DETAILED ACTION
Notice of AIA Status
The instant application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the Leahy-Smith America Invents Act (AIA ).
Status of the Claims
The listing of claims filed 15 September 2023 has been examined. Claims 1–21, 38, 54, 69, 84, 99, 114, and 118 are pending. Claims 22–37, 39–53, 55–68, 70–83, 85–88, 100–113, 115–117, and 119–124 are canceled.
Benefit of Earlier Filing Date
The instant application was filed 25 January 2023; is a continuation application of PCT/US2023/061104, filed 23 January 2023, and claims the benefit of U.S. Prov. Pat. App. Serial No. 63/302,328, filed 24 January 2022. Acknowledgment is made of Applicant’s claim.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 16 May 2023; 15 September 2023; and 12 October 2023 are acknowledged and have been considered.
Objections to the Specification
The abstract of the disclosure is objected to because it recites legal phraseology (“said”) and phrases that can be implied (“The present disclosure relates to”; “In embodiments”; “The present disclosure further relates to”). Appropriate correction is required.
For guidelines for the preparation of patent abstracts, see MPEP § 608.01(b) (Explaining: The abstract should be in narrative form and avoid legal phraseology (e.g., means, said), terms referring to purported merits of the invention (e.g., new, novel), and phrases that can be implied (e.g., The disclosure concerns, The disclosure defined by this invention,). The language should be clear and concise, and not repeat information given in the title. It should not compare the invention with the prior art. The abstract is generally limited to a single paragraph within the range of 50 to 150 words in length.).
Claim Objections
Claim 84 is objected to for minor informalities. Claim 84, step (d), recites “1.1.5 mg,” which appears to be a typographical error because a range of “1–1.5 mg” is described in the specification (e.g., Tables 4.1–4.5B).
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 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.
Graham v. John Deere Co., 383 U.S. 1, 17 (1966); MPEP § 2141(II).
Claims 38, 54, 69, 84, 114, and 118 are directed to treating major depressive disorder (MDD) with brexpiprazole in patients. Claims 69, 84, 114, and 118 are directed to patients who are CYP2D6 poor metabolizers. Claims 38, 54, 69, and 84 are directed to obese patients. Claims 114 and 118 are directed to normal-weight patients who are CYP2D6 poor metabolizers. The claims are summarized in the table below (W = week; normal = normal weight; poor = poor CYP2D6 metabolizer).
Claim
Patient
Step (i), W1
Step (ii), W2
Step (iii), W3
Step (iv), W4+
38
obese
0.625–0.875 mg/day
1.125–1.875 mg/day
2–2.875 mg/day
2–3 mg/day
54
obese
1.125–1.875 mg/day
2.125–3.875 mg/day
2–4 mg/day
2–3 mg/day
69
obese (poor)
0.625–0.875 mg/day
1–1.875 mg/day
1–3 mg/day
1–1.5 mg/day
84
obese (poor)
1.125–1.875 mg/day
2–3.5 mg/day
1–3 mg/day
1–1.5 mg/day
114
normal (poor)
0.375 mg/day
0.625–0.875 mg/day
1.125–1.75 mg/day
1–1.5 mg/day
118
normal (poor)
0.75 mg/day
1.25–2.0 mg/day
1.5–3 mg/day
1–1.5 mg/day
Claims 38 and 69: step (i) is the same; step (ii) has significant overlap; steps (iii) and (iv) are different. Claim 38 has significant overlap in steps (iii) and (iv). Claim 69 has significant overlap in steps (ii), (iii). and (iv).
Claim 118: step (i) is within range of claim 69; steps (ii), (iii), and (iv) have significant overlap with claim 69. Claim 118 has significant overlap in steps (ii), (iii), and (iv).
Claim 114: step (i) is 0.25mg below range of claim 69; steps (ii) is 0.25mg below range of claim 69; steps (iii) and (iv) have significant overlap with claim 69. Claim 114 has significant overlap in steps (iii) and (iv).
