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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1, 2, 5-9, 11-13, 15, 16, 18-20, 22-27, and 42, drawn to a method of preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof; and the followings as the elected method species:
a method of preparing a compound of Formula I or a pharmaceutically acceptable salt thereof in a yield of at least 60% and a purity of at least 98%, comprising the following steps:
(c) forming a third reaction mixture comprising tetrahydrofuran, toluene, iPrMgCl, a compound of Formula III:
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, and 2-bromo-pyridine:
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, wherein the pyridine is present in a molar ratio of about 3.0 to the compound of Formula Ill, and wherein the Grignard reagent is present in a molar ratio of about 3.0 to the compound of Formula III;
(c1) adding acetic acid and water to the third reaction mixture to form a workup
mixture;
(c2) distilling the workup mixture to form an intermediate mixture comprising a
compound of Formula IIb:
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;
(b) forming a second reaction mixture comprising the intermediate mixture, acetonitrile, and methanesulfonic acid, to form a compound of Formula IIa having the structure:
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;
(a) forming a first reaction mixture comprising the compound of Formula IIa, triethylamine, ethyl acetate, and 4-(trifluoromethyl)benzenesulfonyl chloride:
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, wherein the sulfonyl chloride is present in a molar ratio of about 1.0 to the compound of Formula IIa;
(a1) adding N-methylpiperazine to the first reaction mixture to remove unreacted 4-(trifluoromethyl)benzenesulfonyl chloride;
(a1) adding HCl and water to the first reaction mixture to partition the first reaction mixture into a first water mixture and a first organic mixture;
(a3) separating the first water mixture from the first organic mixture;
(a4) concentrating the first organic mixture;
(a5) adding ethanol to the concentrated first organic mixture; and
(a6) adding water to the concentrated first organic mixture to precipitate the compound of Formula I
, in which
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is the elected species of [HX]n;
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is the elected compound species of Formula IIa; triethylamine is the elected species of non-nucleophilic amine base; ethyl acetate is the elected species of first solvent; and N-methylpiperazine is the elected species of amino scavenging agent in the reply filed on January 23, 2026 is acknowledged.
Claims 28, 43, 51, 56-57, 65 and 67-69 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on January 23, 2026.
Expansion of Election of Species Requirement
A reasonable and comprehensive search of the elected species conducted by the Examiner
discover a prior art by Hunt et al. that anticipates the claimed invention, wherein the prior art teaches
HCl as an acid solvate, and N,N-diisopropylethylamine as the non-nucleophilic amine base. The Examiner also discover a prior art by Jung et al. that teaches 3-mereaptopropionic acid as the scavenging agent. In light of this discovery, the search is expanded to the subject matter of the acid solvate to include HCl in addition to the elected species of acid solvate (
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); expanded the subject matter of the non-nucleophilic amine base to include N,N-diisopropylethylamine in addition to the elected non-nucleophilic amine base (triethylamine); and expanded the subject matter of the amino scavenging agent to include 2-aminoethane sulfonic acid in addition to the elected species (N-methylpiperazine), such that it does not encompass the full scope of the claims.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on January 23, 2026, wherein claims 1-2, 5-9, 11-13, 15-16, 18-20, 22-28, 42-43, 51, 56, 57, 65 and 67-69 are unchanged; and claims 3-4, 10, 14, 17, 21, 29-41, 44-50, 52-55, 58-64 and 66 are cancelled.
Claims 1-2, 5-9, 11-13, 15-16, 18-20, 22-28, 42-43, 51, 56, 57, 65 and 67-69 are pending.
Claims 28, 43, 51, 56-57, 65 and 67-69 are withdrawn.
Claims 1-2, 5-9, 11-13, 15-16, 18-20, 22-27 and 42 are under examination in accordance with the elected species along with the expanded compound set forth in the Expansion of Species section above.
Priority
The instant application 18/342,239 filed on June 27, 2023 claims priority to, and the benefits of U.S. Provisional Application No. 63/367,151 filed on June 28, 2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on January 23, 2026 and September 18, 2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Please note that foreign references without an English translation but have an English
translation of the abstract will only have the abstract considered by the Examiner.
Specification
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use, e.g., “The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics.” Exemplification of a species could be illustrative of members of the class. For processes, the type of reaction, reagents and process conditions should be stated, generally illustrated by a single example unless variations are necessary.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because the abstract is non-descriptive. In the instant case, if the invention is drawn to a process, the clear and concise steps should be described by stating the type of reaction, reagents and process conditions.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Drawings
The drawings are objected to because Fig 2, Fig 3 and Fig 4 are blurry and unreadable. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 13, 16, 18, 20, 26 and 42 are objected to because of the following informalities:
Regarding claims 13, 16 and 20, the claims are replated with the term “comprising” when recites the alternative useable members in the Markush language, and that is not being consistent with the Markush claim language. For example, the recitation of “wherein the non-nucleophilic amine base comprises” includes alternatively useable members of non-nucleophilic amine base. The alternatively useable members in the Markush grouping requires selection from a closed group, and therefore, the recitation of “wherein the non-nucleophilic amine base comprises” should read --- wherein the non-nucleophilic amine base is---. According to MPEP § 2117 I, “[a] ‘Markush’ claim recites a list of alternatively useable members. In re Harnisch, 631 F.2d 716, 719-20, 206 USPQ 300, 302-304 (CCPA 1980); Ex parte Markush, 1925 Dec. Comm'r Pat. 126, 127 (1924). The listing of specified alternatives within a Markush claim is referred to as a Markush group or Markush grouping. Abbott Labs v. Baxter Pharmaceutical Products, Inc., 334 F.3d 1274, 1280-81, 67 USPQ2d 1191, 1196-97 (Fed. Cir. 2003) (citing to several sources that describe Markush groups). Claim language defined by a Markush grouping requires selection from a closed group “consisting of” the alternative members. Id. at 1280, 67 USPQ2d at 1196. See also Amgen Inc. v. Amneal Pharmaceuticals LLC, 945 F.3d 1368, 1376-78, 2020 USPQ2d 3197 (Fed. Cir. 2020)”.
Regarding claims 18, 26 and 42, the recitation of “the sulfonyl chloride” is not being consistent with the term “4-(trifluoromethyl)benzenesulfonyl chloride” recites prior to said recitation. For the sake of clarity, said recitation should read –the 4-(trifluoromethyl)benzenesulfonyl chloride– in order to clearly reflect “the sulfonyl chloride” recites therein is referring to the very same “4-(trifluoromethyl)benzenesulfonyl chloride”.
Regarding claim 42, the recitation of “the pyridine” is not consistent with the term “2-bromo-pyridine” recites prior to said recitation. For the sake of clarity, said recitation should read –the 2-bromo-pyridine– in order to clearly reflect “the pyridine” recites therein is referring to the very same “2-bromo-pyridine”. In addition, the recitation of “the Grignard reagent” is not consistent with the term “iPrMgCl” recites prior to said recitation; and should read –the Grignard reagent—for the same reasons.
Appropriate correction is required.
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 13 and 16 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.
