DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
2. The preliminary amendment filed 3/13/2024, cancelled claims 1-51. There are no claims withdrawn and no claims amended. Claims 52-71 are pending in the application and will be examined on the merits.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 12/12/2023 and 3/13/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
4. Claims 58, 60, 61, and 71 are objected to because of the following informalities:
-In claim 58, the abbreviations/acronyms; CDKL5, CDD, DEE, EIDEE, and PCDH19 are not spelled out.
- In claim 60, the abbreviations/acronyms; CDKL5, and CHD2 are not spelled out.
-In claim 61, the abbreviations/acronyms; CDKL5, SCN2A, SCN8A, KCNQ2, KCNQ3, KCNT1, SynGAP1, PCDH19, and CHD2 are not spelled out.
-In claim 71, the abbreviations/acronyms; CSF and (CSF/P Ctrough) are not spelled out.
Appropriate corrections are required
Claim Rejections - 35 USC § 112(a)
5. 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.
Claim 52-71 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for certain thrice daily (TID) dosing regimens of compound 1 does not reasonably provide enablement for a person of ordinary skill in the art to practice the full scope of the twice daily (BID) dosing methods for all 5-HT2c receptor associated disorders, epilepsies, seizure disorders, developmental and epileptic encephalopathies (DEE), and refractory epilepsies without undue experimentation. The claims are extremely broad in both disease scope and dosing scope, whereas the disclosure teaches only a narrow set of human clinical regimens (primarily 6 mg and 12 mg TID, and a single specific BID regimen such as 18 mg BID) supported by pharmacokinetic (PK) and pharmacodynamic (qEEG) data in a limited DEE/seizure population. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The instant claims are drawn to a method for the treatment or prevention of a seizure disorder. The instant specification fails to provide information that would allow the skilled artisan to practice the instant invention. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
Nature of the invention:
The instant invention pertains to a method of treating or preventing a 5-hydroxytryptamine (HT)2c receptor- associated disorder in a patient in need thereof, wherein the method comprises administering to the patient (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro- [1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1), or a pharmaceutically acceptable salt thereof, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily.The invention concerns BID clinical dosing regimens of a CNS-active 5HT2C receptor agonist in patients with severe epileptic and developmental encephalopathies.
The state of the prior art:
The prior art cited in the specification reports that compound 1 was in clinical trials using TID dosing regimens (3, 6, 12, 18, 24 mg) with half-life at steady state of about 4.8-6.5 hours and provides PK data under such TID regimens. That art does not teach or suggest an effective BID regimens across the board array of DEE and epilepsy syndromes now claimed Although, 5HT2C agonists have been explored in other CNS indications and persons of ordinary skill are familiar with general clinical pharmacology, the art does not provide a predictable mapping from TID to BID dosing for this specific compound, nor does it supply generic dose-conversion rules that would obviate the need for extensive, indication- and age-specific experimentation. The skilled artisan would view that the prevention of one or more symptoms of a seizure disorder totally, absolutely, or permanently, is highly unlikely, since one cannot guarantee that the seizures will always be prevented.
For example, Ren et al. (WO 2016176177 (5-HT2C Receptor Agonists and Compositions and Methods of Use Published: 11/03/2016, on page 38) describes that compounds have been found useful for the treatment of seizure disorders but not fully prevent them. “Epilepsy is a syndrome of episodic brain dysfunction characterized by recurrent unpredictable, spontaneous seizures.” In fact, the treatment was effective because it dropped seizure frequency by 55.6%, thus not totally, absolutely, or permanently preventing or treating seizure. 5-HT2c receptor agonists can be useful for treatment of some forms of seizures but not all, especially those recited in claim 58. In particular, Ohtahara syndrome is a broad category of seizures each specific type potentially requiring a different treatment. Ren further states that “Lennox-Gastaut syndrome is a difficult-to-treat form of childhood-onset epilepsy”
The relative skill of those in the art:
The level of skill in the art is a clinician with a PhD.
