DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. The applicant's submission filed on 24 June 2026 has been entered.
Status of the Claims
Amendments to the Claims and Arguments/Remarks filed 11 June 2026, in response to the Office Correspondence dated 25 March 2026, are acknowledged.
The listing of Claims filed 11 June 2026, have been examined. Claims 1, 2, 7, 9, 10, 15, 17, and 21-23 are pending. Claims 1, 9, and 17 are amended; claims 3-6, 8, 11-14, 16, and 18-20 are canceled; and no new claims have been added.
Response to Amendment
The applicant amended claims 1, 9, and 17 to correct “polysaccharaides” to “polysaccharides” and to require that the claimed cross-linked hydrogel is cross-linked by genipin. Applicant identifies ¶[0032] and the specification generally as support. The amendments are entered. The originally filed disclosure provides adequate support for the amended subject matter.
The prior objection to claims 1, 9, and 17 based upon the misspelling “polysaccharaides” is withdrawn because the applicant has corrected the term to “polysaccharides.” The applicant’s argument on this point is persuasive.
The previous § 103 rejections are withdrawn/superseded insofar as they fail to account for the newly added requirement that the hydrogel be cross-linked by genipin. Withdrawal of those grounds, however, does not establish patentability over the prior art developed upon further examination. New grounds of rejection under § 103 are set forth below for the presently pending claims using prior art that expressly supplies the genipin cross-linked hydrogel limitation.
The former rejection of claims 9 relied in part upon Xie et al., identified in the prior action as published 01 October 2024. The instant application claims an effective filing date of 03 November 2021. Therefore, Xie should not be relied upon as prior art establishing what was known or suggested before the effective filing date. The new grounds below do not rely upon Xie. The former rejection also should not be carried forward insofar as it referred to a “nitrate” salt when the claims and Weller concern nitrite or characterized claim 17 as anticipated while rejecting it under § 103. The grounds below are stated exclusively under the proper obviousness framework.
Claim Objections
Claims 2, 10 and 17 are objected to because of the following informalities:
The claims contain apparent nomenclature or typographical errors such as “3-morpholinosdnonimine” appears to be a misspelling of 3-morpholinosydnonimine; “S-nitrosocapttopril” appears to be a misspelling of S-nitrosocaptopril; “sodium nitroprusside dehydrate” appears to require correction of the hydrate nomenclature; “N,N-dicarboxymethyl-N,N-dinotroso-p-phenylenediamine disodium salt” appears to contain the misspelling “dinotroso”; and “N-cyclopropyl-Nprime-hydroxyguanidine” should be stated using conventional N′ nomenclature.
The applicant is required either to correct these expressions to the intended accepted chemical nomenclature or to clarify on the record that the wording is deliberate and identify unambiguously the compound intended and make corresponding corrections to the Specification. Any amendment must comply with 35 U.S.C. § 132(a) and 35 U.S.C. § 112(a).
Claim 2 also redundantly recites S-nitrosoglutathione twice, first as “S-Nitrosoglutathione (GSNO)” and subsequently as “S-nitrosoglutathione.” Although the redundancy does not by itself presently render the scope indefinite, deletion of the duplicative entry is required as a matter of claim clarity.
The foregoing defects are treated as matters of form because the intended compounds appear sufficiently ascertainable at present. If the applicant maintains nomenclature that leaves a person of ordinary skill unable to determine which chemical species is encompassed, an appropriate rejection under 35 U.S.C. § 112(b) may be warranted rather than an objection for informality.
Claim Rejections - 35 USC § 112(b)
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 Applicant regards as his invention.
Claim 23 is 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, regards as the invention.
Claim 1 already requires “administering a nitric oxide donor (NOD) to the site.” Claim 23, which depends from claim 1, recites that “the method further comprises administering a nitric oxide donor (NOD) to the site in conjunction with a surgical sealant.”
The phrase “further comprises administering a nitric oxide donor (NOD)” renders the metes and bounds of claim 23 unclear because it is reasonably susceptible to at least two materially different interpretations, wherein claim 23 requires a second administration of a NOD, in addition to the NOD administration already required by claim 1, with that second administration being performed in conjunction with a surgical sealant. Alternatively, claim 23 merely further characterizes the single administration recited in claim 1 by requiring that the already-recited administration be performed in conjunction with a surgical sealant. The two constructions require different acts and therefore establish different infringement boundaries.
A claim is properly rejected when its language is ambiguous, vague, or otherwise unclear such that the scope cannot be determined with reasonable precision (see In re Packard, 751 F.3d 1307, 1311-12, 110 USPQ2d 1785, 1787-88 (Fed. Cir. 2014); MPEP § 2173, § 2173.02). The specification indicates that the intended embodiment appears to be administration of the NOD in conjunction with a surgical sealant, rather than a mandatory second administration step. Specification ¶[0042] describes administering NOD “in conjunction with a surgical sealant.”
