IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`
`
`C.A. Nos. 09-185-SLR, 09-186-SLR
`(Consolidated)
`
`
`
`OSI PHARMACEUTICALS, INC., PFIZER
`INC. and GENENTECH, INC.,
`
`
` Plaintiffs,
`
`v.
`
`
`TEVA PHARMACEUTICALS USA, INC. and
`MYLAN PHARMACEUTICALS, INC.,
`
`
` Defendants.
`
`
`
`PLAINTIFFS’ POST-TRIAL ANSWERING BRIEF
`
`Jack B. Blumenfeld (#1014)
`Maryellen Noreika (#3208)
`Morris, Nichols, Arsht & Tunnell LLP
`1201 N. Market Street
`Wilmington, DE 19899-1347
`(302) 658-9200
`jblumenfeld@mnat.com
`mnoreika@mnat.com
`
`
`Attorneys for Plaintiffs
`OSI Pharmaceuticals Inc., Pfizer Inc. and
`Genentech Inc.
`
`
`
`
`Of Counsel
`
`Leora Ben-Ami
`Benjamin Hsing
`Daniel Boglioli
`Sapna W. Palla
`Kaye Scholer LLP
`425 Park Avenue
`New York, NY 10022
`
`September 6, 2011
`
`
`60305134_9.DOCX
`
`
`
`APOTEX EX. 1060-001
`
`

`

`
`
`TABLE OF CONTENTS
`
`Page
`
`PRELIMINARY STATEMENT .................................................................................................... 1 
`
`SUMMARY OF ARGUMENT ...................................................................................................... 1 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`Mylan Has a Heightened Burden ........................................................................................ 1 
`
`Mylan Failed to Demonstrate Prima Facie Obviousness of Erlotinib ............................... 1 
`
`Mylan Failed to Show Anticipation or Obviousness of Claim 53 of the ’221
`Patent................................................................................................................................... 2 
`
`Objective Indicia Support Finding of Non-Obviousness .................................................... 3 
`
`STATEMENT OF FACTS ............................................................................................................. 3 
`
`I. 
`
`II. 
`
`III. 
`
`IV. 
`
`V. 
`
`VI. 
`
`NATURE OF THE PROCEEDING ................................................................................... 3 
`
`PATENTS-IN-SUIT ........................................................................................................... 4 
`A. 
`The RE ’065 Patent ................................................................................................ 4 
`B. 
`The ’221 Patent ...................................................................................................... 4 
`
`ERLOTINIB STRUCTURE ............................................................................................... 4 
`
`THE DISCOVERY OF ERLOTINIB ................................................................................. 5 
`A. 
`Pfizer’s Discovery of the 4-Anilinoquinazoline Core ............................................ 5 
`B. 
`Pfizer’s Strategy to Modify the 4-Anilinoquinazoline Core ................................... 6 
`C. 
`Pfizer’s Response to the Zeneca ’226 Application ................................................. 7 
`D. 
`Pfizer’s Discovery of the 6,7-Dimethoxyethoxy Tails ........................................... 9 
`E. 
`Pfizer’s Discovery of the Ethynyl Subsitituent ..................................................... 10 
`F. 
`Pfizer’s Discovery of Erlotinib ............................................................................. 12 
`G. 
`Pfizer Was Not Able to Find A Compound Superior to Erlotinib ........................ 13 
`
`THE WORK OF OTHER PHARMACEUTICAL COMPANIES IN 1994-1995 ............ 14 
`
`FAILED CLINICAL EGFR TYROSINE KINASE INHIBITOR CANDIDATES ......... 15 
`
`VII. 
`
`PFIZER’S DISCOVERY OF ERLOTINIB FOR THE TREATMENT OF NSCLC ....... 16 
`
`VIII.  THE ROLE OF EGFR OVEREXPRESSION WAS NOT CLEAR IN 1999 .................. 18 
`
`IX. 
`
`FDA APPROVED ERLOTINIB FOR NSCLC AND PANCREATIC CANCER ........... 20 
`
`ARGUMENT ................................................................................................................................ 20 
`
`60305134_9.DOCX
`
`i
`
`APOTEX EX. 1060-002
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`

