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, 4, 7, 9-10, 14-26 and 49 filed August 04, 2023 are currently pending. Claim 1 is independent.
Priority
Acknowledgement is made of the continuation of PCT/US2021/060459 filed 11/23/2021 which claims priority to U.S. Provisional Application 63117037 filed 11/20/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/04/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112-Paragraph B
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4, 7, 9-10, 14-26 and 49 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 1 recites the broad recitation of a ganaxolone plasma concentration in the subject of at least about 800 ng/mL throughout the target concentration period of at least about 2.5 hours up to 5 days. The claim also recites a ganaxolone plasma concentration in the subject of at least about 1200 ng/mL throughout the target concentration period of at least about 2.5 hours up to 5 days which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 9 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 9 recites the limitation "the intravenous bolus". There is in insufficient antecedent basis for this limitation in the claim, as the claim from which it depends (claim 1) does not recite “an intravenous bolus” anywhere within the body of the claim.
Accordingly, one of ordinary skill in the art would not have been apprised of the metes and bounds of the subject matter for which Applicant was presently seeking protection.
Claims 20-22, 26 recites the limitation "wherein the continuous intravenous infusion is administered for a treatment period of about 96 hours (claim 20), or 36 hours (Claim 21) or a period of at least about 2 hours to about 96 hours after the initiation of the continuous intravenous infusion (claim 22)". There is insufficient antecedent basis for the limitation “the continuous infusion” in the claim, as the claim from which it depends (claim 1) does not recite “a continuous infusion” anywhere within the body of the claim. Accordingly, one of ordinary skill in the art would not have been apprised of the metes and bounds of the subject matter for which Applicant was presently seeking protection.
Claim 49 is directed to the method of claim 1 further comprising orally administering ganaxolone to the subject after the taper period is stopped. There is insufficient antecedent basis for the limitation of “the taper period is stopped” as the claim from which it depends (claim 1) does not recite a taper period or stopping a taper period. Accordingly, one of ordinary skill in the art at the time of the invention would not have been reasonably apprised of the metes and bounds of the subject matter for which Applicant was presently seeking protection.
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.
Claim(s) 1, 4, 7, 9-10, 14-26 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Zhang (WO2016/127170 published 08/11/2016), Saporito (WO2018/071803 published 04/19/2018) and Reddy (US2014/0057885 published 02/27/2014).
Claim interpretation is as follows: Claim 1 is directed to a method for treating super refractory status epilepticus (SRSE), comprising: a) rapidly weaning a subject in need thereof off an anesthetic agent; and b) administering to the subject a therapeutically effective amount of ganaxolone in an amount sufficient to suppress unacceptable ictal activity, wherein ganaxolone is administered for a target concentration period of at least about 2.5 hours up to about 5 days, and produces a ganaxolone plasma concentration in the subject of at least about 800 ng/ml, at least about 850 ng/ml, at least about 900 ng/ml, at least about 1000 ng/ml or at least about 1200 ng/ml throughout the target concentration period.
Given the broadest reasonable interpretation of the claims, the dosing strategy of the claims embrace a sequential administration of weaning anesthetic followed by administration of ganaxolone as found in Examples 1-2 of the instant specification (pages 69-70). The claims also embrace a sequential administration of ganaxolone found in step (b) prior to the rapidly weaning off an anesthetic in step (a). This situation is found in [0185] of the specification, wherein ganaxolone was administered on hospital day 17 using an IV bolus, followed by infusion over 6 days (with boluses as needed for breakthrough seizures) (FIG. 5). Anesthetic midazolam was discontinued on day 2 of GNX IV protocol; anesthetic ketamine was discontinued by day 8 with the assistance of phenobarbital loads and maintenance Anakinra was initiated on day 2 of GNX IV protocol (hospital day 19).
Zhang (WO2016/127170 published 08/11/2016) teaches the method of treating a seizure disorder including super refractory status epilepticus in a subject in need comprising administering an injectable formulation of a therapeutically effective amount of ganaxolone (claims 1, 30-31). Regarding claims 7 and 9, Zhang teaches administering said ganaxolone over multiple bolus infusions wherein each bolus provides a plasma Cmax of ganaxolone of about 100 ng/mL to about 1000 ng/mL to the patient, wherein each bolus comprises from about 1 mg/kg to about 20 mg/kg of ganaxolone (claims 39-44). Said bolus administration corresponds to a large dose in a short period of 1-30 min ([0018]). Zhang further teaches that an intravenous infusion of ganaxolone is administered after the bolus for a duration of 1-10 days at a dose of 1-10 mg/kg per hour ([0074]-[0077], claims 45, 47). Said intravenous infusion commences within 1-5 hours following the bolus dose ([0075]-[0077]).
