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 on 11/21/2024, is a continuation of International Patent Application No. PCT/IB2024/056341, filed 06/28/2024, which claims the benefit of the priority of U.S. Provisional Patent Application No. 63/524,198, filed 06/29/2023.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 12/24/2024 and 11/17/2025, complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits, except where noted.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/17/2025 has been entered.
Applicant argument filed on 11/17/2025 have been received and have been carefully Considered. Claims 2, 8, 14-30 were previously cancelled. Claims 1, 3-7, 9-13, and 31-46 are pending.
Withdrawn Claim Rejections - 35 USC § 103
Rejection of claims 1, 3-4, 6-7, 10-13, 32, 33, 35, and 37-46 are rejected under 35 U.S.C. 103 as being unpatentable over Ziemichód W, et al. Molecules. 2023 Apr 19;28(8):3575) in view of Dayal S, et al. Pharmacol. Res. Perspect. 2021 Apr; 9(2): e00758) and Berger B, et al. Clin. Pharmacokinet. 2021 Oct; 60(10):1349-1360).
New Rejection
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 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.
§ 103 Rejection over Ziemichód in view of Dayal and Berger
Claims 1, 3-4, 6-7, 10-13, 32-33, 35, and 37-46 are rejected under 35 U.S.C. 103 as being unpatentable over Ziemichód W, et al. Molecules. 2023 Apr 19;28(8):3575, “Ziemichód”, cited in the PTO-892 dated 04/02/2025) in view of S. Brooks et al. (Journal of Psychopharmacology, 2019, Vol. 33(2) 202-209, “Brooks” cited in the PTO-892), Dayal S, et al. Pharmacol. Res. Perspect. 2021 Apr; 9(2):e00758, “Dayal” cited in the PTO-892 dated 04/02/2025) Berger B, et al. Clin. Pharmacokinet. 2021 Oct; 60(10):1349-1360, “Berger” cited in the PTO-892 dated 04/02/2025). R. Weersink, BMJ Open. 2016 Oct 12;6(10):e012991, “Weersink” cited in the PTO-892), and A. Ozbey et al. (CLINICAL PHARMACOLOGY & THERAPEUTICS, VOLUME 113 NUMBER 6, 2023 (05 April 2023), “Ozbey” cited in the PTO-892).
Ziemichód teaches the use of seltorexant, a potent selective antagonist of human OXR-2, for the treatment of insomnia and major depressive disorder. [entire document, Pg. 6, 1st para. and Figure 2.]:
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Ziemichód teaches the potency of seltorexant as a selective OXER antagonist and provides data on pharmacokinetics of seltorexant. [Pg. 7]. Ziemichód teaches the pharmacokinetics parameter including Cmax, Tmax, AUC, and t1/2 for multiple single doses of seltorexant in healthy male subjects including 10 mg and 20 mg of seltorexant. [Pg. 7, Table 1].
Ziemichód teaches that patients with major depressive disorder who had an inadequate response to one to three selective serotonin/serotonin-norepinephrine reuptake inhibitors with Insomnia Severity Index (ISI) scores (ISI ≥15 vs. <15) were randomized to receive 10 mg, 20 mg, or 40 mg of seltorexant or placebo once daily adjunctively to antidepressants currently taken. Interestingly, after a period of 6 weeks, newly recruited patients received only 10 or 20 mg of seltorexant or placebo. The 40 mg dose was no longer assigned. The results of the study confirmed the anti-depressive properties of seltorexant. Moreover, the analysis showed a greater improvement in MADRS total score in the seltorexant 20 mg group than in the placebo group at both week 3 and 6. Interestingly, the greater improvement at week 6 was noticed in patients who had had baseline Insomnia Severity Index (ISI) scores ≥ 15 vs. those with ISI < 15. [Pg. 11, 2nd para.].
