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 .
All previous objections and rejections not reiterated herein were overcome by claim amendments and arguments, filed June 16th, 2026, have been fully considered and found persuasive. As such all objections and rejections not reiterated herein have been withdrawn.
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.
Claims 54, 57 – 69, 71, and 73 – 74 are rejected under 35 U.S.C. 103 as being over Arabzadeh et. al. ((2018), Does oral administration of ketamine accelerate response to treatment in major depressive disorder? Results of a double-blind controlled trial, Journal of Affective Disorders, 235, 236 – 241; cited on the IDS dated January 10th, 2024) in view of Patent Application Publication US 2013/0236573 A1 to Singh et. al. (herein after Singh’573; cited in the office action dated December 16th, 2025).
Regarding claims 54, 57 – 69, 71, and 73 – 74, Arabzadeh et. al. teach that depression (claim 54) is a common disease with a lifetime prevalence of 20–30% worldwide and a huge burden on the healthcare system (page 236 column 1 paragraph 1). Additionally, Arabzadeh et. al. teach that the slow response along with frequent side effects sometimes cause nonadherence and increase risk of suicide (claim 62)(page 236 column 1 paragraph 1). Thus, Arabzadeh et. al. teach that there seems to be a need for faster and more effective treatments (page 236 column 1 paragraph 1). Furthermore, Arabzadeh et. al. teach that ketamine is an NMDA receptor antagonist and was recently found to exhibit a rapid-onset treatment effect on major depressive disorder (MDD) (claim 65) (page 236 column 2 paragraph 1). Moreover, Arabzadeh et. al. teach that the rapid onset effect was even present in patients with treatment resistant depression (claim 66) (TRD) (page 236 column 2 paragraph 1).
Arabzadeh et. al. teach that in a randomized, placebo-controlled double-blind trial was conducted over 6 weeks (page 237 column 1 paragraph 4), patients received sertraline (150 mg a day) in combination with either 50 mg/day ketamine (claim 64) or placebo (claims 54 and 61) (page 237 column 1 paragraph 6). Furthermore, Arabzadeh et. al. teach that different doses of oral ketamine (claim 54) have been used in previous studies ranging from a fixed dose 0.5 mg/kg or 150 mg/day (page 237 column 1 paragraph 6), to the titrated drug range of from 0.5 mg/kg to 0.7mg/kg or 25–300 mg/day (page 237 column 1 paragraph 6 and column 2 paragraph 1). Moreover, Arabzadeh et. al. teach that the frequency of administration also varies from once daily usage to three times a day (page 237 column 2 paragraph 1). Additionally, Arabzadeh et. al. teach that ketamine prescription started with initial dose (claims 61 and 63) of sertraline and was prescribed at 25 mg twice daily (page 237 column 2 paragraph 1).
Regarding claim 57, limitation for a method where the active pharmaceutical agent, that is ketamine, (ii) at a dose of 120 – 240 mg per day; Arabzadeh et. al. teach that different doses of oral ketamine have been used in previous studies ranging from a fixed dose 0.5 mg/kg or 150 mg/day to the titrated drug range of from 0.5 mg/kg to 0.7mg/kg or 25–300 mg/day. See page 237 column 1 paragraph 6 and column 2 paragraph 1. Moreover, Arabzadeh et. al. teach that the frequency of administration also varies from once daily usage to three times a day. See page 237 column 2 paragraph 1. While the examined claim 57 recites the administration of the active pharmaceutical agent, that is ketamine, at a dose of 120 – 240 mg per day; the instant dosage range overlaps with the prior art range of from 0.5 mg/kg to 0.7mg/kg or 25–300 mg/day. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)(MPEP 2144.05(I)).
However, Arabzadeh et. al. fails to teach a method wherein the second anti-depressant agent is administered subcutaneously, intravenously, or intramuscularly (claim 54). Moreover, Arabzadeh et. al. fails to teach a method wherein the second anti-depressant agent is administered subcutaneously: (i) at a dose of 0. 5-1. 0 mg/kg; and/ or (ii) for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7, weeks, 8 weeks, 9 weeks, 10 weeks, 15 weeks, 20 weeks, 25 weeks, 30 weeks, 35 weeks or 40 weeks (claims 57 and 58). Furthermore, Arabzadeh et. al. fails to teach a method wherein the active pharmaceutical agent is comprised within a composition comprising one or more excipients selected from the group consisting of diluents and lubricants (claim 59). Moreover, Arabzadeh et. al. fails to teach a method wherein the composition comprises lactose monohydrate, magnesium stearate, and/or microcrystalline cellulose (claim 60). However, Arabzadeh et. al. fails to teach a method comprising a subcutaneous or intravenous second anti-depressant agent wherein the second anti-depressant is an enantiomer of ketamine (claims 67 and 71). Moreover, Arabzadeh et. al. fails to teach a method wherein the second anti-depressant agent is administered at a dose of 0. 5-1. 0 mg/kg (claim 73) once a week for three to four weeks (claim 68).