Accordingly, the rejection could possibly be overcome, for example, by amending claim 23 to recite, “The method of claim 1, wherein the administering of the nitric oxide donor to the site is performed in conjunction with a surgical sealant.” Other language that unambiguously establishes whether one or two administration steps are required would likewise be considered.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. § 102 and 103 (or as subject to pre-AIA 35 U.S.C. § 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. § 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. § 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 2, and 7 are rejected under 35 U.S.C. § 103 as being unpatentable over Krausz and Friedman (Krausz A and Friedman AJ. Nitric oxide as a surgical adjuvant. Future Sci OA, 1(1):FSO56; publication date 01 August 2015; hereinafter “Krausz”), in view of Jezek and Watson, US20090081279A1; published 26 March 2009, hereinafter “Jezek”), and in further view of Heimbuck et al. (Development of Responsive Chitosan–Genipin Hydrogels for the Treatment of Wounds, ACS Appl Bio Mater. 2019 Jul 15;2(7):2879-2888. Epub 2019 Jun 25; hereinafter “Heimbuck”), and Muzzarelli (Genipin-crosslinked chitosan hydrogels as biomedical and pharmaceutical aids, Carbohydr. Polym. 77:1-9, published 22 May 2009).
Krausz teaches the perioperative use of nitric oxide and expressly identifies angiogenesis, vasodilation, and wound healing among the physiological functions of NO relevant to surgical treatment. Krausz explains that impaired wound healing contributes significantly to morbidity in postsurgical patients and states that NO’s established vasodilatory and angiogenic properties are instrumental to proper wound healing (p. 1, Nitric oxide & wound healing section, ¶1; Abstract). Krausz further characterizes NO as significant in accelerating wound healing and discusses its perioperative translational applications (Abstract).
Krausz further teaches, in the vascular-surgery context, localized delivery of NO donors using polymeric materials and hydrogels, including incorporation of NO-donating drugs such as diazeniumdiolates and S-nitrosothiols into hydrogels and polymers to generate NO locally over extended periods (p.6, Nitric oxide & vascular surgery section;). Thus, Krausz teaches the desirability of administering NO locally from a hydrogel/polymeric matrix in a surgical/vascular environment in which the angiogenic and vascular effects of NO are beneficial.
Krausz does not expressly disclose that the NO donor comprises a nitrite salt, nor does Krausz expressly disclose a chitosan hydrogel cross-linked by genipin.
Jezek teaches localized generation and delivery of nitric oxide from a nitrite-containing hydrogel. More particularly, Jezek teaches a polymeric wound dressing wherein the polymeric matrix may comprise a hydrated hydrogel (claims 5–7), wherein the NO-generating reagents comprise a nitrite and a thiol (claim 11), the nitrite preferably comprises potassium nitrite (claim 12), and a first dressing component containing the nitrite may comprise a hydrated hydrogel (claims 15-17). Jezek further claims a method of therapeutically generating NO by reacting nitrite and thiol to form S-nitrosothiols that spontaneously decompose to deliver NO (claim 33).
Jezek prepares cross-linked poly-AMPS hydrogels using PEG-400 diacrylate as cross-linker and reports a “nitrite gel” comprising 0.25 wt.% potassium nitrite, approximately 30 mM (Poly-AMPS Hydrogel Preparation, Table 1). In Example 2, Jezek states that the primary dressing layer consisted of poly-AMPS hydrogel containing potassium nitrite (30 mM) and that, upon combination with a glutathione-containing layer, GSNO was generated and remained measurable for 48 hours. Example 3 likewise demonstrates gradual release of the generated GSNO into an adjacent hydrogel.
Jezek additionally demonstrates the biological activity of the nitrite-based NO-generating system. In Example 6, potassium nitrite was incorporated into a hydrogel-based carrier at 60 mM after combination with glutathione, wherein laser-Doppler measurements showed increased dermal blood flow, attributed to the increase to NO generated from the nitrite/glutathione reaction. Jezek therefore supplies the limitation missing from Krausz that the localized hydrogel NO-generating system comprises a nitrite salt.
