DETAILED ACTION
Notice of 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 Claims
The amendments filed 7/20/2026 have been entered.
Response to Arguments
Applicant’s arguments, filed 7/20/2026, have been fully considered.
The rejection of claims under 35 U.S.C. 102(a)(1) as being anticipated by Ahmad et al (Clin Transl Sci 9:252-259, 2016; of record), as well as the rejections of claims on the grounds of non-statutory double patenting over US 11,291,640 and US 12,245,997, are WITHDRAWN in view of Applicant’s amendments to the claims, rendering Applicant’s arguments moot.
The claims are NEWLY rejected under 35 U.S.C. 112(a) and 35 U.S.C. 103(a) which constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-6 are NEWLY rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed, had possession of the claimed invention.
The response filed 7/20/2026 has introduced NEW MATTER into the claims.
Amended claim 1 recites a method for managing or decreasing a risk of adverse effects in a patient undergoing treatment of bipolar I disorder, the method comprising:
“identify[ing] a patient undergoing or having undergone treatment of bipolar I disorder with lithium, valproate or divalproex sodium, carbamazepine, or atypical antipsychotics for the treatment of acute bipolar mania and suffering from alteration in thyroid functions or thrombocytopenia as a result of such treatment”
The Specification provides support “for managing or decreasing a risk of adverse effects in a patient undergoing treatment for bipolar I disorder... wherein the said adverse effects are alteration in thyroid functions, and thrombocytopenia” (Paragraph 0015).
However, although the Specification further discloses that “[s]everal drugs have been approved for treatment of bipolar disorders, such as lithium, valproate or divalproex sodium, carbamazepine, and atypical antipsychotics for the treatment of acute bipolar mania” (Paragraph 0003), nowhere does the Specification disclose identifying a patient undergoing or having undergone treatment with one or more of these drugs and/or suffering from alteration in thyroid functions or thrombocytopenia as a result of such treatment, for managing or decreasing the risk of adverse effects therein.
In particular, while the Specification reports “Clinical Study Data” (Paragraphs 0033-0039), the data only provides treatment-emergent adverse events (TEAEs) in endoxifen-treated patients (T) and divalproex-treated patients (R) (Tables 1 and 2). Significantly, the study does not identify any of the endoxifen-treated patients as undergoing or having undergone treatment with treatment for bipolar I disorder as recited by the claim. Nor does the study identify those patients as suffering from alteration in thyroid functions or thrombocytopenia as a result of such treatment.
Although Table 2 indicates that the two incidences of increases in blood thyroid stimulating hormone in the endoxifen-treated patients (Table 1) were not related to endoxifen treatment, whereas the two incidences of increases in blood thyroid stimulating hormone in the divalproex-treated patients (Table 1) were related to divalproex treatment, the study does not disclose the steps of identifying those two divalproex-treated patients as suffering from alteration in thyroid functions, discontinuing treatment in said patients, administering endoxifen citrate to said patients, and managing or decreasing said alteration in thyroid functions for the time in which endoxifen is adminsitered, as recited by the claims.
Accordingly, amended claims 1-6 now recite limitations which were not clearly disclosed in the specification as filed, and now change the scope of the instant disclosure as filed. Such limitations recited in amended claims 1-6, which did not appear in the specification as filed, introduce new concepts and violate the description requirement of 35 U.S.C 112(a).
Applicant is required to provide sufficient written support for the limitations recited in present claims 1-6 in the specification or claims, as filed, or remove these limitations from the claims in response to this Office Action.
Claim Rejections - 35 USC § 103
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.
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.
Claims 1-6 are NEWLY rejected under 35 U.S.C. 103(a) as being unpatentable over Ahmad et al (Clin Transl Sci 9:252-259, 2016; of record) in view of Zhang et al (Seizure 35:72-79, 2016), Buoli et al (Drugs R D 18:1-5, 2018) and Goetz et al (J Clin Oncol 35:3391-3400 and Appendix, 2017).
