`
`
`
`
`
`
`
`Case: 12-1431 Document: 16 Page: 1 Filed: 07/31/2012
`
`
`
`2012-1431
`
`UNITED STATES COURT OF APPEALS FOR THE FEDERAL CIRCUIT
`
`___________________________________________________________
`
`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 DEFENDANT-APPELLANT
`MYLAN PHARMACEUTICALS INC.
`_____________________________________________________________
`
`
`
`James H. Wallace, Jr.
`Mark A. Pacella
`Gregory R. Lyons
`Matthew J. Dowd
`Adrienne G. Johnson
`
`WILEY REIN LLP
`
`1776 K Street NW
`Washington, DC 20006
`(202) 719-7000
`Attorneys for Defendant-
`Appellant Mylan Pharmaceuticals
`Inc.
`
`
`
`APOTEX EX. 1057-001
`
`

`

`Case: 12-1431 Document: 16 Page: 2 Filed: 07/31/2012
`
`
`
`CERTIFICATE OF INTEREST
`
`
`
`Pursuant to Federal Circuit Rule 47.4, counsel for the Defendant-Appellant
`
`Mylan Pharmaceuticals Inc. certifies the following:
`
`1.
`
`The full name of every party or amicus represented by me is:
`
`
`
`Mylan Pharmaceuticals Inc.
`
`
`
`The name of the real party in interest (if the party named in the caption is not
`2.
`the real party in interest) represented by me is:
`
`
`
`Mylan Pharmaceuticals Inc.
`
`
`
`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:
`
`
`
`Mylan Inc.
`
`The names of all law firms and the partners or associates that appeared for
`4.
`the party or amicus now represented by me in the trial court or agency or are
`expected to appear in this court are:
`
`Jack C. Phillips, Jr.
`Megan C. Haney
`Brian E. Farnan
`Phillips, Goldman & Spence, P. A.
`1200 N. Broom Street
`Wilmington, DE 19806
`
`
`
`Date: July 31, 2012
`
`
`
`
`
`
`
`
`James H. Wallace, Jr.
`Mark A. Pacella
`Gregory R. Lyons
`Robert J. Scheffel
`Brian Pandya
`Matthew J. Dowd
`Karin A. Hessler
`Adrienne G. Johnson
`WILEY REIN LLP
`1776 K Street NW
`Washington, DC 20006
`
`
`/s/Mark A. Pacella
`Signature of counsel
`
`
`Mark A. Pacella
`Printed name of counsel
`
`APOTEX EX. 1057-002
`
`

`

`Case: 12-1431 Document: 16 Page: 3 Filed: 07/31/2012
`
`TABLE OF CONTENTS
`
`
`
`Page
`
`TABLE OF AUTHORITIES ...................................................................................iv
`PRELIMINARY STATEMENT ..............................................................................1
`STATEMENT OF RELATED CASES....................................................................5
`STATEMENT OF JURISDICTION.........................................................................6
`STATEMENT OF THE ISSUES..............................................................................7
`STATEMENT OF THE CASE.................................................................................9
`STATEMENT OF FACTS .....................................................................................11
`I.
`THE PATENTS-IN-SUIT AND ASSERTED CLAIMS.............................11
`A.
`The RE ’065 Patent ............................................................................11
`B.
`The ’221 Patent ..................................................................................12
`EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AND THE
`SEARCH FOR EGFR INHIBITORS IN THE 1990’S................................13
`A.
`EGFR And EGFR Inhibitors..............................................................13
`B. Non-Small Cell Lung Cancer And Its Association With EGFR
`Overexpression...................................................................................13
`The Search For Potent And Selective EGFR Inhibitors ....................15
`Pfizer’s Rival, Zeneca, Discloses A Groundbreaking New
`Series Of EGFR Inhibitors, The 4-Anilinoquinazolines (4-AQs) .....15
`III. ZENECA CREATES A ROADMAP TO ERLOTINIB ..............................18
`A.
`Zeneca’s ’226 Application Identifies The Most-Preferred 4-
`AQs.....................................................................................................18
`Zeneca’s ’226 Application Discloses Biological Data Showing
`The 4-AQs As A Class Potently Inhibit EGFR..................................19
`Zeneca’s ’226 Application Omits Coverage Of The Ethynyl
`Group At The 3’-Position...................................................................20
`Barker’s Abstracts Suggest “Small, Non-Polar” Groups At The
`3’-Position Of Zeneca’s 4-AQs..........................................................21
`The Ethynyl Group Is A Small, Non-Polar Group, As Taught In
`Barker’s Abstracts ..............................................................................22
`
`D.
`
`E.
`
`- i -
`
`II.
`
`C.
`D.
`
`B.
`
`C.
`
`APOTEX EX. 1057-003
`
`

