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 .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 13 March 2026 has been entered.
Applicant’s amendment dated 13 March 2026, in which claims 1, 3, 35 have been amended, is acknowledged.
Claims 1-3, 5, 8-9, 17-18, 21-22, 25-28, 35-37, 39-40 are pending in the instant application.
Claims 18, 22, 25, 26, 27, 40 are withdrawn, as being drawn to a non-elected invention or to a non-elected species.
Claims 1-3, 5, 8-9, 17, 21, 28, 35-37, 39 are examined herein.
Response to arguments of 13 March 2026
In view of Applicant’s amendment of 13 March 2026, the objections to claims 1, 3, 35 are herein withdrawn. The claim language has been clarified.
In view of Applicant’s amendment of 13 March 2026, the rejection of claims 8, 9, 35 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is herein withdrawn. Applicant has amended claim 1 to recite that R2 is substituted with one or more substituents selected from a group that includes
PNG
media_image1.png
62
70
media_image1.png
Greyscale
.
Applicant’s arguments (Remarks of 13 March 2026, pages 13-16) against
the rejection of claims 1-3, 5, 8, 17, 21, 28, 36, 37, 39 under 35 U.S.C. over Bahl (WO 2019/057825);
the rejection of claims 1-3, 5, 8, 9, 17, 21, 28, 35, 36, 37, 39 under 35 U.S.C. 103 over Bahl (WO 2019/057825), in view of Patani; and
against the rejection of claims 1-3, 5, 8-9, 17, 21, 28, 35-37, 39 are rejected under 35 U.S.C. 103 over Bondke (US 2016/0362410) in view of Bahl (WO 2019/057825), have been considered.
Applicant argues (page 13, last paragraph) that none of the compounds cited in the office action (taught by Bahl or Bondke) are compounds with the specific substituents in instant claim 1. In response, the point is that the compounds of the instant claims are not the same as disclosed by the prior art, but rather are rendered obvious by the prior art of record.
Applicant argues (page 14, second paragraph) that the cited references do not provide adequate guidance to arrive at the instant compounds with reasonable expectation of success. Applicant argues (page 14, second paragraph) that “a fair reading of Bondke teaches that substitution of the benzyl or phenyl does not lead to a potent CDK7 inhibitor”.
Applicant argues (page 14, last paragraph, page 15) that compounds PPDA-015 and PPDA-018 in Bondke, which have un unsubstituted benzyl as moiety R2, are more potent CDK7 inhibitors than the corresponding PPDA-017 and PPDA-021, which have a substituted benzyl ring as moiety R2. Applicant argues (page 15) that in view of this data in Bondke, a POSITA would not have a reasonable expectation that requiring a substituent on the benzyl ring in the R2 position would result in a potent CDK7 inhibitor. Applicant argues (page 15, last paragraph, page 16, first paragraph) lack of motivation to modify the cited references to arrive at the instant compounds.
In response, first, this argument is relevant only to the rejection of claims 1-3, 5, 8-9, 17, 21, 28, 35-37, 39 under 35 U.S.C. 103 over Bondke in view of Bahl. As such, Applicant did not present any arguments against the rejection of claims 1-3, 5, 8, 17, 21, 28, 36, 37, 39 under 35 U.S.C. over Bahl; or against the rejection of claims 1-3, 5, 8, 9, 17, 21, 28, 35, 36, 37, 39 under 35 U.S.C. 103 over Bahl, in view of Patani. For this reason, these rejections are herein maintained and are reproduced below.
Further, Applicant’s argument (pages 13-15) against the rejection of claims 1-3, 5, 8-9, 17, 21, 28, 35-37, 39 under 35 U.S.C. 103 over Bondke in view of Bahl is not persuasive. Bondke teaches pyrazolo[1,5-1]pyrimidines as CDK7 inhibitors useful to treat a CDK7-dependent disease such as, for example, cancer, and the genus taught by Bondke overlaps with compounds of formula (I) of the instant claims. Bondke teaches that R2 = benzyl can be unsubstituted (PPDA-018) or substituted with halogen (PPDA-021), with retention of anti-cancer activity (Tables 2, 3, page 62).
