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 . Claims 1-19 filed October 30, 2025 are currently pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/04/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Claims
As indicated in the Office Action of 08/18/2025, claims 1-6, 13-15 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/17/2025.
Response to Amendment
Applicant’s amendments, filed 10/30/2025 are acknowledged. Claim 18 has been amended to recite “diagnosed with CDKL5 disorder”. In view of Applicant’s amendment, the pending 35 U.S.C 112 paragraph B rejection of record is withdrawn.
Applicant's arguments, filed 10/30/2025 have been fully considered. Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and objections presently being applied to the instant application.
Claim Rejections - 35 USC § 103-Rejection(s) Maintained
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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) 7-11, 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Silverman (US2017/0101364 published 04/13/2017 with priority to U.S. Provisional Application 62239330 filed 10/09/2015), Silverman (US2013/0041028 published 02/14/2013; referred to as Silverman ‘028) and Reagan-Shaw (FASEBJ Vol. 22 pages 659-661. Published 2007).
Silverman teaches a compound of Formula (I), including compound 1 wherein R1 and R2 are each independently F (claims 1, 7-8).
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As evidence by CAS REGISTRY DATABASE, the compound 1 embraced within claims 1, 7-8 of Silverman is the claimed (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid. Silverman teaches that said compound is a potent inhibitor of GABA aminotransferase (GABA-AT) (abstract, [0027], [0039], Figure 2A). Silverman teaches that compound 1 is more efficient at inhibiting GABA-AT compared to art-recognized GABA-AT inhibitor CPP-115 ([0039]-[0040]).
Silverman teaches the method of treating the seizure disorders of infantile spasms in West’s Syndrome as well as Lennox-Gastaut syndrome in a subject in need comprising administering a therapeutically effective amount of a compound of Formula (I), wherein R1 and R2 are each independently F ([0051], claims 38-39 and 41-42).
Regarding the dosing of said GABA-AT inhibitor, Silverman teaches that the therapeutically effective amount will vary depending on the disease state, route of administration and the duration of treatment ([0053]).
The difference between the presently claimed methodology and that of Silverman is that Silverman does not specifically teach administering a dose of 0.01-750 mg of said GABA-AT inhibitor.
Silverman ‘028 teaches vigabatrin as a potent GABA-aminotransferase (GABA-AT) inhibitor efficacious for treating seizures in infants in subjects in need ([0003]-[0005]). Silverman additionally teaches that vigabatrin comprises long term toxicity, resulting in constriction in the patient’s visual field and high risk of vision damage ([0004]-[0005]). Silverman treating seizure disorders in a subject in need comprising administering a therapeutically effective amount of an alternative GABA-aminotransferase compound (abstract, claim 21). Silverman ‘028 teaches administration of GABA-aminotransferase compounds in doses of 0.05 mg/kg/day to 2.5 mg/kg day are therapeutically effective to treat the disclosed seizure disorders without long term vision toxicity associated with vigabatrin (claims 21, 26-27).
Reagan-Shaw (FASEBJ Vol. 22 pages 659-661. Published 2007) teaches that the average weight of a child is 20 kg (Table 1). As such, the dosing of GABA-AT inhibitor to treat seizures embraced within Silverman ‘028 is from 1 mg to 50 mg per day, which reads on the presently claimed dosage embodied within the instant claims. Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
Therefore, one of ordinary skill in the art prior to the time of the invention knowing that compound (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid is a potent and efficient inhibitor of GABA-aminotransferase as taught by Silverman, said skilled artisan would have found it prima facie obvious to treat patients comprising the seizure disorders of infantile spasms in West’s Syndrome and Lennox-Gastaut syndrome, as Silverman teaches that said GABA-AT inhibitor is efficacious at treating the disclosed seizure disorders.
