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 (drawn to products of a bivalent compound), in the reply filed on 11/01/2024 is acknowledged.
Claims 69-70 and 86-87 are pending of which (Group II)) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected INVENTION, there being no allowable generic or linking claim. Claims 69 and 86-87 read upon the elected species, however, the additional claims rejected herein are rejected to demonstrate the non-allowability of the generic claims. The restriction requirement is still deemed proper and is made Final.
Pending claims 69-70, 86-90 and 92-93 have been examined on the merits. Claims 88-93 are newly added claims.
Please note, for clarity of the record, Applicant’s election of the species of compound P-007- as recited in claim 69, having the following structure:
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During the course of examination, prior art was identified that relates to the elected
subject matter. In the interest of compact prosecution, that prior art has been applied to the
generic claims, as discussed below.
Request for Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/20/2026 has been entered.
Withdrawn Objections
The claim objections are withdrawn in view of the claim amendment.
Maintained Rejection with Changes per Claim Amendment
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 69-70, 86-90 and 92-93 are rejected under 35 U.S.C. 103 as being unpatentable over Romero et al. (WO 2016/086200), in view of Qi, Jun (WO 2020092907), in further view of Scheepstra et al. Comput. Struct. Biotechnol. J. 2019 Jan 25;17:160-176.
Regarding claims 70 and 87, Romero (abstract; page 2, [0007]) teaches compounds (of compounds of formula (I) or formula (II)) are useful as inhibitors of CBP and/or EP300. Also included are pharmaceutical compositions comprising a compound of formula (I) of formula (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Regarding claims 69, 86 and 88-89, 92-93, Romero does not explicitly mention the phrase “CBP/P300 ligand,” however, because the primary function of ligand is to bind to a receptor or other target molecule, a ligand can function as an inhibitor. This conclusion is supported by the specification (page 1, lines 19-20):
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Therefore, it would have been obvious to a person of ordinary skill in the art (POSITA) to interpret the disclosure by Romero of “CBP/P300 inhibitor” as also referring to “CBP/P300 ligand,” because the terms are used interchangeably.
Regarding a CBP/P300 ligand or inhibitor, Romero (page 477, Example 347; abstract) teaches compound “1-[3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl)-l-(lmethyl-4-piperidyl)-6, 7-dihydro-4H-pyrazolo [ 4,3-c ]pyridin-5-yl] ethenone,” which is identical to the instant claim, Formula 3W.
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Furthermore, Romero (page 456, Example 28) teaches compound “1-(1-acetyl-4-piperidy])-3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2Hquinolin-
l-yl]-N-methyl-6, 7-dihydro-4H-pyrazolo[4,3-c ]pyridine-5-carboxamide,” which is identical to the instant claim, Formula 3U.
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Romero, however, does not explicitly teach the CBP and/or EP300 inhibitors are conjugated to a degradation tag or E3 ubiquitin ligase ligand.
However, Qi (page 1-3; page 2, [0004]) teaches a bifunctional compound having the following structure:
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Thus, Qi clearly discloses that an EP300 targeting ligand can be conjugated via a linker to an E3 ubiquitin ligase binding moiety, to form a bifunctional compound that can both target and degrade EP300 protein, also known as p300, a functional domain within the CBP/P300 family.
Therefore, a POSITA would have been motivated to modify Romero’s CBP/P300 inhibitors, like the EP300 ligand, into bifunctional degraders to improve therapeutic efficacy through targeted protein for degradation. This approach is supported by Scheepstra (abstract; page 164) which teaches that a mere inhibition of bromodomain of PCAF (P300/CBP associated factor, which relates to CBP/P300 family) and general control nonderepressible 5 (GCN5) was insufficient to disrupt the immunomodulatory functions of these proteins. For this reason, Scheepstra (page 164; page 168-171, Table 2-3) teaches that adding degradation tags, such as thalidomide and pomalidomide via a linker to a small molecule GSK-4027 (inhibitor of the bromodomains of PCAF and GCN5), significantly enhanced the compound therapeutic efficacy by inducing protein degradation instead of simple inhibition. This is exemplified by Scheepstra (page 164) which teaches that adding an E3 ubiquitin ligase ligand significantly lower DC50 and achieved rapid and significant degradation of the target protein:
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As mentioned above in the 103 rejection, Qi (abstract; page 1-3; page 25-51) teaches a similar concept, wherein thalidomide, pomalidomide, and lenalidomide as an example, were conjugated via a linker to an EP300 targeting ligand, to a form a bifunctional compound that enables targeted protein degradation. More specifically, Qi (page 43) teaches the following thalidomide derivatives:
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wherein R1 is hydrogen; Y is CO; V, X and W are CH; Z is NH.
The specification (page 83) also teaches similar class of E3 ubiquitin ligase ligands as degradation tag moiety:
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Regarding linker moiety, Qi (page 21-25, [0009]) teaches various type of linkers, including, but not limited to
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and
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. Qi (page 25, [0114]) teaches that the length of the linker can range from 0 to 11 chains and may vary in composition. This is further supported by Scheepstra (page 169, Table 2) teaches similar linker composition
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, as an example, covalently linked with pomalidomide, reading on claim 92. While linker, L16, contains an extra methyl group, a POSITA would recognize that the liker variants differ in the number of alkyl substituents. Therefore, adjusting the alkyl chain length would be expected to optimize the linker and expand the library of alkyl-derived linkers.
