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, claims 66-80, drawn to compounds of Formula (Ib) and (Ie) and election of the following species, Example 125, depicted below, in the reply filed on March 11, 2026 is acknowledged.
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Example 125 is a compound of Formula (Ib) wherein RG2 is H; G3, G4, and G5 are all CH; R1 is phenyl substituted with 1 R3 selected from -C(O)-NRaRb, wherein Ra and Rb are each C1 alkyl; and R2 is selected from unsubstituted 7-membered heterocycloalkyl.
Example 125 has been found free of prior art. Thus, examination has been expanded to the encompass the full scope of Group I, the compound claims 66-80. The search has been expanded to encompass compounds containing the following core structures depicted below, which are the core structures of formulas (Ib) and (Ie) and of the compounds recited in claims 78 and 79:
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All compounds of claim 79 contain the above core structures of either formula (Ib) or (Ie), and other than a few exceptions (1.028, 1.029, 1.061, 1.096, and 1.116), all compounds of claim 79 fall within the scope of either formula (Ib) or (Ie). All compounds of claim 78 contain the core structures of either formula (Ib) or (Ie) and are within the scope of formulas (Ib) and (Ie) with the exception of the following:
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.
Claims 81-86 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 11, 2026.
Claims 66-80 are under examination as they relate to the elected Example 125 and compounds of formulas (Ib) and (Ie).
Priority
This application claims priority to U.S. Provisional Application No. 63/191,631, filed May 21, 2021 and is a 371 of PCT/US2022/030227, filed May 20, 2022.
Claim Rejections - 35 USC § 112
112(a) – Scope of Enablement
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.
Claims 66-78 and 80 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 a compound of Formula (Ib) or formula (Ie) wherein:
G3 (CRG3), G4 (CRG4), and G5 (CRG5) are CH, CF, or CNH2;
RG2 is H or F;
R1 is phenyl, pyrimidinyl, or piperidinyl substituted with 0-2 R-2 as described below;
each R2 is C1-7 alkyl, C3-7 cycloalkyl, pyrrolidinyl, morpholinyl, tetrayhydrofuranyl, azetidinyl, or pyranyl substituted as claimed;
each R3 is halogen, hydroxyl, -CN, C1-7 alkyl, C3-7 alkyl, O-(C1-7 alkyl), -S(O-2)-(C1-7 alkyl), -S(O2)-(C3-7 cycloalkyl), -S(O-2)-NH2, -S(O-2)-(azetidinyl), pyrrolidinyl, azetidinyl, piperazinyl, pyrrolidonyl, morphilonyl, tetrayhydrofuranyl, tetrahydropyranyl, oxetanyl, -C(O)NH2, -C(O)NH-(C-1-C7 alkyl) -C(O)-piperazinyl, or -C(O)-piperidinyl, wherein the cycloalkyl or heterocycloalkyl are substituted as claimed;
does not reasonably provide enablement for the full scope of variables of G3 (CRG3), G4 (CRG4), G5 (CRG5), RG2, R1, R2, R3 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 Formulas (Ib) and (Ie) and pharmaceutically acceptable salts thereof, as well as a few compounds with substituents that fall outside the scope of these formulas.
Breadth of the invention:
The scope of the claimed invention is very broad, as it is drawn to compounds of Formulas (Ib) and (Ie):
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allowing for myriad combinations of variables as described in the claims. Claim 66 provides the broadest definitions of variables. Although claims 67-77, which depend on claim 66, narrow the scope of certain variables, the broad scope of the other variables from base claim 66 still allow for numerous combinations of variables in each of these dependent claims.
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. The specification outlines a general method of synthesizing the instantly claimed compounds by connecting fragments as shown below (para [0075]).
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However, the compounds synthesized in the instant disclosure represent only a small set of the full scope of claimed compounds and variables which the general method of synthesis given above does not fully enable. For example, in the example compounds given in the specification RG2, RG3, RG4, and RG5 are only synthesized as CH, CF (Example 15, p. 71), or CNH-2 (Example 19, p. 73), and it would be unclear how to synthesize compounds containing the broad scope of claimed substituents in these positions given considerations such as steric hindrance. As for other examples, no compounds are synthesized wherein R1 has heteroatoms selected from O or S, and no compounds are synthesized where R2 contains a -S(O-2)- sulfonate moiety. These are non-limiting examples of compounds within the scope of the claimed Markush structures that do not have support in the disclosure.
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.
Allowable Subject Matter
Claims 78 and 79 are allowable. The compounds recited in claims 78 and 79 all have support in the specification and appear to be free of the art.
Conclusion
Claims 66-77 and 80 are rejected.
Claims 78 and 79 are free of prior art.
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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