DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/29/2025 has been entered.
Response to Arguments
Applicant’s response from 12/29/2025 is acknowledged.
Claim Rejections - 35 USC § 103
Applicant’s arguments have been carefully considered, but have not been found to be persuasive. Moreover, they are a restatement of previous arguments, which were previously addressed at length.
With respect to NCT ‘758 Applicant has argued as follows:
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(Response at 6).
In response, with respect to NCT ‘758 Applicant does not deny, and the office action itself establishes too, that NCT ‘758 does teach an overlapping dose with Applicant’s claims. Specifically, NCT ‘758 teaches that patients received levetiracetam as monotherapy, and according to Applicant’s claimed daily dose of 250 mg: namely, 125mg twice daily =250 mg. Patients also received 250 mg twice daily. Applicant takes a stand that the higher of the two doses was found to be ineffective. However, since this is a clinical trial with dose searching studies, and one of the two doses clearly overlaps Applicant’s claimed dose range, then a prima facie case of obviousness has been made. It is inappropriate to state that NCT ’758 went in the wrong direction. The law does not require absolute predictability but only a reasonable expectation of success. NCT ‘758 cannot be said to have gone in the wrong direction because one of two studied doses overlaps Applicant’s claimed range, and based on this dose studies, the direction of lower or higher can thus be appropriately determined.
The Examiner further comments on Applicant’s claim amendment, which adds “therapeutically effective amount of the” levetiracetam to the wherein claim limitation of claim 50. It is noted, however, that the office action above already addressed in the office action, as the claim as previously presented recites early on the body of the claim therapeutically effective amount of levetiracetam.
For instance, with respect to NCT ‘758 Applicant does not deny, and the office action itself establishes too, that NCT ‘758 does teach an overlapping dose with Applicant’s claims. Specifically, NCT ‘758 teaches that patients received levetiracetam as monotherapy for improving memory function in amnestic mild cognitive impairment (MCI) and Alzheimer’s disease (AD), and according to Applicant’s claimed daily dose of 250 mg: namely, 125mg twice daily =250 mg. Not only is 125mg twice daily =250 mg an overlapping dose with Applicant’s claims, which recite 50-250 mg of levetiracetam once a day, but the Examiner also notes that twice daily, presumably morning and evening, of 125 mg actually yields a much lower therapeutic dose spread over time. Stated differently, since the drug is metabolized, the first daily dose is 125 mg, which falls on the lower end of Applicant’s claimed dose range, and the administering of another 125 mg, presumably some 8-12 hours later in the day, would give a considerably lower combined dose of the drug in the blood in view of drug pharmacokinetics, than if a total 250 mg of levetiracetam were administered as a single dose. Thus, it would have been obvious to a person of skill in the art that several hours later from first administration a considerable amount of the first dose of levetiracetam would have already metabolized and excreted, and that therefore the therapeutically effective amount of levetiracetam 125mg twice daily would amount to a considerably lower therapeutic area under the curve for the drug than a therapeutic dose of 250 mg given once a day.
Drugs do not go into clinical trials without pharmacokinetic studies. For instance, the drug label Keppra was provided in the second 103 rejection. It has a pharmacokinetic section, which provides:
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This is further consistent with case law. "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003). >See also In re Harris, 409 F.3d 1339, 74 USPQ2d 1951 (Fed. Cir. 2005) (claimed alloy held obvious over prior art alloy that taught ranges of weight percentages overlapping, and in most instances completely encompassing, claimed ranges; furthermore, narrower ranges taught by reference overlapped all but one range in claimed invention). In the case where 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) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Either way, "a prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003).
Applicant has also argued vis-à-vis Exhibits A, B and C, which allegedly report that doses of 1000 mg of levetiracetam cannot be used to treat cognitive impairment. (Response at 6). This is another rehashed point, which the Examiner already addressed. In response, as the Examiner previously noted “In response, the Examiner first notes that the Shannon 2004, 2005 and 2007 dose of 1000 mg in human is significantly higher than Applicant’s claimed range.” The point about ‘subtherapeutic” was also made with respect to other art, but is particularly relevant where as here a later in time reference NCT ‘758- went towards subtherapeutic doses, which are much lower than 1000 mg- specifically 500 and 250 mg. The point the Examiner made was on point.
