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
Applicants’ election without traverse of Group I in the reply filed on 05/12/2025, is acknowledged. Applicants have withdrawn claims 20-23 from consideration.
Applicants’ elected species was free of the prior art. An extended Markush search for the full scope of the instant claim 1 retrieved pertinent prior art reading on the compound.
Current Status of 17/771,204
This Office Action is responsive to the amended claims of 10/17/2025. Claims 1-18 have been examined on the merits.
Priority
This application is a national stage entry of PCT/EP2020/080265, internation filing date 28 October 2020, which claims priority to U.S. Provisional Patent Application No. 62/927,340, filed 29 October 2019.
The instant claims find support in the 62/927,340, and are given the effective filing date of 29 October 2019.
Response to Arguments
Applicants have amended the structures of DG-3 and DG-4 to include a hydrogen atom bound to the glutarimide nitrogen. These amendments are supported on page 13 of the original description, as indicated by Applicants. Additionally, Applicants have amended claims 13 and 14 replacing the reference to the example compounds with structures of the claimed compounds. These amendments render the previous rejections under 35 U.S.C. 112(b) for indefiniteness moot, and the rejections are withdrawn.
Applicants’ arguments have been fully considered and are persuasive. The claims have been amended to remove DG-2, which was relied upon in the Non-Final mailed 06/17/2025 and was taught by Bradner. The remaining references relied upon in the previous rejections do not teach or suggest the other degrons of the instant invention. Therefore, the previous rejections are withdrawn.
Claim Rejections - 35 USC § 103
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.
Claims 1, 2, 5-10, and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Farnaby (Farnaby, W., Koegl, M., Roy, M.J. et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat Chem Biol 15, 672–680 (2019). https://doi.org/10.1038/s41589-019-0294-6, found in IDS filed 4/22/22) in view of Kymera (WO 2019060742 A1, found in IDS filed 05/14/2025).
Farnaby discloses bifunctional PROTAC compounds comprising small-molecule ligand that binds SMARCA2 linked to an E3 ligase recruiting moiety. These compounds induce targeted degradation of SMARCA2. The reference teaches the use of a VHL-binding degron in their PROTACs and does not disclose the use of cereblon binding degrons. The targeting ligand of Farnaby has the following structure
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(pg. 673, Fig. 1, a), reading on the instantly claimed targeting ligand when R3 is hydroxyl, R1 and R2 are hydrogen, Z1-Z3, Cy2, and Cy3 are absent, and Cy1 is a 6-membered heterocycle. The linker of the PROTAC disclosed by the reference is a polyethylene glycol (PEG) chain (pg. 673, Fig. 1, b).
Kymera teaches bifunctional compounds capable of targeted protein degradation. The reference discloses degrons that bind and recruit the E3 ubiquitin ligase cereblon (CRBN) and teaches their use in PROTACs for inducing degradation of target proteins [0009-0010]. The reference further teaches that such CRBN-binding degrons may be linked (via linker) to a targeting ligand that binds a target protein to facilitate targeted protein degradation [0010]. While the specific targeting ligands of Kymera differ from those of the instant claims, the reference generally teaches the use of CRBN-binding degrons and linkers as modular components in PROTAC design. The CRBN-binding degrons used in the reference include
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(I-1, pg. 140) and
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(I-9, pg. 141). These degrons are compounds of formulas DG-3 and DG-4 of the instant application. The linkers (L) of the PROTAC compounds are defined in claim 1 with the following:
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As set forth above, the linker definitions disclosed in Kymera encompass hydrocarbon chains in which methylene units may be replaced with C(O), C(O)NR, or cyclic heterocyclylenyl groups containing nitrogen (piperidine and piperazine rings), which fall within the scope of the linker limitations recited in the instant claims 6 and 7.
The artisan would have a background in medicinal chemistry, chemical biology, or a related discipline, and would have experience in the design and synthesis of small-molecule therapeutics, including bifunctional compounds for targeted protein degradation. The artisan would have been familiar with E3 ligase recruitment, linker optimization, and structure-based ligand design.
The artisan would have been motivated to use the SMARCA2-binding targeting ligand of Farnaby as part of a PROTAC due to its demonstrated binding affinity for SMARC2 and its prior us in bifunctional degraders. Kymera teaches the use of the degrons disclosed above that recruit the E3 ligase CRBN for targeted protein degradation and further teaches that such degrons may be linked, via linker, to a targeting ligand that binds a protein of interest. In view of these teachings, the artisan would have been motivated to substitute the CRBN-binding degrons of Kymera for the VHL-binding degron of Farnaby as a known design alternative in PROTAC development. The artisan would have been further motivated to select a linker from either reference, as both references teach linkers suitable for connecting a targeting ligand and an E3 ligase recruiter, and linker length and composition were known results-effective variables routinely optimized in PROTAC design. The artisan would have reasonably expected that linking a known SMARCA2-binding TL to a known CRBN-binding degron via a suitable linker would yield a PROTAC capable of facilitating targeted degradation of SMARCA2.
Claims 1, 3, and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Farnaby and Kymera in view of Albrecht (WO2016/138114 A1, found in IDS submitted 04/22/22).
The teachings of Farnaby and Kymera as discussed above and are incorporated by reference into this rejection. The references teach the limitations of claim 1. These references do not teach substitutions other than piperazine on the amino substituted pyridazine ring.
