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 .
DETAILED ACTION
A request for continued examination under 37 C.F.R. 1.114, including the fee set forth in 37 C.F.R. 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 C.F.R. 1.114, and the fee set forth in 37 C.F.R. 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 C.F.R. 1.114. Applicant’s submission filed March 16, 2026 has been received and entered into the present application.
Status of claims
The amendment filed on Feb. 13, 2026 is acknowledged. Claims 1-23 have previously been canceled. Claims 24-48 are under examination in the instant office action.
Applicants' arguments, filed on Feb. 13, 2026, have been fully considered but they are moot in view of a new ground of rejection necessitated by the amendments (newly added limitation). Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim interpretation
The independent claims 24 and 35 has been amended to recite “a method of treating seizure in a patient with Dravet syndrome or an intractable form of epilepsy comprising administering a therapeutically effective dose of a (-) norfenfluramine enantiomeric composition to the patient.
When the broadest reasonable interpretation given, “a (-) norfenfluramine enantiomeric composition” is interpreted to encompass a composition comprising (-) norfenfluramine enantiomer, which does not exclude the presence of other components including (+) norfenfluramine enantiomer as well as a composition comprising a (-) norfenfluramine enantiomer only without (+) norfenfluramine.
Claim Rejections - 35 USC § 102
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 –
(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.
(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 24-48 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by WO 2016/138138 (hereafter, Baraban; cited in the IDS filed on 10/28/2022) as evidenced by Rothman (Pharmacology, Biochemistry and Behavior, 71:825-836, 2002).
Baraban teaches a method of treating an epilepsy disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a 5HT receptor agonist, or a pharmaceutically acceptable salt thereof ([0003], [0005], and claim 1).
Baraban teaches the epilepsy disorder is Dravet Syndrome (DS), Lennox-Gastaut Syndrome, infantile spasm, or Ohtahara Syndrome and in an exemplary embodiment, the epilepsy disorder is Dravet Syndrome ([0015]). Baraban further teaches that one of its primary causes is mutations in Navl. l (SCN1A), a voltage-gated sodium channel (inherited disorders) and seizures experienced by those with DS and other epilepsy disorders are inadequately managed using available antiepileptic drugs (AEDs) (intractable epilepsy) and children with DS are poor candidates for neurosurgical resection ([0004]). Baraban further teaches wherein the 5HT receptor agonist reduces the incidence of unprovoked seizures in the subject when compared to the absence of the 5HT receptor agonist ([0022] and [0246]).
Baraban specifically discloses norfenfluramine:
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, as one of said 5HT receptor agonist for use ([0074]-[0075], [0234], and claim 10). Baraban teaches when administered as pharmaceutical composition, the pharmaceutical compositions may include optical isomers, diastereomers, enantiomers, isoforms, polymorphs, hydrates, solvates or products, or pharmaceutically acceptable salts of the 5-HT receptor agonist ([0141]).
Baraban also discloses that the 5-HT receptor agonist is formulated with a carrier in a pharmaceutical composition such as a tablet, a powder, a capsule, a pill, a cachet, or a lozenge ([0140] and [0144]-[0145]). Baraban further discloses that the pharmaceutical composition may be formulated for dissolution into a solution for intravenous administration and the pharmaceutical composition may be formulated for oral administration, suppository administration, topical administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intranasal administration, subcutaneous administration, implantation, transdermal administration, or transmucosal administration ([0140]).
Baraban teaches that the 5-HT receptor may be administered in the dosages described herein at least once a day (e.g. once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, or 12 hours) ([0134]). While Baraban discloses a structure of norfenfluramine without specifying chirality (see [0074]), Baraban teaches that when administered as pharmaceutical composition, the pharmaceutical compositions may include enantiomers ([0141]). The norfenfluramine refers to a racemic mixture of both (+)-norfenfluramine and (−)-norfenfluramine as evidenced by Rothman (abstract and Fig. 2). Thus, the norfenfluramine composition disclosed in Baraban reads on the claimed “(-) norfenfluramine enantiomeric composition” as stated in the claim interpretation.
