Case 1:22-cv-03505 Document 1 Filed 06/06/22 Page 1 of 87 PageID: 1
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`Liza M. Walsh
`Christine I. Gannon
`William T. Walsh, Jr.
`WALSH PIZZI O’REILLY FALANGA LLP
`Three Gateway Center
`100 Mulberry Street, 15th Floor
`Newark, NJ 07102
`(973) 757-1100
`
`Counsel for Plaintiff
`Bristol-Myers Squibb Company
`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
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` Civil Action No. __________________
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`Electronically Filed
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`))))))))))
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`BRISTOL-MYERS SQUIBB COMPANY,
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`Plaintiff,
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`v.
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`BIOCON PHARMA LIMITED,
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`Defendant.
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`COMPLAINT
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`Plaintiff, Bristol-Myers Squibb Company, by its undersigned attorneys, for its Complaint
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`against Defendant, Biocon Pharma Limited, hereby alleges as follows:
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`NATURE OF THE ACTION
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`This is an action for patent infringement arising under the Food and Drug Laws and
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`Patent Laws of the United States, Titles 21 and 35 of the United States Code, respectively, arising
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`from Defendant’s submission of an Abbreviated New Drug Application (“ANDA”) to the Food
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`and Drug Administration (“FDA”) seeking approval to manufacture and sell a generic version of
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`1
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`Plaintiff’s SPRYCEL® (dasatinib) tablets prior to the expiration of United States Patent Nos.
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`7,491,725 and/or 8,680,103.
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`THE PARTIES
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`Plaintiff Bristol-Myers Squibb Company (“BMS”) is a corporation organized and
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`existing under the laws of the State of Delaware, having a principal place of business at Route 206
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`and Province Line Road, Princeton, New Jersey 08540.
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`On information and belief, Defendant Biocon Pharma Limited (“Biocon”) is a
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`corporation organized and existing under the laws of India, having a principal place of business at
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`20th KM, Hosur Road, Electronic City, Bangalore, 560100, India.
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`On information and belief, Biocon is in the business of, among other things,
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`developing, preparing, manufacturing, selling, marketing, and distributing generic drugs,
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`including distributing, selling, and marketing generic drugs throughout the United States,
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`including within the state of New Jersey, through its own actions and through the actions of its
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`agents and subsidiaries.
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`On information and belief, Biocon is listed as the applicant of ANDA No. 217217
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`(the “Biocon ANDA”) and has sent notice to BMS stating that Biocon included a certification in
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`the Biocon ANDA, pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV).
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`On information and belief, Biocon prepared and submitted the Biocon ANDA for
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`Biocon’s 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg dasatinib tablets (“Biocon ANDA
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`Products”).
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`On information and belief, Biocon prepared and submitted the Biocon ANDA for
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`the Biocon ANDA Products, which was done for the direct benefit of Biocon.
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`On information and belief, following FDA approval of the Biocon ANDA, Biocon,
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`through its own actions and through the actions of its partners, agents, and subsidiaries, will
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`manufacture, supply, market, and sell the approved generic product throughout the United States,
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`including New Jersey.
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`JURISDICTION AND VENUE
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`This action arises under the patent laws of the United States, 35 U.S.C. §§ 100 et
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`seq., generally, and 35 U.S.C. § 271(e)(2), specifically, and this Court has jurisdiction over the
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`subject matter of this action under 28 U.S.C. §§ 1331 and 1338(a).
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`Venue is proper in this Court because, among other things, Biocon is a foreign
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`corporation not residing in any United States district and may be sued in any judicial district. 28
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`U.S.C. § 1391(c). Moreover, Biocon has litigated previous Hatch-Waxman patent infringement
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`disputes in the District of New Jersey and has not contested venue in those cases. See, e.g., Celgene
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`Corporation v. Biocon Pharma Limited et al, C.A. No. 21-11261, Dkt. 7 (D.N.J. Jun. 11, 2021);
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`Novartis Pharmaceuticals Corporation v. Alkem Laboratories Ltd. et al, C.A. No. 19-01979, Dkt.
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`56 (D.N.J. Feb. 6, 2020).
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`PERSONAL JURISDICTION OVER BIOCON
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`Plaintiff realleges paragraphs 1–10 as if fully set forth herein.
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`On information and belief, Biocon develops, manufactures, and/or distributes
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`generic drugs for sale and use throughout the United States, including in this judicial district.
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`This Court has personal jurisdiction over Biocon because, inter alia, Biocon, on
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`information and belief: (1) has substantial, continuous, and systematic contacts with this State,
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`either directly or through at least one of its wholly-owned subsidiaries or agents; (2) intends to
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`market, sell, and/or distribute the Biocon ANDA Products to residents of this State upon approval
