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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/23/2026 has been entered.
Status of the Claims
Claims 1-5 and 8-19 are pending in the instant application and subject to examination herein.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/EP2021/064982, filed on 06/04/2021.
Response to Applicant Arguments
Applicant has traversed the Examiner’s explanation provided in the Advisory Action dated 04/02/2026, for why the Affadavit provided by Applicant on 03/26/2026 is not persuasive in refuting Examiner’s rejection of claim 14 in the Final Rejection dated 01/27/2026. Applicant’s traverse includes the assertion that the results presented in the Affadavit do regard the content of Ticagrelor after all steps of synthesis; however, this assertion is not presented anywhere in the Affadavit. The Affadavit states that the author, Kamil Kosik, “performed comparative experiments using (i) the claimed work up (aqueous washing at pH 7.5-12 followed by washing at pH 2-6); and (ii) an alternative work up (basic washing followed by water washing)” for Step (b) of the claimed synthesis. The Affadavit does not assert anywhere that any additional synthetic steps were performed, and the included table merely reports the “Nitrosamine impurity” of the obtained product, and does not state that the samples being assayed for nitrosamine impurity(s) are samples of Ticagrelor. Thus a person of ordinary skill in the art would understand that the assayed samples are the product of the Step (b) reaction.
Claim Rejections - 35 USC § 103 – Withdrawn
The prior rejection of claims 1-6, 8-12, 14-16 and 18-19 under 35 U.S.C. 103 as being unpatentable over Rao (Rao, et al.; Rasayan Journal of Chemistry, v11, pp1088-1095; 2018) in view of Dahanukar (US 2015/0073146 A1) and Larsson (WO 01/92263 A1)1 is withdrawn in response to Applicant’s amendment of claim 1, and cancellation of claim 5.
The prior rejection of claims 1-6, 8-12, 14-19 under 35 U.S.C. 103 as being unpatentable over Rao in view of Dahanukar and Larsson, and further in view of Vogel’s (Vogel’s Textbook of Practical Organic Chemistry, 5th Edition, Furniss, et al.; Ed.s; Longman Scientific & Technical, Essex, England; 1989), is withdrawn in response to Applicant’s amendment of claim 1 and cancellation of claim 5.
The prior rejection of claims 1-6, 8-16 and 18-19 under 35 U.S.C. 103 as being unpatentable over Rao in view of Dahanukar and Larsson, and further in view of Vogel’s, Qiao (CN105801583A) and Lek Pharma (EP2816043A1) is withdrawn in response to Applicant’s amendment of claim 1, and cancellation of claim 5.
Claim Rejections - 35 USC § 103
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.
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 1-5, 8-12, 14-16 and 18-19 are unpatentable over Rao in view of Dahanukar and Larsson.
Claims 1-5, 8-12, 14-16 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Rao (Rao, et al.; Rasayan Journal of Chemistry, v11, pp1088-1095; 2018)2 in view of Larsson (WO 01/92263 A1)3 and Dahanukar (US 2015/0073146 A1).
Claim 1 is drawn to a process for the preparation of the drug ticagrelor4, comprising 3 synthetic steps, (a)-(c), with each of (a) and (b) followed by specific reaction/workup conditions:
Reacting a compound of formula (I)5 with aqueous sodium nitrite in presence of acetic acid to form a compound of formula (II)6;
followed by an aqueous washing within pH range of 2-6, wherein the acidic washing is followed by a second washing of water in a neutral-alkaline pH range (7-11).;
Reacting a compound of formula (II) with a compound of formula (III)7, in an organic solvent, in the presence of a base, specifically N,N-diisopropylethylamine, to provide a compound of formula (IV)8;
followed by a first aqueous washing within pH range of 7.5-12;
followed by a second aqueous washing within pH range of 2-6;
Reacting a compound of formula (IV) with an inorganic acid in a solvent mixture of water and a C1-C3 alcohol to provide ticagrelor after a workup comprising a solvent/aqueous extraction and partial neutralization of the reaction acid (as evidenced by an aqueous layer pH range of 0.5-6).
