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 .
Current Status
This action is responsive to the amended claims of 01/29/2026. Claims 14-15, 18-25, 33-37, 44, 47, and 49-52 are pending. Claims 1-13,16-17, 26-32, 38-43, 45-46, and 48 are canceled. Claims 14-15, 18-25, 33-37, 44, 47, and 49-52 have been examined on the merits.
Election/Restrictions
The amendments and remarks of 01/29/2026 have overcome the pending prior art rejections. Thus, the Markush search was further extended. A search for the compound of Formula (A) (independent claim 14) did not return any prior art (see SEARCH 6 of the attached search notes). Therefore, the Markush search for the compound of Formula (A) has been fully extended and no prior art has been retrieved. The corresponding election for species of cancer, fibrotic disease, and cancer-associated fibroblasts is also considered fully extended since these searches depend on the search for the compound of Formula (A). Thus, the election requirement of 02/24/2025 is rendered moot.
Priority
The effective filing date remains 01/31/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/06/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Examiner acknowledges receipt of and has reviewed the amendments and remarks of 01/29/2026; no new matter is found.
The objection to claim 1 and dependent claims 2, 4, 9-12, 24-25, 33-37, and 44 is withdrawn since Applicant has canceled claim 1.
The objection to claims 1 and 9 and dependent claims 2, 4, 10-12, 24-25, 33-37, and 44 is withdrawn since Applicant has canceled claims 1 and 9.
The objection to claims 23-25 and 33 is withdrawn since Applicant has improved the structure resolution.
The objection to claim 23 is withdrawn: the objection was mistakenly made against claim 23 instead of claim 24. It is withdrawn since Applicant fixed the punctuation in claim 24.
The objection to claim 25 is withdrawn; the objection was mistakenly made against claim 25 instead of claim 35. However, Applicant has fixed the issue at hand by replacing “the targeting ligand” with Fa.
The 112b rejection of claim 2 is withdrawn since claim 2 has been canceled. The note regarding claim 18 was also addressed by Applicant by adding the -CH2CN moiety to parent claim 14.
The 112b rejection of claim 14 and dependent claims 15, 19-21, and 23 is withdrawn since Applicant has added a definition for L to the claim text. This amendment is supported by original claim 1.
The 112b rejection of claim 25 is withdrawn since Applicant has provided definitions for variables R16 and R17. This amendment is supported by the specification (Pg. 40-41 ¶116).
The 112b rejection of claim 33 is withdrawn since Applicant has clarified the attachment of the X to the main Ia radical structure by providing each of the 8 full structures.
The 112d rejection of claim 2 is withdrawn since Applicant has canceled claim 2. The note regarding claim 18 was taken care of by the same amendment mentioned above for claim 18 (¶12).
The 103 rejection of claims 1-2, 4, 9-12, 14-15, 19-21, 23-25, 35-37, and 47-48 as unpatentable over LOW, in view of BERNALES, and in view of POPLAWSKI is withdrawn due to Applicant’s amendments. Applicant has canceled claims 1-2, 4, 9-12, and 48. Applicant has amended, now independent, claim 14 to recite wherein Ia is a PI3K inhibitor. The compounds of LOW do not teach such Ia moieties: LOW teaches FAP-dye conjugate compounds and FAP-tubulysin compounds. As per Applicant’s arguments, tubulysin has a different therapeutic mechanism of action/purpose than a PI3K inhibitor and does not fall under the amended scope of Ia. Further, the artisan would have no motivation to replace a tubulysin with a PI3K inhibitor. Thus, the rejection is withdrawn.
The 103 rejection of claims 1-2, 4, 9-12, 14-15, 19-21, 23-25, 33-35, 44, and 47 as unpatentable over PURDUE, in view of BERNALES, and in view of POPLAWSKI is withdrawn. Applicant has stated the reference PURDUE (applied under 102(a)(2) earlier effective filing date) is a Commonly Owned Disclosure and thus an exception under 102(b)(2)(C). Therefore, PURDUE cannot be prior art.
Similarly, the 103 rejection of claims 1, 14, 36, and 47-48 as unpatentable over PURDUE, in view of BERNALES, in view of POPLAWSKI, and further in view of CHAUDHARI is withdrawn. PURDUE is not art under 102(b)(2)(C).
The obviousness-type nonstatutory double patenting rejection of claims 1-2, 4, 9-12, 14-15, 19-21, 23-25, 33-34, 36, 44, and 47-48 as unpatentable over co-pending Application No. 17/995,806 (reference claims of 06/23/2023) in view of BERNALES and POPLAWSKI is withdrawn. The species of the co-pending claims (06/23/2023) which were analogous to the instant species have been struck from the co-pending claims (co-pending claims of 09/16/2025 & 12/16/2025). The compound of the co-pending claims now differs from the instant at the moiety Z by at least 2 differences (i.e., ring size, unsaturation-level, and heteroatom placement). Thus, the rejection is withdrawn.
The obviousness-type nonstatutory double patenting rejection of claims 1-2, 4, 9, 12, 14-15, 19-21, 24-25, 33-34, 36-37, and 44 as unpatentable over co-pending Application No. 17/759,793 (reference claims of 02/13/2025) in view of BERNALES and POPLAWSKI is withdrawn. While the co-pending claims (amended 03/30/2026) recite an analogous genus Formula (A), the claims do not recite any species thereof. The Formula (A) Fa moiety is defined by subgenera that define the corresponding R22 moiety as methyl. The instant R22 cannot be methyl. Since the compounds of the co-pending claims have at least 1 structural difference and no species are recited in the compounds, the artisan would not be motivated to modify any one species to fit into the instant genus Formula (A). Thus, the rejection is withdrawn.
