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

Filing 919

TRIAL BRIEF by F. Hoffmann-LaRoche LTD, Roche Diagnostics GmbH, Hoffmann LaRoche Inc.. (Fleming, Thomas)

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, and HOFFMANN-LA ROCHE INC. Defendants. Civil Action No. 05 CV 12237 WGY U.S. District Judge William G. Young

ROCHE'S PRE-TRIAL BRIEF

Leora Ben-Ami (pro hac vice) Patricia A. Carson (pro hac vice) Thomas F. Fleming (pro hac vice) Aaron Stiefel (pro hac vice) KAYE SCHOLER LLP 425 Park Avenue New York, NY 10022 Tel: [phone]

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.

Dated: August 31, 2007

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TABLE OF CONTENTS Page I. II. ROCHE'S ACCUSED MIRCERATM PRODUCT ............................................................. 1 AMGEN CANNOT MEET ITS BURDEN OF PROVING THAT ROCHE INFRINGES THE ASSERTED CLAIMS.......................................................................... 4 A. B. Amgen's Burden Of Proving Infringement........................................................ 4 Amgen Cannot Prove That Roche Will Infringe Any Of The Asserted Claims of the `933 Patent ..................................................................................... 5 1. The Asserted Claims Of The `933 Patent. .................................................. 5 2. "Product Of The Expression In A Mammalian Host Cell."........................ 6 3. "Non-Naturally Occurring Glycoprotein." ................................................. 8 4. Amgen Cannot Show That Roche Induces Infringement Of Claims 11 And 14.................................................................................................. 11 Amgen Cannot Prove That Roche Will Infringe The Asserted Claims Of The `868 Patent .............................................................................................. 12 1. The Asserted Claims Of The `868 Patent. ................................................ 12 2. Roche Does Not Practice The Claimed Process In The United States. ........................................................................................................ 13 3. "Cells Transformed Or Transfected With An Isolated DNA Sequence." ................................................................................................ 13 4. "Isolating Said Glycosylated Polypeptide.".............................................. 14 5. Roche Does Not Infringe Under 35 U.S.C. § 271(g) Because The Isolated Glycoprotein Is "Materially Changed." ...................................... 15 Amgen Cannot Prove That Roche Will Infringe The Asserted Claim Of The `698 Patent .............................................................................................. 18 1. The Asserted Claims Of The `698 Patent. ................................................ 18 2. Roche Does Not Infringe Under § 271(a) Because Roche Does Not Make MIRCERATM In The U.S................................................................ 19 3. Amgen Cannot Prove That Roche Practices The Patented Process.......... 19 4. Roche Does Not Infringe Under § 271(g) Because The Crude Isolate Is "Materially Changed" Before Importation................................ 20 Amgen Cannot Prove That Roche Will Infringe The Asserted Claim Of The `349 Patent .............................................................................................. 20 1. The Asserted Claim Of The `349 Patent................................................... 20 2. Roche Does Not Practice The Claimed Process In The U.S..................... 21 3. Roche Does Not Infringe Because The Product Of Roche's Cells Is "Materially Changed" Prior To Importation......................................... 21 4. Amgen Cannot Show That Roche Uses Cells That Have The Required Protein Production Capability. .................................................. 21

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Page F. III. Under the Reverse Doctrine Of Equivalents, Roche Should Be Found Not To Infringe Any Of The Claims Asserted By Amgen............................... 24

