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 .
Status of the Application
This Office Action is in response to applicant’s arguments filed on 12/29/25. Claims 9, 12-27 have been cancelled. Claims 1-8, 10-11, 28-30 are pending. Claims 4-7 have been withdrawn. Claims 1-3, 8, 10-11, 28-30 are 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.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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) 1-3, 8, 10-11, 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over of Ramakrishna et al. (WO 2004/048330 A1, of record), in view of Nirogi et al. (WO 2015/083179 A1, of record), and further in view of Upton et al. (“5-HT6 Receptor Antagonists as Novel Cognitive Enhancing Agents for Alzheimer’s Disease, Neurotherapeutics,” Vol. 5, No. 3, 458–469, 2008, of record).
The instant claims are generally drawn to the method of treating behavioral changes in dementia comprising administering 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate (related to claims 2, 3, and 8), wherein the behavioral change in dementia is selected from selected from aggression or agitation in dementia (related to claims 10, 28, and 29), and wherein the behavioral change in dementia is selected from aggression in Alzheimer's disease, agitation in Alzheimer's disease, aggression in Parkinson's disease, or agitation in Parkinson's disease (related to claims 11 and 30).
Ramakrishna et al. teaches compounds of formula I as 5-HT antagonists for treating Alzheimer's disease, schizophrenia, and Parkinson's disease (see, for example, pg. 1, line 6 to pg. 2, line 14), and that a preferred compound is 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole (i.e. the instant compound; see, for example, example 20 on pg. 61). Ramakrishna et al. further teaches that the compounds are useful for the treatment of related disorders including psychosis and sleep disorders (see, for example, claims 8 and 15).
Ramakrishna et al. does not specifically disclose the treatment of aggression or agitation, or the dimesylate monohydrate.
Nirogi et al. discloses the large scale synthesis of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-piperazinyl)methyl]-1H-indole dimesylate monohydrate, which is a selective 5-HT6 receptor antagonist intended for the symptomatic treatment of Alzheimer's disease and other disorders of memory and cognition like Attention deficient hyperactivity, Parkinson's and Schizophrenia (see, for example, the abstract and the whole document). Nirogi et al. further discloses that said compound was undergoing clinical testing (see, for example, pg. 1 lines 20-27), which those of skill in the art understand requires the use in a pharmaceutically acceptable excipient.
Nirogi et al. discloses that the preferred, front-running, compound of Ramakrishna et al. that was used in clinical testing for treatment is 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate (see, for example, pg. 1 lines 20-27, and the whole document).
Upton et al. teaches that, clinically, Alzheimer’s disease is characterized by progressive cognitive decline associated with impairment in activities of daily living and behavioral symptoms such as depression, agitation, psychosis, and aggression that can vary in severity according to the stage of the disease (see, for example, the Introduction on pg. 458). Upton et al. further teaches that from a therapeutic perspective, the serotonergic system is a particularly attractive target, because it has been implicated in both cognitive processes and also in depression, psychosis, and aggression (see, for example, (see, for example, the Introduction on pg. 458). Upton et al. further teaches that at least one compound has been assayed for effects on sleep and wake (see, for example, Table 2).
It would have been obvious to treat behavioral changes in dementia comprising administering 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate, wherein the behavioral change in dementia is selected from selected from aggression or agitation in dementia, and wherein the behavioral change in dementia is selected from aggression in Alzheimer's disease, agitation in Alzheimer's disease, aggression in Parkinson's disease, or agitation in Parkinson's disease because the prior art makes all of the limitations obvious.
One of ordinary skill would have been motivated to treat Alzheimer’s and dementia with 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate because Ramakrishna et al. and Nirogi et al. teach that the compound is the preferred compound for the clinical trials of the treatment of said patient population. One of ordinary skill would have applied the combined teachings, and would have treated Alzheimer’s and dementia with a reasonable expectation of success.
