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 preliminary amendment filed on 02/13/2024 has been entered. Claims 3-10, 12, 14-16, 20 and 22 have been amended. Thus claims 1-22 are currently pending and are under examination.
Claim Objections
Claim 1 is objected to because of the following informalities: the conjunction word “and” is missing before step b).
Claims 6 and 10 are objected to because of the following informalities: the chemical acronyms TBA, DBU, DIPEA, THA, and TEA have to be preceded by their full chemical names.
Claims 10-13 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.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 15 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The limitation “the amide of Formula 2 is provided at a concentration between about 0.01 M and about 0.5 M” renders claim 15 vague and indefinite as it is unclear what the concentration of the amide of Formula 2 is based upon. Molarity is the number of moles of a solute, in this instance the amide, per liter of solution. Neither the claim nor claim 1 states the use of a solvent for the amide Formula 2 to be in solution and thus the scope of the centration is unclear.
Note: In view of the above, the claim will not be examined for patentability.
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 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.
Claims 1-7, 9, 14, 16-19, 20 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (Liu, B. et al. “Synthesis of Glipizide” Chinese Journal of Pharmaceuticals 2015, 46(10), 1053-1055; cited in IDS 02/13/2024 and machine translation attached herewith) in view of Plutschack (Plutschack, M. B. et al. “The Hitchhiker’s Guide to Flow Chemistry” Chem. Rev. 2017, 117, 11796−11893).
Regarding claims 1, 6 and 22, Liu teaches (Scheme on page 1054) a method for synthesizing Glipizide 1 (specie of Formula 1), the process comprising the steps of:
a) preparing amide 2 (specie of Formula 2)
i) by activating 5-methylpyrazine-2-carboxylic acid (specie of Formula 9) with ethyl chloroformate (specie of Formula 8) in the presence of triethyl amine (TEA) as the organic base to produce an anhydride, and
ii) reacting the anhydride with the sulfonamide 3 (specie of Formula 4) to produce the amide 2,
b) reacting the amide 2 with cyclohexyl isocyanate to obtain Glipizide 1.
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Regarding claims 3-5, R in Glipizide 1 is
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.
Regarding claim 7, 5-methylpyrazine-2-carboxylic acid is dissolved in DMF.
Regarding claim 9, the sulfonamide 3 is dissolved in DMF.
Regarding claim 14, the claim is not given patentable weight as it recites compounds of formulas 2 and 3, which are used as an alternative method in synthesizing the compound of formula 1, whereas Liu teaches the other recited way of synthesizing formula 1, i.e. by the reaction of formula 2 with isocyanate. Thus, the process of Liu would still read on claim 14.
Regarding claim 16, the reaction between 5-methylpyrazine-2-carboxylic acid (specie of Formula 9) and ethyl chloroformate (specie of Formula 8) is conducted at 0° C.
Regarding claim 17, if the reaction between 5-methylpyrazine-2-carboxylic acid (specie of Formula 9) and ethyl chloroformate (specie of Formula 8) proceeds at a temperature as low as 0° C, then changing to a warmer temperature such as room temperature, an ordinary skilled in the art would still have a reasonable expectation of success in conducting the reaction.
Regarding claims 18-19, the reaction in Liu that is equivalent to step (a)(ii) is conducted at room temperature (keep warm for 0.5 h, which is after 0° C of the previous step).
Regarding claim 20, the reaction between amide 2 and isocyanate is conducted at a reflux temperature and since acetone is used as the solvent, a skilled artisan understands that that the reflux temperature is equivalent to the boiling point of acetone, i.e. about 56°C.
Regarding claim 1, while Liu teaches a batch reaction using flasks for the process of synthesizing Glipizide 1 (specie of Formula 1), the reference fails to teach the flow synthesis process as instantly claimed. The deficiency is however cured by Plutschack.
Plutschack teaches the use of continuous flow chemistry for different types of reactions. Plutschack provides different types of reactor units utilized in the flow chemistry, such as chip, coil, or packed bed (Fig. 16). Furthermore, Plutschack teaches a typical continuous flow setup for synthetic applications can be broken into different zones, in which separate reagent A and reagent B supplied to the reactor via a mixing port (Figure 11).
Regarding claim 2, due the reaction in Plutschack being conducted in a continuous stream, a skilled artisan would not have been motivated in isolating any intermediates formed during the reaction steps.
