Amgen Inc. v. F. Hoffmann-LaRoche LTD et al

Filing 1315

MEMORANDUM in Support re #1284 MOTION for Directed Verdict Regarding Invalidity (Leave to file granted on October 4, 2007) filed by F. Hoffmann-LaRoche LTD, Roche Diagnostics GmbH, Hoffmann LaRoche Inc.. (Rizzo, Nicole)

Amgen Inc. v. F. Hoffmann-LaRoche LTD et al

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF MASSACHUSETTS

AMGEN, INC., Plaintiff, v. F. HOFFMANN-LA ROCHE, LTD, ROCHE DIAGNOSTICS GmbH, HOFFMANN-LA ROCHE INC., Defendants. Civil Action No. 05-12237 WGY U.S. District Judge Young Leave to file granted on 10/4/07

ROCHE'S MEMORANDUM IN SUPPORT OF ITS MOTION FOR JUDGMENT AS A MATTER OF LAW REGARDING INVALIDITY

Leora Ben-Ami (pro hac vice) Mark S. Popofsky (pro hac vice) Patricia A. Carson (pro hac vice) Thomas F. Fleming (pro hac vice) Howard S. Suh (pro hac vice) Christopher T. Jagoe (pro hac vice) Peter Fratangelo (BBO# 639775) Krista M. Rycroft (pro hac vice) Kaye Scholer LLP 425 Park Avenue New York, New York 10022 Tel. [phone] Dated: Boston, Massachusetts October 4, 2007

Lee Carl Bromberg (BBO# 058480) Timothy M. Murphy (BBO# 551926) Julia Huston (BBO# 562160) Keith E. Toms (BBO# 663369) Nicole A. Rizzo (BBO# 663853) Bromberg & Sunstein LLP 125 Summer Street Boston, MA 02110 Tel. [phone]

Counsel for Defendants F. Hoffmann-La Roche Ltd, Roche Diagnostics GmbH, and Hoffmann-La Roche Inc.

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TABLE OF CONTENTS Page I. II. INTRODUCTION............................................................................................................... 1 LEGAL STANDARDS ....................................................................................................... 2 A. B. C. III. Judgment as a Matter of Law Pursuant to Fed. R. Civ. P. 50 ................................. 2 Clear And Convincing Evidence Is Not An Insurmountable Burden ..................... 3 The Burden of Proof Does Not Rest Solely With Roche........................................ 4

THE ONLY CONCLUSION THAT A REASONABLE JURY COULD REACH IS THAT CLAIMS 3, 7-9, 11, 12 AND 14 OF THE `933 PATENT ARE ANTICIPATED .................................................................................................................. 6 A. B. C. D. Anticipation and Prior Invention Under § 102(a), (b) and (g) ................................ 6 Level of Skill in the Art and the Critical Date ........................................................ 6 `933 Claims 3, 7 and 8 Are Invalid For Anticipation.............................................. 6 `933 Claims 9, 11, 12 And 14 Are Invalid For Anticipation................................. 10 1. 2. 3. 4. The Baron-Goldwasser Clinical Study...................................................... 11 Dr. Eschbach's Administration of EPO-Rich Human Plasma .................. 13 Dr. Essers' Studies Using EPO-Rich Human Plasma ............................... 14 Miyake et al. (1977) Publication ............................................................... 15

IV.

THE ONLY CONCLUSION THAT A REASONABLE JURY COULD REACH IS THAT THE ASSERTED CLAIMS OF THE PATENTS-IN-SUIT ARE OBVIOUS UNDER 35 U.S.C. § 103................................................................................. 15 A. B. Obviousness Under 35 U.S.C. § 103..................................................................... 15 Dr. Goldwasser's Purified Human Erythropoietin Renders Each of the Claims-In-Suit Obvious Pursuant to §§ 102(f)/103 .............................................. 16 1. 2. The Skilled Worker Could Have Synthesized An EPO Gene Using Goldwasser's Purified Protein Rendering the Claims Obvious ................ 19 Other Available Techniques Render The Cloning Of the EPO Gene Obvious ............................................................................................ 20 a. cDNA Cloning............................................................................... 20 i

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b. 3. 4. C. V.

Genomic Cloning .......................................................................... 23

Expressing The EPO Gene To Make An In Vivo Biologically Active Protein and Pharmaceutical Composition Was Obvious ............... 25 A Person Of Skill In The Art Would Be Motivated To Combine These Elements With A Reasonable Expectation Of Success .................. 30

Amgen Presented No Pertinent Evidence of Secondary Considerations .............. 30

A REASONABLE JURY WOULD FIND THAT THE ASSERTED CLAIMS OF AMGEN'S PATENTS ARE OBVIOUS PURSUANT TO § 102(G) AND § 103 ............... 33 A. B. C. § 102(g)(2) Art Combined with the Prior Art Can Render Claimed Inventions Obvious Pursuant to § 103 .................................................................. 33 Dr. Goldwasser's Tryptic Fragments Are Section 102(g)(2) Prior Art And Render The Claims-In-Suit Obvious..................................................................... 33 Dr. Fritsch's Prior Invention Constitutes Invalidating § 102(g) Prior Art ............ 34

VI.

A REASONABLE JURY WOULD CONCLUDE THAT ROCHE PREVAILS ON ITS SECTION 112 DEFENSES ................................................................................. 34 A. B. C. D. A Reasonable Jury Would Find Claims to "Human Erythropoietin" Invalid For Lack Of Written Description and Indefiniteness................................ 35 A Reasonable Jury Would Find Claim 1 of the `422 Patent is Further Indefinite As Lacking Any Identifiable Structure................................................. 40 A Reasonable Jury Would Find That `349 Claim 7 Is Invalid For NonEnablement Regarding The Limitation to Radioimmunoassay (RIA).................. 42 A Reasonable Jury Would Conclude That Claim 7 Of The `349 Patent Is Invalid For Lack Of Written Description Or Enablement Based on "Vertebrate Cells" ................................................................................................. 44

VII.

CONCLUSION ................................................................................................................. 45

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TABLE OF AUTHORITIES Page(s) Cases A.K. Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) ........................................................................................................ 4 Am. Hoist & Derrick Co. v. Sowa & Sons, Inc., 725 F.2d 1350 (Fed. Cir. 1984) ........................................................................................................ 4 Amgen Inc v. Hoechst Marion Roussel, Inc., 314 F.3d 1313 (Fed. Cir. 2003) ............................................................................................ 5, 12, 37 Amgen v. Chugai, 13 U.S.P.Q.2d 1737 (D. Mass. 1989)...............................................................................................6 Amgen, Inc. v. F. Hoffmann-La Roche Ltd., 494 F. Supp. 2d 54 (D. Mass. 2007). ............................................................................................. 11 B.E. Meyers & Co. v. United States, 47 Fed. Cl. 375 (Fed. Cl. 2000)........................................................................................................5 Bausch & Lomb, Inc. v. Alcon Labs., Inc., 79 F. Supp. 2d 252 (W.D.N.Y. 2000) .............................................................................................. 4 Bausch & Lomb, Inc. v. Barnes-Hind/Hydrocurve, Inc., 796 F.2d 443 (Fed. Cir. 1986) .......................................................................................................... 5 Becton Dickinson & Co. v. C.R. Bard, Inc., 922 F.2d 792 (Fed.Cir.1990) .......................................................................................................... 13 Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368 (Fed. Cir. 2001) ...................................................................................................... 13 Buildex Inc. v. Kason Indus., Inc., 849 F.2d 1461 (Fed. Cir. 1988) ........................................................................................................ 3 Chen v. Bouchard, 347 F.3d 1299 (Fed. Cir. 2003) ...................................................................................................... 38 Dow Chem. Co. v. Astro-Valcour, Inc., 267 F.3d 1334 (Fed. Cir. 2001) ...................................................................................................... 34 Dystar Textilfarben GmbH & Co. Deutschland KB v. C.H. Patrick Co., 464 F.3d 1356 (Fed. Cir. 2006) ...................................................................................................... 16

