DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/21/2025 has been entered.
AIA Status of the Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Arguments
Applicant’s arguments, filed 11/21/2025, have been fully considered.
In the previous Action mailed on 5/21/2025, claims 1-5 were rejected under 35 U.S.C. 103(a) based on Ahmad et al (Clin Transl Sci 9:252-259, 2016; of record) in further view of Rosa et al (Bipolar Disorders 13:679-686, 2011; of record).
In the instant Action, claims 1-5 are NEWLY rejected under 35 U.S.C. 102(a)(1) based solely on Ahmad et al (Clin Transl Sci 9:252-259, 2016; of record), rendering Applicant’s arguments moot.
In the previous Action mailed on 5/21/2025, claims 1-5 were also rejected on the ground of non-statutory double patenting over each of U.S. Patent Nos. 9,333,190, 10,376,479, 11,291,640, 11,672,758 and 12,245,997.
The rejections over U.S. Patent Nos. 9,333,190, 10,376,479 and 11,672,758 are WITHDRAWN.
The rejections over U.S. Patent Nos. 11,291,640 and 12,245,997 are MAINTAINED.
Applicant traverses. In particular, Applicant argues that the claims have been amended “to recite a concentration of 8 mg of endoxifen citrate” and “the cited prior art does not provide for the specific concentration now claimed providing the unexpected clinical results that none of the patients have alteration in thyroid functions and thrombocytopenia at the end of treatment” (Applicant Arguments, Page 4).
The argument is not found persuasive. It is well settled that a showing of unexpected results is generally sufficient to overcome a prima facie case of obviousness. In re Albrecht, 514 F.2d 1389 (CCPA 1975). However, as recognized by the court in In re Schulze, 346 F.2d 600 (CCPA 1965), mere arguments are not sufficient to demonstrate unexpected results. Rather, unexpected results must be established by factual evidence by comparing the claimed invention with that of the closest prior art. In re Burckel, 592 F.2d 1175 (CCPA 1979). As discussed by the court in In re De Blauwe, 736 F.2d 699 (Fed. Cir. 1994), “the absence of tests comparing [Applicant’s claimed invention] with those of the closest prior art… constitute mere argument”. In the instant case, Applicant has not compared the claimed invention with that of the closest prior art (i.e., U.S. Patent Nos. 11,291,640 and 12,245,997) and provided factual evidence which establishes that the instantly claimed about 8 mg daily dose for at least 21 days provided unexpected results compared to other doses within the 2 mg to 16 mg range taught by the prior art.
All additional rejections of claims in the previous Action mailed on 5/21/2025 have been omitted from the instant Action as superfluous.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-5 are rejected 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 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:
maintaining a therapeutically effective concentration of endoxifen in the patient by administering a dose of about 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,
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) to “patients who were diagnosed with BPD I” (Page 253, Column 2 “Patients”) “for 21 days” (Page 253, Column 2 “Methodology”), 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, Ahmad et al teach the instantly claimed method of managing or decreasing a risk of adverse effects in a patient undergoing treatment of bipolar I disorder, comprising:
maintaining a therapeutically effective concentration of endoxifen in the patient by administering a dose of about 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 specify that alterations in thyroid function and thrombocytopenia are managed or decreased.
Nevertheless, the patient population (i.e., a patient suffering from bipolar I) and the active step (i.e., administering a dose of about 8 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days to the patient thereby maintaining a therapeutically effective concentration of endoxifen in the patient without requiring dose adjustment during said period) taught by Ahmad et al are identical to those recited by instant claim 1. And, as recognized by the court in Hoffer v. Microsoft Corp., 405 F.3d 1326 (Fed. Cir. 2005), a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited” (quoting Minton v. Nat ’l Ass ’n of Securities Dealers, Inc., 336 F.3d 1373 (Fed. Cir. 2003)). See also Verdegaal Bros., Inc. v. Union Oil Co. of Calif., 814 F.2d 628 (Fed. Cir.), cert. Denied, 484 U.S. 827 (1987), noting that merely discovering and claiming a new benefit of an old process cannot render the process again patentable. As in Verdegaal Bros., Inc. v. Union Oil Co. of Calif., the burden of proof is limited to establishing that prior art discloses the same process. See also In re Woodruff, 16 USPQ2d 1934 (Fed. Cir. 1990), stating that “a general rule that merely discovering and claiming a new benefit of an old process cannot render the process again patentable.” See also In re King, 801 F.2d 1324 (Fed. Cir. 1986), noting that “[u]nder principles of inherency, if a structure in the prior art necessarily functions in accordance with the limitations of a process or method claim of an application, the claim is anticipated. This is not to say that the discovery of a new use for an old structure based on unknown properties of the structure might not be patentable to the discoverer as a process... [but] if a previously patented device, in its normal and usual operation will perform the function which an appellant claims in a subsequent application for a process patent, then such application for process patent will be considered to have been anticipated by the former patented device”.
