DETAILED ACTION
This office action is in response to applicant’s filing dated November 26, 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. Receipt and consideration of Applicants' amended claim set and remarks/arguments filed on November 26, 2025 are acknowledged. Claims 3, 5, 7 – 11 and 15 – 23 remain withdrawn, as being drawn to an unelected invention or specie. Acknowledgement is made of Applicant's amendment of claim 2.
Claims under consideration in the instant office action are claims 1, 2, 4, 6 and 12 – 14.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/26/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Objections and/or Rejections and Response to Arguments
Applicants' arguments, filed on November 26, 2025, have been fully considered but they are not deemed to be persuasive. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
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.
Response to Arguments
Applicant argues:
- The Proposed Modification (i.e., substitution of one protein binding ligand (CRBN E3 ligase binder) in the bifunctional molecule of Guo with ligand, binding another protein (AMPK binding ligand)) would render the prior art unsatisfactory for its intended purpose and change its principle of operation (MPEP 2143.01(V) and (VI)), since the Guo's PROTAC principle of operation is ubiquitin-mediated proteasomal protein degradation, via recruiting an E3 ubiquitin ligase (CRBN) to ubiquitinate BTK, whereas the claimed invention operates on a different principle: enzyme-induced phosphorylation, where the chimeric small molecules bring AMPK into proximity with a target, inducing phosphorylation rather than degradation;
- If one were to substitute the E3 ligase binding moiety (pomalidomide) in Guo's PROTAC with an AMPK binding moiety, as the Office suggests, the resulting molecule would no longer function as a PROTAC;
- The Office has not specified which components of the PROTAC would be modified;
- the Office has failed to meet any of three requirements of cited MPEP 2143(B) Example 10, which addresses a specific, limited scenario: the simple linkage of two known compounds together, whereas the Examiner's proposed combination requires: (1) substituting the BTK binder in Guo with a different enzyme binder, (2) replacing the CRBN E3 ligase binder with an AMPK activator from Apgar, (3) modifying the electrophile structure using Li, and (4) adapting the linker to accommodate these changes; MPEP 2143(B) Example 10 does not support such complex, multi-component modifications across multiple references;
- the Office has not provided any reason why a person of ordinary skill would be motivated to link AMPK with another enzyme through a bifunctional molecule, none of the cited references suggests creating bifunctional molecules that bring AMPK into proximity with other enzymes for phosphorylation purposes;
- the Office has not demonstrated that a person of ordinary skill would know how to create functional AMPK-targeting bifunctional molecules, particularly where to attach a linker to the AMPK structure and how such attachment would preserve AMPK binding and activation properties;
- the Office has not demonstrated any predictability in creating AMPK-targeting bifunctional molecules;
- the complex interplay between linker length, attachment points, binding affinities, and spatial orientation is required for successful bifunctional molecule design, which cannot be predicted from the cited references without Applicant's disclosure.
Examiner’s response:
Applicant's arguments have been fully considered but they are not persuasive because: instant invention is drawn to a bifunctional molecule, where two protein binding ligands (binding AMPK and e.g. BTK) are connected via chemical linker, and wherein between BTK binding ligand and a linker cyano-acrylamide-based reversible covalent binder (electrophilic reactive group) is incorporated. Guo teaches a bifunctional molecule where two protein binding ligands (binding CRBN E3 ligase and BTK) are connected via chemical linker, and wherein between BTK binding ligand and a linker cyano-acrylamide-based reversible covalent binder (electrophilic reactive group) is incorporated. The structural difference between bifunctional molecule, taught by prior art, and instantly claimed bifunctional molecule is one fragment, in particular, one protein binding ligand (CRBN E3 ligase binder in the bifunctional molecule of Guo) is substituted with ligand, binding another protein (AMPK binding ligand of instant claims). Thus, to arrive at claimed compound, CRBN E3 ligase binding ligand in the molecule, taught by prior art, needs to be substituted with AMPK binding ligand. The chemical structure of AMPK binder is also taught by prior art (see the rejection section above). Considering all said above, the instantly claimed bifunctional molecule is a result of substitution of one known fragment with another known fragment in the chemical structure. Thus, the MPEP 2143(B) Example 10 had been properly used in the obviousness rejection.
Regarding linker length, attachment points, binding affinities etc., Examiner acknowledges the importance of these nuances for successful bifunctional molecule design, however Applicants do not specify in the claims linker structure or point of attachment of protein binders to the linker. MPEP 2111.01(II) states: It is improper to import claim limitations from the specification.
Regarding arguments about change of principle of operation, the argument is not persuasive because although PROTACs are designed for targeted protein degradation, they still belong to the class of bifunctional molecules as well as claimed compounds. The idea of designing bifunctional molecule by connecting two protein binding ligands via linker is to bring into proximity two proteins and induce the desired function. In support of this statement Examiner cites Gerry et al (Nat Chem Biol. 2020 April ; 16(4): 369–378). Gerry et al., teaches: [bifunctional] compounds often comprise two small-molecule binders connected by a covalent linker, yielding “bivalent,” dumbbell-shaped molecules, that can be synthesized using rational design (page 2, 3rd paragraph). Despite differences in structure, source, activity, and nomenclature (e.g. CIPs, CIDs, PROTACs, dimerizers, and molecular glues), many bifunctional small molecules operate via the same general mechanism: modulation of protein proximity. Gerry et al. further teaches that, unifying chemical and biophysical principles, shared by the ensemble of bifunctional small molecules are: 1) binding and co-localization of more than one biomacromolecular binding partner to generate multimeric complexes, 2) arrangement of binding partners in biologically meaningful orientations, and 3) orchestration of extensive networks of intermolecular interactions (page 3, 2nd paragraph). Furthermore, Gerry et al., teaches: to design specific bifunctional molecule, chemists would use small-molecule binders that are already known to both 1) engage the desired targets without altering their activity substantially, and 2) contain a position at which a long, flexible linker can be attached without disrupting binding. Such a modular, “plug and play” type of system can make the syntheses of these types of compounds more efficient ( page 6, 4th paragraph).
Thus, designing a specific bifunctional molecule by choosing certain protein binding ligands and connecting them via linker, pursue the same goals - modulation of protein proximity and inducement of the desired action (degradation, inhibition, protein–protein interaction disruption etc.) and does not change “principle of operation” of bifunctional molecules.
With regards to the argument about motivation to link AMPK with another enzyme through a bifunctional molecule, prior art teaches bifunctional molecules designed for variety of functions, such as degradation, inhibition, protein–protein interaction disruption etc., the motivation “to try” to build a bifunctional molecule using known small-molecule binders, known linker and known electrophilic reactive group, incorporated into the molecule for known reason (enhance drug accumulation and target engagement in cells) is a reasonable motivation in search of compound possessing similar or better desired properties, such as protein-protein interaction. MPEP 2145.X(B): An "obvious to try" rationale may support a conclusion that a claim would have been obvious where one skilled in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. "[A] person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense.
Regarding the argument about predictability in creating AMPK-targeting bifunctional molecules, MPEP 2144.08.II states:[…]However, obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). The reasonable expectation of success of building a bifunctional molecule connecting two certain protein binding ligands is addressed above (see the rejection section).
Conclusion
Claims 1, 2, 4, 6 and 12 – 14 are rejected. 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.
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/E.V.V./ Examiner, Art Unit 1691
/SAVITHA M RAO/ Primary Examiner, Art Unit 1691
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