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 .
Status of the Claims
The status of the claims are as follows:
Claims 1-10 are pending.
Claims 1-10 are rejected.
Priority
Acknowledgement is made that Instant Application 18/850,001, filed on 2024, Sept. 23, is a National Stage entry of PCT/CN2022/082401, filed on 2022, Mar. 23.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 2024, Sept. 23 is/are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement(s) is/are being considered by the examiner.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 1-2 and 5-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yang (CN 110590635 A, published 2019, Dec. 20) in view of Hu (CN 102617436 A, published 2012, Aug. 01).
Claim 1 is directed toa method of purifying a levetiracetam intermediate, wherein the method comprises the following:
Hydrolyzing a crude product of a compound of Formula III (Table 1, left) under alkaline conditions, followed by acidifying, then crystallizing to obtain a compound of Formula IV (Table 1, right); and
Subjecting the compound of Formula IV to an esterification reaction, followed by separation, to obtain a purified compound of Formula III;
Wherein R1 in Formula III is methyl or ethyl
Table 1. Instantly claimed Formula III and Formula IV.
Formula III
Formula IV
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Yang teaches a synthetic process to making high purity, enantiopure levetiracetam and intermediates thereof (title, abstract), comprising the steps shown in Scheme 1.
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Scheme 1. Method of Yang toward enantiopure levetiracetam ethyl ester 5.
Yang teaches a method of synthesizing and purifying levetiracetam acid 3, comprising alkylation of 2-pyrollidone 1 and subsequent hydrolysis of ester 2, chiral resolution of the resultant acid 3, and esterification to form high purity, enantiopure levetiracetam acid 5 (Scheme 1).
Yang teaches step a as dropwise addition of pyrrolidone 1 (1.0 eq) to a solution of sodium methoxide (1.1 eq) in toluene at 0 – 10 °C, followed by dropwise addition of α-bromo ethylbutyrate (1.1 eq), then reacting at 80 – 90 °C for 8 – 10 hours. After cooling to room temp, water was added, the liquid was separated, and the organic phase was concentrated to give crude ester 2 as an oil that was used without further purification.
Yang teaches step b as adding sodium hydroxide (2.2 eq) in and water to a solution of crude ester 2 and stirring at 60 ° for 3 hours, then lowering the temperature to 0 – 10 °C and adding concentrated HCl dropwise until the pH is 4-5 and a solid precipitates. Then DCM and water is added to dissolve the solid, separating the liquid and concentrating the organic phase to dryness to obtain a crude product. The crude product is dissolved in EtOH, heated to 70 °C to dissolve the solid, cooled to 0 – 10 °C, stirred for 1-2 hours, filtered, and dried to obtain the pure acid 3.
Yang teaches step c as a two-step chiral resolution process (page 4, paragraphs 0048-0054).
Yang teaches step d as acid catalyzed esterification, wherein TsOH (0.1 eq) is added to enantiopure acid 4 (1.0 eq) in EtOH and stirred at 60 °C for 7 h followed by concentration. Ethyl acetate was added and washed twice with water, dried and concentrated to give the enantiopure ester 5.
The difference between the method of Yang and the instant application is that Yang fails to teach immediate filtration of the formed solid precipitate in step b, and also teaches additional steps of chiral resolution (step c).
However, Hu teaches a method of synthesizing high purity levetiracetam, wherein the method comprises alkylation of 2-pyrollidone 1 and subsequent hydrolysis of ester 2 as shown in Scheme 2 (abstract).
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Scheme 2: Hu method of synthesizing high purity levetiracetam acid 3.
Hu teaches step e as adding sodium ethylate to pyrrolidone 1 in organic solvent under N2 and reacting for 1-4 hours at 30-45 °C. Then, adding α-bromo ethylbutyrate and reacting for 4-6 hours at 70-90 °C to give ester 2. The molar ratio of pyrrolidone, sodium ethylate, and α-bromo ethylbutyrate is 1:(1-1.3):(1-1.3).
Hu teaches step f as dropwise addition of an aqueous solution of sodium hydroxide (30-32%) to a solution of ester 2 and then 2-6 hours of reflux, followed by cooling to –5 – 10 °C and slowly adjusting pH to 1-2 with an acid to precipitate a solid, and filtering the solid to obtain acid 3. The molar ratio of ester 3 to sodium hydroxide is 1:(1-1.3). The resulting acid is taught to be isolated in 91% yield with a purity of 99.4% (page 7, paragraph 0020, Example 4).
