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 .
Priority
This Application is a 371 of PCT/EP2022/053498, filed Feb. 14, 2022 and claims foreign priority benefit of EP21159595.4, filed Feb. 26, 2021 with the European Patent Office.
Claim Status
Claims 16-36 are currently pending and subject to examination.
Claim Rejections - 35 USC § 102 or 35 USC § 103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
“A person shall be entitled to a patent unless -
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.”
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
“A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.”
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 16-22 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Montel & Jnoff (US 9,630,948 B2, published April 25, 2017).
A 35 U.S.C. 102 and 103 combination rejection is permitted if it is unclear if the reference teaches the range with "sufficient specificity." The examiner must, in this case, provide reasons for anticipation as well as a reasoned statement regarding obviousness. Ex parte Lee, 31 USPQ2d 1105 (Bd. Pat. App. & Inter. 1993) (expanded Board). (MPEP § 2131.03).
Claim 16 is directed towards a method of treating a cognitive disorder in a subject, the method comprising administering a compound of Formula I:
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(I) or a pharmaceutically acceptable salt thereof to the subject, wherein the compound is administered to the subject in an amount of from about 0.2 mg to about 5 mg.
Montel teaches three related test compounds including the compound of Formula I:
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(Montel, Example 1, col. 9-10). Montel teaches that the compound is “useful for the treatment of conditions associated with enhancement or improvement of cognitive ability or to counteract cognitive decline” (id., col. 3, lines 49-52). Montel teaches that the test compounds were used in three different in vivo models for cognition (Examples 5, 6, and 6).
In Example 4, the compound was tested in an “In Vivo Model for Assessing the Efficacy of a Test Compound in Learning and Memory Disorders (Novel Object Recognition Test; NOR)” (id., col. 16-17). The compound was administered intraperitoneally and “displayed typically an activity of 50 mg/kg or less” (id., col. 17, lines 21, 25-27) in mice weighing 0.02 to 0.035 g (id., col. 16, line 52) equating to a dose of 1.0 mg to 1.75 mg or less.
In Example 5, the compound was tested in an “In Vivo Model for Assessing the Efficacy of a Test Compound in Recognition Memory Deficit Induced by Acute Scopolamine Administration and Repeat Sub-Chronic Phencyclidine (PCP) in Novel Object Recognition Task in Rat” (id., col. 17-18, Example 5). The compound was administered per os (by mouth) 60 minutes before acquisition in the scopolamine model and ip (intraperitoneally) 40 min before acquisition in the sub-chronic PCP model (id., col. 18, lines 19-22) The compounds “displayed typically an activity at 1 mg/kg or less in the scopolamine model and at 3 mg/kg or less in the sub-chronic PCP model.” (id., lines 44-47). The rats in the scopolamine model weighed 0.22 kg to 0.30 kg (id., line 14), equating to a dose of 0.22 to 0.30 mg or less. The rats in the sub-chronic PCP model weighed 0.16 kg to 0.22 kg (id., line 18), equating to a dose of 0.48 to 0.66 mg or less.
In Example 6, the compound was tested in a “non-transgenic model of amyloid-induced memory deficit” in young male Swiss mice and “displayed typically an activity at 10 mg/kg or less” (id., col. 18-19). While they do not disclose the weight of the mice in this test, young male lab mice typically weigh 0.02-0.035 kg as demonstrated in example 4, equating to a dosage of 0.20 to 0.35 mg or less.
As Montel gives three different examples showing the efficacy of the compound in treating cognition and gives four different activity: 50 mg/kg or less, 3 mg/kg or less, 1 mg/kg or less, and 10 mg/kg or less, it appears that Montel discloses the activities of 50 mg/kg, 3 mg/kg, 1 mg/kg and 10 mg/kg, which equate to doses falling within the claimed range. If the dose of 50 mg/kg or less was no more of a disclosure of 50 mg/kg than of 5 mg/kg, it would not make much sense to differentiate the activity between the four trials. Therefore, the disclosure of 50 mg/kg or less appears to disclose an activity at 50 mg/kg with sufficient specificity, equivalent to a dose falling within the claimed range. The same case can be made for the disclosed doses of 1 mg/kg or less, 3 mg/kg or less, and 10 mg/kg or less. As such, claim 16 is anticipated.