The predictability or lack thereof in the art:
The specification acknowledges highly heterogeneous etiologies, complex seizure phenotypes, developmental regression, frequent comorbidities (intellectual disability, autism, behavioral problems), and substantial safety concerns with serotonergic agents, including cardiac valvopathy for non-selective 5HT2C receptor agonist such as fenfluramine. The specification also emphasizes that compound 1 has a relatively short half-life at steady state (4.81-6.50 hours) and that prior art dosing regimens for this same compound used TID dosing with specific up-titration and down-titration steps at fixed 3, 6, 12, 18, and 24 mg doses. Given this PK, converting from TID to BID dosing inherently involves non-linear changes in Cmax, Cmin, exposure fluctuations, and time-above-Ki in CSF and plasma. The field of CNS pharmacotherapy -particularly for pediatric DEE and refractory epilepsies- is recognized as relatively unpredictable with respect to: dose-response across different genotypes and etiologies, seizure control vs side-effect balance, drug-drug interactions with a wide range of background anti-seizure medications and ketogenic diet regimens, and long-term neurodevelopmental outcomes. The specifications’’ own data show that BID vs TID dosing regimens produce different PK profiles and time-above-Ki for the same daily dose and highlight that only specific BID doses (e.g., 18 mg for arbitrary BID were modeled and evaluated in comparison to 12 mg TID. There is no indication that therapeutic efficacy or safety can be predicted for arbitrary BID doses across the full claimed disease spectrum. In view of this complexity, the invention resides in a relatively unpredictable art, and changes in BID dose, exposure, or patient population cannot be assumed to produce predictable clinical outcomes or tolerability profiles across the entire claimed scope. The skilled artisan would view that the treatment to prevent seizure disorders, absolutely, or permanently as highly unpredictable. As evidenced above, because different seizure syndromes have different causes, prevention is highly unpredictable and requires different treatment protocols.
The breadth of the claims:
The instant claim 1 is directed to a method treating or preventing a 5-hydroxytryptamine (HT)2c receptor- associated disorder in a patient by administering compound 1, or a pharmaceutically acceptable salt thereof, administered twice daily, without limitation on: dose per administration, total daily dose, duration of treatment, patient age, weight, or comorbidities, or stage or severity of disease. Dependent claims 53, 56, 58, 60, 61 and independent claims 57, 59 similarly recite treatment or prevention of broad epilepsy categories (focal, generalized, combined), seizure disorders, numerous specific DEE syndromes with diverse genetic etiologies, and refractory epilepsy, again only limited to “administered twice daily” and not to any specific BID dose or exposure window. The specification defines DEE and seizure disorders to include a very wide range of etiologies (structural, genetic, infectious, metabolic, immune) and an extensive list of named syndromes (e.g., Ohtahara syndrome, West syndrome, Lennox-Gastaut, Dravet, tuberous sclerosis complex (TSC) associated epilepsies, SCN2A/ SCN8A/ KCNQ2/ KCNQ3/ KCNT1- related epilepsies, Angelman syndrome, SynGAPI related epilepsies, Rett syndrome, PCDH19 epilepsy, ring 14 syndrome, ring 20 syndrome, CHD2 encephalopathy, and others. This breadth encompasses patients of vastly different ages (infants to adults), seizure types, pathophysiologies, and co-therapies. The claims are not limited to any particular PK parameter (e.g., minimum or maximum BID dose, minimum fraction of dosing interval above the 5HT2C Ki, target Cmax or AUC range, or specific CSF: plasma ratio) despite the specification’s own emphasis that BID vs TID regimens are justified by detailed PK modeling, CSF data, and time-above-Ki analysis. Given this breadth, the enablement inquiry must consider whether the specification teaches how to identify and safely implement BID regimens that are therapeutically effective and tolerated for the full spectrum of claimed disorders and patient populations, and not merely for the narrow dose levels, healthy adults and DEE cohorts actually studied.