One of ordinary skill in that art would be motivated to combine the method of Hu with the method of Yang because Hu shows isolation of acid 3 can be achieved in excellent yield and purity without the additional aqueous washes taken by Yang in step b. This is relevant on an industrial scale where superfluous amounts of halogenated solvents (e.g. DCM, as used by Yang), is hazardous and typically avoided where possible. Accordingly, said skilled artisan would have found it prima facie obvious to combine step f of the method of Hu with the method of Yang to eliminate unnecessary washes and isolate acid 3 in high yield and purity.
The difference between the combined teachings of Yang and Hu and the instant invention is the Yang teaches chiral resolution of acid 3 prior to esterification, whereas the instant invention is directed to the racemic mixture.
However, Yang utilizes the chiral resolution to isolate the (R)-isomer, which is the pharmaceutically relevant isomer of the FDA-approved levetiracetam drug. It would have been obvious to a person of ordinary skill in the art that esterification of the acid is not dependent on stereochemical purity. Absent such a teaching, it would have been reasonable to expect the method of Yang to be applicable to racemic mixtures as well, thus arriving at the current invention.
Claim 2 is directed to the method above, wherein the step (A) comprises the following steps:
Mixing the crude product of the compound of Formula III with an aqueous solution of inorganic alkali, and then heating and performing reaction;
Adjusting pH to a pH number between 0.5 and 3.5; and
Lowering temperature and crystallizing, filtering, and drying a mixture obtained in step B to obtain the compound of Formula III.
Hu teaches a method of isolating acid 3 by Example 6, wherein:
A solution of sodium hydroxide (30-32%) is added dropwise to the intermediate ester 2 and refluxed for 6 hours;
Slowly adjusting the pH to 1.5 with hydrochloric acid;
pH adjustment occurs at 10 °C. A solid forms, which is filtered and collected.as acid 3.
Claim 5 is directed to the method of claim 2, wherein step (b) the pH is adjusted to a pH between 2.0 – 2.5.
Hu teaches Example 5, wherein the pH is adjusted 2 (page 4, paragraph 0021), which falls within the recited range.
Claim 6 is directed to the method of claim 2, wherein step (c) is a temperature after lowering temperature is –10 to +10 °C, a duration of crystallization is 1 – 2 hours, a temperature for drying is 80 – 100 °C, and an endpoint of the drying is until a moisture content is ≤0.5 wt%.
Hu teaches Example 5, wherein the temperature after lowering the temperature is –5 °C (page 4, paragraph 0021) and the crystals are collected by filtration.
The difference between the examples taught by Hu and the instant application is that Hu is silent on the duration, temperature, time, and endpoint of the drying process.
However, the recited limitations can be reached through routine optimization. For example, Yang teaches recrystallization of acid 3 from EtOH by heating to 70 °C to dissolve and cooling the solution to 0 – 10 °C for 1-2 hours, followed by vacuum filtering the wet product and drying under vacuum at 40 °C for 4 hours prior to use (page 4, paragraph 0047). Accordingly, prior to the effective filing date of the current invention, it was known in the art that the crystals of acid 3 must be heated and dried prior to use, conditions of which may be optimized based on the recrystallization solvent.
Claim 7 is directed to the method of claim 1, wherein step (B) comprises the following steps:
Adding an alcohol solvent into the compound of Formula IV, adding an esterification reaction catalyst, and then heating and performing reaction;
Adding water, adjusting the pH to a pH between 6 and 8 with alkali, and distilling;
Extracting with an organic solvent and distilling an obtained extract to obtain the purified compound of Formula III.
Yang teaches step 5 (page 5, paragraph 0058), wherein
Ethanol is added to acid 3 and TsOH is added as an esterification reaction catalyst, and the solution is heated to 60 °C to react;
Concentrating to dryness under vacuum;
Extracting with ethyl acetate and washing with water, then concentrating the organic phase to dryness.
The difference between step 5 of Yang and the instant claim is that Yang fails to teach adjusting the pH to between 6 and 8 and purification by distillation.