If the claim is interpreted as not disclosing the claimed range with sufficient specificity, in contrast to the above analysis, one of ordinary skill in the art would have a reasonable expectation of success to administer a dose within the claimed range because the doses of 50 mg/kg or less, 3 mg/kg or less, 1 mg/kg or less and 10 mg/kg or less overlap the claimed range. Furthermore, Montel teaches that the “compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing 0.1 to 2000 mg, preferably 0.1 to 1000 mg, more preferably 0.1 to 500 mg of active ingredient per unit dosage form.” (Montel, Specification, col. 6, lines 49-53), which overlaps the claimed range. “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.” (MPEP § 2144.05). As such, claim 16 was alternatively, prima facie obvious at the time of filing.
Claim 17 is directed towards the method of claim 16, wherein the compound is administered to the subject in an amount of from about 0.3 to about 4 mg. Claim 18 is directed towards the method according to claim 16, wherein the compound is administered to the subject in an amount from about 1 to about 3 mg.
Claims 17 and 18 are anticipated or, in the alternative, obvious over Montel for the reasons given in the rejection of claim 16. Montel appears to disclose specific examples falling within the claimed range with sufficient specificity. In the alternative, Montel discloses examples which overlap the claimed range. Therefore, claims 17 and 18 are anticipated, or in the alternative, were prima facie obvious at the time of filing.
Claim 19 is directed towards the method according to claim 16, wherein the compound is (4R)-1-[(5-chloro-1H-1,2,4-triazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one or a pharmaceutically acceptable salt thereof. Claim 20 is directed towards the method of claim 16, wherein the compound is (4R)-1-[(5-chloro-1H-1,2,4-triazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one. As shown in the rejection of claim 16, Montel teaches the compound (4R)-1-[(5-chloro-1H-1,2,4-triazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one. Therefore, claims 19-20 are anticipated, or in the alternative, were prima facie obvious at the time of filing.
Claim 21 is directed towards the method of claim 16, wherein the cognitive disorder is selected from autism, dyslexia, attention deficit hyperactivity disorder, obsessive compulsive disorders, psychosis, bipolar disorders, depression, Tourette's syndrome and disorders of learning in children, adolescents and adults, Age Associated Memory Impairment, Age Associated Cognitive Decline, Parkinson's Disease, Down's Syndrome, traumatic brain injury, Huntington's Disease, Progressive Supranuclear Palsy (PSP), HIV infection, stroke, vascular diseases, Pick's or Creutzfeldt-Jacob diseases, multiple sclerosis (MS), other white matter disorders and drug-induced cognitive worsening, Alzheimer's disease, schizophrenia, Lewy-bodies disease, front-temporal lobe degeneration, vascular narrowing or blockage in the brain, head trauma, subjective cognitive decline and mild cognitive impairment.
Claim 22 is directed towards the method according to claim 16, wherein the cognitive disorder is selected from subjective cognitive decline, Age Associated Memory Impairment, mild cognitive impairment, Alzheimer's disease, cognitive impairment in major depressive disorder and cognitive impairment in a subject with remitted depression following multiple episodes of major depressive disorder.
As shown in the rejection of claim 16, Montel discloses the compound in rodent models of cognitive, learning and memory disorders (Examples 4-6), which are, in particular, models for Alzheimer’s disease and cognitive deficit in schizophrenia:
In pre-clinical animal models, the compounds according to the present invention improve cholinergic memory deficit induced by scopolamine, a muscarinic receptor antagonist. They also improve the memory deficit induced by beta-amyloid or by subchronic administration of phencyclidine (PCP), a non-competitive NMDA antagonist. Memory deficits in Alzheimer's disease may have both a cholinergic origin as a consequence of specific cholinergic degeneration during disease progression, and an amyloid origin as a consequence of beta-amyloid increase in the brain. Cognitive deficits in schizophrenia result from dysregulation of several neurotransmitter systems, including glutamate and dopamine, mimicked by the effects of NMDA antagonists such as PCP. Therefore, it is believed that the compounds according to the present invention have a strong potential to improve cognitive deficits in Alzheimer's disease and cognitive impairment associated with schizophrenia.
Montel, Specification, col. 8, lines 30-47.
