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 .
Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after allowance or after an Office action under Ex Parte Quayle, 25 USPQ 74, 453 O.G. 213 (Comm'r Pat. 1935). Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant's submission filed on 04/14/2026 has been entered.
Drawings
The drawings were received on 11/05/2026 These drawings are Figures 1-3.
Response to Amendment
The Applicant's amendments and/or arguments filed 14 April 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. In the Applicant’s response, filed 14 April 2026, it is noted that claims 64-7 are have been newly added. No new matter has been added.
Currently claims 40, 44, 45 and 60-71 are pending.
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.
Claims 40, 44, 45 and 60-71 are rejected under 35 U.S.C. 103 as being unpatentable over Krauss et al. (“Seizure freedom with YKP3089 as adjunctive therapy for refractory partial-onset seizure in double-blind placebo-controlled trial,’ Neurology, 2016, Vol. 86, 16 supplement, IDS, hereinafter “Krauss”) in view of Golyala et al. (“Drug development for refractory epilepsy: The past 25 years and beyond,” Seizure, 2017, Vol. 44, pp 147-156, hereinafter “Golyala”), and Zaccara et al. (“Interaction between antiepileptic drug, and between antiepileptic drugs and other drugs,” Epileptic Disord. 2014, Vol. 36 No. 4, pp 409- 431, IDS, hereinafter “Zaccara”) and Majid et al. (“Impact of perampanel on pharmacokinetics of concomitant antiepileptics in patients with partial-onset seizures: pooled analysis of clinical trials”, Br J Cln Pharmacol, 2016, 82, pp. 422-430, hereinafter “Majid”), and further in view of ClinicalTrials.gov Identifier NCT03234699 (“Assess the Influence of Cenobamate on the Pharmacokinetics of Cytochrome P450 (CYP) Probe Drugs as a Means of Predicting Drug-Drug Interaction, 2017, IDS, hereinafter “ClinicalTrials.gov” and Lynch et al. (“The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects, American Family Physician, 2007;76:391-6, hereinafter “Lynch”).
Krauss discloses that in two double-blind placebo-controlled studies of patients with refractory partial-onset seizure (interpreted as it reads on the instant claims 36-37 limitations) in which YK3089 (cenobamate) was significantly more effective than Placebo in traditional primary endpoints (median [percnt] seizure reduction; > 50 percent seizure reduction). In the trials, Adults with >3 or 4 seizures/28 days during 8-wk baseline despite treatment with 1-3, antiepileptic drugs (AEDs) were randomized to Placebo or YKP3089 (C013: 200 mg/day; C017: 100, 200, or 400 mg/day). 6-week titration phase followed by 6-week (C013) or 12-week (C017) maintenance phase, [percnt] patients seizure-free during the entire maintenance phase was determined. The results show that treatment with YKP3089 (as AED) was highly effective in achieving seizure freedom. See, the entire documents.
Kraus does not expressly to use cenobamate as adjuvant with i) other known anti- epileptic drug (AED) with the adjustment of the dosage of other AED as herein defined, and ii) the detailed titration procedure described in claims 40, 44 and 45.
With respect to combination of other known anti-epileptic drugs (AED) such as phenobarbital and/or phenytoin,
Golyala teaches that “Due to ethical reasons, investigational compounds are initially tested as adjunctive treatment in patients with uncontrolled epilepsy. Similar paradigms have been adopted by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for clinical AED development. Generally speaking, a new molecular agent is required to undergo at least two independent studies before regulatory submission can be accepted for approval. Regulatory trials are randomized, double-blind and placebo-controlled, and usually evaluate a number of fixed doses {30}. A Phase III trial typically includes a baseline period, a titration period and a maintenance period. The titration period involves increasing the dose of the drug up to the maximal tolerated dose, or a pre- defined fixed dose, which is maintained for usually 12—16 weeks.” See, particularly, page 148. The right column. Golyala further reveals that carbamazepine lamotrigine, phenobarbital and phenytoin are all old and well-known anti- epileptic drugs (AEDs). See Fig 1 at page 148.