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`of the Biocon ANDA, either directly or through at least one of its wholly-owned subsidiaries or
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`agents; and (3) enjoys substantial income from sales of its generic pharmaceutical products in this
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`State on its own and through at least one of its wholly-owned subsidiaries or agents.
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`This Court has personal jurisdiction over Biocon because, inter alia, Biocon, itself
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`and through its agents, has purposefully availed itself of the benefits and protections of New
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`Jersey’s laws such that it should reasonably anticipate being sued in this Court. On information
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`and belief, Biocon, itself and through its agents, develops, manufactures, imports, markets,
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`distributes, uses, offers to sell, and/or sells generic drugs throughout the United States, including
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`in the State of New Jersey, and therefore transacts business within the State of New Jersey related
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`to BMS’s claims, and/or has engaged in systematic and continuous business contacts within the
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`State of New Jersey.
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`On information and belief, Biocon has not contested jurisdiction in New Jersey in
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`one or more prior cases arising out of the filing of its ANDAs, and it has filed counterclaims in
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`such cases. See, e.g., Celgene Corporation v. Biocon Pharma Limited et al, C.A. No. 21-11261,
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`Dkt. 7 (D.N.J. Jun. 11, 2021); Novartis Pharmaceuticals Corporation v. Alkem Laboratories Ltd.
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`et al, C.A. No. 19-01979, Dkt. 56 (D.N.J. Feb. 6, 2020).
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`Alternatively, to the extent the above facts do not establish personal jurisdiction
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`over Biocon, this Court may exercise jurisdiction over Biocon pursuant to Fed. R. Civ. P. 4(k)(2)
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`because: (a) Plaintiff’s claims arise under federal law; (b) Biocon would be a foreign defendant
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`not subject to personal jurisdiction in the courts of any State; and (c) Biocon has sufficient contacts
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`with the United States as a whole, including, but not limited to, filing ANDAs with the FDA and
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`manufacturing and selling generic pharmaceutical products that are distributed throughout the
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`United States, such that this Court’s exercise of jurisdiction over Biocon satisfies due process, and
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`is consistent with the United States Constitution and Laws.
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`In addition, this Court has personal jurisdiction over Biocon because, Biocon,
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`through its counsel stated it will not contest jurisdiction for purposes of this action only, prior to
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`the filing of this complaint.
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`BACKGROUND
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`U.S. PATENT NO. 7,491,725
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`On February 17, 2009, the United States Patent and Trademark Office (“USPTO”)
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`duly and legally issued United States Patent No. 7,491,725 (“the ’725 patent”) entitled “Process
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`for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors” to inventors Jean
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`Lajeunesse, John D. DiMarco, Michael Galella, and Ramakrishnan Chidambaram. A true and
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`correct copy of the ’725 patent is attached as Exhibit 1. The ’725 patent is assigned to BMS.
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`U.S. PATENT NO. 8,680,103
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`On April 24, 2018, the USPTO duly and legally issued United States Patent No.
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`8,680,103 (“the ’103 patent”) entitled “Process for preparing 2-aminothiazole-5-aromatic
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`carboxamides as kinase inhibitors” to inventors Jean Lajeunesse, John D. DiMarco, Michael
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`Galella, and Ramakrishnan Chidambaram. A true and correct copy of the ’103 patent is attached
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`as Exhibit 2. The ’103 patent is assigned to BMS.
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`SPRYCEL®
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`BMS is the holder of New Drug Application (“NDA”) No. 029186 for dasatinib,
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`for oral use, in 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg dosages, which is sold under
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`the trade name SPRYCEL®.
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`5
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`Pursuant to 21 U.S.C. § 355(b)(1), and attendant FDA regulations, the ’725 and
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`’103 patents are among the patents listed in the Orange Book with respect to SPRYCEL®.
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`The ’725 and ’103 patents cover the SPRYCEL® product.
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`ACTS GIVING RISE TO THIS ACTION
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`COUNT I—INFRINGEMENT OF THE ’725 PATENT
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`Plaintiff realleges paragraphs 1–22 as if fully set forth herein.
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`On information and belief, Biocon submitted the Biocon ANDA to the FDA,
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`pursuant to 21 U.S.C. § 355(j), seeking approval to market the Biocon ANDA Products.
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`Biocon has represented that the Biocon ANDA refers to and relies upon the
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`SPRYCEL® NDA, and contains data that, according to Biocon, demonstrates the bioavailability
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`or bioequivalence of the Biocon ANDA Products to SPRYCEL®.
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`Plaintiff received a letter from Biocon on or about April 25, 2022 stating that
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`Biocon had
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`included a certification
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`in
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`the Biocon ANDA, pursuant
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`to 21 U.S.C.
