CTNF 18/706,266 CTNF 99741 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Status of the Claims Claims 1-19 are pending in the instant application and subject to examination herein. Information Disclosure Statement The information disclosure statement(s) (IDS) submitted on 11/20/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Claim Objections 07-05-05 Applicant is advised that should claim 17 be found allowable, claim 18 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Claim Rejections - 35 USC § 112(a) 07-30-01 AIA 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. 07-31-01 Claims 1-16 and 19 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 the claimed invention. The Invention in General : Applicant has disclosed an invention in the field of treatment of seizures and/or epilepsy. The Claimed Invention : Claim 1 is drawn to a method of treating or mitigating a seizure or epilepsy, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound from a genus of compounds, designated as Formula (I), which allows for hundreds of compounds given the variability at provided substituent positions (R 2a-e , R 1a-d ) and optional pi bonds (“a” and “b”), and includes within its scope the known compound cannabigerol 1 , a cannabinoid phytochemical available from hemp. Formula (I) and cannabigerol are shown below: PNG media_image1.png 138 284 media_image1.png Greyscale Formula (I) PNG media_image2.png 156 452 media_image2.png Greyscale cannabigerol Claims 2-16 further limit Formula (I), each to a narrower genus of compounds to be administered within the method of treatment, and each of these narrower genera continue to include cannabigerol in their scope, along with other compounds. Claim 19 further limits claim 1 to a method of reducing the frequency of seizures, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, without inducing hypnotic effects in the subject, thereby reducing the frequency of seizures. The Supporting Disclosure : The instant Specification includes exemplary studies on the antiseizure effects of the following known cannabinoid phytochemicals listed below, all available from hemp, wherein the mice are administered the cannabinoid compound(s) and subjected to the mouse maximal electroshock test (MES) and monitored for the occurrence of seizures, counted by instances of Tonic Hindlimb Extension (THLE) (paragraph [0095]): Cannabidiol Cannabidiolic acid Cannabigerol Cannbigerolic acid Cannabichromene The Examiner notes that of the studied compounds, only cannabigerol and cannabigerolic acid fall within the scope of Formula (I) of instant claim 1; thus, Applicant has provided exemplary data for precisely two compounds that fall within scope of instant Formula (I), a genus that includes hundreds of distinct compounds. Cannabigerolic acid is shown below. PNG media_image3.png 198 460 media_image3.png Greyscale In the MES assay provided by Applicant, cannabigerolic acid protected just 25% of tested mice from seizure(s), while cannabigerol protected 75% of mice at the same administered dosage (150 mg) (paragraph [0096], including Table 2). Cannibidiol performed similarly to cannabigerol, whereas cannabichromene gave weaker protection (12.5-20%) and cannabidiolic acid protected zero mice. The difference in performance of cannabidiol versus cannabidiolic acid illustrates that significant variability in antiseizure efficacy exists among known cannabinoid compounds of similar structure. The Examiner notes that the majority of the scope of instant Formula (I) represents non-natural cannabinoid compounds that are not prior known in the art and would need to be synthesized and assay. While Applicant has provided references via the Information Disclosure Statement dated 11/20/2024 to establish that the state of the art supports the chemical synthesis of many members of the genus of Formula (I), Applicant does not provide any rationale for why other members of the genus of Formula (I) should be expected to exhibit antiseizure activity comparable to that of cannabigerol and cannabigerolic acid. Furthermore, regarding claim 19, Applicant does not provide any exemplary data regarding the additional limitation of a compound of Formula (I) reducing the frequency of seizures, “without inducing hypnotic effects in the subject”. Mice that were studied in the disclosed examples were not assessed in any way for “hypnotic effects”. The Field of Art, and Predictability in the Field of Art : A review of the neuroprotective effects of phytocannabinoids is provided by Stone (Stone, et al .; British Journal of Pharmacology , v177 , pp4330-4352; 2020 ), who notes that among a family of 7 phytocannabinoids that includes cannabigerol, only 3 compounds showed anti-epileptic/anti-seizure efficacy, and cannabigerol (CBG) is not one of the effective compounds (Table 3, page 4343). The effective compounds were cannabidivarin (CBDV), cannabichromene (CBC) and tetrahydrocannabivarin (THCV). The structures of the discussed compounds are shown in Stone’s Figure 2, shown below. The Examiner notes that none of CBDV, CBC and THCV fall within instant Formula (I), and that Stone’s result of higher estimation of anti-epileptic/anti-seizure efficacy for cannabichromene over cannabigerol is in disagreement with the results of the instant Specification. PNG media_image4.png 744 626 media_image4.png Greyscale Stone’s basis for the non-efficacy of cannabigerol as an anti-epileptic/anti-seizure