A
`
`’
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`OSI PHARMACEUTICALS, INC., PFIZER
`INC., and GENENTECH, INC.,
`
`
`
`Plaintiffs/Counterclaim Defendants,
`
`V.
`
`C.A. Nos. 09—00185 and 00186
`
`(consolidated)
`
`TEVA PHARMACEUTICALS USA, INC. and
`
`MYLAN PHARMACEUTICALS INC.,
`
`Defendants/Counterclaim Plaintiffs.
`
`DEFENDANT MYLAN’S OPENING POST-TRIAL BRIEF
`
`John C. Phillips, Jr. (#110)
`Megan Haney (#5016)
`PHILLIPS, GOLDMAN & SPENCE, PA.
`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, DC. 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
`
`-
`
`r
`
`Page
`
`NATURE AND STAGE OF THE PROCEEDINGS ...................................................... .. 1
`
`SUMMARY OF THE ARGUMENT .............................................................................. .. 1
`
`STATEMENT OF FACTS .............................................................................................. .. 3
`
`II.
`
`111.
`
`A.
`
`The Patents—In—Suit .............................................................................................. .. 3
`
`1.
`
`2.
`
`The “065 Patent ........................................................................................ .. 3
`
`The “221 Patent ........................................................................................ .. 4
`
`B.
`
`Epidermal Growth Factor Receptor (EGFR) Research In The 1990s ................. .. 6
`
`1.
`
`2.
`
`EGFR And EGFR Inhibitors ................ 4. .................................................. .. 6
`
`Non—Small Cell Lung Cancer (NSCLC) And Its Association With
`EGFR Overexpression ............................................................................. .. 6
`
`C.
`
`The Development Of Potent And Selective EGFR Inhibitors ............................. .. 7
`
`1.
`
`2.
`
`3.
`
`4.
`
`The Best Method To Make New EGFR Inhibitors Was To Start
`With Known Inhibitors ............................................................................ .. 8
`
`Zeneca’s “226 Application Identified 4—Anilinoquinazolines As
`Preferred EGFR Inhibitors ....................................................................... .. 9
`
`Zeneca’s “226 Application Had A Gap Not Covering Ethynyl ............. .. 12
`
`a.
`
`b.
`
`An Ethynyl Group Is Closely Related To A Methyl Group ...... .. 13
`
`The Ethynyl Gap In The Zeneca “226 Application.................... .. 14
`
`Zeneca Inventor Barker’s Abstracts Fill The Gap By Teaching
`“Small, Non—Polar” Groups At The 3’—Position .................................... .. 14
`
`a.
`
`b.
`
`c.
`
`Barker Twice Suggested That “‘Small, Non—Polar” Groups
`Are Preferred At The 3’—Position............................................... .. 15
`
`An Ethynyl Group Is A Small, Non-Polar Group, As
`Defined In The Barker Abstracts ............................................... .. 16
`
`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................................................................................. .. 16
`
`D.
`
`Pfizer Followed Zeneca’s Road Map ................................................................. .. 17
`
`1.
`
`2.
`
`Pfizer Used High Throughput Screening And High Speed
`Synthesis To Identify EGFR Inhibitors ................................................. .. 17
`
`Zeneca Scooped Pfizer No Less Than Three Times .............................. .. 18
`
`i
`
`APOTEX EX. 1059—002
`
`
`
`APOTEX EX. 1059-002
`
`

