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 .
Priority
The present application claims priority to the following applications: 63/183,358, 63/316,617, and PCT/US2022/027280, with effective filing dates of 3 May 2021, 3 March 2022, and 2 May 2022.
Claim Status
This Office Action is in response to Applicant’s Amendment filed, 23 July 2026, wherein Applicant amended claim 1 and 16. Claims 4, 14, 17, 21, and 28 were previously canceled. Claims 2, 7-8, 13, 15, 18, 20, 22, and 25-27 were previously withdrawn.
The Examiner notes Applicant’s previous election of Group I (claims 1-3, 5-13, 15-16, 18-20, and 22-24) and species of Compound 17 (
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in the Response to Restriction Requirement filed 10 Mar 2026.
Claims 1, 3, 5-6, 9-12, 16, 19, and 23-24 are under consideration in the instant office action.
Information Disclosure Statement
The Information Disclosure Statement filed on 23 Jul 2026 and the references cited therein have been considered, unless indicated otherwise.
Rejections Withdrawn
Claim Rejections – 35 U.S.C. § 112
1. Claim 16 was rejected as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention. Applicant amended claim 16 to recite structures (D1-a) to (D1-f), see pages 20-22. Accordingly, the rejection of claim 16 is withdrawn.
Claim Rejections – Nonstatutory Double Patenting
2. Claims 1, 3, 5-6, 9-12, 16, 19, and 23-24 were rejected on the ground of nonstatutory double patenting over claim 1 and 13-15 of copending Application No. 17/774,002. Application No. 17/774,002 was abandoned on 26 Aug 2026. Accordingly, the rejection of claims 1, 3, 5-6, 9-12, 16, 19, and 23-24 on the ground of nonstatutory double patenting is withdrawn.
Rejections Maintained
Claim Rejections – 35 U.S.C. § 103
3. (Maintained) Claims 1, 3, 5-6, 9-12, 16, 19, and 23-24 were rejected as being unpatentable over Hebach (U.S. Patent No. 9,056,843, issued 16 June 2015, see IDS filed 25 Oct 2023) in view of Cromm (J. Am. Chem. Soc.¸ 2018, 140(49), 17019-17026) and Crews (U.S. Patent PreGrant Publication 2020/0038513, published 6 Feb 2020) as evidenced by Zagidullin (Explor. Target Antitumor Ther., 2020, 1, 381-390), Wikipedia (“Cereblon,” Wikipedia, 26 Oct 2019,
<web.archive.org/web/20191026111915/https://en.wikipedia.org/wiki/Cereblon>, accessed 13 Apr 2026), and Krieger (ChemMedChem, 2023, 18(e202200615), 1-11).
Applicant’s arguments, see pages 65-70, with respect to the rejection of claims 1, 3, 5-6, 9-12, 16, 19, and 23-24 have been fully considered but they are not persuasive.
Applicant argues that the cited references provide no rationale for transforming Hebach’s compound into a bifunctional compound as presently claimed to initiate HDAC degradation and that none of the cited references disclose a HDAC-degrading compound. Applicant argues that the Office did not properly articulate a motivation to modify the primary reference and that the compounds of the present invention differ from that of Hebach in terms of structure, mechanism of action, and end result. Applicant further argues hindsight reasoning. Applicant argues that none of the other cited art points to or suggests a design need with respect to targeting class IIa HDACs. Applicant asserts that the PROTAC art remains not just challenging but rather empirical and highly unpredictable and that derivatizing them to include a linker and a degron hardly constitutes a simple substitution. Applicant further cites Kossakowski (J. Enzyme Inhib. Med. Chem.¸2025, 40(1: 2542357), 1-76; see IDS filed 23 Jul 2026) and Nandave (PROTAC-Mediated Protein Degradation: A Paradigm Shift in Cancer Therapeutics, Springer, 2024, pages 1-400; see IDS filed 23 Jul 2026).