However, Jezek does not disclose genipin as the cross-linking agent. Heimbuck independently supplies the instant claim 1 polymer species and the genipin-cross-linking limitation combination. Heimbuck states that hydrogel biomaterials composed of chitosan are advantageous in wound-healing applications because of their antimicrobial and hemostatic properties and teaches that “genipin-cross-linked chitosan hydrogels were synthesized and characterized” and evaluated in vitro and in vivo as wound dressings (p. 2879, Abstract). Heimbuck further reports that the chitosan-genipin hydrogels exhibited approximately 230% aqueous-solution uptake, remained biocompatible with fibroblasts and keratinocytes, inhibited bacterial growth, and promoted enhanced immune response and cellular proliferation in induced wounds in mice, concluding that the hydrogels had potential as proactive wound dressings (p. 2879, Abstract). Thus, Heimbuck supplies a hydrogel comprising chitosan and cross-linking of that hydrogel by genipin, in the same general wound-treatment environment contemplated by Krausz and Jezek.
Further, Muzzarelli expressly teaches genipin-crosslinked chitosan hydrogels. Genipin is identified as a water-soluble bifunctional cross-linking reagent that reacts with chitosan to form hydrogels, and the applications expressly include manufacture of drug carriers for controlled release and medication of wounds in animals and humans (p.1, Abstract). Thus, Muzzarelli also supplies the instant claim 1 limitations that the hydrogel comprise a polymer within the claimed Markush group (i.e., chitosan), and that the hydrogel be cross-linked by genipin.
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to employ the nitrite-based NO-generating hydrogel technology of Jezek in implementing Krausz’s localized NO therapy at a surgical treatment site and to employ Heimbuck’s or Muzzarelli’s genipin-cross-linked chitosan hydrogel as the wound-contacting hydrogel matrix. Muzzarelli expressly identifies that material as a biocompatible controlled-release drug carrier and wound-medication material. Thus, the prior art identifies the particular instant claimed polymer/cross-linker pair of chitosan/genipin for the relevant drug-delivery and wound-treatment functions.
Krausz provides an express reason to deliver NO locally from hydrogels or polymers in surgical and vascular applications (i.e., localized and extended NO availability in an environment in which NO’s angiogenic, vasodilatory, and wound-healing activities are desirable). Jezek provides a known and experimentally demonstrated means of achieving localized NO generation from a hydrogel using potassium nitrite. Heimbuck, provides a known genipin-cross-linked chitosan hydrogel specifically developed and experimentally demonstrated for wound contact, and Muzzarelli supplies a known genipin/chitosan controlled-release wound carrier also.
Thus, the proposed combination is not based upon an unsupported assertion that any cross-linker could have been selected. Rather, the prior art identifies the particular instant claimed combination of chitosan and genipin as a known, biocompatible wound hydrogel. A person of ordinary skill seeking a wound-compatible hydrogel matrix for the localized NO delivery contemplated by Krausz and Jezek would have had reason to select Heimbuck’s chitosan-genipin hydrogel because Heimbuck expressly demonstrates that the material is suitable for contact with wounds and compatible with fibroblasts and keratinocytes.
The proposed modification constitutes use of known wound-treatment components according to their established functions as Krausz’s localized NO therapy provides the angiogenic/vascular-healing function, Jezek’s potassium nitrite provides a known hydrogel-compatible NO-generating precursor and Heimbuck’s or Muzzarelli’s chitosan/genipin hydrogel provides the known wound-compatible hydrogel matrix. Where a person of ordinary skill has reason to combine familiar elements according to known methods and the combination would predictably perform the functions taught for those elements, the combination may be obvious. (see KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416-18 (2007); MPEP § 2143).
A person of ordinary skill would have had a reasonable expectation of success in making the combination because Krausz establishes that NO-donor compounds can be delivered locally from polymer/hydrogel matrices, Jezek actually prepares cross-linked hydrogels containing potassium nitrite and demonstrates generation of bioactive NO and increased local blood flow, Heimbuck actually prepares genipin-cross-linked chitosan hydrogels and demonstrates their biocompatibility and suitability for wound contact, and Muzzarelli teaches that genipin/chitosan hydrogels are biocompatible controlled-release drug carriers suitable for wound medication. The combination therefore would not have required reliance upon an unexplored mechanism or an unknown class of materials.
Furthermore, because Krausz expressly identifies angiogenesis as an established biological activity of NO relevant to postsurgical wound healing, the skilled artisan would reasonably have expected localized NO production at a surgical site to promote the vascular response underlying revascularization. Instant claim 1 does not require any particular quantitative degree or rate of revascularization beyond “accelerating” it. Accordingly, instant claim 1 would have been obvious.
Instant claim 2 further requires that the NOD comprise at least one of the enumerated additional NO-donor compounds, one expressly listed species being S-nitrosoglutathione (GSNO). Jezek directly teaches generation of GSNO in its potassium-nitrite hydrogel dressing. In Example 2, Jezek provides a primary poly-AMPS hydrogel layer containing 30 mM potassium nitrite and a secondary PVA layer containing 30 mM L-glutathione; bringing the layers together generates GSNO, which peaks approximately two hours after activation and remains measurable for 48 hours
Example 3 further demonstrates gradual release of the generated GSNO from the activated dressing into an adjacent hydrogel. Thus, Jezek teaches a nitrite-containing NO-generating hydrogel system that additionally contains/generates GSNO, one of the species expressly encompassed by instant claim 2. The same motivation and reasonable-expectation analysis provided for instant claim 1 applies.
