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
This application is a Continuation of PCT/EP2020/060255 filed on 04/09/2020. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in EUROPEAN PATENT OFFICE (EPO) (19460021.9) on 04/17/2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Response to Amendment
Applicant’s amendment filed on October 16, 2025 amending claims 1-13, 17 and 18; and canceling claims 14-16 has been entered.
Claims 1-13, 17 and 18 are currently pending and presented for examination.
Response to Arguments
Applicant's arguments filed October 16, 2025 with respect to the double patenting rejection have been fully considered but they are not persuasive. However, upon further consideration, the previous double patenting rejection is hereby withdrawn since the copending application does not teach all of the steps as claimed in the instant claims.
Applicant's arguments filed October 16, 2025 with respect to the rejection under 35 USC 103 have been fully considered but they are not persuasive.
Applicant argues that there is nothing in the process of Tolf et al. which renders the claims obvious. Applicant argues that the processes of claims 1 and 2 differ from the disclosure of Tolf et al. by steps (i) to (iv), i.e., a procedure wherein a pimavanserin acid addition salt is first retained in the organic layer and basic impurities can be removed by washing with a mixture comprising water, alcohol and an acid, and the pimavanserin acid addition salt is dissolved in an aqueous solvent and neutral impurities can be removed by washing with organic solvent(s). Applicant argues that the claims provide an improved process for the preparation of pimavanserin of acid addition salt thereof, wherein the process allows to efficiently remove impurities of different chemical character. Applicant argues that Tolf et al. does not teach or suggest any washing steps as recited in the claims, and as such, does not render the claims obvious for at least this reason. Applicant argues that neither a step (ii) of washing the solution provided in step (i) with an alcohol/water/acid mixture, nor a step (iv) of washing the aqueous solution obtained in step (iii) with an organic solvent, is taught or suggested by Tolf et al.
These arguments are found not persuasive since the claims of the instant application claim a process for the preparation of pimavanserin comprising: (i) providing an acid addition salt solution of pimavanserin in an organic solvent; (ii) washing the solution provided in step (i) with an alcohol/water/acid mixture; (iii) dissolving the acid addition salt of pimavanserin in an aqueous solvent to form an aqueous solution; (iv) washing the aqueous solution obtained in step (iii) with an organic solvent; (v) adding a base to the washed aqueous solution to form pimavanserin (i) providing an acid addition salt of pimavanserin.
As detailed in the rejection of record, Tolf et al. teaches a similar method of preparing pimavanserin but does not teach washing the solution in the order as provided by the instant claims. For example Tolf et al. teaches a) dissolution in water under stirring of a salt form of formula I, preferably the hemi- tartrate salt; b) addition of a sufficient amount of an organic aprotic solvent for the dissolution of the formed compound of formula I; thus steps a and b of Tolf et al. correspond to steps i and iii of the instant claims since steps i and iii recite providing pimavanserin in an organic solvent and dissolving said mixture in an aqueous solvent to form an aqueous solution. Tolf teaches combing and dissolving the salt in water and an organic solvent. Tolf et al. further teaches c) adjusting of the pH of the aqueous salt solution to a value of at least 8.5 by addition of a base which corresponds to step v of the instant method. Although Tolf et al. does not teach washing at the time points as claimed, Tolf et al. specifically teaches prior to forming the aqueous solution of the acid addition salt of pimavanserin, washing the crude acid addition salt of pimavanserin [0212]. Tolf et al. further teaches that this preparation method that includes washing the crude acid addition salt of pimavanserin prior to mixing it with water and solvent to form an aqueous solution provides a product with fewer impurities [0215]. Thus Tolf et al. teaches washing the acid addition salt form prior to adding the base to form the free base of pimavanserin which serves the same purpose as argued by Applicant which is to remove impurities.
Accordingly, the cited claims of the instant application are rendered obvious over the teachings of Tolf et al. since it has been held that merely changing the order of steps in a multi-step process is not a patentable modification absent a showing of unexpected results. Ex parte Rubin 128 USPQ 440 (POBA 1959). In the instant case, absent a showing that the washing at the timepoints as claimed provides unexpected or improved results over the teaching of the prior art which teaches washing the acid addition salt prior to dissolving it in an aqueous solvent, the cited claims of the instant application are rendered obvious.
Applicant has not provided any evidence or even addressed this rationale as presented in the rejection of record. Applicant merely states that the claims provide an improved process for the preparation of pimavanserin wherein the process allows to efficiently remove impurities of different chemical character. However, arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.").
