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`
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`Case: 12-1431 Document: 31 Page: 1 Filed: 10/25/2012
`
`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.
`_____________________________________________________________
`
`REPLY BRIEF OF DEFENDANT-APPELLANT
`MYLAN PHARMACEUTICALS INC.
`_____________________________________________________________
`
`
`
`James H. Wallace, Jr.
`Mark A. Pacella
`Gregory R. Lyons
`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. 1061-001
`
`

`

`Case: 12-1431 Document: 31 Page: 2 Filed: 10/25/2012
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`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: October 25, 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. 1061-002
`
`

`

`Case: 12-1431 Document: 31 Page: 3 Filed: 10/25/2012
`
`TABLE OF CONTENTS
`
`Page
`INTRODUCTION .......................................................................................... 1
`I.
`II. USE OF ERLOTINIB TO TREAT NSCLC AS CLAIMED IN THE
`’221 PATENT WAS ANTICIPATED ........................................................... 4
`A.
`The ’498 Patent’s Express Disclosure Of Erlotinib Within A
`Discrete Set Of Compounds For Treating A Discrete Set Of
`Disease Anticipated Claim 53 Of The ‘221 Patent .............................. 4
`The Cold Spring Harbor Abstract Anticipated Claim 53 ..................... 9
`B.
`III. USING ERLOTINIB TO TREAT NSCLC AS CLAIMED IN THE
`’221 PATENT WAS OBVIOUS .................................................................. 10
`A.
`By 1999, Erlotinib’s Promise As A NSCLC Treatment Was
`Readily Apparent ................................................................................ 11
`Plaintiffs’ No “Reasonable Expectation Of Success” Argument
`Erroneously Defines “Success” As Proof Of Actual Success
`And FDA Approval ............................................................................ 13
`C. No Secondary Considerations Supported Non-Obviousness ............. 15
`IV. THE ERLOTINIB COMPOUND AS CLAIMED IN THE RE ’065
`PATENT WAS OBVIOUS .......................................................................... 16
`A.
`The District Court’s Rigid Focus On Biological Data As A
`Prerequisite To Obviousness Contravenes Binding Precedent .......... 17
`Contrary To Plaintiffs’ Contention, Mylan’s Obviousness Case
`Was Not Based On Hindsight ............................................................ 21
`The Prior Art Did Not Teach Away From Using The Ethynyl
`Group At The 3’-Position ................................................................... 23
`The District Court Found No Unexpected Results Or Secondary
`Considerations Supporting Non-Obviousness ................................... 26
`V. CONCLUSION ............................................................................................. 29
`
`B.
`
`B.
`
`C.
`
`D.
`
`
`
`
`
`- ii -
`
`APOTEX EX. 1061-003
`
`

`

`Case: 12-1431 Document: 31 Page: 4 Filed: 10/25/2012
`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`In re Arkley,
`455 F.2d 586 (C.C.P.A. 1972) .............................................................................. 5
`
`Akzo N.V. v. United States International Trade Commission,
`808 F.2d 1471 (Fed. Cir. 1986) ............................................................................ 5
`
`In re Blondel,
`499 F.2d 1311 (C.C.P.A. 1974) .......................................................................... 26
`
`Celeritas Technologies, Ltd. v. Rockwell International Corp.,
`150 F.3d 1354 (Fed. Cir. 1998) ............................................................................ 9
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Patent Litigation,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 16
`
`Daiichi Sankyo Co. v. Matrix Labs, Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) .......................................................................... 18
`
`Datascope Corp. v. SMEC, Inc.,
`776 F.2d 320 (Fed. Cir. 1985) ............................................................................ 17
`
`In re Deters,
`515 F.2d 1152 (C.C.P.A. 1975) .......................................................................... 27
`
`Eisai Co. v. Dr. Reddy’s Laboratories, Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) .......................................................................... 19
`
`Eli Lilly & Co. v. Teva Pharmaceuticals USA, Inc.,
`619 F.3d 1329 (Fed. Cir. 2010) .......................................................................... 14
`
`Eli Lilly & Co. v. Zeith Goldline Pharmaceuticals, Inc.
`471 F.3d 1369 (Fed. Cir. 2006) .......................................................................... 16
`
`Ferring B.V. v. Barr Laboratories, Inc.,
`437 F.3d 1181 (Fed. Cir. 2006) .......................................................................... 27
`
`In re Gleave,
`560 F.3d 1331 (Fed. Cir. 2009) ............................................................................ 6
`
`- iii -
`
`APOTEX EX. 1061-004
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`