Identified Gap/Claim-Construction Issue
If claim 2 is construed to require the second named NOD to be pre-existing in the administered composition before administration, rather than generated upon activation/use, evidentiary reference Berns et al. (US20160113941A1; published 28 April 2016, hereinafter “Berns”) expressly identifies GSNO, SNAP, DEA NONOate, spermine NONOate, MAHMA/NO, PROLI/NO, V-PYRRO/NO, sodium nitroprusside, Angeli’s salt, nicorandil, 3-morpholinosydnonimine, and molsidomine among suitable wound-treatment NO donors and expressly permits “various combinations” (claim 6 directed to the NO-donor species).
Instant claim 7 further requires that the surgical treatment site does not comprise a site where cancerous tissue is removed. Jezek discusses using its NO-generating system in connection with prevention or treatment of restenosis and/or thrombosis following percutaneous transluminal angioplasty, identifying vascular endothelial injury produced during that procedure (¶[0036]). Such a vascular treatment site does not involve removal of cancerous tissue. Krausz likewise discusses non-oncologic vascular procedures. The negative limitation therefore does not patentably distinguish the instant claimed method from the applied combination. Accordingly, instant claim 7 would have been obvious.
Claims 9, 10, and 15 are rejected under 35 U.S.C. § 103 as being unpatentable over Kulber et al. (The use of fibrin sealant in the prevention of seromas, Plast. Reconstr. Surg. 99(3):842-849, March 1997; hereinafter “Kulber”), in view of Schek et al. (Genipin-crosslinked fibrin hydrogels as a potential adhesive to augment intervertebral disc annulus repair, Eur. Cell. Mater. 21:373-383, published 18 April 2011; hereinafter “Schek”), and in further view of Jezek and Watson, US20090081279A1; published 26 March 2009, hereinafter “Jezek”), and Joseph et al. (Development of an Injectable Nitric Oxide Releasing Poly(ethylene) Glycol-Fibrin Adhesive Hydrogel. ACS Biomater Sci Eng. 2019 Feb 11;5(2):959-969. Epub 2018 Dec 13; hereinafter “Joseph”).
Kulber directly addresses the instant claimed therapeutic endpoint of reduction of post-surgical seroma formation. Kulber generated postoperative seromas by surgical harvesting of rat latissimus dorsi muscle and compared untreated surgical sites with sites receiving fibrin sealant. The study reports that fibrin sealant reduced seroma incidence and fluid accumulation and concludes that fibrin sealant was effective in preventing seroma when applied intraoperatively (p. 842, Abstract). Thus, Kulber teaches a method of reducing postoperative seroma at a surgical treatment site by locally applying a fibrin material. Kulber does not disclose genipin cross-linking or a nitrite NOD.
Schek teaches a genipin-crosslinked fibrin hydrogel. Schek reports that fibrin gels without genipin exhibited poor handling and readily delaminated, whereas genipin-crosslinked fibrin gels remained adhered to tissue at strains exceeding physiological levels. Schek concludes that the genipin-crosslinked fibrin gel is useful as an adhesive/sealant material (p. 373, Abstract). Thus, Schek upplies the claimed fibrin hydrogel cross-linked by genipin, and additionally provides an affirmative reason for the modification as improved handling and tissue adhesion relative to fibrin alone.
Joseph independently teaches incorporating an NO donor into a fibrin-containing adhesive hydrogel. Specifically, Joseph incorporates fibrin microparticles into PEG-fibrinogen hydrogels and loads SNAP, an NO donor, into the fibrin component. The resulting composition exhibits controlled NO release, improved tissue adhesivity, non-cytotoxicity, and suitability as regenerative support for wound healing (p. 959, Abstract). Thus, Joseph supplies direct evidence, that an NO donor could successfully be incorporated into a fibrin-containing adhesive hydrogel for wound treatment. Joseph does not use a nitrite salt and does not employ genipin.
Jezek supplies the remaining nitrite salt teaching. As stated above, Jezek expressly incorporates potassium nitrite in a cross-linked hydrogel (Poly-AMPS Hydrogel Preparation, Table 1; claims 11-17) and demonstrates NO production and increased local blood flow/vasodilation (Example 6).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, seeking to implement Kulber’s known fibrin-based postoperative-seroma prevention method, to employ the genipin-crosslinked fibrin hydrogel taught by Schek because Schek expressly identifies genipin cross-linking as overcoming poor handling/delamination of fibrin alone and providing strong tissue adhesion. This constitutes application of a known technique to improve a similar fibrin surgical adhesive material for its known adhesion/sealing function (see KSR v. Teleflex, 550 U.S. 419-421 (2007); MPEP § 2143(I)).