One of ordinary skill would have been motivated to treat aggression or agitation in Alzheimer's disease or Parkinson's disease because Ramakrishna et al. teaches that the family of compounds including the instant 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole are useful for both the treatment of Alzheimer's and Parkinson's, and also useful for the treatment of related disorders including psychosis and sleep disorders, and Upton et al. teaches that the family of 5-HT6 receptor antagonists are being actively studied for use in the treatment of Alzheimer’s disease, Parkinson’s disease, psychosis, aggression, and sleep issues. One of ordinary skill would have combined the teachings and would have treated Alzheimer’s or Parkinson’s disease with 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole, including in patients with psychosis, aggression, and sleep issues, and would have performed said treatment with a reasonable expectation of success.
Response to Arguments
Applicant argues that clinical trial results on 5-HT6 receptor antagonists in Alzheimer’s disease patients found no benefit for idalopirdine, mixed results for interpirdine, no benefit for SAM-760, no benefit for latrepirdine, and no benefit for cerlapirdine, as summarized in the Table on page 14. Therefore, four of five 5-HT6 receptor antagonists failed in the latest clinical trial period. The Jayarajan Declaration states that no 5-HT6 receptor antagonists were approved for the treatment of cognitive or non-cognitive symptoms of Alzheimer’s disease. Therefore, an 80% failure rate in treating Alzheimer’s disease symptoms with 5-HT6 receptor antagonists would not provide the skilled person with a reasonable expectation of success in treating behavioral changes in dementia. Unexpected results are also claimed since applicants surprisingly found that the claimed 5-HT6 receptor antagonist, SUVN-502, did not show improvement in cognitive dysfunction over placebo as measured by ADAS-Cog 11, but did show improvement in behavioral changes as measured by NPI-12 scale. The prior art only teaches SUVN-502 for the treatment of cognitive dysfunction in Alzheimer’s disease, whereas none of the prior art teaches SUVN-502 for the treatment of behavioral changes.
This is not persuasive because, as stated previously, all elemental steps of the claimed method have been taught by the cited prior art. Most of the arguments are directed at various 5-HT6 receptor antagonists that failed in treating behavioral changes in Alzheimer’s disease. However, Applicant is reminded that the 103 obviousness rejection is based on the fact that the primary reference, Ramakrishna et al., fails to teach aggression or agitation. In other words, the 103 obviousness rejection was not formulated to substitute one 5-HT6 receptor antagonist for another. Applicant is reminded that Ramakrishna et al. already teaches that the claimed 5-HT6 receptor antagonist, SUVN-502, is useful to be administered to Alzheimer’s patients.
Moreover, the Upton reference clearly shows that Alzheimer’s disease is characterized by progressive cognitive decline associated with impairment in activities of daily living and behavioral symptoms such as depression, agitation, psychosis, and aggression that can vary in severity according to the stage of the disease. Therefore, whether or not the claimed specific symptoms are taught to be treated, it is obvious that these symptoms would be treated since it has been established that these symptoms are associated with Alzheimer disease patients being administered SUVN-502. Applicant has already admitted on record in the response that both cognitive and non-cognitive (behavioral) symptoms are associated with Alzheimer’s disease, such as agitation/aggression, delusions, hallucinations, aberrant motor behavior, anxiety, euphoria/elation, irritability/lability, depression/dysphoria, apathy, disinhibition, sleep and night-time behavior change, and appetite and eating change.
Therefore, the arguments directed at there being no reasonable expectation of success matters carries no weight, since the instant claims essentially require administering the claimed active agent (SUVN-502) to the claimed patient population (Alzheimer’s disease patients). Since Ramakrishna et al. teaches the same active agent and patient population, why wouldn’t the appropriate symptoms (cognitive and/or non-cognitive) also be treated? In fact, these symptoms would be treated. It would be illogical to state that these symptoms wouldn’t be treated just because Ramakrishna et al. didn’t explicitly teach this.
Finally, the alleged surprising results are not persuasive because the evidence does not does support this claim. The declaration states that SUVN-502 did not show improvement in cognitive dysfunction over placebo, but did show improvement in behavioral changes. However, the instant specification clearly shows that SUVN-502 showed improvement in both behavioral changes (example 6) and cognitive changes (example 8).
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Regarding the establishment of unexpected results, a few notable principles are well settled. It is applicant’s 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). The claims must be commensurate in scope with any evidence of unexpected results. See MPEP 716.02 (d). Further, a DECLARATION UNDER 37 CFR 1.132 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). Applicants fail to provide clear and convincing evidence to support the alleged unexpected benefit.
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
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