DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application 18/483,225 filed on October 9, 2023 is a divisional of U.S. Patent Application No. 18/049,589 filed on October 25, 2022, which is a continuation of U.S. Patent Application No. 17/269,470 filed on February 18, 2021, which is a 371 of PCT/US2019/047288 filed on August 20, 2019, which claims priority to, and the benefits of U.S. Provisional Application No. 62/719,935 filed on August 20, 2018.
Status of Claims
Acknowledge is made of the receipt and entry of the amendment to the claims filed on June 9, 2026, wherein claims 1, 14, 33-35, and 63 are amended; claims 2, 4-7, 9-11, 15-17, 24-29, 31-32, 40-44, 46-47, 52 and 54 are canceled; and claims 3, 8, 12, 13, 18-20, 22-23, 30, 36-39, 45, 48-50, 55-62 and 64 are unchanged.
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, 3, 8, 12-14, 20-23, 30, 33-39, 45, 48-51, 53, and 55-64 are pending and under examination.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 5/19/2026 and 6/9/2026 were filed after the mailing date of the Non-Final Office Action on February 10, 2026. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Terminal Disclaimer
The terminal disclaimer filed on June 8, 2026 disclaiming the terminal portion of any
patent granted on this application which would extend beyond the expiration date of U.S. Patent No.
11,793,794 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Action Summary
All rejections pertaining to claims 15-17 and 31-32 are moot because the claims were cancelled in view of the amendments filed on June 9, 2026.
Claims 1 and 63 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention are withdrawn in view of the claim amendments.
Claims 1, 12-13, 31-35, 37-39, 45, 49, 53, 57 and 59 rejected under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017), as evidenced by Andrade (The Journal of Clinical Psychiatry, 2017. Vol. 78, 6: e674-e677; cited in the Non-Final Office Action mailed on December 13, 2023) are maintained, but revisited and modified in view of the claim amendments.
Claims 1, 3, 8, 12-13, 31-39, 45, 49, 51, 53, 57, 59, and 61 rejected under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017) as applied to claims 1, 12-13, 31-35, 37-39, 45, 49, 53, 57 and 59 above, and further in view of Weg et al. (US 6,248,789 B1) are maintained, but revisited and modified in view of the claim amendments.
Claims 14-16, 18, 21-23, 30, 48, 50, 55-56, 58, 60 and 62 rejected under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017) and Weg et al. (US 6,248,789 B1) are maintained, but revisited and modified in view of the claim amendments.
Claims 14-23, 30, 48, 50, 55-56, 58, 60 and 62 rejected under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017) and Weg et al. (US 6,248,789 B1) as applied to claims 14-16, 18, 21-23, 30, 48, 50, 55-56, 58, 60 and 62 above, and further in view of Rey (WO 2018/234568 A2) are maintained, but revisited and modified in view of the claim amendments.
Claims 63 and 64 rejected under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017), and Weg et al. (US 6,248,789 B1) are maintained, but revisited and modified in view of the claim amendments.
Claim 1, 3, 8, 12-23, 30-39, 45, 48-51, 53 and 55-64 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,793,794 B2, in view of Marks et al. (US 2008/0255029 A1), Weg (US 2014/0057988 A1; cited in the previous Office Action mailed on 7/9/2025), Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017) and Rey (WO 2018/234568 A2) are withdrawn in view of the terminal disclaimer filed on June 8, 2026.
Claim Interpretation
The claimed term “about” is reasonably construed in light of page 6, line 6-9 of the specification as shown below:
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, and the term “about” includes the broadest variation of +/- 20% of the value specified; therefore, the
claimed term when used in the context of “less than about”, the upper limit is calculated as the specified value plus 20% of that value. For example, the upper limit for the phrase “less than about 10 mg” in claims 1:
10
+
0.30
×
10
=
13
, and said phrase is reasonably interpreted as less than 13 mg. In addition, the same calculation is applied to the phrase “less than about 5 mg” (see e.g., claim 48),
5
+
0.30
×
5
=
6.5
and said phrase is reasonably interpreted as less than 6.5 mg.
Regarding claim 1, the recitation of “sufficient to treat or ameliorate a mood disorder in a human subject when administered in combination” indicated below:
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, is reasonably construed to be an intended use of the rapid-acting antidepressant and the mTOR inhibitor, respectively. Since the claim is interpretated to be a product, the intended use of the ingredient(s) does not further limit the structural components of said ingredient(s); and therefore, if the prior art(s) meet the structural limitation of the claimed product, it is capable of performing the intended use. See MPEP 2111.02. In addition, the limitation of “
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” is reasonably construed by the Examiner that only one of the limitation (A) or (B) needs to be met. To the extent that the limitation (A) applies to the claimed kit, both the limitation (A)(i) and (A)(ii) need to be met. Regarding the limitation of (A)(i), the limitation recites before and after the coordinating conjunction “or” is being interpreted such only one limitation needs to be met, for instance, “the therapeutically effective dose of the RAAD in a dosage form suitable for oral administration or intravenous administration to the human subject” or “instructions to formulate the therapeutically effective dose of the RAAD in a formulation suitable for intravenous administration to a human
subject”; and same interpretation applies to (A)(ii). To the extent that the limitation (B) applies to the claimed kit, only one of the limitation (B)(i) or (B)(ii) needs to be meet.
Regarding claim 14, the limitation of “for a human subject” recites in the phrase of “at least one dose of from 0.15 mg/kg to 10 mg/kg of a rapid-acting antidepressant (RAAD) for a human subject” are drawn to the intended use of the RAAD. Since the claim is interpretated to be a product, the intended use of the ingredient(s) does not further limit the structural components of said ingredient(s); and therefore, if the prior art(s) meet the structural limitation of the claimed product, it is capable of performing the intended use. See MPEP 2111.02. Same interpretation applies to other instances. If the prior art teaches a rapid-acting antidepressant at the claimed range, it is capable of performing the intended use. In addition, the limitation of “
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” is reasonably construed by the Examiner that only one of the limitation (A) or (B) needs to be met. To the extent that the limitation (A) applies to the claimed kit, both the limitation (A)(i) and (A)(ii) need to be met. Regarding the limitation of (A)(i), the limitation recites before and after the coordinating conjunction “or” is being interpreted such only one limitation needs to be met, for instance, “the therapeutically effective dose of the RAAD in a dosage form suitable for oral administration or intravenous administration to the human subject” or “instructions to formulate the therapeutically effective dose of the RAAD in a formulation suitable for intravenous administration to a human
subject”; and same interpretation applies to (A)(ii). To the extent that the limitation (B) applies to the claimed kit, only one of the limitation (B)(i) or (B)(ii) needs to be meet.