`

`
`
`3.
`
`4.
`
`Pfizer Tried To “Rebound” By Analyzing Zeneca’s ‘226
`Application And Identifying A Gap ...................................................... .. 20
`
`Pfizer Made Erlotinib Just Months After Barker Suggested Small,
`Non~Polar Groups At The 3’—Position ................................................... .. 21
`
`E.
`
`Soon After The Erlotinib Patent Application Was Filed, Pfizer And OSI
`Told The World About Using Erlotinib For Treating NSCLC .......................... .. 21
`
`l.
`
`2.
`
`3.
`
`Pfizer’s ‘498 Patent Disclosed And Claimed The Use Of Erlotinib
`For Lung Cancer, Including NSCLC ..................................................... .. 22
`
`In The 1998 Cold Spring Harbor Abstract, Pfizer And OSI
`Scientists Taught The Use Of Erlotinib For NSCLC ............................. .. 23
`
`OSI, Pfizer, and Others Reported Erlotinib’s Development for
`NSCLC ................................................................................................... .. 24
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`The 1997 AACR Abstracts (DTX 8) and Moyer Cancer
`Research Article (DTX 34) ........................................................ .. 24
`
`The 1997 Klth Article In Current Opinion In Oncology
`(DTX 389) .................................................................................. .. 26
`
`The 1997 OSI Press Release (DTX 63) ..................................... .. 26
`
`The OSI lO—K SEC Filing (DTX 427) ....................................... .. 27
`
`The 1999 ASCO Abstracts (DTX 205A) ................................... .. 27
`
`4.
`
`By 1999, The Idea Of Using Erlotinib To Treat NSCLC Was Well
`Known To The Public ............................................................................ .. 28
`
`IV.
`
`ARGUMENT ................................................................................................................. .. 28
`
`A.
`
`B.
`
`The Legal Standard For Obviousness Under 35 U.S.C. § 103 .......................... .. 29
`
`The Asserted Claims Of The ‘065 Patent Are Obvious ..................................... .. 30
`
`l.
`
`A Medicinal Chemist Would Have Used A Small, Non—Polar
`Group, Such As Ethynyl, To Modify The Closest Prior Art
`Compound, Thus Making Erlotinib ....................................................... .. 31
`
`a.
`
`b.
`
`c.
`
`d.
`
`The Obvious Starting Point Was The 4-Anilinoquinazolines
`Of Zeneca’s ‘226 Application.................................................... .. 32
`
`Zeneca’s ‘226 Application Suggested Preferred Groups For
`EGFR Inhibitors ......................................................................... .. 34
`
`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 Groups In
`Pharmaceutical Compounds ....................................................... .. 35
`
`2.
`
`All Asserted Claims Of The ‘065 Patent Are Obvious .......................... .. 37
`
`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.
`
`d.
`
`e.
`
`f.
`
`Plaintiffs Offered No Relevant Evidence Of Unexpected
`Results And Ignored The Closest Prior Art Compound—
`Example 51 Of The Zeneca ‘226 Application ........................... .. 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 ...................................................................... .. 42
`
`Weak And Irrelevant Evidence Of Commercial Success Is
`Insufficient To Rebut Erlotinib’s Obviousness .......................... .. 43
`
`Erlotinib Has Not Satisfied A Long—Felt Need .......................... .. 46
`
`No Evidence Of Skepticism Of Others ...................................... .. 47
`
`C.
`
`Claim 53 Of The ‘221 Patent Is Anticipated ..................................................... .. 48
`
`l.
`
`2.
`
`3.
`
`4.
`
`Anticipation Occurs When A Prior Art Reference Discloses The
`Claimed Invention.................................................................................. .. 48
`
`The ‘498 Patent Discloses Each And Every Limitation Of Claim
`5 3 ............................................................................................................ .. 49
`
`The 1998 Cold Spring Harbor Abstract Also Discloses Each And
`Every Limitation Of Claim 5 3 And Renders The Claim Invalid ........... .. 52
`
`Instead of Disputing What Is In the Prior Art, Plaintiffs” Experts
`Chose Not To Believe What Was In The Prior Art ............................... .. 52
`
`D.
`
`Claim 53 Of The ‘221 Patent Is Obvious ........................................................... .. 54
`
`1.
`
`2.
`
`3.
`
`All Elements Of Claim 53 Were Disclosed In Various Prior Art
`References .............................................................................................. .. 54
`
`By 1999, A Person Of Ordinary Skill In The Art Would Have
`Reasonably Expected Erlotinib To Be Effective In Treating
`NSCLC ................................................................................................... .. 5 6
`
`Plaintiffs’ Asserted Secondary Factors Cannot Overcome The
`Obviousness Of Claim 53 ...................................................................... .. 58
`
`V.
`
`CONCLUSION .............................................................................................................. .. 60
`
`APOTEX EX. 1059—004
`
`
`
`APOTEX EX. 1059-004
`
`

