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`Case 1:22-cv-04328 Document 1 Filed 06/29/22 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
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`IN THE UNITED STATES DISTRICT COURT
`DISTRICT OF NEW JERSEY
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`BRISTOL-MYERS SQUIBB COMPANY,
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`Plaintiff,
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`v.
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`XSPRAY PHARMA AB,
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`Defendant.
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`Civil Action No. ______________
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`
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`Electronically Filed
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`Plaintiff, Bristol-Myers Squibb Company, by its undersigned attorneys, for their Complaint
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`COMPLAINT
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`against Defendant, Xspray Pharma AB, hereby alleges as follows:
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`NATURE OF THE ACTION
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`1.
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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 a New Drug Application (“NDA”) to the Food and Drug
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`Administration (“FDA”) seeking approval to manufacture and sell a generic version of Plaintiff’s
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`SPRYCEL® (dasatinib) tablets prior to the expiration of United States Patent Nos. 7,491,725 and/or
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`8,680,103.
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`THE PARTIES
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`2.
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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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`3.
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`On information and belief, Defendant Xspray Pharma AB (“Xspray”) is a corporation
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`organized and existing under the laws of Sweden, having a principal place of business at
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`Råsundavägen 12, 169 67 Solna, Sweden.
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`4.
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`On information and belief, Xspray is in the business of, among other things,
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`developing, preparing, manufacturing, selling, marketing, and distributing generic drugs, including
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`distributing, selling, and marketing generic drugs throughout the United States, including within the
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`state of New Jersey, through its own actions and through the actions of its partners, agents and
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`subsidiaries.
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`5.
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`On information and belief, Xspray is listed as the applicant of NDA No. 216195 (the
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`“Xspray NDA”) and has sent notice to BMS stating that Xspray included a certification in the Xspray
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`NDA, pursuant to 21 U.S.C. § 355(b)(2)(A)(IV).
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`6.
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`On information and belief, Xspray initially prepared and submitted the Xspray NDA
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`for Xspray’s 100 mg dasatinib tablets. BMS previously filed a lawsuit against Xspray in this District
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`arising from Xspray’s submission of the Xspray NDA for Xspray’s 100 mg dasatinib tablets. See
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`Bristol-Myers Squibb Co. v. Xspray Pharma AB, C.A. No. 1-22-cv-00964, Dkt. 1 (D.N.J. Feb. 23,
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`2022). On information and belief, Xspray subsequently amended the Xspray NDA to include five
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`additional dosage strengths of 15 mg, 36 mg, 50 mg, 57 mg, and 70 mg tablets (“Xspray NDA
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`Products”).
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`7.
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`On information and belief, Xspray prepared and submitted the Xspray NDA for the
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`Xspray NDA Products, which was done for the direct benefit of Xspray.
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`8.
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`On information and belief, following FDA approval of the Xspray NDA, Xspray,
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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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`9.
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`This action arises under the patent laws of the United States, 35 U.S.C. §§ 100 et seq.,
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`generally, and 35 U.S.C. § 271(e)(2), specifically, and this Court has jurisdiction over the subject
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`matter of this action under 28 U.S.C. §§ 1331 and 1338(a).
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`10.
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`Venue is proper in this Court as to Xspray because, among other things, Xspray is a
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`foreign corporation not residing in any United States district and may be sued in any judicial district.
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`28 U.S.C. § 1391(b), (c); see also 28 U.S.C. § 1400(b); Fed. R. Civ. P. 4(k)(2); In re HTC Corp., 889
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`F.3d 1349 (Fed. Cir. 2018).
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`11.
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`Venue is further proper in this Court as to Xspray because, among other things,
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`Xspray has committed or aided, abetted, contributed to, and/or participated in the commission of,
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`acts of infringement of the asserted patents that will lead to foreseeable harm and injury to BMS by
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`filing the Xspray NDA with the intention of seeking to market the Xspray NDA Products nationwide,
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`including within New Jersey. See 28 U.S.C. § 1400(b).