`

`Case: 12-1431 Document: 31 Page: 5 Filed: 10/25/2012
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`Graham v. John Deere Co.,
`383 U.S. 1 (1966) .......................................................................................... 16, 26
`
`In re Huang,
`100 F.3d 135 (Fed. Cir. 1996) (See Mylan Br. 66-67.) ...................................... 28
`
`Ex Parte Humber,
`217 U.S.P.Q. 265 (B.P.A.I. 1981) ...................................................................... 26
`
`Impax Laboratories, Inc. v. Aventis Pharmaceuticals Inc.,
`545 F.3d 1312 (Fed. Cir. 2008) ............................................................................ 9
`
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc.,
`688 F.3d 1342 (Fed. Cir. 2012) .......................................................................... 11
`
`Koito Manufacturing Co. v. Turn-Key-Tech, LLC,
`381 F.3d 1142 (Fed. Cir. 2004) .......................................................................... 10
`
`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................ 17, 18, 20
`
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009) .......................................................................... 13
`
`Metabolite Labsoratories Inc. v. Laboratory Corp.,
`370 F.3d 1354 (Fed. Cir. 2004) ............................................................................ 6
`
`Motorola, Inc. v. Interdigital Technology Corp.,
`121 F.3d 1461 (Fed. Cir. 1997) .......................................................................... 10
`
`Otsuka Pharmaceutical Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) ...................................................................... 8, 19
`
`In re Payne,
`606 F.2d 303 (C.C.P.A. 1979) ............................................................................ 26
`
`Perricone v. Medicis Pharmaceutical Corp.,
`432 F.3d 1368 ....................................................................................................... 6
`
`Purdue Pharma Products L.P. v. Par Pharmaceutical, Inc.,
`377 F. App’x 978 (Fed. Cir. 2010) ..................................................................... 28
`
`- iv -
`
`APOTEX EX. 1061-005
`
`

`

`Case: 12-1431 Document: 31 Page: 6 Filed: 10/25/2012
`
`Rasmusson v. SmithKline Beecham Corp.,
`413 F.3d 1318 (Fed. Cir. 2005) ............................................................................ 9
`
`Sanofi-Syntholabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) ............................................................................ 5
`
`Sundance, Inc. v. DeMonte Fabricating Ltd.,
`550 F.3d 1356 (Fed. Cir. 2008) .......................................................................... 27
`
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC,
`683 F.3d 1356 (Fed. Cir. 2012) ........................................................................ 6, 7
`
`
`
`- v -
`
`APOTEX EX. 1061-006
`
`

