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 .
Current Status of 17/636,712
This Office Action is responsive to the amended claims and Applicant remarks of 04/01/2026. Claims 8-16 and 21-22 are pending and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/US202/046947, international filing date 08/19/2020, which claims priority to U.S. Provisional Patent Application Nos. 62/888,667, filed 08/19/2019, and 62/890,154, filed 08/22/2019.
Instant claims 8, 10-16, 21, and 22 find support in 62/88,667 and are given the effective filing date of 08/19/2019. Claim 9 finds support in 62/890,154 and is given the effective filing date of 09/22/2019.
Response to Arguments
Applicant's arguments have been fully considered but are not persuasive.
The prior art teaches preparation of the same brominated compound using the same starting material and substantially the same brominating reagents (PBr3 and Br2) to achieve the same bromination transformation to afford the same target product. The main distinction between the claimed process and the prior art resides in the sequence in which the reagents are combined, reagent ratios, and workup conditions. Modification of reagent addition order, reagent loading, and neutralization procedures in an otherwise known chemical process constitutes routine optimization and involves result-effective variables well within the level of ordinary skill in the art. The artisan would reasonably have expected that altering the sequence of addition of known brominating reagents while employing the same substrate under otherwise similar bromination conditions would still result in formation of the same brominated product. Furthermore, the artisan would have been motivated to optimize reagent sequencing and reagent equivalents to improve process efficiency, reduce excess reagent consumption, minimize waste, improve safety, and reduce production costs.
Applicants argue that the claimed process is fundamentally distinct because the prior art allegedly forms PBr5 in situ whereas the claimed process purportedly avoids PBr5 formation entirely. However, the claims do not affirmatively require the absence of PBr5 formation, prevention of reactor fouling, elimination of wall deposition, or exclusion of bromophosphorus intermediate species. The claims merely recite sequential treatment of the substrate with PBr3 followed by Br2. The arguments regarding distinct mechanistic pathways therefore amount to unsupported mechanistic speculation and attorney arguments rather than persuasive evidence of a patentably distinct process. Even assuming transient intermediates differ, differences in unclaimed reactions mechanisms do not render an otherwise obvious process patentable absent demonstration of a truly unexpected technical result attributable to the alleged mechanistic distinction.
Applicants additionally argue that the claimed process uses lower molar equivalents of PBr3 and Br2 relative to the starting material than those disclosed in the prior art and that such reduced reagent loading improves reaction economy, minimizes environmental impact, and improves process safety. These arguments are similarly unpersuasive. Optimization of reagent concentrations and stoichiometric equivalents of a known chemical process constitutes routine experimentation within the ordinary skill in the art. The artisan would have been motivated to reduce excess brominating reagent amount to improve cost efficiency, reduce hazardous reagent handling, and minimize waster generation while maintaining an acceptable conversion and yield of the target product. Applicants' asserted motivations for improving the safety and efficiency of the reactions are the same reasons why the artisan would have optimized reagent loading in the prior art process. Furthermore, the claims do not expressly recite the particular reagent ratios relied upon in Applicants' arguments, therefore the asserted advantages are not commensurate in scope with the claimed invention.
Applicants further argue that the use of inorganic bases such as potassium carbonate or sodium bicarbonate is not inherent to the claimed process and that reliance on additional references teaching bromination workup procedures constitutes impermissible hindsight. This argument is not persuasive. Neutralization of acidic bromination mixtures and quenching of residual halogen-containing reaction mixtures using inorganic bases represents a conventional and well-known workup technique in synthetic organic chemistry. Selection of commonly used inorganic bases such as potassium carbonate, sodium carbonate, or sodium bicarbonate would have constituted routine optimization absent evidence of criticality. References directed to bromination reaction workups are reasonably pertinent to the problem faced by the artisan, namely handling and neutralization of bromination reaction mixtures containing acidic or brominating species. The art relied upon in the rejections therefore constitutes analogous art relevant to optimization of the disclosed bromination process.
Applicants contend that the claimed process achieves unexpected improvements in yield and industrial operability due to avoidance of PBr5 formation and reduced reactor fouling. However, the evidence of record does not demonstrate a sufficiently unexpected improvement to overcome the prima facie case of obviousness. Comparative Example 2 of the speciation reports a yield of 88% while the allegedly inventive processes report yields of 90-92%. These relatively modest yield differences are consistent with expected improvements arising from routine optimization of reagent sequencing, reagent loading, neutralization procedures, and workup conditions rather than evidence of a patentably distinct process. Although the Applicants characterize the operational advantages as significant, improvements in handling characteristics, process convenience, or reactor operability resulting from routine modification of reagent addition sequence and process parameters would have been expect by the artisan as part of standard process development and scale-up activities.