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`§ 355(j)(2)(A)(vii)(IV), that, inter alia, claims of the ’725 and ’103 patents are invalid,
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`unenforceable, and/or will not be infringed by the commercial manufacture, use, or sale of the
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`Biocon ANDA Products (the “Biocon Paragraph IV Certification”). Biocon intends to engage in
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`the commercial manufacture, use, offer for sale, and/or sale of the Biocon ANDA Products prior
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`to the expiration of the ’725 and ’103 patents.
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`On information and belief, Biocon does not deny that the Biocon ANDA Products
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`will satisfy all limitations of certain claims of the ’725 patent, and in the Biocon Paragraph IV
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`Certification, Biocon did not deny that the Biocon ANDA Products will satisfy all limitations of
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`certain claims of the ’725 patent.
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`6
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`Biocon has infringed at least one claim of the ’725 patent, pursuant to 35 U.S.C.
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`§ 271(e)(2)(A), by submitting, or causing to be submitted the Biocon ANDA, by which Biocon
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`seeks approval from the FDA to engage in the manufacture, use, offer to sell, sale, or importation
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`of the Biocon ANDA Products prior to the expiration of the ’725 patent.
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`Biocon has declared its intent to manufacture, use, offer to sell, or sell in the United
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`States or to import into the United States, the Biocon ANDA Products in the event that the FDA
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`approves the Biocon ANDA. Accordingly, an actual and immediate controversy exists regarding
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`Biocon’s infringement of the ’725 patent under 35 U.S.C. §§ 271 (a), (b) and/or (c).
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`Biocon’s manufacture, use, offer to sell, or sale of the Biocon ANDA Products in
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`the United States or importation of the Biocon ANDA Products into the United States during the
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`term of the ’725 patent would further infringe, literally or under the doctrine of equivalents, at least
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`one claim of the ’725 patent under 35 U.S.C. §§ 271 (a), (b) and/or (c).
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`On information and belief, the Biocon ANDA Products, when offered for sale, sold,
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`and/or imported, and when used as directed, would be used in a manner that would directly infringe
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`at least one of the claims of the ’725 patent either literally or under the doctrine of equivalents.
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`On information and belief, the use of the Biocon ANDA Products constitutes a
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`material part of at least one of the claims of the ’725 patent; Biocon knows that the Biocon ANDA
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`Products are especially made or adapted for use in infringing at least one of the claims of the ’725
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`patent, either literally or under the doctrine of equivalents; and the Biocon ANDA Products are
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`not staple articles of commerce or commodities of commerce suitable for substantial noninfringing
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`use.
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`On information and belief, the offering to sell, sale, and/or importation of the
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`Biocon ANDA Products would contributorily infringe at least one of the claims of the ’725 patent,
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`either literally or under the doctrine of equivalents.
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`On information and belief, Biocon had knowledge of the ’725 patent and, by its
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`promotional activities and package inserts for its ANDA Products, knows or should know that it
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`will aid and abet another’s direct infringement of at least one of the claims of the ’725 patent,
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`either literally or under the doctrine of equivalents.
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`On information and belief, the offering to sell, sale, and/or importation of the
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`Biocon ANDA Products by Biocon would actively induce infringement of at least one of the claims
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`of the ’725 patent, either literally or under the doctrine of equivalents.
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`Plaintiff will be substantially and irreparably harmed if Biocon is not enjoined from
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`infringing the ’725 patent.
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`This is an exceptional case within the meaning of 35 U.S.C. § 285, which warrants
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`reimbursement of BMS’s reasonable attorney fees.
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`On information and belief, based on the information provided by Biocon to date,
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`the factual contentions in paragraph 23–37 have evidentiary support. On information and belief,
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`the factual contentions in paragraphs 23–37 will have further evidentiary support following a
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`reasonable opportunity for further investigation or discovery.
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`COUNT II—INFRINGEMENT OF THE ’103 PATENT
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`Plaintiff realleges paragraphs 1–38 as if fully set forth herein.
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`On information and belief, Biocon does not deny that the Biocon ANDA Products
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`will satisfy all limitations of certain claims of the ’103 patent, and in the Biocon Paragraph IV
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`Certification, Biocon did not deny that the Biocon ANDA Products will satisfy all limitations of
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`certain claims of the ’103 patent
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`Biocon has infringed at least one claim of the ’103 patent, pursuant to 35 U.S.C.
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`§ 271(e)(2)(A), by submitting, or causing to be submitted the Biocon ANDA, by which Biocon
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`seeks approval from the FDA to engage in the manufacture, use, offer to sell, sale, or importation
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`of the Biocon ANDA Products prior to the expiration of the ’103 patent.
