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, encompassed by claims 1-14, in the reply filed on March 19, 2026 is acknowledged.
Claims 15 and 17-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 19, 2026.
Application and Claims Status
Claims 1-15 and 17-21 were pending. In the reply filed on March 19, 2026, applicants have amended no claims; cancelled no claims; added no new claims, and withdrew claims 15 and 17-21. Therefore, claims 1-14 are currently pending.
Priority
The instant application is a 35 U.S.C. § 371 of International Application No. PCT/CA2022/050699, filed May 4, 2022, which claims the benefit and priority of U.S. Provisional Application No. 63/184,538, filed May 5, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) filed on July 17, 2025 is in compliance with the provisions of 37 CFR 1.97. All references have been considered except where marked with a strikethrough. A signed copy of Form 1449 is included with this Office Action.
Specification – Abstract
The abstract of the disclosure does not commence on a separate sheet in accordance with 37 CFR 1.52(b)(4) and 1.72(b). A new abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text.
Specification - Drawings
Acknowledgement is made of the drawings received November 2, 2023.
The drawings are objected to because:
Reference characters, sheet numbers, and view numbers are not oriented in the same direction. In the instant drawings, FIG. 1-4 and 8-22 are oriented in the incorrect direction. As recited in 37 CFR 1.84:
(p) Numbers, letters, and reference characters.
(1) Reference characters (numerals are preferred), sheet numbers, and view numbers must be plain and legible, and must not be used in association with brackets or inverted commas, or enclosed within outlines, e.g., encircled. They must be oriented in the same direction as the view so as to avoid having to rotate the sheet. Reference characters should be arranged to follow the profile of the object depicted.
The view numbers should be preceded by the abbreviation “FIG.”, not “FIGURE”. As recited in 37 CFR 1.84:
(u) Numbering of views.
(1) The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation "FIG." Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation "FIG." must not appear.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification – Disclosure
The 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 of the errors of which applicant may become aware of in the specification
Claim Objections
Claims 1 and 7-12 are objected for their use of non-standard Markush claim language. Markush claims are commonly formatted as “selected from the group consisting of A, B, and C” or “wherein R is A, B, C, or D”. As an example, in claim 1, in the limitation of R2-R10, Applicant recites “…R2 to R10 represent hydrogen, deuterium, (C1-C20)-alkyl, (C2-C20)-alkenyl, (C2-C20)-alkynyl, (C3-C20)-cycloalkyl, (C6-C20)-aryl, (C5-C20)-heteroaryl, -C(=O)-(C1-C20)-alkyl, or two adjacent or geminal groups are bonded together to form an optionally substituted ring...”. Proper Markush claim language could optionally recite “…R2 to R10 are selected from the group consisting of hydrogen, deuterium, (C1-C20)-alkyl, (C2-C20)-alkenyl, (C2-C20)-alkynyl, (C3-C20)-cycloalkyl, (C6-C20)-aryl, (C5-C20)-heteroaryl, -C(=O)-(C1-C20)-alkyl, and two adjacent or geminal groups are bonded together to form an optionally substituted ring...”. (emphasis added). Examiner recommends changing the recitation of “represents” to the format of “selected from the group consisting of A, B, and C.” As claims 2-6 and 8-14 depend upon claims 1 or 7 and either have the same problems or do not resolve the problems of claims 1 or 7, they are also rejected. Relevant guidance can be found in the MPEP § 2173.05(h), titled “Markush Claims,” which deals with claims that list alternatives.
Claim 6 is objected to for improper subject/verb agreement, as it should properly recite “The process according to claim 5, wherein the transition metal salts and complexes comprise palladium, nickel, iron, ruthenium, cobalt, rhodium, iridium or copper” (emphasis added).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-11 and 13-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is regarded as vague for its limitation of R1 which recites, “…each of which are optionally substituted with halogen, OH, optionally substituted phenyl or (C1-C6)-alkyl”. Based on the current wording, it is unclear if (C1-C6)-alkyl is also optionally substituted or not.
Claim 1 is regarded as vague for its limitation of R2 to R10, which recites, “…or two adjacent or geminal groups are bonded together to form an optionally substituted ring”. Each of R2-R8 are attached to either an sp2-hybridized carbon or an sp2-hybridized nitrogen. It is unclear how two geminal groups at these positions can then bond together to form a ring. As an example, R6 is adjacent to another group (R5) to which it can bond together to form a ring; however, it is not geminally bonded to another group so it cannot form a ring. Applicant is encouraged to amend the claim for clarification. As claims 2-11 and 13-14 do not resolve the present issue, they are also rejected.
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.
Claim(s) 1, 3-14 are rejected under 35 U.S.C. 103 as being unpatentable over Eastwood et al. (WO 2013/010881 A1, published January 24, 2013)(hereinafter, “Eastwood”) in view of Hama et al. (“Palladium-Catalyzed Intermolecular α-Arylation of Zinc Amide Enolates under Mild Conditions”, published 2006)(hereinafter, “Hama”).