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`12. Moreover, Xspray did not contest venue, and filed counterclaims, in this District in
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`the prior case in which BMS filed a lawsuit against Xspray arising from Xspray’s submission of the
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`Xspray NDA for Xspray’s 100 mg dasatinib tablets. See Bristol-Myers Squibb Co. v. Xspray Pharma
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`AB, C.A. No. 1-22-cv-00964, Dkt. 10 (D.N.J. May 5, 2022).
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`PERSONAL JURISDICTION OVER XSPRAY
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`Plaintiff realleges paragraphs 1–12 as if fully set forth herein.
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`This Court has personal jurisdiction over Xspray because, inter alia, Xspray, on
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`13.
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`14.
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`information and belief: intends to market, sell, and/or distribute the Xspray NDA Products to
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`residents of this State upon approval of the Xspray NDA, either directly or through at least one of its
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`partners or wholly-owned subsidiaries or agents. Xspray’s intent to sell its NDA Products here is
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`sufficient to support a finding of specific personal jurisdiction. See Acorda Therapeutics Inc. v.
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`Mylan Pharms. Inc., 817 F.3d 755, 762–63 (Fed. Cir. 2016).
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`15.
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`Alternatively, to the extent the above facts do not establish personal jurisdiction over
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`Xspray, this Court may exercise jurisdiction over Xspray pursuant to Fed. R. Civ. P. 4(k)(2) because:
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`(a) Plaintiff’s claims arise under federal law; (b) Xspray would be a foreign defendant not subject to
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`personal jurisdiction in the courts of any State; and (c) Xspray has sufficient contacts with the United
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`States as a whole, including, but not limited to, preparing and filing NDAs with the FDA, marketing
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`its drug product candidates, and manufacturing generic pharmaceutical products that will be
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`distributed throughout the United States, such that this Court’s exercise of jurisdiction over Xspray
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`satisfies due process, and is consistent with the United States Constitution and Laws.
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`16.
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`Upon information and belief, if the Xspray NDA is approved, Xspray’s NDA Products
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`will be marketed and distributed by Xspray in the State of New Jersey, prescribed by physicians
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`practicing in the State of New Jersey, dispensed by pharmacies located within the State of New
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`Jersey, and used by patients in the State of New Jersey.
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`17.
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`Upon information and belief, Xspray does not currently maintain a principal place of
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`business, maintain any offices, store its products, or sell its products directly into another forum, and
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`no other forum has a superior claim of personal jurisdiction over Xspray.
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`18. Moreover, Xspray did not contest personal jurisdiction, and filed counterclaims, in
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`this District in the prior case in which BMS filed a lawsuit against Xspray arising from Xspray’s
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`submission of the Xspray NDA for Xspray’s 100 mg dasatinib tablets. See Bristol-Myers Squibb Co.
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`v. Xspray Pharma AB, C.A. No., Dkt. 10 1-22-cv-00964 (D.N.J. May 5, 2022)
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`BACKGROUND
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`U.S. PATENT NO. 7,491,725
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`19.
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`On February 17, 2009, the United States Patent & Trademark Office (“USPTO”) duly
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`and legally issued United States Patent No. 7,491,725 (“the ’725 patent”) entitled “Process for
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`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 correct
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`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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`20.
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`On March 25, 2014, the USPTO duly and legally issued United States Patent
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`No. 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 Galella,
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`and Ramakrishnan Chidambaram. A true and correct copy of the ’103 patent is attached as Exhibit
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`2. The ’103 patent is assigned to BMS.
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`SPRYCEL®
`BMS is the holder of New Drug Application (“NDA”) No. 029186 for dasatinib, for
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`21.
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`oral use, in 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg dosages, which is sold under the trade
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`name SPRYCEL®.
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`22.
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`Pursuant to 21 U.S.C. § 355(b)(1), and attendant FDA regulations, the ’725 and ’103
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`patents are among the patents listed in the Orange Book with respect to SPRYCEL®.
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`23.
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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 1–23 as if fully set forth herein.
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`On information and belief, Xspray submitted the Xspray NDA to the FDA, pursuant
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`24.
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`25.
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`to 21 U.S.C. § 355(b), seeking approval to market the Xspray NDA Products.
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`26.
