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 .
Claim Status
Claims 1-18 are pending.
Claims 3-4, 6, 8, and 10-18 have been amended.
No claims have been cancelled.
Thus, claims 1-18 represent all claims currently under consideration.
Priority
Domestic Priority data as claimed by Applicant:
This application is a 371 of PCT/IB2022/057538 (08/12/2022)
Foreign Applications:
UNITED KINGDOM 2111677.7 (08/13/2021)
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Objections
Claim 1 is objected to because of the following informalities:
In line 2, “salts” should read “salt”.
In line 7, “or amine HCl salt” should read “or its HCl salt”.
In line 7, “with haloformate” should read “with a haloformate”.
Claim 3 is objected to because of the following informalities:
In line 2, “or amine HCl salt” should read “or its HCl salt”.
Claim 8 is objected to because of the following informalities:
In lines 2-3, “1,8-Diazabicyclo[5.4.0]undec-7-ene” should read “1,8-diazabicyclo[5.4.0]undec-7-ene”.
Claim 12 is objected to because of the following informalities:
In line 2, “or amine HCl salt” should read “or its HCl salt”.
Appropriate correction is required.
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 1-6 and 8-18 are rejected under 35 U.S.C. 103 as being unpatentable over Ambulgekar et al. (“A Novel and Facile Process for the Synthesis of Gliclazide”; Lett. Org. Chem. 2018, 15, 760-765; published 2018; IDS of 02-13-2024), in view of Guidi et al. (“How to approach flow chemistry”; Chem. Soc. Rev. 2020, 49, 8910-8932; published 11-03-2020) and Stafford et al. (WO 2020/018970 A1; published 01-23-2020).
Regarding claim 1, Ambulgekar teaches a process for the synthesis of gliclazide (1), whose structure corresponds to Formula 1 of the instant claim when R1 is -CH3 and R is
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. The process comprises the preparation of carbamates 4 or 8, whose structures correspond to Formula 2 of the instant claim when R2 is aryl or alkyl, respectively, through reaction of amine 3 (i.e., RNH2, wherein R is as defined above) with aryl chloroformates 2a-2d or alkyl chloroformates 7a-7b, whose structures correspond to Formula 4 of the instant claim when R2 is as defined above and X is Cl. These carbamates were then reacted in the presence of a base with p-toluene sulfonamide (5), whose structure corresponds to Formula 3 of the instant claim when R1 is as defined above, to provide gliclazide (Title; page 761, Col. 2, paragraphs 1-4; page 762, Schemes 1-2):
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Ambulgekar does not teach (1) a flow synthesis process; (2) conducting the method step a) in the presence of a base; and (3) wherein the process is a continuous multi-step process without the isolation of any intermediates, as recited in claims 1-2.
Regarding points (1) and (3), Guidi teaches that one of the strengths of flow chemistry is the relative ease in the ability to connect two or more modules to create a multi-step process, whether that is combining synthesis and work-up/purification, or stitching together multiple synthesis operations in the pursuit of a target molecule. In flow chemistry, when multiple units of operation are linked together in a continuous system it is called a telescoped process. The advantages of such a process are significant, with reductions in purifications steps, time of synthesis, waste, and manual operations (page, 8912, Col. 1, paragraphs 1-2).
Regarding point (2), although the method of Ambulgekar does not teach a carbamate method synthesis step in the presence of base, as detailed above, does teach that the reaction mixture forms a precipitate, that is isolated by filtration and subsequently neutralized in a biphasic mixture of dichloromethane and 10% aq. sodium bicarbonate (page 763, paragraph 3). The skilled artisan would predictably recognize that the precipitate must be acidic (HCl) from the reaction between chloroformate and amine, and would therefore be sufficiently motivated modify the process of Ambulgekar to quench the acid formed in situ by performing the reaction in the presence of added base, to achieve the same result with a reasonable expectation of success. and avoid the use of a workup step with aqueous base. Such an endeavor would result in the reordering of process steps which is non-inventive in nature. MPEP § 2144.04(IV) states that the “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results.”
In addition, Stafford teaches the synthesis of sulfonylurea compounds, including the same carbamate intermediate taught by Ambulgekar and consistent with Formula 1 of instant claim 1 as detailed above (Title; reaction scheme and step 1 of Example 13:
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Stafford further teaches the preparation of phenyl hexahydrocyclopenta[c]pyrrol-2(1H)-yl carbamate from the dropwise addition of phenyl chloroformate to a solution of hexahydrocyclopenta[c]pyrrol-2(1H)-amine hydrochloride and TEA in anhydrous DCM at 0 ºC, and the reaction was warmed to room temperature and stirred for 3 hours (step 1 of Example 13, 0308). Thus, Stafford teaches an alternative synthesis of the carbamate intermediate of Ambulgekar carried out in the presence of a base (i.e., TEA).
