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 .
Detailed Action
This office action is in response to applicant’s communication filed on 12/9/25.
Claims 1-13 are pending in this application and are being examined in this Office Action.
The examiner acknowledges applicant’s election of the species of claim 1 for examination filed 12/9/25. Thus claims 4-5 and 9-10 are withdrawn as being non readable on the elected species. Claims 1-3, 6-8 and 11-13 are being examined in this office action.
Priority
The applicant claims benefit as follows:
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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 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 of this title, 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 1-3, 6-8 and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (Wu) (The Synthesis of Anti-Alzheimer's Disease Drug 2-Hydroxy-5-[2-(4-Trifluoro Methyl-Phenyl)- Ethylamino]-Benzoic Acid", Chinese Journal of New Drugs, vol. 21, no. 16, December 31, 2012, pp. 1930-1932), in applicant’s IDS filed 6/7/23, the English translation is used herein, in view of Greene et al. (Greene) (Greene's Protective Groups in Organic Synthesis, John Wiley and Sons Inc., 2007, 4th Edition).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Wu teaches the synthesis of 2-hydroxy-5-[2-(4- (trifluoromethylphenyl)ethylamino)]benzoic acid, applicant’s compound IV, which corresponds to Wu’s compound 1, by the following scheme below. Applicant’s compound I, corresponds to Wu’s compound 3, is protected with MsCl (methanesulfonyl chloride) to obtain applicant’s compound II, corresponding to Wu’s compound 4. This is condensed with methyl 5-aminosalicylate, corresponding to Wu’s compound 6, to give applicant’s compound III, which corresponds to Wu’s compound 7. This is subjected to a hydrolysis reaction to obtain the final product, applicant’s compound IV, corresponding to Wu’s product compound 1. (see original Chinese npl on page 1931 and English translation page 3, first paragraph to page 5, top paragraph)
Applicant’s compound I, corresponds to Wu’s compound 3
Applicant’s compound II, corresponds to Wu’s compound 4, in which R = Ms
Methyl 5-aminosalicylate, corresponds to Wu’s compound 6
Applicant’s compound III, corresponds to Wu’s compound 7
Applicant’s compound IV, corresponds to Wu’s compound 1
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Wu teaches the following synthetic procedures for each synthetic step from the reaction scheme above:
Preparation of 2-(4-trifluoromethylphenyl)ethyl methanesulfonate, which is applicant’s compound II, corresponding to Wu’s compound 4, in which R = Ms
(Protection Reaction)
A 500 mL reaction flask was charged with 44.0 g (0.23 mol) of 2-(4-trifluoromethylphenyl)ethanol, 350.0 g of dichloromethane (also known as methylene chloride), and 28.0 g (0.28 mol) of triethylamine. The mixture was cooled to 0-5 C, and 35.5 g (0.31 mol) of methanesulfonyl chloride was added dropwise over 6-8 h. After the addition, the mixture was held for 20 min. When the reaction was complete, 125.0 g of 10% hydrochloric acid solution (0.34 mol HCl) was added. The organic phase was washed with water to neutrality. Dichloromethane was recovered, and the crude product was refined with n-hexane to give 57.7 g (0.215 mol) of compound 4. The GC purity was at least 98%, the melting point was 27-28 C, and the molar yield was 93.5%. (page 3, last line to page 4, first paragraph of the English translation)
Preparation of methyl 2-hydroxy-5-[2-(4-trifluoromethylphenyl)ethylamino]benzoate hemisulfate, which is applicant’s compound III, corresponding to Wu’s compound 7
(Condensation Reaction)
Into a 1 L reaction flask were charged 70 g (0.419 mol) of methyl 5-aminosalicylate, 112.3 g (0.419 mol) of 2-(4-trifluoromethylphenyl)ethyl methanesulfonate, 51.1 g (0.505 mol) of triethylamine, and 400 g of toluene. The mixture was stirred and heated to 80-85 C. The reaction solution gradually became clear and pale yellow. When TLC showed complete reaction, the mixture was worked up. Toluene was removed by rotary evaporation to give a black oily material. Anhydrous ethanol and purified water were then added with stirring, and 50% aqueous sulfuric acid was added dropwise until pH 2 was reached, causing a large amount of solid to precipitate. The mixture was cooled to below 10 C, stirred for 30 min, filtered, and dried to give 129.1 g (0.333 mol) of compound 7 as the hemisulfate, in 79.4% molar yield; HPLC assay 97%. (page 4, last paragraph of the English translation)
Preparation of 2-hydroxy-5-[2-(4-trifluoromethylphenyl)ethylamino]benzoic acid, which is applicant’s compound IV, corresponding to Wu’s compound 1
(Hydrolysis Reaction)
Into a 1 L reaction flask were charged, in sequence, 75.5 g (0.19 mol) of methyl 2-hydroxy-5-[2-(4-trifluoromethylphenyl)ethylamino]benzoate hemisulfate, 114.4 g (1.14 mol) of 98% sulfuric acid, 377.5 g of drinking water, and 70 g (1.17 mol) of glacial acetic acid. The mixture was stirred and heated to 95-100 C. When TLC showed that the starting material had reacted completely, the mixture was cooled to below 10 C and filtered to give a light yellow solid, namely the hemisulfate salt of 2-hydroxy-5-[2-(4-trifluoromethylphenyl)ethylamino]benzoic acid. This solid was dissolved in 360 g of ethanol and 75 g of purified water, then heated with stirring to 50-60 C. Fifty-percent sulfuric acid was added until the solution became clear. The hot mixture was filtered, and the filtrate was neutralized with 25% aqueous ammonia to pH 3.0-3.5, at which point a large amount of solid precipitated. The solid was collected by filtration, and the filter cake was washed successively with purified water and ethanol. After drying under reduced pressure, the target compound 1 was obtained as 60 g (0.184 mol), in 97% molar yield. Melting point: 236.1-236.5 C. (page 5, first paragraph of the English translation)
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
Wu is deficient in the sense that it does not teach applicant’s particular sulfonate protecting group, benzenesulfonate.
