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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/31/2026 has been entered.
Election/Restrictions
Applicant's election with traverse of the following species:
Racemic ketamine as the elected single rapid-acting antidepressant species
Major depressive episode as the elected mood disorder species. Acknowledge is made that the elected major depressive episode is a species of major depressive disorder.
Human subject has a history of non-response to at least one prior antidepressant therapy as the elected human subject species.
Intravenous route as the elected route of administration species.
Co-formulate as a pharmaceutical composition as the elected formulation species
are maintained.
Claims 5-6 and 17 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Expansion of Election of Species Requirement
A reasonable and comprehensive search of the elected species conducted by the Examiner
discover a prior art by Kara et al. that teaches intraperitoneal injection of temrisolimus, reading on peritoneal.; However, it is noted that said prior art does not teach the elected species (intravenous route). In light of this discovery, the search is expanded to the subject matter of route of administering temrisolimus to include peritoneal in addition to the elected intravenous route, such that it does not encompass the full scope of the claims.
Priority
The instant application 18/749,726 filed on June 21, 2024 is a continuation of U.S. Application No. 18/483,225 filed on October 9, 2023, which claims priority to, and the benefits of a divisional of U.S. Application No. 18/049,589 filed on October 25, 2022 (now issued as U.S Patent No. 11,793,794 B2 Published on October 24, 2023), which is a continuation of U.S. Application No. 17/269,470 filed on February 18, 2021 (now issued as U.S. Patent No. 12,090,145 B2 Published on September 17, 2024), which is a 371 of PCT/US2019/047288 filed on August 20, 2019 that claims priority, and the benefits of U.S. Provisional Application No. 62/719,935 filed on August 20, 2018.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on August 31, 2026, wherein claims 1, 4-6, 20, 22 and 30-32 are amended; claims 2-3, 8-9, 11-14, 21, 26-28, 35 are canceled; claims 10, 15-16, 18-19, 23-25, 29, 33-34 and 36-38 are unchanged; and claims 39-42 are newly added.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 4-7, 10, 15-20, 22-25, 29-34, and 36-42 are pending.
Claims 5-6 and 17 remain withdrawn.
Claims 1, 4, 7, 10, 15-16, 18-20, 22-25, 29-34, and 36-42 are under examination in accordance with the elected species along with the expanded species set forth in the Expansion of Election of Species Requirement section above.
Action Summary
Claim 8 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement are withdrawn in view of amendments. Said claim was canceled.
Claims 1, 4, 7-8, 10, 15-16, 18-20, 22-25, and 27-38 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating major depressive disorder in a human subject suffering from the major depressive disorder by administering 6 mg of oral rapamycin 2 hours prior to administering 0.5 mg/kg of intravenous ketamine once every 2 weeks, does not reasonably provide enablement for treating the entire scope of mood disorder instantly claimed in a human subject suffering from said mood disorder comprising administering any therapeutically effective amount of each and every species of RAAD intravenously once every two weeks and a dose of 0.5 mg to 15 mg of temsirolimus intravenously are withdrawn in view of the claim amendments; Upon further consideration, the rejection has been reapplied as necessitated by amendments.
Claims 1, 4, 7-8, 10, 15-16, 18-20, 22-25, and 27-38 rejected under 35 U.S.C. 103 as being unpatentable over Medeiros da Frota Ribeiro et al. (Curr Psychiatry Rep. 2017;19(12):107), in view of Kara et al. (Behavioural Pharmacology. Vol. 29, no. 4: 379-384. Published on June 2018), Nair et al. (J Basic Clin Pharm., 2016. Vol. 7(2): 27-31), Qi et al. (J Neurol Neuromedicine, 2016. Vol. 1(4): 21-24), Bellmunt et al. (Ann Oncol, 2008. Vol. 19(8): 1387-1392), and Di et al. (“Chapter 41: Formulation” in: Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization. 2nd ed. San Diego, CA, USA: Elsevier Science, 2016: 497-510), as evidenced by Andrade (The Journal of Clinical Psychiatry, 2017. Vol. 78, 6: e674-e677; cited in the IDS filed on August 8, 2024) are withdrawn in view of the claim amendments; Upon further consideration, the rejection has been reapplied as necessitated by amendments.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4, 7, 10, 15-16, 18-20, 22-25, 29-34, and 36-42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating major depressive disorder in a human subject suffering from the major depressive disorder by administering 6 mg of oral rapamycin in 2 ounces of orange juice (followed by 4 ounces of water) 2 hours prior to administering 0.5 mg/kg of intravenous ketamine once every 2 weeks, does not reasonably provide enablement for the entire scope of administering a therapeutically effective amount of the claimed rapid-acting antidepressant, and the temsirolimus at the claimed dose for treating a mood disorder in a human subject suffering from said mood disorder. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
I. Legal Standard
The enablement requirement of 35 U.S.C. 112(a) requires the specification to teach a person of
ordinary skill in the art how to make and use the claimed invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and, (8) the quantity of experimentation necessary. No single factor is dispositive, and the factors must be weighed together. MPEP 2164.01(a).
The specification need not exemplify every embodiment within the claim(s). Nevertheless, the
disclosure must enable the full scope of the invention as defined by its claims. The more extensive the
claimed genus and the less predictable the art, more guidance and representative disclosure may be
required. MPEP 2164.08.
The existence of some inoperative embodiments does not necessarily render a claim non- enabled. The relevant is whether the specification and the knowledge in the art permit the skilled artisan to distinguish operative from inoperative embodiments with no more than reasonable
experimentation. Claims encompassing significant number of inoperative embodiments may be non-
enabled when the specification does not identify the operative embodiments and extensive
experimentation would be required to determine which embodiments work. MPEP 2164.08 (b).
Here, the specification identifies treating mood disorder in a human suffering from the mood disorder as the disclosed utility of administering a therapeutically effective amount of a rapid-acting antidepressant and temsirolimus. The issue is therefore not simply based upon whether the claimed rapid-acting antidepressant and the claimed temsirolimus can be administered to humans. Rather, the issue is whether a skilled artisan, using the disclosure and the knowledge existing in the art, could use the full claimed genus for the disclosed mood disorder treatment purpose without conducting an undue experimentation.