Applicant has also argued:
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In response, the Examiner disagrees with this reasoning. A dose less than 3000 mg but above 1000 mg would not be considered “subtherapeutic”, but would fall within the range of “therapeutic”. A drug label is the standard for findings of a therapeutic dose. Further, the Examiner addressed Exhibits A, B and C above. Most importantly, the Examiner did not leave the rejection at Bird, but did indeed introduce multiple other references (Keppra, Minervini, Wulfert, ADR News) to elaborate on this point.
Thus, Bird does not disclose the dosage of levetiracetam in actual number, but provides very clear disclosure in other words what this dosage needs to be- “wherein the amount of anti-epileptic agent is subtherapeutic for mood stabilization treatment of epilepsy or epileptic symptoms.” (claim 1, emphasis added). Looking at the approved label for levetiracetam for the treatment of epilepsy (“Keppra”), one is able to find what the subtherapeutic dosage is by reference to the approved therapeutic dosage. Keppra discloses:
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(p. 1).
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(p. 30).
Based on the Keppra label, the amount of levetiracetam, which is subtherapeutic for mood stabilization treatment of epilepsy or epileptic symptoms is less than 1000 mg/day, which clearly encompasses Applicant’s claimed dose of 50-250 mg/ day.
Minervini, introduced as cumulative art, also discloses single administration of levetiracetam, to include at doses below the Keppra label dose (i.e. 500 mg/ day initial to 1000 mg/day thereafter) specifically for treating mild cognitive impairment in patients. Cumulatively, it provides motivation to optimize the dose in a downward fashion, to include as claimed by Applicant.
Wulfert teaches compounds of formula (I) which reads on levetiracetam (Col. 1, lines 48-55). Wulfert teaches oral compositions comprising between 50 mg and 1000 mg of the compound of formula (I) (Col. 3, lines 25-55). The table in Col. 3, lines 50-55 exemplifies capsules comprised of the compound of formula (I) that comprise 125 mg and 250 mg. Even if one were to take into account disclosure of an oral dose given twice a day, 125 x 2= 250. Further, Wulfert specifically teaches also capsules of 62.5 mg, and assuming they are given as IR twice a day, 62.5 x 2= 125 mg. Wulfert teaches that a daily dosage can vary within a wide range of dosage units. (col. 3, ll. 30-35).
ADR News specifically teaches a dose of 250 mg/day and a dose of 125 mg/day of levetiracetam. The drug was titrated down in a patient who had Huntington’s disease, and who developed Parkinsonism during treatment with levetiracetam at a dose of 500 mg twice daily. The patient’s condition improved when the dose was titrated down first to a dose of first 250 mg/day, and then to a dose of 125 mg/day of levetiracetam. The Examiner acknowledges that ADR News does not report full cure, but it certainly guides in direction of lowering of dose. Moreover, that the art discloses both certain advantages and disadvantageous is not deemed to diminish from a prima facie case of obviousness. See Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006) (A “given course of action often has simultaneous advantages and disadvantages, and this does not necessarily obviate motivation to combine.”). So, this is clearly yet a fifth example of a reference, which goes even lower than the subtherapeutic dose of Bird, the lower dose of Minervini, and the doses of both Jenkins and Wulfert, which are clear ranges within Applicant’s claimed ranges. Cumulatively, it provides motivation to optimize the dose in a downward fashion, to include as claimed by Applicant. Certainly, having therapeutically effective options to control either or both PD or Huntington’s disease is no small matter, and certainly provides motivation to explore these doses, at a minimum for either of these conditions, at the respective doses. That both are being treated, and/or kept at bay, is even more significant.
Applicant’s ongoing argumentation about initiation doses somehow appears to argue that they are not therapeutic, but why? Clearly, the above dose of 500 mg, initiation or otherwise, is half of the dose provided for by the label, and cumulative art towards lower dose adjustment.
