DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of the Application
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/25/25 has been entered.
Claims 1-57, 59, 61-67, 71 have been cancelled. Claims 58, 60, 68-70 are pending and examined herein.
Applicant’s arguments have been fully considered but found not persuasive. The rejection of the last Office Action is maintained for reasons of record and repeated below for Applicant’s convenience.
All claims are drawn to the same invention claimed in the application prior to the entry of the submission under 37 CFR 1.114 and could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Claim Rejections - 35 USC § 103
The following is a quotation of 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 of this title, 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.
The factual inquiries set forth in Graham vs John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 58, 60, 68-70 are rejected under 35 U.S.C. 103(a) as being obvious over Jelic et al. (“Clinical trials in mild cognitive impairment: lessons for the future,” J. Neurol. Neurosurg. Psychiatry, 2006, 77, 429-438, of record) in view of Minervini et al. (“Mild Cognitive Impairment, Focal Epilepsy and Levetiracetam,” Epilepsia, 2007, 48:(S7):110, P256, of record) and Rouits et al. (“Pharmacokinetics of levetiracetam XR 500 mg tablets,” Epilepsy Research, 2009, 84, 224-231, of record).
The instant claims are directed to a method of treating cognitive impairment or for treating or improving cognitive function in a subject suffering from cognitive impairment associated with a CNS disorder by administering a composition comprising donepezil at a daily dose of 0.1 to 10 mg and levetiracetam at a daily dose of 50-250 mg.
Jelic et al. teaches the use of the acetylcholinesterase inhibitor (AChEI), donepezil, for treatment of mild cognitive impairment (MCI) in an individual with a greater risk of developing dementia and most likely can progress to Alzheimer’s disease (abstract). Three AChEI (donepezil, rivastigmine, galantamine) are currently established treatments in AD and are considered to be the first choice candidates for the treatment of MCI (page 430, right column, first full paragraph). Nootropics have been present on the market for more than three decades and were probably the first agents indicated for the treatment of dementia related symptoms and age-related cognitive impairment (page 430, right column, fourth full paragraph). Daily doses of donepezil at 5 mg/day for the first 42 days and 10 mg/day afterwards for 24 weeks resulted in significant positive effect on ADAS-Cog tests (Table 1 on pages 432-433).
However, Jelic et al. fail to disclose levetiracetam.
Minervini et al. teach that mild cognitive impairment (MCI) is regarded as cognitive decline greater than expected for an individual’s age and education level, but does not interfere notably with activities of daily life. More than half of people with MCI progress to dementia within 5 years. Levetiracetam (LEV) was introduced to patients with MCI at 500 mg/day for the first week and 1000 mg/day thereafter. Minervini et al. concludes that LEV monotherapy, even at a low dose, shows positive therapeutic result in the MCI patients, without progression to dementia. The results were promising and even improved cognitive states in the patients.
Rouits et al. teach that the advantages of levetiracetam extended release tablets include improved tolerability due to flatter plasma-concentration profiles, improved outcomes due to simplifying dosing, better adherence to dosing regimens, and the convenience of once daily dosing and potentially improved compliance and safety/efficacy ratio (page 225, left column).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, at the time the claimed invention was made, to have combined levetiracetam at the claimed dosage, as taught by Minervini et al., with donepezil at the claimed dosage in the method of treating MCI, as taught by Jelic et al.
A person of ordinary skill in the art would have been motivated to combine levetiracetam and donepezil because each has been individually known to be useful for treating cognitive impairment, specifically MCI. Therefore, the skilled artisan would have had a reasonable expectation of success in treating MCI by administering the combined therapeutically additive effect of levetiracetam and donepezil.
"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.... The 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).
Further, it would have been obvious to optimize the daily dosage of levetiracetam from 500 mg to 250 mg. The reason is because Minervini et al. teaches a monotherapy, whereas considering the teachings of Jelic et al., the treatment would become a combination therapy, thus requiring lower amounts of each active agent. Furthermore, Minervini et al. teaches that levetiracetam is still effective at lower doses. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success in treating MCI in a subject by administering 250 mg of levetiracetam and less than 5 mg of donepezil.
