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 .
Election/Restrictions
Applicant’s election without traverse of Group I, drawn to a method of treating a disease in a subject in need thereof, comprising administering to the subject: (i) a therapeutically effective amount of tezampanel, a pharmaceutically acceptable salt thereof, or a prodrug thereof; and (ii) a therapeutically effective amount of a benzodiazepine, a pharmaceutically acceptable salt thereof, or a prodrug thereof; and nerve agent-induced seizure as the species of disease, and clorazepate as the species of benzodiazepine in the reply filed on May 28, 2026 is acknowledged.
Status of the Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on May 28, 2026, wherein claims 1, 14-15, 17-18, 20-23 and 25-26 are amended; claims 2-9, 11-13 and 16 are canceled; and claims 10, 19, 24 and 27 are unchanged.
Claims 1, 10, 14-15 and 17-27 are pending and under examination in accordance with the elected species.
Priority
The instant application 18/566,735 filed on December 4, 2023 is a 371 of PCT/US2022/032783 filed on June 9, 2022, which claims priority to, and the benefits of U.S. Provisional Application No.
63/208,885 filed on June 9, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 4/30/2024, 7/28/2025 and 5/28/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Please note that foreign references without an English translation but have an English translation of the abstract will only have the abstract considered by the Examiner.
Drawings
The drawings are objected to because of the following informalities: line with the
Fig. 1: the “control” and “2.5 mg/kg” groups both uses the same square symbol (
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), it is not clear which line with a square is supposed to be a control or 2.5 mg/kg group shown as follows (see arrow):
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.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 10, 14-15 and 17-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Instant claim broadly recites “prodrug thereof”, the specification does not reasonably convey to one of ordinary skill in the art that Applicant was in possession of the full scope of the genus prodrug of tezampanel and the genus prodrug of benzodiazepine.
First, the disclosure fails to identify any particular species of prodrug of benzodiazepine, aside from a broad recitation in the specification that any agent converted in whole or in part to a targeted compound are contemplate for use in the claimed invention (see paragraph [0139] of the specification). The disclosure fails to describe any representative prodrug species across the claimed genus, and no guidance identify which prodrug of benzodiazepine administered at any therapeutically effective amount can retain the same activity for treating the full scope of nerve agent-induced seizure. The mere boiler plate reference to “prodrug” does not provide adequate blaze marks to the vast genus encompassed by the claims.
Second, the specification only discloses single prodrug species of tezampanel, and that is dasolampanel having the structure of:
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(see e.g., [0119] of the specification); and provides no guidance in identifying other prodrug species of tezampanel or synthetic preparation thereof. While applicant is in possession of dasolampanel as the prodrug of tezampanel, applicant is not in possession of the full genus of prodrug of tezampanel.
Therefore, in view of the foregoing, applicant is not in the possession of the entire scope of the genus prodrug of tezampanel and the genus prodrug of benzodiazepine.
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 (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.
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.
Claims 1, 10, 14-15 and 17-25 are rejected under 35 U.S.C. 103 as being unpatentable over Rogawski et al. (WO 2018/169798 A1), in view of Figueiredo et al. (The Journal of Pharmacology and Experimental Therapeutics, 2011. Vol. 336(2): 303–312; cited in the IDS filed on July 28, 2025).