In the Pre-Clinical Studies on Seltorexant, Ziemichód teaches that the studies used seltorexant as an anti-depressive drug for treating insomnia correlated with major depressive disorder. Ziemichód teaches administration of seltorexant for treating a subject with depression and insomnia symptoms. [Pre-clinical studies ending of pg. 7 – 1st para. of pg. 9]. On these pre-clinical studies, Ziemichód teaches that seltorexant is administered at an oral dose ranging from 1 mg -30 mg specifically 5 mg or 10 mg once daily; 5 mg or 10; 5 mg, 10 mg or 20 mg; and 5 mg, 10 mg, 20 mg or 40 mg. [Pg. 9, Table 2, rows 2, 5, 7 and 4 respectively].
However, Ziemichód does not teach that the subjects had moderate hepatic impairment.
Brooks teaches a method of treating major depressive disorder patients with persistent insomnia by administering seltorexant to twenty male and female patients received a single dose of 10, 20, 40 mg of seltorexant, wherein Latency to persistent sleep was significantly shorter for all doses of seltorexant compared to placebo, total sleep time was significantly longer for all doses of seltorexant compared to placebo, and sleep efficiency was significantly improved, [Abstract]. Brooks teaches that 10 mg is the lowest pharmacologically active dose of seltorexant, [page 204, col. 2, 2nd para.]. Brooks teaches that seltorexant primarily metabolized by cytochrome P450 (CYP) 3A4 and CYP2C9. [page 203, col. 2, 2nd para.].
In the same field of endeavor of treatment of orexin-2 mediated disorders using the administration of an orexin receptor antagonist, Dayal teaches the use of orexin receptor antagonist, Lemborexant, for the treatment of insomnia in adults. Dayal teaches the effects of mild or moderate hepatic impairment on lemborexant pharmacokinetics and metabolism. Dayal teaches that the pharmacokinetics, tolerability, and safety of lemborexant were evaluated in subjects with mild (Child–Pugh class A) or moderate (Child–Pugh class B) hepatic impairment and healthy subjects. Dayal teaches that the subjects received a single oral dose of lemborexant 10 mg, and pharmacokinetics parameters including Cmax and AUC of mild and moderate hepatic impairment were compared to healthy subjects. Dayal teaches that hepatic clearance was decreased by 35% in subjects with moderate hepatic impairment compared to healthy subjects. In view of his studies, Dayal teaches that Lemborexant dose is decreased to 5 mg with subjects with moderate hepatic impairment whereas dose reduction was not required with subject with mild hepatic impairment. [Abstract, and Dayal entire document]. Dayal teaches that the dose of orexin receptor antagonist, Lemborexant was decreased because moderate hepatic impairment had a slightly larger effect on Lemborexant exposure, [Pg. 5, col. 1, 1st para.], geometric mean t1/2 of lemborexant was generally higher in moderate hepatic impairment subjects, [Pg. 7, col. 2, 2nd para.]. Dayal teaches that dose adjustment is supported by the linear PK profile of lemborexant over a wide dose range (up to 25 mg), and the dose restricted to no more than lemborexant 5 mg once daily in patients with moderate hepatic impairment. [Pg. 7, col. 2, 1st para. and last para.].
Moreover, Berger teaches the effect of hepatic impairment on the pharmacokinetics of orexin receptor antagonist, daridorexant. Berger teaches that a single-dose of 25 mg of daridorexant is administered orally to subjects with mild hepatic impairment (Child–Pugh A, N = 8) or moderate hepatic impairment (Child–Pugh B, N = 8). Berger teaches that patients with moderate hepatic impairment had a higher AUC 0-inf, a lower apparent plasma clearance, and the same doubling in the half-life observed for total daridorexant. Berger teaches that moderate hepatic impairment causes impaired hepatic clearance of unbound daridorexant, which prolongs the half-life. A 25-mg dose of daridorexant should, therefore, not be exceeded in Child–Pugh B patients. A dose adjustment is not required in Child–Pugh A patients, while avoidance of daridorexant in patients with Child–Pugh C cirrhosis is recommended. [Abstract]. Berger teaches that patients with moderate hepatic impairment showed a significant increase in AUC 0–inf with a corresponding decrease in CL/F compared with healthy controls. [Pg. 1358, col. 1, 2nd para.].
