COMPOUNDS AND THEIR USES FOR TREATING NEURODEGENERATIVE DISEASE

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 . DETAILED ACTION Response to Amendment Acknowledgment is made of the receipt and entry of the amendment filed on July 30, 2026, wherein claims 6 and 9 are cancelled, claim 7 is amended and a new claim 14 is added. Election/Restriction Applicant elected, without traverse, Group II and compound species II-1d, wherein n is 4, R1 is H, R2 is CH3, having following structure (See instant spec [0177]), in the reply filed on 04/02/2026. PNG media_image2.png 148 379 media_image2.png Greyscale The elected species, compound II-1d is a compound of Formula II-1, wherein n is 4, R1 is H, R2 is CH3. Claims 11-13 remain withdrawn from consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions. The elected species, compound II-1d, (CAS # 2919475-49-1, entered STN on April 06, 2023, see STN search note ) PNG media_image3.png 455 735 media_image3.png Greyscale The search/examination was expanded to non-elected species Compound II-1b wherein n=2, R1 is H, R2 is CH3, which was rejected in last office action mailed on June 09, 2026. Other non-elected species remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. The non-elected species Compound II-1b and claim 7 remain rejected in this office action and the action made final. Status of Claims Claims 7-8 and 11-14 are pending in the instant application. Claims 11-13 remain withdrawn. Claims 7, 8 and 14 are currently under examination. Priority This instant application 18/689,852 filed 03/06/2024 is 371 of PCT/US2022/042814, filed September 07, 2022 which claims the priority of U.S. provisional application No. 63/241,543, filed September 08, 2021. Specification The amendment to the name of compound II-1d is acknowledged. Instant specification contain compounds having chiral centers/stereochemistry and lengthy names that are similar. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible error for the chemical names and other errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification. Response to Declaration The Declaration under 37 CFR 1.132 by Dr. Jen-Tse Joseph HUANG, filed on July 30, /2026 is fully considered. HUANG Declaration argues similar structure does not necessarily share similar utilities and “ even if a skilled artisan may be prompted to replace benzene ring in Ferguson compound 12 with pyridine as the Examiner alleged, yet the result is unpredictable as structure similarity does NOT guarantee function similarity”. Please note instant claims are drawn to compounds wherein the intended use does not necessarily contribute to the structural limitation of the compound. Regarding the unpredictability of structure-activity relationships, “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) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute"))”. SEE MPEP 2143.02.I. HUANG Declaration further argues that mHTT aggregate degradation is highly dependent on the precise structure of the Formula II-1 analog. Compounds II-la to II-ld all share the same general PROTAC architecture and differ primarily in the length of the linker, however, only compound II-lb exhibited strong and reproducible degradation activity toward HD-associated mHTT aggregates in the N2a cell studies, whereas compounds II-la and II-lc failed to show comparable activity in reducing mHTT aggregates under the tested conditions. As disclosed by instant Spec ( See Example 2 [0212]) , Compound II-1d reduced the expressed level of pTau by approximately 40% while Compound II-Ib exerted negligible effect on the degradation of pTau protein. As discussed with the attorney on the record, Chih Huai Chiu, in the interview on September 11, 2023, Compound II-1d ( claim 8) exhibiting strong degrading activity for mHTT aggregate and pTau protein might be allowable. However, instant claim 7 is still drawn to compound of II-1 genus comprising different R1, R2 and combination thereof that are not tested. Since mHTT aggregate degradation is highly dependent on the precise structure of Formula II-1 as HUANG Declaration argues, compound of Formula II-1 genus is not allowable in absence of sufficient activity data. Response to Arguments Applicant's remarks filed on July 30, 2026 have been fully considered. Any objection and rejection found in the previous Office Action and not repeated herein has been withdrawn in view of amendment and Applicant’s remarks. The text of those sections of Title 35 U.S. Code not included in this action can be found in a prior Office action. Applicant's arguments regarding 35 USC§103 rejection have been fully considered, but NOT persuasive. Applicant argues the Degron moiety and the ethylene glyco units are linked by “-O(CO)NH- ” group in Ferguson compound 12, whereas in the present compound II-lb are linked by -NH-. It’s noted there is error in Applicant’s recitation of linker group. It’s -OCH2(CO)NH- , not -O(CO)NH- group. A skilled artisan would have known amide group -CONH- and methylene amino group -CH2-NH- are bioisosteres as evidenced by Patani (See page 3170). PNG media_image4.png 287 495 media_image4.png Greyscale The amide group -CONH- in Ferguson compound 12 could have been replaced by -CH2-NH- group which could be modified and attached to the Degron moiety PNG media_image5.png 212 130 media_image5.png Greyscale . Thus, instant Compound II-1b is considered as obvious over Ferguson. Applicant further argues that the utility of a compound is unpredictable based on HUANG Declaration. Instant claims are drawn to compounds wherein the intended use does not necessarily contribute to the structural limitation of the compound. Regarding the unpredictability of structure-activity relationships, “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). More importantly, Compound II-Ib exerted negligible effect on the degradation of pTau protein as disclosed by instant Spec, thus, not allowable. Instant claim 7 is still drawn to compound of II-1 genus comprising different R1, R2 and combination thereof that are not tested. Since mHTT aggregate degradation is highly dependent on the precise structure of Formula II-1 as HUANG Declaration argues, compound of Formula II-1 genus is not allowable in absence of sufficient activity data. Claim Objections Claim 8 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. 