Secondly, said skilled artisan would have found it prima facie obvious to administer a dose of 1-50 mg per day of the art-recognized GABA-AT inhibitor of Silverman to a pediatric patient comprising the seizure disorders of infantile spasms in West’s Syndrome Lennox-Gastaut syndrome in view of Silverman ‘028 and Reagan-Shaw, arriving at the claimed methodology.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, it was known in the art of Silverman ‘028 and Reagan-Shaw that administration of 1-50 mg/day of GABA-AT inhibitors is efficacious at treating seizure disorders in a pediatric patient. Consistent with this reasoning, it would have been obvious to have selected the GABA-AT inhibitor dosing regimen to treat seizures from within the prior art of Silverman ‘028 and Reagan-Shaw above and apply it to the pediatric patient comprising the seizure disorders of infantile spasms in West’s Syndrome or Lennox-Gastaut syndrome being treated with an art-recognized GABA-AT inhibitor (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid in Silverman above, arriving at the claimed methodology “yielding no more than one would expect from such an arrangement”.
Regarding the limitation wherein the therapeutically effective amount of the art-recognized GABA-AT inhibitor (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid embraced within the regimen of Silverman, Silverman ‘028 and Reagan-Shaw provides improvement in at least one symptom selected from the group consisting of frequency of seizures or cognitive impairment (claims 9-10), Applicant is reminded that properties that accrue from the administration of a 1-50 mg/day dose of the GABA-AT inhibitor to a patient comprising the seizure disorder of infantile spasms in West’s Syndrome or Lennox-Gastaut syndrome are considered characteristic features of the claimed therapeutic regimen.
It is noted that MPEP 2112 discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
In the present case the burden is shifted to Applicant to prove that the 1-50 mg/day of the GABA-AT inhibitor (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid administered to a pediatric patient comprising the seizure disorders of infantile spasms in West’s Syndrome or Lennox-Gastaut syndrome as embodied within the combined teachings of Silverman, Silverman ‘028 and Reagan-Shaw will not result in the improvement of frequency of seizures or cognitive impairment.
Applicant traverses. Applicant asserts that Silverman 2017 does not provide an enabling reference for treating infantile spasms in West’s Syndrome or treating Lennox-Gastaut syndrome in a subject in need with the claimed OV-329 (compound of claim 1 of Silverman 2017) as the teaching of Silverman is merely an invitation to try and does not provide any working data. Applicant additionally argues that Silverman 2017 does not teach nor suggest the claimed dosage or dosage frequency of compound 1 (OV329) to treat infantile spasms in West’s Syndrome or treating Lennox-Gastaut syndrome in a subject in need and that Silverman 2017 provides no more than an obvious to try invitation. Thirdly, Applicant argues that that the unexpected results in Applicant’s post-filing data in Epilepsia Vol. 62 pages 3091-3104 (2021) demonstrates an unexpected result over alternative GABA-AT inhibitor vigabatrin wherein the claimed compound (OV329) is more effective at treating seizures in epilepsy animal models than vigabatrin, and is effective in situations wherein vigabatrin was not are each sufficient to overcome a prima facie case of obviousness.
Response to Arguments
Applicant’s arguments, filed 10/30/2025 are acknowledged and have been carefully considered. Regarding Applicant’s contention that Silverman 2017 does not provide an enabling reference for treating infantile spasms in West’s Syndrome or treating Lennox-Gastaut syndrome in a subject in need with the claimed OV-329 (compound of claim 1 of Silverman 2017) as the teaching of Silverman is merely an invitation to try and does not provide any working data for the claimed disorder, this argument is unavailing. Applicant is reminded of MPEP §2121 [R-6](l), which states, "When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to provide facts rebutting the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980).” Applicant has provided nothing more than allegations in the absence of facts to support his assertion that Silverman 2017 et al. is not enabled and, thus, fails to establish a lack of operability of the cited reference.