One of ordinary skill further would have had reason to incorporate an NO-donor wound-healing function into that fibrin-based adhesive hydrogel because Joseph expressly demonstrates that an NO donor can be incorporated successfully into a fibrin-containing adhesive hydrogel to obtain controlled NO release while retaining/improving tissue adhesion and wound-healing utility. In addition, the skilled artisan seeking a locally generated NO source would have had reason to employ Jezek’s known hydrogel-compatible potassium-nitrite NO-generating chemistry because Jezek demonstrates both incorporation of potassium nitrite into a cross-linked hydrogel and generation of bioactive NO producing local vasodilation. The references thus provide a specific chain of reasons to do so, wherein Kulber teaches postoperative-seroma prevention by local fibrin material, Schek teaches genipin-crosslinked fibrin hydrogel with superior tissue adhesion/handling, Joseph teaches successful addition of an NO donor to a fibrin adhesive hydrogel, and Jezek teaches known nitrite-salt hydrogel NO-generating chemistry.
A reasonable expectation of success is supported by Joseph, which directly demonstrates that an NO donor can coexist in and be released from a fibrin-containing adhesive hydrogel without destroying its tissue-adhesive/wound-healing utility. Schek separately demonstrates that genipin-crosslinked fibrin forms an adhesive hydrogel suitable for surgical tissue application, and Jezek demonstrates that nitrite chemistry can operate in a cross-linked hydrogel. Absolute predictability is not required (see O’Farrell, 853 F.2d at 903-04; MPEP § 2143.02). Accordingly, instant claim 9 would have been obvious.
Instant claim 10 further recites an additional NOD selected from an extensive list including SNAP and GSNO. Joseph employs SNAP as the NO donor in its fibrin-containing adhesive hydrogel (p. 959, Abstract). Jezek independently generates and releases GSNO from its nitrite-containing activated hydrogel dressing (Examples 2 and 3). Both SNAP and GSNO fall within instant claim 10. It therefore would have been obvious to include at least one such additional known NO donor in the composition for the known purpose of providing NO release in a wound-treatment hydrogel. Accordingly, instant claim 10 would have been obvious for the reasons stated above.
Instant claim 15 further requires that the surgical site not comprise a site where cancerous tissue is removed. Kulber’s experimental surgical site is created by latissimus dorsi muscle harvest in an animal model for postoperative seroma; the disclosed surgical treatment does not depend upon removal of cancerous tissue (p. 842, Abstract). Accordingly, the applied prior art demonstrates a non-oncologic surgical environment in which the known seroma-prevention treatment is performed, and instant claim 15 would have been obvious.
Claim 17 is rejected under 35 U.S.C. § 103 as being unpatentable over Berns et al., US20160113941A1; published 28 April 2016, hereinafter “Berns”), in view of Heimbuck et al. (Development of Responsive Chitosan–Genipin Hydrogels for the Treatment of Wounds, ACS Appl Bio Mater. 2019 Jul 15;2(7):2879-2888. Epub 2019 Jun 25; hereinafter “Heimbuck”), and in further view of Muzzarelli (Genipin-crosslinked chitosan hydrogels as biomedical and pharmaceutical aids, Carbohydr. Polym. 77:1-9, published 22 May 2009).
Berns expressly teaches a kit for treating a wound, including a chemical compound and instructions for use (claim 46; kit disclosure). Berns further explains that the kit may contain pharmaceutically acceptable carriers, applicators, bandaging materials and other useful components and that the chemical compound may be stored in suitable packaged form (Berns, kit disclosure). Berns separately teaches a wound-treatment composition comprising a nitric oxide donor and a suitable carrier (claim 47), and identifies a time-release hydrogel as a suitable carrier (claim 50).
Berns identifies numerous NOD species falling literally within instant claim 17, including sodium nitroprusside, Angeli’s salt, diazeniumdiolates/NONOates, DEA NONOate, spermine NONOate, MAHMA/NO, PROLI/NO, V-PYRRO/NO, GSNO, SNAP, nicorandil, 3-morpholinosydnonimine, and molsidomine, as well as combinations thereof (claim 6). Berns further states that its NO-donor wound treatment can be used in surgical wound healing (¶[0039]). Thus, Berns teaches a wound-treatment kit containing an NOD composition (including surgical wounds), a hydrogel carrier, and multiple NOD species encompassed by instant claim 17. Berns does not disclose that its hydrogel comprises one of instant claim 17’s recited polymers cross-linked by genipin.