As such, the breadth of the claims is great.
The amount of direction or guidance presented and the presence or absence of working examples:
The specification provides substantial experimental detail for: TID dosing regimens of 6 mg and 12 mg per dose (18 mg/day and 36 mg/day), including PK profiles in CSF and plasma, qEEG data, and comparison to Ki; and a limited set of BID regimens (e.g., 18 mg BID) explicitly compared to the 12 mg TID regimen in terms of Cavg, Cmax, CSF exposure, time above Ki and CSF:plasma ratios (FIGS. 9-17). However, the working examples and figures collectively support only a narrow slice of the claimed BID dosage: specific BID dose (e.g., 18 mg Bid) in a limited DEE/seizure cohort; PK simulations and qEEG analyses around those particular dose levels; and do not provide data for other BID doses, other total daily doses, or for the many claimed disease sub-categories (e.g., encephalopathy vs KCNT1 encephalopathy vs TSC-related epilepsies).
In the instant case, the specification contains no working examples or specific guidance for: BID dosing in infants vs adolescents vs adults; BID dosing in more fragile early-infantile DEE populations such as Ohtahara syndrome or epilepsy of infancy with migrating focal seizures; BID regimens when compound 1 is co-administered with strong CYP inhibitors/inducers or P-gp substrates or in significant hepatic/renal impairment; or BID titration schemes (starting dose, titration increments, titration interval, maximum tolerated dose, tapering) for the numerous specific epileptic syndromes and etiologies listed. Instead, the specification reiterates broad clinical concepts e.g., “therapeutically effective amount”, “tolerate”, “in need of treatment”) and generic practitioner discretion (dose to tolerance and efficacy based on standard clinical judgement), but does not furnish concrete decision rules, exposure windows, or syndrome-specific dose ranges that would guide the skilled artisan in selecting safe and effective BID regimens across the entire claimed disease space. Thus, while the disclosure contains some BID-specific guidance, it is limited to a small subset of doses, patient settings and does not scale to the full breadth of the seizure disorders without specifying the specific treatment protocol for any of the seizure types.
Note that lack of a working example, is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP 2164. Genentech, Inc. v. Novo Nordisk, 108 F.3d at 1366, states that "a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable". Therefore, in view of the Wands factors, e.g., the amount of direction or guidance provided, absence of working examples, and the predictability of the art discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation in order to practice invention based on the details provided and scope of invention defined in claims 52-71
Consequently, claims 52-71 remain rejected for lacking enablement.
Claim Rejections - 35 USC § 112(b)
6. 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.
Claim 60 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.
Regarding claim 60, the phrase "such as" at line 3 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 102
7. 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.
Claims 52-55 and 57-71 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ren et al. WO 2016/176177 (5-HT2C Receptor Agonists and Compositions and Methods of Use; Published: November 3, 2016 and filed on April 26, 2016; provided by applicant in the IDS submitted on March 13, 2024) herein referred to as Ren.
Regarding claim 52, Ren teaches a method of treating preventing a 5-hydroxytryptamine (HT)2c receptor- associated disorder in a patient in need thereof (Pg. 38, lines: 23, 24). Ren further teaches wherein the method comprises administering to the patient (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro- [1,4] diazepino[6,7,1-hi] indole-8-carboxamide (Applicant’s Compound 1), or a pharmaceutically acceptable salt thereof (Pg. 97, Claim 1, Ren’s Compound No. 3; Claim 2 on page 99; Claim 24 on page 104), wherein Applicant’s Compound 1/Ren’s Compound 3, or a pharmaceutically acceptable salt thereof, is administered as two, three, four, or more sub-doses per day (Pg. 76, lines: 24,25).
