DETAILED ACTION
Claims 8-10, 12-14 and 17-20, submitted 06 December 2023, are pending in the application. Claim 14 has been withdrawn. Claims 8-10, 12-13 and 17-20 are subject to examination in the instant Office 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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 8-10, 12-13 and 17-20, in the reply filed on 20 April 2026 is acknowledged.
Claim 14 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 20 April 2026.
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 17 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 term “substantially free” in claim 17 is a relative term which renders the claim indefinite. The term “substantially free” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. There is no definition provided which would lead the Examiner or practitioner to know the implied amount of acceptable impurities.
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.
Claims 8-10, 12-13, and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over St Clair Brown et al. (WO 2010/083414 A1) in view of Kumar et al. ("Electrophilic activation of carboxylic anhydrides for nucleophilic acylation reactions." Synthesis 50.19 (2018): 3902-3910.) and Grabner et al. ("Synthesis of novel adamantoyl cellulose using differently activated carboxylic acid derivatives." Cellulose 9.2 (2002): 193-201.) as evidenced by Scriven ("4-Dialkylaminopyridines: super acylation and alkylation catalysts." Chemical Society Reviews 12.2 (1983): 129-161.).
St Clair Brown teaches the process of preparing cabozantinib (N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclo-propane-1,1 -dicarboxamide) and the (L) malate salt thereof (Abstract; paragraph 0099). However, the process as taught by St Clair Brown differs from that of the claimed invention in that the intermediate (1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid), compound of Formula V of the instant invention, is activated in a mixture of THF, the optional suitable solvent, DMF, and oxalyl chloride (paragraph 00108). The process as taught by St Clair Brown is shown below in Scheme 1. As shown, St Clair Brown shows the addition of the compound 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (compound of Formula III of the instant invention). St Clair Brown also teaches that the resulting compound yield can be isolated (paragraph 0093) and that it can further be converted to its malate salt form, which is also detailed in scheme 1.
Scheme 1 taught by St Clair Brown
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(paragraph 099)
St Clair Brown does not teach a process for preparation wherein the compound of Formula V is activated using a sulfonyl chloride. However, Kumar teaches the electrophilic activation of carboxylic anhydrides using methanesulfonyl chloride (MsCl) as the reagent of choice as it afforded a better yield with higher conversion rates (pg. 3903, Section “Introduction”, Right Col., 1st paragraph). It would have been prima facie obvious for a person skilled in the art to at least try to prepare cabozantinib with a sulfonyl chloride because the use of sulfonyl chlorides in coupling reactions is known in the art. More importantly, the substitution of one activating agent with another presents a case of obviousness regardless of the intermediate produced because the activating agents are equivalent with respect to their function in the chemical reaction. Consequently, this also reads on the limitations of instant claim 18 which recites the limitation “wherein in step (a) or (a’) the suitable solvent is selected from dichloromethane, dichloroethane, THF and acetonitrile”. Instant claim 19 is also rejected as Kumar teaches the use of methane sulfonyl chloride.
Thus, it would have been prima facie obvious for one skilled in the art to modify the teachings of St Clair Brown with the teachings of Kumar to prepare cabozantinib by activating 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid with a sulfonyl chloride instead of an acid chloride. The ordinary skilled artisan would have an expectation of success because Kumar states “the requirement of special or stringent conditions for synthesis, handling, and storage of acid chlorides coupled with limited functional group tolerance, circumvent their synthetic application” (pg. 3902, Section “Introduction”, Right Col., 1st paragraph). Thus, it would have been prima facie obvious for one skilled in the art, prior to the effective filing date of the application, to combine the teachings of St Clair Brown and Kumar to arrive at the instantly claimed invention. Consequently, this also reads on the limitations of instant claim 9 which require that the sulfonyl chloride is methane sulfonyl chloride.
