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 1-8, 10, 11, 13, 15-21, 23 and 24 are pending and under consideration.
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 § 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 1-8, 10, 11, 13, 15-21, 23 and 24 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Roussel et al. (WO 2018211311).
The present application claims a method of preparing buprenorphine or a salt thereof by reacting a benzyl halide, benzyl sulfonate or activated benzyl alcohol with compound HO-I-H to obtain the di-benzyl compound BnO-I-Bn in a polar protic solvent, see step (i)(F) in the scheme below. Compound BnO-I-Bn is reacted with methyl vinyl ketone in a polar protic solvent to obtain the Diels Alder adduct compound BnO-II-Bn, see step (ii)(B) below. The product of the Diels Alder reaction is reacted with t-butylmagnesium in a nonpolar solvent to obtain a Grignard reaction product BnO-IIIA-Bn, see step (iii)(D) below. The Grignard adduct BnOIIIA-Bn is then hydrogenated to remove both benzyl groups and reduce the double bond to afford compound HO-IV-H. The last reaction step converts compound HO-IV-H to buprenorphine, see steps (v)(A1), (v)(A2) and (v)(A3) below.
The ‘331 publication teaches all the steps noted above, see pages 14-16, paragraph [0014]; page 79, Table 10; and pages104-108, Examples 31-35.
The only difference between the process in the present application and the ‘331 publication is wherein compound BnO-I-Bn is reacted with methyl vinyl ketone in a nonpolar solvent, e.g. toluene or see paragraph [0012] on page 53 for other nonpolar solvents, to obtain the Diels Alder adduct compound BnO-II-Bn, see step (ii)(B) below.
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510
681
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The present application provides comparative data to show the difference between using a polar solvent versus a nonpolar solvent, see Table 2 on page 27 of the specification and below.
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762
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Table 2 provides results for wherein compound BnO-I-Bn is reacted with methyl vinyl ketone (MVK) in a Diels Alder cyclization varying the solvent, e.g. isopropanol (a polar protic solvent); 33% water with 67% isopropanol (both polar protic solvents); isopropyl acetate (polar aprotic solvent); and toluene (nonpolar solvent), the equivalents of MVK and at different times. The reference reaction with toluene was not duplicated for a direct comparison because none of the other reported reactions in Table 2 was done with 20 equivalents of MVK. Even if, arguendo, less equivalents of MVK are required with a polar solvent, the referenced reaction with toluene gave better results, 93.8% yield of the major isomer, while none of the other yields were above 86.4% for the major isomer. The 86.4% yield was obtained when isopropanol was used with 16 equivalents of MVK and 2 hours of reaction time compared with the same reaction time and 20 equivalents of MVK and 93.8% yield. The results for the other reactions required longer reaction times although < 16 equivalents of MVK were used.
The specification states, “The above results show that, desirably, Step F can be prepared in the same solvent mixture as Step B. Further, Step F can be efficiently performed utilizing the crude reaction product of Step B without substantial intervening purification or solvent removal,” see page 28, paragraph [0087]. This is a bit confusing since step F occurs prior to step B. So how can step F be efficiently performed utilizing the crude reaction product of Step B? Steps F and B both use a polar protic solvent. May be the crude product of step F may be used in step B is what is intended? One may argue that the solvent system for the next step, step D, is a nonpolar solvent, e.g. toluene, and the crude product from step B can be utilized in step D since the reference teaches both steps in a nonpolar solvent system? It is not clear why changing the solvent system in step B is critical, unless Applicant can provide evidence to the contrary.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 105 USPQ 233, 235 (CCPA 1955). The adjustment of particular conventional working conditions (e.g., determining result effective variables), is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. Accordingly, this type of modification would have been well within the purview of the skilled artisan and no more than an effort to optimize results.
Thus, said claims are rendered obvious.
Applicant traverses by contending, “[A] person of ordinary skill in
the art will appreciate that small molecules such as buprenorphine must be provided in sufficiently pure form for use as a therapeutic. Thus, obtaining a product mixture having a high diastereomeric ratio is material, especially on larger scales, as the minor diastereoisomer is often difficult to remove by purification. While the Diels-Alder reaction with toluene does provide the highest yield of the major isomer, it also provides the highest amount of the minor isomer (i.e., 4.4%), leading to a diastereomeric ratio of 21:1. In contrast, the Diels-Alder reactions performed with polar protic solvents (i.e., EXP.s A, B, and C) all provide unexpectedly higher diastereomeric ratios (i.e., at least 38:1) at reaction times of 20 h.”
This is not persuasive. Applicant’s contention was in response to the Examiner noting that the comparison in Table 2 of the cited reaction in the art is not replicated with the exact conditions. While the Examiner agrees that a diastereoselective reaction may be of interest in the pharmaceutical industry, there is nothing of record indicating the separation of the formed diastereomers is an issue. Thus, a higher yielding reaction may be better than a diastereoselective reaction. Moreover, less time in a reactor versus separating diastereomers, or separating two components versus three components, may be more favorable.
Applicant further argues “Roussel does not disclose the use of polar protic solvents for performing the Diels-Alder reaction of Step B. Furthermore, the art of chemical synthesis can be highly unpredictable, and thus the person of ordinary skill in the art would not have been able to predict how such changes in solvent can result in changes in diastereoselectivity (e.g. through stabilizing transition states and reactive intermediates leading to the desired product through hydrogen bonding and dielectric effects). For at least these reasons, the requirement of a polar protic solvent for Step B is not an instance of routine optimization under In re Aller.”
This is also not persuasive. Changes in temperature, concentrations, reaction times, solvents, etc., is routine optimization in an organic chemistry lab, unless there is evidence to the contrary.
Applicant further states, “The claimed polar protic solvent regime enables the telescoping of Step F and Step B” and Polar protic solvents improve the overall yield of the reaction sequence.” This is partially persuasive. The Examiner agrees that the telescoping of Step F and B unexpected increases the overall yield of the reaction sequence, as noted by Applicant in the Table below:
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705
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66
696
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However, as also noted by Applicant in their Remarks, “[T]he art of chemical synthesis can be highly unpredictable.” Thus, the claims must be commensurate in scope with the unexpected results. The solvent system for step B has only been shown with a solvent system comprising a limited variation of a polar solvent system.
MPEP 716.02(D) states, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of non-obviousness 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). The non-obviousness of 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. In re Kollman, 595 F.2d 48, 201 USPQ 193 (CCPA 1979).
Thus, the rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-8, 10, 11, 13, 15-21, 23 and 24 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1 and 8-12 of U.S. Patent No. 11390628. Although the conflicting claims are not identical, they are not patentably distinct from each other because the same rationale provided in the 103 art rejection is equally applicable here.
Applicant traverses by stating, “As demonstrated in the table above, the claims in the present application are different from those of the '628 patent in that the solvents utilized in the former are polar protic. This difference gives rise to unanticipated benefits, as shown in the improved yields listed on the right-side column of the table shown above. Thus, after close examination of these claims and of the sections of the specification that correspond to them, there is nothing in the '628 patent that suggests that using polar protic solvents could be used in the above-listed reactions, let alone with any expectation of improvement. Due to at least this reason, there would be no reason to utilize polar protic solvents with any expectation of success.”
This is unpersuasive for the same reasons noted above. This rejection may be overcome by limiting the claims based on the unexpected results as noted in the 103 rejection above. Therefore, the rejection is maintained.
Conclusion
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.
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.
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624