Further regarding point (2), Guidi teaches that the simplest flow process is monophasic where no precipitation occurs – as this causes clogging of the tubing and thus failure of the process (page 8912, Col. 2, paragraph 2). Therefore, when considering modifying the batch process of Ambulgekar to arrive at a continuous flow process as taught by Guidi, the skilled artisan would be motivated to select reaction conditions that avoided undesired precipitation events such as disclosed by Ambulgekar who teaches carbamate formation in the absence of base, as detailed above. As such, the skilled artisan would seek alternative reaction conditions, such as those of Stafford, to predictably pursue a synthetic preparation of phenyl hexahydrocyclopenta[c]pyrrol-2(1H)-yl carbamate in the presence of a base to avoid unnecessary precipitation events with a reasonable expectation of success.
Further regarding point (3), Ambulgekar teaches the use of bases including KOtBu, NaOH, KOH, and NaOMe for the reaction between carbamate (4) and p-toluenesulfonamide (5) for the preparation of gliclazide (page 762, Schemes 1-2; page 763, Table 2). Although Ambulgekar teaches the use of n-heptane solvent in the first carbamate forming method step and DMSO, NMP, or THF solvent for the following gliclazide prepration step (page 762, Schemes 1-2), Guidi teaches that well designed mixing units (such as T- or Y-mixers) can be used to form homogenous solutions with miscible solvents or efficiently perform reactions comprising immiscible solvents (page 8912, Col. 2, paragraphs 2-3; page 8913, Col. 1, paragraph 2). Therefore, when envisioning a telescoped continuous process as taught by Guidi (page, 8912, Col. 1, paragraphs 1-2), the skilled artisan would be sufficiently motivated to pursue a telescoped flow process employing a base (i.e., KOtBu, NaOH, KOH, and NaOMe) in the first carbamate forming method step of Ambulgekar that would be expected to also react competently in the following step for the preparation of gliclazide to arrive at a continuous process without intermediate isolation with a reasonable expectation of success.
The process of Ambulgekar and Stafford are analogous because they both teach the preparation of sulfonylureas in batch processes, including the synthesis of phenyl hexahydrocyclopenta[c]pyrrol-2(1H)-yl carbamate, a compound of Formula 1 of claim 1, from the corresponding amine/amine HCl salt and phenyl chloroformate. The teachings of Guidi are analogous to the invention of claims 1-2 because they reside in the overlapping technical field flow synthesis processes, including continuous multistep processes without the isolation of any intermediates (i.e., telescoped processes).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the batch process of Ambulgekar to incorporate the teachings of Guidi to pursue a continuous multistep flow process without isolation of any intermediates with predictable advantages over the corresponding batch process with a reasonable expectation of success to arrive at the claimed invention. See MPEP 2143(I)(A). Furthermore, MPEP 2144.04(V)(E) states that “a continuous operation would have been obvious in light of the batch process of the prior art.” In addition, when considering Ambulgekar in view of Guidi, the skilled artisan would be sufficiently motivated to substitute the reaction conditions of Ambulgekar for the preparation of phenyl hexahydrocyclopenta[c]pyrrol-2(1H)-yl carbamate with the conditions of Stafford (i.e., TEA base in DCM solvent) to avoid unnecessary precipitation events that are known to cause clogging of flow reactor tubing as taught by Guidi with a reasonable expectation of success. See MPEP 2143(I)(B).
Therefore, the skilled artisan would have been sufficiently motivated to arrive at the invention of claims 1-2 with a reasonable expectation of success based on the combined teachings of Ambulgekar, Guidi, and Stafford. The motivation to do so would permit the skilled artisan to pursue, with a reasonable expectation of success, a process with reductions in purifications steps, time of synthesis, waste, and manual operations using reaction conditions that avoid the unnecessary precipitation of intermediates that can cause clogging of flow reactor tubing and failure of the process, as described above.