As to the limitations: “having lower affinity for the patient's 5-HT2B receptors compared to (+) fenfluramine, (-) fenfluramine or (+) norfenfluramine; having lower activity at the 5-HT2B receptors in the patient compared to either (-) fenfluramine or (+) fenfluramine; and lowering the patient's exposure to 5-HT2B agonism as compared to a molar equivalent dose of racemic fenfluramine, dexfenfluramine or (+) norfenfluramine” recited in claim 31-33, those are inherent properties of the (-) norfenfluramine. Since the prior art teaches the same composition comprising (-) norfenfluramine, thus such properties are necessarily present. It is noted that products of identical chemical composition cannot have mutually exclusive properties and a chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). When the claimed and prior art products are identical or substantially identical in structure or composition, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). It is further evidenced by Rothman, which discloses that (−)-norfenfluramine has lower affinity for at 5-HT2B receptor and has lower activity at 5-HT2B receptor compared to (-) fenfluramine or (+) norfenfluramine (page 828, Table 2).
As such, the instant claims are anticipated by Baraban.
In the alternative, the following rejection is applied when “a (-) norfenfluramine enantiomeric composition” is limited to a composition comprising (-) norfenfluramine enantiomer only without (+) norfenfluramine.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 24-48 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/138138 (hereafter, Baraban; cited in the IDS filed on 10/28/2022) in view of Rothman (Pharmacology, Biochemistry and Behavior, 71:825-836, 2002) in further view of Sourbron et al. ACS Chem. Neurosci. 7: 588−598, Jan. 29, 2016).
Baraban teaches a method of treating an epilepsy disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a 5HT receptor agonist, or a pharmaceutically acceptable salt thereof ([0003], [0005], and claim 1).
Baraban teaches the epilepsy disorder is Dravet Syndrome (DS), Lennox-Gastaut Syndrome, infantile spasm, or Ohtahara Syndrome and in an exemplary embodiment, the epilepsy disorder is Dravet Syndrome ([0015]). Baraban further teaches that one of its primary causes is mutations in Navl. l (SCN1A), a voltage-gated sodium channel (inherited disorders) and seizures experienced by those with DS and other epilepsy disorders are inadequately managed using available antiepileptic drugs (AEDs) (intractable epilepsy) and children with DS are poor candidates for neurosurgical resection ([0004]). Baraban further teaches wherein the 5HT receptor agonist reduces the incidence of unprovoked seizures in the subject when compared to the absence of the 5HT receptor agonist ([0022] and [0246]).
Baraban specifically discloses norfenfluramine as one of said 5HT receptor agonist ([0074]-[0075]; [0234], and claim 10). Baraban teaches when administered as pharmaceutical composition, the pharmaceutical compositions may include optical isomers, diastereomers, enantiomers, isoforms, polymorphs, hydrates, solvates or products, or pharmaceutically acceptable salts of the 5-HT receptor agonist ([0141]).
Baraban also discloses that the 5-HT receptor agonist is formulated with a carrier in a pharmaceutical composition such as a tablet, a powder, a capsule, a pill, a cachet, or a lozenge ([0140] and [0144]-[0145]). Baraban further discloses that the pharmaceutical composition may be formulated for dissolution into a solution for intravenous administration and the pharmaceutical composition may be formulated for oral administration, suppository administration, topical administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intranasal administration, subcutaneous administration, implantation, transdermal administration, or transmucosal administration ([0140]).
Baraban teaches that the 5-HT receptor may be administered in the dosages described herein at least once a day (e.g. once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, or 12 hours) ([0134]). While Baraban teaches and suggests the use of norfenfluramine or their enantiomers for treating intractable form of epilepsy such as Dravet Syndrome, Baraban is silent about the use of a specific enantiomer of norfenfluramine such as (−)-norfenfluramine without (+)-norfenfluramine.
