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 06/18/2026, wherein claims 1-83 are cancelled, claim 84, 87 and 112 are amended, new claim 113 is added. Accordingly, rejection of claims 1, 5, 41, 52, 67, 77, 81, 83 and 87 under 35 U.S.C. 112(a) is withdrawn. Rejection of claim 1, 4-5, 41, 52 and 87 under 35 U.S.C. §102 as being anticipated by Webster et al. (US 2012/0172393 A1) is withdrawn.
Election/Restriction
Acknowledgement is made of Applicant’s election without traverse of Group I invention and compound species having following structure (i.e. compound 28, See Example 30 , [0508]), in the reply filed on 11/10/2025.
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The elected compound species is a compound of Formula (I)
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The elected species, (4-fluoro-4-(2-fluoro-4-(trifluoromethyl)benzyl)piperidin-1-yl)(2-(pyrimidin-4-yl)pyridin-3-yl)methanone (CAS# 2778168-45-7, entered into STN database on 06/24/2022) is free of anticipatory prior art. Claim 1-83 are cancelled. Claim 84 and 112 are amended to remove the species rejected in previous office action dated 02/18/2026. The examiner has expanded the search/ examination to non-elected species of claim 84 and 112, e.g.
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which are rejected under following 35 USC§ 103 rejection and on the ground of non-statutory double patenting.
Other non-elected species are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species. It should be noted that prior art search will not be extended unnecessarily to cover all non-elected species. Claims 84-87 and 112-113 are rejected and the action made final.
Status of Claims
Claims 84, 87, and 112-113 are pending and currently under examination in this office action.
Priority
This application 18/201, 885 filed on 05/25/2023, is a continuation of PCT/US2021/060844 filed 11/24/2021 which claims priority to U.S. provisional patent Application No. 63/118,291 filed on 11/25/2020.
Response to Arguments
Applicant’s Remarks filed 06/18/2026 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 Any objection and rejection found in the previous Office Action and not repeated herein has been withdrawn in view of amendment and Applicant’s remarks .The text of those sections of Title 35 U.S. Code not included in this action can be found in a prior office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.
Claims 1-83 are cancelled. Accordingly, rejection of claims 1, 5, 41, 52, 67, 77, 81, 83 and 87 under 35 U.S.C. 112(a) is withdrawn. Rejection of claim 1, 4-5, 41, 52 and 87 under 35 U.S.C. §102 as being anticipated by Webster et al. (US 2012/0172393 A1) is withdrawn.
Applicant’s argument regarding rejection over Koike’034 in view of Meanwell under 35 U.S.C. §103 is fully considered, but NOT persuasive.
Applicant argues Koike does not teach or suggest compounds comprising a fluorine substituent on their central piperidine ring, let alone that the specific compounds as recited in the instant claims would have CYP46A1 inhibitory activity... Meanwell is merely a general reference that describes fluorine bioisosterism. Nowhere in Meanwell is there any teaching or suggestion that replacing a hydroxy group on any of the Koike compounds would produce a compound having activity against CYP46A1.
Examiner’s Response: Koike’034 disclosed compound of Formula I or a salt thereof as cholesterol 24-hydroxylase (CH24H) inhibitors that are very similar to instant compounds (e.g. cpd 105) for treatment of neurodegenerative disease (e.g. Alzheimer's disease). The main difference between Koike’034 compounds and instant claimed compounds is OH versus fluorine on the piperidine ring, wherein OH and fluorine are commonly known bioisosteres in the pharmaceutical industry as taught by Meanwell. Meanwell teaches fluorine is versatile bioisosteric replacement of H, OH, CN, etc. where electronegativity of fluorine is closer to that of oxygen and significantly more lipophilic than OH. A skilled artisan would be motivated to replace OH with fluorine in searching for compound with enhanced lipophilicity that could pass blood-brain barrier for treating neurodegenerative disease (e.g. Alzheimer's disease) since Meanwell teaches fluorine is significantly more lipophilic than OH. A skilled artisan would reasonably expect modified compounds comprising fluorine on the piperidine ring have inhibitory activity on CYP 46A1 (i.e. cholesterol 24-hydroxylase) for treating neurodegenerative disease (e.g. Alzheimer's disease). For example, Compound 105 taught by Koike’034 could have been modified by replacing the OH with fluorine and arrived at instant non-elected species recited in amended claim 84 and 112 (See page 4 and 17 of claim set dated 06/18/2026).
Instant specification discloses CYP46A1 assay for about 57 compounds (See Table 2) while some are inactive, for example compounds 2, 3, 8, 45, etc. Claims 84 and 112 recite about 98 compounds that are similar to Koike’034, but not tested for CYP46A1 activity or inactive, for example,
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. During the interview on 08/03/2026, 08/07/2026 and 08/11/2026, the examiner and the attorney on the record, Marcus J. Jellen, discussed the scope of claim 84 and 112, but no agreement was reached for the amendment. Claims 84, 87 and 112 remain rejected as obvious over Koike’034 in view of Meanwell. Applicant is advised to further amend claim 84 and 112 to recite disclosed compound species that exhibit super property/unexpected result to overcome the obviousness rejection.
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 84, 87, and 112-113 are rejected under 35 U.S.C. 103 as being unpatentable over Koike et al. (US20130090341, hereafter “Koike’034”), in view of Meanwell (J. Med. Chem. 2018, 61, 5822-5880, DOI: 10.1021/acs.jmedchem.7b01788, Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design) (newly reapplied as necessitated by amendment).