Accordingly, the evidence indicates that the claimed process represents an optimization of known bromination methodology employing known reagents, known substrates, and known workup techniques to afford the same expected brominated product. Applicants have not provided sufficient evidence of criticality or truly unexpected results sufficient to overcome the prima facie case of obviousness under 35 U.S.C. §103.
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.
Claims 8-13 are rejected under 35 U.S.C. 103 as being unpatentable over Shangdong (CN 102399211 A, found in IDS filed 03/22/2022).
Determining the scope of the prior art:
Shangdong teaches:
a method of preparing 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ester (reading on the claimed compound of formula (I)) comprising adding phosphorus tribromide to solvent In A, adding bromine and reacting for 0.5 to 3 hours, then adding 2- (3-chloro-2-pyridyl) -5-pyrazolone-3-carboxylic acid ester, warming to 20-80 ℃. After completion, post-treatment gives 3-bromo-1- (3-chloro-2-pyridyl) -4,5-dihydro-1H-pyrazole-5-carboxylic acid ester (Claim 1), reading on instant claim 8;
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the described method avoided the use of highly toxic product tribromo oxygen phosphorus and phosphorous pentabromide (Shangdong, Description), reading on instant claim 8;
the Br substitution of the pyrazole ring in formula (II), see above, reading on instant claim 8;
in Formula (I), R is C1-C4 linear or branched alkyl (Claim 1), reading on instant claim 8;
the temperature of the reaction of reagents PBr3, Br2, and (I) at a temperature between 20°C-80°C (Claim 1), reading on instant claim 9; and
the reaction solvent is acetonitrile (Claim 3), reading on instant claims 10, 11, 12, and 13.
Ascertaining the differences between the prior art and the claims at issue:
The prior art reference Shangdong teaches a different order of addition of the reactants PBr3, Br2, and (I). Shandong shows the predominant 3-oxo-derivative of (I) whereas the instant application shows the 3-hydroxy-derivative (tautomeric form of (I)).
Resolving the level of ordinary skill in the pertinent art:
The artisan would have experience in synthetic organic chemistry, including process chemistry and bromination of heterocyclic compounds. The artisan would have been familiar with PBr3/Br2 bromination systems and routine optimization of reaction conditions including reagent equivalents, order of additions, solvent system selection, and workup/neutralization procedures. The artisan would also be familiar with common scale-up considerations.
Considering objective evidence present in the application indicating obviousness or nonobviousness:
The instant claims 8-13 are prima facie obvious in view of the reference Shangdong.
The artisan would recognize that compound (I) of Shangdong
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is the 3-oxo tautomer of the instant application’s Formula (A) as specified in instant claim 8
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and that (I) and (A) exist in equilibrium. Therefore, the two structures are equivalent when R is Et. Similarly, compound (II) of Shangdong
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is the same as the instant application’s claimed product in instant claim 8 when R is Et
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. Both methods produce the same 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ester (Shangdong II, instant I) by reacting A of the instant application (I of Shangdong) with PBr3, and Br2 in acetonitrile at a temperature of between 15°-80°C. The artisan would expect that the treatment of (A) with PBr3 and Br2 would produce (I). The artisan would be motivated to use the combination of PBr3 and Br2 to accomplish the desired transformation of (A) to (I) because this combination avoids the use of the highly toxic phosphorus pentabromide (PBr5) (Shangdong, Description). The artisan would have reasonably expected that combining PBr3, Br2, and (A) in a different order would result in the formation of product (I). Selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (see, e.g., Ex parte Rubin, 128 USPQ 440, 1959, and In re Burhans, 154 F.2d 690, 69 USPQ 330 - CCPA 1946) MPEP § 2144.04.
Claims 8, 14-16, 21, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Shangdong in view of E. I. du Pont de Nemours and Company, herein after referenced as du Pont (WO 2003/016283 A1, found in IDS submitted 03/22/2022) and Varnado (WO 2019/067883), as evidenced by Palou (Palou, Josefina. "Oxidation of some organic compounds by aqueous bromine solutions." Chemical Society Reviews 23.5 (1994): 357-361.).