Rogawski et al. teaches current standard-of-care emergency treatment for organophospate nerve agent-induced status epilepticus is with a benzodiazepine such as midazolam; Oftentimes, status epilepticus is refractory to benzodiazepines; thus, the combination of a neurosteroid, an AMPA receptor antagonist, and optionally, a benzodiazepine is highly effective in treating organophosphate nerve agent induced status epilepticus (see e.g., [0035]). Rogawski et al. further teaches a method of preventing or terminating a seizure, or accelerating the termination or abortion of an impending seizure in a subject in need thereof, comprising co-administration to the subject of an effective amount of a neurosteroid and an [Symbol font/0x61] amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist selected from the group consisting of, inter alia, perampanel and tezampanel (as known as LY-293,558) (see e.g., claims 35 and 77; [0064])), and further comprising co-administration of a benzodiazepine selected from the group consisting of, inter alia, clorazepate and midazolam (see e.g., claims 51 and 62; [0066]); wherein the subject has been exposed to or is at risk of being exposed an organophosphate nerve agent (see e.g., claim 36), including, inter alia, diisopropylfluorophosphate (DFP) and soman (see e.g., [0045]); wherein the subject is human (see e.g., claim 86). Rogawski et al. further teaches active agents that are co-administered can be delivered concurrently (i.e., at the same time) or sequentially (see e.g., [0013]). Rogawski et al. further teaches the AMPA receptor antagonist is administered at a dose that is less than about 10%, 15%, 25%, 50% or 75% of established doses for their administration for the prevention or mitigation of an epileptic seizure, or for mitigation of depression symptoms; and AMPA receptor antagonist is administered at a dose in the range of about 0.5 mg/kg to about 4.0 mg/kg (see e.g., [0111]). Rogawski et al. further teaches the benzodiazepines are administered at a dose that is less than about 10%, 15%, 25%, 50% or 75% of established doses for their administration for the prevention or mitigation of an epileptic seizure; and benzodiazepine is administered at a dose in the range of about 0.5 mg/kg to about 4.0 mg/kg (see e.g., [0112]). Rogawski et al. further teaches in Example 1, midazolam (1.8 mg/kg, IM) or triple therapy (Midazolam 1.8 mg/kg, IM + Allopregnanolone 6 mg/kg, IM + Perampanel 2 mg/kg, IM) were administered to rats with DFP-induced status epilepticus 40 minutes after DFP exposure; wherein the rats were administered with atropine sulfate and pralidoxime 1 minutes after DFP exposure (see e.g., [0130]-[0134]). Rogawski et al. further teaches said triple combination stopped behavior and electrical seizures in 100 % of the animal tested (see e.g., [0136]); and midazolam alone was ineffective in reducing the behavioral seizure scores (see e.g., [0028]).
Rogawski et al. does not expressly teach tezampanel.
Figueiredo et al. teaches LY293558 (50 mg/kg i.p) is effective against soman-induced seizures and neuropathology, when administered 1 h after soman exposure in rats (see e.g., abstract; p. 304, right column, “Soman Administration and Drug Treatment”, 1st paragraph). Figueiredo et al. teaches LY293558 stopped seizures induced by soman and reduced the total duration of status epilepticus, monitored by electroencephalographic recordings within a 24 h-period after exposure (see e.g., abstract). Figueiredo et al. teaches LY293558, [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid], is a GluK1/[Symbol font/0x61]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist (see e.g., abstract). Please note the LY293558 taught by Figueiredo et al. is the claimed tezampanel; and soman is a nerve agent. Figueiredo et al. further teaches
benzodiazepines are considered to be the first line of defense against nerve agent-induced status epilepticus, but the effectiveness of benzodiazepines is transient (seizures recur), and it is reduced or lost if administration is delayed beyond 30 to 40 min after nerve agent exposure (see e.g., p. 304, left column, line 4-10); However, LY293558 is a potential new emergency treatment for nerve agent exposure that can be expected to be effective against seizures and brain damage even with late administration (see e.g., abstract).
In the present case, Rogawski et al. clearly teaches the administration of an effective amount (about 0.5 mg/kg to about 4.0 mg/kg) of a AMPA receptor antagonist, including tezampanel, and an effective amount (about 0.5 mg/kg to about 4.0 mg/kg) of benzodiazepine for terminating a seizure or accelerating the termination or abortion of an impending seizure in a subject exposed to an organophosphate nerve agent. The difference between the method of Rogawski et al. and the claimed method is that the claimed method selectively chooses to administer tezampanel as the AMPA receptor antagonist. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Rogawski et al. by selectively choose to administer an effective amount of tezampanel as the AMPA receptor antagonist with an effective amount of benzodiazepine for treating organophosphate nerve agent induced status epilepticus. One would have been motivated to do so, because Figueiredo et al. teaches the administration of AMPA receptor antagonist LY293558, also known as tezampanel as taught by Rogawski et al., 1 h after soman exposure is effective against soman-induced seizures. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of a therapeutically effective amount of tezampanel as the AMPA receptor antagonist and a therapeutically effective amount of a benzodiazepine to a subject exposed to an organophosphate nerve agent would successfully terminating a seizure or accelerating the termination or abortion of an impending seizure; and that renders obvious the limitation of “treating nerve agent-induced seizure”.