As amended, claim 1 is drawn to a method for managing or decreasing a risk of adverse effects in a patient undergoing treatment of bipolar I disorder, comprising:
identifying a patient undergoing or having undergone treatment of bipolar I disorder with lithium, valproate or divalproex sodium, carbamazepine, or atypical antipsychotics for the treatment of acute bipolar mania and suffering from alteration in thyroid functions or thrombocytopenia as a result of such treatment;
discontinuing said treatment if the patient is currently undergoing said treatment; and
maintaining a therapeutically effective concentration of endoxifen in the patient by administering a dose of about 8 mg (more specifically, 8 mg (claim 6)) of endoxifen citrate in an enteric coated tablet once per day for at least 21 days to the patient;
wherein said administration maintains a therapeutically effective concentration of endoxifen without requiring dose adjustment during said period,
wherein the adverse effects being managed or decreased are alterations in thyroid function and thrombocytopenia, and
wherein the adverse effects are managed or decreased for the time in which the effective concentration of endoxifen is administered.
Ahmad et al – noting that treatment of bipolar I disorder often involves “adverse effects such as sedation and weight gain” and, recognizing “an urgent need to develop novel and more effective treatments for BP” (Page 252, Column 2) – teach administration of “[e]ndoxifen... orally as enteric coated tablets... 8 mg/day” (Page 253, Column 2, “Methodology”; see also Page 253, Column 1, Figure 1, depicting endoxifen citrate) “for 21 days” (Page 253, Column 2 “Methodology”) to “patients who were diagnosed with BPD I and having displayed acute manic or mixed episode” and “previously treated with at least one of the drugs, vis., lithium, valproate, carbamazepine, or an atypical (except for clozapine) or typical antipsychotic at some time during the course of their bipolar illness” (Page 253, Column 2 “Patients”) wherein “[a]ll psychotropic medications except benzodiazepines were discontinued at least 2 days before randomization” (Page 254, Column 1), reporting that:
the “mean Ctrough of endoxifen (8 mg/day) for Day 14 and Day 20 were found to be 58 ng/mL and 59 nm/mL, respectively... indicating that the steady-state of endoxifen was achieved within 14 days of endoxifen administration; and
“[t]he mean exposure (AUC, day.ng/mL) values on Day 14 (AUC0-14 days) and Day 20 (AUC0-20 days)... for endoxifen at 8 mg/day doses were 399.58 and 586.82, respectively” (Page 256, Column 2, “Pharmacokinetics and pharmacokinetic-pharmacodynamic (PK-PD) relationship of endoxifen”).
Ahmad et al further teach that “[s]afety assessments were based on adverse event (AE) reporting, laboratory testing, daily physical examination, recording of vital signs, and electrocardiograms” (Page 253, Column 1, “Conduct of the clinical study”) wherein “11 AEs were reported by 25.00% (n = 07) of 28 patients in the endoxifen 8 mg arm” (Page 256, Column 2, “Safety and tolerability”). As further taught by Ahmad et al, “[h]eadache was reported in... three patients at endoxifen 8 mg” and “[g]astrointestinal disorders like dyspepsia, nausea, and vomiting were found in... one... patient in the... endoxifen 8 mg... arm” (Page 253, Column 1, “Conduct of the clinical study”). Significantly, Ahmad et al teach that “[n]o patients left the study in the 8 mg/day endoxifen... arm” and “all... AEs were mild in nature” (Page 256, Column 2, “Safety and tolerability”).
As such, Ahmed et al teach a method of managing or decreasing a risk of adverse effects in a patient undergoing treatment of bipolar I disorder, comprising:
identifying a patient undergoing or having undergone treatment of bipolar I disorder with lithium, valproate or divalproex sodium, carbamazepine, or atypical antipsychotics for the treatment of acute bipolar mania;
discontinuing said treatment if the patient is currently undergoing said treatment; and
maintaining a therapeutically effective concentration of endoxifen in the patient by administering a dose of 8 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days to the patient;
wherein said administration maintains a therapeutically effective concentration of endoxifen without requiring dose adjustment during said period, and
wherein the adverse effects are managed or decreased for the time in which the effective concentration of endoxifen is administered.
However, Ahmad et al do not teach managing or decreasing a risk of alterations in thyroid function and thrombocytopenia in a subject identified as suffering from alterations in thyroid function and thrombocytopenia as a result of undergoing or having undergone bipolar I disorder treatment, as recited by the claims.
Yet, as taught by Zhang et al, valproate “use was associated with... increased TSH” and “alteration of thyroid hormones” (Abstract), further noting “VPA-induced thyroid dysfunction” (Page 75, Column 2).