For the record, Applicant’s urging of non-enablement of the reference on the basis that Silverman does not provide data demonstrating efficacy or success of compound 1 (OV329) on treating infantile spasms in West’s Syndrome or treating Lennox-Gastaut syndrome in a subject in need (claims 7, 38-39) contradicts the guidance provided in MPEP §2121.01[R-3] states that, “A reference contains an ‘enabling disclosure' if the public was in possession of the claimed invention before the date of invention. “Such possession is effected if one of ordinary skill in the art could have combined the publication's description of the invention with his [or her] own knowledge to make the claimed invention." In re Donohue, 766 F.2d 531,226 USPQ 619 (Fed. Cir. 1985)." Once again, note that, per the MPEP, a reference does not have to prove efficacy to constitute an enabled disclosure. Rather, so long as the reference provides a clear description of the invention, which, when coupled with the skilled artisan’s own knowledge, is sufficient to describe how to make and use the invention as described, the reference provides an enabled disclosure. Thus, contrary to Applicant’s assertions, the presumption of operability is not negated on the grounds that proof of efficacy, such as, e.g., in the form of data, has not been provided in the reference.
Moreover, Applicants are reminded that MPEP §2123 teaches, “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert, denied, 493 U.S. 975 (1989).” There is no provision in the MPEP to disregard a teaching in a reference based upon its position or location within the reference. Applicant’s intent to discount the teachings of Silverman 2017 on the grounds that the disclosure of the compound 1 as claimed therapy for treating infantile spasms in West’s Syndrome or treating Lennox-Gastaut syndrome in a subject in need without a working example flies in the face of what is taught in the MPEP, namely, that a reference is valid for all that it would have suggested to one of skill in the art. Additionally, note that MPEP §2121 further teaches that a reference applied under 35 U.S.C. 103(a) constitutes prior art for all that it teaches.
Next, regarding Applicant’s contention that Silverman 2017 does not teach nor suggest the claimed dosage or dosage frequency of compound 1 (OV329) to treat infantile spasms in West’s Syndrome or treating Lennox-Gastaut syndrome in a subject in need and that Silverman 2017 provides no more than an obvious to try invitation, this argument is unpersuasive.
As shown above, the rejection of record is not based on the “obvious to try” rationale as found within MPEP 2143 wherein, choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. Applicant is also reminded that “Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references” In re Merck and Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986).
In the present case, administration of a therapeutically effective amount of compound 1 to treat infantile spasms in West’s Syndrome or treating Lennox-Gastaut syndrome in a subject in need was already established within the subject matter of claims 7, 38-39 of Silverman 2017. Silverman 2017 also teaches that compound 1 is a GABA aminotransferase (GABA-AT) inhibitor. While it is noted that Silverman does not explicitly teach administering 0.01 mg to 750 mg per day of said GABA-AT inhibitor to the patient, Silverman ‘028 teaches vigabatrin as a potent GABA-aminotransferase (GABA-AT) inhibitor efficacious for treating seizures in infants in subjects in need ([0003]-[0005]). Silverman additionally teaches that vigabatrin comprises long term toxicity, resulting in constriction in the patient’s visual field and high risk of vision damage ([0004]-[0005]). Silverman treating seizure disorders in a subject in need comprising administering a therapeutically effective amount of an alternative GABA-aminotransferase compound (abstract, claim 21). Silverman ‘028 teaches administration of GABA-aminotransferase compounds in doses of 0.05 mg/kg/day to 2.5 mg/kg day are therapeutically effective to treat the disclosed seizure disorders without long term vision toxicity associated with vigabatrin (claims 21, 26-27). Reagan-Shaw (FASEBJ Vol. 22 pages 659-661. Published 2007) teaches that the average weight of a child is 20 kg (Table 1). As such, the dosing of GABA-AT inhibitor to treat seizures embraced within Silverman ‘028 is from 1 mg to 50 mg per day, which reads on the presently claimed dosage embodied within the instant claims. Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
