Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 1 of 38 PageID #: 3225
`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 1 of 38 PagelD #: 3225
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`OSI PHARMACEUTICALS, INC., PFIZER
`
`INC., and GENENTECH, INC.,
`
`Plaintiffs/Counterclaim Defendants,
`
`V
`
`CA. No. 09-00185-SLR
`
`
`
`TEVA PHARMACEUTICALS USA, INC. and
`
`MYLAN PHARMACEUTICALS lNC.,
`
`Defendants/Counterclaim Plaintiffs.
`
`DEFENDANT MYLAN’S POST—TRIAL REPLY BRIEF
`
`John C. Phillips, Jr. (#110)
`Megan Haney (#5016)
`PHILLIPS, GOLDMAN & SPENCE, PA.
`1200 North Broom Street
`
`Wilmington, Delaware 19806
`Tel: (302) 655-4200
`Fax:
`(302) 655-4210
`jcp@pgslaw.com
`mch@pgslaw.com
`
`James H. Wallace, Jr.
`Mark A. Pacella
`
`Matthew J. Dowd
`
`Adrienne Johnson
`
`WILEY REIN LLP
`
`1776 K Street NW
`
`Washington, DC. 20006
`Tel: (202) 719—7000
`
`Allomeysfor Defendant Mylan
`Pharmaceuticals Inc.
`
`Date: October 7, 2011
`
`APOTEX 1040-001
`
`APOTEX 1040-001
`
`

`

`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 2 of 38 PageID #: 3226
`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 2 of 38 PagelD #: 3226
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`II.
`
`SUMMARY OF THE REPLY ........................................................................................ .. I
`
`THE ASSERTED CLAIMS OF THE RE ‘065 PATENT ARE OBVIOUS ................... .. 2
`
`A.
`
`Zeneca’s Prior Art Suggested Erlotinib Among Other Obvious EGFR
`Inhibitors .............................................................................................................. .. 2
`
`l.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`Plaintiffs Mischaracterize Dr. Heathcock’s Analysis And Opinion ........ .. 3
`
`Plaintiffs Ignore That The Limited Biological Data In The “226
`Application Was Of Little Value In Selecting Preferred
`Compounds .............................................................................................. .. 7
`
`The Testimony Of Plaintiffs’ Expert Dr. Bridges Is Flawed
`Because He Relied On Non-Prior Art ...................................................... .. 9
`
`Zeneca’s Barker Abstracts Provided An Explicit Reason To
`Modify The 3’-Position And Create Erlotinib ....................................... .. ll
`
`Pfizer’s Own Patents Confirm That An Ethynyl Group Is Used
`Routinely By Medicinal Chemists ......................................................... .. 13
`
`Plaintiffs Offered No Evidence To Challenge The Obviousness Of
`The Hydrochloride Salt Of Erlotinib ..................................................... .. 13
`
`B.
`‘
`
`Plaintiffs’ Evidence of Alleged Secondary Factors Does Not Overcome
`The Obviousness Of Erlotinib Based On The Zeneca Prior Art ........................ .. l4
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Plaintiffs Rely On A Legally Flawed Comparison To A Non-Prior
`Art Compound And Thus Offered No Relevant Evidence of
`Increased Potency .................................................................................. .. l4
`
`Plaintiffs Offered No Relevant Evidence Of Unexpected
`Effectiveness Against Pancreatic Cancer ............................................... .. l6
`
`Plaintiffs Point To No Relevant Expert Testimony Concerning The
`Metabolism Of Erlotinib ........................................................................ .. 16
`
`Plaintiffs’ Commercial Success Evidence Is Irrelevant To The
`RE ‘065 Patent And, In Any Event, Is Insufficient To Overcome
`The Strong Prima Facie Obviousness Based On The Zeneca Prior
`Art .......................................................................................................... .. 17
`
`Plaintiffs” Evidence Of Alleged Failures Of Others Is Insufficient
`To Overcome Obviousness .................................................................... .. 19
`
`III.
`
`Claim 53 Of The ‘221 Patent Is Anticipated ................................................................. .. 20
`
`A.
`
`B.
`
`C.
`
`Plaintiffs’ Expert Never Identified A Single Element Of Claim 53 Not
`Disclosed In The ‘498 Patent ............................................................................. .. 20
`
`Plaintiffs Cannot Overcome Anticipation By Ignoring Relevant Precedent ..... .. 22
`
`The 1998 Cold Spring Harbor Abstract Also Anticipates Claim 53 ................. .. 23
`
`i
`
`APOTEX 1040-002
`
`APOTEX 1040-002
`
`

