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 (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.
Current Status of 18/784,840
This Office Action is responsive to the amended claims received 7 May 2025.
Claims 1-13 are currently pending.
Priority
Applicant’s claim for the benefit of the prior-filed patent applications 17/862,962 (filed 12 July 2022), 63/220,865 (filed 12 July 2021, and 63/220,859 (filed 12 July 2021) under 35 U.S.C. 119(e), 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) received on 25 July 2024 and 20 February 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, these information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities: Fig. 1 is described as having an insert image in the specification, but Fig. 1 does not have an insert image. Appropriate correction is required.
Claim Objections
Claim 7 is objected to because of the following informalities: The phrase “wherein the growth factor further is sonic hedgehog” should be amended to read “wherein the growth factor is sonic hedgehog” to aid readability. 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 4 and 6 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 4 recites “adding 1/10th the mass of 0.4% alginate in the heparinized form”. The meaning of this limitation is unclear. One could interpret the limitation to suggest that the artisan calculate the mass of alginate in the 4 % sodium alginate solution, and then add heparinized alginate equivalent to 10 % of the calculated mass. Or, one could interpret the limitation to indicate that the artisan should calculate 1/10th of the total mass of the sodium alginate solution, and then add that mass of heparinized alginate to the solution. Applicant may choose to amend the claim to make one of these choices clear.
Claim 6 recites the limitation “2% alginate solution with 0.2% lyophilized heparinized alginate” in section (a). This limitation renders claim 6 indefinite, because it is unclear how a solution could contain a lyophilized material and it is unclear what “0.2%” is referring to. This could, for example, indicate that 0.2 % of the mass of the solution is heparinized alginate or that 0.2 % of the alginate in the solution is heparinized alginate.
Claim 6 recites obtaining a solution 2 % alginate and 0.2 % heparinized alginate solution (step a) and adding collagen to reach a heparinized alginate concentration of 1 %. It is not clear how adding collagen could increase the concentration of heparinized alginate in the solution. This renders claim 6 indefinite.
Claim 6 recites “mixing a CaCO3 solution in a remaining available volume”. It is not clear if a CaCO3 solution is simply being “mixed” in the normal English sense of the word, meaning mechanically agitated, or if the solution is being mixed with another material or solution. The meaning of the remaining volume is also unclear, because no volume was previously discussed.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 3 restates a limitation already present in its parent claim. Claim 3 fails to further limit claim 2.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Interpretation
The Examiner is interpreting the term “heparin-alginate”, present in instant claims 2 and 5, to indicate a compound wherein heparin is covalently bound to alginate, as is discussed in the parent claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 10-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
ROUNTREE (Rountree, I.; Polucha, C.; Coulombe, K.L.K.; Munarin, F. “Assessing the Angiogenic Efficacy of Pleiotrophin Released from Injectable Heparin-Alginate Gels” TISSUE ENGINEERING: Part A, Volume 27, Numbers 11 and 12, January 2021).
The authors of ROUNTREE differ from the instantly listed inventors.
ROUNTREE teaches an injectable hydrogel (abstract) containing pleiotrophin (PTN, taught to be a growth factor in the introduction section), covalently-linked heparin-alginate (synthesis of heparin-alginate method section), and collagen (last paragraph of Pg. 706), which is caused to gel using a 0.15 M CaCl2 or 5 mg/mL CaCO3 solution (7th paragraph Pg. 704). ROUNTREE also teaches that these hydrogels are useful for regeneration of ischemic tissues (abstract). ROUNTREE specifically teaches the following method for producing hydrogels: mixing 2 % alginate with 0.2 % heparin-alginate and then mixing that solution with calcium carbonate to reach final concentrations of 1 % alginate and 5 mg/mL CaCO3. ROUNTREE also teaches the following alternative method: mixing 1 % alginate with 0.1 % heparin-alginate and then mixing that solution with 0.15 M CaCl2.