`

`
`
`Page
`
`MYLAN HAS NOT MET ITS BURDEN BY CLEAR AND CONVINCING
`EVIDENCE THAT THE RE ’065 PATENT WAS OBVIOUS ....................................... 21 
`Mylan Has Not Demonstrated Prima Facie Obviousness .................................... 22 
`A. 
`Mylan Has a Heightened Burden Because Its Prior Art References
`1. 
`Were Before the Patent Examiner ............................................................. 22 
`Dr. Heathcock’s Opinions Are Fundamentally Flawed ............................ 23 
`Dr. Heathcock’s Remaining Opinions Are Contrary to the
`Teachings of the Prior Art and What People of Ordinary Skill
`Actually Did .............................................................................................. 25 
`Mylan Fails to Demonstrate that the “Salt” Claims Were Obvious .......... 40 
`4. 
`Even If Mylan Could Show Prima Facie Obviousness, Evidence Of The
`Unexpected Properties of Erlotinib Would Establish Non-Obviousness ............. 41 
`Erlotinib Has Unexpectedly Superior Potency Compared to the
`1. 
`Closest Prior Art ....................................................................................... 42 
`Erlotinib’s Metabolism Was Unexpected ................................................. 43 
`Erlotinib’s Effectiveness Against Pancreatic Cancer Was
`Unexpected ............................................................................................... 43 
`Secondary Considerations Support Finding of Non-Obviousness ........................ 44 
`1. 
`Commercial Success ................................................................................. 44 
`2. 
`Failure of Others ....................................................................................... 46 
`3. 
`Copying ..................................................................................................... 47 
`
`B. 
`
`C. 
`
`2. 
`3. 
`
`2. 
`3. 
`
`
`
`I. 
`
`II. 
`
`MYLAN HAS NOT MET ITS BURDEN THAT CLAIM 53 OF THE ’221
`PATENT WAS ANTICIPATED OR WOULD HAVE BEEN OBVIOUS ..................... 47 
`A. 
`The Prior Art Relied On by Mylan ....................................................................... 47 
`1. 
`The ’498 Patent ......................................................................................... 48 
`2. 
`The Cold Spring Harbor Abstract ............................................................. 48 
`3. 
`AACR Abstracts ....................................................................................... 49 
`4. 
`The Moyer Article ..................................................................................... 49 
`5. 
`The Klohs Article ...................................................................................... 49 
`6. 
`OSI Press Release ..................................................................................... 50 
`7. 
`OSI 10K .................................................................................................... 50 
`8. 
`ASCO Abstracts ........................................................................................ 50 
`9. 
`Mendelsohn Papers ................................................................................... 51 
`Claim 53 of the ’221 Patent Is Not Anticipated .................................................... 51 
`1. 
`The ’498 Patent Does Not Disclose All the Elements of Claim 53 .......... 52 
`2. 
`The Cold Spring Harbor Abstract Does Not Anticipate Claim 53 ........... 54 
`Claim 53 of the ’221 Patent Was Not Obvious ..................................................... 55 
`Secondary Considerations Support Finding Non-Obviousness ............................ 59 
`1. 
`Long Felt Need ......................................................................................... 59 
`2. 
`Failure of Others ....................................................................................... 60 
`3. 
`Skepticism ................................................................................................. 60 
`4. 
`Copying ..................................................................................................... 60 
`
`C. 
`D. 
`
`B. 
`
`CONCLUSION ............................................................................................................................. 60 
`
`60305134_9.DOCX
`
`ii
`
`APOTEX EX. 1060-003
`
`

