Detailed Action
The present office action is in response to the amendments filed on 01 Apr 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 33-34 and 43-44 of the pending application have been examined on the merits. Claims 1-3 and 6-12 of the pending application remain withdrawn. Acknowledgement is made of the cancellation of claims 4-5, 35-42, and 45-47.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01 Apr 2026 has been entered.
Priority
Applicants identify the instant application, Serial #: 17/631,390 filed 28 Jan 2022, as a National Stage Entry of International Patent Application #: PCT/US2020/044630, filed 31 Jul 2020, which claims priority from U.S. Provisional Application #: 62/880,801, filed 31 Jul 2019.
Response to Applicant Elections
In the amendments filed 01 Apr 2026, applicant amended claims and limited the scope to compounds that did not include the compound that was part of the expanded Markush search. Accordingly, examiner is extending the Markush search to a bis-indole-derived compound named as CDIM-3,5-Cl2 in claim 33 which Examiner is interpreting as having the following structure:
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Where R1 is H; R2 is Cl; R3 is H; R4 is Cl; and R5 is H. This search retrieved prior art.
Response to Applicant Arguments
Acknowledgement is made of the amendments filed 01 Apr 2026.
The cancellation of claims 35, 37-42, and 45 renders moot all rejections of those claims.
The rejection of claim 33 under 35 U.S.C. § 112(b) is rendered moot following applicant amendments.
The rejection of claims 33-34 and 43-44 under 35 U.S.C. § 102(a)(1) is rendered moot following applicant amendments.
The rejection of claims 33-34 and 43-44 under 35 U.S.C. § 102(a)(2) is rendered moot following applicant amendments.
The rejection of claims 33-34 and 43-44 under 35 U.S.C. § 103 is rendered moot following applicant amendments.
New grounds of rejection for claims 33-34 and 43-44, necessitated by applicant amendments, may be found below.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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) 33-34 and 43-44 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mohankumar et al. (Endocrinology, 2018, 159:1950-1963; provided in IDS 01/28/22), hereinafter Mohankumar, further in view of Nielsen et al. (Bioorg Med Chem, 2004, 12:3047-3054), hereinafter Nielsen.
The instant claims are drawn to bis-indole derived compounds with the following structure:
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where the compound is a 3,5-disubstituted analog of CDIM which is selected from CDIM-3,5-Br2, CDIM-3,5-Cl2, CDIM-3,5-(CH3)2, CDIM-3-Br-5-OCF3, CDIM-3-Br-5-OCH3, CDIM-3-Cl-5-OCH3, CDIM-3-Cl-5-OCF3, CDIM-3-Cl-5-CF3. Examiner has expanded the Markush search to CDIM-3,5-Cl2 and is interpreting CDIM-3,5-Cl2 to have the above structure where R1 is H; R2 is Cl; R3 is H; R4 is Cl; and R5 is H. The instant claims further limit the compounds to those that bind to the NR4A1 and/or NR4A2 receptors (claim 34), to compounds which are ligands of the NR4A1 or NR4A2 receptors (claim 43), and to compounds which antagonize NR4A1, target NR4A1, antagonize NR4A2, and/or target NR4A2 (claim 44).
Mohankumar teaches the NR4A1 ligand DIM-C-pPhOH which has the following structure (pg. 1953, Fig. 1C):
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Where X is -OH. Mohankumar teaches that DIM-C-pPhOH has a short serum half-life and that analogues of the above compound are more potent and these CDIM compounds are a new class of NR4A1-dependent agents that enhance glucose metabolism (pg. 1951, column 1). One of the analogues discussed is DIM-C-pPhOH-3-Cl which has a -Cl substituent on the C3 of the phenyl moiety (pg. 1953, Fig. 1C). Mohankumar teaches the variation of the C3- and C5-attached substituents to create new NR4A1 analogues which have varying activities (pg. 1951, column 1). However, DIM-C-pPhOH-3-Cl differs from the instantly elected compound in having an -OH substituent attached to C4 of the phenyl moiety instead of having a -Cl substituent attached to C5 of the phenyl moiety in the instant compound CDIM-3,5-Cl2.
Nielson teaches the development of antibacterial chalcones by modification of a substituted phenyl ring to get a diverse set of analogues based on size, lipophilicity, and electronic properties for the identification of active antibacterial compounds (pg. 3049, column 2). These substituted phenyls include substituents at the 2-, 3-, and 4-position of the phenyl, and further included 3,5-disubstituted phenyl groups (pg. 3048, Table 2; and pg. 3049, column 2). Nielson further teaches these variations include a 3,5-Di-Cl compound.
MPEP § 2144.09(I) states that a “prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities.” Further, as found in MPEP § 2144.09(III), “[p]rior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979)”
Based on the teachings of Mohankumar and Nielson, the artisan would start with the compounds of DIM-C-pPhOH and DIM-C-pPhOH-3-Cl, taught by Mohankumar, and modify the substituents on the phenyl moiety to create new NR4A1 ligands with higher serum half-lives and greater potency than DIM-C-pPhOH, as taught by Mohankumar. The artisan would create a diverse set of analogues based on size, lipophilicity, and electronic properties and use the list of phenyl substituents, taught by Nielson, with the intent to create a NR4A1 ligand. These compounds would include a 3,5-disubstituted phenyl moiety with two Cl substituents which would have the same structure as the examined compound (see above).
The motivation to make the instantly claimed compounds derives from the expectation that structurally similar compounds would possess similar activity (i.e., they would be pharmacologically NR4A1 ligands) with potential for better bioavailability and lower side effects. There would be a reasonable expectation of success in producing and using the instantly claimed compounds in view of the compounds taught by Mohankumar and Nielson.
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.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Gura et al. (Science, 1997, 278:1041-1042) is considered pertinent for teaching issues with sifting through potential anticancer agents to find promising candidates to make human clinical trials worthwhile. Kunnumakkara et al. (Exp Biol Med, 2019; 244:663-689) is considered pertinent for teaching that cancer is a large group of neoplastic diseases each caused by diverse deregulated cell signaling cascades which are difficult to treat with just a single compound.
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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/J.D.M./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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