As such, said skilled artisan would have found it prima facie obvious to administer a dose of 1-50 mg per day of the art-recognized GABA-AT inhibitor of Silverman to a pediatric patient comprising the seizure disorders of infantile spasms in West’s Syndrome Lennox-Gastaut syndrome in view of Silverman ‘028 and Reagan-Shaw, arriving at the claimed methodology.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, it was known in the art of Silverman ‘028 and Reagan-Shaw that administration of 1-50 mg/day of GABA-AT inhibitors is efficacious at treating seizure disorders in a pediatric patient. Accordingly, it would have been obvious to have selected the GABA-AT inhibitor dosing regimen to treat seizures from within the prior art of Silverman ‘028 and Reagan-Shaw above and apply it to the pediatric patient comprising the seizure disorders of infantile spasms in West’s Syndrome or Lennox-Gastaut syndrome being treated with an art-recognized GABA-AT inhibitor (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid in Silverman 2017 above, arriving at the claimed methodology with a reasonable expectation of success. Furthermore, Applicant has not provided objective evidence demonstrating criticality of the 0.01-750 mg dose of compound 1 of Silverman 2017 found in the present claims in comparison to the amounts of compound 1 and dosing frequency embraced within Silverman 2017.
Thirdly, regarding Applicant’s contention that the unexpected results in Applicant’s post-filing data in Epilepsia Vol. 62 pages 3091-3104 (2021) demonstrates an unexpected result over alternative GABA-AT inhibitor vigabatrin wherein the claimed compound (OV329) is more effective at treating seizures in epilepsy animal models that
the vigabatrin, and is effective in situations wherein vigabatrin was not, said arguments are acknowledged and have been carefully considered but are unpersuasive.
The rejection is not based on the efficacy of vigabatrin on the claimed disorders. Rather, the closest prior art (Silverman 2017) teaches administration of the same compound (compound 1), to treat the same patient population of comprising infantile spasms in West’s Syndrome or treating Lennox-Gastaut syndrome (claims 7, 38-39). The Silverman 2017 reference does not specifically teach administration of the claimed dosage of 0.01-750 mg of compound 1 to the subject. The post-priority data merely validates what is taught in Silverman 2017. As recited in MPEP 716.02(D), to establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). In the present case, the claims embrace a range of 0.01-750 mg of compound 1. Applicant has not provided objective evidence demonstrating criticality of the claimed dosage and dosage frequency of compound 1 to that of Silverman 2017. Nor has efficacy been tested in doses outside the claimed range to demonstrate criticality of the purported range in comparison to the closest prior art of record. In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Claim(s) 19 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Doumlele (Epilepsy and Behavior Case Reports Vol. 6 pages 67-69 published 2016) and Silverman (US2017/0101364 published 04/13/2017 with priority to U.S. Provisional Application 62239330 filed 10/09/2015).
Doumlele (Epilepsy and Behavior Case Reports Vol. 6 pages 67-69 published 2016) teaches West syndrome is an infantile-onset epileptic encephalopathy characterized by clusters of mixed spasms (infantile spasms), cognitive and/or psychomotor disability and hypsarrhythmia on electroencephalogram (EEG). Patients typically develop spasms in the first year of life and are often accompanied by other seizure types (page 67 left col.) Early and effective treatment intervention may reduce developmental delays associated with West syndrome. FDA approved treatments include the GABA-aminotransferase (GABA-AT) inhibitor vigabatrin (page 67 left and right col.). Doumlele also teaches compound (1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1 - carboxylic acid or CPP-115 (title). Doumlele teaches CPP-115 is also a GABA aminotransferase inhibitor that is 187 times more potent than vigabatrin (page 67 right col.). Doumlele teaches that the FDA has granted approval for compound CPP-115 to treat infantile spasms in a patient (page 67 right col.) Doumlele teaches administering CPP-115 to a patient in need following an EEG recording of episodic electrodecremental responses and detection of infantile spasms (page 68 right col.) Doumlele teaches administration of 0.2-1.2 mg/kg CPP-115 to a patient with infantile spasms wherein CPP-115 resulted in a significant reduction in daily seizure frequency compared to without CPP-115 therapy, as well as improving motor function, attention span and environmental interaction (page 68). As shown in Figure 1, removal of vigabatrin and incorporation of CPP-115 resulted in reduced daily seizure frequency and improvement of EEG (page 69 left col.) As evidenced by [0048] of the specification, improving attention and awareness reads on the improvement of cognitive impairment.