As recited in paragraph [0175] of the specification a bolus of 30 mg to a patient ≥ 40 kg for 3 minutes, followed by a continued IV infusion of 80 mg ganaxolone for 2 hours is sufficient to yield a target ganaxolone plasma concentration of at least 800 ng/mL for a person greater than 40 kg, wherein the target concentration period is for at least about 2.5 hours. Said dosing corresponds to a 0.75 mg/kg bolus, which overlaps with the “about” 1 mg/kg bolus dose administered in the regimen of Zhang ([0015], claims 39-44). Additionally, the dose of 1-10 mg/kg per hour for a 1-10 day duration of infused ganaxolone overlaps with the1.33 mg/kg/hour infusion of ganaxolone following the bolus of ganaxolone as recited in [0175] of the specification and also overlaps with the target concentration period of at least about 2.5 hours found within the claims. Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Further, the duration of said ganaxolone intravenous infusion (1-10 days at a dose of 1-10 mg/kg per hour) taught by Zhang overlaps with the duration of the continuous infusion taught within claims 20-22 (at least 2 hours to 4 day/96 hours).
Regarding the scope of claims 23-25, wherein the amount of ganaxolone administered to the subject per hour by continuous infusion is increased after about 24 hours from the initiation of the continuous infusion or is increased for a period of 96 hours after the initiation of the continuous infusion, Zhang provides an infusion dose range of about 1-10 mg/kg per hour for a duration of 1-10 days ([0074]-[0077], claims 45, 47). Said infusion dose range taught by Zhang allows for increasing the infused ganaxolone dose from about 1 mg/kg/hr up to a 10 mg/kg/hour during the 1-10 day infusion cycle range as well as decreasing the infused ganaxolone from about 10 mg/kg/hr up down to about 1 mg/kg/hour during the 1-10 day infusion cycle.
Regarding the scope of claims 14-19, wherein the amount of ganaxolone administered to the subject per hour by continuous infusion is decreased by 50% about 2 hours after the initiation of the continuous infusion (claim 14), or is decreased about 55-75% 10-14 hours after the initiation of the continuous intravenous infusion (claims 16-17), or a second reduction in amount of ganaxolone occurs wherein the first reduction occurs about 2 hours after the initiation of the continuous infusion and 55-75% 10-14 hours after the initiation of the continuous intravenous infusion (claims 18-19), Zhang teaches tapering/step down infusions following the initial dose ([0077], claims 45, 47-49). Step down doses/tapered doses which are 50-75% of the infusion dose are taught by Zhang. Second step down doses/tapered doses which are 5%-95% of the first step down dose are also taught by Zhang ([0077]). Zhang additionally teaches said ganaxolone is administered sequentially with anesthetics to the status epilepticus patient (claims 50-59).
The difference between the presently claimed methodology and that embraced within Zhang is that Zhang does not specifically teach wherein the super-refractory status epilepticus patient is rapidly weaned off an anesthetic agent. As recited in paragraph [0009] of the specification, rapid weaning off anesthesia reads on a reduction of at least 20% or more per day.
Saporito (WO2018/071803 published 04/19/2018) teaches treating status epilepticus in a subject in need comprising administering a therapeutically effective amount of a neurosteroid (abstract). Ganaxolone is taught as a potent neurosteroid for treating said status epilepticus patient ([0002], [0006], [0020]-[0021]) Saporito teaches that status epilepticus is a serious seizure disorder in which the epileptic patient experiences a seizure lasting more than 5 minutes, or more than one seizure in a five minute period without recovering between seizures. Saporito teaches that status epilepticus is treated in the emergency rooms with anticonvulsants. Patients who fail with anticonvulsants and treated with a combination of anesthetics or barbiturates in combination with anticonvulsants. Those who fail anticonvulsant therapy and epileptic therapy are considered refractory. Super-refractory status epilepticus (SRSE) patients are refractory patients that have continued or recurrent seizures 24 hours or more. Said SRSE patients are associated with high rates of mortality and morbidity. Saporito teaches that SRSE patients are being treated with anesthetic therapy and are periodically weaned off the general anesthetic to access their therapeutic response ([0002]).
Reddy (US2014/0057885 published 02/27/2014) teaches treating super-refractory status epilepticus in a subject in need comprising administering a therapeutically effective amount of the neurosteroid allopregnanolone in combination with an anesthetic ([0022], [0028]-[0030], claims 1, 165). Reddy teaches weaning off anesthetics in the patient followed by the administration of the neurosteroid. Linear weaning, including a 20% linear weaning of anesthesia to the status epilepticus patient is embraced within the methodology of Reddy ([0158]-[0160]).
