eee
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`OSI PHARMACEUTICALS, INC., PFIZER
`INC., and GENENTECH,INC.,
`
`Plaintiffs/Counterclaim Defendants,
`
`Vv.
`
`
`
`C.A. Nos. 09-00185 and 00186
`(consolidated)
`
`TEVA PHARMACEUTICALSUSA,INC. and
`MYLAN PHARMACEUTICALSINC.,
`
`Defendants/Counterclaim Plaintiffs.
`
`DEFENDANT MYLAN’S OPENING POST-TRIAL BRIEF
`
`John C. Phillips, Jr. #110)
`Megan Haney(#5016)
`PHILLIPS, GOLDMAN & SPENCE,P.A.
`1200 North Broom Street
`Wilmington, Delaware 19806
`Tel: (302) 655-4200
`Fax:
`(302) 655-4210
`jcp@pgslaw.com
`mch@pgslaw.com
`
`James H. Wallace, Jr.
`Mark A. Pacella
`Matthew J. Dowd
`Adrienne Johnson
`WILEY REIN LLP
`1776 K Street NW
`Washington, D.C. 20006
`Tel: (202) 719-7000
`
`Attorneysfor Defendant Mylan
`Pharmaceuticals Inc.
`
`Date: July 7, 2011
`
`APOTEX EX. 1059-001
`
`
`
`APOTEX EX. 1059-001
`
`

`

`TABLE OF CONTENTS
`
`| oe
`
`Page
`
`B.
`
`C.
`
`NATURE AND STAGE OF THE PROCEEDINGS.....ccscccscseseetretenseeneeteesersnteeenensaenns 1
`SUMMARY OF THE ARGUMENT........ceccessessssseessesneseeeessenseeseesesseessensenneeseceesseeneeaengs 1
`STATEMENTOF FACTS.....cccscsccsssesseeseeeeeceeecsessscesssseessecaseeesseesacesseesnsesenssesesesnsesasenseenns 3
`A.
`The Patents-In-Suit .....cccccccccsessecesecsseersaecessesseesssesseeeseeeeeesenesneesisesseasersseeseeesenaeses 3
`1.
`The [065 Patent ........ccccccessccesecsssccssseseceeeensesecesseeetesseeesesesneseeeesranesnseosses 3
`2.
`The {221 Patent ......ccccccccssccssseceseesecsseesseesseseesserecnseeeseessnensaneesnessoeesearenees 4
`Epidermal Growth Factor Receptor (EGFR) Research In The 199058 ooo.eeeeeeeeee 6
`1.
`EGFR And EGFR Inhibitors.........cccsetesssssecssseessessessesensesseeeeeeeenanenesensenes 6
`2.
`Non-Small Cell Lung Cancer (NSCLC) AndIts Association With
`EGFR Overexpression..........:csscscssssssessseseeceseeeneesesenecaesetsrsesersesessenssseaenenes 6
`The Development Of Potent And Selective EGFR Inhibitors ............scseeeeeeees 7
`1.
`The Best Method To Make New EGFRInhibitors Was To Start
`With Known Inhibitors ..........cccecceeeecencenceeeceeeeseeeesenscessenaeeeseensaeeenaeeerensgs 8
`Zeneca’s ‘226 Application Identified 4-Anilinoquinazolines As
`Preferred EGFR Unhibitors...........ccceeeeeeeeeeseeeeeeeesseeeseeenseesseeeeneecraeeneaneees 9
`Zeneca’s ‘226 Application Had A Gap Not Covering Ethynyl............... 12
`a.
`An Ethynyl Group Is Closely Related To A Methyl Group........ 13
`b.
`The Ethynyl Gap In The Zeneca ‘226 Application.............100+ 14
`Zeneca Inventor Barker’s Abstracts Fill The Gap By Teaching
`“Small, Non-Polar” Groups At The 3’-Position........:::essceteereeereeseees 14
`a.
`Barker Twice Suggested That “Small, Non-Polar” Groups
`Are Preferred At The 3°-POSition.........cceccceeesesseeseeseeeseerteernneee 15
`
`2.
`
`3.
`
`4.
`
`b.
`
`An Ethynyl Group Is A Small, Non-Polar Group, As
`Defined In The Barker Abstracts ..........:.cccceseesseesseeserereresesnecenses 16
`
`c.
`
`The Barker Abstracts, Considered Together With Zeneca’s
`‘226 Application, Suggested Which 4-Anilinoquinazolines
`Were The Best EGFR Inhibitors Not Covered By The ‘226
`Application........cceesecesesesessesseeeneseeenseestererersnseensseneserenscaeaeseseneaees 16
`Pfizer Followed Zeneca’s Road Map..........cccccceseesceseenseesreseeessneeeseeeseeereesensenens 17
`1.
`Pfizer Used High Throughput Screening And High Speed
`Synthesis To Identify EGFR Inhibitors«2.0.2...:seceessessereseeeeeeenenenenteees 17
`Zeneca Scooped Pfizer No Less Than Three Times...........:ssesseseees 18
`
`2.
`
`D.
`
`1
`
`APOTEX EX. 1059-002
`
`IL.
`
`IIL.
`
`
`
`APOTEX EX. 1059-002
`
`