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`Biocon has declared its intent to manufacture, use, offer to sell, or sell in the United
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`States or to import into the United States, the Biocon ANDA Products in the event that the FDA
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`approves the Biocon ANDA. Accordingly, an actual and immediate controversy exists regarding
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`Biocon’s infringement of the ’103 patent under 35 U.S.C. §§ 271 (a), (b), and/or (c).
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`Biocon’s manufacture, use, offer to sell, or sale of the Biocon ANDA Products in
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`the United States or importation of the Biocon ANDA Products into the United States during the
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`term of the ’103 patent would further infringe at least one claim of the ’103 patent under 35 U.S.C.
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`§§ 271 (a), (b), and/or (c).
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`On information and belief, the Biocon ANDA Products, when offered for sale, sold,
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`and/or imported, and when used as directed, would be used in a manner that would directly infringe
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`at least one of the claims of the ’103 patent either literally or under the doctrine of equivalents.
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`On information and belief, the use of the Biocon ANDA Products constitutes a
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`material part of at least one of the claims of the ’103 patent; Biocon knows that its ANDA Products
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`are especially made or adapted for use in infringing at least one of the claims of the ’103 patent,
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`either literally or under the doctrine of equivalents; and its ANDA Products are not staple articles
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`of commerce or commodities of commerce suitable for substantial noninfringing use.
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`On information and belief, the offering to sell, sale, and/or importation of the
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`Biocon ANDA Products would contributorily infringe at least one of the claims of the ’103 patent,
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`either literally or under the doctrine of equivalents.
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`On information and belief, Biocon had knowledge of the ’103 patent and, by its
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`promotional activities and package inserts for its ANDA Products, knows or should know that it
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`will aid and abet another’s direct infringement of at least one of the claims of the ’103 patent,
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`either literally or under the doctrine of equivalents.
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`On information and belief, the offering to sell, sale, and/or importation of the
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`Biocon ANDA Products by Biocon would actively induce infringement of at least one of the claims
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`of the ’103 patent, either literally or under the doctrine of equivalents.
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`Plaintiff will be substantially and irreparably harmed if Biocon is not enjoined from
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`infringing the ’103 patent.
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`This is an exceptional case within the meaning of 35 U.S.C. § 285, which warrants
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`reimbursement of BMS’s reasonable attorney fees.
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`On information and belief, based on the information provided by Biocon to date,
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`the factual contentions in paragraph 39–50 have evidentiary support. On information and belief,
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`the factual contentions in paragraphs 39–50 will have further evidentiary support following a
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`reasonable opportunity for further investigation or discovery.
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`The foregoing factual contentions in paragraphs 1–51 have evidentiary support, or
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`likely will have evidentiary support after a reasonable opportunity for further investigation and
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`discovery.
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`10
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`PRAYER FOR RELIEF
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`WHEREFORE, Plaintiff respectfully requests that the Court enter judgment against
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`Biocon and for the following relief:
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`a. A Judgment be entered that Biocon has infringed at least one claim of the ’725 and/or ’103
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`patents by submitting the Biocon ANDA;
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`b. A Judgment be entered that this case is exceptional, and that Plaintiff is entitled to its
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`reasonable attorneys’ fees pursuant to 35 U.S.C. § 285;
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`c. That Biocon, its officers, agents, servants, employees, and those persons acting in active
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`concert or participation with all or any of them be preliminarily and permanently enjoined
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`from: (i) engaging in the commercial manufacture, use, offer to sell, or sale within the United
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`States, or importation into the United States, of drugs or methods of administering drugs
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`claimed in the ’725 and/or ’103 patents, and (ii) seeking, obtaining or maintaining approval of
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`ANDAs until the expiration of the ’725 and/or ’103 patents or such other later time as the Court
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`may determine;
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`d. A Judgment ordering that pursuant to 35 U.S.C. § 271(e)(4)(A), the effective date of any
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`approval of Biocon’s ANDA under § 505(j) of the Federal Food, Drug and Cosmetic Act (21
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`U.S.C. § 355(j)) shall not be earlier than the latest of the expiration dates of the ’725 and/or
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`’103 patents, including any extensions;
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`e. That BMS be awarded monetary relief if Biocon commercially uses, offers to sell, or sells its
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`respective proposed generic versions of SPRYCEL® or any other product that infringes or
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`induces or contributes to the infringement of the ’725 and/or ’103 patents, within the United