`

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`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 3 of 38 PagelD #: 3227
`
`IV.
`
`Claim 53 Of The ‘221 Patent Is Obvious ....................................................................... .. 24
`
`A.
`
`B.
`
`C.
`
`Plaintiffs Ignore The Plethora Of Prior Art Suggesting The Use Of
`Erlotinib To Treat NSCLC ................................................................................. .. 24
`
`Plaintiffs’ Definition Of A “Success” As Obtaining FDA Approval Is
`Without Legal Support ....................................................................................... .. 26
`
`The Well-Known Relationship Between EGFR Expression And NSCLC
`Continues Today, Despite Plaintiffs’ Misplaced Attempt To Ignore It ............. .. 27
`
`D.
`
`Plaintiffs’ Secondary Factors Fail To Rebut The Obviousness Of Claim 53 .... .. 28
`
`V.
`
`CONCLUSION .............................................................................................................. .. 30
`
`i1
`
`APOTEX 1040-003
`
`APOTEX 1040-003
`
`

`

`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 4 of 38 PageID #: 3228
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`TABLE OF AUTHORITIES
`
`CASES
`
`Page(s)
`
`Akzo N. V. v. US. International Trade Commission,
`808 F.2d 1471 (Fed. Cir. 1986) ........................................................................................ ..22, 23
`
`Aventis Pharma Deutschland GmbH v. Lupin Ltd. ,
`N0. 2:05-CV-421, 2006 WL 2008962 (E.D. Va. July 17, 2006) ............................................. ..20
`
`Avent‘is Pharma Deutschland GmbH v. Lupin Ltd. ,
`403 F. Supp. 2d 484 (ED. 2005) ........................................................................................... ..20
`
`Celeritas Technologies, Ltd. v. Rockwell International Corp,
`150 F.3d 1354 (Fed. Cir. 1998) .............................................................................................. ..21
`
`Datascope Corp. v. SMEC, Inc.,
`776 F.2d 320 (Fed. Cir. 1985) .................................................................................................. ..5
`
`In re Deters,
`515 F.2d 1152 (C.C.P.A. 1975) ............................................................................................. ..16
`
`Disco Vision Associates v. Disc Manufacturing, Inc. ,
`25 F. Supp. 2d 301 (D. Del. 1998) ......................................................................................... ..24
`
`In re Dow Chemical Co.,
`837 F.2d 469 (Fed. Cir. 1988) ................................................................................................ ..29
`
`Eli Lilly & Co. v. Teva Pharmaceuticals USA, Inc,
`No. IP 02-0512-C—B/S, 2004 WL 1724632 (SD. Ind. July 29, 2004) .................................. ..20
`
`Ferring B. V. v. Barr Laboratories, Inc,
`437 F.3d 1181 (Fed. Cir. 2006) .............................................................................................. ..16
`
`Forest Laboratories, Inc. v. Ivax Pharmaceuticals, Inc,
`438 F. Supp. 2d 479 (D. Del. 2006) ....................................................................................... ..11
`
`In re Gleave,
`560 F.3d 1331 (Fed. Cir. 2009) .............................................................................................. ..21
`
`Graham v. John Deere Co,
`383 US. 1 (1966) ......................................................................................................... ..7,15, 18
`
`In re Huang,
`100 F.3d 135 (Fed. Cir. 1996) ................................................................................................ ..l9
`
`1“
`
`APOTEX 1040-004
`
`APOTEX 1040-004
`
`