Compounds of Formulae (I)-(IV) are shown below:
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Rao teaches a synthesis of ticagrelor, including the following 3 steps:
Preparing a compound of formula (II), designated as Rao’s compound 4, by reacting a compound of formula (I), designated as Rao’s compound 5, with sodium nitrite in the presence of acetic acid (page 1092);
Including post-reaction aqueous wash at pH 5.0;
Preparing a compound of formula (IV), designated as Rao’s compound 2, by reacting a compound of formula (III), designated as Rao’s compound 3, in ethyl acetate as solvent in the presence of a base, specifically potassium carbonate (K2CO3) (page 1092);
Including post-reaction aqueous (alkaline) wash;
Preparing ticagrelor by reacting Rao’s compound 2 in hydrochloric acid, followed by full neutralization of the reaction mixture.
Rao’s process differs from the process of instant claim 1 in the following ways:
Step 1 (instant Step (a)) does not include an alkaline post-reaction wash after the acidic wash;
Rao’s Step 2 (instant Step (b)) uses K2CO3 as the base rather than DIPEA and provides only a neutral water quench after the reaction forming the compound of formula (IV);
Rao’s final deprotection step (instant Step (c)) does not include methanol in the mixture during the reaction, and proceeds to a full, rather than partial, neutralization of the reaction acid.
While Rao employs only an acidic wash after Step (a), employs K2CO3 as the base in Step (b), and does not employ a sequence of first alkaline and second acidic aqueous washes, and does not include methanol in Step (c) during the reaction, a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in modifying the method of Rao to include an alkaline wash in Step (a), use an amine base, specifically DIPEA, and to include a post-reaction sequence of alkaline and acidic washes, at the claimed pH ranges for Step (b), and to include methanol during the reaction for Step (c), and use only a partial neutralization of the reaction acid in Step (c), for the following reasons:
It was known in the art that both alkaline wash is a suitable workup step that provides a good result after Step (a), per the disclosure of Larsson, just as it was known in the art that acidic wash is suitable for a good result, per the teaching of Rao; thus, a person of ordinary skill in the art would at once recognize that the reaction would be successful with any substitution or combination of acidic/alkaline washing(s);
It was known in the art that using DIPEA as the base in Step (b) and performing a workup of Step (b) with a first alkaline wash in the claimed pH range and second acidic wash can provide good results for such a reaction, per the disclosure of Dahanukar;
It was known in the art that performing a workup of Step (b) with an acidic aqueous wash in the claimed pH range following use of an organic base (triethylamine) in Step (b) can provide good results for such a reaction, per the disclosure of Larsson;
It was known in the art that including methanol in the corresponding reaction of Step (c) can provide good results for such a reaction, per the disclosure of Larsson;
A person of ordinary skill in the art would at once recognize that the least acidic sites in the structure of Ticagrelor are the anilinic nitrogen atom and the pyrimidine and 1,2,3-triazole rings, and it was known in the art that the dissociation constants of pyrimidine, 1,2,3-triazole, and aniline are all well within the pH range of 0.5-6.0, such that it would be obvious to neutralize an acidic solution of Ticagrelor to a pH that is within the range of 0.5-6.0 and obtain the neutral compound.
Larsson discloses a synthesis of ticagrelor including a reaction to form a compound of instant formula (II) from a compound of instant formula (I), as “Step 2” (page 15, lines 21-25 and page 16, lines 1-12), wherein Larsson reacts the compound of instant formula (I) with sodium nitrite in the presence of acetic acid, and quenches the reaction mixture with an alkaline wash using an aqueous solution of K2CO3, then separates the organic phase and follows up with an additional alkaline wash of aq. K2CO3. Larsson does not report the pH of the alkaline washings, but K2CO3 is known to produce aqueous solutions at pH ~ 11.69. A person of ordinary skill in the art would at once recognize that these conditions are interchangeable and/or combinable with each other and/or any aqueous solution of intermediary pH, because the workup succeeds at pH as low as pH 5 and as high as pH 11.6. None of the ring systems (triazole, pyrimidine) or proton accepting/donating functional groups (aniline NH2, thioether, alcohol) would be expected to donate or accept a proton transfer within this range.
