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 .
Application and Claims Status
Claims 1-15 and 17-21 were pending. In the amendment as filed on 06/02/2026, applicants have amended claims 1, 5, 7-12; cancelled claims 6, 13-14; and added no new claims. Therefore, claims 1-5, 7-12, 15, 17-21 are currently pending and claims 1-5, 7-12 are presently under examination.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 4/28/2026 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.
Claim Objections
The objections to the specification (abstract and drawings) and claims are withdrawn based on Applicant’s amendments.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1-5, 7-12 under AIA 35 U.S.C. 112(b) is withdrawn based on Applicant’s amendments and arguments.
Specifically, Examiner initially rejected claim 1 as vague and indefinite in the limitations of R2 to R10, with the recitation “…or two adjacent or geminal groups are bonded together to form an optionally substituted ring.” While no adjacent groups bonded together to form an optionally substituted ring are demonstrated in the Specification, Examiner recognizes that this claim limitation is not vague and indefinite, as initially posited, and is therefore withdrawn.
Claim Rejections - 35 USC § 103
(Not Necessitated by Claim Amendment)
Applicant’s arguments of the rejection of claims 1-5, 7-12 under AIA 35 U.S.C. 103 is not found persuasive and the rejection is maintained based on Applicant’s arguments.
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, 3-5, and 7-12 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, 3-5, and 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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Eastman teaches an anionic leaving group of bromide
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 claim 5: Eastman teaches the use of Pd catalyst, as well as transition metal salts and complexes (Pd complexes and zinc salts), but Eastman does not teach the specific use of tBuXPhosPdG1.
However, MPEP 2144.06 II, which discusses substituting equivalents known for the same purpose, states: “An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).” Additionally, MPEP 2144.05 II states: "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007).
Changing the Pd catalyst from Pd2(dba)3, Pd(dba)2/Q-Phos, Pd(dba)2/P(t-Bu)3, Pd(dba)2/PCy3, or {[P(t-Bu)3]PdBr}2, as taught in the prior art, to another Pd catalyst, such as tBuXPhosPdG1 as taught by instant claim 5, in order to carry out the same reaction as taught in the prior art, would be prima facie obvious to one of ordinary skill in the art, as evidenced by MilliporeSigma. MilliporeSigma provides a comprehensive catalog of a host of catalysts and pre-catalysts, and boasts (page 2), “All Buchwald G1 to G6 pre-catalysts...allow diverse reactivity, accurate control of the ligand-to-palladium ratio, efficient formation of LPd(0) species under mild conditions, low catalyst loadings, and short reaction times.” Importantly, the Buchwald portfolio specifically includes: t-BuXPhosPdG1 (page 3), P(t-Bu)3 (page 5), PCy3 (page 5), and Qphos (page 6).
It is routine optimization to determine the best catalyst for carrying out a reaction, and one of ordinary skill in the art would have a reasonable expectation of success in testing different catalysts, such as those in instant claim 5.
Thus, said claims are obvious.
Claim(s) 1-5, and 7-12 are 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).
The previous 103 rejection is incorporated herein.
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.
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.
Thus, said claims are obvious.
Applicant traverses by stating that the Hama reference “does not establish a reasonable expectation of success in the specific indole coupling chemistry claimed” (Remarks, page 11).
Examiner does not find this persuasive and refers to MPEP 2143.02 I “Obviousness requires a reasonable expectation of success”, which states:
Where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success. The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016)
and notes that the expectation of success “need only be reasonable, not absolute”.
In instant claims 1-5, and 7-12, there is a reason to modify the prior art to achieve the claimed invention, and additionally, there is a “likelihood of success” in combining these teachings. As explained in the 103 rejection, it would have been obvious 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). Eastman teaches the Negishi coupling of ester-based Reformatsky enolates with 3-bromoindoles, and Hama teaches the use of amide-based Reformatsky enolates in various aryl halides and heteroaryl halides. Furthermore, the aryl- or heteroaryl halide used by Hama run the gamut of electronic (hetero)aromatic systems (e.g. electron-rich, electron-neutral, and electron-poor systems). The indoles of instant application and of Eastman are both electron-rich systems, further justifying the likelihood of success of substituting the reagent taught by Hama with that of Eastman.
Even more so, Hama provides motivation in making Reformatsky reagents of amide enolates, stating “we anticipated that the coupling of zinc enolates [rather than magnesium or lithium enolates] of amides could address the problem of functional group tolerance of the coupling of amide enolates.”
Applicant argues that combining the references is not a matter of routine predictability and asserts, on page 11:
Hama reports palladium-catalyzed coupling of aryl bromides with zinc enolates of amides under selected conditions and states that such reactions may occur at room temperature or 70°C with certain bromoarenes. (see Hama, Abstract; Results and Discussion, Tables I and 2, page 4978). But Hama also emphasizes that the catalyst and temperature requirements for Reformatsky reagents of amides were "much different" from other amide-enolate arylation reactions, that some palladium catalysts gave low yields, and that the successful reactions depended on selected catalyst systems such as Q-phos/Pd(dba)2 or a dinuclear Pd(I) complex.
However, a POSITA would recognize that modifying experimental conditions (e.g. solvent, temperature, catalyst, catalyst loading, order of reagent addition) is routine in the art in order to push a reaction to completion. In fact, MilliporeSigma provides a catalogue of Pd catalysts that are alternatively usable in order to achieve the desired chemical transformation. It is simply a matter of routine screening of the variety of Pd catalysts, that are all tuned to have different electronics and sterics, to meet the need of the desired chemical transformation. In fact, Pd catalyst kits containing a multitude of Pd catalyst types are sold for the express purpose of rapidly screening a chemical transformation in order to find a “hit”.
Altogether, it would have been reasonable to modify the teachings of the prior art to arrive at the instantly claimed invention.
Last, Applicant’s argument that Hama does not teach that amide-based Reformatsky reagents can be substituted into Eastwood’s 3-bromoindole Negishi-type coupling as a matter of routine predictability is not considered persuasive. Examiner responds by citing MPEP 2145(IV), which states that one cannot show nonobviousnesss by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Thus, the rejection is maintained.
Conclusion
All claims are rejected.
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
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/L.A.B./
Examiner, Art Unit 1624
/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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