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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/13/2026 has been entered.
Claim Status
Claims 37-43 and 55-66 are pending. No amendments were made. Claims 56-57, 59, 61, and 64-66 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention (Claims 56-57) and nonelected species (Claims 59, 61 and 64-66). Therefore, Claims 37-43, 55, 58, 60, 62, and 63 are presented for examination.
Election/Restrictions
Applicant elected Group I (drawn to a compound comprising cabotegravir (CAB) covalently linked to a second integrase inhibitor) and the compound species
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with traverse in the reply filed on 4/10/2025.
Claim Rejections - 35 USC § 103
Rejection Maintained
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 37-43, 55, 58, 60, 62, and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Hu et al. (USPN 6,225,321 B1) in view of Spreen et al. (JAIDS Journal of Acquired Immune Deficiency Syndromes 67(5):p 481-486, December 15, 2014. | DOI: 10.1097/QAI.0000000000000301).
Claimed invention
A compound comprising cabotegravir (CAB) as a first integrase inhibitor linked covalently to a second integrase inhibitor such as
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- which is wherein the compound inhibitors are the same, i.e., inhibitor-linker-inhibitor, CAB-linker-CAB, and more specifically,
CAB
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CAB.
Prior art
Hu teaches the general formula of the compound is R-[CO-NAL]n wherein n is an integer from 2-4 and, in which the R is selected from a saturated or nonsaturated, substituted or unsubstituted, aliphatic or aromatic group having 1 to 40 carbon atoms and NAL is nalbuphine drug. See abstract. Hu specifically teaches dimers of nalbuphine with a diacid alkyl linker, particularly, the C10 diacid, sebacic acid. See Fig. 1C and Fig. 2 and col. 3:~59-63. They were developed to increase the release profile of injectable formulations to extend the release time of the drug and, thus, extending the activity of the drug. See Abstract; see also Fig. 6 and paragraph bridging cols. 12 and 13.
Hu does not teach CAB as a dimer linked by an alkyl diacid linker.
Spreen teaches GSK1265744 (i.e., CAB) is a potent integrase inhibitor used in long-acting injectable nanosuspensions for HIV treatment and prevention. See Title, Abstract. Adverse effects (AE) are common with subcutaneous (SC) and include pain, erythema, and nodule formation at the site of injection. Pain was described in 50%, 100%, and 83% of subjects receiving 744 SC 100-mg, 200-mg, or 400-mg split injections, respectively, relative to 33% of placebo subjects describing pain. Pain was more common with an increasing volume of injection, 0.5 mL versus 1 mL. The mean duration of erythema can range from 2 to 10.7 days. Erythema at the injection site is involved with both SC injection and intramuscular (IM) injection. Nodules were described clinically as typically painless. See p. 493. Long-acting (LA) injectable antiretrovirals could provide significant advantages in adherence and patient convenience for both treatment and prevention of HIV infection. See p. 481. Spreen suggests reduction of dosing rates after IM or SC injections suggest that a dosing frequency of once monthly or longer is possible for HIV treatment. The disclosed PK profile also supports an ongoing study as a preexposure prophylaxis agent with an even longer interval between doses. See 486.
