2/11/2010 as applied to claim 1, further in view of Roux et al. (Roux, et al. Journal of peptide science: an official publication of the European Peptide Society 14.3: 354-359 (2008)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 103, claim 1 is obvious as described above. The ‘493 application and Schneider do not disclose the case wherein the peptide is free of TFA.
However, Roux discloses removal of TFA from synthesized peptides:
“Even though the excess TFA is easy to remove by a classic freeze-drying method, it is more challenging to remove the TF-acetate counter-ion, which strongly interacts with the positive charges of cationic peptides. Hitherto, the most convenient procedure to replace the TF-acetate counter-ion by another counter-ion has been mixing the peptide with an excess of a stronger acid than TFA, followed by a freeze-drying step [12]. A stronger acid than TFA is able to reprotonate the TF-acetate into its free acid form, which is then easily removed by freeze-drying [13]. However, this approach has essentially two drawbacks: (i) the very acidic solution can chemically damage the peptides, and (ii) the very restrictive choice of possible counterions, i.e. the counter-ions that are associated with strong acids (e.g. HCl, H2SO4, HF, HNO3).
The TF-acetate exchange was tested on the dicationic octapeptide lanreotide [14] synthesized in our laboratory by SPPS using an Fmoc strategy. Three different approaches were investigated: (i) RP-HPLC using acetic acid in the mobile phase, (ii) ionexchange
resin loaded with diluted acetic acid, and (iii) deprotonation/reprotonation cycle of lanreotide
positive charges (–NH3 +). The removal of TF-acetate counter-ions and its exchange by acetate were followed by quantitative 19F-NMR and 1H-NMR, respectively. Finally, we compared the ATR FT-IR spectra of lanreotide before and after the counter-ion exchange procedures.” (Roux et al., page 354, 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 remove TFA as disclosed by Roux from the peptide of the ‘493 application and Schneider to arrive at the claimed invention because Roux describes this as a routine procedure: “In all cases, TFA needs to be removed due to its drawbacks related to several physicochemical characterizations and biological studies. The presence of TFA can change the behavior of the peptide [3] or modify its conformation.” (Roux et al., page 354, col. 1, para. 2).
A person of ordinary skill in the art would be motivated to remove the TFA due to the problems disclosed by Roux above and would have a reasonable expectation of success because Roux discloses multiple procedures for this process as described above.
Consequently, claim 103 is obvious over the ‘493 application in view of Schneider et al. as applied to claim 1, further in view of Roux et al. and provisionally rejected.
Claim 104 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 8, 12-13, 18-20, 28, 32, 39, 42, 46, 47, 55, 73, 77, 82, 83, 86, 90, 95, 98, and 104-107 of U.S. Patent Application 18/682,493 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Roux et al. (Roux, et al. Journal of peptide science: an official publication of the European Peptide Society 14.3: 354-359 (2008)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 104, claim 3 is obvious as described above. The ‘493 application, Schneider, and Butterick do not disclose the case wherein the peptide is free of TFA.
However, Roux discloses removal of TFA from synthesized peptides:
“Even though the excess TFA is easy to remove by a classic freeze-drying method, it is more challenging to remove the TF-acetate counter-ion, which strongly interacts with the positive charges of cationic peptides. Hitherto, the most convenient procedure to replace the TF-acetate counter-ion by another counter-ion has been mixing the peptide with an excess of a stronger acid than TFA, followed by a freeze-drying step [12]. A stronger acid than TFA is able to reprotonate the TF-acetate into its free acid form, which is then easily removed by freeze-drying [13]. However, this approach has essentially two drawbacks: (i) the very acidic solution can chemically damage the peptides, and (ii) the very restrictive choice of possible counterions, i.e. the counter-ions that are associated with strong acids (e.g. HCl, H2SO4, HF, HNO3).