`

`Case: 12-1431 Document: 31 Page: 7 Filed: 10/25/2012
`
`I.
`
`INTRODUCTION
`
`Plaintiffs’ Opposition1 cannot rebut the fact that the district court committed
`
`three critical legal errors. First, the court erroneously concluded that the ’221
`
`patent’s claimed use of erlotinib to treat NSCLC was not anticipated, even though
`
`the prior art disclosed that same use for erlotinib. Second, in ruling that the ’221
`
`patent’s asserted claim was non-obvious, the court ignored the claim limitations to
`
`equate “reasonable expectation of success” with actual success and FDA approval.
`
`Third, the court applied an unduly restrictive analysis in conflict with Supreme
`
`Court precedent and this Court’s case law to find the RE ’065 patent’s claims to
`
`the erlotinib compound non-obvious. Therefore, contrary to Plaintiffs’ framing of
`
`the issues (Opp. 2-3), the court’s errors are subject to de novo review. The district
`
`court’s legal errors infected its understanding of the factual evidence and led to its
`
`clearly erroneous factual findings on the issue of obviousness.
`
`With respect to the ’221 patent, Plaintiffs seek to impart complexity to a
`
`straightforward case of anticipation. Plaintiffs’ Opposition confirms there is no
`
`factual dispute that the ’498 patent expressly disclosed every limitation of the
`
`asserted claim. Instead, Plaintiffs seek to distract from this fatal flaw by asserting
`
`– incorrectly – that “both sides’ experts agreed that a person of ordinary skill in the
`
`art would not have read the ’498 patent as disclosing a method of administering
`
`1 Brief of Plaintiffs-Appellees OSI Pharmaceuticals, Inc., Pfizer Inc., and
`Genentech, Inc. is cited herein as “Opp. __.”
`
`1
`
`APOTEX EX. 1061-007
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`

`

`Case: 12-1431 Document: 31 Page: 8 Filed: 10/25/2012
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`erlotinib for the treatment of NSCLC.” (Opp. 3.) Indeed, years before Pfizer’s
`
`application for the ’221 patent, Pfizer’s ’498 patent disclosed and claimed both
`
`erlotinib compound itself and its use in treating NSCLC. The only dispute is a
`
`legal one: whether the district court properly found no anticipation, despite the
`
`’498 patent’s disclosure of erlotinib as one of a discrete set of specific preferred
`
`compounds used to treat a discrete set of specific diseases including lung cancer.
`
`The district court committed legal error in ruling that claim 53 was not anticipated
`
`because the ’498 patent did not state “erlotinib for the treatment of lung cancer”
`
`and one of ordinary skill would not have believed “that every compound disclosed
`
`would be a treatment for every disease disclosed.”
`
`The district court also committed legal error and clear errors of fact in
`
`concluding that claim 53 was not obvious. As Plaintiffs’ Opposition highlights,
`
`the § 103 dispute asks whether the prior art created a “reasonable expectation of
`
`success.” Plaintiffs merely adopt the district court’s erroneous reasoning equating
`
`“success” with obtaining FDA approval, rather than successful “treatment” of a
`
`patient as claimed in the ’221 patent, and applying a restrictive standard for a
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`“reasonable expectation” that could only be met by actual success.
`
`Lastly, the district court legally erred in its obviousness analysis with respect
`
`to the RE ’065 patent. Plaintiffs endorse the district court’s focus on biological
`
`data as the sole basis for establishing obviousness of a pharmaceutical compound.
`
`2
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`APOTEX EX. 1061-008
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`

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`Case: 12-1431 Document: 31 Page: 9 Filed: 10/25/2012
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`(Opp. 36-39.) That rigid focus, however, is contrary to the expansive and flexible
`
`approach mandated by the Supreme Court and this Court’s precedent. The district
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`court’s narrow focus on biological data not only led it to discount the most
`
`preferred compounds of the prior art, but also infected its analysis of the
`
`motivation to modify those compounds.
`
`For purposes of analyzing obviousness of the erlotinib compound, it is
`
`undisputed that Example 51 of the prior art ’226 application is structurally similar
`
`to erlotinib – differing only by the substituent at the 3’-position. Plaintiffs and the
`
`district court mischaracterize Mylan’s position as selecting Example 51 as a “lead
`
`compound” in hindsight. Mylan’s expert, however, explained how one of ordinary
`
`skill in the art would have obtained erlotinib by modifying the most preferred,
`
`specifically claimed compounds in Zeneca’s ’226 application (one of which was
`
`the Example 51 compound) based on the teaching of the Barker Abstracts,
`
`authored by that application’s inventor –i.e., to use small, non-polar groups at the
`
`3’-position.
`
`Plaintiffs adopt the district court’s erroneous rationale for dismissing that
`
`evidence, i.e., that compounds for which specific biological data is not identified in
`
`the prior art must be disregarded. Plaintiffs also attempt to bolster their non-
`
`obviousness argument with purported unexpected
`
`results and secondary
`
`3
`
`APOTEX EX. 1061-009
`
`

