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 .
Priority
The present application, filed June 15, 2022, is a national stage application of PCT/IB2020/062024, filed December 16, 2020, which claims foreign priority to application IT102019000024117, filed December 16, 2019.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 9, 2026 has been entered.
Status of the Application
Applicant’s communication, received February 9, 2026, wherein claims 1 and 17, and 19-21 are amended and claims 2-3, 6, 8-13, and 19-21 are canceled, is acknowledged.
Claims 1, 17, and 22-26 are pending in this application.
Claims 22-26 were withdrawn as directed to a non-elected invention in the Office action mailed March 28, 2025.
Claims 1 and 17 are examined on the merits herein.
Withdrawn Objections
Applicant’s amendment, received February 9, 2026, with respect to the objections to claims 8, 10, and 21 for minor informalities, have been fully considered and found to be persuasive to remove the objections because claims 8, 10, and 21 are canceled. Therefore the objection is withdrawn.
Withdrawn Rejections
Applicant’s amendment, received February 9, 2026, with respect to the rejection of claims 1-3, 6, 8-13, and 19-21 under 35 USC § 112(b) as indefinite due uncertainty regarding specific methods steps, has been fully considered and found to be persuasive to remove the rejection because claims 2-3, 6, 8-13, and 19-21 are canceled and claim 1 is amended such that the methods steps required by the claim are clear. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 9, 2026, with respect to the rejection of claims 9 and 11-13 under 35 USC § 112(b) regarding specific limitations relating to R groups and EDC crosslinking, has been fully considered and found to be persuasive to remove the rejection because claims 9 and 11-13 are canceled. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 9, 2026, with respect to the rejection of claim 17 under 35 USC § 112(b) as lacking antecedent basis for arginine or ornithine, has been fully considered and found to be persuasive to remove the rejection because claim 17 is amended to recite arginine methyl ester (Arg-OMe) and ornithine methyl ester (Orn-OMe), terms which have antecedent basis in claim 1. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 9, 2026, with respect to the rejection of claims 19-21 under 35 USC § 112(b) as indefinite, has been fully considered and found to be persuasive to remove the rejection because claims 19-21 are canceled. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 9, 2026, with respect to the rejection of claims 2-3, 6, 8, 9, 19, 20, and 21 under 35 USC § 112(d) 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, has been fully considered and found to be persuasive to remove the rejection because claims 2-3, 6, 8, 9, 19, 20, and 21 are canceled. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 9, 2026, with respect to the rejection of claims 1-3, 11, 13 and 17 under 35 USC § 103 as unpatentable over Wei in view of Bergman and Fratini, has been fully considered and found to be persuasive to remove the rejection of claims 2-3, 11, and 13 because claims 2-3, 11, and 13 are canceled. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 9, 2026, with respect to the rejection of claim 12 under 35 USC § 103 as unpatentable over Wei in view of Bergman, Fratini, and D’Este, has been fully considered and found to be persuasive to remove the rejection because claim 12 is canceled. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 9, 2026, with respect to the rejection of claims 6 and 8-9 under 35 USC § 103 as unpatentable over Wei in view of Bergman, Fratini, Luo, and Schante, has been fully considered and found to be persuasive to remove the rejection because claims 6 and 8-9 are canceled. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 9, 2026, with respect to the rejection of claim 19 under 35 USC § 103 as unpatentable over Wei in view of Bergman, Fratini, Luo, Schante, and Xin, has been fully considered and found to be persuasive to remove the rejection because claim 19 is canceled. Therefore the rejection is withdrawn.
The following are new rejections in response to Applicant’s amendments received February 9, 2026.
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 1 and 17 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 1 recites the limitation “leaving an obtained reaction mixture under stirring until completely cross-linked”. The term “completely” in claim 1 is a relative term which renders the claim indefinite. The term “completely” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For example, does completely cross-linked require all potential cross-linking sites to be cross-linked? Does completely cross-linked require all cross-linking reagent be consumed?
Because claim 17 depends from claim 1 and fails to cure the above deficiency, claim 17 is also indefinite.
The examiner suggests amending this limitation to recite “leaving an obtained reaction mixture under stirring,” which is not indefinite.
Claim 17 recites the process according to claim 1, wherein a ratio between said CDMT or said DMTMM and said arginine methyl ester (Arg-OMe) or said ornithine methyl ester (Orn-OMe) is 1:2:4, 1:3:4 or 1:3:1.5. This claim is indefinite because it appears to require a ratio between CDMT or DMTMM and Arg-OMe or Orn-OMe, but the claim recites ratios that include three components (e.g., 1:2:4). Therefore, it is unclear which values correspond with CDMT/DMTMM and which values correspond with Arg-OMe/Orn-OMe.