The subject matter considered enabled treating major depressive disorder in a human subject suffering from the major depressive disorder by administering 6 mg of oral rapamycin 2 hours prior to administering 0.5 mg/kg of intravenous ketamine once every 2 weeks. However, the rejection is directed to the substantially broader unexplored portions of the method genus, and all of the Wands factors have been considered and discussed below:
II. Detailed analysis under Wands factors
(1, 5) The breadth of the claims and the Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
These factors weigh strongly against enablement of the full scope. In the present case, instant amended claim 1 recites a method encompasses administering a therapeutically effective amount of a rapid-acting antidepressant or a pharmaceutically acceptable salt, solvate, or tautomer thereof, or mixtures thereof; and temsirolimus, or a pharmaceutically acceptable salt, solvate, enantiomer, or tautomer thereof, or mixtures thereof, wherein the temsirolimus is administered at a dose of 0.5 mg to 10 mg, useful in treating a mood disorder in a human subject suffering from the mood disorder selected from the group consisting of major depressive disorder (MDD), major depressive episode in bipolar disorder (bipolar depression), persistent depressive disorder (dysthymia), disruptive mood dysregulation disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, anxiety disorder, and post-traumatic stress disorder. The claimed rapid-acting antidepressant is drawn to at least one of racemic ketamine, or a pharmaceutically acceptable salt, solvate, or tautomer thereof; (R)-ketamine, or a pharmaceutically acceptable salt, solvate, or tautomer thereof; or (S)-ketamine, or a pharmaceutically acceptable salt, solvate, or tautomer thereof. The dependent claims further encompass specific human subject populations, mood disorder species, sequence of administration, formulations (e.g., co-formulated), dosages, and routes of administration.
Instant amended claim 30 also recites a method encompasses administering a therapeutically effective amount of a rapid-acting antidepressant or a pharmaceutically acceptable salt, solvate, or tautomer thereof, or mixtures thereof; and temsirolimus, or a pharmaceutically acceptable salt, solvate, enantiomer, or tautomer thereof, or mixtures thereof useful for the same purpose as set forth in amended claim 1, except said claim 30 requires the temsirolimus to be administered at a dose of 0.5 mg to 5 mg. The dependent claims further encompass specific human subject populations, sequence of administration, formulations (e.g., co-formulated), dosages, and routes of administration.
The breadth of the claims is substantial. The claims permit independent selection of at least one of the listed rapid-acting antidepressants and combined with the temsirolimus at a particular dosing; encompassing numerous formulations, distinct sequence and timing of administration, distinct route of administration, dosages, numerous mood disorders with different etiologies and patient populations, including major depressive disorder and post-traumatic stress disorder.
The specification provides no working examples demonstrating the administration of temsirolimus and ketamine; Instead, the examples cluster around the use of oral rapamycin and intravenous ketamine detailed as follows. Particularly, the working example is directed to treating major depression in human patients who have a history of non-response to at least one prior antidepressant trial, with a different combination that uses a single 6 mg oral dose via oral solution of rapamycin (in 2 ounces of orange juice, followed by 4 ounces of water) approximately two hours prior to 0.5 mg/kg of ketamine infused intravenously over 40 minutes, with a total of two ketamine infusion separated by at least two weeks. The disclosure does not provide guidance demonstrating the temsirolimus, when combined with ketamine, gives predictive therapeutic effect through the entire scope of the claimed mood disorders.
The invention pertains to administering the rapid-acting antidepressant together with temsirolimus to a human subject with a mood disorder, thereby treating said mood disorder. Such utility depends not merely upon the presence of at least one rapid-acting antidepressants and temsirolimus being admisnitered, but upon the combined influence of the sequence and timing of administration, dosing, formulation, route of administration, and the type of mood disorder being treated in the human subject population. The claims permit extensive alterations to the sequence and timing of administration, dosing, formulation, route of administration. The nature of the invention therefore depends on whether administering a therapeutically effective amount of at least one of the rapid-acting antidepressants and the temsirolimus at the claimed dose range can satisfy the method genus of treating the full scope of the claimed mood disorder.
(2) the state of the prior art
As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains”.
This factor weights against enablement to a degree.
At the time the application was filed, the state of the art demonstrates that racemic ketamine and temsirolimus, individually, exhibits antidepressant activity. Specifically, Zanos et al. (CNS Drugs, 2018. Vol. 32(3): 197–227; cited in the previous Office Action) reports ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, is the prototype rapid-acting antidepressant with multiple clinical trials supporting its robust effects in major depressed patients (see e.g., p. 5, second paragraph); and Kara et al. (Behav Pharmacol, 2018. Vol. 29(4):379-384; cited in the previous Office Action) reports temsirolimus is a mTOR inhibitor and water-soluble rapamycin analog that can successfully reduce depression-related immobility in ICR mice, which is routinely utilized in modeling depression (see e.g., abstract; p. 380, left column, 1st paragraph).
The state of the art also demonstrates that mTOR inhibitor rapamycin administered at a specific sequence and timing abolished the antidepressant actions of ketamine, whereas at other sequence and timing does not affect the antidepressant actions of ketamine. Specifically, Li et al. (Science, 2010. Vol. 329(5994): 959–964; cited in the IDS filed on August 8, 2024, cited no. 10) reports a selective mTOR inhibitor rapamycin intracerebroventricular (ICV) infused 30 minutes prior to 10 mg/kg of intraperitoneal ketamine completely abolished the antidepressant actions of ketamine in all three tests (see e.g., Fig. 2-3; p. 3, line 1-4); whereas Autry et al. (Nature, 2011. Vol. 475(7354): 91-5) reports mice pre-treated with rapamycin (1.0 mg/kg, i.p.) for 1 hour and 30 minutes with ketamine (3.0 mg/kg i.p.) does not affect the antidepressant responses and concludes that the mTOR’s role in antidepressant effect of ketamine maybe one of maintenance rather than rapid induction (see e.g., Supplementary figure 11; p. 93, left column, last paragraph to right column, 1st paragraph).
The state of the art also demonstrates racemic ketamine can be split into two individual enantiomers: (S)-ketamine and (R)-ketamine; and administering (S)-ketamine immediately after the administration of mTOR inhibitor rapamycin or AZD8055 block the antidepressant effects, whereas administering (R)-ketamine immediately after the mTOR inhibitor does not affect the antidepressant effects. Specifically, Yang et al. (Biological Psychiatry, 2018. Vol. 83, 1: 18-28; cited in the previous Office Action) reports the mTOR inhibitors (rapamycin and AZD8005) block the antidepressant effects of (S)-ketamine (10 mg/kg, i.p.) in a chronic social defeat stress (CSDS) model of depression, but not (R)-ketamine (10 mg/kg, i.p.) (see e.g., abstract; p. 19, left column, 3rd paragraph).
It is respectfully noted that rapamycin is not the temrisolimus instantly claimed, but they belong to the same art-recognized class of mTOR inhibitor. Each of these references is not relied upon to establish non-enablement by itself; Rather, these references are relied collectively as evidenced that even within the same concept of combining a rapid acting antidepressant and a mTOR inhibitor, the selection of specific enantiomers of rapid acting antidepressant ketamine, the modification made to the sequence, timing and the route of administering these compounds can results in significant or complete loss of antidepressant effect. This evidence not only established what one skilled in the art would have known, at the time the application was filed, about the use of rapid acting antidepressant and mTOR inhibitor together, they are also relevant to the predictability of the art as required under the factors set forth in In re Wands.
