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 .1
Status of the Claims
Claims 1, 3, 6, 8 and 22-31 are pending in this application.
Information Disclosure Statements
The information disclosure statement(s) (IDSs) submitted April 4 2025 and March 11 2026 have/has been considered by the Examiner. The submission(s) is/are in compliance with the provisions of 37 CFR § 1.97.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1, line 1: recites the first instance of “the dose of an administered antipsychotic. . . .“ As this is the first instance of “dose,” it should recite “a dose.”
Claim 1, line 4: recites “an antipsychotic agent . . . . “ As this is not the first instance of “antipsychotic agent,” it should recite “the antipsychotic agent.”
Claim 1, line 9: recites “the absence of ebselen.” As this is the first instance of the term “absence of ebselen,” it should recite “an absence of ebselen.”
Appropriate correction is required.
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.
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.
Claims 1, 3, 6, 8, and 22-31 are rejected under 35 U.S.C. 103 as being unpatentable over Singh et al. “A Safe Lithium Mimetic [Ebselen] for Bipolar Disorder,” Nature Communications 2013, pp. 1-14 Vol. 4 No 1332 and Davies, M.A. et al., “Aripiprazole: a novel atypical antipsychotic drug with a uniquely robust pharmacology,” CNS Drug Reviews,Vol.10,No.4,2004,pp.317-336. Singh and Davies have been cited by Applicant’s IDS and previously by the Examiner in the parent application, U.S. 17/146,360.
Applicant’s specification’s Summary notes the “the present disclosure provides combinations of compounds useful as, for example glutathione peroxidase (GPx) modulators . . . . and method of treatment, prevention, inhibition or amelioration of one or more diseases associated with GPx mediated disorders,” see paragraph 7. The Summary notes that GPx modulators (ebselen) and an antipsychotic drug (aripiprazole) are combined to treat disorder such a bipolar disorder, see paragraphs 8-10, 11-12 and 18-19.
Accordingly, prior art disclosing the treatment of bipolar disorders (and/or schizophrenia) with aripiprazole and ebselen (as per Singh and Davies) will render the claimed invention obvious as follows.
Examined claim 1 is a method of reducing the dose of an administered anti-psychotic agent for treating a psychotic disorder that is bi-polar disorder or schizophrenia, comprising coadministering:
a therapeutically effective amount of ebselen; and
a therapeutically effective amount of an anti-psychotic agent to a subject having bi-polar disorder or schizophrenia,
wherein the therapeutically effective amount of the anti-psychotic agent in the presence of the co-administered ebselen is lower than a therapeutically effective amount of the anti-psychotic agent in the absence of ebselen.
Claim 6 is directed to the treatment of a bipolar disorder or schizophrenia with therapeutically effective amounts of the claimed combination of ebselen and antipsychotic agent.
Regarding claims 1 and 6 and the limitation(s) of treatment of bipolar disorders in a subject in need with ebselen, Singh discloses that inositol is target for treatment of bipolar disorders, where the antioxidant ebselen inhibits inositol monophosphatase and induces lithium-like effects on mouse behavior, see abstract. Singh discloses that there is a need for lithium alternatives for the treatment of bipolar disorder due to lithium’s potential toxicity and many undesirable side effects, see abstract. See also page 4, column 2 first paragraph of Singh noting ebselen’s lithium-like effects on both the manic or the depressive pole of bipolar disorder.
Singh discloses ebselen is a lithium mimetic with the potential both to validate inositol monophosphatase inhibition as a treatment for bipolar disorder and to serve as a treatment itself, see abstract.
Singh Figure 1 demonstrates inhibition of inositol monophosphatase at various concentrations, see page 2. Singh Figure 2 demonstrates permeation of the blood brain barrier of a mouse subject to inhibit endogenous inositol monophosphatase, see page 3. Singh notes that ebselen demonstrates lithium-like effects on a lithium-sensitive mouse model of mania, see page 4, first paragraph column 2.