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 1-2, 5, 8, 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over:
ZUO (Cited by Applicant in IDS of 25 July 2024, Zuo, Q.; Guo, R.; Liu, Q.; et al. “Heparin-conjugated alginate multilayered microspheres for controlled release of bFGF” Biomed. Mater. 10 (2015) 035008)
in view of:
GONZALEZ (Cited by Applicant in IDS of 25 July 2024, Gonzalez-Pujana, A.; Vining, K.H.; Zhang, D.K.Y.; et al. “Multifunctional biomimetic hydrogel systems to boost the immunomodulatory potential of mesenchymal stromal cells” Biomaterials 257 (2020) 120266).
ZUO teaches that heparin was covalently linked to alginate using EDC/NHS chemistry (section 2.2). ZUO teaches that “H-Alg” refers to heparin covalently conjugated to alginate therein (sections 2.2 and 3.1). ZUO teaches the preparation of H-Alg microspheres through the following process: dissolving sodium alginate and H-Alg in phosphate-buffered saline, adding basic fibroblast growth factor (bFGF), spraying the solution into a 0.27 M (30 mg/mL) solution of CaCl2 with 10mg/mL BSA, and washing and collecting the microspheres (section 2.3). ZUO teaches that previous efforts used a collagen/gelatin sponge containing bFGF for the sustained release of bFGF (introduction section). ZUO teaches that the H-Alg solution was produced at a concentration of 20 mg/mL, which is equivalent to a 2 % solution (section 2.2). ZUO teaches that “Research on sustained release of bFGF have [sic] been reported previously”, and cites a reference (18) titled “Preparation of gelatin microspheres encapsulated with bFGF for therapeutic angiogenesis in a canine ischemic hind limb” (introduction and references sections). Therefore, ZUO teaches that the treatment of ischemic tissue with bFGF-releasing systems of the general type taught by ZUO was known in the art. ZUO additionally teaches the loading of the heparinized alginate solution into a syringe (section 2.3).
ZUO does not explicitly teach the addition of collagen to the H-Alg microspheres therein.
GONZALEZ teaches an artificial extracellular matrix (aECM) hydrogel made up of interpenetrating network of alginate and collagen, and teaches the combination of this material with heparin-coated beads to form an alginate-collagen-heparin hydrogel (introduction). IFN-gamma, an endogenous cytokine protein, was also present within this hydrogel (introduction). In this manner, GONZALEZ teaches the production of a hydrogel made up of alginate, collagen, heparin, and a biologically active protein. GONZALEZ specifically teaches the use of rat-tail collagen (8-11 mg/mL), being added to HEPES buffer, and adjusted to a pH of 7 with NaOH for use in a hydrogel composition within section 2.3. GONZALEZ also teaches the use of sterile materials, the mixing of various hydrogel reagents, and gelation within section 2.3. Additionally, GONZALEZ teaches the use of calcium ions to cause crosslinking of alginate hydrogels within Figure 2, and the specific use of a calcium carbonate solution to crosslink alginate hydrogels (section 2.3). GONZALEZ also teaches “Presentation of collagen-I matrix in the hydrogels mimics the collagen-rich architecture of native extracellular matrix (ECM), which promotes hMSCs [(bone-marrow derived primary human mesenchymal stromal cells)] survival” (introduction).
It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, to combine the collagen taught by GONZALEZ with the heparinized alginate system of ZUO, for the purpose of increasing the biocompatibility of the hydrogel as was taught by GONZALEZ. The artisan would have expected success in this combination, because both references teach alginate-heparin-bioactive protein systems.
Regarding claims 2 and 5: GONZALEZ teaches that 8-11 mg/mL rat tail collagen was diluted before being added to the alginate solution (section 2.3), but the exact concentration of the collagen when alginate was added is not clear. One of ordinary skill in the art would have read this teaching of GONZALEZ to indicate the addition of alginate to >8 mg/mL rat tail collagen. The instantly claimed values of 2-6 mg/mL and 0.5-2 mg/mL collagen fall entirely within the range taught by GONZALEZ. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). See MPEP 2144.05(I).
It would have been obvious to one of ordinary skill in the art to exchange the calcium chloride, taught by ZUO, with the calcium carbonate, taught by GONZALEZ, for the purpose of optimizing the particular calcium salt used in the method. The artisan would have expected success in this replacement, because both calcium salts cause gelation in their respective hydrogel preparation methods.