Generally, mere optimization of ranges will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “When the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimal or workable ranges by routine experimentation. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” In re Peterson, 315 F. 3d at 1330, 65 USPQ 2d at 1382; lt has been held that it is within the skills in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. In re Boesch, 205 USPQ 215 (CCPA 1980) MPEP 2114.04
Finally, it is noted that the limitations regarding “increasing the duration of the therapeutic efficacy of donepezil” and “wherein the donepezil is therapeutically effective for a longer time as compared to the duration of the donepezil when administered at a similar dose in the absence of levetiracetam” and “the duration of the therapeutic efficacy of donepezil in the absence of levetiracetam is increased by at least about 1.5x, or 2.0x…” are considered obvious to occur since the combined cited prior art references teaches the same claimed composition.
“Products of identical chemical composition cannot have mutual exclusive properties.” Any properties exhibited by or benefits from are not given any patentable weight over the prior art provided the composition is inherent. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the disclosed properties are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. The burden is shifted to the applicant to show that the prior art product does not inherently possess the same properties as the instantly claimed product.
Response to Arguments
Applicant argues that the beneficial effect of donepezil is short lived and overshadowed by the adverse events reported in Jelic. The nearly three times discontinuation rate in the donepezil treated group would be a reason not to administer donepezil to treat cognitive impairment. Indeed, the prior art teaches that the adverse effects of donepezil at the typical dosage range over time results in nearly a quarter of participants to discontinue the drug. Moreover, donepezil at higher doses of 10 mg were associated with several side effects ranging in severity.
This is not persuasive because none of these factors teach or suggest that donepezil is not effective for treating cognitive impairment. In fact, there is strong evidence that donepezil is effective for the method of treating cognitive impairment as claimed. There are no limitations in the claims drawn to donepezil’s length of effectiveness, dropout rates, adverse events, or discontinuation rates. Furthermore, none of the factors, particularly the 22.0% vs 8.0% difference in discontinuation rates, rises to the level where one of ordinary skill in the art would not administer donepezil for treating cognitive impairment with a reasonable expectation of success.
Applicant argues that they have solved a long-recognized, but unsolved problem regarding the relatively short-term duration of the therapeutic efficacy of donepezil and its adverse side effects in treating cognitive impairment.
This is not persuasive because there is no showing that others of ordinary skill in the art were working on the problem and if so, for how long. In addition, there is no evidence that if persons skilled in the art who were presumably working on the problem knew of the teachings of the above cited references, they would still be unable to solve the problem. See MPEP § 716.04.
Applicant continues to argue that there is no motivation to combine donepezil and levetiracetam to achieve Applicant’s unexpected longer duration of the therapeutic effect of donepezil.
This is not persuasive because both active agents are known to be useful for the same purpose, therefore the motivation to combine is for the therapeutically additive effect of combining two known active agents for the same purpose.
Applicant argues that Minervini’s use of “low” dose levetiracetam are not as low as the claimed doses of 50-250 mg/day.
This is not persuasive because Applicant is reminded of what Minervini actually teaches. Miniverini clearly teaches that levetiracetam (LEV) was introduced to patients with MCI at 500 mg/day for the first week and 1000 mg/day thereafter. Minervini et al. concludes that LEV monotherapy, even at a low dose, shows positive therapeutic result in the MCI patients, without progression to dementia. The results were promising and even improved cognitive states in the patients. Therefore, low doses of 250 mg/day as claimed is obvious over a teaching of 500 mg/day, especially since the reference teaches that even lower doses were effective.
Applicant argues that Minervini teaches levetiracetam for treatment of seizures that characterize epilepsy and not cognitive impairment. Applicant continues to argue that several other studies (Exhibits A-D) confirm that levetiracetam had no significant effect on cognition, memory performance, or attention as compared to placebo, when it was administered at a therapeutic dose for treating epilepsy.