Therefore, one of ordinary skill in the art prior to the time of the invention knowing that administration of the art-recognized neurosteroid ganaxolone with anesthetics is an efficacious strategy at treating super-refractory status epilepticus in a subject in need wherein ganaxolone is administered over multiple bolus infusions wherein each bolus provides a plasma Cmax of ganaxolone of about 100 ng/mL to about 1000 ng/mL to the patient, wherein each bolus comprises from about 1 mg/kg to about 20 mg/kg of ganaxolone and said therapeutic regimen further includes intravenous infusion of ganaxolone after the bolus for a duration of 1-10 days at a dose of 1-10 mg/kg per hour as taught by Zhang, said skilled artisan would have found it prima facie obvious to rapidly wean the super-refractory status epilepticus patient off said anesthetic agent following receiving neurosteroid ganaxolone therapy in view of Saporito and Reddy, arriving at the claimed methodology with a reasonable expectation of success.
MPEP 2143 provides a rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, it was known in the prior art that SRSE patients are being treated with anesthetic therapy and are periodically weaned off the general anesthetic to access their therapeutic response, coupled with the knowledge that rapid weaning of said anesthetic regimen is a known strategy in the treatment of super refractory status epilepticus patient with neurosteroid therapy. Consistent with this reasoning, it would have been obvious to have selected the anesthetic weaning technique in the neurosteroid treatment of super-refractory status epilepticus patient as taught by the combination of Saporito and Reddy and apply it to the anesthetic and neurosteroid ganaxolone super refractory status epilepticus therapeutic regimen from within the prior art of Zhang above, arriving at the claimed methodology yielding no more than one would expect from such an arrangement.
Regarding the scope of claims 14-19 and 26, wherein the amount of ganaxolone administered to the subject per hour by continuous infusion is decreased by 50% about 2 hours, and the scope of claims 23-25 wherein the amount of ganaxolone administered by continuous infusion is increased after about 24 hours from the initiation of said continuous infusion, while Zhang does not explicitly teach when the initial tapering/step down dose occurs following the initial intravenous infusion of ganaxolone to the status epilepticus patient, nor does Zhang explicitly teach the ramp up dose 24 hours following the initiation of the continuous infusion, the optimum step down dosing cycle of ganaxolone, or alternatively, the optimum step up dosing cycle of ganaxolone to the super-refractory status epilepticus patient being treated with anesthetics and receiving ganaxolone intravenous infusions would have been a matter well within the insight of one of ordinary skill in the art. Such a determination would have been made in accordance with a variety of factors, pharmacological considerations, such as activity, efficacy, pharmacokinetics and toxicology profiles of the combined regimen, as well as the age, weight, sex, diet and severity of the medical condition of the patient. Thus, the ramp up and step down dosing cycles of ganaxolone to the super-refractory status epilepticus patient that would have been employed would have varied widely and, in the absence of evidence to the contrary, the current claimed specific administration regimen is not seen to be inconsistent with one that would have been determined by the skilled artisan and the prior art of Zhang, Saporito and Reddy above. Furthermore, absent and evidence demonstrating a patentable difference between the ganaxolone compositions administered and the criticality of the claimed ramp up and step down dosing cycle of ganaxolone to the super-refractory status epilepticus patient, the determination of the optimum or workable frequency of administration given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)(”[W]here the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the workable ranges by routine experimentation.”)
Lastly, regarding the limitation directed to wherein the subject is weaned off the anesthetic agent until unacceptable ictal activity return (claim 4), Reddy teaches that the goal of therapy with general anesthesia is to induce a “burst suppression” state in an attempt to block the excitotoxic cerebral damage believed to occur as a result of the continued seizure activity in the brain. The goal of the neurosteroid therapy is that when a patient is weaned from the general anesthesia, the patient will no longer have clinical or electographic seizure activity ([0272]-[0273]). Accordingly, said skilled artisan would have found it prima facie obvious to wean off the anesthesia until unacceptable intense electrical activity in the brain occurs during a seizure (“ictal activity” returns), in order to titrate the right level of anesthesia that still provides burst suppression state in the status epilepticus, providing the capacity to block the excitotoxic cerebral damage in the afflicted patient.
Claim(s) 49 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Zhang (WO2016/127170 published 08/11/2016), Saporito (WO2018/071803 published 04/19/2018) and Reddy (US2014/0057885 published 02/27/2014) as applied to claims 1, 4, 7, 9-10, 14-26 above in view of Shaw (WO2007/062266 published 05/31/2007).