Greene teaches the equivalency of mesylate (methanesulfonate or Ms) and benzenesulfonate, as sulfonate protecting groups for alcohols. (pages 272-275)
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Therefore, it would be prima facie obvious to one of ordinary skill in the art at the time of the invention, to substitute Greene’s benzenesulfonate for Wu’s mesylate protecting group, since Greene teaches the equivalency of these sulfonate protecting groups for alcohols. Utilizing a different common sulfonate protecting group for the alcohol on Wu’s compound 4, which corresponds to applicant’s compound II, is an obvious optimization step. Thus it would be reasonable to expect that a different sulfonate protecting group, such as benzenesulfonate, would protect the alcohol on Wu’s compound 4 with a reasonable expectation of success, absent evidence of unexpected results with regard to applicant’s particular protecting group. Note that the prior art provides the same effect desired by the applicant, the step-wise synthesis of 2-hydroxy-5-[2-(4- (trifluoromethylphenyl)ethylamino)]benzoic acid, applicant’s compound I, corresponding to Wu’s compound 3 Wu’s compound 1, by the use of a sulfonate protecting group for the chemical industry.
Claims 1-3, 6-8 and 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (Wu) (The Synthesis of Anti-Alzheimer's Disease Drug 2-Hydroxy-5-[2-(4-Trifluoro Methyl-Phenyl)- Ethylamino]-Benzoic Acid", Chinese Journal of New Drugs, vol. 21, no. 16, December 31, 2012, pp. 1930-1932), in applicant’s IDS filed 6/7/23, the English translation is used herein, in view of Greene et al. (Greene) (Greene's Protective Groups in Organic Synthesis, John Wiley and Sons Inc., 2007, 4th Edition), further in view of Abayomi et al. (National Open University of Nigeria, 2013, Introductory Practical Chemistry).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Wu teaches the synthesis of 2-hydroxy-5-[2-(4- (trifluoromethylphenyl)ethylamino)]benzoic acid, applicant’s compound IV, which corresponds to Wu’s compound 1, by the following scheme below. Applicant’s compound I, corresponds to Wu’s compound 3, is protected with MsCl (methanesulfonyl chloride) to obtain applicant’s compound II, corresponding to Wu’s compound 4. This is condensed with methyl 5-aminosalicylate, corresponding to Wu’s compound 6, to give applicant’s compound III, which corresponds to Wu’s compound 7. This is subjected to a hydrolysis reaction to obtain the final product, applicant’s compound IV, corresponding to Wu’s product compound 1. (see original Chinese npl on page 1931 and English translation page 3, first paragraph to page 5, top paragraph)
Applicant’s compound I, corresponds to Wu’s compound 3
Applicant’s compound II, corresponds to Wu’s compound 4, in which R = Ms
Methyl 5-aminosalicylate, corresponds to Wu’s compound 6
Applicant’s compound III, corresponds to Wu’s compound 7
Applicant’s compound IV, corresponds to Wu’s compound 1
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Wu teaches the following synthetic procedures for each synthetic step from the reaction scheme above:
Preparation of 2-(4-trifluoromethylphenyl)ethyl methanesulfonate, which is applicant’s compound II, corresponding to Wu’s compound 4, in which R = Ms
(Protection Reaction)
A 500 mL reaction flask was charged with 44.0 g (0.23 mol) of 2-(4-trifluoromethylphenyl)ethanol, 350.0 g of dichloromethane (also known as methylene chloride), and 28.0 g (0.28 mol) of triethylamine. The mixture was cooled to 0-5 C, and 35.5 g (0.31 mol) of methanesulfonyl chloride was added dropwise over 6-8 h. After the addition, the mixture was held for 20 min. When the reaction was complete, 125.0 g of 10% hydrochloric acid solution (0.34 mol HCl) was added. The organic phase was washed with water to neutrality. Dichloromethane was recovered, and the crude product was refined with n-hexane to give 57.7 g (0.215 mol) of compound 4. The GC purity was at least 98%, the melting point was 27-28 C, and the molar yield was 93.5%. (page 3, last line to page 4, first paragraph of the English translation)
Preparation of methyl 2-hydroxy-5-[2-(4-trifluoromethylphenyl)ethylamino]benzoate hemisulfate, which is applicant’s compound III, corresponding to Wu’s compound 7
(Condensation Reaction)
Into a 1 L reaction flask were charged 70 g (0.419 mol) of methyl 5-aminosalicylate, 112.3 g (0.419 mol) of 2-(4-trifluoromethylphenyl)ethyl methanesulfonate, 51.1 g (0.505 mol) of triethylamine, and 400 g of toluene. The mixture was stirred and heated to 80-85 C. The reaction solution gradually became clear and pale yellow. When TLC showed complete reaction, the mixture was worked up. Toluene was removed by rotary evaporation to give a black oily material. Anhydrous ethanol and purified water were then added with stirring, and 50% aqueous sulfuric acid was added dropwise until pH 2 was reached, causing a large amount of solid to precipitate. The mixture was cooled to below 10 C, stirred for 30 min, filtered, and dried to give 129.1 g (0.333 mol) of compound 7 as the hemisulfate, in 79.4% molar yield; HPLC assay 97%. (page 4, last paragraph of the English translation)
