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 .
As previously indicated, in view of the amendment of September 17, 2024 in which applicant deleted claims with reference to “lorcaserin” (which is not supported in the provisional application 62/120,726), the effective filing date of present application is February 25, 2015 (on which the provisional application was filed).
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
With respect to instant 103 rejections over Ceulemens in view of Semple, applicant argue that as stated in the second 132 declaration by Baraban, it was public knowledge prior to Applicant’s critical date that the SHT2c agonist aripiprazole was ineffective in treating Dravet Syndrome. Applicant thus argue that one of ordinary skill in the art at the time of Applicant’s critical date would have had no reason to substitute fenfluramine disclosed by Ceulemens with a selective 5-HT2c receptor agonist such as lorcaserin for Dravet Syndrome treatment. Applicant also argue that even if the skilled artisan were somehow motivated to replace fenfluramine with a selective 5-HT2c receptor agonist such as lorcaserin, they would have had no reasonable expectation of successfully treating Dravet Syndrome with a selective 5-HT2c receptor agonists such as lorcaserin. See MPEP § 2143.02 I (obviousness requires a reasonable expectation of success). Applicant argue that as set forth in Baraban’s second declaration, one of ordinary skill in the art at the time of publication of the 2013 Nature Communications Paper knew that the 5-HT2c receptor agonist aripiprazole was one of the 316 compounds deemed “ineffective” when screened in the SCN1A zebrafish mutant system. Applicant argue that because a person having ordinary skill in the art knew that the 5-HT2c receptor agonist aripiprazole was ineffective in treating Dravet Syndrome, the skilled artisan would have no reason to pick a selective 5-HT2c receptor agonists such as lorcaserin for treatment of Dravet Syndrome merely because the pan 5-HT agonist fenfluramine showed activity. Applicant argue that it cannot be fairly argued that a person having ordinary skill in the art could have reasonably expected a selective 5-HT2c receptor agonist such as lorcaserin to treat Dravet Syndrome in view of the knowledge that the 5-HT2c receptor agonist aripiprazole was ineffective in treating Dravet Syndrome. Applicant argue that none of the art of record has any scientific data suggesting that lorcaserin would be useful in treating Dravet syndrome and that Semple merely cites to the efficacy of fenfluramine in support of the naked assertion that “5-HT2c receptor agonists such as compounds provided herein” might be useful. Applicant argue that because Semple’s reference to 5-HT2c receptor agonists is based only upon fenfluramine activity, Semple provides no scientific evidence to the skilled artisan beyond Ceulemens. Applicant thus concludes that there is nothing in Semple, or any other art of record, that would provide a reason for a person having ordinary skill in the art to substitute the fenfluramine of Ceulemens with lorcaserin in view of the knowledge that the 5-HT2c receptor agonist aripiprazole was ineffective in treating Dravet Syndrome.
The Examiner disagrees. First of all, with respect to the motivation to replace Ceulemens’s fenfluramine with Lorcaserin, as previously discussed in the last Office Action, as evidenced by Martin et al (“Lorcaserin, a 5-HT2C receptor agonist, reduces body weight by decreasing energy intake without influencing energy expenditure”. J Clin Endocrinol Metab., vol.96(3), (Mar. 2011), pg.837-45, obtained from the website: https://pmc.ncbi.nlm.nih.gov/articles/PMC3047218/ ), 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). Thus, being a selective 5-HT2C agonist is a desirable trait. For such reason, one skilled in the art would actually have a good motivation to substitute fenfluramine with lorcaserin so as to avoid the negative effects of 5-HT2A (hallucination) and 5-HT2B (heart valve disease) receptor activation. Also, as already discussed above, Semple teaches that fenfluramine has a serious side effect (even Ceulemens itself acknowledges the health concerns of fenfluramine ([0002]). Semple, on the other hand, teaches that lorcaserin (which is also a small molecule drug) is an agonist of the 5-HT2C receptor which shows effectiveness at reducing obesity in animal models and humans without increasing the risk of cardiac valvulopathy. Semple further teaches that 5-HT2C receptor agonist (such as lorcaserin) may be suitable for the treatment of epilepsy and even teaches that 5-HT2c receptor agonists such as lorcaserin are useful for the treatment of Dravet Syndrome. Based on Semple’s teachings (and based on what Martin teaches), the Examiner believes that there is a more than a sufficient motivation for one skilled in the art to replace Ceulemens’s fenfluramine with lorcaserin. As to applicant’s argument that since aripiprazole is already known to be an ineffective treatment for Dravet Syndrome (in zebra fish), one skilled in the art would not expect that another 5HT2c receptor agonist, such as locarserine, would be successful in treating Dravet Syndrome, the Examiner first would like to point out that aripiprazole is not a full 5HT2c receptor agonist but a partial 5HT2c receptor (as evidenced by applicant’s cited reference, PAE et al (2008), “Aripiprazole in the treatment of depressive and anxiety disorders: a review of current evidence”, CNS Drugs (22(5), pg.367-388 – see abstract). Secondly, as evidenced by Nguyen et al (“Aripiprazole Partial Agonism at 5-HT2C: A Comparison of Weight Gain Associated With Aripiprazole Adjunctive to Antidepressants With High Versus Low Serotonergic Activities”, The Primary Care Companion for CNS Disorders, (2012), Oct 18;14(5), an internet article found at the website: https://www.psychiatrist.com/pcc/aripiprazole-partial-agonism-htc-comparison-weight/ ) (see abstract), aripiprazole has very little effect on weight loss unlike Lorcaserin or fenfluramine. It is well known in the art that strong or selective 5HT2c receptor agonists have anti-obesity properties and are thus used as weight-loss drugs (see abstract in Miller “Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity”, Mol Interv. 2005 Oct;5(5):282-91, an internet article found at the website: https://pubmed.ncbi.nlm.nih.gov/16249524/ ). Thus, lorcaserin is much more similar to fenfluramine than aripiprazole: as already pointed out above, both fenfluramine and lorcaserin are small molecule agonists of the 5-HT2c receptor and both show effectiveness at reducing obesity. Besides, Semple teaches that 5-HT2C receptor agonists such as compounds provided therein (such as lorcaserin) are useful for the treatment of Dravet Syndrome. Thus, for the reasons stated above, it is still the Examiner’s position that one of ordinary skill in the art would have a reasonable expectation of success in replacing Ceulemens’s fenfluramine with lorcaserin in the treatment of 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
November 1, 2025