Heimbuck teaches that genipin-cross-linked chitosan hydrogels were synthesized and evaluated as wound dressings, and identifies chitosan hydrogels as advantageous for wound-healing applications because of their antimicrobial and hemostatic characteristics (p. 2879, Abstract). Heimbuck establishes that the chitosan/genipin hydrogels were biocompatible with fibroblasts and keratinocytes and demonstrated favorable biological responses in wounds in vivo, supporting their suitability for direct wound use (p. 2879, Abstract). Thus, Heimbuck directly teaches the instant claimed structural combination of a recited polymer hydrogel-chitosan-cross-linked by genipin. In addition, Muzzarelli further teaches that chitosan forms hydrogels when cross-linked by genipin and that such hydrogels are suitable as controlled-release drug carriers and wound medications (p.1, Abstract).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to employ Heimbuck’s genipin-cross-linked chitosan hydrogel as the time-release/wound-contacting hydrogel carrier or Muzzarelli’s genipin-cross-linked chitosan hydrogel for the NOD composition taught by Berns.
Berns directs one of ordinary skill in the art to formulate his wound-treatment NOD composition in a time-release hydrogel but does not require a particular hydrogel chemistry. A person implementing that teaching would therefore have needed to select a pharmaceutically and biologically suitable wound hydrogel. Heimbuck and Muzzarelli provide such a material, a genipin-cross-linked chitosan hydrogel, wherein Heimbuck has experimentally developed for wound treatment and demonstrated to be biocompatible with wound-relevant fibroblasts and keratinocytes.
The reason for choosing Heimbuck’s material arises from the prior art reference rather than from the applicant’s disclosure. Berns creates the design need for a wound-compatible hydrogel carrier for an NOD, and Heimbuck teaches the particular claimed genipin/chitosan hydrogel for that wound-contact function. Further, Muzzarelli expressly identifies the claimed chitosan/genipin hydrogel as a controlled-release drug carrier suitable for wound medication.
This is a predictable application of a known wound-compatible hydrogel to perform the same carrier/wound-contact function contemplated by Berns (see KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416–18 (2007); MPEP § 2143). Muzzarelli provides an express functional reason for the selection and a reasonable expectation that the combination would successfully deliver a therapeutic agent in a wound environment. Heimbuck's experimental biocompatibility and wound studies also provide strong evidence supporting a reasonable expectation of success. The fact that Heimbuck does not itself contain an NO donor does not defeat the combination because the rejection is based upon what the references collectively would have taught to one of ordinary skill, not upon bodily incorporation of every feature of one reference into another (see In re Keller, 642 F.2d 413, 425 (CCPA 1981); MPEP § 2145).
Claims 1 and 21 are rejected under 35 U.S.C. § 103 as being unpatentable over Krausz and Friedman (Krausz A and Friedman AJ. Nitric oxide as a surgical adjuvant. Future Sci OA, 1(1):FSO56; publication date 01 August 2015; hereinafter “Krausz”), in view of Jezek and Watson, US20090081279A1; published 26 March 2009, hereinafter “Jezek”), and in further view of Heimbuck et al. (Development of Responsive Chitosan–Genipin Hydrogels for the Treatment of Wounds, ACS Appl Bio Mater. 2019 Jul 15;2(7):2879-2888. Epub 2019 Jun 25; hereinafter “Heimbuck”), Muzzarelli (Genipin-crosslinked chitosan hydrogels as biomedical and pharmaceutical aids, Carbohydr. Polym. 77:1-9, published 22 May 2009), and Hafezi et al. (3D printed chitosan dressing crosslinked with genipin for potential healing of chronic wounds, Int J Pharm. 2019 Apr 5;560:406-415. Epub 2019 Feb 21; hereinafter “Hafezi”).
Krausz, in view of Jezek, and in further view of Heimbuck and Muzzarelli, teach the limitations of instant claim 1, as described above, from which instant claim 21 depends, however do not explicitly teach the specific limitations of instant claim 21, which requires that the cross-linked hydrogel further comprises at least one plasticizer selected from polyethylene glycol, sorbitol, and glycerol.
Hafezi prepares cross-linked chitosan matrices using genipin as the cross-linker and glycerol or polyethylene glycol (PEG) as plasticizer (p. 406, Abstract). Hafezi reports that the CH-GE-PEG600 formulation was selected for appropriate flexibility and that the plasticized materials had high swelling capability and wound-dressing utility (p. 406, Abstract). Thus, Hafezi teaches plasticizers of instant claim 21 (i.e., PEG and glycerol), in the same chitosan/genipin material system employed by Muzzarelli.