Singh suggests that polypharmacology (i.e., use of pharmacological agents to target multiple receptors) is a desirable property, for example, antipsychotics hitting multiple targets were more efficacious than drugs that were selective, see page 5, column 1 first few lines. Thus Singh notes provides a teaching to combine ebselen with other antipsychotics to treat a subject in need.
Although Singh teaches the use of ebselen for treatment of a bipolar disorder in a mouse subject and teaches/suggests a combination of ebselen with an antipsychotic agent (where it suggests polypharmacology, targeting multiple targets, which can be achieved by combination therapy), he does not explicitly teach antipsychotic agent in combination (such as aripiprazole) so as to administer lower therapeutic doses as opposed to monotherapy to treat bipolar disorders.
However, Singh lays the ground work to combine ebselen with other drugs to provide a combination (polypharmacology) therapy of bipolar (and other) disorders, as noted above.
For example, Davies discloses aripiprazole works by a mechanism different from Singh’s inositol approach, as aripiprazole is a GCPR agonist (such as dopamine D2 and/or 5-HT1A) and Davies notes preliminary data indicates it may be also effective for the treatment of manic symptoms of bipolar disorder, see abstract.
Davies discloses significant improvement in PANNS negative scores and depressive symptoms (MADRS scores) with aripiprazole in comparison to older medications such as haloperidol, see bottom of page 328 bridging to top of page 329.
While there is not a teaching expressly reciting the lowered therapeutic doses for aripiprazole as claimed, it would be obvious to a person having ordinary skill in the art (PHOSITA) to reduce such doses as both the combination of Singh and Davies both teach treating the same disorder to be (bipolar) with two classes of medications, ebselen and aripiprazole. Accordingly, it would be routine for a PHOSITA to adjust a dose of aripiprazole in combination with ebselen as they are both directed to the treatment of not only bipolar disorders in general, but both address the treatment of both the manic and depressive poles of such disorder, see Singh page 4 noted above and Davies abstract and pages 328-329.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of Singh (ebselen to treat bipolar and other psychosis disorders) based on the theory of polypharmacology, combined with those teachings of Davies (aripiprazole to treat bipolar disorders, where aripiprazole works via different mechanism of action from ebselen) (the KSR rationale of MPEP 2143(a) combining prior art elements according to known methods to yield predictable results).
The PHOSITA would have had a reasonable expectation of success as it would be prima facie obvious to combine the teachings of Singh and Davies per the KSR rationale of MPEP 2143(a) and MPEP2144.06 I. COMBINING EQUIVALENTS KNOWN FOR THE SAME PURPOSE, (citing to In re Kerkhoven).2
Claims 3 and 8 further limits claims 1 and 6 (respectively), and require that wherein the antipsychotic agent is selected from a group consisting of aripiprazole (among others). As discussed above, Davies disclose the use of aripiprazole for the treatment of bipolar disorder, see abstract, etc.
Claims 22 and 27 further limit claims 1 and 6 and are limited to bipolar disorder. As noted above, the teachings of Singh and Davies provide a prima face case of obvious to co-administer/combine ebselen and aripiprazole for the treatment of bipolar disorder.
Claims 23, 25, 26, 28, 30 and 31 further limit claims 1 and 6 (directly or indirectly), and requires the antipsychotic drug be aripiprazole. As noted above, the teachings of Singh and Davies provide a prima face case of obvious to co-administer/combine ebselen and aripiprazole for the treatment of bipolar disorder.
Regarding claims 24 and 29 and the treatment of schizophrenia in a subject in need, Davies teaches these claims, as it teaches the recent introduction for clinical use of aripiprazole in the treatment of schizophrenia, see abstract.
Conclusion and Correspondence
In summary, no claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 This application is a CON of 17/146,360 filed 01/11/2021 now abandoned.
17/146,360 is a CON of 15/510,218 03/09/2017, now abandoned. Application No. 15/510,218 is a 371 National Stage Application of PCT/US2015/050255 filed 09/15/2015. PCT application PCT/US2015/050255 has claims priority to 62/050,635 filed 09/15/2014.
2 ““It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). . . .”
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