Nevertheless, Singh’573 teach a method for the treatment of treatment -refractory or treatment resistant depression comprising administering to a patient in need thereof a therapeutically effective amount of esketamine and at least one antidepressant (page 2 paragraph 0014). Furthermore, Singh’573 teach that esketamine is another name for the S-ketamine enantiomer (claim 54) (page 1 paragraph 0006). Moreover, Singh’573 teach that pharmaceutical compositions for the treatment of treatment-refractory or treatment-resistant depression (TRD) containing esketamine, optionally in combination with one or more antidepressants, with a pharmaceutically acceptable carrier (page 5 paragraph 0055).
Additionally, Singh’573 teach that pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques (page 6 paragraph 0055) and that the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral) (page 6 paragraph 0055). Singh’573 teach that for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents (claim 59), granulating agents, lubricants (claim 59), binders, disintegrating agents and the like (page 5 paragraph 0056). More specifically, Singh’573 teach that suitable binders for oral administration to form a tablet or capsule, include magnesium stearate (claim 60) (page 6 paragraph 0061). Furthermore, Singh’573 teach that suitable pharmaceutically acceptable carriers are well known in the art (page 6 paragraph 0063).
Additionally, Singh’573 teach that where the esketamine and the antidepressant(s) are administered in separate dosage forms, the number of dosages administered per day for each compound may be the same or different and that esketamine and the antidepressant(s) may be administered via the same or different routes of administration (page 4 paragraph 0048). Singh’573 teach that suitable methods for administration include oral, intravenous (iv), intranasal (in) intramuscular (im), subcutaneous ( sc ) (claims 67 and 71), transdermal, and rectal (page 5 paragraph 0048). Furthermore, Singh’573 teach that the optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound or compounds used, the mode of administration, the strength of the preparation and the advancement of the disease condition (page 5 paragraph 0049).
Additionally, Singh’573 teach that the pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful, and the like, of from about 0.01 mg to about 1000 mg or any amount or range therein, and may be given at a dosage of from about 0.01 mg/kg to about 1.5 mg/kg (claims 58, 68 and 73) (page 5 paragraph 0056). Moreover, Singh’573 teach that the dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed (page 5 paragraph 0056). Also, Singh’573 teach that the use of either daily administration or post-periodic dosing may be employed (page 5 paragraph 0056).While instant claim recites the administration of the active pharmaceutical agent, that is ketamine, at a dose of 0.5 – 1.0 mg per day; the instant dosage range overlaps with the prior art range of from 0.01 mg/kg to 1.5 mg/kg. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)(MPEP 2144.05(I)).
While instant claims 68 and 73 recite the administration of the active pharmaceutical agent, that is ketamine, at a dose of 0.5 – 1.0 mg per day; the instant dosage range overlaps with the prior art range of from 0.01 mg/kg to 1.5 mg/kg. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)(MPEP 2144.05(I)). In regards to claim 68, recitation for a method wherein once a week for three to four weeks (claim 68). While the prior art is silent about the 3-to-4-week duration, Signh’573 teach that the dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed (page 5 paragraph 0056). Thus Signh’573 suggest that the dosage regimen is highly optimizable and within the purview of one of ordinary skill in the art to determine.
Moreover, the prior art of Arabzadeh et. al. and Signh’573 teach that separately ketamine and esketamine were beneficial for the treatment of depressive disorders including treatment -refractory or treatment resistant depression. Since the prior art taught the usefulness of these two compounds separately for the treatment of depressive disorders it would have been obvious to combine both treatments into a single treatment regimen with the expectation that the combination treatment would be reasonable as beneficial as the monotherapy treatments.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Arabzadeh et. al. that for the administration of the active pharmaceutical ketamine in combination with the second anti-depressant in view of Singh’573, that is to administered the second anti-depressant, that is esketamine subcutaneously at a dosage of 0.5 – 1.0 mg/kg. One of ordinary skill in the art would have been motivated to make this modification since both ketamine and esketamine have been shown to be useful in the treatment of treatment resistant depression. One of ordinary skill in the art would have had a reasonable expectation of success because as taught above both ketamine and esketamine are known to treat treatment resistant depression and both compounds can be formulated for administration as an oral tablet and as an injectable.