However, the purpose of adjusting the pH to between 6 and 8 is to neutralize the organic phase and prevent distillation of unreacted acid 3 and catalytic TsOH along with the pure product ester 2. Yang instead neutralizes the acids in the following step, wherein the ester is treated with ammonia (page 5, paragraph 0059). Furthermore, Hu teaches Examples 1-3 whereby ester 2 is purified by vacuum distillation (page 6, paragraphs 0016-0019). Accordingly, one of ordinary skill in the art would have found it prima facie obvious to neutralize the acids prior to isolation of ester 2 by vacuum distillation.
Claim(s) 3-4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yang in view of Hu in further view of Theodorou (A Simple Method for the Alkaline Hydrolysis of Esters. Tet. Lett., 2007, 48, 2830-8233. Doi:10.1016/j.tetlet.2007.09.074).
Claim 3 is directed to the method of claim 2, wherein in step (a), a temperature of the reaction is 35°C to 65°C, and reaction time is 1 to 5 hours; and the inorganic alkali is one selected from the group consisting of sodium hydroxide and potassium hydroxide, a concentration of the aqueous solution of inorganic alkali is 5wt% to 30wt%, and a weight of the aqueous solution of inorganic alkali is 1 to 10 times a weight of the compound of formula III.
Hu teaches Example 5, wherein the reaction temperature is 100 °C, the reaction time is 2 hours, the inorganic alkali is sodium hydroxide, the concentration of the aqueous solution of inorganic alkali is 32wt%, and the weight ratio of the aqueous solution with respect to acid 3 is approximately 0.68.
While Hu does not teach an explicit embodiment wherein the concentration of aqueous solution of inorganic alkali is 5wt% to 32wt%, Hu teaches that the hydrolysis can occur using a solution of 30-32% sodium hydroxide (claim 3). Accordingly, one of ordinary skill in the art would find it obvious to use a solution of 30% sodium hydroxide, which falls within the recited range.
The difference between Example 5 of Hu and the instant application is that Hu fails to teach where the temperature of the reaction is 35 – 65 °C and the weight of the aqueous solution of inorganic alkali is 1 to 10 times a weight of the compound.
However, these prior to the effective filing date of the instant invention, a person of ordinary skill in the art could have arrived at these ranges through routine optimization. For example, Theodorou teaches saponification processes can vary in temperature from room temperature to the boiling point of the mixture, while the duration of the reaction can vary from 30 minute to 24 hours (page 1, left column, paragraph 3). Theodorou further teaches the use of large excess of the inorganic alkali agent is normally necessary to push the reaction forward (page 1, left column, paragraph 3). Therefore, a skilled artisan could have optimized reaction conditions via monitoring completion by any conventional method (TLC, LCMS, HPLC, etc.) to determine hydrolysis of this particular substrate occurs optimally between 35 – 65 °C with an amount of inorganic alkali solution that is 1 – 10 times the weight of the compound.
Claim 4 is directed to the method of claim 3, wherein in step (a), the temperature of the reaction is 40 °C to 45 °C; the inorganic alkali is sodium hydroxide.
As stated above, Theodorou teaches saponification reactions were known in the art to vary in temperature from room temperature to the boiling point of the mixture (page 1, left column, paragraph 3). Accordingly, a person of ordinary skill in the art could have arrived at a reaction temperature of 40 – 45 °C through routine optimization.
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yang in view of Hu in further view of Khan (Current Developments in Esterification Reaction: A Review on Process and Parameters. J. Ind. Eng. Chem., 2021, 80-101. Doi.org/10.1016/j.jiec.2021.07.018).
Claim 8 is directed to the method of claim 7, wherein in step (a), the alcohol solvent is selected from the group consisting of methanol, ethanol, and a mixture thereof, and a weight of the alcohol solvent is 0.5 to 10 times a weight of the compound of formula III; the esterification reaction catalyst is 90wt% to 98wt% concentrated sulfuric acid, and a weight of the concentrated sulfuric acid is 0.01 to 0.2 times the weight of the compound of formula III; and a temperature of the reaction is 50 °C to 75°C and reaction time is 1 hour to 5 hours.