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to incorporate PEG or glycerol into the genipin-crosslinked chitosan hydrogel of the combination because Hafezi expressly teaches those additives as plasticizers and reports the resulting flexibility and wound-dressing utility. The modification constitutes use of a known additive for its established plasticizing function to improve handling/flexibility of a closely related chitosan/genipin wound material, with a predictable result (see KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007); MPEP § 2143). A reasonable expectation of success follows from Hafezi’s actual preparation and characterization of chitosan/genipin compositions containing PEG or glycerol. Accordingly, instant claim 21 would have been obvious.
Claims 1 and 22 are rejected under 35 U.S.C. § 103 as being unpatentable over Krausz and Friedman (Krausz A and Friedman AJ. Nitric oxide as a surgical adjuvant. Future Sci OA, 1(1):FSO56; publication date 01 August 2015; hereinafter “Krausz”), in view of Jezek and Watson, US20090081279A1; published 26 March 2009, hereinafter “Jezek”), and in further view of Heimbuck et al. (Development of Responsive Chitosan–Genipin Hydrogels for the Treatment of Wounds, ACS Appl Bio Mater. 2019 Jul 15;2(7):2879-2888. Epub 2019 Jun 25; hereinafter “Heimbuck”), Muzzarelli (Genipin-crosslinked chitosan hydrogels as biomedical and pharmaceutical aids, Carbohydr. Polym. 77:1-9, published 22 May 2009), and Kildeeva et al. (Influence of Genipin Crosslinking on the Properties of Chitosan-Based Films, Polymers (Basel). 2020 May 10;12(5):1086; hereinafter “Kildeeva”).
Krausz, in view of Jezek, and in further view of Heimbuck and Muzzarelli, teach the limitations of instant claim 1, as described above, from which instant claim 22 depends, however do not explicitly teach the specific limitations of instant claim 22, which requires that the cross-linked hydrogel have an equilibrium swell of 500% to 1100%.
Kildeeva studies genipin-crosslinked chitosan materials and expressly determines the relationship between genipin concentration and equilibrium swelling. Kildeeva reports that equilibrium swelling decreases as genipin concentration/cross-link density increases and specifically reports approximately 1020 wt.% equilibrium swelling for the composition having a Gp/NH₂ molar ratio of 0.003 (pp. 7-11, § 3.2, Kinetics of the Swelling and Water Vapor Sorption by the Films; Fig. 4). Table 2 reports an equilibrium swelling degree of 1025% for the 0.003 Gp/NH2 material (p.10). Both values fall squarely within instant claim 22’s 500-1100% interval. Kildeeva further teaches that equilibrium swelling changes as the concentration of cross-linking reagent changes, thereby identifying cross-linker concentration/cross-link density as a result-effective variable for swelling (p.10, Table 2).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to configure the genipin/chitosan material of the underlying combination to exhibit an equilibrium swelling within the claimed range because Kildeeva expressly discloses an in-range value and expressly teaches how changing genipin concentration affects equilibrium swelling. The general range principles further support the rejection. A prior-art range encompassing a claimed range ordinarily establishes a prima facie case of obviousness (see In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003)). Likewise, where the general conditions are disclosed and a variable is known to affect the relevant result, routine determination of a workable value is ordinarily obvious (see In re Aller, 220 F.2d 454, 456 (CCPA 1955); MPEP § 2144.05). Further, the result-effective-variable principle is applicable because the art expressly recognizes the relationship between genipin concentration and swelling (see In re Applied Materials, Inc., 692 F.3d 1289, 1297 (Fed. Cir. 2012); MPEP § 2144.05). Accordingly, instant claim 22 would have been obvious.
Claims 1 and 23 are rejected under 35 U.S.C. § 103 as being unpatentable over Krausz and Friedman (Krausz A and Friedman AJ. Nitric oxide as a surgical adjuvant. Future Sci OA, 1(1):FSO56; publication date 01 August 2015; hereinafter “Krausz”), in view of Jezek and Watson, US20090081279A1; published 26 March 2009, hereinafter “Jezek”), and in further view of Heimbuck et al. (Development of Responsive Chitosan–Genipin Hydrogels for the Treatment of Wounds, ACS Appl Bio Mater. 2019 Jul 15;2(7):2879-2888. Epub 2019 Jun 25; hereinafter “Heimbuck”), Muzzarelli (Genipin-crosslinked chitosan hydrogels as biomedical and pharmaceutical aids, Carbohydr. Polym. 77:1-9, published 22 May 2009), and Schek et al. (Genipin-crosslinked fibrin hydrogels as a potential adhesive to augment intervertebral disc annulus repair, Eur. Cell. Mater. 21:373-383, published 18 April 2011; hereinafter “Schek”).