`

`
`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Advanced Display Sys., Inc. v. Kent State Univ.,
`212 F.3d 1272 (Fed. Cir. 2000)................................................................................................47
`
`Akzo N.V. v. U.S. Int’l Trade Comm’n,
`808 F.2d 1471 (Fed. Cir. 1986)................................................................................................54
`
`Am. Hoist & Derrick Co. v. Sowa & Sons, Inc.,
`725 F.2d 1350 (Fed. Cir. 1984)................................................................................................20
`
`Amgen Inc. v. F. Hoffman-La Roche Ltd.,
`580 F.3d 1340 (Fed. Cir. 2009)....................................................................................23, 24, 56
`
`Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp.,
`320 F.3d 1339 (Fed. Cir. 2003)................................................................................................47
`
`Canon Computer Sys., Inc. v. Nu-Kote Int’l, Inc.,
`134 F.3d 1085 (Fed. Cir. 1998)................................................................................................21
`
`Daiichi Sankyo Co.. v. Matrix Labs., Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010)........................................................................................ passim
`
`Datascope Corp. v. SMEC, Inc.,
`776 F.2d 320 (Fed. Cir. 1985)..................................................................................................25
`
`Demaco Corp. v. F. Von Langsdorff Licensing Ltd.,
`851 F.2d 1387 (Fed. Cir. 1988)..........................................................................................44, 46
`
`Eisai Co. v. Dr. Reddy’s Labs., Ltd,
`533 F.3d 1353 (Fed. Cir. 2008)..........................................................................................22, 45
`
`Eli Lilly & Co. v. Teva Pharms. USA, Inc.,
`2004 WL 1724632 (S.D. Ind. July 29, 2004)...........................................................................57
`
`Ex Parte Humber,
`217 U.S.P.Q. 265 (Pat. & Tr. Off. Bd. App. 1981) ..................................................................43
`
`Forest Labs., Inc. v. Ivax Pharms., Inc.,
`438 F. Supp. 2d 479 (D. Del. 2006), aff’d, 501 F.3d 1263 (Fed. Cir. 2007) .....................24, 47
`
`Fujikawa v. Wattanasin,
`93 F.3d 1559 (Fed. Cir. 1996)..................................................................................................38
`
`60305134_9.DOCX
`
`vii
`
`APOTEX EX. 1060-004
`
`

`

`
`
`
`
`Page
`
`Gould v. Quigg,
`822 F.2d 1074 (Fed. Cir. 1987)................................................................................................32
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) .....................................................................................................................21
`
`Hewlett Packard Co. v. Bausch & Lomb, Inc.,
`909 F.2d 1464 (Fed. Cir. 1990)................................................................................................22
`
`Hoganas AB v. Dresser Indus, Inc.,
`9 F.3d 948 (Fed. Cir. 1993) .....................................................................................................41
`
`Hybritech Inc. v. Monoclonal Antibodies Inc.,
`802 F.2d 1367 (Fed. Cir. 1986)................................................................................................22
`
`In re Arkley,
`455 F.2d 586 (C.C.P.A 1972) ..................................................................................................52
`
`In re Blondel,
`499 F.2d 1311 (C.C.P.A 1974) ..........................................................................................41, 43
`
`In re Brana,
`51 F.3d 1560 (Fed. Cir. 1995)..................................................................................................38
`
`In re Chu,
`66 F.3d 292 (Fed. Cir. 1995)....................................................................................................42
`
`In re Chupp,
`816 F.2d 643 (Fed. Cir 1987)...................................................................................................42
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig.,
`2010 WL 3766530 (D. Del. Sept. 21, 2010) ............................................................................47
`
`In re Fouche,
`439 F.2d 1237 (C.C.P.A. 1971) ...............................................................................................41
`
`In re Gleave,
`560 F.3d 1331(Fed. Cir. 2009).................................................................................................55
`
`In re Mahurkar Double Lumen Hemodialysis Catheter Patent Litig.,
`831 F. Supp. 1354 (N.D. Ill. 1993), aff’d, 71 F.3d 1573 (Fed. Cir. 1995) ...............................47
`
`In re Merchant,
`575 F.2d 865 (C.C.P.A. 1978) .................................................................................................41
`
`In re Soni,
`54 F.3d 746 (Fed. Cir. 1995)..............................................................................................38, 41
`
`60305134_9.DOCX
`
`viii
`
`APOTEX EX. 1060-005
`
`

