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 application was filed 25 March 2021 and is the national stage entry of PCT/IB2019/058698 filed 11 October 2019. The Applicant claims priority to foreign application IT102018000009444 filed 15 October 2018. A translated copy of the foreign document has not been provided; therefore, the effective filing date of the application is 11 October 2019.
Examiner’s Note
The Applicant's amendments and/or arguments filed 02 September 2025 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. In the Applicant’s response, filed 02 September 2025, it is noted that claims 1 and 22 have been amended, and no new claims have been added. Support for the amendment(s) and/or new claim(s) can be found on pg. 8 of the specification. No new matter has been added.
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.
Claim(s) 1, 12, 22, and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vetter et al. (WO 2014/056915 A1) and D’Este et al. (WO 2015/048988 A1), as evidenced by Pluda et al. (Hyaluronic acid-alendronate conjugate: A macromolecular drug delivery system for intra-articular treatment of osteoarthritis, Osteoarthritis and Cartilage Open, 2021).
Vetter et al. teach a polymeric carrier, such as hyaluronic acid (entire teaching; pg. 17, ln. 20), alendronate as a biologically active moiety for the polymeric carrier (pg. 115, ln. 38), and various excipients (pg. 15, ln. 30), including viscosifiers/viscosity enhancing agents (pg. 121, ln. 31), addressing claim 12. Alendronate is interpreted as amino-bisphosphonate, as evidenced by Pluda in Fig. 1. The composition comprising alendronate addresses the n variable as 3 in claims 1 and 22. Vetter provides an example of a preferred prodrug formula (XX) of Y1—W-O-D where D is a carboxyl-comprising biologically active moiety (alendronate with a carboxyl group), W may be a linear C1-15 alkyl group (L spacer group), and Y1 is the polymeric carrier of the prodrug (hyaluronic acid) (pg. 114, ln. 1-11), which addresses the L spacer group and m variable as 2 in claim 1. The polymers may have a molecular weight of at least 5 kDa (pg. 6, lns. 7-13). In other embodiments, hyaluronic acid may have a molecular weight range of 0.5 to 1000 kDa (500 Da to 1,000,000 Da) (pg. 79, lns. 1-30), addressing claims 1 and 22. The composition may be used as a medicament for treatment of joints (pg. 127, lns. 1-5) or arthritis (pg. 1, lns. 6-11) and administered through intra-articular injection (pg. 16, lns. 5-6), which addresses claim 22. The limitation with the phosphonic groups and carboxyl groups not involved in the conjugation forming a salt with the sodium cation in claims 1 and 22, as well as the limitation regarding the synthesis of the conjugate in claims 22 and 23, are interpreted as product-by-process limitations and are given minimal patentable weight (see MPEP 2113(I)). Furthermore, Vetter teaches that part of the hydrogel is in its acidic salt form (pg. 22, lns. 28-37), which is interpreted as part of the drug reacting to produce its salt form, addressing the limitation of free functional groups reacting with sodium cations. The composition is used for treatment of the joints and osteoarthritis (pg. 1, ln. 14; pg. 2, ln. 2), and may be in the form of a solution (pg. 15, lns. 7-32), addressing the chondroprotective and osteoprotective limitation in claims 1 and 22. Stabilizers, including calcium and other bivalent ions (pg. 122, lns. 22-23), can be used to strengthen the protein-stabilizing forces, which is interpreted as strengthening the viscosity and forming a viscous solution, addressing the limitations in claims 1 and 22.
Vetter does not teach a degree of substitution of the hyaluronic acid with amino-bisphosphonate in relation to the carboxylic groups of hyaluronic acid.
In regards to selecting a combination of alendronate and hyaluronic acid, “[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G.Pro, 425 U.S. 273, 282 (1976)). “When the question is whether a patent claiming the combination of elements of prior art is obvious,” the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR at 1741. The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742.