With regards to claim 10, St Clair Brown does teach a method of preparing cabozantinib and its malate salt derivatives but does not teach a process of preparing cabozantinib wherein the activating agent in step a) of the instant claim is a sulfonyl chloride, much less wherein the sulfonyl chloride is toluene sulfonyl chloride. However, Grabner discloses the use of the reagent p-toluenesulfony chloride in the activation of carboxylic acids in the synthesis of adamantoyl cellulose (Abstract; pg. 193, Section “Introduction”, Right Col., 1st paragraph). Again, it would have been prima facie obvious to one skilled in the art to substitute the carboxylic acid activating agent with another with the expectation of success because Grabner states “Recently, the efficiency of various reagents for the in situ activation of carboxylic acids in the course of cellulose acylation was studied (Liebert 1991). An efficient reagent was found to be p-toluenesulfonyl chloride (TosCl)…” (pg. 196, Section “Reaction of cellulose with adamantane carboxylic acid…”, Left to Right Col., 1st paragraph). It also applies that these activating agents are interchangeable with respect to the function of activating carboxylic acids. Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to modify the teachings of St Clair Brown and the teachings of Grabner to prepare cabostantinib without an acid chloride addition to activate the carboxylic acid compound of step a) and instead use the p-toluenesulfonyl chloride. A person having ordinary skill in the art would have an expectation of success because the use of sulfonyl chlorides as an activating agent is known in the art based on the teachings of Grabner.
Regarding claim 12, St Clair Brown teaches the above process for preparation of cabozantinib. However, the difference between claim 9 and claim 12 is that the methane sulfonyl chloride is added to the compounds of step a) and step b) in a single step rather than 2 individual steps. Additionally, claim 12 differs in that the compounds are in dichloromethane and a suitable base. Finally, St Clair Brown teaches in the preparation of the cabozantinib L-malate the use of dichloromethane and methanol (paragraph 0134). While St Clair Brown does not teach the use of a base in the chemical reaction, the use of DMAP (N, N-dimethylamino pyridine) is a known base in the art of organic synthesis as evidenced by Scriven which states “The most popular catalyst for laboratory and industrial use has proved to be DMAP” (pg. 132, Section “Preparation and Physical Properties”, 2nd paragraph).
This rationale can also be applied to instant claim 13 which differs from claim 10 in that the toluene sulfonyl chloride is added to the compounds of step a) and step b) in a single step rather than 2, and further adding the dichloromethane and a suitable base. Again, St Clair Brown teaches the preparation of cabozantinib L-malate with dichloromethane and methanol. While this reference doesn’t teach the use of a base in the chemical reaction, the use of DMAP (N, N-dimethylamino pyridine) is a known base in the art of organic synthesis as evidenced by Scriven which states “The most popular catalyst for laboratory and industrial use has proved to be DMAP” (pg. 132, Section “Preparation and Physical Properties”, 2nd paragraph). Therefore, the process of preparation of cabozantinib of the instant claim would be prima facie obvious to one skilled in the art of organic synthesis in view of the teachings of St Clair Brown, Grabner and Scriven because it’s known in the art that DMAP is the most popular catalyst for laboratory and industrial use. Consequently, this also reads on the limitations of instant claim 20 which recites “wherein the suitable base is an organic base selected from N, N-dimethylaminopyridine (DMAP) and N-methylimidazole (NMI)”.
With respect to claim 17, St Clair Brown states “In another embodiment, the disclosure relates to a crystalline form of Compound (I), as described herein in any of the aspects and/or embodiments, is substantially pure N-2 form” (paragraph 0060). This reference teaches the definition of “substantially pure” as “the crystalline form of Compound (I) referred to contains at least about 90wt.%” (paragraph 0097). Additionally, the process as taught by St Clair Brown is completed using similar method steps in an alternate manner with different reagents such as thionyl chloride and oxalyl chloride (paragraphs 0108 and 0110). The process as claimed in the instant application is drawn to the use of alternate reagents which would result in altered intermediates and different impurities throughout the process. Thus, the impurity of Formula IX would not be expected to be present if there is no oxalyl chloride in the chemical reaction and the impurity of Formula XI would not be expected if the coupling agent EDC•HCl is not used in the chemical reaction. Based on the following statement of page 25 of the instant specification, “It was found that the Impurity-2 (N-(4-((6,7-dimethoxy-quinolin-4-yl)oxy)phenyl)-methanesulfonamide) of Formula X was a resultant of the competitive side reaction of methane sulfonyl chloride and 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline compound of Formula III”, this impurity would be unavoidable to an extent in the processes involving methane sulfonyl chloride.
Conclusion
No claims are allowed.
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JUSTIN CHRISTOPHER SANCHEZ
Examiner
Art Unit 1622
/J.C.S./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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