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/EP2020/076933, filed 09/25/2020, which claims the priority benefit of United Kingdom Application No. 1913921.1, filed 09/26/2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/01/2022, and 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 20-30 and 40-46 are pending. Claim 23 been amended. Claims 20-22, 24-30 and 40 have been withdrawn. Claims 1-19 and 31-39 have been cancelled. Claims 23 and 41-46 are currently under examination.
Claim Interpretation
It is noted from the specification that “[a]tropisomers can be classified using the Cahn-Ingold-Prelog R and S system which is illustrated by (S)-6,6'-dinitrobiphenyl-2,2'-dicarboxylic acid shown in Figure 1” (pg. 6, lines 24-26). As such, the term atropisomer is being interpreted as being an optical isomer. See MPEP 2111.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (pg. 91, line 10). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
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 23 and 41-46 are rejected under 35 U.S.C. 103 as being unpatentable over Boyle (WO 2018/197714 Al).
The instant claims are directed to an atropisomer of formula (I) in a composition with an excipient having an optical rotation value of less than 0, wherein at least 90% of the compound of formula (I) present has an optical rotation value of less than 0.
Boyle et al. teach optical isomers of the reference compounds to include all isomeric forms including R, S, +, -, d, 1, enantiomers, epimers, diastereomers and racemic mixtures (pp.36-37). Boyle discloses the compound of 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)-phenyl] pyrrol-2-yl]-N-[2(dimethylamino)ethyl]benzamide in example 33 (pg. 72) Boyle teaches “Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)- mandelic acid, (-)-malic acid, and (-)-camphor sulphonic, separating the diastereomers by preferential crystallisation, and then dissociating the salts to give the individual enantiomer of the free base. Where compounds of the invention exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a plurality of diastereomers. Accordingly, the invention provides compositions containing a compound having one or more chiral centers, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of the formula (1) is present as a single optical isomer (e.g. enantiomer or diastereomer). In one general embodiment, 99% or more (e.g. substantially all) of the total amount of the compound of
the formula (1) may be present as a single optical isomer (e.g. enantiomer or diastereomer).” (sic) (pg. 37, lines 7-25). Boyle discloses tablet compositions using an excipients well known in the art including methyl cellulose (pg. 58, lines 12-22). Boyle discloses example B wherein compound 33 has an EC50 of 0.061+ 0.01 μM (pg. 143, line 7-8).
PNG
media_image1.png
153
205
media_image1.png
Greyscale
PNG
media_image2.png
224
524
media_image2.png
Greyscale
Boyles compound 33 (Left) Formula 1 instant claims (Right)
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 isolate a stable atropisomer of formula (I) having an optical rotation value of less than 0, wherein at least 90-99% of the compound of formula (I) present has an optical rotation value of less than 0 following Boyle’s disclosed methods of isolating desired isomeric forms of compounds which may show a higher degree of potency than other conformations of the same compound. Based on Boyle’s disclosure, example 33 would inherently include the instantly claimed optical isomer as a naturally occurring and isolatable phenomena during the synthesis of 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)-phenyl] pyrrol-2-yl]-N-[2(dimethylamino)ethyl] benzamide. Furthermore, the compound name of atropisomer (R)-4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)-phenyl]pyrrol-2-yl]-N-[2(dimethylamino) ethyl]benzamide in instant claim 23 follows the Cahn-Ingold-Prelog (CIP) sequence rules therefore a skilled artisan following the teachings of Boyle example 33 would at once envisage all the optical isomers encompassed by example 33, especially when Boyle teaches up to 99% or more (e.g. substantially all) of the total amount of the compound of the formula (1) may be present as a single optical isomer. See also MPEP 2131.02(111), MPEP 2144.08 and MPEP 715.03.
It is noted from the specification that “[a]tropisomers can be classified using the Cahn-Ingold-Prelog R and S system which is illustrated by (S)-6,6'-dinitrobiphenyl-2,2'-dicarboxylic acid shown in Figure 1” (pg. 6, lines 24-26).
A person of ordinary skill in the art would have been motivated to identify any stable isomeric forms of Boyle’s example 33 because of the disclosure of a low EC50 of 0.061+ 0.01 μM and would have been further motivated to increase the therapeutic potency of compound 33 by investigating racemic properties to isolate a conformation exhibiting better biological activity over another and therein improve a composition of compound 33 and an excipient. Therefore a skilled artisan would have had a reasonable expectation of success in isolating the (S) and (R) version of 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)-phenyl]pyrrol-2-yl]-N-[2(dimethylamino) ethyl]benzamide from compound 33 following the disclosures of Boyle.
Response to Arguments
Applicants arguments and amendments to the claims overcome the rejections presented in the final rejection mailed September 9, 2025.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C Milligan can be reached at 571-270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/E.V./Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
Prosecution Insights