Yang teaches step 5 (page 5, paragraph 0058), wherein
The alcohol is ethanol;
The amount of the alcohol solvent is 10 mL/g, which equates to a weight of alcohol solvent of about 7.9 a weight of the acid (ρ = 0.789 g/mL);
The esterification catalyst is p-toluene sulfonic acid;
The ratio of the esterification catalyst is 0.1 equivalents. Given the mass of acid 3 used is 21.1 g and the molecular weight of the acid is 171.20 g/mol, 0.1 equivalents of TsOH equates to 2.11 g. Accordingly, the esterification catalyst used is 0.1 times the weight of acid 3, which falls within the recited range.
The temperature of the reaction is 60 °C; and
The reaction time is 7 hours.
The difference between step 5 of Yang and the instant application is that Yang fails to teach where the esterification catalyst is concentrated sulfuric acid and the reaction time is 1 – 5 hours.
However, Khan teaches organic acids, e.g., TsOH and mineral acids e.g., sulfuric acid, are used interchangeably in esterification reactions under homogenous liquid-liquid phase conditions (page 83, left column, paragraph 2). Accordingly, it would have been prima facie obvious for a skilled artisan to use sulfuric acid instead of TsOH thus arriving at the instant invention. Khan further teaches optimum conditions for select esterification reactions, wherein the reaction time ranges from 3 minutes to 1440 minutes (Table 2). Said skilled artisan could have therefore routinely optimized the reaction via monitoring completion by any conventional method (TLC, LCMS, HPLC, etc.) to determine esterification of this substrate occurs optimally at between 1 – 5 hours.
Claim(s) 9-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yang in view of Hu in further view of Vogel (A Textbook of Practical Organic Chemistry Including Qualitative Organic Analysis, Third Edition. Longman Group Limited, 1956).
Claim 9 is directed to the method of claim 7, wherein step (b) a weight of added water is 0.5 to 5 times the weight of the compound of formula III; the alkali is one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; and a weight of distilled solvent is 0.8 to 1.2 times a weight of added alcohol solvent, and a temperature of the distilling is <70°C.
Step (b) of the instant claim is directed to a method of neutralizing the reaction mixture followed by distillation. While the combined teachings of Yang and Hu fail to teach this specific procedure, it can readily be arrived at by a person of ordinary skill because it is known in the art to be a common work up procedure for Fischer esterification reactions. For example, Vogel teaches one method of synthesizing diethyl sebacate comprising the mixing of sebacic acid (100 g) and ethyl alcohol (81 g) with concentrated sulfuric acid (11 g), followed by a work up comprising pouring the solution into water (2-3 volumes), separating and neutralizing the organic phase with sodium bicarbonate solution, then a final distillation step (page 387, paragraph 2).
One would be motivated to utilize this method over the method taught by Yang because neutralization of the acids allows for easy separation of the organic compounds from the resultant salts. In the case of Yang, the acids were neutralized in the following step wherein the mixture was subjected to aminolysis with ammonia gas. However, one of ordinary skill in the art would have the knowledge to isolate the ester by applying common procedure taught by Vogel to the method of Yang, thus arriving at the current invention.
Claim 10 is directed to the method of claim 7, wherein step (c), the organic solvent is one or more selected from the group consisting of toluene, benzene, dichloromethane and ethyl acetate, the extraction is performed 2 to 5 times, a weight of the organic solvent for a single extraction is 1 to 10 times the weight of the compound of formula III, and a temperature of the distilling is <70°C.
Step (c) of the instant claim is directed to extraction of the product from the aqueous phase followed by removal of solvent to isolate said product. While the combined teachings of Yang and Hu fail to teach this specific procedure, it can readily be arrived at by a person of ordinary skill because it is known in the art to be a common work up procedure. For example, Vogel teaches another method of synthesizing diethyl sebacate (page 387, paragraph 3) comprising the mixing of sebacic acid (101 g) with ethyl alcohol (196 g) and concentrated sulfuric acid (20 mL). When the reaction is finished, about half of the alcohol is distilled off, the solution is diluted with water (500-750 mL), the organic phase is removed and the aqueous phase extracted with ether. The combined organic extracts are washed with water and neutralized with sodium bicarbonate, then again with water. The ether is removed by water bath and the residue is distilled under reduced pressure.
Accordingly, one of ordinary skill in the art would have found it prima facie obvious to extract and isolate ester 2 from the method of Yang by using common procedure taught by Vogel to do so.
Conclusions
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/P.A./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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