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E.I. Du Pont de Nemours & Co. v. Phillips Petroleum Co., 849 F.3d 1430 (Fed. Cir. 1988) ...................................................................................................... 33 Ecolochem v. S. California Edison Co., 277 F.3d 1361 (Fed. Cir. 2000) ...................................................................................................... 24 Enzo Biochem, Inc. v. Calgene, Inc. 188 F.3d 1362 (Fed. Cir. 1999) ...................................................................................................... 42 Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002) ........................................................................................................ 35 Gambro Lundia AB v. Baxter Healthcare Corp., 110 F.3d 1573 (Fed. Cir. 1997) ...................................................................................................... 16 Halliburton Energy Servs., Inc. v. MI, LLC, 456 F. Supp. 2d 811 (E.D. Tex. 2006) ........................................................................................... 40 Harvestall Indus., Inc. v. Hochstetler, 656 F.2d 1232 (7th Cir. 1981)........................................................................................................44 Holdings, LLC v. Amazon.com, Inc., 430 F.3d 1377 (Fed. Cir. 2005) ........................................................................................................ 6 In re Brana, 51 F.3d 1560 (Fed. Cir. 1995) ........................................................................................................ 30 In re Kahn, 441 F.3d 977 (Fed. Cir. 2006) .................................................................................................... 6, 16 In re Marosi, 218 U.S.P.Q. 289 (Fed. Cir. 1983) ................................................................................................... 5 In re Moeller, 117 F.2d 565 (C.C.P.A. 1941)..........................................................................................................5 In re Wertheim, 541 F.2d 257 (C.C.P.A. 1976)........................................................................................................35 In re Wright, 999 F.2d 1557 (Fed. Cir. 1993) ...................................................................................................... 10 Jackson Jordan, Inc. v. Plasser Am. Corp., 747 F.2d 1567 (Fed. Cir. 1984) ........................................................................................................ 9 Johns Hopkins Univ. v. Cellpro, Inc., 152 F.3d 1342 (Fed. Cir. 1998) ...................................................................................................... 28 KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727 (2007) ............................................................................................................... 6, 16 iv

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Lewmar Marine, Inc. v. Barient, Inc., 827 F.2d 744 (Fed. Cir. 1987) .......................................................................................................... 9 Lockwood v. Am. Airlines, 107 F.3d 1565 (Fed. Cir. 1997) ...................................................................................................... 36 Loral Fairchild Corp. v. Matsushita Elec. Indus. Co., 266 F.3d 1358 (Fed. Cir. 2001) ........................................................................................................ 6 Merck & Co. v. Teva Pharms. USA, Inc., 395 F.3d 1364 (Fed. Cir. 2005) ...................................................................................................... 32 Morton Int'l. v. Cardinal Chem. Co., 5 F.3d 1464 (Fed. Cir. 1993) .................................................................................................... 39, 40 Nat'l Recovery Techs., Inc. v. Magnetic Separations Sys., Inc., 166 F.3d 1190 (Fed. Cir. 1999) ...................................................................................................... 43 Nat'l Research Development Corp. v. Great Lakes Carbon Corp., 410 F. Supp. 1108 (D. Del. 1975) .................................................................................................. 10 New Railhead Mfg. LLC v. Vermeer Mfg., 298 F.3d 1290 (Fed. Cir. 2002) ................................................................................................ 35, 39 Nobelpharma AB v. Implant Innovations, Inc., 141 F.3d 1059 (Fed. Cir. 1998) ........................................................................................................ 3 OddzOn Prods., Inc. v. Just Toys, Inc., 122 F.3d 1396 (Fed. Cir. 1997) ................................................................................................ 16, 17 OKI Am., Inc. v. Adv. Micro Devices, Inc., 2006 WL 2711555 (N.D. Cal. Sept. 21, 2006).................................................................................9 Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007) .................................................................................................... 3, 4 PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007) ...................................................................................................... 20 Regents of Univ. of Cal. v. Eli Lilly & Co, 119 F.3d 1559 (Fed. Cir. 1997) ................................................................................................ 35, 36 Richmond Steel, Inc. v. Puerto Rican Am. Ins. Co., 954 F.2d 19 (1st Cir. 1992) ............................................................................................................... 3 Schering Corp. v. Amgen Inc., 222 F.3d 1347 (Fed. Cir. 2000) ...................................................................................................... 38 Semmler v. American Honda Motor Co., 990 F. Supp. 967 (S.D. Ohio 1997)................................................................................................40 v

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SmithKline Beecham Corp. v. Apotex Corp., 439 F.3d 1312 (Fed. Cir. 2006) ........................................................................................................ 5 TI Group Automotive Sys., Inc. v. VDO N. Am., L.L.C., 375 F.3d 1126 (Fed. Cir. 2004) ........................................................................................................ 3 TurboCare Div. of Demag Delavel Turbomachinery Corp. v. GE, 264 F.3d 1111 (Fed. Cir. 2001) ...................................................................................................... 35 Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004) ........................................................................................................ 35 Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555 (Fed. Cir. 1991) ................................................................................................ 35, 38 Weatherchem Corp. v. J.L. Clark, Inc., 163 F.3d 1326 (Fed. Cir. 1998) ...................................................................................................... 33 WMS Gaming, Inc. v. Int'l Game Tech., 184 F.3d 1339 (Fed. Cir. 1999) ........................................................................................................ 5 Statutes 35 U.S.C. § 102(g)(2).........................................................................................................................33 35 U.S.C. § 103 .................................................................................................................................. 15 Other Authorities M.P.E.P. § 609.05(b) (8th ed. Aug. 2001) ........................................................................................... 4 Rules Fed. R. Civ. P. 50(a)(1) ........................................................................................................................ 3 Fed. R. Civ. P. 50(a)(2) ........................................................................................................................ 2

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I.