`

`
`
`3.
`
`4.
`
`E.
`
`Pfizer Tried To “Rebound” By Analyzing Zeneca’s ‘226
`Application And Identifying A Gap ........cececseseeeeeererernsseeeesnerssenenseenes 20
`Pfizer Made Erlotinib Just Months After Barker Suggested Small,
`Non-Polar Groups At The 3’-PositiOn........:ccsessesessereeeteeseseesenseseneneenes 21
`Soon After The Erlotinib Patent Application Was Filed, Pfizer And OSI
`Told The World About Using Erlotinib For Treating NSCLC... eens 21
`1.
`Pfizer’s ‘498 Patent Disclosed And Claimed The Use OfErlotinib
`For Lung Cancer, Including NSCLC... :esesseeeseeteeeesesserseetseeneenes 22
`In The 1998 Cold Spring Harbor Abstract, Pfizer And OSI
`Scientists Taught The Use Of Erlotinib For NSCLC........0eset 23
`OSI, Pfizer, and Others Reported Erlotinib’s Developmentfor
`NSCLC..eeeecceccescesceccssecsesssesceacesevsceseceneecesscsesecesesanesesseeseenrenseseeeaeesenarenanenes 24
`
`2.
`
`3.
`
`a.
`
`b.
`
`The 1997 AACR Abstracts (DTX 8) and Moyer Cancer
`Research Article (DTX 34)... .ececsecesseeseeseneneeneeenereeesnneeesereenaes 24
`The 1997 Klohs Article In Current Opinion In Oncology
`(DTX 389)...eeessssesessesssserseneseseseseseeceeeeessnenersvecatanecssensnessesenennenes 26
`The 1997 OSI Press Release (DTX 63) ......eeceesescseeeeseenteeeeeeee 26
`c.
`The OSI 10-K SEC Filing (DTX 427)......ceccecseeeseetseeteeeeeenenees 27
`d.
`The 1999 ASCO Abstracts (DTX 205A).......ccseeeseseeseerereeteeees 27
`e.
`By 1999, The Idea Of Using Erlotinib To Treat NSCLC Was Well
`Known To The Public.......ccccecceeceeeecerreeseeesneessesereeesasesseeeseeecaeersreseneesgs 28
`
`4.
`
`TV.
`
`ARGUMENT uu... ceccccecceccessceseceecseseseesaceesescesseseeessessesasenseseecsesesesseessensresensnsnssatenseneans 28
`A.
`The Legal Standard For Obviousness Under 35 U.S.C. § 103 .....eseseseeseeereee 29
`B.
`The Asserted Claims Of The ‘065 Patent Are ODVIOUS..........:.:::cceceseeeeeereteereees 30
`1.
`A Medicinal Chemist Would Have Used A Small, Non-Polar
`Group, Such As Ethynyl, To Modify The Closest Prior Art
`Compound, Thus Making Erlotimib «0.0.0.0... seseseseessseseseseessesesesesenenenennens 31
`a.
`The Obvious Starting Point Was The 4-Anilinoquinazolines
`Of Zeneca’s £226 Application...........cccccseeeeseereeseeeetsernerreeneeens 32
`Zeneca’s ‘226 Application Suggested Preferred Groups For
`EGFR Inhibitors........ccccccceeceeeeeeesereceeneesssesesesseseeseesseeneeeeasereeaes 34
`
`b.
`
`c.
`
`Barker Provides an Express Motivation To Use A Small,
`Non-Polar Group, Such As Ethynyl, At The 3’-Position............. 34
`The Prior Art Confirms The Use Of Ethynyl GroupsIn
`Pharmaceutical Compounds...........cceccsessessesseseneeecterserseteeeeeasees 35
`All Asserted Claims Of The ‘065 Patent Are ODVIOUS..........:ceeeeeerees 37
`
`d.
`
`2.
`
`ii
`
`APOTEX EX.1059-003
`
`
`
`APOTEX EX. 1059-003
`
`

