CTFR 17/428,080 CTFR 99550 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 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 02/09/2026. Claims 1-4, 6, 10-11, 14, 16, 19, 22, 25, 28, 31, 34-35, 37-39, and 49-54 are pending. Claim 54 is new. Claims 16, 19, 22, 25, 28, 31, 34-35, 39, and 53-54 are withdrawn. Claims 1-4, 6, 10-11, 14, 37-38, and 49-52 have been examined on the merits. Election/Restrictions The amendments of 02/09/2026 have overcome the prior art rejection of 10/07/2025. Thus, the Markush search has been extended to the full scope of the compound of claim 1 wherein A is PNG media_image1.png 235 206 media_image1.png Greyscale . This search retrieved prior art, specifically the two species shown below: PNG media_image2.png 328 912 media_image2.png Greyscale wherein A is FK506 (tacrolimus), L 1 is a covalent linker, and R 1 is a monovalent kinase inhibitor; PNG media_image3.png 270 746 media_image3.png Greyscale ; wherein A is FK506 (tacrolimus), L 1 is a covalent linker, and R 1 is a monovalent kinase inhibitor cyclosporin A. The first species, above, reads on claims 1-4, 6, 10-11, 14, 37-38, and 49-52. The second species, above, reads on claims 1-4, 6, 10-11, 14, and 37-38. Claim 53 appears to be free of the prior art and, thus, is only objected to here for depending from a rejected claim. The closest art is the art applied below. The art does not teach wherein the R 1 linked to FK506 is a monovalent LRRK2 inhibitor. 08-06 AIA Claim s 16, 19, 22, 25, 28, 31, 34-35, and 53-54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/22/2024 . 08-06 AIA Claim 39 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/22/2024 . Priority The effective filing date remains 02/07/2019. Information Disclosure Statement The information disclosure statement (IDS) submitted on 02/09/2026 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 reply of 02/09/2026, no new matter is found. The 112(a) rejection of claims 1-4, 6, 10-11, 37-38, and 49-51 is withdrawn. Applicant has amended independent claim 1 to recite specific immunophilin-binding moieties (A) and removed the term “analog” from the claims. Further, Applicant argues the disclosure includes a representative number of species falling within the scope of the R 1 genera recited in claim 1, that, in view of the relevant art, the artisan would be able to envisage the scope of compounds falling within the recited chemical classes. This argument supported by many prior art documents (provided in the IDS of 02-09-2026) is found persuasive. The 112(b) rejection of claim 10 is withdrawn due to Applicant’s amendment. The claim no longer recites the broad limitation followed by a narrower limitation. The 102(a)(1) rejection of claims 1-4, 6, 10, 37-38, and 49-51 as anticipated by BUTLER, evidenced by MUTZ and GAYLORD is withdrawn. Applicant has amended independent claim 1 to strike R 1 is a monovalent histone-modifying enzyme inhibitor. Thus, the prior art document no longer teaches a species of the claims. Response to Amendment Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 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. 07-07-aia AIA 07-07 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-aia AIA (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. 07-15 AIA Claim s 1-4, 6, 10, 14, and 37-38 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by STRIGGOW (WO 2014/037260; provided IDS of 03/26/2025) evidenced by WALKER (Walker et al., Biochemical and Biophysical Research Communications, 1989, 160(1), 409-415) and MATSUDA (Matsuda et al., EMBO Reports, 2000, 1, 428-434) . Regarding claims 1, 4, 6, and 10, STRIGGOW teaches the complex: PNG media_image3.png 270 746 media_image3.png Greyscale (Pg. 39 claim 8) wherein A is PNG media_image1.png 235 206 media_image1.png Greyscale and each R group is H PNG media_image4.png 226 204 media_image4.png Greyscale (i.e., FK506/tacrolimus); L 1 is a substituted heteroalkylene specifically L 2 is a bond to A, L 3 is substituted heteroalkylene PNG media_image5.png 71 77 media_image5.png Greyscale , L 4 is substituted heteroalkylene PNG media_image6.png 68 97 media_image6.png Greyscale , L 5 is unsubstituted heteroalkylene PNG media_image7.png 37 52 media_image7.png Greyscale , and L 6 is a bond to R 1 ; R 1 is a monovalent kinase inhibitor cyclosporin A. Regarding claims 1-2 and 14, as evidenced by WALKER, the activity of protein kinase C is significantly inhibited by cyclosporin A (Pg. 409 Abstract). Thus, cyclosporin A is a kinase inhibitor wherein the kinase is not mTOR, the kinase inhibitor is not an HIV protease inhibitor, and the kinase inhibitor is not an amyloid β aggregation inhibitor. Regarding claim 3, STRIGGOW teaches the FK506 moiety is an FKBP binding moiety (Pg. 1 ¶3). Regarding claim 37, STRIGGOW teaches the complex does not inhibit calcineurin (Pg. 26 ¶1). Regarding claim 38, STRIGGOW also teaches a pharmaceutical composition comprising the complex or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (Pg. 40 claim 13). Note: the complex of STRIGGOW may also be interpreted in the opposite direction wherein cyclosporin A is the A moiety, FK506 is the R 1 monovalent kinase inhibitor, and the L 1 sub-variables L 2 -L 6 are flipped. MATSUDA discloses the FK506-FKBP complex suppresses the activation of JNK (Pg. 428 Abstract). Thus, FK506 can inhibit a kinase JNK, which is not an mTOR inhibitor, an HIV protease inhibitor, or an amyloid B aggregation inhibitor. Thus, STRIGGOW anticipates claims 1-4, 6, 10, 14, and 37-38 . 