Case: 12-1431 Document: 25 Page: 1 Filed: 09/27/2012
`
`UNITED STATES COURT OF APPEALS FOR THE FEDERAL CIRCUIT
`
`2012-1431
`
`
`
`OSI PHARMACEUTICALS, INC., PFIZER INC.,
`and GENENTECH, INC.,
`
`Plaintiffs-Appellees,
`
`v.
`
`MYLAN PHARMACEUTICALS INC.,
`
`Defendant-Appellant.
`
`
`
`
`
`Appeal from the United States District Court for the District of Delaware
`in case no. 09-CV-0185, Judge Sue L. Robinson.
`
`BRIEF OF PLAINTIFFS-APPELLEES OSI PHARMACEUTICALS, INC.,
`PFIZER INC., AND GENENTECH, INC.
`__________________________________________________________________
`
`
`Benjamin C. Hsing
`Sapna W. Palla
`KAYE SCHOLER LLP
`425 Park Avenue
`New York, NY 10022
`Tel: (212) 836-8000
`
`Leora Ben-Ami
`KIRKLAND & ELLIS LLP
`601 Lexington Avenue
`New York, NY 10022
`Tel: (212) 446-5943
`
`
`
`Attorneys for Plaintiffs-Appellees OSI
`Pharmaceuticals, Inc., Pfizer Inc.,
`and Genentech, Inc.
`
`
`
`APOTEX EX. 1058-001
`
`

`

`Case: 12-1431 Document: 25 Page: 2 Filed: 09/27/2012
`
`CERTIFICATE OF INTEREST
`
`Pursuant to Federal Circuit Rule 47.4, counsel for the Plaintiffs-Appellees,
`
`OSI Pharmaceuticals, Inc., Pfizer Inc., and Genentech, Inc. certifies the following:
`
`1.
`
`
`
`The full name of every party or amicus represented by me is:
`
`OSI Pharmaceuticals, Inc, Pfizer Inc. and Genentech, Inc.
`
`2.
`The name of the real party in interest (if the party named in the caption is not
`the real party in interest) represented by me is:
`
`OSI Pharmaceuticals, LLC (formerly known as OSI Pharmaceuticals, Inc.)1.
`
`3.
`All parent corporations and any publicly held companies that own 10 percent
`or more of the stock of the party or amicus curiae represented by me are:
`
`OSI Pharmaceuticals, LLC is a wholly owned subsidiary of Astellas US
`LLC, which is a wholly owned subsidiary of Astellas US Holding, Inc. Astellas US
`Holding, Inc. is a wholly owned subsidiary of Astellas Pharma Inc., a Japanese
`company. Astellas Pharma Inc. is publicly traded on the Tokyo and Osaka stock
`exchanges and no publicly held corporation owns more than 10% of the stock of
`Astellas Pharma Inc.
`
`Pfizer Inc. has no parent corporations and no publicly held corporation owns
`10% or more of its stock.
`
`Genentech, Inc. is a wholly owned subsidiary of Roche Holdings, Inc.
`Roche Holding, Inc.‟s ultimate parent, Roche Holding Ltd., is publicly traded on
`the Swiss Stock Exchange. Upon information and belief, more than 10% of Roche
`Holding Ltd.‟s voting shares are held either directly or indirectly by Novartis AG,
`a publicly held Swiss corporation.
`
`
`1 As of March 31, 2011, OSI Pharmaceuticals, Inc. became OSI Pharmaceuticals,
`LLC in accordance with Section 18-214 of the Delaware Limited Liability
`Company Act.
`
`APOTEX EX. 1058-002
`
`

`

`Case: 12-1431 Document: 25 Page: 3 Filed: 09/27/2012
`
`4.
`The names of all law firms and the partners or associates that appeared for
`the party or amicus now represented by me in the trial court or agency or are
`expected to appear in this court are:
`
`Jack B. Blumenfeld
`Maryellen Noreika
`Morris, Nichols, Arsht & Tunnell, LLP
`1201 North Market Street
`P.O. Box 1347
`Wilmington, DE 19899-1347
`Tel: (302) 658-9200
`Fax: (302) 658-3989
`
`Benjamin C. Hsing
`Sapna W. Palla
`Kaye Scholer LLP
`425 Park Avenue
`New York, NY 10022
`Tel: (212) 836-8000
`Fax: (212) 836-8689
`
`Leora Ben-Ami
`Kirkland & Ellis LLP
`601 Lexington Avenue
`New York, NY 10022
`Tel: (212) 446-5943
`Fax: (212) 446-6460
`
`
`
`Date: September 27, 2012
`
`/s/ Benjamin C. Hsing
`Signature of counsel
`
`
`
`
`
`
`
`Benjamin C. Hsing
`Printed name of counsel
`
`APOTEX EX. 1058-003
`
`

