DETAILED ACTION
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 3-4, 14-16, 19-20, 25, 31, 33, 43, 48, 52, 54, 63-67, 69, 73, 76, 79-80 and 102 are pending in the application as of the response filed 04/24/2026. Claims 1-2, 5-13, 17-18, 21-24, 26-30, 32, 34-42, 44-47, 49-51, 53, 55-62, 68, 70-72, 74-75, 77-78 and 81-101 are cancelled. Applicant’s original election of group I claims and the elected species is maintained. Claims 19-20, 43, 48, 52, 54, 63, 65-67, 73, 76, 79-80 and 102 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 3-4, 14-16, 25, 31, 33, 64 and 69 are examined herein.
The claim amendments overcome the 35 U.S.C. §102 rejections of record over the Database Registry compounds, as in sections #6 to #13 of the Office action dated 01/26/2026.The 35 U.S.C. §102 rejections of record over the Database Registry compounds are hereby withdrawn.
The claim amendments overcome the 35 U.S.C. §102 rejections of record over Marsilje (#14), Park (#15) and Goldstein (#16) in the Office action dated 01/26/2026. The 35 U.S.C. §102 rejections of record over Marsilje, Park and Goldstein are hereby withdrawn.
The claim amendments overcome the 35 U.S.C. §103 rejection of record over Dyckman since there are at least two changes in going from compound 257 of Dyckman to obtain the instantly elected species of compound or the compounds of the instant invention (the compounds of Dyckman do not satisfy the requirement of the instant claims with respect to R2 being methyl, Y being attached to the 6-position of the indole nucleus and/or R1 as amended cannot be phenyl). Thus, the 35 U.S.C. §103 rejection of record over Dyckman is hereby withdrawn.
In view of the pending claims, a new ground of rejection is made necessitated by the claim amendments and based on a reference cited in the IDS filed on 04/24/2026.
The nonstatutory double patenting rejections of record are maintained and updated to reflect the claim amendments in the instant and co-pending applications.
Applicant’s arguments have been fully considered and was found to be partially persuasive, as is reflected in the withdrawn rejections. Applicant’s arguments have been addressed to the extent to which they apply to the new rejections.
Information Disclosure Statement
The information disclosure statement submitted on 04/24/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Interpretation
Claim 3 recites certain functional groups within the definition of Y are optionally substituted with one Z group and certain functional groups within the definition of Z are optionally substituted with 1-3 groups selected from -OH, halogen, -CN, oxo, -NR11R11, C1-4 alkoxy and C1-5 alkyl. However, claims 31 and 33, do not require Z or the optional substituents to actually be present in the compound, they simply define what Z or the optional substituent must be if present in the compound.
Claim Rejections - 35 USC § 103
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 3-4, 14-16, 31, 33 and 69 are rejected under 35 U.S.C. 103 as being unpatentable over Dyckman et al. (CN 111448190 A, publication date 24 July 2020, hereinafter Dyckman ‘190, in the IDS dated 04/24/2026) (citations are made to the attached English translation).
Regarding instant claim 3, Dyckman ‘190 teaches substituted indole compounds of formula (I) or salts thereof, for use as inhibitors of signaling through Toll-like receptor 7, or 8, or 9 and pharmaceutical compositions comprising such compounds and a pharmaceutically acceptable carrier (Pg. 1, last two paragraphs; Pg. 2, fifth full paragraph).
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Dyckman ‘190 teaches the following exemplary compounds, compound 52, compound 55 (Pg. 42, Table 1) and compound 666 (Pg. 135) with TLR7, TLR8, TLR9 activity (Pgs. 169-170; Pg. 174).
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Compounds 52 and 55 of Dyckman ‘190 overlaps the scope of Formula I as in instant claim 3 wherein,
R1 is 9 membered fused bicyclic heteroaryl;
R2 is methyl;
X1 and X3 are each CR3, R3 being H;
X2 is CH;
Y is a 6 membered monocyclic heterocyclyl (piperidinyl);
which satisfies the proviso that wherein each 8-10 membered fused bicyclic heteroaryl independently have 1-4 ring heteroatoms independently selected from N, O, and S;
which satisfies the proviso that wherein 5-7 membered monocyclic heterocyclyl independently have 1-2 ring heteroatoms independently selected from N, O, and S.