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. Claims 7 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Ferguson et al. (WO 2021/257650 A1) , in view of Patani et. al. (Chem. Rev., 1996, 96, page 3147–3176, Bioisosterism: A rational approach in drug design) and Amyvid (Florbetapir F18) label (2012). Ferguson teaches bifunctional compound of formula I, that target at α-synuclein protein degradation for treating neurodegenerative diseases (e.g. Alzheimer’s, Parkinson’s disease), wherein the targeting ligand TL represents a group that binds α-synuclein protein, a degron moiety that binds an E3 ubiquitin ligase, and a linker moiety that covalently connects the degron and the targeting ligand (See abstract, [0002]-[0003] , [0087], claims 1-22). PNG media_image6.png 64 414 media_image6.png Greyscale Ferguson teaches a variety of targeting ligand moiety, e.g. TL-1, TL-2, TL-3, TL-4, TL-5, (See [0003], [0036] , for example, PNG media_image7.png 88 273 media_image7.png Greyscale Ferguson teaches degron binds the E3 ubiquitin ligase which is cereblon (CRBN), e. g. D1-a to D1-i, etc. (See [0051]-0052]) wherein Y is NH or O. PNG media_image8.png 173 395 media_image8.png Greyscale PNG media_image9.png 212 188 media_image9.png Greyscale Ferguson teaches variety of linker moiety, e. g. polyethylene glycol chain, alkylene chain or a bivalent alkylene chain, etc. at different length (See([0042], [0045], [0047]), for example, PNG media_image10.png 69 232 media_image10.png Greyscale PNG media_image11.png 71 178 media_image11.png Greyscale Ferguson teaches embodiments that are similar to the core structure of instant compound of Formula II-1 except the pyridine ring (See [0041], [0049], [0055], page 24) PNG media_image12.png 115 384 media_image12.png Greyscale PNG media_image13.png 132 486 media_image13.png Greyscale PNG media_image14.png 171 462 media_image14.png Greyscale PNG media_image15.png 171 429 media_image15.png Greyscale Ferguson teaches compounds species that are similar to instantly claimed compound, except the pyridine ring (See page 80, claim 17). PNG media_image16.png 184 467 media_image16.png Greyscale PNG media_image17.png 213 480 media_image17.png Greyscale Ferguson collectively teaches core structure and compounds species that are similar to instantly claimed compounds. The main difference of instant compounds and Ferguson compound is pyridine vs benzene ring. Patani teaches CH2, NH, O are classic bioisosteres based on Grimm’s Hydride Displacement Law and Erlenmeyer’s definition of isosteres (See p. 3148-3149). Patani also teaches benzene, pyridine and thiophene are classical ring equivalent bioisosteres (See page 3158, left column). Amyvid (Florbetapir F18) ( CAS# 956103-76-7, PubChem CID 24822371), having following structure comprising styrylpyridin-2-yl ethoxy moiety (See 11 Description), is approved by FDA in 2012 as positron emission tomography (PET) imaging ligand that binds to amyloid aggregates associated with Alzheimer disease and cognitive impair. PNG media_image18.png 87 397 media_image18.png Greyscale According to MPEP § 2144.09, A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). It would have been prima facie obvious to one of ordinary skilled in the art to explore more bifunctional α-synuclein protein degrader based on the collective teachings of Ferguson, together with structure similarity and bioisosteric modification as taught by Patani and general knowledge of neurodegenerative disease, and arrive at instantly claimed invention with reasonable expected success. Florbetapir comprises styryl-pyridin-2-yl ethoxy moiety PNG media_image19.png 169 496 media_image19.png Greyscale as ligand that binds to amyloid aggregation. A skilled artisan would be motivated to explore more alternative bifunctional compounds comprising PNG media_image19.png 169 496 media_image19.png Greyscale that are reasonably expected to bind with amyloid aggregates /target at α-synuclein aggregate for treating neurodegenerative disease. For example, Ferguson compound 12 comprising polyethylene glycol linker moiety (n =2) could have been modified to instant non-elected compound II-1b (n=2), by replacing the benzene ring with pyridine and attaching the linker moiety directly to the degron moiety since Ferguson taught PNG media_image20.png 234 296 media_image20.png Greyscale (Y= NH) . PNG media_image21.png 449 467 media_image21.png Greyscale Instant non-elected compound II-1b ( n=2) could have been further modified to instant elected species, compound II-1d ( n= 4) by exploring longer polyethylene glycol linker as Ferguson teaches different length of linker moiety . Therefore, the invention as a whole is prima facie obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary. Conclusion No claims are allowed. Claim 8 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. THIS ACTION IS MADE FINAL. 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 LIYUAN MOU whose telephone number is (571)270-1791. The examiner can normally be reached Mon-Fri 9:00-5:30. 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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. /LIYUAN MOU/Examiner, Art Unit 1628 /JARED BARSKY/Primary Examiner, Art Unit 1628