`

`3.
`
`Plaintiffs’ Asserted Secondary Considerations Do Not Overcome
`The Prima Facie Obviousness Of The Claims Of The ‘065 Patent......... 37
`
`a.
`
`b.
`
`C.
`
`Plaintiffs Offered No Relevant Evidence Of Unexpected
`Results And Ignored The Closest Prior Art Compound—
`Example 51 Of The Zeneca ‘226 Application ..........:ssseceesee 38
`To Claim Alleged Unexpected Results, Plaintiffs
`Erroneously Rely On The Testimony Of A Pancreatic
`Oncologist, But A Person Of Ordinary Skill In The Art
`Pertinent To The ‘065 Patent Is A Medicinal Chemist................ 40
`
`Plaintiffs Have Not Proven That Others Tried But Failed
`To Make Erlotinib........cc.cccccsecccecseceecerseseeeseesseenenseesseeneeseeeesesenenses 42
`
`d.
`
`Weak AndIrrelevant Evidence Of Commercial SuccessIs
`Insufficient To Rebut Erlotinib’s Obviousness...........csceseeere 43
`Erlotinib Has Not Satisfied A Long-Felt Need............ cece: 46
`e.
`No Evidence Of Skepticism Of Others.........cccessseeseseereeseeees 47
`f.
`Claim 53 Of The ‘221 Patent Is Anticipated... ccceeseeeeeeeeeeeeeneeneetneeereenseees 48
`1.
`Anticipation Occurs When A Prior Art Reference Discloses The
`Claimed Inventiion.an.....ccccccccccseceseecseeeereessessatesesecnseenssessesseesenecenseesssueregs 48
`
`C.
`
`2.
`
`3.
`
`4.
`
`The ‘498 Patent Discloses Each And Every Limitation Of Claim
`SB icceccceccesccescececessccescesscsecsecensceceescenserseeeseeessessecsseeeesaenscsaeecqesnereeeseneeearas 49
`The 1998 Cold Spring Harbor Abstract Also Discloses Each And
`Every Limitation Of Claim 53 And Renders The Claim Invalid............. 52
`Instead of Disputing WhatIs In the Prior Art, Plaintiffs’ Experts
`Chose Not To Believe What Was In The Prior Art ............cceseeeeeteeereees 52
`Claim 53 Of The ‘221 Patent Is ODVIOUS............::ceeceeseeseeesesseereeeneeeteseeseeeeeetes 54
`1.
`All Elements Of Claim 53 Were Disclosed In Various Prior Art
`References .......ccccecscecessccessscesescecseneesssnsecesesersaesessseeenssersneeesscesrssonseeserenea 54
`By 1999, A Person Of Ordinary Skill In The Art Would Have
`Reasonably Expected Erlotinib To Be Effective In Treating
`NSCLC uo.cececcescesseesscecccesccaceesecscesseeseeesesnessscecsseesssseeeeseeaeeeeneetsersnenssaegs 56
`Plaintiffs’ Asserted Secondary Factors Cannot Overcome The
`Obviousness Of Claim 53 ........cccccccccseeeessseeeereesrersssenesesseesseeeteeenesesennenses 58
`CONCLUSION......ccccceccesssesceccesceesesseeseeceeeeceeeessecseessceseecsesessesesesesneenseeeesnnentesnoeraeeeneeneees 60
`
`D.
`
`2.
`
`3.
`
`iii
`
`APOTEX EX.1059-004
`
`
`
`V.
`
`APOTEX EX. 1059-004
`
`

`

`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`
`Abbott Labs. v. Andrx Pharms., Inc.,
`452 F.3d 1331 (Fed. Cir. 2006)... cececcccccesserseeeeseeessecneeesersneseessesseeseseeseseteesreessesesessesasens39
`
`Altana Pharma AG v. Teva Pharms. USA, Inc.,
`566 F.3d 999, 1007 (Fed. Cir. 2009)... eeesccseccseessessseeseseeseesesseeseneesseessesseaesenseesasentenneraee®31
`
`Aventis Pharma Deutschland GmbH v. Lupin, Ltd.,
`No.No.2:05-CV-421, 2006 WL 2008962 (E.D. Va. July 17, 2006)...ee eeeeseeeeeneee46, 60
`
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir, 1991)... eeccscecsseeeeseceesecscnsceeeseesecsevsessessceesesssersersseeesessseseeasseesaeseaes39
`
`Inre De Blauwe,
`736 F.2d 699 (Fed. Cir. 1984)... cc cececesessessesceeesesseesecssessesseesecesssseseseessseaseoesseeneeseeeeeeeseeseaeos39
`
`In re Dillon,
`919 F.2d 688 (Fed. Cir. 1990) (en banc)...ee eeeeesseesceseeeeeeseeseraceenessesenessessseseseeseeseanensenensees31
`
`DiscoVision Assocs. v. Disc. Mfg., Inc.,
`25 F. Supp. 2d 301 (D. Del. 1998)... ceesssessssesesscsseseesessneesessnsesenssenecseneesesesenseseesereneerees52
`
`In re Donohue,
`766 F.2d 531 (Fed. Cir. 1985)... eeeeeessseeseeceeseseeesseresessessesesscsesseesctenseesseneeaeesenesseenseneens49, 52
`
`Inre Dow Chem. Co.,
`837 F.2d 469 (Fed. Cir. 1988).........ceccscsessseeescsseesseeserseesecseesessaseeseesseeeseneeeseseneessesenseseesseeeseneens47
`
`Inre Eli Lilly & Co.,
`902 F.2d 943 (Fed. Cir. 1990)... ceccesescescesecsceceeeseessessesenssesasessssenessrssesseeneenesseenesssesaseeseeees42
`
`Eli Lilly & Co. v. Zenith Goldline Pharms., Inc.,
`471 F.3d 1369 (Fed. Cir. 2006)... :cccecesceseeseeeceeseeesescesesesessessersnsseeeecsssessessrenesneeeensaeaseasenees50
`
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997)... cess seeecsseeeeseesseeessesesscssesseenessesserseseseseeseesesssessensenses38, 58
`
`Geo M. Martin Co. v. Alliance Mach. Sys. Int’] LIC,
`618 F.3d 1294 (Fed. Cir. 2010)... ccc ccceesesssesceseteceseeseeseeeeesseessessesessecseesesssesseseessseeneeeaeensnaees48
`
`Inre Gleave,
`560 F.3d 1331 (Fed. Cir. 2009)... cscsceccsceeccecenerseceseeceeessssessessseuseeenssesaeseessaeseesseeateneses49, 53
`
`iv
`
`APOTEX EX. 1059-005
`
`
`
`APOTEX EX. 1059-005
`
`