`

`V.
`
`B.
`
`2.
`
`Case: 12-1431 Document: 16 Page: 4 Filed: 07/31/2012
`
`F.
`
`G.
`
`Persons Of Ordinary Skill Involved In Drug Discovery Would
`Be Motivated To Avoid Coverage Of Competitor Patents................22
`Barker’s Abstracts In Conjunction With Zeneca’s ’226
`Application Teach Which 4-AQs Were The Best EGFR
`Inhibitors Not Covered By The ’226 Application .............................23
`H. Making The Single Change Of Replacing The 3’-Substituent
`With The Small, Nonpolar Ethynyl And Vinyl Groups Results
`In Erlotinib .........................................................................................24
`IV. PFIZER FOLLOWED ZENECA’S ROADMAP AFTER FAILING
`TO FIND BETTER EGFR INHIBITORS THAN ZENECA’S 4-AQ’S .....25
`PFIZER DISCLOSES AND CLAIMS THE USE OF ERLOTINIB
`TO TREAT LUNG CANCER AND THEN DISCLOSES ITS
`ERLOTINIB DEVELOPMENT...................................................................27
`A.
`Pfizer’s ’498 Patent Discloses And Claims Using Erlotinib To
`Treat Lung Cancer, Including NSCLC ..............................................28
`Between 1997 And 1999, Erlotinib’s Usefulness For Treating
`EGFR-Associated Cancers Such As NSCLC Is Widely
`Publicized ...........................................................................................30
`1.
`Pfizer/OSI’s 1997 AACR Abstracts and Cancer Research
`Article.......................................................................................30
`Zeneca Discloses Selection of Gefitinib For Clinical
`Trials ........................................................................................32
`The 1997 Klohs Article............................................................32
`3.
`OSI’s 1997 Press Release ........................................................33
`4.
`Pfizer/OSI’s 1998 Cold Spring Harbor Abstract.....................34
`5.
`OSI’s 1998 SEC Filing ............................................................35
`6.
`Pfizer’s 1999 ASCO Abstracts ................................................36
`7.
`By 1999, Using Erlotinib To Treat NSCLC Is Well Known.............36
`C.
`SUMMARY OF THE ARGUMENT .....................................................................38
`ARGUMENT ..........................................................................................................40
`I.
`STANDARDS OF REVIEW........................................................................40
`II.
`THE DISTRICT COURT ERRED IN FINDING CLAIM 53 OF THE
`’221 PATENT NOT ANTICIPATED..........................................................41
`
`- ii -
`
`APOTEX EX. 1057-004
`
`

`

`Case: 12-1431 Document: 16 Page: 5 Filed: 07/31/2012
`
`B.
`
`B.
`
`A.
`
`The District Court Committed Reversible Error In Concluding
`That Pfizer’s ’498 Patent Did Not Anticipate Claim 53 Of The
`’221 Patent..........................................................................................41
`The District Court Committed Reversible Error In Concluding
`That Pfizer/OSI’s 1998 Cold Spring Harbor Abstract Did Not
`Anticipate Claim 53 Of The ’221 Patent............................................46
`III. The DISTRICT COURT ERRED IN FINDING CLAIM 53 OF THE
`’221 PATENT NONOBVIOUS ...................................................................49
`A.
`The Law Of Obviousness...................................................................49
`B.
`The District Court Erred In Its Obviousness Analysis By
`Failing To Consider The Full Scope And Content Of The Prior
`Art And Imposing An Incorrect Standard For Success......................50
`IV. THE DISTRICT COURT ERRED IN FINDING THE ASSERTED
`CLAIMS OF THE RE ’065 PATENT WERE NOT OBVIOUS.................55
`A.
`The District Court Erred By Requiring Selection Of A Single
`Lead Compound Based On Specific Biological Data........................55
`The District Court Erred In Concluding There Was No
`Reasonable Expectation Of Success ..................................................64
`C. No Secondary Considerations Support The Court’s
`Nonobviousness Determination .........................................................66
`CONCLUSION.......................................................................................................67
`
`- iii -
`
`APOTEX EX. 1057-005
`
`