`

`Case: 12-1431 Document: 25 Page: 4 Filed: 09/27/2012
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`STATEMENT OF RELATED CASE ....................................................................... 1
`
`STATEMENT OF THE ISSUES............................................................................... 2
`
`STATEMENT OF THE CASE .................................................................................. 4
`
`STATEMENT OF FACTS ........................................................................................ 6
`
`I.
`
`PATENTS-IN-SUIT ........................................................................................ 6
`
`A.
`
`B.
`
`The RE‟065 Patent ................................................................................ 6
`
`The ‟221 Patent ..................................................................................... 6
`
`II.
`
`ERLOTINIB .................................................................................................... 7
`
`III. THE PRIOR ART TO THE RE‟065 PATENT ............................................... 7
`
`A.
`
`B.
`
`C.
`
`D.
`
`Zeneca‟s ‟722 Application .................................................................... 7
`
`Zeneca‟s ‟226 Application .................................................................... 8
`
`The Barker Abstracts ............................................................................. 8
`
`The Fry Science Article ......................................................................... 9
`
`IV. FAILED EGFR TYROSINE KINASE INHIBITORS .................................10
`
`V.
`
`THE DISCOVERY OF ERLOTINIB ...........................................................11
`
`A.
`
`B.
`
`C.
`
`D.
`
`Pfizer‟s Discovery Of The 4-Anilinoquinazoline Core ......................12
`
`Pfizer‟s Strategy To Modify The 4-Anilinoquinazoline Core ............12
`
`Pfizer‟s Discovery Of A Compound Substituted With 6,7-
`Dimethoxyethoxy Tails .......................................................................15
`
`Pfizer‟s Discovery Of A Compound Substituted With An
`Ethynyl Group .....................................................................................15
`
`E.
`
`Pfizer‟s Discovery of Erlotinib ...........................................................17
`
`VI. PFIZER‟S DISCOVERY OF ERLOTINIB FOR THE TREATMENT
`OF NSCLC ....................................................................................................18
`
`
`
`i
`
`APOTEX EX. 1058-004
`
`

`

`Case: 12-1431 Document: 25 Page: 5 Filed: 09/27/2012
`
`Page
`
`VII. THE ROLE OF EGFR OVEREXPRESSION WAS UNCLEAR IN
`1999 ...............................................................................................................20
`
`VIII. THE REFERENCES CITED BY MYLAN AGAINST CLAIM 53.............22
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`The ‟498 Patent ...................................................................................22
`
`The Cold Spring Harbor Abstract .......................................................23
`
`AACR Abstracts ..................................................................................23
`
`The Moyer Article ...............................................................................23
`
`The Klohs Article ................................................................................24
`
`OSI Press Release And 10-K ..............................................................24
`
`G. ASCO Abstracts ..................................................................................25
`
`IX. FDA APPROVAL OF ERLOTINIB FOR NSCLC AND
`PANCREATIC CANCER .............................................................................26
`
`SUMMARY OF ARGUMENT ...............................................................................27
`
`ARGUMENT ...........................................................................................................30
`
`I.
`
`The District Court Correctly Held That The RE‟065 Patent Was Not
`Obvious ..........................................................................................................30
`
`A.
`
`The Law Of Obviousness ....................................................................30
`
`B. Mylan‟s Obviousness Argument Is Legally Incorrect ........................33
`
`C.
`
`D.
`
`A Person of Ordinary Skill In The Art Would Not Have
`Selected Example 51 As A Lead Compound ......................................33
`
`Persons Of Ordinary Skill Would Not Have Modified The
`Example 51 Compound To Arrive at Erlotinib ...................................40
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Persons of Ordinary Skill Would Have Modified The
`Anilinoquinazoline Core ...........................................................40
`
`The Prior Art Taught A Preference For Halogens ....................41
`
`A Person Of Skill Would Not Have Selected An Ethynyl
`Group As A Substituent ............................................................42
`
`The Barker Abstracts Did Not Teach An Ethynyl Group.........43
`
`The Prior Art Taught Away From Using An Ethynyl
`Group.........................................................................................46
`
`
`
`ii
`
`APOTEX EX. 1058-005
`
`