`

`Inre GPAC, Inc.,
`57 F.3d 1573 (Fed. Cir, 1995)... ecccseeessssseceseseesesenseessenseneeserseneseesensesneeeeenessseeseseeneages38, 58
`
`Grahamv. John Deere Co.,
`383 U.S. 1 (1966)... eeeecesseeeeesesesesesesssensscessesenecsesesesensneaeeeneresseneenarsesesesesevecssnenteesseesanaes29, 42
`
`Inre Hafner,
`A10 F.2d 1403 (C.C.P.A. 1969) o.oceecccececcssssssesneeseseneseeensnenesseseeseeeeracsenssseesesssensaesecasseseaenesasaeas49
`
`In re Huang,
`100 F.3d 135 (Fed. Cir. 1996)... essssssessceseeensssseceeesseresesenseerseaeeeneseessassesssstesessnsesenesesecsenens44
`
`Kao Corp. v. Unilever U.S., Inc.,
`441 F.3d 963 (Fed. Cir. 2006)... ccessccssssseeseesseresenssenesesseseneneeenessenesenenenacensesssesesessesenensenegs38
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007)....cccssesecesececesecesesessssesescsescsssseasscsanenanenenecsescasseseseacsesenerevscaesesssesesecseesateaees29
`
`Leapfrog Enters., Inc. v. Fisher-Price, Inc.,
`485 F.3d 1157 (Fed. Cir. 2007)... ccssessesssessecsesensesesecsesenensesceerensenecacserscsneesensesssessseesensenans38
`
`McNeil-PPC, Inc. v. L. Perrigo Co.,
`337 F.3d 1362 (Fed. Cir. 2003)... csssecssssesssseeesenessesesenseeeseesteneeserersenecarsessessesesssssesesenesenens29
`
`Medichem, S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006)... seccsseseessescsesseseneeseseseesenseereesceesseserecseseesersensnesesersenseeaes29
`
`Merck & Co. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005)... ceseessssseseessesesessseessesencseseensesceeserenenesesecserenenersnesssensnenens45
`
`Inre Merck & Co.,
`800 F.2d 1091 (Fed. Cir. 1986)... ccsesesssecessscsssessseesseseteneesensseesenesseeecersenerseserecsassneeseracanees57
`
`Microsoft Corp. v. i4i Ltd. P’ship,
`131 S. Ct. 2238 (2011) ..ececceeseceseseeseseseesceeesesesssscsessesseseseseeeeseseneeeeseeacsevecsenenssssnsesenensenasesaseess29
`
`Novo Nordisk Pharms., Inc. v. Bio-Tech. Gen. Corp.,
`424 F.3d 1347 (Fed. Cir. 2005)... cccecessessssssssesesseeseesseseneeseeescentenassnerseseesesesenensssessseesesenenes49
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir, 2008)... cccscesscssessessesessnessenensessneeeeeneseeeeersenenseaseeessaseevensenenesenenes29
`
`Inre Paulsen,
`30 F.3d 1475 (Fed. Cir, 1994)... cecsccscsesceesessseeseeneneeeesseeseeresaenenssseresaepenesaseeserees38, 43, 58
`
`Inre Payne,
`606 F.2d 303 (C.C.P.A. 1979) o.eeecesecsecsecssesseeesseeeneaeneesenseeeseneeerseseeserseeesssesesesseeseenneeneneens40
`
`Vv
`
`APOTEX EX. 1059-006
`
`
`
`APOTEX EX. 1059-006
`
`

`

`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005)... cee eeesesceseseeseescssssssessssssesssecseseessssesessnseeenesseneenees48, 53, 54
`
`Inre Petering,
`301 F.2d 676 (C.C.P.A. 1962) wo. eeecescsesecscecesessseesessesnssasseneeeaesesseseeeessesesesseanenenseneasensee®50, 51
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007)... cceeesecssessesseseeseesecseaseseesssesessesseseensesessesessseseeeate29, 38, 39
`
`Procter & Gamble Co. v. Teva Pharms. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009)... eceeceesseseesesssseseeseseenessecaessesecseeseeseeeenesseneesenersetereeseneceteess40
`
`Purdue Pharma Prods. L.P. v. Par Pharm., Inc.,
`377 F. App’x 978 (Fed. Cir, 2010) ..cccccceccsesseesseseseensnsseerenenenenensseeenenseessssenssesesseesesseseneneses43
`
`Purdue Pharma Prods. L.P. v. Par Pharm., Inc.,
`642 F. Supp. 2d 329 (D. Del. 2009)... cecsesceesecsseeeseenecseeseseeeeseneeeeetesecseeseeseesevaessnensessenens29
`
`Rasmusson v. SmithKline Beecham Corp.,
`413 F.3d 1318 (Fed. Cir. 2005)... cececesesecsessesseesscssssesesseseesenneseseessesenessenessesersesseeeaenessevans49
`
`Richardson-Vicks v. Upjohn Co.,
`No. 93-556-SLR, 1996 WL 31209 (D. Del. 1996) 0... eececsesecssesseeeseessessesseeneesseeeseeneeeres44
`
`Ruiz v. A.B. Chance Co.,
`357 F.3d 1270 (Fed.‘Cir. 2004)....cceccsccsescsseecesceceeteersceseeacseescnseeesessessseessscseseeeeseeseeeeneestees47, 59
`
`Inre Ruschig,
`343 F.2d 965 (C.C.P.A. 1965)..eeecccsseeseseescensesesseesecsesssacssseeneneeseneeseneeseseasessassesenesnensensaseesaeses 50
`
`Ryko Mfg. Co. v. Nu-Star, Inc.,
`950 F.2d 714 (Fed. Cir, 1991)... ceesessssesesessesssceseecseneesseesseseeeesesesseseesenenseseaenenseneseeaseenesenees38
`
`Sanofi-Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008)... eescescssesesseecsssessesseesaseceseeeseesensenessenesseneeaeeneaseseneesenassesgs 31
`
`Santarus, Inc. vy. Par Pharm., Inc.,
`720 F. Supp. 2d 427 (D. Del. 2010). 0... eee eececseessesseensteneesesereneneesessaeenenerenseesassceenenenereneneeeees47
`
`In re Schauman,
`572 F.2d 312 (C.C.P.A. 1978) oe eeeeecsessescssesesseseeseeesseseesesecsecsecssncensesessenensesenseensetseserseaees50, 51
`
`Schering Corp. v. Geneva Pharms., Inc.,
`339 F.3d 1373 (Fed. Cir. 2003)........ccceccscscsceessssessescesesresenecsaceacseesensesensenessesensseeesesaeneeseneenenes49
`
`Schering Corp. v. Precision-CosmetCo.,
`614 F. Supp. 1368 (D. Del. 1985)... ee eeeccescseeeeteneceesenesenenseseseseensnerseaneeasneaeseneneneterseeees50
`
`vi
`
`APOTEX EX. 1059-007
`
`
`
`APOTEX EX. 1059-007
`
`