As disclosed above, the combination of Zhang, Saporito and Reddy render obvious the administration of ganaxolone with anesthetics to treat super-refractory status epilepticus in a subject in need wherein ganaxolone is administered over multiple bolus infusions wherein each bolus provides a plasma Cmax of ganaxolone of about 100 ng/mL to about 1000 ng/mL to the patient, wherein each bolus comprises from about 1 mg/kg to about 20 mg/kg of ganaxolone and said therapeutic regimen further includes intravenous infusion of ganaxolone after the bolus for a duration of 1-10 days at a dose of 1-10 mg/kg per hour, and wherein said status epilepticus patient is rapidly weaned off said anesthetic agent following receiving ganaxolone therapy.
The difference between the methodology of Zhang, Saporito and Reddy and that of the present claims is that neither Zhang, Saporito nor Reddy explicitly teach orally administering ganaxolone to the subject after the taper period is stopped.
Shaw (WO2007/062266 published 05/31/2007) teaches oral formulations of the neurosteroid ganaxolone that yield a mean blood plasma concentration AUC 0-48 hours from about 400 to about 1200 ng/mL*h when a dose of 200-500 mg of ganaxolone is orally administered (abstract, [0002]- [0004], [0029], claim 150). Said pharmacokinetic profile of 400-1200 ng/mL*h taught by Shaw overlaps with the plasma concentration of claim 1 that is efficacious at suppressing unacceptable ictal activity. Shaw also teaches that said formulation is efficacious in the treatment of status epilepticus ([0418]).
Therefore, one of ordinary skill in the art of treating super-refractory status epilepticus in a subject in need knowing that administration of the art-recognized neurosteroid ganaxolone with anesthetics is an efficacious strategy at treating super-refractory status epilepticus in a subject in need wherein ganaxolone is administered over multiple bolus infusions wherein each bolus provides a plasma Cmax of ganaxolone of about 100 ng/mL to about 1000 ng/mL to the patient, wherein each bolus comprises from about 1 mg/kg to about 20 mg/kg of ganaxolone and said therapeutic regimen further includes intravenous infusion of ganaxolone after the bolus for 24 hours for a duration of 1-10 days at a dose of 1-10 mg/kg per hour as taught by Zhang, coupled with the knowledge that (1) it is known in the art to taper or step down the dose of intravenously infused ganaxolone after the first infusion as taught by Zhang, and (2) rapid weaning of said anesthetic regimen is a known strategy in the treatment of super refractory status epilepticus patient with neurosteroid therapy as taught by Saporito and Reddy, said skilled artisan would have found it prima facie obvious to administer said ganaxolone orally to the super refractory status epilepticus patient following said tapered regimen in view of Shaw.
Motivation to administer ganaxolone orally following the cessation of the taper period logically flows from the fact that Shaw teaches that said orally administered ganaxolone comprises a pharmacokinetic profile of 400-1200 ng/mL*h taught which overlaps with the plasma concentration that is efficacious at suppressing unacceptable ictal activity as recited in claim 1. Accordingly, said skilled artisan would have readily predicted that oral administration of ganaxolone to the super refractory status epilepticus patient following receiving the step down/tapered intravenous infusion ganaxolone would still yield a desirable concentration of ganaxolone in the plasma of the afflicted status epilepticus patient efficacious at treating super-refractory status epilepticus in a patient, thereby treating the seizure disorder.
It is noted that the combination of Zhang, Saporito, Reddy and Shaw do not specifically teach wherein the orally administered ganaxolone is administered after the taper period has stopped (claim 49). However, the optimum dosing cycle for orally administered ganaxolone to the super refractory status epilepticus patient following a tapered intravenous dose would have been a matter well within the insight of one of ordinary skill in the art. Such a determination would have been made in accordance with a variety of factors, pharmacological considerations, such as activity, efficacy, pharmacokinetics and toxicology profiles of the combined regimen, as well as the age, weight, sex, diet and severity of the medical condition of the patient. Thus, the dosing cycle for orally administered ganaxolone to the super refractory status epilepticus patient following a tapered intravenous dose that would have been employed would have varied widely and, in the absence of evidence to the contrary, the current claimed specific administration regimen is not seen to be inconsistent with one that would have been determined by the skilled artisan. Furthermore, absent and evidence demonstrating a patentable difference between the ganaxolone administered and the criticality of the claimed dosing cycle for orally administered ganaxolone to the super refractory status epilepticus patient following a tapered intravenous dose, the determination of the optimum or workable frequency of administration given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)(”[W]here the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the workable ranges by routine experimentation.”)