And as taught by Buoli et al, “valproate... prescription may be complicated by the development of thrombocytopenia” (Abstract).
Conversely, Goetz et al – in “a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity” (Abstract) – teach administration of “20, 40, 60, 80, 100, 120, or 160 mg of Z-endoxifen by mouth daily until... unacceptable adverse events” (Page 3392, Column 2) to patients exhibiting “platelet count > 75,000/µL” (Page 3392, Column 2), wherein “adverse events were documented... before each 4-week cycle of treatment” and “Z-endoxifen was to be held until emergent toxicities resolved to severity < grade 1 with a reduction of one dose level when treatment was resumed for... grade > 3 platelet count decrease” (Appendix Page 1, Management of Toxicity). And, as further taught by Goetz et al, “[n]o moderate toxicities or DLT [dose-limiting toxicities] were observed among patients enrolled at either the 20- or 40-mg dose level” and, although “[a]ccelerated dose-escalation stopped at the 60-mg dose level after grade 3 thromboembolic event (pulmonary embolus)”, “[n]one of the additional five patients at the 60-mg dose level nor any patients enrolled at the subsequent dose levels developed a DLT” (Page 3393, Column 1). Moreover, “during the course of the study, only one other severe toxicity was reported (grade4 hypertriglyceridemia) after five cycles of treatment at the 60-mg dose. No eye toxicity was observed. As such, all of the planned dose levels were exhausted without observation of an MTD” (Page 3393, Column 1).
In view of all of the foregoing, it would have been prima facie obvious to apply the method of Ahmad et al (directed to the treatment of bipolar I disorder in a subject undergoing or having undergone bipolar I disorder treatment with, for example, valproate) specifically to a patient identified as suffering from alterations in thyroid function and thrombocytopenia as a result of valproate treatment, in order to manage or decrease a risk of alterations in thyroid function and thrombocytopenia therein. Recognizing that valproate is “associated with... increased TSH”, “alteration of thyroid hormones”, and “VPA-induced thyroid dysfunction” (as taught by Zhang et al) and “may be complicated by the development of thrombocytopenia” (as taught by Buoli et al), a person of ordinary skill in the art would have been motivated to identify those patients undergoing or having undergone bipolar I disorder treatment with valproate and suffering from alterations in thyroid function and thrombocytopenia as a consequence of that treatment, for treatment with endoxifen. And the ordinarily skilled artisan would have done so with a reasonable expectation of success in treating bipolar I disorder (based on Ahmad et al) and managing or decreasing a risk of alterations in thyroid function and thrombocytopenia (based on Goetz et al).
As such, claims 1 and 6 are rejected as prima facie obvious.
Claims 2-3 are drawn to the method of claim 1, wherein the patient has manic episodes with mixed features (claim 2) or manic episodes without mixed features (claim 3).
Ahmad et al further teach that “patients... were diagnosed of BPD I and having displayed an acute manic or mixed episode (with or without psychotic features) according to DSM-IV-TR” (Page 252, Column 2, “Patients”).
As such claims 2-3 are also rejected as prima facie obvious.
Claims 4-5 are drawn to the method of claim 1, wherein the patient has depression (claim 4) or depressive episodes (claim 5).
As indicated above, Ahmad et al teach that the “patients... were diagnosed of BPD I and having displayed an acute manic or mixed episode (with or without psychotic features) according to DSM-IV-TR” (Page 252, Column 2, “Patients”). Additionally, Ahmad et al teach that, when “depressive symptoms were assessed with the MADRS score throughout the trial”, “[t]he result indicated the effectiveness of endoxifen... 8 mg in alleviating depressive symptoms of mixed episode of BPD” (Page 256, Column 1, “Efficacy”).
Accordingly, it is evident that the patients treated according to Ahmad et al suffered from depression and depressive episodes.
As such, claims 4-5 are also rejected as prima facie obvious.
Conclusion
The new grounds of rejection presented in this Office action are necessitated by Applicant’s amendments to the claims. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CRAIG D RICCI whose telephone number is (571) 270-5864. The examiner can normally be reached on Monday through Thursday, and every other Friday, 7:30 am - 5:00 pm ET.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on (571) 272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611