`

`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 5 of 38 PageID #: 3229
`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 5 of 38 PagelD #: 3229
`
`Ex parte Humber,
`217 U.S.P.Q. 265 (Pat. & Tr. Off. Bd. App. 1981) ................................................................ ..15
`
`Inline Connection Corp. v. AOL Time Warner Inc,
`470 F. Supp. 2d 424 (D. Del. 2007) ....................................................................................... ..10
`
`Koito Manufacturing Co, Ltd. v. Turn-Key-Tech, LLC,
`381 F.3d 1142 (Fed. Cir. 2004) .............................................................................................. ..14
`
`KSR International Co. v. Teleflex Inc,
`550 US. 398 (2007) ................................................................................................................. ..5
`
`Merck & Co. v. Teva Pharmaceuticals USA, Inc,
`395 F.3d 1364 (Fed. Cir. 2005) .............................................................................................. ..18
`
`In re Merck & Co,
`800 F.2d 1091 (Fed. Cir. 1986) .............................................................................................. ..26
`
`Net MoneyIN, Inc, v. VeriSign, Inc,
`545 F.3d 1359 (Fed. Cir. 2008) ........................................................................................ ..22, 23
`
`Oxford Gene Technology Ltd. v. Mergen Ltd,
`345 F. Supp. 2d 431 (D. Del. 2004) ....................................................................................... ..10
`
`In re Payne,
`606 F.2d 303 (C.C.P.A. 1979) ............................................................................................... ..15
`
`Purdue Pharma Products LP. v. Par Pharmaceutical, Inc,
`642 F. Supp. 2d 329 (D. Del. 2009) ....................................................................................... ..17
`
`Rasmusson v. SmithKiine Beecham Corp,
`413 F.3d 1318 (Fed. Cir. 2005) .............................................................................................. ..21
`
`Sanofi-Syntheiabo v. Apotex, Inc,
`550 F.3d 1075 (Fed. Cir. 2008) .............................................................................................. ..22
`
`Santarus, Inc. v. Par Pharm, Inc,
`720 F. Supp. 2d 427 (D. Del. 2010) ....................................................................................... ..20
`
`Sundance, Inc. v. DeMonte Fabricating Ltd,
`550 F.3d 1356 (Fed. Cir. 2008) .............................................................................................. ..16
`
`STATUTES
`
`35 U.S.C. § 102 ...................................................................................................................... ..10, 30
`
`35 U.S.C. § 103 ............................................................................................................................ ..30
`
`iv
`
`APOTEX 1040-005
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`APOTEX 1040-005
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`

`

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`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 6 of 38 PagelD #: 3230
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`OTHER AUTHORITIES
`
`US. Patent No. 5,747,498 .................................................................................................... ..passz'm
`
`US. Patent No. 6,900,221 .................................................................................................... ..passim
`
`U.S. Reissued Patent No. 41,065 ......................................................................................... .. passim
`
`US Patent & Trademark Office, Manual of Patent Examining Procedure (8th ed. 2010) ......... ..10
`
`APOTEX 1040-006
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`APOTEX 1040-006
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`

`

`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 7 of 38 PageID #: 3231
`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 7 of 38 PagelD #: 3231
`
`fig: 4—anilinoquinazoline.
`
`GLOSSARY
`
`acetylene: an ethynyl group. See, e.g., D.I. 227, 735 :25-736:l (Jorgensen).
`
`alkyl: a hydrocarbon with a carbon-carbon single bond (C—C). See, e. g. , 13.1. 225, 308:4-
`10 (Heathcock).
`
`alkenyl: a hydrocarbon with a carbon-carbon double bond (C=C). See, 6. g, D.I. 225,
`308: l l-l4 (Heathcock).
`
`alkynyl: a hydrocarbon with a carbon-carbon triple bond (CEC). See, e. g., D.I. 225,
`308215-16 (Heathcock).
`
`
`CP—358 774: erlotinib. See, e.g., D.l. 226, 5172—4 (Arnold).
`
`EGFR: epidermal growth factor receptor.
`
`
`erlotinib: also known as CP-358,774. See, e.g., D.l. 226, 517:2-4 (Arnold).
`
`meta position: 3’—position on the aniline ring. See, 6g, UL 225, 316325-3173
`(Heathcock).
`
`
`NSCLC: non—small cell lung cancer.
`
`E: tyrosine kinase inhibitor.
`
`SCLC: small cell lung cancer.
`
`V1
`
`APOTEX 1040-007
`
`APOTEX 1040-007
`
`