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 4, 7, 9-10, 14-22 and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 4-10 and 18 of U.S. Patent No. 11,110,100 in view of Zhang (WO2016/127170 published 08/11/2016), Saporito (WO2018/071803 published 04/19/2018) and Reddy (US2014/0057885 published 02/27/2014).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following. Claim 1 of U.S Patent 11,110,100 is directed to a method of treating status epilepticus (SE), comprising administering to a subject in need thereof an effective amount of ganaxolone to suppress SE, wherein the effective amount of ganaxolone is administered as an intravenous bolus plus continuous infusion to produce and maintain a ganaxolone plasma concentration of about 500 ng/ml to about 1000 ng/ml for about 8 hours to about 12 hours. Said ganaxolone plasma concentration of 500 ng/mL to about 1000 ng/mL overlaps with the target concentration of at least about 800 ng/mL for at least 2.5 hours found within the present claims. Claims 4-10 are directed to the amounts of ganaxolone administered via the continuous infusion for a duration of at least 2 hours, as well as the step down/tapering dosage following the initial infusion for a duration of at least 12 hours, which overlaps with the methodology and duration of treatment found in instant claims 14-19 and 20-22, while claim 18 narrows the patient population to a refractory status epilepticus patient.
The difference between the present claims and that of claims 1, 4-10 and 18 of U.S. Patent 11,110,100 is that claims 1, 4-10 and 18 of U.S. Patent 11,110,100 are not directed to treating super refractory status epilepticus patients, nor do claims 1, 4-10 and 18 specifically teach a rapid weaning of an anesthetic in the treatment protocol.
Zhang (WO2016/127170 published 08/11/2016) teaches the method of treating a seizure disorder including super refractory status epilepticus in a subject in need comprising administering an injectable formulation of a therapeutically effective amount of ganaxolone (claims 1, 30-31). Regarding claims 7 and 9, Zhang teaches administering said ganaxolone over multiple bolus infusions wherein each bolus provides a plasma Cmax of ganaxolone of about 100 ng/mL to about 1000 ng/mL to the patient, wherein each bolus comprises from about 1 mg/kg to about 20 mg/kg of ganaxolone (claims 39-44). Said bolus administration yields a pharmacokinetic profile that overlaps with the ganaxolone pharmacokinetic profile found in claim 1 of U.S. Patent 11, 110,100. Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Said bolus administration corresponds to a large dose in a short period of 1-30 min ([0018]). Zhang further teaches that an intravenous infusion of ganaxolone is administered after the bolus for a duration of 1-10 days at a dose of 1-10 mg/kg per hour ([0074]-[0077], claims 45, 47). Said intravenous infusion commences within 1-5 hours following the bolus dose ([0075]-[0077]).
Regarding the scope of claims 14-19, wherein the amount of ganaxolone administered to the subject per hour by continuous infusion is decreased by 50% about 2 hours after the initiation of the continuous infusion (claim 14), or is decreased about 55-75% 10-14 hours after the initiation of the continuous intravenous infusion (claims 16-17), or a second reduction in amount of ganaxolone occurs wherein the first reduction occurs about 2 hours after the initiation of the continuous infusion and 55-75% 10-14 hours after the initiation of the continuous intravenous infusion (claims 18-19), Zhang teaches tapering/step down infusions following the initial dose ([0077], claims 45, 47-49). Step down doses/tapered doses which are 50-75% of the infusion dose are taught by Zhang. Second step down doses/tapered doses which are 5%-95% of the first step down dose are also taught by Zhang ([0077]). Zhang additionally teaches said ganaxolone is administered sequentially with anesthetics to the status epilepticus patient (claims 50-59).
Saporito (WO2018/071803 published 04/19/2018) teaches treating status epilepticus in a subject in need comprising administering a therapeutically effective amount of a neurosteroid (abstract). Ganaxolone is taught as a potent neurosteroid for treating said status epilepticus patient ([0002], [0006], [0020]-[0021]) Saporito teaches that status epilepticus is a serious seizure disorder in which the epileptic patient experiences a seizure lasting more than 5 minutes, or more than one seizure in a five minute period without recovering between seizures. Saporito teaches that status epilepticus is treated in the emergency rooms with anticonvulsants. Patients who fail with anticonvulsants and treated with a combination of anesthetics or barbiturates in combination with anticonvulsants. Those who fail anticonvulsant therapy and epileptic therapy are considered refractory. Super-refractory status epilepticus (SRSE) patients are refractory patients that have continued or recurrent seizures 24 hours or more. Said SRSE patients are associated with high rates of mortality and morbidity. Saporito teaches that SRSE patients are being treated with anesthetic therapy and are periodically weaned off the general anesthetic to access their therapeutic response ([0002]).