`

`Case: 12-1431 Document: 25 Page: 6 Filed: 09/27/2012
`
`Page
`
`6.
`
`7.
`
`There Is No Basis To Conclude That Compounds With
`An Ethynyl Group Would Have Similar Activity As The
`Compounds Disclosed In The ‟226 Application ......................47
`
`The Prior Art Failed To Suggest 6,7-Dimethoxyethoxy
`Tails ...........................................................................................48
`
`E.
`
`Evidence of Unexpected Results Establish Non-Obviousness ...........49
`
`1.
`
`2.
`
`3.
`
`Erlotinib Has Unexpectedly Superior Potency Compared
`To The Closest Prior Art ...........................................................50
`
`Erlotinib‟s Metabolism Was Unexpected .................................51
`
`Erlotinib‟s Effectiveness Against Pancreatic Cancer Was
`Unexpected ................................................................................51
`
`F.
`
`Secondary Considerations Support Finding Of Non-
`Obviousness .........................................................................................51
`
`1.
`
`2.
`
`Commercial Success .................................................................51
`
`Failure of Others .......................................................................53
`
`II.
`
`The District Court Correctly Found That Claim 53 Of The ‟221 Patent
`Is Not Invalid .................................................................................................53
`
`A.
`
`The District Court Correctly Found That Claim 53 Was Not
`Anticipated ..........................................................................................54
`
`1.
`
`2.
`
`3.
`
`The Law of Anticipation ...........................................................54
`
`The District Court Correctly Found That The ‟498 Patent
`Did Not Anticipate Claim 53 ....................................................55
`
`The District Court Correctly Found That The Cold
`Spring Harbor Abstract Did Not Anticipate Claim 53 .............59
`
`B.
`
`The District Court Correctly Found That Claim 53 Was Not
`Obvious................................................................................................61
`
`1.
`
`2.
`
`The Prior Art Did Not Render Claim 53 Obvious ....................61
`
`Secondary Considerations Support Non-Obviousness .............68
`
`CONCLUSION ........................................................................................................69
`
`
`
`
`
`iii
`
`APOTEX EX. 1058-006
`
`

`

`Case: 12-1431 Document: 25 Page: 7 Filed: 09/27/2012
`
`
`
`TABLE OF AUTHORITIES
`
`Advanced Display Sys., Inc. v. Kent State Univ.,
`212 F.3d 1272 (Fed. Cir. 2000) .......................................................................... 53
`
`Akzo N.V. v. U.S. Int’l Trade Comm’n,
`808 F.2d 1471 (Fed. Cir. 1986) .......................................................................... 57
`
`Alcon Research, Ltd. v. Apotex Inc.,
`687 F.3d 1362 (Fed. Cir. 2012) .......................................................................... 62
`
`Amgen Inc. v. F. Hoffman-La Roche Ltd.,
`580 F.3d 1340 (Fed. Cir. 2009) .................................................................... 32, 62
`
`Biovail Corp. Int’l v. Andrx Pharm., Inc.,
`239 F.3d 1297 (Fed. Cir. 2001) .......................................................................... 27
`
`Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp.,
`320 F.3d 1339 (Fed. Cir. 2003) .......................................................................... 53
`
`Celsis In Vitro, Inc. v. CellzDirect, Inc.,
`664 F.3d 922 (Fed. Cir. 2012) ............................................................................ 27
`
`Continental Can Co. USA v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991) .......................................................................... 60
`
`Daiichi Sankyo Co. v. Matrix Labs., Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) ........................................................ 32, 34, 35, 38
`
`Datascope Corp. v. SMEC, Inc.,
`776 F.2d 320 (Fed. Cir. 1985) ............................................................................ 33
`
`Demaco Corp. v. F. Von Langsdorff Licensing Ltd.,
`851 F.2d 1387 (Fed. Cir. 1988) .......................................................................... 51
`
`Eisai Co. v. Dr. Reddy’s Labs., Ltd,
`533 F.3d 1353 (Fed. Cir. 2008) .......................................................................... 31
`
`Eli Lilly & Co. v. Zenith Goldline Pharms., Inc.,
`471 F.3d 1369 (Fed. Cir. 2006) .............................................................. 35, 55, 68
`
`
`
`iv
`
`APOTEX EX. 1058-007
`
`