Consistent with this reasoning, it would have been obvious to have selected various
combination of various disclosed ingredients from within a prior art disclosure, to arrive at compositions “yielding no more than one would expect from such an arrangement.”
Vetter teaches a composition comprising hyaluronic acid and alendronate, whereas the claimed invention is directed towards a conjugate between hyaluronic acid and an amino-bisphosphonate. Since Vetter teaches the individual components of the claimed composition, it is obvious for one of ordinary skill in the art to select the different combinations of ingredients to arrive at the claimed invention with a reasonable expectation of success.
In regards to the mol ratio for variable x in claim 1, D’Este teaches a hyaluronic acid that may comprise alendronate as the bioactive agent conjugate (abs, pg. 14). D’Este teaches that the hyaluronic acid conjugate may have a degree of substitution of 2.5 to 10% (pg. 13). That being said and in lieu of objective evidence of unexpected results, the degree of substitution can be viewed as a variable that achieves the recognized result of successfully making the hyaluronic acid-alendronate composition. The optimum or workable range of degree of substitution can be accordingly characterized as routine optimization and experimentation (see MPEP 2144.05 (II)B).
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists, thus addressing the molecular weight of hyaluronic acid claim(s) 1 and 22. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). MPEP 2144.05 (I).
Response to Arguments
Applicant's arguments filed 02 September 2025 have been fully considered but they are not persuasive.
The Applicant argues that Vetter does not teach a viscous solution (Remarks, pg. 10-11).
Applicant’s argument is not found persuasive. Vetter teaches a composition used for treatment of the joints and osteoarthritis (pg. 1, ln. 14; pg. 2, ln. 2), and suggests the form of a solution (pg. 15, lns. 7-32). The inclusion of stabilizers, including calcium and other bivalent ions (pg. 122, lns. 22-23), are used to strengthen the protein-stabilizing forces, which is interpreted as strengthening the viscosity and forming a viscous solution. Hydrogels are interpreted as a type of gel (evidenced by nature.com, pg. 1).
The Applicant argues that D’Este’s teachings are irrelevant for the purposes of the claimed invention (Remarks, pg. 11).
Applicant’s argument is not found persuasive. Since Vetter does not specifically teach a mol ratio for variable x in claim 1, D’Este’s teaches a composition wherein hyaluronic acid comprises alendronate as the bioactive agent conjugate (abs, pg. 14). D’Este teaches that the hyaluronic acid conjugate may have a degree of substitution of 2.5 to 10% (pg. 13). The degree of substitution is viewed as a variable that achieves the recognized result of successfully making the hyaluronic acid-alendronate composition. The optimum or workable range of degree of substitution is therefore accordingly characterized as routine optimization and experimentation (see MPEP 2144.05 (II)B).
The Applicant argues that Naito’s composition increased in viscosity only when phosphoric acid is added and that Naito does not disclose the unexpected property of the claimed invention (Remarks, pg. 12).
Applicant’s argument is not found persuasive. As mentioned in the previous office action, Naito is used to show that the changes in properties claimed by the Applicant is not unexpected or surprising. Naito teaches that the viscosity of hyaluronic acid solutions increased after the addition of phosphoric acid, possibly due to the changes in the noncovalent interactions between functional groups (pg. 7). Alendronate contains phosphate groups where it would be reasonable to believe that the functional groups on the alendronate would contribute to changes in the noncovalent interactions with the hyaluronic acid. The inclusion of stabilizers, as taught by Vetter, including calcium and other bivalent ions (pg. 122, lns. 22-23), are used to strengthen the protein-stabilizing forces, which is interpreted as strengthening the viscosity and forming a viscous solution. Therefore, the results of higher viscosity with the addition of alendronate and bivalent ions are not unexpected or surprising.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/D.A.K./Examiner, Art Unit 1613
/BRIAN-YONG S KWON/Supervisory Patent Examiner, Art Unit 1613