The TF-acetate exchange was tested on the dicationic octapeptide lanreotide [14] synthesized in our laboratory by SPPS using an Fmoc strategy. Three different approaches were investigated: (i) RP-HPLC using acetic acid in the mobile phase, (ii) ionexchange
resin loaded with diluted acetic acid, and (iii) deprotonation/reprotonation cycle of lanreotide
positive charges (–NH3 +). The removal of TF-acetate counter-ions and its exchange by acetate were followed by quantitative 19F-NMR and 1H-NMR, respectively. Finally, we compared the ATR FT-IR spectra of lanreotide before and after the counter-ion exchange procedures.” (Roux et al., page 354, 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 remove TFA as disclosed by Roux from the peptide of the ‘493 application, Schneider, and Butterick to arrive at the claimed invention because Roux describes this as a routine procedure: “In all cases, TFA needs to be removed due to its drawbacks related to several physicochemical characterizations and biological studies. The presence of TFA can change the behavior of the peptide [3] or modify its conformation.” (Roux et al., page 354, col. 1, para. 2).
A person of ordinary skill in the art would be motivated to remove the TFA due to the problems disclosed by Roux above and would have a reasonable expectation of success because Roux discloses multiple procedures for this process as described above.
Consequently, claim 104 is obvious over the ‘493 application, Schneider et al., and Butterick et al. as applied to claim 3, further in view of Roux et al. and provisionally rejected.
Claims 1, 2, 17, 23, 31, 58, 92, and 93 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. WO2010/017369, published 2/11/2010.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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 the hydrogel comprising the biological material to a target tissue of the subject..”
The ‘364 application does not specifically disclose a peptide comprising a sequence of Y[XY]N(d)PPT[XY]M wherein N and M are 4.
However, claim 1 of the ‘364 application allows for a peptide that does fit that formula, i.e. 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. Furthermore, Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27).
This peptide reads on the formula Y[XY]4(d)PPT[XY]4 when X=arginine and Y=valine.
This amphiphile is provided in an physiologically compatible solution: “The hydrogels are physiologically compatible, having a pH of 7.4 and containing 150 mM NaCl. Unless referring to a specific experiment, where the pH values and concentrations of ingredients are exact within experimental uncertainty, a pH value of 7.4 should be understood to encompass physiologically acceptable variations around that value and an NaCl concentration of 150 mM NaCl should be understood to encompass physiologically acceptable variations around that value, provided that the desired gel properties are maintained. Thus, the pH value may vary at least within a range of 7.35 to 7.45 and the NaCl concentration may vary at least within in a range of 140 to 160 mM, provided that the desired gel properties are maintained. The pH is maintained with a suitable buffer, typically a nonionic buffer such as bis-tris propane (BTP). As used herein, the term "physiological buffer" will be used to designate an aqueous solution buffered to pH=7.4, containing 50 mM BTP and 150 mM NaCl. The MAX peptide content of hydrogels according to the invention may be at least 0.1 wt%, or at least 0.3 wt%, or at least 0.5 wt%.” (Schneider et al., page 4, para. 3).
The peptide of Schneider may be injected: “The hydrogels of this invention may be of particular value for treating an animal for a medical condition. If the anionic macromolecule is a therapeutic agent, for example an anionic protein, the hydrogel may conveniently be applied by injection through a syringe needle, allowing minimally invasive deposition of the therapeutic agent at a desired localized site. Such treatment may be used for a mammal, a bird, a reptile, or any animal. Treatment of humans may be of particular value. In an animal, final release of all of the anionic macromolecule may depend upon destruction of the hydrogel structure due to enzymatic degradation of the MAX molecules, a process that may take several months to complete.” (Schneider et al., page 9, para 2).
The peptide of Schneider is purified: “Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. Peptide is injected onto the column under isocratic conditions.” (Schneider et al., page 10, para. 1).
The peptide of Schneider may be sterilized: “For the bulk release studies, MAXl and HPL8 peptide stock solutions were first prepared in glass vials by dissolving 1.5 mg or 6 mg of each peptide in 150 μL of sterile, chilled water resulting in two stock solutions for each peptide” (Schneider page 23, para. 2).
Finally Schneider discloses a method of treating a subject with said peptide in claims 16-18:
“16. A method of treating an animal, comprising the step of introducing the hydrogel of any one of claims 1-12 into the body of an animal.
17. The method of claim 16, further comprising a step of shearing the hydrogel prior to introducing it into the body of the animal.
18. The method of claim 17, wherein the shearing results from injection into the animal through a syringe needle.”
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 peptide of Schneider to perform the method of the ‘364 application to arrive at the claimed invention because Schneider discloses a self-assembling peptide that creates a hydrogel that is the appropriate length required by the ‘364 application.
