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 371 of PCT/CN2022/070997 (01/10/2022)
and claims foreign priority to CHINA 202110047911.X (01/14/2021).
Claim Rejections - 35 USC § 103
Claims 1-13 are rejected under 35 U.S.C. 103 as being unpatentable over Uttarwar et al. (US20060189816) in view of Bauer et al. (US5488141) and Furigay et al. (J. Vis. Exp. (134), e57639, doi:10.3791/57639 (2018), 10 pages).
Uttarwar teaches a process of purifying citalopram comprising i) providing crude citalopram in a water immiscible organic solvent, ii) washing with an aqueous solution comprising a polybasic acid to remove citalopram impurities, and iii) recovering purified citalopram from the solvent (Abstract, claim 1). Uttarwar teaches the known citalopram impurities include 5-formyl ([0019]):
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Bauer teaches removal of carbonyl impurities by solvent extraction using an aqueous bisulfite or dithionite solution and a water immiscible organic solvent (col 1, line 29, to col 4, line 46; claims 1-12).
Furigay teaches the general protocol for separation of aldehydes from mixtures using bisulfite extraction where the bisulfite forms an adduct with the aldehyde which is water soluble and can be removed to the aqueous phase (p. 8-9).
Regarding claim 1, Uttarwar does not teach the aqueous washing solution comprises sulfite or thiosulfate. One of ordinary skill in the art following Uttarwar’s teaching of purification of citalopram via extraction and the known 5-formyl impurity would have considered looking to known techniques in the art for removing such impurities and find the teaching of Bauer and Furigay in the same field of endeavor. One of ordinary skill in the art would have considered substituting Uttarwar’s polybasic acid with another agent used in purification as taught by Bauer and Furigay. MPEP 2144.06 (Substituting equivalents known for the same purpose). One of ordinary skill in the art would have had a reasonable expectation of success because each of the prior art references are to related process of purifying organic compounds via extraction and because they share the same structure of a carbonyl/aldehyde/formyl group. One of ordinary skill in the art would consider routine the application of known purification techniques to improve the purity of the pharmaceutical citalopram and arrive at the claimed invention.
Regarding claim 2, Bauer teaches preferred solvents including toluene (col 2, lines 41-48).
Regarding claims 3 and 11, Bauer teaches the use of sodium dithionite (claim 4).
Regarding claim 4, Bauer teaches wt % ratios, 17%, of dithionite within the claimed range the use of sodium dithionite (col 3-4; Table 2).
Regarding claim 5, Uttarwar teaches a range of washing agents (claims 15 and 19) that one of ordinary skill in the art would apply to the teaching of Bauer (col 3, lines 11-14) and optimize to improve the effectiveness of the extraction.
Regarding claim 6-8, Uttarwar teaches the use of a base, including 10% aqueous sodium hydroxide, in the extraction (claim 5; [0025], [0038], [0053]-[0055]) which one of ordinary skill in the art would optimize according to the associated pH adjustment for dithionite as suggested by Bauer.
Regarding claims 9 and 13, Uttarwar teaches the use of oxalic acid (claim 9).
Regarding claim 10, Uttarwar teaches purification of the hydrobromide by extraction ([0005]) and adding a base to obtain the free base (claim 5).
Regarding claim 12, Furigay teaches the use of sodium bicarbonate (p. 9) which one of ordinary skill in the art would readily consider as a means of neutralization and arrive at the claimed invention.
With each of the claims, the level of skill in the art is very high such that one of ordinary skill in the art would consider routine the combination of elements from the teaching of the art. One of ordinary skill in the art would have recognized that the results of the combination would be predictable due to the well-known nature and optimizations routinely performed in the art. Thus, one of ordinary skill in the art would have arrived at the invention as claimed before the effective filing date with a reasonable expectation of success.
Response to Remarks - 35 USC § 103
Applicant argues that Uttwar fails to disclose or suggest a specific washing solution comprising a specific agent and thus does not render obvious the claimed invention.
This is not accurate as Uttwar does teach purifying citalopram with a washing solution comprising a washing agent of a polybasic acid ([0034]-[0035], claims 1, 9-12) which one of ordinary skill in the art would have considered substituting with sodium bisulfite as was successful in related purifications of Bauer and Furigay.
Applicant argues that “the neutral and acid conditions of Bauer are incompatible with Applicant’s claimed process in revised claim 1” as shown in the Examples of the specification where the pH is adjusted to 12.
This argument is not persuasive because pH adjustment to 12 is not a step in the instant claims. Furthermore, one of ordinary skill in the art would have considered adjusting pH as Furigay teaches the protocol is pH dependent and suggests adding a base to facilitate purification (p. 9).
Applicant argues that Furgay teaches the use of a miscible organic solvent to improve bisulfite removal of impurities whereas the claimed invention uses a solution consisting of citalopram and a water-immiscible organic solvent which “should preclude the use of miscible organic solvent.”
This argument is not persuasive because the claimed invention is to “[a] purification method … comprising the following steps:” “treating a solution consisting of citalopram and a water immiscible organic solvent with a washing solution” “wherein, the washing solution in step (a) is an aqueous solution comprising …”. Thus, giving the claims their broadest reasonable interpretation the method comprises the steps and allows for other additional steps including adding miscible solvents and any point in the method. MPEP 2111.03. Furthermore, one of ordinary skill in the art would have recognized that the technique taught by Furgay is adaptable and would consider modifying the steps to utilize the miscible solvent in a washing solution (p. 10: “The method is extremely adaptable to novel situations and can be easily adjusted to account for variability in the polarity of substrates of interest. The functional group tolerance is incredibly broad, which makes this protocol applicable to most chemical separations involving a reactive carbonyl component.”).
Applicant argues that Furigay discloses that aliphatic amines are inappropriate substrates due to acid-base reaction with bisulfite and teaches away.
This argument is not persuasive because Furigay teaches that acid-base is a consideration taken into consideration (p. 9: “Bisulfite is a reducing reagent and a weak acid, which should be taken into consideration for any new adaptation of this protocol. For example, most aliphatic amines are inappropriate substrates due to an unwanted acid-base reaction with bisulfite ion (Figure 3).”), but does not teach away entirely from amines with many amines successfully demonstrated in Figure 3. Thus, one of ordinary skill in the art would have recognized that the technique would be successful with a tertiary amine such as citalopram due to the similar structures and through taking acid-base reactions into consideration.
Conclusion
No claims 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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/ROBERT H HAVLIN/Primary Patent Examiner, Art Unit 1626