agent cites to the research of Hill (Hill, et al .; Neuroscience Letters , v566 , pp269-274; 2014 ), who reports a study on the efficacy of cannabinoids, including cannabidiol (CBD) and cannabigerol (CBG) as agents that blockade voltage-gated sodium channels (Na V ) in comparison to their effect as anticonvulsant agents (Abstract, page 269). Hill observes that CBD is a non-psychoactive, well-tolerated, anticonvulsant plant cannabinoid, although its mechanism(s) of seizure suppression remains unknown, and reports that CBG blocked Na V to a similar degree to CBD in both SH-SY5Y and mouse recordings, but had no effect (50–200 mg/kg) on pentyleneterazole(PTZ)-induced seizures induced in rats (Abstract, page 279). Hill’s notes that while CBG failed to protect rats from PTZ-induced seizures, “CBG’s effects in other models have not yet been explored”, and that the conclusion of the study is that Na V blockade must not be the primary mechanism of anticonvulsant action for CBD, given that CBG matched this ability but failed to produce anticonvulsant effect (page 274). Thus, CBG’s efficacy in protecting mice from electroshock-induced seizures in the instant Specification’s MES test stands in contrast to Hill’s observation that CBG fails to protect from chemical-induced seizures. Both MES and PTZ models have been considered as the gold standard models for the screening of new anticonvulsant compounds by inducing seizures in non-epileptic animals (i.e. rodent species as mice and rats), as noted by Campos (Campos, et al ., Epilepsy Research , v146 , pp63-86; 2018 – see page 66), who provides a review of in vitro and in vivo experimental models employed in the discovery and development of antiepileptic drugs. Thus, two models, both gold standard in the field of art, can completely disagree about the efficacy of a given compound, for example cannabigerol. The Examiner notes that cannabidiol, which is a known successful anticonvulsant did give consistently efficacious results in both the MES results of the instant Specification and Hill’s PTZ-seizure assays. The variance of results in the prior art for cannabigerol casts doubt on whether this compound, the best known compound within scope of instant Formula (I) as per Applicant’s results, will prove an effective anticonvulsant, and shows that anticonvulsant efficacy is not well predictable in the field of art, even for known compounds, let alone unknown compounds. Regarding claim 19, neither Stone nor Hill discuss any observed or potential “hypnotic effects” of cannabigerol or any other cannabinoid agent. The prior art is as silent on this aspect as the instant Specification. The MPEP § 2163 states for inventions charactered by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. The courts state conception of a chemical compound requires that the inventor be able to define it so as to distinguish it from other materials, and to describe how to obtain it. Conception does not occur unless one has a mental picture of the structure of the chemical, or is able to define it by its method of preparation, its physical or chemical properties, or whatever characteristics sufficiently distinguish it. It is not sufficient to define it solely by its principal biological property, e.g., dual binding of two different proteins or non-cleavable bonds, because an alleged conception having no more specificity than that is simply a wish to know the identity of any material with that biological property. In such instances the alleged conception fails not merely because the field is unpredictable or because of the general uncertainty surrounding experimental sciences, but because the conception is incomplete due to factual uncertainty that undermines the specificity of the inventor’s idea of the invention. Burroughs Wellcome Co. v. Barr Labs. Inc., 40 F.3d 1223, 1229, 32 USPQ2d 1915, 1920 (Fed. Cir. 1994). Reduction to practice in effect provides the only evidence to corroborate conception (and therefore possession) of the invention. The exemplary results for cannabigerol and cannabigerolic acid do not suffice as a “reduction to practice” for additional compounds proposed by Applicant that are neither known nor assayed for anticonvulsant efficacy. Claim Rejections - 35 USC § 102 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-12-aia AIA (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, 4-7 and 9-10 are anticipated by Arnold. 07-15 AIA Claim s 1, 4-7 and 9-10 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Arnold (WO 2019/071302 A1) . Claim 1 is drawn to a method of treating or mitigating a seizure or epilepsy, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound from a genus of compounds, designated as Formula (I). discloses a methods and compositions for treatment or prevention of seizures in an individual (page 1, lines 1-4), including a method for preventing or reducing the frequency of seizures in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of cannabigerolic acid (CBGA) thereby preventing or reducing the frequency of seizures in the individual (page 2, lines 17-20). Cannabigerolic acid is shown in the table below: Claim Number(s) of Instant Application Instant Application Arnold 1 PNG media_image1.png 138 284 media_image1.png Greyscale wherein: PNG media_image3.png 198 460 media_image3.png Greyscale Cannabigerolic acid Arnold provides “Example 1” to assess the efficacy of cannabigerolic acid in treating and/or