Detailed Action
The present office action is in response to the amendments filed on 10 Jun 2026.
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
Claims 1-4, 6-11, 21-26, 28-37, and 43-45 of the pending application have been examined on the merits. Claims 5, 12-16, 18-20, 27, 38-42, and 46-57 of the instant application remain withdrawn. Acknowledgement is made of the amendments filed 10 Jun 2026. Acknowledgement is made of the cancellation of claim 17
Priority
Applicants identify the instant application, Serial #: 18/039,661 filed 31 May 2023, as a National Stage Entry of International Patent Application #: PCT/US2021/061720, filed 03 Dec 2021, which claims priority from U.S. Provisional Application #: 63/121,058, filed 03 Dec 2020.
Response to Applicant Arguments
Acknowledgement is made of the reply filed 10 Jun 2026.
The objections to claims 21-22 are rendered moot following applicant amendments.
The rejection of claim 7 is rendered moot following applicant cancellation of the claim.
The rejection of claims 1-4, 6-11, 17, 21-26, 28-37, and 44-45 under 112(a) is rendered moot following applicant amendments.
The rejection of claims 2, 6, 8-9, 21-25, and 29-37 under 112(b) is rendered moot following applicant amendments.
Applicant arguments regarding the rejection of claims 1-4, 6-11, 21-26, 28-37, and 43-45 under 35 U.S.C. § 103 over Bondeson et al (Nat Chem Biol, 2015, 11:611-618), hereinafter Bondeson, further in view of Bullock et al. (Oncotarget, 2015, 6:34057-34058), hereinafter Bullock, Degterev et al. (PNAS, 2019, 116:9714-9722), hereinafter Degterev, Li et al. (J Med Chem, 2018, 61:11398-11414; provided in IDS 04/19/2024), hereinafter Li, Goracci et al. (J Med Chem, 2020, 63:11615-11638), hereinafter Goracci, and Cyrus et al. (Mol BioSyst, 2011, 7:359-364), hereinafter Cyrus, have been fully considered but are not persuasive.
On pages 70-71 the remarks filed 10 Jun 2026, applicant argues that the above references directly refute the predictability that the person of ordinary skill in the art would have in creating the instantly elected compound. Applicant argues that both Goracci and Cyrus teach away from the combination of references and speak to the unpredictability of the art. Goracci teaches that the results of the experiment found in the reference indicate that the metabolism of PROTACs could not be predicted from that of their constituent parts (Abstract). Applicant further argues that Goracci teaches PROTAC compounds as entirely discreet entities whose metabolism cannot be predicted from any one of the ligands used for the design and synthesis (pg. 11623, column 2). Applicant further argues that Cyrus explicitly notes that PROTAC design lacks universal, generalized methodologies and that PROTACs are currently prepared on a case-by-case basis without a general design strategy for optimum PROTACs (Abstract and pg. 360, column 1).
This is not persuasive. Goracci is relied on for teaching a toolbox allowing for the exploration of ADME properties for PROTAC compounds (see below). Goracci further teaches experimenting to determine properties of PROTAC compounds and, while success is not guaranteed, the artisan would have a reasonable expectation of success to use the tools found in Goracci and Cyrus to arrive at the instantly elected compound’s E3 ubiquitin ligase moiety and the linker. Cyrus teaches that despite the promising potential of PROTACs there design has not been generalized for broad application. Cyrus also teaches, however, that the teachings of the reference are the first generalized approach for PROTAC design by fine-tuning distance and that the information gathered offers a generalizable PROTAC design strategy (Abstract). Further Cyrus teaches that the experiments of the reference suggest a genenral strategy to prepare optimum PROTACs by appropriately spacing and orienting the two partner proteins, the ligand and the E3 ubiquitin ligase (pg. 363, column 1). Thus there is a generalized approach taught by Cyrus which involves iterating with known linkers and E3 ubiquitin ligase moieties to optimize for PROTAC ADME properties, as further taught by Goracci.
On pages 71-72 of the remarks, applicant argues that Li demonstrates the standalone structures are highly potent and selective for RIPK and the artisan would not select the inhibitor like Compound 22b, taught by Li, and hope to preserve its activity. Applicant argues that covalently appending a bulky chemical linker group and E3 ubiquitin ligase alters spatial orientation, electronic density, and binding conformation of the parent molecule and that the artisan would recognize converting the kinase inhibitor of Li into a bulky compound would disrupt binding properties.
