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 .
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 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.
Priority
The instant application 18/162,387, filed 01/31/2023, claims domestic benefit of U.S. Provisional Patent Application No. 63/304,800, filed 01/31/2022.
Status of Action/Claims
Receipt of Remarks/Amendments filed on 3/2/2026 and 5/18/2026 is acknowledged. Claims 1, 10-16, 20 are currently pending. Claims 12-15 have been withdrawn. Accordingly, claims 1, 10-11, 16, 20 are presented for examination on the merits for patentability.
Rejection(s) not reiterated from the previous Office Action are hereby withdrawn. The following rejections are either reiterated or newly applied. They constitute the complete set of rejections presently being applied to the instant application.
Claim Objections
Claim 10 is objected to because of the following informalities:
In claim 10, the recitation “The composition claim 1” should recited “The composition of claim 1”.
Appropriate correction is required.
Claim Interpretation
Claims 1 and 16 recite that the ROS-scavenging hydrogel comprises copolymerized NIPAAm, HEMA, and “4-(acryloyloxymethyl)-phenylboronic acid pinacol ester.” As discussed in the previous office action, this broad recitation is interpreted to mean that the hydrogel comprises any copolymer containing copolymerized NIPAAm, HEMA, and “4-(acryloyloxymethyl)- phenylboronic acid pinacol ester” units. “4-(acryloyloxymethyl)-phenylboronic acid pinacol ester” is not a compound name commonly recited in prior art literature. The instant specification makes reference to figure 3B of its disclosure when referring to copolymerization of NIPAAm, HEMA, and 4-(acryloyloxymethyl)-phenylboronic acid pinacol ester (see instant specification p. 33 lines 7-9). Figure 3B of the instant disclosure depicts a synthetic scheme as follows (drawings submitted on 01/31/2023, p. 18/48):
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The Examiner interprets the rightmost molecule before the reaction arrow depicted in the scheme to be the structure for the molecule that the Applicants are attempting to name “4-(acryloyloxymethyl)-phenylboronic acid pinacol ester.” The Examiner will interpret any claim recitation of “4-(acryloyloxymethyl)-phenylboronic acid pinacol ester” to mean any compound having the chemical structure of the compound closest to the reaction arrow depicted in Figure 3B above.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1, 10-11, 16, 20 are rejected under 35 U.S.C. 103 as being unpatentable over Guan, Y. et al. (2020). "Photoluminescent oxygen-release microspheres to image the oxygen release process in vivo." Acta Biomaterialia, 115, 333-342 (previously cited) in view of Niu, H. (2018). "Functional Polymeric Hydrogels in Stem/Progenitor Cell Therapy and Therapeutic Angiogenesis." The Ohio State University, PhD Dissertation. OhioLink, https://etd.ohiolink.edu/acprod/odb_etd/ws/send_file/send?accession=osu1543406270126261&disposition=inline (previously cited).
Guan teaches oxygen-release microspheres (ORMs) wherein a complex of polyvinylpyrrolidone (PVP), H2O2 and a fluorescent drug hypericin (HYP) are used as core, and poly(N-isopropylacrylamide-co-acrylate-oligolactide-co-hydroxyethyl methacrylate-co-N-acryloxysuccinimide) conjugated with catalase is used as shell (Abstract). Guan teaches the abbreviation for this shell polymer is poly(NIPAAm-co-AOLA-co-HEMA-co-NAS) (abbreviated as PNAHN) (p. 335 “2.2. Polymer synthesis” lines 7-9). Guan teaches the hydrogel poly(NIPAAm-co-AOLA-co-HEMA) (abbreviated PNAH) is used to deliver the microspheres into tissues wherein the oxygen release microspheres and bono marrow derived MSCs are encapsulated (i.e. embedded) in PNAH hydrogel (p. 335 “2.2. Polymer synthesis” lines 16-20; Section 2.7). Guan teaches 50 mg/mL of microspheres and 2 million/mL of MSCs are mixed with 6 wt % PNAH hydrogel to generate a gel, and 100 μL of 6 wt% PNAH hydrogel solution with 50 mg/mL microspheres are injected into thigh muscles of 8-week-old nude mice (p. 336 “2.7. Effect of oxygen release on cell survival under hypoxia;” “2.8. Injection of oxygen-release microspheres, MSCs, and hydrogel into thigh muscles”). Guan teaches sustained oxygen release is achieved during the gradual degradation of the shell of the ORM (p. 340 R. Col. final para). Guan teaches future delivery of the oxygen-release microspheres in combination with mesenchymal stem cells (MSCs) into ischemic tissues such as ischemic limb and heart in order to evaluate in vivo oxygen release, MSC survival, and tissue regeneration (p. 341 L. Col. 1st para). The gel composition comprising the PNAH hydrogel and the ORM having a core comprising a complex of H2O2 and PVP and a shell comprising poly(NIPAAm-co-AOLA-co-HEMA-co-NAS) conjugated to catalase reads on a composition for sustained release of oxygen to a tissue comprising ischemic tissue, wherein the composition comprises at least one core-shell ORM wherein the core comprises a water-soluble polymer-reactive oxygen species (ROS) complex and the shell comprises a biodegradable polymer conjugated to a ROS- scavenging enzyme, more specifically wherein the ROS comprises H2O2, the water-soluble polymer comprises PVP, the biodegradable polymer comprises poly(NIPAAm-co-HEMA-co-AOLA-co-NAS), and the ROS-scavenging enzyme comprises catalase, as recited in instant claims.