Weersink teaches dose adjustment for patients with liver cirrhosis as liver cirrhosis can have a major impact on drug pharmacokinetics and pharmacodynamics, and patients with cirrhosis suffer from potentially adverse drug reactions, [Abstract]. Weersink teaches “a reduction or impairment of drug metabolizing enzymes in the liver may cause reduced metabolism. These changes often result in an elevated drug exposure, possibly causing side effects and toxicity. It is also important to consider changes in pharmacodynamics. Hence, the efficacy of drugs could be different in patients with liver cirrhosis. Moreover, patients with cirrhosis are more vulnerable to certain adverse drug reactions (ADRs), such as effects on coagulation or nephrotoxicity” [page 2, col. 1, 1st para.]. Weersink teaches a dose adjustment is necessary for patients with cirrhosis, [page 3, col. 2, last para.].
Moreover, Ozbey teaches that failure to perform adequate dose adjustment in patients with liver cirrhosis associated with increased toxicity. [Abstract]. Ozbey teaches that “in patients with impaired liver function, systemic drug clearance, and/or direct drug elimination into the bile may be impaired, requiring dose adjustment for critical drugs to avoid toxicity” [page 1346, col. 1, 1st para.]. Ozbey teaches procedure for dose adjustment to adapt the CLsys of a specific drug in healthy persons to patients with liver cirrhosis. [page 1348, col. 1, 4th para.].
In view of the foregoing, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to treat orexin-2 mediated disorder i.e., insomnia in a human subject having moderate hepatic impairment by administering seltorexant at a reduced dose of 10 mg daily. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success and pick 10 mg from Ziemichód’s doses because Ziemichód teaches the role of orexin system in treating major depressive disorder and insomnia, teaches the use of the potent and selective orexin receptor antagonist, seltorexant, in treating major depressive disorder and insomnia, and teaches that 10 mg and 20 mg showed greater improvement and confirmed the anti-depressive properties of seltorexant; Brooks teaches administering seltorexant at doses of 10, 20, 40 mg of seltorexant, and teaches that 10 mg is the lowest pharmacologically active dose of seltorexant, [page 204, col. 2, 2nd para.], Brooks teaches that seltorexant primarily metabolized by cytochrome P450 (CYP) 3A4 and CYP2C9 [page 203, col. 2, 2nd para.]; Dayal teaches the use of orexin receptor antagonist, Lemborexant, for the treatment of insomnia in adults, and teaches the effect of moderate hepatic impairment on lemborexant pharmacokinetics and metabolism, wherein the dose of orexin receptor antagonist, Lemborexant decreases in the patients with moderate hepatic impairment, Dayal teaches that the dose of Lemborexant, is decreased because the hepatic clearance was decreased by 35% in subjects with moderate hepatic impairment compared to healthy subjects, moderate hepatic impairment had a slightly larger effect on Lemborexant exposure, and geometric mean t1/2 of lemborexant was generally higher in moderate hepatic impairment subjects. Moreover, Berger teaches the effect of hepatic impairment on the pharmacokinetics of orexin receptor antagonist, daridorexant, and teaches that the dose of the orexin receptor antagonist, daridorexant, should not be exceeded in patients with moderate hepatic impairment. Berger teaches that the dose of orexin receptor antagonist, daridorexant, must be restricted in patients with moderate hepatic impairment because patients with moderate hepatic impairment had a higher AUC 0-inf, a lower apparent plasma clearance, the same doubling in the half-life observed for total daridorexant, and the hepatic clearance of unbound daridorexant, which prolongs the half-life. Therefore, one of ordinary skill in the art would reasonably expect similar effects with respect to hepatic function when administering an orexin receptor antagonist, for example, seltorexant, for treating major depressive disorder with insomnia, and would be reasonably motivated to treat patients with moderate hepatic impairment with the lowest active dose of 10 mg.
Furthermore, one of ordinary skill in the art would have been motivated to administer 10 mg, the lowest pharmacologically active dose of seltorexant as taught by Brooks to patient with moderate liver impairment because Brooke teaches that seltorexant primarily metabolized by cytochrome P450 (CYP) 3A4 and CYP2C9; Weersink teaches that dose adjustment is necessary for patients with liver cirrhosis to avoid adverse drug reactions and teaches that liver cirrhosis have a major impact on drug pharmacokinetics and pharmacodynamics due to reduction or impairment of drug metabolizing enzymes in the liver, changes in pharmacodynamics, and changes in the efficacy of drugs could be different in patients with liver cirrhosis [page 2, col. 1, 1st para., page 3, col. 2, last para.], and Ozbey teaches that failure to perform adequate dose adjustment in patients with liver cirrhosis is associated with increased toxicity, and dose adjustment is required to avoid toxicity” [page 1346, col. 1, 1st para.].
