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 Applicants have withdrawn claims 20-23 from consideration.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 04/28/2026. Claims 1-18 have been examined on the merits.
Priority
This application is a national stage entry of PCT/EP2020/080265, international filing date 10/28/2020, which claims priority to U.S. Provisional Patent Application No. 62/927,340, filed 10/29/20219.
Response to Arguments
Applicants allege that the combined teachings of the references Farnaby, Kymera, and Albrecht fail to render the instantly claimed compounds obvious. Applicants argue that the compounds of Farnaby are structurally different from the instantly claimed compounds and contain a VHL binding moiety (degron) which are distinct from the claimed CRBN binding moieties. Applicants allege that the reference teaches away from using the claimed CRBN degrons because the reference selected “a VHL ligand with high affinity and known binding mode.” This argument has been fully considered, but is not persuasive. First, Applicants argue unclaimed limitations in the claims. The claims at issue are not directed to SMARCA2 or CRBN binding moieties as argued. The claims are instead directed to compounds of formula (I) which comprise a Targeting Ligand of formula (TL), a linker, and a degron. Applicants appear to be incorporating the limitations of withdrawn claims 20-23 into their rationale. Second, Farnaby does not teach away from using other E3-ligase recruiters as alleged by Applicants. A reference teaches away when it discourages a proposed modification or suggests that the modification would be unlikely to achieve the desired effect. Farnaby merely identifies VHL as a preferred embodiment and does not teach away from using other known E3-ligase recruiters as alleged by Applicants. The reference does not disclose a meaningful criticism or incompatibility of other E3-ligases in PROTACs and therefore dose not teach away from their use.
Applicants argue that Kymera fails to teach any specific SMARCA protein degrading compounds and highlights the differences in the SMARCA2 targeting ligands of Kymera from the instant application. Applicants further argue that the reference does not contain the phenyl-pyridanzinyl moiety of the present compounds and that the a,b-unsaturated ketone of the reference differs from the ligands of both Farnaby and the instant disclosure. Kymera was not relied upon for teaching these moieties as they were taught by Farnaby. Applicants contend that Kymera’s exemplification is limited only to the oxyethylene linkers and that the claimed combination of a different linker, SMARCA-targeting ligand, and CRBN could only be achieved through hindsight reconstruction. Applicants further argue that the unpredictability of tertiary complex formation would have discouraged the proposed modifications.
These arguments have been fully considered, but are not persuasive. Kymera’s teaching is not limited to the oxyethylene linkers of the working examples as alleged. Claim 1 of the reference expressly teaches that the linkers may contain linkages of varying length and composition, including heteroatoms, carbonyl containing groups, cyclic groups, and combinations thereof that encompass the instantly claimed linkers. The exemplification of the oxyethylene linkers does not negate or teach away from the broader disclosure of alternative linkers embodied by claim 1 of the reference (see MPEP §2123).
Applicants address Farnaby and Kymera individually rather than considering their combined teachings collectively. Farnaby was relied upon for known SMARCA-targeting ligand and its incorporation into a bifunctional degrader, whereas Kymera was relied upon for known CRBN-recruiting moieties and linker alternatives. Neither reference is required to independently teach the complete claimed compounds (see MPEP §2145).
The rejection does not rely upon an arbitrary reconstruction of isolated structural elements as alleged by Applicants. Farnaby establishes that the claimed targeting ligand is a known SMARCA binding moiety that was suitable for targeted protein degradation. Kymera establishes that CRBN recruiting moieties are known alternative degrons and expressly provides linkers structures capable of joining the targeting ligand and degron in PROTACs. Accordingly, the artisan would have had a reason to prepare and evaluate other E3 ligase recruiting analogues and linker alternatives taught by Kymera using the TL of Farnaby.
The state of the art at the time of filing further supports the proposed modifications. Neklesa teaches that PROTACs are modular heterobifunctional compounds comprising a target-binding ligand, an E3-ligase-recruiting moiety, and linker connecting these moieties (Abstract). The reference identifies both VHL- and CRBN-recruiting ligands as established degrons in PROTAC design (pg. 139, right Col., second para.). Thus, the artisan would have understood that joining a compound with a known binding affinity for a protein to be degraded with a known moiety having demonstrated E3-ligase-recruiting ability represented a conventional next step in the design of PROTACs for selective degradation of the target protein.
Applicants argue that Albrecht does not disclose any protein-degradation compounds and therefore does not remedy the alleged deficiencies of the other cited references. Although Albrecht teaches SMARCA2 inhibitors, Applicants contend that the reference’s ligands are structurally distinct from those of the other cited references and Albrecht fails to provide guidance for incorporating these SMARC2-binding moieties into a PROTAC.
Applicants further argue that combining the teachings of the references would require multiple independent structural changes to the targeting ligand, linker, and degron moieties. According to the Applicants, the cited references provide no motivation to make those modifications to arrive at the instantly claimed compounds absent hindsight reconstruction.
These arguments have been fully considered, but are not persuasive. Applicants mischaracterize the purpose for which Albrecht was cited. Albrecht was not relied upon as teaching a complete SMARCA2 protein degradation compound. Rather, the reference was relied upon to teach that the recited SMARCA2-targeting ligand was known in the art to bind SMARCA2 and that structural modifications were tolerated while preserving SMARCA2 affinity. Albrecht provides evidence that the targeting ligand of the claimed compound was a known SMARCA2-binding motif suitable for use in modular PROTAC design.
The combined teachings of the cited references, not the individual teachings of any one reference disclose each of the elements of the instantly claimed compound. Farnaby discloses SMARCA-directed degradation using a bifunctional compounds, Kymera teaches known E3-ligase-recruiting moieties and linker alternatives, and Albrecht teaches the known SMARCA2-binding ligand and tolerated structural modifications thereof. In view of the modular nature of PROTAC design, these teachings would have provided the artisan with a reason to combine a known SMARCA2-binding ligand with a known E3-ligase recruiter using conventional linker alternatives to prepare and evaluate additional SMARCA2 degraders.
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.
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.
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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