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 1-3, 5-6, 8-9, 11-12, 14-15, 17-18, 20-22, 24, and 32 are pending in the instant application.
Claims 4, 7, 10, 13, 16, 19, 23, 25-31, and 33-45 have been canceled.
Election/Restriction
This action is in response to an election from a restriction requirement filed on November 10th, 2025. There are 18 claims pending and 17 claims under consideration. Claim 32 has been withdrawn as a claim drawn to a non-elected invention. This is the first action on the merits. The present invention relates to a compound of Formula II, III, IV, V, VI, VII, or VIII as recited at instant Claim 1.
Applicant’s election of Group I, Claims 1-3, 5-6, 8-9, 11-12, 14-15, 17-18, 20-22, and 24 and species election of Compound 1:
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in the reply filed January 9th, 2026 is acknowledged. Applicant did not indicate whether or not these elections were made with traverse. As such, the examiner has construed this as an election without traverse.
The requirement for restriction is deemed proper and therefore made FINAL.
The elected species was found to be free of the prior art. Therefore, examination has been extended to all species of compound of Formulas II, III, IV, V, VI, VII, or VIII.
Domestic Benefit
Acknowledgement is made of Applicant’s claim for domestic benefit based on the U.S. Provisional Application No. 63/144,580, filed on February 2nd, 2021. Claims 1-3, 5-6, 8-9, 11-12, 14-15, 17-18, 20-22, 24, presently under examination, are fully supported by this application, and will be evaluated with an effective filing date of February 2nd, 2021.
Information Disclosure Statement
The Information Disclosure Statement filed on August 1st, 2023 has been fully considered by the examiner, except where marked with a strikethrough.
Specification
The disclosure is objected to because of the following informalities:
At Page 5, Last Line, “proviso” is misspelled as “priviso”.
Appropriate correction is required.
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 Rejections - 35 USC § 112
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 1-2, 5, 8, 11, 14, 17, 20, and 24 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 Formulas II, III, IV, V, VI, VII, or VIII in which R1 is chloro, R2 is chloro, R3 is H, cyano, or methyl, R5 is H or C1-3 alkyl, R6 is CO2CH3, CH2OCH3, CH2S(O)2C1-2 alkyl, ((optionally substituted 6-membered heterocyclyl)oxy)C1 alkyl, (optionally substituted C1-6 alkoxy)C1-6 alkyl, amino C6 alkyl, optionally substituted C3-4 cycloalkyl, optionally substituted 6-membered heterocyclycl, optionally substituted C6 aryl, optionally substituted 5 to 10-membered heteroaryl , (optinally substituted 3-4 membered heterocyclycl)C1 alkyl, or
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, R7 is C1-6 alkyl, C3 cycloalkyl, or ((dialkylamino)carbonyl)C1 alkyl, R6 and R7 together with the carbon atom to which they are attached form 6-7 membered heterocyclycl or indanyl, R8 and R9 together with the nitrogen atom to which they are attached form an optionally substituted 4 to 12 membered heterocyclic ring, R10 and R11 together with the carbon atom to which they are attached form an optionally substituted 6 membered heterocyclyl, R12 is H, R12 and R13 together with the carbon atom to which they are attached form an optionally substituted C3-4 cycloalkyl, optionally substituted 4 to 6-membered heterocyclyl, or optionally substituted phenyl, R14 is H or C1-3 alkyl, R17 is optionally substituted 6 membered heterocyclyl, and R18 and R19 together with the nitrogen to which they are attached form an optionally substituted 5 to 6 membered heteroaryl group does not reasonably provide enablement for compounds of formulas II, III, IV, V, VI, VII, or VIII in which these variables are otherwise defined. 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 II, III, IV, V, VI, VII, or VIII:
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Breadth of the invention:
The scope of the claimed invention is very broad, as it is drawn to compounds of any of the individual formulas shown above, allowing for myriad combinations of the variables recited thereof.
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.
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 example of any compound in which R1-3 and R5-19 were defined as anything other than the options as noted above in the instant 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.
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 and 24 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.