This is not persuasive. Applicant does not provide evidence that the art teaches away from the combination of references. Applicant arguments are not a replacement for evidence where evidence is needed. See MPEP § 2145(I).
On page 72 of the remarks, applicant argues that the rejection depends on a combination of six references to assemble the instantly elected compound and that this only could have been done using the instant disclosure as a blueprint for the rejection.
This is not persuasive. In response to applicant’s argument that the examiner’s conclusion of obviousness is based on improper hindsight reasoning, it must be recognized that any judgement on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill before the time of the claimed invention’s effective filing date, and does not include knowledge gleaned only from the applicant’s disclosure, such a reconstruction is proper. See MPEP § 2145(X).
In light of the discussion above, the rejection of claims 1-4, 6-11, 21-26, 28-37, and 43-45 under 35 U.S.C. § 103 as obvious over Bondeson, Bullock, Deterev, Li, Goracci, and Cyrus is maintained for the reasons of record and restated below
The new grounds of rejection for claims 1-4, 6-10, 21-26, 28-37, and 44-45 under 35 U.S.C. § 112 (see “Improper Markush Grouping Rejection” below) is necessitated by applicant amendment.
Improper Markush Grouping Rejection
Claims 1-4, 6-10, 21-26, 28-37, and 44-45 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of Ring A, Ring B, and Ring C of formula TPM-1:
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is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: The claims define Ring A, Ring B, and Ring C as being independently an aryl ring, a heteroaryl ring, a cycloalkyl, or a heterocycloalkyl ring. The specification defines cycloalkyl rings as including cyclic alkyl groups having a single cyclic ring or multiple condensed rings (pg. 94, lines 19-20); heterocycloalkyl rings are defined as cycloalkyl rings but can contain O, S, or N heteroatoms within the cyclic backbone (pg. 95, lines 1-3); aryl rings as including cyclic hydrocarbons that incorporate one or more planar sets of, typically, six carbon atoms that are connected by delocalized electrons numbering the same as if they consisted of alternating single and double covalent bonds and can include additional fused rings (pg. 95, lines 9-11 and lines 16-17); and heteroaryl rings as including substitutions along their main cyclic chain of atoms such as O, N, or S and can include additional fused rings (pg. 95, lines 12-13 and lines 16-17). The variability of the definitions for each of the rings in the claimed structure of formula TPM-1 results in there being no shared structural similarity that a person of ordinary skill in the art would recognize. Further, based on the breadth of the structures claimed, the artisan would have no reasonable expectation of success that all compounds claimed would have the same use. Claims 2-4,6-10, 21-26, 28-37, and 44-45 are rejected for failing to remedy the deficiencies of claim 1.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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.
Claim(s) 1-4, 6-11, 17, 21-26, 28-37, and 43-45 is/are rejected under 35 U.S.C. § 103 as being unpatentable over Bondeson et al (Nat Chem Biol, 2015, 11:611-618), hereinafter Bondeson, further in view of Bullock et al. (Oncotarget, 2015, 6:34057-34058), hereinafter Bullock, Degterev et al. (PNAS, 2019, 116:9714-9722), hereinafter Degterev, Li et al. (J Med Chem, 2018, 61:11398-11414; provided in IDS 04/19/2024), hereinafter Li, Goracci et al. (J Med Chem, 2020, 63:11615-11638), hereinafter Goracci, and Cyrus et al. (Mol BioSyst, 2011, 7:359-364), hereinafter Cyrus.
Applicant elected the following species in the reply filed 01 Dec 2025:
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Applicant further claims pharmaceutical compositions comprising the elected species and a pharmaceutically acceptable carrier. Applicant claims a kit comprising the elected species and a pharmaceutically acceptable carrier.
