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 .
Priority
This application is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/CA2022/000034, filed 07/08/2022, which claims the priority benefit of PRO Application No. 63/219,524, filed 07/08/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/30/2025, and 02/12/2026 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Election/Restrictions
Applicant's election without traverse of Group I claims 1-5, 7-11 and 15-17 with a species election of tadalafil and methyl (3aR,4S,7aR)-4- hydroxy-4-[2-(3-methylphenyl) ethynyl] octahydro-1H-indole-l-carboxylate (mavoglurant), in the reply filed 05/15/2026 is acknowledged. In addition to the applicants elected species, to expedite prosecution, the examiner also expanded the search to include the species where an mGlur5 blocking agent is not required.
Status of the Application
Claims 1-5, 7-11, 15-17, 33-36, 39-40 and 58 are pending. Claims 6, 12-14, 18-32, 37-38 and 41-57 have been cancelled by applicant without prejudice or disclaimer. Claims 33-36, 39-40 and 58 have been withdrawn by from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-5, 7-11, 15-17 are currently under examination.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 9 is objected to because of the following informalities: there appears to be numerous occurrences of transcription errors for several of the compounds in claim 9, for instance, the letter “j” appears several times in the claim as in the compound name of AZD9272 in claim 9, line 9 which may be a typo for a bracket “]”, the letter “j” appears in the compound name for HTL-0014242 in line 17 as a typo for “)”, the character for alpha “α” is replaced with “a” in the compound LY-344545, the compound name for VU-0431316 has “-cQpyrimidin” in the chemical name and may be a typo that occurred during transcription. Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2 and 5 and 15-16 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Hendrick et al (WO 2015/106032 Al) herein after Hendrick ‘032.
This rejection applies to the expanded specie where the additional mGluR5 agent is not required.
Hendrick ‘032 teaches products and pharmaceutical compositions for the treatment of diseases characterized by disruption of or damage to cAMP and cGMP mediated pathways by preventing the degradation of cAMP and cGMP by PDE1 and PDE2, thereby increasing intracellular levels of cAMP and cGMP, particularly cGMP, and provides methods of treatment for mental disorders including anxiety and fragile X syndrome [0014]. Hendrick ‘032 discloses one of the PDE1 inhibitors as (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino )-2-((4-Pyridin-2yl)-benzyl)-cyclopent[4,5]imidazo [1,2-α]pyrazolo [4,3-e ]pyrimidin-4(2H)-one [0012].
The disclosures of Hendrick ‘032 satisfy the limitations of instant claims 1-2, and 5 where a method of mitigating at least one symptom of Fragile X syndrome and anxiety in an individual by administering a phosphodiesterase inhibitor (PDE) capable of hydrolyzing cGMP and cAMP.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-5, 7-11 and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Hendrick et al (US 2016/0324860 A1) herein after Hendrick ‘860 in view of Brown et al (US 20190314309A1).
The instant claims are directed to a method of treating fragile X syndrome and its symptoms by administering one or more phosphodiesterase inhibitors and mGluR5inhibitor.