Reddy (US2014/0057885 published 02/27/2014) teaches treating super-refractory status epilepticus in a subject in need comprising administering a therapeutically effective amount of the neurosteroid allopregnanolone in combination with an anesthetic ([0022], [0028]-[0030], claims 1, 165). Reddy teaches weaning off anesthetics in the patient followed by the administration of the neurosteroid. Linear weaning, including a 20% linear weaning of anesthesia to the status epilepticus patient is embraced within the methodology of Reddy ([0158]-[0160]).
Therefore, one of ordinary skill in the art prior to the time of the invention knowing that administering to a subject in need thereof an effective amount of ganaxolone is effective to suppress status epilepticus in said subject, wherein the effective amount of ganaxolone is administered as an intravenous bolus plus continuous infusion to produce and maintain a ganaxolone plasma concentration of about 500 ng/ml to about 1000 ng/ml for about 8 hours to about 12 hours as taught by claims 1, 4-10 and 18 of U.S. Patent 11,110,100, said skilled artisan would have found it prima facie obvious to administer said ganaxolone intravenous bolus plus continuous infusion that yields a concentration of about 500 ng/mL to about 1000 ng/mL to treat super refractory status epilepticus in said subject in view of Zhang, arriving at the claimed methodology, as Zhang teaches that said ganaxolone intravenous bolus plus continuous infusion yields an overlapping plasma concentration of about 100 ng/mL to about 1000 ng/mL, said plasma concentration is efficacious at treating super refractory status epilepticus (claims 1, 30-31, 39-41).
Secondly, said skilled artisan would have found it prima facie obvious to administer the ganaxolone regimen of claims 1, 4-10 and 18 of U.S 11,110,100 to a super refractory status epilepticus patient in combination with an anesthetic as well as rapidly wean said subject in need thereof off said anesthetic in view of the combination of Zhang, Saporito and Reddy as Zhang teaches that administration of the art-recognized neurosteroid ganaxolone with anesthetics is an efficacious strategy at treating super-refractory status epilepticus in a subject in need wherein ganaxolone is administered over multiple bolus infusions wherein each bolus provides a plasma Cmax of ganaxolone of about 100 ng/mL to about 1000 ng/mL to the patient, coupled with the knowledge that (1) it was known in the prior art that SRSE patients are being treated with anesthetic therapy and are periodically weaned off the general anesthetic to access their therapeutic response and (2) rapid weaning of said anesthetic regimen is a known strategy in the treatment of super refractory status epilepticus patient with neurosteroid therapy. Consistent with this reasoning, it would have been obvious to have selected the anesthetic weaning techniques in the neurosteroid treatment of super-refractory status epilepticus patient as taught by the combination of Zhang, Saporito and Reddy and apply it to the neurosteroid ganaxolone super refractory status epilepticus therapeutic regimen from within the prior art of Zhang and U.S. Patent 11,110,100 above, arriving at the claimed methodology yielding no more than one would expect from such an arrangement.
Lastly, regarding the limitation directed to wherein the subject is weaned off the anesthetic agent until unacceptable ictal activity return (claim 4), Reddy teaches that the goal of therapy with general anesthesia is to induce a “burst suppression” state in an attempt to block the excitotoxic cerebral damage believed to occur as a result of the continued seizure activity in the brain. The goal of the neurosteroid therapy is that when a patient is weaned from the general anesthesia, the patient will no longer have clinical or electographic seizure activity ([0272]-[0273]). Accordingly, said skilled artisan would have found it prima facie obvious to wean off the anesthesia until unacceptable intense electrical activity in the brain occurs during a seizure (“ictal activity” returns), in order to titrate the right level of anesthesia that still provides burst suppression state in the status epilepticus, providing the capacity to block the excitotoxic cerebral damage in the afflicted patient.
Claims 1, 4, 7, 9-10, 14-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15, 24-28 of U.S. Patent No. 11,679,117 in view of Zhang (WO2016/127170 published 08/11/2016), Saporito (WO2018/071803 published 04/19/2018) and Reddy (US2014/0057885 published 02/27/2014).