`

`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 8 of 38 PageID #: 3232
`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 8 of 38 PagelD #: 3232
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`I.
`
`SUMMARY OF THE REPLY
`
`Throughout their brief, Plaintiffs ignore the explicit disclosures and suggestions of the
`
`prior art and instead conflate the invalidity issues of the two patents. For the RE ‘065 patent, Dr.
`
`Heathcock explained that, based on the key prior art documents—Zeneca’s ‘226 patent
`
`application and Zeneca’s two Barker Abstracts——the easiest EGFR inhibitors for a person of
`
`ordinary skill1 to make were a small group of 4-anilinoquinazolines (“4—AQs”), one of which
`
`was erlotinib. Instead of rebutting Dr. Heathcock’s explanation of why erlotinib was primafacz’e
`
`obvious in view of this prior art, Plaintiffs incorrectly accuse Dr. Heatheock of applying
`
`hindsight.
`
`Plaintiffs also erroneously rely on the missteps of Dr. Lee Arnold and his Pfizer
`
`colleagues in responding to the obviousness evidence. Dr. Arnold was tasked with making
`
`compounds that could inhibit EGFR, which he did. During the entire process, however, Dr.
`
`Arnold knew that Zeneca was ahead of Pfizer. After pursuing different classes of EGFR
`
`inhibitors—some of which lead to arguably nonobvious compounds—Arnold and his Pfizer
`
`scientists returned to the very compounds suggested by Zeneca’s ‘226 application and the Barker
`
`Abstracts. The path laid out by Zeneca is no less obvious simply because Pfizer scientists first
`
`pursued less obvious EGFR inhibitors before ultimately returning to and following prior art
`
`teachings.
`
`Had Zeneca not suggested the preference for “small, non-polar” groups at the 3’—position
`
`of the 4—AQs, erlotinib might have been nonobvious at the time. Under the controlling law on
`
`obviousness, however, a patent is not granted for simply following the specific suggestions laid
`
`out in the prior art. As Dr. Heathcock explained, a person of ordinary skill would have looked at
`
`1 It is undisputed that the person of ordinary skill in the art in the context of the RE ‘065 patent is
`a medicinal chemist.
`(See D.I. 226, 61029—16 (Bridges); D.I. 227, 706:21-707:7 (Jorgensen).)
`
`l
`
`APOTEX 1040-008
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`APOTEX 1040-008
`
`

`

`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 9 of 38 PageID #: 3233
`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 9 of 38 PagelD #: 3233
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`the “gap” in the claim coverage of Zeneca’s ‘226 application and, in combination with Zeneca’s
`
`specific suggestion of specifically selecting small non-polar groups at the 3’-position (from the
`
`Barker Abstracts), would have made a small group of easily prepared 4—AQs, one of which was
`
`erlotinib.
`
`As for claim 53 of the ‘221 patent—using erlotinib to treat NSCLC—Plaintiffs still
`
`cannot identify a single claim limitation that is not expressly disclosed in Plaintiffs’ own prior
`
`art. Everything an oncologist needed to practice the treatment method of claim 53 is described
`
`within the four corners of Pfizer’s ‘498 patent, and independently, in the 1998 Cold Spring
`
`Harbor Abstract. 2
`
`In response, Plaintiffs adopt the legally flawed argument that the person of
`
`ordinary skill would not believe the prior art. But the law is clear: If all claimed elements are in
`
`a single prior art document, the claim is anticipated.
`
`Additionally, when Plaintiffs eventually filed for the ‘221 patent for using erlotinib to
`
`treat NSCLC—«years after disclosing the use in the ‘498 patentM—the oncologist knew much more
`
`about erlotinib, including that it had been safely administered to lung cancer patients. Thus, in
`
`addition to being anticipated, claim 53 is obvious. Plaintiffs’ non—obviousness arguments are
`
`fundamentally flawed and rest in large part on the legally erroneous concept that a reasonable
`
`expectation of success does not occur until actual success-in-fact has been demonstrated.
`
`II.
`
`THE ASSERTED CLAIMS OF THE RE ‘065 PATENT ARE OBVIOUS
`
`A.
`
`Zeneca’s Prior Art Suggested Erlotinib Among Other Obvious EGFR
`Inhibitors
`
`Plaintiffs do not overcome the evidence demonstrating that claims 1, 2, 4, 8, 34, and 35
`
`of the RE ‘065 patent were obvious in View of Zeneca’s prior art ‘226 application and the Barker
`
`2 It is undisputed that the person of ordinary skill in the art in the context of the ‘221 patent is a
`medical oncologist. (See D.I. 233 (“Pls’ Br”) 57.)
`
`APOTEX 1040-009
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`APOTEX 1040-009
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`

