CTNF 17/049,237 CTNF 95281 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. Priority This application was filed on and is a U.S. national Stage application under 35 U.S.C. 371 of International Patent Application No. PCT/US2019/028558 filed 04/22/2019, which claims the benefit of the priority of US Provisional application 62/660379 filed 04/20/2018. 02-26 AIA Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Claim Status Claims 1-2, 4-28 are pending. Claim 3 is canceled. Claims 1 is amended. Claims 18-27 are withdrawn from consideration. Claims 1-2, 4-17 and 28 are being examined on the merits in this office action. Claim Rejections - Withdrawn The rejection of claims 1-2, 5, 8-14, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over US-Jha et al . (US20150352156A1– hereinafter “US-Jha”) in view of Jha et al . (Biomaterials 89 (2016) 136-147) and Liang et al . (Acta Biomaterialia 10 (2014) 1588–1600) is withdrawn in view of the arguments. The rejection of claims 4, 6-7, 15-16, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over US-Jha et al . (US20150352156A1– hereinafter “US-Jha”) in view of Jha et al . (Biomaterials 89 (2016) 136-147) and Liang et al . (Acta Biomaterialia 10 (2014) 1588–1600) as applied to claim 1 above, and further in view of Liu et al . (Biomed Res Int. 2018; 2018: 1984879), Hernandez et al . (Gels.2017 Sep; 3(3): 26), Xu et al . (Soft Matter. 2012;8(12):3280–3294) and Fenn et al . (J Biomed Mater Res B Appl Biomater. 2015; 104 (6): 1229–1236) is withdrawn in view of the arguments. Claim Rejections - 35 USC § 103 - New 07-06 AIA 15-10-15 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. 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. 07-20-02-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 1-2, 5, 8-14, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over US-Jha et al . (US20150352156A1– hereinafter “US-Jha”) in view Liang et al . (Acta Biomaterialia 10 (2014) 1588–1600*) and Kim et al . (ACS Appl. Mater. Interfaces 2017, 9, 8581−8588). *Reference supplied in previous office action . US-Jha teaches a hydrogel cell matrix that includes a plurality of hydrogel polymers; a cell adhesion peptide conjugated to one or more hydrogel polymers; and a cross-linker polymer that links one or more hydrogel polymers of the plurality of hydrogel polymers to another hydrogel polymer of the plurality. In certain embodiments, the hydrogel polymer is a hyaluronic acid (HyA) polymer. In specific embodiments, the hydrogel polymer is an acrylated hyaluronic acid (HyA) polymer and that the hydrogel cell matrix includes a factor release molecule conjugated to one or more hydrogel polymers, that the factor release molecule is heparin [0006-0011]. US-Jha teaches that the cell adhesion peptide has the amino acid sequence CGGNGEPRGDTYRAY (SEQ ID NO:1) [0010], and that the cross-linked peptide is CQPQGLAKC (SEQ ID NO:46) [0015]. US-Jha teaches that exogenous growth factors are used in other embodiments, which means that other embodiments only comprise heparin and not exogenous growth factors. US-Jha teaches that the HyA hydrogels were generated by in situ crosslinking of the HyA precursors with the MMP-13-cleavable peptide sequence CQPQGLAKC [0105-0106]. US-Jha does not explicitly teach a hydrogel system that is free of exogenous growth factors and biological cells. However, Examiner notes that one of ordinary skill in the art would be motivated to treat muscle loss with a hydrogel system that is free of exogenous growth factors and biological cells since Jha et al. teaches such a system and gives an option of including exogenous growth factors or use of endogenous growth factors. Regarding a hydrogel free of exogenous growth factors and biological cells, Liang teaches hydrogel system comprising heparin and hyaluronic acid (Page 1590, left col. Section 2.1.1, line 1-7), and further teaches that heparin-based hydrogels without addition of any exogenous growth factors exhibited effective redifferentiation and production of expected glycosaminoglycans (GAGs) and ECM proteins within a week (Page 1591, right col., 2 nd paragraph, line 15-19). Liang teaches that the hydrogels have the ability to sequester endogenous growth factors (Page 1591, right col., 2 nd paragraph, line 28-29). Further, Kim teaches a cell-free hydrogel system containing protein such as heparan and that the hydrogel significantly enhanced host-derived adipogenesis and angiogenesis without exogenous cells or bioactive molecules e.g. growth factors (Title; Abstract; Table 1). Kim teaches that the cell-free hydrogel for use for tissue regeneration (Page 8486, right col., last paragraph). Kim teaches that cell-free hydrogel system is preferred in order to avoid immune rejection, limited survival and retention after treatment, and difficulties of controlling cell fate (Page 8581, left col., “Introduction” section, 1 st paragraph). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method taught by US-Jha and use a hydrogel system free of exogenous growth factors and biological cells to treat VML since Liang teaches that a heparin-based hydrogels without addition of any exogenous growth factors exhibited effective redifferentiation and production of expected glycosaminoglycans (GAGs) and Kim teach that a cell-free hydrogel system containing protein such as heparan and that the hydrogel significantly enhanced host-derived adipogenesis and angiogenesis. One of ordinary skill in the art would be motivated and would have had a reasonable expectation of success in using a hydrogel system comprising heparin and hyaluronic acid that is free exogenous growth factors and biological cells since Kim teaches that a hydrogel system without exogenous cells or bioactive molecules e.g. growth factors is preferred in order to avoid immune rejection, limited survival and retention after treatment, and difficulties of controlling cell fate (Page 8581, left col., “Introduction” section, 1 st paragraph). With regards to the recitation of “20% and about 90% muscle recovery, Examiner notes that MPEP 2111.04 states: claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. In the instant case, the limitation expresses the intended result of the method step of claim 1 and is given little patentable weight. The disclosures render obvious claim 1. Regarding claim 2, US-Jha teaches a cell adhesion peptide conjugated to one or more hydrogel polymers; and a cross-linker polymer that links one or more hydrogel polymers of the plurality of hydrogel polymers to another hydrogel polymer of the plurality, that the hydrogel cell matrix includes a factor release molecule conjugated to one or more hydrogel polymers, and that the factor release molecule is heparin [0006-0011]. Regarding claims 5 and 8, US-Jha teaches a cell adhesion peptide conjugated to one or more hydrogel polymers; and a cross-linker polymer that links one or more hydrogel polymers of the plurality of hydrogel polymers to another hydrogel polymer of the plurality, that the hydrogel cell matrix includes a factor release molecule conjugated to one or more hydrogel polymers, and that the factor release molecule is heparin [0006-0011]. US-Jha teaches lyophilization of the system [0103-0104]. Regarding claim 9, US-Jha teaches wherein the hydrogel polymer is a hyaluronic acid (HyA) polymer or an acrylated hyaluronic acid (HyA) polymer (claim 2; [0006-0008]). Regarding claim 10, US-Jha teaches a cell adhesion peptide conjugated to one or more hydrogel polymers [0006-0009]. Regarding claims 11-12, US-Jha teaches wherein the cell adhesion peptide comprises the amino acid sequence RGD and that the cell adhesion peptide has the amino acid sequence CGGNGEPRGDTYRAY (SEQ ID NO: 1) [0010, 0012]. Regarding claim 13, US-Jha teaches wherein the cross-linked peptide is CQPQGLAKC (SEQ ID NO:45) [0015, 0061, 00105]. Regarding claim 14, Liang teaches that the heparin has average molecular weight of about 15 kDa (Page 1588, right col.1 st paragraph). It would have been obvious to use the heparin taught by Liang since Liang teaches comprising the instant heparin and hyaluronic acid and teaches that the heparin had a longer half-life. Regarding claim 17, US-Jha teaches that the subject is a human [0084] . 07-22-aia AIA Claim s 4, 6-7, 15-16, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over US-Jha et al . (US20150352156A1– hereinafter “US-Jha”) in view of Liang et al . (Acta Biomaterialia 10 (2014) 1588–1600) and Kim et al . (ACS Appl. Mater. Interfaces 2017, 9, 8581−8588) as applied to claim 1 above, and further in view of Liu et al . (Biomed Res Int. 2018; 2018: 1984879*), Hernandez et al . (Gels.2017 Sep; 3(3): 26*), Xu et al . (Soft Matter. 2012;8(12):3280–3294*) and Fenn et al . (J Biomed Mater Res B Appl Biomater. 2015; 104 (6): 1229–1236*). *Reference supplied in previous office action . The teachings of US-Jha, Liang and Kim are disclosed above and incorporated herein by reference. US-Jha does not teach does not teach suturing the crosslinked hydrogel matrix in place as recited in claim 4, and does not teach wherein the administering comprises placing a removable mold on injury site and removing the mold after 10 minutes as recited in claim 28. Liu teaches hydrogels derived from decellularized skeletal muscle matrix have been shown to enhance the proliferation of skeletal myoblasts when injected into an ischemic rat limb, for repair of VML (Page 3, right col., 3 rd paragraph, line 1-16) and that synthetic scaffolds can be easily engineered to facilitate the controlled release of growth factors for inducing muscle regeneration (Page 3, right col., 2 nd paragraph, line 6-9) and that growth factors such as IGF-1 and TGF-ß1 can drive endogenous skeletal muscle regeneration (Page 4, left col., section 3.3, lines 1-4). Hernandez teaches a bioactive hydrogel or a hybrid system consisting of 3D printed polycaprolactone (PCL) filled with hydrogel was developed as an application for reconstruction of long bone defects (Abstract). Hernandez teaches hydrogel implant can be applied to an in vivo application within a desired and short time frame (Section 2.3, 1 st paragraph). Examiner notes that “short time frame” reads on removable. Hernandez further teaches using the scaffold as a sheet (Section 3 – discussion, 1 st paragraph). With regards to placing a removable mold, Xu teaches hyaluronic acid-based hydrogels that comprise heparin (Page 2, 1 st paragraph). Xu teaches a micromolding approach for the preparation of shape-controlled hydrogels and that after crosslinking via exposure to UV light, the microgels were removed (Page 10, 1 st paragraph). Further, Fenn teaches hyaluronan hydrogels for tissue repair and teaches crosslinking of the hydrogel and that the molds were exposed to light for 10 minutes for crosslinking to occur (Page 4, 3 rd paragraph). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify US-Jha and include the teachings of Liu, Hernandez, Xu, and Fenn and administer the crosslinked hydrogel as a mold and remove it after 10 minutes as taught by Xu and Fenn to allow for crosslinking. One of ordinary skill in the art would be motivated and would have had a reasonable expectation of success in using the hydrogel system as taught by Liu, Hernandez, Xu, and Fenn since the references all relate to a hyaluronic hydrogel system and successfully teaches suturing it to the injury site and as a removable mold. Regarding claim 4, Liu teaches the treatment wherein the matrix is sutured at the defect corners and subcuticularly closed with a vicryl-suture (Page 3, section 2.4, line 20-21). It would have been obvious to one of ordinary skill in the art to suture the hydrogel system to the injury site since Liu teaches that this method helped with skeletal muscle repair (Abstract). Regarding claims 6-7, Hernandez teaches a bioactive hydrogel or a hybrid system consisting of 3D printed polycaprolactone (PCL) filled with hydrogel was developed as an application for reconstruction of long bone defects (Abstract). Hernandez teaches hydrogel implant can be applied to an in vivo application within a desired and short time frame (Section 2.3, 1 st paragraph). Hernandez further teaches using the scaffold as a sheet (Section 3 – discussion, 1 st paragraph). Further, Liu teaches polymers that comprises freeze-dried scaffolds (Page 3, 1 st paragraph, line 1-8). It would have been obvious to one of ordinary skill in the art to freeze dry the hydrogel system as sheet and freeze-dried scaffolds as taught by Hernandez so as to accelerate the regeneration of the damaged tissue (Section 3). Regarding claims 15-16, Liu teaches that the hydrogels resulted in functional recovery, revascularization, and reinnervation in lacerated muscles (Page 4, line 1-2). Further, with regards to the limitation “…improved muscle vascularization…or increased muscle function…”, Examiner notes that MPEP 2111.04 states: claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. In the instant case, the limitation expresses the intended result of the method step of claim 1 and is given little patentable weight. Regarding claim 28, Hernandez teaches a bioactive hydrogel or a hybrid system consisting of 3D printed polycaprolactone (PCL) filled with hydrogel was developed as an application for reconstruction of long bone defects (Abstract). Hernandez teaches hydrogel implant can be applied to an in vivo application within a desired and short time frame (Section 2.3, 1 st paragraph). Examiner notes that “short time frame” reads on removable. Hernandez further teaches using the scaffold as a sheet (Section 3 – discussion, 1 st paragraph). Further, Xu teaches hyaluronic acid-based hydrogels that comprise heparin (Page 2, 1 st paragraph). Xu teaches a micromolding approach for the preparation of shape-controlled hydrogels and that after crosslinking via exposure to UV light, the microgels were removed (Page 10, 1 st paragraph). Examiner notes that this reads on removable mold. Further, Fenn teaches hyaluronan hydrogels for tissue repair and teaches crosslinking of the hydrogel and that the molds were exposed to light for 10 minutes for crosslinking to occur (Page 4, 3 rd paragraph). One of ordinary skill in the art would be motivated to administer the hydrogel system of US-Jha as a removable mold and removed after 10 minutes so as to accelerate the regeneration of the damaged tissue a taught by Hernandez (Section 3) . Response to Arguments 07-38-02 AIA Applicant’s arguments, see Applicant Arguments , filed 03/18/2026 , with respect to the rejection(s) of claim(s) 1-2, 4-17 and 28 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Kim et al . Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mercy H. Sabila whose telephone number is (571)272-2562. The examiner can normally be reached Monday - Friday 5:00 am - 3:00 pm. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571)270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /MERCY H SABILA/Examiner, Art Unit 1654 /LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654 Application/Control Number: 17/049,237 Page 2 Art Unit: 1654 Application/Control Number: 17/049,237 Page 3 Art Unit: 1654 Application/Control Number: 17/049,237 Page 4 Art Unit: 1654 Application/Control Number: 17/049,237 Page 5 Art Unit: 1654 Application/Control Number: 17/049,237 Page 6 Art Unit: 1654 Application/Control Number: 17/049,237 Page 7 Art Unit: 1654 Application/Control Number: 17/049,237 Page 8 Art Unit: 1654 Application/Control Number: 17/049,237 Page 9 Art Unit: 1654 Application/Control Number: 17/049,237 Page 10 Art Unit: 1654 Application/Control Number: 17/049,237 Page 11 Art Unit: 1654 Application/Control Number: 17/049,237 Page 12 Art Unit: 1654
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