`

`Case: 12-1431 Document: 16 Page: 6 Filed: 07/31/2012
`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Altana Pharma AG v. Teva Pharmaceuticals USA, Inc.,
`566 F.3d 999 (Fed. Cir. 2009) ............................................................................57
`
`Daiichi Sankyo Co. v. Matrix Laboratories, Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) ..............................................................56, 58, 62
`
`In re Dillon,
`919 F.2d 688 (Fed. Cir. 1990) (en banc) ......................................................57, 58
`
`In re Donohue,
`766 F.2d 531 (Fed. Cir. 1985) ............................................................................48
`
`Eisai Co. v. Dr. Reddy’s Laboratories, Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) ..........................................................................58
`
`Eli Lilly & Co. v. Barr Laboratories, Inc.,
`251 F.3d 955 (Fed. Cir. 2001) ............................................................................47
`
`Eli Lilly & Co. v. Zenith Goldline Pharmaceuticals, Inc.,
`471 F.3d 1369 (Fed. Cir. 2006) ..........................................................................43
`
`Environemntal Designs, Ltd. v. Union Oil Co. of California,
`713 F.2d 693 (Fed. Cir. 1983) ............................................................................51
`
`In re Gleave,
`560 F.3d 1331 (Fed. Cir. 2009) ..............................................................44, 45, 46
`
`In re Graves,
`69 F.3d 1147 (Fed. Cir. 1995) ............................................................................48
`
`Impax Laboratories, Inc. v. Aventis Pharmaceuticals Inc.,
`468 F.3d 1366 (Fed. Cir. 2006) ..........................................................................45
`
`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 (2007)............................................................................................49
`
`In re Longi,
`759 F.2d 887 (Fed. Cir. 1985) ......................................................................50, 53
`
`- iv -
`
`APOTEX EX. 1057-006
`
`

`

`Case: 12-1431 Document: 16 Page: 7 Filed: 07/31/2012
`
`In re Montgomery,
`677 F.3d 1375 (Fed. Cir. 2012) ..........................................................................54
`
`Oakley, Inc. v. Sunglass Hut International,
`316 F.3d 1331 (Fed. Cir. 2003) ..........................................................................40
`
`OSI Pharmaceuticals, Inc. v. Mylan Pharmaceuticals Inc.,
`Civ. No. 09-185-SLR, 2012 WL 1548224 (D. Del. May 1, 2012).......................9
`
`Otsuka Pharmaceutical Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed Cir. 2012) ...........................................................................58
`
`Perricone v. Medicis Pharmaceutical Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) ..........................................................................43
`
`In re Petering,
`301 F.2d 676 (C.C.P.A. 1962)............................................................................45
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ....................................................................50, 53
`
`Procter & Gamble Co. v. Teva Pharmaceuticals USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ............................................................................50
`
`Rasmusson v. SmithKline Beecham Corp.,
`413 F.3d 1318 (Fed. Cir. 2005) ....................................................................46, 48
`
`Sanofi-Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) ..........................................................................57
`
`In re Schauman,
`572 F.2d 312 (C.C.P.A. 1978)............................................................................45
`
`Schering Corp. v. Geneva Pharmaceuticals, Inc.,
`339 F.3d 1373 (Fed. Cir. 2003) ..........................................................................48
`
`Symbol Technologiess, Inc. v. Opticon, Inc.,
`935 F.2d 1569 (Fed. Cir. 1991) ..........................................................................53
`
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA, LLC,
`683 F.3d 1356 (Fed. Cir. 2012) ....................................................................43, 45
`
`- v -
`
`APOTEX EX. 1057-007
`
`

