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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-16) in the reply filed on 8/18/2026 is acknowledged.
Claims 17-19 arewithdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/18/2026.
Claim Objections
Claims 1 and 9 are objected to because of the following reasons:
In claim 1, line 8, the “hyaluronic” should be followed with “compound” to read as “hyaluronic compound” to be consistent with recitation in line 3.
In claim 9, line 3, there should be a space in “solutionor” so that it reads as “solution or.”
Appropriate correction is required.
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 of this title, 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 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over Maudens (US 2019/0119486) in view of Wang (CN 111647193, machine translation) .
With respect to claims 1, 2, and 5, Mauden discloses a graft polymer of hyaluronic acid polymer and N-isopropylacrylamide polymer (abstract) which is prepared by reacting hyaluronic acid and a poly(N-isopropylacrylamide) (paragraphs 0214-0217). Mauden exemplifies a copolymer having a degree of substitution of hyaluronic acid with poly(N-isopropylacrylamide) is 8% (paragraph 0218), i.e., molar ratio of hyaluronic acid to poly(N-isopropylacrylamide) is 92:8. In the exemplified process, Mauden adds a carbodiimide crosslinking agent that is a mixture of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide is used (paragraph 0214). Mauden teaches that the pH for crosslinking is 5 and that crosslinking occurs while stirring for overnight (equivalent to a day) at room temperature (i.e., 23°C) and subsequently drying (paragraph 0216). Mauden discloses that hyaluronic acid has molecular weight of 500-5,000,000 Daltons (paragraph 0030) and exemplifies molecular weight cutoff (i.e., minimum) is 25,000 (paragraph 0216).
Mauden fails to disclose (i) the ratio of hyaluronic acid and poly(N-isopropylacrylamide) to carbodiimide crosslinking agent or (ii) a method which adjusts the pH to 7.2-7.8.
With respect to (i), Wang discloses a method for improving the self-crosslinking degree of hyaluronic acid that is crosslinked with a mixture of carbodiimide substance ad succinimide substances (abstract) which includes mixtures of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and N-hydroxysuccinimide (paragraph 0017), i.e., the same as exemplified by Mauden. Wang states that the molar ratio of carboxyl groups from the hyaluronic acid to carbodiimide compounds to succinimide compounds is 1: 0.2-2: 0.1-2 (paragraph 0022). From this molar ratio and a molecular weight hyaluronic acid of 25,000 g/mol, the molar ratio of hyaluronic acid to poly(N-isopropylacrylamide) to carbodiimide crosslinking agent can be calculated. Specifically, the hyaluronic acid (molecular weight of monomer unit is 379 g/mol) having molecular weight of 25,000 has 66 –COOH groups (25,000/379 = 66). Selecting a minimum 1:0.3 molar ratio of –COOH groups in hyaluronic acid to total carbodiimide crosslinking agent and assuming that all –COOH groups are reacted with carbodiimide crosslinking agent, the molar ratio of 0.92 : 0.08 : 20 = 0.01 : 0.004 : 1. While this molar ratio does not fall within the claimed range of 0.1-0.2 : 0.0025-0.0125 : 1 for hyaluronic acid, the calculation is based on full reaction of –COOH groups of hyaluronic acid. Because the amount of –COOH groups that will react are not expected to be 100% (due to salt formation or other reactivity issues), the relative amount of hyaluronic acid would be expected to be higher. Also, the relative amount of crosslinking agent would be readily adjusted by one of ordinary skill in the art to control crosslinking degree.
Given that both Mauden and Wang are drawn to hyaluronic acid crosslinked with the same carbodiimide crosslinking agent mixture and further given that Wang teaches suitable relative amounts of hyraluronic acid and carbodiimide crosslinking agent, it would have been obvious to one of ordinary skill in the art to expect the claimed molar ratio or to control the molar ratio in order to adjust total crosslinking.
With respect to (ii), Wang teaches that the crosslinking reaction between hyaluronic acid and the carbodiimide is most effective at a pH of 7-10 because less than this, the degree of crosslinking is weak because the nucleophilicity of the hydroxyl groups of hyaluronic acid is not strong enough and at greater than 10 the hyaluronic acid and carbodiimides are easily degraded by alkali (paragraph 0059). Wang teaches that the reaction occurs at room temperature for at least 24 hours (paragraph 0054).
Given that both Mauden and Wang are drawn to hyaluronic acid crosslinked with the same carbodiimide crosslinking agent mixture and further given that Wang teaches that a pH of 7-10 is most advantageous to crosslink, it would have been obvious to one of ordinary skill in the art to utilize a pH that overlap with claimed range 7.2-7.8.
With resect to claim 3, Wang discloses that the molar ratio of carboxyl groups from the hyaluronic acid to carbodiimide compounds to succinimide compounds is 1: 0.2-2: 0.1-2 (paragraph 0022), which provides for molar ratio of 0.2-2 : 0.1-2 which overlaps with claimed range of 1:0.5 to 1:1.5.
With respect to claim 4, Mauden discloses that hyaluronic acid has molecular weight of 500-5,000,000 Daltons (paragraph 0030) and exemplifies molecular weight cutoff (i.e., minimum) is 25,000 (paragraph 0216), which overlaps with claimed range of 30,000-60,000 Daltons.
With respect to claims 6 and 7, Mauden teaches that pharmaceutically acceptance salts of hyaluronic acid includes sodium and potassium (paragraph 0110).
With respect to claim 8, Mauden teaches that the N-isopropylacrylamide based polymer has molecular weight of 500-35,000 Daltons (paragraph 0033), which overlaps with claimed range of 4,000-6,000.
With respect to claims 9 and 10, Mauden exemplifies a process using distilled water as solvent (paragraph 0216).
With respect to claim 11, Mauden discloses mixing at pH of 4 (paragraph 0216) which is a low reactive pH as taught by Wang. Because of its nonreactivity, it would have been obvious to one of ordinary skill in the art to just mix at the lower pH, for a sufficient time, including 0.5-2 hours like claimed, optimized by one of ordinary skill in the art, an then adjusted to within pH of 7.2-7.8 in order to effectively crosslink hyaluronic acid grafted N-isopropylacrylamide based polymer. Case law holds that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980). In view of this, it would have been obvious to one of ordinary skill in the art to utilize appropriate pH and time during mixing, including those within the scope of the present claims, so as to produce desired end results
With respect to claims 12 and 13, Wang teaches that a common pH adjusters include hydrochloric and sulfuric acid and sodium hydroxide (paragraph 0018).
With respect to claims 14-16, Mauden teaches purifying polymer with dialysis (paragraph 0216). Wang teaches steps of removing impurities (i.e., purifying) by dialysis and filtration and then drying by freeze or vacuum drying (paragraph 0024).
Conclusion
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/Vickey Nerangis/
Primary Examiner, Art Unit 1763
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