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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 19, 2026 has been entered.
Detailed Action
This office action is a response to applicant’s communication submitted January 19, 2026, wherein the rejection of record in the previous action is traversed. This application claims benefit of provisional application 61/871352, filed August 29, 2013.
Claims 1 and 14-18 are pending in this application.
Non-elected claims 14 and 15 are withdrawn from consideration.
Claims 1 and 16-18 as amended are examined on the merits herein.
The following rejections of record in the previous action are maintained:
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.
Claims 1 and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Bilkova et al. (Curr Pharm Design, 2011, of record in previous action) in view of Prestwich et al. (US patent 5874417, of record in previous action) in view of Tamura et al. (EP1082963, of record in 9/19/2016 IDS) in view of Hochberg et al. (Sem Arthr Rheum, 2000, Reference of record in previous action)
Independent claim 1 claims a compound which consists of a conjugate between hyaluronic acid and prednisolone succinate through adipic dihydrazide. This structure is infringed by a conjugate comprising these three elements covalently linked together, for example:
PNG
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Dependent claims 16-18 claim pharmaceutical compositions comprising these compounds in combination with an excipient or diluent.
Bilkova reviews the state of the art with respect to the design and synthesis of prednisolone (PD) and methylprednisolone (MPD) conjugates. (See abstract, p. 3577 left column). These two drugs are nearly identical structurally and both exhibit high anti-inflammatory potential and are useful in the treatment of a number of inflammatory and autoimmune conditions. (See section 1 and Scheme 1)
Scheme 2 of Bilkova identifies prednisolone-hemisuccinate as a prodrug of prednisolone.
Section 3 of the reference discusses various polymeric conjugates. Several of the conjugates comprise PD or MPD with a succinate linker, which may further comprise and additional linker entity. See Schemes 14-16 and 21. The use of the succinate linker amounts to preparing a conjugate of a prednisolone prodrug. The reference further suggests the preparation of polymeric conjugates for intravenous administration. See Sections 3.1 and 3.2.
The reference further teaches an HA conjugate of MPD. See Scheme 17. The molecular weight of the HA used in the conjugate is 500-750 kDa. See Section 3.3. Bilkova additionally discloses that polymeric conjugation can ameliorate undesirable properties and side-effects and allow for better targeting of the drugs. See section 4.
The reference does not exemplify PD-succinate conjugated to HA via an adipic dihydrazide linker.
Prestwich teaches a conjugate of HA and a drug, wherein the drug is linked to HA by a hydrazido linker. See col 5-6, col 10 and col 13. The reference teaches conjugates of anti- inflammatory drugs, such as hydrocortisone and exemplifies the preparation of an HA-hydrocortisone succinate conjugate. The reactive HA species is prepared by the reaction with adipic dihydrazide (ADH), and this is reacted with a reactive carboxylic acid site of hydrocortisone hemisuccinate. See col 14, lines 38-45 and Example 3. The reference further teaches the preparation of pharmaceutical compositions comprising conventional excipients for topical and parenteral administration. See col 15.
Tamura teaches that it is well known to conjugate a wide variety of anti-inflammatory drugs, such as steroids, to HA. See abstract and paragraph [0034], section (4). The reference reiterates known benefits, such as reducing systemic side effects. It further notes that the medical effect of HA, per se, may provide a synergistic effect with the anti-inflammatory agent. See paragraph [0019]. Hochberg confirms that HA has anti-inflammatory effects. See page 4, rt col.
It would have been obvious to one having ordinary skill in the art at the time the application was filed to prepare a conjugate comprising PD-succinate covalently attached to HA via an adipic dihydrazide linker with a reasonable expectation of success. Bilkova had established to utility of conjugating MPD or its functional equivalent, PD, or PD-prodrug, PD- hemisuccinate, to a polymer. The reference had exemplified MPD conjugated to HA. It would have been obvious to modify this compound by preparing a PD-HA conjugate because Prestwich had taught the conjugation of a steroid-hemisuccinate to HA via adipic di-hydrazido linker. In the absence of unexpected results, it would be further obvious to use any known linker, such as succinate-dihydrazido, for the preparation of the conjugate.
It is further noted that the intended use “for intravenous injection” is given patentable weight only to the extent that the product must be suitable for the purpose. Claim 1 requires only the compound, per se. Regarding the route of administration, the art encompasses routes wherein a suitable formulation would also be suitable for intravenous administration. Prestwich suggests a sterile, aqueous composition, and it is known in the art to administer polymeric conjugates intravenously.
Response to Arguments
Applicant’s arguments, submitted January 19, 2026, with respect to the above grounds of rejection, have been fully considered but they are not persuasive to remove the rejection.
