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 .
Response to Amendments
The claims are not amended.
Response to Arguments
Applicant’s arguments and allegations of unexpected results have been considered and are addressed below.
Applicant argues that there is no reason to think that LEV would potentiate activity in cognition because half of the compounds that were enhanced by LEV (i.e., phenobarbital and valproate) did not improve cognition.
The examiner notes that Mekonnen teaches the claimed compound to be a GABAAα5 receptor agonist that treats age related cognitive impairment, mild cognitive impairment (MCI), and other cognitive conditions. Mekonnen does not refer to valproate or phenobarbital. Even if Mekonnen did, we already know that the claimed compound will treat cognitive impairment among other cognitive behaviors.
LEV is also taught to treat MCI and to potentiate the potency of positive allosteric modulator of GABAA receptors, GABA transporter inhibitors, or GABA transaminase inhibitors.
Koh teaches, “potentiating the effects of GABAA α5 receptors has benefit for cognitive deficits associated with aging.” See p9, 3rd par. Koh explains that GABAAα5 receptors may be an important therapeutic target for age-related cognitive impairment. Further, “potentiating the effects of GABAA α5 receptors has benefit for cognitive deficits associated with aging.”
Kaminski teaches: “levetiracetam opposes inhibitory effects of Zn2+ and β-carbolines on GABA- and glycine-gated currents….” LEV is known to enhance GABAergic inhibition. Further, the potency of drugs was enhanced by more than 16-fold when administered in combination with LEV, and this includes the potency of positive allosteric modulator of GABAA receptors, GABA transporter inhibitors, or GABA transaminase inhibitors, which also considerably increased (up to 11-fold increase). See Table 1 for change in potency of GABA compounds when administered in combination with LEV. All examples include a greater than additive synergistic effect of the combinations.
Not all agents discussed by the prior art treat cognitive impairment as claimed. However, the claimed agent does. LEV is taught to synergistically enhance and potentiate the effect of many drugs, including valproate and phenobarbital. These drugs are not, however, known to improve cognitive impairment nor required to do so. They are used to treat epilepsy.
Domonique et al., “Chapter 73 - Cognitive side-effects of antiepileptic drugs in children,” Handbook of Clinical Neurology Volume 111, 2013, pages 707-718, teaches: “With phenobarbital there is a high risk for serious cognitive effects impacting attention and memory.” Abstract.
Moon et al., “Effect of valproate and lithium on dementia onset risk in bipolar disorder patients,” Scientific Reports, Nature (2022) 12:14142, teaches: valproate only uses showed a higher risk of dementia and valproate increased the dementia risk when prescribed for at least 59 days or 23 defined daily doses. See Abstract.
A person of ordinary skill would expect LEV and the claimed compound “Component B” to treat cognitive impairment because they each do independently. Unexpected results are not established because Component B is taught to be a GABAAα5 receptor agonist that treats age related cognitive impairment, mild cognitive impairment (MCI), and other cognitive conditions. LEV is taught to synergistically enhance the potency of positive allosteric modulator of GABAA receptors, GABA transporter inhibitors, or GABA transaminase inhibitors, which also considerably increased (up to 11-fold increase). See Table 1 for change in potency of GABA compounds when administered in combination with LEV. All examples include a greater than additive synergistic effect of the combinations. Thus, it is not unexpected that the effect of the claimed combination is synergistic. While Applicant argues that valproate and phenobarbital do not treat cognitive impairment, this is not unexpected as they are also recognized through evidentiary references as compounds that are known to cause cognitive impairment. Moreover, the cited prior art does not teach these compounds to treat cognitive impairment while Applicant’s own prior art explicitly teaches Component B to cognitive impairment.
As requested, the DP rejections are held in abeyance and maintained.
Applicant’s arguments and showing of unexpected results are not persuasive.
Status of the Claims
Claims 57, 63, 67, and 70 are pending and examined.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, 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.
Claims 57, 63, 67, and 70 remain rejected under 35 U.S.C. 103 as being unpatentable over Gallagher et al., (US2010/0099735 A1) (cited in IDS), in view of Gallagher et al., (US2011/0212928) (“Gallagher2”), in view of Koh et al., “Selective GABA(A) α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment. Neuropharmacology,” 2013 Jan;64(1):145-52 (cited in IDS), in view of Mekonnen et al., (U.S. Pat. No. 11,414,425), and in view of Kaminski et al., “Benefit of combination therapy in epilepsy: A review of the preclinical evidence with levetiracetam,” Epilepsia March 4, 2009.
Gallagher teaches treating conditions, including mild cognitive impairment by administering an inhibitor of synaptic vesicle protein 2A (SV2A). More specifically, Gallagher teaches treating MCI and other cognitive impairments with levetiracetam. It can be administered at a dosage of 40-130 mg per day. See par. 9.Administration can be through multiple routes, including oral, buccal, nasal, parenteral, and others. See par. 867. The SV2A inhibitor can be mixed with excipients and carriers. See par. 869.
Gallagher2 teaches treating cognitive impairments including MCI with an inhibitor of SV2A. Similarly, a beneficial effect is an amount that “increases GABAergic activity, reduces excitatory neurotransmission, among others, that results in an improvement in cognitive function. See par. 2125.
Gallagher does not teach co-administering a GABAAα5 receptor agonist.