As such, claims 1, 6, 7, 10, 12, 32, 37, 42, and 46 are obvious over Ziemichód, Dayal and Berger.
Claims 4 and 35 are met because Ziemichód’s seltorexant meets the limitation of free base seltorexant.
Claims 13 and 39 are met because Ziemichód teaches that seltorexant is administered orally at doses of 5 mg, 10 mg, and 20 mg. [Pg. 9, Table 2].
With regards to claims 3 and 33, Berger teaches that subjects have a Child-Pugh Score of 7, 8, and 9. [Pg. 1353, Table 1].
With regards to claims 11 and 38, Ziemichód teaches that patients with Insomnia Severity Index (ISI) scores (ISI ≥15 vs. <15) were randomized to receive 10 mg, 20 mg, or 40 mg of seltorexant or placebo once daily. [Pg. 11, 2nd para.].
With regards to claims 40-41 and 43-45, Ziemichód teaches that patients with major depressive disorder who had an inadequate response to one to three selective serotonin/serotonin-norepinephrine reuptake inhibitors with Insomnia Severity Index (ISI) scores (ISI ≥15 vs. <15) were randomized to receive 10, 20, or 40 mg of seltorexant or placebo once daily adjunctively to antidepressants currently taken. [Pg. 11, 2nd para.].
§ 103 Rejection over Ziemichód in view of Dayal and Berger, further in view of De Boer
Claims 5, 9, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Ziemichód W, et al. Molecules. 2023 Apr 19;28(8):3575, “Ziemichód”, cited in the PTO-892 dated 04/02/2025) in view of S. Brooks et al. (Journal of Psychopharmacology, 2019, Vol. 33(2) 202-209, “Brooks” cited in the PTO-892), Dayal S, et al. Pharmacol. Res. Perspect. 2021 Apr; 9(2):e00758, “Dayal” cited in the PTO-892 dated 04/02/2025) Berger B, et al. Clin. Pharmacokinet. 2021 Oct; 60(10):1349-1360, “Berger” cited in the PTO-892 dated 04/02/2025). R. Weersink, BMJ Open. 2016 Oct 12;6(10):e012991. “Weersink” cited in the PTO-892), and A. Ozbey et al. (CLINICAL PHARMACOLOGY & THERAPEUTICS, VOLUME 113 NUMBER 6, 2023 (05 April 2023), “Ozbey” cited in the PTO-892) as applied above to claims 11, 3-4, 6-7, 10-13, 32, 33, 35, and 37-46, further in view of P. De Boer et al. (US PG-PUB 2022/0105094 A1, 04/07/2022, “De Boer” cited in the PTO-892 dated 04/02/2025).
The combination of Ziemichód, Brooke, Dayal, Berger, Weersink and Ozbey teaches a method of treating an orexin-2 mediated disorder in a human subject having moderate hepatic impairment by administering about 10 mg seltorexant or a pharmaceutically acceptable salt or hydrate thereof, and wherein the orexin-2 mediated disorder is depression and insomnia.
However, the combination of Ziemichód, Brooks, Dayal, Berger, Weersink and Ozbey does not teach wherein a hydrochloride salt of seltorexant is administered, or wherein the depression is bipolar depression.
De Boer teaches a method of treating a subject suffering from or diagnosed with depression comprising administering to the subject in need of such treatment an effective amount of seltorexant hydrochloride, [Pg. 1, [0007], and claim 7]:
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De Boer teaches that the method of treating depression includes major depressive disorder, persistent depressive disorder, bipolar depression, etc. [Pg. 2, [0021], Pg. 10., [0135]].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to use the method of treating an orexin-2 mediated disorder in a human subject having moderate hepatic impairment taught by Ziemichód, Brooks, Dayal, Berger, Weersink and Ozbey for treating bipolar depression and use seltorexant hydrochloride in place of seltorexant in view of the teachings of De Boer. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because De Boer teaches a method of treating depression and bipolar depression using seltorexant and seltorexant hydrochloride. Therefore, the combination of Ziemichód, Brooks, Dayal, Berger, Weersink and Ozbey in view of De Boer teach the limitations of claims 5 and 9.