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`States, prior to the expiration of those patents, including any extensions, and that any such
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`monetary relief be awarded to BMS with prejudgment interest;
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`f. Costs and expenses in this action; and
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`g. Such other and further relief as the Court deems just and appropriate.
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`Dated: June 6, 2022
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`OF COUNSEL:
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`Jeanna M. Wacker
`Sam Kwon
`Christopher Ilardi
`KIRKLAND & ELLIS LLP
`601 Lexington Avenue
`New York, NY 10022
`(212) 446-4679
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`s/Liza M. Walsh
`Liza M. Walsh
`Christine I. Gannon
`William T. Walsh, Jr.
`WALSH PIZZI O’REILLY FALANGA LLP
`Three Gateway Center
`100 Mulberry Street, 15th Floor
`Newark, New Jersey
`07102 (973) 757-1100
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` Counsel for Plaintiff
` Bristol-Myers Squibb Company
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`CERTIFICATION PURSUANT TO LOCAL CIVIL RULES 11.2 AND 40.1
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`I hereby certify that, to the best of my knowledge, the matter in controversy is not the
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`subject of any other pending or anticipated litigation in any court or arbitration proceeding, but is
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`related to the following action:
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`Bristol-Myers Squibb Company v. Xspray Pharma AB, Civil Action No. 1:22-cv-0964,
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`pending in the United States District Court, District of New Jersey before the Honorable Noel L.
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`Hillman, U.S.D.J.
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`Dated: June 6, 2022
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`WALSH PIZZI O’REILLY FALANGA LLP
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`s/ Liza M. Walsh
`Liza M. Walsh
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`CERTIFICATION PURSUANT TO LOCAL CIVIL RULE 201.1
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`I hereby certify that the above-captioned matter is not subject to compulsory arbitration
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`in that the Plaintiff seeks, inter alia, injunctive relief.
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`Dated: June 6, 2022
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`WALSH PIZZI O’REILLY FALANGA LLP
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`s/ Liza M. Walsh
`Liza M. Walsh
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`Case 1:22-cv-03505 Document1 Filed 06/06/22 Page 15 of 87 PagelD: 15
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`EXHIBIT 1
`EXHIBIT 1
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`Case 1:22-cv-03505 Document 1 Filed 06/06/22 Page 16 of 87 PageID: 16
`case 122-0r03608 Document?MFA
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`US007491725B2
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`a2) United States Patent
`US 7,491,725 B2
`(0) Patent No.:
`Lajeunesseet al.
`Feb. 17, 2009
`(45) Date of Patent:
`
`(54)
`
`(75)
`
`PROCESS FOR PREPARING
`2-AMINOTHIAZOLE-5-AROMATIC
`CARBOXAMIDES AS KINASE INHIBITORS
`
`Inventors: Jean Lajeunesse, Candiac (CA); John
`D. DiMarco, East Brunswick, NJ (US);
`Michael Galella, Kendall Park, NJ (US);
`Ramakrishnan Chidambaram,
`Pennington, NJ (US)
`
`(73)
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`Assignee: Bristol-Myers Squibb Company,
`Princeton, NJ (US)
`
`(*)
`
`Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 251 days.
`
`(21)
`
`Appl. No.: 11/192,867
`
`(22)
`
`Filed:
`
`Jul. 29, 2005
`
`(65)
`
`(63)
`
`(60)
`
`Prior Publication Data
`
`US 2006/0004067 Al
`
`Jan. 5, 2006
`
`Related U.S. Application Data
`
`Continuation-in-part of application No. 11/051,208,
`filed on Feb. 4, 2005, now abandoned.
`
`Provisional application No. 60/542,490,filed on Feb.
`6, 2004, provisional application No. 60/624,937, filed
`on Nov.4, 2004, provisional application No. 60/649,
`722, filed on Feb. 3, 2005.
`
`(51)
`
`Int. Cl.
`
`(2006.01)
`A61K 31/506
`(2006.01)
`CO7D 403/04
`US. Ch. eect creecees 514/252.19; 544/295
`Field of Classification Search.
`................. 544/295;
`514/252.19
`
`See application file for complete search history.
`References Cited
`
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`WO
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`WO2005/072826
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`Byrnetal. (Sold-State Chemistry of Drugs, 2nd Edition, 1999, SSCI,
`Inc. Publishers).*
`U.S. Appl. No. 11/049,815, filed Feb. 3, 2005, Chenet al.
`Autenrieth, W., “Regarding our knowledgeofthefive isomeric acids
`C,H,O,”, Chem. Ber., vol. 38, pp. 2534-2551, English Translation.
`Eremeevet al., “Absolute Configuration of Diastereomeric Deriva-
`tives of N-Substituted Aziridine-2-Carboxylic Acids”, Chem.
`Heterocycl. Compd. Engl. Transl., vol. 20, pp. 1102-1107, 1984
`(translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10,
`pp. 1342-1348, 1984).
`Hartmann et al., “On the coupling of aryldiazonium salts with N,N-
`disubstituted 2-aminothiophenes and some of their carbocyclic and.
`heterocyclic analogues”, J. Chem. Soc.; Perkin Trans. vol. 1, pp
`4316-4320, 2000.
`Kantlehner et al., “Ein neues Herstellungsverfahren fiir 2,2,2-
`Trialkoxyacetonitrile
`und
`2-Dialkylamino-2-
`alkoxycarbonsaurenitrile”, Synthesis, pp. 358-360, 1984.
`Kantlehneret al., “Orthoamides. IL Reaction of Orthoamide Deriva-
`tives with Sulfur and Selenium, Syntheses of 1,3-Thiazole- and 1,3-
`Selenazole Derivatives”, J. prakt. Chem., vol. 338, pp. 403-413,
`1996.
`
`Knollet al., “Formylation Products ofThioamides; VII’ . Synthesis of
`New
` N-(3-AMinothioacryloyl)-formamidines
`and
`=6N,N-
`Bis[aminomethylidene]thioureas
`by Bis-iminoformylation
`of
`Thioacetamides and Thiourea with Formamide Acetals”, Synthesis
`Communications, pp. 51-53, 1984.
`Landreau et al., “[4+2] Cycloaddition Reactions Between 2,4-
`Diamino-1-Thia-3-Azabutadienes and Ketene. Synthesis of New
`1,3-Thiazin-6-ones,
`1,3-Thiazine-6-Thiones
`and
`2-Thioxopyrimidin-4-ones”, Heterocycles, vol. 53, No. 12, pp. 2667-
`2677, 2000.
`
`(Continued)
`
`Primary Examiner—Kamal A Saeed
`Assistant Examiner—Jason Nolan
`
`(74) Attorney, Agent, or Firm—Mary K. VanAtten
`
`U.S. PATENT DOCUMENTS
`
`(57)
`
`ABSTRACT
`
`The invention relates to processes for preparing compounds
`having the formula,
`
`mMib/
`
`s
`
`Kulkaet al.
`Blade et al. we. 514/248
`Daset al.
`Daset al.
`Daset al.
`Daset al.
`Daset al.
`
`Hynesetal.
`Lee
`Chenetal.
`
`12/1970
`5/1992
`7/2003
`2/2004
`3/2004
`4/2004
`4/2004
`11/2004
`1/2005
`9/2005
`
`ok
`
`A A
`
`Bl
`Al
`Al
`Al
`Al
`Al
`Al
`Al
`
`3,547,917
`5,114,940
`6,596,746
`2004/0024208
`2004/0054 186
`2004/0073026
`2004/0077875
`2004/0220233
`2005/0009891
`2005/0215795
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`WO
`WO
`WO
`WO
`
`639574
`WO0062778
`WO2004071440
`WO2004085388
`WO2005013983
`
`2/1995
`10/2000
`8/2004
`10/2004
`2/2005
`
`and crystalline forms thereof, wherein Ar is aryl or het-
`eroaryl, L is an optional alkylene linker, and R,, R;, Ry,
`and R., are as defined in the specification herein, which
`compoundsare useful as kinase inhibitors, in particular,
`inhibitors of protein tyrosine kinase and p38 kinase.
`
`16 Claims, 7 Drawing Sheets
`
`