The state of the art also demonstrates that mTOR inhibitors have different PK/PD profiles even though they inhibit mTOR pathway via a similar mechanism of action. Particularly, Pal et al. (Cancer Treat Rev, 2013. Vol. 39(7): 709–719) reports temsirolimus and everolimus are structural derivatives of the macrocyclic lactone rapamycin (also known as sirolimus) that inhibits mTOR via similar mechanism of action, the metabolism, formulations, dosing schedules and routes of administration are distinctly different, resulting in varying PK/PD profiles; and explicitly reports temsirolimus is an ester with low oral bioavailability, but as an IV formulation, temsirolimus acts as prodrug which is metabolized to the active compound sirolimus (see e.g., p3, “Rapamycin and its analogs”, 1st paragraph; and p. 6, “PK/PD profiles and mTOR pathway inhibition”, 1st paragraph).
One skill in the art would have known bipolar depression and post-traumatic stress disorder represents two different mental health diagnosis even though the symptoms may overlap, but there are plenty of differences between these two conditions. Specifically, Raypole (“Bipolar Disorder and PTSD: 4 FAQs to Help You Tell Them Apart” [Online]. Healthline) reports post-traumatic stress disorder is categorized under DSM-5 as a trauma- and stressor-related disorder that involves other trauma-specific symptoms that do not overlap with bipolar disorder, including difficulty remembering the trauma, a physical stress response when remembering the trauma (see e.g., p. 1-2, “1. How are bipolar disorder and PTSD different?”); and concludes but treatment for these conditions, i.e., bipolar disorder and PTSD, can take two very different routes (see e.g., p. 8-9, “the bottom line”).
While the art reflects that racemic ketamine and temsirolimus independently demonstrates antidepressant effect, the prior art also demonstrates that administering mTOR inhibitor rapamycin and ketamine at specific sequence and timing abolished the antidepressant effects, and further established that temsirolimus, an ester analog of rapamycin, exhibits varying PK/PD profile such as poor oral bioavailability. In view of the foregoing, the state of the art does not established a generally applicable rule by which a skilled artisan could select arbitrary species of the rapid-acting antidepressant within the present Markush definition and combined it with the claimed temsirolimus, administered these compounds together using any formulations (individual or co-formulated) given at any sequence, timing, and routes of administration, and reasonably predict that said combination would retain asserted utility of treating the full scope of mood disorder, especially armed with the knowledge that the treatment of each mood disorder with non-overlapping symptoms can be very different.
(3) the relative skill of those in the art
As stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed”.
This factor favors Applicant to a degree but does not outweigh the remaining factors.
A person of ordinary skill in the art would likely possess substantial training to conduct experimentations in the field of neuropharmacology and psychiatry, thereby reducing the difficulty in testing the claimed combination of the rapid-acting antidepressant and the temsirolimus (mTOR inhibitor) in a human subject. However, enablement is not evaluated soley on whether conducting a clinical trial for treating the full scope of mood disorder is technically familiar. A skilled artisan’s ability to conduct experiments or clinical trials in humans does not supply the missing predictive guidance concerning which sequence and timing of administration, dosing, formulation, and route of administration as broadly encompassed by the instant claims will possess the disclosed utility of treating the entire scope of the claimed mood disorder. In other words, while the relative skill of those in the art may have the knowledge of conducting research, it does not make the scope enabled where the artisan must discover operable variables, including sequence and timing of administration, through extensive trial-and-error screening.
(4) the predictability or unpredictability of the art
Lastly, the art is highly unpredictable. As noted above, Li et al. demonstrates that mTOR inhibitor rapamycin administered 30 minutes prior to ketamine abolish the antidepressant actions whereas Autry et al. demonstrates mTOR inhibitor rapamycin pretreated for 1 hour and 30 minutes with ketamine does not abolish the antidepressant action. Therefore, the art would not have provided a reasonable expectation of that combining any art-recognized mTOR inhibitor and a species of ketamine, such as individual enantiomer of ketamine, at any sequence, time and routes of administration would exhibit an universal therapeutic effect across the broad genus of mood disorder encompassed by the claims, because one of ordinary skill in the art would be required to conduct extensive search to determine which particular combination, including sequence and timing of administration, dosing, formulation, and route of administration, are predictive for treating the mood disorder genus.
(6, 7, 8) The amount of guidance given, the presence of working example and the quantitation
of experimentation required:
These factors weigh against enablement of the full scope. While the specification describes temsirolimus and rapamycin both belong to the same art-recognized class of mTOR inhibitor, and describes a therapeutically effective amount of said mTOR inhibitor can be administered with a therapeutically effective amount of a rapid-acting antidepressant in the method of treating or preventing a mood disorder in a human subject (see e.g., p. 34, line 10-14; p. 36, line 28-29), the disclosure contains only one working example directed to treating particular mood disorder (major depressive disorder) in a specific patient population (who have a history of non-response to at least one prior antidepressant trial) that is insufficient to supply general predictive rule in identifying which mTOR inhibitor alternative in placed of rapamycin at the dose of 0.5 mg to 10 mg or 0.5 mg to 5 mg can administer with the rapid-acting antidepressant in any formulation through any routes of administration at any sequence, timing, and routes of administration as broadly encompassed by the claims will remain operative for the disclosed mood disorder treatment utility.
Specifically, the specification discloses a single working example (see “Example 1”) that emulates the therapeutic effects of oral rapamycin and ketamine infusion in patients with major depression who have a history of non-response to at least one prior antidepressant trial. The disclosure describes said patients were then treated with a single 6 mg oral rapamycin (in 2 ounces of orange juice, followed by 4 ounces of water) approximately two hours prior to 0.5 mg/kg of ketamine infused intravenously over 40 minutes (see e.g., p. 33); and completed two ketamine infusion test days separated by at least two weeks. The working example shows prolong antidepressant effects for at least 2 weeks following the treatment, reduction in their depressive symptoms as measured by MADRS and QIDS, reduction in anxiety per HAMA (see e.g., p. 33, line 25 to p. 34, line 1).
It is noted that the specification only exemplifies the treatment of a single species of mood disorder (major depressive disorder) in a particular human subject species (patients with major depressive disorder with a history of non-response to at least one prior antidepressant trial), but the instant claims broadly encompasses other mood disorders. The specification only exemplified the method of treating using a different species of mTOR inhibitor, and administered it through a particular route of administration in particular formulation at particular sequence and time, i.e., 6 mg oral rapamycin (in 2 ounces of orange juice) approximately two hours prior to 0.5 mg/kg of intravenous ketamine infusion over 40 minutes; However, the instant claim is drawn to a broad combination genus of temsirolimus and the listed rapid-acting antidepressant, encompassing any sequence and timing of administration, formulations, dosages, and routes of administration.
