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 is a National Phase Application of international Application No. PCT/JP2021/
034445, filed on September 13, 2021, which claimed priority to EP Application No. 20195704.0,
filed on September 11, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/07/2023, 04/05/2023 and
06/04/2025 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the
information disclosure statements are being considered by the examiner.
Status of the application
Claims 1-6 are pending and currently under examination.
Applicant’s arguments, filed 02/12/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. They constitute the complete set presently being applied to the instant application.
The obviousness rejection below is repeated from the 11/13/2025 Office Action and modified in order to address the most recent amendments.
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 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Ogawa (WO2019/189766A1) in view of Takahashi (EP 3153511 Al) and further in view of Aboulhoda (Evaluating the effect of three newly approved overactive bladder syndrome treating agents on parotid and submandibular salivary glands: Modulation of CXCL10 expression).
The instant claims are directed to a method of treating dry mouth in a subject by administering a maleic acid salt of compound of (2S)-4-[5-[[[4-(4-Chloro-2-thienyl)-5-[[(2R)-2-methyl-1-pyrrolidinyl]methyl]-2-thiazolyl]amino]carbonyl]-2-pyrazinyl]-2-methyl-l-piperazinepropanoic acid, CAS RN 1839583-42-4 shown below, with an anticholinergic agent and pilocarpine.
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Ogawa et al. teach the compound of formula I as a muscarinic M3 receptor positive allosteric modulator which is disclosed as a preventive and/or therapeutic agent for diseases associated with muscarinic M3 receptors (e.g., Sjogren's syndrome)(Abstract).
However, Ogawa et al. fail to disclose the specific compound of instant claim 1.
Takahashi et al. teach 2-acylaminothiazole derivatives useful for treating bladder or urinary tract diseases, related to bladder contraction by a muscarinic M3 receptor [0001]. Takahashi also discloses the compound of example 1 (table 72, pg. 100), example 142 (table 103, pg. 131), and example 144 (table 104, pg. 132) which have the equivalent structure of the compound of claim 1 of the instant claims. Takahashi also discloses compounds of formula (I) may form an acid addition salts with inorganic acids including maleic acid [0055]. Takahashi discloses example 144 (3-[(2S)-4-(5-{[ 4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-methylpyrrol idin-1-yl]methyl }-1,3-thiazol-2-yl]carbamoyl }pyrazin-2-yl)-2-methylpiperazin-l-yl]propanoic acid) is a maleic acid salt version of applicants (2S)-4-[5-[[[4-( 4-Chloro-2-thienyl)-5-[[(2R)-2-methyl-1-pyrrolidinyl]methyl]-2-thiazolyl]amino]carbonyl]-2-pyrazinyl]-2-methyl-l-piperazinepropanoic acid. See MPEP 2112.
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Takahashi also teaches that the compound of formula (I) is a muscarinic M3 receptor-positive
allosteric modulator, and can thus be used as an agent for preventing or treating bladder/urinary
tract diseases associated with bladder contractions via a muscarinic M3 receptor [0208].
However, Takahashi et al. fail to disclose co-administering the compound of pilocarpine.
Aboulhoda et al. teach trospium, darifenacin, and solifenacin for the treatment of over
active bladder (OAB) and the histological and ultrastructural effects of those compounds on
parotid and submandibular salivary glands (Abstract). Aboulhoda also teaches a salivation study
wherein pilocarpine-induced salivary secretion was minimally suppressed in rats with only slight
non-significant reduction after solifenacin administration (3.6 salivation study section, page
277). Aboulhoda also discloses" Maintenance of relatively adequate salivary secretion along
with weak suppression of cholinergic salivation by darifenacin and solifenacin treatment in the
current study may be driven primarily by the potential higher selectivity of these drugs for M3
receptors," and "Results of solifenacin group after pilocarpine stimulation goes fairly well with
the human pharmacodynamic studies which showed that the salivary flow rate after solifenacin
administration was similar to that of placebo"(pg. 280, left column, bottom 2 para.). Aboulhoda
also discusses symptoms of xerostomia in conditions like Sjogren's syndrome (pg. 278, right
column, 1st para.).
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 treat dry mouth in a subject by administering an muscarinic M3 receptor positive allosteric modulator as taught by Takahashi and would have through ordinary experimentation tested compounds with similar structures disclosed by Ogawa which are also disclosed as muscarinic M3 receptor positive allosteric modulators. See MPEP 2144.05 (II). Further more the skilled artisan seeking to solve the problem of a combination of said compound with another compound known to have side effects of dry mouth such as anticholinergics would counteract the dry mouth effect of the anticholinergic with another compound known to treat dry mouth, such as pilocarpine as taught by Aboulhoda and would therefore also be obvious.
A person of ordinary skill in the art would have been motivated to treat dry mouth in a subject in need thereof by administering the compounds taught by Takahashi and Ogawa who disclosed administering muscarinic M3 receptor positive allosteric modulators for use in the treatment of dry mouth, xerostomia and Sjogren’s disease in light of Aboulhoda’s disclosure of darifenacin and solifenacin and pilocarpine to counteract the dry mouth effect of the anticholinergic. Furthermore the skilled artisan familiar with the properties of the M3 positive allosteric modulators as compared with agonists, exhibit enhanced effects dependent on endogenous agonist stimulation, so that side effects can be avoided – applicants claimed compound would be predicted to stimulate the salivary glands while avoiding the undesirable side effect of hyperhidrosis.
Response to Arguments
Applicant's arguments filed 02/12/2026 have been fully considered but they are not persuasive.
Applicant argues Takahashi discloses a compound that is a muscarinic M3 receptor-positive allosteric modulator (M3PAM) (Table 103 in Example 142). However, Takahashi merely discloses the compound itself, and does not suggest the use for dry mouth associated with Sjogren's disease, effects during chronic administration, persistence, or any association with desensitization.
Applicant also argues Aboulhoda discloses that pilocarpine-induced salivary secretion in rats was minimally suppressed by antimuscarinics and slight non-significant reduction was observed even after administration of solifenacin that is anticholinergics acting on muscarinic M3 receptors in bladder smooth muscle (item "3.6 Salivation study" on page 277). However, Aboulhoda does not suggest the use of M3PAM for treatment of dry mouth.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The combination of Ogawa, Takahashi and Aboulhoda would lead a person of ordinary skill in the art to treat dry mouth in a subject in need thereof by administering the compounds of example 1, 142, and 144 disclosed by Takahashi which affect the M3 receptor and anticipates applicants disclosed compound, furthermore Takahashi’s compounds are structurally similar to the compounds effective at treating Sjogren’s disclosed by Ogawa and would have given a person of ordinary skill a reasonable expectation of treating the same conditions such as Sjogren’s. Both Ogawa and Takahashi are also linked by teachings of muscarinic M3 receptors including Aboulhoda which also teaches Sjogren’s as well as the additional compounds of pilocarpine and trospium, Darifenacin, Solifenacin in salivary glands.
Conclusion
Claims 1-6 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
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/E.V./Examiner, Art Unit 1623
/SAMANTHA L SHTERENGARTS/Primary Examiner, Art Unit 1623