`

`Case 1:22-cv-03505 Document 1 Filed 06/06/22 Page 17 of 87 PageID: 17
`Case 1:22-cv-03505 Document1 Filed 06/06/22 Page 17 of 87 PagelD: 17
`
`US 7,491,725 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`Landreauet al., “Cationic 1,3-Diazadienes in Annulation Reactions.
`Synthesis of Pyrimidine, Thiadiazinedioxide and Triazine Deriva-
`tives”, J. Heterocyclic Chem., vol. 38, pp. 93-98, 2001.
`Linet al., “The Synthesis of Substituted 2-Aminothiazoles”, J. Het-
`erocyclic Chem., vol. 16, pp. 1377-1383, 1979.
`Marsham et al., “Quinazoline Antifolate Thymidylate Synthase
`Inhibitors: Heterocyclic Benzoyl Ring Modifications”,
`J. Med.
`Chem., vol. 34, pp. 1594-1605, 1991.
`Noack et al., “Synthesis and characterization of N,N-disubstituted
`2-amino-5-acylthiophenes and 2-amino-5-acylthiazoles”, Tetrahe-
`dron, vol. 58, pp. 2137-2146, 2002.
`
`Noacket al., “Synthesis and Spectral Characterisation of a New Class
`of Heterocyclic Analogues of Crystal Violet Dyes”, Angew. Chem.
`Int. Ed., vol. 113, No. 16, pp. 3008-3011, 2001.
`Roberts et al., “Folic Acid Analogs. Modifications in the Benzene-
`Ring Region. 2. Thiazole Analogs”, J. Medicinal Chemistry, vol. 15,
`No. 12, pp. 1310-1312, 1972.
`Zhao et al.,
`“A new facile synthesis of 2-aminothiazole-5-
`carboxylates”, Tetrahedron Letters, vol. 42, pp. 2101-2102, 2001.
`Shah et al., “Overriding Imatinib Resistance with a Novel ABL
`Kinase Inhibitor’, Science, vol. 35, pp. 339-401, 2004.
`U.S. Appl. No. 11/271,626, Office Action Jan. 31, 2008.
`
`* cited by examiner
`
`