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`Case: 12-1431 Document: 31 Page: 10 Filed: 10/25/2012
`
`considerations evidence, although the district court correctly gave that evidence
`
`little or no weight.
`
`II. USE OF ERLOTINIB TO TREAT NSCLC AS CLAIMED IN THE
`’221 PATENT WAS ANTICIPATED
`
`A. The ’498 Patent’s Express Disclosure Of Erlotinib Within A
`Discrete Set Of Compounds For Treating A Discrete Set Of
`Disease Anticipated Claim 53 Of The ‘221 Patent
`
`The only dispute as to anticipation by the ’498 patent is a legal one: whether
`
`the district court properly found claim 53 of the ’221 patent not anticipated, despite
`
`the ’498 patent’s specific disclosures of erlotinib as one of a discrete number of
`
`preferred EGFR inhibitors to be used in treating a discrete number of specific
`
`diseases associated with the overexpression of EGFR, including lung cancer.
`
`Plaintiffs’ Opposition does not identify any claim 53 limitation absent from the
`
`’498 patent.2 Rather, Plaintiffs endorse the district court’s erroneous reasoning that
`
`there is no anticipation here because the limitations are not “arranged or combined
`
`in the same manner as in the claim – i.e., erlotinib for the treatment of NSCLC.”
`
`
`2 Plaintiffs’ claim that their expert “demonstrated that the ’498 patent did not
`disclose every limitation of claim 53” (Opp. 55, n.10) is demonstrably false. The
`cited testimony did not identify any limitation as not being expressly disclosed, but
`simply adopted Plaintiffs’ flawed legal construct. Similarly, Plaintiffs’ statement
`that “both sides’ experts [testified] that a person of ordinary skill would not read
`the ’498 patent to disclose the method of using erlotinib for the treatment of
`NSCLC” (Opp. 57) is inaccurate. Mylan’s expert, Dr. Ratain, explained in detail
`how the ’498 patent disclosed every claim limitation. (A696:24-A698:8; A700:1-
`20; A714:6-A717:11.) He agreed only that one of ordinary skill might not believe
`that every one of the compounds disclosed in the ’498 patent would work for all of
`the diseases mentioned in the patent (A731:20-23), but did not concede that the
`specific claimed method of treatment was not disclosed. Such belief is not
`material to anticipation.
`
`4
`
`APOTEX EX. 1061-010
`
`

`

`Case: 12-1431 Document: 31 Page: 11 Filed: 10/25/2012
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`(Opp. 55.) That argument invites this Court to commit the same legal error
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`committed by the district court when it found no anticipation because the
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`disclosure lacked the words “erlotinib for the treatment of NSCLC” and that to
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`anticipate, the ’498 patent must “teach that every compound disclosed would be a
`
`treatment for every disease disclosed.”
`
`The cases Plaintiffs rely on to support the court’s reasoning are inapposite.
`
`In Sanofi-Syntholabo v. Apotex, Inc., a reference was non-anticipatory because it
`
`included only a general statement that compounds could exist as mixtures of
`
`enantiomers, but the claim was to a specific isolated enantiomer of one of the
`
`compounds that had never been separated, identified and characterized in the prior
`
`art. 550 F.3d 1075, 1084 (Fed. Cir. 2008). Akzo N.V. v. United States
`
`International Trade Commission noted the ALJ’s reliance on precedent explaining
`
`that anticipation cannot be based on “random picking and choosing” of prior art.
`
`808 F.2d 1471, 1480 (Fed. Cir. 1986) (citing In re Arkley, 455 F.2d 586, 587
`
`(C.C.P.A. 1972). Arkley, and the subsequent cases that applied it, however, simply
`
`stand for the proposition that a reference does not anticipate where the claimed
`
`invention must be cobbled together from various disclosures that are “not directly
`
`related to each other by the teachings of the cited reference.” 455 F.2d 587. That
`
`5
`
`APOTEX EX. 1061-011
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`

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`Case: 12-1431 Document: 31 Page: 12 Filed: 10/25/2012
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`is not the case here, where the ’498 patent expressly contemplates using the
`
`disclosed compounds to treat a limited category of cancers that includes NSCLC.3
`
` In Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356 (Fed.
`
`Cir. 2012), this Court distinguished Net MoneyIn, Inc. v. Verisign, Inc., 545 F.3d
`
`1359 (Fed. Cir. 2008), cited by Plaintiffs (Opp. 54). The Court explained that in
`
`Net MoneyIn “an ‘internet payment system’ was not anticipated by a prior art
`
`reference that disclosed all the components of the invention, because the reference
`
`disclosed two separate payment protocols, each of which contained only a subset
`
`of the components claimed in the patent at issue. . . . Therefore, the reference did
`
`not ‘prove prior invention of the thing claimed.’” Wrigley, 683 F.3d at 1361
`
`(citing Net Money In, 545 F.3d at 1371). In contrast, here the reference describes a
`
`category of specifically disclosed compounds related to the treatment of a category
`
`of diseases, and thus “[t]he question . . . for anticipation is . . . whether the number
`
`of categories and components . . . was so large that the combination . . . would not
`
`be immediately apparent to one of ordinary skill in the art.” Id.
`
`The ’498 patent describes a class of inhibitor compounds and expressly
`
`discloses erlotinib as among a discrete set of “specific preferred” and specifically
`
`3 Genus-species cases such as Metabolite Labsoratories Inc. v. Laboratory Corp.,
`370 F.3d 1354, 1367 (Fed. Cir. 2004), cited by Plaintiffs (Opp. 54) are equally
`inapplicable. This Court has repeatedly rejected the notion that a list of species is
`analogous to a genus disclosure. See Wrigley, 683 F.3d at 1361; In re Gleave, 560
`F.3d 1331, 1337-38 (Fed. Cir. 2009); Perricone v. Medicis Pharm. Corp., 432 F.3d
`1368, 1376 (“This Court rejects the notion that one of [14] listed ingredients
`cannot anticipate because it appears without special emphasis in a longer list.”).
`
`6
`
`APOTEX EX. 1061-012
`
`

`

`Case: 12-1431 Document: 31 Page: 13 Filed: 10/25/2012
`
`claimed compounds (A1721, 3:47-4:64; A1739, 39:33-40:64). The ’498 patent
`
`also discloses as a “preferred embodiment” using the compounds to treat a discrete
`
`category of cancers including lung cancer.4 (A1722, 5:56-60). Thus, using
`
`erlotinib for NSCLC is immediately apparent.5
`
`Plaintiffs incorrectly argue that “Mylan seeks to rely only on claims 8 and 14
`
`of the ’498 patent rather than the disclosure as a whole.” (Opp. 56.) While the
`
`’498 patent as a whole discloses a class of compounds that are said to be useful for
`
`treating a larger number of conditions, claims 8 and 14 focus on only 49 specific
`
`compounds – one of which is erlotinib – and 12 specific EGFR-related cancers –
`
`one of which is lung cancer. (A1738:39-40:65; A1739:41:61-63.) Thus, it is
`
`evident that the inventors of the ’498 patent envisioned and claimed using erlotinib
`
`for, among the other things, lung cancer (i.e., NSCLC). This is the case even if
`
`one considers all of the 105 specifically disclosed compounds and all of the 34
`
`conditions mentioned in the ’498 patent, rather than the more focused disclosures
`
`of preferred and specifically claimed embodiments.
`
`
`4 Although Plaintiffs mention that the words “non-small lung cancer” do not appear
`in the ’498 patent (Opp. 22), they do not dispute that, in the context of the ’498
`patent, “lung cancer” can only refer to NSCLC. (See Mylan 44-45 (citing, e.g.,
`Plaintiffs’ expert’s concession that one of ordinary skill would have understood
`“lung cancer” “at least included” NSCLC and inventor Karen Ferrante’s testimony
`(A1519:15-18) that one’s mind would “leap” to NSCLC when reading lung cancer
`in the context of EGFR inhibitors)).
`5 Contrary to Plaintiffs’ assertion that the Wrigley prior art disclosed “only three
`potential combinations” (Opp. 58), it listed at least three possible cooling agents
`and 23 possible flavoring agents that could be used to make the claimed
`compositions. 683 F.3d at 1360.
`
`7
`
`APOTEX EX. 1061-013
`
`