The difference between the present claims and that of Doumlele is that Doumlele does not specifically teach administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid to the patient with infantile spasms comprising an abnormal EEG signature.
Silverman (US2017/0101364 published 04/13/2017 with priority to U.S. Provisional Application 62239330 filed 10/09/2015) teaches a compound of Formula (I), including compound 1 wherein R1 and R2 are each independently F (claims 1, 7-8).
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As evidence by CAS REGISTRY DATABASE, the compound 1 embraced within claims 1, 7-8 of Silverman is the claimed (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid. Silverman teaches that said compound is a potent inhibitor of GABA aminotransferase (GABA-AT) (abstract, [0027], [0039], Figure 2A). Silverman teaches that compound 1 is more efficient at inhibiting GABA-AT compared to art-recognized GABA-AT inhibitor CPP-115 ([0039]-[0040]). Silverman teaches the method of treating the seizure disorders of infantile spasms in West’s Syndrome in a subject in need comprising administering a therapeutically effective amount of a compound of Formula (I), wherein R1 and R2 are each independently F ([0051], claims 38-39 and 41-42). Regarding the dosing of said GABA-AT inhibitor, Silverman teaches that the therapeutically effective amount will vary depending on the disease state, route of administration and the duration of treatment ([0053]).
Therefore, one of ordinary skill in the art prior to the time of the invention knowing that compound CPP-115 of Doumlele is a potent and efficient inhibitor of GABA-aminotransferase and is efficacious at reducing daily seizure frequency and improving both cognitive impairment and EEG in patients with infantile spasms with abnormal EEG signatures, said artisan would have found it prima facie obvious to administer the GABA-AT inhibitor (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid to said infantile spasm patient with an abnormal EEG signature in view of Silverman, arriving at the presently claimed methodology.
MPEP 2143 provides rationale for a conclusion of obviousness including (B): Simple substitution of one known element for another to obtain predictable results;
In the present case, it was known in the prior art of Doumlele that administration of the GABA-AT inhibitor CPP-115 is efficacious at reducing daily seizure frequency and improving both cognitive impairment and EEG in patients with infantile spasms with abnormal EEG signatures. Considering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid is a more potent GABA-AT inhibitor than CPP-115 of Doumlele and is art-recognizes as efficacious at treating infantile spasms (West syndrome) in a subject in need as taught by Silverman above, said artisan would have readily predicted that substitution of the GABA-AT inhibitor CPP-115 in the regimen of Doumlele for another GABA-AT inhibitor, such as (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid of Silverman, the resulting GABA-AT therapeutic regimen would have effectively treated said infantile spasm patient with an abnormal EEG signature.
Applicant traverses. Applicant asserts that the teachings of Doumlele provide a number of caveats casting doubts on the results including that CPP-115 was given with other anti-epileptic drugs including vigabatrin and that it is unclear whether the results are attributable to CPP-115 or other drugs. Applicant further asserts that Silverman does not support the assertion that (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid was effective at treating seizure disorders for the same reasons as discussed above. Further, Applicant’s contends that that the unexpected results in Applicant’s post-filing data in Epilepsia Vol. 62 pages 3091-3104 (2021) demonstrates an unexpected result over alternative GABA-AT inhibitor vigabatrin wherein the claimed compound (OV329) is more effective at treating seizures in epilepsy animal models than vigabatrin, and is effective in situations wherein vigabatrin was not is sufficient to overcome a prima facie case of obviousness.