Contrary to Applicant’s argument that there is a lack of motivation to substitute the benzyl ring in R2, based on the data presented by Applicant on page 15, Bondke clearly teaches that unsubstituted and substituted benzyl rings as R2 maintain potency as anti-cancer agents and as CDK7 inhibitors. One of ordinary skill in the art, a medicinal chemist, would readily recognize that the nature and position and number of substituents on the benzyl ring R2 may influence the selectivity CDK7 vs. other CDKs, yet such an exercise in exploring substituents on a benzyl ring R2 is expected to generate compounds within the genus of Bondke, expected to maintain efficacy against cancer.
Bahl is used in the rejection for teaching the advantage of replacing the isopropyl with cyclopropyl in compounds disclosed by Bondke.
Based on the combined teachings of Bondke and Bahl, the person of ordinary skill in the art would have replaced R3 = isopropyl in the compounds specifically disclosed by Bondke, with cyclopropyl, to arrive at the instant invention, with a reasonable expectation that the resulting compounds retain biological activity as anti-cancer agents and CDK7 inhibitors.
At least for these reasons, the rejection of claims 1-3, 5, 8-9, 17, 21, 28, 35-37, 39 under 35 U.S.C. 103 over Bondke in view of Bahl is herein maintained and is reproduced below.
In the interest of compact prosecution, on 17 June 2025, the examiner has extended the search to a subgenus of compounds of formula (I) encompassing the elected species
PNG
media_image2.png
190
206
media_image2.png
Greyscale
,
namely compounds of formula (I) where
L is
PNG
media_image3.png
28
100
media_image3.png
Greyscale
wherein Ra = Rb = H; n is 1; and
R3 is piperidinyl (as heterocyclyl) substituted with hydroxy. Claims 1-3, 5, 8-9, 17, 21, 28, 35-37, 39 have been examined to the extent they read on this subgenus, and the following rejections are made below.
Claim Rejections - 35 USC § 103
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 5, 8, 17, 21, 28, 36, 37, 39 are rejected under 35 U.S.C. 103 as being unpatentable over Bahl et al. (WO 2019/057825, international filing date 20 September 2018, cited in IDS).
Bahl discloses (page 9) the following compound as a CDK7 inhibitor:
PNG
media_image4.png
114
590
media_image4.png
Greyscale
,
which is a H versus methyl direct homolog of a compound of instant formula (I)
PNG
media_image5.png
150
148
media_image5.png
Greyscale
,
for which the following definitions apply:
R1 = cyclopropyl (cycloalkyl);
R2 = benzyl (arylalkyl) substituted with methyl (as in instant claims 1, 8);
L is
PNG
media_image3.png
28
100
media_image3.png
Greyscale
wherein Ra = Rb = H; n is 1;
R3 = piperidinyl (heterocyclyl) substituted with hydroxyl.
Bahl teaches pharmaceutically acceptable salts of the compounds of the invention (page 9, first paragraph), as in instant claim 36, specifically hydrochloric acid salt (page 12, line 24), as in instant claim 37, and pharmaceutical compositions thereof, as in instant claim 39.
It would have been obvious to a person of ordinary skill in the art to synthesize a direct homolog methyl vs. H substituted benzyl part of the 7-benzylamino substituent on the pyrazolo[1,5-a]pyrimidine in compound APPAMP-002 taught by Bahl. The person of ordinary skill in the art would have synthesized a direct methyl vs. H homolog of compound APPAMP-002 taught by Bahl, with the expectation that said homolog will retain therapeutic effect.
In the absence of unexpected results, stereoisomers are considered obvious variants of each other. "Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties". In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
As such, a compound of instant claims 1-3, 5, 8, 17, 21, 28, 36, 37, 39, or a pharmaceutically acceptable salt thereof, and a composition comprising said compound, are rendered obvious by Bahl.
