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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/11/2026 has been entered.
Status of the Application
Claims 185-200 and 205-210 are pending.
Receipt and consideration of Applicants' amended claim set and remarks/arguments filed on 03/11/2026 are acknowledged. Claims 187-188, 190, and 192-198 remain withdrawn, as being drawn to an unelected invention or specie. Claims 185-200 and 205-208 are amended and new claims 209-210 are added. Claims under consideration in the instant office action are claims 185-186, 189, 191, 199-200, and 205-210.
Applicants' arguments, filed 03/11/2026, have been fully considered but they are not deemed to be persuasive regarding the rejection of claims 185-186,189, 191, 199-200, and 205-208 under 35 U.S.C. 103. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 (i.e., changing from AIA to pre-AIA ) 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.
Claims 185, 199, and 205-210 are rejected under 35 U.S.C. 103 as being unpatentable over Murrough (WO 2016/172672, as disclosed in IDS) in view of Schalkwyk et al. (Acute psychoactive effects of intravenous ketamine during treatment of mood disorders: Analysis of the Clinician Administered Dissociative State Scale, Journal of Affective Disorders, 2018, 227, pp. 11-16) and Fu et al. (Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation with Intent: Double-Blind, Randomized Study (ASPIRE I), J. Clin. Psychiatry, 2020, 81(3), pp. e1-e9).
Murrough teaches a method of rapidly treating suicidal ideation in a patient comprising the administration of ketamine (i.e. racemic ketamine) (see abstract). Murrough teaches administration “once a day, three times per week on days 1, 3 and 5, for a treatment period of two weeks.” (Example 3). Murrough teaches a dosage range of 1.0 – 1.5 mg/kg, resulting in a range of 70 – 105 mg (see Example 1, pg. 15, last paragraph). Murrough teaches that such dosages are effective to reduce or eliminate suicidal ideations in less than 8 hours in most instances and often in less than two hours (pg. 12, first paragraph). Murrough teaches intranasal administration (pg. 14). Murrough teaches intranasal administration (pg. 9, first paragraph). Murrough teaches that “The effectiveness of ketamine in reducing suicidal ideation can be measured using any of the available scales for scoring a patients suicidality-including for example the suicide item of the Montgomery-Asberg Depression Rating Scale (MADRS-SI) or the Columbia-Suicide Severity Rating Scale (C-SSRS). Prior to beginning ketamine therapy for suicidal ideation the patient is tested using one of the standard suicidality rating scales.” (pg. 9, bridging paragraph). Regarding claim 210, Murrough teaches that “a growing body of literature supports the rapid antidepressant effect of ketamine in patients with treatment resistant depression (TRD), and major depressive disorder (MDD) and bipolar disorder.” (pg. 4, 1st paragraph). As a consequence it would follow that a goal of one of ordinary skill in the art would be the improvement of a patient’s MADRS score within hours of administering ketamine.
Murrough does not teach identifying the subject as having a Clinician Administered Dissociative States Scale (CADSS) of 0-2 units and a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score from 35-60 units.
Schalkwyk et al. is drawn towards the psychoactive effects of intravenous ketamine during treatment of mood disorders using the CADSS (see abstract). Schalkwyk et al. teaches that patients had a mean score of 6.2, and that 25% of participants had scores of 0 (pg. 14, left column, first paragraph). Schalkwyk et al. teaches that participants with low CADSS scores did experience prominent acute psychoactive effects (pg. 15, left column, fourth paragraph).
Fu et al. is drawn towards the use of an esketamine nasal spray for the treatment of MDD symptoms, including suicidal ideation (see abstract). Fu et al. teaches eligibility criteria of the study to include having a MADRS total score greater than 28 predose on day 1 (pg. e2, left column, second paragraph). As a consequence it would follow that one of ordinary skill in the art would not administer esketamine to a patient with MDD wherein their MADRS score is below 28 since they were excluded from eligibility as taught by Fu et al. above. Fu et al. teaches that patients favored esketamine among patients with prior suicide attempt and more severed depressive symptoms, wherein the MADRS total score is greater than the median (pg. e4, right column, first paragraph). Fu et al. teaches monitoring adverse events, vital signs, and scores for clinician-reported outcomes as assessed through CADSS (pg. e3, right column, 6th paragraph).