Response to Arguments
Applicant’s arguments, filed 10/30/2025 are acknowledged and have been carefully considered. Regarding Applicant’s contention that there is doubt that CPP-115 effectively treating infantile spasms (West syndrome) based on the teachings of Doumlele, this argument is unpersuasive. Doumlele does not criticize, discredit, or otherwise discourage the solution as claimed. Rather, Doumlele teaches the administration of GABA-AT inhibitor CPP-115 is efficacious at reducing daily seizure frequency and improving both cognitive impairment and EEG in patients with infantile spasms with abnormal EEG signatures. While the patient receiving GABA-AT inhibitor CPP-115 was given with other anti-epileptic drugs including vigabatrin, the results embraced within Doumlele still establish that daily seizure frequency is reduced and both cognitive impairment and EEG are improved in patients with infantile spasms with abnormal EEG signatures by administration of therapeutic regimens comprising GABA-AT inhibitor CPP-115. The pending claims recite the transitional phrase “comprising” and are not directed to the administration of solely GABA-AT inhibitor OV329, but embrace the administration of additional, unrecited elements, such as additional anti-epileptic therapeutics, which reads on the methodology of Doumlele above. See MPEP 2111.03 wherein the transitional term “comprising” is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004).
Secondly, regarding arguments pertaining to Applicant’s contention that Silverman 2017 does not support the assertion that (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid was effective at treating seizure disorders as well as the unexpected results in Applicant’s post-filing data in Epilepsia Vol. 62 pages 3091-3104 (2021) demonstrating an unexpected result over alternative GABA-AT inhibitor vigabatrin wherein the claimed compound (OV329) is more effective at treating seizures in epilepsy animal models, said arguments have been addressed above.
Claim(s) 7-12, 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Bahi-Buisson (Molecular Syndromology Vol. 2 pages 137-152 published 2011), Silverman (US2013/0041028 published 02/14/2013; referred to as Silverman ‘028), Silverman (US2017/0101364 published 04/13/2017 with priority to U.S. Provisional Application 62239330 filed 10/09/2015) and Reagan-Shaw (FASEBJ Vol. 22 pages 659-661. Published 2007)
Bahi-Buisson (Molecular Syndromology Vol. 2 pages 137-152 published 2011) teaches CDKL5 disorders are the result of a mutation in the CDKL5 gene and present as early-onset epileptic encephalopathy including infantile spasms (before 5 months) and severe intellectual disability (abstract, Table 1). Bahi-Buisson teaches that epileptic encephalopathy is the core symptom of CDKL5-related disorders wherein said epileptic encephalopathy presents as 3-stage evolution. Stage 1 is early epilepsy which presents with prolonged generalized tonic-clonic seizure with impaired EEG. Stage 2 is characterized by infantile spasms while stage 3 presents as multifocal and refractory myoclonic epilepsy (page 142 left col.) Bahi-Buisson teaches management of CDKL5 disorders is to treat symptoms of said disorder and maximize developmental and cognitive potential. Anti-elliptic drugs including vigabatrin should be used during the early stages of said CDKL5 disorders (page 149 right col.).
Silverman (US2013/0041028 published 02/14/2013; referred to as Silverman ‘028) teaches vigabatrin as a potent GABA-aminotransferase (GABA-AT) inhibitor efficacious for treating seizures in infants in subjects in need ([0003]-[0005]). Silverman additionally teaches that vigabatrin comprises long term toxicity, resulting in constriction in the patient’s visual field and high risk of vision damage ([0004]-[0005]). Silverman treating seizure disorders in a subject in need comprising administering a therapeutically effective amount of an alternative GABA-aminotransferase compound (1S,3S)-3-amino-4-(difluoromethylenyl)cyclopentanoic acid (abstract, claim 21, 25). Silverman ‘028 teaches administration of GABA-aminotransferase compounds in doses of 0.05 mg/kg/day to 2.5 mg/kg day are therapeutically effective to treat the disclosed seizure disorders without long term vision toxicity associated with vigabatrin (claims 21, 26-27).
