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 1-58, 60 and 71-82 are canceled claims.
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.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 59, 61-65, 67-70 and 83 are rejected under 35 U.S.C. 103 as being unpatentable over Ceulemens et al (US 2014/0329908 A1) in view of Semple et al (WO 2015/066344 A1) (with Miller (“Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity”, Mol Interv. Vol.5(5) (2005), pg. 282-91), which is cited here merely to support the Examiner’s assertion that fenfluramine is known to agonize 5-HT2C receptor).
Ceulemens teaches (abstract) a method of treating Dravet Syndrome in a patient by administering an effective dose of fenfluramine (or its pharmaceutically acceptable salt) to the patient. As evidenced by Miller (see abstract), fenfluramine is known to agonize 5-HT2C receptor. Ceulemens teaches ([0002]) that fenfluramine had been administered in combination with phentermine to prevent and treat obesity, which means that fenfluramine is suited to or able to treat obesity. Also, fenfluramine has a molecular weight of 231.262 g/mol (and thus is a small molecule). Ceulemens further teaches ([0042] and [0049]) that its method treats a patient that exhibits a mutation of SCN1A gene, which is indicative of Dravet Syndrome.
Fenfluramine does not meet instant limitation “the 5HT receptor agonist is not fenfluramine”. Semple teaches (pg.102, lines 32-38, pg.2, lines 17-20)) that although administering low dose of fenfluramine is known to be effective for treating patients with Dravet Syndrome, it has a serious side effect: up to one third of patients treated with d-fenfluramine report cardiac valve defects. Semple further teaches (pg.3, lines 14-15, lines 18-26) that lorcaserin (a small molecule having Mw of 195.688 g/mol) is an agonist of the 5-HT2C receptor and shows effectiveness at reducing obesity in animal models and humans. In a case study involving 7,200 patients for two years, lorcaserin was able to produce on average 8% weight loss in patients, and secondary endpoints, such as body composition, lipids, cardiovascular risk factors and glycemic parameters, improved compared to placebo. Furthermore, Lorcaserin did not increase the risk of cardiac valvulopathy. Semple further teaches (pg.104, lines 34-35, pg.105, lines 5-12) that 5-HT2C receptor agonist (such as lorcaserin) may be suitable for the treatment of epilepsy and even teaches (pg.102, last two lines) that 5-HT2c receptor agonists such as compounds provided in the reference (lorcaserin being one of them) are useful for the treatment of Dravet Syndrome. Since both fenfluramine and lorcaserin are small molecule agonists of the 5-HT2c receptor and both show effectiveness at reducing obesity, and also since Semple teaches that 5-HT2C receptor agonist, such as lorcaserin, may be suitable for the treatment of epilepsy and useful for the treatment of Dravet Syndrome, it would have been obvious to one skilled in the art to use Lorcaserin instead of fenfluramine in Ceulemens in treating Dravet Syndrome patients that exhibit SCN1A gene mutation (especially those suffering from a cardiovascular disease) in order to avoid serious side effect of using fenfluramine (such as the risk of cardiac valve damage).
Thus, Ceulemens in view of Semple renders obvious instant claims 59, 61-64 and 83 (with respect to claim 62, it would be obvious to one skilled in the art to change the drug treatment if it is ineffective).
With respect to instant claim 65, Dravet syndrome is also known as severe myoclonic epilepsy of infancy as evidenced by Semple (see pg.102, lines 32-33). Since Ceulemens in view of Semple teaches instant method of claim 59, such method would naturally reduce or prevent myoclonus seizures or status epilepticus in the subject when compared to the absence of 5HT receptor agonist. Thus, Ceulemens in view of Semple renders obvious instant claim 65.
With respect to instant claims 67-69, Ceulemens teaches ([0056]) that fenfluramine can be co-administered simultaneously, sequentially or separately with one or more co-therapeutic agents, such as carbamazepine, ethosuximide, fosphenyltoin, lamotrigine, levetiracetam, phenobarbital, topiramate and benzodiazepines (such as clobazam or clonazepam). It would be obvious to one skilled in the art to use Lorcaserin (instead of fenfluramine) simultaneously with one or more co-therapeutic agents taught by Ceulemens in treating Dravet Syndrome patients in Ceulemens with a reasonable expectation of avoiding the risk of cardiac valve damage. Thus, Ceulemens in view of Semple renders obvious instant claims 67-69.