The teachings of Guan have been set forth above.
It is reiterated that Guan teaches a hydrogel of its gel composition which comprises poly(NIPAAm-co-AOLA-co-HEMA) (abbreviated PNAH) (p. 335 “2.2. Polymer synthesis” lines 16-20). Guan teaches that in general, when delivering transplanted cells, long-term survival of the transplanted cells remains a problem, because the low oxygen environment compromises normal cell metabolism; to address the above hurdles, one of the strategies is to use hydrogels capable of releasing oxygen and will enhance cell-matrix interaction to increase cell survival (p. 334 L. Col. 1st para).
Guan differs from the instantly claimed invention in that it fails to teach the hydrogel of its composition is a ROS-scavenging hydrogel, as recited in instant claims; thus, Guan fails to teach the ROS-scavenging hydrogel comprises copolymerized NIPAAm, HEMA, and 4-(acryloyloxymethyl)-phenylboronic acid pinacol ester, and recited in instant claims. Guan fails to explicitly teach that the composition is used for sustained release of oxygen to ischemic tissue comprising a tissue associated with an ischemic condition selected from diabetes, peripheral artery disease, and coronary heart disease, more specifically a chronic diabetic wound bed, as recited in instant claims. Guan also fails to explicitly teach a “kit” (interpreted as packaged collection) comprising the composition of the core-shell ORM, and a ROS-scavenging hydrogel, as recited in instant claims, and that the kit is used to treat ischemic conditions, as recited in instant claim 20, and instructions for use.
Niu teaches a dual-responsive hydrogel system for application in tissue engineering which is injectable and capable of ROS sensitivity, thermosensitivity, and growth and proliferation of MSCs (pp. 134-135 “3.5 Conclusion”). Niu teaches the hydrogel is used in wound healing for diabetes and improves cell survival by scavenging ROS content under ischemia; furthermore, the hydrogel is biocompatible and non-toxic in vivo (p. 30 final para). Niu teaches the hydrogels provide as a reliable carrier for treating the remodeling phase of chronic wounds (p. 133-134 bridging para).
Niu teaches the hydrogel contains poly(NIPAAm-co-HEMA-co-NAS-co-AAcPB) (abbreviated PNHNA), which is copolymerized NIPAAm, HEMA, AAcPB, and NAS (p. 111 “3.2.3 Synthesis of poly(NIPAAm-co-HEMA-co-NAS-co-AAcPB”; p. 113 “3.2.5 Characterization and physical properties of PNHNA hydrogels”; p. 115 1st sentence). Niu teaches that “AAcPB” has the following chemical structure (p. 111 Figure 3.1):
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The Examiner notes that Niu’s AAcPB has the same chemical structure as the instantly claimed “4-(acryloyloxymethyl)-phenylboronic acid pinacol ester” (see Claim Interpretation section supra). Therefore, Niu’s hydrogel containing copolymer of NIPAAm, HEMA, AAcPB and NAS reads on a ROS-scavenging hydrogel comprising copolymerized NIPAAm, HEMA, and 4-(acryloyloxymethyl)-phenylboronic acid pinacol ester.
