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 .
Current Status of 18/685,603
This Office Action is responsive to the amended claims and Applicant Remarks of 06/30/2026. Claims 27 and 47-63 are pending and have been examined on the merits.
Election/Restrictions
Applicant’s election without traverse of (A-I) and species
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in the reply filed on 06/30/2026 is acknowledged. Formulae (F-I) and (G-I) were inadvertently omitted from the species identified in the Election of Species requirement of 03/30/2026. Formulae (F-I) and (G-I) likewise lack unity of invention with the identified species for the reasons set forth in the CTRS of 03/30/2026.
A search of the elected species depicted above was conducted in STN, and no prior art was identified that reads on the elected compound. The search was broadened to encompass the full genus of (A-I), at which point relevant prior art was identified.
Priority
The instant application is a national stage entry of PCT/US2022/041603, filed 06/25/2022, which claims the benefit of priority to U.S. Provisional Patent Applications 63/240,701; 63/240, 700; 63/240,699; filed 09/03/2021 and U.S. Provisional Patent Applications 63/237,127; 63/237,130; 63/237,129; 63/237,128; and 63/237,126, filed 08/25/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/07/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered 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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 61-63 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for modulating GluN1/GLuN2A NMDA receptors with some compounds of formula (A-I), does not reasonably provide enablement for a method of treating any CNS-related condition with any compound of formula (A-I), nor does it provide enablement for inducing sedation or anesthesia using any compound of formula (A-I). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a method of treating any CNS-related disorder using any compound of formula (A-I) and a method of inducing sedation or anesthesia using any compound of formula (A-I). Thus, the claims taken together with the specification imply that any compound of formula (A-I) is capable of treating any CNS-related disorder and that any compound of formula (A-I) is capable of inducing sedation or anesthesia. Thus, the scope of the claims is extremely broad.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The state of the prior art is that there is a high degree of unpredictability in extrapolating positive modulation of GluN1/GluN2A NMDA receptors to therapeutic efficacy in CNS disorders. Geoffroy et al. teaches that both hyper- and hypo-activation of NMDA receptors are deleterious to neuronal function (Abstract). The reference further teaches that the anatomical and functional diversity of NMDA receptor subtypes gives rise to distinct physiological and pathological roles in vivo, and that activity characterized in recombinant systems does not readily predict the function of a particular NMDA receptor population in intact neuronal circuits (pg. 235, right col, first para).
Hackos et al. teach a class of NMDA receptor positive allosteric modulators (PAM) selective for GluN2A-containing receptors (Abstract). Despite sharing GluN2A positive modulatory activity, the compounds exhibited different effects on receptor kinetics and synaptic plasticity, demonstrating that a common receptor-level modulatory activity does not necessarily predict the downstream physiological effects of individual compounds (Results, Figs 5-8).
Hardingham et al. that NMDA receptor activation may produce opposing neuroprotective or neurotoxic effects depending upon the receptor population and physiological context. The reference also teaches that comparable levels of receptor-mediated signaling can result in markedly different downstream cellular effects. The reference teaches that GluN2A-containing receptors themselves may mediate both neuronal survival and neuronal death, such that receptor subunit identity alone does not predict the physiological consequences of activation. The reference further demonstrates the context-dependent nature of therapeutic NMDA receptor modulation, noting failures of NMDAR antagonists in stroke and traumatic brain injury and differential therapeutic effects depending on receptor population, dose, and disease stage. (See, The ‘NMDAR paradox, pgs. 682-684; Fig 1; The basis for differences between synaptic versus extra-synaptic NMDAR signalling: outstanding questions pgs. 690-691; and Therapeutic targeting of extrasynaptic NMDARs pg. 693).
(5) The relative skill of those in the art:
The artisan would have experience in the field of medicinal chemistry, pharmacology, neuroscience, biochemistry, or a related field. The artisan would have experience in the design and evaluation of small-molecule CNS-active compounds, including NMDA receptor modulators and would be familiar with methods for evaluating NMDA receptor activity.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided guidance for a cell-based electrophysiology assay evaluating the ability of compounds A-1 through A-24 to positively modulate GluN1/GluN2A NMDA receptor activity (Example 85, Table A-2).
However, the specification does not provide any working examples or sufficient guidance demonstrating that the exemplified compounds of Table A-2 are effective for treating the claimed CNS-related disorders or for inducing sedation or anesthesia. Nor does the specification demonstrate that substantially all compounds encompassed by Formula (A-I) are capable of treating the claimed CNS-related disorders or inducing sedation or anesthesia.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to the lack of an established and predictable relationship between positive modulation of GluN1/GluN2A NMDAR activity and therapeutic efficacy across the broad range of claimed CNS-related disorders and the high unpredictability in the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
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.
Claims 27 and 47-63 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0158903 A1 (found in IDS of 03/07/2025).
‘903 teaches that compounds of Formula
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(Claim 1) and further teaches the following species of the claimed compound
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(claim 29) which reads on the compound of (A-I) of the instant application with the following substitutions: R2a/b are each H; R3 is H; R5 is absent; R6 is H; R9 is H; R11a is H; R11b is H; R15/16 are each H; R18 is C1 alkyl; R19 is C1 alkyl; R20a/b are each methyl; R23a/b are each H; R24a/b are each C1 alkyl; X is –(C(RX)2)n-, RX is H, n is 1; q, u, and s are each 1. The only difference between the species of ‘903 and the compounds of the instant application is that R3 is H, which is not an allowed substitution in the instant claims. However, ‘903 teaches that this position (R3a) can be selected from a group which includes substituted or unsubstituted alkyl. The reference also teaches that position R20 (equivalent to R20b of the instant application) may be selected from hydrogen or methyl (claim 1). The reference teaches that when Z is selected as (i) R1 (equivalent to R20a of the instant application) can be hydrogen or substituted or unsubstituted alkyl and that the bond between C5 and C6 can be either a single or double bond. The reference teaches that these compounds are potential NMDA receptor modulators ( [0007]) and teaches pharmaceutical compositions comprising the compounds and pharmaceutically acceptable carriers (claim 36).
Based on the teachings of the reference discussed above, the artisan would have been motivated to modify the identified species by selecting methyl for R3, hydrogen for R20, an unsubstituted alkyl group for R1, and a single bond in place of the double bond present between C5 and C6 of the exemplified species. Each of these substitutions is expressly disclosed by the reference as an alternative substituent at the corresponding position. These modifications generate the first species of instant claim 58. The artisan would therefore have had reason to select these expressly disclosed substituent alternatives to obtain additional compounds encompassed by the reference’s disclosed genus. The artisan would have reasonably expected this modification to retain the desired NMDA receptor-modulating activity because the reference teaches both substituent alternatives within compounds having the same disclosed utility.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
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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.
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/C.K.E./ Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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