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 with traverse of Group I, (drawn to a pharmaceutical composition), in the reply filed on 05/18/2026 is acknowledged.
Claims 1-16 are pending of which claims 7-16 (Group II-V) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention there being no allowable generic or linking claim. The restriction requirement is still deemed proper and is made Final.
Pending claims 1-6 have been examined on the merits.
Please note, for clarity of the record, Applicant elected the following species: 1-[1-(4-chlorophenyl)-2,5-dimethyl-lH-pyrrol-3-yl]-2-(1-piperidinyl) ethenone; cyclin-dependent kinase 9 (CDK9)/CDK family; and ovarian cancer.
Per MPEP 803.02, the Examiner determined that the elected compound is not allowable over the prior art, therefore, the examination was not extended over the non-elected compounds.
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 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al., Frontiers in Oncology, vol. 10, Feb. 2021, p. 621294 and Chen et al., Intern. J. of Mol. Sci., vol. 22, no. 9, Apr. 2021, p. 4546.
Regarding claims 1-4 and 6. Zhang (page 1-2; page 4) teaches dysregulation of the ubiquitin proteasome system (UPS) contributes to cancer development and UPS inhibitors as effective strategy for cancer treatment. Zhang (page 12) teaches inhibitors of USP14 have been found to stimulate proteasomal degradation of oxidized proteins, causing resistance to oxidative stress. For example, Zhang (page 11-12) discloses b-AP15 (i.e., (3E)-3,5-bis[(4-nitrophenyl)methylidene]-1-prop-2-enoylpiperidin-4-one), USP14 inhibitor, selectively block the deubiquitylating activity of USP14 and inhibits multiple myeloma cancer cell growth. Furthermore, Zhang (page 1-2; page 12-13) discloses proteolysis targeting chimeras (PROTACs) technology represents a novel anticancer therapeutic strategy that modulates protein target levels through the UPS. For some E3s involved in cancer see Table 1 (pg. 4) of Zhang. For some DUBs involved in cancer, see Table 2 (pg. 5) of Zhang. For anti-cancer compounds, which target the ubiquitin-proteasome system and DUBs, that are in clinical trials see Table 3 (pgs. 10-11) of Zhang.
However, Zhang does not explicitly teach the elected USP14 inhibitor species of 1-[1-(4-chlorophenyl)-2,5-dimethyl-lH-pyrrol-3-yl]-2-(1-piperidinyl)ethenone.
Chen (page 5, 9 and 19) teaches that USP14 plays a role in tumorigenesis and further discloses compound IU1-47 (at page 19 of 29 in section 5.2.15. USP14 Inhibitors), a USP14-targeting compound, Applicant’s elected species of USP14 inhibitor:
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Moreover, Chen (page 19) also discloses that USP14 inhibitors can be used in the treatment of neurodegenerative diseases. Similar to Zhang, Chen (page 22) teaches that USP inhibitors and PROTACs are two therapeutic technologies that exploit the ubiquitin-proteasome system to induce targeted protein degradation, expressly comparing the two approaches. Chen (page 22) teaches that PROTACs promote UPS-mediated degradation of target proteins by recruiting an E3 ligase to induce ubiquitination, whereas USP inhibitors promote degradation by inhibiting the deubiquitylation process, thereby preserving ubiquitinated proteins for proteasomal degradation. Moreover, Chen (page 22) further recognizes both PROTAC and USP inhibition as promising therapeutic strategies while explaining that the two approaches achieve protein degradation through different but complementary mechanism within the same ubiquitin-proteasome pathway.
Therefore, it would have been obvious to a person of ordinary skill in the art (POSITA) to formulate a pharmaceutical composition comprising a known PROTAC together with a known USP14 inhibitor, such as IU1-47. Both Zhang and Chen recognize that PROTACs and USP14 inhibitors are directed to the same therapeutic objective. Therefore, a POSITA would have reasonably expected that combining these complementary technologies would provide at least an additive or synergistic therapeutic benefit, by simultaneously promoting ubiquitination of target proteins through the PROTAC while, at the same time, reducing removal of ubiquitin chains through inhibition of USP14; leading to proteosome-mediated degradation of the target proteins and enhancing the protein degradation effect of the PROTAC, as recited in the instant claims.
Regarding claim 5, Zhang (page 12-13) discloses BRD4/BET-targeting PROTACs, including QCA570 and ARV-825, which recruit an E3 ubiquitin ligase to induce ubiquitination and proteasome-mediated degradation of BRD4.
Conclusion
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES H ALSTRUM-ACEVEDO can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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