In contrast, Applicant’s own specification provides no data whatsoever as to whether Applicant itself intends to use the single 250 mg dose studied as an initiation dose, or an ongoing therapeutic dose. Applicant only studied a 250 mg dose, a single dose and not the claimed range doses, and for a short period of two weeks only. Accordingly, for this single dose studied for two weeks only, a legitimate question also remains, if it too also falls under an “initiation” dose, following the logic of Applicant’s own arguments. And somehow, because it claimed other lower doses, for which its specification provides no support whatsoever, Applicant somehow seems to think that this creates an entitlement to differentiation from the prior art. The facts of Applicant’s own specification provide no support to underlie any such assertion on this record, where Applicant’s specification provides: “[2089] As described above, the drug treatment period is the two weeks preceding Visit 1 or 2 (with the two week period preceding the other Visit being the placebo phase). For the subjects receiving the drug treatment, half a scored 250 mg tablet of levetiracetam is used to achieve a dose of 125 mg/kg twice a day, which is approximately 3.6 mg/kg/day (assuming an average adult human weight of 70 kg).” Again, the only dose studied by Applicant, and claimed by Applicant on the high end of its dose range, squarely falls under a dose disclosed by the prior art. Any doses claimed by Applicant as to a lower dose range than the highest dose studied, have no support in Applicant’s own specification.
Further, the full paragraph cited by Applicant is considerably broader than the exemplary dose cited for the treatment of anxiety alone, which Applicant has pointed to. Further, Applicant’s citation is as to anxiety, while Applicant’s claims are directed instead to cognitive impairment associated with a CNS disorder. “As regards the daily dosage, this can vary within a wide range of dosage units and is preferably between 5 and 70 mg/kg. An average dose of 250 mg, twice a day, has proved to be effective in relief of anxiety in man. It is to be understood, however, that the specific doses can be adapted for particular cases, depending on individual need, at the discretion of the responsible physician. The above-mentioned dosages are given exemplary only and by no means limit the scope of practice of the invention.” (col. 3, ll. 36-44).
So, again, Applicant cannot just “write off” the dose of 125 x 2= 250mg, as it is in its claims. Nor can it just ignore the disclosure of the even lower dose of 62.5 x 2= 125 mg. So, this is clearly one more example of a reference, which goes even lower than the subtherapeutic dose of Bird, the lower dose of Minervini, and the doses of Jenkins, which are clear ranges within Applicant’s claimed ranges. Cumulatively, it provides motivation to optimize the dose in a downward fashion, to include as claimed by Applicant.
Applicant has responded to this point with arguments regarding after filing date studies of a daily dose of 125 mg levetiracetam. (Response at 9). The Examiner notes that the prior art of record already teaches such a dose- e.g. ADR News at 125 mg/day, NCT ‘758- 125 mg twice daily. These are two very specific examples, which show that the prior art did not look for a needle in a haystack (a term which Applicant used at p. 10 of its Response), but that the prior art had already laid the road with specific studies in the exact dose range claimed by Applicant.
In sum, as can be glimpsed from Applicant’s response, these are nothing more than generalities in the form of attorney argument, not data, and they reaffirm nothing more than what was already said on the record. Specifically, Applicant has shown that a levetiracetam dose of 500 mg daily was not effective in treating cognitive impairment, but that dose of 125 mg twice a day (250 mg daily total) was effective in treating cognitive impairment. As to the doses administered, Applicant’s specification provides: “[2089] As described above, the drug treatment period is the two weeks preceding Visit 1 or 2 (with the two week period preceding the other Visit being the placebo phase). For the subjects receiving the drug treatment, half a scored 250 mg tablet of levetiracetam is used to achieve a dose of 125 mg/kg twice a day, which is approximately 3.6 mg/kg/day (assuming an average adult human weight of 70 kg).” Stated simply, Applicant has done a clinical trial with doses squarely within the prior art, and simply done nothing more than optimize the dose, as obviousness does not require absolute predictability but only reasonable expectation of success.”
This is further confirmed by a review of Fig. 11 and 12, as to which Applicant’s specification provides: “[2102] The normalization of DG/CA3 and EC activity during memory judgments by levetiracetam treatment is mirrored in the change seen in the aMCI subjects' performance in the cognitive task. With placebo treatment, aMCI patients perform worse that control subjects, correctly identify lure items as "similar" less often and incorrectly identifying them as "old" more often (p = 0.009). See FIG. 11. However, the performance of aMCI subjects improves significantly under levetiracetam treatment. See FIG. 12.”
Thus, not only is there not criticality shown across the claimed range. In fact, there isn’t even a single additional dose to compare to.