Therefore, given that both Scheepstra and Qi teach conjugating CBP/P300-related ligands to E3 ligase-recruiting moieties, such as pomalidomide, via a linker to induce degradation, thus
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a POSITA would be motivated and expected success at the time of filing of the instant application to modify Romero’s disclosed inhibitors, such as compound of Example 347 and 328, in view of Scheepstra and Qi’s disclosure, leading to bifunctional compounds or degraders. This approach would enhance therapeutic efficacy by shifting from inhibition to targeted protein degradation, and arrive at a compound identical to the claimed invention, compound P-119 and the elected species or compound P-007. This is because, Romero (page 515 and 516) teaches the compounds of Example 328 and 347 have an IC50 of 0.0007 µM (0.7 nM) and 0.0020 µM (2 nM), respectively; which indicates the compounds act as potent inhibitors against targets. Therefore, conjugating such compounds with an E3 ubiquitin ligase ligand would likely result in a superior bifunctional molecule capable of inducing targeted protein degradation. This is because, Scheepstra (page 164) teaches that adding an E3 ubiquitin ligase ligand to EP300 ligand, via a linker, significantly lower DC50, and achieved rapid and significant degradation of the target protein, which demonstrates superior activity compared to mere inhibition by the same compound.
Subject Matter Free of the Art of Record
The subject matter of claim 91 is free of the art of record. The closest prior art is Qi, Jun (WO 2020092907). While Qi teaches compound of formula (I) targeting cereblon, however there is no motivation for an ordinary skill in the art to modify Qi’s teachings to arrive at the claimed compound. These claims are not allowable until the 103 rejection is overcome.
Response to Argument
Applicant argues that the prior art does not explicitly teach the term “PROTAC.” Applicant’s argument is not persuasive because, the prior art explicitly describes the same core system as a PROTAC. For example, Qi describes (i) a ligand that binds EP300/p300, (ii) a degron that binds an E3 ubiquitin ligase, and (iii) a linker connecting the two moieties. This arrangement corresponds to the canonical architecture of PROTAC. Furthermore, while individual prior art does not explicitly teach the exact claimed compound, however, the combined teachings of the cited prior art, as indicated in the 103 rejection above, render the claimed compound obvious. For instance, Romero (abstract; page 2, [0007]) teaches compounds (of compounds of formula (I) or formula (II)) are useful as inhibitors of CBP and/or EP300. Scheepstra (page 164; page 169, Table 2) and Qi(abstract; page 1-3; page 25-51) teach conjugating CBP/P300-related ligands to E3 ligase-recruiting moieties, such as pomalidomide, via a linker to induce degradation. Thus, a POSITA would be motivated and expected success at
before the effective filing date of the claimed invention to modify Romero’s disclosed inhibitors, such as compound of Example 347 and 328, in view of Scheepstra and Qi’s disclosure, leading to bifunctional compounds or degraders, and to arrive at the claimed compound.
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)
Furthermore, in response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Therefore, Applicant should consider the combined teachings of the prior art as a collective disclosure for the obviousness rejection, rather on differences found in any single prior art.
Applicant argues that PROTAC design is inherently unpredictable, and therefore a POSITA would not have been motivated to modify the prior art to arrive at the claimed compound. Applicant’s argument is not persuasive because, PROTACS and derivatives are well-known in the art, with numerous published examples: POI (Protein of interest) ligand, Linker and E3 Ligase Ligand (E3 ubiquitin ligase ligand). The fact that some aspects of PROTAC performance are unpredictable, e.g., degradation efficiency, does not negate a reasonable expectation of success or motivation to combine known PROTAC components, as indicated in the 103 rejection above. It is also worth noting that, because PROTAC construction routinely involves combining known target ligands with standard E3 ligase ligand and with linker variation as routine optimization, thus a POSITA would have been motivated to combine these components into a PROTAC core system with expectation of obtaining a functional degrader.
Applicant argues that discrepancies among the linkers disclosed in the individual prior art demonstrate that PROTAC linkers are inherently unpredictable. Thus, a POSITA would not have been motivated to modify or combine the prior art to obtain the claimed linker. Applicant’s argument is not persuasive because, a POSITA would understand that linker optimization in the art is a routine and well-established aspect of designing bifunctional degrader, critical for PROTAC. The fact that different references disclose different linker lengths or composition is not evidence of unpredictability; it reflects the ordinary optimization processes used to position the target ligand and the E3 ligase ligand in a spatial arrangement critical for ubiquitination. Moreover, the cited prior art, such as Qi expressly teaches linker types and structural motifs that are the same as, or substantially similar to, those cited in the claimed invention. Thus, such disclosures would have provided a POSITA clear guidance that the claimed linker represents known and interchangeable design option within the art. For this reason, the differences emphasized by the Applicant correspond at most to routine selection and optimization among known linker structures and do not establish that the claimed compounds possess a patentably distinct or nonobvious linker system as disclosed in the 103 rejection above. Thus, the rejection is maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622