Regarding claims 1, 7-12: Eastwood teaches the synthesis of tert-Butyl {1-[2-{[(cyclopropylcarbonyl)(ethyl)amino]methyl}-4-(trifluoromethyl)phenyl]-6-fluoro-1H-indol-3-yl}acetate, as Preparation 96, on page 98. Notably, the substrate of the reaction is a 3-bromoindole. The reaction is shown below:
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The organozinc used in the reference reaction, as well as in the instant claims, is referred to as a Reformatsky reagent. Eastwood uses an ester-based Reformatsky reagent, specifically 2-tert-butoxy-2-oxoethyl)zinc(II) chloride, but does not teach the use of an amide-based Reformatsky reagent.
Hama teaches a full account of the scope and limitations of the α-arylation of amides by palladium-catalyzed coupling of aryl bromides with zinc enolates of amides. The arylation of isolated Reformatsky reagents was found to occur at room temperature with electron-rich, electron-neutral, and electron-poor aryl bromides (Table 2, page 4978; Table 5, page 4981). The Reformatsky reagents reported by Hama (Table 1 and 2, page 4978; and elsewhere) read on the Reformatsky reagents of the instant application. Furthermore, Hama notes “the palladium-catalyzed α-arylation of carbonyl compounds has been introduced as a mild catalytic method to form the C-C bond between an aryl ring and the α-position of a carbonyl compound” (page 4976, Introduction) and that a variety of ester enolates have been reported and well-established, but the “α-arylation of amides, with one exception, has been limited to reactions of lactams or intramolecular reactions of acyclic amides” (page 4976-4977, Introduction). Thus, the report of Hama is among the first to disclose a wide range of reactions of aryl halides with zinc enolates of amides.
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to modify the preparation of Eastwood to use the Reformatsky reagents disclosed by Hama because it is no more than substituting equivalents known for the same purpose (see MPEP 2144.06 II): it is the simple substitution of one known element for another with the predictable result of preparing α-arylated carboxamides, especially since Hama teaches the successful implementation of amide-based Reformatsky reagents on electron-rich, electron-neutral, and electron-poor substrates, thoroughly exploring the success of the reaction with substrates of widely varying electronics. Furthermore, while not every R variable of the substrate taught by Eastman reads on the instant invention (for instance, reference variable R5 is F, and reference variable R1 is a substituted C6H5 beyond the optional substitutions of instant R1), the chemical process that is occurring is an expected reaction. The use of a novel and unobvious starting material, or a novel and unobvious final product, does not render an obvious, predictable process patentable. In a chemical process, all of the evidence must be considered on the subject matter as a whole from the viewpoint of one skilled in the art, in the determination of obviousness, and not simply to the patentability of one of the starting materials or final products in the process. The process is deemed obvious to one of ordinary skill in the art since it involves a predictable and expected reaction. In re Durden, 763 F.2d 1405. 226 U.S. P.Q. 359 (Fed, Cir. 1985).
Regarding claim 3: Eastman teaches the synthesis of achiral compounds.
Regarding claim 4: Hama teaches the following chiral organozinc reagent (Table 1, page 4978, Entries 2, 4, and 5) which, when employed in an α-arylation reaction, would produce a chiral product, as well.
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Regarding claims 5 and 6: Eastman teaches the use of Pd catalyst, as well as transition metal salts and complexes (Pd complexes and zinc salts).
Regarding claims 13 and 14: Eastman teaches an anionic leaving group of bromide.
Claim(s) 2 is rejected under 35 U.S.C. 103 as being unpatentable over Eastwood in view of Hama and Elmore (“The Use of Isotopically Labeled Compounds in Drug Discovery”, published 2009)(hereinafter, “Elmore).
Regarding claim 2: The teachings of Eastwood and Hama were previously discussed, as applied to claim 1. Eastwood and Hama do not teach replacing one or more of the carbon-12 atoms in a compound of Formula (III) with carbon-13. Elmore teaches, on page 515, that “isotopically labeled compounds are critical to the drug development process for use as radioligands in lead discovery, as metabolic tracers in development, and in phase IV clinical studies.” Given that there is always a need to enhance the pharmacological effects of a compound (e.g. increased in vivo half-life) without significantly altering its basic chemical structure (first branch), or that there is always a need to reduce the time, cost, risk, and statistical imprecision of pharmacokinetic studies (e.g. measure bioavailability or identify metabolites) (second branch), and that there is only a limited number of ways that this can be done, it would be obvious to pursue a potential solution that has a reasonable expectation of success. See e.g. KSR International Co. v. Teleflex Inc., 1385, 1397; Pfizer, Inc. v. Apotex, Inc., 82 USPQ2d 1321; Alza Corp. v. Mylan Laboratories, Inc., 80 USPQ2d 1001; In re Kubin, 90 USPQ2d 1417; In re O’Farrell, 7 USPQ2d 1673, 1681; In re Eli Lilly & Co., 14 USPQ2d 1741; In re Ball Corp., 18 USPQ2d 1491.
Thus, it would have been obvious to one of ordinary skill in the pharmaceutical art to have applied this known improvement technique in the same way to the compound of the primary reference to obtain the results reasonably predictable from the secondary references. See e.g. KSR International Co. v. Teleflex Inc., 1385, 1396; Ruiz v. AB Chance Co., 69 USPQ2d 1686; In re Nilssen, 7 USPQ2d 1500.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
CONCLUSION
No claims are allowed.
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUKE ALAN BORALSKY whose telephone number is (571)272-9746. The examiner can normally be reached Monday - Friday 7:30 am - 5:00 am.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey H Murray can be reached at 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.A.B./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624
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