Regarding claims 3, 6, and 8, Stafford teaches the use of 1.23 mmol hexahydrocyclopenta[c]pyrrol-2(1H)-amine hydrochloride and 1.85 mmol of TEA in anhydrous dichloromethane (step 1 of Example 13; 0308). This corresponds to an amine HCl salt to base molar ratio of 1:1.5 and therefore resides within the range recited in instant claim 3. MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”
Further regarding claim 6, Stafford teaches embodiments of carbamate synthesis reactions using phenyl chloroformate in acetonitrile solvent (step 1 of Example 4, 0298). Thus, Stafford demonstrates that acetonitrile can be predictably used interchangeably with DCM for this transformation.
Further regarding claim 8, Stafford teaches the use of triethylamine (TEA) based for the synthesis carbamate method synthesis step, as detailed above (step 1 of Example 13; 0308). This base is structurally homologous with trimethylamine and tributylamine, as it differs by 1 or 2 methylene (-CH2- units) on each carbon chain, respectively. MPEP 2144.09(II) states that “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.”
Regarding claims 4-5 and 10-11, Ambulgekar teaches the preparation of phenyl hexahydrocyclopenta[c]pyrrol-2(1H)-yl carbamate (4) from the dropwise addition of phenyl chloroformate to a solution of hexahydrocyclopenta[c]pyrrol-2-amine at 0-5 ºC, and the temperature of the reaction was increased to 25 ºC and stirred for 1 hour (page 763, paragraph 3). In addition, Stafford teaches the preparation of phenyl hexahydrocyclopenta[c]pyrrol-2(1H)-yl carbamate from the dropwise addition of phenyl chloroformate to a solution of hexahydrocyclopenta[c]pyrrol-2(1H)-amine hydrochloride and TEA in anhydrous DCM at 0 ºC, and the reaction was warmed to room temperature and stirred for 3 hours (step 1 of Example 13, 0308). The reaction temperature range of Ambulgekar and Stafford overlaps with the ranges recited in claims 10-11. MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”
Regarding claim 9, Ambulgekar, Guidi, and Stafford do not explicitly teach wherein the base used in step (a) and step (b) is the same, as recited in the instant claim.
However, Guidi does teach that byproducts and unused reagents from previous steps are carried through to the subsequent modules, and the general rule of thumb is once something is added to a multistep flow process, it is there throughout (page 8912, Col. 1, paragraph 3). Therefore, in view of the combination of the prior art cited above, the skilled artisan could predictably arrive at a continuous multistep flow process wherein the TEA base as taught by Stafford is used in both step (a) and step (b) with a reasonable expectation of success due to the general nature of continuous multistep flow reactors as taught by Guidi.
Regarding claim 12, Stafford teaches a reaction solution of 1.23 mmol of hexahydrocyclopenta[c]pyrrol-2(1H)-amine hydrochloride in 5 mL of DCM solvent (step 1 of Example 13, 0308). This corresponds to a concentration of 0.25 M and resides within the range recited in the instant claim. MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”
Regarding claims 13-15, Ambulgekar teaches a solution of 0.0584 mol p-toluene sulfonamide in 50 mL solvent, and its subsequent reaction with 0.0642 mol of carbamate (4) (page 764, Col. 2, paragraph 3). This corresponds to a sulfonamide concentration of 1.17 M, and a sulfonamide to carbamate molar ratio of 1:1.1. The sulfonamide concentration of 1.17 M resides within the range of instant claim 13, and the sulfonamide to carbamate molar ratio of 1:1.1 resides within the ranges of instant claims 14-15. MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”
Regarding claim 16, Ambulgekar teaches a sulfonylurea synthesis step with a solution of 0.0584 mol p-toluene sulfonamide and 0.0642 mol of added base (page 764, Col. 2, paragraph 3). This corresponds to a sulfonamide to base molar ratio of 1:1.1.
However, Stafford also teaches a sulfonylurea synthesis step from the same carbamate intermediate of Ambulgekar, wherein 0.25 mmol of sulfonamide are used with 0.62 mmol of added base (step 2 of Example 13; 0308). This corresponds to a sulfonamide to base molar ratio of 1:2.5 and resides within the range recited in the instant claim. MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” Therefore, the skilled artisan could arrive at the claimed invention with a reasonable expectation of success based on the combined teachings of Ambulgekar, Guidi, and Stafford and through means of routine optimization that is non-inventive in nature. MPEP § 2144.05(II) states that “[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.”