Regarding claims 13 and 16, the recitation of “mixtures thereof” renders the claim indefinite, because the plural form of mixture (“mixtures”) is used to refer to multiple sets of two or more mixtures. In the present case, when the term “mixture” is used within the context of alternative members (for example, the non-nucleophilic amine base is mixtures thereof), it is not clear if applicant is intending to claim any combination of at least two members from the list, or is intending to claim a combination of a first combination (a combination of at least two members) with a second combination (another combination of at least two members from the list). If applicant is intending to refer to the second scenario, the “members thereof” recites therein requires the presence of at least four members from the recited list. The lack of clarity renders the claim indefinite as one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 27 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 27, the recitation of “the compound of Formula I contains less than 1 % of the compound of Formula X-5:
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” fails to further limit the compound of Formula I sets forth in claim 1, which it depends upon. It is noted that the “compound of Formula I” set forth in claim 1 is a compound having the structure of:
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rather than a combination of two or more compounds. In order to advance prosecution, the Examiner is examining claim 27 to the extent that the compound of Formula X-5 is drawn to an impurity obtained in the method of preparing the compound of Formula I.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 12-13, 15, and 27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hunt et al. (WO 2013/177559 A2), as evidenced by Shen et al. (Bioorg Med Chem, 2011. Vol. 19(21): 6182-6195).
Hunt et al. teaches a compound of Example 1, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4.4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoqninolin-4a-yI)(pyridin-2-yl)methanone, having the structure of:
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(see e.g., p. 116, line 4-5); and a method of preparing said compound comprising: deprotecting (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate in HCl/dioxane solution to give a HCl salt as an amber oil; then reacting the salt in dichloromethane and Hunig’s base with a solution 4-(trifiuoromethyl)benzenesulfonyl chloride in dichloromethane to produce the compound of Example 1 (see e.g., [0286]). Please note Hunig’s base is an alternative name of N,N-diisopropylethylamine, as evidenced by Shen et al. (see e.g., p. 2, line 11-12). Hunt et al. further teaches (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate dissolved in HCl/dioxane gives (R)-(1-(4-fluorophenyl)-4,4a,5,(5,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone having the structure of:
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(see e.g., [0170]).
According to MPEP 2112 I, “[t]here is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003)”. In the instant case, Hunt et al. teaches a method of preparing a compound of Example 1 (equivalent to a compound of Formula I instantly claimed) comprising removing the tert-butoxycarbonyl protecting group from (R)-tert-butyl 1-(4-fluoropiienyi)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazoio[3,4-g]isoquinoline-6(4H)-carboxylate by treatment with HCl in dioxane to arrive at the salt that is then reacting with 4-(trifiuoromethyl)benzenesulfonyl chloride in a mixture containing Hunig’s base and dichloromethane to arrive at the compound of Example 1. In other words, the reaction mixture in the step of reacting the HCl salt with 4-(trifiuoromethyl)benzenesulfonyl chloride is one and the same as the claimed invention, because said reaction clearly comprises a HCl salt of
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(i.e., removing the tert-butoxycarbonyl protecting group from (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate, and then treated with HCl as the acid solvate), Hunig’s base (base), dichloromethane (solvent) and 4-(trifiuoromethyl)benzenesulfonyl chloride. The prior art is silent regarding "the compound of Formula I in a yield of at least 60% and a purity of at least 98%" in claim 1; However, by practicing the method of preparing the compound of Example 1 of Hunt et al. that forms a reaction mixture that is one and the same as disclosed, one will necessarily arrive at the same yield of the compound of Example 1 even though the prior art does not expressly teach it.
Regarding the limitation of “wherein the compound of Formula I contains less than 1% of the compound of Formula X-5:
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” in claim 27, said limitation is reasonably construed to be an impurity that stems from the process of preparing a compound of instant Formula I. In the instant case, Hunt et al. is silent regarding the presence of “less than 1% of the compound of Formula X-5”; However, by practicing the method of preparing the compound of Example 1 of Hunt et al. that forms a reaction mixture that is one and the same as disclosed, one will also be arriving at the same amount of the compound of Formula X-5 even though the prior art was not aware of it.
Therefore, the claimed invention is being anticipated by Hunt et al.
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 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 1-2, 5-9, 11-13, 15, 18 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Hunt et al. (WO 2013/177559 A2; cited in the IDS), as evidenced by Shen et al. (Bioorg Med Chem, 2011. Vol. 19(21): 6182-6195).
Hunt et al. teaches a compound of Example 1, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4.4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoqninolin-4a-yI)(pyridin-2-yl)methanone, having the structure of:
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(see e.g., p. 116, line 4-5); and a method of preparing said compound comprising: deprotecting (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate in HCl/dioxane solution to give a HCl salt as an amber oil; the salt was suspended in dichloromethane and Hunig’s base was added; when the suspension had cleared a solution of 4-(trifiuoromethyl)benzenesulfonyl chloride in dichloromethane was added; the reaction mixture was allowed to stir overnight at 20-25°C, then was quenched with water; the organic layer was washed with 15% aqueous sodium chloride solution and then concentrated; the crude product, was purified by column chromatography on silica gel, eluting with heptane/ethyl acetate (4:1 to 1:1), to give the compound of Example 1 as a pale yellow powder (see e.g., [0286]). Please note Hunig’s base is an alternative name of N,N-diisopropylethylamine, as evidenced by Shen et al. (see e.g., p. 2, line 11-12). Hunt et al. further teaches (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate dissolved in HCl/dioxane gives (R)-(1-(4-fluorophenyl)-4,4a,5,(5,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone having the structure of:
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(see e.g., [0170]). Hunt et al. further teaches the compounds of the invention can be synthesized by a variety of methods known to one of skill in the art or by an appropriate combination of generally well-known synthetic methods (see e.g., [0083]). Hunt et al. further teaches various synthetic scheme for making the compounds of the present invention, including the followings:
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(see e.g., [0009]; Fig 1). Hunt et al. further teaches the tert-butoxycarbonyl protecting group is removed from IV by treatment with an acid, such as, inter alia, HCl or methanesulfonic acid, optionally in a solvent such as, inter alia, dioxane or ethanol, either under anhydrous or aqueous conditions; Amines V are converted to the compounds of formula (I) by treatment with an appropriate substituted sulfonyl halide, such as the sulfonyl chloride VI, in an inert solvent such as dichloromethane, toluene or tetrahydrofuran, preferably dichloromethane, in the presence of a base such as N,N-di-isopropylethylamine or triethyl amine. It may be convenient to carry out the sulfonylation reaction in situ, without isolation of the amine V (see e.g., [0084]).
In short, in the method of preparing a compound of Example 1 as taught by Hunt et al., the reaction mixture clearly comprises a HCl salt of (R)-(1-(4-fluorophenyl)-4,4a,5,(5,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (
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) , and 4-(trifiuoromethyl)benzenesulfonyl chloride. The difference between the method of prior art and the claimed method is that the prior art uses HCl as the acid rather than methanesulfonic acid. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of preparing the compound of Example 1 as taught by Hunt et al. by substituting the HCl with an methanesulfonic acid to arrive at the claimed invention. One would have been motivated to do so, because Hunt et al. the tert-butoxycarbonyl protecting group can be removed from IV:
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((R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate) by treatment with an acid, including HCl and methanesulfonic acid, to arrive at V:
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((R)-(1-(4-fluorophenyl)-4,4a,5,(5,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone). Please note the methanesulfonic acid has the chemical structure of:
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. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by replacing the HCl with methanesulfonic acid as the acid would have successfully remove the tert-butoxycarbonyl protecting group from the (R)-tert-butyl 1-(4-fluoropiienyi)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazoio[3,4-g]isoquinoline-6(4H)-carboxylate.