Plutschack further teaches that flow chemistry involves the use of channels or tubing to conduct a reaction in a continuous stream rather than in a flask and that it provides chemists with unique control over reaction parameters enhancing reactivity. Thus, a skilled artisan would have been motivated to use the continuous flow chemistry of Plutschack in the place of the use of the batch flask reactors of Liu with a reasonable expectation of success in enhancing the reactivity of Liu’s production of Glipizide 1.
It would thus have been prima facie obvious to the skilled artisan before the effective filing date of the instant invention to conduct a flow synthesis process for producing a sulfonylurea compound of the Formula 1 or its pharmaceutically acceptable salts, the process comprising the steps of: a) preparing the amide of Formula 2 i) by activating a carboxylic acid of Formula 9 with a haloformate of Formula 8 in the presence of an organic base to produce an anhydride of Formula 5, and ii) reacting the anhydride of Formula 5 with the sulfonamide of Formula 4 to produce the amide of Formula 2; and b) reacting the amide of Formula 2 with a carbamate of Formula 3 or isocyanate R3—NCO in view of the teachings of Liu and Plutschack.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Liu (Liu, B. et al. “Synthesis of Glipizide” Chinese Journal of Pharmaceuticals 2015, 46(10), 1053-1055; cited in IDS 02/13/2024 and machine translation attached herewith) in view of Plutschack (Plutschack, M. B. et al. “The Hitchhiker’s Guide to Flow Chemistry” Chem. Rev. 2017, 117, 11796−11893) as applied to claims 1-7, 9, 14, 16-19, 20 and 22 above, and further in view of McConvey (McConvey, I. F. et al. “The Importance of Acetonitrile in the Pharmaceutical Industry and Opportunities for its Recovery from Waste” Org. Process Res. Dev. 2012, 16, 612−624).
The teachings of Liu and Plutschack have been set forth above.
Regarding claim 8, while Liu teaches the chloroformate is dissolved in DMF, the reference fails to teach dissolving in acetonitrile.
However, McConvey teaches the importance of acetonitrile as a solvent in the pharmaceutical industries. The reference teaches that MeCN is regarded as a good solvent because of its ability to dissolve a wide variety of fine chemical and pharmaceutical ingredients, with an acceptable environmental profile, even though a sustainable supply cannot be guaranteed.
Liu teaches that Glipizide 1 is used to treat type 2 diabetes, thus with pharmaceutical application. Thus, in view of the advantages of using acetonitrile as a solvent in pharmaceutical industries, a skilled artisan would have been motivated in using acetonitrile as a solvent in the reaction between 5-methylpyrazine-2-carboxylic acid (specie of Formula 9) and ethyl chloroformate.
It would thus have been prima facie obvious to the skilled artisan before the effective filing date of the instant invention to conduct a flow synthesis process for producing a sulfonylurea compound of the Formula 1 or its pharmaceutically acceptable salts, the process comprising the steps of: a) preparing the amide of Formula 2 i) by activating a carboxylic acid of Formula 9 with a haloformate of Formula 8 in the presence of an organic base to produce an anhydride of Formula 5, and ii) reacting the anhydride of Formula 5 with the sulfonamide of Formula 4 to produce the amide of Formula 2; and b) reacting the amide of Formula 2 with a carbamate of Formula 3 or isocyanate R3—NCO, wherein the haloformate of formula 8 is dissolved in acetonitrile in view of the teachings of Liu, Plutschack and McConvey.
Claims 1-6, 9, 14, and 16-22 are rejected under 35 U.S.C. 103 as being unpatentable over Ambrogi (Ambrogi, V. et al. Patent number US3,669,966) in view of Plutschack (Plutschack, M. B. et al. “The Hitchhiker’s Guide to Flow Chemistry” Chem. Rev. 2017, 117, 11796−11893).
Regarding claims 1 and 6, Ambrogi teaches in Example 2 a method for synthesizing several sulfonylurea compounds (species of Formula 1), the process comprising the steps of:
a) preparing amide (specie of Formula 2)
i) by activating pyrazine-2-carboxylic acids (species of Formula 9) with ethyl chloroformate (specie of Formula 8) in the presence of triethyl amine (TEA) as the organic base to produce an anhydride, and
ii) reacting the anhydride with the sulfonamide (specie of Formula 4) to produce the amide,
b) reacting the amide with cyclohexyl isocyanate to obtain sulfonylurea compounds.
Regarding claims 3-4, R in the final compounds is pyrazyl group.