THE ASSERTED PATENT CLAIMS ARE INVALID .................................................. 26 A. The Legal Grounds For Invalidity .................................................................... 26 1. Anticipation Under 35 U.S.C. § 102......................................................... 26 2. Obviousness Under 35 U.S.C. § 103. ....................................................... 26 3. Prior Invention Under 35 U.S.C. § 102(g)................................................ 26 4. Derivation Under 35 U.S.C. § 102(f)........................................................ 27 5. The Doctrine Of Obviousness-Type Double Patenting. ........................... 27 6. Indefiniteness Under 35 U.S.C. § 112. ..................................................... 28 7. Lack Of Written Description Under 35 U.S.C. § 112............................... 29 8. Lack Of Enablement Under 35 U.S.C. § 112. .......................................... 29 The Asserted Claims Of The `933 Patent Are Invalid..................................... 29 1. The Asserted Claims Of The `933 Patent Are Invalid As Anticipated Under 35 U.S.C. § 102(a)...................................................... 29 2. The Inventions Of The Asserted Claims Of The `933 Patent Would Have Been Obvious To One Of Skill In The Art In October 1983. ......... 32 3. Claims 3, 7, 8, 9, 11, 12 and 14 Of The `933 Patent Are Invalid ............ 34 The Asserted Claim Of The `422 Patent Is Invalid.......................................... 34 1. Claim 1 Of The `422 Patent Is Anticipated Or Made Obvious By Prior Art Relating To Purification Of Human Urinary EPO. ................... 34 2. Claim 1 Of The `422 Patent Would Have Been Obvious Given The State of The Art With Respect to Recombinant Proteins. ........................ 36 3. Claim 1 Of The `422 Patent Is Anticipated By The Baron Clinical Study. ........................................................................................................ 37 4. The Baron Clinical Study Is A Prior Invention That Invalidates Claim 1 Of The `422 Patent Under 35 U.S.C. §§ 102(g), 102(f).............. 38 5. Claim 1 Of The `422 Patent Is Anticipated Or Rendered Obvious By The Essers EPO-Rich Plasma Studies................................................. 39 6. Claim 1 Of The `422 Patent Is Anticipated Or Rendered Obvious By The Eschbach EPO-Rich Plasma Study. ............................................. 39 7. Claim 1 Of The `422 Patent Is Anticipated Or Rendered Obvious By The Baron And Goldwasser Hamster Study. ...................................... 40 8. Claim 1 of the `422 Patent Is Invalid ........................................................ 40 9. Claim 1 Of The `422 Patent Is Invalid Under 35 U.S.C. § 112. ............... 41 The Asserted Claims Of The `868 Patent Are Invalid..................................... 42 1. Claims 1 and 2 Of The `868 Patent Would Have Been Obvious In View Of The Prior Art. ............................................................................. 42

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Page 2. Claims 1 and 2 Of The `868 Patent Are Invalid For ObviousnessType Double Patenting Over Claims 2, 4, 6, 7, 25 And 27 Of The `008 Patent. ............................................................................................... 43

E.

The Asserted Claims Of The `698 Patent Are Invalid..................................... 44 1. Claims 4-9 of the `698 Patent Would Have Been Obvious. ..................... 44 2. Claims 4-9 Of The `698 Patent Are Invalid For Obviousness-Type Double Patenting Over Claims 2, 4, 6, 7, 25 Or 27 Of The `008 Patent......................................................................................................... 45 3. Claims 4 And 5 Of The `698 Patent Are Invalid For Lack Of Written Description And Indefiniteness. .................................................. 47 The Asserted Claim Of The '349 Patent Is Invalid.......................................... 49 1. Claim 1 Of The `349 Patent Is Invalid For Obviousness.......................... 49 2. Claim 7 of the `349 Patent Is Invalid ........................................................ 50 3. The `349 Patent Claims Are Not Enabled And Lack Written Description................................................................................................ 50 4. Claim 7 Should Have Expired With The `008 Patent............................... 52

F.

IV.