`

`
`
`
`
`Page
`
`In re Wagner,
`371 F.2d 877 (C.C.P.A. 1967) .................................................................................................41
`
`In re: Rosuvastatin,
`719 F. Supp.2d 388 (D. Del. 2010) ..........................................................................................23
`
`Intel Corp. v. U.S. Int’l Trade Comm’n,
`946 F.2d 821 (Fed. Cir. 1991)..................................................................................................20
`
`J.T. Eaton & Co. v. Atlantic Paste & Glue Co.,
`106 F.3d 1563 (Fed. Cir. 1997)................................................................................................44
`
`Kao Corp. v. Unilever U.S., Inc.,
`441 F.3d 963 (Fed. Cir. 2006)..................................................................................................41
`
`Kaufman Co. v. Lantech, Inc.,
`807 F.2d 970 (Fed. Cir. 1986)..................................................................................................21
`
`Knoll Pharm. Co. v. Teva Pharms. USA, Inc.,
`367 F.3d 1381 (Fed. Cir. 2004)..........................................................................................41, 44
`
`Koito Mfg. Co. v. Turn-Key-Tech, LLC,
`381 F.3d 1142 (Fed. Cir. 2004)................................................................................................41
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...........................................................................................................22, 23
`
`Mahurkar v. C.R. Bard, Inc.,
`79 F.3d 1572 (Fed. Cir. 1996)..................................................................................................49
`
`Metabolite Labs., Inc. v. Laboratory Corp.,
`370 F.3d 1354 (Fed. Cir. 2004)..........................................................................................22, 52
`
`Microsoft Corp. v. i4i Ltd. P’ship,
`131 S. Ct. 2238 (2011) .............................................................................................................20
`
`Monarch Knitting Mach. Corp. v. Sluzer Morat GmbH,
`139 F.3d 877 (Fed. Cir. 1988)..................................................................................................60
`
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008)..........................................................................................52, 54
`
`Ortho Pharm. Corp. v. Smith,
`959 F.2d 936 (Fed. Cir. 1992)............................................................................................38, 39
`
`Ortho-McNeil Pharm. Inc., v. Mylan Lab. Inc.,
`520 F.3d 1358 (Fed. Cir. 2008)..........................................................................................23, 45
`
`60305134_9.DOCX
`
`ix
`
`APOTEX EX. 1060-006
`
`

`

`
`
`
`
`Page
`
`Ortho-McNeil Pharm, Inc. v. Mylan Labs. Inc.,
`2006 WL 3019689 (D.N.J. Oct. 23, 2006)...............................................................................45
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs, Inc.,
`348 F. Supp.2d 713 (N.D.W. Va. 2004) ..................................................................................47
`
`Procter & Gamble Co. v. Teva Pharm. Inc.,
`566 F.3d 989 (Fed. Cir. 2009)..................................................................................................56
`
`Ruiz v. A.B. Chance Co.,
`234 F.3d 654 (Fed. Cir. 2000)..................................................................................................21
`
`Sanofi-Synthelabo v. Apotex, Inc.,
`470 F.3d 1368 (Fed. Cir. 2006)..........................................................................................52, 53
`
`Sanofi-Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008)..............................................................................25, 41, 52, 54
`
`Star Scientific, Inc. v. R.J, Reynolds Tobacco Co.,
`2011 W.L. 3768983 (Fed. Cir. Aug. 26, 2011) ........................................................................34
`
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983)................................................................................................22
`
`Takeda Chem. Indus. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007)..............................................................................22, 26, 45, 46
`
`Unigene Labs., Inc. v. Apotex, Inc.,
`2011 W.L. 3715557 (Fed. Cir. Aug. 25, 2011) ........................................................................34
`
`Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc.,
`231 F.3d 1339 (Fed. Cir. 2000)..........................................................................................21, 23
`
`STATUTES
`
`35 U.S.C. § 103(a) ...................................................................................................................21, 23
`
`35 U.S.C. § 282 ..............................................................................................................................20
`
`
`
`60305134_9.DOCX
`
`x
`
`APOTEX EX. 1060-007
`
`