Accordingly, claim 1 is anticipated.
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”).
Accordingly, claims 2-3 are also anticipated.
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”).
As such, it is evident that the patients treated according to Ahmad et al suffered from depression and depressive episodes.
Accordingly, claims 4-5 are also anticipated.
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 §§ 706.02(l)(1) - 706.02(l)(3) 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 1-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 11,291,640.
Although the claims at issue are not identical, they are not patentably distinct from each other. The ‘640 patent recites “[a] method for maintaining a therapeutically effective concentration of endoxifen for treatment of a patient with bipolar I disorder, said method comprising... administering to the patient a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days, wherein the method does not comprise monitoring a therapeutic dose of the patient...”
As such, the ‘640 patent differs from the instantly claimed method in that the ‘640 patent administers “a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days” as opposed to “a dose of about 8 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days”, and the ‘640 patent does not specify managing/decreasing risk of alterations in thyroid function and thrombocytopenia.
Yet, as discussed by MPEP 2144.05, “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists” (citing In re Wertheim, 541 F.2d 257 (CCPA 1976); In re Woodruff, 919 F.2d 1575 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465 (Fed. Cir. 1997)).
And it is asserted, absent evidence the contrary, carrying out the method of the prior art would necessarily would result in managing/decreasing the risks of alterations in thyroid function and thrombocytopenia in said patients.
While the fact that a certain result or characteristic may occur or be present in the prior art is not sufficient to establish the inherency of that result or characteristic (In re Rijckaert, 9 F.3d 1531 (Fed. Cir. 1993); see also In re Robertson, 169 F.3d 743 (Fed. Cir. 1999), “[i]nherency may not be established by probabilities or possibilities”), it is well settled that “inherency may supply a missing claim limitation in an obviousness analysis” so long as “the limitation at issue necessarily must be present or the natural result of the combination of elements explicitly disclosed by the prior art” (PAR Pharm., Inc. v. TWI Pharm., Inc. 773 F.3d 1186 (Fed. Cir. 2014)). “If… the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient” (quoting In re Oelrich, 666 F.2d 578 (C.C.P.A. 1981). Thus, as stated by the court in PAR Pharm., Inc. v. TWI Pharm., Inc., “inherency... is present… when the limitation at issue is the ‘natural result’ of the combination of prior art elements” (Id.). And, as stated by the court in In re Dillon (919 F.2d 688 (Fed. Cir. 1990)), “it is not necessary in order to establish a prima facie case of obviousness… that there be a suggestion in or expectation from the prior art that the claimed [invention] will have the same or similar utility as one newly discovered by applicant”.
While the court in PAR Pharm., Inc. v. TWI Pharm., Inc. further indicates that “the concept of inherency must be limited when applied to obviousness” and “[a] party must… meet a high standard in order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis”, it must also be remembered that the U.S. Patent Office is not equipped with analytical instruments to test prior art compositions for the infinite number of ways that a subsequent Applicant may present previously unmeasured characteristics. As such, a prior art disclosure of a product or method “appearing to be substantially identical” to that instantly claimed, and rationale or evidence “tending to show inherency”, shifts the burden to the Applicant to prove otherwise (MPEP 2112 (IV)-(V)). As stated in In re Best, Bolton, and Shaw (562 F2d 1252 (CCPA 1977)), “[w]here… the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product” (see also In re Fitzgerald 619 F2d 67 (CCPA 1980): the burden is shifted to the applicants to “prove that subject matter shown to be in the prior art does not possess characteristic relied on”).
This is especially true in cases where the newly discovered, inherent limitation is claimed functionally rather than structurally. For example, in In re Kubin (561 F.3d 1351 (Fed. Cir. 2009)), discussing claims drawn to an isolated nucleic acid molecule encoding a polypeptide “wherein the polypeptide binds CD48”, the court stated that there is “no obligation to predicate [an] obviousness finding on factual findings regarding a prior art teaching of [the polypeptide’s] binding to the CD48 protein” – the limitation is “not an additional requirement imposed by the claims on the [polypeptide], but rather a property necessarily present in” the polypeptide. As stated by the court in Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 (Fed. Cir. 2012), “[t]o hold otherwise would allow any formulation – no matter how obvious – to become patentable merely by testing and claiming an inherent property” (discussing claims drawn to methods of administering a active agent “wherein upon oral administration… an initial serum concentration of the [active agent] greater than about 0.1 µg / ml is obtained at any time within about 30 minutes after administration” and further noting that “[t]he initial blood serum concentration resulting from administering [the active agent] is an inherent property of the formulation, and an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations”).
