Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 1 of 61
`AnthonyI. Viola
`Andre K. Cizmarik
`Jennifer L. Dereka
`Zachary W. Silverman
`ED\JVARDS WILDMAN PALMER LLP
`Attorneys for Pl aintiffs
`Kowa Company, Ltd.,
`Kowa Pharmaceuticals America, Inc., and
`Nissan Chernical Industries, Ltd.
`750 Lexington Ave.
`New York, Nff 10022
`Qtz) 308-44n
`
`TJNITED STATES DISTRICT COURT
`SOUTHERN DISTRICT OF IYE\ry YORI(
`
`Kowa Company, Ltd.,
`Kowa Pharmaceuticals Americ4 [nc., and
`Nissan Chemical Industries, Ltd.,
`
`Plaintiffs,
`
`v.
`
`Mylan,Inc. and
`Mylan Pharmaceuticals, Inc.,
`
`Defendants.
`
`gr 96,4ï
`
`No.
`
`ïfE
`
`APR 1 4 20t4
`
`U.S.D .c. s.D. N.Y.
`CAS}TIER.S
`
`Plaintiff,s, Kowa Company., Ltd. (*KCL'), Kowa Pharmaceuticals America, Inc.
`
`('KPA")(collectivel¡ "Kowa"), and Nissan Chemical lndustries, Ltd. ("NCI") by their
`
`undersigned counsel, for their Complaint against defendants Mylan Pharmaceuticals, Inc.
`
`C'MPI") and Mylan, Inc. ("Mylan,Inc.") (collectively, "Mylan"), allege as follows:
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 2 of 61
`Jurisdiction and Venue
`
`1.
`
`This is an action for patent infringernent arising under the patent laws of the
`united states, Title 35, united states code and arising under 35 u.s.c. gg 271(e)(2),271þ),
`271(c), arñ281'283- Subject matter jurisdiction is proper under 28 U.S.C. gg l33l and l33g(a).
`Venue is proper under 28 U.S.C. $$ 1391(b)-(c) and 1400(b). Personal jurisdiction over the
`defendants in New York is proper under N.Y. C.P.L.R. $$ 301 and 302(a) and because
`
`defendants are doing business in this jurisdiction.
`
`Parties
`2. KCL is a Japanese corporation having its coqporate headquarters and principal
`place of business in Aichi, Japan. KPA is a wholly owned U.S. subsidiary of KCL. KpA has its
`corporate headquarters and principal place of business in Montgornery, Alabama and is
`
`orgarúzed under the Iaws of Delaware.
`3- NCI is a Japanese corporation having its corporate headquarters and principal
`place of business in Tokyo, Japan.
`4.
`
`KCL and NCI are engaged in the business of research, developing,
`
`manufacturing and marketing of a broad spectrum of innovative pharmaceutical products,
`
`including Livalo@.
`5. Upon information and belief, MPI is incorporated. in West Virginia having a place
`of business in Morgantown, West Virginia, and is a wholly owned subsidiary of Mylan, Inc.
`
`Upon information and belief, Abbreviated New Drug Application ("ANDA") No. 20-6070 was
`
`filed under the name of MpI.
`6- Upon information and belief Mylan, Inc. is a Pennsylvania corporation having its
`corporate headquarters in Canonsburg Pennsylvania. Upon information and belief, Mylan, Inc.
`has actual control over the activities of MPI including MPI's filing of ANDA No. 20-6070.
`
`?
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 3 of 61
`7.
`Upon information and belieÇ Mylan is currently transacting business in the
`Southern District of New York, at least by making and shipping into this Judicial District, or by
`using, offering to sell or selling or by causing others to use, offer to sell or sell, pharmaceutical
`
`products into this Judicial District.
`8.
`
`Upon information and belieÇ Mylan derives substantial revenue from interstate
`and/ot international commerce, including substantial revenue from goods used or consumed or
`services rendered in the State of New York and the Southem Dishict of New york. Both Mylan,
`Inc' and MPI are registered with the N.Y. State Department of State, Division of Corporations, to
`do business as foreign coqporations in New York. Upon information and belief, Mylan also has a
`place of business at 405 Lexington Avenue, New York, NY 10754. Additio nally,Mylan, Inc.
`common stock is listed on the NASDAQ, and Mylan, Inc. has contractual dealings with at least
`tlre American Stock Transfer & Trust Company located at 59 Maiden Lang plazalevel, New
`York, NY 10038. By filing its ANDA, Mylan has committed, and unless enjoined, will
`continue to commit a tortious act without the state of New York, that Mylan expects or should
`
`reasonably expect to have consequences in the State of New York including in this Judicial
`
`District.
`
`9.
`
`The New Drug ApplÍcatÍon
`KPA sells drug products containing pitavastatin calcium (the'þitavastatin drug
`product') under the trade name Livalo@ in the United States pursuant to the United States Food
`and Drug Administration's approval of a New Drug Application (*NDA-) held by KCL Ct\rDA
`No.22-363).
`
`3
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 4 of 61
`10' Livalo@ is approved for use as an adjunctive therapy to diet to reduce elevated
`total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and to
`increase HDL-C in adult patiørts with primary h¡,perlipidernia or mixed dyslipidemia.