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Second, the data does not even relate to an extended-release formulation of levetiracetam, per Applicant’s new claim 101, and claim 50 before the instant claim amendment. It is widely known to one of skill in the art that an IR and an ER formulation of a drug will have different release profiles, different AUC, and thus potentially different dose-response.
Second, the Examiner notes that even though Applicant’s own claims are broadly directed to treating any cognitive impairment associated with a CNS disorder, in fact Applicant’s own specification provides that levetiracetam treatment does not help aMCI subjects with performance in other cognitive tests. It further shows mismatch in dose ranges, and lack of performance, in experimental rats.
“[2103] The performance of control-placebo subjects and aMCI subjects with drug or placebo treatment is also compared in other common cognitive tests, such as the Buschke Selective Reminding Test ― Delayed Recall (FIGS. 14A and 14B), the Benton Visual Rentention Test (FIGS. 15A and 15B), Verbal Paired Associates Test ― Recognition (FIGS. 16A and 16B) and Verbal Paired Associates Test ― Delayed Recall (FIGS. 17A and 17B). In all of these tests, aMCI subjects treated with placebo perform worse than placebo-treated control subjects, and levetiracetam treatment fail to rescue performance in aMCI subjects.
[2104] There are a number of possible reasons why levetiracetam treatment does not help aMCI subjects with performance in these other cognitive tests. The explicit 3-alternative forced choice task done in the fMRI study is a task that is especially sensitive to DG/CA3 function. As such, the performace of the subjects in this task may be particularly attuned to the changes in DG/CA3 activity resulting from levetiracetam treatment. Further, the aMCI subjects were treated with levetiracetam for only two weeks prior to the administration of the cognitive tests. It is contemplated that a treatment duration of longer than two weeks, e.g., 16 weeks or 8 months, for the drug treatment will result in improved efficacy. Finally, comparative animal studies (see Example 1) indicate that an even lower dose would be more effective. The human dosage of 125 mg twice a day is equivalent to a rat dosage of 22.3 mg/kg/day. As is shown in Example 2 and FIG. 3, 20 mg/kg levetiracetam is too high a dose in rats, and it fails to improve the performace of AI rats in the radial maze task. The effective doses of levetiracetam used in the animal model are 5-10 mg/kg. The human equivalent dose (HED) of the optimal rat dose is 0.8-1.6 mg/kg/day. Such a dosage would result in the administration of 28-56 mg twice a day (which is substantially lower than the 125 mg twice a day used in this study). Thus, it is contemplated that aMCI subjects will exhibit a further normalization of DG/CA3 and EC activity, as well as further improved performance in cognitive tests, if they are treated with lower doses equivalent to the effective doses in rat, e.g., 25-60 mg twice a day of levetiracetam.”
The Examiner further comments on Applicant’s claim amendment, which adds “therapeutically effective amount of the” levetiracetam to the wherein claim limitation of claim 50. It is noted, however, that the office action above already addressed in the office action, as the claim as previously presented recites early on the body of the claim therapeutically effective amount of levetiracetam.
Double patenting
Applicant has asked that the rejection be held in abeyance, in view of which it is restated for the record.
Claims 50 and 101 are pending, and have been examined herewith.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 50 and 101 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over NCT01044758, Levetiracetam and Memory Function in Amnestic Mild Cognitive Impairment (MCI), January 7, 2010 update, available at https://www.clinicaltrials.gov/ct2/history/NCT01044758?V_1=View#StudyPageTop (“NCT ‘758”, of record), and further in view of WO 2008/062446 A2 to Kshirsagar et al. (“Kshirsagar”, of record).
NCT ‘758 discloses a Phase 2 clinical study with the following description: “Increasing research is focused on conditions that precede the clinical diagnosis of Alzheimer's disease (AD) in order to detect patients at risk for early intervention. One such condition is mild cognitive impairment (MCI). Functional magnetic resonance imaging (fMRI) studies in this group of patients have reported increased activation in the Medial Temporal Lobe (MTL) during performance of memory tasks. The functional significance of increased activation is unclear. One possibility is that greater activity reflects the increased effort needed in order to maintain performance, and as such would be a compensatory response. An alternative possibility is that increased activation reflects aberrant physiology related to the disease process itself and as such would be a sign of greater underlying disease severity and would interfere with brain function.
