DETAILED ACTION
This office action is in response to applicant’s filing dated September 23, 2025.
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 Claims
Claims 1-8, 14, 15, 23-25, 28-33, 35-40, 43, 45-51, and 53-63 are pending in the instant application. Acknowledgement is made of Applicant's remarks filed September 23, 2025. Claims 9-13, 16-22, 26, 27, 34, 41, 42, 44, 52 were previously canceled.
Election/Restrictions
Applicant’s election without traverse of Group I, drawn to a compound of Formula (I) in the reply filed on September 23, 2025 is acknowledged.
Claims 56-63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 September 23, 2025.
Applicant’s election without traverse of Compound 56:
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as the elected compound species of formula (I) in the reply filed on September 23, 2025 is acknowledged.
Compound 56 is a compound of formula (I) wherein m and n are 0; r and s are 0; p is 2 and q is 2, wherein each R6 is halogen, F and each R7 is halogen, F; Ring C and Ring D are 6-membered aryl, phenyl; R1A and R1B are each hydrogen; R2, R3, R4, and R5 are each hydrogen; and Ring A and Ring B are each 5-membered heteroaryl containing 4 ring heteroatoms (N), tetrazole. Compound 56 has been found to be free of prior art. Thus, examination has been expanded to encompass Compound 11:
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Compound 11 is a compound of formula (I) wherein m and n are each 0; r and s are 0; p is 1 and q is 1, wherein R6 is halogen, F and R7 is halogen, F; Ring C and Ring D are 6-membered aryl, phenyl; R1A and R1B are each hydrogen; R2, R3, R4, and R5 are each C1 alkyl, methyl; and Ring A and Ring B are each 5-membered heteroaryl containing 2 ring heteroatoms, N and S, thiazole.
Claims 1-7, 14, 15, 23-25, 28, 33, 35, 43, 46, 47, 54, and 55 read on the elected compound, Compound 56.
Claims 1-3, 5, 6, 14, 15, 23-25, 28, 33, 35, 43, and 46-48 read on expanded species, Compound 11.
Claims 8, 28-32, 36-40, 45, 49-51, and 53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 September 23, 2025.
Claims 1-7, 14, 15, 23-25, 28, 33, 35, 43, 46-48, 54, and 55 are presently under examination as they relate to the elected species: Compound 56:
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and expanded species: Compound 11:
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Priority
The present application is a 371 of PCT/US2021/044388 filed on August 3, 2021, which claims benefit of priority to Provisional Application No. 63/060,345 filed on August 3, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 20, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner, except where marked with a strikethrough.
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 Rejections – Improper Markush Groupings
Claims 1-7, 14, 15, 23-25, 28, 33, 35, 43, 46, 47, 54, and 55 are rejected on the basis that it contains 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). 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.
The Markush grouping of compounds of Formula (I) is improper because the alternatives defined by the Markush grouping do not share both a substantial structural feature and a common use that flows from the substantial structural feature for the following reasons:
The Markush grouping is directed to compounds of Formula (I):
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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 three compounds of Formula (I) presented in claim 54 of the instant specification demonstrates a lack of significant structural similarity and shows compounds of the formula (I) recited in instant Claim 1 are not obvious variants of each other:
Compound 6:
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Compound 56 (elected):
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Compound 112:
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As these compounds demonstrate, the compounds of 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.
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(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 1-7, 14, 15, 23-25, 28, 33, 35, 43, 46, 47, and 55 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 (I) wherein Ring A and Ring B are each triazolyl or tetrazolyl; Ring C and Ring D are each phenyl, cyclohexyl, tetrahydrofuranyl, quinolinyl, pyrimidinyl, pyridinyl, benzothiazolyl, dihydrobenzofuranyl, quinoxalinyl, benzoimidazolyl, benzodioxolyl, naphthyridinyl, or imidazopyridinyl; m is 0 or 1, wherein RA and RB are each H; n is 0; R1A, R1B, R2, R3, R4, R5, R6, R7, R8, and R9 are substituted as described does not reasonably provide enablement for the full scope of variables of Ring A, Ring B, Ring C, Ring D, RA, RB, m, and n 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 the 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 with only a urea moiety in common between the myriad of compounds.
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 Discover, 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 undrugable 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. Applicant has provided no working examples of any compounds, compositions, or pharmaceutically acceptable salts where R4- was not defined as mentioned above in the present application.
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.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 5, 6, 14, 15, 23-25, 28, 33, 35, 43, 46, 47, and 48 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhao et al (Org. Process Res. Dev., 2015; 19(5):576-581).
Regarding claims 1-3, 5, 6, 14, 15, 23-25, 28, 33, 35, 43, 46, 47, and 48, Zhao teaches Compound 11:
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Compound 11 is a compound of formula (I) wherein m and n are each 0; r and s are 0; p is 1 and q is 1, wherein R6 is halogen, F and R7 is halogen, F; Ring C and Ring D are 6-membered aryl, phenyl; R1A and R1B are each hydrogen; R2, R3, R4, and R5 are each C1 alkyl, methyl; and Ring A and Ring B are each 5-membered heteroaryl containing 2 ring heteroatoms, N and S, thiazole.
Thus, Zhao anticipates the compounds of claims 1-3, 5, 6, 14, 15, 23-25, 28, 33, 35, 43, 46, 47, and 48.
Conclusion
Claims 1-7, 14, 15, 23-25, 28, 33, 35, 43, 46, 47, 54, and 55 are rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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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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/Rayna Rodriguez/ Primary Examiner, Art Unit 1628