Regarding the limitation of “prepare the compound of Formula I in a yield of at least 60% and a purity of at least 98%” in claim 6, and the limitation of “wherein the compound of Formula I is prepared in a yield of at least 75% and a purity of at least 98%” in claim 7, such parameters represent result-effective variables that would have been routinely optimized by one of ordinary skill in the art. Hunt et al. teaches the same reaction sequence and purification techniques (e.g., chromatography and solvent systems), which directly impact yield and purity. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to optimize reaction conditions (e.g., solvent, temperature, equivalents, workup, and purification) to obtain acceptable or improved yield and purity, including the claimed values, with a reasonable expectation of success. Moreover, in the absence of evidence to the contrary, practicing the method of Hunt et al. using conventional optimization techniques would reasonably be expected to produce the compound in comparable purity and yield range, particularly where purification by column chromatography is expressly taught.
Regarding the limitation of “wherein the first reaction mixture further comprises a first solvent” in claim 15, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to include dichloromethane as the solvent in the modified method of Hunt et al. set forth above. One would have been motivated to do so, because Hunt et al. clearly teaches 4-(trifiuoromethyl)benzenesulfonyl chloride is dissolved in dichloromethane. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that dichloromethane can successfully dissolve 4-(trifiuoromethyl)benzenesulfonyl chloride in the reaction mixture.
Regarding the limitation of “wherein the first reaction mixture further comprises a non-nucleophilic amine base” in claim 12, and the limitation of “wherein the non-nucleophilic amine base comprises… triethylamine” in claim 13, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to include Hunig’s base in the modified method of Hunt et al. set forth above. One would have been motivated to do so, because Hunt et al. teaches the salt, which is obtained after deprotection, is suspended in dichloromethane and Hunig’s base before adding a solution comprising the 4-(trifiuoromethyl)benzenesulfonyl chloride in dichloromethane. Please note Hunig’s base is an alternative name of N,N-diisopropylethylamine, as evidenced by Shen et al. (see e.g., p. 2, line 11-12). One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonic acid can successfully dissolve in a mixture comprising N,N-diisopropylethylamine as a base. To the extent the non-nucleophilic amine base is the elected triethylamine, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to further modify the modified method of Hunt et al. set forth above by replacing the N,N-diisopropylethylamine with triethylamine as the base in the mixture that dissolve the amine V ((R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonic acid) to arrive at the claimed invention. One would have been motivated to do so, because Hunt et al. teaches amine V is converted to the compound of formula (I) by treating with an appropriate substituted sulfonyl halide (4-(trifiuoromethyl)benzenesulfonyl chloride) in an inert solvent in the presence of a base, such as N,N-di-isopropylethylamine or triethylamine. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by replacing the N,N-di-isopropylethylamine with triethylamine would have successfully act as a base in an inert solvent for suspending the amine V ((R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonic acid).
Regarding the limitation of “wherein the sulfonyl chloride is present in a molar ratio of about 1.0 to the compound of Formula IIa” in claim 18, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to use equimolar amount of the 4-(trifluoromethyl)benzenesulfonyl chloride and the amine V ((R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonic acid) in modified method of Hunt et al. set forth above to arrive at the claimed invention through routine optimization. One would have been motivated to do so, because Hunt et al. teaches a synthetic scheme of amine V and compound VI to arrive at the compound of Formula I
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. One would have reasonable expectation of success to arrive at the claimed invention through routine optimization, because one would have reasonably expected that the reaction take place between equimolar amount of reactants, in this case, at least one amine V and at least one compound VI; and therefore, one would have reasonably expected to use equimolar amount of 4-(trifluoromethyl)benzenesulfonyl chloride and the amine V ((R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonic acid) in the sulfonylation reaction and optimize said amount, including the claimed molar ratio, in order to arrive at the compound of Example 1 with better yield.
Regarding the limitation of “wherein the compound of Formula I contains less than 1% of the compound of Formula X-5:
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” in claim 27, said limitation is reasonably construed to be an impurity that stems from the process of preparing a compound of instant Formula I. In the instant case, Hunt et al. is silent regarding the presence of “less than 1% of the compound of Formula X-5”; However, by practicing the method of preparing the compound of Example 1 of Hunt et al. that forms a reaction mixture that is one and the same as disclosed, one will also be arriving at the same amount of the compound of Formula X-5 even though the prior art was not aware of it.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed.
Claims 1-2, 5-9, 11-13, 15-16, 18 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Hunt et al. (WO 2013/177559 A2) as applied to claims 1-2, 5-9, 11-13, 15, 18 and 27 above, and further in view of Majima (US 9,487,485 B2).
The teachings of Hunt et al. are set forth above and applied as before.
Hunt et al. does not teach ethyl acetate in claim 16.
Majima et al. teaches in step 2:
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(see e.g., Col. 20, 55-65), the reaction is advantageously performed in an inert solvent; while such solvent is not particularly limited as long as the reaction proceeds, examples thereof include, inter alia,
halogenated hydrocarbons (e.g., dichloromethane, chloroform and the like) and esters (e.g., ethyl acetate and the like)(see e.g., Col. 21, line 38-49).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Hunt et al. set forth above by replacing one inert solvent for another, in this case, replacing the dichloromethane with ethyl acetate taught by Majima et al. as the inert solvent. One would have been motivated to do so, because Majima et al. teaches dichloromethane and ethyl acetate can be both be employed as inert solvent in the sulfonylation reaction comprising sulfonyl chloride. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by replacing one inert solvent for another, in this case, dichloromethane with ethyl acetate would have successfully dissolve the reagent in the reaction mixture.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed.
Claims 1-2, 5-9, 11-13, 15, 18-19, 22 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Hunt et al. (WO 2013/177559 A2) as applied to claims 1-2, 5-9, 11-13, 15, 18 and 27 above, and further in view of Jung et al. (US 5,632,898).
The teachings of Hunt et al. are set forth above and applied as before.
Hunt et al. does not teach adding an amino scavenging agent to the first reaction mixture to remove unreacted 4-(trifluoromethyl)benzenesulfonyl chloride in claim 19. Hunt et al. also does not teach the amino scavenging agent is present in a molar ratio as claimed in claim 22. However, Hunt et al. teaches the crude product of Example 1 was purified by column chromatography on silica gel (see e.g., p. 117, line 12-15).
