DETAILED ACTION
This Office Action is in response to Applicant’s Amendment and Remarks filed on 03 December 2025 in which claims 2-3 were canceled, and claim 1 was amended to change the scope and breadth of the claims.
Claims 1 and 4-10 are pending in the current application and are examined on the merits herein.
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 .
Response to Arguments
Applicant's arguments filed 03 December 2025 have been fully considered but they are not persuasive.
Applicant contends the present method is different from Moutou et al., because the present claims require oxidation to be performed first (while Moutou teaches deglycosylation before oxidation), the present claims require the use of t-butanol (while Moutou only teaches “acetonitrile or an alcohol in C1-C6”), the claims require crude intermediate C to be recrystallized (not taught by Moutou), and the hydrogenation reaction of present claim 1 is performed at 30 °C (while Moutou teaches a range of 40-60 °C).
While Moutou et al. teach deglycosylation before oxidation, one of ordinary skill in the art would have known from the teachings of Yan et al., that selamectin can be prepared by oxidation and then a one-pot oximation/deglycosylation.
While Moutou does not expressly disclose t-butyl alcohol, the genus of solvents taught by Moutou et al. is small, and only includes acetonitrile and C1-C6 alcohol: methanol, ethanol, propanol/iso-propanol, butanol/iso-butanol/butan-2-ol/tert-butanol, pentanol and hexanol. Thus, one of ordinary skill in the art would have been able to select the solvent from the small genus of possible solvents.
The ordinary artisan would have been motivated to perform multiple recrystallization steps to increase the purity of the desired product. Furthermore, Moutou et al. teach the use of acetonitrile to recrystallize a product after deglycosylation; and the use of toluene to recrystallize a product after deglycosylation.
With respect to temperature, the ordinary artisan would have optimized routinely these conditions to optimize yield, reaction time, formation of side-products and purity.
Applicant also contends the claimed method results in a total yield of 57% and 97.11% purity, while Moutou reports a yield of 52% and 96.7% purity (process 1) or yield of 53% and 96.2% purity (process 2). Applicant argues the yield reported by Moutou is only for a single step, while the 57% yield of the present claims is for all of the steps.
The above arguments have been carefully considered, but are not found persuasive, because Moutou et al. report obtaining 100% yield until the recrystallization step. Thus, the overall yield reported by Moutou is 52%.
The yield and purity obtained from Applicant’s claimed method does not appear to be statistically significantly better than the prior art.
The rejection is hereby maintained.
Maintained Rejection
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.
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.
Claim(s) 1 and 4-10 are rejected under 35 U.S.C. 103 as being unpatentable over Moutou et al. (WO2017/055502, cited in previous Office Action) in view of Yan et al. (CN111116692A, original and machine translation cited in previous Office Action) and Omura et al. (US Patent No. 6,605,595, cited in previous Office Action).
Moutou et al. teach a process for preparing selamectin, which comprises the steps of (1) deglycosidation of doramectin, (2) oxidizing doramectin, (3) oximation, (4) catalytic hydrogenation, and (5) recrystallizing selamectin (claim 1; also see p.4 and scheme 2). Moutou et al. teach previous synthetic routes utilize a high quantity of Wilkinson’s catalyst in the first stage, which is disadvantageous because the catalyst is particularly expensive (p.2). Moutou et al. found performing hydrogenation in a subsequent step considerably reduced the quantity of Wilkinson’s catalyst used compared to the quantities used when it’s implemented in a first step.
Deglycosidation/step (1) is performed using a strong acid in an organic solvent (claim 1). The organic solvent may be acetonitrile or a C1-C6 alcohol, such as ethanol (p.8:24-29). Oximation/step (3) is performed using hydroxylamine hydrochloride in water and an organic solvent, at 20-50°C or 20-30 °C (claims 6-8). Oximation/step (3) is generally complete after a period of 6-12 hours (p.6, 11-13). Hydrogenation/step (4) is performed using Wilkinson’s catalyst in toluene or acetone, preferably at 3-5 bar, for about 1-6 hours (col.6:28-31; claim 3).
