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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/25/26 has been entered.
Maintained rejections
The sole rejection of the claims under 35 USC 103 over Chen et al., is maintained. Reply to applicant’s remarks filed on 4/24/26 are addressed following the repeated text of the rejection of record. Rejection has been altered to address the new limitation of claim 1 where the administration of the composition prevents or delays stress induced fear, stress induced depressive-like, and stress induced anxiety-like behavior. Claims now require that all 3 of the stress induced disorders are prevented.
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.
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.
Claim(s) 1 and 10-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (Neuropsychopharmacology, 2020, 45, 542-552; published on 10/10/2019).
Scope of prior art
Chen is directed to prophylactic efficacy of 5-HT4R agonists against stress. Specifically, Chen teaches RS-67,333, prucalopride and PF-o4995274 as 5-HT4R agonists. Chen teaches that chronic administration of RS-67,333, in mice models, is prophylactic against stress (page 543, Results, 1st paragraph) and against a wide range of CORT induced behavioral abnormalities (page 543, Results, 4th paragraph). Chen further teaches that a single injection of RS-67,333 attenuates learned fear and protects against stress induced hypophagia (page 545, column 1). Chen also teaches prucalopride attenuated learned fear and decreased depressive-like behavior (page 548, column 1, paragraph 2). Chen teaches prucalopride as a monohydrochloride salt (paragraph bridging pages 542 and 543).
Regarding ketamine, Chen teaches that ketamine is prophylactic against stress-induced depressive-like behavior and like RS-67,333 also attenuates learned fear (page 545, column 1). Ketamine meets the limitations of claims 3 and 5 directed to antagonist of NMDAR (claim 3) and agonist of AMPAR (claim 5). On page 548, Chen teaches that ketamine is known to inhibit NMDAR and activate AMPAR (page 548, second column, first paragraph).
Ascertaining the difference
Chen only performs studies using mice and does not treat actual human subjects.
While Chen teaches anti-stress prophylactic activity of RS-67,333 and of Ketamine, art does not teach administration of the both agents as a combination treatment.
Obviousness
A person of ordinary skill in the art, prior to the earliest effective filing date of the current application would have found it obvious to try to prophylactically treat stress induced disorders by administration to a subject in need a combination of ketamine and prucalopride. Chen teaches both agents as prophylactic agents for reducing stress induced behavior. Prucalopride and ketamine are taught to be effective in reducing stress induced fear and depressive and anxiety-like behavior (abstract). Chen also teaches that stress exposure is a significant risk factor for MDD and PTSD and that ketamine is known as a resilience enhancing drug against stress and has potential to prevent PTSD. Given that both prucalopride and ketamine are taught to be used for the same purpose, a skilled artisan would have found it obvious to use them together in a combination therapy against stress induced pathologies. Ketamine is a known agent with a well-known safety profile, and RS-67,333 is taught to not result in adverse side effects even after chronic administration (page 548, column 2, third paragraph). Since both agents are effective against stress-induced pathologies and both are taught to be safe, or not result in adverse effects, a skilled artisan would have found it obvious to try administering the combination to a subject in need of reduction of stressed induced pathologies. With regards to timing of administration, a skilled practitioner would have found to obvious to determine through routine practice, the optimal time periods for administering the combination treatment prior to the onset of stress-induced disorders.
With regards to limitation of claim 1 directed to prevention or delay in delays stress induced fear, stress induced depressive like and stress induced anxiety-like behavior:
Chen renders obvious a method of prophylactically administering to a subject a combination of prucalopride and ketamine. Since the claimed combination is administered to the claimed subject population, the subject inherently benefits from prevention or delay of the currently claimed stress induced disorders.
Reply to applicants’ remarks
Applicants’ remarks file don 4/24/26 have been fully considered and found to be not persuasive. Applicants argue that they have made a surprising discovery derived from administering a combination of ketamine and prucalopride. This argument was addressed in the non-final rejection. The data presented in the specification examples 2-7 does not support the argument directed to unexpected results.
In Figure 1D 3mg.kg of prucalopride resulted in less immobility then when it was combined with 10mg/kg of ketamine. In fact, no amount of ketamine improved the efficacy 3mg/kg of prucalopride or of 10mg/kg of prucalopride.
In figure 1G, which measures time spent in center, only 30+1.5 appears to have an unexpected result. However, the graph is misleading because the error bars in the 30+1.5 column are so large that it’s not possible to say that there was any improvement over administration of saline or of only 30mg/kg of ketamine or of 1.5mg/kg of prucalopride.
Analysis of the remainder of the data also indicates that applicants’ assertion of unexpected results is not supported. Even where it appears that an unexpected result exists, it’s limited to a very narrow dose combination and has error bars so large that the data is inconclusive.
Conclusion
Claims 1 and 10-25 are pending
Claims 1 and 10-25 are rejected
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YEVGENY VALENROD whose telephone number is (571)272-9049. The examiner can normally be reached Mon-Fri 9am-5pm.
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/YEVGENY VALENROD/Primary Examiner, Art Unit 1628
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