It is Applicant’s burden to demonstrate unexpected results over the prior art. See MPEP 716.02, also 716.02 (a) - (g). Furthermore, the unexpected results should be demonstrated with evidence that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). Moreover, evidence as to any unexpected benefits must be of a scope reasonably commensurate with the scope of the subject matter claimed, In re Linder, 173 USPQ 356 (CCPA 1972).
Thus, since Applicant has not provided any evidence of improved results over the prior art with respect to the washing steps, Applicant’s arguments are found not persuasive and the previous rejection under 35 USC 103 is hereby maintained and reproduced below. This action is FINAL.
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.
Claims 1-13, 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Tolf et al. WO 2008/144326 A2 (provided on IDS).
The cited claims of the instant application claim a process for the preparation of pimavanserin
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comprising: (i) providing an acid addition salt of pimavanserin; (ii) dissolving the acid addition salt of pimavanserin in an aqueous solvent to form an aqueous solution; (iii) washing the aqueous solution obtained in step (ii) with an organic solvent; and (iv) adding a base to the washed aqueous solution to form pimavanserin and further (v) converting pimavanserin into an acid addition salt of pimavanserin such as pimavanserin hemitartrate.
Tolf et al. teaches a crystalline form of N-(4-fluorobenzyl)-N-(l-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (pimavanserin) [0005]-[006]. Tolf et al. teaches a method of preparing crystalline pimavanserin comprising synthesizing pimavanserin and then preparing a salt form of pimavanserin [0019]-[0024]. Tolf et al. further teaches purification of the pimavanserin salt form and that purification can be effectively improved by forming salts of the carbamide, which can be precipitated as crystalline compounds and re-crystallized from solvents to remove impurities [0025]. Tolf et al. teaches the free carbamide of formula I (pimavanserin) is then deliberated by dissolution of the salt in water, addition of a base, and extraction of the carbamide with an organic solvent [0025]. Tolf et al. teaches that the organic solutions may be washed with water and aqueous sodium chloride before removal of the solvent by distillation, optionally under reduced pressure [0025]. Tolf et al. further teaches that impurities may be removed in this method by precipitation or dissolution in water in the use of a two phase systems. When precipitation of the salt is desired for easy isolation by filtration or centrifugation, partial removal of the organic solvent and addition of fresh solvent may be carried out. Suitable solvents with low salt solubility are aprotic organic solvents such as hydrocarbons, halogenated hydrocarbons, ethers, ketones, carboxylic acid esters and lactones, acetonitrile, and alcohols having at least 3 carbon atoms [0025].
Tolf et al. teaches the salt forming acids may be selected from inorganic or organic acids, such as mineral acids (HCl, HBr, HI, H2SO4), mono- or dicarboxylic acids (formic acid, acetic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, succinic acid, tartaric acid) or sulfonic acids (methylsulfonic acid) [0026]. The acids may be added as aqueous solutions in amounts sufficient to form a solid or crystalline precipitate [0026]. The amount may range from about 0.5 to about 2 equivalents relative to the compound of formula I, depending mainly on the functionality of the acid and the desired excess for complete and fast salt formation [0026].
Tolf et al. teaches the salts may be dissolved in water and a non-water miscible organic solvent for the compound of formula I added to dissolve the deliberated compound of formula I when the base is added [0027]. Suitable bases include, but are not limited to, alkaline earth metal hydroxides such as LiOH, NaOH or KOH [0027]. In one embodiment, the pH of the aqueous phase is greater than about 8.5. The reaction may be terminated from minutes to 1 hour. The organic phase is then separated, optionally washed with water and brine and/or filtered. The desired product may be obtained by removal of the solvent and drying, or by precipitation with a non-solvent, filtration, and drying of the solid residue. The compound of formula I is obtained in high purity and yields [0027].
Tolf et al. teaches the compound of formula I is soluble in various organic solvents and shows a low solubility in water, and in contrast, salts of the compound of formula I are well soluble in water [0037]. Tolf et al. teaches a) dissolution in water under stirring of a salt form of formula I, preferably the hemi- tartrate salt; b) addition of a sufficient amount of an organic aprotic solvent for the dissolution of the formed compound of formula I; c) adjusting of the pH of the aqueous salt solution to a value of at least 8.5 by addition of a base; d) optionally extracting the aqueous phase with the organic solvent and collecting all organic phases; e) removing a part of the solvent and cooling the remaining organic solution to less than 15°C; f) holding at this temperature while optionally stirring; and g) filtering off the precipitate, washing the solid residue, and drying it [0037]. Salt forming acids may be selected from inorganic or organic acids, such as mineral acids (e.g., HCl, HBr, HI, H2SO4, H3PO4), mono- or dicarboxylic acids (e.g., formic acid, acetic acid, oxalic acid, malonic acid, tartaric acid, maleic acid, fumaric acid, succinic acid), sulfonic acids (e.g., methylsulfonic acid), citric acid, glucuronic acid, malic acid, pamoic acid, or ethane- 1,2- disulfonic acid [0037].