`

`Case: 12-1431 Document: 25 Page: 8 Filed: 09/27/2012
`
`
`
`Eli Lilly and Co. v. Teva Pharms. USA, Inc.,
`619 F.3d 1329 (Fed. Cir. 2010) .......................................................................... 65
`
`Ex Parte Humber,
`217 U.S.P.Q. 265 (B.P.A.I 1981) ....................................................................... 50
`
`Fujikawa v. Wattanasin,
`93 F.3d 1559 (Fed. Cir. 1996) ............................................................................ 47
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ................................................................................................ 31
`
`Hoganas AB v. Dresser Indus, Inc.,
`9 F.3d 948 (Fed. Cir. 1993) ................................................................................ 49
`
`Impax Labs., Inc. v. Aventis Pharms. Inc.,
`545 F.3d 1312 (Fed. Cir. 2008) .................................................................... 30, 31
`
`In re Arkley,
`455 F.2d 586 (C.C.P.A 1972) ............................................................................. 54
`
`In re Blondel,
`499 F.2d 1311 (C.C.P.A 1974) ........................................................................... 50
`
`In re Brana,
`51 F.3d 1560 (Fed. Cir. 1995) ............................................................................ 47
`
`In re Chu,
`66 F.3d 292 (Fed. Cir. 1995) .............................................................................. 50
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent
`Litigation,
`676 F.3d 1063 (Fed. Cir. 2012) .............................................................. 53, 61, 69
`
`In re Gleave,
`560 F.3d 1331(Fed. Cir. 2009) ........................................................................... 58
`
`In re Soni,
`54 F.3d 746 (Fed. Cir. 1995) .............................................................................. 49
`
`J.T. Eaton & Co. v. Atlantic Paste & Glue Co.,
`106 F.3d 1563 (Fed. Cir. 1997) .......................................................................... 52
`
`
`
`v
`
`APOTEX EX. 1058-008
`
`

`

`Case: 12-1431 Document: 25 Page: 9 Filed: 09/27/2012
`
`
`
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc.,
` 688 F.3d 1342 (Fed. Cir. 2012)............................................................................ 62
`
`Knoll Pharm. Co. v. Teva Pharms. USA, Inc.,
`367 F.3d 1381 (Fed. Cir. 2004) .......................................................................... 50
`
`Koito Mfg. Co. v. Turn-Key-Tech, LLC,
`381 F.3d 1142 (Fed. Cir. 2004) .......................................................................... 60
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 32
`
`Life Technologies, Inc. v. Clontech Labs., Inc.,
`224 F.3d 1320 (Fed. Cir. 2000) .......................................................................... 62
`
`Medichem, S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) .......................................................................... 62
`
`Metabolite Labs., Inc. v. Laboratory Corp.,
`370 F.3d 1354 (Fed. Cir. 2004) .......................................................................... 54
`
`Microsoft Corp. v. i4i Ltd. P’ship,
`131 S. Ct. 2238 (2011) ........................................................................................ 30
`
`Motorola, Inc. v. Interdigital Tech. Corp.,
`121 F.3d 1461 (Fed. Cir. 1997) .......................................................................... 60
`
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) .......................................................................... 54
`
`Ortho-McNeil Pharm. Inc., v. Mylan Lab. Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 32
`
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) .................................................................... passim
`
`Procter & Gamble Co. v. Teva Pharm. Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ................................................................ 61, 68, 69
`
`Sanofi-Synthelabo v. Apotex, Inc.,
`470 F.3d 1368 (Fed. Cir. 2006) .......................................................................... 55
`
`
`
`vi
`
`APOTEX EX. 1058-009
`
`

