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 .
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.
Current Status of 18/003,561
This Office Action is responsive to the amended claims received 6 January 2026.
Claims 31-39, 41-44, and 46-50 are currently pending.
Priority
Applicant’s claim for the benefit of the prior-filed patent applications PCT/IL2021/050787 (filed 28 June 2021) and 63/046,791 (filed 1 July 2020) under 35 U.S.C. 119(e), 120, 121, 365(c), or 386(c) is acknowledged.
Response to Amendments
The objections to the claims, present in the previous office action, are hereby withdrawn due to Applicant’s amendments. New objections are presented herein.
The 35 U.S.C. 112 rejections to the claims, present in the previous office action, are hereby withdrawn due to Applicant’s amendments.
The 35 U.S.C. 103 rejections to the claims, present in the previous office action, are maintained herein, although they have been altered as necessitated by Applicant’s amendments.
Response to Arguments
Applicant argues that “the mere fact that two compounds are separately known to treat the same condition does not automatically render their combination obvious”. Applicant argues that the Examiner does not make clear why one of ordinary skill in the art would have combined ibogaine or a derivative thereof with imipramine. Applicant argues that Friedhoff teaches imipramine as a positive control and not a “therapeutic agent to be combined with ibogaine or its derivatives”. Applicant further argues that the use of imipramine as a control compound does not motivate the combination of these agents. Applicant also argues that there is no reasonable expectation of success in their combination, because the prior art does not teach or suggest that the therapeutic effect of the combination would be greater than each of the compounds individually.
FRIEDHOFF teaches the use of ibogaine and derivatives thereof for the treatment of depression within the abstract. FRIEDHOFF teaches imipramine as a positive control within a rat study in the context of therapies for depression (Examples 1 and 2). The Examiner agrees with the Applicant that FRIEDHOFF does not explicitly state that imipramine (used as a positive control in a rat model therein) should be combined with ibogaine or a derivative thereof. And obviously, FRIEDHOFF cannot then teach a synergistic effect of the same combination. KOO (Koo, O. "Manufacturing Process Considerations for Fixed-Dose Combination Drug Products" The Review of American Pharmaceutical Business & Technology, 1 April 2010) teaches that it is attractive to those of skill in the art to produce combination drug products because of potential synergistic effects arising from multiple mechanisms of action. One of ordinary skill in the art would have generally been motivated to test combinations of drugs known to treat the same condition, as evidenced by KOO. It is the Examiner’s opinion that KOO is not needed in the rejections below, but is entered here to rebut Applicant’s argument that a direct teaching of probable synergistic effects would be necessary within the prior art to motivate the artisan to test a combination drug product.
One of ordinary skill in the art would have read the details of Example 2 of FRIEDHOFF, which teaches that animals were treated with vehicle (negative control), a test compound (understood to be ibogaine or an ibogaine derivative), or imipramine (positive control). Example 4 of FRIEDHOFF then teaches the “Effect of Ibogaine on Depression in Humans”. It would have been clear to one of ordinary skill in the art that the forced swim test in Examples 1 and 2 of FRIEDHOFF are testing a rat model of depression, and are intended to be translated over to human patients, which is clear from Example 4. Given the teaching that imipramine and ibogaine/ibogaine derivatives are separately useful to treat depression (from FRIEDHOFF), and being motivated to test drug combinations (as evidenced by KOO), one of ordinary skill in the art would have quickly envisioned combining imipramine and ibogaine/ibogaine derivatives for the treatment of depression.
Claim Objections
Claim 34 is objected to because of the following informalities: The word “and” is missing before the final item in the list in claim 34. Applicant may choose to insert the word “and”. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 31-39, 41-44, 46-47, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over:
FRIEDHOFF (Cited by Applicant in IDS of 23 February 2023; Publication Number US 2015/0258112 A1; Publication Date 17 September 2015)
in view of:
EXCELLIUM (FDA Label IMIPRAMINE HYDROCHLORIDE; Excellium Pharmaceutical, Inc; Revised Oct 2012).
FRIEDHOFF teaches the administration of ibogaine or a derivative thereof for the treatment of depression and post-traumatic stress disorder (PTSD) in a patient (title, abstract). FRIEDHOFF specifically provides an exemplary dosage of 80 mg of ibogaine, or alternatively, 40 mg of noribogaine (paragraph [0138]). FRIEDHOFF teaches imipramine as a positive control within a rat study in the context of therapies for depression (Examples 1 and 2). FRIEDHOFF teaches the administration of the compounds therein once daily (paragraph [0136]).
FRIEDHOFF does not explicitly teach imipramine to be an antidepressant.