Although Ren may not explicitly indicate Compound 3 of Ren’s claim 1 is used as a treatment of a 5-hydroxytryptamine (HT)2c receptor- associated disorder such as seizure disorder, Ren’s claim 24 does indicate using one of the nine compounds recited in Ren’s claim 1 to treat seizure disorders. One of ordinary skill in the art would have at once envisaged selection of Compound 3 for the treatment of a seizure disorder because it is one of only nine specific compounds recited in Ren’s claim 1 (see In re Petering, 301 F.2d 676, 133 USPQ 275 (CCPA 1962) and In re Schauman, 572 F.2d 312, 197 USPQ 5 (CCPA 1978)),
Regarding claim 53, Ren teaches the method of claim 52, wherein the 5-hydroxytryptamine (HT)2c receptor- associated disorder is epilepsy (Pg. 38, lines: 37-38- the 5-HT2c receptor agonists such as compound 1 are useful for the treatment of epilepsy).
Regarding claim 54, Ren teaches the method of claim 52, the administering results in a reduction in severity of an epileptic seizure in the patient (Pg. 38, lines 23-24-5-HT2c receptor agonists such as compounds provided herein (i.e., Ren’s claim 1), are useful for the treatment of seizure disorders).Pg.14, line 32-reduction in severity of one or more symptoms associated with a particular disorder).
Although Ren may not explicitly indicate using Compound 3 of Ren’s claim 1 results in the reduction in severity of an epileptic seizure, Ren does disclose that the term treating in reference to a disorder can mean a reduction in severity of one or more symptoms associated with a particular disorder (Pg. 14, line 32). One of ordinary skill in the art would have at once envisaged selection of Compound 3 for the treatment of a seizure disorder because it is one of only nine specific compounds recited in Ren’s claim 1 thereby resulting in a reduction in severity of one or more symptoms as defined by Ren (see In re Petering, 301 F.2d 676, 133 USPQ 275 (CCPA 1962) and In re Schauman, 572 F.2d 312, 197 USPQ 5 (CCPA 1978)).
Regarding claim 55, Ren teaches the method of claim 52, wherein the administering results in a reduction in the frequency of epileptic seizures in the patient (Pg. 39, line 20-two-thirds reduction in seizure frequency during treatment).
Regarding claim 57, Ren teaches or a method of treating a seizure disorder in a patient in need thereof (Pg. 38, lines: 23, 24). Ren further teaches wherein the method comprises administering to the patient (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro- [1,4] diazepino[6,7,1-hi] indole-8-carboxamide (Applicant’s Compound 1), or a pharmaceutically acceptable salt thereof (Pg. 97, Claim 1, Ren’s Compound No. 3; Claim 2 on page 99; Claim 24 on page 104), wherein Applicant’s Compound 1/Ren’s Compound 3, or a pharmaceutically acceptable salt thereof, is administered as two, three, four, or more sub-doses per day (Pg. 76, lines: 24,25).
Although Ren may not explicitly indicate Compound 3 of Ren’s claim 1 is used as a treatment of a seizure disorder, Ren’s claim 24 does indicate using one of the nine compounds recited in Ren’s claim 1 to treat seizure disorders. One of ordinary skill in the art would have at once envisaged selection of Compound 3 for the treatment of a seizure disorder because it is one of only nine specific compounds recited in Ren’s claim 1 (see In re Petering, 301 F.2d 676, 133 USPQ 275 (CCPA 1962) and In re Schauman, 572 F.2d 312, 197 USPQ 5 (CCPA 1978)),
Regarding claim 58, Ren teaches a method of claim 57, wherein seizure disorder is epilepsy or Dravet syndrome (claim 25, Claim 26, page 104). Ren further teaches wherein the method comprises administering to the patient (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro- [1,4] diazepino[6,7,1-hi] indole-8-carboxamide (Applicant’s Compound 1), or a pharmaceutically acceptable salt thereof (Pg. 97, Claim 1, Ren’s Compound No. 3; Claim 2 on page 99; Claim 24 on page 104), wherein Applicant’s Compound 1/Ren’s Compound 3, or a pharmaceutically acceptable salt thereof, is administered as two, three, four, or more sub-doses per day (Pg. 76, lines: 24,25).