Tolf et al. teaches that suitable solvents are hydrocarbons such as toluene, halogenated hydrocarbons such as di- or trichloromethane, tetrachloroethane, esters of aliphatic carboxylic acids and alcohols (C2-C4alkyl esters of acetic acid) (ethyl acetate), lactones (valerolactone), ethers (diethylether, methylpropyl ether, t-butyl-methyl-ether, dibutyl ether, dimethyl ether), aliphatic ketones (methyl propyl ketone, diethyl ketone or methyl i- or t-butyl ketone) [0038]. Suitable bases include, but are not limited to aqueous alkaline or earth alkaline metal hydroxides such as LiOH3 NaOH, KOH or Ca(OH)2 [0038].
Tolf et al. teaches in one embodiment, the compound of Formula I is synthesized according to Scheme I wherein it was found that the method of Scheme I provided several surprising advantages over previous syntheses of the compound of Formula (I), particularly for large scale industrial synthesis [0030]. For example, it was found that increased yield and decreased aldehyde formation could be obtained by using a Raney-Ni catalyst and a large excess of NH3 (e.g., 13-16 equivalents) in Step 4. Step 4 comprises the step of producing
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and step 5 utilizes said compound to formulate pimavanserin [0030]. Tolf et al. further teaches that it was also found that by extracting with toluene in Step 5, the drying of the base was improved by azeotropic distillation [0030]. Tolf et al. specifically teaches a process which comprises the step wherein 1-[4-(2-methylpropyloxy)phenyl]methanamine acetate is purified by recrystallization, wherein the 1-[4-(2- methylpropyloxy)phenyl]|methanamine acetate is recrystallized from an alcoholic solvent, or a mixture of an alcoholic solvent and non-alcoholic solvent (page 33 paragraph [0118]; pages 61-62 paragraph [0191]; pages 66-67 paragraph [0204]).
Tolf et al. further teaches that the compound of formula I can be obtained as a substantially amorphous solid, which may be admixed with small amounts of a crystalline form [0033]. Tolf et al. teaches that it was surprisingly found that a pure crystalline form can be obtained from the salt form, such as the hemi- tartrate salt, when deliberating the base under certain condition and this crystallization can even be used to purify the base by re-crystallization of salts or by re-crystallization of the base itself [0033].
Tolf et al. further teaches the preparation of crystalline Form C comprises forming a suspension of a solid compound of formula IV in an aprotic solvent at elevated temperature and stirring the suspension, optionally adding crystal seeds of Form C, until substantial complete conversion in pure Form C [0058]. Suitable solvents for conversion to Form C may be selected from the group comprising aliphatic or cyclic ethers, carboxylic esters, lactones, alkanes and aliphatic ketones [0059]. Some specific examples and preferred solvents are diethyl ether, propyl methyl ether, t-butyl methyl ether, tetrahydrofuran, ethyl acetate, t-butyl methyl ketone, acetone, and methyl ethyl ketone, and most preferred solvents are ketones and especially preferred are methyl ethyl ketone and tetrahydrofuran [0062].
Tolf et al. teaches that the pimavanserin forms described therein have very good solubility in aqueous systems and have improved stability and can be easily formulated into tablets or any other pharmaceutically acceptable dosage form with pharmaceutically acceptable excipients [0076]-[0082].
Tolf et al. teaches one embodiment is a process for the preparation of crystalline Form C of N-(4-fluorobenzyl)-N-(l-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)- carbamide tartrate of formula IV, comprising: a) suspending the amorphous form or crystalline forms A, B, D, E, or F or mixtures thereof under stirring in a polar and aprotic solvent at temperatures from 30 to 70°C; b) continuing stirring at temperatures from 30 to 70°C and adding crystal seeds of crystalline Form C, when crystalline Form C is not present in the starting material; c) continuing stirring at temperatures from 30 to 70°C until formation of crystalline Form C is completed; d) cooling to the process end temperature; e) isolating of the crystalline solid from the suspension; and f) optionally washing and then drying the crystalline solid [0060].