Niu teaches MSCs encapsulated (i.e. embedded) in the PNHNA hydrogel with H2O2 are formed by adding a total of 200 μL PNHNA hydrogel solution to a tube, mixing with 8 million/mL MSCs and incubating to form a gel, before further addition of cell culture medium containing H2O2 (100 μM) (p. 120 “3.2.9 MSCs encapsulated in APLA and PNHNA hydrogels with H2O2”). Niu teaches that more MSC cell death occurs in hydrogel without the presence of AAcPB in the copolymer of the hydrogel, whereas MSCs continue to proliferate after 7 days when encapsulated in PNHNA hydrogels under H2O2 (pp. 127-128 bridging para).
Niu teaches injectability of the PNHNA hydrogel is excellent via 26G needle with 1 mL syringe commonly used for animal surgeries (pp. 125-126 bridging para). Niu teaches injection of the PNHNA hydrogel into wounds of diabetic mice models, and demonstrates accelerated healing with wound closure rates reaching 60% after 10 days, which is significantly higher than groups without treatment (p. 129 “3.3.9 In vivo wound healing using db/+ and db/db mice”).
It would have been prima facie obvious, before the effective filing date of the instantly claimed invention, to substitute Guan’s poly(NIPAAm-co-AOLA-co-HEMA) (PNAH) hydrogel (used to deliver the ORMs and MSCs to ischemic tissue) with Niu’s ROS-scavenging, injectable hydrogel containing poly(NIPAAm-co-HEMA-co-NAS-co-AAcPB) (PNHNA), and arrive at the instantly claimed invention. The ordinarily skilled artisan would have been motivated to perform this substitution based on the many disclosed benefits of the hydrogel taught by Niu, which include its ROS sensitivity, thermosensitivity, capabilities toward growth and proliferation of MSCs, improval of cell survival under ischemic conditions, biocompatibility, non-toxicity, and acceleration of wound healing rates. The ordinarily skilled artisan would have a reasonable expectation of success performing this substitution because Guan teaches the PNAH hydrogel for carrying the ORMs and MSCs comprises a similar copolymer to the copolymer of Niu PNHNA, including at least its NIPAAm and HEMA units; additionally, the hydrogels are formed using similar gelation methods when incorporating MSCs; therefore, the ordinarily skilled artisan would expect successful gel formation using the PNHNA hydrogel when encapsulating at least the MSCs taught by Guan. Additionally, there is no indication in the prior art that the ORMs of Guan would be incompatible with Niu’s PNHNA, which is a highly similar hydrogel to the PNAH hydrogel that is demonstrably compatible with Guan’s ORMs.
It would have been prima facie obvious, before the effective filing date of the instantly claimed invention, for a person having ordinary skill in the art to use the ORM- and MSC-containing hydrogel rendered obvious by the combined teachings of Guan and Niu to supply oxygen to chronic diabetic wound bed ischemic tissue, and arrive at the instantly claimed invention. The ordinarily skilled artisan would have been motivated to do so because Guan directly suggests delivery of the ORMs and MSCs encapsulated by hydrogel into ischemic tissues for oxygen release and wound healing, and Niu teaches that diabetic wounds, particularly chronic ones, are ischemic tissues treatable by its hydrogel. The ordinarily skilled artisan would have a reasonable expectation of success using the ORM- and MSC-containing hydrogel rendered obvious by the combination of Guan and Niu to supply oxygen to chronic diabetic wound bed ischemic tissue because both teachings are used for ischemic wound treatment, and a simple combination of elements from each teaching would not appear to the ordinarily skilled artisan to hinder their effects on ischemic diabetic wound treatment.
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to use a syringe (e.g. kit) to contain the ORM- and MSC-containing hydrogel rendered obvious by the combined teachings of Guan and Niu, along with instructions for use, and use the syringe containing the obvious ORM- and MSC-containing hydrogel to treat a diabetic wound, and arrive at the instantly claimed invention. The ordinarily skilled artisan would have been motivated to do so because Niu teaches its hydrogel is injectable for facilitating diabetic wound healing in mice, and injects the hydrogel using syringe; therefore, in order to facilitate diabetic wound healing using the obvious ORM- and MSC-containing hydrogel, the ordinarily skilled artisan would seek to follow Niu’s syringe injection method for the treatment of diabetic wounds using the ORM- and MSC-containing hydrogel. The ordinarily skilled artisan would have a reasonable expectation of success because Niu teaches its hydrogel is injectable, and Guan also teaches its combination of ORM and MSC within hydrogel to be injectable into mice; therefore, all individual components are injectable and the ordinarily skilled artisan would find no reason to doubt the combination of the ORM, MSC and hydrogel in a syringe for injection would result in an uninjectable composition.