`

`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 10 of 38 PageID #: 3234
`Case 1:09-cv—00185-SLR Document 234 Filed 10/07/11 Page 10 of 38 PagelD #: 3234
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`Abstracts.
`
`1.
`
`Plaintiffs Mischaracterize Dr. Heathcock’s Analysis And Opinion
`
`Plaintiffs resort to sophistry in their attack on Dr. Heathcock’s analysis. Dr. Heathcock
`
`provided a clear and cogent explanation of why an ordinary medicinal chemist would: (1) start
`
`with the preferred 4—AQs from Zeneca’s c226 application; and (2) make a single modification to
`
`those preferred 4,-AQs based on the suggestions in the Barker Abstracts and the gap in claim
`
`coverage in the ‘226 application. Using either a small, non—polar ethynyl or a vinyl group at the
`
`3’—position as suggested,
`
`this single modification produced a small group of twenty EGFR
`
`inhibitors, one of which is erlotinib. Rather than address this prior art—based analysis, Plaintiffs
`
`try to manufacture a hindsight argument, even citing Dr. Heathcock’s experience in an unrelated
`
`litigation.
`
`(See Pls.’ Br. 23 n.11.)
`
`There is no reasonable dispute that Zeneca’s ‘226 application was the best starting point.
`
`Several prior art references identified the 4-AQs as the preferred EGFR inhibitors.
`
`(See, e.g.,
`
`DTX 354, DTX 428, PTX 43.)
`
`Plaintiffs” expert Dr. Bridges agreed that Zeneca’s ‘226
`
`application is “probably one of the best pieces of prior art.” (D.I. 226, 674:9-14.) The fact that
`
`Dr. Arnold and his colleagues eventually turned to the ‘226 application for guidance after
`
`making different EGFR inhibitors merely confirms the opinions of Drs. Bridges and Heathcock.
`
`At trial, Dr. Heathcock explained the medicinal Chemist’s motivation to make EGFR
`
`inhibitors falling outside the scope of Zeneca’s ‘226 patent application. An ordinarily skilled
`
`medicinal chemist would be motivated to find the compounds not covered by existing patents
`
`and patent applications.
`
`(D.I. 225, 290:6—15 (Heathcock).) Plaintiffs’ expert Dr. Jorgensen
`
`agreed. (DI. 227, 766:3-15.) Pfizer documents confirm this motivation.
`
`(See PTX 525 (listing
`
`“Assessment of Patent Opportunities”); DTX 23 (stating that certain analogs “are distinct
`
`analogs not covered under the Zeneca patent, but probably not as desirable as CP292597 from a
`
`APOTEX 1040-010
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`APOTEX 1040-010
`
`

`

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`patent viewpoint”).)
`
`Even Plaintiffs’ witness Dr. Arnold confirmed that making EGFR
`
`compounds outside the scope of Zeneca’s prior art application “would be the goal of any
`
`medicinal chemist in the program.” (DI. 226, 556: 14-17.)
`
`Of course, a medicinal chemist could have made many changes to the 4—AQs to get
`
`outside the scope of Zeneca’s ‘226 application.
`
`In fact, Dr. Arnold and his Pfizer team initially
`
`did make structurally diverse, non—4-AQ EGFR inhibitors. But that is irrelevant to the objective
`
`obviousness analysis, and most of that work was done before Pfizer became aware of Zeneca’s
`
`key prior art suggesting the 3 ’-ethynyl group.3
`
`More importantly, an ordinarily skilled medicinal chemist would not have made random
`
`modifications to Zeneca’s 4-AQS.
`
`Instead, the ordinarily skilled artisan would look to the prior
`
`art to identify modifications that could be made to what others had already done. This would
`
`include the potent 4—AQ EGFR inhibitors taught in Zeneca’s ‘226 application—the obvious gap
`
`in the claim coverage at
`
`the 3’-position (DI. 225, 290222—291214 (Heathcock))—and the
`
`guidance of the Barker Abstracts, which suggested the specific addition of small, non—polar
`
`groups at that position. (Id, 316:12-317:10; 326: 1 5-327: 19 (Heathcock).) In short, the person of
`
`ordinary skill would take the easiest path to arrive at EGFR inhibitors most similar in structure to
`
`Zeneca’s proven EGFR inhibitors, yet outside the scope of Zeneca’s ‘226 application.4
`
`The ordinarily skilled medicinal Chemist’s job was made easy by the explicit teachings of
`
`the prior art. First, Zeneca had a gap in its claim coverage: The claims did not cover ethynyl (or
`
`Vinyl) at the 3’—position of the 4—AQs. Plaintiffs attempt to obfuscate this fact by calling it an
`
`3 Plaintiffs cite PTX 555 and PTX 558 in their brief, but those exhibits were not admitted into
`evidence. (See D.I. 226, 483210-48724, 502:4-50326.)
`
`4 For this reason, Plaintiffs’ argument and evidence about modifying the so-called “core” of the
`4-AQ misses the point. (Pls.’ Br. 32.) Modifying the 4-AQ core ignores the express suggestions
`of the Zeneca prior art.
`
`APOTEX 1040-01 1
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`APOTEX 1040-011
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`

