DETAILED ACTION
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
Claims 1-20 are pending.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/CN2023/092648, filed on May 8, 2023. This application also claims the benefits of foreign priority to CN202210515735.2, filed on May 12, 2022 and CN202210515612.9, filed on May 12, 2022.
Specification - Disclosure
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Note on 35 USC § 102 and § 103 Rejections
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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4-6, and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
Guan et al. (Guan) (CN106632288A; published May 10, 2017)
All paragraph numbers are referring to the paragraph numbers from the English translated document.
Guan teaches the following reactions:
Preparation of compound 3 (reaction scheme below is from pg. 2 of original Chinese document):
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(Note: compounds 1, 2, and 3 of Guan corresponds to compounds of instant formulas III, IV, and V, respectively.)
In THF (i.e., an organic solvent), compound 1 (i.e., compound represented by instant formula III) is reacted with compound 2 (i.e., compound represented by instant formula IV) under the action of n-BuLi (i.e., an organic metal lithium) (see para. 0023 and 0037-0038 of Guan).
Anticipates instant claim 1(a).
According to Guan, para. 0038, 2nd sentence, when adding the n-BuLi, the temperature of the reaction should be controlled between -90 and -85oC. And according to Guan, para. 0038, 5th sentence, the reaction can be completed at a reaction temperature between -80 and -70oC.
Anticipates 1st half of instant claim 5: “The method according to claim 1, characterized in that the reaction in step (a) is carried out at a temperature of -90oC to -60oC…”
Anticipates 1st half of instant claim 14: “The method according to claim 1, wherein the reaction in step (a) is carried out at a temperature of -80oC to -70oC…”
After the reaction of (a) above is complete, a quencher is added to the reaction system to quench the reaction. Guan specifically states that an ammonium chloride aqueous solution (which is a mixture of water and ammonium chloride), is preferably used as the quenching agent (see para. 0039 of Guan).
Anticipates instant claim 1(b).
Even though instant claim 1(b) states “quenching the reaction of step (a) with water” instead of stating “quenching the reaction step (a) with ammonium chloride aqueous solution,” the “comprising” transitional phrasing of claim 1 allows water, for instance, to also comprise other components including ammonium chloride.
Guan specifically states that they employ quenching treatment under weakly acidic conditions (i.e., use ammonium chloride aqueous solution as the quencher), while simultaneously ensuring clear separation of the two phases during extraction (see 2nd to last sentence of para. 0039).
Guan also states that after adding the ammonium chloride aqueous solution as the quencher, the temperature is raised to room temperature (15-30oC) and stirred for 10-20 minutes (see 3rd to last sentence of para. 0039; anticipates instant claim 4).
The mixed solution obtained in step (b) is subjected to phase separation into an organic phase and an aqueous phase, and concentrating the organic phase to obtain compound 3 (see para. 0040-0041 and 1st sentence of 0042).
Anticipates instant claim 1(c).
Preparation of compound 4 (reaction scheme below is from pg. 2 of original Chinese document):
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(Note: compound 4 of Guan corresponds to a compound of instant formula II.)
Compound 3, obtained from step (c) above, is reacted with methanesulfonic acid in an organic solvent (i.e., compound 3 is reacted under an acidic condition) (see Guan, para. 0043), wherein the organic solvent is methanol (see Guan, para. 0044).
Anticipates instant claim 1(d).
This etherification reaction of step (d) is controlled at 40-43oC (see Guan, para. 0044, 2nd sentence).
Anticipates 2nd half of instant claims 5 and 14: “… and the reaction in step (d) is carried out at a temperature of -80oC to 40oC.”
Note: The range 40-43oC (recited in Guan) overlaps with the range -80oC to 40oC (recited in instant claim 5) at the temperature, 40oC.
Preparation of compound 5 (reaction scheme below is from pg. 2 of original Chinese document):
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(Note: compound 5 of Guan corresponds to a compound of instant formula I.)