Preparation of 2-hydroxy-5-[2-(4-trifluoromethylphenyl)ethylamino]benzoic acid, which is applicant’s compound IV, corresponding to Wu’s compound 1
(Hydrolysis Reaction)
Into a 1 L reaction flask were charged, in sequence, 75.5 g (0.19 mol) of methyl 2-hydroxy-5-[2-(4-trifluoromethylphenyl)ethylamino]benzoate hemisulfate, 114.4 g (1.14 mol) of 98% sulfuric acid, 377.5 g of drinking water, and 70 g (1.17 mol) of glacial acetic acid. The mixture was stirred and heated to 95-100 C. When TLC showed that the starting material had reacted completely, the mixture was cooled to below 10 C and filtered to give a light yellow solid, namely the hemisulfate salt of 2-hydroxy-5-[2-(4-trifluoromethylphenyl)ethylamino]benzoic acid. This solid was dissolved in 360 g of ethanol and 75 g of purified water, then heated with stirring to 50-60 C. Fifty-percent sulfuric acid was added until the solution became clear. The hot mixture was filtered, and the filtrate was neutralized with 25% aqueous ammonia to pH 3.0-3.5, at which point a large amount of solid precipitated. The solid was collected by filtration, and the filter cake was washed successively with purified water and ethanol. After drying under reduced pressure, the target compound 1 was obtained as 60 g (0.184 mol), in 97% molar yield. Melting point: 236.1-236.5 C. (page 5, first and second paragraphs of the English translation)
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
Wu is deficient in the sense that it does not teach applicant’s particular sulfonate protecting group, benzenesulfonate.
Greene teaches the equivalency of mesylate (methanesulfonate or Ms) and benzenesulfonate, as sulfonate protecting groups for alcohols. (pages 272-275)
Wu is also deficient in the sense that it does not teach applicant’s claim 13, using nitrogen bubbling.
Abayomi et al. teaches cooling of a reaction by the addition of liquid nitrogen to the solvent with causes bubbling by the evaporation of gaseous nitrogen (page 153, last paragraph to page 154, second to the last paragraph)
Further Abayomi et al. teaches it is common practice for laboratory benches to have a nitrogen gas nozzle for laboratory experiments. (page 152, last paragraph)
Thus it is reasonable to expect that the use of bubbling inert gases, such as nitrogen through a reaction solution would displace air and oxygen in the reaction solution, lower side-oxidation reactions that can form impurities, and improve product purity.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Therefore, it would be prima facie obvious to one of ordinary skill in the art at the time of the invention, to substitute Greene’s benzenesulfonate for Wu’s mesylate protecting group, since Greene teaches the equivalency of these sulfonate protecting groups for alcohols. Utilizing a different common sulfonate protecting group for the alcohol on Wu’s compound 4, which corresponds to applicant’s compound II, is an obvious optimization step. Thus it would be reasonable to expect that a different sulfonate protecting group, such as benzenesulfonate, would protect the alcohol on Wu’s compound 4 with a reasonable expectation of success, absent evidence of unexpected results with regard to applicant’s particular protecting group. Note that the prior art provides the same effect desired by the applicant, the step-wise synthesis of 2-hydroxy-5-[2-(4- (trifluoromethylphenyl)ethylamino)]benzoic acid, applicant’s compound I, corresponding to Wu’s compound 3 Wu’s compound 1, by the use of a sulfonate protecting group for the chemical industry.
It is also obvious to use Abayomi et al. liquid nitrogen addition, which causes bubbling, to cool the hydrolysis reaction, since Wu et al. teaches cooling the reaction mixture. Or alternatively, to use the bubbling of gaseous nitrogen to displace any air or oxygen and to perform the reaction under a blanket of inert nitrogen gas. The common use of performing reactions by bubbling inert nitrogen gas is not a patentable distinction, absent evidence to the contrary.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jennifer Cho Sawyer whose telephone number is (571) 270 1690. The examiner can normally be reached on Monday-Friday 9 AM - 6 PM PST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Renee Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-274-1690.
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Jennifer Cho Sawyer
Patent Examiner
Art Unit: 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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