`

`TABLE OF AUTHORITIES
`
`CASES
`
`Page(s)
`
`Abbott Labs. v. Andrx Pharms,, Inc.,
`452 F.3d 1331 (Fed. Cir. 2006) .............................................................................................. ..39
`
`Altana Pharma AG v. Teva Pharms. USA, Inc. ,
`566 F.3d 999, 1007 (Fed. Cir. 2009) ...................................................................................... ..31
`
`Aventis Pharma Deutschland GmbH v. Lupin, Ltd,
`No. No. 2:05—CV-421, 2006 WL 2008962 (E.D. Va. July 17, 2006) .............................. ..46, 60
`
`In re Baxter Travenol Labs,
`952 F.2d 388 (Fed. Cir. 1991) ................................................................................................ ..39
`
`In re De Blaitwe,
`736 F.2d 699 (Fed. Cir. 1984) ................................................................................................ ..39
`
`In re Dillon,
`919 F.2d 688 (Fed. Cir. 1990) (en banc) ................................................................................ ..31
`
`Disco Vision Assocs. v. Disc. Mfg, Inc.,
`25 F. Supp. 2d 301 (D. Del. 1998) ......................................................................................... ..52
`
`In re Donohue,
`766 F.2d 531 (Fed. Cir. 1985) .......................................................................................... ..49, 52
`
`In re Dow Chem. Co.,
`837 F.2d 469 (Fed. Cir. 1988) ................................................................................................ ..47
`
`In re Eli Lilly & Co,
`902 F.2d 943 (Fed. Cir. 1990) ................................................................................................ ..42
`
`Eli Lilly & Co. v, Zenith Goldline Pharms., Inc.,
`471 F.3d 1369 (Fed. Cir. 2006) .............................................................................................. ..50
`
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) ........................................................................................ ..38, 58
`
`Geo M Martin Co. v. Alliance Mach. Sys. Int ’1 LLC,
`618 F.3d 1294 (Fed. Cir. 2010) .............................................................................................. ..48
`
`In re Gleave,
`560 F.3d 1331 (Fed. Cir. 2009) ........................................................................................ ..49, 53
`
`iv
`
`APOTEX EX. 1059-005
`
`
`
`APOTEX EX. 1059-005
`
`

`

`In re GPAC, Inc.,
`57 F.3d 1573 (Fed. Cir. 1995) .......................................................................................... ..38, 58
`
`Graham v. John Deere Co.,
`383 US. 1 (1966) ............................................................................................................. ..29, 42
`
`In re Hafiier,
`410 F.2d 1403 (C.C.P.A. 1969) ............................................................................................. ..49
`
`In re Huang,
`100 F.3d 135 (Fed. Cir. 1996) ................................................................................................ ..44
`
`Kao Corp. v. Unilever US, Inc.,
`441 F.3d 963 (Fed. Cir. 2006) ................................................................................................ ..38
`
`KS'R Int’l Co. v. Teleflex Inc.,
`550 US. 398 (2007) ............................................................................................................... ..29
`
`Leapfiog Enters, Inc. v. Fisher-Prz'ce, Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) .............................................................................................. ..38
`
`McNeil-PPC, Inc. v. L. Perrigo Co,
`337 F.3d 1362 (Fed. Cir. 2003) .............................................................................................. ..29
`
`Mea'z'chem, SA. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) .............................................................................................. ..29
`
`Merck & Co. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .............................................................................................. ..45
`
`In re Merck & Co,
`800 F.2d 1091 (Fed. Cir. 1986) .............................................................................................. ..57
`
`Microsoft Corp. v. 1'41' Ltd. P’ship,
`131 S. Ct. 2238 (2011) ........................................................................................................... ..29
`
`Novo Nordisk Pharms., Inc. v. Bio—Tech. Gen. Corp,
`424 F.3d 1347 (Fed. Cir. 2005) .............................................................................................. ..49
`
`Ortho-McNez'Z Pharm, Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .............................................................................................. ..29
`
`In re Paulsen,
`30 F.3d 1475 (Fed. Cir. 1994) .................................................................................... ..38, 43, 58
`
`In re Payne,
`606 F.2d 303 (C.C.P.A. 1979) ............................................................................................... ..40
`
`v
`
`APOTEX EX. 1059—006
`
`
`
`APOTEX EX. 1059-006
`
`

`

`Perricone v. Medicis Pharm. Corp,
`432 F.3d 1368 (Fed. Cir. 2005) .................................................................................. ..48, 53, 54
`
`In re Peterz'ng,
`301 F.2d 676 (C.C.P.A. 1962) ......................................................................................... ..50, 51
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .................................................................................. ..29, 38, 39
`
`Procter & Gamble Co. v. Teva Pharms. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ................................................................................................ ..40
`
`Purdue Pharma Prods. L.P. v. Par Pharm, Inc.,
`377 F. App’x 978 (Fed. Cir. 2010) ........................................................................................ ..43
`
`Purdue Pharma Prods. L.P. v. Par Pharm., Inc.,
`642 F. Supp. 2d 329 (D. Del. 2009) ....................................................................................... ..29
`
`Rasmusson v. SmithKline Beecham Corp,
`413 F.3d 1318 (Fed. Cir. 2005) .............................................................................................. ..49
`
`Richardson—Vick v. Upjohn Co.,
`No. 93-556—SLR, 1996 WL 31209 (D. Del. 1996) ................................................................ ..44
`
`,
`Ruiz v. A.B. Chance Co.,
`357 F.3d 1270 (Fed. Cir. 2004) ........................................................................................ ..47, 5
`
`In re Ruschig,
`343 F.2d 965 (C.C.P.A. 1965) ............................................................................................... ..50
`
`Ryko Mfg. Co. v. Nu-Star, Inc.,
`950 F.2d 714 (Fed. Cir. 1991) ................................................................................................ ..38
`
`Sanofi~Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) .............................................................................................. ..31
`
`Santarus, Inc. v. Par Pharm., Inc.,
`720 F. Supp. 2d 427 (D. Del. 2010) ....................................................................................... ..47
`
`In re Schauman,
`572 F.2d 312 (C.C.P.A. 1978) ......................................................................................... ..50, 51
`
`Schering Corp. v. Geneva Pharms., Inc.,
`339 F.3d 1373 (Fed. Cir. 2003) .............................................................................................. ..49
`
`Scherz'ng Corp. v. Precision-Cosmet Co,
`614 F. Supp. 1368 (D. Del. 1985) .......................................................................................... ..50
`
`V1
`
`APOTEX EX. 1059—007
`
`
`
`APOTEX EX. 1059-007
`
`

`

`Scripps Clinic & Research Found. v. Genentech, Inc.,
`927 F.2d 1565 (Fed. Cir. 1991).............................................................................................. ..48
`
`Senju Pharm. Co. v. Apotex, Inc,
`717 F. Supp. 2d 404 (D. Del. 2010) ....................................................................................... ..45
`
`In re Soni,
`54 F.3d 746 (Fed. Cir. 1995) .................................................................................................. ..40
`
`Stratoflex, Inc. v. Aeroquip Corp,
`713 F.2d 1530 (Fed. Cir. 1983) ........................................................................................ ..42, 59
`
`Symbol Techs., Inc. v. Opticon, Inc.,
`935 F.2d 1569 (Fed. Cir. 1991) .............................................................................................. ..42
`
`In re Wright,
`569 F.2d 1124 (C.C.P.A. 1977) ............................................................................................. ..39
`
`STATUTES
`
`35 U.S.C. § 102 ...................................................................................................................... ..48, 60
`
`35 U.S.C. § 103 .......................................................................................................... ..29, 30, 38, 60
`
`35 U.S.C. § 252 .............................................................................................................................. ..4
`
`OTHER AUTHORITIES
`
`U.S. Patent & Trademark Office, Manual of Patent Examining Procedure (8th ed., rev.
`July 2010) ............................................................................................................................... ..53
`
`US. Patent No. 5,747,498 .................................................................................................... .. passim
`
`US. Patent No. 6,900,221 .................................................................................................... .. passim
`
`U.S. Reissued Patent No. 41,065 ......................................................................................... .. passim
`
`
`
`Vii
`
`APOTEX EX. 1059—008
`
`APOTEX EX. 1059-008
`
`