Claims 54 and 84: step (i) is the same; steps (ii) and (iii) have significant overlap; step (iv) is different. Claim 54 has significant overlap in steps (ii), (iii). and (iv). Claim 84 has significant overlap in steps (iii) and (iv).
Claims 38, 54, 69, 84, 114, and 118 have at least two consecutive steps with overlap doses of brexpiprazole. Thus, while four steps may be recited, two or more steps can be merged into a single step for numerous embodiments. For example, claim 38, step (c) requires 2–2.875 mg dose and step (d) requires 2–3 mg dose. Steps (c) and (d) overlap for numerous embodiments (2–2.875 mg dose) and would merge into a single step in the process. Based on the overlap in steps (ii), (iii), and/or (iv), claims 54, 69, and 118 require only two steps, and claims 38, 84, and 114 require only three steps.
Claims 38, 54, 69, 114, and 118 are rejected under 35 U.S.C. § 103 as being unpatentable over REXULTI (brexpiprazole) Revised Highlights of Prescribing Information (2020) (“Highlights”) [IDS] in view of Erstad, Brian, Clin. Drug Investig. (2017), 37, 1–6 (“Erstad”), Hanley et al., Clinical Pharmacokinetics (2010), 49(2), 71–87 (“Hanley”) [IDS], and Elmokadem et al., Journal of Clinical Pharmacology (2021), 00(0), 1–10 (early online pub) (“Elmokadem”) [IDS].
The Graham factors are addressed in turn below.
Determining the scope and contents of the prior art
Highlights discloses a method of initiating treatment of major depressive disorder (MDD) for patients who are CYP2D6 poor metabolizers (“poor”) and patients who are not CYP2D6 poor metabolizers, comprising orally administering brexpiprazole. (Highlights, p.1).
Highlights discloses a multi-step dosing schedule starting with either 0.5 or 1.0 mg/day. (Id.). Dosage increases should occur at weekly intervals. (Id., p.2). The recommended daily dose is 2 mg/day. (Id.). The maximum daily dose is 3 mg/day. (Id.). The dose should be adjusted by half for patients who are CYP2D6 poor metabolizers. (Id., pp.1, 3). For MDD patients, Highlights advises: “Periodically reassess to determine the continued need and appropriate dosage for treatment.” (Id., p.2). Highlights discloses studies in which patients were given 2mg or 3mg doses once daily. The initial dose was 0.5mg for one week, then increased to 1mg for a week, and then increased to 2mg or 3mg. (Id., p.21). Both doses were efficacious. (Id., p.22).
The Highlights schedule is summarized in the table below (W = week).
Patient
Step (i), W1
Step (ii), W2
Step (iii), W3
Step (iv), W4
MDD
0.5 mg/day
1 mg/day
2 mg/day
3 mg/day as needed
MDD (poor)
0.25 mg/day
0.5 mg/day
1 mg/day
2 mg/day as needed
MDD
1 mg/day
2 mg/day
3 mg/day as needed
MDD (poor)
0.5 mg/day
1 mg/day
1.5 mg/day as needed
2 mg/day as needed
(Id., pp.1–3).
Erstad states: “Medication dosing recommendations in product labeling are likely to be inadequate for dosing patients of more extreme body composition.” (Erstad, p.1 “Key Points”).
Hanley states: “Drug clearance (CL) is the primary determinant to consider when designing a maintenance dose regimen. CL is largely controlled by hepatic and renal physiology. In the obese, increases in cytochrome P450 2E1 activity and phase II conjugation activity have been observed. . . . Therefore, clinicians should apply a weight-normalized maintenance dose, suing a size descriptor that corrects for differences in absolute CL between obese and non-obese individuals.” (Hanley, p.72). Hanley states: “Drugs that undergo renal or phase I metabolic CL [drug clearance] have little change in CL as a function of bodyweight.” (Hanley, p.85).
