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 .
Acknowledgments and Claim Status
The Examiner acknowledges receipt of the amendment filed 10/30/2025 wherein claims 1-4, 12, 14, 19, 22, and 26-28 were canceled and claims 25 and 29 were amended. In addition, the Examiner acknowledges amendments filed on 12/9/2022 and 6/6/2022 wherein the claims, abstract, and/or specification were amended.
Note(s): Claims 5-11, 13, 15-18, 20, 21, 23-25, and 29 are pending.
Priority and Priority Document
This application is a 371 of PCT/SG2020/050723 filed 12/7/2020 which claims benefit to Singapore SG10201911767R filed 12/6/2019.
Note(s): The earliest effective filing date is 12/6/2019 as the pending invention is fully disclosed in the priority document.
The Examiner acknowledges receipt of certified copies of papers required by 37 CFR 1.55 filed 6/6/2022.
Claim Interpretation
Independent claim 5 is directed to a drug-loaded protease-responsive hydrogel comprising; (a) a drug covalently conjugated to a protease-cleavable peptide anchor having a functional moiety; (b) a polymer building block comprising a multi-arm-PEG polymer having at least one functional moiety; and (c) a bis-functional crosslinker comprising a peptide substrate flanked by spacer sequences containing functional moieties wherein the functional moiety of the peptide anchor covalently links the drug to an arm of the multi-arm PEG polymer, and wherein a functional moiety of said polymer building block covalently links to said moiety of said bis-functional crosslinker to form a gel.
Claim 18 is directed to a dressing comprising the drug loaded protease responsive hydrogel of claim 5.
Claim 20 is directed to a method of treatment as set forth therein.
Claim 21 is directed to a kit comprising the hydrogel of claim 5.
Applicant’s Election
Applicant's election without traverse of Group I (pending claims 5-11, 13, 15-18, and 21) filed 10/30/2025 is acknowledged. Hence, the restriction requirement is still deemed proper and is therefore made FINAL.
Applicant elected the following species on 10/30/2025 for initial examination: drug (NSAID), protease cleavable substrate (GPRSLSG, SEQ ID NO: 10), protease cleavable peptide anchor (GPRSLSGRRCG, SEQ ID NO: 20), bifunctional crosslinker comprising a peptide substrate flanked by spacer sequences containing functional moieties (GCRR-GPRSLSG-RRCG, SEQ ID NO: 21), polymer comprising at least one functional moiety (4-arm-PEG-maleimide), and protease of interest (MMP9). Claims 5-11, 13, 15-18, and 21 read on Applicant’s elected species. Initially, Applicant’s elected species was searched. However, since no prior art was found which could be used to reject the elected species, the search was extended to the prior art cited below. The search was not further extended because prior art was found which could be used to reject the claims.
Withdrawn Claims
Claims 20, 23-25, and 29 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Information Disclosure Statement
The information disclosure statement filed 6/6/2022 and 4/28/2025 were considered.
112 Second Paragraph Rejections
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 5-11, 13, 15-18, and 21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 5-11, 13, 15-18, and 21: Independent claim 5 is ambiguous for the following reasons: (1) according to MPEP 2173.05(h), while a Markush grouping may include a large number of alternatives, and not necessarily be indefinite under, in certain circumstances, a Markush group may be so expansive that a skilled artisan cannot determine the metes and bounds of the claimed invention. In the pending claims, the invention is directed to drug loaded protease responsive hydrogels wherein the first component is a drug, any drug, that is conjugated to any protease cleavable peptide anchor having any functional moiety. The second component is any polymer that comprises a multi-arm-PEG polymer having at least any one functional moiety. The third component is any bifunctional crosslinker that comprises any peptide substrate that is flanked by any spacer sequences.
It is unclear what protease(s), cleavable peptide(s), functional moieties, and spacer sequences combination Applicant is referring to that result in drug loaded protease hydrogels that responsive hydrogel. Thus, claim 5 encompasses multiple Markush groups and subgroups thereof. As a result, pending claim 5 encompasses a massive number of distinct alternative members such that one skilled in the art cannot determine the metes and bounds of the claim. Hence, due to an inability to envision all of the hydrogels defined by the Markush groups, the claim is deemed to be vague and indefinite.