`

`Case: 12-1431 Document: 31 Page: 14 Filed: 10/25/2012
`
`The district court’s standard, which Plaintiffs urge this Court to adopt,
`
`conflates anticipation with obviousness, reasoning that the ’498 patent does not
`
`anticipate because “there is no disclosure or direction . . . that one should select
`
`erlotinib and NSCLC out of all the possible combinations.” (Opp. 57.) Plaintiffs’
`
`citation to Otsuka Pharmaceutical Co. v. Sandoz, Inc., 678 F.3d 1280, 1294 (Fed.
`
`Cir. 2012) is misplaced. Otsuka is an obviousness case and does not address
`
`anticipation. Moreover, unlike the Otsuka patent, the ’498 patent does not provide
`
`a mere “laundry list” of potential diseases to be targeted, but instead identifies a
`
`discrete class of diseases known to be associated with EGFR.
`
`Similarly, Plaintiffs misconstrue the law of anticipation, arguing that there is
`
`no anticipation because “Dr. Ratain . . . testified that ‘it would be difficult for a
`
`person of ordinary skill in the art’ to read the ’498 patent and believe that all the
`
`compounds would work” for “all the different diseases.” (Opp. 57.) The ’498
`
`patent expressly states that the disclosed inhibitor compounds “are all adapted to
`
`therapeutic use as antiproliferative agents (e.g., anticancer)
`
`in mammals,
`
`particularly humans” and that “in particular, the compounds of this invention are
`
`therapeutants or prophylactics for the treatment of a variety of human tumors
`
`[including] . . . lung . . . .” (A1726:14:1-12.)
`
`A purported lack of “belief” in what the reference says cannot defeat
`
`anticipation. Indeed, a reference need not even disclose proof of efficacy to
`
`8
`
`APOTEX EX. 1061-014
`
`

`

`Case: 12-1431 Document: 31 Page: 15 Filed: 10/25/2012
`
`anticipate a method of treatment claim. See, e.g., Impax Labs., Inc. v. Aventis
`
`Pharms. Inc., 545 F.3d 1312, 1315 (Fed. Cir. 2008); Rasmusson v. SmithKline
`
`Beecham Corp., 413 F.3d 1318, 1326 (Fed. Cir. 2005). Moreover, a “reference is
`
`no less anticipatory if, after disclosing the invention, the reference then disparages
`
`it.” Celeritas Techs., Ltd. v. Rockwell Int’l Corp., 150 F.3d 1354, 1361 (Fed. Cir.
`
`1998).
`
`B.
`
`The Cold Spring Harbor Abstract Anticipated Claim 53
`
`
`
`Plaintiffs do not dispute that the Cold Spring Harbor Abstract (“CSH
`
`Abstract”) expressly discloses erlotinib and identifies NSCLC as one of its targets.
`
`Contrary to Plaintiffs’ argument (Opp. 61), the CSH Abstract also discloses an
`
`effective oral dosage of erlotinib. That dosage, according to Dr. Ratain’s
`
`unrebutted expert testimony, corresponds to a human dose of 50 mg, which falls
`
`within the range of effective doses for erlotinib disclosed in the ’221 patent.
`
`(A683:3-15; A1710, 24:19-32.) Although Plaintiffs deny that the district court
`
`required disclosure of an actual treatment, they repeatedly assert that argument to
`
`buttress the court’s erroneous holding. (Opp. 59.) Additionally, Plaintiffs again
`
`conflate obviousness and anticipation, arguing that these disclosures cannot be
`
`anticipatory because “results from xenograft models could not be used to
`
`reasonably predict success in treatment of cancers.” (Id.) Anticipation, however,
`
`does not require any “reasonable prediction of success.”
`
`9
`
`APOTEX EX. 1061-015
`
`