A person of ordinary skill in the art would be motivated to use the peptide of Schneider because it meets all the physical requirements of the ‘364 application.
A person of ordinary skill in the art would have a reasonable expectation of success because the peptide of the ‘364 application and Schneider also forms self-assembling hydrogels.
Consequently, claim 1 is obvious over the ‘364 application in view of Schneider et al. and provisionally rejected.
Regarding claim 2, claim 1 is obvious as described above. The peptide of Schneider has a net charge of +8, which falls between +2 and +11.
Consequently, claim 2 is obvious over the ‘364 application in view of Schneider et al. and provisionally rejected.
Regarding claim 17, claim 1 is obvious as described above. Schneider discloses combining the hydrogel peptide with a buffer in order to induce self-assembly: “ Proteins of varying size and charge (Table 3) were incorporated in the high salt buffered solution and then added to the aqueous HPL8 solution to trigger self-assembly.” (Schneider et al., page 24, para. 3).
Consequently, claim 17 is obvious over the ‘364 application in view of Schneider et al. and provisionally rejected.
Regarding claim 23, claim 17 is obvious as described above. Schneider discloses the following buffer:
“The pH is maintained with a suitable buffer, typically a nonionic buffer such as bis-tris propane (BTP). As used herein, the term "physiological buffer" will be used to designate an aqueous solution buffered to pH=7.4, containing 50 mM BTP and 150 mM NaCl.” (Schneider et al., page 4, para. 3)
Consequently, claim 23 is obvious over the ‘364 application in view of Schneider et al. and provisionally rejected.
Regarding claim 31, claim 1 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 31 is obvious over the ‘364 application in view of Schneider et al. and provisionally rejected.
Regarding claim 58, claim 1 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
MPEP 2131.03 states: “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘obvious’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
Consequently, claim 58 is obvious over the ‘364 application in view of Schneider et al. and provisionally rejected.
Regarding claim 92, claim 31 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 92 is obvious over the ‘364 application in view of Schneider et al. and provisionally rejected.
Regarding claim 93, claim 93 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 93 is obvious over the ‘364 application in view of Schneider et al. and provisionally rejected.
Claims 3, 4, 12, 13, 86, 89, 90, 91, and 94-98 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. WO2010/017369, published 2/11/2010 as applied to claim 1, further in view of Butterick et al. WO2009117497, published 9/24/2009.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 3, claim 1 is obvious as described above. The ‘364 application and Schneider do not explicitly disclose topical application of the hydrogel comprising the claimed peptide amphiphile.
However, Butterick discloses the topical usage of the exact same peptide:
“The hydrogel can also comprise a therapeutic agent and be utilized to deliver the therapeutic agent to a target site, such as to a tissue in vivo or in vitro. For example, the hydrogel may contain agents that stimulate cell proliferation or differentiation, stimulate wound healing, or inhibit bacterial growth. Such agents may include, but are not limited to analgesics, antibiotics, antineoplastics, hemostatic agents, anticoagulants, cytokines, growth factors, anti-inflammatories, small molecules, proteins, peptides, nucleotides, or cells. Spray delivery for β-sheet peptide hydrogels has broad medical application in, for example, tissue and bone engineering, regenerative and cosmetic treatment for hair and skin, cell-based diagnostics, surgery, wound-healing and wound-sealing”. (Butterick et al., page 3, para. 2).
Butterick discloses the same peptide as SEQ ID NO: 46, also called MAX28.
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 hydrogel of the ‘299 and Schneider topically as disclosed by Butterick to arrive at the claimed invention because Butterick is applying the same peptide to skin.
A person of ordinary skill in the art would be motivated to do this to avoid injection and to distribute the hydrogel over a wider area of skin than injection provides. A person of ordinary skill in the art would have a reasonable expectation of success because Butterick is using the same peptide on skin.
Consequently, claim 3 is obvious over the ‘364 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 4, claim 3 is obvious as described above. The peptide disclosed by Schneider (and Butterick) has a charge of +8.
Consequently, claim 4 is obvious over the ‘364 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 12, claim 3 is obvious as described above. Butterick discloses delivery by spray: “A method for delivering β-sheet peptide hydrogels to a target surface by shear- thinning and spraying the peptide hydrogel onto the surface is provided. The peptide hydrogels can be applied over a range of thicknesses and can cover broad surface areas. The β-sheet peptide hydrogels may also include a therapeutic agent.” (Butterick et al., Abstract).