Albrecht teaches the compounds of formula (Ia)
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(pg. 12, line 18) which are useful as inhibitors of BRM ,also known as SMARCA2 (Abstract, pg. 2, lines 14-15). R4 is taught as being phenyl,
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,
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,
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,
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, and
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(pg. 13-19). Inhibitor is defined as compounds that bind to and inhibit BRM (SMARCA2, pg. 10, lines 1-4).
The artisan would have a background in medicinal chemistry, chemical biology, or a related discipline, and would have experience in the design and synthesis of small-molecule therapeutics, including bifunctional compounds for targeted protein degradation. The artisan would have been familiar with E3 ligase recruitment, linker optimization, and structure-based ligand design.
The artisan would have been motivated to modify the TL at the position adjacent to the amino group of the pyridazine ring based on the teachings of Albrecht, which discloses heterocyclic substitutions at this position. Albrecht teaches that these modifications are well-tolerated and do not disrupt the ligand’s ability to bind SMARCA2 (see Table pg. 177-224), encouraging further exploration of similar analogs. The artisan would recognize that the key binding interactions of the TL reside in the conserved 2-(6-aminopyridazin-3-yl)phenol core, and that modifications to the adjacent position are distal to the critical binding interface.
Albrecht demonstrates that a variety of substitutions at this position retain SMARCA2 binding affinity. Given this, the artisan would expect that incorporating similar substituents would result in a compound with comparable binding affinity to the desired protein. The artisan would expect that these modifications may afford advantageous properties such as improved pharmacokinetics, solubility, or bioavailability without impairing the ligand’s function. The selection of such substituents would have been an obvious design choice, made with an expectation of success, particularly in the context of generating functional TLs for use in PROTACs targeting SMARCA2.
Claims 1 and 11-14 are rejected under 35 U.S.C. 103 as being unpatentable over Farnaby, Kymera, and Albrecht.
The teachings of Farnaby, Kymera, and Albrecht are discussed above and are incorporated by reference into this rejection. Farnaby and Kymera teach claim 1.
The artisan would have a background in medicinal chemistry, chemical biology, or a related discipline, and would have experience in the design and synthesis of small-molecule therapeutics, including bifunctional compounds for targeted protein degradation. The artisan would have been familiar with E3 ligase recruitment, linker optimization, and structure-based ligand design.
The artisan would have been motivated to incorporate up to three separate heterocyclic groups at the position adjacent to the amino group of the pyridazine ring based on the teachings of Albrecht. Albrecht demonstrates that the introduction of one or two heterocyclic substituents at this position is well-tolerated and does not disrupt the ligand’s ability to bind SMARCA2. Although Albrecht does not explicitly disclose the incorporation of more than two such substituents, the absence of any adverse effects on SMARCA2 binding in the disclosed examples would lead the artisan to reasonably expected that additional substitutions, with similar group, would likewise not impair binding.
Moreover, the artisan would understand that these heterocyclic groups, when appended at this position, are positioned distal to the ligand’s key binding elements. As such, the artisan would recognize that these groups function not as essential components of the targeting ligand, but rather as early elements of the linker. In light of this, the artisan would be further motivated to incorporate heterocycles such as those taught by Kymera, to improve linker properties without negatively impacting the activity of the PROTAC.
The use of heterocyclic rings in PROTAC linkers was well-established and routine at the time of invention. Based on the combined teachings of Albrecht and Kymera, the artisan would have been motivated to explore additional substitutions at this position to optimize the linker functionality, and would have a reasonable expectation of success in doing so. These modifications represent no more than predictable combinations of known linker and TL variations that would have been obvious to one of ordinary skill in the art. These teachings make obvious the claimed TL structures of instant claims 11-14.
The combined teachings of Farnaby and Kymera are discussed above make obvious the claimed linker structures. The above discussion is incorporated into this rejection by reference.
Based on the discussion above, the artisan would have been motivated by the teachings of Farnaby, Kymera, and Albrecht to use the specific TL and degron moieties recited in the instant claims. These references collectively disclose the same or structurally similar TLs and degrons that have been shown to successfully engage SMARCA2 and E3 ligases, respectively, thereby enabling targeted protein degradation. The artisan would understand from these teachings that these components are effective and interchangeable within the modular PROTAC framework.
The teachings of Farnaby and Kymera would motivate the artisan to employ the linker structures of the instant claims. These references describe all the claimed linker elements and demonstrate that such linkers are effect in modulating PROTAC properties such as those discussed above. The artisan would recognize these linkers as interchangeable elements that can be routinely optimized without affecting the core binding functionalities of the TL and degron.
Given the modular nature of PROTACs and the routine experimentation involved in their development, the artisan would have been motivated to combine these known TL, degron, and linker components based on their demonstrated utility in prior art systems Each component had been shown to perform its respective function in facilitating SMARCA2 degradation, and the artisan would have had a reasonable expectation that combining them would result in a functional PROTAC with similar activity.
Therefore, the compounds of instant claims 13 and 14 represent a predictable combination of known elements, each of which had been previously used successfully in PROTACs targeting SMARCA2. The claimed PROTACs are therefore obvious amalgamations of known and well-characterized PROTAC components.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
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/C.K.E./Examiner, Art Unit 1625
/Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625