Compound 4 (as prepared according to steps (a)-(d) listed above) is reacted with triethylsilane (i.e., a reducing agent; see Guan, para. 0050, 2nd to last sentence) in the presence of boron trichloride diethyl ether (i.e., a Lewis acid; see Guan, para. 0050, last sentence) in an organic solvent to obtain compound 5.
According to Guan, para. 0050, 2nd sentence, the organic solvent can be of various types including but not limited to acetone, dichloromethane, ethyl acetate, and isopropyl acetate.
Anticipates instant claim 6.
For the above reasons, instant claims 1, 4-6, and 14 are anticipated by Guan.
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.
Rejection Part 1:
Claims 1, 4-6, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over:
Guan et al. (Guan) (CN106632288A; published May 10, 2017);
All paragraph numbers are referring to the paragraph numbers from the English translated document.
The teachings of Guan as they apply to claims 1, 4-6, and 14 are as discussed in the “Claim Rejections - 35 USC § 102” section above and incorporated herein. Given that the claimed invention is anticipated by the prior art, a POSITA would have found it obvious to reproduce the subject matter disclosed.
Furthermore, once the reaction of (a) (as recited in instant claim 1(a)) is complete, Guan teaches an ammonium chloride aqueous solution being used to quench the reaction mixture from step (a) (see para. 0039 of Guan). Guan does not teach pure water being used to quench the reaction mixture. However, according to Guan, the main purpose of adding ammonium chloride to the water is to “reduce the adsorption of solids” (see 2nd to last sentence of para. 0039).
Therefore, one of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the claimed invention to use water as the quenching medium (instead of ammonium chloride aqueous solution). Guan’s preference for aqueous ammonium chloride does not teach that pure water is incapable of quenching the reaction. Rather, Guan identifies an advantage associated with conducting the quench under weakly acidic conditions which is to reduce the adsorption of solids to, therefore, yield purer compounds. A POSITA would therefore have reasonably expected water to quench the reaction and permit recovery of the desired intermediate, even if the product purity was less than with aqueous ammonium chloride.
Rejection Part 2:
Claims 2 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over:
Guan et al. (Guan) (CN106632288A; published May 10, 2017);
All paragraph numbers are referring to the paragraph numbers from the English translated document;
Chemical Forums. Topic: Quenching reactions fast vs. slowly. Post published: April 19, 2014.; and
Ovaska et al. (Ovaska) (Ovaska, T. V. et al. n-Butyllithium. Encyclopedia of Reagents for Organic Synthesis, (Ed.). 2009.)
Instant claim 1 is anticipated by Guan as discussed in the “Claim Rejections - 35 USC § 102” section above. Guan further states that when adding the ammonium chloride aqueous solution (i.e., a mixture of water + ammonium chloride) as the quencher, “control the temperature below 10oC” (para. 0039, 3rd sentence). This temperature limitation is also recited in instant claim 2. Note: when the quencher is added to the reaction mixture of instant claim 1-step (a), there may still be organic metal lithium present in the reaction mixture.
Guan does not disclose the rate at which the reaction solution of step (a) in instant claim 1 and water (the quencher) are added together. A chemical forums post (written by TheUnassuming) is relied upon for information regarding the rate of adding a quencher to a reaction mixture and the importance of controlling the temperature of a reaction mixture that is actively being quenched. Ovaska provides further details related to the properties of n-butyl lithium.
According to a chemical forums post published on April 19, 2014 by TheUnassuming:
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.
Ovaska further discloses that solutions of n-butyllithium are pyrophoric and the reagent may catch fire if exposed to air or moisture (i.e., water) (see Ovaska, abstract-“Handling, Storage, and Precautions”).