It would have been obvious to one of ordinary skill in the art to identify the subject as having a Clinician Administered Dissociative States Scale (CADSS) of 0-2 units and a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score from 35-60 units, as suggested by Schalkwyk et al. and Fu et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to select a subject as having a Clinician Administered Dissociative States Scale (CADSS) of 0-2 units since patients with a low CADSS score do experience prominent acute psychoactive effects as taught by Schalkwyk et al. (pg. 15, left column, fourth paragraph), with a reasonable expectation of success absent evidence of criticality of the particular steps.
One of ordinary skill in the art would have been motivated to select a patient with a MADRS score of 35-60 units since Fu et al. teaches a MADRS greater than 28 as an eligibility criterion, and that patients with suicidal ideation having a higher MADRS score favor esketamine, with a reasonable expectation of success absent evidence of criticality of the particular steps.
Even though the range for the MADRS score as taught by Fu et al. is not the same as the claimed MADRS score, Fu et al. does teach an overlapping range of MADRS score, and it has been held that 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). See MPEP § 2144.05(I). Furthermore, the determination of MADRS score is well within the purview of those skilled in the art through routine experimentation, and it has been held that “it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP § 2144.05(II). It would have been obvious to one of ordinary skill in the art to optimize the MADRS score in order to select the appropriate patient population.
The amounts of active agents to be used, the pharmaceutical forms, e.g., tablets, etc; mode of administration, flavors, surfactant are all deemed obvious since they are all within the knowledge of the skilled pharmacologist and represent conventional formulations and modes of administration.
Furthermore, no unobviousness is seen in the ratio claimed because once the usefulness of a compound is known to treat a condition, it is within the skill of the artisan to determine the optimum ratio.
When the composition recitations are met, the desired properties are met, as any component that materially affects the composition and its properties would have to be present in the claim to be commensurate in scope (e.g. claims 185, 205, 209). Additionally, when the composition is delivered in the same manner as claimed, the effects of the composition would be the same such as the therapeutic profile, as they are a direct result of the components of the composition and the mode of administration which are met by the art, whereby the resulting properties and effects would intrinsically be met. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. The court held that when a "‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention." Id. However, the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). (MPEP 2111.04 I).
Claims 186, 189, 191, and 200 are rejected under 35 U.S.C. 103 as being unpatentable over Murrough (WO 2016/172672, as disclosed in IDS), Schalkwyk et al. (Acute psychoactive effects of intravenous ketamine during treatment of mood disorders: Analysis of the Clinician Administered Dissociative State Scale, Journal of Affective Disorders, 2018, 227, pp. 11-16), and Fu et al. (Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation with Intent: Double-Blind, Randomized Study (ASPIRE I), J. Clin. Psychiatry, 2020, 81(3), pp. e1-e9 as applied to claims 185, 199, and 205-210 above, and further in view of Charney et al. (WO 2007/111880, as disclosed in IDS).
The teachings of Murrough, Schalkwyk et al., and Fu et al. are presented above.
Murrough, Schalkwyk et al., and Fu et al. do not teach further administering an antidepressant.
Charney et al. is drawn towards the intranasal administration of ketamine to treat depression (see abstract). Charney et al. teaches “Depression is characterized by depressed mood, and markedly diminished interest or pleasure in activities. Other symptoms include significant w:eight Joss or weight gain, decrease or increase in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate or indecisiveness, recurrent thoughts of death, suicidal ideation or suicidal attempts.” (paragraph 0005). Charney et al. teaches “The limitations in sustaining disorder remission are increasingly apparent for standard treatments of treatment-resistant depression. The first phase of the STAR*D study, the largest effectiveness study of its kind in "real world" patients, measured the efficacy of a SSRI, citalopram, in outpatients with depression (n=2,876). Remission rates were 28%, a similar remission rate to that achieved in standard randomized placebo-controlled acute efficacy trials [48]. As the presence of residual symptoms is a strong predictor of relapse or recurrence [ 49), therapeutic strategies going forward require a focus on achieving and sustaining remission, by presumably addressing core pathophysiological processes.” (paragraph 0014).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to further administer an antidepressant, as suggested by Charney et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since it is prima facie obvious to combine components known for the same purpose for their combined additive effects, with a reasonable expectation of success absent evidence of criticality of the particular formulation. Additionally, “[T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Therefore, it would have been prima facie obvious to combine ketamine and citaprolam in a composition cojointly to treat suicidal ideation.
