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
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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Claims 1, 4-5, 41, 52, 58, 61, 67, 77, 81, 83, 84, 87, and 112 read on the elected compound.
Claims of Group II are cancelled by Applicant. Claims 20, 36 and 52-57 directing to non-elected compound species are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
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 prior art. The examiner has expanded the search/ examination to non-elected species of compound Formula I, wherein R1 is aryl (e.g. phenyl), Ra, Rb, Rc, Rd, Re and Rf are hydrogen, which are rejected under following 35 USC§102 and 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Other non-elected species are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species.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. Should Applicant overcome the rejection by amending the claim, the amended claim will be reconsidered. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during reconsideration that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
Status of Claims
Claims 1, 4-5, 20, 36, 41, 52, 55-58, 61, 67, 77, 81, 83-84, 87, and 112 are pending in the instant application.
Claims 20, 36, 55-57 are withdrawn.
Claims 1, 4-5, 41, 52, 58, 61, 67, 77, 81, 83, 84, 87, and 112 are currently under examination.
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.
Information Disclosure Statement
The information disclosure statement dated 11/20/2023 and 11/10/2025 are in compliance with the provisions of 37 CFR 1.97. The reference listed in IDS are being considered by the examiner. Reference written in foreign language is considered to the degree of English abstract or patent family of foreign patent by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1, 5, 41, 52, 67, 77, 81, 83 and 87 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of full scope of compound of Formula I. This is a written description rejection, rather than an enablement rejection under 35 U.S.C. 112, first paragraph. Applicant is directed to the MPEP 2163 and Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, 1st "Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.
Independent claim 1 refers to compound of formula I with multiple rings A and B, substituted with multiple R groups that are further substituted. The Applicant is required to provide adequate written description and evidence of possession of the claimed genus, compound of Formula I that aligns with the instantly claimed broad scope.
MPEP 2163 II states; “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above)”. While applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. “A representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus” MPEP 2163 II.
Instant specification only disclosed examples wherein p is 1 , i.e. piperidine. Instant specification only disclosed compounds species wherein Rc Re, Rd and Re on the piperidine ring are H. Instant specification does not disclose any example wherein Rc and Re , Rd and Rf together with the carbons to which they are attached form C1-C3 alkylene bridge. Instant specification does not disclose any examples wherein R1 is 3-7-memebered heterocyclyl. Instant specification does not disclose any example comprising multiple R2 and R3 as recited. Instant specification does not disclose any compound species wherein R4 is C6-C10 aryl, C3- C7 cycloalkyl, and 3-7 membered heterocyclyl. Instant specification dose not disclose any compound species wherein Ra and Rb is alkoxy, halo, haloalkyl, haloalkoxy, or Ra and Rb together with the carbon to which they are attached forms a C3-C7 cycloalkyl.
In absence of sufficient examples to support the substantial structural variation within compound of Formula I, an ordinary skilled artisan would not know if the Applicant is in possession of the full scope of compound of Formula I.
Claim Rejections - 35 USC § 102
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 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 –
(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.
(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.
Claims 1, 4-5, 41, 52, 67, 77 are rejected under 35 U.S.C. §102(a)(1) as being anticipated by compounds having following structures, CAS# 2192745-38-1, 2305354-99-6, based upon a public use or sale or other public availability of the invention (See Applicant’s IDS dated 11/10/2025 ).
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Compound (CAS# 2192745-38-1) falls within the scope of Formula (I), wherein
R1 is C6 aryl (phenyl) substituted with one R4, OMe;
B is an C6 heteroaryl (pyridine)
A is a 5 membered nitrogen-containing heteroaryl;
each of Ra, Rb, Rc, Rd, Re and Rf are hydrogen;
R2 and R3 are absent;
m is 0; n is 0; o is 0; p is 1.
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Compound (CAS# 2305354-99-6) falls within the scope of Formula (I), wherein
R1 is C6 aryl (phenyl) substituted with two R4, OMe;
B is an C6 heteroaryl.
A is a 5 membered nitrogen-containing heteroaryl;
each of Ra, Rb, Rc, Rd, Re and Rf are hydrogen;
m is 0; n is 0; o is 0; p is 1.
Claims 1, 4-5, 41, 52 and 87 are rejected under 35 U.S.C. §102(a)(1) and (a)(2) as being anticipated by Webster et al. (US 2012/0172393 A1).
Webster disclosed (4-phenyl-piperidin-1-yl)-5-(1H-pyrazol- 4-yl)-thiophen-3-yl)-methanone compound as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD) inhibitors, pharmaceutical composition comprising aforementioned compounds for treating disease /disorder associated with 11β-hydroxysteroid dehydrogenase, e.g. CNS disorders, Alzheimer’s disease (See abstract, [0036], [0318], claims 125-156).
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Webster disclosed compound species wherein W is F that are encompassed by instant compound of Formula I, e.g. AA-19, AA-36, AA-37, AA-41, etc. (See claim 135).
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Webster compounds fall within the scope of instant compound of Formula I, wherein
R1 is C6 aryl (phenyl) substituted with one or two R4 (halogen, F or Cl);
B is an C5 heteroaryl.
A is a 5 membered nitrogen-containing heteroaryl;
each of Ra, Rb, Rc, Rd, Re and Rf are hydrogen;
R2 and R3 are absent;
m is 0; n is 0; o is 0; p is 1.
As such, Webster anticipates instantly claimed invention.
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 1, 4-5, 41, 52, 58, 61, 67, 77, 81, 83, 84, 87, and 112 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).
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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Regarding claim 67, 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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Regarding claims 81 and 83, 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 compounds of Koike’034 overlaps the scope of Formula (I) of instant claim 1, wherein
R1 is C6 aryl (phenyl) substituted with one instance or two R4 ( fluoro, CN)
Each of Ra, Rb, Rc, Rd, Re and Rf are hydrogen;
B is a 6 membered heteroaryl (pyridinyl);
A is a 6 membered nitrogen-containing heteroaryl (pyridinyl or pyrimidine);
m is 0; n is 1; o is 0; p is 1.
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 92 taught by Koike’034 could have been modified by replacing the OH with fluorine and arrived at instant non-elected species.
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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 1, 4-5, 41, 52, 58, 61, 67, 77, 81, 83, 84, 87, and 112 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). 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 very similar to non-elected species recited in instant claims 84 and 112.
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The difference of reference compounds and instant compounds are nitrile group versus fluoro group 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 as a nitrile bioisostere (See page 5864, right column).
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.
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/L.M./ Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628