Larrson further includes a reaction to form a compound of instant formula (IV) from compounds of instant formulae (II) and (III), as “Step 3” (page 16, lines 14-20 and page 17, lines 1-13). Larsson employs triethylamine, in excess, as the base for the reaction rather than Rao’s K2CO3, showing that the precise choice of base is not critical for the reaction, and Larsson provides a post-reaction workup wherein the aqueous phase of the water/ethyl acetate extraction step (“washing”) is acidified to pH 4 by addition of aqueous HCl. Additionally, whereas Rao conducts the final deprotection Step (c) in concentrated hydrochloric acid without any C1-C3 alcohol, Larsson shows that the same reaction can be conducted in a mixture of 3 molar aqueous HCl and methanol.
Addressing the claimed workup for Step (c), Larsson neutralizes the acidic reaction mixture to pH 7.2 and adds ethyl acetate to isolate Ticagrelor by liquid-liquid extraction, while Rao neutralizes the post-reaction mixture to pH 7-8; however, a person of ordinary skill in the art would at once recognize that the main purpose of neutralizing the reaction mixture is to provide a chemical environment wherein Ticagrelor would be present in neutral form, which only requires raising the pH to a level wherein the least acidic protonation site that induces a positive charge is deprotonated, and given that the pKa values of the analogous nitrogen atoms on Ticagrelor, corresponding to aniline, pyrimidine and triazole are all well known in the art to be below pH 6.0, as evidenced by PubChem,10,11,12 it would be obvious to a person of ordinary skill in the art that the isoelectric point of Ticagrelor can be reached by partially (rather than fully) neutralizing the acid from the reaction of Step (c), which will result in an acidification of the aqueous layer during liquid-liquid extraction, thus the water wash will have a pH within the claimed range of 0.5-6. A person of ordinary skill in the art would be motivated to use the minimum amount of neutralizing base to isolate Ticagrelor in neutral form because doing so will minimize the expenditure of base reagent, and at a large scale this may be of economic advantage to the process.
Dahanukar discloses processes for providing ticagrelor and its intermediates, including a final step of synthesizing ticagrelor from a compound of instant formula (III) and a derivative of instant formula (II) lacking the ketal protecting group, as shown in the scheme below (Example 8, paragraph [0196]). Dahanukar’s Example 8 reaction proceeds in ethyl acetate solvent and uses an excess of DIPEA, rather than Rao’s use of K2CO3, to neutralize the HCl formed from the nucleophilic bonding between the reactants. Dahanukar provides an initial wash with water, followed by a second wash with 2% aqueous HCl.
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(Scheme representing the reaction described in Dahanukar’s Example 8).
While the triazolo-pyrimidine reactant used by Dahanukar lacks the ketal protecting group found in instant formula (II), a person of ordinary skill in the art would at once recognize that the difference will have no effect on the reaction or workup and therefore the reaction procedure of Dahanukar would readily substitute for the procedure that Rao uses to synthesize a compound of formula (II). Additionally, while Dahanukar does not stipulate a first aqueous wash with pre-alkalinized water, a person of ordinary skill in the art would at once recognize that the excess of DIPEA present in the reaction would render the aqueous phase alkaline when water is added to the reaction mixture. The arrival at the claimed pH range of 7.5-12 for the first water wash is inherent in the method, as the known pKa of 10.8 for protonated DIPEA13 will limit the ability of this base to lift an aqueous phase above pH 12.