This is not persuasive because Applicant has misunderstood the Minervini reference, which clearly teaches that levetiracetam is useful in the treatment of MCI. Since by definition, patients with MCI inherently have and are in need of cognitive impairment, administering levetiracetam would obviously meet the claimed limitations.
Applicant argues that the prior art does not suggest a method of increasing the duration of the therapeutic efficacy of donepezil by administering levetiracetam.
This is not persuasive because the limitation regarding “increasing the duration of the therapeutic efficacy of donepezil” is considered a mechanism of action or property that results when the claimed patient population is administered the claimed active agent. Therefore, since the prior art teaches administering donepezil and levetiracetam to a patient suffering from cognitive impairment, the duration of donepezil’s therapeutic efficacy will automatically be increased. Should Applicant disagree, a side-by-side comparison between the instant invention and the prior art is requested to determine whether the therapeutic duration of donepezil is increased or not.
Applicant continues to argue surprising super-additive or synergistic effects of combining levetiracetam and donepezil at the claimed doses. Specifically, the surprising results involve not only improving the cognitive effects but importantly can reduce the loss of efficacy and severe side effects long recognized to be associated with donepezil. Figure 2 shows that 1 mg/kg/day of donepezil alone or 2.5 mg/kg/day of levetiracetam alone was not able to improve the memory performance of aged-impaired rats as compared to a vehicle control. However, the combination of 1 mg/kg/day of donepezil alone and 2.5 mg/kg/day of levetiracetam when administered together, significantly improved the memory performance of the aged-impaired rats.
This is not persuasive because the dosage amounts of both donepezil and levetiracetam are still not commensurate with the scope of the claims. Figure 2 shows a single data point for both donepezil and levetiracetam, whereas the instant claims recite a broad range for donepezil (0.1 to 10 mg daily dosage) and levetiracetam (50 to 250 mg daily dosage). As an example, for an average male rat weighing 400 g, this would equate to 0.4 mg for donepezil and 1 mg for levetiracetam, which are both at the lower end of the claimed ranges. Finally, Applicant is reminded that any evidence of unexpected or surprising results, such as synergism, must be presented in a declaration format.
Regarding the establishment of unexpected results or synergism, a few notable principles are well settled. The Applicant has the initial burden to explain any proffered data and establish how any results therein should be taken to be unexpected and significant. See MPEP 716.02 (b). It is applicant’s burden to present clear and convincing factual evidence of nonobviousness or unexpected results, i.e., side-by-side comparison with the closest prior art in support of nonobviousness for the instant claimed invention over the prior art. The claims must be commensurate in the scope with any evidence of unexpected results. See MPEP 716.02 (d). With regard to synergism, a prima facie case of synergism has not been established if the data or result is not obvious. The synergism should be sufficient to overcome the obviousness, but must also be commensurate with the scope of the claims. Further, if the Applicant provides a DECLARATION UNDER 37 CFR 1.132, it must compare the claimed subject matter with the closest prior art in order to be effective to rebut a prima facie case of obviousness. See MPEP 716.02 (e).
Applicant argues that the Examiner is mistaken for thinking that the dosage amounts in Figure 2 do not equate to 0.4 mg donepezil and 1 mg levetiracetam in humans. After normalizing from rats to humans, the extrapolation data is equivalent to 75 mg in a human, which falls squarely with the claimed dosage range for levetiracetam.
This is also not persuasive because a single extrapolated showing of 75 mg for a human is not commensurate with a large range of 50-250 mg of levetiracetam that is currently claimed.
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 Yong S. Chong whose telephone number is (571)-272-8513. The examiner can normally be reached Monday to Friday: 9 AM to 5 PM EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam Milligan, can be reached at (571)-270-7674. The fax phone number for the organization where this application or proceeding is assigned is (571)-273-8300.
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/Yong S. Chong/Primary Examiner, Art Unit 1623