Regarding the limitation of “wherein the subject is human” in claim 10, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to select human as the subject in the method of Rogawski et al. and Figueiredo et al. set forth above, because Rogawski et al. teaches the subject treated is a human. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the tezampanel and the benzodiazepine can successfully be administered to a human subject.
Regarding the limitation of “wherein the benzodiazepine is clorazepate” in claim 19, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Rogawski et al. and Figueiredo et al. set forth above by selectively administering an effective amount of clorazepate as the benzodiazepine, because Rogawski et al. clearly teaches clorazepate in the list of benzodiazepine alternatives that are contemplated for use in terminating a seizure. One would have a reasonably expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of a therapeutically effective amount of clorazepate as the benzodiazepine in the method of Rogawski et al. and Figueiredo et al. set forth above would successfully terminating a seizure or accelerating the termination or abortion of an impending seizure.
Regarding the limitation of “wherein the method further comprises administering to the subject a supportive care” in claim 24, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Rogawski et al. and Figueiredo et al. set forth above by further administering atropine sulfate and pralidoxime to the subject, because Rogawski et al. teaches the rats with status epilepticus induced by nerve agent (DFP) received atropine sulfate and pralidoxime after the nerve agent exposure in addition to the triple therapy comprising a benzodiazepine and a AMPA receptor antagonist successfully stopped behavior and electrical seizures. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected by further administering atropine sulfate and pralidoxime to the subject would have successfully terminating a seizure or accelerating the termination or abortion of an impending seizure.
Regarding the limitation of “arrests the nerve agent-induced seizure” in claim 17, the limitation of “alleviates an adverse effect of tezampanel, the pharmaceutically acceptable salt thereof, or the prodrug thereof” in claim 18, the limitation of “reduces the frequency, severity, or duration of the nerve agent-induced seizure” in claim 20, the limitation of “arrests the nerve agent-induced seizure” in claim 21, and the limitation of “alleviates an adverse effect of the benzodiazepine, the pharmaceutically acceptable salt thereof, or the prodrug thereof” in claim 22, the limitation of “the adverse effect is a sedating effect” in claim 23, and the limitation of “reduces the frequency, severity, or duration of the nerve agent-induced seizure” in claim 25, each of these limitations simply express the intended result or the intended outcome of the method step(s) positively recited. According to MPEP 2145, II "[t]he fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)). Applying the same logic to the instant process claim(s), the fact that the prior art teaches or render obvious the same method steps, said intended result or intended outcome would naturally flow from the method of Rogawski et al. and Figueiredo et al. set forth above since products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances.