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 non-obviousness.
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, 12-13, 33-35, 37-39, 45, 49, 53, 57 and 59 remain rejected under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017), as evidenced by Andrade (The Journal of Clinical Psychiatry, 2017. Vol. 78, 6: e674-e677; cited in the Non-Final Office Action mailed on December 13, 2023).
Marks et al. teaches a combination of an mTOR inhibitor with at least one second drug substance, e.g. for any use as indicated under 1.1 to 1.8, including a method for treating endocrine tumors and a method for treating endocrine tumor invasiveness or symptoms associated with such tumor growth (see e.g., [0041], [0045], [0064]); wherein the mTOR inhibitor is selected from, inter alia, rapamycin, 40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoate]-rapamycin (also known as temsirolimus), and/or compound A (see e.g., [0101]-[0112]; [0005]). Marks et al. further teaches the mTOR inhibitor may be used, e.g., in any method of 1.1 to 1.8 alone or in combination with one or more, at least one, second drug substance, in which 1.1 is drawn to a method for treating endocrine tumors (see e.g., [0041]; [0062]). Marks et al. further teaches endocrine tumors include endocrine or neuroendocrine tumor symptoms and pituitary tumor symptoms (see e.g., [0061]), wherein the endocrine or neuroendocrine tumor symptoms includes, inter alia, chest pain (see e.g., [0057]); and the pituitary tumor symptoms includes, inter alia, moodiness or depression, anxiousness (see e.g., [0059]). Marks et al. further teaches in the combination, an mTOR inhibitor, such as rapamycin or rapamycin derivative, may be administered as appropriate, e.g. in dosages which are known for mTOR inhibitors, by any administration route, e.g. orally or parenterally; e.g. everolimus may be administered, e.g. orally, in dosages from 0.1 mg up to 15 mg, in dosages more preferably from 0.5 mg to 10 mg, e.g. in the form of (dispersible) tablets; Rapamycin or e.g. temsirolimus may be administered parenterally in similar dosage ranges (see e.g., [0089]). Marks et al. teaches combinations include fixed combinations, in which an mTOR inhibitor and at least one second drug substance are in the same formulation; kits, in which an mTOR inhibitor and at least one second drug substance in separate formulations are provided in the same package, e.g. with instruction for co-administration; and free combinations in which an mTOR inhibitor and at least one second drug substance are packaged separately, but instruction for concomitant or sequential administration are given (see e.g., [0071]). Marks et al. further teaches a second drug substance according to the present invention may be administered by any conventional route, for example enterally, e.g. including oral administration; and parenterally; e.g., in form of capsules, (injectable) solutions (see e.g., [0091]); unit dosage form may contain, for example, from about 0.1 mg to about 1500 mg (see e.g., [0092]).
Marks et al. does not teach the rapid-acting antidepressant instantly claimed.
Grassi et al. teaches the use of psychotropic drugs, namely those with an antidepressant profile, is a mandatory part of an integrated treatment of psychiatric disorders among cancer patients (see e.g., abstract, background). Grassi et al. further teaches antidepressants have been shown to be effective in the treatment of both psychiatric (depressive spectrum, stress-related disorder and anxiety disorders) and non-psychiatric cancer-related symptoms (e.g., pain, hot flashes and fatigue) (see e.g., abstract, design; p. 101, right column, line 5-11). Grassi et al. further teaches psychostimulants and other drugs, including ketamine (N-methyl-D-aspartate receptor antagonist) and psilocybin, have been used to rapidly alleviate depression in cancer patients (see e.g., Table 1, class - “psychostimulants and other drugs”; p. 105, right column, line 16-30). Grassi et al. further teaches in setting of terminal disease, the rapid onset of action of psychostimulants/ketamine may be preferable (see e.g., p. 107, Table 2, “Factors to be considered when prescribing Ads in cancer” section).
Regarding claims 1, 33-35, 37-38, 45, 53, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to combine a dosage of 0.5 mg-10 mg rapamycin or temsirolimus taught by Marks et al., with a dosage of a therapeutically effective amount of a ketamine taught by Grassi et al. as the second drug substance in a kit to arrive at the claimed invention. Please note the ketamine taught by Grassi et al. is a psychostimulant with rapid onset of action, and that is a rapid-acting antidepressant. One would have been motivated to do so, because each is taught by the prior art to be useful for treating cancer-related symptoms. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). One would have been further motivated to do so, because Marks et al. teaches a mTOR inhibitor, including rapamycin and temsirolimus, can be used alone for treating endocrine tumors, and said mTOR inhibitor can also be combine with a second drug substance for treating endocrine tumor invasiveness or symptoms associated with such tumor growth; and Grassi et al. teaches a psychostimulant, including ketamine and psilocybin, can be used to treat cancer-related symptoms in cancer patients. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the combination of 0.5 mg-10 mg rapamycin or temsirolimus and a therapeutically effective amount of a psychostimulant ketamine of Grassi et al. each in an appropriate formulation suitable for administration, such as oral or intravenous, in a kit would have reasonably expected to be useful for treating cancer-related symptoms or treating endocrine tumors in addition to treating cancer-related symptoms. Please note the ketamine taught by Grassi et al. is a NMDA receptor modulator, and a racemic mixture of the enantiomers (R)-ketamine and (S)-ketamine, as evidenced by Andrade; and that meets the limitations of claims 33-35.