Elmokadem discloses that brexpiprazole does not undergo renal metabolic clearance. (Elmokadem, p.2).
Ascertaining the differences between the prior art and the claims at issue
Highlights is silent with respect to the obese patient population. (Highlights, pp.15–16).
Highlights is silent with respect to increasing dosage from the recommended dose (2mg) to the maximum dose (3mg) or an amount therebetween.
Highlights recommends a starting dose of 0.5mg or 1.0mg, and half a starting dose of 0.25mg or 0.5mg for patients known as poor CYP2D6 metabolizers. The instant claims require a starting dose that is 0.125mg/day higher (0.625 or 1.125) for obese patients, regardless if they are poor CYP2D6 metabolizers (claims 38, 54, 69, 84); and a starting dose that is 0.125mg/day lower (0.375) (claim 114) and 0.25 mg/day higher or lower (0.75) (claim 118) for poor CYP2D6 metabolizers.
Hanley discusses maintenance dose, whereas the claimed methods are directed to initiating treatment.
Resolving the level of ordinary skill in the pertinent art
The level of one of ordinary skill may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of the factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the pharmaceutical art and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
Considering objective evidence present in the application indicating obviousness or nonobviousness
The instant application provides AUC24 and Cmax data for MDD patients treated with brexpiprazole. (Spec., FIGs. 4A–9C; ¶¶ 59–76, 255–262).
The question of obviousness
Based on the above factors, it would have been obvious for a person having ordinary skill in the art prior to the filing of the instant application to combine the teachings of Highlights, Erstad, and Hanley to arrive at the claimed methods.
Highlights discloses a multi-step dosing schedule with weekly dosage adjustments, and the claimed methods are consistent with that approach. Highlights discloses doses of 0.5, 1.0, 2.0, and 3.0 mg/day (starting, recommended, and maximum doses). The differences between the instant claims and Highlights is the dose utilized in certain steps, as outlined below.
In claim 38 (not poor CYP2D6 metabolizers), the first week dosage (0.625–0.875 mg/day) falls within a range defined with endpoints based on the starting dose in Highlights (0.5 or 1.0 mg/day); the second week dosage (1.125–1.875 mg/day) falls within a range defined with endpoints based on based on the recommended dose in Highlights (1.0 or 2.0 mg/day); and the range of doses for weeks thereafter include the recommended dose in Highlights (2.0 mg/day).
In claim 114 (poor CYP2D6 metabolizers), the first week dosage (0.375 mg/day) falls within a range defined with endpoints based on the starting dose in Highlights (0.25 or 0.5 mg/day); the second week dosage (0.625–0.875 mg/day) includes the recommended dose in Highlights (0.5 or 1.0 mg/day); and the dosage for weeks thereafter include the recommended dose in Highlights (2.0 mg/day).
For claims 38 and 114, the claims require dosages at each step that are within a range defined by the starting doses and recommend doses for normal and poor CYP2D6 metabolizers in Highlights. A prima facie case of obviousness exists when the claimed ranges overlap with or fall inside of ranges disclosed in the prior art. MPEP § 2144.05(I).
In claim 54 (not poor CYP2D6 metabolizers), the first week dosage (1.125–1.875 mg/day) is greater than the starting dose in Highlights (0.5 or 1.0 mg/day); however, the other dosage steps recite a range that includes the recommend dose or maximum dose in Highlights (2.0 and 3.0 mg/day). Because brexpiprazole does not undergo renal metabolic clearance, it would have been expected to see an increased drug clearance for obese patients with relatively higher body weight. As such, one of ordinary skill in the art would have been motivated to modify the dosage for obese patients, including obese patients who are poor CYP2D6 metabolizers. Because that modification would be based on body weight, one of ordinary skill in the art would have been expected to a weight-normalized dose.