Consequently, claim 12 is obvious over the ‘364 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 13, claim 3 is obvious as described above. Butterick discloses that the target tissue may be soft tissue: “Hydrogels are a class of materials that have significant promise for use in soft tissue and bone engineering and wound sealing, in part because of their well-hydrated, porous structure.” (Butterick et al., page 1, para. 3).
Consequently, claim 13 is obvious over the ‘364 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 86, claim 3 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 86 is obvious over the ‘364 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 89, claim 3 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
MPEP 2131.03 states: “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘obvious’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
Consequently, claim 89 is obvious over the ‘364 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 90, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 90 is obvious over the ‘364 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 90, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 90 is obvious over the ‘364 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 91, claim 89 is obvious as described above. Schneider discloses a wt% range of 0.5% to 2.0%: “Comparing the diffusion coefficients of each of the macromolecules in 0.5 wt% and 2.0 wt% (the two weight percent extremes), macromolecular mobility was restricted by a factor of 2 in both MAXl and HPL8 gels.” (Schneider et al., page 17, para. 2).
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) .”
Consequently, claim 91 is obvious over the ‘364 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 94, claim 3 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 94 is obvious over the ‘364 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 95, claim 94 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 95 is obvious over the ‘364 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 96, claim 95 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 96 is obvious over the ‘364 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 97, claim 96 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27). The charged amino acids are all arginine in this case.
Consequently, claim 97 is obvious over the ‘364 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Regarding claim 98, claim 86 is obvious as described above. Schneider discloses an amphiphilic peptide MAX28: VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4). The charged amino acids are all lysine in this case.
Consequently, claim 98 is obvious over the ‘364 application and Schneider et al. as applied to claim 1, further in view of Butterick et al. and provisionally rejected.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. WO2010/017369, published 2/11/2010 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 because the patentably indistinct claims have not in fact been patented.
Regarding claim 5, claim 1 is obvious as described above.
The ‘364 application and Schneider 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 the ‘364 application and Schneider.
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 and Schneider et al. as applied in claim 1, further in view of Jin et al. and provisionally rejected.
Claim 9 on the ground of nonstatutory double patenting over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. WO2010/017369, published 2/11/2010 in view of Butterick et al. WO2009117497, published 9/24/2009 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 ‘364 application, Schneider, and Butterick 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 the ‘364 application, Schneider, and Butterick 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, Schneider et al., and Butterick et al. 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 over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. WO2010/017369, published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009 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 ‘364 application, Schneider, and Butterick 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 Schneider and Butterick 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, Schneider et al., and Butterick et al. as applied to claim 3 above, further in view of Nunez et al. and provisionally rejected.
Claims 18 and 20 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. WO2010/017369, published 2/11/2010 as applied to claim 1, further in view of Mehta et al. ((US 20170072008, published 3/16/2017)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 18, claim 17 is obvious as described above. The ‘364 application and Schneider do not specifically disclose combining the preparation and buffer less than 10 minutes before administration.
However, 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 of the method of the ‘364 application and Schneider using the timing 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 Schneider et al. as applied to claim 1, further in view of Mehta et 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 and chloride ions are not present.
The ‘364 application Schneider do not specifically disclose this buffer condition.
However, 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 disclosed by Mehta with the method of the ‘364 application and Schneider. Such a buffer optimization is also a matter of routine optimization.
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 and both Schneider and Mehta disclose self-assembling hydrogels. 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 and both Schneider and Mehta disclose self-assembling hydrogels.
Consequently, claim 20 is obvious over the ‘364 application in view of Schneider et al. as applied to claim 1, further in view of Mehta et al. and provisionally rejected.
Claim 40 is provisionally rejected on the ground of nonstatutory double over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. as applied to claim 1, further in view of Mehta et al. and provisionally rejected., further in view of Mant et al. (Mant, et al. Peptide characterization and application protocols. Totowa, NJ: Humana Press, 3-55 (2007)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 40, claim 1 is obvious as described above. The ‘364 application and Schneider do not disclose a specific purity. Schneider does disclose purification by RP-HPLC: “ Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. “ (Schneider et al., page 10, para. 1).