Regarding the limitations of “wherein the kit further comprises instructions…” in claims 12 and 13, each of these limitations is drawn to the content of the printed matter that describes the administering step(s) of the RAAD and the mTOR inhibitor, respectively, in the kit instantly claimed. Since the claim is interpreted to be a product, said method step(s) recites in the printed matter does not appear to further limit the structural component of the kit instantly claimed. According to MPEP 2112.01, III, “[where] the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004)”. In the present case, the kit of Marks et al. and Grassi et al. sets forth above meets the structural limitation of the kit instantly claimed. Given that a kit or a package is required by law for pharmaceutical preparations and applications, and the FDA Guideline for Industry gives specific instructions for packaging and distributing medication for intended use and instructions for customers, one of ordinary skill in the art would have recognized the need for providing the instructions for the caregiver as those are mandated by federal law to include such instructions; and that renders obvious the limitations instantly claimed. In alternatives, it would have been prima facie obvious to one of ordinary skill in the art the time the application was filed to further modify the kit of Marks et al. and Grassi et al. sets forth above to include instruction for administration, including sequential administration. One would have been motivated to do so, because Marks et al. teaches the kit can provide instruction for co-administration, concomitant or sequential administration. One would have reasonable expectation of success to arrive the claimed invention by further incorporating the instruction(s) for administering the mTOR inhibitor and the second drug substance, including sequential administration.
Regarding the limitation of “wherein the human subject has a history of non-response
to at least one prior antidepressant therapy” in claim 39, the limitation pertains to the intended use of the RAAD and the mTOR inhibitor. Since the claim is interpreted to be a product, the human subject recites in the claim does not create a structural difference to the claimed product; and therefore, the human subject is not limiting, and the kit of Marks et al. and Grassi et al. sets forth above meets the structural limitation of the kit instantly claimed.
Regarding the limitation of “wherein the mood disorder is…” in claims 49, 57 and 59, the limitation pertains to the intended use of the RAAD and the mTOR inhibitor. Since the claim is interpreted to be a product, the mood disorder recites in the claim does not create a structural difference to the product; and therefore, the mood disorder is not limiting, and the kit of Marks et al. and Weg et al. sets forth above meets the structural limitation of the kit instantly claimed.
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 June 9, 2026 with respect to the rejection of claims 1, 12-13, 31-35, 37-39, 45, 49, 53, 57 and 59 under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017), as evidenced by Andrade (The Journal of Clinical Psychiatry, 2017. Vol. 78, 6: e674-e677; cited in the Non-Final Office Action mailed on December 13, 2023) have been fully considered but they are not persuasive.
All rejections pertaining to claims 31-32 are moot because the claims were cancelled in view of the amendments filed on June 9, 2026.
Applicant amends independent claim 1 by adding the following new limitation:
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, which part of the limitation are found in previous claim 33-36, in which claims 33-35 are now amended to recite new limitation of “or a pharmaceutically acceptable salt, tautomer, or solvate thereof”. Each of these findings demonstrate that the claim amendment changes the scope of the claims.
In Summary, applicant argues there is no reasonable expectation of success that ketamine would be useful for treating any cancer-related symptoms or endocrine tumors in a cancer patient administered an mTOR inhibitor, because the intended purpose of using rapamycin or temsirolimus from Marks et al. is to inhibit mTOR signaling and multiple different references, including Grassi et al., teach that mTOR signaling is required for the rapid-acting antidepressant activity of ketamine. Specifically, applicant directs attention to Fan et al. (Oncotarget 2017; 8(2): 2356-2360; cited in the IDS filed on June 9, 2026) cited in Grassi et al., which states "[p]reclinical evidence indicates that mammalian target of rapamycin signaling ... underlie the rapid antidepressant responses of ketamine" (see e.g., p. 2358, right column); and further argues Li et al. (Science (New York, NY), 2010; 329: 959-964; cited in the IDS filed on August 6, 2025) cited by Grassi et al. and Dwyer et al. (Biological Psychiatry, 2013. Vol. 73(12): 1189-1198; cited in the IDS filed on October 9, 2023) supports the blockade of mTOR signaling completely blocked ketamine-induction of synaptogenesis and behavioral responses in models of depression (see e.g., p. 12-13 of the remark). Applicant further argues Grassi et al. discourages the use of psychotropic drugs in cancer patients if there are potential negative drug-drug interactions with other medication that the patient is taking; and argues the Examiner fails to established how two contraindicated drugs can be administered together, e.g., if ketamine requires the functioning of mTOR receptor that is inhibited by the administration of rapamycin, then such as combination teaches away from using the claimed drug combination. Applicant argues merely because Marks et al. teaches mTOR inhibitors indicated for the treatment of cancer can be combined with a second agent does not automatically mean that any second agent can be used; and the use of ketamine in cancer patients in Grassi et al. is not even for treatment of cancer or any other type of tumor but rather for psychological effects as a result of having cancer.