Response to Arguments
Applicant's arguments filed 03/11/2026 have been fully considered but they are not persuasive.
Applicant argues that “one of ordinary skill in the art would not have been motivated to combine the teachings of Murrough, which is silent with respect to the claimed patient population of subjects having a CADSS total score of O, 1, or 2 units and a MADRS total score from 35-60 units, with Fu, which is directed to the use of esketamine not racemic ketamine, to arrive at the presently claimed methods.” The Examiner respectfully disagrees since Murrough does teach a method of treating suicidality comprising administering ketamine generally (claim 1), which would read on racemic mixtures of ketamine. Murrough thus reads on the active steps of the claimed invention, wherein racemic ketamine is a drug known for the treatment of suicidal ideation. Thus, the only difference between Murrough and the limitations of the claimed invention is the assessment of the specific CADSS and MADRS scores of the patient population. However, given the teachings of Schalkwyk et al. and Fu et al. as discussed above, it would have been obvious to one of ordinary skill in the art to assess the particular CADSS and MADRS score of patients with suicidal ideation for treatment with ketamine.
Applicant also argues that “Murrough and Fu, when viewed alone or in combination, do not have provide support for predictable results with a reasonable expectation of success as the references do not teach the claimed patient population and treatment resulting in a CADSS score of equal or less than 4 at 40 minutes post intranasal administration.” The Examiner respectfully disagrees since there would be a reasonable expectation of success given that Murrough teaches a method of treating suicidal ideation in a patient wherein ketamine was administered at a dosage of 0.5 mg/kg (30 mg based on average weight of 70 kg) (Example 3). Murrough teaches administration “once a day, three times per week on days 1, 3 and 5, for a treatment period of two weeks.” (Example 3). Murrough teaches intranasal administration (pg. 14). The teachings of Murrough thus read on the active steps of the claimed invention, and when the composition recitations are met, the desired properties are met, as any component that materially affects the composition and its properties would have to be present in the claim to be commensurate in scope (i.e. claim 205). Additionally, when the composition is delivered in the same manner as claimed, the effects of the composition would be the same such as the therapeutic profile, as they are a direct result of the components of the composition and the mode of administration which are met by the art, whereby the resulting properties and effects would intrinsically be met. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. The court held that when a "‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention." Id. However, the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). (MPEP 2111.04 I).
Applicant also argues that “These superior and unexpected results demonstrate that the claimed methods for treating suicidality in this severely depressed patient population produce no clinically meaningful dissociation (i.e. dissociation >4). Avoiding clinically meaningful dissociation reduces patient monitoring requirements, facilitates earlier discharge, and materially changes how and where patients can be treated. These unexpected results indicate a clear clinical and operational advantage for the claimed method of treatment.” The Examiner respectfully disagrees since it would be expected that treating suicidality produces no clinically meaningful dissociation, since Schalkwyk et al. teaches that patients had a mean score of 6.2, and that 25% of participants had scores of 0 (pg. 14, left column, first paragraph). Schalkwyk et al. teaches that participants with low CADSS scores did experience prominent acute psychoactive effects (pg. 15, left column, fourth paragraph).
Conclusion
Claims 185-186, 189, 191, 199-200, and 205-210 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREW P LEE whose telephone number is (571)270-1016. The examiner can normally be reached Monday-Friday 9am-5pm.
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, Renee Claytor can be reached at (571)272-8394. 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.
/ANDREW P LEE/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691