Applicant’s invention is unpatentable over the teaching of Rao in view of the disclosures of Dahanukar and Larsson, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in modifying Rao’s method for preparing ticagrelor to use in Step (b) an organic base, specifically DIPEA, and employ a two-step (alkaline/acidic) aqueous washing at the instantly claimed pH range for each wash, and to include methanol in Step (c), for the following reasons:
The teaching of Rao and the disclosure of Larsson show that the pH of aqueous washes are not critical for obtaining a good result in the reaction of Step (a), and a are therefore interchangeable and/or combinable among the different methods of these prior art references;
The teaching of Rao and the disclosures of Dahanukar and Larsson show that the choice of base and pH of aqueous washes are not critical for obtaining a good result in the reaction of Step (b), and are therefore interchangeable among the different methods of these prior art references;
Rao, Dahanukar and Larsson all show the use of excess base in the reaction of Step (b), which will make any simple water wash become an alkaline water wash, and an organic amine base in particular will limit the pH of the aqueous phase to the claimed range;
Rao provides all elements of the process of claim 1 except for the two-step aqueous (alkalkine/acid) washing/extraction of Step (b) and the use of methanol in Step (c);
Dahanukar shows that a comparable reaction for Step (b) works well with DIPEA as the base and a two-step aqueous (alkaline/acid) washing/extraction;
Larsson shows that a comparable reaction for Step (b) works well with an acidic washing/extraction at pH 4, in the claimed range for the acidic wash.
Larsson shows that the final deprotection of Step (c) can be conducted in a mixture of aqueous HCl and methanol as alternative to Rao’s use of concentrated aqueous HCl alone.
A person of ordinary skill in the art would at once recognize that the isolation of Ticagrelor in neutral form does not require complete neutralization of the acid from the reaction of Step (c), would be motivated to use the minimum amount of base to neutralize the acid to economize the process, and a partial neutralization of the acid to reach the neutral state of Ticagrelor would result in the acidification of the ensuing water wash, thereby providing a pH of the aqueous layer in the claimed range of 0.5-6.
Thus, the invention was prima facie obvious at the time of filing.
Claim 2 further limits claim 1 to wherein the Step (a) to make a compound of instant Formula (II) is performed in a two-phase-system comprising water, acetic acid and an organic solvent, and is met by the rejection above.
Claim 3 further limits claim 2 to wherein the organic solvent is selected from a Markush group that includes ethyl acetate, and is met by the rejection above.
Claim 4 further limits claim 1 to wherein the rection of Step (a) is held between 0-10°C. Rao holds the temperature of this step, to make Rao’s compound 4, to 10-15°C (page 1092). Larsson, preparing the same compound under comparable conditions (water, acetic acid, sodium nitrite), conducts the reaction below 7°C (page 16, lines 1-12).
Claim 6 further limits claim 1 to wherein Step (b) uses organic solvent selected from a Markush group that includes ethyl acetate and dichloromethane. Claim 16 further limits claim 6 to wherein the organic solvent is dichloromethane. Rao uses ethyl acetate in Step 2 (page 1092), and Dahanukar uses ethyl acetate in the comparable reaction to directly make ticagrelor (paragraph [0196]), and Dahanukar further discloses a list of solvents suitable for the reactions of the synthesis of Ticagrelor that specifically includes both ethyl acetate and dichloromethane on the basis that they are inert to the reaction conditions (paragraph [0098]).
Claim 8 further limits claim 1 to wherein the reaction of Step (b) is held between 15-35°C. Rao conducts this reaction at room temperature (page 1092), while Larsson maintains the reaction at 20-25°C (page 17, lines 1-12), and Dahanukar conducts the analogous reaction to directly form ticagrelor at 15-20°C (paragraph [0196]).
Claim 9 further limits claim 1 to wherein the organic solvent added after the Step (c) reaction is selected from a Markush group that includes ethyl acetate. Larsson adds ethyl acetate after this reaction.
Claim 10 further limits claim 1 to wherein the acid used in Step (c) is selected from a Markush group that includes hydrochloric acid. Claim 18 further limits claim 10 to wherein the inorganic acid is hydrochloric acid. Rao uses HCl for this step (page 1092) as does Larsson (“Step 4”, page 17, lines 15-27 to page 18, lines 1-15).
Claim 11 further limits claim 1 to wherein the C1-C3 alcohol in Step (c) is selected from a Markush group that includes methanol, and is met by the rejection above. Claim 19 further limits claim 11 to wherein the C1-C3 alcohol in Step (c) is methanol, and is met by the rejection above.