§ 103 Rejection over Ziemichód, Dayal and Berger in view of Jurczak
Claims 31 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Ziemichód W, et al. Molecules. 2023 Apr 19;28(8):3575, “Ziemichód”, cited in the PTO-892 dated 04/02/2025) in view of S. Brooks et al. (Journal of Psychopharmacology, 2019, Vol. 33(2) 202-209, “Brooks” cited in the PTO-892), Dayal S, et al. Pharmacol. Res. Perspect. 2021 Apr; 9(2):e00758, “Dayal” cited in the PTO-892 dated 04/02/2025) Berger B, et al. Clin. Pharmacokinet. 2021 Oct; 60(10):1349-1360, “Berger” cited in the PTO-892 dated 04/02/2025). R. Weersink, BMJ Open. 2016 Oct 12;6(10):e012991. “Weersink” cited in the PTO-892), and A. Ozbey et al. (CLINICAL PHARMACOLOGY & THERAPEUTICS, VOLUME 113 NUMBER 6, 2023 (05 April 2023), “Ozbey” cited in the PTO-892) as applied above to claims 11, 3-4, 6-7, 10-13, 32, 33, 35, and 37-46, further in view of E. Jurczak et al. Pharmaceutics, 2020 Oct 11; 12(10):959, “Jurczak” cited in the PTO-892).
The combination of Ziemichód, Brooke, Dayal, Berger, Weersink and Ozbey teaches a method of treating an orexin-2 mediated disorder in a human subject having moderate hepatic impairment by administering about 10 mg seltorexant or a pharmaceutically acceptable salt or hydrate thereof, and wherein the orexin-2 mediated disorder is depression and insomnia.
However, the combination of Ziemichód, Brooke, Dayal, Berger, Weersink and Ozbey does not teach wherein a hydrate of seltorexant is administered.
Jurczak teaches hydrates are of particular interest among solid APIs solvates for several reasons. First, the unique character of the water molecule—its relatively small size and the possibility to form the interactions as both a donor and acceptor of H-bonding, sometimes simultaneously, make it an important “building material” in the field of crystal engineering. Further, from the pharmaceutical point of view, it is a non-toxic substance, in contrast to most of the other organic solvents. Finally, owing to the presence of moisture in the air, spontaneous hydration may occur at any stage of drug production or storage, leading to hydrate formation. [Pg. 2, 2nd para.]. Jurczak teaches that in comparison with anhydrous forms, hydrates are thermodynamically more stable under normal conditions. Hydrates show better compressibility and tabletability than anhydrates, are less affected by wet granulation process, and are less susceptible for the tablet storage conditions like temperature and relative humidity (RH). In such cases, it could be reasonable to find and produce the most stable API hydrate to prevent the form alteration during production or storage. [Pg. 4, 1st para.].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to use the hydrate of seltorexant in the method of treating an orexin-2 mediated disorder in a human subject taught by Ziemichód, Brooks, Dayal, Berger, Weersink and Ozbey in view of the teachings of Jurczak. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because Jurczak teaches the advantages of using hydrates of APIs including the relatively small size and the possibility to form the interactions as both a donor and acceptor of H-bonding, hydrates are non-toxic substance, hydrates are thermodynamically more stable under normal conditions, hydrates show better compressibility and tabletability, are less affected by wet granulation process, and are less susceptible for the tablet storage conditions. Therefore, the combination of Ziemichód, Brooks, Dayal, Berger, Weersink and Ozbey in view of Jurczak teach the limitations of claims 31 and 34.
Response to Argument
Applicant ant argues:
Ziemichód erroneously states that Letavic indicates that seltorexant is metabolized in the liver and shows moderate CYP inhibition.