Montel also specifically teaches that the cognitive impairment associated with a disease or disorder includes “autism, dyslexia, attention deficit hyperactivity disorder, compulsive disorders, psychosis, bipolar disorders, depression, Tourette's syndrome and disorders of learning in children, adolescents and adults, Age Associated Memory Impairment, Age Associated Cognitive Decline, Parkinson's Disease, Down's Syndrome, traumatic brain injury Huntington's Disease, Progressive Supranuclear Palsy (PSP), HIV, stroke, vascular diseases, Pick's or Creutzfeldt-Jacob diseases, multiple sclerosis (MS), other white matter disorders and drug-induced cognitive worsening.” (id., col. 7, lines 12-23). Montel teaches that the suitability of the compounds for treating such conditions may be tested through assays which are well known in the art, which include “include in particular the novel object recognition tests set out in Example 4 and 5, as well as the Y-maze test set out in Example 6.” (id., lines 1-7).
Therefore, claims 21-22 are anticipated, or in the alternative, were prima facie obvious at the time of filing.
Claim 23 is directed towards the method according to claim 16, wherein the compound is administered orally. As shown in the rejection of claim 16 above, in Example 5, the compound was administered per os (orally). Therefore, claim 23 is anticipated, or in the alternative, was prima facie obvious at the time of filing.
Claim Rejections - 35 USC § 103
Claim(s) 16-36 is/are rejected under 35 U.S.C. 103 as obvious over Montel & Jnoff (US 9,630,948 B2, published April 25, 2017), as applied to claims 16-23 above, and further in view of Gallagher et al. (US 8,604,075 B2, published Dec. 10, 2013) and Sharma & McNeill (British Journal of Pharmacology, Volume 157, Issue 6, Jul 2009, Pages 863-1096).
The rejection of claims 16-23 as anticipated by, or in the alternative, as obvious over Montel above is incorporated by reference.
Claim 24 is directed towards the method of claim 16, wherein the compound is administered daily.
Montel teaches that the compound of the instant invention is a racetam-like drug (Montel, Specification, Background). While Montel only teaches specific examples where the compound was administered once to the subject, one of ordinary skill in the art would have a reasonable expectation of success to administer the compound to the subject daily because it is commonly known in the art to administer racetam-like compounds daily for the treatment of cognitive decline, such as cognitive decline associated with Alzheimer’s disease.
For example, Gallagher teaches “the use of inhibitors of synaptic vesicle protein 2A (SV2A), such as levetiracetam, seletracetam, and brivaracetam, in improving cognitive function in subjects that exhibit age-related cognitive impairment or are at risk thereof, including, without limitation, subjects having or at risk for Mild Cognitive Impairment (MCI), Age-related Cognitive Decline (ARCD) or Age-Associated Memory Impairment (AAMI).” (Gallagher, Abstract). Gallagher teaches, for example, that “the SV2A inhibitor is administered every 12 or 24 hours at a total daily dose of 0.1 to 5 mg/kg (e.g., in the case of administration every 12 hours of a daily dose of 2 mg/kg, each administration is 1 mg/kg” (Gallagher, Specification, col. 61, lines 36-39).
Therefore, claim 24 was prima facie obvious at the time of filing.
Claim 25 is directed towards a method for treating a cognitive disorder in a subject, the method comprising administering a compound of formula (I):
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(I) or a pharmaceutically acceptable salt thereof, wherein the compound is administered to the subject in an amount that provides a synaptic vesicle glycoprotein 2A (SV2A) occupancy of from 10% to 80% at trough level after once daily dosing for at least 10 days.
As shown in the rejection of claim 16, Montel teaches to administer an effective amount of the compound of formula (I) for the treatment of cognitive disorders in a subject in need thereof. While Montel does not teach that the compound is administered to the subject in an amount that provides SV2A occupancy of from 10% to 80% at trough level after once daily dosing for at least 10 days, one of ordinary skill in the art would have a reasonable expectation of success to administer the compound of formula (I) at this amount because Montel teaches that the effective amount is an amount which falls within this range and because daily dosing of racetam-like compounds is commonly known in the art for the treatment of cognitive decline.