Claims 1-2, 5, 8-13 are rejected under 35 U.S.C. 103 as being unpatentable over:
ZUO (Cited by Applicant in IDS of 25 July 2024, Zuo, Q.; Guo, R.; Liu, Q.; et al. “Heparin-conjugated alginate multilayered microspheres for controlled release of bFGF” Biomed. Mater. 10 (2015) 035008)
in view of:
GONZALEZ (Cited by Applicant in IDS of 25 July 2024, Gonzalez-Pujana, A.; Vining, K.H.; Zhang, D.K.Y.; et al. “Multifunctional biomimetic hydrogel systems to boost the immunomodulatory potential of mesenchymal stromal cells” Biomaterials 257 (2020) 120266)
and in view of:
SON (Cited by Applicant in IDS of 25 July 2024, Son, J.; Bae, C.Y.; Park, J. “Construction of Modular Hydrogel Sheets for Micropatterned Macro-scaled 3D Cellular Architecture” Journal of Visualized Experiments, January 2016 | 107 | e53475 | Pages 1-6).
Teachings of ZUO and GONZALEZ are discussed above.
Regarding claim 9: Neither ZUO nor GONZALEZ clearly teach the production of a thin-film from the hydrogels therein.
PARK teaches that the handleability of an alginate-containing hydrogel is increased by producing thin-films of the hydrogel (PARK abstract). PARK teaches the addition of an alginate solution into a hydrophilic mold, with the addition of a CaCl2 solution to cause crosslinking within the alginate. This produces a thin-film from the hydrogel (see sections 2-3 of the Protocol section). According to PARK, the hydrogel film is removed from the hydrophilic mold by washing with PBS (see section 4 of the Protocol section).
It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, to produce a thin-film form of the hydrogel taught by ZUO, for the purpose of increasing the handleability of the hydrogel, as taught by PARK. The artisan would have expected success in this combination, because both references teach alginate-containing hydrogels that are caused to gel via the addition of calcium ions.
Claims 1-2, 5, 7-8, 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over:
ZUO (Cited by Applicant in IDS of 25 July 2024, Zuo, Q.; Guo, R.; Liu, Q.; et al. “Heparin-conjugated alginate multilayered microspheres for controlled release of bFGF” Biomed. Mater. 10 (2015) 035008)
in view of:
GONZALEZ (Cited by Applicant in IDS of 25 July 2024, Gonzalez-Pujana, A.; Vining, K.H.; Zhang, D.K.Y.; et al. “Multifunctional biomimetic hydrogel systems to boost the immunomodulatory potential of mesenchymal stromal cells” Biomaterials 257 (2020) 120266)
and in view of:
KUMAR (Cited by Applicant in IDS of 25 July 2024, EP 2,946,011 B1, Publication Date 17 April 2019).
Teachings of ZUO and GONZALEZ are discussed above.
Regarding claim 7: Neither ZUO nor GONZALEZ clearly teach the incorporation of Shh protein into a hydrogel therein.
The prior art reference KUMAR teaches the incorporation of Shh protein into a heparin-bearing hydrogel (paragraph [0016]) to promote myocardial regeneration (paragraph [0080]).
It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, to incorporate Shh protein (as taught by KUMAR) into the heparin-bearing hydrogel of ZUO, for the purpose of adding the myocardial regeneration benefit of Shh to the hydrogel of ZUO. The artisan would have expected success in this combination, because both KUMAR and ZUO teach heparin-bearing hydrogels containing bioactive proteins.
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 1-2 and 4-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claims 1-2 and 4-12 of U.S. Patent No. 12,076,437 (referred to below as the ‘437 patent).
Although the claims at issue are not identical, they are not patentably distinct from each other because: Claims 1-2 and 4-11 of the ‘437 patent anticipate instant claims 1-2 and 4-11. Claim 12 of the ‘437 patent anticipates instant claims 12-13.
Conclusion
No claims are currently allowable.
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/JDMc/Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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