Claim Objections
Claim 48 is objected to because of the following informalities: per MPEP 714.II.C. “A claim being canceled must be indicated as "canceled;" the text of the claim must not be presented.” Claim 48 has been indicated as (Canceled), but the text of the claims has still been presented as struck through text. Please delete all text from canceled claim 48. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 14-15, 18-25, 33-37, 44, 47, and 49-52 are 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.
Claim 14 recites the limitation under variable Z "wherein * indicates an attachment point" in the final line of Page 2. There is insufficient antecedent basis for this limitation in the claim. By the amendment of 01/29/2026, the asterisk (*) on each of the Z moieties were dropped from claim 14. There is no annotation in this portion of the claim to indicate that such asterisks have been struck. It appears the asterisks have just disappeared. Thus, there is an internal lack of antecedent basis for the recitation of “* indicates an attachment point”. This also makes the attachment point unclear, since the claim is attempting to define it but lacks the asterisks. Further, the lines from the Z moieties now are unclear as to whether they represent a bond or a methyl group: e.g.,
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. Thus, the metes and bounds of the claim are undefined rendering the claim indefinite. Dependent claims 15, 18-25, 33-37, 44, 47, and 49-52 are similarly rejected since they do not rectify the underlying issue.
To overcome: please restore the * to each of the structures recited under Z.
Claim 14 recites the limitation under variable Z "
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indicates an attachment point to L in formula (A) and Ia in formula (B)" in the first line of Page 3. There is insufficient antecedent basis for this limitation in the claim. By the amendment of 01/29/2026, the Formula (B) has been struck from claim 14. Thus, there is an internal lack of antecedent basis for the recitation of “and Ia in formula (B)". Therefore, the metes and bounds of the claim are undefined rendering the claim indefinite. Dependent claims 15, 18-25, 33-37, 44, 47, and 49-52 are similarly rejected since they do not rectify the underlying issue.
To overcome: please strike “and Ia in formula (B)" from the claim.
Conclusion
Claims 14-15, 18-25, 33-37, 44, 47, and 49-52 are rejected.
Note: a search for the compound of independent claim 14 did not retrieve any prior art (see SEARCH 6 of the attached search notes); wherein the claimed Z moieties are attached to the carbonyl of Formula (Y) at the annotated sites:
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. It appears, by the amendment of 01/29/2026, the asterisk (*) at each of these sites was accidentally dropped from claim 14 (the claim still recites “* indicates an attachment point”). Further based on the totality of the disclosure (e.g., Pg. 5-6 of the specification which define Formula (Y)), Examiner believes the Applicant intends for the annotated lines to be bonds to the carbonyl of the Formula (Y).
Based on this search, the close art is considered LOW (WO 2018/111989, cited in IDS of 07/29/2022), HETTIARACHCHI (Hettiarachchi, S.U. et al., Science Translational Medicine, pub. 28 Oct. 2020, 12, 1-14), and BERNALES (WO 2020/142742, effectively filed 01/04/2019; provided by Examiner 07/29/2025).
LOW teaches a conjugate of a fibroblast activation protein (FAP) inhibitor, a linker, and a therapeutic effective against cancer cells and cancer-associated fibroblasts (CAFs) (Pg. 56 claim 1) wherein the therapeutic is a tubulysin (Pg. 65 Claim 39). LOW does not teach covalent conjugates of the FAP inhibitor with a therapeutic inhibitor of PI3K. Tubulysins are known to inhibit microtubule formation – based on a review of relevant literature, Examiner cannot find prior art teaching a role of tubulysins in inhibition of PI3K. Since the mechanism of action of tubulysin is different to that of PI3K inhibitors, the artisan would not have motivation to swap a tubulysin with a PI3K inhibitor. Thus, the conjugate compounds of LOW do not anticipate and cannot make obvious the instant compounds.
HETTIARACHCHI, an NPL document published after the instant EFD, teaches an FAP-PI3K conjugate compound
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(Pg. 2 Fig. 1A); however, this compound differs from the instant compounds at the annotated moiety (corresponding to the instant R22 which cannot be Me but may be H). While this difference amounts to bioisosterism, since HETTIARACHCHI is published after the instant EFD it cannot be considered prior art, only close art.
BERNALES teaches a series of 32 FAP modulators which share the core structure of
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(Pg. 42-47 Table 1; PD Pg. 38-43 Table 1) which are selective for FAP alpha (Pg. 200 Table 3A; PD Pg. 89 Table 3). The FAP modulators of BERNALES share the core structure of the instant Fa moiety; however, BERNALES does not suggest covalently conjugating the compound with any other therapeutics. In fact, the compounds of BERNALES are used individually to effect treatment (Pg. 225 claim 31; PD claim 31). Thus, the artisan would have no motivation to covalently conjugate the FAP modulators with a PI3K inhibitor to arrive at the instant conjugate compounds of Formula (A).
Further, while administration of two compounds which share a common goal (e.g., treating cancer) may be obvious and while PI3K and FAP inhibitors may be known in the art, the artisan would need proper motivation to conjugate the two compounds to create an overall new structure. Since conjugation of the two compounds would inherently affect the structural conformation of the conjugate, the artisan would not have an inherent expectation of success that the new molecule would retain the pharmaceutical properties of the two separate compounds without proper guidance from the prior art. Thus, while the art may teach the two components separately, since there is no prior art which teaches the instant conjugate, the instant claims are considered novel and non-obvious.
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.
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/S.E.B./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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