FINAL REJECTION
Receipt is acknowledged of Applicants' Amendments and Remarks, filed Dec. 3, 2025.
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The rejections and/or objections set forth below are either maintained or newly applied, and constitute the complete set presently applied to the instant claims.
STATUS OF THE CLAIMS
Claims 1, 4, and 7 have been amended and incorporate no new matter.
No new claims have been added.
Claims 8, 10, and 11 stand withdrawn as drawn to nonelected inventions and/or species.
Thus, claims 1-7 and 9 now represent all claims currently pending and under consideration.
INFORMATION DISCLOSURE STATEMENT
No new Information Disclosure Statements (IDS) have been submitted.
MAINTAINED REJECTIONS
The following rejection is maintained from the previous Office Action dated Sep. 4, 2025, on the ground that the references cited therein continue to read on the limitations of the amended claims.
Claim Rejections - 35 USC § 103
Claims 1-6 and 9 stand rejected under 35 U.S.C. 103 as being unpatentable over Marineau et al. (WO 2018/013867).
Marineau et al. disclose compounds of formula (I) as selective CDK7 inhibitors, and exemplify compound 176 (Fig. 1F), having the structural formula,
Marineau et al. Compound 176
Claimed Formula (I)
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which reads on formula (I) as recited by claims 1 and 3-6, and formula (II) as recited by claim 2, to the extent that
ring A is pyrimidine, and R2 is trifluoromethyl;
ring B is 6-membered heterocyclyl (piperidine);
L is -NH-;
ring C is indolyl,
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,
where X1 and X2 are CH, R1 is hydrogen, and R4 is 1-methyl-imidazolidin-2-one,
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,
where m is 1, X6 is NR1, and R1 is methyl.
The compounds of Marineau et al. are disclosed in pharmaceutical compositions together with a pharmaceutically acceptable excipient (claim 24), i.e., a carrier, as recited by claim 9.
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Compound 176 is disclosed a selective inhibitor of CDK7, as compared to CDK2, CDK9, and CDK12; i.e., the IC50 of compound 176 is less than 20 nM against CDK7, but between 200 nM and 5 μM against CDK2, CDK9, and CDK12 (paras. [854]-[855]; Table 1, p. 368).
CDK2: C = calculated IC50 between 200 nM to less than 5 μM
CDK7: A = calculated IC50 less than 20 nM
CDK9: C = calculated IC50 between 200 nM to less than 5 μM
CDK12: C = calculated IC50 between 200 nM to less than 5 μM
The much lower IC50 of compound 176 against CDK7 is a measure of its greater potency against, and hence selectivity for, CDK7.
Compound 176 differs from the claims in that the 1-methyl-imidazolidin-2-one moiety substitutes the 7-position of the indolyl ring (R4), rather than the 6-position (R2'):
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.
However, as recognized by MPEP § 2144.09, a structural isomer of the prior art compound is unpatentable unless it possesses some unexpected advantage or property not possessed by the prior art compound. Compounds which are positional isomers can be sufficient to establish a prima facie case of obviousness because they are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.
In addition, the compounds of Marineau et al. are disclosed to have the same biochemical activity and use as the claimed compounds: as cyclin-dependent kinase 7 (CDK7) selective inhibitors useful for treating or preventing proliferative diseases, cancers, benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases (abstract).
Therefore, it would have been predictable to one of ordinary skill in the art as of the filing date to modify the compounds of Marineau et al. to arrive at the claimed compounds with a reasonable expectation of success, because the compounds of Marineau et al. are disclosed to have the same mechanism of action (as selective inhibitors of CDK7) and are useful for treating the same diseases.
As recognized by MPEP § 2144.09, a prima facie case of obviousness may be made when chemical compounds have (1) very close structural similarities and (2) similar utilities. "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."
“When chemical compounds have ‘very close’ structural similarities and similar utilities, without more a prima facie case may be made" (In re Grabiak, 769 F.2d 729, 731, 226 USPQ 870, 871 (Fed. Cir. 1985)). Thus, evidence of similar properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious. See also In re Dillon, 919 F.2d at 697-98, 16 USPQ 2d at 1905; In re Wilder, 563 F.2d 457, 461, 195 USPQ 426, 430 (CCPA 1977); and In re Linter, 458 F.2d 1013, 1016, 173 USPQ 560, 562 (CCPA 1972).
A prima facie case of obviousness based on structural similarity is rebuttable by proof that the claimed compounds possess unexpectedly advantageous or superior properties. In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963).
RESPONSE TO ARGUMENTS
Applicant's arguments filed Dec. 3, 2025 have been fully considered but they are not persuasive.
With respect to the rejection of claims 1-6 and 9 under 35 U.S.C. 103 over Marineau
et al., Applicant contends that the claimed compounds are very different from Marineau et al. because the amended claims include a 1-methyl-imidazolidin-2-one substituent at R2' (the 6-position of the indolyl ring), but not at R4 (the 7-position of the indolyl ring) (Remarks, p. 15).
Applicant further submits that the Liang declaration (dated Dec. 3, 2025) demonstrates that the compounds of amended claim 1 achieve unexpected technical effects.