`

`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 12 of 38 PageID #: 3236
`Case 1:09-cv—00185-SLR Document 234 Filed 10/07/11 Page 12 of 38 PagelD #: 3236
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`“erroneous legal theory.” (Pls.’ Br. 24.) Little could be further from the truth. The prior art gap
`
`is based on factual testimony, not legal fiction. As Dr. Heathcock explained, an ordinary
`
`medicinal chemist would have easily recognized that Zeneca’s ‘26 application claimed “alkyl”
`
`V but not the “very closely related” ethynyl and vinyl groups.
`
`(D.I. 225, 291:19-292222.) Thus, to
`
`fill the gap and arrive at erlotinib, one needed only to select the ethynyl group.5
`
`Additionally, Dr. Heathcock explained that the Zeneca ‘226 application contained “an
`
`implicit suggestion that Zeneca preferred compounds that had a substituent at the 3’-positi0n.”
`
`(D.I. 225, 310:4—13.) Of all the compounds made in the ‘226 application, the vast majority had
`
`the small, non-polar methyl group at the 3’-position, further suggesting that small, non—polar
`
`groups are preferred.
`
`(1d,, 297:7—18 (Heathcock).) Moreover, Zeneca’s Barker Abstracts
`
`explicitly targeted the 3’-position, telling the medicinal chemist that small, non-polar groups at
`
`the 3’-position produce the most active EGFR inhibitors.
`
`(1d,, 316212—317110; 326:15-327:19
`
`(Heathcock); DTX 107; DTX 112.) Because an ethynyl,
`
`like the methyl,
`
`is a non—polar
`
`hydrocarbon group,
`
`(D1. 225, 317:11—318:4 (Heathcock); see also D.I. 227, 712:18—713:1
`
`(Jorgensen)), and ethynyl
`
`is indisputably a small group, as Plaintiffs’ expert Dr. Jorgensen
`
`admitted, (D.I. 227, 772:2—6), it required no stretch of the medicinal Chemist’s imagination to use
`
`ethynyl at the 3 ’-position.6
`
`5 Plaintiffs’ reliance on Dat‘ascope Corp. v. SMEC, Inc, 776 F.2d 320, 324 (Fed. Cir. 1985)—for
`the proposition that Mylan’s obviousness theory is “improper”—is misplaced. Dal’ascope
`condemns only the explicit treatment of the difference between the claims and the prior art as
`“the invention,” while acknowledging that “that difference may serve as one element
`in
`determining the obviousness/nonobviousness issue.” Id. In the present case, the gap provides the
`medicinal Chemist’s reason for selecting ethynyl. See KSR Int”! Co. v. Teleflex Inc, 550 US.
`398, 418 (2007) (“[I]t can be important to identify a reason that would have prompted a person
`of ordinary skill
`in the relevant field to combine the elements in the way the claimed new
`invention does”). After that, the obviousness analysis turns to comparing what is claimed, i.e.,
`erlotinib, to the closest prior art, i.e., Example 51 of Zeneca’s 226 application.
`
`6 Plaintiffs’ unconvincingly allege that the “unpredictability of medicinal chemistry” would
`
`APOTEX 1040-012
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`APOTEX 1040-012
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`

