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 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/16/2025 has been entered.
The Amendment filed 11/18/2025, amended claims 1 and 14, and added claims 19-29.
Claims 1, and 8-20 are pending.
Support for applicant’s amendments to the claims can be found in the original claim set of 05/14/2024, in which a therapeutically effective amount of a sigma-1 agonist or a sigma- positive modulator is administered, wherein fenfluramine is recited in a Markush group in reference to the sigma-1 positive modulator, and in Figs. 2 and 3, which show a dose response relationship with increasing fenfluramine concentrations and KCl concentration to initiate spreading depolarizations, and a box plot of time to onset of spreading depolarization with and without fenfluramine treatment.
Priority
This application claims the following priority:
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Election/Restrictions
Applicant’s election of a) fenfluramine and salts thereof as the sigma-1 agonist/sigma-1 positive modulator, and b) migraine as the disease, in the reply filed on 03/10/2025, is acknowledged.
In the course of the search, the species elections was broadened to include epilepsy as a disease and citalopram as the sigma-1 agonist/sigma-1-postive modulator.
It is noted that the 07/08/2025 Amendment to the claims limited the sigma-1-agonist or sigma-1-positive modulator to fenfluramine.
Claims 1 and 8-20 are examined on the merits herein.
REJECTIONS-NEW
Applicant’s amendments to the claims have resulted in the below new prior art rejections. Some secondary references relied upon in the previous Office Action, continue to be relied upon.
Claim Rejections - 35 USC § 102
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 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 1, 9, 14, and 19-20 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US 2019/0091179 to Morrison (published 2019, PTO-892).
Morrison teaches a method of improving neurological function in a patient by administering fenfluramine, wherein the patient has been diagnosed with traumatic brain injury (pgs. 26-27, claims 1-2, 16-17).
As evidenced by the instant specification, traumatic brain injury is a disease state associated with spreading depolarization ([0092]-[0093]).
Since Morrison administers the same sole active ingredient in therapeutically effective amounts, to the same patient population, as that taught by the instant specification and claims, it would necessarily “inhibit spreading depolarization.” See MPEP 2112.02.
Regarding claim 9, since the patients of Morrison, are diagnosed with traumatic brain injury, the patients have been diagnosed with a disease characterized by spreading depolarization, prior to administration of the fenfluramine.
Claim Rejections - 35 USC § 103
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 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.
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.
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, 9, 13-17, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 5470846 to Sandyk (published 1995, PTO-892) in view of Hamel (Serotonin and Migraine: Biology and Clinical Implications, Cephalagia, published 2007, PTO-892 of 09/18/2025) and Cleveland Clinic (Migraine Headaches, published 11/17/2021, PTO-892).
Sandyk teaches a method of treating neurological and mental disorders which are associated with and related pathogenetically to deficient serotonin neurotransmission and impaired pineal melatonin functions in human, and for treating neurological and mental disorders which are associated with or related pathogenetically to deficient serotonin neurotransmission and impaired pineal melatonin functions in humans, which comprises administering to a human in need thereof an effective amount of a composition which increases serotonin transmission to the patient to be treated followed by the application to the brain of the patient of a sufficient amount of AC pulsed magnetic field of proper intensity and frequency to treat the disorder (Col. 18, claim 1).
Sandyk teaches its compositions as comprising an effective amount of a stimulant of serotonin release, wherein fenfluramine is taught as the stimulant of serotonin release (Col. 18-19, claims 3, 9).
Sandyk exemplifies fenfluramine as a preferred active ingredient (Col. 11, lines 15-34).
Sandyk teaches its methods for the treatment of migraine (Col. 19, claim 15).
Regarding claims 1 and 14, the method of Sandyk does not explicitly teach a method of treating migraine by administering fenfluramine followed by AC pulsed magnetic field.
Hamel teaches that migraine is a consequence of a central neurochemical imbalance that involves a low serotonergic disposition (abstract).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select fenfluramine as the sole agent ingredient in a method of treating migraine in Sandyk, to arrive at instant claims 1 and 14. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Sandyk exemplifies fenfluramine as a preferred active ingredient,
-Sandyk teaches fenfluramine as a stimulant of serotonin release, and
-Hamel teaches that migraine is a consequence of a central neurochemical imbalance that involves a low serotonergic disposition.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection, to predictably arrive at a method of treating migraine by increasing serotonin levels.
Regarding claims 1 and 14, and further regarding claims 13 and 15-17, while the combination of Sandyk and Hamel teaches a method of treating migraine, if differs from that of the instantly claimed invention in that it does not explicitly teach the migraine as with or without aura.