Tolf et al. specifically exemplifies preparing pimavanserin; followed by the preparation of a salt of pimavanserin; the salt of pimavanserin was then mixed with ethanol, filtered and washed with ethanol; this salt of pimavanserin was then mixed with water and toluene and the base NaOH added to form the free base of pimavanserin including the use of heptane; followed by the conversion of the free base to the acid pimavanserin form; pimavanserin crystalline form C hemitartrate was then formed utilizing the acid pimavanserin form, methyl ethyl ketone and seeds of crystalline form C [0209]-[0215].
Thus Tolf et al. teaches a process for the preparation of pimavanserin comprising: providing an acid addition salt of pimavanserin; dissolving the acid addition salt of pimavanserin in an aqueous solvent to form an aqueous solution; and adding a base to the aqueous solution to form pimavanserin and further converting pimavanserin into an acid addition salt of pimavanserin such as pimavanserin hemitartrate comprising dissolving pimavanserin in a solvent to form a solution and adding a seed of pimavanserin hemitartrate form C.
Tolf et al. does not specifically teach washing the aqueous solution of the pimavanserin salt dissolved in the aqueous solvent with an organic solvent prior to adding the base. Tolf et al. does not specifically teach starting with an acid addition salt of pimavanserin selected from pimavanserin hydrochloride, pimavanserin hydrogen sulfate or pimavanserin acetate.
Although Tolf et al. does not specifically teach washing the aqueous solution of the pimavanserin salt dissolved in the aqueous solvent with an organic solvent prior to adding the base, Tolf et al. specifically teaches prior to forming the aqueous solution of the acid addition salt of pimavanserin, washing the crude acid addition salt of pimavanserin [0212]. Tolf et al. further teaches that this preparation method that includes washing the crude acid addition salt of pimavanserin prior to mixing it with water and solvent to form an aqueous solution provides a product with fewer impurities [0215]. Thus Tolf et al. teaches washing the acid addition salt form prior to adding the base to form the free base of pimavanserin.
Accordingly, the cited claims of the instant application are rendered obvious over the teachings of Tolf et al. since it has been held that merely changing the order of steps in a multi-step process is not a patentable modification absent a showing of unexpected results. Ex parte Rubin 128 USPQ 440 (POBA 1959). In the instant case, absent a showing that washing the aqueous solution of the acid addition salt dissolved in the aqueous solvent provides unexpected or improved results over the teaching of the prior art which teaches washing the acid addition salt prior to dissolving it in an aqueous solvent, the cited claims of the instant application are rendered obvious.
With respect to claim 6 of the instant application, which claims utilizing one of the organic solvents recited in claim 6 for washing the aqueous solution of the acid addition salt of pimavanserin, although Tolf et al. specifically teaches using ethanol for the wash step, it would have been obvious to a person of ordinary skill in the art to use any suitable solvent taught in Tolf et al. to was the acid addition salt of pimavanserin. Tolf et al. teaches that suitable solvents are hydrocarbons such as toluene, halogenated hydrocarbons such as di- or trichloromethane, tetrachloroethane, esters of aliphatic carboxylic acids and alcohols (C2-C4alkyl esters of acetic acid) (ethyl acetate), lactones (valerolactone), ethers (diethylether, methylpropyl ether, t-butyl-methyl-ether, dibutyl ether, dimethyl ether), aliphatic ketones (methyl propyl ketone, diethyl ketone or methyl i- or t-butyl ketone) [0038]. Thus in addition to alcohols such as ethanol, other solvents such as hydrocarbons including toluene, and ethers such as diethylether and t-butyl-methyl-ether, would be considered obvious alternatives. Thus in the absence of secondary considerations such as unexpected results claim 6 of the instant application is rendered obvious in view of the cited prior art teachings.
Although Tolf et al. does not specifically teach starting with an acid addition salt of pimavanserin selected from pimavanserin hydrochloride, pimavanserin hydrogen sulfate or pimavanserin acetate, Tolf et al. specifically teaches salt forming acids may be selected from inorganic or organic acids, such as mineral acids including HCl, HBr, HI, H2SO4, as well as mono- or dicarboxylic acids including formic acid, acetic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, succinic acid, tartaric acid and sulfonic acids such as methylsulfonic acid [0026]. Accordingly, a person of ordinary skill in the art would have been motivated to select any of the salt forms taught in Tolf et al. including HCl, acetic acid or H2SO4 with a reasonable expectation of similar success.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 1-13, 17 and 18 are rejected. Claims 14-16 are canceled. No claims are allowed.
THIS ACTION IS MADE FINAL. 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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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM