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 .
Priority
Acknowledgement is made that instant application 18/723,043, filed on 2024, Jun. 21, is a national stage entry of PCT/CN2022/138852, filed on 2022, Dec. 14, which claims foreign priority to CN 202111577892.8, filed on 2021, Dec. 22.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 2024, Jun. 21 is/are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 3 is 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.
The limitations of claim 3 are positively demonstrated whereby a multi-temperature stage reaction is incorporated in the presence of a catalyst and sodium azide to obtain losartan, wherein the temperature of the first stage of the multi-temperature stage reaction is 90 °C – 110°C with a time period of 20 h – 30 h and the temperature of the second stage is 75 °C – 85 °C with a time period of 40 h – 60 h. This is evidenced by Example 3 in the instant specification (page 11, lines 11-25), wherein the above conditions were utilized and resulted in a yield of 93.8%, a purity of 99.2%, the content of impurity dime L is 0.07%, and the content of impurity dimer M is 0.09%. Applicant offers Comparative Example 3 (page 13, lines 4-15) utilizing the same procedure absent the multi-temperature conditions, resulting in a yield of 82.9%, a purity of 98.4%, the content of impurity dimer L is 0.44% and the content of impurity dimer M is 0.49%.
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.
Claims 6-7, 9, and 11-13 are 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance:
Claim 6 recites the broad recitation “the molar ratio of compound I to the catalyst is 1:1.5 to 1:1.3”, and the claim also recites “preferably 1:1.8 to 1:2.2” which is the narrower statement of the range/limitation.
Claim 7 recites the broad recitation “the Lewis acid can be zinc chloride or lithium chloride”, and the claim also recites “preferably zinc chloride”, which is the narrower statement of the range/limitation.
Claim 7 also recites the broad recitation “the strong acid salt of a weak base is triethylamine hydrochloride, pyridine hydrochloride, triethylamine sulfate or pyridine sulfate”, and the claim also recites “preferably triethylamine hydrochloride”, which is the narrower statement of the range/limitation.
Claim 9 also recites the broad recitation “wherein the organic solvent is an aromatic solvent”, and the claim also recites “preferably toluene or xylene”, which is the narrower statement of the range/limitation.
Claim 11 also recites the broad recitation “wherein the phase transfer catalyst is a quaternary ammonium salt phase transfer catalyst”, and the claim also recites “preferably benzyl triethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, or tetrabutylammonium hydrogen sulfate, and more preferably tetrabutylammonium bromide”, which is the narrower statement of the range/limitation.
Claim 12 also recites the broad recitation “the molar ratio of the phase transfer catalyst to the compound I is 0.01:1 to 0.5:1”, and the claim also recites “preferably 0.01:1 to 0.04:1”, which is the narrower statement of the range/limitation.
Claim 13 also recites the broad recitation “the molar ratio of the compound I to sodium azide is 1:2.0 to 1:4”, and the claim also recites “preferably 1:2.3 to 1:3.3”, which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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 7 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.
Claim 7 includes the phrase “the Lewis acid can be zinc chloride or lithium chloride”, which is open to multiple interpretations. As a result, the scope of the claim is ambiguous as to whether or not other Lewis acids can also be included. Accordingly, the claim is rejected for lack of clarity and definiteness.
Claim 7 also includes the phrase “ the strong acid is preferably hydrochloric acid or sulfuric acid”, which is open to multiple interpretations. As a result, the scope of the claim is ambiguous as to whether hydrochloric acid or sulfuric acid is a non-limiting preference or a required feature. Accordingly, the claim is rejected for lack of clarity and definiteness.
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 1-2, 4, 6-10, and 13-16 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by He, et al (hereafter, He. CN 110467604A; published 2019, Nov. 19).