(2) Claim 5 is ambiguous because it is directed to protease responsive hydrogels, but do not set forth the responsive property of the hydrogels (e.g., temperature).
Since claims 6-11, 13, 15-18, and 21 depend upon independent claim 5 for clarity, those claims are also vague and indefinite.
Claim 6: The claim is ambiguous because it is unclear what crosslinkers are being referenced that are not cleavable to a protease and compatible with a responsive hydrogel comprising a drug, peptide, multiple PEG polymers, and spacer sequences.
Claim 11: The claim is ambiguous because it contains improper Markush terminology. Specifically, according to MPEP 803.02, proper Markush terminology requires ‘closed’ language. The use of the term ‘comprising’ in a Markush grouping is ‘open’ language and allows for unnamed components to be present in the Markush grouping.
Claim 13: The phrase ‘cysteine and/or lysine residue and/or azide- or alkyne-containing unnatural amino acid and/or wherein the said flanking spacer sequences comprises a sequence of 1-6 amino acids’ is confusing. Specifically, it is unclear how Applicant intended the phrases to be interpreted. For example, ‘lysine residue and/or azide- or alkyne- containing unnatural amino acid’. Should this be interpreted ‘lysine residue’ separate from azide- or alkyne-containing unnatural amino acid OR if the interpretation is ‘lysine residue’ in combination with the azide- or alkyne-containing, cysteine, and the spacer sequence of 1-6 amino acids. It is unclear whether the phrase is intended to be interpreted as ‘cysteine, lysine, azide- or alkyne-containing unnatural amino acid, and/or wherein the said flanking spacer sequences comprises a sequence of 1-6 amino acids’ or not. Thus, clarification is respectfully requested to enable one to readily determine the metes and bounds of the claim.
Claim 13: The claim recites the limitation "the protease cleavable substrate" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 13: The phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 13: The claim is ambiguous because it contains improper Markush terminology. Specifically, according to MPEP 803.02, proper Markush terminology requires ‘closed’ language. The use of the term ‘comprising’ in a Markush grouping is ‘open’ language and allows for unnamed components to be present in the Markush grouping.
Claim 13: The claim is ambiguous because of the ‘etc.’ appearing in lines 4 and 5. Applicant is respectfully reminded that according to MPEP 803.02, Markush language claims should contain ‘closed’ language. The use of ‘etc.’ is ‘opened‘ language as it allows for unnamed substances to be present in the Markush listing.
Claims 15 and 16: The claim recites the limitation "the protease cleavable substrate" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 16: The claim is ambiguous because it contains improper Markush terminology. Specifically, according to MPEP 803.02, proper Markush terminology requires ‘closed’ language. The use of the term ‘comprising’ in a Markush grouping is ‘open’ language and allows for unnamed components to be present in the Markush grouping.
Claim 17: The claim is ambiguous because the phrase ‘formulated for infection or topical administration’ is an active step. Specifically, according to MPEP 2173.05(p), a single claim directed to both a product and method steps for using such product is indefinite. In particular, the claim is indefinite because while the claim initially sets forth a product (hydrogel), the claim limitation is not directed to the product, but rather to actions involving the product which creates confusion as to when direct infringement occurs. It is unclear whether infringement occurs when one has a product (hydrogel) or when the hydrogel is formulated such that it becomes an injection or topical formulation.
102/103 Rejection
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 5, 6, 9, 13, and 15 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Kim et al (Soft Matter, 2016, Vol. 12, No. 7, pages 2076-2085).
Independent claim 5 is directed to a drug-loaded protease-responsive hydrogel comprising; (a) a drug covalently conjugated to a protease-cleavable peptide anchor having a functional moiety; (b) a polymer building block comprising a multi-arm-PEG polymer having at least one functional moiety; and (c) a bis-functional crosslinker comprising a peptide substrate flanked by spacer sequences containing functional moieties wherein the functional moiety of the peptide anchor covalently links the drug to an arm of the multi-arm PEG polymer, and wherein a functional moiety of said polymer building block covalently links to said moiety of said bis-functional crosslinker to form a gel.
Claim 6 is directed to a hydrogel having one or more crosslinkers and a peptide anchor.
Claim 9 is directed to a hydrogel wherein the multi-arm PEG polymer has 3-8 PEGs.