Data in animal models suggest the possibility that low dose levetiracetam (well-tolerated anti-convulsant) treatment may reduce the observed hyperactivity and improve memory performance among individuals with MCI. The investigators are therefore conducting a within-subjects trial of 8 weeks duration, involving 144 subjects and low dose treatment with levetiracetam. During the course of the study, each subject may receive both drug and placebo for two weeks, with the order of administering those treatments counterbalanced. Cognitive testing and fMRI imaging will be obtained after 2-weeks on drug/placebo. The overall goal of the study is to determine if treatment of MCI subjects with low dose levetiracetam reduces hyperactivity within the MTL and improves memory performance.”
Patients received levetiracetam as monotherapy, and according to Applicant’s claimed daily dose of 250 mg: namely, 125mg twice daily =250 mg. Patients also received 250 mg twice daily.
NCT ‘958 does not specifically disclose once per day administration. However, it is not inventive to discover such regimens by routine experimentation when the general conditions of a claim are disclosed in the prior art. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) and MPEP §2144.05(11). The medical arts recognize that drug therapy may be optimized by designing regimens that account for the concentration of a drug, for example, to achieve a desired pharmacological response. Factors such as weight, age, gender, renal and hepatic status, inter alia, are always considered. Therefore, the determination of the optimum characterization of a particular dosing amount, and frequency of administration, would have been a matter well within the purview of one of ordinary skill in the art, at the time of the invention, through no more than routine experimentation.
The Examiner further comments on Applicant’s claim amendment, which adds “therapeutically effective amount of the” levetiracetam to the wherein claim limitation of claim 50. It is noted, however, that the office action above already addressed in the office action, as the claim as previously presented recites early on the body of the claim therapeutically effective amount of levetiracetam.
For instance, with respect to NCT ‘758 Applicant does not deny, and the office action itself establishes too, that NCT ‘758 does teach an overlapping dose with Applicant’s claims. Specifically, NCT ‘758 teaches that patients received levetiracetam as monotherapy for improving memory function in amnestic mild cognitive impairment (MCI) and Alzheimer’s disease (AD), and according to Applicant’s claimed daily dose of 250 mg: namely, 125mg twice daily =250 mg. Not only is 125mg twice daily =250 mg an overlapping dose with Applicant’s claims, which recite 50-250 mg of levetiracetam once a day, but the Examiner also notes that twice daily, presumably morning and evening, of 125 mg actually yields a much lower therapeutic dose spread over time. Stated differently, since the drug is metabolized, the first daily dose is 125 mg, which falls on the lower end of Applicant’s claimed dose range, and the administering of another 125 mg, presumably some 8-12 hours later in the day, would give a considerably lower combined dose of the drug in the blood in view of drug pharmacokinetics, than if a total 250 mg of levetiracetam were administered as a single dose. Thus, it would have been obvious to a person of skill in the art that several hours later from first administration a considerable amount of the first dose of levetiracetam would have already metabolized and excreted, and that therefore the therapeutically effective amount of levetiracetam 125mg twice daily would amount to a considerably lower therapeutic area under the curve for the drug than a therapeutic dose of 250 mg given once a day.
NCT ‘958 does not specifically disclose extended release levetiracetam, per Applicant’s new claim 101 (and claim 50 as was previously presented).
Kshirsagar specifically discloses extended release compositions of levetiracetam (LEV) as known in the art. (Abstract). Kshirsagar discloses that the instant formulation seeks by way of an ER once-daily regimen to improve therapeutic efficacy, reduce incidence of adverse events and enhance patient compliance over the available IR release levetiracetam formulation. (p. 2, ll. 24-29). Kshirsagar teaches that the tablets are for oral administration. (p. 1, ll. 19-28). Kshirsagar teaches how to prepare such tablets with levetiracetam at e.g. 500 mg. (p. 11, Example 3).