Compound 666 of Dyckman ‘190 overlaps the scope of Formula I as in instant claim 3 wherein,
R1 is 10 membered fused bicyclic heteroaryl (quinolinyl);
R2 is methyl;
X1 and X3 are each CR3, R3 being H;
X2 is CH;
Y is a 6 membered monocyclic heterocyclyl (piperidinyl) substituted with 1 C1-5 alkyl (ethyl), wherein the C1-5 alkyl is substituted with 1 Rc, Rc being NR12R12, R12 is independently H and C1-3 alkyl (methyl);
which satisfies the proviso that wherein each 8-10 membered fused bicyclic heteroaryl independently have 1-4 ring heteroatoms independently selected from N, O, and S;
which satisfies the proviso that wherein 5-7 membered monocyclic heterocyclyl independently have 1-2 ring heteroatoms independently selected from N, O, and S.
Compounds 52, 55 and 666 of Dyckman ‘190 differs from the instant compounds of Formula I with respect to the position of attachment of the “Y” group in the 5- position versus the instantly claimed 6-position of the indole nucleus.
According to MPEP 2144.09 (II), “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). In the instant case, the compounds of the instant invention are taught to be inhibitors of Toll-like receptors (TLRs) TLR7, TLR8 and TLR9 (Para. [0003]; Paras. [0006]-[0011]). The compounds of Dyckman ‘190 are taught to be inhibitors of signaling through Toll-like receptor 7, or 8, or 9 (Pg. 1, last paragraph; Pgs. 169-170 showing IC50 values). Here, the cited positional isomers of Dyckman ‘190 are so close in structure that, correspondingly, the instant compounds would be expected to have very similar or identical utilities and functional properties, rendering them prima facie obvious.
It would have been prima facie obvious to one of ordinary skill in the art before
the effective filing date of the claimed invention in view of the teachings of Dyckman ‘190, to have arrived at the closely-structurally-related compounds of the instant claims. Dyckman ‘190 teaches substituted indole compounds of formula (I) or salts thereof, for use as inhibitors of signaling through Toll-like receptor 7, or 8, or 9. The compounds of Dyckman ‘190 are positional isomers of the instant compounds. The compounds of Dyckman ‘190 and the instantly claimed compounds act as inhibitors of Toll-like receptors TLR7, TLR8 and TLR9. Therefore, one of ordinary skill in the art would be motivated to synthesize the positional isomers of Dyckman ‘190 to obtain the instantly claimed compounds with a reasonable expectation that the resultant compounds would exhibit Toll-like receptors (TLR7, TLR8 and TLR9) inhibitory activity. The motivation being to provide additional candidates for further pharmacological and/or commercial development.
Compounds 52 and 55 of Dyckman ‘190 renders the compounds of instant claims 3, 14-16, 31, 33, prima facie obvious. Compound 666 of Dyckman ‘190 renders the compounds of instant claims 3-4, 14-16, 31, 33, prima facie obvious. Dyckman ‘190 renders the pharmaceutical composition of instant claim 69 prima facie obvious.
Response to Arguments
Applicants argue on pages 30-31 of the remarks dated 04/24/2026, that “Specifically, the presently claimed compounds bear substituents at the 6-position of the indole as shown below (i.e., the same plane as the nitrogen of the indole), whereas the Dyckman compounds bear substituents at the 5-position (i.e., the opposite plane of the nitrogen of the indole)”. Applicants argue “To support Applicants' argument regarding the lack of expectation of success of positional isomers of indoles, the literature provides further evidence that moving a substituent from the 5-position to the 6-position (or more generally changing the position of a substituent on the indole core) can change biological activity - and sometimes substantially so”, citing to exhibits A and B.
Applicant's arguments have been fully considered but they are not persuasive.
While the examiner does not dispute that the compounds of Dyckman ‘190 bear substituents at the 5-position of the indole nucleus versus the instantly claimed compounds that bear substituents at the 6-position of the indole nucleus, the examiner notes that exhibit A cited by Applicant teaches GPR17 agonists having an indole core, while the instant compounds are toll-like receptor inhibitors. Generally speaking, structure-activity relationships (SAR) for one target (GPR17) do not reliably predict SAR for an entirely different target (TLR7/8/9). SAR is highly target-specific because the binding pockets, active sites, and biological mechanisms of G protein-coupled receptors (GPCRs) differ fundamentally from those of toll-like receptors (TLRs). Here, the change in substituent position from a 5- to 6-position on the indole core may sufficiently alter the spatial arrangement to selectively bind to the structurally similar yet distinct binding cavity of the TLR 7, 8, 9 domains. Moreover, exhibit B generically discusses substitutions and activities of indole scaffolds towards their pharmacological activity. Exhibit B highlights indole derivatives as an important scaffold for the development of new and efficient drugs with low toxicity. The exhibits do not conclusively demonstrate favored substituent positions on the indole nucleus with respect to toll-like receptor inhibitory activity, nor do they discourage any of the substituent positions.
