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 .
Election/Restrictions
Applicant’s election without traverse of Group I, Claims 1-6, 12-30, 32-33, and 54-58, drawn to a compound of Formula I, and a compound having the structure of:
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in the reply filed on June 10 2026 is acknowledged.
Upon review, claims 1-3, 12, 16, 17, 19, 20, 23, 28, 32, 33, 54, and 55 are deemed to read on the elected species are examined herein.
Claims 4-6, 13-15, 18, 21-22, 24-27, 29-30, 56-58, and 62-63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species
Claims 34, 36-38, 49-53, 59-61, and 64 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/process.
Rejoinder of withdrawn process claims will be considered if all elected product claims are found allowable and if the withdrawn process claims include all limitations of the allowable product claims, consistent with MPEP § 821.04.
Status of the Claims
Claims 1-6, 12-30, 32-34, 36-38, and 49-64 are pending.
Claims 7-11, 31, 35, and 39-48 have been canceled.
Claims 1-3, 12, 16-17, 19-20, 23, 28, 32-33, and 54-55 are examined herein.
Priority
The instant application 18/293,329 filed on January 29, 2024 is a 371 of PCT/US2022/074257 filed on 07/28/2022, which claims priority to, and the benefits of U.S. Provisional Application No. 63/227,467 filed on July 30, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on June 10, 2026, October 16, 2025 and March 10, 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112(a)
Written Description
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 1-3, 12, 16, 17, 19, 20, 23, 28, 32, and 33 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claim 1 is drawn to a broad genus of Formula (Ia) compounds containing numerous alternative selections for X, Y, Z, R1, R2, R3, R4, R5, R6, R7, R9, R10, X1, X2, and m. By way of providing the working examples, the specification reasonably conveys possession of the particular exemplified Formula (Ia) compounds that were actually made and characterized, including compounds having the specifically disclosed combinations of a 2-benzyl-2-azaspiro[3.3]heptan-6-yl carbamate moiety, a substituted piperazine core, and the particular heteroaryl substituents shown in the examples, such as the elected Example 13 compound, 2-benzyl-2-azaspiro[3.3]heptan-6-yl (2R,6S)-4-[5-(ethanesulfonyl)pyrimidin-2-yl]-2,6-dimethylpiperazine-1-carboxylate.
However, those specific compounds do not reasonably describe the full scope of amended claim 1. The disclosure does not provide representative species across the full breadth of the alternative X, Y, Z heteroaryl patterns; the R2 alternatives; the R5, R6 hydrogen, alkyl, and ring-forming alternatives; the R7 and m aryl substitution alternatives; the R9 alkyl, cycloalkyl, and heterocyclyl options; the R10 alternatives; and the X1 O/NH and X2 hydrogen/alkyl alternatives. The disclosure does not identify sufficient representative species across the full breadth of these alternatives, nor does it identify common structural features that would allow one of ordinary skill in the art to recognize that Applicant possessed the entire Formula (Ia) genus rather than the narrower set of specifically disclosed compounds.
The written description requirement is not satisfied by merely disclosing a broad formula together with a limited number of examples when the claim encompasses a large number of structurally diverse compounds and the specification does not provide sufficient guidance identifying which structural features are critical to the claimed genus. Accordingly, the specification does not reasonably convey to those skilled in the art that Applicant had possession of the full scope of claims 1-3, 12, 16, 17, 19, 20, 23, 28, 32, and 33 as of the filing date.
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.
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 1-3, 12, 16-17, 19-20, 23, 28, 32-33, and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (WO2019183636A1) in view of Brown et al. (WO2017021728A1).
Zhang et al. teaches piperazine azaspiro derivatives, salts thereof, and pharmaceutical compositions thereof, which are agonists of the muscarinic M4 receptor and are useful for treating M4-mediated diseases and disorders (see e.g., p. 1, line 4). Zhang et al. teaches piperazine-containing azaspiro compounds having heteroaryl substitution and pharmaceutically acceptable salts thereof (see e.g., p. 7, line 27). Zhang et al. further teaches pharmaceutical compositions comprising such compounds with pharmaceutically acceptable carriers (see e.g., p. 30, line 26).
Zhang et al. teaches the piperazine/azaspiro/carbamate M4 receptor ligand scaffold corresponding to the core of claim 1. Zhang et al. further teaches or suggests the subgeneric Formula (IIa)-(VIIa) embodiments of claims 2 and 3, the R2 hydrogen selection of claim 12, the oxygen-containing carbamate linkage of claim 16, the X2 hydrogen selection of claim 17, the combined X1/X2 selection of claim 19, the R5/R6 hydrogen selection of claim 20, the m=0 aryl embodiment of claim 23, and the pharmaceutical product and composition limitations of claims 32 and 33.
However, Zhang et al. does not expressly teach the presently claimed Formula (Ia) compound having the R1 sulfonyl substituent recited in claim 1 or the C1-C4 alkylsulfonyl selection recited in claim 28.