In the instant case, the claimed and prior art methods are substantially identical. As such, absent evidence to the contrary, it is asserted that administering “a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days” to a patient with bipolar I disorder would manage/decrease the risks of alterations in thyroid function and thrombocytopenia in said patient.
Claims 1-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12/245,997.
Although the claims at issue are not identical, they are not patentably distinct from each other. The ‘997 patent recites “[a] method for maintaining a therapeutically effective concentration of endoxifen for treatment of a patient with bipolar I disorder, said method comprising... administering to the patient, a dose in a range from 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for up to 21 days...”
As such, the ‘997 patent differs from the instantly claimed method in that the ‘640 patent administers “a dose in a range from 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for up to 21 days” as opposed to “a dose of about 8 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days”, and the ‘997 patent does not specify managing/decreasing risk of alterations in thyroid function and thrombocytopenia.
Yet, as discussed by MPEP 2144.05, “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists” (citing In re Wertheim, 541 F.2d 257 (CCPA 1976); In re Woodruff, 919 F.2d 1575 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465 (Fed. Cir. 1997)).
And it is asserted, absent evidence the contrary, carrying out the method of the prior art would necessarily would result in managing/decreasing the risks of alterations in thyroid function and thrombocytopenia in said patients.
While the fact that a certain result or characteristic may occur or be present in the prior art is not sufficient to establish the inherency of that result or characteristic (In re Rijckaert, 9 F.3d 1531 (Fed. Cir. 1993); see also In re Robertson, 169 F.3d 743 (Fed. Cir. 1999), “[i]nherency may not be established by probabilities or possibilities”), it is well settled that “inherency may supply a missing claim limitation in an obviousness analysis” so long as “the limitation at issue necessarily must be present or the natural result of the combination of elements explicitly disclosed by the prior art” (PAR Pharm., Inc. v. TWI Pharm., Inc. 773 F.3d 1186 (Fed. Cir. 2014)). “If… the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient” (quoting In re Oelrich, 666 F.2d 578 (C.C.P.A. 1981). Thus, as stated by the court in PAR Pharm., Inc. v. TWI Pharm., Inc., “inherency... is present… when the limitation at issue is the ‘natural result’ of the combination of prior art elements” (Id.). And, as stated by the court in In re Dillon (919 F.2d 688 (Fed. Cir. 1990)), “it is not necessary in order to establish a prima facie case of obviousness… that there be a suggestion in or expectation from the prior art that the claimed [invention] will have the same or similar utility as one newly discovered by applicant”.
While the court in PAR Pharm., Inc. v. TWI Pharm., Inc. further indicates that “the concept of inherency must be limited when applied to obviousness” and “[a] party must… meet a high standard in order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis”, it must also be remembered that the U.S. Patent Office is not equipped with analytical instruments to test prior art compositions for the infinite number of ways that a subsequent Applicant may present previously unmeasured characteristics. As such, a prior art disclosure of a product or method “appearing to be substantially identical” to that instantly claimed, and rationale or evidence “tending to show inherency”, shifts the burden to the Applicant to prove otherwise (MPEP 2112 (IV)-(V)). As stated in In re Best, Bolton, and Shaw (562 F2d 1252 (CCPA 1977)), “[w]here… the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product” (see also In re Fitzgerald 619 F2d 67 (CCPA 1980): the burden is shifted to the applicants to “prove that subject matter shown to be in the prior art does not possess characteristic relied on”).
This is especially true in cases where the newly discovered, inherent limitation is claimed functionally rather than structurally. For example, in In re Kubin (561 F.3d 1351 (Fed. Cir. 2009)), discussing claims drawn to an isolated nucleic acid molecule encoding a polypeptide “wherein the polypeptide binds CD48”, the court stated that there is “no obligation to predicate [an] obviousness finding on factual findings regarding a prior art teaching of [the polypeptide’s] binding to the CD48 protein” – the limitation is “not an additional requirement imposed by the claims on the [polypeptide], but rather a property necessarily present in” the polypeptide. As stated by the court in Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 (Fed. Cir. 2012), “[t]o hold otherwise would allow any formulation – no matter how obvious – to become patentable merely by testing and claiming an inherent property” (discussing claims drawn to methods of administering a active agent “wherein upon oral administration… an initial serum concentration of the [active agent] greater than about 0.1 µg / ml is obtained at any time within about 30 minutes after administration” and further noting that “[t]he initial blood serum concentration resulting from administering [the active agent] is an inherent property of the formulation, and an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations”).
In the instant case, the claimed and prior art methods are substantially identical. As such, absent evidence to the contrary, it is asserted that administering “a dose in a range from 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for up to 21 days” to a patient with bipolar I disorder would manage/decrease the risks of alterations in thyroid function and thrombocytopenia in said patient.
Conclusion
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611
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