Bondeson teaches the following RIPK2 targeting PROTAC compound (pg. 612, Fig. 1):
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Bondeson teaches that RIPK2 is a serine-threonine kinase and is an important mediator of innate immune signaling (pg. 612, column 1). Bondeson further teaches varying RIPK2 inhibitors, linkers, and VHL-binding ligands to optimize the degradation effects of RIPK2 (pg. 612, column 1). Bondeson further teaches preparing a composition of RIPK2 PROTAC compound in growth medium as a carrier (pg. 618, column 2). However, Bondeson does not teach the instantly elected compound.
Bullock teaches that RIPK1, RIPK2, RIPK3, and RIPK7 are all members of a serine/threonine and tyrosine kinase class which have been implicated in human disease (pg. 34057, column 1). Bullock further teaches that cellular pathways regulated by RIPK1/3 and RIPK2 are relevant for the development of new therapeutic approaches against human inflammatory pathologies (pg. 34057, column 1). Bullock teaches that RIPK1 and RIPK3 play a role in a poorly understood cell death-independent regulation by these kinases (pg. 34057, column 1). Bullock teaches that all RIPK1, RIPK2, and RIPK3 may represent drug-targetable kinase activities contributing to an overlapping range of inflammatory pathologies associated with perturbations in the human microbiome (pg. 34057, column 2).
Degterev teaches that understanding the modalities of RIPK1 involvement in different diseases is important for uncovering pathophysiology of human diseases and development of the specific predictive biomarkers of the drug responses (pg. 9721, columns 1-2).
Li teaches compounds 22a-f which are RIPK1 inhibitors with selective activity towards RIPK1 (pg. 11403, column 1; pg. 11404, column 1). Compounds 22a-f align with the RIPK1 binding moiety of the instantly elected compound (circled below):
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Goracci teaches that proteolysis targeting chimeras (PROTACS) are hetero-bifunctional molecules that induce a ligand to bind with the protein of interest, another ligand to recruit an E3 ubiquitin ligase, and a linker to concatenate the two ligands (pg. 11615). Goracci teaches that PROTACs can degrade proteins in a catalytic manner and open a new therapeutic modality (pg. 11615, column 2). Goracci teaches that better understanding of ADME properties of PROTACs are needed to better enable rational design of these molecules (pg. 11616, column 1). Goracci teaches a data set of two E3 ligase ligands, nineteen linkers, and four target proteins to gain insight into ADME properties of PROTACs (pg. 11619, column 1; pg. 11621, Fig. 1). Included in the data set in the linker of the instant compound and the E3 ubiquitin ligase binding moiety of the instant compound (circled below):
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Cyrus teaches experimenting with the linker length and connectivity of PROTAC molecules to identify the optimal conditions for efficacy of the compound (Abstract). Cyrus further teaches alkyl linkers with the same attachment group as the instantly elected compound (pg. 361, column 1) (circled below):
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Based on the teachings of Bondeson, Bullock, Degterev, Li, Goracci, and Cyrus, a person of ordinary skill in the art would modify the RIPK2 targeting PROTAC, taught in Bondeson, to create a RIPK1 targeting compound with the same target protein binding moiety, taught in Li, as the instant claims, as well as the same linker, taught in Goracci and Cyrus, and the same E3 ligase binding moiety, taught in Goracci, as the instantly elected compound. The artisan would be motivated to target RIPK1 to understand the modalities of RIPK1 in human disease, as taught by Degeterev, and to better understand how RIPK1 effects necrotic cell death, as taught by Bullock. The artisan would be motivated to use the compounds taught by Li because of their excellent binding to RIPK1 and selectivity for RIPK1 over other kinases, as taught by Li. The artisan would further modify the linker and VHL-binding ligand, as taught by Goracci, to determine the best ADME properties of the PROTAC compound. The artisan would further experiment with the connectivity between the linker and ligands and the spacers between the linker and ligands to identify the optimal conditions for efficacy of the compound, as taught by Cyrus. Taking the art into account, a person of ordinary skill in the art would arrive at compounds of the instant claims.
MPEP § 2112.01 states, “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).” The kit of the instant claims and the compound taught by Bondeson, Bullock, Degterev, Li, Goracci, and Cyrus are identical and thus the art teaches a kit of the instantly elected compound.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was 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
No claim is allowed. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jonathan D. Mahlum whose telephone number is (703)756-4691. The examiner can normally be reached 8:30 AM - 5:00 PM ET, M-F.
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/J.D.M./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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