Claim 1 of U.S Patent 11,679,117 is directed to the method of treating status epilepticus (SE), comprising administering to a subject in need thereof an effective amount of ganaxolone to suppress SE for a period of at least 8 hours, wherein the effective amount of ganaxolone is administered as an intravenous bolus plus continuous infusion to produce and maintain a ganaxolone plasma concentration of at least about 500 ng/ml for at least about 8 hours to about 12 hours, the amount of ganaxolone infused into said subject by said continuous infusion is decreased at least once during said about 8 hours to about 12 hours to produce and maintain a ganaxolone plasma concentration of at least about 500 ng/ml to about 1000 ng/ml for the remainder of said about 8 hours to about 12 hours; and the total daily dose of ganaxolone administered is from about 500 mg to about 900 mg. Said ganaxolone plasma concentration of 500 ng/mL to about 1000 ng/mL overlaps with the target concentration of at least about 800 ng/mL for at least 2.5 hours found within the present claims. The tapered continuous intravenous infusion dosing of said ganaxolone therapy embodied in claims 6-8 overlaps with the duration and dose-reduction found within instant claims 14-19 and 26. Additionally, the ramp up of said continuous infusion dosing of said ganaxolone therapy in claims 9-10 overlaps with the duration and ramp up ganaxolone dosing found in instant claims 23-25. Further, the duration of continuous infusion therapy administered in claims 13-15 overlaps with the duration of ganaxolone continuous infusion therapy found in claims 20-22 of the instant application.
The difference between the present claims and that of claims 1-15, 24-28 of U.S. Patent No. 11,679,117 is that claims 1-15, 24-28 of U.S. Patent No. 11,679,117 are not directed to treating super refractory status epilepticus patients, nor do claims 1-15, 24-28 of U.S. Patent No. 11,679,117 specifically teach a rapid weaning of an anesthetic in the treatment protocol.
Zhang (WO2016/127170 published 08/11/2016) teaches the method of treating a seizure disorder including super refractory status epilepticus in a subject in need comprising administering an injectable formulation of a therapeutically effective amount of ganaxolone (claims 1, 30-31). Regarding claims 7 and 9, Zhang teaches administering said ganaxolone over multiple bolus infusions wherein each bolus provides a plasma Cmax of ganaxolone of about 100 ng/mL to about 1000 ng/mL to the patient, wherein each bolus comprises from about 1 mg/kg to about 20 mg/kg of ganaxolone (claims 39-44). Said bolus administration yields a pharmacokinetic profile that overlaps with the ganaxolone pharmacokinetic profile found in claim 1 of U.S. Patent 11, 679,167. Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Said bolus administration corresponds to a large dose in a short period of 1-30 min ([0018]). Zhang further teaches that an intravenous infusion of ganaxolone is administered after the bolus for a duration of 1-10 days at a dose of 1-10 mg/kg per hour ([0074]-[0077], claims 45, 47). Said intravenous infusion commences within 1-5 hours following the bolus dose ([0075]-[0077]).
Regarding the scope of claims 14-19, wherein the amount of ganaxolone administered to the subject per hour by continuous infusion is decreased by 50% about 2 hours after the initiation of the continuous infusion (claim 14), or is decreased about 55-75% 10-14 hours after the initiation of the continuous intravenous infusion (claims 16-17), or a second reduction in amount of ganaxolone occurs wherein the first reduction occurs about 2 hours after the initiation of the continuous infusion and 55-75% 10-14 hours after the initiation of the continuous intravenous infusion (claims 18-19), Zhang teaches tapering/step down infusions following the initial dose ([0077], claims 45, 47-49). Step down doses/tapered doses which are 50-75% of the infusion dose are taught by Zhang. Second step down doses/tapered doses which are 5%-95% of the first step down dose are also taught by Zhang ([0077]). Zhang additionally teaches said ganaxolone is administered sequentially with anesthetics to the status epilepticus patient (claims 50-59).
Saporito (WO2018/071803 published 04/19/2018) teaches treating status epilepticus in a subject in need comprising administering a therapeutically effective amount of a neurosteroid (abstract). Ganaxolone is taught as a potent neurosteroid for treating said status epilepticus patient ([0002], [0006], [0020]-[0021]) Saporito teaches that status epilepticus is a serious seizure disorder in which the epileptic patient experiences a seizure lasting more than 5 minutes, or more than one seizure in a five minute period without recovering between seizures. Saporito teaches that status epilepticus is treated in the emergency rooms with anticonvulsants. Patients who fail with anticonvulsants and treated with a combination of anesthetics or barbiturates in combination with anticonvulsants. Those who fail anticonvulsant therapy and epileptic therapy are considered refractory. Super-refractory status epilepticus (SRSE) patients are refractory patients that have continued or recurrent seizures 24 hours or more. Said SRSE patients are associated with high rates of mortality and morbidity. Saporito teaches that SRSE patients are being treated with anesthetic therapy and are periodically weaned off the general anesthetic to access their therapeutic response ([0002]).
Reddy (US2014/0057885 published 02/27/2014) teaches treating super-refractory status epilepticus in a subject in need comprising administering a therapeutically effective amount of the neurosteroid allopregnanolone in combination with an anesthetic ([0022], [0028]-[0030], claims 1, 165). Reddy teaches weaning off anesthetics in the patient followed by the administration of the neurosteroid. Linear weaning, including a 20% linear weaning of anesthesia to the status epilepticus patient is embraced within the methodology of Reddy ([0158]-[0160]).