To practice the full scope of treating mood disorder, substantial experimentation would be required to determine whether temsirolimus can successfully be administered with ketamine at any sequence, timing and routes of administration without abolishing the antidepressant effect of ketamine. A skilled artisan also would have to evaluate pharmacokinetic (PK) and pharmacodynamic (PD) profiles of temriolimus to determine a direct dose conversion between oral rapamycin and temsirolimus administered through each route to establish optimal dose conversion without losing the therapeutic effect. Given the breadth of the claimed genus and the unpredictability of the art surrounding the use of mTOR inhibitor with ketamine together, a skilled artisan would be required to screen numerous untested dosing, sequence, timing and routes of administration to determine which combination thereof would retain the antidepressant effect of ketamine, thereby be useful for treating the full scope of mood disorder. The fact that the specification only provides limited guidance to select temsirolimus as one of the alternated mTOR inhibitor, the task left by the present disclosure is therefore not simply to reproduce the disclosed procedure by replacing rapamycin with another art-recognized mTOR inhibitor, i.e., temsirolimus, and replacing racemic ketmiane with another species of ketamine, such as (S)-ketamine, for reasonable number of times; Rather, it involves extensive experimentation across exceptionally broad method genus.
Conclusion
A skilled artisan therefore would not be able, based upon the specification and ordinary knowledge alone, to use the full scope of the claims for treating a mood disorder without undertaking an extensive research program. Accordingly, the experimentation required is not merely routine confirmation of predictable results, it constitutes undue experimentation directed to discovering which sequence and timing of administration, dosing, formulation, and route of administrations are operative. Therefore, the entire scope of clamed invention is not enabled by the instant specification.
Response to Arguments
Applicant's arguments filed on August 31, 2026 with respect to the scope of enablement rejection of claims 1, 4, 7, 10, 15-16, 18-20, 22-25, 29-34, and 36-42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, have been fully considered but they are not found persuasive for the reasons set forth below.
All rejections pertaining to claims 8, 27-28 and 35 are moot, because these claims are cancelled in view of the amendments filed on August 31, 2026.
In this case, applicant amends claim 1 by deleting the limitations of “the RAAD is administered once every two weeks”, “the RAAD is administered to the human subject intravenously” and “the temsirolimus is administered to the human subject intravenously”; and further adding the limitation of “major depressive episode in bipolar disorder (bipoar depression)” to the list of mood disorder. Applicant further amends claim 30 by adding the limitation of “the RAAD is at least one of: (i) racemic ketamine…(ii) (R)-ketamine… (iii) (S)-ketamine…”, and “major depressive episode in bipolar disorder (bipoar depression)” to the list of mood disorder; further deleting the limitations of “the RAAD is administered to the human subject intravenously” and “the temsirolimus is administered to the human subject intravenously”. Applicant also newly added claims 39-42. Each of these findings demonstrates the amendments change the scope of claims; therefore, the previous rejection has been withdrawn in view of the amendments but reapplied for the reasons set forth herein.
In Summary, applicant asserts no experimentation is required to make and use the invention of amended claims 1 and 3; and argues that even if experimentation might be required, it would not be undue. Applicant argues that a person of ordinary skill in the field of clinical and translational neuropharmacology, psychiatry, and drug development possesses research or clinical experience with sophisticated level of expertise that enable the person to extrapolate the working example in Example 1 to practice the full scope of the claimed invention without undue experimentation.
In response, it may well be true that a person of ordinary skill in the art possesses the baseline scientific and technical knowledge, and substantial training required to conduct routine experiments in their field, thereby allowing the person skilled in the art to conduct experiments in human for the disclosed utility. However, the enablement is not evaluated soley on whether conducting an experiment or clinical trial for treating a mood disorder is technically familiar. A skilled artisan’s ability to conduct experiments or clinical trials in humans does not supply the missing predictive guidance concerning which sequence and timing of administration, dosing, formulation, and route of administration as broadly encompassed by the instant claims possess the disclosed utility of treating mood disorder, based upon the specification and ordinary knowledge alone.
Applicant argues the state of the art are in their favor; and further argues the results from a rodent study cannot be used to demonstrate unpredictability of the art when the claimed invention is drawn to a human subject. Applicant further argues the results presented by Yang et al., which demonstrates mTOR inhibitor (rapamycin and AZD8005) block the antidepressant effects of (S)-ketamine but not the (R)-ketamine, conflicts with the rejection under 35 U.S.C. 103, because the § 112(a) rejection and a § 103 rejection may only coexist if the teachings and suggestions in the art are in conflict with one another. Applicant further argues modern psychiatry recognized that patients with MDD, PTSD, anxiety, and/or dysthymia exhibit synaptic deficits in the prefrontal cortex and dysregulated mTOR signaling; and because the combination of a RAAD and an mTOR inhibitor specifically targets synaptogenesis and glutamate neurotransmission, and the fact that the application as-filed demonstrates patients who received rapamycin with ketamine report significant reduction in their depressive symptoms as measured by the clinician administered MADRS, one skilled in the art would expected the mechanism enabling the treatment of MDD to successfully apply to these related mood and stress disorders. In response, applicant’s arguments specifically against Iadarola et al. and Du et al. cited in the previous Office Action have been fully considered but they are moot because the enablement rejection of record no longer requires these two references to establish the unpredictability of the art. However, with respect to applicant’s assertion that animal studies (e.g., rodent studies) cannot be used to establish predictability or unpredictability of the art when the claims are drawn in humans, the examiner respectfully disagrees. Soley to rebut such assertion, Wang et al. (Prog Neuropsychopharmacol Biol Psychiatry, 2017. Vol. 77: 99-109) teaches when studying major depression disorder, tissue samples like peripheral blood or post-mortem brain samples are used to elucidate underlying mechanisms; and animal models provide a crucial approach to examine neural circuitry and molecular and cellular pathways in a controlled environment (see e.g., abstract). Particularly, manipulations with pharmacological agents and gene editing are accepted methods of studying depression in animal models, which is impossible to employ in human patient studies (see e.g., abstract); and concludes that “animal models that can elucidate the neurobiology of depression, allow the testing of novel neurobiological hypotheses, and have translational value, can be applied in humans” (see e.g., p. 16, 2ns paragraph). In other words, animal studies, for instance, animal models of depression, are conventional and routine in the art to help researchers study the disease biology and test new treatments before human use, and are expected to translate, either direct or indirect, to human situation to a degree. Applicant cannot simultaneously challenge animal studies in the references while admitting that the study of Kara et al. cited above, which reports temsirolimus reduces depression-related immobility in ICR mice in modeling depression, favors them to a degree. Because the results in animal models used to establish what one skilled in the art would have known, at the time the application was filed, would be irrelevant to the claimed invention.
However, to the extent that applicant’s position is accepted and animal studies cannot supply predictability or unpredictability of the art, then applicant has not yet provided any factual evidence conducted solely in humans to support the method genus drawn to administrating temsirolimus and a rapid-acting antidepressant would, in fact, replicate the administration of oral rapamycin and ketamine infusion exemplified in the specification as filed as one cannot readily anticipate the effect without confirmation in human studies. With respect to applicant’s assertion that the claimed combination RAAD and temsirolimus targets synaptogenesis and glutamate neurotransmission, and can reasonably be extrapolated from MDD to PTSD, anxiety, and/or dysthymia based on their common, recognized pathology of depression (i.e., dysregulated mTOR signaling pathway), it is respectfully noted that arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). While applicant appears to be citing National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) as evidenced, said reference has not been cited in the IDS nor provide in the form of declaration or affidavit. Therefore, the Examiner cannot make a comment on the reference. If applicant contends that dysregulated mTOR signaling pathway is the universal target across the mood disorder genus instantly claimed, and that can be resolved by targeting synaptogenesis and glutamate neurotransmission through the administration of a RAAD with mTOR inhibitor temsirolimus, said evidenced is respectfully requested.