Claim 12 further limits claim 1 to wherein the Step (c) reaction is conducted within the temperature range 10-35°C. Larsson conducts the reaction at 20°C.
Claim 14 further limits claim 1 to wherein the overall product ticagrelor is obtainable by the process of claim 1, characterized by below-threshold concentrations of certain known nitrosamines, as follows:
N-nitrosodiethylamine (NDEA) is below 0.0009 ppm;
N-nitrosoethylisopropylamine (NEIPA) is below 0.018 ppm;
N-nitrosodiisopropylamine (NDIPA) is below 0.018 ppm.
While none of Rao, Dahanukar or Larsson provide concentrations of the claimed nitrosamines, the claimed result of low-concentration nitrosamines is inherent to the modification of Rao’s method described in the rejection above with the methods of Dahanukar and Larsson, when the organic amine base is DIPEA as selected by Dahanukar. Applicant has asserted in the instant Specification that the method of Larsson, for example, provides equally low concentrations of NEIPA and NDIPA, but provides higher levels of NDEA compared to the “Example 1” synthesis of ticagrelor of the claimed method as provided by Applicant (instant Specification, see pages 11-13 for “Example 1” synthesis and pages 13-14 for “Example 2” evaluation of nitrosamine content of produced ticagrelor). A person of ordinary skill in the art will at once recognize that the operative difference between Applicant’s “Example 1” and the method of Larsson as regards the concentration of produced NDEA is that Larsson uses triethylamine in the Step (b) whereas Applicant uses DIPEA. The use of DIPEA inherently suppresses the formation of NDEA because the nitrosation pathway for DIPEA will not produce NDEA, as evidenced by Smith (Smith, P.A.S. and Loeppky, R. N; Journal of the American Chemical Society, v89, pp1147-1157;1967). Smith teaches a study in the nitrosative cleavage of tertiary amines, and shows that the overall reaction provides (1) a dealkylated (i.e., secondary) nitrosamine and (2) a carbonyl compound (e.g., ketone or aldehyde) from the alkyl group lost by the amine (Abstract, page 1147), as shown in Smith’s formula (1), below (page 1148):
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Smith confirms that triethylamine nitrosation produces NDEA and this observation was originally reported in 1864 (pages 1147-1148, bridging paragraph). By the formula (1) shown above, a person of ordinary skill in the art would at once recognize that DIPEA can nitrosate/de-alkylate by each of two pathways:
Loss of ethyl group (forming acetaldehyde) to give N-nitrosodiisopropylamine (NDIPA);
Loss of isopropyl group (forming acetone) to give N-nitrosoethylisopropylamine (NEIPA).
Thus, there is no pathway for DIPEA to form NDEA by nitrosation, and so Applicant’s comparison of Larsson’s method for synthesis of ticagrelor to the instant “Example 1” is not meaningful with regard to the relative production of NDEA, and Larsson’s method already produces NEIPA and NDIPA below the claimed threshold levels. In view of these observations, the modification of Rao’s method to incorporate Dahanukar’s use of DIPEA as the base in Step (b), along with the washings of Dahanukar and Larsson as discussed above, and Larsson’s use of methanol in the deprotection of the ketal protecting group, inherently produces the below-threshold levels of nitrosamines as instantly claimed. Applicant has discovered a new property or advantage of the method that was already made obvious by the teaching of Rao in view of the disclosures of Larsson and Dahanukar. Applicant’s Affadavit dated 03/26/2026 does not refute this assertion, as the Affadavit does not specify what base was used in the reaction of Step (b) used for each of the comparative syntheses of Ticagrelor that compare of alkaline-only vs. alkaline-acidic washes, thus a person of ordinary skill in the art would not understand from the Affadavit whether Applicant is simply disputing the nitrosamine result(s) reported by Dahanukar or otherwise disclosing some unexpected advantage of the instant invention. MPEP 2112 I. states: “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).”
Claim 15 further limits claim 1 to wherein the second washing of Step (b) is performed in an alkaline pH range (8-9.5), and is met by the rejection above.