`

`Scripps Clinic & Research Found. v. Genentech, Inc.,
`927 F.2d 1565 (Fed. Cir. 1991)... ceeeecesessesessssesessseeessscseseesssessssensesssnsseneseesensneesensenseneaesecetats48
`
`Senju Pharm. Co. v. Apotex, Inc,
`717 F. Supp. 2d 404 (D. Del. 2010)... eeeceeseseneeessesesenenneseseneseeneesenssensseseseesesensnneneaeaees45
`
`In re Soni,
`54 F.3d 746 (Fed. Cir, 1995)... eeesecsesseessessscessssessecseseeeessescsesessesensessseaceseeeessssessseesseneeesnens40
`
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983)... cesessssssessecssrsesseseesrssesssesseecsesssseeeeesenensensaresensensessneeeees42,59
`
`Symbol Techs., Inc. v. Opticon, Inc.,
`935 F.2d 1569 (Fed. Cir. 1991)... cesesesesessesesseecsessescsssesseessesesseseseesseeseeeessnseaseeseseeneseneees42
`
`Inre Wright,
`569 F.2d 1124 (C.C.P.A. 1977)..eeeecsssessessssescsseseseseesesusensescesenssecseneeseseeesssessesenenseaseneeseseenseneees39
`
`STATUTES
`
`35 UVS.C. § 102. ccecsccssecceeceesceceeeseseeecscsecersesscsvseesessaesesesesseseceesenecaeseneesenasecasseseesenenensenseneeasas48, 60
`
`35 US.C. § 103. eceesceceessesesessesesessesesessescsceecscsseseassesassescsesesaenseaenenessenenecseseensasseares29, 30, 38, 60
`
`35 ULS.C. § 252. ccecccccscscescecceeseeseserescsesssecsesssessessvecsesecsseesenessesensesenesesseneneesseeeaenecseasseresserseasasonsierss4
`
`OTHER AUTHORITIES
`
`U.S. Patent & Trademark Office, Manual of Patent Examining Procedure (8th ed., rev.
`July 2010)... .cececceceececeeceecsesceeescseesesessescsesececsesscsssasesssesesensseseneesenessesseseaseetassesseasasenesessegessoaegeas 53
`
`U.S. Patent No. 5,747,498.......cccccsscccssccsseesseessrecsseessnecseecesessnssesssesscesssesesseessecssessnaesseseseeerenees passim
`
`US. Patent No. 6,900,221... cceccccsccsssceesseeessceeesscesessesessseseseeesesesessseerereserenseessseeesseeeeneeeenaes passim
`
`U.S. Reissued Patent No. 41,065.00... ce eeeseeseesesseessesseesseseressesseessseeesensenseenseenseeseeseeseeteaeees passim
`
`vii
`
`APOTEX EX. 1059-008
`
`
`
`APOTEX EX. 1059-008
`
`

`

`4-AQ:4-anilinoquinazoline.
`
`GLOSSARY
`
`acetylene: an ethynyl group. See, e.g., D.I. 227, 735:25-736:1 (Jorgensen).
`
`alkyl: a hydrocarbon with a carbon-carbon single bond (C—C). See, e.g., D.I. 225, 308:4-
`10 (Heathcock).
`
`alkenyl: a hydrocarbon with a carbon-carbon double bond (C=C). See, e.g., D.I. 225,
`308:11-14 (Heathcock).
`
`alkynyl: a hydrocarbon with a carbon-carbontriple bond (C=C). See, e.g., D.[. 225,
`308:15-16 (Heathcock).
`
`CP-358,774: erlotinib. See, e.g., D.I. 226, 517:2-4 (Arnold).
`
`
`EGFR:epidermal growth factor receptor.
`
`erlotinib: also known as CP-358,774. See, e.g., D.I. 226, 517:2-4 (Arnold).
`
`meta position: 3’-position on the aniline ring. See, e.g., D.I. 225, 316:25-317:3
`(Heathcock).
`
`NSCLC: non-small cell lung cancer.
`
`TKI: tyrosine kinase inhibitor.
`
`SCLC: small cell lung cancer.
`
`
`
`Vill
`
`APOTEX EX. 1059-009
`
`APOTEX EX. 1059-009
`
`

`

`I.
`
`NATURE AND STAGE OF THE PROCEEDINGS
`
`In this Hatch-Waxman case, Mylan Pharmaceuticals
`
`Inc.
`
`(“Mylan”)
`
`and Teva
`
`Pharmaceuticals USA, Inc. (“Teva”) filed Abbreviated New Drug Applications (“ANDAs”),
`
`seeking approval to market a generic form of the Tarceva® product, which is approved for
`
`treating certain indications of non-small cell lung cancer (“NSCLC”) and pancreatic cancer. On
`
`March 19, 2009, OSI Pharmaceuticals, Inc., Pfizer Inc., and Genentech, Inc. (collectively,
`
`“Plaintiffs”) sued Mylan and Teva for patent infringement. At issue is the validity of U.S.
`
`Reissued Patent No. 41,065 (“the ‘065 patent”) and U.S. Patent No. 6,900,221 (“the ‘221
`
`patent”). Plaintiffs’ infringementaction triggered a thirty-month stay for Mylan and Teva, both
`
`first-ANDAfilers, which expires on or about May 18, 2012.” The Court held a 5-day benchtrial
`
`from March 14 to 18, 2011.
`
`Ih.
`
`SUMMARY OF THE ARGUMENT
`
`This case presents a straightforward invalidity analysis with respect to the patents-in-suit.
`
`The Court need only consider a limited numberof plain and undisputed facts to find the patents
`
`invalid. The ‘065 patentis invalid because:
`
`e Rival pharmaceutical company Zeneca published a patent application disclosing
`4-anilinoquinazoline (“4-AQ”) EGFRinhibitor compounds;
`
`subset
`specific
`application claimed and identified a
`e The Zeneca patent
`of preferred 4-AQ EGFR inhibitors, most of which had the small, non-polar
`methyl] groupat the 3’-position;
`
`for
`e The Zeneca patent application had a gap in its coverage because,
`the 3’-position,it did not claim the ethynyl group—asibling of the methyl group;
`
`
`
`The ‘065 patentis a reissue of U.S. Patent No. 5,747,498 (“the ‘498 patent”), filed May
`}
`5, 1998. The ‘065 patent claimspriority to June 6, 1995. The non-provisional ‘221 patent
`application wasfiled on November9, 2000.
`2
`Tevasettled with Plaintiffs shortly beforetrial, and a stipulated consent order of dismissal
`wasentered on March 15, 2011. (D.I. 223.)
`
`]
`
`APOTEX EX. 1059-010
`
`APOTEX EX. 1059-010
`
`

`

`inventor Barker
`application published,the
`patent
`Zeneca
`his
`e After
`disclosed through separately published Abstracts
`that 4-AQ EGFR inhibitor
`compounds
`could beimproved byusing small, non-polar
`groups at
`the
`3’-position; and
`
`e Using the small, non-polar ethynyl group, as suggested by Barker, to make one
`small change to the specific subset of preferred 4-AQs, including the Example 51
`compound, of the Zeneca application yields a small set of obvious and easily
`made compounds, includingerlotinib.
`
`It is undisputed that Pfizer was aware of these facts prior to the claimed invention.
`
`Indeed, Pfizer had been scooped repeatedly by Zenecain its race to find EGFR inhibitors. When
`
`Pfizer compared the compounds claimed in the Zeneca patent application with the compounds
`
`disclosed by the inventor of the Zeneca application in his later publications, Pfizer recognized
`
`that some of the compounds taught by the inventor in his published presentations were not
`
`covered by his patent application. Recognizing an opportunity, Pfizer moved to fill the clear
`
`“patent gap” left by Zeneca and filed its own patent application covering erlotinib that matured
`
`into the ‘498 patent, which was subsequently reissued as the ‘065 patent. Pfizer’s simple
`
`combination of two sources of prior art to claim what was taught but not claimed by Zenecais
`
`not invention. Accordingly, the Court should find the asserted claims of the ‘065 patent invalid
`
`as obvious.
`
`The invalidity of claim 53 of the ‘221 patent is equally clear from Pfizer’s and OSI’s own
`
`publications:
`
`e
`
`Pfizer’s prior art ‘498 patent described the claimed invention, expressly teaching the
`use of a therapeutically effective amount of erlotinib with a pharmaceutically
`acceptable carrier to treat lung cancer; and
`
`e After the ‘498 application was filed, Pfizer and OSI scientists described the use of
`erlotinib for treating NSCLC in a publication (the 1998 Cold Spring Harbor
`Abstract), expressly disclosing every element of claim 53 except the carrier — which,
`in and ofitself, is an inherent and obvious feature of orally administered drugs.
`
`2
`
`APOTEX EX. 1059-011
`
`
`
`APOTEX EX. 1059-011
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`

`

`None of Plaintiffs’ witnesses disputed that all the elements of the claimed method of
`
`treating NSCLC by using erlotinib were disclosed in these anticipatory references.
`
`Instead, they
`
`attempted to sidestep the overwhelming evidence by suggesting that a person of ordinary skill in
`
`the art would not have believed what the prior art taught. That argument, however,is legally
`
`irrelevant to a defense of anticipation. And, even if a belief in the therapeutic efficacy of the
`claimed method were relevant, the clear and convincing evidence demonstrates that, by 1999, the
`
`prior art disclosed a method of treating NSCLC by administering a therapeutically effective
`
`amount oferlotinib and a carrier, precisely what claim 53 sets forth. Moreover, there is no doubt
`
`that by 1999 all of the elements of the claimed method were in the prior art. Numerous
`
`publications, including publications made by OSI and Pfizer themselves, specifically pointed out
`
`erlotinib’s usefulness in treating EGFR-related cancers such as NSCLC. Accordingly, the Court
`
`should find claim 53 of the ‘221 patent invalid as anticipated and/or obvious.
`
`TW.
`
`STATEMENT OF FACTS
`
`A.
`
`The Patents-In-Suit
`
`This case involves two patents: the ‘065 patent and the ‘221 patent. OSI and Pfizer are
`
`ownersof the ‘065 patent; and OSIis the ownerof the ‘221 patent. Genentech is a co-exclusive
`
`licensee of both the ‘065 and ‘221 patents. (D.I. 212-1 at pp. 1-2.)
`
`1.
`
`The ‘065 Patent
`
`The
`
`‘065
`
`patent
`
`covers
`
`4-anilinoquinazolines
`
`that
`
`are
`
`useful
`
`for
`
`treating
`
`hyperproliferative diseases, such as cancer. Plaintiffs have alleged infringementof claims 1, 2,
`
`covererlotinib. Claims 34 and 35 further specify that erlotinib is in the form of, respectively, a
`
`pharmaceutically acceptablesalt or a hydrochloridesalt.
`
`3
`
`APOTEX EX. 1059-012
`
`4, 8, 34, and 35. Claim8is specific for the compounderlotinib. Claims 1, 2, and 4 generically
`
`
`
`APOTEX EX. 1059-012
`
`

`

`The ‘065 patent teaches that the disclosed compounds are EGFR inhibitors. The ‘065
`
`patent does not disclose any in vivo data for the claimed compounds, nordoesthe patent disclose
`
`any pharmacokinetic or pharmacodynamic data for the disclosed compounds.
`
`(D.I. 225, 286:19-
`
`287:2 (Heathcock); D.I. 226, 546:8-14 (Arnold).) The only data disclosed for the claimed
`
`compounds is the following single sentence: “Although the inhibitory properties of the
`
`compounds of Formula I vary with structural change as expected, the activity generally exhibited
`
`by these agents, determined in the manner described above, is in the range of ICs9=0.0001-30
`
`uM.” (JTX 1, col.14, 11.66 to col.15, 1.2.) The ‘065 patent identifies erlotinib as one of the
`
`specifically preferred compounds.
`
`(JTX 1, col.4, 1.15.) The ‘065 patent also specifically claims
`
`erlotinib. (JTX 1, Claim 8.)
`
`The ‘065 patent is a reissue of the ‘498 patent.
`
`(JTX 3.) The ‘498 patent issued on May
`
`5, 1998. Ud) The specification of the ‘065 patent is essentially identical to that of the ‘498
`patent; the claims differ, however. For example, the ‘498 patent included claims 14, 23, and 29,
`
`directed to using the compoundsfor treating certain cancers, including lung cancer.
`
`(JTX 3,
`
`col.41, 1161-63; col.44, I1.3-7; col.44 11.23-27.) Plaintiffs’ expert Dr. Sandler admitted that one
`
`skilled in the art at the time of the ‘065 patent would have understood that lung cancer included
`
`NSCLC. (D.L 227, 886:17-21.)
`
`The ‘498 patent was surrendered, as a matter of law, when the ‘065 reissue patent issued.
`
`See 35 U.S.C. § 252. Thus, from May 1998 until December 2009, the use of erlotinib to treat
`
`lung cancer wasprotectedbyat least claims 14, 23, and 29 of the ‘498 patent.
`
`2.
`
`The ‘221 Patent
`
`In pertinent part, the ‘221 patent is directed to the use of erlotinib to treat several
`
`conditions, including non-small cell lung cancer (“NSCLC”). The ‘221 patent issued on May
`
`4
`
`APOTEX EX. 1059-013
`
`
`
`APOTEX EX. 1059-013
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`

`

`31, 2005.
`
`(JTX 2.) The ‘221 patent was filed on November 9, 2000 and claimspriority to three
`
`provisional applications: U.S. Provisional Application No. 60/206,420, filed May 23, 2000, U.S.
`
`Provisional Application No. 60/193,191, filed March 30, 2000, and U.S. Provisional Application
`
`No. 60/164,907, filed November 11, 1999. Ud.) Plaintiffs offered no evidence that any of these
`
`provisional applications provide support for the asserted claim.
`
`Plaintiffs assert only claim 53 of the ‘221 patent. Claim 53 recites: “The method of claim
`
`44 for the treatment of non-small cell lung cancer (NSCLC).
`
`Incorporating the relevant
`
`limitations of claim 44, the method of claim 53 is directed to:
`
`lung
`[a] method for the treatment of NSCLC (non small cell
`cancer) in a mammal comprising administering to said mammal a
`therapeutically effective amount of a pharmaceutical composition
`comprised of at
`least one of N-(3-ethynylphenyl)-6,7-bis(2-
`methoxyethoxy)-4-quinazolinamine
`[i.e.,
`erlotinib],
`or
`pharmaceutically acceptable salts thereof in anhydrous or hydrate
`forms, and a carrier.
`
`The ‘221 patent defines a broad range of erlotinib dosages as being therapeutically
`
`effective.
`
`(JTX 2, col.24, Il.19-32.) The dosage range defined as being therapeutically effective
`
`is the same range set forth in the ‘498 patent.
`
`(See D.I. 224 at 121:3-22 (Ratain‘); compare JTX
`
`2, col.24, 11.19-32 with JTX 3 at col.15, 11.55-62.) Similarly, the ‘221 patent’s definition of
`
`Claim 44 reads: “A method for the treatment of NSCLC (non small cell lung cancer),
`3
`pediatric malignancies, cervical and other tumors caused or promoted by human papilloma virus
`(HPV), Barrett's esophagus (pre-malignant syndrome), or neoplastic cutaneous diseases in a
`mammal comprising administering to said mammala therapeutically effective amount of a
`pharmaceutical composition comprised ofat least one of N-(3-ethynylphenyl)-6,7-bis(2-
`methoxyethoxy)-4-quinazolinamine, or pharmaceutically acceptable salts thereof in anhydrous or
`hydrate forms, and a carrier.” (JTX 2, col.35, I.26-36.)
`4
`Dr. Mark Ratain testified as an expert on behalf of Mylan. Dr. Ratain has been a medical
`oncologist and faculty memberat the University of Chicago since 1983, serves as director of the
`University’s Advanced Solid TumorClinic, and has considerable experience in designing and
`conducting clinical trials for cancer drugs. (D.I. 224, 53:2-59:11; DTX 732.)
`
`5
`
`APOTEX EX. 1059-014
`
`APOTEX EX. 1059-014
`
`