Additionally, applicant argues that the enablement rejection under 35 U.S.C. 112(a) is against the rejection under 35 U.S.C. 103 unless there are conflicting arts. However, conflicting prior art is not a standard to establish enablement rejection nor the obviousness-type rejection. Under 35 U.S.C. 112(a), In re Wands, 8 USPQ2d 1400 (CAFC 1988) were utilized as a standard to determine whether the specification teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation, whereas the obviousness type rejection is established by combing or modifying the teachings of the prior art to produce the claimed invention where there is some teachings, suggestion or motivation to do so with some degree of predictability. In other words, the obviousness-type rejection is not required to meet the Wands factors as the reference is presumed to be operable. In this case, enabling the full scope of the claimed invention does not simply mean whether the specification itself literally disclosed every embodiment; Rather, it is evaluated under all Wands factors collectively to determine whether the specification provides sufficient guidance that would allow a person with ordinary knowledge to practice the full scope of the claims. In the present case, Yan et al. is not used as establishing non-enablement for administering racemic ketamine for treating major depressive disorder; rather, said reference is relied upon as evidenced that when a single enantiomer of ketamine is selected for administration with rapamycin, which is under the same concept of combining a rapid acting antidepressant with a mTOR inhibitor, that selection can results in significant or complete loss of antidepressant effect of ketamine.
Applicant argues the experimentation needed is merely routine dosing optimization for specific patient population or mood disorder subtype. Applicant argues that the Examiner has failed to provide any adequate technical reasoning or evidence as to why a person skilled in the art cannot extrapolate the data of Example 1. Applicant further argues that the claimed temsirolimus is an ester analog of rapamycin that is known to metabolize in vivo into rapamycin, thus, one would understand that the results shown for rapamycin would apply to temsirolimus. Applicant further argues the fact that the working example (Example 1) demonstrates the patient with major depressive disorder who received rapamycin with ketamine improves depressive symptoms per MARDS and QIS, and improves anxiety in HAMA are sufficient for one skilled in the art to extrapolate such data to other indications without undue experimentation.
In response, applicant’s arguments are not found persuasive. The fact that a skilled artisan would have the ability or knowledge to conduct experiments or clinical trials in humans by substituting rapamycin with another art-recognized mTOR inhibitor listed in the disclosure, i.e., temsirolimus, does not mean it provides predictive guidance concerning which sequence and timing of administration, dosing, formulation, and route of administration as broadly encompassed by the instant claims will possess the disclosed utility of treating the mood disorder. The task left by the present disclosure is not simply to reproduce the disclosed procedure by replacing rapamycin with another art-recognized mTOR inhibitor, and then replacing racemic ketmiane with another species of ketamine, such as (S)-ketamine, for reasonable number of times; Rather, it involves extensive experimentation across exceptionally broad method genus, including (a) evaluating PK/PD profiles of temriolimus with an understanding that it has poor oral bioavailability as evidenced by Pal et al.; (b) evaluating the timing, sequence and routes of administration of the two drugs with an understanding that mTOR inhibitor rapamycin intracerebroventricular (ICV) infused 30 minutes prior to 10 mg/kg of intraperitoneal ketamine completely abolished the antidepressant actions of ketamine per Li et al.; and (c) confirming that the claimed combination would work in human with another mood disorder that presents symptoms that do not overlap in scope as evidenced by Raypole (each reference are cited and presented above). Therefore, the issues not merely substituting one drug for another drug that fails within the same art-recognized class, it is whether the specification and the knowledge in the art permits the skilled artisan to distinguish operative from inoperative embodiments with no more than reasonable experimentation.
Given that the claim amendments change the scope of the claims, it necessitates a new ground of rejection for the reasons set forth herein.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 7, 10, 15, 18-20, 22-25, 29-34, 36-37, and 39-42 are rejected under 35 U.S.C. 103 as being unpatentable over Medeiros da Frota Ribeiro et al. (Curr Psychiatry Rep, 2017. Vol. 19(12): 107), in view of Kara et al. (Behavioural Pharmacology. Vol. 29, no. 4: 379-384. Published on June 2018), Qi et al. (J Neurol Neuromedicine, 2016. Vol. 1(4): 21-24), Nair et al. (J Basic Clin Pharm., 2016. Vol. 7(2): 27-31), and TORISEL® Kit (temsirolimus) injection package insert (Wyeth Pharmaceuticals, Inc. Revised June, 2011), as evidenced by Andrade (The Journal of Clinical Psychiatry, 2017. Vol. 78, 6: e674-e677; cited in the IDS filed on August 8, 2024).
Please note Medeiros da Frota Ribeiro et al., Kara et al., Qi et al., Nair et al., and Andrade are cited in the previous Office Action.
Medeiros da Frota Ribeiro et al. teaches a patient diagnosed with major depressive disorder who presented with depression was started on intravenous infusions of ketamine at a standard dose of 0.5 mg/kg over 40 minutes, and shows a sustained antidepressant response (see e.g., p. 107, “Case 2”; Fig. 1). Medeiros da Frota Ribeiro et al. further teaches previous trials with fluoxetine, venlafaxine, desvenlafaxine, duloxetine, and lurasidone were of limited efficacy (see e.g., p. 107; “Case 2”). Please note the ketamine taught by Medeiros da Frota Ribeiro et al. is a racemic mixture of the enantiomers (R)-ketamine and (S)-ketamine, as evidenced by Andrade. Please also note the patient taught by Medeiros da Frota Ribeiro et al. is a human subject. Please also note the ketamine infusion taught by Medeiros da Frota Ribeiro et al. is administered intravenously.
Medeiros da Frota Ribeiro et al. does not teach temsirolimus is administered to the human subject at a dose of 0.5 mg to 10 mg as claimed in claim 1. Medeiros da Frota Ribeiro et al. also does not teach temsirolimus is administered to the human subject at a dose of 0.5 mg to 5 mg as claimed in claim 30.
