Detailed Action
The present office action is in response to the amendments filed on 05 Sep 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 33-35 and 37-45 of the pending application have been examined on the merits. Claims 1-12 of the pending application remain withdrawn. Claims 46-47 of the pending application are newly withdrawn (see “Response to Applicant Elections” below). Acknowledgement is made of the cancelation of claims 13-32 and 36.
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.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 21 May 2025, 27 Jun 2025, and 11 Nov 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
In the amendments filed 05 Sep 2025, 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 compound 1,1-bis(3'-indolyl)-1-(4-chloro-3-trifluoromethylphenyl)methane (3-CF3-4-Cl) in claim 37 (below) which reads on claims 33-35 and 37-45. This search retrieved prior art.
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During the search, additional art relevant to the claims addressing species where the phenyl ring has two or more of the claimed substituents was discovered. Rejections set forth below with regards to this additionally discovered art are included below.
Response to Applicant Arguments
Acknowledgement is made of the amendments filed 05 Sep 2025.
The objection to the title of the application is withdrawn following applicant amendments.
The objection to the disclosure is rendered moot following applicant amendments.
The rejection of claims 33-45 under 35 U.S.C. § 112(a) is rendered moot following applicant amendments.
The rejection of claim 35 under 35 U.S.C. § 112(d) is rendered moot following applicant amendments.
The rejection of claim 41 under 35 U.S.C. § 112(d) is withdrawn following applicant arguments.
The rejections of claims 33-45 under 35 U.S.C. § 102(a)(1) are rendered moot following applicant amendments. New grounds of rejection for claims 33-35 and 37-45, necessitated by applicant amendments, may be found below.
The anticipatory-type nonstatutory double patenting rejections of claims 33-45 are rendered moot following applicant amendments.
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.
Claim 33 is 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.
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 1 recites the broad recitation "wherein R1, R2, R3, R4, and R5 are independently selected from the group consisting of H, Cl, Br, F, CH3, CF3, OCH3, and OCF3", and the claim also recites "wherein two or more of R1, R2, R3, R4, and R5 are independently selected from the group consisting of Cl, Br, F, CH3, CF3, OCH3, OCF3" 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 the rejection by clearly indicating whether the narrower limitation is meant to be exemplary or if it indicates that at least two or more of R1, R2, R3, R4, and R5 are not H. Examiner is interpreting claim 33 to mean that at least two or more of R1, R2, R3, R4, and R5 are not H for the purposes of applying prior art.
Claim Rejections - 35 USC § 102
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.
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 33-35, 37-38, and 40-45 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Li et al. (Chem Biol Drug Des, 2019, 94:1711-1720; provided in IDS 08/10/23), hereinafter Li.
The instant claims are drawn to bis-indole compounds of the following generic formula (claim 33):
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Examiner has expanded the Markush search to include 1,1-bis(3'-indolyl)-1-(4-chloro-3 trifluoromethylphenyl)methane (3-CF3-4-Cl) which reads on the generic formula when R1 is H; R2 is H; R3 is Cl; R4 is CF3; and R5 is H (claim 37). Further limitations of the instant claims include ability to bind NR4A1 or NR4A2 (claim 34), the ability of the compound to induce activity in a cell (claim 35), the ability of the compound to perform a function in cells (claims 38 and 44), and limitations related to the type of cells the activity is performed in (claims 40-43 and 45).
Li teaches six analogs that are NR4A2 agonists, including 1,1-bis(3'-indolyl)-1-(3-trifluoromethyl-4-chlorophenyl)methane (3-CF3-4-Cl) which is identified by the following structure (pg. 1713, column 1):
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where X is Cl, R1 is CF3, and R2 and R3 are H. Li further teaches that Panc1 and Panc28 are pancreatic cancer cell lines which express NR4A2 and that 3-CF3-4-Cl activated NR4A2 in both Panc1 and Panc28 cells (pg. 1713 column 1; pg. 1714, Fig. 1). Therefore, Li anticipates the instant claims.
Claim(s) 33, 35, 38, 41-42, and 45 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Maciejewska et al. (Eur J Med Chem, 2009, 44:4136-4147; provided in IDS 11/11/25), hereinafter Maciejewska. During the search, additional art relevant to the claims addressing species where the phenyl ring has two or more of the claimed substituents was discovered. A rejection is set forth below with regards to this additionally discovered art.