`

`Case 1:09-cv-00185-SLR Document 234 Filed 10/07/11 Page 13 of 38 PageID #: 3237
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`With all of Zeneca’s prior art suggesting the small, non—polar ethynyl group at the
`
`3 ’-position, the question for the medicinal chemist was: which known EGFR inhibitors should be
`
`modified to include an ethynyl group at the 3’-position? Again, Dr. Heathcock explained that
`
`the ordinarily skilled medicinal chemist would have read Zeneca’s application to find that the
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`inventor himself had nominated thirty-two 4-AQs as “specific preferred” compounds. (UL 225,
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`335:6—10.) Moreover, the ordinarily skilled medicinal chemist knew that compounds specifically
`
`claimed are important.
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`(1d, 336:2-12 (Heathcock).) Only thirteen 4-AQs were specifically
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`recited in claims 7 and 9 of Zeneca’s ‘226 application.
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`(Id) These thirteen compounds were
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`also described as “specific preferred,” in the specification of the ‘226 application, thus yielding
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`only thirteen leading 4—AQs as both specifically claimed and “specific preferred.”
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`Dr. Heathcock’s opinion is neither hindsight nor cherry picking. Rather, he explained
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`how the ordinarily skilled medicinal Chemist’s easiest path to EGFR inhibitors was (1) starting
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`with the thirteen “specific preferred” and specifically claimed 4-AQs from Zeneca’s ‘226
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`application; and (2) making a single modification of those preferred 4—AQs at the 3’-position, to
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`include a small, non—polar group as suggested by the Barker Abstracts and the claim gap in the
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`‘226 application. (D.l. 232 (“Mylan Br”) 30—31.)
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`The focus in obviousness is of course the prior art, not what the inventors did or did not
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`preclude reasonable expectation of success. (Pls.’ Br. 38.) Here, however, the prior art confirmed
`that 4-AQs of varying structures exhibited consistently potent EGFR inhibition in the nanomolar
`range. (D.l. 225, 29722-298215 (Heathcock).) Accordingly, Plaintiffs’ cases (Pls.’ Br. 38) are
`inapposite. Moreover, contrary to his speculation that the ethynyl group would be assumed to be
`too large based on the alleged unpredictability, Plaintiffs’ medicinal chemistry expert agreed that
`it would be a “normal exercise” for one of ordinary skill to explore what size substituents can be
`used while still retaining activity. (D1. 227, 781:1-6 (Jorgensen).) Because the ‘226 application
`demonstrated a preference for the smallest hydrocarbon group,
`i.e., methyl,
`the ordinary
`medicinal chemist would logically pick the next smallest hydrocarbon,
`tie. ,
`the ethynyl.
`Plaintiffs’ argument that the person of ordinary skill would try “at least 80” small groups at the
`3 ’-position (Pls.’ Br. 36) is illogical and inconsistent with the testimony of their own expert.
`
`APOTEX 1040-013
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`APOTEX 1040-013
`
`

`

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`do. Dr. Heathcock’s analysis of the prior art from the perspective of the person of ordinary skill
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`is therefore legally sound. Plaintiffs” criticism that Dr. Heathcock knew the structure of erlotinib
`
`before conducting his analysis is misplaced. He did exactly what the Supreme Court has
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`mandated: compared the claimed invention with the prior art. See Graham v. John Deere C0,,
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`383 US. 1, 17-18 (1966).
`
`2.
`
`Plaintiffs Ignore That The Limited Biological Data In The ‘226
`Application Was Of Little Value In Selecting Preferred Compounds
`
`Plaintiffs also misguidedly attack Dr. Heathcock’s explanation of why a medicinal
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`chemist would not have simply looked at the biological data in Zeneca’s ‘226 application. Dr.
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`Heathcock testified that the ‘226 application did not contain enough data to distinguish between
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`the compounds.
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`(D.I. 225, 409:6-410z5.) Plaintiffs’ expert Dr. Bridges agreed that Zeneca’s
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`‘226 application contains “no useful biological information which allows you to choose, for
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`instance, between halogen and methyl.”
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`(D.I. 226, 68521-6; id, 686:3—7 (agreeing that “the
`
`biological data in the ‘226 application doesn’t give a person of ordinary skill in the art enough
`
`information to decide a lead compound to select from the ‘226 application”).) Additionally, an
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`ordinarily skilled medicinal chemist would have known that Zeneca’s ‘226 application did not
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`disclose biological data for its most potent compound.
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`(D.I. 225, 302:18-303:6 (Heathcock).)
`
`That data was instead published in a separate Science publication.
`
`(Id. ; PTX 43.) Because the
`
`data in Zeneca’s ‘226 application was on its face incomplete, the medicinal chemist had to rely
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`on other tell—tale indicators of preferred compounds, such as which compounds were claimed and
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`which compounds were explicitly described as “specific preferred.”
`
`In response, Plaintiffs contort Mylan’s brief by removing the qualifier “In many
`
`instances” from the quote “in vitro potency of the EGFR inhibitors drives the selection of
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`compounds.” (Pls.’ Br. 26 (quoting Mylan Br. 9).) Mylan’s qualified statement is consistent
`
`APOTEX 1040-014
`
`APOTEX 1040-014
`
`