EXCELLIUM teaches that imipramine hydrochloride, being a tricyclic antidepressant, is known to treat depression (description section and indications and usage section). EXCELLIM specifically teaches imipramine hydrochloride in the form of a film-coated tablet (description section). EXCELLIUM teaches that geriatric patients should be provided 30-40 mg/day of imipramine hydrochloride (dosage and administration section).
It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, to combine the method of treating depression through administration of noribogaine or ibogaine (as taught by FRIEDHOFF) with another therapeutic agent known to treat depression, being imipramine hydrochloride (as taught by EXCELLIUM), for the purpose of increasing the antidepressant effect of the therapy. The artisan would have expected success in this combination because both compounds are separately known to treat depression.
This is an example of combining equivalent therapeutic agents known to be useful for the same purpose. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06.
Regarding claim 41: Wherein a particular disease or condition was known to be treated by a specific therapy, it would have been obvious to one of ordinary skill in the art to treat all subtypes of the same disease or condition with the same therapy, unless there is prior art that would teach away from the combination of the therapy and the subtype disease or condition. The Examiner has not found such prior art during the course of their search, nor have they found such prior art in the instant specification. Applicant is invited to provide such prior art.
Regarding claims 42-44: The outcomes within instant claims 42-44 are solely the result of administering the compound therein to a patient having a psychiatric disease or disorder. There are no positive steps recited therein that would alter these outcomes unrelated to administering the combination of instant claim 31 to the patient. Therefore, because the method of administering the combination of instant claim 31 to a patient having a psychiatric disease or disorder has been found to be obvious, these direct outcomes are also rendered obvious.
Regarding claim 46: EXCELLIUM teaches imipramine hydrochloride to be in the form of a tablet, and FRIEDHOFF teaches the compounds therein to be able to be formed into tablets (paragraph [0140]). It would have been obvious to one of ordinary skill in the art to incorporate noribogaine and imipramine hydrochloride into a single tablet composition to increase patient compliance.
Regarding claim 50: It would have been obvious to one of ordinary skill in the art to experiment with the dosage of the antidepressant imipramine hydrochloride for the purpose of increasing efficacy and decreasing unwanted effects. It would have been obvious to decrease the dosage in a patient, at least slightly, to decrease unwanted effects of the tricyclic antidepressant of EXCELLIUM.
Claims 31-39, 41-44, and 46-50 are rejected under 35 U.S.C. 103 as being unpatentable over:
FRIEDHOFF (Cited by Applicant in IDS of 23 February 2023; Publication Number US 2015/0258112 A1; Publication Date 17 September 2015)
in view of:
EXCELLIUM (FDA Label IMIPRAMINE HYDROCHLORIDE; Excellium Pharmaceutical, Inc; Revised Oct 2012)
and in view of:
MAILLET (Cited by Applicant in IDS of 23 February 2023; WO 2015/134405 A1; International Publication Date 11 September 2015).
Teachings of FRIEDHOFF and EXCELLIUM are described above.
Regarding claims 48-49: Neither FRIEDHOFF nor EXCELLIUM explicitly teach an initial high dosage of ibogaine, followed by a lower maintenance dosage.
MAILLET teaches that therapeutic dosing of ibogaine for treating depression is described therein (paragraph [0016]). MAILLET teaches that, preferably, the therapeutic dose of ibogaine or a derivative thereof is from 1 mg/kg to 8 mg/kg for the treatment of depression (paragraph [104]). MAILLET teaches that a “maintenance amount” of a drug is an amount less than the therapeutically effective amount that provides attenuation of a disease or disorder (paragraph [0194]). MAILLET teaches a range of maintenance doses for ibogaine in paragraph [0141], from 0.1 to 1.5 mg/kg. MAILLET teaches that a high initial therapeutic dose can be followed by a lower maintenance dose (paragraph [0066]).
It appears that the teachings of MAILLET, regarding a high initial dose and a lower maintenance dose, are at least primarily focused on treating addiction, but at least some of these teachings appear to be generic to all diseases and disorders therein. At 8 mg/kg, a 75 kg patient would require a 600 mg therapeutic dose of ibogaine for treating depression. Based upon the teachings of paragraph [0141] of MAILLET, the maintenance dose of ibogaine would be from 6.5 mg to 97.5 mg. 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). See MPEP 2144.05(I).
It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, to apply the dosing schedule for the administration of ibogaine (taught by MAILLET) to the method of treating depression through administering ibogaine and imipramine hydrochloride (rendered obvious by FRIEDHOFF and EXCELLIUM), for the purpose of decreasing unwanted effects of these compounds. The artisan would have expected success when applying the dosing schedule of MAILLET, because MAILLET claims this dosing schedule is advantageous for the same compound that is taught by FRIEDHOFF.
Conclusion
No claims are currently allowable.
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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/JDMc/Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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