Regarding Applicant’s contention of lack of expectation of success of positional isomers of indoles, according to MPEP 2143.02(I), “The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016) … Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019)”.
It is known to a person of ordinary skill in the field of drug discovery that exploring positional isomers is a highly effective and widely used strategy by medicinal chemists. In the instant case, as discussed above, the exemplary compounds of Dyckman ‘190 are taught to have toll-like receptor (TLR) TLR7, TLR8 and TLR9 inhibitory activity, identical to the activity of the instant compounds. Further, the compounds of Dyckman ‘190 are taught to be effective in the treatment of inflammatory diseases (Pg. 1, second to last paragraph), similar to the instant compounds (Para. [0012] of the instant specification). Therefore, one of ordinary skill in the art would be motivated to modify the exemplary compounds of Dyckman (by synthesizing positional isomers) to obtain the instantly claimed compounds with a reasonable expectation of success.
Further, according to MPEP 2145(I), “Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). In the instant case, Applicant’s arguments do not conclusively demonstrate that there would have been no reasonable expectation of success.
Applicants are encouraged to provide a clear and convincing evidence of nonobviousness or unexpected results in light of the prior art (i.e., unexpected TLR 7/8/9 activity for the compounds having substituents in the 6-position of the indole nucleus versus 5-position), to overcome the 35 U.S.C. 103 rejection of record.
Double Patenting – Maintained and modified
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 3, 14-16, 25, 31, 33 and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3, 8, 52-53 and 86 of co-pending Application No 18/268,440.
Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims are drawn to compounds having similar core structures.
The claims of the instant application are drawn to a compound of Formula I with variables as defined in instant claim 3 and a pharmaceutical composition thereof.
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The claims of the reference ‘440 application are drawn to a compound of Formula I with variables as defined in instant claim 3 of the reference application and a pharmaceutical composition thereof.
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There is considerable overlap in scope of the claims between the reference ‘440 application and the instant claims, rendering the instant claims prima facie obvious. Specifically, the following compounds of claim 52 (Pg. 7 of claim set dated 05/06/2026) of the reference ‘440 application anticipates the compound of Formula I of instant claim 3.
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The above compounds anticipate the compound of Formula I of instant claim 3, wherein
R1 is a 6 membered monocyclic heterocyclyl or 10-membered fused bicyclic heterocyclyl;
R2 is C1 alkyl (methyl);
X1 is CR3, R3 being H;
X2 is CH;
X3 is CR3, R3 being H;
Y is a 6 membered monocyclic heteroaryl substituted with two C1 alkyl (methyl);
which satisfies the proviso that wherein each 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heterocyclyl independently have 1-4 ring heteroatoms independently selected from N, O, and S;
which satisfies the proviso that wherein 5-7 membered monocyclic heterocyclyl independently have 1-2 ring heteroatoms independently selected from N, O, and S.
Claim 86 of the reference ‘440 application anticipates instant claim 69 drawn to a pharmaceutical composition.
The instant claims 3, 14-16, 25, 31, 33 and 69 and the claims 3, 8, 52-53 and 86 of the reference co-pending Application No 18/268,440 are therefore not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicants argue on page 31 of the remarks dated 09/16/2024 that 04/24/2026 that “Claim 3 was not rejected in the ODP rejection. As such, the present claims are patentable over co-pending Application No. 18/268,440, and the rejection should be withdrawn”.
Applicant's arguments have been fully considered but they are not persuasive.
The examiner notes that claim 3 has been amended in this response and the scope of claim 3 has changed. Moreover, as discussed in the provisional nonstatutory double patenting rejection above, the species of compounds of claim 52 of the reference ‘440 application anticipates the compound of Formula I of instant claim 3. Therefore, the nonstatutory double patenting rejection over co-pending Application No. 18/268,440 is maintained.
Allowable subject matter
Claim 64 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 3-4, 14-16, 25, 31, 33 and 69 are rejected.
Claim 64 is objected to.
Applicant's amendment and submission of an information disclosure statement under 37 CFR 1.97(c) with the timing fee set forth in 37 CFR 1.17(p) on 04/24/2026 prompted the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 609.04(b) and § 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PADMAJA S RAO whose telephone number is (571)272-9918. The examiner can normally be reached on 9:00-5:30pm EDT.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L Klinkel can be reached on (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PADMAJA S RAO/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
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