07-07-aia AIA 07-07 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-12-aia AIA (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. 07-15-03-aia AIA Claim s 1-4, 6, 10, 14, 37-38, and 49-52 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by HATHAWAY (WO 2019/028426; effectively filed on 03 August 2018) evidenced by MUTZ (US 2009/0054334; provided by Examiner 10/01/2024) and HATHAWAY_2 (US 2024/0287492; effectively filed 03 August 2018 – priority document is the PCT underlying WO 2019/028426). The effectively filed date of the HATHAWAY references is the international filing date of WO 2019/028426 . Regarding claims 1, 4, 6, 10, and 49-50, HATHAWAY teaches CEM87 (Pg. 54 ¶1, Figs. 19A & 20A-D), reproduced below for clarity: PNG media_image2.png 328 912 media_image2.png Greyscale ; wherein A is PNG media_image1.png 235 206 media_image1.png Greyscale and each R group is H PNG media_image4.png 226 204 media_image4.png Greyscale (i.e., FK506/tacrolimus); L 1 is a substituted heteroalkylene specifically L 2 is a bond to A, L 3 is substituted heteroalkylene PNG media_image8.png 38 56 media_image8.png Greyscale , L 4 is substituted heteroalkylene PNG media_image9.png 53 60 media_image9.png Greyscale , L 5 is unsubstituted heteroalkylene PNG media_image10.png 67 145 media_image10.png Greyscale , and L 6 is a bond to R 1 ; R 1 is a monovalent kinase inhibitor iBet762 an inhibitor of BRD2-4 (Pg. 54 ¶1). Regarding claim 2, 14, and 52, therefore, the R 1 is not an HIV protease inhibitor or an amyloid β aggregation inhibitor and the kinase target is not mTOR. Regarding claim 3, HATHAWAY teaches the FK506 moiety is an FKBP binding moiety (Pg. 2 ¶1). Regarding claim 37, the complex does not inhibit calcineurin since evidentiary reference MUTZ discloses the calcineurin binding mode of FK506 is eliminated by substituting a linker and a target binding moiety (i.e., kinase inhibitor) at the same position shown in the compound CEM87 (Pg. 2 ¶16). Regarding claim 38, HATHAWAY teaches pharmaceutical compositions comprising the CEM and a pharmaceutically acceptable carrier (i.e., excipient) (Pg. 35 ¶3). Regarding claim 51, if the linker is considered to run from FK506-iBet762 from the second carbon to the second to last carbon before the triazole PNG media_image11.png 62 251 media_image11.png Greyscale , the linker is a 17-membered substituted heteroalkylene. Note, the image of CEM87 in HATHAWAY is somewhat unclear. Examiner’s STN search of 05-20-2026 pulled the above structure (see attached SEARCH 6) and family member HATHAWAY_2 discloses the same structure for CEM87 on Pg. 32 claim 76. Since HATHAWAY_2 claims priority of PCT/US2018/045266, which underlies HATHAWAY, and both HATHAWAYs disclose the compound CEM87, Examiner relies on HATHAWAY_2 as an evidentiary reference to further support the structure of CEM87. Thus, HATHAWAY anticipates claims 1-4, 6, 10, 14, 37-38, and 49-52. Conclusion Claims 1-4, 6, 10, 14, 37-38, and 49-52 are rejected. Claims 11 and 53 are rejected for depending from a rejected claim. Here claim 11 may be rejected in a future action since the Markush search covering the genus of Formula I has not been fully extended. Claim 53 is free of the prior art (as stated ¶5). To expedite time to allowance : Examiner asks Applicant kindly address the following issues with claim 54. The “Compound 4”, “Compound 12k”, and “DLK inhibitor 8” do not retrieve any compounds in a search of SciFinder. Thus, these names do not clearly convey the claimed species – please replace these names with the corresponding structures if supported by the original disclosure. In the second half of the claim: each species listed from the second occurrence of “monovalent staurosporine” to “monovalent DNL201” and the second occurrence of “monovalent sunitinib” are repeats of the same species listed earlier in the claim. Please remove the duplicates. 07-40 AIA 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. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA ELIZABETH BELL whose telephone number is (703)756-5372. The examiner can normally be reached Monday-Friday 9:00-5:30. 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. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /S.E.B./Examiner, Art Unit 1625 /JOHN S KENYON/Primary Patent Examiner, Art Unit 1625 Application/Control Number: 17/428,080 Page 2 Art Unit: 1625 Application/Control Number: 17/428,080 Page 3 Art Unit: 1625 Application/Control Number: 17/428,080 Page 4 Art Unit: 1625 Application/Control Number: 17/428,080 Page 5 Art Unit: 1625 Application/Control Number: 17/428,080 Page 6 Art Unit: 1625 Application/Control Number: 17/428,080 Page 7 Art Unit: 1625 Application/Control Number: 17/428,080 Page 8 Art Unit: 1625 Application/Control Number: 17/428,080 Page 9 Art Unit: 1625 Application/Control Number: 17/428,080 Page 10 Art Unit: 1625
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