Cleveland Clinic teaches migraines with and migraines without aura as types of migraines, wherein migraines without aura are classified as a common migraine, and wherein approximately 15-20% of people with migraine headaches experience an aura (pg. 3).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select migraine with or without aura as treated by the combined method of Sandyk and Hamel. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because Cleveland Clinic teaches migraines without aura as common, and teaches that 15-20% of patients with migraine experience an aura.
Thus, since the combination of Sandyk and Hamel teaches its method for the treatment of migraine, an ordinary skilled artisan would predictably expect this method to treat migraines with and without aura, since these types of migraines are common.
As evidenced by the instant specification, migraine is a disease state associated with spreading depolarization ([0005], [0015], [0092]-[0093]).
Since the combined method of Sandyk, Hamel, and Cleveland Clinic administer the same sole active ingredient in therapeutically effective amounts, to the same patient population, as that taught by the instant specification and claims, it would necessarily “inhibiting the spreading depolarization.” See MPEP 2112.02.
Regarding claim 9, since the patients of the combined method of Sandyk, Hamel, and Cleveland Clinic, are being treated for migraine with or without aura, the patients have been diagnosed with a disease characterized by spreading depolarization, prior to administration of the fenfluramine.
Claims 8 and 12 are rejected under 35 U.S.C. 103 as being unpatentable US Patent No. 5470846 to Sandyk (published 1995, PTO-892) in view of Hamel (Serotonin and Migraine: Biology and Clinical Implications, Cephalagia, published 2007, PTO-892 of 09/18/2025) and Cleveland Clinic (Migraine Headaches, published 11/17/2021, PTO-892). as applied to claims 1, 9, 13-17, and 19-20 above, and further in view of Silberstein (Preventive Migraine Treatment, Neurologic Clinics, published 2009, PTO-892 of 09/18/2025).
Sandyk, Hamel, and Cleveland Clinic are applied as discussed above and incorporated herein.
Regarding claim 8. while the combination of Sandyk, Hamel, and Cleveland Clinic teaches a method of treating migraine with or without aura by administering fenfluramine, it differs from that of the instantly claimed invention in that it does not teach prophylactic administration.
Silberstein teaches that preventative therapy is required for patients with frequent severe headaches and that preventative therapy reduces frequency, duration and severity of migraine attacks (abstract). Preventative therapy also improves responses to acute treatment, which can result in reduced health care resource use and an improved quality of life.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select prophylactic administration of the combined method of Sandyk, Hamel, and Cleveland Clinic, to arrive at instant claim 8. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because Silberstein teaches preventative therapy as reducing the frequency duration and severity of migraine.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive at a method that reduces health care resource use and improves patient quality of life.
Regarding claim 12, while the combination of Sandyk, Hamel, and Cleveland Clinic teaches a method of treating migraine with or without aura by administering fenfluramine, it differs from that of the instantly claimed invention in that it does not teach administration between 30 seconds and 60 minutes after diagnosis.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select administration of the combined method of Sandyk, Hamel, and Cleveland Clinic, between 30 seconds and 60 minutes after diagnosis, to arrive at instant claim 12. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because Silberstein teaches preventative therapy as reducing the frequency duration and severity of migraine.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive at a method that provides an immediate prophylactic effect to decrease the incidence and/or severity of the migraines.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 5470846 to Sandyk (published 1995, PTO-892) in view of Hamel (Serotonin and Migraine: Biology and Clinical Implications, Cephalagia, published 2007, PTO-892 of 09/18/2025) and Cleveland Clinic (Migraine Headaches, published 11/17/2021, PTO-892), as applied to claims 1, 9, 13-17, and 19-20 above, and further in view of Akben et al. (Classification of multi-channel EEG signals for migraine detection, Biomedical Research, published 2016, PTO-892 of 09/18/2025).
Sandyk, Hamel, and Cleveland Clinic are applied as discussed above and incorporated herein.
While the combination of Sandyk, Hamel, and Cleveland Clinic teaches a method of treating migraine with or without aura by administering fenfluramine, it differs from that of the instantly claimed invention in that it does not teach performing an EEG.
Akben teaches diagnosing migraine by EEG. Akben teaches that T3, F7, O1, and O2 channels are the most decisive for diagnosis of migraine based on PSD magnitude increase under flash stimulation (abstract).