Response to Arguments
Applicant argued neither of the cited references discloses or suggests the ROS-scavenging hydrogel comprising copolymerized NIPAAm, HEMA, and 4- (acryloyloxymethyl)-phenylboronic acid pinacol ester in which the ORMs are embedded. Instead, Guan is silent as to any hydrogel within which the ORMs are embedded, and Niu discloses a hydrogel comprising poly(NIPAAm-co-HEMA-co-NAS-co-AAcPB), which includes an extra NAS monomer in addition to the NIPAAm, HEMA, and 4- (acryloyloxymethyl)-phenylboronic acid pinacol ester as required by claims 1 and 16 as amended.
In response, firstly as discussed supra, Guan teaches the hydrogel poly(NIPAAm-co-AOLA-co-HEMA) (abbreviated PNAH) is used to deliver the microspheres into tissues wherein the oxygen release microspheres and bono marrow derived MSCs are encapsulated (i.e. embedded) in PNAH hydrogel (p. 335 “2.2. Polymer synthesis” lines 16-20; Section 2.7). Further, as discussed supra, it would have been prima facie obvious to substitute Guan’s poly(NIPAAm-co-AOLA-co-HEMA) (PNAH) hydrogel (used to deliver the ORMs and MSCs to ischemic tissue) with Niu’s ROS-scavenging, injectable hydrogel containing poly(NIPAAm-co-HEMA-co-NAS-co-AAcPB) (PNHNA), and arrive at the instantly claimed invention. The ordinarily skilled artisan would have been motivated to perform this substitution based on the many disclosed benefits of the hydrogel taught by Niu, which include its ROS sensitivity, thermosensitivity, capabilities toward growth and proliferation of MSCs, improval of cell survival under ischemic conditions, biocompatibility, non-toxicity, and acceleration of wound healing rates. The ordinarily skilled artisan would have a reasonable expectation of success performing this substitution because Guan teaches the PNAH hydrogel for carrying the ORMs and MSCs comprises a similar copolymer to the copolymer of Niu PNHNA, including at least its NIPAAm and HEMA units; additionally, the hydrogels are formed using similar gelation methods when incorporating MSCs; therefore, the ordinarily skilled artisan would expect successful gel formation using the PNHNA hydrogel when encapsulating at least the MSCs taught by Guan. Additionally, there is no indication in the prior art that the ORMs of Guan would be incompatible with Niu’s PNHNA, which is a highly similar hydrogel to the PNAH hydrogel that is demonstrably compatible with Guan’s ORMs.
Regarding the argument that Niu discloses a hydrogel comprising poly(NIPAAm-co-HEMA-co-NAS-co-AAcPB), which includes an extra NAS monomer in addition to the NIPAAm, HEMA, and 4- (acryloyloxymethyl)-phenylboronic acid pinacol ester, the examiner argues that the claims recite a ROS-scavenging hydrogel comprising copolymerized NIPAAm, HEMA, and 4-(acryloyloxymethyl)-phenylboronic acid pinacol ester. The comprising language used in the claimed limitation does not exclude an extra monomer in the ROS scavenging hydrogel. As discussed supra and in the previous office action, the recitation is interpreted to mean that the hydrogel comprises any copolymer containing copolymerized NIPAAm, HEMA, and “4-(acryloyloxymethyl)- phenylboronic acid pinacol ester” units. Thus, even though Niu discloses a hydrogel comprising poly(NIPAAm-co-HEMA-co-NAS-co-AAcPB), this still reads on the ROS scavenging hydrogel of instant claims because the comprising language in the claimed limitation b does not exclude an extra monomer. Therefore, applicant’s arguments are not found persuasive at this time to overcome the prior art rejection above.
Conclusion
Applicant's amendment necessitated the new ground(s) 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.
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/ALI S SAEED/ Examiner, Art Unit 1616
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