Jung et al. teaches a simple, efficient and effective method for scavenging electrophiles from a reaction mixture (see e.g., Col. 1, line 33-35); wherein the method comprising adding to said reaction mixture a compound having the formula I:
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in an amount sufficient to react with said electrophile in said reaction mixture to form an addition compound; and separating said addition compound from the reaction mixture (see e.g., claim 1); and exemplary preferred compounds of the formula I include, inter alia, 2-aminoethane sulfonic acid (see e.g., Col. 4, line 1-11). Jung et al. further teaches the electrophile is an ion or molecule that takes part in an electrophilic process; and exemplary electrophiles which can be removed from a reaction mixture by the present invention include, inter alia, acid anhydrides, sulfonyl chlorides and similar species (see e.g., Col. 2, line 55-67). Jung et al. further teaches in a nucleophilic substitution reaction, unreacted electrophile must be removed from the reaction mixture prior to any subsequent reactions; otherwise, unreacted electrophile will compete with the subsequent reactions resulting in the formation of undesired compounds (see e.g., Col. 1, line 10-15). Jung et al. further teaches nucleophilic substitution reactions are well known per se; typically, such reactions use an excess of reagent, often electrophile, and the excess or unreacted electrophile is removed by distillation, crystallization, chromatography, high pressure liquid chromatography (HPLC), medium pressure liquid chromatography (MPLC) or a combination thereof, before other nucleophilic substitution or other reactions are carded out; these traditional methods are generally labor intensive and can require many hours to effectively remove the excess electrophile (see e.g., Col. 1, line 16-28). Jung et al. further teaches the determination of the exact amount of unreacted electrophile is usually not necessary; for example, one may conveniently add an equal or excess molar amount of the nucleophilic reagent to the original amount of the electrophile added to the reaction mixture (see e.g., Col. 4, line 20-25).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to further modify the modified method of Hunt et al. set forth above by further adding 2-aminoethane sulfonic acid as the compound of formula I and the nucleophilic reagent taught by Jung et al. to scavenge unreacted electrophile from the reaction mixture to arrive at the claimed invention. One would have been motivated to do so, because Hunt et al. teaches the crude product of Example 1 undergoes purification using column chromatography after the sulfonylation reaction; and Jung et al. teaches adding a compound of formula I, including 2-aminoethane sulfonic acid, to the reaction mixture is a simple, efficient and effective method to remove unreacted electrophile, such as sulfonyl chlorides and similar species, that may cause the formation of undesired compound in organic synthesis. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected by adding 2-aminoethane sulfonic acid to the reaction mixture would have successfully remove unreacted 4-(trifiuoromethyl)benzenesulfonyl chloride as the unreacted electrophile in order to reduce the formation of impurities.
Regarding the limitation of “wherein the amino scavenging agent is present in a molar ratio of about 0.25 to the compound of Formula Ila” claim 22, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by optimizing the molar amount of the 2-aminoethane sulfonic acid added to the reaction mixture in method of Hunt et al. and Jung et al. set forth above through routine optimization. One would have been motivated to do so, because Jung et al. teaches the compound of formula I (nucleophilic reagent), including 2-aminoethane sulfonic acid, should be added in an amount sufficient to react with the unreacted electrophile in the reaction mixture. One would have a reasonable expectation of success to arrive at the claimed invention with the claimed molar ratio through routine optimization, because one would have reasonably expected that by changing the amount of 2-aminoethane sulfonic acid added to the reaction mixture, including the claimed values, would have successfully optimize the removal of unreacted 4-(trifiuoromethyl)benzenesulfonyl chloride in the reaction mixture.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 1-2, 5-9, 11-13, 15, 18-20, 22 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Hunt et al. (WO 2013/177559 A2) in view of Jung et al. (US 5,632,898) as applied to claims 1-2, 5-9, 11-13, 15, 18-19, 22 and 27 above, and further in view of Allison et al. (ACS Omega, 2017. Vol. 2: 397−408).
The teachings of Hunt et al. and Jung et al. are set forth above and applied as before.
Hunt et al. also does not teach N-methylpiperazine in claim 20; However, Jung et al. further teaches in a nucleophilic substitution reaction between a nucleophile and an electrophile, the nucleophile contributes an electron pair to form a new bond with the electrophile by displacing a leaving group from the electrophile; and preferred nucleophiles are amine, hydroxyl and thiol groups (see e.g., Col. 3, line 32-40); and amine nucleophilic moieties may be represented by the group -NR2R3 where R2 and R3 are hydrogen or C1-C5 alkyl (see e.g., Col. 3, line 54-56).
Allison et al. teaches the reaction mixture was cooled in an ice bath and treated with N-methylpiperazine to scavenge unreacted Boc anhydride (Boc2O) in the chemical synthesis (see e.g., p. 406, left column, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Hunt et al. and Jung et al. set forth above by replacing the 2-aminoethane sulfonic acid with N-methylpiperazine taught by Allison et al. to scavenge unreacted electrophiles in the reaction mixture to arrive at the claimed invention. One would have been motivated to do so, because Jung et al. teaches amine is a preferred nucleophile that contributes an electron pair to form a new bond with the electrophile; and Allison et al. teaches N-methylpiperazine can scavenge unreacted electrophile (Boc anhydride) in the chemical synthesis. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected by replacing nucleophilic reagent for another, in this case, replacing 2-aminoethane sulfonic acid with N-methylpiperazine would have successfully act as a nucleophile to scavenge the unreacted electrophile.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 1-2, 5-9, 11-13, 15, 18-19, 22-25 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Hunt et al. in view of Jung et al. (US 5,632,898) as applied to claims 1-2, 5-9, 11-13, 15, 18-19, 22 and 27 above, and further in view of Mohrig et al. (Techniques in Organic Chemistry, 3rd edition. W. H. Freeman, 2010) and Nicholas (“4.8: Acid-Base Extraction”[Online]. Published online on September 27, 2021).
The teachings of Hunt et al. and Jung et al. are set forth above and applied as before.
Hunt et al. and Jung et al. does not teach adding a first acid as claimed in claim 23. Hunt et al. and Jung et al. also does not teach the first acid comprises hydrochloric acid as claimed in claim 24. Hunt et al. and Jung et al. also does not teach concentrating the first organic mixture, adding ethanol to the concentrated first organic mixture, and adding water to the concentrated first organic mixture to precipitate the compound of Formula I as claimed in claim 25. However, Jung et al. further teaches after allowing a sufficient time for a nucleophilic reagent of the invention to react with an electrophile, the reaction mixture may be partitioned into aqueous and organic layers; due to the water solubility of the nucleophilic reagent, any excess nucleophilic reagent will be substantially partitioned into the aqueous layer; the addition compound formed by the nucleophilic reagent and the electrophile will also be substantially soluble in water and, thus, may be removed with the removal of the aqueous layer (see e.g., Col. 5, line 6-22).
Mohrig et al. teaches the process of liquid-liquid extraction involves the distribution of a compound (solute) between two solvents that are immiscible (insoluble) in each other (see e.g., p. 114, 1st paragraph); and in a typical extraction procedure, an aqueous phase (water) and an immiscible organic solvent, often called the organic phase, are gently shaken in a separatory funnel (see e.g., p. 114, 3rd paragraph). Mohrig et al. further teaches when inorganic acids or bases are present in an organic phase, extraction with water, followed by extraction with a base or an acid, will usually remove the acid or base (see e.g., p. 120, 1st paragraph). Mohrig et al. further teaches after an extraction is completed and the two immiscible liquids are separated, the organic layer is often extracted, or washed, with water or perhaps a dilute aqueous solution of an acid or a base; for example, a chemical reaction involving alkaline (basic) reagents often yields an organic extract that still contains some alkaline material, and this alkaline material can be removed by washing the organic phase with a 5% solution of hydrochloric acid (see e.g., p. 120). Mohrig et al. further teaches recrystallization is one of the major techniques for purifying solid compounds (see e.g., p. 183, abstract of Technique 15); and when no single solvent seems to work for a recrystallization, a pair of miscible solvents—solvents that are very soluble in one another—can often be used (see e.g., p. 188, p. 188, “Two-Solvent Recrystallizations” section). Mohrig et al. further teaches mixed-solvent usually include one solvent in which a particular solute is very soluble and another in which its solubility is marginal to poor, and typical mixed-solvent pairs includes, inter alia, ethanol as solvent 1 and water as solvent 2 (see e.g., p. 188, “Two-Solvent Recrystallizations” section).
Nicholas teaches in acid-base extraction, basic compounds such as amines can be extracted from organic solutions by shaking them with acidic solutions to convert them into more water-soluble salts. In this way, they can be extracted from an organic layer into an aqueous layer:
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(see e.g., p. 2, “Extracting bases”).