INTRODUCTION Defendants F. Hoffmann-La Roche, Ltd, Roche Diagnostics, GmbH, and Hoffmann-La

Roche Inc. ("Roche") submit this memorandum of law in support of their motion for judgment as a matter of law regarding their defenses of invalidity.1 Roche has presented substantial evidence to allow a reasonable jury to conclude by clear and convincing evidence that each asserted claim is invalid. Moreover, Amgen has presented no competent evidence to defeat Roche's clear and convincing evidence. Accordingly, a reasonable jury could be led to make just one conclusion: the claims-in-suit are invalid. ˇ Claims 3, 7, 8, 9, 11, 12 and 14 of the `933 patent, all product-by-process claims, are anticipated pursuant to §§ 102(a), 102(b) and 102(g)2: The Baron-Goldwasser clinical trial in 1979, Dr. Essers' studies in 1973-75, Dr. Eschbach's clinical study in 1984, Dr. Fritsch's work at Genetics Institute and the Miyake publication independently anticipate every claim limitation, as confirmed by the testimony of Drs. Lowe, Spinowitz, Baron, Goldwasser and Bertozzi. Other than the conclusory testimony of its paid experts that squarely contradicts Amgen's own prior admissions, Amgen has presented no evidence to defeat the clear and convincing teachings of these prior art references. Moreover, the law is crystal clear that anticipation by an earlier product disclosure cannot be avoided by claiming the product as produced by a particular process or from a particular source. Amgen has presented no evidence to sustain its burden of showing that the process or source of production imparts novel structural features to its claimed products. Claim 1 of the `422 patent and claims 3, 7, 8, 9, 11, 12 and 14 of the `933 patent also would have been obvious to one of skill in the art in light of the prior art studies by Drs. Baron and Goldwasser, Dr. Essers and Dr. Eschbach. Amgen presented no competent evidence to defeat Roche's clear and convincing evidence on this issue. The asserted claims of the patents-in-suit are obvious pursuant to 35 U.S.C. § 103, § 102(f)/§ 103 and § 102(g)/§ 103 in light of the prior art. There is substantial evidence that every element of the asserted claims was known in the prior art and one of ordinary skill in

ˇ

ˇ

1

2

Similarly, this memorandum serves as an opposition to Amgen's motion for judgment as a matter of law. (D.N. 1136, 1137-2, 1270). While Roche hereby recapitulates the evidence presented at trial pertaining to its invalidity defenses, Roche also incorporates by reference the evidence and arguments set forth in its Opposition to Amgen's Motion for Judgment as a Matter of Law, and accompanying papers. (See D.N. 1141, 1142, 1144, 1145, 1146, 1148). Roche respectfully maintains its position that claim 1 of the `422 patent is similarly invalid for anticipation. However, in light of the Court's ruling that claim 1 is not anticipated as a matter of law, (Trial Tr. 1380:7-12), Roche limits its arguments in this memorandum to the related claims of the `933 patent.

1

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the art was motivated to combine these elements, such that each claim would have been obvious in the 1983-84 time period. Substantial evidence has demonstrated that subject matter "critical" to each of these claimed inventions was derived from the work of Dr. Goldwasser, as admitted by Drs. Goldwasser, Orkin and Lin, and confirmed by Dr. Lowe. This subject matter, which includes Table 1 of Example 1 of Lin's patent specification, in combination with the prior art would have rendered each of the asserted claims obvious to one of ordinary skill in the art in 1984. Amgen presented no relevant evidence to defeat Roche's clear and convincing evidence. Each of Amgen's witnesses presented conclusory testimony that was squarely contradicted by the prior art and their own prior non-litigationdriven admissions. ˇ Claim 1 of the `422 patent, claims 1-2 of the `868 patent, claims 6-9 of the `698 patent, claim 7 of the `349 patent and claims 3, 7, 8, 9, 11, 12 and 14 of the `933 patent are invalid for lack of written description and/or indefiniteness pursuant to § 112 based on the limitation "human erythropoietin," as explained by Drs. Bertozzi and Flavell.3 Claim 7 of the `349 patent is invalid pursuant to § 112 because it lacks enablement regarding its claim limitation of using radioimmunoassay (RIA) to measure the production of human erythropoietin expressed by vertebrate host cells. As confirmed by Dr. Flavell's testimony, RIA cannot distinguish "erythropoietin" from fragments, non-human EPO and other crossreacting substances. Claim 7 of the `349 is invalid for lack of written description and non-enablement of the term "vertebrate cells." There can be no dispute that vertebrate cells covers a broad class of cells, including mammalian cells, reptile cells, amphibian cells, bird cells and fish cells. Yet, the common specification of the patents-in-suit only mention COS and CHO cells, two discrete species mammalian cells. Amgen's own witnesses, including Drs. Lin and Varki, admit that different host cells have different properties and have mixed results in terms of protein expression. Accordingly, any description or enablement of CHO or COS cells -- to the extent such description is even present in the specification -- cannot amount to description of the much broader genus of vertebrate cells. There has been no evidence to counter these facts. LEGAL STANDARDS A. Judgment as a Matter of Law Pursuant to Fed. R. Civ. P. 50

ˇ

ˇ

II.

"[A] motion for judgment as a matter of law may be made at any time before the case is submitted to the jury." Fed. R. Civ. P. 50(a)(2). Judgment as a matter of law is appropriate when

3

Roche respectfully maintains that claims 3, 7, 8 and 11 of the `933 patent are similarly invalid for lack of written description based on the term "human erythropoietin." In light of the Court's ruling that these claims are not invalid for lack of written description as a matter of law, (Trial Tr. 1380:7-12), Roche limits its arguments in this memorandum to the remainder of the asserted claims. However, because the Court made no rulings on indefiniteness, Roche still maintains that claims 3, 7, 8 and 11 of the `933 patent are invalid for indefiniteness.

2

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"`there is no legally sufficient evidentiary basis for a reasonable jury to find for that party on that issue.'" TI Group Automotive Sys., Inc. v. VDO N. Am., L.L.C., 375 F.3d 1126, 1133 (Fed. Cir. 2004), quoting Fed. R. Civ. P. 50(a)(1). Where, as here, the movant bears the burden of proof, JMOL may be granted where "(1) the movant `has established [its] case by evidence that the jury would not be at liberty to disbelieve' and (2) `the only reasonable conclusion is in [the movant's] favor.'" Nobelpharma AB v. Implant Innovations, Inc., 141 F.3d 1059, 1065 (Fed. Cir. 1998). To warrant submission of these issues to the jury, Amgen must have presented "more than a mere scintilla" of evidence and may not simply rely on conjecture or speculation. Richmond Steel, Inc. v. Puerto Rican Am. Ins. Co., 954 F.2d 19, 22 (1st Cir. 1992). As the record clearly establishes, Amgen's evidence supporting validity is, at best, a "mere scintilla." B. Clear And Convincing Evidence Is Not An Insurmountable Burden

Amgen has, in the past, argued that Roche cannot meet its burden of providing clear and convincing evidence, characterizing the burden as essentially insurmountable. However, "under the `clear and convincing' standard, proof need not be airtight. The law requires persuasion, not perfection." Buildex Inc. v. Kason Indus., Inc., 849 F.2d 1461, 1464 (Fed. Cir. 1988). "Although an exact definition is elusive, `clear and convincing evidence' has been described as evidence that `place[s] in the ultimate fact finder an abiding conviction that the truth of its factual contentions are highly probable.'" Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1360 n.5 (Fed. Cir. 2007); (see also D.N. 1141-4). Not only has Roche more than met its burden, no reasonable jury could conclude that Amgen presented any competent evidence to rebut the only clear and convincing conclusion: that Roche must prevail. Amgen argues that because certain of the references relied upon by Roche to support its obviousness and anticipation defenses were submitted to the PTO examiner, Roche has a heightened burden in rebutting the presumption of validity afforded to patents. Amgen is wrong. 3

