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 17/759,480
This Office action is responsive to the Applicant remarks of 09/23/2025 and the amended claims of 12/01/2025. Claims 1-4, 6, 8, 10, 12, 14-16, 18, 19, 21-22, and 24-28 are pending and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/US2020/049671, filed 09/08/2020, which claims priority to U.S. Provisional Application No. 62/972,677, filed 02/11/2020. The claims find support in the Provisional Application and are given the effective filing date of 02/11/2020.
Response to Arguments
The drawings remain rejected because the figures remain illegible. These issues are discussed below in greater detail.
Regarding the 112(b) rejections, Applicants have amended claim 24 to remove the word "about" from the claim language. This amendment is sufficient to overcome the previous rejection and the rejection is hereby withdrawn.
Regarding the 103 rejections, Applicants contend that the compounds of the instant application are novel over the compounds of Wu based on the amendments excluding R6 and R7 as hydrogen or deuterium. Applicants further argue that the Examiner’s rationale relies on improper hindsight reasoning. These arguments have been fully considered but are not persuasive.
The modification of hydrogen to fluorine at positions R6 and R7 represent a well-established and routine substitution in medicinal chemistry. Fluorine substitution is commonly employed to modulate pharmacokinetic and pharmacodynamic properties while maintaining biological activity. Such modifications would have been well understood by the artisan at the time of the invention.
Additionally, replacement of a methylenedioxy group with fluorine substituents is a recognized bioisosteric modification in biologically active molecules. This demonstrates that the claimed substitutions constitute predictable variations rather than a patentable distinction. Accordingly, the amendments do not overcome the obviousness of the claimed compounds as set forth in the rejections below. The rationale for these substitutions are grounded in the state of the art at the time of the invention and does not rely on knowledge of the Applicants’ disclosure.
Drawings
The drawings are objected to because Figures 5C and 5D remain illegible. The NIC bar has an indicator inside the colored portion of the bar that is not readable. The examiner suggests either changing the font to white or placing the indicator above the bar so they are readable.
Figure 9C pretreated, Figures 10C and 10D Ach+THB5, Figure 11B THB5, THB5+NIC, and NIC all suffer from the same defect. The examiner suggests the same solutions presented above to make the figures clear and legible to the reader. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 1-4, 8, 15, 16, 18, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Wu (WO 2011/139983 A1, found in IDS filed 02/07/2024) in view of Silverman (Silverman, Richard B., and Mark W. Holladay. The Organic Chemistry of Drug Design and Drug Action (Third Edition). Academic Press, 2014) as evidenced by Werbovetz (Werbovetz, K A et al. “Analysis of stereoelectronic properties of camptothecin analogues in relation to biological activity.” Bioorganic & medicinal chemistry vol. 8,7 (2000): 1741-7. doi:10.1016/s0968-0896(00)00111-5).
Wu teaches Tetrahydroberberine (THB) and its analogs potently block functional KATP channels (Abstract); compositions containing THB and its analogs for the treatment of diseases/conditions associated with KATP channel signaling through administering a therapeutically effective amount of the composition (Claim 1); l-tetrahydropalmatine (l-THP) and l-stepholidine (l-SPD) are analogs of THB and are members of the tetrahydroprotoberberine (THPB) family of molecules (pg. 1, third paragraph); l-THP and l-SPD used in a method of treating diseases/conditions associated with KATP channel signaling (claim 3); THPB molecules are useful in the treatment of drug addiction (pg. 1, third paragraph); and the method wherein the KATP channel signaling is part of a dopaminergic receptor, an adrenergic receptor, and/or a serotonin receptor (claim 4), wherein the dopaminergic receptor is a D1, D2, D3, or D4 receptor subtype (claim 5). Wu does not expressly teach fluorine substitution at the methylenedioxy group of THB, however such substitutions are routine in the art.
Silverman teaches that F is an isostere of H (Table 2.10, Entry 15). Reference Werbovetz evidences that artisans routinely implement fluorine substitution at methylene positions, including methylenedioxy groups (see pg. 1742, left column final paragraph through end of page, and compounds 6 and 7 of Table 1).
The artisan would have experience in the design, synthesis, and evaluation of small-molecules for therapeutic use. The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical sciences, or a related field. The artisan would be familiar with techniques to optimize potency, selectivity, and drug-like properties of promising compounds. The artisan would understand common medicinal chemistry principles such as bioisosteric replacement, scaffold modification, and functional group optimization to improve pharmacokinetic and pharmacodynamic properties.
The artisan would have been motivated to substitute the hydrogens of the dioxolane ring of THB with fluorine because they are well-known isosteres of hydrogen and are commonly used in the art and such substitutions of the methylenedioxy moiety are common in the art (see Werbovetz). The artisan would expect that such substitutions would result in sterically similar analogs with minimal impact on binding affinity to the target. Moreover, the artisan would expect that incorporating these analogs into a pharmaceutical composition comprising a therapeutically effective amount of the compound would result in therapeutic effects comparable to those of the original THB composition.
Furthermore, Wu discloses the relevant core structure of the claimed compounds but does not specify the stereochemistry at the position corresponding to R1 in the instant application. The artisan would recognize that this chiral center yields stereoisomeric forms, including enantiomers, diastereomers, and racemic mixtures. Given the routine nature of stereochemical investigation in drug development, the artisan would expect that mixtures or individual stereoisomers of the disclosed compound would retain the desired therapeutic activity.
The discussion above makes obvious the instantly claimed compound of Formula IV and its compositions, reading on the instant claims 1-4, 8, 16, 18, and 19.
Claims 18, 21, 22, and 24-28 are rejected under 35 U.S.C. 103 as being unpatentable over Wu and Silverman as evidenced by Werbovetz in view of Wu2 (US 2008/0176887 A1).
The teachings of Wu and Silverman as evidenced by Werbovetz are discussed above and are incorporated by reference into this rejection. The combined teachings of these references teach the compositions of instant claim 18, see above.
Wu 2 teaches methods for decreasing nicotine use in humans through administration of THB and its analogs (Abstract). Wu 2 additionally teaches the administration of the compound at doses as low as 1 mg/kg of body weight are capable of the desired effects [0054].
Wu does not explicitly teach the method of reducing nicotine addiction through administering their compounds. Wu2 does not teach the compounds of formulae III-VI.
The artisan would have experience in the design, synthesis, and evaluation of small-molecules for therapeutic use, particularly in the context of central nervous-system active agents, such as nicotine cessation agents. The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical sciences, or a related field. The artisan would be familiar with techniques to optimize potency, selectivity, and drug-like properties of promising compounds. The artisan would understand common medicinal chemistry principles such as bioisosteric replacement, scaffold modification, and functional group optimization to improve pharmacokinetic and pharmacodynamic properties.
The artisan would have been motivated to use THB and its analogs (including l-THP and l-SPD) as components of berberine compositions for reducing nicotine addiction, based on the teachings of Wu 2, which demonstrate the efficacy of these compounds in similar therapeutic methods. The artisan would expect that administering one or more of these analogs as part of a composition in a dose of at least 1 mg/kg of body weight would block KATP channel signaling of dopaminergic, adrenergic, and/or serotonin receptors. Furthermore, the artisan would anticipate that the compositions would block KATP channel signaling of dopaminergic receptors of D1, D2, D3, and D4 subtypes.
The discussion above makes obvious the claimed compositions and their administration as part of a method of reducing nicotine addition, reading on the instant claims 18, 21, 22, and 24-28.
Conclusion
Claims 1-4, 8, 15, 16, 18, 19, 21, 22, and 24-28 are rejected.
Claims 6, 10, 12, and 14 are 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.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 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