Applicant argues that the molecular weight range recited in claim 1 differentiates the claims from the prior art. Specifically, Applicant argues that the cited references do not suggest the specific combination of elements including high molecular weight HA. This argument is based on an analysis of each reference individually. Bilkova is described as disclosing only direct conjugation of a steroid and high molecular weight HA, without the use of a linker. Prestwich is described as only describing coupling of low molecular weight HA oligomers, not higher mw HA, which is only mentioned in the context of crosslinking. Applicant then concludes that generic disclosure of high molecular weight HA does not by itself teach the specific combination of drug, linker, and point of attachment recited in claim 1. However, Applicant is reminded of MPEP 2145(IV), which states, “ Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually.” The question at issue is not whether any particular reference teaches the combination of all the structural elements in the claimed compositions, but rather whether the prior art disclosures collectively render such a combination of structural features obvious. For example, the relevant teaching of Prestwich is that prior art methods of conjugating other molecules to hyaluronic acid, for example esterification or deacetylation/amine coupling, lead to degradation of the HA and adversely affect the utility of the resulting conjugates. This is particularly relevant when looking to improve compound 55 on p. 3588 of BIlkova, for example, since this is in fact an ester and could be expected to suffer from the drawbacks to HA esterification described by Prestwich. The relevant teaching by this reference is the suggestion that using hydrazide coupling, for example adipic dihydarzide, solves this problem by providing a conjugation chemistry that does not adversely affect the integrity of the HA. While the specific examples given used low molecular weight oligomers of HA, there is nothing that would lead one of ordinary skill in the art to confine this teaching to only low molecular weight oligomers. In fact, the disclosure by Prestwich of using the same chemistry to crosslink high molecular weight HA (columns 28-31, examples 5 and 6) actually provides evidence of a reasonable expectation of success in applying hydrazide chemistry to HMW HA for any purpose, including conjugation, since this chemical reaction would be expected to function similarly if it were used to attach a linker and drug to the polysaccharide instead of forming a crosslink. Therefore the fact that other references in the art (e.g. BIlkova or Tamura) describe that high molecular weight HA is preferred as a carrier for drug moieties would serve as enough of a basis for one of ordinary skill in the art to improve these conjugates by using the hydrazide linkers described by Prestwich, in the expectation that this would avoid compromising the integrity of the HA.
Applicant further argues that the claimed combination of carrier, linker, and drug would require the coordinated substitution of various elements, and that Tamura’s generic description does not reduce the selection to a routine substitution of equivalents. However, taken as a whole, the cited references describe a field of art in which such substitutions may be routinely made. For example Bilkova describes that a wide variety of PD and MPD conjugates have been made to various carriers by various linkers. Prestwich describes a wide variety of different therapeutic agents that have been conjugated to HA, and Tamura, while focusing on MMP inhibitors as a preferred embodiment teaches that a wide variety of different agents for treating joint disease can be conjugated to HA. Overall, one of ordinary skill in the art would have seen the art as teaching that a wide variety of therapeutic agents can be conjugated to HA of various molecular weights by various linkers. In such a situation there is a significant degree of predictability in substituting particular elements from each of these categories, which supports the obviousness of modifying a similar prior art conjugate (e.g. Bilkova’s HMW-MPD direct ester conjugate)
Finally, Applicant argues that the evidence provided in figures 11-12 of the disclosure, for example, demonstrate a valid finding of unexpected results. Specifically, Applicant points to differences between the closest conjugates described by each of the cited references and concludes that none of the cited constructs are polymer HA having the claimed molecular weight conjugated to AHD and prednisolone succinate. This is merely stating the obvious, namely that the exact claimed construct is not anticipated by any of the cited references. Such a fact is not relevant to what the closest prior art is that could reasonably be compared to the claimed invention. The one element disclosed by all three references Bilkova, Prestwich, and Tamura is the covalent linkage of a corticosteroid to a hyaluronic acid. This is an absolutely essential element to the functioning of both the present invention and the prior art, and is specifically mentioned in all of the cited references. In reality, an appropriate comparison would be a different conjugate, for example using a different corticosteroid such as hydrocortisone or methylprednisolone, or a different linkage connecting the steroid to the HA. What the presented data actually include is a comparison of the claimed conjugate to either unconjugated prednisolone or unmodified HA, neither of which is a conjugate possessing this essential feature. One of ordinary skill in the art would immediately recognize that these species are not conjugates and would be easily expected to be inferior to the prior art conjugates as therapeutic agents for treating joint inflammation, as evidenced by the very fact that those of skill in the art are undertaking to make conjugates of steroids in the first place. Therefore the fact that Applicant demonstrates them to be inferior to a conjugate of the two agents together is unsurprising and expected.
For these reasons the rejection is deemed proper and maintained.
Conclusion
No claims are allowed in this action. All rejected claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
/ANDREA OLSON/ Primary Examiner, Art Unit 1693 2/4/2026