Therefore, one of ordinary skill in the art prior to the time of the invention knowing that administration of an effective amount of ganaxolone is efficacious to suppress status epilepticus in said subject, wherein the effective amount of ganaxolone is administered as an intravenous bolus plus continuous infusion to produce and maintain a ganaxolone plasma concentration of at least about 500 ng/ml for at least about 8 hours to about 12 hours, the amount of ganaxolone infused into said subject by said continuous infusion is decreased at least once during said about 8 hours to about 12 hours to produce and maintain a ganaxolone plasma concentration of at least about 500 ng/ml to about 1000 ng/ml for the remainder of said about 8 hours to about 12 hours; and the total daily dose of ganaxolone administered is from about 500 mg to about 900 mg as embraced within claim 1-15 and 24-28 of U.S. Patent 11,679,167, said skilled artisan would have found it prima facie obvious to administer said ganaxolone intravenous bolus plus continuous infusion that yields a concentration of about 500 ng/mL to about 1000 ng/mL to treat super refractory status epilepticus in said subject in view of Zhang, arriving at the claimed methodology, as Zhang teaches that said ganaxolone intravenous bolus plus continuous infusion that yields a concentration of about 100 ng/mL to about 1000 ng/mL is efficacious at treating super refractory status epilepticus (claims 1, 30-31, 39-41).
Secondly, said skilled artisan would have found it prima facie obvious to administer the ganaxolone regimen of claims 1-15 and 24-28 of U.S 11,679,167 to a super refractory status epilepticus patient in combination with an anesthetic as well as rapidly wean said subject in need thereof off said anesthetic in view of the combination of Zhang, Saporito and Reddy as Zhang teaches that administration of the art-recognized neurosteroid ganaxolone with anesthetics is an efficacious strategy at treating super-refractory status epilepticus in a subject in need wherein ganaxolone is administered over multiple bolus infusions wherein each bolus provides a plasma Cmax of ganaxolone of about 100 ng/mL to about 1000 ng/mL to the patient, coupled with the knowledge that (1) it was known in the prior art that SRSE patients are being treated with anesthetic therapy and are periodically weaned off the general anesthetic to access their therapeutic response and (2) rapid weaning of said anesthetic regimen is a known strategy in the treatment of super refractory status epilepticus patient with neurosteroid therapy. Consistent with this reasoning, it would have been obvious to have selected the anesthetic weaning techniques in the neurosteroid treatment of super-refractory status epilepticus patient as taught by the combination of Zhang, Saporito and Reddy and apply it to the neurosteroid ganaxolone super refractory status epilepticus therapeutic regimen from within the prior art of Zhang and U.S. Patent 11,679,167 above, arriving at the claimed methodology yielding no more than one would expect from such an arrangement.
Lastly, regarding the limitation directed to wherein the subject is weaned off the anesthetic agent until unacceptable ictal activity return (claim 4), Reddy teaches that the goal of therapy with general anesthesia is to induce a “burst suppression” state in an attempt to block the excitotoxic cerebral damage believed to occur as a result of the continued seizure activity in the brain. The goal of the neurosteroid therapy is that when a patient is weaned from the general anesthesia, the patient will no longer have clinical or electographic seizure activity ([0272]-[0273]). Accordingly, said skilled artisan would have found it prima facie obvious to wean off the anesthesia until unacceptable intense electrical activity in the brain occurs during a seizure (“ictal activity” returns), in order to titrate the right level of anesthesia that still provides burst suppression state in the status epilepticus, providing the capacity to block the excitotoxic cerebral damage in the afflicted patient.
Claims 1, 4, 7, 9-10, 14-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 12,246,026 in view of Zhang (WO2016/127170 published 08/11/2016), Saporito (WO2018/071803 published 04/19/2018) and Reddy (US2014/0057885 published 02/27/2014).
Claim 1 of U.S Patent 12,246,026 is directed to a method for treating status epilepticus (SE), comprising administering to a subject in need thereof: a) an intravenous bolus of ganaxolone in an amount sufficient to suppress SE, and b) a continuous intravenous infusion of ganaxolone in an amount sufficient for continued SE suppression, wherein the continuous intravenous infusion i) is initiated periprocedurally with the intravenous bolus, ii) is administered for a treatment period of about 24 hours to about 36 hours and the amount of ganaxolone infused is decreased at least twice during the treatment period, and iii) is intended to produce a ganaxolone plasma concentration in the subject of at least about 500 n