Examiner response:
Applicant’s arguments with respect to Letavic have been fully considered, and are persuasive. Ziemichód interpreted Letavic’s study in Table 7 as seltorexant is metabolized in the liver, see Ziemichód’s Table 2. However, Letavic Table 7 does not support Ziemichód’s interpretation, thus, the statement is removed from the new 103 Rejection. In the new rejection above, evidence of seltorexant metabolism in the liver is taught by Brooke, see ending of page 6 above.
Applicant argues:
The examiner's premise that all orexin receptor antagonists would be expected to have similar effects on hepatic function is not supported by Berger and Dayal. Dayal discloses that subjects with moderate hepatic impairment should receive a lower dose of 5 mg (as opposed to 10 mg) of lemborexant (Dayal at Abstract). But Berger does not require a dose reduction for patients with mild, moderate, or severe hepatic impairment. Berger teaches: "A 25-mg dose of daridorexant should, therefore, not be exceeded in Child-Pugh B patients. A dose adjustment is not required in Child-Pugh A patients, while avoidance of daridorexant in patients with Child-Pugh C cirrhosis is recommended" (FOA at 13, emphasis added). In one case, there is a dose adjustment and in the other there is not. If anything, these references show the need for dose adjustment is not the same for lemborexant and daridorexant. It may be that the Examiner misreads Berger as teaching administration of both 25 mg and 50 mg (see FOA at 13). This is not accurate. Berger clearly indicates that the subjects received 25 mg of daridorexant (Berger at 1349, Abstract, Methods). To the extent 50 mg is mentioned, it is simply said to be one of the doses investigated in phase III studies (id. at 1351, second column), but it is the 25 mg dose that was selected for the Berger study. Not all orexin receptor antagonists will share the same metabolic pathway and require the same dose adjustment for hepatic impairment. Given the structural differences, one would not have a reasonable expectation of similar effects with respect to hepatic function. Applicant subsequently supported this position with documentary evidence of chemical structure of a drug determines its physicochemical properties.
Examiner response:
Applicant's arguments filed have been fully considered but they are not persuasive. The presumption that orexin receptor antagonist, seltorexant requires dose adjustment to 10 mg in patients with moderate hepatic impairment is based on the fact that other orexin receptor antagonists require dose adjustment in patients with moderate hepatic impairment. Case law has established that it is prima facie obvious to substitute one known element for another to obtain predictable results. KSR Int'I Co. v. Teleflex, Inc., 550 U.S. 398 (2007). One of ordinary skill in the pharmaceutical art would reasonably predict that seltorexant would require dose adjustment in patients with moderate hepatic impairment. Note that obviousness does not require absolute predictability, instead, at least some degree of predictability, is required. MPEP § 2143.02(II). One of ordinary skill in the art having access to the teachings of Dayal and Berger would understand that patients with moderate hepatic impairment should be administered reduced doses of orexin receptor antagonists, and therefore, would reasonably administer a reduced dose, for example 10 mg (i.e., pick 10 mg from Ziemichód’s doses of 10 mg, 20 mg or 40 mg) for treatment of a human subject having normal hepatic function. Note that the orexin receptor antagonists Lemborexant and daridorexant are not referenced for structural similarity to seltorexant but rather, for their functional similarity, as orexin receptor antagonists. Note that it is not necessary for all orexin receptor antagonists to have the same therapeutically effective amount. It is well known in the art that the therapeutically effective amount of an active agent depends on many factors, one of which is the potency. One would not expect that all orexin receptor antagonists have the same potency and same therapeutically effective amount. Lemborexant dose decreases form 10 mg to 5 mg in patients with moderate hepatic impairment. Berger teaches that Moderate hepatic impairment causes impaired hepatic clearance of unbound daridorexant, which prolongs the half-life. A 25-mg dose of daridorexant should, therefore, not be exceeded in Child–Pugh B patients. A dose adjustment is not required in Child–Pugh A patients, while avoidance of daridorexant in patients with Child–Pugh C cirrhosis is recommended. [Abstract]. Thus, skilled artisan in pharmaceutical science would clearly know that dose adjustment does not means the doses of lemborexant and daridorexant (and seltorexant) will