However, neither Bahi-Buisson nor Silverman ‘028 specifically teach treating said patient with CDKL5 disorders containing infantile spasms comprising administering a therapeutically effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid. Nor does the combination of Bahi-Buisson and Silverman ‘028 embrace administering a dose of said compound in 0.01 mg to 750 mg per 24 hour period.
Reagan-Shaw (FASEBJ Vol. 22 pages 659-661. Published 2007) teaches that the average weight of a child is 20 kg (Table 1). As such, the 0.05 mg/kg/day to 2.5 mg/kg dosing of GABA-AT inhibitor to treat seizures embraced within Silverman ‘028 above corresponds to 1 mg to 50 mg per day, which reads on the presently claimed dosage embodied within the instant claims. Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
However, neither Bahi-Buisson nor Silverman ‘028 nor Reagan-Shaw specifically teach treating said patient with CDKL5 disorders containing infantile spasms comprising administering 0.01 mg to 750 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid.
Silverman (US2017/0101364 published 04/13/2017 with priority to U.S. Provisional Application 62239330 filed 10/09/2015) teaches a compound of Formula (I), including compound 1 wherein R1 and R2 are each independently F (claims 1, 7-8).
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As evidence by CAS REGISTRY DATABASE, the compound 1 embraced within claims 1, 7-8 of Silverman is the claimed (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid. Silverman teaches that said compound is a potent inhibitor of GABA aminotransferase (GABA-AT) (abstract, [0027], [0039], Figure 2A). Silverman teaches that compound 1 is more efficient at inhibiting GABA-AT compared to art-recognized GABA-AT inhibitor (1S,3S)-3-amino-4-(difluoromethylenyl)cyclopentanoic acid of Silverman ‘028 ([0039]-[0040]).
Silverman teaches the method of treating the seizure disorders of infantile spasms in West’s Syndrome in a subject in need comprising administering a therapeutically effective amount of a compound of Formula (I), wherein R1 and R2 are each independently F ([0051], claims 38-39 and 41-42).
Regarding the dosing of said GABA-AT inhibitor, Silverman teaches that the therapeutically effective amount will vary depending on the disease state, route of administration and the duration of treatment ([0053]).
Therefore, one of ordinary skill in the art prior to the time of the invention knowing that patients with CDKL5 mediated comprise early epilepsy which manifests to infantile spasms and multifocal and refractory myoclonic epilepsy and are traditionally treated with vigabatrin as taught by Bahi-Buisson, coupled with the knowledge that vigabatrin as a potent GABA-aminotransferase (GABA-AT) inhibitor efficacious for treating seizures in infants in subjects in need but comprises long term toxicity, resulting in constriction in the patient’s visual field and high risk of vision damage as taught by Silverman ‘028, said skilled artisan would have found it prima facie obvious to substitute the GABA-AT inhibitor regimen of vigabatrin of Bahi-Buisson, for an alternative GABA-AT inhibitor, such as (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid of Silverman, arriving at the presently claimed methodology.
MPEP 2143 provides rationale for a conclusion of obviousness including (B): Simple substitution of one known element for another to obtain predictable results;
In the present case, considering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid of Silverman is a potent GABA-AT inhibitor, efficacious at treating infantile spasms (West syndrome) in a subject in need and does not comprise the visual toxicity of GABA-AT inhibitor vigabatrin of Bahi-Buisson and Silverman ‘028, said artisan would have readily predicted that substitution of the GABA-AT inhibitor vigabatrin in the regimen of treating CDKL5 mediated infantile spasms of Bahi-Buisson and Silverman ‘028, for another GABA-AT inhibitor, such as (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid of Silverman, the resulting GABA-AT therapeutic regimen would have effectively treated said infantile spasm patient diagnosed with a CDLK5 disorder.
Secondly, said skilled artisan would have found it prima facie obvious to administer a dose of 1-50 mg per day of the art-recognized GABA-AT inhibitor (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid of Silverman to a pediatric patient comprising the CDKL5 mediated disorder of infantile spasms in view of Silverman ‘028 and Reagan-Shaw, arriving at the claimed methodology.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, it was known in the art of Silverman ‘028 and Reagan-Shaw that administration of 1-50 mg/day of GABA-AT inhibitors is efficacious at treating seizure disorders in a pediatric patient. Consistent with this reasoning, it would have been obvious to have selected the GABA-AT inhibitor dosing regimen to treat seizures from within the prior art of Silverman ‘028 and Reagan-Shaw above and apply it to the pediatric patient comprising the CDKL5 mediate disorder being treated with an art-recognized GABA-AT inhibitor (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid in Silverman above, arriving at the claimed methodology “yielding no more than one would expect from such an arrangement”.
Regarding the limitation wherein the therapeutically effective amount of the art-recognized GABA-AT inhibitor (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid embraced within the regimen of Bahi-Buisson, Silverman ‘028, Reagan-Shaw and Silverman provides improvement in at least one symptom selected from the group consisting of frequency of seizures or cognitive impairment (claims 9-10), Applicant is reminded that properties that accrue from the administration of a 1-50 mg/day dose of the GABA-AT inhibitor to a patient comprising the seizure disorder of infantile spasms in a CDKL5 mediated patient are considered characteristic features of the claimed therapeutic regimen.
It is noted that MPEP 2112 discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
In the present case the burden is shifted to Applicant to prove that the 1-50 mg/day of the GABA-AT inhibitor (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid administered to a pediatric patient comprising the seizure disorders of infantile spasms in a CDKL5 mediated disorder as embodied within the combined teachings of Bahi-Buisson, Silverman ‘028, Reagan-Shaw and Silverman will not result in the improvement of frequency of seizures or cognitive impairment.
Applicant asserts that Bahi-Buisson does not remedy the deficiencies of Silverman 2017, Silverman ‘028 and Reagan Shaw as described above. Applicant argues that Bahi-Buisson does not teach nor suggest administering OV329 nor doses, nor frequency of administration nor routes of OV329 administration, nor CPP-115. Applicant argues that Bahi-Buisson describes CDKL5 disorders and that vigabatrin can be used in stage 1 (early epilepsy) but for infantile spasms (stage 2), steroids are recommended.
Response to Arguments
Applicant’s arguments, filed 10/30/2025 are acknowledged and have been carefully considered. Regarding Applicant’s contention that Bahi-Buisson does not remedy the deficiencies of Silverman 2017, Silverman, ‘028 and Reagan-Shaw, arguments pertaining to the combined teachings of Silverman 2017, Silverman, ‘028 and Reagan-Shaw in the 35 U.S.C. 103 rejection of claims 7-11 and 16-17 have been addressed above.
In the present case, the combination of Silverman 2017, Silverman, ‘028 and Reagan-Shaw render obvious the treatment of infantile spasms (West’s Syndrome) and Lennox-Gastaut syndrome comprising administering compound 1 of Silverman 2017 in a dose of 1-50 mg per day. Considering infantile spasms are art-recognized phenotypes of patients diagnosed with CDKL5-mediated disorders (page 142 of Bahi-Buisson), said skilled artisan would have readily predicted that administering 1-50 mg of the infantile spasms treating compound 1 as embraced within the combined teachings of Silverman 2017, Silverman ‘028 and Reagan-Shaw would have treated the patient afflicted with a CDKL5 phenotype.
Conclusion
In view of the rejections set forth above, no claim is allowed.
THIS ACTION IS MADE FINAL. 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.
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/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621