Accordingly, it would have been obvious to a person of skill in the art at the time of the invention to combine the teachings of NCT ‘758 and Kshirsagar in order to practice Applicant’s claimed invention with a reasonable expectation of success. The skilled artisan would have been guided by factors such as improvement of therapeutic efficacy with the release profile of the drug on administration for the particular indication sought, and would have been specifically motivated by FDA guidance and the art to assess for this indication relevant pharmacokinetic factors such as dose, AUC, Cmax, food effect, side effects, bioavailability, etc. Doing so as to dose optimization for a given SR, IR, etc. formulation, is routine in the pharmaceutical arts.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 50 and 101 are rejected under pre-AIA 35 U.S.C. 103(a) as obvious over WO 2010015029 A1 to Bird (“Bird”, of record), and further in view of JP 2011-529923 A (“JP ‘923”), Keppra (levetiracetam) label, April 2009 revision, available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021035s078s080%2C021505s021s024lbl.pdf (“Keppra”, of record), Minervini et al., Mild cognitive impairment, focal epilepsy and levetiracetam, Epilepsia, Vol. 48, Suppl. 7, 2007, p. 100 (“Minervini”), WO 2008062446 A2 to Kshirsagar et al. (“Kshirsagar”, of record), US Patent 5,447,952 to Wulfert et al. (“Wulfert", of record), and ADR news: Levetiracetam. Parkinsonism: case report. Reactions (Nov 30, 2006) ISSN:0114-9954 (“ADR News”, of record), and US 20070298098 to Jenkins et al. (“Jenkins”, of record).
Bird claims a method of treating a psychiatric disorder, such as mild cognitive impairment (“MCI”), comprising administering to the subject one or more anti-epileptic agents, or a pharmaceutically acceptable salt thereof, to thereby treat the psychiatric disorder, wherein the amount of anti-epileptic agent is subtherapeutic for mood stabilization treatment of epilepsy or epileptic symptoms. (Claims 1, 5). Claim 6 specifically recites that the anti-epileptic agent is a single one, and claim 11 recites that the anti-epileptic agent is levetiracetam.
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The exact language of claim 5 is as follows: “dementia and Mild Cognitive impairment addiction”. It is apparent that this language has a translation or printing error, because there is no such term as “dementia and Mild Cognitive Impairment addiction”. To keep the record clear that the intended/ original language is ““Mild Cognitive Impairment”, the Examiner introduces for the record JP 2011-529923 A, which states on its face that it published as WO 2010015029 A1, i.e. Bird of the instant rejection. It clearly discloses “dementia and mild cognitive impairment”.
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Bird specifically discloses amnesic MCI: “[00319] Mild cognitive impairment (MCI), also known as incipient dementia, or isolated memory impairment, is a diagnosis given to individuals who have cognitive impairments beyond that expected for their age and education, but that do not interfere significantly with their daily activities. It is considered to be the boundary or transitional stage between normal aging and dementia. MCI can present with a variety of symptoms, but when memory loss is the predominant symptom it is termed "amnesic MCI" and is frequently seen as a risk factor for Alzheimer's disease. Studies suggest that these individuals tend to progress towards probable Alzheimer's disease at a rate of approximately 10% to 15% per year.” The skilled artisan would clearly understand “amnesic” to be an alternative spelling of “amnestic” as this is a coined term in the art with overlapping description.
Bird does not disclose the dosage of levetiracetam in actual number, but provides very clear disclosure in other words what this dosage needs to be- “wherein the amount of anti-epileptic agent is subtherapeutic for mood stabilization treatment of epilepsy or epileptic symptoms.” (claim 1, emphasis added). Looking at the approved label for levetiracetam for the treatment of epilepsy (“Keppra”), one is able to find what the subtherapeutic dosage is by reference to the approved therapeutic dosage. Keppra discloses:
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Based on the Keppra label, the amount of levetiracetam, which is subtherapeutic for mood stabilization treatment of epilepsy or epileptic symptoms is less than 1000 mg/day, which clear encompasses Applicant’s claimed dose of 50-250 mg/ day.
As cumulative art, the Examiner introduces for the record Minervini, which also discloses single administration of levetiracetam, to include at doses below the Keppra label dose (i.e. 500 mg/ day initial to 1000 mg/day thereafter) specifically for treating mild cognitive impairment in patients.
Bird further does not specifically disclose single daily administration for levetiracetam specifically. It does disclose it, however, as examples for other claimed drugs. (See, e.g. [104], [106]).
With respect to optimal dosing regimens, as in Applicant’s claim 50, it is not inventive to discover such regimens by routine experimentation when the general conditions of a claim are disclosed in the prior art. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) and MPEP §2144.05(11). The medical arts recognize that drug therapy may be optimized by designing regimens that account for the concentration of a drug, for example, to achieve a desired pharmacological response. Factors such as weight, age, gender, renal and hepatic status, inter alia, are always considered. Therefore, the determination of the optimum characterization of a particular dosing amount, and frequency of administration, would have been a matter well within the purview of one of ordinary skill in the art, at the time of the invention, through no more than routine experimentation.