Akben teaches that since the diagnosis of migraine is a difficult task for a neurologist, automatic diagnosis and determination by administering EEG has great importance (pg. 746, Discussion).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to add EEG diagnosis of migraine to the combined method of Sandyk, Hamel, and Cleveland Clinic, to arrive at instant claim 10. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-an ordinarily skilled artisan would be motivated to diagnosis a disease prior to treating a disease,
-Akben teaches that migraine can be diagnosed by EEG and Akben teaches that the diagnosis of migraine is a difficult task for a neurologist and that automatic diagnosis and determination by administering EEG, has great importance
As such, an artisan having ordinary skill in the art would have been motivated to make such an addition to predictably arrive at a method that more accurately diagnoses migraine.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 5470846 to Sandyk (published 1995, PTO-892) in view of Hamel (Serotonin and Migraine: Biology and Clinical Implications, Cephalagia, published 2007, PTO-892 of 09/18/2025), Cleveland Clinic (Migraine Headaches, published 11/17/2021, PTO-892).and Akben et al. (Classification of multi-channel EEG signals for migraine detection, Biomedical Research, published 2016, PTO-892 of 09/18/2025), as applied to claims 1, 9-10, and 13-17 above, and further in view of Bewernitz (Int. J. Clin. Pharmacol. Ther., published 2012, IDS of 05/14/2024).
Sandyk, Hamel, Cleveland Clinic, and Akben are applied as discussed above and incorporated herein.
While the combination of Sandyk, Hamel, Cleveland Clinic, and Akben teaches a method of diagnosing migraine with EEG and a method of treating migraine with or without aura by administering fenfluramine, it differs from that of the instantly claimed invention in that it does not teach performing a first EEG, administering fenfluramine, and performing a second EEG.
Bewernitz teaches electroencephalogram-based pharmacodynamic measures (see whole document).
Pharmacokinetics and pharmacodynamics can provide a useful modeling framework for predicting drug activity and can serve as a basis for dose optimization (abstract). The electroencephalogram (EEG) is a widely available and non-invasive tool for recording brain-wave activity (abstract). Characterization of such a drug-induced EEG effect can produce pharmacokinetic/pharmacodynamic models useful for titrating drug levels and expediting development of chemically similar drug analogs (abstract).
Pharmacokinetics and pharmacodynamics are fields of study which aim to provide a means to predict drug activity. Pharmacodynamic effect models are designed to bypass the need to collect and assay fluid samples by predicting underlying drug concentration based on the measured effect (pg. 162, Col. 1). These models can provide a safe, rapid and inexpensive method to help ensure that a drug’s concentration remains within the safe, therapeutic range (pg. 162, Col. 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to add a step of evaluating the pharmacokinetic and pharmacodynamics of fenfluramine by EEG, as taught by Bewernitz, in the combined method of Sandyk, Hamel, Cleveland Clinic, and Akben, to arrive at instant claim 11. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-Bewernitz teaches that characterization of a drug-induced EEG effect can produce pharmacokinetic/pharmacodynamic models useful for titrating drug levels and expediting development of chemically similar drug analogs, and
-Bewernitz teaches that these models can provide a safe, rapid and inexpensive method to help ensure that a drug’s concentration remains within the safe, therapeutic range.
As such, an artisan having ordinary skill would have been motivated to make this addition to predictably arrive at a method that accurately provides feedback on the effectiveness of fenfluramine to treat the migraine, and which optimizes the amount of fenfluramine administered.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 5470846 to Sandyk (published 1995, PTO-892) in view of Hamel (Serotonin and Migraine: Biology and Clinical Implications, Cephalagia, published 2007, PTO-892 of 09/18/2025) and Cleveland Clinic (Migraine Headaches, published 11/17/2021, PTO-892). as applied to claims 1, 9, 13-17, and 19-20 above, and further in view of MedlinePlus (Familial hemiplegic migraine, published 2014, PTO-892 of 09/18/2025).
Sandyk, Hamel, and Cleveland Clinic are applied as discussed above and incorporated herein.
While the combination of Sandyk, Hamel, and Cleveland Clinic teaches a method of treating migraine with or without aura by administering fenfluramine, it differs from that of the instantly claimed invention in that it does not teach the migraine as familial hemiplegic migraine.
Medline teaches familial hemiplegic migraine as a form of migraine that runs in families that typically begin in childhood or adolescence. Medline teaches these migraines as migraine with aura (pg. 1, Description).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select familial hemiplegic migraine as the migraine treated in the combined method of Sandyk, Hamel, and Cleveland Clinic, to arrive at instant claim 18. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-the combined method of Sandyk, Hamel, and Cleveland Clinic teaches a method of treating migraine with aura, and
-Medline teaches familial hemiplegic migraine as a migraine with aura.
As such, an artisan having ordinary skill would have been motivated to make such a selection to predictably arrive at a method that successfully treats familial hemiplegic migraine.
Response to Arguments
Since the rejections are new, the arguments over the previously relied upon prior art references are no longer pertinent.
Conclusion
No claims are allowed.
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/LAUREN WELLS/Examiner, Art Unit 1622