Mant discloses that RP-HPLC has purity yields of 95%: “As shown in Fig. 18, the purified product had a purity of <95% and a yield of <90% recovery.” (Mant et al., page 45, para. 3).
Consequently, claim 40 is obvious over the ‘364 application in view of Schneider et al. as applied to claim 1, further in view of Mant et al. and provisionally rejected.
Claim 44 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. 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 because the patentably indistinct claims have not in fact been patented.
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 and Schneider 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 ‘364 application and Schneider 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 Schneider et al. as applied to claim 1 above, further in view of Mauri et al. and provisionally rejected.
Claim 85 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Mehta et al. ((US 20170072008, published 3/16/2017)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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 and chloride ions are not present.
The ‘364 application, Schneider, and Butterick do not specifically disclose this buffer condition.
However, 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 disclosed by Mehta with the method of the ‘364 application, Schneider, and Butterick. Such a buffer optimization is also a matter of routine optimization.
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 and both Schneider and Mehta disclose self-assembling hydrogels. 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 and both Schneider and Mehta disclose self-assembling hydrogels.
Consequently, claim 85 is obvious over the ‘364 application, Schneider et al., and Butterick et al. as applied to claim 3, in view of Mehta et al. and provisionally rejected.
Claim 87 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Mant et al. (Mant, et al. Peptide characterization and application protocols. Totowa, NJ: Humana Press, 3-55 (2007)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 87, claim 3 is obvious as described above. The ‘364 application, Schneider, and Butterick do not disclose a specific purity. Schneider does disclose purification by RP-HPLC: “ Purification of the crude peptides was performed by RP-HPLC using a preparative Vydac Cl 8 peptide column with a flow rate of 8 mL/min. “ (Schneider et al., page 10, para. 1).
Mant discloses that RP-HPLC has purity yields of 95%: “As shown in Fig. 18, the purified product had a purity of <95% and a yield of <90% recovery.” (Mant et al., page 45, para. 3).
Consequently, claim 87 is obvious over the ‘364 application, Schneider et al., and Butterick et al. as applied to claim 3, further in view of Mant et al. and provisionally rejected.
Claim 88 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, 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 because the patentably indistinct claims have not in fact been patented.
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.
The ‘364 application, Schneider, and Butterick 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 ‘364 application, Schneider, and Butterick 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, Schneider et al. and Butterick et al. as applied to claim 3 above, further in view of Mauri et al. and provisionally rejected.
Claims 99 and 100 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. published 2/11/2010, as applied to claim1, further in view of Henikoff et al. (Henikoff, et al. Proceedings of the national academy of sciences 89.22: 10915-10919 (1992)) and Salick et al. US20110171304, published 7/14/2011.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 99, claim 1 is obvious as described above. The ‘364 application and Schneider et al. do not explicitly discloses these amino acid sequences.
However, Schneider et al. discloses : VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27) and VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4).
Furthermore, Salick discloses the peptide MARG1:VKVKVRVKVDPPTKVKVRVKV-NH2, which also forms a hydrogel: “MARG1 forms a hydrogel that shear-thins and rapidly re-forms upon cessation of shearing, so that the peptide hydrogel can be applied by injection via a syringe or other similar device to a contaminated surface where it kills MRSA on contact. The hydrogel can also be used as a coating to inhibit MRSA infection.” (Salick et al., para. [0019]).
Henikoff teaches that arginine and lysine are conservative substitutions for each other in Fig. 2, the Blosum62 substitution matrix (Henikoff, et al., page 10917, Fig. 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 make the conservative mutations disclosed by Henikoff to the positively charged residues of the sequences of the ‘364 application and Schneider to arrive at the claimed invention, for example, VKVRVRVRVDPPTRVRVRVKV-NH2 (Applicant SEQ ID NO: 2) because Salick teaches that mixing lysine and arginine residues in a MAX peptide results in a functional product and because Schneider discloses one peptide with all lysine residues and one with all arginine residues.
A person of ordinary skill in the art would be motivated to make these substitutions to modulate the exact activity of the hairpin peptide and would have a reasonable expectation of success because of the peptide of Salick shows that mixing these residues can result in a functional peptide. Furthermore, a finite group of possible conservative substitutions are possible with this peptide.