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See Pfizer, Inc., 480 F.3d at 1359-60 ("presumption [of validity] remains intact and [the burden of proof remains] on the challenger throughout the litigation, and the clear and convincing standard does not change") (emphasis added). As an initial matter, not all references relied upon by Roche were submitted to the PTO examiner, including highly relevant pages of the Maniatis manual (TRX 10) and documents pertaining to the Baron-Goldwasser study, among others. Moreover, the

references that were submitted to the examiner were buried among hundreds of references that the examiners reviewed in one or two days. (See, e.g., TRX 2009.558-595 (reviewing 436 references in 1 day), 2012.951-977 (reviewing 372 references in 1 day), 2007.177-206 (reviewing 437 references over 2 days), 2011.515-540 (reviewing 390 references over 2 days), 2017.240-268 (reviewing 437 references over 2 days); see also M.P.E.P. § 609.05(b) (8th ed. Aug. 2001) ("[t]he examiner must also fill in his or her name and the date the information was considered"); Bausch & Lomb, Inc. v. Alcon Labs., Inc., 79 F. Supp. 2d 252, 255 (W.D.N.Y. 2000) (If there is "evidence that there actually were defects in the particular application process at issue in this case, thus suggesting that deference to the PTO's determination may not be appropriate," such evidence may be relevant to overcoming the presumption of validity). Accordingly, despite Amgen's contention, even if some - or even all, as Amgen erroneously contends -- of the references relied upon by Roche were submitted to the PTO examiner, Roche's burden does not change and all relevant evidence must be considered. See Am. Hoist & Derrick Co. v. Sowa & Sons, Inc., 725 F.2d 1350, 1360 (Fed. Cir. 1984) ( "[a]ll evidence bearing on the validity issue, whether considered by the PTO or not, is to be taken into account by the tribunal in which validity is attacked"); see also A.K. Steel Corp. v. Sollac, 344 F.3d 1234, 1245 (Fed. Cir. 2003) ("the presumption is far from determinative"). C. The Burden of Proof Does Not Rest Solely With Roche

Despite Amgen's repeated suggestion, Roche does not carry all the weight in the invalidity portion of this trial. 4

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The asserted claims of the `933 patent are indisputably product-by-process claims. Similarly, `422 claim 1 contains a source limitation. The law makes clear that recitation of source or process limitations such as "non-naturally occurring," "product of the expression ... in a mammalian host cell" or "purified from mammalian cells grown in culture" does not distinguish product-by-process claims over the prior art unless the source or process imparts unique structure to the product. SmithKline Beecham Corp. v. Apotex Corp., 439 F.3d 1312, 1317 (Fed. Cir. 2006); Amgen Inc v. Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1354 (Fed. Cir. 2003).4 "Where a product-by-process claim is rejected over a prior art product that appears to be identical, ... the burden is upon the applicants to come forward with evidence establishing an unobvious difference between the claimed product and the prior art product." In re Marosi, 218 U.S.P.Q. 289, 293 (Fed. Cir. 1983); see also In re Moeller, 117 F.2d 565, 567 (C.C.P.A. 1941). Moreover, to defeat Roche's clear and convincing evidence of prima facie obviousness, Amgen relies on secondary considerations of non-obviousness, such as long felt need. The law makes clear that Amgen has the burden of proving a sufficient nexus between its satisfaction of a long felt need and the patents-in-suit. See WMS Gaming, Inc. v. Int'l Game Tech., 184 F.3d 1339, 1359 (Fed. Cir. 1999) ("[t]he patentee bears the burden of showing that a nexus exists between the claimed features of the invention and the objective evidence offered to show nonobviousness"); see also B.E. Meyers & Co. v. United States, 47 Fed. Cl. 375, 378 (Fed. Cl. 2000) (same). Finally, Amgen has the burden of proving a date of conception prior to November 30, 1984. The date of invention for prior art purposes is the filing date of the application until an earlier date is proved. Bausch & Lomb, Inc. v. Barnes-Hind/Hydrocurve, Inc., 796 F.2d 443, 449 (Fed. Cir. 1986). To establish an earlier filing date, Amgen had to "present evidence of its asserted actual

4

See Roche Motions in Limine D.N. 1047 and 1046; see also D.N. 1141-5.

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reduction to practice prior to the filing date of its patent application." Loral Fairchild Corp. v. Matsushita Elec. Indus. Co., 266 F.3d 1358, 1361 (Fed. Cir. 2001). Amgen has presented no evidence to meet its burden. Accordingly, the critical date for assessing anticipation is November 30, 1984. Moreover, the 1984 filing date is a later date of invention than in Amgen v. Chugai, 13 U.S.P.Q.2d 1737 (D. Mass. 1989), making any findings regarding obviousness in that case irrelevant here due to, inter alia, the advances in the prior art during the intervening time period together with the standard for obviousness under the present law. See KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727 (2007); (see also D.N. 1070-2, 1146). III. THE ONLY CONCLUSION THAT A REASONABLE JURY COULD REACH IS THAT CLAIMS 3, 7-9, 11, 12 AND 14 OF THE `933 PATENT ARE ANTICIPATED A. Anticipation and Prior Invention Under § 102(a), (b) and (g)

As to Roche's claim that claims 3, 7-9, 11, 12 and 14 are invalid as anticipated, a reasonable jury could only find in Roche's favor, as Roche has presented clear and convincing evidence that each and every element of these claims is present in a single prior art reference. Holdings, LLC v. Amazon.com, Inc., 430 F.3d 1377, 1381 (Fed. Cir. 2005). Amgen presented no evidence to rebut this clear conclusion. B. Level of Skill in the Art

The evidence has shown that a person of ordinary skill in the art in the period 1983-84 was someone who has earned a M.D. or Ph.D degree and who has one or two years of post-graduate laboratory research experience. (Lowe 193:8-12; Bertozzi 1061:19-25; Spinowitz 768:16-19). It is from this person's understanding and perspective that the prior art and obviousness must be judged. In re Kahn, 441 F.3d 977, 985 (Fed. Cir. 2006). C. `933 Claims 3, 7 and 8 Are Invalid For Anticipation

Roche presented clear and convincing evidence such that a reasonable jury could only conclude that claims 3, 7 and 8 are invalid for anticipation over Dr. Goldwasser's prior art EPO 6

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purified from human urine. As noted above, because source and process limitations cannot confer patentability to an otherwise non-novel product, Amgen must show that these limitations confer a novel structure. Amgen has presented wholly insufficient evidence to contradict the presumption that the source and process limitations in claim 3 are irrelevant.5 Even if, as Amgen suggests in direct contradiction of established principles of law, this burden should fall on Roche, Dr. Bertozzi presented clear and convincing evidence demonstrating that "Goldwasser's EPO has structures that can all be made according to claim 3. So the product of claim 3 is basically the same as

Goldwasser's EPO." (Bertozzi 1018:13-15; Bertozzi 988:19-21 ("nothing distinguishes them. The EPO that comes from mammalian cells in culture is the same, the molecules are the same as Goldwasser's EPO") (emphasis added); see also Bertozzi 1027:20-1028:2, 1028:15-18, 1146:2324 (there is a "statistical certainty" that the molecules of the prior art EPO and the claimed recombinant EPO have the same structure)). For example, Dr. Bertozzi showed that different lots of recombinant EPO submitted for regulatory approval by Amgen have a range of specific activity that spans the reported specific activity for Dr. Goldwasser's EPO glycoproteins. (Bertozzi 1159:11161:2). Dr. Strickland, Amgen's witness, confirmed these conclusions, and agreed that his own patent recognized as much. (Strickland 2157:12-2159:4; compare TRX 2104 with TRX 2002). Moreover, Amgen's own PLA and published articles confirm Dr. Bertozzi's opinions: ˇ Amgen's PLA states that "[t]his gene, when inserted into mammalian cells, yields a recombinant product that is immologically and biologically indistinguishable from naturally derived erythropoietin." (TRX 2056 at AM-ITC 00092263 (emphasis added); Bertozzi 1032:7-1033:1). It further states that "[a]ll physical tests performed on both r-HuEPO and u-HuEPO as discussed in this Section show these proteins to be indistinguishable, as

5

Claims 7 and 8 limit the "mammalian host cell" limitation of claim 3 to a "non-human mammalian cell" and a "CHO cell," respectively. For the same reasons, these limitations do not serve to confer patentability to claims 7 and 8.

