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 .
Priority
This application, filed 13 October, 2023, is a national stage application of PCT/US2022/024848, filed 14 April, 2022, which claims the benefit of U.S. Provisional Application 63/238,502, filed 30 August, 2021, 63/189,946, filed 18 May, 2021, 63/175,379, filed 15 April, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5 June, 2024 is acknowledged and has been considered.
Status of the Application
Receipt is acknowledged of Applicant’s claimed invention, filed 5 June, 2024, in the matter of Application N° 18/286,944. Said documents have been entered on the record.
Claims 3, 5, 19-20, 22, 24, 26, 30, 32, 34, and 38-39 are amended. Claims 6-18, 21, 23, 25, 27-29, 31, 33, 35-37, and 40-43 are canceled. No new matter was introduced.
Therefore, Claims 1-5, 19-20, 22, 24, 26, 30, 32, 34, and 38-39 represent all claims currently under consideration.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-5, 19-20, 22, 24, 26, 30, 32, 34, and 38-39 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding Claim 2, the phrase “if, and because, the patient is a CYP2D6 poor metabolizer” introduces ambiguity as to whether poor metabolizer status is a required patient characteristic or a subjective rationale for administering the claimed dose. As a result, it is unclear whether infringement depends on the patient’s actual metabolic status, the clinician’s knowledge of intent, or a determination made prior to administration.
Regarding Claim 3, the recited comparison to metabolite levels “in a patient who is not a CYP2D6 poor metabolizer” lacks clarity. The claim does not specify the basis for this comparison, including whether the comparator is the same patient under different conditions or a different patient, or when and how the comparison is to be performed. In the absence of an objective reference point for determining when exposure is considered increased, the claim fails to inform, with reasonable clarity, when the reduction step is required.
Although Claim 4, which depends upon Claim 3, specifies that metabolite exposure is measured as AUC or Cmax, this limitation does not resolve the ambiguity in Claim 3 regarding the comparator baseline or the condition under which exposure is considered increased.
Additionally, Claim 5, which depends upon Claim 3, recites that increased metabolite exposure increases the risk of one or more exposure-related adverse reactions without defining the baseline risk, the manner of assessing risk, or the degree of risk increase, further rendering the scope of the claim indefinite.
Claims 19-20, 22, 24, 26, 30, and 32 depend from Claims 2 or 3, and fail to cure the deficiencies as stated above.
Similarly Claim 34, which also depends from Claims 2 or 3, fails to cure the deficiencies as stated above. Additionally, the claim recites monitoring for “exposure-related adverse reactions” without defining the adverse reactions or providing an objective standard for identifying them, rendering the scope of the claim unclear.
Claims 38-39 depend from Claim 32, and fail to cure the deficiencies as stated above.
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.
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.
Claims 1-5, 19-20, 22, 24, 26, 30, 32, 34, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Stamler and Huang (WO 2016/144901 A1, cited in IDS.)
Regarding Claims 1-2, Stamler and Huang teach a method of treating abnormal involuntary movement in a subject, comprising administering to the subject an initial daily amount of deutetrabenazine of at least about 6 mg per day; (‘901, Pg. 5-6, Para 023), and is less than about 36 mg (‘901, Pg. 8, Para 042.)
Although Stamler and Huang do not expressly require selecting patients based on CYP2D6 poor metabolizer status, the reference acknowledges that reduced CYP2D6 metabolic capacity results in increased exposure to deutetrabenazine and its metabolites (‘901, Pg. 86, Para 0413.) At the time of the invention, it is well known that CYP2D6 poor metabolizers exhibit reduced metabolic activity and increased exposure to CYP2D6-substrate drugs. A person of ordinary skill in the art would therefore have been motivated to apply the dose-limiting teachings of Stamler and Huang to patients who are CYP2D6 poor metabolizers as a predictable and routine optimization to manage exposure-related safety concerns, with a reasonable expectation of success.