`

`“carrier” is the same definition that was set forth in the ‘498 patent.
`
`(D.I. 224, 121:23-122:11
`
`(Ratain); JTX 2, col.23, 11.33-36; JTX 3, col.16, Il.21-24.)
`
`B.
`
`Epidermal Growth Factor Receptor (EGFR) Research In The 1990s
`
`1.
`
`EGFR And EGER Inhibitors
`
`Epidermal growth factor receptor (EGFR) is a transmembrane receptor found in normal
`
`human cells and various cancer cells.
`
`In normal cells, the natural ligand, epidermal growth
`
`factor binds to the EGFR to cause a numberof downstream effects, including cell growth.
`
`(D.I.
`
`226, 466:14-467:2 (Arnold).) As of 1990, it was understood that the EGFR pathway was “an
`important pathway in the development of cancer.” (D.I. 227, 832:19-23 (Sandler).)
`
`John Mendelsohn conducted someof the early leading EGFR research.
`
`(D.I. 224, 72:2-
`
`73:13 (Ratain).) Mendelsohn’s work in the 1980s established the various biological roles of
`
`EGFR (id., 71:6-73:13 (Ratain)), and provided proof that blocking the biological activity of
`
`EGFR would inhibit the growth of certain cancercells (id., 73:1-13 (Ratain)).
`
`2.
`
`Non-Small Cell Lung Cancer (NSCLC) AndIts Association With
`EGFR Overexpression
`
`Lung cancer consists of two general types: NSCLC and small-cell lung cancer (“SCLC”).
`
`Since at least 1990, it has been known that NSCLC makes up the substantial majority of lung
`
`cancer, with 80% to 85% ofall lung cancer being NSCLC.” (See DTX 365at p. 365 (“Roughly
`
`80% of all lung cancers are classified as non-small-cell lung cancer (NSCLC)... .””); D.I. 227,
`
`806:18-24 (Sandler).)
`
`NSCLChasalso long been recognized as being quite different from SCLC. (DTX 433 at
`
`p. 310, 329-331; DI. 224, 106:3-107:8; 108:6-15 (Ratain).) For example, it is well established
`
`NSCLCis generally divided into three types: adenocarcinoma, squamouscell carcinoma,
`°
`and large cell carcinoma. (D.I. 224, 70:12-19 (Ratain)).
`
`6
`
`APOTEX EX. 1059-015
`
`APOTEX EX. 1059-015
`
`

`

`that EGFR overexpression wasassociated with NSCLC,and not SCLC.
`
`(See DTX 365at p. 368
`
`(“Compared to normal lung epithelium, NSCLC has been shown to express elevated levels of
`
`epidermal growth factor (EGF)receptor... .”); DTX 3 at p. 265 (summary); DTX 2 at 91; D.I.
`
`224, 78:23-79:25, 80:23-81:20 (Ratain).) According to Mendelsohn’s publications, as early as
`
`1981, researchers “first reported that EGF receptors were found on nonsmall-cell lung cancer
`
`(NSCLC) cell lines, and were absent on small-cell lines.” (DTX 414 at p. 365; D.I. 224, 74:20-
`
`77:8, 106:3-107:8 (Ratain).)
`
`In another publication from 1998, Mendelsohn explained that
`
`numerous studies had shown that the EGFR pathway “is overexpressed in many malignancies of
`
`epithelial origin, including most NSCLC tumors, and somestudies suggest that overexpression
`
`tends to be associated with tumors that are more aggressive and have a worse prognosis, thus
`
`indicating this pathway’s potential role in contributing to the sustained growth of these tumors.”
`
`(DTX 433 at p. 310; see also generally DTX 443.)
`
`Because EGFR overexpression is associated with NSCLC,researchers knew by 1997 of
`
`the “substantial literature demonstrating that highly specific TKIs [i.e., tyrosine kinase inhibitors]
`
`for the EGFr tyrosine kinase can induce significant antitumor activity in EGFr-positive tumors”
`
`such as NSCLC.
`
`(DTX 389at pp. 567; see also DTX 34 at