`

`Case: 12-1431 Document: 16 Page: 8 Filed: 07/31/2012
`
`Zenon Environemntal, Inc. v. U.S. Filter Corp.,
`506 F.3d 1370 (Fed. Cir. 2007) ....................................................................40, 46
`
`STATUTES
`
`28 U.S.C. § 1295(a)(1)...............................................................................................6
`
`28 U.S.C. § 1338(a) ...................................................................................................6
`
`35 U.S.C. § 102(b) ...................................................................................................43
`
`35 U.S.C. § 103........................................................................................................49
`
`35 U.S.C. § 271(e)(2).................................................................................................9
`
`35 U.S.C. § 271(e)(4)(A) .........................................................................................10
`
`RULES AND REGULATIONS
`
`Fed. R. App. P. 4(a)(1)(A) .........................................................................................6
`
`OTHER AUTHORITIES
`Manual of Patent Examining Procedure § 2107.03 (8th ed., rev. 8, July
`2010) ...................................................................................................................54
`
`
`
`- vi -
`
`APOTEX EX. 1057-008
`
`

`

`Case: 12-1431 Document: 16 Page: 9 Filed: 07/31/2012
`
`PRELIMINARY STATEMENT
`
`This is a patent infringement action relating to Mylan’s application to market
`
`a generic version of Plaintiffs’ erlotinib hydrochloride product sold under the name
`
`Tarceva®. Tarceva® is FDA approved for certain indications of non-small cell
`
`lung cancer (“NSCLC”) and pancreatic cancer. Two patents are at issue: Reissued
`
`U.S. Patent No. 41,065 (“RE ’065 patent”) claims certain compounds, including
`
`erlotinib, that inhibit the epidermal growth factor receptor (“EGFR”); and U.S.
`
`Patent No. 6,900,221 (“’221 patent”) claims the use of erlotinib to treat certain
`
`EGFR-associated cancers, including NSCLC. Mylan appeals the district court’s
`
`determination that the asserted claims of both patents are not invalid.
`
`The RE ’065 and ’221 patents are directed to different arts and objectives,
`
`and must be viewed in their proper contexts. Specifically, the asserted claims of
`
`the RE ’065 patent are directed to biologically active compounds that inhibit the
`
`EGFR as measured by their in vitro activity. Thus, the person of ordinary skill in
`
`the art related to the obviousness analysis here is a medicinal chemist seeking
`
`compounds with such activity. The asserted claim of the ’221 patent, on the other
`
`hand, is directed to treating NSCLC. Here, the person of ordinary skill in the art
`
`relevant to the anticipation/obviousness analyses is an oncologist seeking a
`
`treatment for NSCLC.
`
`1
`
`APOTEX EX. 1057-009
`
`

`

`Case: 12-1431 Document: 16 Page: 10 Filed: 07/31/2012
`
`Erlotinib was not the first small molecule EGFR inhibitor, nor was
`
`Tarceva® the first small molecule EGFR inhibitor to successfully treat NSCLC. In
`
`the early 1990s, Pfizer trailed its rival, Zeneca, in the search for new EGFR
`
`inhibitors. In particular, Zeneca was the first to discover and disclose the class of
`
`potent EGFR inhibitors known as the 4-anilinoquinazolines (4-AQs). Before
`
`Pfizer first made erlotinib, Zeneca’s 4-AQs had been singled out in the literature as
`
`by far the best EGFR inhibitors of the time and those compounds’ inventor had
`
`published scientific abstracts explicitly suggesting the single modification needed
`
`to produce the most potent of such compounds, namely, the use of a “small, non-
`
`polar” substituent at a particular position. Zeneca, however, apparently through
`
`oversight, failed to claim small, non-polar alkynyl and alkenyl groups at that
`
`position. Pfizer researchers spotted what they referred to as Zeneca’s “patent gap,”
`
`and after unsuccessful efforts to find an EGFR inhibitor superior to Zeneca’s 4-
`
`AQs, exploited that gap to arrive at erlotinib.
`
`Armed with Zeneca’s prior art roadmap and the incentive to avoid the
`
`coverage of a competitor’s patent claims, it would have been obvious for a
`
`medicinal chemist of ordinary skill to arrive at the erlotinib compound. Indeed,
`
`Pfizer ultimately arrived at erlotinib by following the roadmap in Zeneca’s prior art
`
`teachings and exploiting the gap in Zeneca’s patent claims.
`
`2
`
`APOTEX EX. 1057-010
`
`

