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 .
Change of Examiner
This application has been reassigned to Examiner Valenrod whose contact information is provided in the conclusion portion of this document
Withdrawn rejections
Rejection of claims 1-3, 7-13 and 16-21 under 35 USC 112(a) as being enabling for treatment of migraine, anxiety, depression, psychosis and paranoia but not other types of cognitive or neurological disorders is withdrawn in view of amendments limiting the scope of disorders to migraine, anxiety, depression, psychosis and paranoia.
Rejection of claims 1, 4, 7 and 9-11 under 35 USC 102(a)(1) over Yoon et al is withdrawn in view of amendments removing ketamine from a list of 5-HT3 agonists.
Rejection of claims 1-4, 7, 9-13, 16-17 and 19-21 under 35 USC 103 over Yoon in view of NIDA Staff is withdrawn in view of amendments
Rejection of claims 1, 4 and 7-11 under 35 U.S.C. 103 over Yoon in view of Desert Biologicals is withdrawn in view of amendments
Rejection of claims 2-3, 12-13 and 16-21 under 35 U.S.C. 103 over Yoon in view of Desert Biologicals and NIDA Stass is withdrawn in view of amendments.
New rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4, 9, 11-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (a) the nature of the invention; (b) the breadth of the claims; (c) the state of the prior art; (d) the amount of direction provided by the inventor; (e) the existence of working examples; (f) the relative skill of those in the art; (g) whether the quantity of experimentation needed to make or use the invention based on the content of the disclosure is "undue"; and (h) the level of predictability in the art (MPEP 2164.01 (a)).
Nature of the invention and Breadth of the claims:
The claims are directed to a method of treating a cognitive or neurological disorder in a patient comprising administering to the patient a composition comprising a) naltrexone, 6-beta-naltrexol, methylnaltrexone, nalmefene and nalorphine and b) a composition comprising an agonist of a 5-HT3 receptor selected from the vast list presented in claim 1. The claim requires clinical activity in treatment of depression anxiety, psychosis, migraine and paranoia. It is incumbent upon Applicant to teach the skilled artisan how to treat the claimed disorders according to the method in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to treat cancer without undue experimentation.
State of the prior art and level of predictability in the art:
Art does not recognize monotherapy with naltrexone or its derivatives in treatment of the claimed disorders. This rejection will focus on depression since it is the elected species.
With regards to role of 5HT-3 receptors in treatment of depression, art suggests that antagonism of the receptor is a potential therapeutic approach for treatment of depression (Bhatt, Current Neuropharmacology, 2021, 19, 1545-1559). Bhatt teaches that antagonists of 5HT3 receptors inhibit binding of serotonin and increase its availability to other receptors such as 5HT1A 5HT1D and 5HT2 receptors from which therapeutic efficacy is derived. Notably the pending claims are directed to the opposite activity at 5HT3R. Current claims are directed to compounds that are agonists of 5HT3R, and the inventive concept comprises administration of naltrexone which increases availability of 5HT3R. If the logic of Bhatt is applied to the currently claimed method, increase in 5HT3R expression will bind more serotonin and would therefore decrease the amount of serotonin available to interact with other 5HT receptors from which clinical efficacy is derived. According to Bhatt, the current method would result in decreased efficacy of treatment of depression.
Betry et al (Pharmaceuticals 2011, 4, 603-629), like Bhatt, also teaches that 5HT3R agonists seem to counteract the effects of antidepressants, while antagonists of the receptor present antidepressant-like activity (abstract).
With regards to effect of naltrexone when administered with 5HT3R agonist relevant teaching is Williams et al (Am. J. Psychiatry, 2018, 175(12), 1205-1215). Williams examines the effect naltrexone on antidepressant efficacy of ketamine (ketamine is a 5HT3R agonist). Naltrexone + ketamine is compared to placebo + ketamine. Williams finds that pretreatment with oral naltrexone dramatically blocked the antidepressant effect of ketamine.
Amount of direction provided by the inventor and existence of working examples:
Specification teaches that applicants have made the following discovery: naltrexone selectively increases 5HT3 receptor levels and therefore can be used to aid the effectiveness of 5HT3R agonists. The described activity of naltrexone to increase 5HT3R levels is allegedly supported by in vitro experiments that demonstrate increase in levels of mRNA for 5-HT3 receptor proteins (page 2, lines 8-15; pages 8-9, Examples). Notably, the sole Example provided only indicates that the increase in expression is in mRNA coding for the proteins that are present in 5HT3R. Examples do not demonstrate that actual expression of 5HT3R is increased. Prior to expression, mRNA must undergo numerous other transformations such as transcription, post transcriptional modifications, folding and membrane integration before a fully functional receptor is expressed.
Specification lacks data demonstrating efficacy of the claimed combination in treatment of any disorder. Applicants are relying entirely on the hypothesis that increase in 5HT3R protein mRNA expression will result in increased number of expressed 5HT3 receptors and that increase will improve efficacy of antidepressants. However, the hypothesis is not supported by experimental data.
Relative skill of those in the art and quantity of experimentation needed to make or use the invention:
Although the relative level of skill in the art is high, one of ordinary skill would not be able to treat cancer according to the claimed method without engaging in undue experimentation. The art teaches that agonists of 5HT3 receptor seem to counteract efficacy of antidepressants, while antagonists improve antidepressant-like activity. Art provides mechanistic explanation for this which relies on 5HT3R interacting with serotonin, thereby resulting in less serotonin being available for activity at other 5HT receptors and thereby decreasing antidepressant effect. Applicants are suggesting increasing the expression of 5HTR as a strategy to improve antidepressant effects, which is opposite to the teachings of the art. Additionally, there is evidence in the art that pretreatment with naltrexone reduces antidepressant efficacy of ketamine (a 5HT3 agonist). In view of these teachings and lack of experimental data suggesting otherwise, a skilled artisan would indeed question the clinical efficacy of the claimed invention. Without experimental data that supports applicants’ hypothesis, it falls on the practitioner to carry out the necessary experimentation to enable each claimed combination.
Thus, given these considerations, one of ordinary skill in the art clearly would not be able to practice the claimed method such that it can be used as contemplated in the specification without first engaging in substantial and undue experimentation. Therefore, the claims are rejected under 35 U.S.C. §112, first paragraph, as lacking and enabling disclosure.
Conclusion
Claims 1, 4, 9, 11-13 are pending
Claims 1, 4, 9, 11-13 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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/YEVGENY VALENROD/Primary Examiner, Art Unit 1628
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