Bird further discloses, per Applicant’s claim 50 as before the amendment, and Applicant’s new claim 101, that the active ingredient may be formulated for sustained release. It also provides motivation to do so, i.e. that it provides different release times or bioavailability, and discloses many patents with numerous examples of techniques for formulating sustained release preparations. ([00135] -[00139]). Extended release is a form of sustained release.
Accordingly, it would have been obvious to a person of skill in the art at the time of the claimed invention to formulate levetiracetam as either immediate release or extended release based on the teachings of Bird alone. The skilled artisan would have been motivated to do so based on considerations of pharmacokinetics of the drug sought to be achieved, in combination with the particular number of times of administration, so as to optimize drug pharmacokinetics and bioavailability.
As cumulative art, the Examiner notes that there is abundant prior art, which guides to both the specific use of levetiracetam as extended release, per Applicant’s claim 50 as before the instant amendment, and Applicant’s new claim 101, and the specific use of levetiracetam at low doses, and to specifically include 50-250 mg. At least the following cumulative art applies.
Kshirsagar specifically discloses extended-release compositions of levetiracetam (LEV) as known in the art. (Abstract). Kshirsagar discloses that the instant formulation seeks by way of an ER once-daily regimen to improve therapeutic efficacy, reduce incidence of adverse events and enhance patient compliance over the available IR release levetiracetam formulation. (p. 2, ll. 24-29). Kshirsagar teaches that the tablets are for oral administration. (p. 1, ll. 19-28). Kshirsagar teaches how to prepare such tablets with levetiracetam at e.g. 500 mg. (p. 11, Example 3).
Kshirsagar does not exemplify a formulation that comprises 50-250 mg. However, it would have been obvious to a person of ordinary skill in the art at the time of the invention to formulate an ER pharmaceutical composition comprising LEV in an amount ranging between 50-250 mg in view of the teachings of Bird, Keppra and Kshirsagar. One of skill would have been further motivated to do so, in addition to the reasons outlined above, because Kshirsagar places no limit on the amount of LEV in the tablet, and further teaches that drug doses, and the way a drug has been formulated has to be evaluated in a multifactorial analysis taking into account things, such as therapeutic efficacy, reduction of incidence of adverse events, enhancement of patient compliance, food effect, absorption, bioavailability, etc. (p. 1, ll. 19-27, p. 2, ll. 24-29).
Moreover, additional cumulative prior art clearly teaches oral compositions of levetiracetam in the claimed amounts. Wulfert teaches compounds of formula (I) which reads on levetiracetam (Col. 1, lines 48-55). Wulfert teaches oral compositions comprising between 50 mg and 1000 mg of the compound of formula (I) (Col. 3, lines 25-55). The table in Col. 3, lines 50-55 exemplifies capsules comprised of the compound of formula (I) that comprise 125 mg and 250 mg. Even if one were to take into account disclosure of an oral dose given twice a day, 125 x 2= 250. Further, Wulfert specifically teaches also capsules of 62.5 mg, and assuming they are given as IR twice a day, 62.5 x 2= 125 mg. Wulfert teaches that a daily dosage can vary within a wide range of dosage units. (col. 3, ll. 30-35).
As even further cumulative prior art, the Examiner notes the reference of ADR News, which specifically teaches a dose of 250 mg/day and a dose of 125 mg/day of levetiracetam. The drug was titrated down in a patient who had Huntington’s disease, and who developed Parkinsonism during treatment with levetiracetam at a dose of 500 mg twice daily. The patient’s condition improved when the dose was titrated down first to a dose of first 250 mg/day, and then to a dose of 125 mg/day of levetiracetam.