Koike’034 disclosed heterocyclic compound of Formula I or a salt thereof as cholesterol 24-hydroxylase (CH24H) inhibitors and composition comprising aforementioned compounds for the prophylaxis or treatment of neurodegenerative disease (e.g. Alzheimer's disease) ( See abstract, [0045], [0047]-[0071], Tables 1-7, claims 1-23). Koike’034 teaches Cyp46 (same as “cholesterol 24-hydroxylase (CH24H)), a cholesterol oxidase specifically expressed in the brain, is associated with variety of neurodegenerative disease ( See [0003]-[0004]).
Koike’034 teaches compounds of formula (I), with variables as defined (See [0047]-[0071], claims 1-8, etc.).
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Regarding instant claims 5 and 41, Koike’034 teaches R1 is
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Koike’034 teaches embodiments wherein ring B is benzene, thiazole, isoxazole, pyrazole, pyridine or pyrazine, etc. (See [0051], claims 5, 6)
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Koike’034 teaches embodiments wherein R3 is 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 halogen atoms (See [0258])
Koike’034 teaches compound species that are very similar to instant claimed compounds (See Table 1-12 , Examples, claims 1-12), For example,
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The difference between Koike’034 compounds and instant claimed compounds is OH versus fluorine. According to MPEP 2144.09 (I), 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).
Hydroxy group and fluorine are commonly known bioisosteres in the pharmaceutical industry. Meanwell teaches fluorine and fluorinated motifs in the design and application of bioisosteres for drug design, wherein fluorine is a versatile bioisosteric substitute for lone pairs of electrons, hydrogen, methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties(See whole article, page 5822). Meanwell teaches the electronegativity of fluorine is closer to that of oxygen, fluorine is modestly more lipophilic than a hydrogen atom and significantly more lipophilic than OH, C=O, CN, and fluorine does not engage in halogen bonding and is nonpolarizable as versatile bioisostere of the hydrogen atom, carbonyl, the carbinol moiety, and the nitrile (See page 5823, left column). Meanwell also teaches fluorine as a nitrile bioisostere, and example of bioisosteric relationship between fluorine and the nitrile moiety(See page 5864, right column).
It would have been prima facie obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention, in view of the teachings of Koike’034 and Meanwell, to have replaced the hydroxyl group of Koike’034 compounds with a fluorine as taught by Meanwell and general knowledge of structure similarity/ bioisosteric modification for SAR study , and arrive at instant invention with a reasonable expectation of success. For example, Compound 105 taught by Koike’034 could have been modified by replacing the OH with fluorine and arrived at instant non-elected species (See page 4 of claim set dated 06/18/2026).
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A skilled artisan would be motivated to replace OH with fluorine atom in searching for compound with enhanced lipophilicity that could pass blood-brain barrier for treating neurodegenerative disease (e.g., Alzheimer's disease) since Meanwell teaches fluorine is a versatile bioisostere and significantly more lipophilic than OH. Further exploration/optimization of Koike’034 compounds based on the combined teachings of prior art, together with general knowledge of structure similarity/ bioisosteric modification of SAR would provide alternative heterocyclic compounds that are expected to have inhibitory activity on CYP 46A1 (i.e. cholesterol 24-hydroxylase) for treating neurodegenerative disease (e.g., Alzheimer's disease).
One of ordinary skill in the art would have had reasonable expectation of success in producing instant claimed invention based on the combined teaching of prior art, together with general knowledge of structure similarity/ bioisosteric modification for SAR study. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill 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.
Double Patenting
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 84, 87, and 112-113 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 93-104 of copending Application No. 17/613,870 in view of Meanwell (J. Med. Chem. 2018, 61, 5822-5880, DOI: 10.1021/acs.jmedchem.7b01788, Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design) (newly reapplied as necessitated by amendment).
This is a provisional nonstatutory double patenting rejection, because the patentably indistinct claims have not in fact been patented.
Reference claims are drawn to compound of Formula I-a that are similar to instant claimed compounds with variables as defined in reference claims and 93.
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Reference claim 100 recite compounds species that are similar to species recited in instant claims 84 and 112.
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The main difference of reference compounds and instant compounds are nitrile group versus fluorine attached to the piperidinyl ring.
According to MPEP 2144.09 (I), 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).
The collective teachings of Meanwell is elaborated in preceding 103 rejection and applied as before. Meanwell teaches fluorine is versatile bioisostere of hydrogen and nitrile.
It would have been prima facie obvious to one of ordinary skilled in the art to further explore more heterocyclic compounds based on the combined teachings of reference claims and Meanwell, together with general knowledge of structure similarity/ bioisosteric modification of SAR. A skilled artisan would be motivated to replace nitrile with fluorine in searching for alternative compound with enhanced lipophilicity for treating neurodegenerative disease (e.g. Alzheimer's disease) since Meanwell teaches fluorine is a versatile bioisostere and significantly more lipophilic than nitrile.
The instant application shares at least one common inventor and applicant with the reference application. Further, the instant application is not related to the reference application thus no 35 USC 121 shield exists. See MPEP 804.01.
Conclusion
No claims are allowed.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached on (571)272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.M./ Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628
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