The following rejection is maintained from the previous office action, updated to reflect Applicant’s amendments received February 9, 2026.
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.
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 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Wei (Publication No. CN105713211A; of record) in view of Bergman (Bergman, K.; et al. Biomacromolecules 2007, vol. 8, pp. 2190-2195; of record) and (Fratini U.S. pre-grant publication No. 20030096879 A1; of record), as evidenced by D’Este (D’Este, M.; et al. Carbohydrate Polymers 2014, vol. 108, pp. 239-246; cited in IDS received June 15, 2022).
Wei was published in a language other than English. Both the original document and an English language machine translation of Wei were included with the previous restriction/election requirement mailed January 3, 3025. Citations below refer to the English language machine translation document included with the office action.
Wei teaches and claims a skin filler prepared from sodium hyaluronate with DMTMM as a condensation agent and natural amino acids as cross-linking agents (document p. 11, claim 1, lines 1-3). Wei teaches that after the reaction is completed, the gel product is cut into small pieces and placed in a phosphate buffer for dialysis, and then the cross-linked sodium hyaluronate gel is obtained through granulation and sterilization processes (document p. 11, claim 1, lines 5-6). Wei further teaches and claims L-lysine and L-arginine as cross-linking agents (document p. 11, claim 2, lines 1-3).
This process using DMTMM as a condensation agent is expected to form amide bonds between the amino groups of the amino acid cross-linking agent and sodium hyaluronate, as evidenced by the instant specification. The specification provides that DMTMM is the product of a spontaneous reaction between CDMT and NMM and that the resulting product when using DMTMM in a reaction is similar to the product obtained when CDMT/NMM are added to a reaction separately (p. 10, lines 9-12). In addition, the specification provides that the use of CDMT/NMM yields amide bonds between the amino acid and hyaluronic acid (pp. 10-11, Scheme 1). Therefore, one of ordinary skill in the art would have expected formation of amide bonds in the product of the reaction between hyaluronic acid and an amino acid cross-linking agent in the presence of DMTMM.
In addition, NMM is necessarily present when performing cross-linking with DMTMM. As evidenced by D’Este, activation of a carboxylic acid releases NMM (p. 241, Scheme 1). In addition, as evidenced by Bergman, when NMM is present in a reaction wherein hyaluronic acid is activated by a triazine group, it forms an ionic bond with chloride ions, which is interpreted as equivalent to neutralizing released chloride ions.
With respect the difference between hyaluronic acid and sodium hyaluronate, in addition to teaching the method described above involving cross-linking sodium hyaluronate, Wei refers to a cross-linked hyaluronic acid polymer gel obtained by cross-linking hyaluronic with a cross-linking agent (p. 2, [0004], lines 7-8) (emphasis added). Therefore, because sodium hyaluronate is the sodium salt of hyaluronic acid, and because Wei refer to both a cross-linked sodium hyaluronate and cross-linked hyaluronic acid product, the disclosure of Wei is interpreted as applying to both hyaluronic acid as well as sodium hyaluronate.
To prepare their product, Wei teaches that lysine is dissolved in water, sodium hyaluronate powder added, stirred, and cooled at 4 °C overnight. Wei teaches on the next day, DMTMM is dissolved in water, added to the gel, and after being completely stirred, reacted at 4° C for 3 days (English translation, document p. 6, [0023]).
Wei does not teach some specific steps of present claim 1, including adding acetonitrile as the solvent for the reaction, adding CDMT or DMTMM before cross-linking agent, or the cross-linking agent as arginine methyl ester or ornithine methyl ester, as required by claim 1.
Bergman teaches a method for preparation of hyaluronic acid derivatives using triazine-mediated amidation (p. p. 2190, Abstract, lines 1-2). Bergman teaches that hyaluronic acid was dissolved in 3 mL of deionized water in a 10 mL round-bottomed flask followed by the dropwise addition of 2 mL of acetonitrile while stirring (p. 2191, left column, fourth full paragraph, lines 4-6). Bergman teaches that to the solution was added 4-methylmorpholine (NMM), and the solution was then cooled to 4 °C, and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) was added and stirred at room temperature for 1 h. Bergman teaches that the solution was then mixed with 0.2 mmol of amine, stirred for 20 h at room temperature, and purified by ion exchange resin, dialysis, and lyophilization (p. 2191, left column, fourth full paragraph, lines 6-17). Bergman teaches that each amidation reaction was performed in a mixture of water and acetonitrile (3:2), because this was found capable of dissolving both hyaluronic acid and CDMT (p. 2192, left column, Results and Discussion section, lines 8-10).