Maciejewska teaches compound 1c (pg. 4137, column 1):
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Maciejewska further teaches that compound 1c was evaluated against nine cancer cell lines and moderately inhibited growth of renal cancer cell line UO-31 (pg. 4141, column 1). Therefore, Maciejewska anticipates the instant claims.
Claim(s) 33-35, 38, 40-45 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO 2019/183527, hereinafter ‘527. ‘527 was published 26 Sep 2019 and claims priority to U.S. Provisional Application No. 63/646,841, filed 22 Mar 2018. During the search, additional art relevant to the claims addressing species where the phenyl ring has two or more of the claimed substituents was discovered. A rejection is set forth below with regards to this additionally discovered art.
‘527 teaches compound 103 (pg. 136, Example 107):
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and its non-oxidized counterpart, compound 103a (paragraph [00308]-[00309]). ‘527 teaches that both compounds 103 and 103a inhibit the growth of HCT116 colon cancer cells (paragraph [00309]). ‘527 further teaches that the compounds of the disclosure are modulators of the Nur77 (paragraph [004]), which the instant specification recognizes as a synonym for NR4A1 (instant specification, paragraph [0027]). Therefore, ‘527 anticipates the instant claims.
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) 33-35 and 37-45 is/are rejected under 35 U.S.C. 103 as being unpatentable over ‘527 further in view of Wilcken et al. (J Med Chem, 2013, 56:1363-1388), hereinafter Wilcken, and Chang et al. (J Surg Oncol, 2011, 103:442-450), hereinafter Chang. ‘527
‘527 teaches compound 103 (pg. 136, Example 107):
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and its non-oxidized counterpart, compound 103a (paragraph [00308]-[00309]). ‘527 teaches that both compounds 103 and 103a inhibit the growth of HCT116 colon cancer cells (paragraph [00309]). ‘527 further teaches that the compounds of the disclosure are modulators of the Nur77 (paragraph [004]), which the instant specification recognizes as a synonym for NR4A1 (instant specification, paragraph [0027]). ‘527 also teaches compound 5 (pg. 93, Example 9) and its non-oxidized counterpart, compound 5a (paragraphs [00308]-[00309]):
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Compound 103a differs from the instant compound in two ways. First, the CF3 is in the para- position on the phenyl moiety instead of the meta- position. Second, compound 103a has a fluorine where the instant compound has a chlorine. Further, ‘527 does not teach treating glioblastoma cells with compound 103a.
Wilcken teaches that halogens, especially the lighter fluorine and chlorine, are widely used substituents in medicinal chemistry (pg. 1363, column 1) and that halogens can be exchanged to modify the σ-hole to facilitate halogen bonding with the solvent (abstract). Wilcken further teaches Cl is known to modify how the drug would interact with nucleophiles in solution (pg. 1365, column 1).
Chang teaches that glioblastoma multiform (GBM) is the most aggressive type of CNS gliomas and that Nur77-mediated apoptosis was observed in GBM cells treated with n-butylidenephthalide (pg. 442, column 1). Chang teaches that GBM cells treated with a derivative of n-butylidenephthalide, PCH4, Nur77 expression was increased which induced apoptosis for the GBM cells (pg. 449, column 1).
MPEP § 2144.09(II) teaches, “compound 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.”
By following the teachings of ‘527 and Wilcken, a person having ordinary skill in the art would modify compounds 103 and 103a by replacing the fluorine substituent on the phenyl group with a chlorine. There would be a reasonable expectation that Nur77 modulating activity would be retained by changing fluorine for chlorine because compounds taught by ‘527 with chlorine substituents retain activity. The artisan would be motivated to perform this change to facilitate halogen bonding with the solvent and modify how the drug interacts with nucleophiles in solution.
The artisan would further modify compounds 103 and 103a by swapping the positions of the CF3 substituent and Cl substituent to facilitate a positional isomer which has a sufficiently close structural similarity that the artisan would have a presumed expectation of the compounds having similar properties, and so arrive at the instantly claimed compound. The motivation to make the instantly claimed compound derives from the expectation that structurally similar compounds would possess similar activity (i.e., they would be pharmacologically active Nur77 modulators) with potential for better bioavailability and lower side effects. There would be a reasonable expectation of success in producing and using the instantly claimed compound in view of the compounds taught by ‘527.
By following the teachings of ‘527, Wilcken, and Chang, a person of ordinary skill in the art would produce and use the instantly claimed compounds in GBM cells to determine if modulating Nur77 would induce apoptosis. The artisan would be motivated to perform this experiment because GBM is the most aggressive type of CNS gliomas.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (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