`

`43g): 4-anilinoquinazoline.
`
`GLOSSARY
`
`ac_ety1_ezrrc_: 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,
`308211-14 (Heathcock).
`
`allgynyl: a hydrocarbon with a carbon-carbon triple bond (CEC). See, e. g., D.I. 225,
`308: 1 5-16 (Heathcock).
`
`
`CP-358 774: erlotinib. See, e. g., D.I. 226, 5172-4 (Arnold).
`
`EGFR: epidermal growth factor receptor.
`
`
`erlotinib: also known as CP—358,774. See, e. g., D1. 226, 5172—4 (Arnold).
`
`meta position: 3’-position on the aniline ring. See, eg., D.I. 225, 316:25-317z3
`(Heathcock).
`
`
`NSCLC: non—small cell lung cancer.
`
`11g: tyrosine kinase inhibitor.
`
`SCLC: small cell lung cancer.
`
`
`
`viii
`
`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 US.
`
`Reissued Patent No. 41,065 (“the ‘065 patent”) and US. Patent No. 6,900,221 (“the ‘221
`
`patent”).1 Plaintiffs” infringement action triggered a thirty-month stay for Mylan and Teva, both
`
`first-ANDA filers, which expires on or about May 18, 2012.2 The Court held a 5—day bench trial
`
`from March 14 to 18, 2011.
`
`II.
`
`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 number of plain and undisputed facts to find the patents
`
`invalid. The ‘065 patent is invalid because:
`
`a Rival pharmaceutical company Zeneca published a patent application disclosing
`4—anilinoquinazoline (“4-AQ”) EGFR inhibitor compounds;
`
`subset
`specific
`application claimed and identified a
`6 The Zeneca patent
`of preferred 4-AQ EGFR inhibitors, most of which had the small, non-polar
`methyl group at the 3 ’—position;
`
`for
`0 The Zeneca patent application had a gap in its coverage because,
`the 3’-position, it did not claim the ethynyl group—a sibling of the methyl group;
`
`
`
`The ‘065 patent is a reissue of US. Patent No. 5,747,498 (“the ‘498 patent”), filed May
`1
`5, 1998. The ‘065 patent claims priority to June 6, 1995. The non-provisional ‘221 patent
`application was filed on November 9, 2000.
`
`Teva settled with Plaintiffs shortly before trial, and a stipulated consent order of dismissal
`2
`was entered on March 15, 2011. (D.I. 223.)
`
`1
`
`APOTEX EX. 1 059-010
`
`APOTEX EX. 1059-010
`
`

`

`inventor Barker
`application ' published, the
`patent
`Zeneca
`his
`a After
`disclosed through separately published Abstracts
`that 4-AQ EGFR inhibitor
`compounds
`could be improved by using small,
`non—polar
`groups at
`the
`3 ’—position; and
`
`6 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, including erlotinib.
`
`It is undisputed that Pfizer was aware of these facts prior to the claimed invention.
`
`Indeed, Pfizer had been scooped repeatedly by Zeneca in 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 Zeneca is
`
`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 081’s own
`
`publications:
`
`a
`
`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
`
`a After the ‘498 application was filed, Pfizer and 031 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 of itself, is an inherent and obvious feature of orally administered drugs.
`
`2
`
`APOTEX EX. 1059—011
`
`
`
`APOTEX EX. 1059-011
`
`