Moutou et al. teach a method of crystallizing selamectin by heating crude selamectin in toluene to 75-80 °C for 1 hour, cooling, precipitating, filtering, washing with toluene to give a 52% yield (96.7% purity; process 1). Moutou et al. teach crystallizing selamectin by dissolving crude selamectin in acetonitrile at room temperature for 1 hour, after which the reaction mass was cooled to 0 °C, precipitated, filtered, washed with cold acetonitrile to give 53% selamectin (96.2% purity), (p.13, step 6; process 2).
Moutou et al. do not expressly disclose oxidizing with manganese dioxide (claim 1, step 1). While Moutou et al. teach desugaring/deglycosidation and oximation, Moutou et al. do not expressly disclose performing these steps simultaneously (present claim 1, step 2). Moutou et al. do not expressly disclose t-butyl alcohol (present claim 1, step 2).
Yan et al. teach a method of preparing selamectin from doramectin, the method comprises oxidation with manganese dioxide, followed by desugarization and oximation with hydroxylamine hydrochloride (claim 8, step 3). The oxidation reaction was performed at 25-30 °C for 1 hour (para [0038]). The oxidized intermediate was dissolved in methanol, after which dioxane was added, and hydroxylamine hydrochloride dissolved in water was added (para [0040]. The reaction was heated to 33 °C for 6 hours. The reaction was terminated, after extraction, the solvent was removed under reduced pressure, and crystallized from toluene/heptane. In addition, or the selamectin was further recrystallized from aqueous methanol (para [0019], [0025]). Yan et al. note previous methods carry out the desugaring reaction separately from the oximation reaction (para [0007]).
Omura et al. teach an oximation reaction, comprising the reagent hydroxylamine hydrochloride (examples 9, 50, 51, 58). The reaction was neutralized using aqueous sodium hydrogen carbonate.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to first oxidize doramectin, perform simultaneous deglycosidation/oximation reaction, hydrogenate with Wilkinson’s catalyst and recrystallize selamectin with toluene.
The claimed process is no more than a selective combination of prior art teachings done in a manner obvious to one of ordinary skill in the art since each step of the process appears to be relatively complete in itself and there is no indication of an interaction between steps of such a type that would lead one of ordinary skill in the art to doubt that a substitution of alternative steps known to the art could be made. In re Mostovych, 144 USPQ 38 (1964).
While traditional methods for synthesizing selamectin include hydrogenation with Wilkinson’s catalyst as a first step, Moutou et al. found performing hydrogenation in a subsequent step considerably reduced the quantity of Wilkinson’s catalyst used compared to the quantities used when it’s implemented in a first step. Thus, one having ordinary skill in the art would have been motivated to perform hydrogenation with Wilkinson’s catalyst last, as taught by Moutou et al.
Additionally, Yan et al. teach another improvement from traditional methods wherein deglycosidation and oximation are performed simultaneously. Since the compound needs to be oxidized prior to oximation, the ordinary artisan would have been motivated to first oxidize doramectin, then simultaneously hydrolyze a sugar and convert the ketone to hydroxylamine as taught by Yan et al. (deglycosidation/oximation), and then hydrogenate with Wilkinson’s catalyst. as taught by Moutou et al.
With respect to the protic solvent, Moutou et al. teach deglycosidation/step (1) is performed using a strong acid in an organic solvent (claim 1). The organic solvent may be acetonitrile or a C1-C6 alcohol, such as ethanol. A C1-C6 alcohol encompasses butyl alcohol and its positional isomer, tert-butyl alcohol.
From Omura et al., the ordinary artisan would have known to neutralize oximation reaction with aqueous sodium carbonate.
The ordinary artisan would have routinely optimized reaction conditions including temperature and time to ensure completion of the reaction, while minimizing formation of any side products.
With respect to recrystallization conditions, the ordinary artisan would have optimized the amount of solvent to compound ratio to ensure adequate dissolution of the compound and impurities, while ensuring nucleation and crystallization can occur. The use of acetonitrile to recrystallize an intermediate after deglycosidation was taught by Moutou et al. And the use of toluene to recrystallize crude selamectin to give pure selamectin was also taught by Moutou et al.
See MPEP 2144.05, “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. "[W]here 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”.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Conclusion
In view of the rejections to the pending claims set forth above, no claim is 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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/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699