Claims 1-3, 5, 8, 9, 17, 21, 28, 35, 36, 37, 39 are rejected under 35 U.S.C. 103 as being unpatentable over Bahl et al. (WO 2019/057825, international filing date 20 September 2018, cited in IDS), in view of Patani et al. (Chemical Reviews 1996, 96, 3147-3176, cited in PTO-892).
Bahl discloses (page 9) the following compound as a CDK7 inhibitor:
PNG
media_image4.png
114
590
media_image4.png
Greyscale
,
which is a H versus F or Cl substituted analog of a compound of instant formula (I)
PNG
media_image5.png
150
148
media_image5.png
Greyscale
,
for which the following definitions apply:
R1 = cyclopropyl (cycloalkyl);
R2 = benzyl (arylalkyl) substituted with F or Cl;
L is
PNG
media_image3.png
28
100
media_image3.png
Greyscale
wherein Ra = Rb = H; n is 1;
R3 = piperidinyl (heterocyclyl) substituted with hydroxyl.
Bahl teaches pharmaceutically acceptable salts of the compounds of the invention (page 9, first paragraph), as in instant claim 36, specifically hydrochloric acid salt (page 12, line 24), as in instant claim 37, and pharmaceutical compositions thereof, as in instant claim 39.
Bahl does not teach the instant compounds of formula (I), where R2 is substituted with one or more halogens such as F or Cl.
Patani et al. (Chemical Reviews 1996, 96, 3147-3176, cited in PTO-892) teach that fluorine vs. hydrogen replacement is a classical bioisosteric replacement based on monovalent atoms, frequently used in drug design (see page 3149, Chapter II.A.1., lines 1-5 below):
PNG
media_image6.png
193
621
media_image6.png
Greyscale
Patani teaches bioisosteric replacement being commonly used in drug design to create safer and more clinically effective therapeutic agents (page 3147, first paragraph) with improved bioavailability.
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to combine the teachings of Bahl and Patani in a compound of the instant application. The person of ordinary skill in the art would have been motivated to replace a H atom with a F on the benzyl ring part of the 7-benzylamino substituent on the pyrazolo[1,5-a]pyrimidine in compound APPAMP-002 taught by Bahl, based on the teachings of Patani, because such fluorine vs. hydrogen replacements often result in better biological activity (here anti-cancer activity) and better overall physicochemical and pharmacological properties of the molecules. Thus, absent some demonstration of unexpected results with the instantly claimed compounds versus the prior art by Bahl, the instant compounds would have been obvious at the time of applicant's invention.
As such, claims 1-3, 5, 8, 9, 17, 21, 28, 35, 36, 37, 39 are rejected as prima facie obvious.
Claims 1-3, 5, 8-9, 17, 21, 28, 35-37, 39 are rejected under 35 U.S.C. 103 as being unpatentable over Bondke et al. (US 2016/0362410, cited in PTO-892 of 17 June 2025) in view of Bahl et al. (WO 2019/057825, international filing date 20 September 2018, cited in IDS).
Bondke (US 2016/0362410) teaches broadly ([0046]-[0090], also claim 1) the following pyrazolo[1,5-1]pyrimidines as CDK7 inhibitors and compositions thereof, useful to treat a CDK7-dependent disease such as, for example, cancer
PNG
media_image7.png
130
184
media_image7.png
Greyscale
where
R7 is, for example, benzyl or phenyl, unsubstituted or substituted with, for example, F, Cl, CF3, CN, -SO2NH2, -SO2CH3, or C1 alkyl;
R3 is branched saturated C1-6 alkyl or saturated C3-7 cycloalkyl [0083]-[0085] (isopropyl as R3 listed in claim 90; cyclopropyl, cyclobutyl as R3 in claim 91);
R2 and R6 are, for example, H;
R5Y is, for example H [0062];
R5x is -L5x-Q, wherein L5x is, for example, C1 alkylene; Q is a non-aromatic heterocyclic ring having 5-7 atoms, including at least one nitrogen atom, the ring being optionally substituted with hydroxyl [0053]-[0057].