Regarding claims 17-18, Ambulgekar teaches a reaction embodiment wherein based was added to a solution of p-toluene sulfonamide at 25 ºC, the reaction mixture was heated to 100 ºC for 3 h, and then the reaction mixture was cooled to 25 ºC before the addition of carbamate (4) (page 764, Col. 2, paragraph 3). The skilled artisan could predictably recognize that the process of Ambulgekar could alternately be carried out with the presence of carbamate (4) in the initial reaction mixture, rather than adding it after heating the sulfonamide with base, to achieve the same result with a reasonable expectation of success at a temperature that resides within the range recited in claim 17. See MPEP § 2144.05(I). Such an endeavor would result in the reordering of process steps which is non-inventive in nature. MPEP § 2144.04(IV) states that the “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results.”
Further regarding claim 18, although Ambulgekar does not explicitly teach a step (b) reaction temperature of about 80 ºC, as recited in the instant claim, the method of Ambulgekar does teach reacting the sulfonamide in the presence of base in a range from 25 C to 100 C, as detailed above (page 764, Col. 2, paragraph 3). Therefore, the skilled artisan could arrive at the claimed invention with a reasonable expectation of success through means of routine optimization that is non-inventive in nature. MPEP § 2144.05(II) states that “[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.”
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Ambulgekar et al. (“A Novel and Facile Process for the Synthesis of Gliclazide”; Lett. Org. Chem. 2018, 15, 760-765; published 2018; IDS of 02-13-2024), in view of Guidi et al. (“How to approach flow chemistry”; Chem. Soc. Rev. 2020, 49, 8910; published 11-03-2020) and Stafford et al. (WO 2020/018970 A1; published 01-23-2020) as applied to claims 1-6 and 8-18 above, and further in view of Jordan et al. (“Chlorinated Solvents: Their Advantages, Disadvantages, and Alternatives in Organic and Medicinal Chemistry”; Chem. Rev. 2021, 121, 1582-1622; published 12-22-2020).
Regarding claim 7, claim 6 is rendered obvious over Ambulgekar, Guidi, and Stafford, as detailed above.
Ambulgekar, Guidi, and Stafford do not teach wherein the reaction of step (a) is performed in chloroform. Instead, Stafford teaches the preparation of phenyl hexahydrocyclopenta[c]pyrrol-2(1H)-yl carbamate from the dropwise addition of phenyl chloroformate to a solution of hexahydrocyclopenta[c]pyrrol-2(1H)-amine hydrochloride and TEA in anhydrous DCM, as detailed above (step 1 of Example 13, 0308).
However, Jordan teaches that both chloroform and DCM are the only commonly used chlorinated solvents with any hydrogen-bonding character, i.e., the ability to act as a H-bond donor, and chloroform displays superior solubility phenomena to DCM as indicated by their Hansen solubility parameters and Kamlet-Taft parameters (page 1586, Col. 1, paragraph 4 and Col. 2, paragraph 1; page 1587, Col. 1, paragraph 1 and Tables 2-3). Jordan further teaches that chlorinated solvents such as DCM and chloroform see widespread use in electrophilic reactions with amines such as amine acylation, i.e., amide bond formation) (page 1598, Col. 2, paragraph 5). The skilled artisan would recognize from the teachings of Jordan that DCM and chloroform are interchangeable reaction solvents for amine acylation reactions, which include the carbamate formation of reaction step (a) of the instant claim.
Further regarding claim 7, Guidi teaches that the simplest flow process is monophasic where no precipitation occurs – as this causes clogging of the tubing and thus failure of the process, as detailed above (page 8912, Col. 2, paragraph 2). Thus, the skilled artisan would be motivated to predictably select reaction solvents with superior solubility profiles, such as chloroform as taught by Jordan and detailed above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Ambulgekar, Guidi, and Stafford to incorporate the teachings of Jordan to substitute the dichloromethane solvent of Stafford with chloroform as taught by Jordan to pursue a reaction solvent with predictable application in amine acylation reactions and with solubility properties superior to have of dichloromethane to arrive at the claimed invention with a reasonable expectation of success. See MPEP 2143(I)(B). The motivation to do so would permit the skilled artisan to pursue, with a reasonable expectation of success, a reaction solvent with improved solubility properties compared to dichloromethane that avoids the unnecessary precipitation of intermediates that can cause clogging of flow reactor tubing and failure of the process, as described above.
Based on the combined teachings of the references, the Examiner submits that a person of ordinary skill in the art would have had a reasonable expectation of success of arriving at the instantly claimed process. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, and absent a clear showing of evidence to the contrary.
Conclusion
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/D.R./Examiner, Art Unit 1692
/AMY C BONAPARTE/Primary Examiner, Art Unit 1692
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