Regarding the limitation of “(a2) adding a first acid and water to the first reaction mixture to partition the first reaction mixture into the first water mixture and the first organic mixture; and (a3) separating the first water mixture from the first organic mixture” in claim 23, and the limitation of “wherein the first acid comprises hydrochloric acid” in claim 24, in this instant case, Hunt et al. clearly teaches the reaction mixture was quenched with water before obtaining the organic layer. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the modified method of Hunt et al. and Jung et al. set forth above to include the extraction process taught by Hunt et al., and then substituting said extraction process with a conventional liquid-liquid extraction taught by Mohrig et al. by using aqueous HCl (water and HCl) as taught by Nichols et al. to arrive at the claimed invention. One would have been motivated to do so, because Jung et al. teaches when the reaction mixture partitioned into aqueous and organic layers, and water can solubilize the excess nucleophilic reagent, the addition compound formed by the nucleophilic reagent, and the electrophile and be removed by disposing the aqueous layer; Mohrig et al. teaches liquid-liquid extraction, including acid-base extraction, is well-known and routine technique for isolating basic compounds from the organic mixture; and Nicholas teaches the use of aqueous HCl for extracting basic compounds. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by substituting one known purification technique with another can successfully obtain the same compound, in this case, the compound of Example 1.
Regarding the limitation of “the steps of: (a4) concentrating the first organic mixture; (a5) adding ethanol to the concentrated first organic mixture; and (a6) adding water to the concentrated first organic mixture to precipitate the compound of Formula I” in claim 25, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to further modify the modified method of Hunt et al., Jung et al., Mohrig et al. and Nicholas set forth above by purifying the isolated compound by concentrating the organic phase and inducing precipitate using a ethanol and water as a mixed-solvent pair as taught by Mohrig et al. One would have been motivated to do so, because Mohrig et al. teaches recrystallization is well-known and routine technique in the art for purifying solid compounds; and water/ethanol is a typical mixed-solvent pairs that include one solvent in which a particular solute is very soluble and another in which its solubility is marginal to poor to induce crystallization. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by contacting the concentrated organic phase with water/ethanol as mixed-solvent pairs would have successfully modulate solubility and obtain the solid compound of Example 1.
Claims 1-2, 5, 6-9, 11-13, 15-16, 18, 19-20 and 22-27 are rejected under 35 U.S.C. 103 as being unpatentable over Hunt et al. (WO 2013/177559 A2), in view of Majima (US 9,487,485 B2), Jung et al. (US 5,632,898), Allison et al. (ACS Omega, 2017. Vol. 2: 397−408), Mohrig et al. (Techniques in Organic Chemistry, 3rd edition. W. H. Freeman, 2010) and Nicholas (“4.8: Acid-Base Extraction”[Online]. Published online on September 27, 2021), as evidenced by Shen et al. (Bioorg Med Chem, 2011. Vol. 19(21): 6182-6195).
Hunt et al. teaches a compound of Example 1, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4.4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoqninolin-4a-yI)(pyridin-2-yl)methanone, having the structure of:
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(see e.g., p. 116, line 4-5); and a method of preparing said compound comprising: deprotecting (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate in HCl/dioxane solution to give a HCl salt as an amber oil; the salt was suspended in dichloromethane and Hunig’s base was added; when the suspension had cleared a solution of 4-(trifiuoromethyl)benzenesulfonyl chloride in dichloromethane was added; the reaction mixture was allowed to stir overnight at 20-25°C, then was quenched with water; the organic layer was washed with 15% aqueous sodium chloride solution and then concentrated; the crude product, was purified by column chromatography on silica gel, eluting with heptane/ethyl acetate (4:1 to 1:1), to give the compound of Example 1 as a pale yellow powder (see e.g., [0286]). Please note Hunig’s base is an alternative name of N,N-diisopropylethylamine, as evidenced by Shen et al. (see e.g., p. 2, line 11-12). Hunt et al. further teaches (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate dissolved in HCl/dioxane gives (R)-(1-(4-fluorophenyl)-4,4a,5,(5,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone having the structure of:
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(see e.g., [0170]). Hunt et al. further teaches the compounds of the invention can be synthesized by a variety of methods known to one of skill in the art or by an appropriate combination of generally well known synthetic methods (see e.g., [0083]). Hunt et al. further teaches various synthetic scheme for making the compounds of the present invention, including the followings:
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(see e.g., [0009]; Fig 1). Hunt et al. further teaches the tert-butoxycarbonyl protecting group is removed from IV by treatment with an acid, such as, inter alia, HCl or methanesulfonic acid, optionally in a solvent such as, inter alia, dioxane or ethanol, either under anhydrous or aqueous conditions; Amines V are converted to the compounds of formula (I) by treatment with an appropriate substituted sulfonyl halide, such as the sulfonyl chloride VI, in an inert solvent such as dichloromethane, toluene or tetrahydrofuran, preferably dichloromethane, in the presence of a base such as N,N-di-isopropylethylamine or triethyl amine. It may be convenient to carry out the sulfonylation reaction in situ, without isolation of the amine V (see e.g., [0084]).
Hunt et al. does not teach ethyl acetate. Hunt et al. also does not teach adding N-methylpiperazine to the first reaction to remove unreacted 4-(trifluoromethl)benzenesulfonyl chloride. Hunt et al. also does not teach adding HCl and water to the first reaction mixture to partition the first
reaction mixture into the first water mixture and the first organic mixture; adding ethanol to the concentrated first organic mixture; and adding water to the concentrated first organic mixture.
Majima et al. teaches in step 2:
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(see e.g., Col. 20, 55-65), the reaction is advantageously performed in an inert solvent; while such solvent is not particularly limited as long as the reaction proceeds, examples thereof include, inter alia,
halogenated hydrocarbons (e.g., dichloromethane, chloroform and the like) and esters (e.g., ethyl acetate and the like)(see e.g., Col. 21, line 38-49). This reaction is preferably performed in the presence of a base; examples of the base include, inter alia, tertiary amines such as triethylamine (see e.g., Col. 21, line 52-61).
Jung et al. teaches in a nucleophilic substitution reaction, unreacted electrophile must be removed from the reaction mixture prior to any subsequent reactions; otherwise, unreacted electrophile will compete with the subsequent reactions resulting in the formation of undesired compounds (see e.g., Col. 1, line 10-15). Jung et al. further teaches a simple, efficient and effective method for scavenging electrophiles from a reaction mixture (see e.g., Col. 1, line 33-35); wherein the method comprising adding to said reaction mixture a compound having the formula I:
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in an amount sufficient to react with said electrophile in said reaction mixture to form an addition compound; and separating said addition compound from the reaction mixture (see e.g., claim 1); and exemplary electrophiles which can be removed from a reaction mixture by the present invention include, inter alia, acid anhydrides, sulfonyl chlorides and similar species (see e.g., Col. 2, line 55-67). Jung et al. further teaches in a nucleophilic substitution reaction between a nucleophile and an electrophile, the nucleophile contributes an electron pair to form a new bond with the electrophile by displacing a leaving group from the electrophile; and preferred nucleophiles are amine, hydroxyl and thiol groups (see e.g., Col. 3, line 32-40); and amine nucleophilic moieties may be represented by the group -NR2R3 where R2 and R3 are hydrogen or C1-C5 alkyl (see e.g., Col. 3, line 54-56). Jung et al. further teaches after allowing a sufficient time for a nucleophilic reagent of the invention to react with an electrophile, the reaction mixture may be partitioned into aqueous and organic layers; due to the water solubility of the nucleophilic reagent, any excess nucleophilic reagent will be substantially partitioned into the aqueous layer; the addition compound formed by the nucleophilic reagent and the electrophile will also be substantially soluble in water and, thus, may be removed with the removal of the aqueous layer (see e.g., Col. 5, line 6-22).