`11- The approval letter for Livalo@, with approved labeling, was issued by the FDA
`on August 3,2009.
`
`t2.
`
`approved.
`
`Certain amendments to the approved labeling for Livalo@ have subsequently been
`
`The Patents in Suit
`13- United States Patent No. 5,856,336 ('the '336 patent"), entitled .,euinoline Type
`Mevalonolactones," a true and correct copy of which is appended hereto as ExhÍbit A, was duly
`issued on January 5,1999 to inve¡rtors Yoshihiro Fujikawa, Mikio Suzuki, Hiroshi Iwasaki,
`Mitsuaki Sakashita, and Masaki Kitahara, and assigned to plaintiff NCI. The,336patent claims,
`intet alia, the pitavastatin drug product, and a method for reducing hyperlipidemia,
`hyperlipoproteinemia or atherosclerosis, which comprises administering an effective amount of
`the pitavastatin drug product.
`14' PlaintiffNCl has been and still is the owner through assignment of the .336
`patent, which expires on Decemb er 25,2020 pursuant to a patent-term extension. KCL is NCI,s
`licensee for the '336 patentand KPA holds a license from KCL for the .336 patent.
`15. united states patent No. 6,465,477 (,the,477 patent',), entitled ..Stable
`Pharmaceutical Composition," a true and correct copy of which is appended hereto as Exhibit B,
`was duly issued on October 15,2002 to inventors Toyojiro Muramatsu, Katsumi Mashita, yasuo
`Shinoda, Hironori Sassa, Hiroyuki Kawashima, Yoshio Tanizawa,and Hideatsu Takeuchi, and
`
`4
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 5 of 61
`jointly assigned to plaintiffs KCL and NCI. The '477 patuftclaims, inter alia, pharmaceutical
`compositions containing pitavastatin salts.
`16. Plaintiffs KCL and NCI have been and still are the owners through assignment of
`rhe'477 patent, which expires on Decernber 20,2016. KPA holds a license from KCL for the
`'477 paterft.
`17- United States Patent No. 8,557,993 ('the '993 patent"), entitled..Crystalline
`Forms of Pitavastatin Calcium," a true and correct copy of which is appended hereto as Exhibit
`C, was duly issued on October 15, 2Ol3 to inventors Paul Adriaan Van Der Schaafi, Fritz Blatter,
`Martin Szelagiewicz, and Kai-Uwe Schoening and ultimately was assigned to plaintiffNCl
`The'993 patent claims, inter 4!ig, crptalline polymorphs or the amorphous form of pitavastatin
`or processes for preparing the same.
`t 8- PlaintiffNCl has been and still is the owner through assignment of the .993
`patent, which expires on February 2,2024. KCL is NCI's licensee for the ,993 patentand KpA
`holds a license from KCL for the ,993 patent.
`19- In accordance with its license, KPA sells the pitavastatin dn¡g product under the
`trade name Livalo@ in the United States. Sales of Livalo@ are made pursuant to approval by the
`FDA of NDA No. 22-363.
`20- PlaintiffKCl manufactures the Livalo@ drug products as sold byKpA.
`21. Plaintifß Kowa and NCI will be substantially and irreparably harmed by
`infringement of any of the '336,'477, or '993 patents (the "Livalo@ patents"). There is no
`adequate remedy at law.
`
`5
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 6 of 61
`COUNT I
`
`INFRINGEÙIENT OF TIIE '336 PATENT UNDER 35 U.S.C. I27llell2Xat
`
`22. Plaintifß repeat and incorporate herein by reference the allegations contained in
`each ofthe foregoing paragraphs.
`23- Upon information and belief, defendant Mylan filed an Abbreviated New Drug
`Application ("ANDA") with the Food and Drug Administration ('FDA') under 2l U.S.G g
`
`355(i) (ANDA No. 20-6070) seeking approval to market I *g, 2 mg, and 4mg rablets
`
`comprising pitavastatin calcium.
`24- By this ANDA filing, Mylan has indicated that it intends to engage, and that there
`is substantial likelihood that it will engage,in the commercial manufacture, importation, use,
`
`offer for sale, and/or sale, or inducement thereof, of Plaintifß' patented pitavastatin drug product
`
`immediately or imminently upon receiving FDA approval to do so. Also by its ANDA filing,
`
`Mylan has indicated that its drug product is bioequivalent to Plaintifß' pitavastatin drug product.
`25- By its ANDA filing Mylan seeks to obtain approval to commercially
`
`manufacture, use, import, offer for sale, and/or sell, alleged generic equivalents of plaintifß,
`
`Livalo@ pitavastatin drug product prior to the expiration date of the '336 paterfi.
`26- By a letter dated February 27,2014 (the "Notice Letter"), Mylan informed Kowa
`and NCI that Mylan had filed a certification to the FDA, pursuant to 2l U.S.c. g
`
`355(D(2XBXivXI). On or about February 28,2014,KP4 received the Notice Letter. On or
`
`about March 3,2014, KCL and NCI received the Notice Letter.
`27 -
`
`The Notice Letter, purporting to be Mylan's Notification Pursuant to 2l U.S.C. $
`355(D(2XB), asserts that in Mylan's opinion, the'336 patent purportedly is "invalid,
`
`6
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 7 of 61
`unenforceable, and/or will not be infringed by the commercial manufacfure, use, sale or
`
`importation of the drug products described in Mylan's ANDA."
`28- Mylan's filing of ANDA No. 20-6070 for the purpose of obtaining FDA approval
`to engage in the commercial manufacture, use, importation, offer for sale and/or sale, or
`
`inducement thereo{, of its proposed pitavastatin drug product before the expiration of the .336
`
`patent is an act of infringernent under 35 U.S.C. g 271(e)e)(A,,).
`29. Mylan's manufacture, use, importation, offer for sale, and/or sale, or inducement
`
`thereo{, of its proposed pitavastatin drug product will directly infringe or induce infringement of
`
`at least one claim of the '336 patent under 35 U.S.C. g Z7l(e)(\(f).
`30. Upon information and belief, Mylan's proposed label for its pitavastatin drug
`product will include the treatment of at least one of hyperlipidemia, hyperlipoproteinemia, and
`
`atherosclerosis.
`31. Unless Mylan is enjoined from infringing and inducing the infringement of the
`'336 patent, Plaintifß will suffer substantial and irreparable injury. Plaintifß have no adequate
`
`remedy atlaw.
`
`COUNT II
`
`INFRTNGEMENT OF THE METHOD CLAIM OF THE '336 PATENT
`UNDER 35 U.s.c. 8 27thr
`
`32- Plaintifß repeat and incorporate herein by reference the allegations contained in
`each ofthe foregoing paragraphs.
`33- Upon information and belie{, approval of ANDA 20-6070 is substantially likely to
`result in the commercial manufacture, use, importation, offer for sale, and/or sale, or inducement
`
`thereo{, of a pitavastatin drug product which is marketed and sold for use in a method claimed in
`
`7
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 8 of 61
`one or more claims of the '336 patent, ímmediately or imminently upon approval of the ANDA,
`and prior to the expiration of the ,336 patent.
`34- Upon information and belie{, Mylan's proposed label for its pitavastatin drug
`product wíll include the treatment of at least one of hlperlipidemia, hyperlipoproteinemia or
`atherosclerosis.
`
`35. Upon information and belief, Mylan is aware or reasonably should be aware, of
`the widespread use of pitavastatin as an adjunctive therapy to diet to reduce elevated total
`
`cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and to increase
`HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia. The beneficial
`ef[ects ofpitavastatin as an adjunctive therapy to diet to reduce elevated total cholesterol, low-
`density lipoprotein cholesterol, apolipoprotein B, triglycerides, and to increase HDL-C in adult
`patients with primary h¡,perlipidemia or mixed dyslipidernia would be readily apparent to
`customers of Mylan (g.g., including, without limitation, physicians, pharmacists, pharmacy
`
`benefits management companies, health care providers who establish drug formularies for their
`insurers and/or patients). Mylan will be marketing its pitavastatin drug product with specific
`intent to actively induce, aid and abet infringement of the '336 patent. Mylan knows or
`reasonably should know that its proposed conduct will induce infringønent of the .336 patent.
`36- Unless Mylan is enjoined from infringing and inducing the infringement of the
`'336 patent, Plaintifß will suffer substantial and irreparable injury. Plaintifß have no adequate
`remedy at law.
`
`8
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 9 of 61
`COUNT III
`TNFRTNGEMENT OF THry METHOp CLArM OF THE ,336 PATENT
`UNDER 35 U.S.C. g 27íc)
`37 - Plaintifß repeat and incorporate herein by reference the allegations contained in
`each ofthe foregoing paragraphs.
`38' Upon information and belie{, Mylan's proposed pitavastatin drug product
`comprises pitavastatin calcium as referenced in the claims of the'336 patent.
`39. Upon information and belief,, Mylan's proposed pitavastatin drug product will be
`especially made for use in a manner that is an infringønent of the '336 patent.
`40. Upon information and belief Mylan knows that Mylan's proposed pitavastatin
`drug product will be especially made for use in a manner that is an infringement of the .336
`patent.
`
`41. Upon information and belie{, sale of Mylan's proposed pitavastatin drug product
`will result in direct infringernent ofthe .336 patent.
`42- Upon information and belie{, Mylan's proposed pitavastatin drug product is not a
`staple article or cornmodity of commerce which is suitable for a substantial noninfringing use.
`43. Upon information and belie{, Mylan knows that Mylan's proposed pitavastatin
`drug product is not a staple article or commodity of commerce which is suitable for substantial
`
`noninfringing use.
`44- Upon information and belief, approval of ANDA 20-6070 is substantially likely to
`result in the commercial usg manufacfure, offer for sale and/orsale (or the inducement thereof
`or contribution thereto) of a drug product which is especially made, adapted, marketed, sold, and
`approved exclusively for use in a method claimed in the '336 patent, immediately or imminently
`upon approval of the ANDA.
`
`9
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 10 of 61
`45. Plaintifß will be substantially and ineparably harmed if defendants are not
`enjoined from conhibuting to the infringement of the '336 patent. plaintiffs have no adequate
`remedy atlaw.
`
`COUNT TV
`
`,4
`
`46- Plaintiffs repeat and incoqporate herein by reference the allegations contained in
`each of the foregoing paragraphs.
`47 - Mylan's Notice Letter, purporting to be Mylan's Notice of Certification under 2l
`U'S'C'$ 355Ú)Q)@), indicates that Mylan intencls to manufacture, use, sell, or offer for sale, its
`proposed pitavastatin drug product prior to the expiration of the '477 patent.
`48- The Notice Letter asserts that in Mylan's opinion, the'477 patent purportedly is
`"invalid, unenforceable, and/or will not be infringed by the commercial manufacture, use, sale or
`importation of the drug products described in Mylan's ANDA."
`49' Mylan's filing of ANDA No. 20-6070 forthe purpose of obtaining FDA approval
`to engage in the commercial manufacture, use, importation, offer for sale and/or sale, or the
`inducement thereof,, of its proposed pítavastatin drug product before the expirati on of the,477
`patent is an act of infringønenr under 35 U.S.C. g 27t(e)e)@).
`50. Mylan's manufacture, use, importation, offer for sale, sale, and/or importation of
`its proposed pitavastatin drug product will directly infringe or induce infringement of at least one
`claim of the '477 patenr under 35 U.S.C. g 271(e)e)([t).
`51. Unless Mylan is enjoined from infringing the '477 patent, plaintifß will suffer
`substantial and irreparable injury. plaintiffs have no adequate remedy at law.
`
`l0
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 11 of 61
`
`COI]NT V
`INFRTNGEMENT oF THE .993 pATBNT UNDER 35 u.s.c. g 27(eì(21(Aì
`
`52- Plaintiffs rep€at and incorporate herein by reference the allegations contained in
`each of the foregoing paragraphs.
`53- Mylan's Notíce Letter, purporting to be Mylan's Notice of Certification under2l
`U's'C.$ 355OQ)@)(iv), indicates that Mylan intends to manufacture, usq sell, or offer for sale,
`its proposed pitavastatin dnrgproduct prior to the expiration of the .993 patent.
`54- The Notice Letter asserts that in Mylan's opinion, the'993 patent purportedly is
`"invalid, unenforceable, and/or will not be infringed by the commercial manufacture, usg sale or
`importation of the drug products described in Mylan's ANDA..
`55. Mylan's filing of ANDA No. 20-6070 for the purpose of obtaining FDA approval
`to engage in the commercial manufacture, use, importation, offer for sale and/or sale, or the
`
`inducement thereof,, of its proposed pitavastatin drugproduct before the expiration of the.993
`
`patent is an act of infringønent under 35 U.S.C. g 271(e)e)(A).
`56. Mylan's manufacture, use, importation, offer forsale, sale, and/or importation of
`its proposed pitavastatin drugproduct will directly infringe or induce infringement of at least one
`claim of the '993 patenr under 35 U.S.C. g 27t(e)e)(ft).
`57- Unless Mylan is enjoined from infringing the '993 paterú, plaintifß will suffer
`substantial and irreparable injury. Ptaintifß have no adequate rønedy at law.
`
`ll
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 12 of 61
`
`WHEREFORE, Plaintiffls request the following relief;
`(a)
`
`adeclaratoryjudgment pursuant to 28 U.S.C. ç 2201et seg. that making, using,
`
`selling, offering to sell and/or importing Mylan's pitavastatin drug product for
`
`which it seeks FDA approval or any drug product containing pitavastatin will
`
`infringe at least one claim of one or more of the Livalo@ patents;
`
`(b)
`
`a declaratory judgment pursuant to 28 U.S.C . ç 2201et seq. that the making,
`
`using offering for sale, selling and/or importing of Mylan's pitavastatin drug
`
`product or any drug product containing pitavastatin, will induce the infringement
`
`at least one claim of one or more of the Livalo@ patents; .
`
`(c)
`
`(d)
`
`a declaratory judgment pursuant to 28 U.S.C. ç 22Ol et gg{1. that the making,
`
`using, offering for sale, selling and/or importing of Mylan's pitavastatin drug
`
`product or any drug product containing pitavastatin, will contribute to the
`
`infringement of at least one claim of one or more of the Livalo@ patents;
`
`a declaratory judgment pursuant to 28 u.S.c . ç z20l et geg. and an order
`
`pursuant to 35 U.S.C. $ 271(e)(4XA) providing that the effective date of any
`
`FDA approval for Mylan to commercially make, use, sell, offer to sell or import
`
`its pitavastatin drug product or any drug product containing pitavastatin be no
`
`earlier than the date following the expiration date of the last to expire of the
`
`Livalo@ patents (as extended, if applicable);
`
`(e)
`
`a petmanent injunction restraining and enjoining against any infringønent by
`
`defendants, their ofücers, agents, attorneys, employees, successors or assigns, or
`
`those acting in privity or concert with them, of the Livalo@ patents, through the
`
`commercial manufacture, use, sale, offer for sale or importation into the United
`
`t2
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 13 of 61
`
`States of Mylan's pitavastatin drug product or any drug product containing
`
`pitavastatin, and/or any inducement of or contribution to the same;
`
`Attorneys' fees in this action under 35 U.S.C. g 2g5; and
`
`Such ftrther and other relief in favor of Plaintifß and against defendants as this
`
`(Ð
`(g)
`
`Court may deem just and proper.
`
`Dated: New York, New york
`April 14,2014
`
`Kowa Company, Ltd.,
`Kowa Pharmaceuticals America, Inc., and.
`Nissan Chemical Industries, Ltd.
`
`attorneys,
`
`AnthonyJ. Viola
`Andre K.
`Jennifer L. Dereka
`Zachary rù/. Silverman
`EDIVARDS WILDMAN PALMER LLP
`750 Lexnglon Avenue
`New York,I{Y 10022
`Qtz)308-Mtt
`
`David G. Conlin (to be admittedpro hac více)
`Kathleen B. Ca¡r (to be admjttedpro hac vice)
`Adam P. Samansþ
`ED\MARDS WILDMAN PALMER LLP
`1l I Huntington Avenue
`Boston, MA02l99
`(617)239-0100
`
`t3
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 14 of 61
`. Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 14 of 61
`
`EXIIIBIT A
`. EXHIBIT A
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 15 of 61
`us00585ô?36A
`United States Patent rre¡
`Patent Number:
`tlu
`Fqiikawa et al.
`Date of Patent:
`[451
`
`5,856,336
`Jan.5, 1999
`
`I flt rfffi f, ilil m flt il ffi tilt flt ffi Í]t ll ruil il
`
`[54J QUINOL|NE TypE MEVALONOT-A,CTONOS
`Í751 lnvcnrors: Yashlhf¡o Fqflkawa; Mlklo Snzulc!
`Hh,oshl lwasolcl, all of Funabashi;
`Mlts¡¡ald Sakoshlta; Masokl Kltàhara,
`b¡rth of Shi¡aok¡-machi, all of Japao
`I73l Assignee: Ntssn Chemlcal l¡dr¡strle Ltd.
`Tokyo, Japao
`[2rl Appl. No.: S83¡9S
`lzl Filed: May IS, t992
`Rehted U5. Appllcatlon Data
`Í@l DivÍsion of Ser. No. 63tfftZ Dec. t9, 199O. whích b o
`continuatíor of Ser. No. ß3;152, eug. iC, ts3g.
`t30J
`Forelgn Appllcatlon hlorlry Data
`Attg.20, I9C7
`Japan
`Jan. 26, f988
`Iapan
`Ang.3, l9&3
`J@o
`t5U Int. Cl.ó
`[s21 U.s. Ct
`[58] Fleld of
`
`tJP¡
`IJP]
`IJPJ
`
`Search
`
`62-207724
`63-r5585
`
`A6LK3U4ll. CVTD 215/12
`514l3ll,;546/173
`546!t73;514/3lL
`
`Prínøry ExamÍnerlaura L Stockton
`Anorney, Agent, or F¡'nr--Oblon, Spivak, McC¡ellaod,
`Moier & Neustadt, P.C.
`lsq
`ABsrRAcr
`A coapound of thc formula
`
`[A]
`
`z
`
`+Pr
`N
`z--CH(o H)-CH:-cH( o H)-C H:-COo. %Ca
`havc lfMG-CoA iuhilriting cftcts making thcm use-
`ful as inhibitors of cholesterol biosyothesis. The com-
`pouad oay be prepared as a pbaroaceutical for ¡cduc-
`ing hypcrlipidcmia, hyperlipoprotcincmia or
`atherosclerosis
`
`[56]
`
`Refereuces Clted
`U.S. PÁíTENTDOCUMENTS
`5,753,675 5/1998 S/u¡¡¡a¡in ...........,.................. 5t4l31r
`
`2 Chl¡ns, No Drawlnç
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 16 of 61
`5,856,336
`
`o
`
`o
`
`2
`
`CO3R(¿
`
`Ril
`
`o
`
`o R
`
`ll
`
`o
`
`Rrt
`R.,Y
`o
`
`(rvhcrein Q is -C(O>-, -C(OR¡a- or -CHloH!-:
`q/ is -C(O)-, --C1OnrJ, or-õ(R'IXOHÈ; nr' ¡á
`hyclrogen or Cr.3 alþl; Rrz is hydrogen or Rra (wherein Rta
`Þ_phlsiologically hydrolyzabl¿ alkyl or M (wberein M is
`NHu, sodium, potassiuo, }É calcium or a hyùrate of lower
`alkylamine, di-lowe r alkylnaine <¡r rri-lowir alkylaminc));
`twt¡ R"'ar-e iodependently primary orsecrndary C,-" alkíii
`or !yg.R" rogcther form {CFl.).- or {C}I^}r-; Rl"
`a¡d R^" are iadependently bydrogen or C,_, aþf aø R5 is
`hydrogen. Cr-o alkyl, Co, alkeoyl, Cr.o cycloilkyl,
`
`Re
`
`5
`
`t
`QUINOTJNE TYPE MEVALONOT^A,CTONES
`-. This is a divisioo, of agplicarioo Scr. No. O7/631,U)2,
`9lqd ql Dec. 19, 1990, whiib is a cooriouarion ot W|UZ,
`752,. ñled Aug. .t 9, 1988.
`The prescnt inventioo relares to novcl mevatonolac¡ones
`having a quinoline riog, proc-esscs for their production,
`pbarmaeutical coøposirions coutaioing ¡hem and ¡heii
`pbaroacculical uses particularly as auti-hyperlipidemic,
`bypolrpoprotcinemic nnd arti-ath€ro*lcrotic
`ageuüs, and .-
`iotermediates useftrl for their productioo and prúesscs for l0
`the productioo of such intcrmèdiates"
`Some fcrmcntatioo mctabolic products such as
`compactinc, C.S-51 4, Mcvino tin or seri i-syorhetic deriva-
`livcs eç fully syotbetic dcrivatives thercof àre knowu to bc
`inhibitors against HMG-CoA'reductase which is a ratc r-s
`liPiliqS cozyme for cbolesrerol biosynthesis. (A. Endo J.
`Med Chem., ?ß(4)4OL (1985))
`CS-514 aod Meviooliu have beeo clioically proved ro be
`poteotially useftrl anri-hyperlipoprotcinemic àgeoæ, and
`they are conside¡ed to be eEcctive f<rr curing or preveotiog 20
`disease.s of coronary artcry sclerosis or ãtheòsclerosis.
`(D(th {nt Syæp. Drugs Affect. Lipid Metab., 1986, p30,
`p3L, p66)
`However, with respcct to frrlly synthetic dcrivatives,
`P-articularly hetero aromatic derivatives of inhibiOrs against 25
`HMG-CoA rcctuctasc, limited informatioo È discloscd in rhe
`followiog literaturcs:
`wPI ACC NO. 84- 158675, 86-028274, 86498816,
`86-332U7Q, 87-t24519" 87 -nO987, 88-07781, 88-00&tó0,
`88{91798 and 88-112505
`The presenr invcotors bave lì¡uncl that mevalonolac(ooe
`derivatives having a quinoline riog, thc ærresponding diby-
`drory carboxylic acids aod s¡lts acd csters the¡eofhave hish
`iohibitory acdvities againsr cholesrerol biosynthesis whereio
`HMG-CoA reductasc acts as a rat6 limí¡i¡g eozyme. the 35
`Preseot inventiou
`has becn accomplishcd oo tbe busis of this
`discovery.
`The novel oevalooolactoue derivatives of the pfescot
`inveotioo aæ represented by the tb[owing forúula
`I:
`
`JO
`
`Q
`
`Rt
`
`R¡
`
`R¿
`
`Y-z
`
`(t)
`
`45
`
`N
`
`R5
`
`Rl
`whereia R1'R2, R3, Ro aucl Ró nre ia<Iependeatty hydrogen,
`Cr-o. alkyl, C_r. cycloalk¡rl, C,-, alkory, n-butory, i-t,utõxy,
`sec.-burox¡ RIREN- (whereio R7 aod Rg are indêpendeotly
`!¡jroge o or Cr_. alky t), trifl uoromerhyl, trifl.uoromethoxy,
`diffuoromethox¡ û,uoro. chloro, brom-o, pbeoyl, phenoxy,
`beoey.lo.ty, bydroxy, rrimetbylsilytoiy, âip-Ueoyt-i-
`lyp lsily lox¡ hydroxymetby I or
`-O(CI!¡rORrd 1 where in
`K.- rs hydrogen or Cr., alkyl, ancl t is l, 2 or 3); or wheo
`located at the ortbo posirioo to each other, Rr aod R:, or Re
`und R" togcthcr tbrm -{H-CH-CH:CH-;
`or whcn
`located ar the ortbo positioo ¡o each orher, Rr and R:
`together tbron -OC(RttXR'o)O-(wh'èrein Rt5 aod Rrd are
`independe_otly hydrogeo or C,-, alkyt); y as -Cft-,
`-CH--CH:CH-- or
`-CH¿CFI:-. -CH:CH-.
`a nd Z is -e-CFt¿-tVCf 12-CO2R t2,
`-CH:CH-{:l-l-;
`
`includes, for example, methyl, ethyl,
`n-butyl, i-butyl, sec-butyl, t-butyl,
`
`50 CO"M includes, tbr example,
`-CO¿NH. aod -CO"H.
`(tiary lower alkylamine such as
`(primary to te
`trimethylaoine).
`Cr-o alkyl for R5
`o-propyl, i-propyl,
`s5 o-peatyl and o-hexyl.
`Cr-o cycloalkyl tbr Rt iucludes, for exaople, cyclopropyl,
`cyclobutyl, cyclopeotyl
`aod cyclobexyl.
`C=., alkenyl tbr R5 includes, tbr example, vinyl aod
`i-propeoyl.
`60 - Pheoyt-((}1")-- for R5 iocludes, for example, bcnzyl,,
`B-pheoylethyl aod y-pheoylpropyl.
`Pùeoyl(CHr)"çH(CHr)- tbr R5 i¡cludes, for exaople,
`ct-phenylcthyt and cr-benzylerhyl.