`

`Case: 12-1431 Document: 31 Page: 16 Filed: 10/25/2012
`
`With regard to the carrier limitation, Plaintiffs cite inapposite cases not
`
`involving sufficiency of inherent disclosure testimony. The expert in Koito
`
`Manufacturing Co. v. Turn-Key-Tech, LLC simply identified five references and
`
`did not explain where they disclosed any claim limitation. 381 F.3d 1142, 1151-52
`
`(Fed. Cir. 2004). Similarly, in Motorola, Inc. v. Interdigital Technology Corp., the
`
`expert failed to explain where any one of four specific functions required by the
`
`claim was disclosed in the reference, either expressly or inherently. 121 F.3d
`
`1461, 1472-73 (Fed. Cir. 1997). Here, Dr. Ratain’s unrebutted testimony
`
`established that a carrier would have been used to orally administer erlotinib as
`
`described in the CSH Abstract. (See Mylan Br. 47-48.)6 It was clear error for the
`
`district court to simply disregard that testimony.
`
`III. USING ERLOTINIB TO TREAT NSCLC AS CLAIMED IN THE ’221
`PATENT WAS OBVIOUS
`
`Even assuming, arguendo, no anticipation, the ’498 patent, the CSH
`
`Abstract, and the multitude of other information that was known by the ’221
`
`patent’s filing date made using erlotinib to treat NSCLC as claimed in the ’221
`
`patent obvious.
`
`
`6 Brief of Defendant-Appellant Mylan Pharmaceuticals Inc. is cited herein as
`“Mylan Br. __.”
`
`10
`
`APOTEX EX. 1061-016
`
`

`

`Case: 12-1431 Document: 31 Page: 17 Filed: 10/25/2012
`
`A. By 1999, Erlotinib’s Promise As A NSCLC Treatment Was
`Readily Apparent
`
`Plaintiffs attack each piece of prior art individually and thus, like the district
`
`court, avoid considering the prior art as a whole. By doing so, Plaintiffs ignore the
`
`progression of publications making clear that erlotinib, as well as Zeneca’s EGFR
`
`inhibitor gefitinib, were promising treatments for, among other things, NSCLC.
`
`(See Mylan Br. 29-37, 50-53.) Indeed, by 1999, Pfizer and others had repeatedly
`
`and consistently described in scientific papers, review articles, and corporate
`
`disclosures erlotinib’s promise and progression into clinical trials in cancer
`
`patients. (Id.) Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 688 F.3d 1342
`
`(Fed. Cir. 2012) does not, as Plaintiffs suggest (Opp. 62-63), require a specific
`
`showing of motivation to combine certain references that Mylan did not meet.
`
`Here, all the references related to using erlotinib to treat EGFR-related cancers
`
`including NSCLC, and Mylan’s expert explained how
`
`they collectively
`
`demonstrated a reasonable expectation of success. (A667:21-709:14; A725:4-15;
`
`A726:18-727:2; Mylan Br. 50-53.)
`
`Plaintiffs attempt to distance themselves from the prior art by claiming that
`
`testing in cell lines other than NSCLC “has nothing to do with treatment of
`
`NSCLC with erlotinib.” (Opp. 24). In fact, various EGFR-expressing cell lines of
`
`general applicability were used to test the effects of EGFR inhibitors on EGFR-
`
`11
`
`APOTEX EX. 1061-017
`
`