Allison et al. teaches the reaction mixture was cooled in an ice bath and treated with N-methylpiperazine to scavenge unreacted Boc anhydride (Boc2O) in the chemical synthesis (see e.g., p. 406, left column, last paragraph).
Mohrig et al. teaches the process of liquid-liquid extraction involves the distribution of a compound (solute) between two solvents that are immiscible (insoluble) in each other (see e.g., p. 114, 1st paragraph); and in a typical extraction procedure, an aqueous phase (water) and an immiscible organic solvent, often called the organic phase, are gently shaken in a separatory funnel (see e.g., p. 114, 3rd paragraph). Mohrig et al. further teaches when inorganic acids or bases are present in an organic phase, extraction with water, followed by extraction with a base or an acid, will usually remove the acid or base (see e.g., p. 120, 1st paragraph). Mohrig et al. further teaches after an extraction is completed and the two immiscible liquids are separated, the organic layer is often extracted, or washed, with water or perhaps a dilute aqueous solution of an acid or a base; for example, a chemical reaction involving alkaline (basic) reagents often yields an organic extract that still contains some alkaline material, and this alkaline material can be removed by washing the organic phase with a 5% solution of hydrochloric acid (see e.g., p. 120). Mohrig et al. further teaches recrystallization is one of the major techniques for purifying solid compounds (see e.g., p. 183, abstract of Technique 15); and when no single solvent seems to work for a recrystallization, a pair of miscible solvents—solvents that are very soluble in one another—can often be used (see e.g., p. 188, p. 188, “Two-Solvent Recrystallizations” section). Mohrig et al. further teaches mixed-solvent usually include one solvent in which a particular solute is very soluble and another in which its solubility is marginal to poor, and typical mixed-solvent pairs includes, inter alia, ethanol as solvent 1 and water as solvent 2 (see e.g., p. 188, “Two-Solvent Recrystallizations” section).
Nicholas teaches in acid-base extraction, basic compounds such as amines can be extracted from organic solutions by shaking them with acidic solutions to convert them into more water-soluble salts. In this way, they can be extracted from an organic layer into an aqueous layer:
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(see e.g., p. 2, “Extracting bases”).
In the instant case, the difference between the method of preparing a compound of Example 1 of Hunt et al. and the claimed method is that the prior art method uses HCl as an acid rather than methanesulfonic acid (MeS(O)2OH); the prior art suspended the salt of said compound in dichloromethane and Hunig’s base (N,N-diisopropylethylamine) rather than ethyl acetate and triethylamine; the prior art does not add N-methylpiperazine to remove unreacted 4-(trifluoromethyl)benzenesulfonyl chloride; the prior art add water to partition the reaction mixture to obtained organic mixture rather than adding HCl and water; the prior art purify the crude product in the concentrated organic mixture using column chromatography on silica gel rather than adding ethanol and water to the concentrated organic mixture. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention through routine optimization by modify the method of preparing the compound of Example 1 taught by Hunt et al. by substituting HCl with methanesulfonic acid as the acid, substituting Hunig’s base with triethylamine as the base in accordance with the teachings of Hunt et al., and then substituting dichloromethane with ethyl acetate as the inert solvent as taught by Majima, and then further incorporate N-methylpiperazine of Allison et al. as a nucleophile reagent to scavenge unreacted electrophile in the reaction mixture as taught by Jung et al. and then substitute the extraction using water with conventional acid-base extraction using HCl/water as taught by Nicholas, and then substitute the purification process using the column chromatography with another conventional purification technique taught by Mohrig et al. that induce precipitate using an ethanol/water pair. One would have been motivated to do so, because Hunt et al. teaches HCl and methanesulfonic acid can both be employed as an acid, and Hunig’s base (N,N-diisopropylethylamine) and triethylamine both can be employed as a base; Majima et al. teaches both dichloromethane and ethyl acetate can be both be employed as inert solvent in the sulfonylation reaction comprising sulfonyl chloride, and in the presence of base such as triethylamine; Allison et al. teaches N-methylpiperazine can scavenge unreacted electrophile in the chemical synthesis; Jung et al. teaches amine is a preferred nucleophile that contributes an electron pair to form a new bond with the electrophile; Nicholas teaches the use of aqueous HCl for extracting basic compounds; and Mohrig et al. teaches liquid-liquid extraction, including acid-base extraction, is well-known and routine technique for isolating compounds , and recrystallization is well-known and routine technique in the art for purifying solid compounds; and water/ethanol is a typical mixed-solvent pairs to induce crystallization. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, because synthesizing known compound by interchanging one art recognized technique for another and combining them is well known, routine and conventional to those skilled in the art; Especially, one would have reasonably expected that by switching one art recognized equivalent acid (from HCl to MeS(O)2OH), base (from Hunig’s base to triethylamine) and inert solvent (from dichloromethane to ethyl acetate) would have exerted the same or substantially similar effect; one would have also reasonably expected that by incorporating N-methylpiperazine as a scavenger in the reaction mixture can successfully remove unreacted electrophile in the chemical synthesis in order to reduce impurities; one would have also reasonably expected that by substituting one extraction for another that includes acid-base extraction (from water to water/HCl) would have successfully extract basic compounds; and one would have also reasonably expected that by substituting one purification technique for another (from column chromatography to recrystallization using water/ethanol) would have successfully purify the product (compound of Example 1) in the concentrated organic mixture; and that renders obvious the limitation of “in a yield of at least 75% and a purity of at least 98%”.
Regarding the limitation of “wherein the sulfonyl chloride is present in a molar ratio of about 1.0 to the compound of Formula IIa” in claims 18 and 26, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to use equimolar amount of the 4-(trifluoromethyl)benzenesulfonyl chloride and the amine V ((R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonic acid) in method set forth above to arrive at the claimed invention through routine optimization. One would have been motivated to do so, because Hunt et al. teaches a synthetic scheme of amine V and compound VI to arrive at the compound of Formula I
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. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the reaction take place between equimolar amount of reactants, in this case, one amine V and one compound VI; and therefore, one would have reasonably expected that using equimolar amount of 4-(trifluoromethyl)benzenesulfonyl chloride and the amine V ((R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonic acid) in the method above would have successfully arrive at the compound of Example 1.
Regarding the limitation of “wherein the amino scavenging agent is present in a molar ratio of about 0.25 to the compound of Formula Ila” claim 22, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by optimizing the molar amount of the 2-aminoethane sulfonic acid added to the reaction mixture in method of Hunt et al., Majima, Jung et al., Allison et al., Mohrig et al., and Nicholas set forth above through routine optimization. One would have been motivated to do so, because Jung et al. teaches the nucleophilic reagent used for scavenging the electrophile should be added in an amount sufficient to react with the unreacted electrophile in the reaction mixture. One would have a reasonable expectation of success to arrive at the claimed invention with the claimed molar ratio, because one would have reasonably expected that by changing the amount of 2-aminoethane sulfonic acid added to the reaction mixture, including the claimed values, would have successfully optimize the removal of unreacted electrophile in the reaction mixture.
