The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election without traverse of Group VI, claims 16-19, in the reply filed on March 25, 2026 is acknowledged.
Claims 1-15 are withdrawn. Claims 16-19 are under consideration.
Priority: This application claims benefit to foreign applications CN 2022112245930, filed October 8, 2022, and CN 2022113785160, filed November 4, 2022. Copies of the foreign priority documents have been received in the instant application on January 13, 2024 and are not in the English language.
Claim Objections
Claim 1 is objected to because of the following informalities: in claim 1, the terms “EDC/sNHS” should be spelled out in full the first time that they are recited in the claims. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 16-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 16 recites the limitation "the preparation method" in the claim. There is insufficient antecedent basis for this limitation in the claim.
The claims are generally narrative and indefinite, failing to conform with current U.S. practice. They appear to be a literal translation into English from a foreign document and are replete with grammatical and idiomatic errors. For instance, in claim 16, the steps recite dissolving polymer derivative in a buffer solution, “added” with EDC/sNHS solution for reaction. The verb tenses are not consistent throughout the claim(s). Additionally, claim 16 recites wherein an amino acid sequence of the recombinant collagen protein comprises N basic repetitive units and the basic repetitive unit comprises n1 amino acid sequence with the following characteristic: “G-Xaa1-Xaa2-G-E-Xaa3”. It is not clear if the amino acid sequence comprises the unit “G-Xaa1-Xaa2-G-E-Xaa3” since the claim recites that it is just a characteristic of the recombinant collagen protein. Further, it is not clear what the residues Xaa1, Xaa2, and Xaa3 are. Further clarification and/or correction is requested. Further, the steps recited does not need to be capitalized.
Claims 17-18 are rejected under 112(b) for the reasons similarly noted above for instant claim 16. Further, claim 17 recites a molecular weight cut-off of 8,000-14,000; however it is not clear what the units for the molecular weight cut-off are. Further clarification and/or correction is requested.
Claim 19 is confusing because it is drawn to a different method but is dependent on the method of claim 16. Claim 16 is not a product-by-process claim drawn to a cartilage repair matrix. Claim 19 should clarify that is dependent on the method of claim 16 and further comprises the step of mixing chondrocytes or bone marrow mesenchymal stem cells, and so forth. Further clarification and/or correction is requested.
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.
Claims 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Shoseyov et al. (US 20210138113) in view of G-Biosciences (High Efficiency & Stability Protein Crosslinking with EDC & NHS 2017: 2 pages) and Yang (US 20200165319). Shoseyov et al. disclose dermal filler composition comprising different formulations, including a formulation comprising a crosslinked network comprising rhCollagen (recombinant human collagen) and MA-HA (at least paragraphs 0241, 0244, 0251). Shoseyov et al. disclose methacrylate is an ester or salt derived from methacrylic acid; addition of methacrylate results in collagen methacrylate (rhCollagen-MA or MA-rhCollagen) which is photocurable; addition of methacrylate groups to hyaluronic acid (HA) results in hyaluronic acid-methacrylate (HAMA or MA-HA) which is photocurable (at least paragraph 0221). Shoseyov et al. disclose a formulation comprising rhCollagen and crosslinked hyaluronic acid comprising crosslinked and non-crosslinked hyaluronic acid (at least paragraphs 0034-0037), the crosslinker is selected from among others EDC (l-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide) (at least paragraph 0038). Shoseyov et al. disclose a method for preparing a dermal filler formulation comprising dissolving hyaluronic acid in a buffer solution comprising a crosslinker, where the hyaluronic acid comprises methacrylate-HA, adding rhCollagen to the solution, dialyzing the rhCollagen-methacrylate-HA material, adding photoinitiator to the rhCollagen-methacrylate-HA material solution (at least paragraphs 0039-0046, 0074, examples 21-24). Shoseyov et al. disclose that in one aspect, the composition comprising rhCollagen and MA-HA is a solution for use inducing a cell growth promoting scaffold, comprising introducing a polymerizable solution into a tissue space under an epidermis, the polymerizable solution comprising the rhCollagen and MA-HA and a photo-initiator (at least paragraphs 0076-0090), the cellular growth promoting scaffold promotes healing or replacement due to degradation or injury of a collagen-comprising tissue selected from among others cartilage (at least paragraphs 0226-0231). Shoseyov et al. disclose do not teach sNHS with the EDC crosslinker or that the rhCollagen comprises the basic repetitive unit “G-Xaa1-Xaa2-G-E-Xaa3”.
G-Biosciences discloses that EDC is the most popular zero-length crosslinker for biochemical conjugations because it can efficiently form conjugates between two protein molecules (p. 1). G-Biosciences discloses that another advantageous quality of EDC is that it is water soluble and dissolves in aqueous buffer solutions (p. 1). G-Biosciences discloses that for higher coupling efficiency and more stable amine-reactive intermediates, EDC crosslinking protocols often include N-hydroxysuccinimide (NHS) or its water-soluble analog (sulfo-NHS) (p. 1).