Therefore, one of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the claimed invention to slowly add the reaction solution of step (a) to water. A POSITA would have been motivated to slowly add the reaction solution of step (a) to water (the quencher) since the prior art explicitly teaches that slowly quenching a reaction can help control the reaction temperature better, prevent solvent from boiling out, and prevent the reaction material from erupting out of the flask. This consideration would have been particularly applicable to Guan because the reaction mixture may comprise excess n-butyllithium which, according to Ovaska, is pyrophoric and reacts upon exposure to moisture (i.e., water). Slowly introducing the n-butyllithium-containing reaction solution into water would have allowed the reactive material to be quenched incrementally, thereby moderating the rate of heat generation and facilitating maintenance of the quench temperature below 10oC. Thus, instant claim 2 is rendered obvious.
One of ordinary skill in the art would have also found it prima facie obvious before the effective filing date of the claimed invention to pre-cool the water to 0-5oC, as recited in instant claim 3. Because Guan expressly teaches maintaining the quenching temperature to below 10oC, a POSITA would have recognized that using water having an initial temperature below the maximum permitted quench temperature would predictably ensure that the quenching temperature is maintained at a temperature below 10oC. Selection of an initial water temperature of 0-5oC, which is below Guan’s expressly desired maximum quench temperature of 10oC, would have been considered as routine optimization of a known result-effective process variable to obtain the predictable result of maintaining temperature control during quenching. A POSITA, therefore, would have had a reasonable expectation of successfully maintaining the quench temperature below 10oC. Thus, instant claim 3 is also rendered obvious.
Rejection Part 3:
Claims 7, 11-13, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over:
Guan et al. (Guan) (CN106632288A; published May 10, 2017);
All paragraph numbers are referring to the paragraph numbers from the English translated document;
Cui et al. (Cui) (CN110655511A; published January 7, 2020)
All paragraph numbers are referring to the paragraph numbers from the English translated document.
Instant claim 6 is anticipated by Guan as discussed in the “Claim Rejections - 35 USC § 102” section above and reproduced below:
Preparation of compound 5 (reaction scheme below is from pg. 2 of original Chinese document):
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(Note: compound 5 of Guan corresponds to a compound of instant formula I. Compound 5 is also called empagliflozin.)
Compound 4 (prepared according to steps (a)-(d) as described in the “Claim Rejections - 35 USC § 102” section above) is reacted with triethylsilane (i.e., a reducing agent; see Guan, para. 0050, 2nd to last sentence) in the presence of boron trichloride diethyl ether (i.e., a Lewis acid; see Guan, para. 0050, last sentence) in an organic solvent to obtain compound 5.
According to Guan, para. 0050, 2nd sentence, the organic solvent can be of various types including but not limited to acetone, dichloromethane, ethyl acetate, and isopropyl acetate.
Anticipates instant claim 6.
Further details related to the reaction from Guan are provided below:
Step (e) continued: An 8-12% sodium bicarbonate solution is used as a quencher, which can not only effectively neutralize the acid or alkali produced in the reaction, but also help to improve the ionic strength of the aqueous phase, creating good separation conditions for the next extraction step (Guan, para. 0052, last sentence). After the quenching reaction, “the obtained product [i.e., compound 5 = empagliflozin] is subjected to sequential layering, extraction, washing, and concentration treatments” (Guan, para. 0053). After additional crystallization and filtering/rinsing, the crude compound 5 was obtained by vacuum drying (Guan, para. 0054).
Reads on instant claim 7(e).
Then, “dichloromethane is added to the crude compound 5, and the mixture is refluxed and stirred for 20-40 minutes, specifically 30 minutes; the temperature is then lowered to 10-15oC, and the mixture is stirred to crystallize for 2-4 hours, specifically 3 hours” (Guan, para. 0055, 1st sentence).
According to the prior art, the liquid in a reaction mixture within a reflux setup remains at the boiling point of the solvent (or solution) during active reflux.
See the 1st and 2nd sentence of: Nichols, L. 1.4K: Reflux. Chemistry Libretexts. 2021.
Therefore, when Guan adds dichloromethane to the crude compound 5 and subsequently heats the mixture at reflux for 20-40 minutes, the temperature of the reflux will be around the boiling point of dichloromethane: 39.75oC (which is within the temperature range recited in instant claim 12).