Although Ren may not explicitly indicate Compound 3 of Ren’s claim 1 is used as a treatment of these specific seizure disorders, Ren’s claim 24 does indicate using one of the nine compounds recited in Ren’s claim 1 to treat seizure disorders. One of ordinary skill in the art would have at once envisaged selection of Compound 3 for the treatment of a seizure disorder because it is one of only nine specific compounds recited in Ren’s claim 1 (see In re Petering, 301 F.2d 676, 133 USPQ 275 (CCPA 1962) and In re Schauman, 572 F.2d 312, 197 USPQ 5 (CCPA 1978)),
Regarding claim 59, Ren teaches a method of treating or preventing developmental and epileptic encephalopathy (DEE) in a patient in need thereof (Pg. 38 line 38 to Pg. 39, line 10, 5HT2C receptor agonists such as compounds provided herein, are useful for treatment of infantile spasms, childhood epilepsy, as well as others listed), wherein the method comprises administering to the patient (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1- hi]indole-8-carboxamide (Compound 1), or a pharmaceutically acceptable salt thereof, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily (Pg. 76, lines: 24, 25).
Although Ren may not explicitly indicate Compound 3 of Ren’s claim 1 is used as a treatment of a 5-hydroxytryptamine (HT)2c receptor- associated disorder such as DEE, Ren’s claim 24 does indicate using one of the nine compounds recited in Ren’s claim 1 to treat seizure disorders. One of ordinary skill in the art would have at once envisaged selection of Compound 3 for the treatment of a seizure disorder because it is one of only nine specific compounds recited in Ren’s claim 1 (see In re Petering, 301 F.2d 676, 133 USPQ 275 (CCPA 1962) and In re Schauman, 572 F.2d 312, 197 USPQ 5 (CCPA 1978)), Regarding claim 60, Ren teaches the method of claim 59, wherein the DEE is selected from Lennox-Gastaut syndrome (Pg. 39, line 20), Dravet syndrome (Pg. 39, line 10 and pg. 104, claim 26), Doose syndrome (EM AS), West syndrome (infantile spasms (Pg. 39, line 3), Landau-Kleffner syndrome, and genetic disorders such as CDKL5 encephalopathy (CDK5L deficiency disorder) or CHD2 encephalopathy (each sections cited states that 5HT2C receptor agonists such as the compounds taught by Ren are useful for the treatment).
Regarding claim 61, Ren teaches the method of claim 60, wherein the DEE is selected from Ohtahara syndrome (EIDEE), Lennox-Gastaut syndrome (Pg. 39, line 20) , Dravet syndrome (Pg. 39, line 10 and pg. 104, claim 26), Doose syndrome (EM AS), West syndrome (infantile spasms (Pg. 39, line 3), Landau-Kleffner syndrome, tuberous sclerosis complex,CDKL5 encephalopathy (CDKL5 deficiency disorder), dup15q syndrome, SCN2A related epilepsies, SCN8A related epilepsies, KCNQ2 related epilepsies, KCNQ3 related epilepsies, Angelman syndrome, KCNT1 related epilepsies, SynGAPI related epilepsies, Rett syndrome, PCDH19 epilepsy, ring 14 syndrome, ring 20 syndrome, CHD2 encephalopathy, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, and epileptic encephalopathy with continuous spike-wave (each sections cited states that 5HT2C receptor agonists such as the compounds taught by Ren are useful for the treatment).
Regarding claim 62 Ren teaches the method of claim 52, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a dosage equivalent to about 3 mg/dose of Compound 1, or about 6 mg/dose of Compound 1, or about 12 mg/dose of Compound 1, or about 15 mg/dose of Compound 1, or about 18 mg/dose of Compound 1 (Pg. 75, lines: 29-31 and 35-37; range of dosages).