7

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summarized below." (TRX 2057 at AM-ITC 00092880; Bertozzi 1034:5-1035:5, 1036:201037:9). ˇ A 1986 publication by Amgen personnel, including Drs. Lin, Strickland, Egrie and Browne, states "As seen in Figure 4, purified recombinant human erythropoietin migrates identically to human urinary erythropoietin with an apparent molecular weight of approximately 36,000 daltons, suggesting that both molecules are glycosylated to the same extent." (TRX 2058 at p. 218 (emphasis added); Bertozzi 1038:15-1039:18). Another 1986 publication by the same Amgen personnel contains similar conclusions. (TRX 2059 at p. 698; Bertozzi 1042:6-18). A 1984 presentation by Amgen's Dr. Egrie similarly concludes that "COS cells [which are covered by claims to mammalian cells] transfected with the human EPO gene produce and secrete fully glycosylated EPO which migrates identically to the human EPO standard." (Bertozzi 1043:23-1044:22; TRX 2060). A 1985 publication by Amgen personnel, including Drs. Egrie, Browne, Lin and Lai, contains similar conclusions. (TRX 2061; Bertozzi 1045:23-1046:1). A 1988 publication by Amgen personnel, including Drs. Vapnek, Egrie, Browne, Lin and Strickland, concludes "[i]n all physical measurements made to date, the natural material cannot be distinguished from the recombinant material." (TRX 2062 at p. 249 (emphasis added); Bertozzi 1047:7-14).

ˇ

ˇ

Accordingly, pursuant to the testimony of Dr. Bertozzi and Dr. Strickland and corresponding documentary evidence, a reasonable jury could be led to only one conclusion: that claims 3, 7 and 8 of the `933 patent are anticipated by Dr. Goldwasser's prior art urinary EPO. (See Bertozzi 1048:26, 1048:8-9).6 Moreover, as explained below, numerous studies using pharmaceutical compositions comprising EPO that cannot be shown to be structurally distinct from the EPO claimed in claims 3, 7 and 8 also render these claims invalid for anticipation. See Lewmar Marine, Inc. v. Barient, Inc.,

6

Moreover, evidence from Dr. Edward Fritsch of Genetics Institute ("G.I.") demonstrated that G.I. cloned an EPO cDNA, transfected it into COS and CHO cells and expressed high levels of in vitro and in vivo biologically active human EPO. As Amgen acknowledges, all of this work was completed before November 30, 1984, the effective filing date of Amgen's patents, and thus constitutes prior art under Section 102(g) that was not abandoned, suppressed or concealed since this work was published in February 1985. (See Fritsch 350:19-360:21; see also TRX 2090, 2084). Accordingly, a reasonable jury could only conclude that even if the source and process limitations confer structural distinctiveness to Amgen's claimed product, Dr. Fritsch's prior work anticipates claims 3, 7 and 8 of the '933 patent.

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827 F.2d 744, 747 (Fed. Cir. 1987) ("[t]hat which would literally infringe if later in time anticipates if earlier") (emphasis in original). Amgen presented no competent evidence to rebut the clear conclusion that there is no structural difference between Dr. Goldwasser's urinary EPO and EPO produced in mammalian cells. Amgen's claims are directed to any EPO glycoproteins that can be produced in any

mammalian host cells, under any conditions, in any populations, with any specific activity and purified in any way. All of the experiments discussed by Dr. Varki compared urinary EPO to a limited number of samples of recombinant EPO produced in mammalian cells. As Dr. Varki readily acknowledged, there are at least 30,000 different types of mammalian cells, not including mutated mammalian cells, all of which would fall within the scope of the claim limitation to "mammalian cells." (Varki 2247:16-22). He further acknowledged that these different types of cells can have different properties in terms of creating recombinant EPOs depending on many factors including mutations, pH, nutrient conditions and purification techniques. (Varki 2249:5-10). Yet, Dr. Varki limited his analysis to only three mammalian cells, at most, out of at least 30,000 choices. (Varki 2251:9-17). The law is clear that patentability can not be shown simply by showing differences between one embodiment of a claim and the prior art. The entire scope of the claim must be distinct from the prior art. See Jackson Jordan, Inc. v. Plasser Am. Corp., 747 F.2d 1567, 1578 (Fed. Cir. 1984); OKI Am., Inc. v. Adv. Micro Devices, Inc., 2006 WL 2711555, *6 (N.D. Cal. Sept. 21, 2006). Aside from the fact that Dr. Varki's analysis was limited to a mere subset of the claimed products, he discussed SDS-PAGE experiments comparing recombinant EPO to urinary EPO and repeatedly admitted that many SDS-PAGE experiments do not show any structural difference. (Varki 2188:2-25, 2193:6-8). The best explanation that Dr. Varki could proffer was simply that just because no difference was shown in those experiments, "that does not mean the difference does not exist." (Varki 2193:6-8). This is hardly sufficient for Amgen to meet its burden in demonstrating 9

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structural distinctiveness. Moreover, Dr. Varki's discussion of Dr. Strickland's IEF experiments, which are not even described in the patents, was based on the assumption that the experiment tested Amgen's recombinant EPO. (Varki 2206:5). Even if this assumption was correct, as discussed above, the results of the experiment are insufficient to establish that the broad range of recombinant EPOs covered by Amgen's claims are all different than Dr. Goldwasser's EPO. Similarly, the Dionex experiments relied upon were also based on the assumption that the urinary EPO was Dr. Goldwasser's EPO that was being compared to what Dr. Varki assumed to be one sample of recombinant EPO within the broad spectrum of recombinant EPOs within the scope of Amgen's claims. (Varki 2213:17-20, 2214:20-21). Even if the Dionex test showed a conclusive difference -which it did not -- Amgen cannot rely on this test to show what was known in 1984 because this test was not available at the time. See Nat'l Research Development Corp. v. Great Lakes Carbon Corp., 410 F. Supp. 1108, 1124 (D. Del. 1975) ("[t]o satisfy the statue, there must have been a test available at the time of the filing of the patent application which could have been employed by a person skilled in the art"); In re Wright, 999 F.2d 1557, 1563 n.8 (Fed. Cir. 1993); see also D.N. 1274. Accordingly, as Amgen has not proven any structural distinction based on source and process claims, a reasonable jury could only conclude that these claims are invalid. D. `933 Claims 9, 11, 12 And 14 Are Invalid For Anticipation

Roche presented the jury with substantial testimony and documentary evidence that at least four separate pieces of prior art anticipate `933 claims 9, 11, 12 and 14. Amgen provided no credible evidence in rebuttal. These claims are limited to pharmaceutical compositions and

methods of using these pharmaceutical compositions to treat kidney dialysis patients and increase hematocrit.