Specifically, the positional isomer of compound 176 of Marineau et al. (1-methyl-imidazolidin-2-one at position 7 of indolyl ring) was prepared as compound A (1-methyl-imidazolidin-2-one at position 6 of indolyl ring) (Liang declaration, p. 2):
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Using the same method in "Test Example 1 Enzyme Activity Test" of the instant application, the IC₅₀ values of compound 176 and compound A were measured for CDK7, CDK9, CDK12 and CDK2 kinase, as follows (Liang declaration, pp. 2-3):
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Applicant contends that, compared with compound 176 in Marineau et al., compound A has significantly better selectivity for CDK7 kinase:
compared with CDK2, the selectivity of compound A for CDK7 is 6.9 times
(= 467/67) of that of compound 176;
compared with CDK9, the selectivity of compound A for CDK7 is 3 times (= 441/147) of
that of compound 176; and
compared with CDK12, the selectivity of compound A for CDK7 is 2.6 times (= 242/94)
of that of compound 176.
Applicant further contends that, similar to compound A, the elected compound species, T-16, also has a substituent at position 6 of the indolyl ring, and also has significantly better selectivity for CDK7 kinase than compound 176 of Marineau et al.
In summary, Applicant contends that compound A and elected compound T-16 both show better selectivity for CDK7 kinase compared with compound 176 of Marineau et al. (Remarks, pp. 17-18). Thus, Applicant argues, by optimizing the position of the substituent on the indolyl ring, compounds of amended claim 1 have achieved unexpected technical effects, which advantage rebuts any presumed obviousness against amended claim 1 (Remarks, p. 19).
In response, it is acknowledged that the data presented in the Liang declaration demonstrates that compound A, falling within the scope of formula (I), has greater selectivity for CDK7 than Marineau compound 176. Again, the sole difference between compound A and compound 176 is the identical substituent in positions 6 and 7 of the indolyl ring, respectively.
However, the compounds of Marineau are explicitly disclosed as selective CDK7 inhibitors. Thus, one of ordinary skill in the art would have expected the compounds of Marineau et al. to have some degree of selectivity for CDK7.
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Further, while compound 176 is highly selective for CDK7, e.g., compound 221 of Marineau et al., having a 6-substituted indolyl ring, is even more selective (Fig. 1I):
CDK2: D = calculated IC50 of equal to or greater than 5 μM
CDK7: A = calculated IC50 less than 20 nM
CDK9: D = calculated IC50 equal to or greater than 5 μM
CDK12: D = calculated IC50 equal to or greater than 5 μM
Marineau et al. report that the IC50 of compound 221 is less than 20 nM against CDK7, but equal to or greater than 5 μM against CDK2, CDK9, and CDK12 (paras. [854]-[855]; Table 1). The much lower IC50 of compound 221 against CDK7 is a measure of its greater potency against, and hence selectivity for, CDK7. Thus, Marineau et al. present data demonstrating that compounds having a 6-substituted indolyl moiety are exceptionally selective for CDK7.
Furthermore, Marineau et al. exemplify at least 120 compounds having a substituent at position 6 of the indolyl ring – more than twice as many as those having a substituent at position 7 (about 50) (see Figs. 1A through 1V). Thus, a skilled artisan would have readily inferred that enhancing selectivity for CDK7 could be achieved by routine experimentation, by moving the indole ring substituent from position 7 to position 6.
Thus, Applicant's argument that compound A achieves an unexpected advantage not recognized in the prior art – higher selectivity for CDK7 against other CDKs – is not persuasive. In fact, Applicant's results are expected, based on the teachings of Marineau et al. The results presented in the Liang declaration show a difference of degree, not of kind: an expected result which confirms that one of ordinary skill in the art would have had a reasonable expectation of success in preparing a positional isomer of a compound exemplified by Marineau et al.
As recognized by MPEP §716.02(c)(II), "[e]xpected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
Finally, the evidence presented in the Liang declaration demonstrates that one compound species within the broad scope of formula (I) is particularly selective for CDK7. However, Applicant has not shown that this high selectivity occurs across the full scope of formula (I).
As recognized by MPEP §716.02(d), unexpected results must be commensurate with the scope of the claims:
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of non-obviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
Finally, evidence of secondary considerations does not always overcome a prima facie case of obviousness. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics. v. Viacell, 491 F.3d 1342 at 1364 (Fed. Cir. 2007). “Even though applicant’s modification results in great improvement and utility over the prior art, it may still not be patentable if the modification was within the capabilities of one skilled in the art. Pfizer v. Apotex, 82 USPQ2d 1321 at 1338 (Fed. Cir. 2007, citing In re Aller, 220 F.2d at 456).
For the foregoing reasons, the rejection of claims 1-6 and 9 under 35 U.S.C. § 103 over Marineau et al. is maintained.
Citation of Additional Prior Art
Additional references made of record are considered pertinent to applicant's disclosure:
WO 2010051781 and WO 2021/138392 (cited on PTO-892).
Allowable Subject Matter
Claim 7 is allowed.
CONCLUSION
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.
CORRESPONDENCE
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA E. TOWNSLEY whose telephone number is 571-270-7672. The examiner can normally be reached on Mon-Fri from 9:00 am to 6:00 pm (EST). If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jeff S. Lundgren, can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARA ELIZABETH TOWNSLEY/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629