The boiling point of dichloromethane is referenced in the following prior art:Dichloromethane solvent properties. CAS 75-09-2. Published: February 13, 2016. https://macro.lsu.edu/howto/solvents/Dichloromethane.htm
Reads on instant claims 7(f)/(g) and instant claim 12.
The main difference between instant claim 7(f)/(g) and Guan is that in the instant claim, an organic solvent (like dichloromethane) is combined with water and subsequently added to the crude empagliflozin. However, in Guan, only dichloromethane (not a mixture of dichloromethane and water) is added to crude empagliflozin.
Lastly, the pure empagliflozin can be filtered out according to para. 0057-0058 of Guan
Reads on instant claim 7(h).
Guan teaches the addition of crude empagliflozin to dichloromethane (not a mixed solvent of an organic solvent and water). Cui discloses the crystallization of empagliflozin using a mixture of dichloromethane and water.
Cui compares the solvent effects for crystallization of crude empagliflozin (para. 0083). Table 1 compares the impurities and purity of crude empagliflozin product after crystallization in different solvents (para. 0087). A Google translated version of Table 1 (disclosed in the original Chinese document of Cui) is reproduced below:
1st half of Table 1:
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2nd half of Table 1 (wherein rows 1 through 6 in the table below corresponds to serial numbers 1 through 6 in the table above):
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. According to Table 1, the ratio of crude empagliflozin (i.e., the oil) to solvent (i.e., dichloromethane + water) is 1:3:3. In other words, the volume ratio of dichloromethane (in mL, according to Table 1) to water (in mL, according to Table 1) is 3 : 3 which is the same as 1 : 1.
Using the volume ratio of dichloromethane : water (as discussed above), the weight ratio of dichloromethane : water can also be calculated accordingly:
Dichloromethane density at room temperature: 1.33 g/mL;
Water density at room temperature: 0.998 g/mL;
See Table 4.1 of: Nichols, L. 4.4 Which Layer is Which? Chemistry LibreTexts 2021.
According to Table 1 in Cui, the volume ratio of dichloromethane : water is 3 : 3 (which is the same as 1 : 1);
1 mL of dichloromethane has a mass of 1.33 g;
1 mL of water has a mass of 0.998;
Therefore, the weight ratio of dichloromethane : water, according to Table 1 of Cui, is 1.33 : 0.998 = 1.33 : 1 (which is within the weight ratio recited in instant claim 7).
Further note that in Table 1 of Cui, when only dichloromethane was used to crystallize crude empagliflozin, the overall purity of the resulting product was 93.60%, whereas when a mixture of dichloromethane and water was used to crystallize crude empagliflozin, the overall purity of the resulting product was higher at 98.26%.
Therefore, one of ordinary skill in the art would have found it prima facie obvious to replace the crystallization solvent (i.e., dichloromethane) used by Guan with a mixture of dichloromethane and water (as used by Cui). One of ordinary art would have been motivated to use the dichloromethane + water mixture instead of only dichloromethane because Cui shows that a purer empagliflozin can be obtained when the crystallization solvent used is a mixture of dichloromethane and water rather than just dichloromethane. As such, for the above reasons, instant claims 7 and 12 are rendered obvious.
A POSITA would have also found it prima facie obvious before the effective filing date of the claimed invention to vary the dichloromethane : water ratio for the crystallization of empagliflozin (as disclosed in Cui) to be within the ranges as recited in instant claims 7, 11, 19, and 20. A POSITA would have had a reasonable expectation of success because this modification merely adjusts the relative amounts of the same two solvents (i.e., dichloromethane and water) used by Cui for crystallizing the same compound (i.e., empagliflozin), without changing the identity of the solvents or the product being crystallized. Furthermore, even though the ratios of dichloromethane : water would have changed, a POSITA would still have expected empagliflozin to crystallize and be recovered from the solvent mixture.