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).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify the POI ligand of Hebach to incorporate the PEG linker and VHL ligand of Cromm and Crews to arrive at Compound 17:
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, to create a more selective HDAC4 compound. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Hebach teaches trifluromethyl-oxadizaole derivatives as inhibitors of HDAC4 for treating Huntington’s disease, which is a neurodegenerative disease,
-Hebach teaches the compound,
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, which is the protein of interest (POI) ligand of Compound 17,
-Hebach teaches Class IIa-selective HDAC4 inhibitors (column 2, lines 45-50),
-Cromm teaches heterobifunctional degraders that induced protein degradation via small molecule inhibitors that failed in initial clinical trials,
-Cromm teaches the compound,
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, (PROTAC-3), which utilizes VHL and a flexible PEG linker to best enable formation of the ternary complex as evidenced by Zagidullin. Zagidullin teaches that PEG linkers are soluble and flexible and that PEG linkers stabilize the ternary complex by cooperative binding,
-Cromm teaches utilizing VHL and cereblon (CRBN) E3 ligase ligands, which have been extensively used in the degrader landscape. While both VHL and CRBN are popular E3 ligase ligands, a significant drawback to utilization of CRBN is the associated teratogenic effect as evidenced by Wikipedia,
-Cromm teaches that CRBN-recruiting analogs are less effective than VHL-recruiting analogs,
-Cromm teaches that while some previous small molecules were proven effective in preclinical studies, clinical success had yet to be observed and the leading Fak inhibitor (defactinib) failed its initial clinical trial targeting malignant pleural mesothelioma stem cells,
-Cromm teaches that heterobifunctional degraders exhibit better selectivity: defactinib binds to 100 kinases, while PROTAC-3 binds to 20 kinases,
-Cromm teaches that PROTAC-3 outperforms the clinical candidate (defactinib) with respect to Fak activation (autophosphorylation) and inhibition of downstream signaling (including Fak’s kinase-independent signaling),
-Cromm teaches that degraders are able to target an increasing range of kinases and therapeutic areas (i.e. resistance mechanisms and protein targets that were inaccessible) and thus drug the undruggable,
-Cromm teaches that the VHL ligand having the same stereochemical assignments as the VHL ligand in Compound 17: 1) the t-butyl is (S); 2) the alcohol of the hydroxyproline is (R); and (3) the amide is (S),
-Crews teaches heterobifunctional degraders comprising defactinib, PEG linkers, and VHL for targeting FAK,
-Crews teaches that that protein-protein interactions are notoriously difficult to target using small molecules,
-Crews teaches that that E3 ubiquitin ligases confer substrate specificity for ubiquitination and therefore are more attractive therapeutic targets than general proteasome inhibitors due to specificity for certain protein substrates,
-Crews teaches that non-specific effects at treating FAK-mediated diseases and disorders and inability to target and modulate FAK remain as obstacles to the development of effective treatments and that small-molecule therapeutic agents that target FAK and leverage VHL’s substrate specificity would be very useful,
-Crews teaches the VHL ligand,
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, wherein the methyl of the ligand has the stereochemical assignment of (S) and -Crews teaches other VHL ligands possessing a methyl at the benzylic position, and all the VHL ligands having 1) a methyl at the benzylic position and 2) specified stereochemistry have the methyl at the wedge position and the hydrogen at the hash position (i.e. producing a stereochemical assignment of (S), as evidenced by Krieger. Krieger teaches that the (R) enantiomer is known in the art to be significantly less active (Table 2, page 3; page 2, column 2, paragraph 1).
As such, an artisan having ordinary skill in the art would have been motivated to substitute one known element for another to predictably arrive at a compound of Formula (I):
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.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant’s argument that the PROTAC art remains not just challenging but rather empirical and highly unpredictable and that derivatizing them to include a linker and a degron hardly constitutes a simple substitution, the Examiner notes that Kossakowski teaches that the widespread use of commercially available kinase inhibitors, E3 ligase ligands, and linker libraries reduces both the cost and time associated with PROTAC synthesis (page 70, paragraph 1). Additionally, Applicant is using a known HDAC4 selective inhibitor as taught by Hebach. Further, the Examiner notes that Applicant uses 1) a flexible PEG linker, which best enables formation of the ternary complex as taught by Cromm (page 17020, column 2, paragraph 1; page 17020, Figure 1) and evidenced by Zagidullin (page 383, paragraph 3) and 2) a VHL-recruiting ligand, which are more effective than CRBN-recruiting ligands and that CRBN ligands exhibit teratogenic effects as taught by Cromm and Crews (Cromm: page 17020, column 2, paragraph 1; Crews: [0012]; page 111) and evidenced by Wikipedia (page 1, paragraph 2). Additionally, Kossakowski teaches that amines are natural derivatization points for direct conjugation with linkers with classical medicinal chemistry transformations and that the use of robust and scalable synthetic methodologies facilitates the efficient production of PROTACs, ensuring reproducibility and feasibility for further preclinical and clinical development (page 70, paragraph 1). With respect to Nandave, page 81 does not appear to have the cited quotation. In order to properly construe the meaning of the quotation, it is imperative that the correct citation is provided as context can impact the meaning. Accordingly, the Examiner cannot address Applicant’s argument regarding Nandave.
Accordingly, the rejection of claims 1, 3, 5-6, 9-12, 16, 19, and 23-24 as being unpatentable over Hebach in view of Cromm and Crews as evidenced by Zagidullin, Wikipedia, and Krieger is maintained.
Conclusion
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Madeline M Dekarske whose telephone number is (571)272-1789. The examiner can normally be reached Monday - Thursday 10am - 4pm.
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