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`Xspray has represented that the Xspray NDA refers to and relies upon the
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`SPRYCEL® NDA, and contains data that, according to Xspray, demonstrates the bioavailability or
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`bioequivalence of the Xspray NDA Products to SPRYCEL®.
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`27.
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`Plaintiff received a letter from Xspray on or about May 18, 2022 stating that Xspray
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`had included a certification in the Xspray NDA, pursuant to 21 U.S.C. § 355(b)(2)(A)(IV), that, inter
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`alia, certain claims of the ’725 and ’103 patents are either invalid or will not be infringed by the
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`commercial manufacture, use, sale, offer to sell or importation into the United States of the Xspray
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`NDA Products (the “Xspray Paragraph IV Certification”). Xspray intends to engage in the
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`commercial manufacture, use, offer for sale, and/or sale of the Xspray NDA Products prior to the
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`expiration of the ’725 and ’103 patents.
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`28.
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`The Xspray Paragraph IV Certification offered confidential access to unspecified
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`portions of the Xspray NDA (“Offer of Confidential Access” or “OCA”) on terms and conditions set
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`by Xspray. The OCA did not grant access to the Drug Master File (“DMF”) that supports the Xspray
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`NDA, or samples of the Xspray NDA Products.
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`29.
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`Xspray has not provided any access by BMS to the DMF or samples of the Xspray
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`NDA Products. Under the Hatch-Waxman Act, an owner of a patented drug must file an action in
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`federal court within 45 days of receiving a Paragraph IV letter (“45-day window”) in order to receive
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`certain benefits under the Act, including a stay of approval of the generic drug for 30 months during
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`the pendency of litigation, as appropriate. 21 U.S.C. § 355 (c)(3)(c).
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`30.
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`Lack of access to the DMF and samples of the Xspray NDA Products have hindered
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`BMS’s ability to consider information that is relevant to its infringement analysis of the ’725 and
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`’103 patents. See Hoffman-La Roche, Inc. v. Invamed, Inc., 213 F.3d 1359, 1363–64 (Fed. Cir. 2000).
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`Upon information and belief, the samples of the Xspray NDA Products and DMF, if provided to
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`BMS, would reveal additional information that is relevant to Xspray’s infringement of the ’725 and
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`’103 patents.
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`31.
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`Xspray 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 Xspray NDA, by which Xspray seeks
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`approval from the FDA to engage in the manufacture, use, offer to sell, sale, or importation of the
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`Xspray NDA Products prior to the expiration of the ’725 patent.
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`32.
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`Xspray 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 Xspray NDA Products in the event that the FDA
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`approves the Xspray NDA. Accordingly, an actual and immediate controversy exists regarding
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`Xspray’s infringement of the ’725 patent under 35 U.S.C. §§ 271 (a), (b) and/or (c).
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`33.
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`Xspray’s manufacture, use, offer to sell, or sale of the Xspray NDA Products in the
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`United States or importation of the Xspray NDA Products into the United States during the term of
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`the ’725 patent would further infringe, literally or under the doctrine of equivalents, at least one claim
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`of the ’725 patent under 35 U.S.C. §§ 271 (a), (b) and/or (c).
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`34.
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`On information and belief, the Xspray NDA 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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`35.
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`On information and belief, the use of the Xspray NDA Products constitutes a material
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`part of at least one of the claims of the ’725 patent; Xspray knows that the Xspray NDA Products are
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`especially made or adapted for use in infringing at least one of the claims of the ’725 patent, either
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`literally or under the doctrine of equivalents; and the Xspray NDA Products are not staple articles of
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`commerce or commodity of commerce suitable for substantial noninfringing use.
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`36.
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`On information and belief, the offering to sell, sale, and/or importation of the Xspray
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`NDA Products would contributorily infringe at least one of the claims of the ’725 patent, either
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`literally or under the doctrine of equivalents.
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`37.
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`On information and belief, Xspray had knowledge of the ’725 patent and, by its
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`promotional activities and package inserts for its NDA Products, knows or should know that they
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`will aid and abet another’s direct infringement of at least one of the claims of the ’725 patent, either
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`literally or under the doctrine of equivalents.
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`38.
