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 .
DETAILED ACTION
The amendment to the claims filed after non-final office action on June 20, 2025 is acknowledged.
Claims 1-9, 15 were canceled, claims 10, 14, 16-18 were amended and claims 10-12, 14, 16-18 are pending in the instant application.
The restriction is deemed proper and was made FINAL in the previous office action.
Claims 10-12, 14, 16-18 are examined on the merits in this office action.
Withdrawn Rejections
The rejection of claims 10-12, 17-18 under pre-AIA 35 U.S.C. 102(b) as being anticipated by Wang (US20060234912) is withdrawn in view of amendment of the claims filed June 20, 2025.
Maintained/Revised Rejections
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 (i.e., changing from AIA to pre-AIA ) 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) 10-12, 14, 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (US20060234912, cited previously) in view of Yu (Neuropharmacology 133 (2018) 155e162, cited previously), ,Zhang (NATURE COMMUNICATIONS, (2018) 9:4272, cited previously) and Bailey (2017, 'Tianeptine: An atypical antidepressant with multimodal pharmacology', Current Psychopharmacology, vol. 6, no. 2, pp. 94-110).
Regarding claims 10-12, Wang teaches a method of treating depression (claim 68, see also paragraph 0155, and 0158, Example 10) via inhibiting AMPA receptor endocytosis (see claim 55) comprising administering instant SEQ ID NO:1 (claim 58) fused to instant SEQ ID NO:2 (claim 59) resulting in instant SEQ ID NO:3 (referred to as Tat-GluR2-3Y, paragraph 0155 PGPUB). Regarding claim 17, Wang teaches 10 nmol/g which is equivalent to 26.34 mg/kg based on the molecular weight of 2633.97 g/mol of the fusion peptide. Wang additionally teaches doses ranging from .5-30 nmoles/g with additional examples of 3 nmoles/g which is equivalent to 7.9 mg/kg based on the molecular weight of the peptide which falls within the range of instant claim 17.
Wang is silent to treating major depressive disorder, suicidality and a Hamilton score.
Yu teaches that “we found that inhibition of AMPAR endocytosis by a synthetic peptide
Tat-GluA23Y (3 mmol/kg, i.p.) not only increased level of AMPARs and reduced LTD, but also restored LTP. Moreover, treatment with Tat-GluA23Y peptide markedly alleviated the sleep deprivation-induced impairments of spatial learning and memory; and decreased depressive- and anxiety-like behaviors”.
Zhang teaches that disturbed AMPAR surface diffusion is rescued by tianeptine (see abstract). Zhang teaches “We have demonstrated that deregulated AMPAR surface diffusion primarily contributes to the impaired LTP in stress/depression models. Most importantly, we found that AMPAR surface
diffusion can be pharmacologically modulated by the clinically used antidepressant tianeptine (S 1574, [3-chloro-6-methyl-5, 5- dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid), which restores impaired LTP in a stress/depression models” (page 2, left column, last 15 lines).
Bailey teaches “Clinical trials show that tianeptine is at least as efficacious as first-line antidepressant treatments, with improved tolerability as it is significantly less prone to disrupting the patient's normal functionality” (See Results). Bailey further teaches “recent data highlight a multimodal pharmacology for tianeptine including actions at glutamatergic synapses (inhibiting NMDA receptors and an indirect effect on AMPA receptors)” (See background). Tianeptine is thought to perturb NMDA receptor function while it potentiates the function of AMPA receptors. Chronic administration of tianeptine (10mg/Kg/day) is associated with changes in the amplitude ratio of NMDA receptors to AMPA/kainate receptor-mediated currents that are altered during stress in CA3 hippocampal neuron. AMPA receptor blocker NBQX reduced tianeptine’s antidepressant-like effects (See page 12). Bailey teaches Tianeptine for treating major depression (See page 5, lines 1-10) and in patients with a Hamilton depression rating (see page 4, section 2 and Table 1 that starts on Page 32). The HAMD, or Hamilton Depression Rating Scale, is a clinical questionnaire used to assess the severity of depression. Item 3 on the HAMD scale measures suicidal ideation and behavior. Bailey teaches improvement in Hamilton depression rating scale in in patients with MDD with treatment of tianeptine.
It would have been obvious before the effective filing date of the claimed invention to treat patients with major depressive disorder and thoughts of suicide (which is a hallmark risk factor of MDD) with Tat-GluR2-3Y of Wang. One of ordinary skill in the art would have been motivated to do so given that blocking AMPAR endocytosis with a TAT-GluA23Y peptide would result in greater AMAPR receptors present, subsequent activity and which it has an antidepressant effects which would be beneficial in patients with Major depressive disorder, suicidal thoughts and a rating on the HAMD. There is a reasonable expectation of success given other therapeutics, tianeptine in particular, are effective in treating patients with major depressive disorder, HAMD rating and do so via modulating AMAPR and has a direct effect on AMPARs. There is further reasonable expectation of success given Tat-GluR2-3Y is effective at treating depression, depression and anxiety like behaviors.
A person of ordinary skill in the art would have been motivated to apply Wang’s peptide (which comprises instant SEQ ID NO:1), shown effective in depression, to the MDD patient populations described by Bailey including those with severe MDD and HAMD scores (which include suicidality as a core diagnostic and outcome measure) with a reasonable expectation of reducing depressive symptoms and associated suicide risk. Selecting suicidal MDD patients via HAMD scoring is a routine matter of patient stratification in clinical practice.
Regarding claims 11-12, the peptide of Wang comprises SEQ ID NO:1 and is fused to T at the N-terminus resulting in instant SEQ ID NO:3.
Regarding claim 14, Bailey discloses that patient enrollment and efficacy evaluation in MDD trials is based on rating scales such as HAMD, BI and SDS (Table 1), which measure severity and include suicidality items. Patients with high scores are routinely included as sever MDD patients.
Regarding claim 16, Wang discloses administration of the same peptide of the instant claims to subjects exhibiting depressive or stress-induced behaviors (Examples 8-10). Bailey discloses clinical administration of AMPAR-modulating antidepressants (tianeptine) specifically to severe MDD patients as assessed via HAMD scores (which is inclusive to suicidality). A person of ordinary skill in the art would have been motivated to administer Wang’s peptide when a subject shows suicidality with MDD given that it is a recognized risk factor/symptom of severe MDD and blocking AMPAR endocytosis with a TAT-GluA23Y peptide would result in greater AMAPR receptors present, subsequent activity and which it has an antidepressant effects which would be beneficial in patients with Major depressive disorder, suicidal thoughts and a rating on the HAMD. There is a reasonable expectation that modulating AMPAR activity would alleviate depressive symptoms and thereby reduce suicide risk.
Regarding claim 17, Wang teaches administration of the peptide at doses ranging from approximately 2-30 µmol/kg, equivalent to about 1.7-9.7 mg/kg based on the molecular weight of the peptide (Example 10). These values fall within the claimed range.
Regarding claim 18, Wang teaches administration of the peptide, including injection routes (see Examples 9-10).
Response to Applicant’s Arguments
Applicant argues that treating depression is different than reducing suicide risk. Applicant asserts that he conventional antidepressants take 3-4 weeks to act and thus may not be suitable for reducing the immediate risk of suicide.
Applicant’s arguments have been fully considered but not found persuasive. Bailey discloses clinical administration of AMPAR-modulating antidepressants (tianeptine) specifically to severe MDD patients (which suicidality is a common risk factor/behavior as assessed via HAMD scores (which is inclusive to suicidality)). A person of ordinary skill in the art would have been motivated to administer Wang’s peptide when a subject shows suicidality with MDD given that it is a recognized symptom/risk factor of severe MDD and blocking AMPAR endocytosis with a TAT-GluA23Y peptide would result in greater AMAPR receptors present, subsequent activity and which it has an antidepressant effects which would be beneficial in patients with Major depressive disorder, suicidal thoughts and a rating on the HAMD. The fact that some antidepressants act slowly does not mean that reducing suicide risk is a distinct therapeutic indication; it remains an inherent outcome of treating depression in the severe (higher risk of suicidality) MDD patient population.
Applicant argues that the instant peptide has a rapid effect. Applicant asserts that it was surprisingly found that the peptide acts within 1 hour and lasts 24 hours, unlike conventional antidepressants.
Applicant’s arguments have been fully considered but not fond persuasive. Wang discloses the identical peptide (Tat-GluA2(3Y), SEQ ID NO:1 attached to Tat) and demonstrates acute effects in animal models, such as rapid restoration of LTP and reversal of stress induced deficits. Any pharmacological properties, including onset of action, are inherent to Wang’s peptide. Furthermore, rapid acting antidepressants (such as ketamine, HNK) were already known in the art for suicidal MDD patients, so a rapid effect is not unexpected to be beneficial.
Applicants argue the prior art is silent to rapid onset. Applicant claims that the cited references do not disclose rapid acting effects. Therefore, a person of ordinary skill in the art would not have expected the peptide to reduce suicide risk.
Applicants arguments have been fully considered but not found persuasive. The absence of express disclosure does not establish patentability. Wang discloses the identical peptide and its rapid functional effects, which are inherent. Bailey further teaches that AMPAR modulation is clinically effective in severe MDD patients (which have increased risk for suicidality) with HAMD scores. Thus, a person of ordinary skill in the art would have had a reasonable expectation of success in applying Wangs peptide to such patients.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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/ERINNE R DABKOWSKI/ Examiner, Art Unit 1654
/JULIE HA/ Primary Examiner, Art Unit 1654