The genus taught by Bondke overlaps with compounds of formula (I) of the instant claims
PNG
media_image5.png
150
148
media_image5.png
Greyscale
where
R2 is, for example, benzyl or phenyl, substituted with, for example, F, Cl, CF3, CN, -SO2NH2, -SO2CH3, or C1 alkyl (as in instant claims 1, 8, 9, 35);
R1 is cycloalkyl (cyclopropyl, or cyclobutyl as in instant claims 2, 3, 35);
L is
PNG
media_image3.png
28
100
media_image3.png
Greyscale
wherein Ra = Rb = H; n is 1 (as in instant claims 28, 35) or n = 0;
R3 = heterocyclyl (such as, for example, piperidinyl, as in instant claims 17, 21) substituted with hydroxyl (as in instant claims 21, 35).
Bondke exemplifies (pages 16-19) compounds PPDA-011, PPDA-012, PPDA-017, PPDA-021:
PNG
media_image8.png
156
170
media_image8.png
Greyscale
PNG
media_image9.png
162
188
media_image9.png
Greyscale
PNG
media_image10.png
126
198
media_image10.png
Greyscale
PNG
media_image11.png
148
188
media_image11.png
Greyscale
.
These compounds correspond to compounds of instant formula (I)
PNG
media_image5.png
150
148
media_image5.png
Greyscale
where
R2 is benzyl substituted with halogen or with haloalkyl;
L is
PNG
media_image3.png
28
100
media_image3.png
Greyscale
wherein Ra = Rb = H; n is 1 or n = 0;
R3 = heterocyclyl (such as, for example, piperidinyl, or pyrrolidinyl) substituted with hydroxyl or hydroxyalkyl, or alkoxy;
but differ from compounds of instant formula (I)
PNG
media_image5.png
150
148
media_image5.png
Greyscale
in that substituent R3 in Bondke (corresponding to R1 in instant compounds of formula I) is isopropyl,
while in the instant compounds R1 = cyclopropyl, cyclobutyl.
Bondke teaches that R2 = benzyl can be unsubstituted (PPDA-018) or substituted with halogen (PPDA-021), with retention of anti-cancer activity (Tables 2, 3, page 62).
PNG
media_image12.png
126
186
media_image12.png
Greyscale
PNG
media_image13.png
144
186
media_image13.png
Greyscale
Bondke also teaches (pages 16-19) the following compounds, where R2 is unsubstituted benzyl, as CDK7 inhibitors:
PNG
media_image14.png
162
394
media_image14.png
Greyscale
PNG
media_image15.png
186
246
media_image15.png
Greyscale
PNG
media_image16.png
144
226
media_image16.png
Greyscale
PNG
media_image17.png
162
248
media_image17.png
Greyscale
PNG
media_image18.png
312
250
media_image18.png
Greyscale
PNG
media_image19.png
174
240
media_image19.png
Greyscale
PNG
media_image20.png
324
238
media_image20.png
Greyscale
PNG
media_image21.png
324
288
media_image21.png
Greyscale
PNG
media_image22.png
446
292
media_image22.png
Greyscale
.
Bondke particularly teaches (Table 1, page 61) compound
PNG
media_image14.png
162
394
media_image14.png
Greyscale
as a potent and selective CDK7 inhhibitor, effective to treat cancer [0864] in vivo.
Bondke teaches enantiomers, stereoisomers of the compounds, as well as HCl salts and pharmaceutical compositions comprising said compounds, as in instant claims 36, 37, 39.
Bondke does not specifically teach the instant compounds.
Bahl (WO 2019/057825, international filing date 20 September 2018) teaches (pages 45-46) the advantage of replacing the R3 = isopropyl in compound PPDA-001 disclosed by Bondke (corresponds to R1 in instant claims), with cyclopropyl to arrive at the compound below
(page 9)
PNG
media_image14.png
162
394
media_image14.png
Greyscale
PNG
media_image23.png
116
198
media_image23.png
Greyscale
PPDA-001, Bondke
PNG
media_image24.png
48
84
media_image24.png
Greyscale
, Bahl.