`

`Case: 12-1431 Document: 25 Page: 10 Filed: 09/27/2012
`
`
`
`Sanofi-Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) ........................................................ 33, 54, 57, 58
`
`Sciele Pharma Inc. v. Lupin Ltd.,
`684 F.3d 1253 (Fed. Cir. 2012) .......................................................................... 30
`
`Star Scientific, Inc. v. R.J. Reynolds Tobacco Co.,
`655 F.3d 1364 (Fed. Cir. 2011) .......................................................................... 44
`
`Takeda Chem. Indus. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) ........................................................ 31, 32, 34, 39
`
`Unigene Labs., Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) .......................................................................... 43
`
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA, LLC,
`683 F.3d 1356 (Fed. Cir. 2012) .......................................................................... 58
`
`Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc.,
`231 F.3d 1339 (Fed. Cir. 2000) .......................................................................... 32
`
`35 U.S.C. § 271(e)(4)(A) ........................................................................................... 5
`
`35 U.S.C. § 282 ........................................................................................................ 30
`
`
`
`vii
`
`APOTEX EX. 1058-010
`
`

`

`Case: 12-1431 Document: 25 Page: 11 Filed: 09/27/2012
`
`
`
`STATEMENT OF RELATED CASE
`
`No appeal in or from this action was previously before this or any other
`
`appellate court. Counsel for appellees is not aware of any case pending before this
`
`Court that will be directly or indirectly affected by the outcome of this appeal.
`
`
`
`
`
`
`
`APOTEX EX. 1058-011
`
`

`

`Case: 12-1431 Document: 25 Page: 12 Filed: 09/27/2012
`
`
`
`STATEMENT OF THE ISSUES
`
`1. Was it clearly erroneous for the district court to conclude that Mylan
`
`failed to carry its burden of proving by clear and convincing evidence that the
`
`asserted claims of the U.S. Reissued Patent No. RE 41,065 (“RE‟065 patent”),
`
`covering the compound erlotinib, are invalid as obvious, where:
`
`a. The prior art relied upon by Mylan including Zeneca‟s European
`
`Patent Application No. 0566226 (“‟226 application”) had been
`
`considered by the USPTO;
`
`b. One of ordinary skill in the art would have had no reason to choose
`
`any of the compounds claimed in the Zeneca ‟226 application,
`
`including the Example 51 compound, as a lead;
`
`c. One of ordinary skill in the art would have had no reason to modify
`
`Zeneca‟s Example 51 compound to arrive at erlotinib; and
`
`d. Unexpected results and other secondary considerations supported non-
`
`obviousness.
`
`2. Was it clearly erroneous for the district court to conclude that Mylan
`
`failed to carry its burden of proving by clear and convincing evidence that claim 53
`
`of the U.S. Patent No. 6,900,221 (“‟221 patent”), directed to a method of treatment
`
`of non-small cell lung cancer (“NSCLC”), was anticipated, where:
`
`
`
`2
`
`APOTEX EX. 1058-012
`
`

`

`Case: 12-1431 Document: 25 Page: 13 Filed: 09/27/2012
`
`
`
`a. U.S. Patent No. 5,747,498 (“‟498 patent”), already considered by the
`
`USPTO during prosecution, did not disclose to one of ordinary skill in
`
`the art, i.e., an oncologist, a method of treating NSCLC with erlotinib;
`
`b. Both sides‟ experts agreed that a person of ordinary skill would not
`
`have read the ‟498 patent as disclosing a method of administering
`
`erlotinib for the treatment of NSCLC; and
`
`c. The Cold Spring Harbor abstract disclosed only preclinical in vitro
`
`and mouse xenograft model experiments of non-NSCLC cell lines,
`
`which both sides‟ experts agreed did not constitute disclosure of
`
`treatment of NSCLC.
`
`3. Was it clearly erroneous for the district court to conclude that Mylan
`
`failed to carry its burden of proving by clear and convincing evidence that claim 53
`
`of the ‟221 patent was obvious, where:
`
`a. The prior art cited by Mylan, in combination or otherwise, showed
`
`that there was no reasonable expectation of success of the claimed
`
`method of treatment of NSCLC; and
`
`b. Secondary considerations, i.e., satisfaction of an unmet need and
`
`failure of others, established non-obviousness.
`
`
`
`3
`
`
`
`
`
`APOTEX EX. 1058-013
`
`