Consequently, claim 99 is obvious over the ‘364 application in view of Schneider et al. as applied to claim 1, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Regarding claim 100, claim 99 is obvious as described above. The analysis of claim 99 shows how a person of ordinary skill in the art would arrive at Applicant SEQ ID NO: 2.
Consequently, claim 100 is obvious over the ‘364 application in view of Schneider et al. as applied to claim 1, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Claims 101 and 102 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Henikoff et al. (Henikoff, et al. Proceedings of the national academy of sciences 89.22: 10915-10919 (1992)) and Salick et al. US20110171304, published 7/14/2011.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 101, claim 3 is obvious as described above. The ‘364 application, Schneider, and Butterick do not explicitly discloses these amino acid sequences.
However, Schneider et al. discloses : VRVRVRVRVDPPTRVRVRVRV-NH2 (SEQ ID NO:27) and VKVKVKVKVDPPTKVEVKVKV-NH2 (SEQ ID NO:4).
Furthermore, Salick discloses the peptide MARG1:VKVKVRVKVDPPTKVKVRVKV-NH2, which also forms a hydrogel: “MARG1 forms a hydrogel that shear-thins and rapidly re-forms upon cessation of shearing, so that the peptide hydrogel can be applied by injection via a syringe or other similar device to a contaminated surface where it kills MRSA on contact. The hydrogel can also be used as a coating to inhibit MRSA infection.” (Salick et al., para. [0019]).
Henikoff teaches that arginine and lysine are conservative substitutions for each other in Fig. 2, the Blosum62 substitution matrix (Henikoff, et al., page 10917, Fig. 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 make the conservative mutations disclosed by Henikoff to the positively charged residues of the sequences of the ‘364 application, Schneider, and Butterick to arrive at the claimed invention, for example, VKVRVRVRVDPPTRVRVRVKV-NH2 (Applicant SEQ ID NO: 2) because Salick teaches that mixing lysine and arginine residues in a MAX peptide results in a functional product and because Schneider discloses one peptide with all lysine residues and one with all arginine residues.
A person of ordinary skill in the art would be motivated to make these substitutions to modulate the exact activity of the hairpin peptide and would have a reasonable expectation of success because of the peptide of Salick shows that mixing these residues can result in a functional peptide. Furthermore, a finite group of possible conservative substitutions are possible with this peptide.
Consequently, claim 101 is obvious over the ‘364 application in view of Schneider et al. and Butterick et al. as applied to claim 3, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Regarding claim 102, claim 101 is obvious as described above. The analysis of claim 101 shows how a person of ordinary skill in the art would arrive at Applicant SEQ ID NO: 2.
Consequently, claim 102 is obvious over the ‘364 application in view of Schneider et al. and Butterick et al. as applied to claim 3, further in view of Henikoff et al. Salick et al. and provisionally rejected.
Claim 103 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. published 2/11/2010 as applied to claim 1, further in view of Roux et al. (Roux, et al. Journal of peptide science: an official publication of the European Peptide Society 14.3: 354-359 (2008)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 103, claim 1 is obvious as described above. The ‘364 application and Schneider do not disclose the case wherein the peptide is free of TFA.
However, Roux discloses removal of TFA from synthesized peptides:
“Even though the excess TFA is easy to remove by a classic freeze-drying method, it is more challenging to remove the TF-acetate counter-ion, which strongly interacts with the positive charges of cationic peptides. Hitherto, the most convenient procedure to replace the TF-acetate counter-ion by another counter-ion has been mixing the peptide with an excess of a stronger acid than TFA, followed by a freeze-drying step [12]. A stronger acid than TFA is able to reprotonate the TF-acetate into its free acid form, which is then easily removed by freeze-drying [13]. However, this approach has essentially two drawbacks: (i) the very acidic solution can chemically damage the peptides, and (ii) the very restrictive choice of possible counterions, i.e. the counter-ions that are associated with strong acids (e.g. HCl, H2SO4, HF, HNO3).