With respect to instant claim 70, Semple teaches (pg.255, lines 1-5, lines 29-38, pg.256, lines 13-17) that during studies assessing the safety and effectiveness of Lorcaserin, 10 mg of Lorcaserin BID (twice a day) was given to patients, and the treatment was well tolerated. Since the average weight of an adult is between 60 to 80 kg (see Wikipedia webpage: https://en.wikipedia.org/wiki/Human_body_weight#:~:text=Average%20adult%20human%20weight%20varies,average%20weighing%20more%20than%20women. ), this gives a dosage amount of 0.125-0.167 mg/kg per dose. Thus, Ceulemens in view of Semple renders obvious instant claim 70.
Claim 61 is rejected under 35 U.S.C. 103 as being unpatentable over Ceulemens et al (US 2014/0329908 A1) in view of Semple et al (WO 2015/066344 A1) as applied to claim 59 above, and further in view of Lima et al (“Neurobiochemical mechanisms of a ketogenic diet in refractory epilepsy”, Clinics, vol.69(10) (2014), pg.699-705).
Ceulemens in view of Semple does not teach that its Dravet Syndrome patients have a ketogenic diet. Lima teaches (see abstract and the 1st paragraph under INTRODUCTION) that a ketogenic diet is an important therapy used in the control of drug-refractory seizures (epilepsy) regardless of etiology. Lima further teaches that a ketogenic diet is an important coadjuvant treatment for Dravet Syndrome. Thus, it would have been obvious to one skilled in the art that the Dravet Syndrome patients in Ceulemens are on a ketogenic diet. Thus, Ceulemens in view of Semple, and further in view of Lima renders obvious instant claim 61.
Claim 66 is rejected under 35 U.S.C. 103 as being unpatentable over Ceulemens et al (US 2014/0329908 A1) in view of Semple et al (WO 2015/066344 A1) as applied to claim 59 above, and further in view of Fisher ("The 2014 Definition of Epilepsy: A perspective for patients and caregivers" an internet article obtained from: https://www.ilae.org/guidelines/definition-and-classification/the-2014-definition-of-epilepsy-a-perspective-for-patients-and-caregivers#:~:text=Epilepsy%20is%20a%20disease%20characterized,disease%20involving%20recurrent%20unprovoked%20seizures.).
As evidenced by Fisher (see the first 4 paragraphs under “A person is considered to have epilepsy if they meet any of the following conditions:”), epilepsy is a disease that involves unprovoked seizures. Thus, when Lorcaserin (5HT receptor agonist) is administered to the patients of Dravet Syndrome, it would naturally reduce the incidence of unprovoked seizures in the patients as recited in claim 66. Thus, Ceulemens in view of Semple, and further in view of Fisher renders obvious instant claim 66.
Response to Arguments
(i) Applicant argue that there is no scientific evidence which indicates that a selective 5-HT2C receptor agonist would be capable of treating Dravet Syndrome. Applicant argue that all the evidence of record indicates that one skilled in the art had no reason to believe (in 2015) that 5-HT2C receptor agonism would effectuate an antiepileptic effect: Ceulemens (according to Schoonjans’s review article) admitted that it was unknown whether any specific 5-HT receptor is responsible for antiepileptic effects; Sourbron taught that there was no direct evidence that the 5-HT subtypes are implicated in FFA’s pharmacological activity; Perez-Perez taught that the mechanisms by which fenfluramine effected its pharmacologic anti-epileptic activity remained unknown as late as 2024; Schoonjans and Semple demonstrated that FFA could effectuate its anti-convulsive effects through disruption of SERT mediated reuptake of serotonin rather than through 5-HT2C receptor agonism. Applicant further argue that one skilled in the art at the time would have known from Gentsch that 5-HT1A agonism may be important for achieving anti-epileptic effects and would have known from Buchanan that 5-HT2A agonists are protective against seizure-induced breathing disruption and death while 5-HT2C receptor activity has no effect. Applicant argue that therefore there is absolutely no evidence on the record that 5-HT2C receptor agonism would have anti-epileptic effects. Applicant thus argue that the Office has failed to provide any evidence that one skilled in the art would understand that a selective 5-HT2C receptor agonist, such as lorcaserin, would be effective in treating Dravet Syndrome. (ii) Applicant argue that lorcaserin’s “huge advantage” over a pan 5-HT agonist is only in the context of obesity treatment and argue that one skilled in the art would appreciate that efficacious therapeutics for one disorder may be completely different for another, even if the disorders are related.