`

`Case: 12-1431 Document: 25 Page: 14 Filed: 09/27/2012
`
`
`
`STATEMENT OF THE CASE
`
`Plaintiffs-Appellees OSI Pharmaceuticals, Inc. (“OSI”), Pfizer Inc.
`
`(“Pfizer”) and Genentech, Inc. (“Genentech”), are owners or exclusive licensees of
`
`the patents-in-suit, the RE‟065 patent and the ‟221 patent. The RE‟065 patent
`
`claims the compound erlotinib, the active ingredient in Tarceva®, and the ‟221
`
`patent claims a method of treating NSCLC with erlotinib. Tarceva® is approved by
`
`the Food and Drug Administration (“FDA”) for treatment of NSCLC and, in
`
`combination with gemcitabine, pancreatic cancer. Annual worldwide sales of
`
`Tarceva® are about $1 billion.
`
`Defendant-Appellant Mylan Pharmaceuticals Inc. (“Mylan”) filed an
`
`Abbreviated New Drug Application (“ANDA”) with a Paragraph IV certification
`
`seeking approval to sell a generic copy of Tarceva®. On March 19, 2009, plaintiffs
`
`brought this action in the United States District Court for the District of Delaware,
`
`alleging infringement of claims 1, 2, 4, 8, 34, and 35 of the RE‟065 patent and
`
`claim 53 of the ‟221 patent. Mylan conceded infringement. (A309-A310.)
`
`The district court held a five-day bench trial in March 2011. On May 1,
`
`2012, the court entered final judgment in favor of plaintiffs holding that “Mylan
`
`has not proven, by clear and convincing evidence, that claims 1, 2, 4, 8, 34, and 35
`
`of the RE‟065 patent are invalid as obvious in view of the prior art or that claim 53
`
`
`
`4
`
`APOTEX EX. 1058-014
`
`

`

`Case: 12-1431 Document: 25 Page: 15 Filed: 09/27/2012
`
`
`
`of the ‟221 patent is invalid as anticipated or as obvious in view of the prior art.”
`
`(A3.)
`
`On May 31, 2012, the district court entered an amended final judgment
`
`further ordering, pursuant to 35 U.S.C. § 271(e)(4)(A), that the effective date of
`
`approval of Mylan‟s ANDA shall not be earlier than the expiration of the patents-
`
`in-suit. (A1-2.)
`
`
`
`
`
`
`
`
`5
`
`APOTEX EX. 1058-015
`
`

