CTFR 17/233,594 CTFR 98414 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Claim Status Applicants' arguments filed on 02/20/2026 have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. Claim 3 is cancelled. Claims 1-2 and 4-6 are withdrawn. Claims 7-21 are under current examination. Information Disclosure Statement The information disclosure statements (IDS) submitted on 02/20/2026 has been considered by the Examiner. 07-30-03-h AIA Claim Interpretation The recitation in the preamble of independent claims 7 and 12 “for healing volumetric muscle loss” recites the intended use of the biomimetic glycosaminoglycan hydrogel and kit, respectively, and is not considered limiting. From MPEP 2111.02, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020)”. The limitations of instant claims 7 and 12, “being formed using 7.5% w/v CS”, instant claim 17, “being formed using 1 % w/v HA and 25% w/v PEGDA”, and of instant claim 19, “wherein said hydrogel is formed using 1 % w/v HA and 25% w/v PEGDA” are product-by-process limitations. From MPEP 2113 I., “The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted). Here, the structure of the claimed products is fully set forth in independent claims 7 and 12, and the method of production is not considered limiting. Rejections Maintained Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim s 7-21 are rejected under 35 U.S.C. 103 as being unpatentable over Kuang et al. (“Bioinspired glycosaminoglycan hydrogels via click chemistry for 3D dynamic cell encapsulation” J Appl Polym Sci. 2019 (first published 01 November, 2018) , 136(5) , 47212; of record), hereafter “Kuang” in view of Song (US 8,124,757 B2, patented Feb. 28, 2012; of record) and Chen et al. (“Uniaxial Stretching of Cell-Laden Microfibers for Promoting C2C12 Myoblasts Alignment and Myofibers Formation” ACS Appl. Mater. Interfaces 2020 (published December 20, 2019) , 12 , 2162-2170; of record), hereafter “Chen”, as evidenced by Diokmetzidou et al. (“Strategies to Study Desmin in Cardiac Muscle and Culture Systems” Methods in Enzymology 2016 , 568 , 427-459; of record), hereafter “Diokmetzidou” . Regarding instant claims 7 and 12, Kuang teaches a tunable biomimetic hydrogel system synthesized by cross-linking thiolated hyaluronic acid and thiolated chondroitin sulfate with poly (ethylene glycol) diacrylate (abstract; Figure 2). The hydrogels of Kuang are taught to encapsulate human mesenchymal stem cells (abstract) which offer a promising cell source for musculoskeletal regenerative engineering (pg. 1, “Introduction”, paragraph 1). Hyaluronic acid and chondroitin sulfate are taught to be natural glycosaminoglycans (GAGs) (pg. 1, “Introduction”, paragraph 2). Kuang further teaches that a thiol degree of substitution of hyaluronic acid of 16.5% (about 17%) was achieved by increasing the amount of DTT used to prepare the thiol-functionalized hyaluronic acid (pg. 4-5, “HCP hydrogel synthesis, gelation, swelling, and morphology”, paragraph 1). Kuang further teaches that the thiol degree of substitution of chondroitin sulfate can be increased by altering the pH of the reaction mixture (pg. 4-5, “HCP hydrogel synthesis, gelation, swelling, and morphology”, paragraph 1). Kuang further teaches that various hydrogel properties, including gelation kinetics, modulus, swelling, and morphology, can be modulated by varying thiol degree of substitution (DS) of GAG or modulating molecular weight (MW) of PEGDA (pg. 2, column 1, paragraph 2). Adjusting the MW of PEGDA allows for control over gelation kinetics and G’ plateau /stiffness in a broad range (pg. 5, column 2, paragraph 3). The gelation kinetics and stiffness of HCP hydrogels could also be tuned by varying the thiol DS of GAG (pg. 6, column 2, paragraph 2). Kuang does not teach the limitation of instant claims 7 and 12 that the chondroitin sulfate has a degree of substitution at about 47% for the thiol groups. Song teaches a thiol-modified macromolecule derivative with a high degree of modifying that can be cross-linked and used as a matrix for cell attachment growth (abstract). Preferred macromolecules include chondroitin sulfate (column 2, lines 31-53). Example 9 (column 26) of Song exemplifies thiol-modified chondroitin sulfate with a substitution degree of 47%; this modified chondroitin sulfate is further taught to form a cross-linked hydrogel (column 30, Examples 14-2 and 14-3). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the degree of substitution of thiol groups on the thiol-substituted chondroitin sulfate of Kuang to achieve a degree of substitution of 47%, as suggested by Song. This could be achieved by routine optimization of the pH of the reaction mixture, taught by Kuang to affect the thiol degree of substitution of chondroitin sulfate, to reach a degree of thiol substitution taught by Song to be suitable for use in cross-linked hydrogels for cell attachment and growth; as noted above, the cross-linked hydrogels of Kuang encapsulate human mesenchymal stem cells which offer a promising cell source for musculoskeletal regenerative engineering. From MPEP 2144.05 II. A., "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Kuang does not teach the limitation of instant claims 7 and 12 that the hydrogel has a storage modulus G’ of about 13 kPa. Chen teaches the encapsulation of C2C12 myoblast cells (a type of stem cell) in hydrogel microfibers (abstract; “Materials and Methods”). Chen further teaches that the stiffness of substrates plays a key role in governing stem fate determination. Soft substrates with stiffness below 1 kPa are suitable for the regeneration of neurogenic tissues, moderate substrates with stiffness range from 10 to 17 kPa are suitable for the regeneration of myogenic tissues, and rigid substrates with stiffness ranging from 25 to 40 kPa are suitable for the regeneration of osteogenic tissues (pg. 2166, column 1, paragraph 1). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the storage modulus of the hydrogel of Kuang to achieve a stiffness range of 10 to 17 kPa (overlapping the “about 13 kPa of the instant claims”), as suggested by Chen. This could be achieved by routine optimization of the MW of PEGDA and thiol DS of GAG, taught by Kuang to affect the hydrogel stiffness, to reach a stiffness taught by Chen to be suitable for myogenic (muscle) tissue stem cell fate determination; as noted above, the hydrogels of Kuang encapsulate human mesenchymal stem cells which offer a promising cell source for musculoskeletal regenerative engineering. From MPEP 2144.05 II. A., "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Instant claim 12 does not recite any structural limitations that differentiate it from claim 7. Given that the prior art combination of Kuang in view of Song and Chen renders obvious (as described above) and arrives at the structural components of the kit and hydrogel of instant claim 12, the property that “the hydrogel facilitates migration of Pax7 positive cells and promotes at least de novo myofiber formation” would necessarily follow, absent evidence to the contrary. Regarding instant claims 8 and 13, as noted above, the hydrogels of Kuang are taught to encapsulate human mesenchymal stem cells (abstract). Regarding instant claims 9 and 14, the limitation that “said hydrogel promotes expression of myogenic markers MyoD, MyoG and MYH8, and supports myoblast proliferation and myogenic differentiation and integration of said hydrogel with its surrounding body tissue of said patient” is a property of the hydrogel that does not structurally limit the claimed hydrogel. Given that the prior art combination of Kuang in view of Song and Chen renders obvious (as described above) and arrives at the structural components of the hydrogel of instant claims 7 and 12, the property recited in instant claims 9 and 14 would necessarily follow, absent evidence to the contrary. Additionally, Kuang teaches that cross-linked hydrogels have been widely investigated as engineered matrices to support cell growth, differentiation, and organization to form regenerated tissue (pg. 1, “Introduction”, paragraph 1). Regarding instant claims 10 and 15, the limitation that “said hydrogel promotes integration with surrounding host tissue of said patient, facilitates migration of Pax7 positive cells, and promotes de novo myofiber formation, angiogenesis, and innervation” and “wherein said hydrogel promotes integration with surrounding host tissue of said patient, and promotes angiogenesis, and innervation” are properties of the hydrogel that do not structurally limit the claimed hydrogel. Given that the prior art combination of Kuang in view of Song and Chen renders obvious (as described above) and arrives at the structural components of the hydrogel of instant claims 7 and 12, the properties recited in instant claims 10 and 15 would necessarily follow, absent evidence to the contrary. Additionally, Kuang teaches that cross-linked hydrogels have been widely investigated as engineered matrices to support cell growth, differentiation, and organization to form regenerated tissue (pg. 1, “Introduction”, paragraph 1). Regarding instant claims 11 and 16, the limitation that “said hydrogel minimizes scar tissue formation” is a property of the hydrogel that does not structurally limit the claimed hydrogel. Given that the prior art combination of Kuang in view of Song and Chen renders obvious (as described above) and arrives at the structural components of the hydrogel of instant claims 7 and 12, the property recited in instant claims 11 and 16 would necessarily follow, absent evidence to the contrary. As noted above, the limitations of instant claims 7 and 12, “being formed using 7.5% w/v CS”, instant claim 17, “being formed using 1 % w/v HA and 25% w/v PEGDA”, and of instant claim 19, “wherein said hydrogel is formed using 1 % w/v HA and 25% w/v PEGDA” are product-by-process