The recitation of “optionally substituted” in Claim 1 renders the claim indefinite, as the metes and bounds of suitable substituents is not clear. The specification provides no definition of suitable substituents that would allow a person having ordinary skill in the art to understand which moieties are suitable for substituting the moieties listed as being “optionally substituted”. Appropriate clarification is required. Claim 24 is including in the rejection as it does not sufficiently limit the scope to overcome the indefiniteness of the limitation of “optionally substituted”.
Claim Rejections - 35 USC § 103
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.
Claims 1 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Gray et. al. (WO 2019/147783A1; cited on Applicant’s Information Disclosure Statement filed August 1st, 2023 hereinafter referred to as Gray) in view of Heinrich et. al. (“Bioisosterism of Fluorine and Cyano as Indole Substituents. Theoretical, in vitro and in vivo Examination”, Chimia, 2004; hereinafter referred to as Heinrich).
At Page 62, Gray teaches the following structure as Compound P14:
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This compound reads on a compound of Formula V, as recited at instant Claim 1, when the variables are defined as follows:
R2 is methyl.
R3 is H.
R12 is H.
R13 is -CH2NHCOCH3.
This compound differs from a compound of Formula V, only in the definition of R1. In the compound shown above, R1 would be defined as cyano, which is not recited as a possible definition of R1 at instant Claim 1.
The instant specification discloses the instantly claimed compounds as inhibitors of DCAF15. Data supporting this utility are presented, for example, at Table 2 beginning at Page 280 of the instant specification.
Similarly, Gray teaches activity against DCAF15 from administration of compounds including the compound noted above. At Page 56, Paragraph 0226, Gray teaches an assay for evaluating activity of compounds against DCAF15. At Claim 72, Gray claims the above compound as compound P14. At Claim 75, Gray claims a method of degrading RRM proteins comprising contacting a cell with a compound according to any one of Claims 1-73, inclusive of compound P14, above. As demonstrated by the aforementioned assay, the degradation of the RRM protein is a result of the DCAF15 activity of these compounds.
Regarding Claim 24, Gray teaches at Claim 74 a pharmaceutical composition comprising a compound according to any of the preceding claims, which includes the aforementioned compound.
Therefore, despite the difference in R1, both the instantly claimed compounds and the compound taught by Gray are taught to exhibit activity against DCAF15.
At the abstract, Heinrich teaches the fluoro and cyano substituents, specifically as substituents of an indole moiety, are bioisosteric. Further, at the first column of Page 143, Heinrich teaches cyanide is described as a “pseudo-halogen”. At Page 144, under “F and CN Most Comparable Electron-withdrawing Groups”, Heinrich teaches chloro-substituted compound 7a and cyano-substituted compound 7b, as shown in Table 1, demonstrated comparable in vivo results in inhibiting 5-HT1a, and therefore demonstrate bioisosterism. Regarding predictability of bioisosterism, Heinrich addresses this under “Prediction of Bioisosterism” beginning at Page 145. At Page 146, second column, Heinrich notes the fluorine and cyano derivatives examined “show comparability with regard to two centres of negative charge and the dipole vector in length and direction.”
Taken together, Heinrich establishes the fluoro and cyano groups as bioisosteric substituents of an indole moiety.
Therefore, given that the compound taught by Gray, above, and the instantly claimed compounds are both taught to have activity against DCAF15, in view of Heinrich establishing cyano and fluoro groups as bioisosteric to each other, applying KSR exemplary rationale B, it would have been prima facie obvious to substitute the cyano group in the R1 position as taught by Heinrich for a fluoro group, as instantly recited, to arrive at a compound of Formula V with reasonable expectation of success.
Allowable Subject Matter
Claims 3, 6, 9, 12, 15, 18, and 21-22 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 1-2, 5, 8, 11, 14, 17, 20, and 24 are rejected.
Claims 3, 6, 9, 12, 15, 18, and 21-22 are objected to.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANIEL JOHN BURKETT whose telephone number is (703)756-5390. The examiner can normally be reached Monday - Friday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey 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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/D.J.B./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624