He teaches a method of making losartan by cyclizing the aryl cyano intermediate (abstract). Specifically, He teaches the following procedure (page 7, paragraph 0057): add 40 g of toluene to a four-necked flask and slowly add 20 g of cyano intermediate, 10.3 g of sodium azide and 18 g of triethylamine hydrochloride while stirring. After the addition is complete, heat to 90-95 °C and keep the temperature for 35-45 hours. After the reaction is complete, add 40 g of water, cool to 60-70 °C, let stand to separate the layers separate the middle layer, add 40 mL of n-butanol to dissolve, wash twice with 20 g of saturated sodium chloride aqueous solution, add 1.0 g of triphenylphosphine and 0.8 g of activated carbon, stir and heat to 50-60 °C for decolorization for 2 hours. Hot filtration was performed, followed by washing the filter cake with 10 mL of n-butanol. The filtrates were combined and dried under reduced pressure at a controlled temperature of 50-80 °C and a vacuum of 0.08 MPa or higher. The dried product was then mixed with 7.7 g of liquid alkali (approximately 50% concentrated sodium hydroxide solution) and 160 g of water, stirred until dissolved and extracted twice with 10 g toluene from the aqueous layer. 80 mL dichloromethane was then added to the aqueous layer, and the mixture was cooled to 10-50 °C. 7.5% hydrochloric acid was added dropwise to adjust the pH to 3-4, and the mixture was kept at 10-15 °C for 1 hour, then cooled to 0-5 °C and kept at that temperature for another. The mixture was then filtered, and the filter cake was washed with 20 mL of dichloromethane and 40 g of water, respectively.
Regarding claim 1, the procedure as taught by He includes heating the cyano intermediate, sodium azide, and triethylamine hydrochloride catalyst to 90-95 °C and then cooling to 60-70 °C (page 7, paragraph 0057). This falls within the scope of instant claim 1 by reacting the cyano intermediate with sodium azide and a catalyst in a multi-temperature reaction, wherein the first stage is at a higher temperature than the second stage. Triethylamine hydrochloride is considered a catalyst in the present case based on at least instant claim 6, wherein the catalyst is a strong acid salt of a weak base and instant claim 7, wherein the strong acid salt of a weak base is triethylamine hydrochloride.
Regarding claim 2, He teaches conducting the first stage of the reaction at 90-95 °C and the second stage at 60-70 °C (page 7, paragraph 0057). The recited limitation of claim 2 is the multi-temperature stage reaction is a two-temperature-stage reaction between 70-110 °C. Both stages of the procedure as taught by He falls within the range set forth.
Regarding claim 4, He teaches the first stage of the two-temperature-stage reaction is 90-95 °C. The disclosed reaction temperature falls within the range set forth by instant claim 4 of 90-100 °C or 90-95 °C.
Regarding claim 6, He teaches the catalyst is a strong acid salt of a weak base and in some embodiments the molar ratio of the cyano intermediate to the catalyst is 1:2-3 (page 5, paragraph 0019). This ratio falls within the ratio of cyano intermediate to catalyst set forth by instant claim 6 of 1:18 to 1:2.2.
Regarding claim 7, He teaches the use of the strong acid salt of a weak base, triethylamine hydrochloride, as the catalyst (page 7, paragraph 0057). He discloses that reagents used are the commercially available products unless stated otherwise (page 6, paragraph 0051). As it is not stated otherwise, is assumed the catalyst is in the form of the commercially available triethylamine mono hydrochloride (CAS Number 554-68-7), which has a 1:1 molar ratio of the weak base to the strong acid, as recited in instant claim 7.
Regarding claims 8-10, He teaches the tetrazole cyclization is performed using 40 g toluene and 20 g of the cyano intermediate (page 7, paragraph 0057). He further teaches that the mass ratio of the cyano intermediate to the toluene may be 1:1-5 g/g (page 5, paragraph 20), which falls within the recited ratio of the volume of the organic solvent to the mass of the cyano intermediate of 1 mL/g to 1.5 mL/g (toluene ρ = 0.867 g/mL).
Regarding claim 13, He teaches the molar ratio of the cayno intermediate and the sodium azide to be 1:2.5-3 (page 5, paragraph 19). This ratio falls within the ratio set forth by the limitations of instant claim 13 of 1:2.3-3.3.
Regarding claim 14, He teaches the use of a mixed weak base, strong acid system as the catalyst in the form of triethylamine hydrochloride, wherein the weak base and strong acid are added to the system together at room temperature (page 7, paragraph 0057).
Regarding claims 15-16, He teaches adding water to divide the reaction system into three layers (abstract). The difference between the teachings of He and the instant application is that He fails to teach the use of an alkaline solution, e.g., aqueous sodium carbonate. However, He also teaches embodiment 1, wherein the triethylamine hydrochloride is formed in situ by “feeding the amine hydrochloride” (page 7, paragraph 56). One of ordinary skill in the art would have found it obvious to use an alkaline solution of aqueous sodium carbonate to quench any excess hydrochloride that may be present, and therefore arrive at the current invention.