Yang discloses a recombinant human collagen that has stronger cell adhesion and higher stability in aqueous solution (at least paragraph 0028). Yang discloses the recombinant human collagen comprising the polypeptide of SEQ ID NO: 3, where SEQ ID NO: 3 comprises the basic repetitive unit “G-Xaa1-Xaa2-G-E-Xaa3” repeated more than 4 times.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the prior art references and arrive at the claimed method for preparing a matrix, comprising dissolving MA-HA in solution with EDC/sNHS, adding a recombinant collagen comprising the basic repetitive unit “G-Xaa1-Xaa2-G-E-Xaa3” repeated more than 4 times to the HA-MA solution, dialyzing the recombinant collagen-MA-HA solution, and adding a photoinitiator to the recombinant collagen-MA-HA solution (instant claim 1). The motivation to do so is given by the prior art. Shoseyov et al. disclose a method for preparing a collagen/hyaluronic acid composite scaffold composition comprising bringing together essentially the same components recited, i.e. MA-HA, EDC, and recombinant collagen, to form the same composition recited, i.e. a collagen/hyaluronic composite scaffold or matrix. G-Biosciences discloses that for higher coupling efficiency and more stable amine-reactive intermediates, EDC crosslinking protocols often include NHS or its sulfo-NHS. Yang discloses a recombinant human collagen having stronger cell adhesion and higher stability in aqueous solution, comprising the instant basic repetitive unit “G-Xaa1-Xaa2-G-E-Xaa3” repeated more than 4 times (see SEQ ID NO: 3 of Yang). Therefore, one of ordinary skill would have reasonable motivation to incorporate the sulfo-NHS of G-Biosciences with the EDC in the method of Shoseyov et al. and further incorporate the recombinant collagen of Yang for the recombinant collagen in the method of Shoseyov et al. noted above for preparing a collagen/hyaluronic acid composite scaffold composition because there is interest in forming collagen/hyaluronic acid compositions and/or scaffolds for tissue repair. One of ordinary skill would have a reasonable expectation of success because the materials, components, and steps for forming a collagen/hyaluronic acid composite matrix are known and recognized in the prior art.
Additionally, regarding the instant “drying” step after dialyzing the recombinant collagen-MA-HA solution (instant claim 1), Shoseyov et al. disclose that solutions of collagen or MA-HA can be lyophilized after dialyzing (at least paragraphs 0519-0521, 0560); therefore, it would be obvious to one of ordinary skill that the recombinant collagen-MA-HA solution in the method of Shoseyov et al., G-Biosciences, and Yang above, can be dried after dialyzing, before addition of the photoinitiator in solution.
Regarding instant claim 17, it is known that “[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). MPEP 2144.05. Shoseyov et al. disclose dissolving lower weight HA (50 KDa to 1000 KDa) comprising MA-HA at 1-30% of the total HA amount at a concentration 10-100 mg/mL, addition of crosslinker at a ratio of 1-50% crosslinker to HA, reaction time 24 hr., in buffer solution (at least paragraphs 0044, 0611-0613, 0614, 0615-0617). G-Biosciences discloses an EDC concentration of 0.4 mg and sulfo-NHS concentration of 1.1 mg, reaction time 2 hr., in buffer solution (p. 1-2). Shoseyov et al. disclose addition of the recombinant rhCollagen at a ratio range of MA-HA:rhCollagen including 6:1 to 1:6, reaction time 2-3 hr., dialysis in buffer solution (at least paragraphs 0621-0625). Shoseyov et al. disclose a dialysis bag having a MWCO 14,000 Da (at least paragraph 0479). As noted above, Shoseyov et al. disclose that solutions of collagen or MA-HA can be lyophilized after dialyzing (at least paragraphs 0519-0521, 0560); therefore, it would be obvious to one of ordinary skill that the recombinant collagen-MA-HA solution in the method of Shoseyov et al., G-Biosciences, and Yang above, can be dried after dialyzing, before addition of the photoinitiator in solution. Shoseyov et al. disclose a recombinant collagen-MA-HA solution comprising photoinitiator, the concentration of HA 12-25 mg/mL, concentration of recombinant collagen 1-24 mg/mL (at least examples 24-25). Therefore, it would have been obvious to arrive at the recited conditions comprising a HA molecular weight within 100-1500 kDA, grafting degree within 20-60%, 0.5-5mM EDC and sulfo-NHS resulting in pH adjustment 5 to 7 for the reaction, a reaction time 2-5hr.; a recombinant collagen to MA-HA ratio including 1:6 and a reaction conjugation time 5-15 hrs., dialyzing at a MWCO 14,000 Da in an aqueous solution for 2-4 days, lyophilizing to obtain a recombinant collagen-MA-HA composite matrix, obtaining a solution of the recombinant collagen-MA-HA with a photoinitiator where the concentration of the recombinant collagen-MA-HA is within 2-30 mg/mL by routine optimization because the recited conditions for obtaining a photocurable collagen-HA composite matrix are similar to the conditions disclosed in the prior art for obtaining a collagen-HA composite matrix that is photocurable.