The recitation that the method is performed “outside of a clinical trial setting” does not distinguish the claimed methods form the prior art. Stamler and Huang is directed to therapeutic methods of administering deutetrabenazine to patients and is not limited to performance within a clinical trial or experimental setting. The exclusion of a clinical trial environment merely reflects the intended context of use and does not impose a structural or operational limitation on the claimed method.
Regarding Claims 3-5, Stamler and Huang teach administering deutetrabenazine and adjusting dosage based on tolerability and exposure-related effects (‘901, Pg. 5-6, Para 023 and Pg. 7, Para 033.)
Stamler and Huang fail to monitor specific metabolites by name, or compare metabolite exposure relative to monotherapy.
However, Stamler and Huang does teach that in humans d6-tetrabenazine is rapidly and extensively converted in the liver (similarly to non-isotopically enriched tetrabenazine) to major, active dihydrotetrabenazine (HTBZ) metabolites referred to as d6-a-HTBZ and d6-P-HTBZ (as a mixture of the + and - isomers) which are believed to drive clinical efficacy (‘901, Pg. 42, Para 0250.)
Therefore, it would have been prima facie obvious to one skilled in the art before the effective filing date of the invention to monitor concentrations of deutetrabenazine metabolites and reduce the administered dose when exposure is increased relative to monotherapy, as a routine and predictable way to implement the dose-adjustment teachings of Stamler and Huang with a reasonable expectation of success.
Regarding Claims 19-20, 22, 24, Stamler and Huang teach wherein the abnormal involuntary movement is caused by a movement disorder (‘901, Pg. 6, Para 024), wherein the movement disorder is chosen from chorea, Huntington's Disease, and tardive dyskinesia (‘901, Pg. 6, Para 025.)
Regarding Claims 26, 30, and 32, Stamler and Huang teach a daily amount of deutetrabenazine is chosen from about 12 mg, about 18 mg, and about 24 mg (‘901, Pg. 7, Para 036.) The recitation of “maximum” daily dose does not distinguish over the prior art as Stamler and Huang expressly disclose administration of deutetrabenazine at daily doses at or below the claimed maximum, which necessarily satisfies the claimed limitation.
Regarding Claims 34 and 38-39, Stamler and Huang repeatedly emphasize that adverse reactions are clinically relevant considerations in determining appropriate dosing and that dose adjustment is used as a mechanism to manage safety and tolerability during treatment (‘901, Pg. Pg. 68, Para 0352, Pg. 10, Para 051-053, and Pg. 47, Table 12.)
In view of these teachings, a person of ordinary skill in the art would have been motivated to include an explicit step of monitoring patients for exposure-related adverse reactions when practicing the disclosed treatment methods, as monitoring for adverse effects is a routine and predictable means of implementing the safety-driven dosing strategies described in Stamler and Huang. Further, specifying particular known adverse reactions, such as somnolence – the most common AE observed in the deutetrabenazine group (‘901, Pg. 47, Para 0414) – and sedation, or other adverse reactions disclosed in the reference, would have been an obvious refinement of such monitoring, as these adverse reaction are recognized, expected, and directly related to the deutetrabenazine exposure. A person of ordinary skill in the art would have had a reasonable expectation of success in monitoring for such adverse reactions and using that information to guide safe administration of the drug.
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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claim 1-5, 19-20, 22, 24, 26, 30, 32, 34, and 38-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 1-5, 17-18, 20, 22, 24-25, 28, 32, and 36-37 of copending Application No. 18/286,935 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because they differ only in the manner in which CYP2D6 impairment is characterized, and would have been obvious variants of one another to a person skilled in the art.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Donna M. Nestor whose telephone number is (703)756-5316. The examiner can normally be reached generally (w/flex): 5:30a-5p EST M-Th.
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/D.M.N./ Examiner, Art Unit 1627
/SARAH PIHONAK/ Primary Examiner, Art Unit 1627