In response, applicant’s arguments are not found persuasive for the reasons set forth below:
First, applicant’s arguments that the ketamine taught by Grassi et al., which belongs to psychotropic drugs with an antidepressant profile taught to be useful for treating psychiatric disorders among cancer patients and non-psychiatric cancer-linked symptoms (e.g., neuropathic pain, nausea and vomiting, and fatigue) (see e.g., abstract; Table 1), is not for treatment of cancer and cannot be use as the at least one second drug substance in the kit of Marks et al. are not found persuasive. According to MPEP 2141.02, “[a] prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984)”. In this case, the obviousness-type rejection of record is form on the basis that Marks et al. discloses “kits, in which an mTOR inhibitor and at least one second drug substance in separate formulations are provided in the same package, e.g. with instruction for co-administration” (see e.g., [0071]); and further teaches “[a]n mTOR inhibitor may be used, e.g. in any method of 1.1 to 1.8 as described herein alone or in combination with one or more, at least one, second drug substance” (see e.g., [0062]), in which the method of 1.5 recites “[a] method for treating endocrine tumor invasiveness or symptoms associated with such tumor growth, comprising administering to a subject in need thereof a therapeutically effective amount of an mTOR inhibitor” (see e.g., [0045]). In other words, Marks et al. clearly teaches that the “at least one second drug substance” in a kit can be those that are useful for treating symptoms associated with tumor growth, and does not criticize, discredit, or otherwise discourage the incorporation of any second drug substance known to be useful for treating symptoms associated with tumor growth without anticancer activity. It is respectfully noted that according to MPEP 2123, II, “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971)”. Therefore, the mere fact that Marks et al. teaches “treating endocrine tumor invasiveness” (see e.g., [0045]), or “an anticancer drug” as an exemplary second drug substance in the preferred embodiments, e.g., “for example, a second drug substance as used herein includes, e.g., an anticancer drug, preferably an anti-endocrinetumor agent, anti-inflammatory and/or immunomodulatory and/or antiallergic drug…” (see e.g., [0095]-[0097]), it does not mean only “an anticancer drug” or a second drug substance for treating endocrine tumor invasiveness can be incorporated as the second drug substance in the kit. Rather, the disclosure of Marks et al. clearly teaches the incorporation of at least one second drug substance useful for treating symptoms associated with tumor growth. Thus, the mere fact that the ketamine taught by Grassi et al. is not used for the treatment of cancer does not constitute a teaching away from incorporating said ketamine as the second drug substance, because said ketamine is clearly taught by the prior art to be useful for treating symptoms associated with tumor growth and that is clearly not excluded by the teachings of Marks et al.
Second, applicant’s argument that rapid-acting antidepressants (such as ketamine) and mTOR inhibitors (such as rapamycin) are “two contraindicated drugs” that are expected to fail for combining in a kit are not found persuasive (see e.g., p. 14, 2nd paragraph in the remark), this appears to be mere arguments without any objective evidence supported by an appropriate affidavit or declaration. It is respectfully noted that applicant was citing Fan et al., Li et al. and Dwyer et al., respectfully, to support that the ketamine of Grassi et al. incorporated as the second drug substance in the kit of Marks et al. would render the kit inoperable; However, none of these references states rapid-acting antidepressants and mTOR inhibitors are “contraindicated”. Additionally, Marks et al. and Grassi et al. set forth in the rejection of record also does not teach these two agents are “contraindicated”. While the rejection of record does not rely on Fan et al., Li et al. and Dwyer et al. to form the basis of rejection, each of these references has been fully considered by the Examiner. Soley to rebut applicant’s assertion that the proposed modification or combination of the prior art(s) would change the principle of operation of the prior art invention being modified (i.e., treating symptoms associated with such tumor growth), it is respectfully noted that applicant fails to evaluate these reference(s) in its entirety. For instance, applicant appears to rely on page 2358, right column, 2nd paragraph of Fan et al. shown below:
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(see e.g., p. 2358, right column, 2nd paragraph), to support that mTOR signaling is required for the rapid-acting antidepressant activity of ketamine; However, such assertion is not found within the disclosure of Fan et al. noted above. Instead, Fan et al. clearly teaches ketamine, a high-affinity, noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist (see e.g., p. 2357, right column), demonstrates rapid antidepressant effects on suicidal ideation and overall depression level in patients with
newly-diagnosed cancer (see e.g., abstract). Fan et al. explicitly teaches the biological mechanism underlying the rapid-acting antidepressant activity of ketamine remains largely unknown, and further indicates that there are several mechanisms involved in its antidepressant action, including activation of [Symbol font/0x61]-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, protein synthesis through eukaryotic translation elongation factor 2 dephosphorylation, and the mammalian target of rapamycin signaling noted by the Applicant. In other words, while mammalian target of rapamycin signaling is one of the many underlying mechanisms of ketamine, one of ordinary skill in the art would have reasonably understood that said mammalian target of rapamycin signaling is not the sole mechanism attributed to ketamine’s rapid antidepressant response. Therefore, the fact that a mTOR inhibitor is in the kit of Mark et al., it does not mean an NMDA receptor antagonist ketamine, that exhibits antidepressant action through several mechanisms, including mTOR signaling, would absolutely be unusable in said kit.
Furthermore, soley to rebut applicants’ assertion that the use of rapamycin (a mTOR inhibitor) completely abolishes the antidepressant effect of ketamine (a rapid-acting antidepressant), such assertion is not found persuasive because according to Autry et al. (Nature, 2011. Vol. 475(7354): 91-95), “[i]n earlier work, rapamycin prevented ketamine-mediated antidepressant responses; however, the link between rapamycin and antidepressant-like effects is equivocal. We tested whether pre-treatment with rapamycin could block acute ketamine-mediated FST behaviour. Thirty minutes after ketamine administration, wild-type mice showed antidepressant responses unaffected by rapamycin treatment“ (see e.g., p. 93, left column, last paragraph; Supplementary Fig. 11h); and concludes “fast-acting antidepressant like effects cannot be elicited by disinhibition of behavioural circuitry, or by evoked neurotransmission, but must rely on enhanced neurotransmission after NMDAR-antagonist-induced plasticity, occurring at rest … the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 kinase, resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor … inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects” (see e.g., abstract). In other words, while applicant relies on Li et al. to teach intracerebroventricular (ICV) infusion of rapamycin given 30 minutes before the intraperitoneal administration of ketamine (10 mg/kg) fails to produce antidepressant responses in the force swim test (FST), novelty suppressed feeding test (NSFT), or learned helplessness (LH) (see e.g., Fig. 3) to support ketamine of Grassi et al. cannot be use as the second drug substance with the mTOR inhibitor of Marks et al. in a kit, one of ordinary skill in the art would have also understood that rapamycin pretreatment does not necessarily block the antidepressant effects of ketamine, and the fast-acting antidepressant-like effects of ketamine cannot simply rely on disinhibition of behavioural circuitry, as evidenced by Autry et al. noted above. Especially, the obviousness-type rejection of the record is not form on the basis that Marks et al. teaches the administration of mTOR inhibitor and second drug substance in the kit in a time specific manner specially challenged by applicant (rapamycin given 30 minutes before the ketamine); rather, the rejection is form on the basis whether there is some teaching, suggestion, or motivation to combine or modify the teachings of the Marks et al. to produce the claimed kit by selecting ketamine of Grassi et al. as the second drug substance for the purpose of treating cancer-related symptoms.
According to MPEP 2143.02, I, the Examiner is not required to provide conclusive proof of efficacy to demonstrate a reasonable expectation of success for the obviousness-type rejection. See In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). In addition, obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g.,In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). In this case, the claimed invention(s) is drawn to a product (i.e., a kit) that combines the rapid-acting antidepressant and the mTOR inhibitor rather than a method of use. The mere fact that rapamycin (a mTOR inhibitor) scheduled 30 minutes before ketamine (a rapid-acting antidepressant) fails to produce antidepressant responses in FST, NSFT, and LH in rat in the studies disclosed by other authors, it does not mean there is no motivation or reasonable expectation of success to combine the mTOR inhibitor of Marks et al., including rapamycin, with ketamine of Grassi et al. in a kit, which can be administered at a different schedule, such as concomitant use or 12 hours apart, for treating symptoms associated with tumor growth. If applicant contends the incorporation of rapamycin or temsirolimus with ketamine in a kit arrive at an unusable kit, said objective evidence is respectfully requested.
In view of the foregoing, applicant’s arguments are not found persuasive. The rejection of record has been maintained but revisited and modified in view of the claim amendments.
Claims 1, 3, 8, 12-13, 33-39, 45, 49, 51, 53, 57, 59, and 61 remain rejected under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017) as applied to claims 1, 12-13, 33-35, 37-39, 45, 49, 53, 57 and 59 above, and further in view of Weg et al. (US 6,248,789 B1).
The teachings of Marks et al. and Grassi et al. are sets forth above and applied as before.
Marks et al. and Grassi et al. does not teach the therapeutically effective dose of the RAAD in claims 3, 36, 51 and 61. Marks et al. and Grassi et al. also does not teach an applicator in claim 8.
Weg et al. teaches oral administration of ketamine, a NMDA receptor antagonist (see e.g., Col. 1, line 60-61), for the treatment of pain from many causes, including but not limited to, inter alia, cancer (see e.g., Col. 5, line 3 to 14). Weg et al. further teaches the dose of ketamine is about 0.01 mg per kg of body weight (0.01 mg/kg) to about 1 mg/kg, preferably about 0.05 mg/kg to about 0.7 mg/kg (see e.g., Col.6 , line 36-39). Weg et al. further teaches in yet another embodiment, the dose ranges from about 1 mg to about 30 mg (see e.g., Col. 6, line 39-41). Weg et al. further teaches the term “ketamine,” as one of ordinary skill would presume, are isomers and enantiomers thereof that demonstrate analgesic properties, e.g., with greater potency or fewer side effects, or both (see e.g., Col. 7, line 22-25). Weg et al. further teaches in addition to the effects of ketamine alone administered via a transmucosal, transdermal, or oral route, which is particularly effective for breakthrough or spike pain conditions, the present invention is directed to administration of ketamine via any route, including parenteral administration in addition to transmucosal, transdermal, and oral administration parenteral administration (see e.g., p. 10, line 16-22). Weg et al. further teaches the advantages of transmucosal, transdermal, and oral administration for drug delivery are that they do not require injection using a syringe and needle (see e.g., Col. 7, line 39-41).
Regarding claims 3, 36, 51, and 61, 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). 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 kit of Marks et al. and Grassi et al. sets forth above by incorporating the second drug substance ketamine at the dose of about 0.01 mg/kg to about 1 mg/kg taught by Weg et al. One would have been motivated to do so, because Marks et al. teaches the second drug substance can be in an unit dosage from about 0.1 mg to about 1500 mg; and Weg et al. teaches the dose of ketamine ranges from about 1 mg to about 30 mg, and about 0.01 mg/kg to about 1 mg/kg for the treatment of pain caused by cancer. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the ketamine in the kit of Marks et al. and Grassi et al. at the therapeutically effective dose of 0.01 mg/kg to about 1 mg/kg taught by Weg et al. would successfully treat the cancer-related symptoms.
Regarding the limitation of “the kit further comprises an applicator” in claim 8, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to further modify the kit of Marks et al. and Grassi et al. sets forth above to further incorporate a syringe and needle taught by Weg et al. to arrive at the claimed invention. One would have been motivated to do so, because Marks et al. teaches the second drug substance can be in form of (injectable) solutions; and Weg et al. teaches the administration of ketamine can include any route, such as parenteral administration, and injection requires the use of a syringe and needle. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the incorporation of a syringe and a needle as an applicator in the kit is essential for injection.
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 June 9, 2026 with respect to the rejection of claims 1, 3, 8, 12-13, 31-39, 45, 49, 51, 53, 57, 59, and 61 are rejected under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017) as applied to claims 1, 12-13, 31-35, 37-39, 45, 49, 53, 57 and 59 above, and further in view of Weg et al. (US 6,248,789 B1) have been fully considered but they are not persuasive.
All rejections pertaining to claims 31-32 are moot because the claims were cancelled in view of the amendments filed on June 9, 2026.
In Summary, applicant presents the same arguments against Marks et al. and Grassi et al., and argues that Weg et al. does not cure the deficiencies of Marks et al. and Grassi et al.
In response, as Applicant's arguments over Marks et al. and Grassi et al. are not persuasive for the reasons set forth above and are applied as before, the rejection of record has been maintained but revisited and modified in light of the claim amendment.
Claims 14, 18, 21-23, 30, 48, 50, 55-56, 58, 60 and 62 remain rejected under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017) and Weg et al. (US 6,248,789 B1).
Marks et al. teaches a combination of an mTOR inhibitor with at least one second drug substance, e.g. for any use as indicated under 1.1 to 1.8, including a method for treating endocrine tumors and a method for treating endocrine tumor invasiveness or symptoms associated with such tumor growth (see e.g., [0041], [0045], [0064]); wherein the mTOR inhibitor is selected from, inter alia, rapamycin, 40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoate]-rapamycin (also known as temsirolimus), and/or compound A (see e.g., [0101]-[0112]; [0005]). Marks et al. further teaches the mTOR inhibitor may be used, e.g., in any method of 1.1 to 1.8 alone or in combination with one or more, at least one, second drug substance, in which 1.1 is drawn to a method for treating endocrine tumors (see e.g., [0041]; [0062]). Marks et al. further teaches endocrine tumors include endocrine or neuroendocrine tumor symptoms and pituitary tumor symptoms (see e.g., [0061]), wherein the endocrine or neuroendocrine tumor symptoms includes, inter alia, chest pain (see e.g., [0057]); and the pituitary tumor symptoms includes, inter alia, moodiness or depression, anxiousness (see e.g., [0059]). Marks et al. further teaches in the combination, an mTOR inhibitor, such as rapamycin or rapamycin derivative, may be administered as appropriate, e.g. in dosages which are known for mTOR inhibitors, by any administration route, e.g. orally or parenterally; e.g. everolimus may be administered, e.g. orally, in dosages from 0.1 mg up to 15 mg, in dosages more preferably from 0.5 mg to 10 mg, e.g. in the form of (dispersible) tablets; Rapamycin or e.g. temsirolimus may be administered parenterally in similar dosage ranges (see e.g., [0089]). Marks et al. teaches combinations include fixed combinations, in which an mTOR inhibitor and at least one second drug substance are in the same formulation; kits, in which an mTOR inhibitor and at least one second drug substance in separate formulations are provided in the same package, e.g. with instruction for co-administration; and free combinations in which an mTOR inhibitor and at least one second drug substance are packaged separately, but instruction for concomitant or sequential administration are given (see e.g., [0071]). Marks et al. further teaches a second drug substance according to the present invention may be administered by any conventional route, for example enterally, e.g. including oral administration; and parenterally; e.g., in form of capsules, (injectable) solutions (see e.g., [0091]); unit dosage form may contain, for example, from about 0.1 mg to about 1500 mg (see e.g., [0092]).
Marks et al. does not teach the rapid-acting antidepressant instantly claimed.
Grassi et al. teaches the use of psychotropic drugs, namely those with an antidepressant profile, is a mandatory part of an integrated treatment of psychiatric disorders among cancer patients (see e.g., abstract, background). Grassi et al. further teaches antidepressants have been shown to be effective in the treatment of both psychiatric (depressive spectrum, stress-related disorder and anxiety disorders) and non-psychiatric cancer-related symptoms (e.g., pain, hot flashes and fatigue) (see e.g., abstract, design; p. 101, right column, line 5-11). Grassi et al. further teaches psychostimulants and other drugs, including ketamine (N-methyl-D-aspartate receptor antagonist), have been use to rapidly alleviate depression in cancer patients (see e.g., Table 1, class - “psychostimulants and other drugs”; p. 105, right column, line 16-30). Grassi et al. further teaches in setting of terminal disease, the rapid onset of action of psychostimulants/ketamine may be preferable (see e.g., p. 107, Table 2, “Factors to be considered when prescribing Ads in cancer” section).
Weg et al. teaches oral administration of ketamine, a NMDA receptor antagonist (see e.g., Col. 1, line 60-61), for the treatment of pain from many causes, including but not limited to, inter alia, cancer (see e.g., Col. 5, line 3 to 14). Weg et al. further teaches the dose of ketamine is about 0.01 mg per kg of body weight (0.01 mg/kg) to about 1 mg/kg, preferably about 0.05 mg/kg to about 0.7 mg/kg (see e.g., Col.6 , line 36-39). Weg et al. further teaches in yet another embodiment, the dose ranges from about 1 mg to about 30 mg (see e.g., Col. 6, line 39-41). Weg et al. further teaches the term “ketamine,” as one of ordinary skill would presume, are isomers and enantiomers thereof that demonstrate analgesic properties, e.g., with greater potency or fewer side effects, or both (see e.g., Col. 7, line 22-25). Weg et al. further teaches in addition to the effects of ketamine alone administered via a transmucosal, transdermal, or oral route, which is particularly effective for breakthrough or spike pain conditions, the present invention is directed to administration of ketamine via any route, including parenteral administration such as intravenous injection (see e.g., p. 10, line 16-22 and 46-47).
Regarding claims 14, 18, 21-23, 48, 55, 56 and 62, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to combine a dose of 0.5 mg-10 mg rapamycin or temsirolimus of Marks et al. with a dose of about 0.01 mg/kg to 1 mg/kg ketamine of Weg et al. as the second drug substance in the form of a kit to arrive at the claimed invention. Please note the ketamine taught by Weg et al. is a racemic ketamine. One would have been motivated to do so, because each is taught by the prior art to be useful for treating cancer-related symptoms. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). One would have been further motivated to do so, because Marks et al. teaches 0.5 mg to 10 mg of an mTOR inhibitor, including temsirolimus, can be used alone for treating endocrine tumors, and said mTOR inhibitor can also be combined with a second drug substance in the same formulation administered by any conventional route, such as intravenous, for treating symptoms associated with such tumor growth; Grassi et al. teaches a psychostimulant, including ketamine, can be used to treat cancer-related symptoms in cancer patients; and Weg et al. teaches the dose of ketamine is 0.01 mg/kg to about 1 mg/kg ketamine for treating cancer-related pain, and said administration of ketamine can includes any route, including intravenous. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the combination of a dose of 0.5 mg-10 mg rapamycin or temsirolimus with a dose of 0.01 mg/kg to 1 mg/kg ketamine suitable for administration, such as intravenous, in a kit would reasonably expected to be useful for treating cancer-related symptoms or treating endocrine tumors in addition to treating cancer-related symptoms.
Regarding the limitation of “the kit further comprises an applicator” in claim 30, 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 kit of Marks et al., Grassi et al. and Weg et al. sets forth above to further incorporate a syringe and needle taught by Weg et al. to arrive at the claimed invention. One would have been motivated to do so, because Marks et al. teaches the second drug substance can be in form of (injectable) solutions; and Weg et al. teaches the administration of ketamine can include any route, such as parenteral administration, and injection requires the use of a syringe and needle. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the incorporation of a syringe and a needle as an applicator in the kit is essential for injection.
Regarding the limitation of “wherein the mood disorder is…” in claims 50, 58 and 60, the limitation pertains to the intended use of the RAAD and the mTOR inhibitor. Since the claim is interpreted to be a product, the mood disorder recites in the claim does not create a structural difference to the claimed product; and therefore, the mood disorder is not limiting, and the kit of Marks et al., Grassi et al. and Weg sets forth above meets the structural limitation of the kit instantly claimed.
Therefore, the claimed invention is prima facie obvious for 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 June 9, 2026 with respect to the rejection of Claims 14-16, 18, 21-23, 30, 48, 50, 55-56, 58, 60 and 62 under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017) and Weg et al. (US 6,248,789 B1) have been fully considered but they are not persuasive.
All rejections pertaining to claims 15-17 are moot because the claims were cancelled in view of the amendments filed on June 9, 2026.
In this case, applicant amends claim 14 by deleting the recitation that includes the dose of the mTOR inhibitor (“less than about 15 mg”), and further amends the claims by adding the new limitation that recites “
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”, and that changes the scope of the claims.
In Summary, applicant presents the same arguments against Marks et al. and Grassi et al., and argues that Weg et al. does not cure the deficiencies of Marks et al. and Grassi et al.
In response, as Applicant's arguments over Marks et al. and Grassi et al. are not persuasive for the reasons set forth above and are applied as before, the rejection of record has been maintained but revisited and modified in light of the claim amendment.
Claims 14, 18-23, 30, 48, 50, 55-56, 58, 60 and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017) and Weg et al. (US 6,248,789 B1) as applied to claims 14, 18, 21-23, 30, 48, 50, 55-56, 58, 60 and 62 above, and further in view of Rey (WO 2018/234568 A2).
The teachings of Marks et al., Grassi et al., and Weg et al. are set forth above and applied as before.
Marks et al., Grassi et al., and Weg et al. does not teach the (R)-ketamine as claimed in claim 19. Marks et al., Grassi et al., and Weg et al. does not teach the (S)-ketamine in claim 20.
Rey teaches hydroxynorketamine for the use in the treatment of depression (see e.g., title; page 1, line 2-4). Rey further teaches the antidepressant effect of intraperitoneal administered (R,S)-ketamine
revealed that the metabolism of (R,S)-ketamine into (2S,6S;2R,6R)-hydroxynorketamine is essential for the antidepressant effect (see e.g., p. 1, line 32-35). Rey further teaches hydroxynorketamine is administered in form of at least one prodrug selected from, inter alia, (S)-Ketamine, (R)-Ketamine, (R,S)-Ketamine or pharmaceutically salts or solvates or mixtures thereof (see e.g., claims 1 and 4).
Regarding the limitation of “(R)-Ketamine” in claim 19, 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 kit of Marks et al., Grassi et al. and Weg et al. sets forth above by substituting the ketamine with (R)-ketamine of Rey to arrive at the claimed invention. One would have been motivated to do so, because Rey teaches the prodrug of hydroxynorketamine, including (R,S)-ketamine and (R)-ketamine, can be interchanged for treating depression. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by substituting the ketamine in the kit with (R)-ketamine would have exerted the same or substantially similar effects as ketamine in treating cancer-related symptoms.
Regarding the limitation of “(S)-Ketamine” in claim 20, 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 kit of Marks et al., Grassi et al. and Weg et al. sets forth above by substituting the ketamine with (S)-ketamine of Rey to arrive at the claimed invention. One would have been motivated to do so, because Rey teaches the prodrug of hydroxynorketamine, including (R,S)-ketamine and (S)-ketamine, can be interchanged for treating depression. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by substituting the ketamine in the kit with (S)-ketamine would have exerted the same or substantially similar effects as ketamine in treating cancer-related symptoms.
Therefore, the claimed invention is prima facie obvious for 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 June 9, 2026 with respect to the rejection of claims 14-23, 30, 48, 50, 55-56, 58, 60 and 62 under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017) and Weg et al. (US 6,248,789 B1) as applied to claims 14-16, 18, 21-23, 30, 48, 50, 55-56, 58, 60 and 62 above, and further in view of Rey (WO 2018/234568 A2) have been fully considered but they are not persuasive.
All rejections pertaining to claims 15-17 are moot because the claims were cancelled in view of the amendments filed on June 9, 2026.
In Summary, applicant presents the same arguments against Marks et al. and Grassi et al., and argues that Weg et al. and Rey do not cure the deficiencies of Marks et al. and Grassi et al.
In response, as Applicant's arguments over Marks et al. and Grassi et al. are not persuasive for the reasons set forth above and are applied as before, the rejection of record has been maintained but revisited and modified in light of the claim amendment.
Claims 63 and 64 remain rejected under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017), and Weg et al. (US 6,248,789 B1).
Marks et al. teaches a combination of an mTOR inhibitor with at least one second drug substance, e.g. for any use as indicated under 1.1 to 1.8, including a method for treating endocrine tumors and a method for treating endocrine tumor invasiveness or symptoms associated with such tumor growth (see e.g., [0041], [0045], [0064]); wherein the mTOR inhibitor is selected from, inter alia, rapamycin, 40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoate]-rapamycin (also known as temsirolimus), and/or compound A (see e.g., [0101]-[0112]; [0005]). Marks et al. further teaches the mTOR inhibitor may be used, e.g., in any method of 1.1 to 1.8 alone or in combination with one or more, at least one, second drug substance, in which 1.1 is drawn to a method for treating endocrine tumors (see e.g., [0041]; [0062]). Marks et al. further teaches endocrine tumors include endocrine or neuroendocrine tumor symptoms and pituitary tumor symptoms (see e.g., [0061]), wherein the endocrine or neuroendocrine tumor symptoms includes, inter alia, chest pain (see e.g., [0057]); and the pituitary tumor symptoms includes, inter alia, moodiness or depression, anxiousness (see e.g., [0059]). Marks et al. further teaches in the combination, an mTOR inhibitor, such as rapamycin or rapamycin derivative, may be administered as appropriate, e.g. in dosages which are known for mTOR inhibitors, by any administration route, e.g. orally or parenterally; e.g. everolimus may be administered, e.g. orally, in dosages from 0.1 mg up to 15 mg, in dosages more preferably from 0.5 mg to 10 mg, e.g. in the form of (dispersible) tablets; Rapamycin or e.g. temsirolimus may be administered parenterally in similar dosage ranges (see e.g., [0089]). Marks et al. teaches combinations include fixed combinations, in which an mTOR inhibitor and at least one second drug substance are in the same formulation; kits, in which an mTOR inhibitor and at least one second drug substance in separate formulations are provided in the same package, e.g. with instruction for co-administration; and free combinations in which an mTOR inhibitor and at least one second drug substance are packaged separately, but instruction for concomitant or sequential administration are given (see e.g., [0071]). Marks et al. further teaches a second drug substance according to the present invention may be administered by any conventional route, for example enterally, e.g. including oral administration; and parenterally; e.g., in form of capsules, (injectable) solutions (see e.g., [0091]); unit dosage form may contain, for example, from about 0.1 mg to about 1500 mg (see e.g., [0092]).
Marks et al. does not teach the rapid-acting antidepressant, racemic ketamine, instantly claimed.
Grassi et al. teaches the use of psychotropic drugs, namely those with an antidepressant profile, is a mandatory part of an integrated treatment of psychiatric disorders among cancer patients (see e.g., abstract, background). Grassi et al. further teaches antidepressants have been shown to be effective in the treatment of both psychiatric (depressive spectrum, stress-related disorder and anxiety disorders) and non-psychiatric cancer-related symptoms (e.g., pain, hot flashes and fatigue) (see e.g., abstract, design; p. 101, right column, line 5-11). Grassi et al. further teaches psychostimulants and other drugs, including ketamine (N-methyl-D-aspartate receptor antagonist), have been use to rapidly alleviate depression in cancer patients (see e.g., Table 1, class - “psychostimulants and other drugs”; p. 105, right column, line 16-30). Grassi et al. further teaches in setting of terminal disease, the rapid onset of action of psychostimulants/ketamine may be preferable (see e.g., p. 107, Table 2, “Factors to be considered when prescribing Ads in cancer” section).
Weg et al. teaches oral administration of ketamine, a NMDA receptor antagonist (see e.g., Col. 1, line 60-61), for the treatment of pain from many causes, including but not limited to, inter alia, cancer (see e.g., Col. 5, line 3 to 14). Weg et al. further teaches the dose of ketamine is about 0.01 mg per kg of body weight (0.01 mg/kg) to about 1 mg/kg, preferably about 0.05 mg/kg to about 0.7 mg/kg (see e.g., Col.6 , line 36-39). Weg et al. further teaches in yet another embodiment, the dose ranges from about 1 mg to about 30 mg (see e.g., Col. 6, line 39-41). Weg et al. further teaches the term “ketamine,” as one of ordinary skill would presume, are isomers and enantiomers thereof that demonstrate analgesic properties, e.g., with greater potency or fewer side effects, or both (see e.g., Col. 7, line 22-25). Weg et al. further teaches in addition to the effects of ketamine alone administered via a transmucosal, transdermal, or oral route, which is particularly effective for breakthrough or spike pain conditions, the present invention is directed to administration of ketamine via any route, including parenteral administration such as intravenous injection (see e.g., p. 10, line 16-22 and 46-47).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to combine 0.5 mg to 10 mg temsirolimus of Marks et al. with about 0.01 mg/kg to 1 mg/kg ketamine of Weg et al. as the second drug substance in the same formulation in the kit to arrive at the claimed invention. Please note the ketamine taught by Weg et al. is a racemic ketamine. One would have been motivated to do so, because each is taught by the prior art to be useful for treating cancer-related symptoms. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). One would have been further motivated to do so, because Marks et al. teaches 0.5 mg to 10 mg of an mTOR inhibitor, including temsirolimus, can be used alone for treating endocrine tumors, and said mTOR inhibitor can also be combined with a second drug substance in the same formulation administered by any conventional route, such as intravenous, for treating symptoms associated with such tumor growth; Grassi et al. teaches a psychostimulant, including ketamine, can be used to treat cancer-related symptoms in cancer patients; and Weg et al. teaches the dose of ketamine is 0.01 mg/kg to about 1 mg/kg ketamine for treating cancer-related pain, and said administration of ketamine can includes any route, including intravenous. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the combination of 0.5 mg-10 mg temsirolimus with 0.01 mg/kg to 1 mg/kg ketamine in the same formulation suitable for intravenous administration in a kit would have reasonably expected to be similarly useful for treating cancer-related symptoms or treating endocrine tumors in addition to treating cancer-related symptoms.
Therefore, the claimed invention is prima facie obvious for 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 June 9, 2026 with respect to the rejection of claims 63 and 64 under 35 U.S.C. 103 as being unpatentable over Marks et al. (US 2008/0255029 A1) in view of Grassi et al. (Ann Oncol, 2018. Vol. 29(1):101-111. Published online on October 9, 2017), and Weg et al. (US 6,248,789 B1) have been fully considered but they are not persuasive.
In this case, applicant amens the claims by deleting the recitation of “when administered
in combination with a therapeutically effective dose of a mammalian target of rapamycin
(mTOR) inhibitor” from the rapid-acting antidepressant, and deletes “sufficient to treat or
ameliorate the major depressive disorder in the human subject when administered in combination
with the therapeutically effective dose of the RAAD,” from the mTOR inhibitor.
In Summary, applicant presents the same arguments against Marks et al. and Grassi et al.
In response, as Applicant's arguments over Marks et al. and Grassi et al. are not persuasive for the reasons set forth above and are applied as before, the rejection of record has been maintained but revisited and modified in light of the claim amendment.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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