However, it was known in the art that norfenfluramine is a metabolite of fenfluramine and present in two stereoisomers, (+)-norfenfluramine and (−)-norfenfluramine as evidenced by Rothman (abstract and Fig. 2). Rothman discloses that (+)-norfenfluramine and (−)-norfenfluramine are more potent agonists at 5-HT2A than their parent compound, (+)-fenfluramine and (−)-fenfluramine while (−)-norfenfluramine has lower activity at 5-HT2B receptor than (-)-fenfluramine (p828, Table 2). Rothman also teaches that (+)-norfenfluramine is a potent 5-HT2B and 5-HT2C receptor agonist, wherein 5-HT2B activity increases the risk of developing valvular heart disease and 5-HT2C receptor activity is implicated in the anorectic effects of (±)-fenfluramine and (+) fenfluramine which increase the risk of developing primary pulmonary hypertension (abstract, p828, col 1 para 1, and p829, col 2, last para). In addition, Rothman discloses that (-)-norfenfluramine has much lower affinity (about 20 times lower) at the 5-HT2B receptors compared to (+)-norfenfluramine (p828, Table 2).
Sourbron et al. teaches that in a clinical study, add-on treatment with fenfluramine, a potent 5-HT releaser activating multiple 5-HT receptor subtypes, made 70% of Dravet Syndrome children seizure free (abstract). Sourbron et al. confirmed that the antiepileptic activity in the zebrafish model of Dravet syndrome is associated with 5-HT1D, 5-HT1E, 5-HT2A, 5-HT2C, and 5-HT7-agonists, and especially the 5-HT2A-agonists (abstract). Sourbron et al. discloses significant decrease of serotonin in the heads of homozygous scn1Lab−/− mutants as compared to the wild type zebrafish, which suggest that neurochemical defects might play a crucial role in the pathophysiology of DS (abstract and Fig. 5).
The enantiomers of norfenfluramine have been previously separated into a pure composition of (+)-norfenfluramine and (−)-norfenfluramine as evidenced by Rothman. The treatment of intractable seizures such as Dravet syndrome with norfenfluramine was known as evidenced by Baraban. One of ordinary skilled in the art would have been motivated to use the better enantiomer of norfenfluramine for the treatment of intractable seizures such as Dravet syndrome treatable with racemic norfenfluramine because the skilled artisan would have known that a single enantiomer is often therapeutically superior to the racemic mixture or the other enantiomer and each separate enantiomer was available. Different enantiomers are reasonably expected to have differing activities such that one enantiomer is generally expected to be more active than the other, due to the fact that living systems are chiral and thus preferentially process certain stereochemical configurations over others. The expectation with regards to enantiomers is that activities as they pertain to living systems are expected to be different. In re Adamson, 275 F.2d 952, 125 USPQ 233 (CCPA 1960). Indeed, as evidenced by Rothman, (-)-norfenfluramine has much lower activity at the 5-HT2B receptors which are related to increased risk of developing valvular heart disease than (+)-norfenfluramine while retaining potent 5-HT2A agonistic activity which is related to antiepileptic activity in Dravet syndrome as evidenced by Sourbron et al. Such differences can result in different adverse side effects or toxicity due to one of the isomers in the racemic mixture. Thus, the skilled artisan would have been motivated to use the optically pure (−)-norfenfluramine enantiomer for reducing potential risk of cardiac adverse effects in the method of treating an intractable epilepsy such as Dravet syndrome as taught by Baraban. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and use a (−)-norfenfluramine enantiomeric composition over (+)-norfenfluramine or the racemic mixture for treating intractable form of epilepsy such as Dravet syndrome on the reasonable expectation of success.
Response to Applicant’s arguments
Responses are limited to Applicants' arguments relevant to either reiterated or newly applied rejections.
As to the argument regarding Ex parte Robin Paul Sherrington et al., which is a decision from the Patent Trial and Appeal Board (PTAB) issued on July 9, 2025 for Patent Application 16/523,568 examined by another examiner, the arguments are not considered to be persuasive because of the following reasons: First, the scope of instant claims as amended are now different from those of the ‘568 application; each application is examined on its own merit depending on its disclosure, the state of art at the time of the invention and evidence provided by Applicant. In addition, it should be noted that the PTAB reversed the examiner’s obvious rejection only because the examiner failed to address the Bialer’s Declaration; and further, it should be noted that PTAB decisions are not legal precedent and thus they have no binding effect on examination.
For the foregoing reasons, Applicants’ arguments have not been found to be persuasive.
Conclusion
No claims are allowed.
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/BONG-SOOK BAEK/Primary Examiner, Art Unit 1611
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