THE PATENTS-IN-SUIT SHOULD BE HELD UNENFORCEABLE FOR INEQUITABLE CONDUCT............................................................................................ 53 A. B. C. The Law Of Inequitable Conduct...................................................................... 53 Amgen's Misrepresentations And Omissions Aimed At Extending Its Monopoly ............................................................................................................. 56 Amgen Regularly Withheld From The PTO Examiner In One Case Material Information Regarding The Rejections Made By Another Examiner In Related Co-Pending Applications ............................................... 62 1. Rejection in the `179 Application ............................................................. 62 2. Rejection in the `178 Application ............................................................. 65 Amgen's Misrepresentations Regarding The Apparent Molecular Weight Of Recombinant EPO............................................................................ 68 Amgen's Affirmative Misrepresentations And Omissions Regarding COS rEPO ........................................................................................................... 70 Amgen Made Affirmative Misrepresentations And Omissions Regarding CHO rEPO ....................................................................................... 73 Amgen Concealed Information Regarding The Standard Used In RIA From The `349 Examiner ................................................................................... 76 Non-Disclosure Of Amgen Work With The 1411 Cell Line............................ 77 iii

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Page I. Misrepresentations Regarding The State Of The Prior Art As To The Expression Of Biologically Active Recombinant Glcyoproteins .................... 79 1. Amgen's Misrepresentations Regarding tPA............................................ 80 2. Amgen's Non-Disclosure Of Interferon Art ............................................. 82 Misrepresentation Regarding The Prior Art Use Of Compositions Of EPO and Human Serum Albumin..................................................................... 84

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TABLE OF AUTHORITIES Page(s) CASES A.B. Dick Co. v. Burroughs Corp., 617 F. Supp. 1382 (N.D. Ill. 1985), aff'd, 798 F.2d 1392 (Fed. Cir. 1986).................52, 67 Amgen, Inc. v. Hoechst Marion Roussel, Inc., 126 F. Supp. 2d 69 (D. Mass. 2001) ..............................................................................5, 27 Amgen, Inc. v. Hoechst Marion Roussel, Inc., 287 F. Supp. 2d 126 (D. Mass. 2003) ..................................................................................6 Amgen, Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313 (Fed. Cir. 2003)....................................................................................27, 33 Amgen, Inc. v. Hoechst Marion Roussel, Inc., 339 F. Supp. 2d 202 (D. Mass. 2004) ..........................................................................23, 24 Amgen Inc. v. Hoechst Marion Roussel, Inc., Civil Action No. 97-10814-WG4 ........................................................................................1 Apotex USA, Inc. v. Merck & Co., 254 F.3d 1031 (Fed. Cir. 2001)..........................................................................................26 Astra Aktiebolag v. Andrx Pharms., Inc., 483 F.3d 1364 (Fed. Cir. 2007)..........................................................................................25 Athletic Alternatives, Inc. v. Prince Manufacturing, Inc., 73 F.3d 1573 (Fed. Cir. 1996)............................................................................................28 In re Berg, 140 F.3d 1428 (Fed. Cir. 1998)..........................................................................................27 Boyden Power-Brake Co. v. Westinghouse, 170 U.S. 537 (1898).....................................................................................................23, 24 Centricut, LLC v. Esab Group, Inc., 390 F.3d 1361 (Fed. Cir. 2004)............................................................................................5 DSU Med. Corp. v. JMS Co., 471 F.3d 1293 (Fed. Cir. 2006)..........................................................................................11 Digital Control Inc. v. Charles Machine Works, 437 F.3d 1309 (Fed. Cir. 2006)..........................................................................................51 Eaton Corp. v. Rockwell Int'l Corp., 323 F.3d 1332 (Fed. Cir. 2003)....................................................................................26, 37 v