Claim 13 is directed to a hydrogel having cysteine, lysine, azide- or alkyne-containing unnatural amino acid, and/or a sequence spacer having 1-6 amino acid residues.
Claim 15 is directed to a hydrogel that is sensitive to a protease.
Kim et al disclose multi-arm poly(ethylene glycol) hydrogels. The hydrogen was crosslinked with a tri-functional protease sensitive crosslinking peptide (GCYKNRGCYKNRCG). The hydrogel incorporates RGD, an integrin binding sequence. Reactive functional groups (vinyl sulfones) were present (see entire document, especially, abstract). The PEG hydrogels were prepared using Michael-type addition chemistry wherein cysteine-containing peptides react with the unsaturated groups of the multi-arm PEG. Modification of PEG with RGD peptides promotes cell adhesion and crosslinking with bi- or tri-functional protease sensitive peptides. This allows for migration and proliferation of the encapsulated cells. For tissue engineering applications, cysteine containing peptides react with the unsaturated groups of the end functionalized multi-arm PEG to form PEG hydrogels. Still, a higher concentration of peptides results in a greater degree of swelling which contributes to dilution of the incorporated bioactive molecule concentrations in the hydrogel (pages 2076-2077, bridging paragraph; page 2077, Figure 1).
The crosslinking kinetics and macroscopic properties of the Michael type addition PEG hydrogels is depend on pH, PEG solid concentration, and the presence of charged amino acid residues (page 2077, left paragraph, first complete paragraph). In the Experimental section, the hydrogel materials is further discussed. There were formed via Michael type addition with plasmin sensitive trifunctional crosslinking peptides GCYK, NRGCYK, and NRCG (page 2077, right column, ‘Hydrogel materials’).
For the reasons set forth above, the limitations of claims 5, 6, 9, 13, and 15 are met. Alternatively, if Applicant does not consider RGD to be the drug. It would have been obvious to one of ordinary skill in the art prior to the pending invention to incorporate drugs into the hydrogel because Kim et al disclose modification of PEG with monofunctional RGD peptides promotes cell adhesion and crosslinking with bi- or trifunctional protease sensitive peptides to allow migration and proliferation of the encapsulated cells (page 2076, right column, first complete paragraph). In addition, Kim et al disclose that their finding support their hypothesis that PEG macromers with increased functionality allow a greater degree of bioactive modification without compromising the mechanical properties of the hydrogel and result in and improved hydrogel design for various biomedical applications (page 2077, left and right columns, bridging paragraph; pages 2083-2084, bridging paragraph). Thus, incorporating other components into the hydrogel would be obvious. Furthermore, a drug as defined using any standard dictionary (e.g., Merriam-Webster’s Dictionary) is any substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of a disease. Thus, the limitation of the claims are met.
103 Rejection
Claims 18 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al (Soft Matter, 2016, Vol. 12, No. 7, pages 2076-2085) in view of Blaskovich et al (US 2011/0091549).
Independent claim 5 is encompassed by Kim et al as set forth supra in the 102/103 section.
Claim 18 is directed to a dressing comprising the hydrogel of claim 5.
Claim 21 is directed to a kit comprising the hydrogel of claim 5.
Blaskovich et al is made of record to illustrate that it is well known in the art to generate hydrogel kits that are used for pharmaceutical purposes (see entire document, especially, abstract; page 2, paragraphs [0023] – [0025]; page 3, paragraphs [0027] - [0228]; page 9, paragraph [0076]). Hence, the limitations of claims 18 and 21 are met.
Since both Blaskovich et al and Kim et al are directed to responsive hydrogels that may contain multi-PEG arms, the references may be considered to be within the same field of endeavor. Thus, the reference teachings are combinable.
Comments/Notes
Due to the complexity and ambiguity of the claims, one could not readily ascertain the metes and bounds of the pending claims as discussed above. In addition, a full scope of the pending claims was not performed.
Conclusion
Claims 5-11, 13, 15-18, and 21 and claims 20, 23-25, and 29 are withdrawn.
Future Correspondences
Any inquiry concerning this communication or earlier communications from the examiner should be directed to D L Jones whose telephone number is (571)272-0617. The examiner can normally be reached M-F.
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/D. L. Jones/
Primary Patent Examiner
Art Unit 1618
February 18, 2026