Regarding the limitation of “wherein the nerve agent-induced seizure is resistant to a treatment without tezampanel, the pharmaceutically acceptable salt thereof, or the prodrug thereof” in claim 14, and the limitation of “wherein the nerve agent-induced seizure is resistant to a treatment with the benzodiazepine, the pharmaceutically acceptable salt thereof, or the prodrug thereof and without tezampanel, the pharmaceutically acceptable salt thereof, or the prodrug thereof” in claim 15, the difference between the method of Rogawski et al. and Figueiredo et al. sets forth above and the claimed method is that the prior art does not expressly teach the organophosphate nerve agent induced status epilepticus or seizure is resistant to benzodiazepine. It would have been prima facie to one of ordinary skill in the art at the time the application was filed to modify the method of Rogawski et al. and Figueiredo et al. set forth above and selectively choose the nerve agent-induced seizure that is refractory to benzodiazepine administered alone as taught by Rogawski et al. One would have been motivated to do so, because Rogawski et al. teaches organophospate nerve agent-induced status epilepticus is oftentimes refractory to benzodiazepines, and the combination of neurosteroid, an AMPA receptor antagonist, and a benzodiazepine is more effective than benzodiazepine alone, and further teaches said combination can stopped behavior and electrical seizures in rats with DFP-induced seizure whereas benzodiazepine alone cannot. One would have a reasonable expectation of success to arrive the claimed invention, because one would have reasonably expected that the administration of the therapeutically effective amount of tezampanel and the therapeutically effective amount of benzodiazepine is more effective when compared to benzodiazepine alone; and therefore, said combination can successfully terminating a seizure or accelerating the termination or abortion of an impending seizure that is refractory to benzodiazepines administered alone in a subject exposed to nerve agent. Please note a seizure that is refractory to benzodiazepines renders obvious the limitation of “a treatment without tezampanel” in claim 14, and “a treatment with benzodiazepine and without tezampanel” in claim 15, because benzodiazepines does not contain tezampanel. Please also note a organophosphate nerve agent-induced seizure that is refractory renders obvious “the nerve agent-induced seizure is resistant”.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 1, 10, 14-15 and 17-27 are rejected under 35 U.S.C. 103 as being unpatentable over Rogawski et al. (WO 2018/169798 A1), in view of Figueiredo et al. (The Journal of Pharmacology and Experimental Therapeutics, 2011. Vol. 336(2): 303–312) as applied to claims 1, 10, 14-15 and 17-25 above, and further in view of Schmidt (Epilepsy & Behavior, 2010. Vol. 19: 176–181; cited in the IDS filed on July 28, 2025).
The teachings of Rogawski et al. and Figueiredo et al. are set forth above and applied as before.
Rogawski et al. and Figueiredo et al. does not teach measured by Likert Scale Score as claimed in claims 26-27; However, Rogawski et al. teaches determination of a reduction of the frequency, severity and/or duration of seizures can be made by comparing patient status before and after treatment (see e.g., [0019]).
Schmidt teaches the Likert scale measures parental/guardian global evaluation of
seizure severity and the patient's condition using a 7-point scale (see e.g., p. 178, left column, “2.1.5 Likert scale of seizure severity”).
Regarding claim 26, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Rogawski et al. and Figueiredo et al. set forth above to measure the seizure severity and the condition of the subject using Likert Scale Score as taught by Schmidt before and after the treatment. One would have been motivated to do so, because Schmidt teaches Likert scale is a tool to measure seizure severity and the patient's condition in a 7-point scale; and Rogawski et al. teaches the severity of seizures before and after treatment can be compare to determine the reduction. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the severity of seizure of the subject can successfully be measured using Likert Scale Score before and after the treatment; and the score obtained after the treatment can successfully be compared to determine a reduction of a severity.
Regarding the limitation of “the administration results in a reduced LSS of the subject” in claim 27, this limitation simply expresses the intended result or the intended outcome of the method step(s) positively recited. According to MPEP 2145, II "[t]he fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)). In the present case, even though Rogawski et al. and Figueiredo et al. does not expressly teach measuring the severity of the nerve agent-induced seizure in a subject using a Likert Scale Score; However, the fact that the prior art teaches or render obvious the same method steps, said intended result or intended outcome would naturally flow from the method of Rogawski et al. and Figueiredo et al. set forth above. Therefore, by practicing the method of Rogawski et al. and Figueiredo et al. and measuring the seizure severity and the condition of the subject using Likert Scale Score as taught by Schmidt before and after the treatment (see rejection above), one will also result in “a reduced LSS of the subject”.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chihyi Lee whose telephone number is (571)270-0663. The examiner can normally be reached Monday - Friday 8:30 am - 5:00 pm EST.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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