Moreover as taught above the formulation and combination can be readily determined by those skilled in the art, and will vary with the particular compound or compounds used, the mode of administration, the strength of the preparation and the advancement of the disease condition. Furthermore, one of ordinary skill in the art would have been motivated to make this modification as an alternative dosage form. One of ordinary skill in the art would have had a reasonable expectation of success because may be readily determined by those skilled in the art and will vary with the particular compound or compounds used, the mode of administration, the strength of the preparation and the advancement of the disease condition.
Claims 70, and 72 are rejected under 35 U.S.C. 103 as being unpatentable over Arabzadeh et. al. ((2018), Does oral administration of ketamine accelerate response to treatment in major depressive disorder? Results of a double-blind controlled trial, Journal of Affective Disorders, 235, 236 – 241; cited on the IDS dated January 10th, 2024) and Patent Application Publication US 2013/0236573 A1 to Singh et. al. (herein after Singh’573; cited in the office action dated December 16th, 2025) as applied to claims 67 – 69, 71, and 73 above, further in view of European Patent Application EP 3501542 A1 to Canuso et. al. (herein after Canuso’542; cited in the office action dated December 16th, 2025).
The teachings of Arabzadeh et. al. and Singh’573 as it relates to claims 67 and 70, from which claims 70, and 72 depend, is given previously in this office action and are fully incorporated here.
However, the prior art of Arabzadeh et. al. and Singh’573 fail to teach a method where the active pharmaceutical agent is administered at a dose of 120 – 240 mg per day, once a week for between 1 and 8 weeks and then twice a week thereafter (claim 70). Moreover, the prior art Arabzadeh et. al. and Singh’573 fail to teach a method comprising: first bringing the depressive disorder into remission using the oral dose of the active pharmaceutical agent combined with the subcutaneous or intravenous dose of the second antidepressant agent; and then maintaining the depressive disorder in remission by administering a further oral dose of the active pharmaceutical agent to the subject (claim 72).
Nevertheless, Canuso’542 teach methods for the treatment of depression which includes major depressive disorder and treatment resistant depression (page 8 paragraph 0026). Moreover, Canuso’542 teach methods of maintaining stable remission (claim 72) or stable response following the administration of a therapeutically effective amount of esketamine during an initial administration phase followed by at least five months of a subsequent administration phase (claim 72) (page 8 paragraph 0028). Canuso’542 teach that one skilled in the art will recognize that the maintenance phase described herein may continue until further treatment is not required and as indicated by, for example, prolonged remission of the depression (including for example, the remission of one or more symptoms associated with depression), social and/or occupational functional improvement to normal or premorbid levels, or other known measures of depression (page 15 paragraph 0084). Moreover, Canuso’542 teach that the antidepressant would be dosed as labeled for the treatment of major depressive disorder (MDD), in a manner appropriate for the patient's condition/health (page 16 paragraph 0089).
Additionally, Canuso’542 teach that the disclosed methods include administering esketamine
in one or two phases, i.e., an initial induction phase, and optionally in certain circumstances a maintenance phase (page 16 paragraph 0088). Furthermore, Canuso’542 teach that the induction phase should be about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, most preferably about 4 weeks (page 16 paragraph 0088). Canuso’542 also teach an embodiment wherein the patient has not responded to at least two oral antidepressants in the current depressive episode, the patient may be administered esketamine at least twice weekly solely with esketamine or along with a first oral antidepressant that is the same or different than the previously ineffective oral antidepressant in a first induction phase (page 16 paragraph 0091).
While the prior art of Canuso’542 fails to explicitly teach the administration of a dose of 120-240 mg per day once a week for 1 and 8 weeks and then twice a week thereafter (claim 70); the prior art does teach the administration of the esketamine in a series of phases that are dependent on the induvial patients’ response. Moreover, as taught above, Canuso’542 teach that the antidepressant would be dosed as labeled for the treatment of major depressive disorder (MDD), in a manner appropriate for the patient's condition/health (page 16 paragraph 0089). Thus Canuso’542 suggest that the dosage amount and frequency/duration are highly optimizable and patient dependent. Hence as established by the prior art of Arabzadeh et. al., Singh’573, and Canuso’542 it would have been within the purview of one of ordinary skill in the art to use the information taught, to optimize for the appropriate dosage regime and frequency.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Arabzadeh et. al. and Signh’573 for the administration of the active pharmaceutical ketamine in combination with the second anti-depressant is esketamine in view of Canuso’542 that is wherein the active pharmaceutical agent is administered at a dose of 120 – 240 mg per day, once a week for between 1 and 8 weeks and then twice a week thereafter maintaining the depressive disorder in remission. One of ordinary skill in the art would have been motivated to make this modification to improve and maintain the mental health of the subject until complete remission. One of ordinary skill in the art would have had a reasonable expectation of success because the prior art teach that the dosage range and frequency are highly optimizable and within the purview of one of ordinary skill in the art.