Brown et al. teaches muscarinic receptor agonist compounds of Formula (1a), including compounds useful as M1 and/or M4 muscarinic receptor agonists (see e.g., p. 4, line 15). Brown et al. further teaches that the compounds may include substituted heterocyclic groups and substituent groups including sulfanyl, sulfinyl, and sulfonyl substituents, such as SR, SOR, and SO2R groups (see e.g., p. 4, line 28). Brown et al. also teaches pharmaceutical compositions comprising the muscarinic receptor compounds and pharmaceutically acceptable excipients (see e.g., p. 37, line 25).
Brown et al. therefore supplies the sulfur-containing substituent options that are not expressly taught by Zhang et al., including the sulfonyl substituent options relevant to the R1/R9-SO2 limitation of claim 1 and the C1-C4 alkylsulfonyl selection of claim 28.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the piperazine azaspiro M4 receptor ligand scaffold taught by Zhang et al. to include the sulfur-containing sulfonyl substituent options taught by Brown et al. because both references are directed to nitrogen-containing muscarinic receptor ligands useful for modulating muscarinic receptor activity, including M4 receptor activity. One of ordinary skill in the art would have been motivated to use a sulfonyl substituent in the piperazine azaspiro scaffold taught by Zhang et al. to obtain additional M4 receptor ligands having predictable muscarinic receptor activity.
Regarding claim 54, the claim recites selected compounds falling within the same Formula (Ia) scaffold. The selected compounds are rendered obvious by the combined teachings of Zhang et al. and Brown et al. for the same reasons discussed above.
Claims 1-3, 12, 16-17, 19-20, 23, 28, 32-33, and 54-55 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (WO2019183636A1) in view of Brown et al. (WO2017021728A1), and further in view of Patani et al. (Chemical Reviews, 1996, 96(8), 3147-3176).
Zhang et al. and Brown et al. teach the limitations of claims 1-3, 12, 16-17, 19-20, 23, 28, 32-33, and 54 as set forth above. However, Zhang et al. and Brown et al. do not expressly teach the elected compound of claim 55, 2-benzyl-2-azaspiro[3.3]heptan-6-yl (2R,6S)-4-[5-(ethanesulfonyl)pyrimidin-2-yl]-2,6-dimethylpiperazine-1-carboxylate.
Patani et al. teaches that sulfanyl, sulfinyl, and sulfonyl groups are known medicinal chemistry oxidation-state variants and that oxidation of sulfides to sulfinyl and sulfonyl groups may be used to modify or improve the potency and properties of drug candidates (see e.g., p. 3167, Table 40). Patani et al. also teaches that bioisosteric replacement is a recognized medicinal chemistry strategy for modifying potency, polarity, and pharmacokinetic properties of drug candidates (see e.g., p. 3165, Table 36).
It would further have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select an alkylsulfonyl substituent, including the elected ethanesulfonyl substituent, because Brown et al. teaches sulfonyl substituent options in muscarinic receptor ligands, and Patani et al. teaches the medicinal chemistry rationale for modifying sulfanyl/sulfinyl groups to the corresponding sulfonyl oxidation state and for using bioisosteric replacement to tune potency, polarity, and drug properties.
Regarding claim 55, the elected compound retains the piperazine azaspiro carbamate M4 receptor ligand scaffold taught by Zhang et al. and differs by the specific 5-ethanesulfonyl pyrimidin-2-yl substituent. Brown et al. teaches sulfonyl substituent options in muscarinic receptor ligands, and Patani et al. provides the medicinal chemistry rationale for selecting sulfonyl and bioisosteric polarity-modifying substituents. Therefore, the elected compound of claim 55 would have been obvious to one of ordinary skill in the art.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 12, 16-17, 19-20, 23, 28, 32-33, and 54-55 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 14, 21-23, 43-45, 50, and 56 of co-pending Application No. 17/797,368 in view of Patani et al. (Chemical Reviews, 1996, 96(8), 3147-3176).
The claims of co-pending Application No. 17/797,368 are directed to structurally similar Formula (Ia) muscarinic receptor 4 compounds and pharmaceutical compositions. The compounds of co-pending Application NO. 17/797,368 and the compounds of the instant application share the same piperazine core, the same azaspiro/carbamate region, the same aryl or heteroaryl ring systems, and similar stereochemical and substituent patterns.
Regarding claim 1, the claims of co-pending Application No. 17/797,368 encompass Formula (Ia) compounds having the same piperazine core, the same azaspiro/carbamate region, the same aryl or heteroaryl ring systems, and corresponding stereochemical and substituent patterns. Claim 50 of co-pending Application No. 17/797,368 further claims specific Table A compounds that are structurally close to the presently claimed compounds, including compounds 529, 489, 471, 511, 169, and 170.
The principal difference between the instant claims and the most relevant co-pending claims is the nature of the substituent at the 5-position of the pyrimidin-2-yl or related heteroaryl ring. The co-pending claims include compounds bearing 5-dimethylphosphoryl, 5-dimethylcarbamoyl, 5-methylcarbamoyl, and sulfur-containing pyrimidinyl substituents. The present claims recite sulfonyl-containing substituents, including the 5-ethanesulfonyl pyrimidin-2-yl group of claim 55.