Claim(s) 17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zheng, et al (hereafter, Zheng. CN 108047208 A; published 2018, May 18).
Zheng teaches a method for reducing the dimer impurities of losartan to below 0.2% or even less than 0.1% (title, abstract). The losartan product not being entirely absent of dimer impurity is a losartan composition wherein the impurity is present in an amount less than 0.2% and therefore reads on the limitations of claim 17.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 5, 7 and 11-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over He in view of Yao, et al. (hereafter, Yao. WO 2020/248341 A1; published 2020. Dec. 17) and evidenced by Starks, et al. Phase-Transfer Catalysis, Fundamentals, Applications, and Industrial Perspectives. Chapman & Hall, 1994).
The teachings of He are discussed above and incorporated herein by reference.
Regarding claim 5, the difference between the teachings of He and the instant application is that He fails to teach a multi-temperature-stage reaction wherein the temperature of the second stage is 72 – 83 °C or 83 – 85 °C.
However, Yao teaches a method of preparing valsartan through conversion of an aryl cyanide to the tetrazole (title, abstract). Yao further teaches the tetrazolium cyclization reaction can be conducted at temperatures ranging from 70 – 150 °C for 10 – 60 hours (page 5, paragraph 0020). One skilled in the art would have been motivated to combined the teachings of Yao with the teachings of He because both valsartan and losartan are angiotensin II receptor blockers. Moreover, the two drugs and their intermediates are structurally similar (Table 1). Accordingly, there exists a reasonable expectation of success that similar reaction conditions will produce similar results.
Table 1. Structural similarity of losartan and valsartan intermediates
Losartan
Valsartan
Intermediate
PNG
media_image1.png
157
222
media_image1.png
Greyscale
PNG
media_image2.png
187
212
media_image2.png
Greyscale
Cyclized Product
PNG
media_image3.png
188
244
media_image3.png
Greyscale
PNG
media_image4.png
150
162
media_image4.png
Greyscale
Regarding claims 11-12, the difference between the teachings of He and the instant application is that He fails to teach the use of a phase transfer catalyst in the tetrazole cyclization.
However, Yao teaches a tetrazole cyclization reaction comprising a phase transfer catalyst (abstract). Yao further teaches that the phase transfer catalyst is an organic amine compound, including alkyl amines and amides, preferably tertiary amine compounds. One skilled in the art would be motivated to combine the phase transfer catalyst of Yao with the reaction conditions taught by He because losartan and valsartan are structurally similar compounds and so there is a reasonable expectation of success if similar reaction conditions were applied.
The difference between the teachings of Yao and those from the instant application is that Yao fails to teach a phase transfer catalysts that are quaternary ammonium salts, e.g., tetrabutylammonium halide. However, quaternary ammonium salts are well-known in the art , as evidenced by Starks (page 125 “Use of Quaternary Salts as Phase-Transfer Catalysts”). As stated by Starks, “The most commonly used phase-transfer catalysts are quaternary ammonium and phosphonium salts. Of these, tetrabutylammonium salts, trioctylmethylammonium chloride (or its commercial equivalent), benzyltriethylammonium chloride, and hexadecyltributylphosphonium bromide are the most frequently reported quaternary salts used as phase-transfer catalysts.” Therefore, one skilled in the art would have known to use a tetrabutylammonium salt as the phase transfer catalyst in the combined teachings of He and Yao to arrive at the current invention.
Regarding claim 7, the difference between He and the instant application is that He teaches a weak base-strong acid catalyst and fails to teach a Lewis acid catalyst, e.g., zinc chloride or lithium chloride. However, Yao teaches a method of valsartan cyano cyclization that comprises a Lewis acid (abstract). Yao further teaches that the Lewis acid is zinc chloride, zinc bromide, or zinc iodide, inter alia (page 4, paragraph 0017). One skilled in the art would have been motivated to combined the teachings of Yao with the teachings of He because both valsartan and losartan are angiotensin II receptor blockers with very similar chemical structures similar (Table 1). Therefore, there exists a reasonable expectation of success that similar reaction conditions will produce similar results.
Conclusion
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/P.A./ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621
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