Bergman teaches that one amine linked to hyaluronic acid is glycine ethyl ester, and the product of HA and the amine is an amide bond formed between the carboxylic acid groups of Bergman and the amine group of glycine (p. 2192, Scheme 1).
Regarding the requirement that NMM neutralize the released chloride ions, as described above, Bergman teaches NMM as forming an ionic bond with the chloride (p. 2192, Scheme 1), which is interpreted as equivalent to neutralizing chloride ions.
In addition, Bergman teaches that their derivatization reactions were performed with both 0.25 and 0.5 equivalents of CDMT to hyaluronic acid carboxyl groups and affected the degree of substitution of their hyaluronic acid, with 0.5 equivalents of CDMT giving a higher degree of substitution of for all amines compared with 0.25 equivalents (p. 2192, Table 1 and Table 1 caption).
Fratini teaches gels consisting of hyaluronic acid cross-linked with bifunctional L-amino acids or L-amino esters (cover page, Abstract). Fratini teaches a specific example wherein 1 g of hyaluronic acid sodium salt is dissolved in water at 4 °C, and the pH is adjusted to pH 5 using HCl. Fratini teaches that 1.0 eq of L-lysine and 1.0 eq of N-3-dimethylamino-propylethylcarbodiimide hydrochloride are added, and after 2 hours, the solution is dialysed with water, precipitated with acetone, dissolved in water, and freeze-dried (p. 2, Example 1, [0034]-[0035]). Fratini additionally teaches the same method above, but wherein the L-lysine ethyl ester di-hydrochloride is used as the cross-linking agent (e.g., p. 2, Example 2, [0036]).
Furthermore, Fratini teaches the cross-linking agents are α-L-amino acids (p. 1, [0018], lines 1-2), and teaches that the use of amino esters instead of amino acids allows the protection of the carboxylic functions of amino acids in relation to a possible activation and involvement in secondary reactions (p. 1, [0018], lines 1-4) (emphasis added). Fratini further discloses that the cross-linking agents are preferably methyl or ethyl esters (p. 2, [0032], line 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to substitute the synthesis method of Wei for the synthesis method for derivatizing hyaluronic acid taught by Bergman. One of ordinary skill in the art would have been motivated to substitute the synthesis method of Wei for the derivatization of hyaluronic acid taught by Bergman because each of these methods form amide bonds between hyaluronic acid and amino acid cross-linking agents, and thus one would have recognized the conditions taught by Bergman may be reasonably applied to prepare the product of Wei. In this instance, the KSR rationale “simple substitution of one known element for another to obtain predictable results” would apply. Because the method of Wei and the method Bergman are each used to derivatize hyaluronic acid with amino acids by forming amide bonds, one of ordinary skill in the art would have reasonably contemplated substituting one method for the other with a reasonable expectation of forming the same product.
Regarding the use of arginine methyl ester in place of arginine as taught by Wei, because Fratini teaches that use of amino esters instead of amino acids allows the protection of the carboxylic functions of amino acids in relation to a possible activation and involvement in secondary reactions, one of ordinary skill in the art would have considered using the Arg-OMe group instead of arginine to avoid these secondary reactions taught by Fratini.
Regarding the timing of adding NMM after Arg-OMe or Orn-OMe, absent evidence that the timing of NMM addition has an effect on this synthesis process, one of ordinary skill in the art would have recognized that the reaction should include NMM, and would have considered its addition before or after CDMT and the amino substrate. In addition, in view of Bergman disclosing the presence of NMM to form ionic bonds with chloride (and neutralize any HCl that forms in situ), one of ordinary skill in the art would have contemplated adding NMM after the addition of Arg-OMe, to maintain the neural pH disclosed by Bergman as one advantage for the reaction conditions (p. 2192, left column, Results and Discussion section, lines 6-8).
Regarding claim 17 and the required ratios CDMT and arginine methyl ester, because Bergman teaches the effect of different ratios of CDMT to hyaluronic acid and differences in degrees of substitution in the products formed under different conditions, one of ordinary skill in the art would have recognized these ratios as result-effective variables.
MPEP 2144.05 II at A states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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).” In this instance, because varying the ratios of CDMT and hyaluronic acid is shown to affect the degrees of substitution hyaluronic acid, one of ordinary skill in the art would have contemplated differing ratios of hyaluronic acid, coupling agent, and amine to produce a hydrogel with the desired physical and chemical properties.
Therefore the invention taken as a whole is prima facie obvious.