`

`Case: 12-1431 Document: 16 Page: 11 Filed: 07/31/2012
`
`
`
`Despite the clear and convincing evidence of this obvious path to erlotinib,
`
`the district court applied an unduly rigid “lead compound” analysis, requiring
`
`identification of a single “lead compound” with specific published biological data.
`
`In addition, the court dismissed the explicit suggestion in the prior art to use small,
`
`non-polar groups. The clear and convincing evidence, when applied to the proper
`
`legal standard, established prima facie obviousness. No probative evidence of
`
`secondary considerations existed to overcome that prima facie case.
`
`Asserted claim 53 of the ’221 patent claims the administration of an
`
`effective amount of erlotinib, with a carrier, to treat NSCLC. Years before filing
`
`for the ’221 patent, however, Pfizer had already obtained U.S. Patent No.
`
`5,747,498 (“’498 patent”), which later reissued as the RE ’065 patent. The ’498
`
`patent disclosed and claimed not only erlotinib, but also its use for treating certain
`
`EGFR-associated cancers, including NSCLC. There is no dispute that the four
`
`corners of the ’498 patent expressly disclosed every limitation of claim 53.
`
`Nevertheless, the district court misapplied the law in finding the ’498 patent did
`
`not anticipate claim 53, reasoning that despite the express disclosure of every
`
`limitation, the ’498 patent failed to “teach that every compound disclosed would be
`
`a treatment for every disease disclosed” and did not precisely state “erlotinib for
`
`the treatment of lung cancer.”
`
`3
`
`APOTEX EX. 1057-011
`
`

`

`Case: 12-1431 Document: 16 Page: 12 Filed: 07/31/2012
`
`Similarly, another reference, the Cold Spring Harbor Abstract, expressly
`
`disclosed every claim limitation, with the exception of a pharmaceutical carrier,
`
`which unrebutted expert testimony established was an inherent feature of the oral
`
`administration disclosed in the Abstract. The court also misapplied the law in
`
`dismissing the expert testimony on the Abstract’s inherent disclosure of claim 53’s
`
`“carrier” limitation, and erroneously required the Abstract to disclose an actual
`
`reduction to practice to be anticipatory.
`
`
`
`The district court further erred in concluding that claim 53 was not obvious.
`
`In addition to the ’498 patent and the Cold Spring Harbor Abstract, between 1997
`
`and 1999, Pfizer, OSI, and others widely publicized additional information about
`
`the progress of erlotinib’s development as a treatment for, inter alia, NSCLC,
`
`including its progression into clinical trials in human cancer patients. The court
`
`dismissed this large body of prior art that unquestionably suggested erlotinib be
`
`used to treat NSCLC and that evidenced a reasonable expectation that it would
`
`work. Additionally, the court erred in incorrectly defining “success” and “failure”
`
`for purposes of its obviousness analysis in terms of a likelihood of FDA approval.
`
`For these reasons, the district court’s rulings should be reversed.
`
`4
`
`APOTEX EX. 1057-012
`
`

`

`Case: 12-1431 Document: 16 Page: 13 Filed: 07/31/2012
`
`STATEMENT OF RELATED CASES
`
`Pursuant to Federal Circuit Rule 47.5, Appellant states as follows:
`
`a.
`
`b.
`
`There have been no previous appeals in this case.
`
`Appellant is aware of no other case that will be directly affected by
`
`the Court’s decision in this case.
`
`5
`
`APOTEX EX. 1057-013
`
`