Regarding claim 5, Example 2 teaches R with
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group.
Regarding claim 14, the claim is not given patentable weight as it recites compounds of formulas 2 and 3, which are used as an alternative method in synthesizing the compound of formula 1, whereas Ambrogi teaches the other recited way of synthesizing formula 1, i.e. by the reaction of formula 2 with isocyanate. Thus, the process of Ambrogi would still read on claim 14.
Regarding claim 16, the reaction between pyrazine-2-carboxylic acids (species of Formula 9) and ethyl chloroformate (specie of Formula 8) is conducted at 0° C.
Regarding claim 17, if the reaction between pyrazine-2-carboxylic acids (species of Formula 9) and ethyl chloroformate (specie of Formula 8) proceeds at a temperature as low as 0° C, then changing to a warmer temperature such as room temperature, an ordinary skilled in the art would still have a reasonable expectation of success in conducting the reaction.
Regarding claims 18-19, the reaction in Ambrogi that is equivalent to step (a)(ii) is conducted at room temperature (col. 4, line 20).
Regarding claims 20-21, the reaction between amide 2 and isocyanate is conducted at a reflux temperature and since a mixture of acetone and water (from NaOH solution) are used as the solvent, a skilled artisan understands that that the reflux temperature is set in between the boiling points of acetone, about 56°C, and water, about 100°C.
Regarding claim 22, Example 2 of Ambrogi teaches claimed formula 1a.
Regarding claim 1, while Ambrogi teaches a batch reaction using flasks for the process of synthesizing Glipizide compounds (specie of Formula 1), the reference fails to teach the flow synthesis process as instantly claimed. The deficiency is however cured by Plutschack.
Plutschack teaches the use of continuous flow chemistry for different types of reactions. Plutschack provides different types of reactor units utilized in the flow chemistry, such as chip, coil, or packed bed (Fig. 16). Furthermore, Plutschack teaches a typical continuous flow setup for synthetic applications can be broken into different zones, in which separate reagent A and reagent B supplied to the reactor via a mixing port (Figure 11).
Regarding claim 2, due the reaction in Plutschack being conducted in a continuous stream, a skilled artisan would not have been motivated in isolating any intermediates formed during the reaction steps.
Plutschack further teaches that flow chemistry involves the use of channels or tubing to conduct a reaction in a continuous stream rather than in a flask and that it provides chemists with unique control over reaction parameters enhancing reactivity. Thus, a skilled artisan would have been motivated to use the continuous flow chemistry of Plutschack in the place of the use of the batch flask reactors of Ambrogi with a reasonable expectation of success in enhancing the reactivity of Ambrogi’s production of Glipizide 1.
It would thus have been prima facie obvious to the skilled artisan before the effective filing date of the instant invention to conduct a flow synthesis process for producing a sulfonylurea compound of the Formula 1 or its pharmaceutically acceptable salts, the process comprising the steps of: a) preparing the amide of Formula 2 i) by activating a carboxylic acid of Formula 9 with a haloformate of Formula 8 in the presence of an organic base to produce an anhydride of Formula 5, and ii) reacting the anhydride of Formula 5 with the sulfonamide of Formula 4 to produce the amide of Formula 2; and b) reacting the amide of Formula 2 with a carbamate of Formula 3 or isocyanate R3—NCO in view of the teachings of Ambrogi and Plutschack.
Allowable Subject Matter
The subject matter of claims 10-13 is free of prior art. The closest prior art references and their teachings have been set forth above. Liu and Ambrogi further teach that the reaction that is equivalent to the claimed step (b) is conducted in the presence of anhydrous potassium carbonate and sodium hydroxide solution, respectively. However, the references fail to teach the reaction in the presence of the organic base selected from TBA, DBU, DIPEA, THA and TEA. Furthermore, neither anhydrous potassium carbonate nor sodium hydroxide solution is an obvious variant of the claimed organic base. Thus, a skilled artisan would not have been motivated in substituting the anhydrous potassium carbonate and sodium hydroxide with the organic phase as claimed and would not have a reasonable expectation of success in obtaining sulfonylurea compound from the amide and isocyanate.
Conclusion
Claims 1-9 and 14-22 are rejected and no claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MEDHANIT W BAHTA whose telephone number is (571)270-7658. The examiner can normally be reached Monday-Friday 8am-5pm.
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/MEDHANIT W BAHTA/Primary Examiner, Art Unit 1692
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