DETAILED ACTION
This office action is in response to applicant’s filing dated August 6, 2025.
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 .
Status of claims
Claims 1 - 23 are pending in the instant application. Acknowledgment is made of Applicant’s amendments filed August 6, 2025.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1 – 14, drawn to a chimeric small molecule, according to the formula A-L-E-B or A-L1-E-L2-B in the reply filed on August 6, 2025 is acknowledged.
Claims 15 – 23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 6, 2025.
Applicant’s election without traverse of:
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;
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;
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and
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as a single species in the reply filed on August 6, 2025 is acknowledged. However, since none of the claims recite the structure of fragment A and L of the molecule of formula A-L-E-B, Examiner withdraws election of species, fragment A and L of the molecule of formula A-L-E-B.
Claims 3, 5 and 7 – 11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 6, 2025.
Claims 1, 2, 4, 6 and 12 – 14 are presently under examination as being drawn to elected species, fragments B and E of A-L-E-B molecule.
Priority
This application is a CON of U.S. Patent Application No.17/999,364, filed November 18, 2022, which is a 371 of PCT/US2022/024120, filed April 8, 2022, which claims the benefit of U.S. Provisional Application No. 63/291,942, filed December 20, 2021; U.S. Provisional Application No. 63/211,307, filed June 16, 2021; U.S. Provisional Application No. 63/173,351, filed April 9, 2021; and U.S. Provisional Application No. 63/173,357, filed April 9, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/20/2024 and 06/26/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
Acknowledgement is made of the drawings received on December 20, 2024. These drawings are accepted.
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, 2, 4, 6 and 12 – 14 are rejected under 35 U.S.C. 103 as being unpatentable over Guo et al (Nat Commun. 11, 4268 (2020, cited in IDS, filed 06/26/2025, hereinafter Guo)) in view of Li et al (WO 2017/172979 A1, hereinafter Li) and Apgar et al (WO 2014/031515 A1, hereinafter Apgar).
Instant claims are drawn to a chimeric small molecule having a formula A-L-E-B, wherein A is a kinase such as BTK binding moiety, L is a linker, E is an electrophilic reactive group of structure:
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and B is an AMPK binding moiety of structure:
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( MK8722 derivative). Electrophilic reactive group (E) in the structure of bifunctional compounds designed to react with a nucleophilic amino acid side chain reactive group, such as cysteine (specification, page 183, [0510]).
Guo teaches bifunctional PROTAC molecule of formula RC-1:
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(page 3, Fig. 2a), where BTK binding ligand (ibrutinib) connected via linker with CRBN E3 ligase binder (pomalidomide) (page 2, “results”) and where between BTK binding ligand and linker cyano-acrylamide-based reversible covalent binder (electrophilic reactive group) was incorporated:
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.
Guo teaches that cyano-acrylamide-based reversible covalent binder to BTK can significantly enhance drug accumulation and target engagement (TE) in cells. The electrophilic reactive group of Guo is a positional isomer of the same of instant claims (see structure above), where -CN group is attached to the second carbon of acrylamide, versus -CN in position three of acrylamide of instant invention, thus presumably expected to possess similar properties. MPEP 2144.09 states: A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Moreover, Li teaches the electrophile E which binds the cysteine residue at position 12 of a G12C mutant K-Ras, H-Ras or N-Ras protein and has the structure:
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, where Q is -C(O)-; R9 and R10 are each independently H or cyano (page 64, [0121] and page 65, [0123]. If R9 is H and R10 is cyano, the structure taught by Li is equivalent to the instantly claimed structure of electrophilic reactive group.
Guo or Li do not teach where the bifunctional molecule has an AMPK binding ligand. However, Apgar teaches compounds, acting as a activators of AMP-activated protein kinase (AMPK) (page 5, line3) and having a structure (e.g. MK8722 derivative):
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(page 196, Table 13, ex. 151). The compound, taught by Apgar has a structure which is a closest homologue of the instantly claimed AMPK binding moiety (see the structure above) and different in structure by -CH2- group. Since compound, taught by prior art and instantly claimed compound have close structural similarity it is reasonably expected to have similar properties. MPEP 2144.09.II. states: Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Thus, Guo teaches bifunctional molecule where two protein binding ligands connected via chemical linker and where electrophilic reactive group of cyano-acrylamide structure was incorporated to enhance certain drug properties, Li teaches electrophilic reactive groups having cyano-acrylamide structure and capable to bind nucleophilic amino acid side chain reactive group, such as cysteine, Apgar teaches compounds, activators of AMPK having a structure of MK8722 derivative. MPEP 2143.B states: as a second example, it could be possible to view a claimed compound as consisting of two known compounds attached via a chemical linker. The claimed compound might properly be found to have been obvious if there would have been a reason to link the two, if one of ordinary skill would have known how to do so, and if the resulting compound would have been the predictable result of the linkage procedure. Thus, Office personnel should recognize that in certain situations, it may be proper to reject a claimed chemical compound as obvious even without identifying a single lead compound.
Hence, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to try to make various known in the art bifunctional compounds possessing similar or better desired properties, where certain protein binding ligand of known structure is connected via known linker, to known in the art ligand binding another protein and modified with known electrophilic reactive group, to arrive at claimed compounds. The one of ordinary skills would be motivated to do so to modulate proteins proximity and inducement of the desired action with the reasonable expectation of success.
Therefore, taking all together, taught by prior art, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
Claims 1, 2, 4, 6 and 12 – 14 are rejected. No claim is allowed.
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/E.V.V./Examiner, Art Unit 1691
/SAVITHA M RAO/Primary Examiner, Art Unit 1691