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 .
DETAILED ACTION
Status of 17/775,265
Claims 1-6, 8-66, 70-83, and 85-113 are currently pending.
Priority
Instant application 17/775,265, filed 5/6/2022, claims priority as follows:
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The PCT application provides support for the instant claims, and thus the instant claims are therefore granted the priority date of 11/8/2019.
Information Disclosure Statement
All references from the IDS’s submitted 9/9/2022, 5/10/2023, 7/29/2025, and 12/5/2025 have been considered unless marked with a strikethrough.
Response to Applicant’s Arguments/Amendments
The amendment filed 8/5/2026 has been entered. Claims 1, 44, and 82 have been amended. Claims 7 and 84 have been cancelled.
In the Final dated 4/6/2026, the abstract was objected to for a minor informality. In response, Applicant has submitted a corrected abstract, which overcomes the objection. Thus, the objection is withdrawn.
Claims 1-10, 12-15, 23-51, and 108 were rejected in the Final dated 4/6/2026 on the basis that they contain an improper Markush grouping of alternatives. In response, Applicant has amended claim 1 to recite that A4 is nitrogen, A5 is C-R15, and each D is nitrogen or CH, and has cancelled claim 7. Further, Applicant argues that the core in fact does share a singular similarity/substantial structural feature as the cores are coplanar regardless of the atoms available as variables of the core. Applicant also argues that the claimed alternatives are members of a recognized chemical class or art-recognized class in view of the Examiner’s art used in the “Close Prior Art Not Cited” section of the Final dated 4/6/2026, and thus also have a common use. Applicant’s amendment and arguments have been considered, and are persuasive for the reasons above. Thus, the rejection is overcome, and withdrawn.
In the Final dated 4/6/2026, claims 3, 70-73, 81-83, 86-94, and 96-106 were rejected under 35 U.S.C. 112(b). In response, Applicant has amended claim 84 and has provided alternative interpretations of variables previously identified as unclear, which overcomes the rejection. Thus, the rejection is withdrawn.
However, the Examiner has reconsidered the prior art, and additional rejections are made herein.
Election/Restriction
Applicant’s election of Group I, claims 1-108, drawn to compounds and compositions of Formula I, without traverse, in the reply filed 3/7/2025, is acknowledged. Applicant’s election of compound 25:
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without traverse in the reply filed 3/7/2025, is also acknowledged.
Examination will begin with the elected species. In accordance with MPEP § 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non- elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be examined again. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during further examination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
The elected species was searched and no prior art was identified. The search was expanded to Formula (III-A):
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In the Non-Final dated 4/1/2025, and the prior art rejection was withdrawn. See the “Response to Arguments/Amendments” section above. Subsequent examination is based on the species expansion to Formula I-A:
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where A4 and A5 are C-R15, where R15 is H, D is CH, and R3 is C1 alkyl, and prior art was identified. In response, Applicant has amended the claims to recite that A4 is solely N, which overcomes the rejection. Thus, the Examiner expanded the search to the full scope of Formula (I). However, the Examiner has reconsidered the prior art, and a new rejection has been made. See the 103 rejection below. Claims 1-6, 8-66, 70-83, and 85-108 are currently the subject of this Office Action. Claims 109-113 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species and/or group, there being no allowable or generic linking claim.
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 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, 8-22, 25-51, 81-83, and 85-108 are rejected under 35 U.S.C. 103 as being unpatentable over Dana-Farber Cancer Institute, Inc. (WO 2019/148150 A1, herein after “Dana-Farber”) in view of Crawford (Crawford, J. J. J. Med. Chem. 2018, 61, 2227-2245).
Determining the scope and contents of the prior art
The reference Dana-Farber, which is drawn to bifunctional compounds capable of degrading Bruton’s tyrosine kinase (BTK) of the modular genus Formula (X) (abstract and page 193, claim 1):
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Where the targeting ligand is capable of binding to BTK, the linker group covalently binds to the targeting ligand and the degron, and the degron is capable of binding to the ubiquitin ligase. Dana Farber teaches compounds with the targeting ligand genera of Formula TL-I and TL-II (page 192, claim 1):
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And further teaches specific compounds such as Compound I-0 (page 130, Table A1):
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Which overlaps with a compound of Formula I:
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When ring A is
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, C is a 6-membered fully unsaturated carbocycle substituted with R1 and R2, where R1 is 3-membered cycloaliphatic and R2 is a fluoro, XB is C, ---- is a bond, X1 is -CH=, r is 1, A5 is C-R15, where R15 is H, D is CH, R3 is C1 alkyl, Xy is
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, ring B is 6 membered monocyclic heteroaryl having 1 nitrogen atom, ring D is a 6-membered heterocycle having two nitrogen atoms, L is Y1-Y2-Y3-Y4-Y5-Y6, where Y1 is (CH2-CH2-O)m, where m is 1, Y2 is –(CH2-CH2-O)n, where n is 1, Y3 is C2 alkyl, and Y4 is -N(R)C(O)-, where R is H, and Y6 is a bond, Z is Z-1
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, A1-A3 are -C(RB)=, RB is H, W is -C(O)-, and RA is H. Various additional interpretations of the Y1-Y2-Y3-Y4-Y5-Y6 are not explicitly stated herein. Additional combinations of linkers Y1-Y2-Y3-Y4-Y5-Y6 can be constructed from the teachings of Dana-Farber (pages 82-118 and page 148). Further, compound I-0 was found to degrade levels of BTK in MOLM-14 cells and inhibits proliferation of TMD8 cells (page 218, Figures 1 and 2). With respect to claims 3 and 4, Dana-Farber teaches the D0 series as possible degrons (page 71).