limitations. From MPEP 2113 I., “The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted). Here, the product of the instant claims is rendered obvious by the prior at combination of Kuang in view of Song and Chen (as described above). While Kuang teaches that the hydrogels encapsulate human mesenchymal stem cells (abstract), Kuang does not teach the limitation of instant claims 18 and 20 that the hydrogel comprises myogenic cells. Chen teaches the encapsulation of C2C12 myoblast cells in hydrogel microfibers (abstract; “Materials and Methods”). As evidenced by Diokmetzidou, C2C12 cells were originally derived from satellite cells from the thigh muscle of a mouse (pg. 437-438, “2.4.1 Skeletal Muscle: C2C12”), and are therefore interpreted as myogenic. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to substitute the C2C12 myoblast cells taught by Chen into the hydrogel of the modified Kuang. As noted above, the hydrogels of Kuang are taught to encapsulate human mesenchymal stem cells (abstract) which offer a promising cell source for musculoskeletal regenerative engineering (pg. 1, “Introduction”, paragraph 1). The C2C12 myoblast cells of Chen are taught to be encapsulated in hydrogel microfibers (abstract; “Materials and Methods”) which can provide applications in the field of muscle regeneration (“Conclusions”). Simple substitution of one cell known in the art for use in encapsulated hydrogels for the regeneration of muscle for another is within the purview of the skilled artisan and would yield predictable results (see MPEP 2143 I. B.). Regarding instant claim 21, the limitation that “wherein, at 4 weeks post-implantation of the hydrogel on a damaged muscle tissue, there are no substantial macroscopic differences in the damaged muscle tissue as compared to an uninjured muscle tissue” is a property of the hydrogel that does not structurally limit the claimed hydrogel. Given that the prior art combination of Kuang in view of Song and Chen renders obvious (as described above) and arrives at the structural components of the hydrogel of instant claim 8, the property recited in instant claim 21 would necessarily follow, absent evidence to the contrary. Response to Arguments Applicant’s arguments filed 02/20/2026 have been fully considered. Regarding the claim rejections under 35 USC § 103, Applicant argues that Kuang does not indicate routine optimization would produce a degree of substitution at about 47%. Particularly, Applicant argues that Kuang does not identify pH as a results-effective variable for increasing thiol degree of substitution beyond the disclosed range of 18.2% to 38.3% and does not disclose any trend, linear relationship, or monotonic increase extending toward 47%, and does not suggest that further increases in pH would continue to increase DS, let alone approach 47%. Applicant argues that a 47% DS represents a substantial increase over 38.3%, and not a minor incremental adjustment, that constitutes a significant compositional shift in the modified polysaccharide. Applicant argues that optimization applies only where a parameter is recognized as affecting the result and where the skilled artisan would expect improvement through further adjustment. The Office has not identified any disclosure in Kuang indicating that DS values approaching 47% were attainable, desirable, or even contemplated. These arguments are unpersuasive. The Examiner respectfully maintains that Kuang teaches that pH is a result-effective variable affecting the chondroitin sulfate DS (pg. 5, column 1, paragraph 1). The Examiner further maintains that the ordinary skilled artisan would have been motivated to optimize the degree of substitution as Kuang further teaches that varying the thiol DS affects the gelation kinetics and stiffness of the resulting hydrogels (pg. 6, column 2, paragraph 2); stiffer hydrogels result in higher equilibrium FAK activity and enhanced actin protrusions (abstract). The Examiner maintains that the teachings of Kuang suggest that the ordinary skilled artisan could routinely optimize the pH of the reaction of Kuang to reach a desired DS of CS-SH and therefore the desired gelation kinetics and stiffness of hydrogels, and that optimization of these parameters is within the purview of the skilled artisan that is not an automaton. Regarding the argument that Kuang does not indicate that DS values approaching 47% were attainable, desirable, or even contemplated, the Examiner notes that it is the prior art of Song which teaches the desirability of thiol-modified chondroitin sulfate with a high degree of modification (exemplifying 47%), for use in cross-linked hydrogels for cell attachment and growth (see particularly abstract, Example 9, and column 30, Examples 14-2 and 14-3 of Song); the cross-linked hydrogels of Kuang are similarly taught to encapsulate human mesenchymal stem cells for musculoskeletal regenerative engineering. The test for