`

`Case: 12-1431 Document: 25 Page: 16 Filed: 09/27/2012
`
`
`
`STATEMENT OF FACTS
`
`I.
`
`PATENTS-IN-SUIT
`
`A. The RE’065 Patent
`
`The RE‟065 patent (A51-75) is a reissue of the ‟498 patent (A1719-41). The
`
`application for the ‟498 patent was filed on May 28, 1996 with a priority date of
`
`June 6, 1995. The inventors are Rodney Schnur and Lee Arnold, medicinal
`
`chemists at Pfizer who were working on developing compounds that inhibited
`
`epidermal growth factor receptor (“EGFR”) tyrosine kinase. Claim 1 of the
`
`RE‟065 patent recites a chemical formula, which covers 4-anilinoquinazoline
`
`compounds having an aniline ring substituted with an ethynyl or azido group.
`
`Claim 1 encompasses the compound now known as erlotinib. (A72, 37:14-38:12.)
`
`Claim 8 of the RE‟065 patent recites erlotinib specifically. (A72, 38:33-A73,
`
`39:67.) Claims 34 and 35 are drawn to pharmaceutically acceptable salts of
`
`erlotinib. (A75, 44:3-5.)
`
`B.
`
`The ’221 Patent
`
`The application for the ‟221 patent was filed on November 9, 2000. (A76.)
`
`The inventors are Pfizer scientists, including Sandra Silberman and Karen
`
`Ferrante. The specification describes clinical studies of erlotinib, including results
`
`from Phase II studies reflecting that erlotinib “is a well tolerated, oral medication
`
`which is active in non-small cell lung cancer.” (A98, 31:1-2.) Claim 53 of the ‟221
`
`patent depends from claim 44 and recites a method “for the treatment of non-small
`
`
`
`6
`
`APOTEX EX. 1058-016
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`Case: 12-1431 Document: 25 Page: 17 Filed: 09/27/2012
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`cell lung cancer (NSCLC)” “comprising administering to [a] mammal a
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`therapeutically effective amount of a pharmaceutical composition comprised of . . .
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`[erlotinib], or pharmaceutically acceptable salts thereof in anhydrous or hydrate
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`forms, and a carrier.” (A100, 35:26-36, 64-65.)
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`II. ERLOTINIB
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`Erlotinib (below) has a quinazoline core (yellow) and an anilino group
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`comprised of an amine linker (purple) and an aniline ring (orange). It is known as a
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`4-anilinoquinazoline compound. Erlotinib is substituted at the 3‟-position (red)
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`with an ethynyl substituent and at the 6,7-positions (green) with dimethoxyethoxy
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`tails. (A1206:1-23.) The internal Pfizer identification number for erlotinib was CP-
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`358774. (A4389.)
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`III. THE PRIOR ART TO THE RE’065 PATENT
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`A. Zeneca’s ’722 Application
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`Zeneca‟s European Patent Application No. 520722 (“‟722 application”)
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`published on December 30, 1992. (A5707.) It discloses 4-anilinoquinazoline
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`compounds which are said to be inhibitors of EGFR tyrosine kinase. (A5707-
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`7
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`APOTEX EX. 1058-017
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`Case: 12-1431 Document: 25 Page: 18 Filed: 09/27/2012
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`5727.) The ‟722 patent does not disclose the erlotinib structure, nor does it disclose
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`any compound substituted at the 3‟-position with an ethynyl group. (A1215:3-5.)
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`The ‟722 application discloses four compounds with biological activity. The data
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`showed that compounds with a halogen at the 3‟-position were the most potent and
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`all of the halogen-substituted compounds were more potent than the 3‟-methyl
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`compound. (A1211:6-1215:2; A5713:4-13.)
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`B.
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`Zeneca’s ’226 Application
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`The ‟226 application published on October 20, 1993. (A5293.) It also
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`discloses 4-anilinoquinazoline compounds said to be inhibitors of EGFR tyrosine
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`kinase. (A5293-5356.) It does not disclose the erlotinib structure, nor does it
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`disclose any compound substituted at the 3‟-position with an ethynyl group.
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`(A1218:11-13; A959:18-A960:5.) The ‟226 application discloses five compounds
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`with biological data. (A5313:17-30; A891:5-12; A1216:17-23.) It does not provide
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`biological data for any of the thirteen compounds claimed in claims 7 and 9 of the
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`application, which includes the compound of Example 51. (A945:6-A946:8;
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`A1116:2-21; A1217:17-19; A1340:7-13.)
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`C. The Barker Abstracts
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`The two Barker abstracts are substantially identical. (A922:7-19; A1221:20-
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`A1224:6.) The author is Andrew Barker, the inventor of Zeneca‟s ‟226 and ‟722
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`applications. They do not disclose the erlotinib structure, nor do they disclose any
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`8
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`APOTEX EX. 1058-018
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`Case: 12-1431 Document: 25 Page: 19 Filed: 09/27/2012
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`compound substituted with an ethynyl group. (A5090; A5092; A1221:20-
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`A1224:6.) They merely exemplified a 4-anilinoquinazoline compound substituted
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`at the 3‟-position with chlorine—a halogen—which was previously disclosed in
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`Zeneca‟s ‟722 application. (A1222:4-A1224:6; A1302:9-A1303:4.)
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`D. The Fry Science Article