`

`Case: 12-1431 Document: 31 Page: 18 Filed: 10/25/2012
`
`expressing tumors. (A763:4-15.) Plaintiffs’ suggestion that the ASCO abstracts
`
`were of interest only to head and neck doctors (Opp. 67) is similarly misleading –
`
`they were presented in a session directed towards EGFR-related cancers generally.
`
`(A1466:21-A1468:16; A5744-46.) Indeed, Pfizer reported that the results of tests
`
`conducted on HN5 tumors “illustrated that after an oral dose of CP358774
`
`[erlotinib], drug penetrated uniformly into HN5 tumors and other tissues, such as
`
`the pancreas and lung, the desired target tissues for antitumor effects.” (A5000; see
`
`also A686:15-A687:20 (emphasis added).) As such, this disclosure confirms to a
`
`person of ordinary skill that the desired targets include lung cancer. (A687:12-20.)
`
`Additionally, Plaintiffs’ criticisms of OSI’s press release and 10-K as prior
`
`art (Opp. 66) miss the point. Their relevance to the obviousness analysis does not
`
`flow from whether an oncologist would rely on them in making treatment
`
`decisions, but rather the message they convey to the public: that Plaintiffs (1) were
`
`aggressively pursuing erlotinib as a treatment for EGFR-associated cancers,
`
`including NSCLC; (2) believed erlotinib would work; and (3) were therefore
`
`investing substantial resources into further clinical studies in cancer patients. This
`
`evidence, in combination with all the scientific literature regarding erlotinib’s
`
`favorable properties and preclinical and clinical results, pointed to using erlotinib
`
`to treat NSCLC.
`
`12
`
`APOTEX EX. 1061-018
`
`

`

`Case: 12-1431 Document: 31 Page: 19 Filed: 10/25/2012
`
`B.
`
`Plaintiffs’ No “Reasonable Expectation Of Success” Argument
`Erroneously Defines “Success” As Proof Of Actual Success And
`FDA Approval
`
`Before the ’221 application filing date, there was ample evidence
`
`establishing a “reasonable expectation” that administering erlotinib would result in
`
`“treatment” of a patient. (See supra, III.B; Mylan Br. 51-52.) As such, under a
`
`correct application of the “reasonable expectation of success” test, that test is
`
`satisfied here. Plaintiffs’ assertion that “[t]he first proof of anti-tumor activity in
`
`an NSCLC patient” occurred in April 2000 (Opp. 20 (emphasis added)) highlights
`
`the heightened standard that Plaintiffs seek to impose. Moreover, the fact that just
`
`months after publication of the 1999 ASCO Abstracts erlotinib was proven
`
`successful in treating NSCLC suggests that there was a “reasonable expectation” in
`
`the prior art that erlotinib would treat NSCLC.7
`
`Plaintiffs also claim that Pfizer’s scientists had no “reasonable expectation
`
`of success” because they “didn’t know” that erlotinib would work for NSCLC until
`
`it was proven. (Opp. 19.) A “reasonable expectation of success” is not precluded
`
`because it was not known a priori that erlotinib would work. See, e.g., In re Kubin,
`
`561 F.3d 1351, 1360 (Fed. Cir. 2009) (“Obviousness does not require absolute
`
`predictability of success . . . [;] all that is required is a reasonable expectation of
`
`
`7 In fact, all one needed to do to obtain that proof of efficacy was to administer the
`same doses reported in the 1999 ASCO Abstracts to NSCLC patients. (Cf.
`A706:18-708:7; A5104 (Siu Abstract: 100-200 mg/day) with A722:5-723:6;
`A3398 (Tarceva® label: 150 mg/day)).
`
`13
`
`APOTEX EX. 1061-019
`
`

`

`Case: 12-1431 Document: 31 Page: 20 Filed: 10/25/2012
`
`success.” (citing In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988))). The
`