Detailed Action
The present office action is in response to the reply filed on 01 Dec 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
Claims 1-4, 6-11, 17, 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 Claims 5, 12-16, 18-20, 27, 38-42, and 46-57 of the instant application are withdrawn (see “Response to Applicant Elections” below).
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.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 19 Apr 2024 and 06 Jun 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Applicant Elections
Acknowledgement is made of the reply filed 01 Dec 2025.
Applicant's election with traverse of Group I, claims 1-45, and the species of Compound 5 (below) in the reply filed on 01 Dec 2025 is acknowledged. A search revealed prior art for the elected species.
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The traversal is on following grounds:
Applicant argues that the Office has not shown a serious burden would be required to examine all of the pending claims (pg. 2).
This is not found persuasive because the instant application is subject to the “Unity of Invention” restriction standard and not the “Independent and Distinct/Undue Search Burden” restriction standard. Examiner respectfully reminds applicant that, as set forth in Rule 13.1 of the Patent Cooperation Treaty (PCT), "the international application shall relate to one invention only or to a group of inventions so linked as to form a single general inventive concept.” Moreover, as stated in PCT Rule 13.2, "where a group of inventions is claimed in one and the same international application, the requirement of unity of invention referred to in Rule 13.1 shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features." Furthermore, Rule 13.2 defines "special technical features" as "those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art."
Applicant argues a lack of unity was not raised in the examination of the priority PCT application and was searched together in the PCT application. Applicant argues this is evidence that the claims have unity of invention (pg. 2).
This is not persuasive. See MPEP § 1893.03(d) which states that the "examiner may make a lack of unity requirement in a national stage application even if no such requirement was made by the ISA or IPEA."
Applicant argues that the claims of Group II depend from the claims of Group I and that the compounds of both Groups are the same (pg. 2).
This is not persuasive. While the groups are linked by the technical feature of Formula (I), the groups are drawn to different categories of inventions. See 37 CFR 1.475(b)(2). See also the restriction requirement mailed 01 Oct 2025.
Applicant further argues the species election should be reconsidered because the Office has not shown a serious burden would be required to examine more than one species of compound (pg. 3).
This is not found persuasive because the instant application is subject to the “Unity of Invention” restriction standard and not the “Independent and Distinct/Undue Search Burden” restriction standard. Examiner respectfully reminds applicant that, as set forth in Rule 13.1 of the Patent Cooperation Treaty (PCT), "the international application shall relate to one invention only or to a group of inventions so linked as to form a single general inventive concept.” Moreover, as stated in PCT Rule 13.2, "where a group of inventions is claimed in one and the same international application, the requirement of unity of invention referred to in Rule 13.1 shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features." Furthermore, Rule 13.2 defines "special technical features" as "those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art."
Applicant further argues that the compound encompassed by the genus recited in claim 1 share a common structural moiety (pg. 3).
This is not persuasive. See the restriction requirement mailed 01 Oct 2025 which shows that the compounds of Formula (I) do not share a common structural moiety and further that the compounds of Formula (I) are defined by function with no significant structure shared by the species.
The requirement is still deemed proper and is therefore made FINAL.
Claims 46-57 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected group, there being no allowable generic or linking claim.
Claims 5, 12-16, 18-20, 27, and 38-42 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.
Applicant timely traversed the restriction (election) requirement in the reply filed on 01 Dec 2025.
Claim Objections
Claim 21 is objected to because of the following informalities: claim 21 includes the definition of the variable T twice. Appropriate correction is required.
Claim 22 is objected to because of the following informalities: claim 22 includes the phrase “wherein R14a, R14b, are independently…” This should be “wherein R14a and R14b- are independently…” Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 6-11, 17, 21-26, 28-37, and 44-45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 claims compounds with the structure TPM-L-ELM where TPM is a targeting protein binding moiety, L is a bond or chemical linker, and ELM is an E3 ubiquitin ligase binding moiety. However, it is not clear that applicant had possession of all ELMs and TPMs at the time of filing.
Applicant does provide support for ELMs that bind VHL, cereblon, and MDM2, but a person of skill in the art would recognize the breadth of ELMs in the art which are not described in the disclosure. Examiner cites Li et al. (PloS One, 2008, 3:e1487), hereinafter Li (2008), for evidence of the state of the art. Li (2008), cited for evidence, teaches there are potentially upwards of 600 genes encoding putative E3s and substrate recognition subunits of multimeric E3 complexes (pg. 10, column 2). There is nothing found in the specification to suggest the claims cover even a small portion of E3 ubiquitin ligases.
Further, there is ample evidence in the disclosure for the artisan to conclude that applicant had possession of TPMs with the structures of TPM-1 and TPM-2 at the time of filing (see structures below), but there is nothing in the specification to lead the artisan to believe that applicant had possession of all TPMs.
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Examiner cites Tan et al. (Chin J Chem, 2018, 36:971-977), hereinafter Tan, as evidence of the state of the art. Tan, cited for evidence, teaches multiple PROTAC molecules which have targeting protein binding moieties which do not fall under the structures of TPM-1 and TPM-2 (pg. 973, Fig. 2). Based on the disclosure, a person of skill in the art would not think applicant has possession of all TPMs at the time of filing.
Claims 2-4, 6-11, 17, 21-26, 28-37, and 44-45 are rejected for failing to remedy the deficiencies of claim 1. Accordingly, the instant claims do not comply with the written description requirement of 35 U.S.C. § 112(a), since to practice the claimed invention a person of ordinary skill in the art would be left unconvinced that applicant had possession of all ELMs and TPMs.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 6, 8-9, 21-25, and 29-37 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 2, 8, 9, 22-25, 30, 33, and 35-37 contain Markush groupings which do not have the coordinating conjunctions “and” or “or” to properly limit the alternatives defined in the list. See MPEP § 2117(I). Applicant may overcome this rejection by adding the proper coordinating conjunction to each Markush group in need of one and ensuring that all Markush groupings with coordinating conjunctions have the correct one. Examiner requests applicant ensure that all other claims have the correct coordinating conjunctions for each Markush grouping.
Regarding claim 21, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 21 recites the broad recitation “wherein the RY3 and RY4 groups are optionally substituted by 0-3 Rp groups” and the claim also recites “wherein Rp is one to three groups” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Applicant may overcome this rejection by striking one of the definitions from the claim.
Regarding claims 29-34, claim 29 recites the limitation "The compound of claim 28, wherein L is represented by the formula -(AL)-". -(AL)- is not found in claim 28, from which claim 29 depends. There is insufficient antecedent basis for this limitation in the claim. Claims 30-34 are rejected as they do not remedy the deficiencies of claim 29. Applicant may overcome this rejection by amending to clarify where -(AL)- is found in the claims.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 6 is dependent on claim 2.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached on (571) 272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.D.M./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625