Regarding instant claim 18, for the reasons similarly noted above for instant claim 17, it would have been obvious to arrive at the recited conditions comprising a HA molecular weight within 300-600 kDA, grafting degree within 30-50%, 0.5-5mM EDC and sulfo-NHS resulting in pH adjustment 5 to 7 for the reaction, a reaction time 2-5hr.; a recombinant collagen to MA-HA ratio including 1:6 and a reaction conjugation time 8-12 hrs., dialyzing at a MWCO 14,000 Da in an aqueous solution for 2-4 days, lyophilizing to obtain a recombinant collagen-MA-HA composite matrix, obtaining a solution of the recombinant collagen-MA-HA with a photoinitiator where the concentration of the recombinant collagen-MA-HA is within 2-30 mg/mL by routine optimization because the recited conditions for obtaining a photocurable collagen-HA composite matrix are similar to the conditions disclosed in the prior art for obtaining a collagen-HA composite matrix that is photocurable.
Claims 16-18, 19 are rejected under 35 U.S.C. 103 as being unpatentable over Shoseyov et al. (US 20210138113) in view of G-Biosciences (High Efficiency & Stability Protein Crosslinking with EDC & NHS 2017: 2 pages), Yang (US 20200165319), and Brigham et al. (2009 Tissue Engineering: Part A 15(7): 1645-1653). The teachings of Shoseyov et al., G-Biosciences, and Yang over at least instant claims 16-18 are noted above.
Regarding instant claim 19, as noted above, Shoseyov et al. disclose that in one aspect, the composition comprising rhCollagen and MA-HA is a solution for use inducing a cell growth promoting scaffold, comprising introducing a polymerizable solution into a tissue space under an epidermis, the polymerizable solution comprising the rhCollagen and MA-HA and a photo-initiator (at least paragraphs 0076-0090), the cellular growth promoting scaffold promotes healing or replacement due to degradation or injury of a collagen-comprising tissue selected from among others cartilage (at least paragraphs 0226-0231). Shoseyov et al. disclose the monomer solution can contain additional materials including pharmacologically active molecules, cells, and so on (at least paragraph 0226). Shoseyov et al. disclose an illuminating means for activating the photoinitiator, and which can activate the photoinitiator from outside of the body (at least paragraph 0225). Shoseyov et al. do not explicitly teach the cells are chondrocytes.
Brigham et al. disclose photo-cross-linkable HA and collagen in a hydrogel network have favorable mechanical properties and are suitable for cell encapsulation at high levels of cell viability (p. 1645). Brigham et al. disclose chondrocytes can be photoencapsulated in HA networks (p. 1652).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate chondrocytes as disclosed in Brigham et al. in the polymerizable solution comprising recombinant collagen-MA-HA and a photoinitiator obtained in the method of Shoseyov et al., G-Biosciences, and Yang noted above and further inject the polymerizable solution comprising chondrocytes and recombinant collagen-MA-HA into a tissue space or site of cartilage damage and activating the polymerizable solution by light exposure (instant claim 19). The motivation to do so is given by the prior art, which disclose developing photo-cross-linkable collagen-hyaluronic hydrogels comprising encapsulated cells for tissue repair. One of ordinary skill would have a reasonable expectation of success because the materials, components, and steps for forming a collagen/hyaluronic acid composite matrix are known and recognized in the prior art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 16-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application No. 18483493 (‘493) (reference application) in view of Shoseyov et al. (supra), G-Biosciences (supra) and Brigham et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘493 application claims are drawn to a method for preparing or forming a recombinant collagen-hyaluronic acid matrix comprising combining solutions of photo-crosslinkable hyaluronic acid and recombinant collagen comprising repeats of “G-Xaa1-Xaa2-G-E-Xaa3” and a photoinitiator. The ‘493 application claims differ from the instant claims by not explicitly reciting sNHS, adding chondrocytes to the recombinant collagen-hyaluronic acid solution, and/or the reaction conditions. However, in view of the teachings of Shoseyov et al., G-Biosciences, and Brigham et al. noted above, it would have been obvious to incorporate the crosslinking conditions, including EDC with sulfo-NHS, for crosslinking recombinant collagen and MA-HA and a photoinitiator, in combination with chondrocytes, as noted above, in the ‘493 application claims because EDC with sulfo-NHS is a recognized and known crosslinking method and developing photo-cross-linkable collagen-hyaluronic hydrogels comprising encapsulated cells for tissue repair is known. One of ordinary skill would have a reasonable expectation of success because the materials, components, and steps for forming a collagen/hyaluronic acid composite matrix are known and recognized in the prior art.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
No claim is allowed.
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/Marsha Tsay/Primary Examiner, Art Unit 1656
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