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Page(s) Eli Lilly & Co. v. American Cyanamid Co., 82 F.3d 1568 (Fed. Cir. 1996)......................................................................................15, 16 Eli Lilly & Co. v. Barr Labs., Inc., 251 F.3d 955 (Fed. Cir. 2001)............................................................................................27 Enzo Biochem, Inc. v. Calgene, Inc., 188 F.3d 1362 (Fed. Cir. 1999)..........................................................................................28 eSpeed Inc. v. Brokertec USA, L.L.C., 417 F. Supp. 2d 580 (D. Del. 2006), aff'd, 480 F.3d 1129 (Fed. Cir. 2007) .....................51 Ferring B.V. v. Barr Labs. Inc., 437 F.3d 1181 (Fed. Cir. 2006)..........................................................................................51 Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., 535 U.S. 722 (2002).......................................................................................................6, 10 Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., 2007 WL 1932269 (Fed. Cir. 2007).....................................................................................6 In re Fisher, 427 F.2d 833 (C.C.P.A. 1970) ...........................................................................................28 Fox Indus., Inc. v. Structural Preservation Systems, Inc., 922 F.2d 801 (Fed. Cir. 1990)............................................................................................86 Fritsch v. Lin, 21 U.S.P.Q.2d 1737 (Bd. Pat. App. 1991) .........................................................................55 Genentech, Inc. v. Boehringer Mannheim GmbH, 47 F. Supp. 2d 91 (D. Mass. 1999) ........................................................................13, 15, 16 General Electric Co. v. United States, 206 U.S.P.Q. 260 (Ct. Cl. 1979) ........................................................................................52 Golden Valley Microwave Foods Inc. v. Weaver Popcorn Co. Inc., 837 F. Supp. 1444 (N.D. Ind. 1992), aff'd, 11 F.3d 1072 (Fed. Cir. 1993).......................52 In re Gosteli, 872 F.2d 1008 (Fed. Cir. 1989)..........................................................................................28 Graver Tank & Mfg. Co. v. Linde Air Products Co., 339 U.S. 605 (1950)...........................................................................................................23

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Page(s) Hoechst Marion Roussel v. Kirin-Amgen Inc., [2002] EWHC 471 .............................................................................................................67 McKesson Info. Solutions, Inc. v. Bridge Med., Inc., 2006 WL 1652518 (E.D. Cal. 2006), aff'd, 487 F.3d 897 (Fed. Cir. 2007) ..........50, 53, 64 Morton Int'l, Inc. v. Cardinal Chem. Co., 5 F.3d 1464 (Fed. Cir. 1993)..............................................................................................27 Nat'l Recovery Techs., Inc. v. Magnetic Separations Sys., Inc., 166 F.3d 1190 (Fed. Cir. 1999)..........................................................................................29 Oakley, Inc. v. Sunglass Hut, Int'l, 316 F.3d 1331 (Fed. Cir. 2003)..........................................................................................27 Oddzon Prods., Inc. v. Just Toys, Inc., 122 F.3d 1396 (Fed. Cir. 1997)....................................................................................26, 32 Personalized Media Communications, LLC v. Int'l Trade Comm'n, 161 F.3d 696 (Fed. Cir. 1998)......................................................................................27, 28 Phillips v. AWH Corp., 415 F.3d 1303 (Fed Cir. 2005)...........................................................................................10 In Re Portola Packaging, Inc., 110 F.3d 786 (Fed. Cir. 1997)............................................................................................51 Rohm & Haas Co. v. Crystal Chem. Co., 722 F.2d 1556 (Fed. Cir. 1983)..........................................................................................50 Rosco, Inc. v. Mirror Lite Co., 304 F.3d 1373 (Fed. Cir. 2002)..........................................................................................26 Scripps Clinic & Research Found. v. Genenech, Inc., 927 F.2d 1565 (Fed. Cir. 1991)......................................................................................8, 23 Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004)............................................................................................28 Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348 (Fed. Cir. 2003)..........................................................................................11 STATUTES 35 U.S.C. § 102..............................................................................................................................25