`.Cr-, alkyl fr¡r Rt uocl R8 includcs. fcrr example, methyl,
`ethyl, n-p(opyl and i-propyl.
`Further, these compouodsmay have rt lÈast oûe or two
`asymmetric carbou atoos nnd oay have at least two to tbur
`
`ó5
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 17 of 61
`5,856,336
`34
`optictl isomcrs. The compcrun$ o! tfe formula t ioclude all
`dimethyt, 6,8dimethyl. 6,7dimethoxy, 6,Tdierhox¡ 6,7-
`of ttcse optical iso@e¡s aod ¡ll of the oixtures thercot'. clibromô'o. o.gdib.o;u. -
`. Amoog.compounds having carboxylic acid oroicti-es firll-
`Wheu Rt, ß' ¡nd Itó are oot hydrogeo, they together
`ing ouæide the de6oi¡ion ot' -co=Rrz of the carboxylic represeor 3,2-aimãtto"y-c-ïi¿räii,'5,g-dichloro.6-
`acid moictyof subsriruent Z.of the co-mpounds ofthc.praicnr s !r!roxy, 6,7f+rimerhoxy, 6,7,g-trimethyl, 6,7,g-trichloro,
`invention, lh<se which r¡ndcrgo physiological hydiotysis, - slRuoró¡,óáitr"m"ãi3*r,iàã-eji-auío.o.
`¿å;,:if¿f,,9:*ï"'YåîË8,"åXiiïYä#6îÍ: ,,frË::"-g'i'îi:";:::¡,5",ål,li,g,*J;tiS;
`",til:1"11?.^g:.¡rm¡1yds oi the preseàr inveotion. úu"iuoit R' úd ñi;; ;iÏyd.s"", tn"y toçtuer
`Now' pretèrred substitueots of the coopounds <¡f the ,^ rupresen¿ 3's'-di6cthyl or 3,-methyi-4'-ñuo..r.
`ru -As
`pryf o! iuvention will be described.
`more prefened .ix.mp¡es for hl, thË abooe-meotiooed
`fn tbe. following prefcrred, æorè preferrcd s¡ill Â.rrthcr pretbned "inmptoãi-iüå;iËn"äiiõoeo.
`Pertèrred aqd qost prefened cxamptcs, thc numerals for thc
`4S-pr"igfAixamples for y,
`-CHZ--CH"- aod @þ-
`positions of the substitueots indicìte the positions on the -cHtcg-may
`6e mentión"A. Ã" onoì" li"fäí"a
`gu$orine |ng.F9l example' tf .showo by
`1'.or 2l .. cxaoplestbcZ,úe.uou"ft"f".rJ.inrpr"stor|..yo"
`".g.
`indicatcs the position o[ thc s¡bstihrent on the pbeoyl t-s ocntibncd.
`substitutcd at the .l-position of.the quinoline ring (rhc èarboo Now, still t'urther prefeneclsubstituents of the compounds
`connected to the quincrline ring is designated as l). The of the present inveniion will be described. As examótes for
`meaoings of the-respective subs¡iruents arc rhe.same as the R¡. Rtaod Ró , wheo both R: aod Rd arc ¡i¿õgcå. R¡Ë
`above'oentiooed meaniags.
`hydrogeo, 6-methyf 6-erhyl, 6-triñuorooerhyl,6"-htd¿xi
`Preferrcd substitucûts fo-r R¡, R2 aad Ró arc hydrogcs, æ 6-methoxy, 6-chloro, 6-b.omo, O-ã-Uutyt aoã
`fluoro, chloro, brooo, C,-, alkyl, Cr-, allioxy, Õr-o 7-dimethylamino.
`cycloalkyl, dimethylamino, hydroxy, hyclroxymethyl, WUeo only Ró is hydrogcq Rr and Rz represent 6,8-
`by_droxycthyl, triü,uorooethyl, tcifluoromerhoxy, dichloro, 5,8dimethyl, 6,8idimethyl, 6,ZdimåUoxy, ó,7-
`difluoromethorf_p!9oory andbertyloxy.
`dietbox¡ 6,7-dibom-o,6,8-dibromó,'6,2-difluoro .,iá Oþ-
`-Further, when Ro is hydrogeo, it is preferred th¡t R¡ and zs difluoro.
`R" logether form methyleacdioxy.-
`As still further prefcrred examples for R3 and Ra, wheo R3
`.ds prctèncd examples for R3 and R{, when R{ is
`ishydrogeo,Raishydrogen,4'cùloroor4'-fluoro,orir.oA
`9l¿tug_.q' R' is hydrogeo, 3'-flu<¡ro, 3'-chloro, 3'-methyl, R{ together represeor 3'-methyl-4'-fluoro.
`4'-methyl, 4'-cbloro aod 4'-tuoro.
`Stitl ftrthei p'rctèned cxroples for Rt include othyl,
`- other ¡refegcd combinations of R3 aod R{ inclucle io o-prcpyl, Èpropyl aod cyctopropyl.
`for y include (E)--
`3'-me¡hyl-4'-chloro, 3',5'-dichloro, 3'5'-difluoro, 3',5'-
`,Stilt funher-pretèncd
`dimethyl ancl 3'-oethyl-4'-Èuoro.