Bahl teaches similar CDK7 biochemical potency (Table 3), but better CDK7 vs. CDK2 selectivity (Table 4, higher therapeutic index expected), and substantially higher free fraction in human plasma (Table 5, advantage in cancer therapy) with compound APPAMP-002 (R1 = cyclopropyl) vs. PPDA-001 (R1 = isopropyl).
Bahl teaches pharmaceutically acceptable salts of the compounds of the invention (page 9, first paragraph), as in instant claim 36, specifically hydrochloric acid salt (page 12, line 24), as in instant claim 37, and pharmaceutical compositions thereof, as in instant claim 39.
It would have been obvious for a person of ordinary skill in the art to prepare a compound from the genus taught by Bondke to arrive at the instant invention.
The person of ordinary skill in the art would have replaced R3 = isopropyl in the compounds PPDA-011, PPDA-012, PPDA-017, PPDA-021 disclosed by Bondke, with cyclopropyl, or cyclobutyl, to arrive at the instant invention, because Bondke teaches that R3 is branched saturated C1-6 alkyl or saturated C3-7 cycloalkyl, and specifically teaches isopropyl, cyclopropyl, cyclobutyl as R3. Thus, the person of ordinary skill in the art would have replaced R3 = isopropyl in the compounds specifically disclosed by Bondke, with cyclopropyl, or cyclobutyl, with a reasonable expectation that the compounds retain biological activity as CDK7 inhibitors, and are effective to treat cancer.
Furthermore, the person of ordinary skill in the art would have replaced R3 = isopropyl in the compounds specifically disclosed by Bondke, with cyclopropyl, to arrive at the instant invention, because Bahl discloses the advantages (similar or better CDK7 potency, better CDK7 vs. CDK2 selectivity, and/or higher free fraction in human plasma (advantage in cancer therapy))
of replacing the R3 = isopropyl in compound PPDA-001 disclosed by Bondke (corresponds to R1 in instant claims), with cyclopropyl. Thus, the person of ordinary skill in the art would have replaced R3 = isopropyl in the compounds specifically disclosed by Bondke, with cyclopropyl, with a reasonable expectation that the resulting compounds retain biological activity as CDK7 inhibitors, and have better CDK7 vs. CDK2 selectivity, and/or higher free fraction in human plasma, and thus an expected improved effectiveness in treating cancer.
Further, the person of ordinary skill in the art would have explored substituted phenyl or benzyl rings as substituent R7 in the genus taught by Bondke, and would have replaced the isopropyl as R3 with a cyclopropyl or cyclobutyl, because Bondke teaches R7 is benzyl or phenyl, unsubstituted or substituted with, for example, F, Cl, CF3, CN, -SO2NH2, -SO2CH3, or C1 alkyl; and Bondke also teaches isopropyl as R3 being used interchangeably with cyclopropyl, cyclobutyl, with retention of CDK7 inhibitory activity. Thus, the person of ordinary skill in the art would have synthesized a compound from the genus taught by Bondke, where R7 is benzyl or phenyl, substituted with one or more of F, Cl, CF3, CN, -SO2NH2, -SO2CH3, or C1 alkyl, and where R3 = cyclopropyl, or cyclobutyl, with a reasonable expectation that the resulting compounds retain biological activity as CDK7 inhibitors, and are effective to treat cancer.
As such, claims 1-3, 5, 8-9, 17, 21, 28, 35-37, 39 are rejected as prima facie obvious.
Conclusion
Claims 1-3, 5, 8-9, 17, 21, 28, 35-37, 39 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IRINA NEAGU whose telephone number is (571)270-5908. The examiner can normally be reached Mon-Fri 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY 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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/IRINA NEAGU/Primary Examiner, Art Unit 1629