Krausz, in view of Jezek, and in further view of Heimbuck, and Muzzarelli, teach the limitations of instant claim 1, as described above, from which instant claim 23 depends, however do not explicitly teach the specific limitations of instant claim 23, further requiring administering the NOD at the site in conjunction with a surgical sealant.
Schek teaches a genipin-crosslinked fibrin hydrogel as a tissue adhesive and concludes that the material is suited for use as a sealant for small tissue defects and as an adhesive to augment larger repairs (p. 373, Abstract). The study further demonstrates that the genipin-crosslinked fibrin material remains adhered to tissue beyond physiological strain levels, whereas non-genipin fibrin readily delaminates (p. 373, Abstract).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to use the localized NOD hydrogel treatment of instant claim 1’s combination in conjunction with Schek’s known surgical/tissue sealant because the two adjuncts provide complementary functions at a wound or operative site- the NOD system provides localized NO delivery for biological wound/vascular-healing purposes, while the sealant provides mechanical tissue adhesion and sealing.
The proposed combination does not require either component to perform a new or unpredictable function. Each continues to perform its established function in the same surgical/wound environment. Combining known elements according to known methods where each performs its established function and the combination yields the predictable aggregate benefit is an obviousness rationale recognized in KSR Int’l Co. v. Teleflex Inc., 550 U.S. 416-418 (2007) and MPEP § 2143(I)(A).
A reasonable expectation of success exists in doing so because Schek experimentally demonstrates tissue adhesion of the genipin/fibrin sealant, while the instant claim 1 references independently demonstrate localized NO delivery. No modification is proposed that would render either element unsuitable for its established function. Accordingly, instant claim 23 would have been obvious.
Response to Arguments
Applicant Arguments/Remarks of the reply, filed 11 June 2026, have been fully considered.
The applicant argues that Krausz, Malone-Povolny, Weller, Wong, Chiang, Xie, and Li do not disclose a hydrogel “cross-linked by genipin.” This argument is persuasive as to the previously stated combinations. The former grounds are therefore withdrawn rather than maintained through a generalized assertion that cross-linker selection would have been routine. The new grounds, as outlined above, cure the identified evidentiary deficiency.
The applicant’s characterization of Li does not overcome the new grounds because the new rejection of claim 17 does not rely upon Li to supply genipin and does not contend that physical cross-linking is equivalent to genipin cross-linking. The new rejection outlined above addresses the claimed chemical cross-linking limitation directly. In addition, the argument that Malone-Povolny’s hydrogen-bonded system does not teach genipin is likewise moot with respect to the new grounds. The new rejections do not rely upon hydrogen bonding in Malone-Povolny as satisfying the genipin limitation.
The applicant further argues that there would have been no motivation to modify the prior art to use genipin. This argument is not persuasive against the newly applied art. As detailed above, the reason for using genipin does not arise from hindsight reconstruction of applicant’s disclosure. The prior art therefore establishes that this was an existing wound-compatible hydrogel technology before the effective filing date.
Under KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), obviousness analysis may consider the inferences and creative steps that a person of ordinary skill would employ, but the determination must remain grounded in an articulated reason having a rational underpinning (see In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006)). That requirement is satisfied here by the overlapping wound-treatment and localized-delivery teachings of the applied references, as applied above. A reasonable expectation of success does not require absolute predictability (see In re O’Farrell, 853 F.2d at 903-04). Here, the proposed combinations cited above do not require development of an unknown hydrogel chemistry. The skilled artisan therefore would not have been proceeding with merely a general hope that experimentation might succeed.
The applicant’s general assertion that the amended claims are distinguishable does not establish criticality of claim 22’s 500-1100% equilibrium-swell interval from the cited prior art. Where the prior art expressly discloses a value within a claimed range, the claimed numerical range ordinarily supports a prima facie case of obviousness absent evidence of criticality or unexpected results (see In re Peterson, 315 F.3d 1325, 1329–30 (Fed. Cir. 2003); MPEP § 2144.05), subject to rebuttal by evidence of criticality or unexpected results.
The applicant has not presently submitted comparative data or other objective evidence showing that use of genipin in the claimed NO-donor wound systems produces an unexpected property or result relative to the known wound-hydrogel technology. This observation is not used to supply a missing element of the prima facie case. Rather, the prior art discussed above independently teaches or suggests each claimed limitation and supplies reasons to combine. In the absence of rebuttal evidence of sufficient weight, the prima facie case therefore remains unrebutted.
The applicant’s request that all rejections be withdrawn and the claims allowed is not granted. Although the particular prior grounds identified by the applicant no longer adequately address the newly added genipin limitation, the additional prior art developed upon further examination expressly supplies that limitation and establishes new grounds of obviousness as stated above.
Conclusion
No claims are allowed.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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