`CH:CH-.
`"ximpìõs
`As still further pretbncd cxamples for Z, the above-
`_ keferred exunples for R5 iqcludc primruy ancl secvnclary
`Cr. alkyt and C3-6 cycloaþ|.
`æentiooed prcferred example for Z ouy be meotionecl.
`$gfcrryd cxamptes fcrr Y include -CH2-CH3- and 3s
`No% the most preferred suktinreots for the crmpouods
`of the preseot i¡¡vcorioo will be clescribed.
`-Ctl:CH-.
`P¡eferred examples foc Z iuclude
`As the most preferrect examples for Rt, R2 and Ro, whcn
`both R- and Ro are hydrogen, Rr is hydrogeo,6-aetbyl or
`6-cbloro.
`40 When only Ró is bydrogen, Rr and Rr togetbcr reprqs€n¡,
`tbr example, 6.7-dimethoxy.
`As the oosr pretèaed examplcs for R3 and R4, R3 is
`hydrogeo aad Ra is hydogen, 4'-chloro or 4'-Euoro.
`The øost preferred examples tbr Rs include i-propyl aad
`+s cyclopropyl. Tho most prefemd cxaople fur y oay be
`(ËF--CH-cH-.
`As the most prefened cxamples for Z, the above-
`meotioned preferred examples lor Z olty be mentiooed.
`Norv, pzu'ticularly prefenrd specific compounds of the
`50 presenl inventioo will be prcsented. The following com-
`pounds (a) ro (z) are shown in tbe form of carborylic acicls.
`Howover, the preseot ioveatioo inclucle oot only the coo-
`pouods in the tbrm of carborylic acids but a.lso the corre-
`spondiog lactones formcd by the coodensatioa of thc car-
`5t boxylic acids q¡ith hydroxy ar the s-posirioa, aod sodium
`salts and lowcr alkyl esters (such 0s merhyl, ethyl, i-propyt
`and n-pnrpyl esters) of the c.arboxylic ucids, whicb õao-óe
`
`-cr(oFDcrlCtt(oH)crtco2Rr '' _crr(orÐcFr"c(o)
`crtcolR'. and
`-cH(oH)cH2C(ORr3)2CH2CO1RÍ2.
`Now, more prcferrcd substitucnrs o[ the compounds of thc
`iovcotioo will be dcscribed.
`prÈs€ot
`^As more preferred examplcs for Rr, R2 aod Ró, wheo both
`R'and Ro are hyclrogcu, R¡ is hydrogeo, S-tuoro,6-8uoro,
`7-fluoro. 8-üuoro, 5-cbloro, 6-chloro, 7-chloro, 8<hlo¡o,
`5-bromo, 6-bromo, 7-bromo, 8-bromo, S-methyl, 6-methyl,
`7-methyl, 8-methyl, 5-merhox¡ 6-methoxy 7-øethoxy,
`8-metboxy, 5-trifluoromethyl, 6-rrifluorooethyl,
`7-tcifluoroocthyl, 8-triEuoromethyl, 6-trifluorooethoin
`6difluorooethox¡ 8-hydroryerhyl, 5-hydrox¡ 6-hydroxy,
`7-hydroxy, 8-hyclroxy, 6-cthyl, 6-o-buryl aod
`T<limerbylaodno.
`- Wþeo Ró is bydrogen, Rt and R¿ together represeot
`6+hloro-8-methyl, 6-brooo-7-methox¡ 6-oethyl-7+htoro,
`6-chloro-8-hydroxy, 5-mctbyl-2-hydroxy, 6-methoxy-7-
`chlorcr, 6-chloro-7-metho x¡ 6-hydroxy-7-ch lor<¡, 6-c hlõrtr-
`7-hydroxy, 6-chloro-8-bromo, 5-chloro-6-hydroxy,
`6-bromo{-chloro, 6-brooo-8-hydroxy, 5-methyl$<iloo,
`7-hyclroxy-8-chloro, 6-bromo-8-bydrox¡ 6-methoxy-7-
`methyl ti-cbft¡¡o€-hromo, 6-oethyl-8-brooo, 6,7difluãro,
`6.E-di8uoro, 6,7-merhytcoedioxy, 6,8-dichloro, 5,g-
`
`ô1)
`
`melhylo
`acicl
`6_s (d) (
`E)-3,5-d ihydro xy-7-[4'-(4"-
`rophcayl)-3'-
`( t "oethylethy l)-6',7'-dimerhoxy-t¡
`uioo tin-3'-yll-bep r-6-
`enoíc acid
`
`o
`
`o
`
`o
`
`(.)
`
`

`

`Case 1:14-cv-02647-PAC Document 2 Filed 04/14/14 Page 18 of 61
`
`5
`) (E)-3,5-díhydrox
`7 -14' -(4' - fl,uo r opb,c o y I)-2' -
`acid
`(f) (
`-3,5-dibydroxy- 7 -(4'-(4"-1.rceop
`
`-2'-
`
`5,956,336
`
`6
`+ootinued
`Rr
`
`R,
`
`5
`
`(g)
`
`acid
`(