In claim 69 (poor CYP2D6 metabolizers), the first week dosage (0.625–0.875 mg/day) is greater than the starting dosage in Highlights (0.25 or 0.5 mg/day); however, the other dosage steps recite a range that includes the recommend dose for poor CYP2D6 metabolizers in Highlights (1.0 or 2.0 mg/day). Because brexpiprazole does not undergo renal metabolic clearance, it would have been expected to see an increased drug clearance for obese patients with relatively higher body weight. As such, one of ordinary skill in the art would have been motivated to modify the dosage for obese patients, including obese patients who are poor CYP2D6 metabolizers. Because that modification would be based on body weight, one of ordinary skill in the art would have been expected to a weight-normalized dose.
In claim 118 (poor CYP2D6 metabolizers), the first week dosage (0.75 mg/day) is greater than the starting dose in Highlights (0.25 or 0.5 mg/day), but falls within a range defined with endpoints based on the starting dose for poor CYP2D6 metabolizers (e.g., 0.5 mg/day) and patients who are not poor CYP2D6 metabolizers (1.0 mg/day). The ranges of doses for weeks thereafter include the recommended dose in Highlights (2.0 mg/day). One of ordinary skill in the art would have been motivated to modify the dosage for the first week because Highlights advises: to “reassess to determine the continued need and appropriate dosage for treatment.” Because the claimed modification fall within the scope of doses disclosed in Highlights, one of ordinary skill in the art would have had a reasonable expectation of success.
The evidence presented in the instant specification has been considered. One of ordinary skill in the art would have expected a higher concentration of brexpiprazole in a patient’s blood when administering doses higher than the recommended dosage. As such, the data confirming that is not necessarily unexpected. Moreover, the claimed dosage ranges are all based on the doses disclosed in Highlights. For example, claims 38 and 54 recite initial doses that are merely 0.125 mg/day more than the disclosed doses of 0.5 and 1.0 mg/day in Highlights. Such minor modifications are deemed to be an optimization of the disclosed doses.
Because the claimed methods are directed to optimizing a dosage schedule for a specific patient population (obese or normal weight patient; poor or normal CYP2D6 metabolizers), some variability would have been expected, and there would have been a reasonable expectation of success at arriving at the claimed methods because Highlights provides the standard dosing protocol, and optimizing dosage for a specific patient is within the skill and knowledge of the highly skilled and educated ordinary artisan.
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 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046 (Fed. Cir. 1993); In re Longi, 759 F.2d 887 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937 (CCPA 1982); In re Vogel, 422 F.2d 438 (CCPA 1970); In re Thorington, 418 F.2d 528 (CCPA 1969).
Please note the following information regarding terminal disclaimers:
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(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 21 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11–16 of US Pat. No. 11,229,644 (reference claims) in view of Frampton, James, Drugs (2019), 79, 189–200 (“Frampton”), and Ishigooka et al., Pharmacokinetics (2018), 58(1), 74–80 (“Ishigooka”) [IDS].
18/101,340
11,229,644
21. A method of initiating treatment of schizophrenia with brexpiprazole in an obese patient who is a CYP2D6 poor metabolizer, comprising:
(a) orally administering 1.125-2 mg brexpiprazole once daily on each of the first 4 days of brexpiprazole treatment;
(b) orally administering at least 2.125-3.875 mg brexpiprazole once daily on each of the next 3 days following step (a);
(c) orally administering at least 4.125-7 mg brexpiprazole on each of the next 7 days following step (b); and then
(d) orally administering 1-2 mg brexpiprazole once daily thereafter;
wherein the obese patient has one or more of the following characteristics: (i) BMI of at least about 35. . .
11. A method of initiating treatment of schizophrenia with brexpiprazole in an obese patient who is a CYP2D6 poor metabolizer, comprising:
(a) administering 0.5 mg brexpiprazole twice daily on each of the first 4 days of brexpiprazole treatment;
(b) administering 1 mg brexpiprazole twice daily on each of the next 3 days following step (a);
(c) administering 1-2 mg brexpiprazole twice daily on each of the next 7 days; and then
(d) administering 1-2 mg/day of brexpiprazole once daily thereafter;
wherein the obese patient has a BMI of at least about 35.