10

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1.

The Baron-Goldwasser Clinical Study

Dr. Spinowitz explained that the 1979-1980 Baron-Goldwasser study shows administration of a pharmaceutical composition of human EPO comprising a diluent, suitable for human administration.7 (Spinowitz 706:9-11, 707:1-9, 705:20-706:1, 707:23-708:16; TRX 2004). The human EPO in this composition is the same human EPO that renders claims 3, 7 and 8 anticipated, as discussed above. This pharmaceutical composition further comprised a therapeutically effective amount of human EPO because, after administration to patients, it elicited a measurable reticulocyte response, an increase in the number of nucleated red blood cells in the bone marrow, an increase in red blood cell mass, and positive ferrokinetic effects including a decrease in radioactive iron in plasma indicating that iron was being used to form new red blood cells. (Spinowitz 711:3-712:12, 713:17-714:3, 715:19-716:19, 718:15-22, 719:7-18; Baron 671:8-21; TRX 2004, 2045, 2049). These responses each report the stimulation of red blood cell formation.8 Moreover, Amgen reported to the FDA in its EpogenŽ IND filing that based on prior art studies, "[t]herapy with erythropoietin has been shown to be effective in selected patients with ESRD."9 (TRX 2054 at p. 4; Spinowitz 790:24-791:9, 792:3-23; Friedman 1475:4-12). Amgen's own expert, Dr. Friedman, acknowledged that he previously testified under oath that this statement referred to the Baron-Goldwasser study and that when Amgen used the word "effective," Amgen
7

The Baron-Goldwasser study is prior art under Sections 102(a), 102(b), 102(f) and 102(g)(2). (See D.N. 1141-5; 10/1/07 Electronic Order denying D.N. 1202). Importantly, these responses are entirely consistent with the Court's claim construction: a therapeutically effective amount is one that elicits any one or all of the effects often associated with in vivo biological activity of natural EPO, such as those listed in the specification, column 33, lines 16 and 22, stimulation of reticulocyte response, development of ferrokinetic effects (such plasma iron turnover effects and marrow transit time effects), erythrocyte mass changes, stimulation of hemoglobin C synthesis and, as indicated in Example 10, increasing hematocrit levels in mammals

8

9

(emphasis added). Amgen, Inc. v. F. Hoffmann-La Roche Ltd., 494 F. Supp. 2d 54, 67 (D. Mass. 2007). ESRD stands for end-stage renal disease, and is a synonym for chronic renal failure (CRF).

11

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meant "it met one of the criteria stipulated by the judge." (Friedman 1475:4-1476:6, 1477:12-22). The only evidence Amgen has conjured to detract from the clear teachings of the Baron-Goldwasser study is Dr. Friedman's personal opinion regarding the merits of the study, which in no way limits the prior art status. Dr. Friedman appears to argue that the Baron-Goldwasser study is not

sufficiently enabling, but this is irrelevant. See Amgen Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d at 1357 (if art is not enabling, it "qualifies as prior art, regardless, for whatever is disclosed therein"). Moreover, Dr. Brugnara's disparaging testimony concerning the teachings of this study have no merit. He admitted that he did not consider the totality of the data in his expert report while, at the same time, admitting that a reasonable scientist would have to consider all the data. (Brugnara 2044:17, 2045:12-18). Indeed, Dr. Baron's data (TRX 2049) is 945 pages long and Dr. Brugnara only had 17 days to review documents and provide "independent" conclusions in a detailed expert report. (Brugnara 2046:1-2047:7). It would have been impossible for him to provide the thorough and complete analysis provided by Drs. Spinowitz, Goldwasser and Baron, all of whom performed an extensive review of the data over several years, and at the time, out of the shadow of litigation, concluded that the Baron-Goldwasser study had been effective in stimulating erythropoiesis in three kidney dialysis patients.10 Dr. Brugnara admitted that he did not attempt to supplement his meager review of incomplete information from any other source, including Drs. Baron or Goldwasser to understand the basis for their past representations to the federal government and Amgen that the study had achieved its limited goals. (Brugnara 2064:25-2065:3, 2074:16-21). Accordingly, based

10

Indeed, Dr. Brugnara's expert report indicates that he only reviewed approximately 70 pages of the Baron data in forming his opinions.

12

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on the Baron-Goldwasser study, a reasonable jury could be led to only one conclusion: that claims 9 and 12 of the `933 patent are invalid for anticipation. (Bertozzi 1049:12-1050:7). Moreover, the Baron-Goldwasser study and related documents lead to the clear conclusion that claims 11 and 14 are invalid for anticipation. Roche's expert Dr. Spinowitz testified without contradiction by Amgen that the Baron-Goldwasser clinical study teaches the administration of a pharmaceutical composition comprising human erythropoietin to patients with chronic renal failure on dialysis. (Spinowitz 705:20-706:1, 769:11-15). Dr. Baron corroborated Dr. Spinowitz's

testimony and opinions. (Baron 667:19-22). As a clinical investigator with personal knowledge of the patient responses observed first-hand over 20 years ago, Dr. Baron testified that following the administration of the EPO pharmaceutical composition to patients in his clinical study who were kidney dialysis patients, hematocrit values increased. (Baron 672:6-18; see also TRX 2049 at Baron 00858).11 As Amgen has not provided any rebuttal to this clear evidence, a reasonable jury could only conclude that claims 11 and 14 are invalid for anticipation.12 2. Dr. Eschbach's Administration of EPO-Rich Human Plasma

In 1984, Dr. Eschbach infused EPO-rich plasma (a pharmaceutical composition with a pharmaceutically-acceptable diluent) from one human patient into another, and observed an increase in reticulocytes and the movement of radioactive iron into new red blood cells, each an

11

12

Although Dr. Baron wrote that there was "no significant increase in hematocrit" measured in the kidney dialysis patients in his study, (Baron 668:10-12 (emphasis added)), the evidence demonstrates that a hematocrit increase was observed. Because claims 11 and 14 do not include any quantitative or qualitative increase in hematocrit as a claim limitation such a requirement cannot be read into the claim. Becton Dickinson & Co. v. C.R. Bard, Inc., 922 F.2d 792, 799 & n. 6 (Fed.Cir.1990) ("Nothing in any precedent permits judicial redrafting of claims"). As a result, any increase in hematocrit, including the increase elicited in the kidney dialysis patients who participated in the BaronGoldwasser clinical study, provides evidence that would allow a reasonable jury to conclude that claims 11 and 14 of the `933 patent are invalid for anticipation under § 102 (a) or (b). Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1377-78 (Fed. Cir. 2001) (finding claim to a method of administration invalid due to anticipation). Moreover, as explained above, the Baron-Goldwasser study anticipates claims 3, 7 and 8 of the `933 patent because Amgen cannot show that the source and process limitations in these claims provide structural distinctiveness.

