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 .
All previous objections and rejections not reiterated herein were overcome by claim amendments and arguments, filed April 6th, 2026, have been fully considered and found persuasive. As such all objections and rejections not reiterated herein have been withdrawn.
Claim Objections
Claims 3 – 5 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 102
Response to Arguments
Applicant’s arguments and claim amendments, see page 6 paragraph 1, filed April 6th, 2026, with respect to 35 U.S.C. 102(a)(1) rejection of claims 1 – 3 over International Patent Publication WO 2009/099177 A1 to Yasuhara et. al. (herein after Yasuhara’177; cited on the ISR Form) have been fully considered and are persuasive. The 35 U.S.C. 102(a)(1) rejection of claims 1 – 3 has been withdrawn.
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 – 2, and 6 are rejected under 35 U.S.C. 103 as being unpatentable over International Patent Publication WO 2009/099177 A1 to Yasuhara et. al. (herein after Yasuhara’177; cited on the ISR Form) in view of Patani et. al. ((1996) Bioisosterism A rational approach in drug design, Chem. Rev., 96, 3147-3176).
Regarding claims 1 – 2, and 6, Yasuhara’177 teach compound species 4-(chloromethyl)-N-[1-(2-methoxyphenyl)-4-phenyl-1Himidazol-2-yl]benzamide of structure
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(page 27 paragraph 0088) which is embraced by general formula (I) wherein instant R1 , that is Ar1, is a phenyl wherein instant R5 is H (claim 6); instant R2 is H; instant R3 is a phenyl with meta-OCH3; instant R4 is phenyl wherein instant R4a is CH2Cl in the para-position.
However, Yasuhara’177 fails to teach a compound of claim 1, having Formula (II)
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wherein instant R3a is in the para-position with respect to the imidazole (claims 1 – 2).
Nevertheless, Nevertheless, Patani et. al. teach that the concept of bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents (page 3147 column 1 paragraph 1 and column 2 paragraph 1). Additionally, Patani et. al. teach that the substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements (page 3149 column 1 paragraph 5). Moreover, Patani et. al. teach that the steric parameters for hydrogen and fluorine are similar, their van der Waal’s radii being 1.2 and 1.35 Å, respectively (page 3149 column 1 paragraph 5). Furthermore, Patani et. al. teach that the difference in the electronic effects (fluorine being the most electronegative element in the periodic table) is often the basis for the major differences in the pharmacological properties of agents where fluorine has been substituted for hydrogen (page 3149 column 1 paragraph 5). Additionally, Patani et. al. teach that the pharmacological differences can be attributed to the influence of the electron-withdrawing effect that the fluorine substitution causes on interaction with either a biological receptor or enzyme, as well as its effect on the metabolic fate of the drug (page 3149 column 1 paragraph 5). Moreover, Patani et. al. teach that the ability of fluorine to replace hydrogen is an effective method of exploring the affinity of an agent to the target site (receptor or enzyme) by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are maintained (page 3150 column 1 paragraph 2).
Therefore, it would have been obvious before the effective filing date if the instant application to modify the compound of Yasuhara’177 to move the methyl ester to the para position then modify the ortho H in view of Patani et. al., that is to substitute the H atoms on the instant R3 phenyl for a F atoms. One of ordinary skill in the art would have been motivated to make this modification to explore the affinity of the compound to the target site while the steric size and lipophilicity if maintained. One or ordinary skill in the art would have had a reasonable expectation of success because substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements. Moreover, given that the only difference between instant Formula (II) of structure
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and prior art compound is the position of the methoxy, that is prior art (meta position) versus instant claim (para-position), both the prior art compound and the instant compound are positional isomers. Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978)(MPEP 2144.09(II)).
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over International Patent Publication WO 2009/099177 A1 to Yasuhara et. al. (herein after Yasuhara’177; cited on the ISR Form) Patani et. al. ((1996) Bioisosterism A rational approach in drug design, Chem. Rev., 96, 3147-3176), as applied above to claims 1 – 2, and 6.
The teachings of Yasuhara’177 and Patani et. al. as they relate to claim 1, from which claim 16 depend, are given previously in this office action and are fully incorporated here.
However, the prior art of Yasuhara’177 and Patani et. al. fail to teach a pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt hereof and a pharmaceutical acceptable carrier, diluent, or excipient (claim 16).
Nevertheless, Yasuhara’177 further teach that in the metabotropic glutamate receptor mGluR5 the compounds, which includes compound species 4-(chloromethyl)-N-[1-(2-methoxyphenyl)-4-phenyl-1Himidazol-2-yl]benzamide of structure
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(page 27 paragraph 0088) was dissolved in 100 µL of the evaluation buffer which is (20 mM HEPES solution, pH 7.4, containing 130 mM sodium chloride, 5 mM potassium chloride, 1.8 mM calcium chloride, 1 mM magnesium chloride, 10 mM glucose, 2.5 mM probenecid and 0.1% bovine serum albumin (BSA)) (translation pdf page 128 paragraph 1). Thus Yasuhara’177 suggest that the compounds of the disclosure which include, 4-(chloromethyl)-N-[1-(2-methoxyphenyl)-4-phenyl-1Himidazol-2-yl]benzamide, can be dissolved in buffer which further includes water which is a pharmaceutically acceptable carrier.
Therefore it would have been obvious to one of ordinary skill in the art to use the compound of Yasuhara’177 as modified in view of Patani et. al., that is to move the methyl ester to the para position and to substitute the H atoms on the instant R3 phenyl for a F atoms in a pharmaceutical composition which includes water. One of ordinary skill in the art would be motivated to make this modification to administer the compound to a patient as a therapeutic. One of ordinary skill in the art would have had a reasonable expectation of success because the compounds of the disclosure were dissolvable in the solution.
Response to Arguments
Applicant’s arguments and claim amendments, see page 6 paragraphs 5 – 6 and page 7 paragraph 1, filed April 6th, 2026, with respect to 35 U.S.C. 103 rejection of claims 1 – 2, 6, and 16 over International Patent Publication WO 2009/099177 A1 to Yasuhara et. al. (herein after Yasuhara’177; cited on the ISR Form) in view of Patani et. al. ((1996) Bioisosterism A rational approach in drug design, Chem. Rev., 96, 3147-3176) have been fully considered but are not persuasive.
Applicant argues that prior art reference of Yasuhara’177 fails to teach that the phenyl ring can be substituted by three non-hydrogen substituents at specific positions on the phenyl ring (see applicant’s remarks page 6 paragraph 6). Moreover, applicant argues that the specific substitutions improve the stimulatory action of the compounds on the mGluR5 receptors (see applicants arguments page 7 paragraph 1).
The examiner contends that the prior art reference of Yasuhara’177 in view of Patani et. al. renders the instant claims obvious. As stated in the above rejection, structures with the same substituents at different positions especially around a ring structure are position isomers (compounds having the same radicals in physically different positions on the same nucleus) and are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978)(MPEP 2144.09(II)). Moreover, as taught about by Patani et. al. the substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements (page 3149 column 1 paragraph 5) since the steric parameters for hydrogen and fluorine are similar, their van der Waal’s radii being 1.2 and 1.35 Å, respectively (page 3149 column 1 paragraph 5). Thus the combination of Yasuhara’177 and Patani et. al. renders obvious the compounds and composition of instant claims 1 – 2, 6, and 16.
Conclusion
Claims 1 – 2, 6, and 16 are rejected. Claims 3 – 5 are objected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAWANNA S WHITE whose telephone number is (703)756-4687. The examiner can normally be reached 7:00 am - 5:00 pm [EST] M - Th.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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