Moreover, as explained in MPEP §2144.05:
“II. ROUTINE OPTIMIZATION
A. Optimization Within Prior Art Conditions or Through Routine Experimentation
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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.);”
The instant specification does not establish that the claimed range produces a result different in kind from the expected effects of optimizing a crystallization solvent system. Accordingly, selecting a dichloromethane: water ratio within the claimed range would have amounted to routine optimization of a known result-effective variable, and instant claims 7, 11, 19, and 20 are rendered obvious.
A POSITA would have also found it prima facie obvious before the effective filing date of the claimed invention to first heat the crystallization solvent + empagliflozin mixture and subsequently cool the mixture to a temperature that is between 0-5oC. According to Guan, after heating the mixture comprising empagliflozin and the crystallization solvent, the temperature of the mixture is cooled down to 10-15oC (see para. 0055, 1st sentence). Guan does not explicitly disclose gradual reducing of the temperature to 0-5oC, as recited in instant claim 13.
However, as explained in MPEP §2144.05:
“II. ROUTINE OPTIMIZATION
A. Optimization Within Prior Art Conditions or Through Routine Experimentation
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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.);”
Although the claimed range of 0-5oC (recited in instant claim 13) does not overlap the prior art range of 10-15oC, both ranges represent cooling conditions to crystallize empagliflozin from solution. Therefore, selecting 0-5oC to crystallize empagliflozin from solution would have amounted to the routine determination of an optimal crystallization temperature, and a POSITA would have had a reasonable expectation of successfully obtaining the crystalline product, empagliflozin, whether at a cooling temperature of 10-15oC or 0-5oC. Thus, instant claim 13 is also rendered obvious.
Rejection Part 4:
Claims 7, 10, 12, 13, 17, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over:
Guan et al. (Guan) (CN106632288A; published May 10, 2017);
All paragraph numbers are referring to the paragraph numbers from the English translated document;
Gupta et al. (Gupta) (IN201621021804; published December 29, 2017)
All line numbers are referring to the lines from the English translated document.
The teachings of Guan reads on instant claim 7 step (e) as explained above in Rejection Part 3 of this section (i.e., the “Claim Rejections - 35 USC § 103” section).
Guan does not teach the crystallization of empagliflozin using ethyl acetate and water. Gupta is relied upon for this disclosure.
Gupta teaches how to crystallize and purify empagliflozin in example-13: preparation of pure empagliflozin (last 10 lines of specification in Gupta) which encompasses the following steps:
To the obtained residue [i.e., crude empagliflozin], ethyl acetate (1080 mL) was added and heated to 55±2°C (5th and 4th to last line of specification in Gupta);
To this mixture, water (54 mL) was added, heated to 60±2°C and stirred for 10 minutes (4th to last line of specification in Gupta);
Corresponds to instant claims 7(f) and 12;
Note: the weight ratio of ethyl acetate (1080 mL) to water (54 mL) is calculated as follows:
Density of ethyl acetate at room temperature is 0.902 g/mL;
Density of water at room temperature is 0.998 g/mL;
1080 mL ethyl acetate = 974 g ethyl acetate;
54 mL of water = 54 g water;
974 g ethyl acetate : 54 g water = 18 : 1 weight ratio of ethyl acetate : water.
The mixture was cooled to 25±5°C and stirred for 1 hour (4th and 3rd to last line of specification in Gupta);
Subsequently, the mixture was further cooled to 7±2°C and stirred for 1 hour (3rd to last line of specification in Gupta);
Corresponds to instant claims 7(g) and 13.
The separated solid was filtered, washed with ethyl acetate (200 mL) and dried under vacuum at 55°C for 8 hours. The dried solid was once again purified in a mixture of ethyl acetate and water to obtain pure empagliflozin (last two sentences of specification in Gupta);
Corresponds to instant claim 7(h).
