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 .
Status of the Claims
Claims 1-2, 4, 6-14, 16, 21-23, 25, 27, and 29-30 are pending in the instant application. Acknowledgment is made of Applicant’s amendments filed May 01, 2026 and cancelation of claims 3, 5, 15, 17-20, 24, 26, 28, and 31-34.
Election/Restrictions
Applicant’s election without traverse of group I, in the reply filed on May 01, 2026 is acknowledged.
Applicant’s election without traverse of compound 54, depicted, in the reply filed on May 01, 2026 is acknowledged.
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Compound 54 is a compound of formula (I) wherein Ra1 is
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with X2a = CH, X3a = C-R3a, X4a = N, X5a = CH, and X6a = CH;
Ra2 is H; R3a is S(O)(NR9)R7; R7 is methyl; R9 is H;
R4b1 is H;
R4b2 is methyl;
R5b1 is methyl;
R5b2 is CF3;
R2c is -OR15 wherein R15 is C1 alkyl (methyl);
X3c is C-R3c wherein R3c is H;
X4c is C-R4c;
X5c is C-R5c; X6c is C-R6c;
R4c and R5c are F; and R6c is H.
Compound 54 is also recited in claim 23 (p. 11, 4th row, left col.).
Compound 54 has been found free of the prior art. Thus, the search has been expanded to the below compound:
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This is a compound of formula I wherein Ra1 is
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, wherein X2a is C-R2a, X3a is C-R3a, X4a is C-R4a, X5a is C-R5a, X6a is C-R6a, wherein R2a, R3a, R5a, and R6a are each H, and R4a is -C(O)NR9R10, wherein R9 and R10 are each H;
Ra2 is H;
Rab1 is H;
Rab2 is C1 alkyl, methyl;
R5b1 is C1 alkyl, methyl;
R5b2 is C1 haloalkyl, -CF3;
X3c is C-R3c, wherein R3c is halo, F;
X4c is C-R4c, wherein R4c is halo, F;
X5c is C-R5c, wherein R5c is H;
X6c is C-R6c, wherein R6c is H; and
R2c is C1 haloalkoxy.
Claims 27 and 29-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 May 01, 2026.
Claims 7-10 and 14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 01, 2026.
Claims 1-2, 4, 6, 11-13, 16, 21-23, and 25 are presently under examination as the relate to the elected invention of Group I and species of compound 54.
Priority
This application claims priority to U.S. Provisional Application No. 63/197,253, filed June 04, 2021, and is a 371 of PCT/US2022/032238.
Specification
The lengthy 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 errors of which applicant may become aware in the specification.
Claim Objections
Claim 1 is objected because the following limitation “R9 and R10 together with the atom to which they are attached form a 37 membered heterocycloalkyl” (p. 4, para. 1) is different from the corresponding limitation in the specification which reads: “R9 and R10 together with the atom to which they are attached form a 3-7 membered heterocycloalkyl” (p. 7, para. 3). For examination purposes, the definition of R9 and R10 will be construed as having the meaning laid out in the specification.
Claim 4 is objected because the structure of formula (I-B) depicted therein is different from the structure of formula (I-B) depicted in the specification (see para. [0066]). The structures are compared below.
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It appears the formula (I-B) depicted in claim 4 has an extraneous methyl group coming off of R4b1 (see arrow). For examination purposes, formula (I-B) will be taken as the formula depicted in the specification.
Appropriate correction is required.
Claim Rejections – Improper Markush
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Claims 1-2, 4, 6, 11-13, 16, 21-23, and 25 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
The Markush grouping of compounds represented by the formula recited in claim 1 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The Markush grouping is directed to compounds of formula (I) or pharmaceutically acceptable salts thereof:
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The variables Ra1, Ra2, R2c, R4b1, R4b2, R5b1, R5b2, X3c, X4c, X5c, and X6c, encompass a myriad of substituents forming compounds so diverse, that they will confer the above structure complete different structural and biological properties. Moreover, these variables can be substituted with X2a, X3a, X4a, X5a, X6a, R7, R8, R9, R10, R11, R12, R13, Ra’, Ra’’, Ra3 substituents which would confer the above structure with completely different structural and biological properties. For example, Ra1 can be a 6-membered heteroaryl, 5-membered heteroaryl, 3-7-membered heterocycloalkyl, 9-10-membered aryl, or 9-10-membered heteroaryl, any of which can be substituted by one or more Ra3 independently selected from halo C1-C6 alkyl, C1-C6 haloalkyl, 3-7 membered heterocycloalkyl, -C(O) C1-C6 alkyl, -OR11 , -C(O)NR9R10, or-S(O)2R7, wherein said C1-C6 alkyl, C1-C6 haloalkyl, 3-7 membered heterocycloalkyl or -C(O)C1-C6 alkyl is optionally substituted by one or more halo, -OR11 , -CN, or-NR9R10, or two Ra3 attached to the same atom combine to form oxo, or two Ra3 attached to adjacent atoms together with the atoms to which they are attached combine to form a fused 3-7 membered ring containing up to two heteroatoms selected from the group consisting of N, O, and S. With the myriad of compounds that arise from the various definitions and combinations of the variables present in this formula, the result is a group of compounds that include distinct ring systems and a variety of substitution patterns resulting in compounds with no single structural similarity that are not obvious variants of each other. To this end, a comparison of four compounds of the formula (I) presented in claim 1 of the instant specification demonstrates a lack of significant structural similarity and shows compounds of the formula recited in instant Claim 1 are not obvious variants of each other:
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(p. 8, right col., row 3)
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(p. 47, right col. row 1)
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(p. 89, right col., row 2)
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(p. 115, left col., row 4)
These compounds also demonstrate that compounds recited in claim 23 are not obvious variants of each other.