Applicant’s invention is unpatentable over the teaching of Rao in view of the disclosures of Dahanukar and Larsson, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in modifying the method of Rao for preparing Ticagrelor with aspects of the methods of Dahanukar and Larsson, including the use of an organic base, particularly DIPEA, in Step (b), the claimed sequences of washes at the claimed pH ranges, the use of ethyl acetate or dichloromethane as the reaction solvent in Step (b), and to include methanol in Step (c), for the following reasons:
The teaching of Rao and the disclosures of Dahanukar and Larsson show that the choice of base in Step (b) and sequence and pH of aqueous washes after each the steps (a/b/c) are not critical for obtaining good results in the reactions, and are therefore interchangeable among the different methods of these prior art references;
Claimed solvent(s) and temperature ranges for each of the reactions have been disclosed or employed in at least one of the prior works among Rao, Larsson and Dahanukar and are interchangeable among the different methods of these prior art references;
Larsson shows that the final deprotection can be conducted in a mixture of aqueous HCl and methanol as alternative to Rao’s use of concentrated aqueous HCl alone;
The claimed result of obtaining nitrosamines below disclosed thresholds is an inherent result in the modification of Rao’s method to include DIPEA as the base in Step (b) along with the washing parameters of Dahanukar and Larsson for Step (b) and Larsson’s inclusion of methanol in Step (c).
Thus, the invention was prima facie obvious at the time of filing.
Claims 1-5, 8-12, 14-19 are unpatentable over Rao in view of Dahanukar and Larsson and further in view of Vogel’s.
Claims 1-5, 8-12, 14-19 are rejected under 35 U.S.C. 103 as being unpatentable over Rao in view of Dahanukar and Larsson and further in view of Vogel’s (Vogel’s Textbook of Practical Organic Chemistry, 5th Edition, Furniss, et al.; Ed.s; Longman Scientific & Technical, Essex, England; 1989).
The limitations of claims 1-5, 8-12, 14-16 and 18-19 and the teaching of Rao and the disclosures of Dahanukar and Larsson are discussed in the rejection above and hereby incorporated into the instant rejection.
Claim 17 further limits claim 9, regarding a Markush group of acceptable solvents for addition to the post-reaction mixture of Step (c) and ensuing aqueous wash(s), to wherein the solvent to be added is dichloromethane.
As discussed in the rejection above, the synthesis of Ticagrelor by Rao does not employ methanol during the reaction of Step (c), while the variant method of Larsson does employ methanol during the reaction, and adds ethyl acetate to the post-reaction mixture, followed by aqueous washings. Dahanukar does not include a step analogous to instant Step (c). While none of Rao, Dahanukar, or Larsson includes the use of dichloromethane for liquid-liquid extraction/washing after a reaction corresponding to instant Step (c), a person of ordinary skill in the art would have a reasonable expectation of success in using dichloromethane for the workup after deprotecting the dimethyl acetal protecting group on the compound corresponding to instant Formula (IV), because the use of dichloromethane for post-reaction workup/extractions was well known in the art: see, for example, the teaching of Vogel’s.
Vogel’s teaches principles of organic synthesis including experimental techniques of reaction setup, workup, and purification and identification of products, and specifically addresses solvent extraction following synthetic reactions (pages 156-164). Vogel’s teaches that the crude products of most organic reactions are multicomponent mixtures, and a convenient initial isolation procedure, for the first stages of both the separation of such mixtures and of the purification of the components, may involve solvent extraction processes (page 156). Vogel’s further teaches that one of the most frequent cases that is encountered is the separation of a neutral organic compound (or compounds) from a solution or suspension (as either a solid or liquid) in an aqueous medium, by shaking with an organic solvent in which the compound is soluble and which is immiscible (or nearly immiscible) with water. The solvents generally employed for extraction are diethyl ether or diisopropyl ether, toluene, dichloromethane and light petroleum (page 156). Vogel’s teaches that diethyl ether, owing to its powerful solvent properties and its low boiling point (facilitating easy evaporation) is very widely used, how to perform a trial extraction with diethyl ether and a sample of reaction mixture, and that if extraction with diethyl ether proves unsatisfactory the experiment is repeated with a fresh sample of reaction mixture and dichloromethane (pages 156-157, bridging paragraph). Vogel’s further teaches the step-by-step process of performing a solvent/water extraction, including dispersing emulsion(s) that may form and drying the organic layer after completing the separation (pages 157-158). Thus, Vogel’s teaches a foundational approach to performing post-reaction solvent/water extractions and recommends dichloromethane as a common solvent for such purpose.