`

`Case: 12-1431 Document: 16 Page: 14 Filed: 07/31/2012
`
`STATEMENT OF JURISDICTION
`
`This is an appeal from the district court’s entry of a final order and
`
`judgment. The district court had jurisdiction under 28 U.S.C. § 1338(a). The
`
`district court entered final judgment on May 1, 2012 (A1-2) and an amended
`
`judgment on May 31, 2012 (A3). Mylan timely filed its notice of appeal on May
`
`31, 2012. (A1651-52.) See Fed. R. App. P. 4(a)(1)(A). This Court has jurisdiction
`
`under 28 U.S.C. § 1295(a)(1).
`
`6
`
`APOTEX EX. 1057-014
`
`

`

`Case: 12-1431 Document: 16 Page: 15 Filed: 07/31/2012
`
`STATEMENT OF THE ISSUES
`
`1. Whether the district court committed clear error in concluding that a
`
`prior art reference specifically disclosing a number of preferred compounds and
`
`their use to treat specified cancers does not anticipate the ’221 patent’s later claim
`
`to a method of using one of the disclosed compounds to treat one of the specified
`
`cancers because the prior art fails to “teach that every compound disclosed would
`
`be a treatment for every disease disclosed.”
`
`2. Whether the district court committed clear error in concluding that the
`
`asserted claim of the ’221 patent was not anticipated where the court (a)
`
`misapplied the law of inherent anticipation, and (b) required that a reference
`
`disclose the actual treatment of a patient to anticipate a method of treatment claim.
`
`3. Whether the district court committed legal error in concluding that the
`
`asserted claim of the ’221 patent was not obvious where the court (a) failed to
`
`consider the full scope and content of the prior art, and (b) applied a heightened
`
`definition of “success” for both reasonable expectation of success and failure of
`
`others.
`
`4. Whether the district court committed legal error in concluding that a
`
`claimed chemical compound was not obvious where the court (a) required
`
`selection of a single “lead compound” based on its specific biological data, and (b)
`
`7
`
`APOTEX EX. 1057-015
`
`

`

`Case: 12-1431 Document: 16 Page: 16 Filed: 07/31/2012
`
`discounted the express suggestion in the prior art to modify the closest prior art
`
`compounds in a particular manner that led to the claimed invention.
`
`8
`
`APOTEX EX. 1057-016
`
`

`

`Case: 12-1431 Document: 16 Page: 17 Filed: 07/31/2012
`
`STATEMENT OF THE CASE
`
`Plaintiffs-Appellees OSI Pharmaceuticals, Inc., Pfizer Inc. and Genentech,
`
`Inc.’s (“Plaintiffs”) brought this action under the Hatch-Waxman Act, 35 U.S.C.
`
`§ 271(e)(2), based on Defendant-Appellant Mylan Pharmaceuticals
`
`Inc.’s
`
`(“Mylan”) filing of an Abbreviated New Drug Application (“ANDA”) containing a
`
`certification that, inter alia, each patent listed in the U.S. Food and Drug
`
`Administration’s (“FDA”) “Orange Book” as covering Plaintiffs’ product
`
`Tarceva® is invalid. (A5.) On March 19, 2009, Plaintiffs filed a complaint
`
`asserting infringement of those patents, i.e., U.S. Patent Nos. 6,900,221, 7,087,613,
`
`and 5,747,498. (A6.) In December 2009, the ’498 patent was reissued as Reissued
`
`Patent No. RE 41,065. (A51.) In January 2010, Plaintiffs amended their
`
`complaint to assert the RE ’065 patent. (A6.) Plaintiffs later withdrew their
`
`assertion of the ’613 patent, leaving only the RE ’065 and ’221 patents at issue.
`
`(A309-12.)
`
`The court held a five-day bench trial in March 2011. (A6.) On May 1,
`
`2012, the court issued its decision and entered final judgment in favor of Plaintiffs,
`
`holding the asserted claims of the patents-in-suit not invalid. OSI Pharms., Inc. v.
`
`Mylan Pharms. Inc., Civ. No. 09-185-SLR, 2012 WL 1548224 (D. Del. May 1,
`
`2012); (A4-50; A3.) On May 31, 2012, Mylan filed its notice of appeal. (A1651-
`
`52.) That same day, the district court entered an amended judgment consistent
`
`9
`
`APOTEX EX. 1057-017
`
`