be adjusted to the same amount. Nevertheless, each drug is adjusted from its therapeutically active amount to a lower dose when the drug is administered to a subject with moderate hepatic impairment. Therefore, one of ordinary skill in the art would have been motivated by Dayal and Berger to administer antagonist of human OXR-2, seltorexant to a subject of moderate hepatic impairment at a reduce dose of 10 mg because both Dayal and Berger administer antagonists of human OXR-2 to subject with hepatic impairment at adjusted dose for treating exact same conditions. Furthermore, one of ordinary skill in the art would have been motivated to administer 10 mg, the lowest pharmacologically active dose of seltorexant as taught by Brooks to patient with moderate liver impairment because Brooke teaches that seltorexant primarily metabolized by cytochrome P450 (CYP) 3A4 and CYP2C9; Weersink teaches that dose adjustment is necessary for patients with liver cirrhosis to avoid adverse drug reactions and teaches that liver cirrhosis have a major impact on drug pharmacokinetics and pharmacodynamics due to reduction or impairment of drug metabolizing enzymes in the liver, changes in pharmacodynamics, and changes in the efficacy of drugs could be different in patients with liver cirrhosis [page 2, col. 1, 1st para., page 3, col. 2, last para.], and Ozbey teaches that failure to perform adequate dose adjustment in patients with liver cirrhosis is associated with increased toxicity, and dose adjustment is required to avoid toxicity” [page 1346, col. 1, 1st para.]. While Examiner agreed with the supported evidences that drugs with different chemical structure have different physicochemical properties, Dayal and Berger compounds, lemborexant and daridorexant, despite having different chemical structure, share utility with the claimed seltorexant, i.e., all compounds are antagonist of human OXR-2, for treating the same conditions. Dayal and Berger administered the antagonists of human OXR-2 to subjects with hepatic impairment at adjusted dose (i.e., lower dose), which would motivate one of ordinary skill in the art to administer the antagonist of human OXR-2, seltorexant to a subject with hepatic impairment at a lower dose of 10 mg. See the modified 103 Rejection above.
Applicant argues:
Drug metabolism is complex and unpredictable and does not support the examiner's "class-based" rationale. Applicant cited various references supporting the position that a drug's metabolism, even those in the same class, is unpredictable (see reply filed November 17, 2025 at 8-9). As evidenced by the Liu document, there are many in vivo metabolic pathways. But the "metabolism of drugs in the [gastrointestinal tract] GIT and liver is a complex process. and, generally, drugs experienced complex metabolic reactions under various drug-metabolizing enzymes (especially hepatic drug-metabolizing enzymes) and transporters action." Liu at 2, column 2. Indeed, the unpredictability of drug metabolism, even among drugs with similar mechanisms of action, is well-documented in the literature and the record:
Examiner response:
Applicant's arguments filed have been fully considered but they are not persuasive. The cited references to support unpredictability of drugs metabolism, are acknowledged. The references teaches that drugs of same class/mechanism may have different metabolic mechanism. However, Berger teaches that OXR-2 antagonist, Daridorexant metabolizes by CYP3A4, [page 1357, Discussion, col. 1, 2nd para.]; Dayal teaches that OXR-2 antagonist, lemborexant is primarily metabolized via CYP3A pathway, [page 2, col. 1, last para.]; and Brooks teaches that OXR-2 antagonist, seltorexant primarily metabolized by cytochrome P450 (CYP) 3A4 and CYP2C9 [page 203, col. 2, 2nd para.]. Thus, the cited drugs are OXR-2 antagonists, metabolized by hepatic enzymes CYP, and targeted the treatment of exact same conditions. Therefore, one of ordinary skill in the art would have been motivated to also administer OXR-2 antagonist, seltorexant to a subject having hepatic impairment at a reduced dose of 10 mg for treating OXR-2 mediated disorder e.g., insomnia. Moreover, obviousness does not require absolute predictability, instead, at least some degree of predictability, is required. MPEP § 2143.02(II). See the modified 103 Rejection above.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MANAHIL MIRGHANI ALI ABDALHAMEED whose telephone number is (571)272-1242. The examiner can normally be reached M-F 7:30 am - 5:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H Alstrum-Acevedo can be reached at 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/M.M.A./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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