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indication that a therapeutically effective amount of human erythropoietin was present in the composition. (Spinowitz 743:1-9, 748:19­749:11, 750:19-751:6).13 As discussed above, the EPO in Dr. Eschabach's EPO-rich plasma is physically indistinguishable from human erythropoietin created from the processes disclosed in the Lin patents and, accordingly, the source and process limitations in the `933 claims cannot confer patentability. Moreover, Amgen's nephrologist expert, Dr. Friedman, admitted that the Eschbach study showed therapeutic effectiveness in human patients. (Friedman 1485:2-10). Amgen's other expert, Dr. Brugnara, who is not a nephrologist, offered no credible explanation as to why plasma is not a pharmaceutical composition comprising a diluent, adjuvant or carrier, given that Dr. Eschbach administered this preparation to humans with institutional review board approval. (See Brugnara 2043:6-10). Accordingly, a reasonable jury

would only conclude, based on the unrefuted testimony of Dr. Spinowitz and the Eschbach study, that claims 9 and 12 of the `933 patent are invalid for anticipation.14 3. Dr. Essers' Studies Using EPO-Rich Human Plasma

As with the Eschbach human patient study, three articles by Dr. Essers published between 1973 and 1975 show that use of EPO-rich human plasma (a pharmaceutical composition with a pharmaceutically-acceptable diluent or carrier) in humans caused a measurable reticulocyte response, evidencing the stimulation of erythropoiesis by human EPO (i.e. therapeutic effectiveness). (Spinowitz 752:15-762:22; TRX 2051, 2052, 2053). The only contrary testimony came from Dr. Friedman, who testified that the Essers studies did not show an increase in

13

14

The jury also heard evidence of another Eschbach study, in which the treatment of sheep with the EPO-rich plasma of other sheep was observed to "completely correct[] the anemia" and that therefore EPO therapy "should be effective in treating the anemia of chronic renal failure in humans." (TRX 2032; Spinowitz 749:15-750:24). While this reference is not anticipatory with respect to human EPO, it is powerful evidence of obviousness, and Dr. Spinowitz testified that claim 1 was in indeed obvious in light of this reference. (Spinowitz 751:17-20). Moreover, as explained above, because the EPO used in Dr. Eschbach's study cannot be shown to be structurally distinct from the recombinant EPO claimed in `933 claims 3, 7 and 8, a reasonable jury would could only conclude that Dr. Eschbach's study anticipates claims 3, 7 and 8.

14

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hematocrit or that there was a change in the "clinical outcome of her patients." (Friedman 1496:1424). This "evidence" ignores the fact that neither claims 9 or 12 of the `933 patent require an increase in hematocrit or beneficial "clinical outcome." It remains unrefuted that these studies resulted in an increased reticulocyte response from administration to humans of a pharmaceutical composition containing EPO that is structural identical to Amgen's recombinant EPO. Thus, a reasonable jury could only conclude that the Essers studies anticipate `933 claims 9 and 12.15 4. Miyake et al. (1977) Publication

Dr. Bertozzi also explained that the Miyake et al. (1977) article describing a purification method for erythropoietin from human urine discloses a pharmaceutical composition comprising a therapeutically effective amount of human EPO and a pharmaceutically acceptable diluent -- salt water. (Bertozzi 1006:3-1007:15, 1053:5-12; TRX 2002). Accordingly, based on this paper, a reasonable jury would have to conclude that claims 9 and 12 of the `933 patent are invalid for anticipation.16 IV. THE ONLY CONCLUSION THAT A REASONABLE JURY COULD REACH IS THAT THE ASSERTED CLAIMS OF THE PATENTS-IN-SUIT ARE OBVIOUS UNDER 35 U.S.C. § 103 A. Obviousness Under 35 U.S.C. § 103

Roche has presented clear and convincing evidence, which was unrefuted by any competent Amgen evidence, such that a reasonable jury would have to find the asserted claims invalid for obviousness. Under 35 U.S.C. § 103, "[a] claimed invention is unpatentable if the differences between it and the prior art are such that the subject matter as a whole would have been obvious at

15

16

Moreover, as explained above, because the EPO used in Dr. Essers' studies cannot be shown to be structurally distinct from the recombinant EPO claimed in `933 claims 3, 7 and 8, a reasonable jury would could only conclude that Dr. Essers' studies anticipate claims 3, 7 and 8. Moreover, as explained above, because the EPO described in the Miyake/Goldwasser paper cannot be shown to be structurally distinct from the recombinant EPO claimed in `933 claims 3, 7 and 8, a reasonable jury would could only conclude that this paper anticipates claims 3, 7 and 8.

15

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the time the invention was made to a person having ordinary skill in the pertinent art." In re Kahn, 441 F.3d at 985; (see also D.N. 1141-4). Motivation to combine prior art references for purposes of § 103 "need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself." See Dystar Textilfarben GmbH & Co. Deutschland KB v. C.H. Patrick Co., 464 F.3d 1356, 1361 (Fed. Cir. 2006). As the Supreme Court has recently held in KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1742 (2007): When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp .... any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed.17 B. Dr. Goldwasser's Purified Human Erythropoietin Renders Each of the ClaimsIn-Suit Obvious Pursuant to §§ 102(f)/10318

Dr. Goldwasser's transfer of purified human EPO to Amgen, including tryptic fragments created from this purified material, constitutes subject matter derived from another pursuant to § 102(f) which, in combination with other prior art, renders the asserted claims obvious to one of ordinary skill in the art. The Federal Circuit has held that "subject matter derived from another not only is itself unpatentable to the party who derived it under § 102(f), but, when combined with other prior art, may make a resulting obvious invention unpatentable ... under a combination of §§ 102(f) and 103." OddzOn Prods., Inc. v. Just Toys, Inc., 122 F.3d 1396, 1403-04 (Fed. Cir. 1997); see also Gambro Lundia AB v. Baxter Healthcare Corp., 110 F.3d 1573, 1576 (Fed. Cir. 1997) (another person need only invent part of the invention to qualify under § 102(f)). Prior art pursuant to §

17

18

Additionally, for purposes of determining whether it would be obvious to combine elements into a claim, a "person of ordinary skill is also a person of ordinary creativity, not an automaton." Id. See also D.N. 1148.

16

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102(f) "does not pertain only to public knowledge, but also applies to private communications between the inventor and another which may never become public." OddzOn, 122 F.3d at 1401-02. The evidence pertaining to Dr. Goldwasser's contribution to the patents-in-suit remains undisputed. Prior to 1977, Dr. Goldwasser received a large supply of human urine concentrates containing EPO from Dr. Miyake. (TRX 2002). Prior to receiving this supply of human EPO, Dr. Goldwasser had been unable to obtain enough human EPO from other sources. (GW 522:23-25).19 Drs. Goldwasser and Miyake then developed, under government grants from the National Institute of Health ("NIH") and the Department of Energy, a purification technique to obtain approximately 8 mg of pure human EPO. (GW 484:1-485:10, 526:10-13). Dr. Goldwasser made only very small amounts of this pure EPO available to parties other than Amgen and solely to perform radioimmunoassays ("RIA"). (GW 527:1-3). Dr. Goldwasser testified that he did not make

amounts of protein sufficient for sequencing available to anyone other than Amgen. (GW 527:411). Indeed, Dr. Goldwasser testified that the amount of EPO needed for RIA was much smaller than that needed for sequencing and that, while crude EPO could be used for RIA, pure EPO was absolutely necessary for sequencing. (GW 527:18-20, 598:12­601:10, 604:10­605:2, 640:8-23). In fact, Dr. Goldwasser chose not to make sufficient amounts of pure EPO available to competitors of Amgen for sequencing because he knew it could result in someone other than Amgen cloning the EPO gene first and Amgen expressly ordered him not to provide such information to others. (GW 544:5-545:5, 538:23-25, 522:9-1, 546:18-21, 560:14-21; TRX 2038, 2044) The evidence shows that once one of ordinary skill had Dr. Goldwasser's pure EPO protein, cloning the EPO gene would have been obvious. (Lowe 206:23-207:19, GW 531:5-17, 531:24532:7, 639:11-20). Dr. Goldwasser testified that he conducted all of the work disclosed in Example

19

"GW" refers to the trial testimony of Dr. Goldwasser.