`

`Case 1:22-cv-03505 Document 1 Filed 06/06/22 Page 18 of 87 PageID: 18
`Case 1:22-cv-03505 Document1 Filed 06/06/22 Page 18 of 87 PagelD: 18
`
`U.S. Patent
`
`Feb. 17, 2009
`
`Sheet 1 of 7
`
`US 7,491,725 B2
`
`1.5418A--->mi
`
`Figure1
`
`425°C
`
`FormH1-7 T
`
`a«>aG
`
`SDB
`
`w3 =“
`
`
`
`20(deg)forCuko,2
`
`
`
`ObservedPXRD
`
`

`

`Case 1:22-cv-03505 Document 1 Filed 06/06/22 Page 19 of 87 PageID: 19
`Case 1:22-cv-03505 Document1 Filed 06/06/22 Page 19 of 87 PagelD: 19
`
`U.S. Patent
`
`Feb. 17, 2009
`
`Sheet 2 of 7
`
`US 7,491,725 B2
`
`%(
`
`) YBa
`
`OL
`
`001+~
`
`06
`
`084
`
`OL-;
`
`Saws]WLDPE[esleqqur)
`
`09
`
`OSEoot
`
`IDe6L'982
`
`(9,)
`
`Zainbi4
`
`:tDeSZb9OGWOYSSO7YBIEM%EP'E
`eunjesaduua|osz002OS00+os
`
`
`
`3.05‘OBL
`
`cremeBB
`
`2.0P'66
`
`(yaa) Moly 3228H
`
`

`

`Case 1:22-cv-03505 Document 1 Filed 06/06/22 Page 20 of 87 PageID: 20
`Case 1:22-cv-03505 Document1 Filed 06/06/22 Page 20 of 87 PagelD: 20
`
`U.S. Patent
`
`Feb. 17, 2009
`
`Sheet 3 of 7
`
`US 7,491,725 B2
`
`
`
`ObservedPXRD
`
`1.54184--—->
`
`20(deg)torCuKe.2
`
`
`
`SimulatedPXRD
`
`FormBU-2 T=425°C
`
`
`
`24
`
`|
`
`1618
`
`Figure3if
`
`

`

`Case 1:22-cv-03505 Document 1 Filed 06/06/22 Page 21 of 87 PageID: 21
`Case 1:22-cv-03505 Document1 Filed 06/06/22 Page 21 of 87 PagelD: 21
`
`U.S. Patent
`
`Feb. 17, 2009
`
`Sheet 4 of 7
`
`US 7,491,725 B2
`
`A
`
`3
`z
`2
`
`
`
`20(deg)forCuKa2,
`
`a
`s
`3
`§
`&
`
`aer
`
`a
`R
`Bag
`2 £4
`
`|
`
`ue
`°
`e-
`a
`
`42 |
`
`82022||
`
`8101214161i'{i
`
`Figure4
`
`

`

`Case 1:22-cv-03505 Document 1 Filed 06/06/22 Page 22 of 87 PageID: 22
`Case 1:22-cv-03505 Document1 Filed 06/06/22 Page 22 of 87 PagelD: 22
`
`U.S. Patent
`
`Feb. 17, 2009
`
`Sheet 5 of 7
`
`US 7,491,725 B2
`
`
`
`ObservedPXRD
`
`1.5418A--->
`
`26(deg)forCuko.2
`
`PXRD
`Simulated
`
`18
`
`| Figure5
`
`
`
`