The Compound I-0 does not teach a pyridinyl-methanol core and does not teach a linker that maps to the instant variables Y1-Y2-Y3-Y4-Y5-Y6. However, additional compounds of Dana-Farber that claim to be BTK inhibitors contain linkers that do map to compounds of the instant claims. Specifically, the following compound (page 125, entry 3):
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Contains a linker that maps to Y1-Y2-Y3-Y4-Y5-Y6, where Y1-Y4 are C1-4 alkyl, Y5 is -N(R)-, R is H, and Y6 is a bond.
The reference Crawford teaches the known oral BTK inhibitor GDC-0853 (page 2240, scheme 2, compound 29):
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Which partially maps to the instant expanded species of Formula (III-A):
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where R4 is C1 alkyl, and further partially maps to Formula I:
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When ring A is
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, C is a 5-membered fully unsaturated heterocycle substituted with R1 and R2, where R1 and R2 together with the atoms to which they are attached form a 5-membered cycloalkyl fused to ring C substituted with two instances of R6, where R6 is C1 alkyl, XB is C, ---- is a bond, X1 is -CH=, r is 1, A4 is N, A5 is C-R15, where R15 is H, D is CH, R3 is C1 alkyl, Xy is
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, ring B is 6 membered monocyclic heteroaryl having 1 nitrogen atom and ring D is a substituted 6-membered heterocycle having two nitrogen atoms.
With respect to claim 108, Crawford teaches the compound in DMSO, indicating a pharmaceutical composition (page 2240, Experimental Section Step 3).
Ascertaining the differences between the prior art and the claims at issue
The compounds of Dana-Farber fail to teach the pyridinyl-methanol core that maps to A4 of the instant claims.
Crawford fails to teach the L and Z variables of instant Formula I. Stated differently, Crawford fails to teach the linker and the degron of the bifunctional compound.
Resolving the level of ordinary skill in the pertinent art
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of bifunctional compounds capable of degrading BTK via a ubiquitin proteolytic pathway. An artisan possesses the technical knowledge necessary to make adjustments to the bifunctional compounds to enhance their effectiveness. Said artisan has also reviewed the problems in the art as regards to use of said bifunctional compounds capable of degrading BTK via a ubiquitin proteolytic pathway and understands the solutions that are widely known in the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness
Applying KSR Prong (B), it would have been prima facie obvious to one having ordinary skill in the art to substitute the linkers of the compounds of Dana-Farber and the carbon at the A4 position of the compounds of Dana-Farber with a nitrogen at the same position as Crawford, because the compounds are known to inhibit BTK. Structurally similar compounds are expected to have similar properties. A skilled artisan would have been motivated before the effective filing date to make such substitutions to identify additional bifunctional compounds able to degrade BTK. Further, one of ordinary skill would reasonably expect success with the substitutions in light of the teachings of Dana-Farber and Crawford.
Furthermore, an additional argument can be made to substitute the terminal cyclopropyl-fluoro-isoquinoline phenylmethanol moiety of Dana-Farber
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with the tricyclic piperidine pyridinyl-methanol moiety of Crawford
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. Applying KSR Prong (B), it would have been prima facie obvious to one having ordinary skill in the art to substitute the terminal cyclopropyl-fluoro-isoquinoline phenylmethanol moiety of Dana-Farber with the tricyclic piperidine pyridinyl-methanol moiety of Crawford because the compounds are known to inhibit BTK. Structurally similar compounds are expected to have similar properties. A skilled artisan would have been motivated before the effective filing date to make such substitutions to identify additional bifunctional compounds able to degrade BTK. Further, one of ordinary skill would reasonably expect success with the substitutions in light of the teachings of Dana-Farber and Crawford.
Claim Objections
Claims 23-24, 52-66, and 70-80 are objected to as they are dependent on a rejected base claim.
Conclusion
Claims 1-6, 8-22, 25-51, 81-83, and 85-108 are rejected. Claims 23-24, 52-66, and 70-80 are objected. Claims 109-113 remain withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kendall Heitmeier whose telephone number is (703)756-1555. The examiner can normally be reached Monday-Friday 8:30AM-5:00PM ET.
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/K.N.H./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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