Hendrick ‘860 et al. teaches a PDE1 and PDE2 inhibitor in a pharmaceutical composition used for the treatment of cAMP and cGMP related disorders (Abstract). Hendrick ‘860 discloses treatment of fragile X syndrome “[b]y preventing the degradation of cAMP and cGMP by PDE1 and PDE2, thereby increasing intracellular levels of cAMP and cGMP, particularly cGMP, the products and pharmaceutical compositions of the invention potentiate the activity of cyclic nucleotide synthesis inducers. Therefore, the invention provides methods of treatment of any one or more of the following conditions [0016]: (i) neurodegenerative diseases, [0017] and (ii) Mental disorders, including, anxiety, cognitive impairment, fragile X syndrome” [0016]- [0018]. Hendrick ‘860 teaches an embodiment wherein the PDE1 inhibitor is (6aR,9aS)-5,6a,7,8,9,9a-hexa-hydro-5-methyl-3-(phenylamino)-2-((4-Pyridin-2yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a ]pyrazolo[4,3-e] pyrimidin-4(2H)-one and (6aR,9aS)-5, 6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-(( 4-( 6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo [l ,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one [0014] and PDE2 inhibitor is 2-(3,4-Dimethoxybenzyl)-7-{(1R)-1-[(1R)-hydroxyethyl]-4-phenylbutyl}-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (BAY 60-7550) [0015]. Hendrick ‘860 also teaches “Preferably, the PDE2 inhibitors of the invention inhibit phosphodiesterase mediated (e.g., PDE2-mediated) hydrolysis of cGMP, e.g., with an IC50 of less than 100 nM in an immobilized-metal affinity particle reagent PDE assay, for example, as described in Example 5. Preferably, the PDE2 inhibitor of the invention is 2-(3 ,4-Dimethoxybenzyl)-7-{(1R)-1-[(1R)-1-hydroxyethyl]-4-phenylbutyl }-5-methylimidazo[ 5, 1-f] [1,2,4]triazin-4(3H)-one (BAY 60-7550), in free or salt form” [0127].
However, Hendrick ‘860 et al. fails to disclose administering a therapeutically effective amount of a mGluR5 blocking agent. Hendrick ‘860 discloses a list of mental disorders treatable by preventing the degradation of cAMP and cGMP by PDE1 and PDE2 inhibitors which includes fragile X syndrome but does not explicitly teach an embodiment where a PDE inhibitor is administered for treatment of fragile X syndrome with a pharmaceutically effective amount of a PDE inhibitor.
Brown et al. teach Mavoglurant is a metabotropic glutamate receptor (mGluR5) antagonist [0050]. Brown also teaches that symptoms of fragile X syndrome which can be treated include social anxiety, hyperactivity and repetitive behavior and aggression [0024]-[0025]. Brown also teaches “[t]he kit according to the present invention provides for the administration of more than one drug, and they can be administered simultaneous, sequentially or separately” [0087]. Brown teaches kits or compositions wherein compound A is selected from basimglurant, mavoglurant, sildenafil, and tadalafil” [0031] and a preferred embodiment wherein basimglurant, mavoglurant are selected for kits or compositions [0032]. Brown discloses “[t]he present invention also relates to a method of treating fragile x syndrome comprising administering the patient with a kit or composition as described herein. This embodiment of the invention may have any of the preferred features described above. The method of administration may be according to any of the routes described above” [0098].
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to administer a pharmaceutical composition of PDE1 and PDE2 inhibitor of sildenafil or tadalafil together with mavoglurant or basimglurant to a patient diagnosed with fragile X syndrome because Brown disclosed mavoglurant as a mGluR5 antagonist and that sildenafil and tadalafil compounds are useful in treating fragile X syndrome while Hendrick ‘860 disclosed PDE1 and PDE2 inhibitors are capable of hydrolyzing cGMP and cAMP and also disclosed that fragile X syndrome is a condition treatable by PDE1 and PDE2 inhibitors. See MPEP 2112.01.
A person of ordinary skill in the art would have been motivated to administer the phosphodiesterase inhibitors of sildenafil or tadalafil together with a compound of mavoglurant or basimglurant to a patient diagnosed with fragile X syndrome because both Brown and Hendrick ‘860 disclosed that PDE1 and PDE2 inhibitors are used in the treatment of fragile X syndrome and that PDE1 and PDE2 inhibitors hydrolyze cAMP and cGMP and would therefore give a person of ordinary skill a reasonable expectation of success to produce favorable results in treating patients diagnosed with fragile X syndrome following the teachings of Hendrick ‘860 and Brown without undue experimentation to select sildenafil or tadalafil in a composition together with a compound of mavoglurant or basimglurant. See MPEP 2144.06.
Conclusion
All claims are rejected. No claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
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/E.V./Examiner, Art Unit 1623
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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