Regarding the limitation of “wherein the compound of Formula I contains less than 1% of the compound of Formula X-5:
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” in claim 27, said limitation is reasonably construed to be an impurity that stems from the process of preparing a compound of instant Formula I. In the instant case, Hunt et al. is silent regarding the presence of “less than 1% of the compound of Formula X-5”; However, by practicing the method of preparing the compound of Example 1 of Hunt et al. that forms a reaction mixture that is one and the same as disclosed, one will also be arriving at the same amount of the compound of Formula X-5 even though the prior art was not aware of it.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 1-2, 5-9, 11-13, 15-16, 18-20, 22-27 and 42 are rejected under 35 U.S.C. 103 as being obvious over Dener et al. (WO 2022/134033 A1; cited in the IDS), in view of Hunt et al. (WO 2013/177559 A2; cited in the IDS), as evidenced by CAS Registry Number 864972-21-4 (Entered STN on October 11, 2005).
The applied reference has a common Applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Dener et al. teaches a method of preparing a compound of Formula I having a low impurity levels than the methods previously described in U.S. Patent No. 8,859,774 and PCT Publication No. WO 2013/177559 (see e.g., [0003];[0022];[0141]):
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or a pharmaceutically acceptable salt thereof, comprising:
forming the sixth reaction mixture comprising tetrahydrofuran, toluene, iPrMgCl, the compound of Formula III:
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, and 2-bromo-4-(trifluoromethyl)pyridine:
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, wherein the pyridine is present in the molar ratio of about 1.4 to the compound of Formula III, and wherein the Grignard reagent is present in the molar ratio of 1.65 to the compound of Formula III;
adding acetic acid and water to the sixth reaction mixture to form the workup mixture;
distilling the workup mixture to form the intermediate mixture comprising the compound of Formula Ila:
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(IIa); and
forming the fifth reaction mixture comprising the intermediate mixture, acetonitrile, and methanesulfonic acid, to form the compound of Formula IIb-2:
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;
forming fourth reaction mixture comprising the compound of Formula IIb-2, triethylamine, ethyl acetate, and 1-methyl-1H-pyrazole-4-sulfonyl chloride:
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,
wherein the sulfonyl chloride is present in a ratio of about 1.0 to the compound of Formula IIb-2;
adding methanol to the fourth reaction mixture; and
adding water to the reaction mixture to precipitate the compound of Formula I in a yield of at least 75% and a purity of at least 98%. (see e.g., claims 64; Example 4).
Dener et al. further teaches after reacting the Tris MSA salt (compound of Formula IIb-2) in ethyl acetate and triethylamine with 1-methyl-1H-pyrazole-4-sulfonyl chloride, excess sulfonyl chloride is removed by reaction with the scavenging agent N-methylpiperazine; the reaction is then worked up by washing with HCl followed by water (see e.g., [0218]; Example 4). Dener et al. further teaches representative polar protic solvents include alcohols, such as methanol and ethanol (see e.g., [0035]).
Dener et al. does not teach a compound of Formula I:
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, a compound of Formula II:
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, and 4-(trifluoromethyl)benzenesulfonyl chloride:
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. Dener et al. also does not teach 2-bromo-pyridine
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.
Hunt et al. teaches a synthetic scheme for making the compounds of formula I, including a compound of Example 1:
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(see e.g., p. 116, line 4-5) and a compound of Example 18:
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(see e.g., p. 227, line 19-22), shown below (see the box):
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(see e.g., [0009]; Fig 1). Hunt et al. further teaches a method of preparing the compound of Example 1 comprising: deprotecting (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate:
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(see e.g., p. 71, line 16-18) in HCl/dioxane solution to give a HCl salt of (R)-(1-(4-fluorophenyl)-4,4a,5,(5,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone:
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as an amber oil (see e.g., [0170]); the salt was suspended in dichloromethane and Hunig’s base was added; when the suspension had cleared a solution of 4-(trifiuoromethyl)benzenesulfonyl chloride in dichloromethane was added; the reaction mixture was allowed to stir overnight at 20-25°C, then was quenched with water; the organic layer was washed with 15% aqueous sodium chloride solution and then concentrated; the crude product, was purified by column chromatography on silica gel, eluting with heptane/ethyl acetate (4:1 to 1:1), to give the compound of Example 1 as a pale yellow powder (see e.g., [0286]). Hunt et al. further teaches the method of preparing (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate:
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comprising: reacting (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-teirahydro-1H-pyrazoio[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate with a solution comprising 2-bromopyridine, diethyl ether and n-BuLi; quenching the reaction mixture with glacial acetic acid and diluted with water; the organic layer was washed with aqueous sodium chloride solution, dried over magnesium sulphate, concentrated, and purified over silica gel to obtained the crude product (see e.g., [0169]). ). Hunt et al. further teaches the tert-butoxycarbonyl protecting group is removed from IV by treatment with an acid, such as, inter alia, HCl or methanesulfonic acid (see e.g., [0084]). Hunt et al. further teaches the compounds of the invention can be synthesized by a variety of methods known to one of skill in the art or by an appropriate combination of generally well known synthetic methods (see e.g., [0083]). Please note (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-teirahydro-1H-pyrazoio[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate has the chemical structure of:
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, as evidenced by CAS Registry Number 864972-21-4.
In the instant case, the difference between the method of Dener et al. and the claimed invention is that the prior art teaches the method of preparing
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rather than
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instantly claimed, and these compounds are both taught by Hunt et al.; However, Dener et al. clearly teaches their methods of preparing have a low impurity levels than the methods previously described in Hunt et al. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to employ the method of Dener et al. for preparing the compound of Example 1 of Hunt et al. by modifying the method of Dener et al. through substituting the reagents, specifically, substituting the 2-bromo-4-(trifluoromethyl)pyridine with 2-bromo-pyridine in the sixth reaction mixture, substituting the 1-methyl-1H-pyrazole-4-sulfonyl chloride with 4-(trifluoromethyl)benzenesulfonyl chloride in the fourth reaction mixture, substituting the methanol with ethanol in the fourth reaction mixture, and then optimizing molar amount of the reagents, including the molar ratio of the 2-bromo-pyridine and iPrMgCl to the compound of Formula III, and the scavenging agent to the Formula IIa. One would have been motivated to do so, because Dener et al. teaches their methods of preparing have a low impurity levels than the methods previously described in Hunt et al., and further teaches methanol and ethanol can both be employed as polar protic solvents in the method; and Hunt et al. teaches the method of preparing the compound of Example 1, comprising forming a mixture comprising
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with 2-bromo-pyridine to arrive at the salt, such as HCl or methanesulfonic acid, that can then be reacted with 4-(trifluoromethyl)benzenesulfonyl chloride to give a reaction mixture comprising the compound of Example 1. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, because one would have reasonably expected that by employing the synthesis method of Dener et al. to prepare a compound of Example 1 of Hunt et al. would have successfully lower than the impurity levels; and therefore, by substituting the reagents of Dener et al. with the reagents taught by Hunt et al. (substituting 2-bromo-4-(trifluoromethyl)pyridine with 2-bromo-pyridine; and substituting 1-methyl-1H-pyrazole-4-sulfonyl chloride with 4-(trifluoromethyl)benzenesulfonyl chloride), substituting the methanol with ethanol as the solvent added to the concentrated organic mixture, and then optimize the amount and molar amount, including the claimed molar ratio, of each reagent would have reasonably expected to arrive at the compound of Example 1 of Hunt et al. with better yield and lower impurity; and that renders obvious the limitation of “in a yield of at least 75% and a purity of at least 98%”. Please note by practicing the method of Dener et al. and Hunt et al. set forth above, one will also be arriving at the same intermediate as claimed, which is the compound of instant Formula IIa; and the same Formula X-5 as claimed in the reaction mixture.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 5-9, 11-13, 15-16, 18-20, 22-27 and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 12,152,028 B2 in view of Hunt et al. (WO 2013/177559 A2) and Mohrig et al. (Techniques in Organic Chemistry, 3rd edition. W. H. Freeman, 2010).