`

`
`
`
`
`RE ’065 patent
`
`’221 patent
`
`’498 patent
`
`
`
`
`
`’226 application
`
`’722 application
`
`’105 patent
`
`’307 patent
`
`ANDA
`
`Br.
`
`
`
`
`
`
`
`
`
`
`
`CA ’968 patent
`
`
`
`
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`
`
`TABLE OF ABBREVIATIONS
`
`U.S. Reissued Patent No. 41,065
`
`U.S. Patent No. 6,900,221
`
`U.S. Patent No. 5,747,498
`
`EP 0566226 patent application
`
`EP 0520722 patent application
`
`U.S. Patent No. 5,457,105
`
`U.S. Patent No. 5,654,307
`
`Abbreviated New Drug Application
`
`Defendant Mylan’s Opening Post-Trial Brief
`
`Canadian Patent No. 2,086,968
`
`Epidermal Growth Factor Receptor
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`EGFR
`
`FDA
`
`
`
`Genentech
`
`Mylan
`
`NSCLC
`
`OSI
`
`
`
`Pfizer
`
`PTO
`
`Teva
`
`
`
`
`
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`
`
`United States Food and Drug Administration
`
`Genentech, Inc.
`
`Mylan Pharmaceuticals USA Inc.
`
`Non-small cell lung cancer
`
`OSI Pharmaceuticals, Inc.
`
`Pfizer Inc.
`
`United States Patent and Trademark Office
`
`Teva Pharmaceuticals USA, Inc.
`
`60305134_9.DOCX
`
`vii
`
`APOTEX EX. 1060-008
`
`

`

`
`
`PRELIMINARY STATEMENT
`
`Plaintiffs Pfizer, OSI and Genentech brought this suit against Mylan for infringement of
`
`patents covering Tarceva®. Tarceva® is the end result of ground-breaking research efforts by two
`
`companies and dozens of scientists, screening more than 340,000 compounds and creating more
`
`than 1,100 new molecules, and testing them and sifting the data to find a compound with the
`
`unique combination of properties possessed by its active ingredient, erlotinib. The drug is a
`
`blockbuster used to treat NSCLC and pancreatic cancer. It satisfies a need not met by other prior
`
`treatments. Mylan now seeks to copy Tarceva®. Mylan concedes infringement (D.I. 198) and
`
`asks this Court to invalidate the asserted claims of the two patents-in-suit. The evidence set forth
`
`at trial demonstrates that Mylan has failed to meet its high burden.
`
`SUMMARY OF ARGUMENT
`
`1.
`
`Mylan Has a Heightened Burden: The PTO exhaustively reviewed plaintiffs’
`
`erlotinib invention, not once, but twice: the original application leading to the ’498 patent and the
`
`reissue application leading to the RE ’065 patent. During these examinations, the PTO
`
`considered the prior art relied on by Mylan, including Mylan’s (and Teva’s) Paragraph IV notice
`
`letters setting forth their invalidity arguments. (JTX 1, pp. 2-3.) Because the PTO has already
`
`considered the prior art upon which Mylan relies, Mylan faces, under Federal Circuit precedent,
`
`“an even heavier burden to prove invalidity.” Mylan utterly failed to meet this burden.
`
`2.
`
`Mylan Failed to Demonstrate Prima Facie Obviousness of Erlotinib: Mylan’s
`
`argument that erlotinib would have been obvious is based on speculation and hindsight. Mylan
`
`argues that it would have been obvious to select the 3’-ethynyl substituent of erlotinib -- not
`
`because of any prior art -- but because it was “omitted” from certain Zeneca patent applications,
`
`and that this “gap” would have led one of ordinary skill to select it. This turns the law of
`
`60305134_9.DOCX
`
`
`
`APOTEX EX. 1060-009
`
`