The TF-acetate exchange was tested on the dicationic octapeptide lanreotide [14] synthesized in our laboratory by SPPS using an Fmoc strategy. Three different approaches were investigated: (i) RP-HPLC using acetic acid in the mobile phase, (ii) ionexchange
resin loaded with diluted acetic acid, and (iii) deprotonation/reprotonation cycle of lanreotide
positive charges (–NH3 +). The removal of TF-acetate counter-ions and its exchange by acetate were followed by quantitative 19F-NMR and 1H-NMR, respectively. Finally, we compared the ATR FT-IR spectra of lanreotide before and after the counter-ion exchange procedures.” (Roux et al., page 354, 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 remove TFA as disclosed by Roux from the peptide of the ‘364 application and Schneider to arrive at the claimed invention because Roux describes this as a routine procedure: “In all cases, TFA needs to be removed due to its drawbacks related to several physicochemical characterizations and biological studies. The presence of TFA can change the behavior of the peptide [3] or modify its conformation.” (Roux et al., page 354, col. 1, para. 2).
A person of ordinary skill in the art would be motivated to remove the TFA due to the problems disclosed by Roux above and would have a reasonable expectation of success because Roux discloses multiple procedures for this process as described above.
Consequently, claim 103 is obvious over the ‘364 application in view of Schneider et al. as applied to claim 1, further in view of Roux et al. and provisionally rejected.
Claim 104 is provisionally rejected on the ground of nonstatutory double patenting over claims 1-5, 12-14, 17, 20-22, 24, 26, 29, 32-34, 39, 45, 49, 63, 67, 70, 78, 81, 86, 89-92 of U.S. Patent Application 18/040,364 in view of Schneider et al. published 2/11/2010, and Butterick et al. WO2009117497, published 9/24/2009, as applied to claim 3, further in view of Roux et al. (Roux, et al. Journal of peptide science: an official publication of the European Peptide Society 14.3: 354-359 (2008)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 104, claim 3 is obvious as described above. The ‘364 application, Schneider, and Butterick do not disclose the case wherein the peptide is free of TFA.
However, Roux discloses removal of TFA from synthesized peptides:
“Even though the excess TFA is easy to remove by a classic freeze-drying method, it is more challenging to remove the TF-acetate counter-ion, which strongly interacts with the positive charges of cationic peptides. Hitherto, the most convenient procedure to replace the TF-acetate counter-ion by another counter-ion has been mixing the peptide with an excess of a stronger acid than TFA, followed by a freeze-drying step [12]. A stronger acid than TFA is able to reprotonate the TF-acetate into its free acid form, which is then easily removed by freeze-drying [13]. However, this approach has essentially two drawbacks: (i) the very acidic solution can chemically damage the peptides, and (ii) the very restrictive choice of possible counterions, i.e. the counter-ions that are associated with strong acids (e.g. HCl, H2SO4, HF, HNO3).
The TF-acetate exchange was tested on the dicationic octapeptide lanreotide [14] synthesized in our laboratory by SPPS using an Fmoc strategy. Three different approaches were investigated: (i) RP-HPLC using acetic acid in the mobile phase, (ii) ionexchange
resin loaded with diluted acetic acid, and (iii) deprotonation/reprotonation cycle of lanreotide
positive charges (–NH3 +). The removal of TF-acetate counter-ions and its exchange by acetate were followed by quantitative 19F-NMR and 1H-NMR, respectively. Finally, we compared the ATR FT-IR spectra of lanreotide before and after the counter-ion exchange procedures.” (Roux et al., page 354, 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 remove TFA as disclosed by Roux from the peptide of the ‘364 application, Schneider, and Butterick to arrive at the claimed invention because Roux describes this as a routine procedure: “In all cases, TFA needs to be removed due to its drawbacks related to several physicochemical characterizations and biological studies. The presence of TFA can change the behavior of the peptide [3] or modify its conformation.” (Roux et al., page 354, col. 1, para. 2).
A person of ordinary skill in the art would be motivated to remove the TFA due to the problems disclosed by Roux above and would have a reasonable expectation of success because Roux discloses multiple procedures for this process as described above.
Consequently, claim 104 is obvious over the ‘364 application, Schneider et al., and Butterick et al. as applied to claim 3, further in view of Roux et al. and provisionally rejected.
Conclusion
No claim is allowed.
Claims 1-5, 9, 11-13, 17-18, 20, 23, 31, 40, 44, 58, 76, and 78-104 are rejected.
The submitted sequence listing is defective.
Applicant's amendment necessitated the new grounds of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/JEANETTE M LIEB/ Primary Examiner, Art Unit 1654
Prosecution Insights