For example, in Example 5, Montel teaches that the effective amount in the rat model for Alzheimer’s related cognitive decline and schizophrenia related cognitive decline 1 mg/kg or less and at 3 mg/kg or less, respectively (Montel, Specification, col. 18, lines 44-47). Sharma teaches how to allometrically scale this to a dose in mg/kg for a human by multiplying by 0.162 (Sharma, Table 1, p. 912). Sharma uses a 60 kg reference body weight for humans (id., col. 2, p. 912). Using these equivalencies, we can calculate a dose of 0.162 mg/kg of less for Alzheimer’s disease and 0.486 mg/kg for schizophrenia, which for a 60 kg reference weight, means administering 9.72 mg or less and 29.16 mg or less to a human subject.
Instant Figure 6 shows that a daily dose of 10 mg in human subjects is sufficient to achieve greater than 70% SV2A occupancy after daily dosing for 10 days. 10 mg is very close to 9.72 mg or less and lies within the range of 29.16 mg or less and as such a prima facie case of obviousness exists for administering 10 mg (see MPEP § 2144.05).
While Montel does not teach daily dosing for at least 10 days, one of ordinary skill in the art would have a reasonable expectation of success to administer 9.72 mg or less and 29.16 mg or less to the human subject to give the claimed occupancy levels after 10 days of dosing because it is known to administer similar racetam-like drugs daily for 10 days.
For example, Gallagher teaches that “the SV2a inhibitor may be administered for a period of 1-4 weeks, 1-3 months, 3-6 months, 6-12 months, 1-2 years or more, up to the lifetime of the patient (Gallagher, Specification, col. 62, lines 1-3).
Therefore, claim 25 was prima facie obvious at the time of filing.
Claim 26 is directed towards the method of claim 25, wherein the compound is administered to the subject in an amount that provides an SV2A occupancy of from 10% to 70% at trough level after once daily dosing for at least 10 days. Claim 27 is directed towards the method of claim 25, wherein the compound is administered to the subject in an amount that provides an SV2A occupancy of from 20% to 50% at trough level after once daily dosing for at least 10 days.
Instant figure 6 shows that for 10% to 70% receptor occupancy, doses from about 0.5 mg to about 10 mg are required; and for 20% to 50% receptor occupancy, doses from about 1 mg to about 2 mg are required. As shown in the rejection of claim 25, one of ordinary skill in the art could infer from the rat dosage that about 9.72 mg or less and 29.16 mg or less is the effective amount in human subjects. About 9.72 mg or less overlaps the range from about 0.5 mg to about 10 mg and from about 1 mg to about 2 mg, as such there is a prima facie case of obviousness. Furthermore, in a routine optimization of the drug in humans, one of ordinary skill in the art would generally consider doses which much lower than the calculated pharmacologically active dose: “it is important to start with a dose that is below the pharmacologically active dose” (Sharma, col. 2, p. 915).
Therefore, claims 26-27 were prima facie obvious at the time of filing.
Claim 28 is directed towards the method according to claim 25, wherein the compound is administered to the subject in an amount of from about 0.2 to about 5 mg. Claim 29 is directed towards the method according to claim 25, wherein the compound is administered to the subject in an amount of from about 0.3 to about 4 mg. Claim 30 is directed towards the method according to claim 25, wherein the compound is administered to the subject in an amount of from about 1 to about 3 mg.
As shown in the rejection of claim 27, one of ordinary skill in the art would have a reasonable expectation of success to administer to a human subject amounts falling within the range of 9.72 mg or less. Therefore, claims 28-30 were prima facie obvious at the time of filing.
Claims 31-34 have the same limitations as claims 19-22, but are dependent from claim 25 and not claim 16. As Montel teaches the compound and disorders as claimed, claims 31-35 were prima facie obvious at the time of filing.
Claim 35 is directed towards the method of claim 28, wherein the compound is administered orally. One of ordinary skill in the art would have a reasonable expectation of success to administer the compound orally because Montel teaches to administer the compound orally. Therefore, claim 35 was prima facie obvious at the time of filing.
Claim 36 is directed towards the method of claim 28, wherein the compound is administered to the subject daily. While Montel only teaches specific examples where the compound was administered once to the subject, one of ordinary skill in the art would have a reasonable expectation of success to administer the compound to the subject daily because it is commonly known in the art to administer racetam-like compounds daily for the treatment of cognitive decline, such as cognitive decline associated with Alzheimer’s disease. For example, see Gallagher, as in the rejection of claim 24.
Therefore, claim 36 was prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
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/HEATHER DAHLIN/Examiner, Art Unit 1629