preventing epilepsy/seizures, wherein mice, including mice bearing a mutation in the gene that encodes voltage-gated sodium ion channels (SCN1A) are subjected to hyperthermic conditions to induce seizures, after pretreatment with cannabigerolic acid (pages 25-27). Arnold reports that a dose of 100 mg/kg cannabigerolic acid (CBGA) significantly increased the temperature threshold for thermally induced seizures in Scnla +/- mice (genetic deletion) and Scn1aR x/+ mice (genetic mutation). In Scn1a +/- mice an additional dose (30 mg/kg) of CBGA was examined and provided a significant dose-dependent effect for CBGA on thermal seizures (pages 26-27, bridging paragraph) Thus, claim 1 is anticipated by the disclosure of Arnold. Claims 4-7 and 9-10 further limit claim 1, each to a narrower genus of compounds to be administered, and each is met by the method of Arnold for administering cannabigerolic acid. Thus, claims 4-7 and 9-10 are anticipated by the disclosure of Arnold . Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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, 4-10 and 13-18 are unpatentable over Arnold in view of Anderson. 07-21-aia AIA Claim s 1, 4-10 and 13-18 are rejected under 35 U.S.C. 103 as being unpatentable over Arnold (WO 2019/071302 A1) in view of Anderson (Anderson, et al .; British Journal of Pharmacology , v178 , pp4826-4841; 2021 ) 2 . The limitations of claims 1, 4-7 and 9-10 and the disclosure of Arnold are discussed in the rejection above and hereby incorporated into the instant rejection. Claims 8 and 13-18 further limit claim 1, each to a narrower genus of compounds to be administered that is not anticipated by Arnold’s disclosure of administering cannabigerolic acid. While Arnold does not disclose the administration of any additional cannabinoid(s) in scope of instant Formula (I), a person of ordinary skill in the art would have a reasonable expectation of success in substituting cannabigerol for cannabigerolic acid in the method of Arnold, because it was known in the art that cannabigerol also provides protection from seizures under the same experimental conditions as used by Arnold to show efficacy for cannabigerolic acid, per the teaching of Anderson. Anderson teaches a study on anticonvulsant effects among a family of phytocannibinoids (Abstract, page 4826), including cannabigerol (CBG) and cannabigerolic acid (CBGA), both within scope of instant Formula (I), as shown in the table below: Claim Number(s) of Instant Application Instant Application Anderson 1 PNG media_image1.png 138 284 media_image1.png Greyscale wherein: PNG media_image2.png 156 452 media_image2.png Greyscale Cannabigerol 1 PNG media_image1.png 138 284 media_image1.png Greyscale wherein: PNG media_image3.png 198 460 media_image3.png Greyscale Cannabigerolic acid Anderson teaches the effects of pre-treating Scn1a +/- mice with a phytocannabinoid selected from a group that includes both cannabigerol and cannabigerolic acid, and subjecting the mice to elevated temperature such that the hyperthermia will generate seizures and reports, similar to Arnold, that cannabigerolic acid pre-treatment raised the threshold level of temperature required to generate seizures (page 4831, including Figure 1). Anderson reports that cannabigerol did not significantly elevate the threshold temperature for generating seizures; however, Anderson also reported that some mice pre-treated with cannabigerol were fully protected from seizures, and this was the only group of mice to experience a cohort enjoying full protection (page 4831, Figure 1, caption). Cannabigerol meets the structural limitations of the genera of compounds claimed in claims 1, 4-10 and 13-18. Applicant’s invention is unpatentable over the disclosure of Arnold in view of the teaching of Anderson, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in modifying the method of Arnold to substitute cannabigerol for cannabigerolic acid in a method of treatment of epilepsy and/or seizures, because it was known in the art that cannabigerol offers protection from seizures under the same model conditions by which Arnold exemplifies the protective effect of cannabigerolic acid ( i.e ., hyperthermia-induced seizures in Scn1a +/- mice). Thus, the invention was prima facie obvious at the time of filing. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center to authorized users only. Should you have questions about access to the USPTO patent electronic filing system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). Examiner interviews are available via a variety of formats. See MPEP § 713.01. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/InterviewPractice. /W.J.Y./Examiner, Art Unit 1629 /JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629 Application/Control Number: 18/706,266 Page 2 Art Unit: 1629 Application/Control Number: 18/706,266 Page 3 Art Unit: 1629 Application/Control Number: 18/706,266 Page 4 Art Unit: 1629 Application/Control Number: 18/706,266 Page 5 Art Unit: 1629 Application/Control Number: 18/706,266 Page 6 Art Unit: 1629 Application/Control Number: 18/706,266 Page 7 Art Unit: 1629 Application/Control Number: 18/706,266 Page 8 Art Unit: 1629 Application/Control Number: 18/706,266 Page 9 Art Unit: 1629 Application/Control Number: 18/706,266 Page 10 Art Unit: 1629 1 As specifically indicated in dependent claims 17-18. 2 First published: 21Aug2021
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