Applicant’s invention is unpatentable over the teaching of Rao in view of the disclosures of Dahanukar and Larsson, and further in view of the teaching of Vogel’s, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in using dichloromethane as organic solvent for solvent/water extraction after the acidic deprotection of the compound of instant Formula (IV), because it was known in the art that dichloromethane is a suitable and commonly used solvent for post-reaction liquid-liquid extractions, per the teaching of Vogel’s.
Thus, the invention was prima facie obvious at the time of filing.
Claims 1-5 and 8-19 are unpatentable over Rao in view of Dahanukar and Larsson, and further in view of Vogel’s, Qiao, and Lek Pharma.
Claims 1-5 and 8-19 are rejected under 35 U.S.C. 103 as being unpatentable over Rao in view of Dahanukar and Larsson, and further in view of Vogel’s, Qiao (CN105801583A) and Lek Pharma (EP2816043A1).
Claim 13 further limits claim 1 to wherein the final product ticagrelor is recrystallized from a mixture of toluene and acetonitrile.
Rao purifies Ticagrelor using either a water/methanol mixture or pure acetonitrile (page 1092). Dahanukar advocates purification of ticagrelor by preparing salt form(s), and then neutralizing said salt form(s) to obtain the pure free base form (paragraph [0009]). Larsson purifies ticagrelor by recrystallization from ethyl acetate/iso-octane (page 18, lines 19-26), or by slurry-forming (i.e., partially dissolving) ticagrelor with either n-butyl acetate (pages 18-19, bridging paragraph) or isopropanol (page 19, lines 3-8).
While none of Rao, Dahanukar or Larsson uses a specific mixture of toluene/acetonitrile to purify ticagrelor by crystallization, a person of ordinary skill in the art would have a reasonable expectation of success in purifying ticagrelor by recrystallization using a mixture of toluene/acetonitrile, because a successful recrystallization mixture is a result-effective variable, and the determination of a successful recrystallization mixture was known in the art at the effective time of filing, for example in the teaching of Vogel’s, and because acetonitrile and toluene were known as strong and weak solvents for ticagrelor, respectively, per the disclosures of Qiao and Lek Pharma, respectively.
Vogel’s teaches recrystallization techniques, including the following basic tenets (pages 135-136, bridging paragraph):
The purification of solids by crystallisation is based upon differences in their solubility in a given solvent or mixture of solvents. In its simplest form, the crystallization process consists of: (i) dissolving the impure substance in some suitable solvent at or near the boiling point; (ii) filtering the hot solution from particles of insoluble material and dust; (iii) allowing the hot solution to cool thus causing the dissolved substance to crystallise out; and (iv) separating the crystals from the supernatant solution (or mother-liquor). The resulting solid, after drying, is tested for purity (usually by a melting point determination. . ., but also by spectroscopic methods. . . or by thin-layer chromatography, . . .), and if found impure is again recrystallised from fresh solvent. The process is repeated until the pure compound is obtained; this often means until the melting point is unchanged, but confirmation by the other methods specified above is desirable.
Vogel’s further provides the following guidance on selection of solvent or solvent mixture for recrystallization (page 136):
The most desirable characteristics of a solvent for recrystallisation are as follows:
1. A high solvent power for the substance to be purified at elevated temperatures and a comparatively low solvent power at the laboratory temperature or below.
2. It should dissolve the impurities readily or to only a very small extent.
3. It should yield well-formed crystals of the purified compound.
4. It must be capable of easy removal from the crystals of the purified compound, i.e. possess a relatively low boiling point.
Vogel’s provides a list of common solvents for recrystallization, and a secondary list of additional crystallization solvents, the latter including both acetonitrile and toluene (page 137, including Table 2.8).