A person of ordinary skill in the art (POSA) would have found it obvious to apply the strategy of dimerization via hydrolysable alkyl diacid linkers (e.g., sebacic acid) to CAB and arrive at the instant formula
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(meets Claim 63 wherein n=2, which is only 1 iteration of -CH2- from elected compound) because Hu teaches the strategy of diacid ester dimerization using sebacic acid (HOOC-C8-COOH) as a linker attached at the hydroxyl group of 2 nalbuphine molecules (forming sebacoyl dinalbuphine) to create a compound with a longer-acting release profile for nalbuphine and Spreen teaches that extending the release of CAB can be used to minimize intervals between dosing of CAB in order to reduce known AEs observed in patients with HIV being treated with CAB. The POSA would have done so in order to extend its release profile, reduce the number of injections and increase patient convenience and potentially adherence to CAB treatment due to the lower number of injections. The POSA would recognize Spreen’s disclosure of CAB’s limitations and its suggestion to extend the release profile to aid in reducing these limitations and Hu’s teaching of a diacid ester dimerization strategy to increase the release profile of a drug can be combined to extend CAB’s release profile and thereby reduce its known limitations. The POSA would recognize that the hydroxyl functional group of CAB is analogous to the nalbuphine alcohol used in esterification.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
The compound suggested by Hu and Spreen differs from the structure in Claim 44 (
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) by a single -CH2- group in the linker between the two CAB molecules, i.e., the suggested compound has one additional -CH2- group. Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See MPEP 2144.09 (II). Thus, this supports the position that one would reasonably recognize that the change in a single iteration of a repeating substituent as an obvious design choice. Thus, the POSA would have found the claimed compound (
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) obvious as there would have been a presumed expectation that the compound as modified would possess similar properties a as the compound
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. Thus, the suggested compound of
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(i.e., CAB-linker-CAB or more specifically CAB
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CAB) meets the limitations of Claims 37-43, 58, 60, and 62.
Regarding Claim 55, Spreen teaches the compositions containing CAB at 200 mg/mL nanosuspension at doses of 100–800 mg IM and 100–400 mg subcutaneous, thus, indicating the compound is in a pharmaceutically acceptable liquid carrier. See ‘Methods’ at p. 481.
Response to arguments
Applicant argues that Spreen reports successful long-acting CAB and therefore provides no motivation to develop a further long-acting CAB compound. This argument is not persuasive. The rejection does not require Spreen to expressly identify its formulation as unsuccessful or to expressly direct further structure modification of CAB. Spreen establishes that prolonged CAB exposure, reduced dosing frequency, and long-acting administration were desirable. Hu teaches a specific means for obtaining prolonged drug release-covalently linking 2 drug molecules through a hydrolysable diacid ester linker. Thus, the POSA would apply Hu’s known prolonged release strategy to CAB to obtain the known benefit of prolonged exposure. The fact that Spreen has already achieved a useful long-acting CAB formulation does not teach away from alternative ways of obtaining that desirable result.
Applicant further argues that there are many other long-acting drug delivery strategies that existed and therefore, a POSA would not have selected Hu. However, obviousness does not require that Hu’s strategy have been the only or preferred approach. Hu teaches dimerization through diacid ester linker extends drug release and CAB possesses the hydroxyl functional group through which Hu’s esterification strategy may be applied. The existence of other known approaches to prolong drug delivery does not negate the specific reason supplied by Hu for employing its dimerization strategy.
Applicant further argues that Hu is non-analogous because it teaches nalbuphine (an analgesic), not an integrase inhibitor such as CAB. On the contrary, Hu is indeed analogous art because it teaches a general prodrug/dimer strategy directed to modulating pharmacokinetics (PK) and extending duration of action of systemically administered drugs via hydrolysable linkers. The field of endeavor and problem addressed – prolonged release/extended activity through covalent linkage – are reasonably pertinent to the problem identified in Spreen for CAB long-acting therapy. Mechanism of action or therapeutic indication is not determinative here since the cited teaching is a broadly applicable chemical/PK strategy not necessarily limited by therapeutic purpose or action. Applicant’s reference to the existence of other known strategies are unpersuasive as outlined above.
Applicant also argues that the PK effect of modifying CAB would have been unpredictable and the there was no reasonable expectation of success. However, reasonable expectation of success does not require absolute certainty as to the precise PK properties ultimately obtained. Hu demonstrates that the particular diacid ester dimerization strategy relied upon produces prolonged delivery and CAB contains the hydroxyl functionality necessary to employ that strategy as mentioned above.
Accordingly, Applicant’s hindsight and obvious-to-try arguments are also not persuasive. The rejection does not select randomly from immeasurable possible modification using Applicant’s disclosure as guidance. Spreen identifies CAB and the desirability of prolonged CAB exposure, Hu provides the specific diacid ester dimerization strategy for obtaining prolonged release, and the remaining linker-length difference is a homologous variation.
Therefore, the rejection is deemed to still be proper and is, therefore, maintained.
Conclusion
No claims are allowed.
All 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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