17

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1, Table 1 of the patents in suit, including isolating the human EPO from urine and subjecting it to digestion with trypsin, resulting in the development and isolation of 17 discrete tryptic fragments. (GW 486:22-487:7, 486:9-21, 539:22-540:8, 613:2-9).20 Moreover, Dr. Goldwasser testified that without his pure protein, Amgen could not have obtained the DNA sequence encoding human EPO. (GW 539:17-19). Amgen admits that Goldwasser's pure EPO was "critical to [its] program and eventual use of EPO as a therapeutic." (TRX 2041). Further, in the period from 1980-1983, Dr. Goldwasser was the sole source of significant amounts of purified EPO.21 (GW 485:12-15, 485:22486:2, 526:20-22; Lowe 179:1-4). None of this clear and convincing evidence was refuted by Amgen's witnesses. Dr. Orkin's testimony about his own failures in isolating and cloning the EPO gene is entirely consistent with the critical nature of Dr. Goldwasser's contribution to the claimed "inventions." Dr. Orkin admitted that, unlike Amgen, he did not receive the tryptic fragments from Dr. Goldwasser, and he had "no erythropoietin in [his] hands that [he] sequenced." (Orkin 1603:20-1604:1). Moreover, in reporting to the NIH in 1983 on the progress of his own government-funded research on EPO, long before being retained as an expert in this case, Dr. Orkin, who considers himself to be "highly skilled in the art," stated "[t]he most likely explanation [for his failure to sequence the gene] is that the portion of the amino acid sequence used to construct the oligonucleotide probes, the C-terminal end of the 28 residue sequence is incorrect." (Orkin 1604:2-1607:20, 1653:1-6; TRX 2097 at AM-ITC

00260546). Had Dr. Orkin been fortunate enough to have Dr. Goldwasser's fragments, like Amgen did, he would not have faced this hurdle. Moreover, in a prior deposition Dr. Orkin testified under oath that he "stood ready to reactivate the [EPO] project at any time should there be more sequence

20 21

Amgen expressly relied on Example 1 to support its claims to human erythropoietin. (TRX 2009.554). Dr. Goldwasser defined pure EPO to mean that it has no discernible non-EPO present. (GW 525:14-16).

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available," the very sequence that only Amgen had from Dr. Goldwasser. (Orkin 1649:14-24, 1651:2-16). Finally, when Dr. Orkin tried to suggest that one of skill in the art essentially had Dr. Goldwasser's protein from when he presented only a partial sequence at a 1981 presentation, Dr. Orkin admitted that this portion of the sequence was "highly degenerate." (Orkin 1667:10-24). He further admitted that "one of ordinary skill in the art would have been very discouraged by the high degree of codon degeneracy reflected by the identified amino acids." (Orkin 1669:22-1670:4; see also Hood 1990:12-14). Similarly, Dr. Lin, the sole inventor, admitted that Dr. Goldwasser's EPO protein was "critical" and that early problems in sequencing could be attributed to not having enough of the EPO protein. (Lin 1811:14-1812:8, 1815:5-16; TRX 2041, 2042). 1. The Skilled Worker Could Have Synthesized An EPO Gene Using Goldwasser's Purified Protein Rendering the Claims Obvious22

Before Dr. Lin had cloned the EPO gene, many other scientists were also working to make recombinant EPO, "because there was an apparent and obvious need to have sufficient human EPO to treat patients that had anemias, that had low blood counts for a variety of reasons, including kidney failure and cancer treatments." (Lowe 184:17-23, 186:18-25). Given the crucial tool, a sufficient amount of purified EPO to sequence, the prior art taught a predictable step-by-step solution using synthetic methods. (Lowe 205:17­207:12; see also Lowe 369:7-12). Indeed, "the most logical, straightforward way [to get the EPO gene], was to have the protein sequence of EPO" and then synthesize the gene using chemical methods available in the prior art. (Lowe 188:11-23; see also Lowe 178:11-18, 257:12-14). By 1983, routine techniques were available to obtain accurate protein sequence from sufficient amounts of protein, including the use of a commercially-available machine for
22

Amgen has, in the past, argued that Roche is required to show that the prior art must disclose the specific DNA structure of the EPO gene for the claims-in-suit to be rendered obvious. Amgen's position is untenable, as Roche explained in D.N. 1142, and Roche incorporates those arguments by references.

19

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"microsequencing." (Lowe 217:23­218:11; TRX 2010). Indeed, Dr. Goldwasser admitted that if someone had Dr. Hood's gas-phase microsequencer, which Amgen did, they could have synthesized the tryptic fragments of EPO. (GW 531:5-532:5; see also Lin 1829:3-1830:7, 1839:20-24). Dr. Browne testified that this work would have been routine. (Browne 1992:11-14). Dr. Lowe stated that using a protein sequence and the standard codon table, one of skill in the art would have known to "work backwards" to obtain a corresponding DNA sequence encoding the protein. (Lowe 177:1178:22, 206:2-207:11). The Lin specification expressly states that when the complete protein sequence is known, the "method of choice" is the manufacture of synthetic DNA, as disclosed in the Alton WO 83/04053 application. (TRX 2 cols. 3:22-47, 30:48-63, 37:11-19; TRX 2034; see also Lowe 228:19-22). Admissions in a patent specification are binding on the patentee. PharmaStem

Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342, 1362 (Fed. Cir. 2007). Moreover, the prior art demonstrates that it would have been obvious to make a synthetic gene, including a January 1979 Goeddel article which reports expression of "chemically synthesized genes that encode the two chains of human insulin" and a 1977 Itakura article describing expression of a synthetic recombinant human somatostatin gene. (Lowe 229:20-25; TRX 2019; Lowe 169:20-22). Amgen presented no evidence to counter the clear conclusion that gene synthesis would have been an obvious approach with a reasonable expectation of success. Indeed, even the Patent Office agreed that protein sequencing was non-inventive. (Lowe 225:20-24; TRX 2011.455).

Accordingly, based on this method alone, obtaining the EPO gene would have been obvious in 1983-84, and no reasonable jury could conclude otherwise. Even if this technique was not obvious, however, multiple other obvious techniques were available. 2. Other Available Techniques Render The Cloning Of the EPO Gene Obvious a. cDNA Cloning 20

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As Dr. Lowe explained, in 1983, techniques for cDNA cloning had been described in a "widely known" 1982 treatise by Dr. Maniatis which, "akin to a cookbook," taught one of skill in the art "recipes" for isolating and cloning DNA sequences. (Lowe 164:15-25, 167:16-168:12). Using this technology, genes encoding several clinically useful proteins had been synthesi