Kara et al. teaches autophagy enhancer temsirolimus injected intraperitoneally to ICR mice at a dose of 5 or 10 mg/kg and 10 ml/kg volume once daily for 4 days caused an antidepressant-like effect (reduced immobility) in the forced-swim test (see e.g., p. 382, “Results”, “Experiment 2: temsirolimus in ICR mice”; Table 2); and further teaches the ICR (CD-1) mice are routinely utilized in modeling depression (see e.g., p. 380, left column, line 13-16). Kara et al. further teaches these data support the notion that enhancing autophagy may have mood-stabilizing effects (see e.g., abstract). Please note intraperitoneal administration of temsirolimus as taught by Kara et al. is the peritoneal administration as claimed in claims 40 and 42. Kara et al. further teaches temsirolimus induces severe toxic effects including increased susceptibility to infections because of their immunosuppressant properties, thrombocytopenia, anemia, fever, pain, increased plasma creatinine levels, hypertension, hypercholesterolemia and hypertriglyceridemia, peripheral edema, constipation, diarrhea and nausea (see e.g., p. 383, left column, 2nd paragraph).
While Kara et al. does not expressly teach a human subject and the claimed dose, Qi et al. teaches even though the mechanism associated with the pathogenesis of major depressive disorder have yet to be completely understood, animal models are predictive of antidepressant activity, especially the force swim test (FST) is one of the most widely used tests across laboratories for accessing symptoms of depression (see e.g., page 21, “Introduction” section); and further teaches CD-1 is one of the most frequently used out strain that respond positively to most of the antidepressant when subject to the FST (see e.g., p. 22, “strain” section, 1st paragraph), and ICR mice provide opportunities for identifying drugs that are effective in patients with drug-resistant depression (see e.g., p. 23, left column, “conclusion” section, 2nd paragraph).
Nair et al. teaches a method of converting doses between species, including mouse to human, shown below (see e.g., Table 1):
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127
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.
TORISEL® Kit (temsirolimus) injection package insert teaches TORISEL® (temsirolimus) should be held for absolute neutrophil count (ANC) < 1,000/mm3, platelet count < 75,000/mm3, or NCI CTCAE grade 3 or greater adverse reactions; once toxicities have resolved to grade 2 or less, TORISEL® (temsirolimus) may be restarted with the dose reduced by 5 mg/week to a dose no lower than 15 mg/week (see e.g., p. 2, “2.3 Dosage Interruption/Adjustment”); and reports dose range of 7.5- 15 mg for severe hepatic function (see e.g., Table 3). TORISEL® Kit (temsirolimus) injection package insert further teaches the pharmacokinetics profile over the dose range of 1 mg to 25 mg, temsirolimus exposure increased in a less than dose proportional manner while sirolimus exposure increased proportionally with dose (see e.g., p. 18, “12.3 Pharmacokinetic”, “Absorption”).
The difference between the method of Medeiros da Frota Ribeiro et al. and the claimed method is that the prior art does not teach administering the temsirolimus at a dose of 0.5 mg to 15 mg or 0.5 mg to 5 mg to the human subject. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by combining the method of Medeiros da Frota Ribeiro et al. with the autophagy enhancer temsirolimus taught by Kara et al., and then optimizing the dose of said temsirolimus through routine experimentation in order to form another method to be used for treating major depressive disorder in a human subject.
One would have been motivated to do so, because Kara et al. expressly teaches 5 or 10 mg/kg dose of temsirolimus, a mTOR inhibitor and autophagy enhancer, exhibits antidepressant effect in the ICR (CD-1) mouse model for depression; and Qi et al. teaches the ICR (CD-1) mouse is an animal model for mimicking major depressive disorder in humans to assess antidepressant efficacy. Accordingly, Kara et al. and Qi et al. would have suggested that temsirolimus has antidepressant effect that is useful for treating major depressive disorder in humans.
With respect to the dosing of temsirolimus, Nair et al. expressly teaches a method for calculating the human-equivalent doses from the dose given to mouse. Thus, determining the corresponding human-equivalent dose based on the doses selected by Kara et al. in the mouse model of depression would have been routine mathematical conversion within the ordinary skill of clinical and translational pharmacology. For instance, if a human subject weights 60 kg and 5 mg/kg of temsirolimus adminsitered to mouse as taught by Kara et al. can be calculated as follows:
5
m
g
k
g
×
0.081
×
60
k
g
=
24.3
m
g
, and that gives a human equivalent dose of 24.3 mg. The TORISEL® Kit (temsirolimus) injection package insert further established that temsirolimus dosage was a known result-effective and routinely adjustable parameter. Particularly, said package insert includes explicit teachings for adjusting the dose of temsirolimus by 5 mg decrements in response to toxicities; reporting that doses as low as 7.5 mg were known in human; and recognized its human pharmacokinetic profile over the 1 to 25 mg intravenous dose range. Accordingly, one of ordinary skill in the art seeking to arrive at the dose of temsirolimus starting from Kara/Nair et al.'s human equivalent dose for intraperitoneal administration would have been motivated to perform downward dose-ranging while monitoring antidepressant activity and toxicity, with the claimed dosing range (0.5 mg to 15 mg or 0.5 mg to 5 mg) that lies within temsirolimus’ known human pharmacokinetic dosing range of 1 mg to 25 mg.
One of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention while retaining the antidepressant activity through routine optimization, including the claimed doses, because Kara et al. expressly identifies temsirolimus exhibits antidepressant effect in animal model of major depressive disorder; and Kara et al., Nair et al., and TORISEL® Kit (temsirolimus) injection package insert together provides the workable dosing ranges. In view of these teachings, one would have reasonably expected that by optimizing the dose of temsirolimus administered to human through routine optimization and combining it with another method useful for treating major depressive disorder would reasonably be expected to be similarly useful for treating major depressive disorder.
Regarding the limitation of “wherein the human subject has a history of inadequate response to at least one prior antidepressant therapy” in claims 10, 24-25, and 36, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to treat a human subject with a history of inadequate response to fluoxetine in the method set forth above. One would have been motivated to do so, because Medeiros da Frota Ribeiro et al. teaches ketamine demonstrates sustained antidepressant response in a human subject with previous trials of fluoxetine for depression with limited efficacy, which is an antidepressant; and Qi et al. teaches the ICR mice, which is used in the method of Kara et al., provides opportunities for identifying drugs that are effective in patients with drug-resistant depression. Accordingly, Medeiros da Frota Ribeiro et al. and Qi et al. both would have suggested that ketamine and temsirolimus demonstrates antidepressant effect in subject with drug-resistant depression that has limited efficacy to antidepressant. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the method set forth above would have successfully treated a human subject with a history of inadequate response to an antidepressant.