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`On information and belief, the offering to sell, sale, and/or importation of the Xspray
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`NDA Products by Xspray would actively induce infringement of at least one of the claims of the ’725
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`patent, either literally or under the doctrine of equivalents.
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`39.
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`Plaintiff will be substantially and irreparably harmed if Xspray is not enjoined from
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`infringing the ’725 patent.
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`40.
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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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`41.
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`On information and belief, based on the information provided by Xspray to date, the
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`factual contentions in paragraph 24–40 have evidentiary support. On information and belief, the
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`factual contentions in paragraphs 24–40 will have further evidentiary support following a reasonable
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`opportunity for further investigation or discovery.
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`COUNT II—INFRINGEMENT OF THE ’103 PATENT
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`Plaintiff realleges paragraphs 1–41 as if fully set forth herein.
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`Xspray has infringed at least one claim of the ’103 patent, pursuant to 35 U.S.C.
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`42.
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`43.
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`§ 271(e)(2)(A), by submitting, or causing to be submitted the Xspray NDA, by which Xspray seeks
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`approval from the FDA to engage in the manufacture, use, offer to sell, sale, or importation of the
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`Xspray NDA Products prior to the expiration of the ’103 patent.
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`44.
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`Xspray 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 Xspray NDA Products in the event that the FDA
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`approves the Xspray NDA. Accordingly, an actual and immediate controversy exists regarding
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`Xspray’s infringement of the ’103 patent under 35 U.S.C. §§ 271 (a), (b), and/or (c).
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`45.
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`Xspray’s manufacture, use, offer to sell, or sale of the Xspray NDA Products in the
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`United States or importation of the Xspray NDA Products into the United States during the term of
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`the ’103 patent would further infringe at least one claim of the ’103 patent under 35 U.S.C. §§ 271
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`(a), (b), and/or (c).
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`46.
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`On information and belief, the Xspray NDA 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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`47.
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`On information and belief, the use of the Xspray NDA Products constitutes a material
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`part of at least one of the claims of the ’103 patent; Xspray knows that the Xspray NDA Products are
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`especially made or adapted for use in infringing at least one of the claims of the ’103 patent, either
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`literally or under the doctrine of equivalents; and the Xspray NDA Products are not staple articles of
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`commerce or commodity of commerce suitable for substantial noninfringing use.
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`48.
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`On information and belief, the offering to sell, sale, and/or importation of the Xspray
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`NDA Products would contributorily infringe at least one of the claims of the ’103 patent, either
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`literally or under the doctrine of equivalents.
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`49.
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`On information and belief, Xspray had knowledge of the ’103 patent and, by its
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`promotional activities and package inserts of its NDA Products, knows or should know that they will
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`aid and abet another’s direct infringement of at least one of the claims of the ’103 patent, either
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`literally or under the doctrine of equivalents.
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`50.
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`On information and belief, the offering to sell, sale, and/or importation of the Xspray
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`NDA Products by Xspray would actively induce infringement of at least one of the claims of the ’103
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`patent, either literally or under the doctrine of equivalents.
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`51.
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`Plaintiff will be substantially and irreparably harmed if Xspray is not enjoined from
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`infringing the ’103 patent.
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`52.
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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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`53.
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`On information and belief, based on the information provided by Xspray to date, the
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`factual contentions in paragraph 42–52 have evidentiary support. On information and belief, the
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`factual contentions in paragraphs 42–52 will have further evidentiary support following a reasonable
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`opportunity for further investigation or discovery.
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`54.