Qiao teaches a series of recrystallizations of ticagrelor, using a variety of strong (polar) solvents to initially dissolve the compound, including ethyl acetate, acetone, n-butanol, dichloromethane, and acetonitrile/methanol, and in each recrystallization, a non-polar (weak) solvent is added subsequently to induce crystallization, including n-hexane, iso-octane and cyclohexane (Examples 1-5, paragraphs [0021]-[0025]). Thus, Qiao shows that acetonitrile is a strong solvent for ticagrelor.
Lek Pharma provides a method for purification of ticagrelor into spherical crystalline particles, including providing a solution of ticagrelor in a (strong) solvent, adding the obtained solution to a weak solvent (“antisolvent”), isolating the obtained spherical crystals, and drying said crystals (paragraph [0015]). Lek Pharma identifies a select group of “antisolvents” that includes toluene and specifically picks toluene as the preferred antisolvent (paragraph [0021]).
Applicant’s invention is unpatentable over the teaching of Rao in view of the disclosures of Dahanukar and Larsson, and further in view of the teaching of Vogel’s and the disclosures of Qiao and Lek Pharma, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of preparing ticagrelor by a modification of Rao’s method with parameters of the methods of Dahanukar and Larsson, as discussed in the rejection above, and purifying the obtained ticagrelor using a mixture of toluene and acetonitrile, because the selection of solvents for recrystallizing a compound is a result-effective variable, and the knowledge of how to crystallize compounds using a mixture of strong and weak solvents and the evaluation of recrystallization effectiveness was known in the art per the teaching of Vogel’s, and because the identification of acetonitrile and toluene as a strong and weak solvents for ticagrelor, respectively, was separately known in the art, per the disclosures of Qiao and Lek Pharma, respectively.
Thus, the invention was prima facie obvious at the time of filing.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Cited in Applicant’s Information Disclosure Statement dated 01/09/2023.
2 Cited in Applicant’s Information Disclosure Statement dated 01/09/2023.
3 Cited in Applicant’s Information Disclosure Statement dated 01/09/2023.
4 (1S,2S,3R,5S)‐3‐(7‐{[(1R,2S)‐2‐(3,4‐difluorophenyl)cyclopropyl]amino}‐5‐(propylsulfanyl)‐3H‐[1,2,3]triazolo[4,5‐d]pyrimidin‐3‐yl)‐5‐(2‐hydroxyethoxy)cyclopentane‐1,2‐diol
5 2-((3aS,4R,6S,6aR)-4-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-tetrahydro-2, 2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-6-yloxy)ethanol
6 2-((3aS,4R,6S,6aR)-4-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-6-yloxy)ethanol
7 (3,4‐difluorophenyl)cyclopropan‐1‐amine
8 2‐{[(3aR,4S,6R,6aS)‐6‐(7‐{[(1R,2S)‐2‐(3,4‐difluorophenyl)cyclopropyl]amino}‐5‐(propylsulfanyl)‐3H‐[1,2,3]triazolo[4,5‐d]pyrimidin‐3‐yl)‐2,2‐dimethyl‐hexahydrocyclopenta[d][1,3]dioxol‐4‐yl]oxy}ethan‐1‐ol
9 See Merck Index Online: Potassium Carbonate. https://merckindex.rsc.org/monographs/m9010
10 The well known pKa of protonated aniline is 4.6: see PubChem_Aniline_CID 6115, section 3.2.27; https://pubchem.ncbi.nlm.nih.gov/compound/Aniline
11 The well known pKa of protonated pyrimidine is 1.2: see PubChem_Pyrimidine_CID 9260, section 3.2.6; https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine
12 The well known pKa of protonated 1,2,3-triazole is 1.17: see PubChem_Triazoles_CID 67516, section 3.2.1; https://pubchem.ncbi.nlm.nih.gov/compound/67516
13 The acidity of protonated DIPEA, also known as “Hünig’s base” is well known in the art: see for example, page 7244 of Delgado (Delgado, et al.; Inorganic Chemistry, v54, pp7239-7248; 2015).
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