Regarding the limitation of “wherein the RAAD and the temsirolimus are co-administered to the human subject” in claims 15 and 37, the instant situation is amenable to the type of analysis set forth in Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) and also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), where the court found that the selection of any order of performing process steps is prima facia obvious in the absence of new or unexpected results. As such, applying the same logic to the instant process claims, one of ordinary skill in the art would have a reasonable expectation of success to arrive at the claim invention, because one would have reasonably expected that by co-administering the racemic ketamine and temsirolimus in the method set forth above would successfully treat major depressive disorder.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 1, 4, 7, 10, 15-16, 18-20, 22-25, 29-34, and 36-42 are rejected under 35 U.S.C. 103 as being unpatentable over Medeiros da Frota Ribeiro et al. (Curr Psychiatry Rep, 2017. Vol. 19(12): 107), in view of Kara et al. (Behavioural Pharmacology. Vol. 29, no. 4: 379-384. Published on June 2018), Qi et al. (J Neurol Neuromedicine, 2016. Vol. 1(4): 21-24), Nair et al. (J Basic Clin Pharm., 2016. Vol. 7(2): 27-31), and TORISEL® Kit (temsirolimus) injection package insert (Wyeth Pharmaceuticals, Inc. Revised June, 2011) as applied to claims 1, 4, 7, 10, 15, 18-20, 22-25, 29-34, 36-37, and 39-42 above, and further in view of Di et al. (“Chapter 41: Formulation” in: Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization. 2nd ed. San Diego, CA, USA: Elsevier Science, 2016: 497-510).
Please note Di et al. is cited in the previous Office Action.
The teachings of Medeiros da Frota Ribeiro et al., Kara et al., Qi et al., Nair et al., and TORISEL® Kit (temsirolimus) injection package insert are set forth above and applied as before.
Medeiros da Frota Ribeiro et al., Kara et al., Qi et al., Nair et al., and TORISEL® Kit (temsirolimus) injection package insert does not teach the elected intravenous administration of temsirolimus as claimed in claims 40 and 42. Medeiros da Frota Ribeiro et al., Kara et al., Qi et al., Nair et al., and TORISEL® Kit (temsirolimus) injection package insert does not teach co-formulated as claimed in claims 16 and 38.
Di et al. teaches intravenous has rapid onset and complete bioavailability as it precisely delivers the complete dose (see e.g., p. 498, “41.2.2 Intravenous (IV)” section). Di et al. further teaches intraperitoneal injection is particularly useful in discovery laboratories for small animal studies, where it is often preferred over IV due to ease of administration (see e.g., 498, “41.2.3 Intraperitoneal [IP]). Di et al. further teaches intraperitoneal bypass first-pass metabolism from the gut, but is still subject to first-pass metabolism by the liver, since absorption is via the portal system (see e.g., p. 499, line 1-2).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method set forth above to selectively choose to administer the temsirolimus intravenously. One would have been motivated to do so, because Di et al. teaches intraperitoneal injection is often employed in small animal studies primary due to its relative ease of administration and further teaches that intravenous has the benefit of rapid onset and complete bioavailability with more precise delivery. Therefore, Di et al. itself would have suggested the selection of intravenous route as a route of administration in order to deliver precise dosage that overcomes first-pass metabolism by the liver. One of ordinary skill in the art would have a reasonable expectation of success to arrive at the claimed invention through routine experimentation, because TORISEL® Kit (temsirolimus) injection package insert established the human pharmacokinetics profile of i.v. temsirolimus over the dose range of 1 mg to 25 mg; and therefore, one of ordinary skill in the art seeking to administer the temsirolimus intravenously would have reasonably optimize the dose within temsirolimus’ known human pharmacokinetic intravenous dosing range.
Regarding the limitation of “wherein the RAAD and the temsirolimus are co-formulated as a pharmaceutical composition” in claims 16 and 38, the instant situation is amenable to the type of analysis set forth in Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) and also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), where the court found that the selection of any order of performing process steps is prima facia obvious in the absence of new or unexpected results. As such, same logic is applicable to the instant process claims drawn to co-formulation, one of ordinary skill in the art would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by co-formulating the racemic ketamine and temsirolimus in the method set forth above would successfully treat major depressive disorder.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Response to Arguments
Applicant's arguments filed on August 31, 2026 with respect to the rejection of claims 1, 4, 7-8, 10, 15-16, 18-20, 22-25, and 27-38 rejected under 35 U.S.C. 103 as being unpatentable over Medeiros da Frota Ribeiro et al., in view of Kara et al. Nair et al., Bellmunt et al., and Di et al., as evidenced by Andrade have been fully considered but they are not persuasive.
All rejections pertaining to claims 8, 27-28 and 35 are moot, because these claims are cancelled in view of the amendments filed on August 31, 2026.
In this case, applicant amends claim 1 by deleting the limitations of “the RAAD is administered once every two weeks”, “the RAAD is administered to the human subject intravenously” and “the temsirolimus is administered to the human subject intravenously”; and further adding the limitation of “major depressive episode in bipolar disorder (bipoar depression)” to the list of mood disorder. Applicant further amends claim 30 by adding the limitation of “the RAAD is at least one of: (i) racemic ketamine…(ii) (R)-ketamine… (iii) (S)-ketamine…”, and “major depressive episode in bipolar disorder (bipoar depression)” to the list of mood disorder; further deleting the limitations of “the RAAD is administered to the human subject intravenously” and “the temsirolimus is administered to the human subject intravenously”. Applicant also newly added claims 39-42. Each of these findings demonstrates the amendments change the scope of claims; therefore, the previous rejection has been withdrawn in view of the amendments but reapplied for the reasons set forth herein.
In Summary, applicant argues Bellmunt does not teach or suggest dosing below 20 mg with temsirolimus monotherapy. Applicant further argues Bellmunt cannot bridge the gap from the extrapolated 24.3 mg human dose of temsirolimus to the claimed ranges, because the teachings of Bellmunt is drawn to dose management in oncology, and managing toxicity does not establish a therapeutically effect dose for a mood disorder. Applicant argues there is no staring point from which to reduce dose while maintaining relevant efficacy, because that “24.3 mg” is the lowest effective dose from Kara’s data.
In response, applicant’s arguments are not found persuasive for the reasons set forth below:
First, it may well be true that Kara et al. exemplified two selected doses of temsirolimus (5 or 10 mg/kg) in the mouse model of depression (see e.g., p. 382, “Results”, “Experiment 2: temsirolimus in ICR mice”; Table 2), in which the 5 mg/kg is the lowest dose among the two; However, there is nowhere in Kara’s teachings stating that any dose lower than 5 mg/kg is ineffective. Therefore, applicant’s assertion that reducing the doses lower than the one taught by Kara et al. would exhibits no antidepressant efficacy appears to be mere argument without factual support, said evidence is respectfully requested.