The Examiner disagrees. (i) First of all, as already stated in Paragraph 5 above, Semple does teach that 5-HT2C receptor agonists (such as lorcaserin) may be suitable for the treatment of epilepsy and even teaches (pg.102, last two lines) that 5-HT2c receptor agonists such as compounds provided in the reference (lorcaserin being one of them) are useful for the treatment of Dravet Syndrome. Furthermore, Jakus et al (Jakus, R., Bagdy, G. (2011). The Role of 5-HT2C Receptor in Epilepsy. In: Di Giovanni, G., Esposito, E., Di Matteo, V. (eds) 5-HT2C Receptors in the Pathophysiology of CNS Disease. The Receptors, vol 22. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-941-3_22) teaches (see abstract) that pharmaceuticals that alter the concentration of 5-HT or exert 5-HT2C receptor agonist and/or antagonist properties must be considered as important factor for the pathogenesis or treatment of epilepsies (citing work that mutant mice lacking the 5HT2C receptor subtype are extremely susceptible to audiogenic seizures and are prone to death from seizures); Isaac (“5-HT2C receptors as a potential therapeutic target for the design antiepileptic drugs”, Curr Top Med Chem. 2005;5(1):59-67, obtained from the website: https://pubmed.ncbi.nlm.nih.gov/15638778/ ) teaches (abstract) that the recent finding that the 5-HT2B/2C receptor agonist, 1-(m-chlorophenyl)-piperazine (mCPP) is anticonvulsant has kindled an interest into the investigation of the serotonergic 5-HT2C receptor subtype as a potential target for the treatment of epilepsy; Jakus et al (“5-TH2C receptors inhibit and 5-HT1A receptors activate the generation of spike-wave discharges in a genetic rat model of absence epilepsy”, Experimental Neurology (vol.184(2), December 2003, pg.964-972, obtained from the website: https://www.sciencedirect.com/science/article/pii/S0014488603003522 ) teaches (abstract) that increase in endogenous 5-HT produces a dual effect on spike-wave discharges (SWD) in genetic absence epilepsy model Wistar rats: the inhibition of epileptiform activity is mediated by 5-HT2C receptors, the activation by 5-HT1A receptors. Thus, the Examiner believes that there was sufficient scientific evidence as of 2015 which indicates that a selective 5-HT2C receptor agonist would be capable of effectuating an anti-epileptic effect. Since Semple teaches that 5-HT2C receptor agonist, such as lorcaserin, may be suitable for the treatment of epilepsy and useful for the treatment of Dravet Syndrome, it would have been obvious to one skilled in the art to use Lorcaserin instead of fenfluramine in Ceulemens with a reasonable expectation of treating Dravet Syndrome while avoiding serious side effect of using fenfluramine (such as the risk of cardiac valve damage). (ii) The fact that Lorcaserin is a selective 5-HT2c agonist is a huge advantage over a pan 5-HT agonist (if fenfluramine were indeed a pan 5-HT agonist) because it means that Lorcaserin is not associated with the negative effects of 5-HT2A (hallucination) and 5-HT2B (heart valve disease) receptor activation (see pg.838, left-hand column, 2nd paragraph), and not being associated with negative effects of 5-HT2A and 5-HT2B (such as hallucination and heart valve disease) is desirable whether one is treating obesity or Dravet Syndrome.
For the reasons stated above, instant 103 rejections over Ceulemens in view of Semple still stand.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SIN J. LEE whose telephone number is (571)272-1333. The examiner can normally be reached on M-F 9 am-5:30pm.
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/SIN J LEE/
Primary Examiner, Art Unit 1613
June 26, 2026
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