Determining the scope of the prior art:
Shangdong teaches the limitations of claim 8, see above.
du Pont teaches:
the preparation of the same compound of Formula (I) using PBr5 as the brominating agent. When the bromination reaction is complete, “the reaction mass is then neutralized with an inorganic base, such as sodium bicarbonate, sodium hydroxide, and the like” (Page 10, lines 1-2). Example 9B further describes this neutralization of the bromination reaction mixture where “[a] second 1-L four-necked flask equipped with a mechanical stirrer was charged with 40g (0.48 mol) sodium bicarbonate and 200 mL of water (i.e. a sodium carbonate solution). The concentrated reaction mixture was added to the sodium bicarbonate slurry over a period of 5 minutes” (Page 20, lines 3-6), reading on instant claims 8, 14-16, and 21, but does not explicitly teach claim 22; however, one of ordinary skill in the art would recognize the phrase “and the like” to encompass the species of potassium carbonate as an inorganic base. This is evidence by Varnado, which is in the same field of endeavor as it teaches a method of bromination of alcohols. [0034] of Varnado teaches a quenching with a base of reactive bromine species and states “[t]he aqueous base solutions can include hydroxide, carbonate, or bicarbonate salts, including alkali hydroxides, alkaline earth hydroxides, alkali carbonates, alkaline earth carbonates, alkali bicarbonates, and alkaline earth bicarbonates. The terms hydroxide, carbonate, and bicarbonate are meant to reference the inorganic metal salt or base, where the hydroxyl, carbonate, or bicarbonate anion is accompanied by an inorganic counterion, i.e. a cation, such as sodium, potassium, calcium, ammonium, and the like.” . Additionally, Varnado exemplifies this teaching in [0042] where the reaction mixture was quenched by pouring it into a 20% aq. potassium carbonate solution. This reads on claim 22.
Ascertaining the differences between the prior art and the claims at issue:
Shangdong does not teach a workup procedure using an inorganic base, nor does it teach the oxidation reaction of the instant application’s compound of formula (I) to produce compound of formula (II) of the instant claims.
du Pont broadly teaches the use of halogenating reagents for the formation of (I) (Page 9, lines 7-8, Scheme 2). du Pont does not explicitly teach potassium carbonate or a solution of potassium carbonate as an exemplary inorganic base.
Resolving the level of ordinary skill in the pertinent art:
The artisan would have experience in synthetic organic chemistry, including process chemistry and bromination of heterocyclic compounds. The artisan would have been familiar with PBr3/Br2 bromination systems and routine optimization of reaction conditions including reagent equivalents, order of additions, solvent system selection, and workup/neutralization procedures. The artisan would also be familiar with common scale-up considerations.
Considering objective evidence present in the application indicating obviousness or nonobviousness:
Claims 8, 14-16, 21, and 22 are prima facie obvious in view of the references Shangdong, du Pont and Varnado. Shangdong teaches the limitations of claim 8, see above. The artisan would find it obvious before the effective filing date of the claimed invention to combine the method of producing
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from Shangdong with the neutralization method taught by du Pont to arrive at the instant invention.
The artisan would have been motivated to combine the teachings of Shangdong with the teachings of du Pont due to the efficiency of the du Pont neutralization which only required a single wash and mixing (Page 20, lines 4-8) compared to multiple washes with water (Shangdong Description, Examples 1 to 8). The artisan would have expected that neutralization of the bromine reactant with an inorganic base in water would generate the desired product in high yields (du Pont, page 20, line 15). In view of the teaching of Varnado discussed above, it would have been obvious to use potassium chloride as this is taught to be equivalent to the carbonate salts taught by Shangdong and Shangdong teaches that inorganic base, such as sodium bicarbonate, sodium hydroxide, and the like can be used. This teaches claims 14-16, 21, and 22.
Furthermore, du Pont teaches all limitations of compound (I) and (II) as it discloses the same substitutions of R1, X, R2, and n that are not taught by Shangdong (du Pont Page 2, lines 3-13). Although the methods of synthesis of du Pont and the instant claims differ on the reagents used, the products are identical in the totality of their scope. It would have been prima facie obvious to a skilled artisan to adapt the method of Shangdong and expand this method to all compounds of the Markush group for the substitutions of (I) of du Pont. The artisan would be motivated to combine the method of Shangdong with the substrate scope of du Pont due to the success of the Shangdong method in synthesizing the desired product (I) without the use of PBr5. The artisan would expect that the substitutions taught by du Pont would result in the formation for the desired products of formula (I) with the given substitutions.
Conclusion
No claims are allowed.
Applicants have amended the claims to limit the scope of the claimed process to the synthesis of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate. Claims 1-7 previously directed to a Markush genus have been cancelled. However, the amended claims are not directed to subject matter that is patentably distinct from that previously examined rejection. The amended claims continue to recite preparation of the same brominated compounds using the same starting material, substantially the same brominating reagents, and substantially the same reaction conditions previously considered during prosecution. The presently claimed species of instant claim was encompassed within the scope of the prior claims and within the scope of the prior art previously applied. Accordingly, the present rejection is properly made final because the amendments do not necessitate a new ground of rejection.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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