As these compounds demonstrate, the compounds according to the formula (I) include compounds with no common core structure that are not obvious variants of each other. With no significant structural similarity, the Markush grouping is improper.
Although claims 2, 4, 6, 11-13, 16, 21-22, and 25, which depend on claim 1, narrow the scope of certain variables of the broad Markush structure, they still nonetheless embody a myriad of chemical compounds without both a single structural similarity and a common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope of Enablement – Compounds
Claims 1-2, 4, 6, 11-13, 16, 21-22, and 25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for compounds of formula (I-B-3) (see specification page 19):
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and formula (I-C-3) (see specification page 20):
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wherein R2c is H, halo, or C1-C-6 alkoxy; R3c is H or F; R4c is H or F; and other variables substituted as claimed; does not reasonably provide enablement for the full scope of variables in the instant claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to compounds of formula (I) or a pharmaceutically acceptable salt thereof.
Breadth of the invention:
The scope of the claimed invention is very broad, as it is drawn to compounds of the formula:
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allowing for myriad combinations of variables as described in the claims. The substituents of this core structure that are not enumerated here provide further breadth.
State of the prior art and predictability in the art:
The invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F. 2d 833, 839, 166, USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F. 2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F. 2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F. 2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Tautermann (Quantum Mechanics in Drug Discovery, Humana Press, 2020, Chapter 1, pp. 1-17), cited for evidentiary purposes, teaches drug discovery is a very challenging, cost-intensive, and in terms of investment risky endeavor; on average, it takes 10–15 years and an investment of more than 2.5 billion dollars to get a new drug to the Market; especially the clinical phases cause extremely high costs and late-stage failures, especially in phase II studies, are quite common (page 1, 1st paragraph). Tautermann teaches the largest attrition in clinical phases is observed in phase II studies; the main goal is the assessment of the efficacy of the compound yielding a clinical proof of concept; a recent analysis from four major pharma companies revealed that the cause for attrition in phase II is mainly caused by lack of efficacy followed by safety issues; efficacy for a certain indication is usually preclinically tested in animal models; however, the translatability from animal models to the human situation is not always given; there are several reasons for this; often the disease condition cannot adequately be induced in animals (page 3, last paragraph). Tautermann teaches small molecules have several advantages, such as being cell and brain permeable, the lower cost of goods in their production, and oral administration; however, they are not always the easiest path forward for challenging targets; especially in the case of difficult or so far undruggable targets, new design strategies are required to be successful (page 5, last paragraph). Thus, Tautermann further establishes that the state of the art of drug design is highly unpredictable.
Level of ordinary skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing chemical compounds for particular activities. The synthesis of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can be employed, developing a therapeutic method, as claimed, prior to synthesizing and testing compounds is generally not well-known or routine, given the complexity of certain biological systems.
The amount of direction provided and working examples:
The compound core depicted with specific substituents represents a narrow subgenus for which applicant has provided sufficient guidance to make and use; however, the disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the compounds instantly claimed. As an example, Applicant has provided no working examples of any compounds, compositions, or pharmaceutically acceptable salts where any of X3c, X4c, X5c, or X6c are N.
Within the specification, “specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p).
MPEP § 2164.01 (a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here that Applicant is not enabled for making these compounds.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4, 6, 13, 21-23, and 25 are rejected under on the ground of nonstatutory double patenting as being unpatentable over claims 6, 7, and 10 of US 11,919,887 B2 (herein ‘887, cited in the IDS filed April 01, 2025).
‘887 teaches compounds of the following formula (claim 1):
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‘887 also teaches a pharmaceutical composition of compounds of the above formula (claim 7), and teaches these compounds are useful for treating pain (claim 10).
In a specific embodiment, ‘887 claims the following compound (claim 6, col. 405, lines 50-65):
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Regarding claims 1, 2, 4, 6, 13, and 21-22, the above claimed compound is a compound of instant formula I wherein Ra1 is
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, wherein X2a is C-R2a, X3a is C-R3a, X4a is C-R4a, X5a is C-R5a, X6a is C-R6a, wherein R2a, R3a, R5a, and R6a are each H, and R4a is -C(O)NR9R10, wherein R9 and R10 are each H;
Ra2 is H;
R4b1 is H;
R4b2 is C1 alkyl, methyl;
R5b1 is C1 alkyl, methyl;
R5b2 is C1 haloalkyl, -CF3
X3c is C-R3c, wherein R3c is halo, F;
X4c is C-R4c, wherein R4c is halo, F;
X5c is C-R5c, wherein R5c is H;
X6c is C-R6c, wherein R6c is H; and
R2c is C1 haloalkoxy.
Regarding claim 23, although 887 does not teach wherein the amide groups are directly opposite to each other (para) such as depicted below:
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,
a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. See MPEP 2144.09.I: "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) (discussed below and in MPEP § 2144) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. See also MPEP § 2144.08, subsection II.A.4.(c).”
In the instant case, it would have been obvious to modify the compound of ‘887 to arrive at the compound depicted below from instant claim 23 (p. 14, left col., row 3) since ‘887 teaches very similar compounds useful in the treatment of pain. One would have been motivated and had a reasonable expectation of success that these compounds will have similar properties.
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Regarding claim 25, ‘887 teaches a pharmaceutical composition of compounds of their formula (I).
Conclusion
Claims 1-2, 4, 6-14, 16, 21-23, and 25 are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OLIVER D. HEES whose telephone number is (571)272-9840. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, AMY L. CLARK can be reached at (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/O.D.H./Examiner, Art Unit 1628
/Rayna Rodriguez/Primary Examiner, Art Unit 1628
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