Regarding claims 63 Ren teaches the method of claim 52, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a dosage equivalent to about 12 mg/dose (Pg. 75, lines: 29-31 and 35-37; range of dosages).
Regarding claim 64, Ren teaches the method of claim 52, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a dosage equivalent to about 15 mg/dose (Pg. 75, lines: 29-31 and 35-37; range of dosages).
Regarding claim 65, Ren teaches the method of claim 52, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a dosage equivalent to about 18 mg/dose (Pg. 75, lines: 29-31 and 35-37; range of dosages).
Regarding claims 66, Ren teaches the method of claim 52, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered via a titration scheme that comprises the up-titration of Compound 1, or a pharmaceutically acceptable salt thereof, until an optimized dosage is administered (Pg. 76, lines: 29; optimized dosage, deviate upward).
Regarding claims 67, Ren teaches the method of claim 52, wherein the administration results in an improvement in the frequency of convulsive/motor seizures (38, line 35; the median seizure frequency dropped by 55.6%).
Regarding claims 68, Ren teaches the method of claim 52, the administration results in an improvement in one or more of: frequency of observed countable motor seizures; number of total seizures; frequency of non-convulsive seizure; number of episodes of status epilepticus; frequency of use of rescue medication; and number of countable motor seizure-free days (Pg. 38, line 35; the median seizure frequency dropped by 55.6%).
Regarding claims 69, Ren teaches the method of claim 52, wherein the method provides improvement in at least one symptom selected from ataxia, gait impairment, speech impairment, vocalization, impaired cognition, abnormal motor activity, clinical seizure, subclinical seizure, hypotonia, hypertonia, drooling, mouthing behavior, aura, convulsions, repetitive movements, unusual sensations, frequency of seizures and severity of seizures (Pg. 38, line 35; the median seizure frequency dropped by 55.6%). .
Regarding claims 70, Ren teaches the method of claim 52, wherein the Compound 1, or a pharmaceutically acceptable salt thereof, is an HCl salt of Compound 1 (Pg. 79, lines: 25-28; pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including but not limited to hydrochloric acid).
Regarding claim 71, Ren teaches the method of claim 52 as discussed above. Additionally, given that claim 52 is directed towards treating or preventing a disorder and the qEEG results and their formats are not material to the administration of the treatment. Thus the assessments to determine efficacy and its associated ranges would be an inherent part of the treating or preventing process. Thus, Ren’s treatment or prevention of seizure disorders would necessarily result in a ratio of a geometric mean steady-state Ctrough of Compound 1 in CSF to a geometric mean steady- state Ctrough of Compound 1 in plasma (CSF/P Ctrough) of at least about 1.4.
Therefore, claims 52-55 and 5771 are rejected as being anticipated by Ren.
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.
Claim 71 is rejected under 35 U.S.C. 103 as being unpatentable over Ren (Ren et al. WO 2016/176177 (5-HT2C Receptor Agonists and Compositions and Methods of Use Published: 11/03/2016) in view of Longboard Pharmaceuticals (Longboard Pharmaceuticals, Inc. Annual Report:2021 (December 31, 2021 SEC Filing).
As to claim 56, Ren teaches the method of claim 53 as discussed above.
However, Ren does not explicitly indicate wherein the epilepsy is a refractory epilepsy. Longboard Pharmaceuticals teaches wherein the epilepsy is a refractory epilepsy (Pg. 3, Part I, Item 1. LP352-LP359 is a 5HT2C superagonist used to treat seizures associated with different types of epilepsy including a group of severe early-childhood onset epilepsies characterized by refractory seizures and developmental delay and/or regression).
It would have been obvious to one of ordinary skill in the art before the effective filing date to incorporate the teachings of Longboard Pharmaceuticals into those of Ren in order to overcome known or perceived safety limitations of available drugs in the 5HT2C class.
Conclusion
No claims are allowed.
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/S.I./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622