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As further cumulative art, Jenkins teaches an oral controlled release composition containing levetiracetam ([0012], [0019]). Administration is preferably once a day. ([0021]. The controlled release composition may deliver levetiracetam in a pulsatile manner, preferably during a period of up to twenty-four hours, which would indicate to one of skill in the art one dosage unit ([0022]). Levetiracetam is in amounts from 0.1-500 mg (which includes 50-250 mg, as claimed by Applicant) and preferably in the amount from 1-100 mg, but generally the levetiracetam is present in the first component and in any subsequent component in any amount sufficient to elicit a therapeutic response. ([0045]). Jenkins specifically emphasizes that the LEV is present in any amount sufficient to elicit a therapeutic response. The invention is indicated to be useful in improving compliance and, therefore, therapeutic outcome for all treatments requiring levetiracetam, including but not limited to, adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy. ([0021]).
Accordingly, it would have been obvious to the skilled artisan at the time of the invention to combine the teachings of Bird, JP ‘923, Keppra, Minervini, Kshirsagar, Wulfert, ADR News and Jenkins, in order to practice Applicant’s claimed invention with a reasonable expectation of success. The skilled artisan would have been motivated to do so because the prior art specifically recognized the utility of using levetiracetam for treating mild cognitive impairment, to specifically include amnestic MCI, with subtherapeutic to the treatment of epilepsy doses. The skilled artisan would have been motivated to do so, because the art recognized the making of such specific dosage forms, their therapeutic utility at 125 mg/day and 250 mg/day specifically, and their preparation and administration as oral extended release formulations for once a day, or for twice a day administration. Therefore, a composition according to the claimed invention can be prepared by routine experimentation. The specific dose for the treatment of amnestic MCI is therefore subject to routine experimentation, with multiple studies guiding to evaluate the lower range doses for their therapeutic efficacy. The skilled artisan would have been guided by factors such as therapeutic efficacy for the particular indication sought, and would have been specifically motivated by FDA guidance and the art to assess for this indication relevant pharmacokinetic factors such as dose, AUC, Cmax, food effect, side effects, bioavailability, etc. Doing so as to dose optimization for a given SR, IR, etc. formulation, is routine in the pharmaceutical arts.
The Examiner further comments on Applicant’s claim amendment, which adds “therapeutically effective amount of the” levetiracetam to the wherein claim limitation of claim 50. It is noted, however, that the office action above already addressed in the office action, as the claim as previously presented recites early on the body of the claim therapeutically effective amount of levetiracetam, to include at doses of 250 mg/day or less.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 50 and 101 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 8,604,075. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and the issued patent disclose overlapping subject matter. Specifically, the issued patent claims:
“1. A method for treating age-related cognitive impairment in a human subject in need thereof, the method comprising the step of administering to said human subject levetiracetam or a pharmaceutically acceptable salt thereof at a daily dose of 125-250 mg.
2. The method of claim 1, wherein the age-related cognitive impairment is selected from the group consisting of mild cognitive impairment, age-associated memory impairment, and age-related cognitive decline.
3. The method of claim 1, wherein the levetiracetam or the pharmaceutically acceptable salt thereof is administered once or twice daily.”
The definition of “MCI” in the issued patent specifically discloses that it covers the amnestic type. “Mild Cognitive Impairment" or "MCI" refers to a condition characterized by isolated memory impairment unaccompanied other cognitive abnormalities and relatively normal functional abilities. One set of criteria for a clinical characterization of MCI specifies the following characteristics: (1) memory complaint (as reported by patient, informant, or physician), (2) normal activities of daily living (ADLs), (3) normal global cognitive function, (4) abnormal memory for age (defined as scoring more than 1.5 standard deviations below the mean for a given age), and (5) absence of indicators of dementia (as defined by DSM-IV guidelines). Petersen et al., Srch. Neurol. 56: 303-308 (1999); Petersen, "Mild cognitive impairment: Aging to Alzheimer's Disease." Oxford University Press, N.Y. (2003).”
Instant new claim 101 recites that the levetiracetam is formulated for extended release. The definition of “administering” in the specification in the issued patent also further discloses that it specifically covers extended release. “"Administering" or "administration of" a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitonealy, intravenously, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorbtion, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.”
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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
Amended claim 50 submitted with the RCE is patentably indistinct from original claim 50. MPEP 706.07(h). Further, amended claim 50 would have been properly rejected with the same prior art if it had been earlier filed in the final office action. MPEP 706.07(b).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SVETLANA M IVANOVA whose telephone number is (571)270-3277. The examiner can normally be reached 8:30-5:00.
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/SVETLANA M IVANOVA/Primary Examiner, Art Unit 1627