`

`
`
`obviousness on its head. Indeed, not only was there no suggestion or teaching for an ethynyl
`
`group, the prior art actually taught away from it. Mylan’s position is also internally inconsistent.
`
`It argues that “the ethynyl group offered Pfizer an opportunity to take a proprietary position,”
`
`(Br. at 21) but then contends that erlotinib, which has “the ethynyl group,” would have been
`
`obvious (Br. at 32) and hence would afford Pfizer no “proprietary position.” Mylan also argues
`
`that one skilled in the art would have selected the 6,7-dimethoxyethoxy tails of erlotinib because
`
`one could derive them from one of the 13 compounds specifically claimed in a Zeneca
`
`application. Mylan speculates that one would focus on these compounds because they must have
`
`been important or Zeneca would not have claimed them. But the Zeneca application provided no
`
`data about any of them. To the contrary, concrete biological data provided in the same Zeneca
`
`application and other prior art would have led one of ordinary skill to different compounds.
`
`Mylan blithely argues that one of ordinary skill would make only 20 compounds. But the people
`
`who actually worked in the field made thousands of compounds, and no one made erlotinib, or
`
`any compound with an ethynyl substituent, except the inventors of the RE ’065 patent.
`
`3.
`
`Mylan Failed to Show Anticipation or Obviousness of Claim 53 of the ’221
`
`Patent: Mylan’s invalidity arguments against claim 53 of the ’221 patent are also meritless.
`
`Mylan fails to recognize that this invention is about a method for the treatment of NSCLC -- an
`
`extremely difficult cancer to treat. The method involves the use of a small molecule, erlotinib,
`
`having a mechanism of action, EGFR tyrosine kinase inhibition, which at the time of the
`
`invention had never been shown to be able to treat any cancer, let alone NSCLC. It took ten
`
`years after erlotinib was first made before it was approved by the FDA for treating NSCLC.
`
`None of the references Mylan relies on disclose treatment of NSCLC with erlotinib. Nor do they
`
`render the claimed cancer treatment obvious. Mylan argues that cancer treatment was obvious
`
`60305134_9.DOCX
`
`2
`
`APOTEX EX. 1060-010
`
`

`

`
`
`because NSCLC was known to overexpress EGFR and erlotinib inhibits EGFR. However, the
`
`cell pathways leading to cancer tumors are extremely complex and the correlation between
`
`overexpression of EGFR and EGFR inhibition was poorly understood. In fact, to this date
`
`erlotinib is the only small molecule EGFR inhibitor that has received full FDA approval to treat
`
`any type of cancer by itself. Simply put, one of ordinary skill in the art had no reasonable
`
`expectation that using erlotinib to treat NSCLC would have been successful.
`
`4.
`
`Objective Indicia Support Finding of Non-Obviousness: Objective indicia of
`
`non-obviousness such as unexpected results, commercial success, failure of others, long-felt
`
`need, and copying demonstrate that the inventions of the patents in suit were not obvious.
`
`I.
`
`NATURE OF THE PROCEEDING
`
`STATEMENT OF FACTS
`
`Plaintiffs are the owners or exclusive licensee of the patents in suit, which are listed in
`
`the FDA Orange Book for Tarceva®: (1) the ‘RE ’065 patent claims, inter alia, the compound
`
`erlotinib, the active ingredient in Tarceva® (JTX 1, col. 38:33-col. 39:67) and (2) the ’221 patent
`
`claims (as pertinent here) a method of treating NSCLC with erlotinib. (JTX 2, col. 35:64-65.)
`
`On November 18, 2008, Mylan filed an ANDA with a Paragraph IV certification seeking
`
`approval to market generic erlotinib products. (D.I. 212, Ex.1 ¶ 23.) This action commenced on
`
`March 20, 2009. (D.I. 1.) Plaintiffs assert that Mylan has infringed claims 1, 2, 4, 8, 34, and 35
`
`of the RE ’065 patent and claim 53 of the ’221 patent. Mylan has conceded infringement. (D.I.
`
`198 at 2.) On June 30, 2011, the Court entered an Order enjoining Mylan from launching its
`
`generic products until the Court’s decision issues. (D.I. 231.) The statutory stay pursuant to the
`
`Hatch-Waxman Act expires on or about May 18, 2012.
`
`A bench trial was held on March 14-18, 2011. Plaintiffs maintain the evidentiary
`
`objections raised at the trial.
`
`60305134_9.DOCX
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`3
`
`APOTEX EX. 1060-011
`
`