Patani et al. teaches that oxidation of sulfides leading to sulfinyl and sulfonyl groups is a known medicinal chemistry modification and may increase potency of potential drugs (see, e.g., p. 3167, Table 40). Patani et al. also teaches that bioisosteric replacement is a recognized medicinal chemistry strategy for modifying potency, polarity, and pharmacokinetic properties (see, e.g., p. 3165, Table 36).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the substituents taught by the claims of co-pending Application No. 17/797,368 to the corresponding alkylsulfonyl substituent because oxidation-state variation and bioisosteric replacement of polar electron-withdrawing groups were recognized medicinal chemistry modifications, and Patani provides motivation to make such modifications to improve or tune biological potency and drug properties.
Regarding claims 2 and 3, co-pending Application No. 17/797,368 discloses corresponding Formula (Ia) subgenera and stereochemical variants of the piperazine-containing muscarinic receptor compounds. Thus, the presently claimed subgenera would have been obvious for the same reasons discussed above.
Regarding claim 12, the selection of R² as hydrogen is encompassed or rendered obvious by the corresponding unsubstituted aryl/heteroaryl embodiments in the co-pending claims.
Regarding claims 16, 17, and 19, the recited selections of X₁ as O and X₂ as hydrogen correspond to the carbamate-linked embodiments of the related Formula (Ia) claims and would have been obvious structural selections.
Regarding claim 20, the recited selection of R⁵ and R⁶ as hydrogen corresponds to unsubstituted azaspiro embodiments of the related claims and would have been obvious.
Regarding claim 23, the recited selection of m as 0 corresponds to the unsubstituted aryl embodiments of the related claims and would have been obvious.
Regarding claim 28, the recited R⁹ alkyl substituent corresponds to the small alkyl sulfanyl/sulfinyl/sulfonyl substituent pattern addressed above. The use of C₁-C₄ alkyl substituents is a routine medicinal chemistry selection, and conversion to the sulfonyl oxidation state would have been obvious in view of Patani.
Regarding claims 32 and 33, co-pending Application No. 17/797,368 discloses pharmaceutical compositions comprising Formula (Ia) compounds and a pharmaceutically acceptable carrier. Once the compound is not patentably distinct, the pharmaceutical product or composition comprising the compound and a pharmaceutically acceptable carrier is likewise not patentably distinct.
Regarding claim 54, the claim recites selected compounds falling within the same Formula (Ia) scaffold. The selected compounds are not patentably distinct from the corresponding compounds of co-pending Application No. 17/797,368 in view of Patani et al. for the same reasons discussed above.
Regarding claim 55, claim 50 of co-pending Application No. 17/797,368 claims structurally close Table A compounds, including compounds 529, 471, 489, 511, 169, and 170. Compounds 471 and 489 are shown below:
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Compound 529, 2-benzyl-2-azaspiro[3.3]heptan-6-yl (2R,6S)-4-[5-(dimethylphosphoryl)pyrimidin-2-yl]-2,6-dimethylpiperazine-1-carboxylate, is the closest claimed species because it has the same 2-benzyl-2-azaspiro[3.3]heptan-6-yl carbamate moiety, the same (2R,6S)-2,6-dimethylpiperazine core, and the same 5-substituted pyrimidin-2-yl group as the instantly claimed compound of claim 55. The difference is replacement of the 5-dimethylphosphoryl substituent of compound 529 with the 5-ethanesulfonyl substituent of claim 55.
Compounds 471 and 489 provide additional support because they have the same 2-benzyl-2-azaspiro[3.3]heptan-6-yl carbamate moiety, the same (2R,6S)-2,6-dimethylpiperazine core, and the same 5-substituted pyrimidin-2-yl group, but contain 5-methylcarbamoyl or 5-dimethylcarbamoyl substituents. Compound 511 provides a related 5-dimethylphosphoryl heteroaryl analog, and compounds 169 and 170 provide sulfur-containing pyrimidinyl analogs. Patani et al. teaches that bioisosteric replacement is a recognized medicinal chemistry strategy for modifying potency, polarity, and pharmacokinetic properties of drug candidates (see. p.3165, table 36). It would have been obvious to one of ordinary skill in the art before the effective filing date to replace the 5-dimethylphosphoryl or 5-carbamoyl substituent of the co-pending compounds with a 5-alkylsulfonyl substituent, such as the claimed 5-ethanesulfonyl substituent, as a bioisosteric and polarity-modifying substituent at the same pyrimidinyl position, with a reasonable expectation of obtaining a structurally close M4 receptor ligand. Therefore, the compound of claim 55 is not patentably distinct from the compounds claimed in co-pending Application No. 17/797,368.
Conclusion
No claims are allowed.
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/G.S./Examiner, Art Unit 1628
/AMY L CLARK/ Supervisory Patent Examiner, Art Unit 1628
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