Second, applicants’ argument with respect to Bellmunt has been fully considered. It is respectfully noted that said reference has been removed from the rejection of record in view of the claim amendments; However, applicant’s argument that dose management of temsirolimus taught in oncology cannot be extrapolated to a human with a mood disorder have been fully considered but they are not found persuasive. It may well be true temsirolimus has an oncology indication approved by FDA; However, such indication does not make the reference’s teachings irrelevant to the obviousness-type rejection analysis, because the prescribing information of temsirolimus is not relied upon as teaching that temsirolimus at the disclosed doses treat mood disorder. Rather, Kara et al. is relied upon for the teaching of temsirolimus produces antidepressant-like activity in a recognized model of depression. In the present case, the TORISEL® Kit (temsirolimus) injection package insert is relied upon for the separate teaching concerning the known dosing and dose adjustment of the same drug, temsirolimus, in human subjects. Specifically, the prescribing information establishes that temsirolimus dosage was a known adjustable parameter, including explicit teachings that temsirolimus treatment could be interrupted in response to toxicity and resumed at a dose reduced by 5 mg/week; human subjects had received temsirolimus doses as low as 7.5-10 mg; and the pharmacokinetic of temsirolums had been characterized over a dose range of 1-25 mg. The fact that these human dosing teachings arose from oncology setting does not negate their relevance to what one of ordinary skill would have known regarding the administration, tolerability, pharmacokinetics, and adjustment of temsirolimus dosage in humans. The reference is not relied upon to supply the antidepressant therapeutic indication; rather, it demonstrates that human disease within the presently claimed range were known and that temsirolimus dose was conventionally varied and adjusted, Kara et al. supplies the antidepressant activity that would have provided the therapeutic endpoint to be maintained during dose optimization.
Applicant further argues the unexpected results (mTOR inhibitor prolongs rather than blocking ketamine’s antidepressant effect) demonstrates using oral rapamycin and intravenous ketamine is clearly commensurate in scope with the claimed invention, because a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range if one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof. Applicant argues that rapamycin and temsirolimus both share the same pharmacological mechanism of inhibiting mTOR signaling pathway, the unexpected results would have been expected because a person of skill in the art would have understood temsirolimus metabolize in vivo into rapamycin, thus, the full scope is supported.
In response, applicant’s arguments that having a single working example disclosed in the specification (Example 1) is sufficient to provide a person of ordinary skill in the art to determine “a trend in the exemplified data”. However, that singular working example provided in the disclosure (see e.g., p. 33 of the specification) only administer a single, fixed amount of oral rapamycin (6 mg) with a single weight-based dose of ketamine (0.5 mg/kg), and that particular regimen only provides a single data point that is insufficient to establish “a trend” because determining the trend requires multiple data points collected across different combination (e.g., a combination of different doses or a combination of different route of administration) to establish a pattern. Therefore, applicant’s assertion that the single regimen of rapamycin and ketamine exemplified therein establish a trend appears to be mere argument without any factual support.
Second, the mere fact that temsirolimus and rapamycin belongs to the same art recognized class of mTOR inhibitor, it does not necessarily mean drugs in the same pharmacological class would, in fact, have identical dosage guidance, potencies, or pharmacokinetics. Soley to rebut applicant’s assertion that one of ordinary skill in the art can directly extrapolate the data of oral rapamycin to temsirolimus in the claimed method genus, encompassing any routes of administration, Pal et al. (Cancer Treat Rev, 2013. Vol. 39(7): 709–719) reports temsirolimus is an ester analog and structural derivatives of rapamycin that inhibits mTOR via similar mechanism of action, the metabolism, formulations, dosing schedules and routes of administration are distinctly different, resulting in varying PK/PD profiles; and particularly reports temsirolimus has low oral bioavailability, but as an IV formulation, temsirolimus acts as prodrug which is metabolized to rapamycin (see e.g., p3, “Rapamycin and its analogs”, 1st paragraph; and p. 6, “PK/PD profiles and mTOR pathway inhibition”, 1st paragraph). In other words, it is well-recognized in the art that each mTOR inhibitor has different PK/PD profile even though they inhibit mTOR pathway via a similar mechanism of action. Such assertion undermines the allegation of unexpected results because it indicates that the observed unexpected result would have been reasonably expected. Applicant cannot simultaneously rely upon the similarity between rapamycin and temsirolimus to establish relevance of the data while asserting the claimed temsirolimus exhibits unexpected properties.
Again, according to MPEP 716.02(d), “whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the ‘objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.’ In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”.
In short, as set forth in the previous Office Action, the unexpected results applicant relies upon are demonstrated in Example 1 of the specification (see e.g., page 33 of the specification); in which the results were obtained by administering a single oral dose of rapamycin (6 mg) in 2 ounces of orange juice approximately 2 hours prior to 0.5 mg/kg of ketamine infused intravenously over 40 minutes (two ketamine infusion test days separated by at least two weeks) to a symptomatic antidepressant-treated patient with major depression who have a history of non-response to at least one prior antidepressant trial.
In contrast, instant amended claim 1 broadly recites a method encompasses administering a therapeutically effective amount of a rapid-acting antidepressant or a pharmaceutically acceptable salt, solvate, or tautomer thereof, or mixtures thereof; and temsirolimus, or a pharmaceutically acceptable salt, solvate, enantiomer, or tautomer thereof, or mixtures thereof, wherein the temsirolimus is administered at a dose of 0.5 mg to 10 mg, useful in treating a mood disorder in a human subject suffering from the mood disorder selected from the group consisting of major depressive disorder (MDD), major depressive episode in bipolar disorder (bipolar depression), persistent depressive disorder (dysthymia), disruptive mood dysregulation disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, anxiety disorder, and post-traumatic stress disorder. The claimed rapid-acting antidepressant is drawn to at least one of racemic ketamine, or a pharmaceutically acceptable salt, solvate, or tautomer thereof; (R)-ketamine, or a pharmaceutically acceptable salt, solvate, or tautomer thereof; or (S)-ketamine, or a pharmaceutically acceptable salt, solvate, or tautomer thereof. Instant amended claim 30 also recites a method encompasses administering a therapeutically effective amount of a rapid-acting antidepressant or a pharmaceutically acceptable salt, solvate, or tautomer thereof, or mixtures thereof; and temsirolimus, or a pharmaceutically acceptable salt, solvate, enantiomer, or tautomer thereof, or mixtures thereof useful for the same purpose as set forth in amended claim 1, except said claim 30 requires the temsirolimus to be administered at a dose of 0.5 mg to 5 mg.
Applicant only exemplified unexpected result using a particular combination species (comprising a single, oral, 6 mg dose of rapamycin in 2 ounces of orange juice) that is different than the one instantly claimed, and that does not provide adequate basis for concluding that similar results would be obtained for temsirolimus at the claimed dose range, in any formulation, through any route of administration. Applicant only exemplified major depressive disorder, and that does not provide adequate basis for concluding that similar results would be obtained in any human subject suffering from other species of mood disorder, such as premenstrual dysphoric disorder. The disclosure only exemplifies a single dosing regimen of ketamine and rapamycin administered at a particular sequence and timing (6 mg of oral rapamycin administered approximately two hours prior to 0.5 mg/kg of ketamine infused intravenously over 40 minutes), and that is not commensurate in scope to include any administration order, including co-administration, performed in any timing.
These findings, at a minimum, demonstrate that applicant’s assertion of unexpected results is not commensurate in scope with the claimed invention, thus, the argument is not found persuasive for the same reasons.
Therefore, the rejection is withdrawn in light of the claim amendments that changes the scope of the claims; However, the new ground of rejection has been applied as necessitated by amendment for the reasons set forth herein.
Conclusion
No claims are allowed.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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