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`The Fry Science paper (A5100-02) describes the work of scientists from
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`Warner-Lambert who were also working on EGFR inhibitor research at about the
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`same time as the scientists from Zeneca and Pfizer. (A1218:14-A1219:11.) A co-
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`author of this paper is Dr. Bridges who was a medicinal chemist at Warner-
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`Lambert heavily involved in the research of EGFR tyrosine kinase inhibitors at the
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`time. (A1201:25-A1203:3.) This paper discloses a 4-anilinoquinazoline compound
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`substituted with a bromine—another halogen—at the 3‟-position and dimethoxy at
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`the 6,7-tails. (A5100.) This compound was 170 times more potent than the most
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`potent compound with data disclosed in the ‟226 application, which is identical to
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`the Fry compound except that the ‟226 compound is substituted at the 3‟-position
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`with a methyl group (-CH3). (A1218:14-A1221:16.)
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` Fry ‟226 application
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`9
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`APOTEX EX. 1058-019
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`Case: 12-1431 Document: 25 Page: 20 Filed: 09/27/2012
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`IV. FAILED EGFR TYROSINE KINASE INHIBITORS
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`Several pharmaceutical companies were developing and patenting potential
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`EGFR inhibitors during the 1994-1995 timeframe. Other than Pfizer, none of these
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`companies developed an EGFR tyrosine kinase inhibitor that received final
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`approval from the FDA. (A1421:8-11; A1423:19-A1424:24.) Zeneca did not
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`develop the Example 51 compound or any compound recited in claims 7 and 9 of
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`the ‟226 application. Instead, Zeneca progressed another compound covered by the
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`‟226 application, gefitinib (Iressa®) (below), which has a chlorine at the 3‟-
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`position. (A1236:16-A1237:4; A1189:24-A1191:9; A3611.) Although Iressa®
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`received tentative FDA approval, the FDA withdrew the approval because the
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`Phase III trial showed that Iressa® did not provide any survival benefit, and
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`AstraZeneca is no longer pursuing any further approvals for it. (A1417:21-
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`A1421:7; A1546:23-A1547:13; A1625:4-A1626:3; A3443-A3453; A3698-A3709;
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`A3925.)2
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`2 At trial, Mylan wrongly suggested Iressa®‟s failure was due to the use of an
`incorrect lower dose. A study had shown that at a higher dose, Iressa® not only
`failed to show improved response but also exhibited increased toxicity. (A3583;
`A3443-53; A1422:7-A1423:18; A1475:21-A1476:5.)
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`10
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`APOTEX EX. 1058-020
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`Case: 12-1431 Document: 25 Page: 21 Filed: 09/27/2012
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`Other companies, including Warner-Lambert (CI-1033), Wyeth (EKB569),
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`and Boehringer Ingelheim (BIBX1382), all advanced compounds with a halogen at
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`the 3‟-position and all failed. (A3611; A3600-A3609; A1237:5-14; A1237:25-
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`A1238:18; A1239:1-11; A1423:19-A1424:24.)
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`V. THE DISCOVERY OF ERLOTINIB
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`Pfizer discovered erlotinib by screening more than 340,000 compounds in
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`Pfizer‟s compound library and synthesizing more than 1,180 compounds.
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`(A1125:12-A1126:9; A1064:16-A1066:7; A3831; A4280-A4471.) Contrary to
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`Mylan‟s assertion that Pfizer arrived at erlotinib by following “Zeneca‟s roadmap,”
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`erlotinib was the result of independent research and hard work that was contrary to
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`the teaching of the prior art. At the time, the art taught a preference for halogen
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`substitution on the aniline ring. (Infra, 41-42.) The art also taught that compounds
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`with an ethynyl group tended to be toxic and should be avoided. (Infra, 42-43, 46-
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`47.) The Pfizer inventors, nonetheless, substituted with an ethynyl group. (Infra,
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`15-18.)
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`Pfizer first made erlotinib three years after Pfizer‟s EGFR project began. At
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`any given time, Pfizer had 15 to 20 medicinal chemists working on the EGFR
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`Project. (A1086:3-9.) Even though the Zeneca applications were known to those
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`working in EGFR research, no one in the industry—other than the Pfizer
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`inventors—arrived at erlotinib. (A1257:11-A1258:15.)
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`11
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`APOTEX EX. 1058-021
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`Case: 12-1431 Document: 25 Page: 22 Filed: 09/27/2012
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`A.
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`Pfizer’s Discovery Of The 4-Anilinoquinazoline Core
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`Pfizer began its EFGR Project in September 1991, in collaboration with OSI,
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`to conduc