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 .
This is a Final Office Action.
Claims 1, 2, 7, 8, 11-16, 21, 28, 30, 37, 39, 40 and 44-46 are pending and claims 1, 2, 7, 8, and 11 are under examination. Claims 12-16, 21, 28, 30, 37, 39, 40 and 44-46 are currently withdrawn based on the species election and the restriction requirement.
Election/Restrictions
Applicant's election without traverse of Group (I) in the reply filed on November 10, 2025 is acknowledged. Group (I), drawn to the compounds in claim 1, igobaine analogues, embraced by claims 1, 2, 7, 8 and 11-13 was elected by Applicant. Applicant has not pointed to any errors in the Examiner’s analysis of the different inventions. The requirement is still deemed proper and is therefore made FINAL.
Applicant elects the following species:
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, and indicates claims 1, 2, 7, 8 and 11 read on said species. The elected species was not found during the search, and therefore, the search was expanded.
Specification
The objection to the abstract of the disclosure is withdrawn based on the amendments.
Claim Objections
Claim 11 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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 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.
Claim Rejections - 35 USC § 102
The rejection of claim(s) 1 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mash et al. (Life Sciences, 1995, 57(3), PL 45-50), is withdrawn based on the amendments.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1, 2, 7 and 8 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Mash et al. (Life Sciences, 1995, 57(3), PL 45-50).
The present application claims compounds of the following general formula, wherein X1= H, R1= H or methyl, R2= OCH3, H or methyl, R3= H or methyl, R4= H or methyl, Y1= H or methyl, Y2= H or methyl, Z1= ethyl and Z2= H or methyl:
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.
The Mash reference teaches the following species, wherein X1= H, R1= H, R2= OCH3, R3= H, R4= H, Y1= H, Y2= H, Z1= ethyl and Z2= H:
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, which is ibogaine, wherein ibogaine and ibogaine’s N-methyl (at X1) derivative have been specifically excluded by proviso by name.
Any methylated derivative at R1, R3, R4, Y1, Y2 and/or Z2 is rendered obvious by the Mash reference since a hydrogen is considered a homologue of methyl. Since a methyl group is considered a homolog of hydrogen these compounds are considered equivalent. The MPEP 2144.09 states “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Moving the methoxy on the phenyl ring of ibogaine to any of R1, R3 or R4 is also obvious based on the positional isomer rationale presented above.
The Mash reference further teaches the following species, wherein X1= H, R1= H, R2= OH, R3= H, R4= H, Y1= H, Y2= H, Z1= ethyl and Z2= H:
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,
which is noribogaine, wherein noribogaine and noribogaine’s N-methyl (at X1) derivative have been specifically excluded by proviso by name.
Again, any methylated derivative at R1, R3, R4, Y1, Y2 and/or Z2 is rendered obvious by the Mash reference since a hydrogen is considered a homologue of methyl. Moving the hydroxy on the phenyl ring of noribogaine to any of R1, R3 or R4 is also obvious based on the positional isomer rationale presented above.
Thus, the present claims are rendered obvious over Mash et al.
Applicant traverses by stating, “The subject application reports experimental data showing that methylation produces compounds having properties that would not be expected. Applicant points to Table 1 of the subject application which compares the inhibitory activity of selected ibogaine and ibogamine analogues. By directly comparing isomeric methylated analogues, it is clear that the activities of each are significantly different.”
This is not persuasive. Most of the compounds in Table 1 on page 82 of the specification are not embraced by the 103 rejection above.
Applicant further states, “For example, ibogaine (see below) is the O-methylated analogue of noribogamine (also identified by Mash as 12-hydroxyibogamine). Compound 8 is the N-methyl analogue of noribogamine. Against VMAT2, ibogaine has an IC50 value that is approximately 23.5 times higher than that of compound 8. This would indicate that, for this core structure, N-methylation improves inhibition to a much higher degree than O-methylation. As such, it is clear that the site of methylation plays a significant role in each compounds' respective activity. Therefore, the indiscriminate installation of a methyl group does not universally improve inhibitory properties of the parent compound, otherwise methylation at either site would produce compounds with similar activities against VMAT2.
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”
This is also unpersuasive. The obviousness is not over OH and OCH3 but adding a methyl group to any other position on the molecule, except nitrogen at X1 since these compounds have been removed by proviso. Also, moving the OCH3 or OH to different locations on the phenyl ring as being positional isomers.
Applicant goes to state, “Further, by directly comparing compounds with their various methylated analogues, the differences in activity are not consistent. Against VMAT2, noribogaine has an ICSO value which is nearly one-seventh than that of the O-methylated analogue, ibogaine. However, noribogaine has an ICOo value that is approximately 3.4 times higher than compound 8, its N-methylated analogue. Ibogaine itself has an ICoo value that is approximately 5.4 times higher than that of its N-methylated analogue, compound 7 (see below). This demonstrates that installation of a methyl group may either diminish or enhance a compound's efficacy
depending upon both the site and compound, and even then in the context of a specific receptor. It is also evident from comparing the inhibitory activities that a methyl group cannot be treated as or considered a homolog of a hydrogen atom, otherwise its installation would have little influence on the respective compounds' activities, regardless of the site.
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”
Again, this is not persuasive because the obviousness is not over OH and OCH3 as states above, which is equally applicable here.
Thus, the rejection is maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached Monday - Friday, 10:00 am to 7:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached on 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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