Response to Applicant’s arguments: With respect to the previous rejection of claims 1 and 17 as unpatentable over Wei in view of Bergman and Fratini, Applicant argues that the examiner is of the opinion that replacing Wei's amino acids with Fratini esters is obvious. However, Wei uses natural amino acids (zwitterions) in an aqueous environment, a condition where free acid groups create ionic interference. The claimed process, specifically using arginine and ornithine methyl ester, blocks the carboxyl group and forces selective reactivity on the amino groups, preventing self-condensations. Applicant argues that this is not a trivial variant but rather is the only way to obtain the specific ordered "cage" structure that Wei neither achieves nor describes.
Applicant further argues the combination of references cited by the examiner fails to consider the fundamental synergy of the solvent system. Citing Bergman for the use of the water/acetonitrile mixture is misleading. Applicant argues that Bergman uses the water/acetonitrile mixture for simple conjugations (grafting), not for massive crosslinking to create a structured hydrogel. Applicant provides the use of acetonitrile in the claimed process is not a random choice, but is essential for solubilizing the specific cross-linking agents (esters) and the activator (DMTMM), allowing for reaction kinetics that would not occur with the same efficiency and structural order in water alone (as in Wei).
Finally, Applicant argues that the detailed description and comparative data provided in the present application demonstrates how the use of the "known" chemistry implicitly suggested by the combination (i.e., the EDC/NHS system cited by Fratini) applied to reagents leads to failure ("NO product") or poor results. Applicant argues that by applying the methods that the Examiner deems "obvious," the product does not form, the entire accusation of obviousness is invalidated, and the success of the method is an unexpected result in view of the prior art.
Applicant’s arguments have been fully considered but they are not found persuasive.
Regarding Applicant’s arguments concerning the choice of arginine methyl ester and ornithine methyl ester and not their amino acids, the potential for crosslinking side reactions is recognized by the prior art. As stated above, Fratini teaches that cross-linking agents are bi-functional α L-amino acids or L-amino esters (p. 1, [0017]; lines 1-6), and that the use of amino esters instead of amino acids allows the protection of the carboxylic functions of amino acids in relation to a possible activation and involvement in secondary reactions (p. 1, [0018]). Therefore, because the prior art recognizes that crosslinking with amino acids can involve carboxylic acids involvement, in secondary reaction, one of ordinary skill in the art would have considered substituting the arginine crosslinking agent of Wei for the arginine methyl ester or ethyl ester, because use of arginine methyl ester or ethyl ester would avoid the possible involvement of arginine in secondary reactions, as taught by Fratini. In addition, Fratini discloses examples in which the amino esters are used to prepare hyaluronic acid gel products in aqueous reaction conditions (for example, see p. 3, Example 5, [0054]-[0055], wherein the L-lysine ethyl ester is used as a cross-linking agent). Accordingly, one of ordinary skill in the art would have recognized the amino esters may be used in aqueous conditions with a reasonable expectation of success.
Regarding Applicant’s arguments concerning the selection of a specific solvent system, Bergman teaches that each amidation reaction was performed in a mixture of water and acetonitrile (3:2), because this was found capable of dissolving both hyaluronic acid and CDMT (p. 2192, left column, Results and Discussion section, lines 8-10). Therefore, one of ordinary skill in the art would have considered such a solvent system for preparing the hyaluronic acid skin filler product taught by Wei using the method of Bergman. Moreover, Bergman teaches that prolonged in vivo residence time and improved mechanical properties can be obtained by cross-linking to form hydrogels or by adding groups that lower the aqueous solubility (p. 2190, left column, second paragraph, lines 1-3). Therefore, one of ordinary skill in the art would have found the derivations of hyaluronic acid taught by Bergman as reasonably pertinent to preparing the gel product taught by Wei.
Regarding Applicant’s arguments relating to the EDC/NHS system cited by Fratini, the examiner believes these arguments are moot because claim 1 is limited to crosslinking with CDMT and DMTMM. In the present rejection, Fratini is cited to further support the use of amino esters as crosslinking agents, as described above.
Therefore, for the reasons described above, the present rejection of claims 1 and 17 as unpatentable over Wei in view of Bergman and Fratini is maintained.
Allowable Subject Matter
Canceled claim 20 required conjugation of a compound of the structure below with the cross-linked hyaluronic acid. The examiner has not identified prior art that would teach or suggest a cross-linked hyaluronic acid as presently claimed and also conjugated with this compound. Incorporation of a limitation that requires conjugation of this compound into the present claims, provided the present issues of indefiniteness are resolved, would be allowable.
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Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BENJAMIN BRANDSEN whose telephone number is (703)756-4780. The examiner can normally be reached Monday - Friday from 9:00 am to 5:00 pm.
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/B.M.B./ Examiner, Art Unit 1693
/ANDREA OLSON/ Primary Examiner, Art Unit 1693