`

`Case: 12-1431 Document: 16 Page: 18 Filed: 07/31/2012
`
`with its original judgment as to validity and further setting forth relief pursuant to
`
`35 U.S.C. § 271(e)(4)(A), i.e., that the effective date of approval of Mylan’s
`
`ANDA shall not be earlier than the expiration of both patents-in-suit. (A1-2.)
`
`10
`
`APOTEX EX. 1057-018
`
`

`

`Case: 12-1431 Document: 16 Page: 19 Filed: 07/31/2012
`
`STATEMENT OF FACTS
`
`I.
`
`THE PATENTS-IN-SUIT AND ASSERTED CLAIMS
`
`The asserted claims of the patents-in-suit relate to the compound now known
`
`as erlotinib, and its use in treating EGFR-associated cancers, including NSCLC.
`
`A. The RE ’065 Patent
`
`The RE ’065 patent issued in December 2009 as a reissue of the ’498 patent,
`
`which issued on May 5, 1998. (A1665.) The RE ’065 patent, like its
`
`predecessor, discloses and claims 4-anilinoquinazoline (4-AQ) compounds that are
`
`useful for inhibiting EGFR and thus for treating EGFR-associated cancers such as
`
`NSCLC. Unlike the ’498 patent, however, the RE ’065 patent does not claim the
`
`use of erlotinib to treat NSCLC.
`
`The only biological data disclosure in the RE ’065 patent is a single sentence
`
`generally referring to in vitro testing of the compounds as a class. (A1675, 14:66-
`
`15:2.) The patent provides no in vivo data. (A881:19-A882:2; A1141:8-14.)
`
`Plaintiffs asserted 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 and a hydrochloride salt. (A1687-88, 37:14-
`
`38:12, 38:19-27, 38:33-39:67; A1690, 44:3-7.)
`
`11
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`APOTEX EX. 1057-019
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`

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`Case: 12-1431 Document: 16 Page: 20 Filed: 07/31/2012
`
`B.
`
`The ’221 Patent
`
`The ’221 patent is directed to the use of erlotinib to treat several conditions,
`
`including NSCLC. The ’221 patent issued on May 31, 2005, was filed on
`
`November 9, 2000, and claims priority to three provisional applications. (A1691.)
`
`Plaintiffs offered no evidence that the provisional applications support asserted
`
`claim 53.
`
`Claim 53 recites: “The method of claim 44 for the treatment of non-small
`
`cell lung cancer (NSCLC).” (A1716, 35:64-65.) Incorporating the relevant
`
`limitations of claim 44, claim 53 claims:
`
`[a] method for the treatment of NSCLC (non small cell lung 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
`[erlotinib], or pharmaceutically acceptable salts thereof in anhydrous or
`hydrate forms, and a carrier.
`
`(See id., 35:26-36, 35:64-65.)
`
`The ’221 patent describes the same ranges of effective dosages as do the RE
`
`’065 and ’498 patents. (Compare A1710, 24:19-32 with A1727, 15:55-62 and
`
`A1676, 15:46-53; see also A716:3-22.) Similarly, the ’221 patent sets forth the
`
`same description of “carrier” as do the RE ’065 and ’498 patents. (Compare
`
`A1710, 23:33-36 with A1727, 16:21-24 and A1676, 16:11-14; see also A716:23-
`
`A717:11.)
`
`12
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`APOTEX EX. 1057-020
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`

