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 .
Claim Status
Claims 1-21 are pending. Claims 1-21 are rejected.
Claim Rejections - 35 USC § 112(b)
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 1-10 and 15-21 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.
Regarding claim 1, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 2-10 and 15-21 are rejected for failing to obviate the indefiniteness of claim 1.
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.
Claim(s) 1-3, 5-8 and 13-21 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0315677 A1 by Silverman in view of Zhu et al. J. Am. Chem. Soc. 2020, 142, 10, 4892–4903. (cited in the IDS filed 07/02/2025).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
The prior art teaches cyclopentene compounds for use as inhibitors of gamma-aminobutyric acid (GABA) aminotransferase (AT) and/or ornithine aminotransferase (OAT) (abstract). The following compound is analogous to a compound of the instant claims where R1 is fluorine and a double bond exists between the α and ε carbons (paragraph [0090]):
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Regarding instant claims 6-7 and 14, the prior art teaches that the compound may be an ammonium salt having a counter ion that is the conjugate base of a protic acid (paragraph [0091]).
Regarding instant claims 8 and 15, the prior art discloses a pharmaceutical composition comprising the prior art compound and a pharmaceutically acceptable carrier (paragraph [0092]).
Regarding instant claims 16-17, the prior art discloses methods of treating a subject having a disease associated with OAT activity wherein the subject is administered an amount of the compound sufficient to modulate/reduce OAT activity (paragraph [0097]). Silverman lists hepatocellular carcinoma as a cancer for treatment in accordance with instant claims 18-19 and 21 (paragraph [0097]).
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art teaches 3-carbon substituted 4-aminocyclopent-l-ene-1-carboxylic acid compounds capable of modulating OAT activity but does not disclose compounds with two halogen substituents as required by the instant claims.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Zhu et al. report (title) “A Remarkable Difference That One Fluorine Atom Confers on the Mechanisms of Inactivation of Human Ornithine Aminotransferase by Two Cyclohexene Analogues of γ-Aminobutyric Acid”. In the prior art Zhu et al. prepared the following GABA analogs wherein compound 8 has a single fluorine substituent like the compound of Silverman and compound 9 is difluoro-substituted as required by the instant claims (abstract):
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Zhu et al. conclude, “[w]hile monofluoro substituted analogue 8 inactivates hOAT via an enamine pathway (Scheme 2, pathway a), difluoro analogue 9 inactivates hOAT via a novel addition-aromatization mechanism (Scheme 2, pathway c), contributing to its significantly enhanced potency” (page 4901).
Accordingly, a person of ordinary skill seeking to prepare OAT inhibitors with improved potency would be motivated by the teachings of Zhu et al. to modify the compound of Silverman to be difluoro-substituted as recited in instant claims 1-3, 5 and 13. The resulting compound is represented below:
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Regarding instant claim 20, Zhu et al. report that specific knockdown of hOAT was found to suppress the growth on nonsmall cell lung cancer in vitro and in vivo (page 4893). Accordingly, a person of ordinary skill seeking to treat hOAT related cancers would be motivated to administer the prior art compound to improve therapeutic outcomes.
Closest Prior Art
Regarding instant claims 9-12, the closest prior art appears to be the combined teachings of WO 2016/073983 A2 by Silverman et al. and Shen et al.
ACS Medicinal Chemistry Letters 2020 11 (10), 1949-1955. (cited in the IDS filed 07/02/2025).
Silverman et al. discuss compounds for use in OAT inhibition or inactivation (paragraph [0013]) and disclose the following genus:
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Compound 22 is analogous to a compound of the instant claims but differs by the absence of a double bond between the α and β or α and ε carbon (Figure 3):
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Shen et al. discuss (title) “Mechanism-Based Design of 3-Amino-4-Halocyclopentenecarboxylic Acids as Inactivators of GABA Aminotransferase” and report that modifying FCP to include a double bond between the α and β carbon resulted in “a 2-fold greater binding affinity with reduced transition state energy for the rate-determining deprotonation step, which is responsible for a 12-fold enhancement in the rate constant, making 6a 25-fold more efficient as an inactivator of GABA-AT than FCP” (page 1953). However, when the compounds were tested for selectivity over ornithine aminotransferase 6a had 10-fold weaker binding affinity relative to its effect with GABA-AT (page 1953). Accordingly, a person of ordinary skill seeking to prepare compounds with improved properties for OAT inhibition would not have been motivated by the teachings of Shen et al. to modify the compound of Silverman et al. to include a double bond between the α and β carbon because this modification may result in a decrease in binding affinity for ornithine aminotransferase.
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 1-3, 5-8 and 13-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 10822301 in view of Zhu et al. J. Am. Chem. Soc. 2020, 142, 10, 4892–4903.
Claim 14 of the patent discloses the following compound which serves as the basis of a rejection under 35 USC 103 (Col. 23):
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The teachings and rationale of Silverman and Zhu et al. relative to instant claims 1-3, 5-8 and 13-21 are incorporated here by reference. The instant claims are deemed to be variants of the subject matter of the patent for the same reasons as under 35 USC 103.
Claims 1-2, 4-12 and 15-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 11993569 in view of Zhu et al. J. Am. Chem. Soc. 2020, 142, 10, 4892–4903.
Claims 1 and 6 of the patent disclose a zwitterion form of the following compound (Col. 45-46):
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The compound is analogous to a compound of the instant claims where R1 is fluorine and a double bond exists between the α and β carbons.
Zhu et al. report (title) “A Remarkable Difference That One Fluorine Atom Confers on the Mechanisms of Inactivation of Human Ornithine Aminotransferase by Two Cyclohexene Analogues of γ-Aminobutyric Acid”. In the prior art Zhu et al. prepared the following GABA analogs wherein compound 8 has a single fluorine substituent like the compound of patent and compound 9 is difluoro-substituted as required by the instant claims (abstract):
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Zhu et al. conclude, “[w]hile monofluoro substituted analogue 8 inactivates hOAT via an enamine pathway (Scheme 2, pathway a), difluoro analogue 9 inactivates hOAT via a novel addition-aromatization mechanism (Scheme 2, pathway c), contributing to its significantly enhanced potency” (page 4901).
Accordingly, a person of ordinary skill seeking to prepare OAT inhibitors with improved potency would be motivated by the teachings of Zhu et al. to modify the patent compound to be difluoro-substituted as recited in instant claims 1-2, 4-5, 9 and 11. The resulting compound is represented below:
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Regarding instant claims 6-7, 10 and 12, claim 7 of the patent teaches that the compound may be in salt form having a counter ion that is the conjugate base of a protic acid (Col. 46).
Regarding instant claims 8 and 15, claim 8 of the patent discloses a pharmaceutical composition comprising the patent compound and a pharmaceutically acceptable carrier (Col. 46).
Regarding instant claims 16-17, claims 25-28 of the patent disclose methods of treating a subject having a disease associated with OAT activity wherein the subject is administered an amount of the compound sufficient to modulate/reduce OAT activity (Col. 48). Claim 28 recites hepatocellular carcinoma and non-small cell lung cancer cancers for treatment in accordance with instant claims 18-21 (Col. 48).
Conclusion
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/A.A.C./Examiner, Art Unit 1626
/MATTHEW P COUGHLIN/Primary Examiner, Art Unit 1626