`

`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 of erlotinib 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 081 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.
`
`III.
`
`STATEMENT OF FACTS
`
`A.
`
`The Patents-In-Suit
`
`This case involves two patents: the ‘065 patent and the ‘221 patent. 081 and Pfizer are
`
`owners of the ‘065 patent; and 081 is the owner of 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 infringement of claims 1, 2,
`
`4, 8, 34, and 35. Claim 8 is specific for the compound erlotinib. Claims 1, 2, and 4 generically
`
`cover erlotinib. Claims 34 and 35 further specify that erlotinib is in the form of, respectively, a
`
`pharmaceutically acceptable salt or a hydrochloride salt.
`
`3
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`APOTEX EX. 1 059-012
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`APOTEX EX. 1059-012
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`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, nor does the patent disclose
`
`any pharmacokinetic or pharmacodynarnic 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 IC50=0.0001~3O
`
`uM.” (JTX l, col.l4, 11.66 to col.15, 1.2.) The ‘065 patent identifies erlotinib as one of the
`
`specifically preferred compounds.
`
`(JTX l, 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.
`
`(1d,) 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 compounds for treating certain cancers, including lung cancer.
`
`(JTX 3,
`
`col.4l, 11.61-63; col.44, 11.3—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.I. 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 was protected by at 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
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`31, 2005.
`
`(JTX 2.) The ‘221 patent was filed on November 9, 2000 and claims priority to three
`
`provisional applications: US. Provisional Application No. 60/206,420, filed May 23, 2000, US.
`
`Provisional Application No. 60/193,191, filed March 30, 2000, and US. Provisional Application
`
`No. 60/ 164,907, filed November 11, 1999. (Id) 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).”3
`
`Incorporating the relevant
`
`limitations of claim 44, the method of claim 5 3 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, 1119-32.) The dosage range defined as being therapeutically effective
`
`is the same range set forth in the ‘498 patent.
`
`(See D.1. 224 at 121:3—22 (Ratain4); compare JTX
`
`2, col.24, 1119-32 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 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, or pharrnaceutically acceptable salts thereof in anhydrous or
`hydrate forms, and a carrier.” (JTX 2, col.35, 1126—36.)
`
`Dr. Mark Ratain testified as an expert on behalf of Mylan. Dr. Ratain has been a medical
`4
`oncologist and faculty member at the University of Chicago since 1983, serves as director of the
`University’s Advanced Solid Tumor Clinic, and has considerable experience in designing and
`conducting clinical trials for cancer drugs. (D.I. 224, 53:2~59:11; DTX 732.)
`
`5
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`“carrier” is the same definition that was set forth in the ‘498 patent.
`
`(D.I. 224, 12123—122111
`
`(Ratain); JTX 2, col.23, 11.33-36; JTX 3, col.l6, 11.21-24.)
`
`B.
`
`Epidermal Growth Factor Receptor (EGFR) Research In The 1990s
`
`1.
`
`EGFR And EGFR 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 grth
`
`factor binds to the EGFR to cause a number of 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 some of 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 (z‘d., 71:6—73:13 (Ratain)), and provided proof that blocking the biological activity of
`
`EGFR would inhibit the grth of certain cancer cells (id, 73:1—13 (Ratain)).
`
`2.
`
`Non—Small Cell Lung Cancer (NSCLC) And Its 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% of all lung cancer being NSCLC.5 (See DTX 365 at p. 365 (“Roughly
`
`80% of all lung cancers are classified as non—small-cell lung cancer (NSCLC) .
`
`.
`
`. .”); D.I. 227,
`
`806:18~24 (Sandler).)
`
`NSCLC has also long been recognized as being quite different from SCLC. (DTX 433 at
`
`p. 310, 329—331; D.I. 224, 106:3—10728; 108z6~l5 (Ratain).) For example, it is well established
`
`NS CLC is generally divided into three types: adenocarcinoma, squamous cell carcinoma,
`5
`and large cell carcinoma. (D.I. 224, 70:12—19 (Ratain)).
`
`6
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`that EGFR overexpression was associated with NSCLC, and not SCLC.
`
`(See DTX 365 at 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