Claims 75 – 77 are rejected under 35 U.S.C. 103 as being unpatentable over Arabzadeh et. al. ((2018), Does oral administration of ketamine accelerate response to treatment in major depressive disorder? Results of a double-blind controlled trial, Journal of Affective Disorders, 235, 236 – 241; cited on the IDS dated January 10th, 2024) and Patent Application Publication US 2013/0236573 A1 to Singh et. al. (herein after Singh’573; cited in the office action dated December 16th, 2025) as applied to claims 54, 57 – 69, 71, and 73 – 74 above, further in view of National Center for Biotechnology Information (NCBI), PubChem Open Chemistry Database, ((2016 April 9) Esketamine. Compound Summary for CID 182137, Esketamine. Archived by the Internet Archive on 2016, April 9. https://web.archive.org/web/20160409221209/http://pubchem.ncbi.nlm.nih.gov/compound/182137) and as evidenced by Moss ((1996), Basic Terminology of Stereochemistry, Pure & Appl. Chem., 68, 2193 – 2222).
The teachings of Arabzadeh et. al. and Singh’573 as it relates to claims 54, 67 and 71, from which claims 75 – 77 depend, is given previously in this office action and are fully incorporated here.
However, the prior art of Arabzadeh et. al. and Singh’573 fail to teach a method where the active pharmaceutical agent and the second anti-depressant agent are independently selected from
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(claims 54, 67, and 71).
Nevertheless, NCBI teach that the chemical structure for esketamine is
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where the amine is on a wedge bond. See page 1.
Regarding claims 75 – 77 limitations for a method where the active pharmaceutical agent and the second anti-depressant agent are independently selected from
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; as evidenced by Moss chemical structures drawn with plain lines do not depict stereochemistry but bonds that are approximately in the plane. See page 2195. Given that the skill of one of ordinary skill in the art is relatively high being that of a PharmD or PhD it would have been obvious to such artisan that esketamine represents a stereoisomer of ketamine and is encompassed with the chemical structure as recited in claims 75 – 77. Thus, the structure as recited in the claim encompasses both the R and S stereoisomers of ketamine and would thus include esketamine.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Arabzadeh et. al. and Signh’573 for the administration of the active pharmaceutical ketamine in combination with the second anti-depressant is esketamine in view of NCBI where the compound is
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. One of ordinary skill in the art would have been motivated to make this modification because the structure of
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lack specific stereochemistry and would thus include ketamine and the R/S stereoisomers of ketamine. One of ordinary skill in the art would have had a reasonable expectation of success because the prior art teach both ketamine and its S-stereoisomer esketamine are effective in treating depressive disorders.
Response to Arguments
Applicant’s arguments and claim amendments, see Applicant’s remarks pages 9 – 10, filed June 16th, 2026, with respect to prior art rejections of claims 54, and 57 – 77 have been fully considered and were persuasive thus the prior art rejections were modified in view of the claim amendments.
Applicant argues that as amended the prior art of Arabzadeh et. al. and Singh’573 does not fail to teach or render obvious the method of the claims as newly amended. See applicant remarks page 9 paragraphs 4 – 5.
The examiner contends that 103 rejections have been amended to address the claims as newly amended. As taught above in the rejection, the prior art of Arabzadeh et. al. and Signh’573 teach that separately ketamine and esketamine were beneficial for the treatment of depressive disorders including treatment -refractory or treatment resistant depression. Since the prior art taught the usefulness of these two compounds separately for the treatment of depressive disorders it would have been obvious to combine both treatments into a single treatment regimen with the expectation that the combination treatment would be reasonable as beneficial as the monotherapy treatments.
Applicant argues that the results of example 5 and 6 of the specification demonstrate superior therapeutic effects. See applicant remarks page 10 paragraph 4.
The examiner contends that examples 5 and 6 of the specification show that the administration of ketamine orally in a dosage range of 120 – 240 mg in combination with ketamine subcutaneously administered at a dosage range of 0.5 mg – 1.0 mg kg had an effect in patients diagnosed with treatment resistant depression. See the examined specification page 45 lines 29 – 34, page 46 lines 1 – 35, and page 47 lines 1 – 34. Given that the results presented in the examined specification were not compared to the closet prior art of record, which would be to prior art of Arabzadeh et. al. and Singh’573 for a method combining ketamine with esketamine, there is no showing for secondary considerations.
Conclusion
Claims 54, and 57 – 77 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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