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`Case: 12-1431 Document: 16 Page: 21 Filed: 07/31/2012
`
`II. EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AND THE
`SEARCH FOR EGFR INHIBITORS IN THE 1990’S
`
`A. EGFR And EGFR Inhibitors
`
`EGFR is a transmembrane receptor found in normal human cells and various
`
`cancer cells. In normal cells, epidermal growth factor binds to the EGFR to cause
`
`several downstream effects, including cell growth. (A1061:14-A1062:2.) In the
`
`early 1980s, researcher John Mendelsohn made the important discovery that
`
`certain cancer cells overexpressed EGFR, and inhibiting that expression blocked
`
`the cancer cells’ growth (A666:6-A668:13.) As Plaintiffs’ oncology expert Dr.
`
`Sandler testified, by 1990, it was understood that the EGFR pathway was “an
`
`important pathway in the development of cancer.” (A1425:19-23.1)
`
`B. Non-Small Cell Lung Cancer And Its Association With EGFR
`Overexpression
`
`Lung cancer consists of two general categories: non-small cell lung cancer
`
`(NSCLC) and small cell lung cancer (SCLC). (A665:3-8.) Since at least 1990, it
`
`was known that “[r]oughly 80% of all lung cancers are classified as non-small-cell
`
`lung cancer (NSCLC).” (A5381; see also A1399:18-24.) As Plaintiffs’ expert
`
`admitted, by 1995—the RE ’065 patent’s earliest possible priority date—one
`
`skilled in the art would have understood that lung cancer included NSCLC.
`
`(A1479:17-21.)
`
`
`1 Corrections to certain transcript cites (e.g., A1425:21) can be found at A1647-50.
`
`13
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`APOTEX EX. 1057-021
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`Case: 12-1431 Document: 16 Page: 22 Filed: 07/31/2012
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`By the early 1990s, it was also well-established that EGFR overexpression
`
`was associated with NSCLC. (See A4661; A4653; A673:23-A674:25; A675:23-
`
`A676:20.) Later publications confirmed this. For example, a 1998 publication
`
`explained that “[c]ompared to normal lung epithelium, NSCLC has been shown to
`
`express elevated levels of epidermal growth factor (EGF) receptor . . . .” (A5384.)
`
`Another explained that numerous studies had shown that the EGFR pathway “is
`
`overexpressed in many malignancies of epithelial origin, including most NSCLC
`
`tumors, and some studies suggest that overexpression tends to be associated with
`
`tumors that are more aggressive and have a worse prognosis, thus indicating this
`
`pathway’s potential role in contributing to the sustained growth of these tumors.”
`
`(A5508; see also A5540-48.)
`
`Because EGFR overexpression is associated with NSCLC, researchers knew
`
`of the “substantial literature demonstrating that highly specific TKIs [tyrosine
`
`kinase inhibitors] for the EGFr tyrosine kinase can induce significant antitumor
`
`activity in EGFr-positive tumors” such as NSCLC. (A5417; see also A4744;
`
`A689:9-A691:10, A692:5-A694:2.)
`
`In contrast, SCLC was understood not to be associated with overexpression
`
`of EGFR. By 1981 researchers had “first reported that EGF receptors were found
`
`on nonsmall-cell lung cancer (NSCLC) cell lines, and were absent on small-cell
`
`14
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`APOTEX EX. 1057-022
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`Case: 12-1431 Document: 16 Page: 23 Filed: 07/31/2012
`
`lines.” (A5423; see also A4661; A4653; A673:23-A674:25, A675:23-A676:20,
`
`A669:20-A672:8, A701:3-A702:8.)
`
`C. The Search For Potent And Selective EGFR Inhibitors
`
`The association between EGFR overexpression and certain cancers, such as
`
`NSCLC, spurred efforts to make potent and selective EGFR inhibitors. During the
`
`early 1990s, at least three major pharmaceutical companies—Zeneca, Parke-Davis,
`
`and Pfizer—were engaged in such efforts. (See A5293-356; A5707-27; A5501-03
`
`A5005; A5357-77.) In 1991, Pfizer and OSI joined forces with the objective of
`
`making potent and selective EGFR inhibitors. (A1144:1-6; A1063:7-11.)
`
`D.
`
`Pfizer’s Rival, Zeneca, Discloses A Groundbreaking New Series
`Of EGFR Inhibitors, The 4-Anilinoquinazolines (4-AQs)
`
`By the early 1990s, several classes of EGFR-inhibiting compounds had been
`
`reported, but most were weak in potency. (A892:22-893:5; A889:25-A890:1.)
`
`That changed in 1992-93, when Zeneca discovered a class of EGFR inhibitors
`
`kn