Even though the weight ratio of ethyl acetate : water used in the crystallization of empagliflozin in Gupta is 18 : 1 (i.e., outside of the 1:10 to 5:1 range recited in instant claim 7), a POSITA would have found it prima facie obvious before the effective filing date of the claimed invention to also use the ethyl acetate : water ratio recited in instant claim 7 (and in instant claims 10, 17, and 18). This is because a POSITA would have understood that changing the relative amounts of ethyl acetate and water changes the solvent properties of the crystallization medium and consequently can affect the solubility, precipitation, recovery, and purity of empagliflozin. Accordingly, a POSITA would have been motivated to vary the relative amounts of ethyl acetate and water through routine experimentation to identify a solvent ratio that provides optimal crystallization, product recovery, and product purity.
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to vary the ethyl acetate : water ratio for the crystallization of empagliflozin (as disclosed in Gupta) to be within the ranges as recited in instant claims 7, 10, 17, and 18. A POSITA would have had a reasonable expectation of success because this modification merely adjusts the relative amounts of the same two solvents (i.e., ethyl acetate and water) used by Gupta for crystallizing the same compound (i.e., empagliflozin), without changing the identity of the solvents or the product being crystallized. Furthermore, even though the ratios of ethyl acetate : water would have changed, a POSITA would still have expected empagliflozin to crystallize and be recovered from the solvent mixture.
Moreover, as explained in MPEP §2144.05:
“II. ROUTINE OPTIMIZATION
A. Optimization Within Prior Art Conditions or Through Routine Experimentation
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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.);”
The instant specification does not establish that the claimed range produces a result different in kind from the expected effects of optimizing a crystallization solvent system. Accordingly, selecting an ethyl acetate : water ratio within the claimed range would have amounted to routine optimization of a known result-effective variable, and instant claims 7, 10, 17, and 18 are rendered obvious.
Rejection Part 5:
Claims 8, 9, 15, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over:
Guan et al. (Guan) (CN106632288A; published May 10, 2017);
All paragraph numbers are referring to the paragraph numbers from the English translated document;
Cui et al. (Cui) (CN110655511A; published January 7, 2020)
All paragraph numbers are referring to the paragraph numbers from the English translated document.
Gupta et al. (Gupta) (IN201621021804; published December 29, 2017)
All line numbers are referring to the lines from the English translated document.
Rejection Part 3 of this section (i.e., “Claim Rejections - 35 USC § 103” section) discloses why using the dichloromethane + water solvent system to crystallize empagliflozin (recited in instant claim 7) is obvious according to the teachings of Guan and Cui.
Rejection Part 4 of this section also discloses why using the ethyl acetate + water solvent system to crystallize empagliflozin (recited in instant claim 7) is obvious according to the teachings of Guan and Gupta.
Guan, Cui, and Gupta do not disclose the volume-to-weight ratios of ethyl acetate to the compound (or dichloromethane to the compound) to be within the ratio ranges recited in instant claims 8 and 15 (or claims 9 and 16).
However, once a solvent is known to be suitable for crystallizing a particular compound (i.e., the compound being empagliflozin in the instant case), determining the amount of solvent relative to the amount of compound would have been a matter of routine optimization. A POSITA would have understood that determining the amount of solvent to add directly affects the crystallization of empagliflozin. Using too little solvent may prevent complete dissolution (i.e., the obtained product will not be as pure), whereas using too much solvent may leave more product dissolved and reduce product recovery. A POSITA would, therefore, have routinely adjusted the amount of ethyl acetate or dichloromethane relative to amount of empagliflozin to provide optimal purity and product recovery of empagliflozin.
Furthermore, as explained in MPEP §2144.05:
“II. ROUTINE OPTIMIZATION
A. Optimization Within Prior Art Conditions or Through Routine Experimentation
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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.);”
The instant specification does not establish that the claimed amount of solvent is beyond what a chemist would normally expect from adjusting the amount of solvent used relative to the compound being crystallized. Therefore, selecting the ethyl acetate-to-compound ratio (recited in instant claims 8 and 15) and the dichloromethane-to-compound ratios (recited in instant claims 9 and 16) would have amounted to routine optimization of a known result-effective variable and instant claims 8, 9, 15, and 16 are rendered obvious.
Conclusion
No claims allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
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 H. MURRAY can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624
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