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`The foregoing factual contentions in paragraphs 1–53 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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`PRAYER FOR RELIEF
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`WHEREFORE, Plaintiff respectfully requests that the Court enter judgment against Xspray
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`and for the following relief:
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`a. A Judgment be entered that Xspray has infringed at least one claim of the ’725 patent by
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`submitting the Xspray NDA;
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`b. A Judgment be entered that Xspray has infringed at least one claim of the ’103 patent by
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`submitting the Xspray NDA;
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`c. 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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`d. That Xspray, its officers, agents, partners, servants, employees, and those persons acting in
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`active concert or participation with all or any of them be preliminarily and permanently
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`enjoined from: (i) engaging in the commercial manufacture, use, offer to sell, or sale within
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`the United States, or importation into the United States, of drugs or methods of administering
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`drugs claimed in the ’725 and ’103 patents, and (ii) seeking, obtaining or maintaining
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`approval of NDAs until the expiration of the ’725 and ’103 patents or such other later time as
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`the Court may determine;
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`e. 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 Xspray’s NDA under § 505(b) of the Federal Food, Drug and Cosmetic Act (21
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`U.S.C. § 355(b)) shall not be earlier than the latest of the expiration dates of the ’725 and
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`’103 patents, including any extensions;
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`f. That Plaintiff be awarded monetary relief if Xspray commercially uses, offers to sell, or sells
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`its respective proposed generic versions of SPRYCEL® or any other product that infringes
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`or induces or contributes to the infringement of the ’725 and ’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 Plaintiff with prejudgment interest;
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`g. Costs and expenses in this action; and
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`h. Such other and further relief as the Court deems just and appropriate.
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`Dated: June 29, 2022
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`Respectfully submitted,
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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 actions: Bristol-Myers Squibb Company v. Xspray Pharma AB, Civil
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`Action No. 1:22-cv-0964, pending in the United States District Court, District of New Jersey
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`before the Honorable Renee Marie Bumb, U.S.D.J.; Bristol-Myers Squib Company v. Biocon
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`Pharma Limited, Civil Action No. 1:22-cv-3505, pending in the United States District Court,
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`District of New Jersey before the Honorable Renee Marie Bumb, U.S.D.J., and the Honorable
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`Matthew J. Skahill, U.S.M.J.; and Bristol-Myers Squib Company v. Accord Healthcare Inc., Civil
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`Action No. 1:22-cv-3743, pending in the United States District Court, District of New Jersey
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`before the Honorable Renee Marie Bumb, U.S.D.J., and the Honorable Matthew J. Skahill,
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`U.S.M.J.
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`Dated: June 29, 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
`
`in that the Plaintiff seeks, inter alia, injunctive relief.
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`Dated: June 29, 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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`14
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`Case 1:22-cv-04328 Document 1 Filed 06/29/22 Page 15 of 87 PageID: 15
`Case 1:22-cv-04328 Document1 Filed 06/29/22 Page 15 of 87 PagelD: 15
`
`EXHIBIT 1
`EXHIBIT 1
`
`
`
`Case 1:22-cv-04328 Document 1 Filed 06/29/22 Page 16 of 87 PageID: 16
`case 122-0r04828 Document? aFFTLATE
`
`US007491725B2
`
`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)
`
`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
`
`(52)
`(58)
`
`(56)
`
`WO
`
`WO2005/072826
`
`8/2005
`
`OTHER PUBLICATIONS
`
`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-04328 Document 1 Filed 06/29/22 Page 17 of 87 PageID: 17
`Case 1:22-cv-04328 Document1 Filed 06/29/22 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-04328 Document 1 Filed 06/29/22 Page 18 of 87 PageID: 18
`Case 1:22-cv-04328 Document1 Filed 06/29/22 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-04328 Document 1 Filed 06/29/22 Page 19 of 87 PageID: 19
`Case 1:22-cv-04328 Document1 Filed 06/29/22 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-04328 Document 1 Filed 06/29/22 Page 20 of 87 PageID: 20
`Case 1:22-cv-04328 Document1 Filed 06/29/22 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-04328 Document 1 Filed 06/29/22 Page 21 of 87 PageID: 21
`Case 1:22-cv-04328 Document1 Filed 06/29/22 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-04328 Document 1 Filed 06/29/22 Page 22 of 87 PageID: 22
`Case 1:22-cv-04328 Document1 Filed 06/29/22 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-04328 Document 1 Filed 06/29/22 Page 23 of 87 PageID: 23
`Case 1:22-cv-04328 Document1 Filed 06/29/22 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-04328 Document 1 Filed 06/29/22 Page 24 of 87 PageID: 24
`Case 1:22-cv-04328 Document1 Filed 06/29/22 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-04328 Document 1 Filed 06/29/22 Page 25 of 87 PageID: 25
`Case 1:22-cv-04328 Document1 Filed 06/29/22 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
`kin