`

`
`
`II.
`
`PATENTS-IN-SUIT
`
`A.
`
`The RE ’065 Patent (JTX 1)
`
`The RE ’065 patent is a reissue of the ’498 patent. (JTX 3.) The ’498 patent was filed on
`
`May 28, 1996 based on a PCT application filed on June 6, 1995. The inventors are Rodney
`
`Schnur and Lee Arnold, who were scientists at Pfizer working on developing compounds that
`
`inhibited EGFR tyrosine kinase. Claim 1 of the RE ’065 patent recites compounds having a
`
`chemical formula which covers, among others, the compound now known as erlotinib, the active
`
`ingredient in Tarceva®. Claim 8 of the RE ’065 patent differs from original claim 8 in that it is
`
`limited to the compound erlotinib. Claim 34 of the RE ’065 patent is drawn to a
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`pharmaceutically acceptable salt of erlotinib and claim 35 is to the hydrochloride salt of
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`erlotinib, the salt form of erlotinib used in Tarceva.®
`
`B.
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`The ’221 Patent (JTX 2)
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`The ’221 patent was filed on November 9, 2000. The inventors are Pfizer scientists and
`
`include James Moyer, Sandra Silberman, Karen Ferrante, Michael Morin, and Richard Connell.
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`Claim 53 depends from claim 44 and recites a method “for the treatment of non-small cell lung
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`cancer (NSCLC)” “comprising administering to [a] mammal a therapeutically effective amount
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`of a pharmaceutical composition comprised of . . . [erlotinib], or pharmaceutically acceptable
`
`salts thereof in anhydrous or hydrate forms, and a carrier.” (JTX 2 col. 35:23-36, 64-65.)
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`III. ERLOTINIB STRUCTURE
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`The structure of erlotinib and its features are set forth below. Erlotinib is commonly
`
`referred to as a 4-anilinoquinazoline because it is comprised of the quinazoline core (yellow) and
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`an anilino group comprised of the amine linker (purple) and the aniline ring (orange). Erlotinib is
`
`substituted at the 3’-position (red) with an ethynyl substituent and at the 6,7-positions (green)
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`with dimethoxyethoxy tails. The Pfizer identification number for erlotinib is CP-358774.
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`60305134_9.DOCX
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`APOTEX EX. 1060-012
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`IV.
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`THE DISCOVERY OF ERLOTINIB
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`A.
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`Pfizer’s Discovery of the 4-Anilinoquinazoline Core
`
`In September 1991, in connection with a collaboration agreement with OSI to conduct
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`research for cancer drugs, Pfizer embarked on its EFGR Project. (D.I. 226, 469:1-5 (Arnold).)
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`The goal was “to identify a potent, selective, well tolerated, orally efficacious small molecule
`
`inhibitor of EGFR kinase as a potential therapeutant for human cancer.” (Id. at 468:7-11.) From
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`the beginning, Pfizer was skeptical of its ability to achieve this goal because “nobody had ever
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`advanced a small molecule, EFGR kinase inhibitor” and Pfizer “was quite concerned about the
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`potential side effects of . . . inhibiting EGFR.” (Id. at 475:15-476:2.)
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`In December 1991, Pfizer and OSI embarked on a massive screening effort, which
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`resulted in screening about 340,000 compounds in Pfizer’s compound library. (Id. at 469:16-
`
`471:7.) It was not until November 1992, after screening in excess of 120,000 compounds, that
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`Pfizer identified its first potential lead compound -- UK-95276, which has a 4-anilinoquinazoline
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`core. (Id. at 472:13-473:7; 475:2-5.)
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`Pfizer’s identification of UK-95276 as a potential lead came more than one month before
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`the publication of Zeneca’s European ’722 patent application on December 30, 1992, which also
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`disclosed the structure of UK-95276. (Id. at 473:8-473:20; DTX 772.)
