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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 July 20, 2026 has been entered.
Detailed Action
This office action is a response to applicant’s communication submitted July 20, 2026, 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Non-elected claims 14 and 15 are withdrawn from consideration.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:
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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 an 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 July 20, 2026, with respect to the above grounds of rejection, have been fully considered but they are not persuasive to remove the rejection.
Applicant summarizes their argument as being that the cited references, even when considered collectively, do not provide a reasoned basis that would have led a person of ordinary skill in the art at the time of the invention to select and combine the specific elements recited in claim 1 with a reasonable expectation of success. In particular, the specific elements referred to as prednisolone succinate as a glucocorticoid anti-inflammatory agent, high molecular weight hyaluronic acid as a carrier, and adipic dihydrazide (ADH) as a conjugation chemistry for covalently linking the therapeutic agent to the carrier.
With respect to the particular species prednisolone succinate, Applicant admits that the various corticosteroid species described in the art share anti-inflammatory activity, but argues that this does not establish whether they are interchangeable, based on the fact that the present claims are directed to a “Structurally defined conjugate” rather than a selection of a member of a therapeutic class. However, all of the recited therapeutic moieties pointed to in the art (prednisolone, methylprednisolone, dexamethasone, and hydrocortisone) share a common structural motif, namely the steroid carbon skeleton, and differ only by minor differences in substituents around this skeleton, as illustrated, for example in scheme 1 on p. 3578 of Bilkova. Furthermore not only do all of these drugs share anti-inflammatory activity, they all produce said activity by the same mechanism, namely binding to the glucocorticoid receptor. Therefore the conclusion that these glucocorticoids can be substituted for one another with a high degree of predictability is based not only on the fact that they are all anti-inflammatory agents, but also that they share a very high degree of structural similarity and act by the same molecular pathway. There is no reason that one of ordinary skill in the art would expect the minor differences in the substitution pattern around the steroid skeleton to produce sufficient unpredictability to render the substitution of these agents for one another nonobvious.
Applicant further argues that even if it were concluded that the various glucocorticoids were interchangeable with one another, the prior art describes a large number of different corticosteroids and no particular suggestion to choose prednisolone succinate from among the various glucocorticoids described in the art. However, the mere fact that the prior art recognizes a number of different alternatives to be equally useful for a purpose and does not particularly suggest the claimed alternative does not render said claimed species nonobvious. As described in MPEP 2143(I)(B) and further elaborated in MPEP 2144.06(II), if a number of different elements are known to be equivalents suitable for the same purpose and expected to function predictably when substituted for one another, it is prima facie obvious to substitute one element for another. There is no requirement that a particular element be specifically described in the art as optimal or otherwise preferred, so long as the various interchangeable elements are described as suitable for the same purpose and functioning predictably when exchanged for one another.
Applicant further argues that the rejections of record do not establish that the substitutions relied upon would have been predictable or would have preserved the characteristics or behavior of the resulting conjugate. However, what is established by the cited references is that multiple different conjugates similar to the claimed conjugate, utilizing a variety of different glucocorticoids, polymers, conjugation chemistries, and molecular weights all function as intended. This establishes an overall pattern in the art that conjugates having structural and functional similarity to the presently claimed conjugate all function in a predictable manner for controlled delivery of glucocorticoid anti-inflammatory agents. Still further, the benefits of using ADH coupling as described by Prestwich, namely the use of mild coupling chemistry that does not degrade the HA or alter its properties, are expected to be relevant independent of whether the HA is high or low mw, or whether the chemistry is being used to crosslink HA or couple it to an active compound.
For these reasons, as well as those of record in the previous actions, 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 8/21/2026
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