Although the claims at issue are not identical, they are not patentably distinct from each other because they both cover four-step methods for initiating treatment of schizophrenia in the same patient population (an obese patient who is a CYP2D6 poor metabolizer with a BMI of at least about 35) with the same drug (brexpiprazole). The four steps for initiating treatment comprise administering: (i) a total amount of about 1 mg per day for 4 days; (ii) a total amount of about 2 mg per day for the next 3 days; (iii) a total amount of about 4 mg per day for the next 7 days; and (iv) a total amount of about 1–2 mg per day thereafter.
The instant claim administers brexpiprazole once daily in steps (a), (b), and (d), whereas step (c) permits twice-daily administration. The reference claims administer brexpiprazole twice daily in steps (a), (b), and (c), whereas step (d) is a once daily administration. The instant claim administers brexpiprazole at 1.125–2 mg per day in step (a), whereas the reference claims administer 1 mg per day in step (a). The instant claim administers brexpiprazole at 2.125–3.875 mg per day in step (b), whereas the reference claims administer 2 mg per day in step (b). The instant claim administers brexpiprazole at 4.125–7 mg per day in step (c), whereas the reference claims administer 2–4 mg per day in step (c). Accordingly, the differences include once- versus twice-daily administration for some steps and an amount of 1.125mg in steps (a), (b), and (c).
Frampton explains that patients who are CYP2D6 poor metabolizers, brexpiprazole is typically administered once daily but a twice-daily divided dose may be preferred for some patients. (Frampton, p.196).
Ishigooka discloses the administration of 1 mg, 4 mg, and 6 mg doses of brexpiprazole once daily to patients with schizophrenia. (Ishigooka, p.78). Ishigooka states: “Overall, all doses of brexpiprazole were well tolerated.” (Id.).
Based on the disclosures of Ishigooka, Frampton, and Erstad, one of ordinary skill in the art would have appreciated, at the time the instant application was filed, that (i) dosage adjustments may be required during the loading phase for patients characterized as obese and/or poor CYP2D6 metabolizers; and (ii) administering higher doses of brexpiprazole, e.g., 6 mg, to patients with schizophrenia are well tolerated. Because the instant claim and the reference claims are directed to administering the same medication to the same patient population, adjustments to the dosage would have been routine or well within the skills and knowledge of an ordinary artisan. As such, one of ordinary skill in the art would have had a reasonable expectation of success of arriving at the instant claim from the reference claim.
Allowable Subject Matter
Claim 21 would be allowable if the above issues are resolved.
Claims 1–20, 84, and 99 are allowable. The closest prior art is the product label for brexpiprazole (“Highlights”) [IDS]. Highlights 2020 discloses a method of initiating treatment of schizophrenia and MDD for patients who are CYP2D6 poor metabolizers (“poor”) and who are not CYP2D6 poor metabolizers, comprising orally administering brexpiprazole. The schedule for treating MDD is above. The schedule for treating schizophrenia is below (D = day):
schizophrenia
1 mg/day, D1–D4
2 mg/day, D5–D7
4 mg/day, D8+
schizophrenia (poor)
0.5 mg/day, D1–D4
1 mg/day, D5–D7
2 mg/day, D8+
(Highlights, pp.1–3).
Claims 1, 21, and 99 require four steps with different dose ranges of brexpiprazole (there is no overlap between consecutive steps). Highlights does not disclose or suggest a four-step process. Claim 84 requires a first week dose that is greater than the dose in Highlights, a second week dose that is greater than the recommended dose in Highlights, and subsequent doses that are lower than the second week dose. Highlights does not disclose an elevated dose prior to tapering down to the recommended dose.
Conclusion
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/JASON M. NOLAN/Patent Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623