Koh teaches GABAA alpha receptors modulate cognitive conditions and Alzheimer’s disease (AD), e.g. Treatment in the past has focused on negative allosteric modulators (NAM). See p2, 1st par. However, animal models show that excess neural activity in the hippocampal formation contributes to cognitive impairment in aging and in conditions that confer increased risk for AD. “In this context, GABAA α5 receptors could be an important therapeutic target for age-related cognitive impairment.” Moreover, “In conditions of excess neural activity, therefore, the use of positive allosteric modulators (PAMs), rather than NAMs, might be indicated.” See p3, 1st par. The studies and data shows that augmenting GABAA α5 receptors reduced excess hippocampal output that occurs in a model of schizophrenia and improves behavioral abnormalities associated with psychiatric illness. See p9-10, bridging par. Evidence shows that excess neural activity is associated with symptomatic function and progress of AD. Further, “potentiating the effects of GABAA α5 receptors has benefit for cognitive deficits associated with aging.” See p9, 3rd par. Compounds were administered through intracerebroventricular infusion and systemically at a dose of 3 mg/kg, e.g. See abstract.
Mekonnen teaches the claimed GABAAα5 receptor agonist compounds. See col. 711, 1st compound. It is claimed and taught to treat cognitive impairment, MCI, schizophrenia, and other claims conditions. See Abstract. Doses used for GABAAα5 receptor agonist compounds throughout Mekonnen include a range of up to 100 mg/kg/day. See col. 254, line 27. Dosages are also used in the examples that fall within the claimed range. See Example 107, 108, and others.
Kaminski teaches: “levetiracetam opposes inhibitory effects of Zn2+ and β-carbolines on GABA- and glycine-gated currents….” LEV is known to enhance GABAergic inhibition. Further, the potency of drugs was enhanced by more than 16-fold when administered in combination with LEV, and this includes the potency of positive allosteric modulator of GABAA receptors, GABA transporter inhibitors, or GABA transaminase inhibitors, which also considerably increased (up to 11-fold increase). See Table 1 for change in potency of GABA compounds when administered in combination with LEV. All examples include a greater than additive synergistic effect of the combinations.
Kaminski also explains that drugs enhancing GABAergic inhibition (i.e., benzodiazepines) were most effectively enhanced by levetiracetam. See p388, 3rd full par. The degree of enhancement by LEV was different for benzodiazepines (approximately 20 fold shift), barbiturates, and neurosteroids- each of which are positive allosteric modulators of GABAA receptors. See p393, 4th full par.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to combine Gallagher, Gallagher2, Koh, Mekonnen, and Kaminski to treat a claimed CNS disorder, including AD, mild cognitive impairment. One would be motivated to do so because Gallagher teaches administering a synaptic vesicle protein 2A (SV2A) inhibitor, including levetiracetam to treat the same and Koh teaches administration of an agent that augments and/or potentiates GABAA α5 receptors will have a benefit for AD and cognitive decline associated with aging. Gallagher2 indicates that a beneficial effect is to increase GABAergic activity and/or reduce excitatory neurotransmission with an inhibitor of SV2A. Mekonnen teaches treating claimed conditions with the claimed GABAA α5 receptor agonist. According to M.P.E.P. § 2144.06, “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Even further, a POSA would expect that LEV would potentiate the effect of a GABAA α5 receptor agonist. Overall, LEV reduces negative allosteric effects on GABA receptors thereby potentiating treatment when combined with a PAM, and such is known to treat cognitive impairment.
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 57, 63, 67, and 70 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-51 of U.S. Patent No. 11,414,425 in view of Koh et al., “Selective GABA(A) α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment. Neuropharmacology,” 2013 Jan;64(1):145-52. The ‘425 patent is directed to methods of using the claimed SVA2 inhibitors, including the elected species (see claim 26) to treating conditions of the CNS, including conditions associated with MCI. Those conditions including brain cancer, PD, PTSD, ALS, and others. See claims 30, 33, and others. Mild Cognitive Impairment is claimed in claim 42. KOH teaches using GABA alpha 5 agonists to treat and improve cognitive function. As such, it would be obvious to treat the claimed subject with a claimed combination because each agent is taught to independently treat a claimed condition.
Claims 57, 63, 67, and 70 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10,154,988, in view of Koh et al., “Selective GABA(A) α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment. Neuropharmacology,” 2013 Jan;64(1):145-52. The ‘988 patent is directed to methods of using the claimed SVA2 inhibitors, including the elected species (see claim 26) to treating conditions of the CNS, including conditions associated with MCI. Those conditions including brain cancer, PD, PTSD, ALS, and others. See claims 30, 33, and others. Mild Cognitive Impairment is claimed in claim 42. KOH teaches using GABA alpha 5 agonists to treat and improve cognitive function. As such, it would be obvious to treat the claimed subject with a claimed combination because each agent is taught to independently treat a claimed condition.
Claims 57, 63, 67, and 70 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 10,159,648, in view of Koh et al., “Selective GABA(A) α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment. Neuropharmacology,” 2013 Jan;64(1):145-52. The ‘875 patent is directed to methods of using the claimed SVA2 inhibitors, including the elected species (see claim 26) to treating conditions of the CNS, including conditions associated with MCI. The conditions include schizophrenia and bipolar disorder, which are taught to be associated with MCI. Those conditions including brain cancer, PD, PTSD, ALS, and others. See claims 30, 33, and others. Mild Cognitive Impairment is claimed in claim 42. KOH teaches using GABA alpha 5 agonists to treat and improve cognitive function. As such, it would be obvious to treat the claimed subject with a claimed combination because each agent is taught to independently treat a claimed condition.
Claims 57, 63, 67, and 70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 10-19, 22, 57, 63, 65-67, and 70 of copending Application No. 18/015,439. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘439 application are directed towards a composition comprising an inhibitor of SV2A and a GABA alpha 5 receptor agonist. Claims directed to treatment include those with Mild Cognitive Impairment (MCI). See claim 74 of the ‘439 application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
As such, no claim is allowed.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
Prosecution Insights