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`60305134_9.DOCX
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`5
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`APOTEX EX. 1060-013
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`B.
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`Pfizer’s Strategy to Modify the 4-Anilinoquinazoline Core
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`While simultaneously continuing to screen its compound library for additional potential
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`leads, Pfizer undertook “a medicinal chemistry effort” around UK-95276 and “modified every
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`region of the molecule” in order to find novel analogs. (PTX 353 at PFE00225813; D.I. 226,
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`474:3-475:14; 476:3-478:2(Arnold).) As detailed below, Pfizer made modifications to the (a)
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`quinazoline core (yellow), (b) amine linker (purple) and (c) the aniline ring (orange):
`
`
`
`
`
`
`
`
`
`
`
`(PTX 291; D.I. 226, 478:3-478:19; 479:19-481:2 (Arnold).) Indeed, Pfizer “basically explored
`
`almost every possible variation you can imagine.” (See PTX 555 (exemplifying the changes
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`made); D.I. 226, 479:19-481:2; 481:7-484:11, 486:11-25 (Arnold).) None of these compounds
`
`made by changing the quinazoline core, amine linker, and aniline ring were covered by the
`
`Zeneca patent applications relied upon by Mylan. (Id., 487:23-488:5 (Arnold).)
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`Pfizer also made modifications to the 6,7 tails (green). On October 19, 1993 -- two years
`
`after embarking on its EGFR project -- Pfizer synthesized the compound CP-288865:
`
`
`
`
`
`
`
`(PTX 548, p. 7, No. 24; D.I. 226, 488:8-13(Arnold).) Pfizer’s synthesis of CP-288865 predated
`
`the publication on October 20, 1993 of a second Zeneca European patent application, the ’226
`
`application (DTX 286) which also disclosed the structure of CP-288865. Indeed, Pfizer did not
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`60305134_9.DOCX
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`APOTEX EX. 1060-014
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`become aware of the ’226 application until December 1993. (D.I. 226, 489:19-490:10 (Arnold).)
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`Although CP-288865 had a dramatic increase in in vitro activity, it had “very poor activity in
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`[Pfizer’s] animal models.” (Id. at 488:20-489:5.)
`
`C.
`
`Pfizer’s Response to the Zeneca ’226 Application
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`When the Pfizer scientists learned of the Zeneca applications which disclosed two of
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`Pfizer’s compounds, UK-95276 and CP-288865, they were understandably disappointed, but
`
`they did not give up. To the contrary, they “doubled” their efforts, adding more chemists to the
`
`team, and “began to explore even more broadly the structural variations for EGFR inhibitors.”
`
`(Id. at 490:22-491:2.)
`
`On December 2, 1993, after reviewing the ’226 application, Dr. Arnold prepared a
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`summary. (Id. at 519:5-7, 22-24; PTX 310.) He focused on the five compounds in the ’226
`
`application for which biological data were provided (D.I. 226 at 519:25-521:13; PTX 310 at
`
`PFE00336973; DTX 286 at p. 21.) His summary did not “illustrate or mention any of” the
`
`compounds in claims 7 and 9 of the ’226 application, which Mylan asserts would be the focus of
`
`one of ordinary skill in the art. (PTX 310; DTX 286 at 61; D.I. 226, 521:14-21 (Arnold).)
`
`Furthermore, although Dr. Arnold’s summary also referenced ways he believed one could
`
`achieve “possible novel agents,” all of which “were outside the scope of the Zeneca ’226
`
`application,” (D.I. 226, 521:23-523:10 (Arnold)), it did not mention that “the ethynyl group was
`
`omitted from [the ’226 application].” (Id. at 523:7-10.) In addition, the “possible novel agents”
`
`did not include any ethynyl-substituted compound. (PTX 310 at PFE 00336976.)
`
`By March 1994, Pfizer even concluded that the ’226 application “effectively eliminated
`
`any opportunity to improve on the initial 4-anilinoquinazoline lead [UK-95276] outside the
`
`confines of the Zeneca patents.” (D.I. 226, 492:8-493:17 (Arnold); PTX 355 at PFE00332782.)
`
`Thus, six months after the publication of the ’226 application, Pfizer had not contemplated a 4-
`
`60305134_9.DOCX
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`APOTEX EX. 1060-015
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`anilinoquinazoline with an ethynyl a