`

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`with Dr. Heathcock’s opinion that biological data may, but do not always, inform the selection of
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`starting compounds.
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`(D.l. 225, 353:6—10.) Both Drs. Heathcock and Bridges recognized that
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`incomplete biological data, as in the “226 application, is of the diminished value.7
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`Moreover, Plaintiffs’ complaint that Dr. Heathcock allegedly had “no idea” of why
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`Zeneca claimed certain compounds misses the mark.
`
`(Pls.’ Br. 27.) The proper objective
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`analysis considers how an ordinary medicinal chemist would view the prior art. Zeneca’s ‘226
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`application identified “32 specific compounds that are called specific preferred.”
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`(D.I. 225,
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`335 :2-336:1 (Heathcock).) With this explicit teaching,
`
`the medicinal chemist would have
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`“like[d] these better out of all the things they made and disclosed” in the ‘226 application.
`
`(161)
`
`The ordinarily skilled medicinal chemist would further narrow these “specific preferred”
`
`compounds to the 13 compounds claimed because, as Dr. Heathcock explained, “a medicinal
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`chemist would take away the message that there is something really that Zeneca likes about these
`
`13 compounds or they wouldn’t have taken the trouble to claim them individually by name.”
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`(Id, 335:11-24.) Plaintiffs’ own witnesses confirmed the importance attributed to claimed
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`compounds.
`
`(See D.l. 226, 477:13-24 (Arnold)
`
`(stating that Pfizer wanted to “generate
`
`compounds that were outside the confines of the ICI [Zeneca] patent”); D.l. 226, 687:2—13
`
`(Bridges: confirming that “claim 1, which is normally the broadest claim, .
`
`.
`
`. tells you if you are
`
`moving into infringing other people’s IP space”).) Accordingly, Dr. Heathcock’s testimony was
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`far from the “speculation” Plaintiffs allege.
`
`(See Pls.’ Br. 27.)
`
`Plaintiffs also mischaracterize Dr. Heathcock’s analysis regarding the 6- and 7-positions.
`
`7 Plaintiffs confuse Dr. Heathcock’s position in asserting that he opined that a person of ordinary
`skill would “ignore biological data and focus instead only on the compounds claimed in a prior
`art patent application.” (Pls.’ Br. 27.) Rather, Dr. Heathcock explained the important guidance
`revealed by what was claimed, given the limited value of the biological data in Zeneca’s ‘226
`application for determining the preferred compounds, particularly in View of the explicit
`statements of “specific preferred” and specifically claimed compounds.
`
`APOTEX 1040-015
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`APOTEX 1040-015
`
`

`

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`Dr. Heathcock did not opine that an ordinary medicinal chemist would specifically select only
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`the dimethoxyethoxy group for the 6- and 7—positions.
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`Instead, the medicinal chemist would
`
`have focused on the EGFR inhibitors from Zeneca’s ‘226 application identified as leading
`
`compounds. Having found those thirteen compounds, the medicinal chemist would make the
`
`ethynyl or Vinyl version and produce twenty EGFR inhibitors with various groups at the 6- and
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`7-position, one of which had the 6—,7-dimethoxyethoxy group. Thus, there was no hindsight
`
`selection of the 6—,7—dimethoxyethoxy group, or cherry