`

`Case 1:22-cv-03505 Document 1 Filed 06/06/22 Page 23 of 87 PageID: 23
`Case 1:22-cv-03505 Document1 Filed 06/06/22 Page 23 of 87 PagelD: 23
`
`U.S. Patent
`
`Feb. 17, 2009
`
`Sheet 6 of 7
`
`US 7,491,725 B2
`
` 28(deg)forCuka.X=1.5418A--->
`
` Simulated
`
`FormT1H1-7
`PXRD
`
`ObservedPXRD
`
` Th
`
`{
`
`18
`
`Figure6
`
`

`

`Case 1:22-cv-03505 Document 1 Filed 06/06/22 Page 24 of 87 PageID: 24
`Case 1:22-cv-03505 Document1 Filed 06/06/22 Page 24 of 87 PagelD: 24
`
`U.S. Patent
`
`Feb. 17, 2009
`
`Sheet 7 of 7
`
`US 7,491,725 B2
`
`~¢
`5
`
`sl,
`
`a
`
`g Ds
`g—rr
`
`5
`
`.
`
`a
`
`s
`
`°o
`
`a
`
`Eq
`
`Our
`
`"2=
`e_ 2
`
`o—
`
`

`

`Case 1:22-cv-03505 Document 1 Filed 06/06/22 Page 25 of 87 PageID: 25
`Case 1:22-cv-03505 Document1 Filed 06/06/22 Page 25 of 87 PagelD: 25
`
`US 7,491,725 B2
`
`1
`PROCESS FOR PREPARING
`2-AMINOTHIAZOLE-5-AROMATIC
`CARBOXAMIDES AS KINASE INHIBITORS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation-in-part of U.S. Non-
`Provisional Application Ser. No. 11/051,208, filed Feb. 4,
`2005 now abandoned, which claims the benefit of U.S. Pro-
`visional Application No. 60/542,490,filed Feb. 6, 2004, U.S.
`Provisional Application No. 60/624,937, filed Nov. 4, 2004
`and U.S. Provisional Application No. 60/649,722, filed Feb.
`3, 2005, which are all hereby incorporated by reference in
`their entirety.
`
`FIELD OF THE INVENTION
`
`The present invention relates to processes for preparing
`2-aminothiazole-Saromatic carboxamides which are useful
`as kinase inhibitors, such as inhibitors of protein tyrosine
`kinase and p38 kinase, intermediates and crystalline forms
`thereof.
`
`BACKGROUND OF THE INVENTION
`
`Aminothiazole-aromatic amides of formula I
`
`mAaSyo
`
`]
`
`s
`
`wherein Ar is aryl or heteroaryl, L is an optional alkylene
`linker, and R,, R;, R,, and R;, are as defined in the specifi-
`cation herein, are useful as kinase inhibitors, in particular,
`inhibitors of protein tyrosine kinase and p38 kinase. They are
`expected to be useful in the treatment of protein tyrosine
`kinase-associated disorders such as immunologic and onco-
`logical disorders [see, U.S. Pat. No. 6,596,746 (the ’746
`patent), assigned to the present assignee and incorporated
`herein by reference], and p38 kinase-associated conditions
`such as inflammatory and immuneconditions, as described in
`USS. patent application Ser. No. 10/773,790, filed Feb. 6,
`2004, claiming priority to U.S. Provisional application Ser.
`No. 60/445,410,filed Feb. 6, 2003 (hereinafter the ’410 appli-
`cation), both of which are also assigned to the present
`assignee and incorporated herein by reference.
`The compound of formula (IV),
`'N-(2-Chloro-6-meth-
`ylpheny])-2-[[6-[4-(2-hydroxyethy])-1-piperaziny1]-2-me-
`thyl-4-pyrimidiny]]amino]-5-thiazolecarboxamide,
`is
`an
`inhibitor of SRC/ABLandis useful in the treatment of onco-
`logical diseases.
`
`qv)
`
`Cl
`
`|
`
`n
`
`Zo
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`2
`Other approaches to preparing 2-aminothiazole-5-car-
`boxamidesare described in the ’746 patent and in the ’410
`application. The ’746 patent describes a process involving
`treatmentof chlorothiazole with n-BuLi followedby reaction
`with pheny] isocyanates to give chlorothiazole-benzamides,
`which are further elaborated to aminothiazole-benzamide
`final products after protection, chloro-to-amino substitution,
`and deprotection, e.g.,
`
`O=N=C—Ph
`
`_LY n-BuLioll
`XL \
`NHPh NEG
`cumA
`
`N
`
`cl
`
`Ss
`
`Prot.—__——
`
`Deprot.
`
`The ’410 application describes a multi-step process involv-
`ing first, converting N-unsubstituted aminothiazole carboxy-
`lic acid methyl] or ethyl esters to bromothiazole carboxylic
`