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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02 April 2026 has been entered.
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 arguments filed 02 April 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Rejections not reiterated from previous Office Actions are hereby withdrawn. The following rejections 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 April 2026, it is noted that claims 1 and 22 have been amended and no new claims have been added. Support for the amendment can be found on pg. 9 of the specification. No new matter has been added.
Declaration
The declaration under 37 CFR 1.132 filed 02 April 2026 is insufficient to overcome the rejection of claims 1, 12, 22, and 23 based upon Vetter and D’Este as set forth in the last Office action because: The Applicant argues that when calcium ions are present, the claimed HA-alendronate derivative shows hydrogel behavior and when calcium ions are not present, the HA-alendronate derivative shows viscous solution. The Applicant further compares the rheological data with D’Este and alleges that the HA-alendronate derivatives are different from the claimed invention.
Applicant’s argument is not found persuasive. In regards to any alleged unexpected results regarding formation of a hydrogel with the presence of calcium ions, Lopez-Perez teaches self-healing hydrogel formation through complexation of calcium ions and bisphosphonate. Lopez-Perez found that increasing the calcium concentrations resulted in stronger hydrogels (pgs. 6-7). Therefore, any alleged results showing that the presence of calcium forms hydrogels in comparison to no hydrogel formation when calcium ions are not present, is not unexpected or surprising. Furthermore, the Applicant is encouraged to show comparative data to Vetter, which is considered the closer prior art.
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 in the presence of calcium ions, addressing the limitations in claims 1 and 22. Additionally, Vetter teaches that beneficial viscosity changes necessary for injection purposes, such as decreasing the viscosity with a spreading or diffusing agent to allow the diffusion of the drugs, which is interpreted as a solid composition without the use of a said agent (pg. 121, lns. 30-34; pg. 123, ln. 35-pg. 125, ln. 6). The formation of a more solid gel or composition is interpreted as addressing the broadness of “compact gel” in claim 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 claims 1 and 22.
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).
In regards to including calcium ions in the composition in claims 1 and 22, Vetter teaches that 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 in the presence of calcium ions. Therefore, a skilled artisan would have been led to specifically use calcium ions to strengthen the viscosity and improve the physical properties of the composition.
Response to Arguments
Applicant's arguments filed 02 April 2026 have been fully considered but they are not persuasive.
The Applicant argues that D’Este conjugates HA with another polymer and cites Examples 1, 10, and 11 for their different activators and rheological properties (Remarks, pgs. 11-13).
Applicant’s argument is not found persuasive. The Applicant is erroneously pointing to narrow embodiments expressly disclosed within the prior art reference as representing the sum total of information conveyed by each. Art is art, not only for what it expressly teaches, but also for what it would reasonably suggest to the skilled artisan, including alternative or non-preferred embodiments (see MPEP § 2123). D’Este broadly teaches that hyaluronic acid may comprise alendronate as the bioactive agent conjugate (abs, pg. 14) and that the hyaluronic acid conjugate may have a degree of substitution of 2.5 to 10% (pg. 13). Therefore, a skilled artisan would have been reasonable motivated to use the general teaching of a broad degree of substitution range in Vetter’s composition.
The Applicant cites the Declaration in regards to comparative data between D’Este and the claimed invention and how the two compositions differ (Remarks, pgs. 13-14).
Applicant’s argument is not found persuasive. In regards to any alleged unexpected results regarding formation of a hydrogel with the presence of calcium ions, Lopez-Perez teaches self-healing hydrogel formation through complexation of calcium ions and bisphosphonate. Lopez-Perez found that increasing the calcium concentrations resulted in stronger hydrogels (pgs. 6-7). Therefore, any alleged results showing that the presence of calcium forms hydrogels in comparison to no hydrogel formation when calcium ions are not present, is not unexpected or surprising. Furthermore, the Applicant is encouraged to show comparative data to Vetter, which is considered the closer prior art.
The Applicant argues that the mixture in Figures 2 and 3 would have gelled like the conjugate if the viscosity change depended on the phosphorus of the bisphosphonate (Remarks, pgs. 14-15).
Applicant’s argument is not found persuasive. 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.
The Applicant is encouraged to clarify the results in Figures 2 and 3, as it appears that the HA-ALD, which is presumably the conjugate, yielded different results to HA+ALD, which is presumably a simple mixture of the two components. Therefore, Applicant’s data regarding the phosphorus and the viscosity change in the presence of bivalent ions is not clear.
Conclusion
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/D.A.K./Examiner, Art Unit 1613
/ANDREW S ROSENTHAL/Primary Examiner, Art Unit 1613
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