The claims of the reference patent is drawn to a method of preparing a compound of Formula Ia:
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or a pharmaceutically acceptable salt thereof, comprising:
forming the sixth reaction mixture comprising tetrahydrofuran, toluene, iPrMgCl, the compound of Formula III:
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, and 2-bromo-4-(trifluoromethyl)pyridine:
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, wherein the pyridine is present in the molar ratio of about 1.4 to the compound of Formula III, and wherein the Grignard reagent is present in the molar ratio of 1.65 to the compound of Formula III;
adding acetic acid and water to the sixth reaction mixture to form the workup mixture;
distilling the workup mixture to form the intermediate mixture comprising the compound of Formula Ila:
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(IIa); and
forming the fifth reaction mixture comprising the intermediate mixture, acetonitrile, and methanesulfonic acid, to form the compound of Formula IIb-2:
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;
forming fourth reaction mixture comprising the compound of Formula IIb-2, triethylamine, ethyl acetate, and 1-methyl-1H-pyrazole-4-sulfonyl chloride:
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,
wherein the sulfonyl chloride is present in a ratio of about 1.0 to the compound of Formula IIb-2;
adding methanol to the fourth reaction mixture; and
adding water to the reaction mixture to precipitate the compound of Formula I in a yield of at least 75% and a purity of at least 98% (see e.g., claim 32).
Please see the claims indicated in the statement above.
The reference patent does not teach a compound of Formula I:
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, a compound of Formula II:
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, and 4-(trifluoromethyl)benzenesulfonyl chloride:
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. The reference patent also does not teach 2-bromo-pyridine
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. The reference patent also does not teach ethanol to the fourth reaction mixture.
Hunt et al. teaches a synthetic scheme for making the compounds of formula I, including a compound of Example 1:
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(see e.g., p. 116, line 4-5) and a compound of Example 18:
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(see e.g., p. 227, line 19-22), shown below (see the box):
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(see e.g., [0009]; Fig 1). Hunt et al. further teaches a method of preparing the compound of Example 1 comprising: deprotecting (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate:
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(see e.g., p. 71, line 16-18) in HCl/dioxane solution to give a HCl salt of (R)-(1-(4-fluorophenyl)-4,4a,5,(5,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone:
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as an amber oil (see e.g., [0170]); the salt was suspended in dichloromethane and Hunig’s base was added; when the suspension had cleared a solution of 4-(trifiuoromethyl)benzenesulfonyl chloride in dichloromethane was added; the reaction mixture was allowed to stir overnight at 20-25°C, then was quenched with water; the organic layer was washed with 15% aqueous sodium chloride solution and then concentrated; the crude product, was purified by column chromatography on silica gel, eluting with heptane/ethyl acetate (4:1 to 1:1), to give the compound of Example 1 as a pale yellow powder (see e.g., [0286]). Hunt et al. further teaches the method of preparing (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate:
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comprising: reacting (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-teirahydro-1H-pyrazoio[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate with a solution comprising 2-bromopyridine, diethyl ether and n-BuLi; quenching the reaction mixture with glacial acetic acid and diluted with water; the organic layer was washed with aqueous sodium chloride solution, dried over magnesium sulphate, concentrated, and purified over silica gel to obtained the crude product (see e.g., [0169]). ). Hunt et al. further teaches the tert-butoxycarbonyl protecting group is removed from IV by treatment with an acid, such as, inter alia, HCl or methanesulfonic acid (see e.g., [0084]). Hunt et al. further teaches the compounds of the invention can be synthesized by a variety of methods known to one of skill in the art or by an appropriate combination of generally well known synthetic methods (see e.g., [0083]).
Mohrig et al. teaches recrystallization is one of the major techniques for purifying solid compounds (see e.g., p. 183, abstract of Technique 15); and when no single solvent seems to work for a recrystallization, a pair of miscible solvents—solvents that are very soluble in one another—can often be used (see e.g., p. 188, p. 188, “Two-Solvent Recrystallizations” section). Mohrig et al. further teaches mixed-solvent usually include one solvent in which a particular solute is very soluble and another in which its solubility is marginal to poor, and typical mixed-solvent pairs includes:
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(see e.g., p. 188, “Two-Solvent Recrystallizations” section).
In the instant case, the difference between the method of reference patent and the claimed invention is that the reference patent teaches the method of preparing
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instantly claimed, which are both taught in Hunt et al.; However, Hunt et al. teaches these compounds can be synthesized by a variety of methods known to one of skill in the art. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to employ the method of Dener et al. for preparing the compound of Example 1 of Hunt et al. by modifying the method of Dener et al. through substituting the reagents, specifically, substituting the 2-bromo-4-(trifluoromethyl)pyridine with 2-bromo-pyridine in the sixth reaction mixture, substituting the 1-methyl-1H-pyrazole-4-sulfonyl chloride with 4-(trifluoromethyl)benzenesulfonyl chloride in the fourth reaction mixture, substituting the methanol with ethanol taught by Mohrig et al. in the fourth reaction mixture, and then optimizing molar amount of the reagents, including the molar ratio of the 2-bromo-pyridine and iPrMgCl to the compound of Formula III, and the scavenging agent to the Formula IIa. One would have been motivated to do so, Hunt et al. teaches any synthesis methods known to one of skill in the art can be employed for preparing the method of Formula I, including the compound of Example 1 and the compound of reference patent (referred to therein as compound of Example 18); and further teaches the method of preparing the compound of Example 1, comprising forming a mixture comprising
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with 2-bromo-pyridine to arrive at the salt, such as HCl or methanesulfonic acid, that can then be reacted with 4-(trifluoromethyl)benzenesulfonyl chloride to give a reaction mixture comprising the compound of Example 1; and Mohrig et al. teaches ethanol/water and methanol/water are both typical mixed-solvent pairs for recrystallization, which is a well-known technique for purifying solid compounds. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, because one would have reasonably expected that the synthesis method of Dener et al. can also be employed to prepare a compound of Example 1 of Hunt et al., which is structurally similar to the compound of reference patent; and therefore, by substituting the reagents of Dener et al. with the reagents taught by Hunt et al. (substituting 2-bromo-4-(trifluoromethyl)pyridine with 2-bromo-pyridine; and substituting 1-methyl-1H-pyrazole-4-sulfonyl chloride with 4-(trifluoromethyl)benzenesulfonyl chloride), substituting the methanol with ethanol as the solvent added to the concentrated organic mixture for recrystallization, and then optimize the amount and molar ratio of each reagent would have reasonably expected to arrive at the compound of Example 1 with better yield; and that renders obvious the limitation of “in a yield of at least 75% and a purity of at least 98%”. Please note by practicing the method of Dener et al. and Hunt et al. set forth above, one will also be arriving at the same intermediate as claimed, which is the compound of instant Formula IIa; and the same Formula X-5 as claimed in the reaction mixture.
Conclusion
No claims are allowed.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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