obviousness is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller , 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Regarding the argument that a 47% DS represents a substantial increase over 38.3% that constitutes a significant compositional shift in the modified polysaccharide, the Examiner notes that the instant claims recite “about 47%”, and the instant specification does not provide a clear definition of the term “about”. Per [0018] of the specification (emphasis added), “In the present disclosure the term “about” can allow for a degree of variability in a value or range, for example , within 10%, within 5%, or within 1%”. The Examiner therefore cannot conclude that a DS of “about 47%” represents a “significant compositional shift” over the 38.3% exemplified by Kuang. Applicant further argues that Kuang expressly states that pH 7.2 was selected to avoid possible degradation of chondroitin sulfate and this express caution teaches away from indiscriminately increasing pH to drive higher substitution levels. A person of ordinary skill in the art would not have reasonably expected that further increasing the pH would predictably yield a structurally intact product with a DS of about 47%; rather, Kuang signals that stability, not maximization of substitution governs pH selection. Applicant refers to the enclosed IDS references as demonstrating that under very basic conditions (pH 12.10), chondroitin sulfate undergoes backbone cleavage, resulting in decreased molecular mass, and studies on related polysaccharides confirm that pH-dependent degradation proceeds through multiple mechanisms and is structure dependent. Increasing pH to drive higher apparent substitution may simultaneously reduce effective thiol functionality through side reactions, further undermining any reasonable expectation that a higher DS would be expected in a structurally and functionally intact material. Applicant argues that the Examiner must establish that pH affects DS and that a person at a person of ordinary skill would have had a reasonable expectation that adjusting pH would yield a degree of substitution of about 47% without unacceptable degradation of the polysaccharide backbone or loss of functional thiol groups. These arguments are unpersuasive. Particularly, regarding the argument that Kuang teaches away from pH higher than 7.2 and signals that stability, not maximization of substitution governs pH selection, the Examiner notes that Kuang teaches the process for thiolation of HA and CS wherein (emphasis added) “Then, a calculated amount of DTT, depending on designed thiol DS, was added to the flask and pH was adjusted to the range of 7–8 with 1 M NaOH” (pg. 2, “Thiolation of HA and CS”). This reasonably suggests to one of ordinary skill in the art that the pH range can be adjusted, including to a pH higher than 7.2, and does not result in unacceptable degradation for the purposes of forming the hydrogels of Kuang. Per MPEP 2123 I., “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989).” The Examiner further notes that the instant specification states at paragraphs [0070]-[0071] that thiolation and hydrogel formation were performed as previously reported, citing to Kuang. Thus, the evidence of record suggests that the methods described in Kuang will not result in an unacceptable amount of degradation. In view of the forgoing, and as set forth in the above rejection, the Examiner maintains that the balance of evidence suggests that the instant claims are prima facie obvious over the teachings of the modified Kuang. Conclusion 07-39 AIA Applicant’s arguments are considered unpersuasive. Accordingly, THIS ACTION IS MADE FINAL. 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 JUDITH M KAMM whose telephone number is (703)756-4575. The examiner can normally be reached M-F 8:00 am-4:30 pm EST. 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, Bethany Barham can be reached at (571)272-6175. 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. /BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611 /J.M.K./Examiner, Art Unit 1611 Application/Control Number: 17/233,594 Page 2 Art Unit: 1611 Application/Control Number: 17/233,594 Page 3 Art Unit: 1611 Application/Control Number: 17/233,594 Page 4 Art Unit: 1611 Application/Control Number: 17/233,594 Page 5 Art Unit: 1611 Application/Control Number: 17/233,594 Page 6 Art Unit: 1611 Application/Control Number: 17/233,594 Page 7 Art Unit: 1611 Application/Control Number: 17/233,594 Page 8 Art Unit: 1611 Application/Control Number: 17/233,594 Page 9 Art Unit: 1611 Application/Control Number: 17/233,594 Page 10 Art Unit: 1611 Application/Control Number: 17/233,594 Page 11 Art Unit: 1611 Application/Control Number: 17/233,594 Page 12 Art Unit: 1611 Application/Control Number: 17/233,594 Page 13 Art Unit: 1611 Application/Control Number: 17/233,594 Page 14 Art Unit: 1611
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