Zaccara teaches that taking two or more AEDs for treating epilepsy or for controlling the seizure of epilepsy have been a common practice in the art and the interaction between the AEDs have been well recognized and understood in the art. The interaction may markedly affect the serum level of the AEDs, either increase or decrease. See, particularly, pages 410-415, and table 2 at page 416.
Majid is cited as an evidentiary reference to demonstrate that phenytoin and phenobarbital are well known agent that is useful as concomitant AEDs for treatment of partial-onset seizures.
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, at the time before the effective filing date of the claimed the invention, to use cenobamate as adjuvant with other known anti-epileptic drug (AED) such as phenytoin and/or phenobarbital for the treatment of refractory partial onset seizure, with reasonable expectation of success.
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
A person of ordinary skill in the art would have been motivated to use cenobamate as adjustive therapy to other known anti-epileptic drug (AED) such as phenytoin and/or phenobarbital with the adjustment of the dosage of other AED as herein defined, or the detailed titration procedure described in the instant claims 49-52 and 54-59 because use the newly developed AED with known AED and titrate the AED have been common practice in the art. Further, the interaction between AED have been well-recognized and understood and determining the interaction through routine experimentation would have been with the skill of ordinary skill in the art. Thus, one of ordinary skill in the art would have been motivated to adjust the effective dosage of the other AED from that of monotherapy to accommodate the interaction of the AEDs. Further, the optimization of a result effective parameter, e.g., the effective amounts of each of the AEDs of the combinational therapy or their corresponding serum levels , is considered within the skill of the artisan. See, In re Boesch and Slaney (CCPA) 204 USPQ 215. The detailed steps of titration within the guidance of the prior art would have been a matter of routine optimization of result affecting parameter. "Where the general conditions of a claim are disclosed in the prior art 41s not inventive to discover the optimum or workable ranges by routine experimentation." in re Aller, 220 F.2d 454, 436, 10S USP 233, 235 (CCPA 1955).
With respect to the specific titration steps disclosed in claims 40 and 44-45,
ClinicalTrials.gov describes a study investigating the influence of cenobamate on the activity of cytochrome P450 (CYP) probe drugs (midazolam, warfarin, omeprazole, and bupropion). The study employs a titration regimen starting at 12.5 mg once daily for 2 weeks, then increasing every 2 weeks to 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg (see Study Description — “Brief Summary”; “Arms and Interventions”). The reference states that the drug–drug interaction (DDI) results will inform appropriate dose recommendations to enable safe concomitant use of drugs metabolized via these isoenzymes (e.g., CYP3A, CYP2C9, and CYP2C19).
Lynch is cited as a supplemental reference establishing that phenytoin and phenobarbital are antiepileptic drugs whose metabolism is primarily mediated by cytochrome P450 enzymes, including CYP2C9, CYP2C19, and/or CYP3A4, and that they may exhibit drug–drug interactions with other medications (see abstract; pp. 392–94; Table 2).
Therefore, further in view of NCT03234699 and Lynch, a person of ordinary skill in the art at the time would have been motivated to administer cenobamate according to the claimed titration schedule to minimize drug–drug interactions with co‑administered AEDs (e.g., phenytoin, phenobarbital) metabolized by CYP enzymes (CYP3A, CYP2C9 and/or CYP2C19), and would have had a reasonable expectation of success.
With respect to the specific percentage difference of AUC obtained after the administration of antiepileptic drug to the patient without cenobamate recited in claims 40, 44 and 45, the U.S. Patent Office is not equipped with analytical instruments to test prior art compositions for the infinite number of ways that a subsequent applicant may present previously unmeasured characteristics. When as here, the prior art appears to contain the exact same ingredients and applicant's own disclosure supports the suitability of the prior art composition as the inventive composition component, the burden is properly shifted to applicant to show otherwise.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian-Yong Kwon whose telephone number is (571)272-0581. The examiner can normally be reached usually except 2nd Friday (6-9am); Tues-Thurs 6am-3pm except Mon, Fri 6am-4:00pm 2nd Thurs 6am-12 noon.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BRIAN-YONG S KWON/ Supervisory Patent Examiner, Art Unit 1613
Prosecution Insights