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Page(s) 35 U.S.C. § 102(a) .............................................................................................................29, 78, 79 35 U.S.C. § 102(f)........................................................................................................26, 31, 32, 37 35 U.S.C. § 102(g) .............................................................................................................26, 27, 37 35 U.S.C. § 103...........................................................................................................25, 32, 49, 62, 63, 74, 76, 78, 79, 82 35 U.S.C. § 103(b) ...................................................................................................................49, 50 35 U.S.C. § 112...........................................................................................................25, 27, 28, 39, 74 35 U.S.C. § 121....................................................................................................................1, 41, 45 35 U.S.C. § 271..............................................................................................................................11 35 U.S.C. § 271(a) .............................................................................................................12, 19, 20 35 U.S.C. § 271(b) .........................................................................................................................11 35 U.S.C. § 271(e)(1).......................................................................................................................2 35 U.S.C. § 271(g) ......................................................................................................14, 15, 16, 18, 19, 20 37 C.F.R. § 1.4(b) ..............................................................................................................52, 66, 70 37 C.F.R. § 1.4(c)...............................................................................................................52, 66, 70 37 C.F.R. § 1.56(a).........................................................................................................................50 MISCELLANEOUS Collen et al., J. Pharm. & Expt. Therapeutics, 231 (1984) ...........................................................77 Donald S. Chisum, (2007) Chisum on Patents, Vol. 3, § 7.03(4)(b) .............................................29 Egrie et al., 1986, Characterization and Biological Effects of Recombinant Human Erythropoietin, Immunobiol., vol. 172 (1986) ...................................................................71 Eschbach et al., Correction Of The Anemia Of End-Stage Renal Disease With Recombinant Human Erythropoietin, NEJM 316:73-78 (1987)........................................71 MPEP § 609 (5th ed. Aug. 2001)...................................................................................................51 viii

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Page(s) MPEP § 706.02 (5th ed. Rev. 6, Oct. 1987) ..................................................................................80 MPEP § 804 (5th ed. Rev. 8, May 1988).......................................................................................57 MPEP § 804 (8th ed. Rev. 5, Aug. 2006) ......................................................................................57 MPEP § 2001.04 (5th ed. Rev. 14, 1992) .......................................................................................50 MPEP § 2001.06(b) (5th ed. Rev. 3, May 1986) .....................................................................64, 65 MPEP § 2002.03 (5th ed. Rev. 3, May 1986)................................................................................52 Spivak et al., "Use of Immobilized Lectins and Other Ligands for the Partial Purification of Erythropoietin," Blood 52(6):1178-88 (1978)...........................................29 Takaji Miyake, Charles Kung, and Eugene Goldwasser, "Purification of Human Erythropoietin," J. Biol. Chem., 252, 5558-64 (1977).....................................29, 36, 62, 82 Takeuchi et al., "Comparative Study of Asparagine-linked Sugar Chains of Human Erythropoietins Purified from Urine and the Culture Medium of Recombinant Chinese Hamster Ovary Cells"....................................................................69 U.S. Gen. Accounting Office, GAO-RCED-89-120BR, Biotechnology, Backlog of Patent Applications (1989) ................................................................................................51 Webber and Clemens, "Purification of Erythropoietin from Human Urine," Fed. Proceed, 42(7):1872 (1983) ...............................................................................................29 Yanagawa et al., "Isolation of human erythropoietin with monoclonal antibodies," J. Biol. Chem., 259(5):2707-10 (1984)..................................................................................29

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Defendants F. Hoffman-La Roche, Ltd, Roche Diagnostics GmbH and Hoffman-La Roche Inc. (collectively "Roche") submit this pre-trial brief outlining for the Court what the evidence adduced at trial will show. For years Roche has been a leader in the anemia treatment field, selling its own erythropoietin product Neorecorman®, worldwide outside the U.S. Roche developed MIRCERATM as a new anemia drug to provide patients with improved treatment. MIRCERATM is not human erythropoietin.1 It is a new chemical entity (as recognized by the United States FDA) and has significant medical advantages including allowing once monthly dosing as compared to 2-3 times weekly for currently available erythropoietin products, fewer injections for patients leading to a better quality of life, and essentially more choice for physicians in treating seriously ill patients. Just recently patients outside the U.S. gained access to this drug and are now enjoying the significant benefits that it offers. I. ROCHE'S ACCUSED MIRCERATM PRODUCT MIRCERATM represents the culmination of nearly a decade of intensive scientific research by Roche scientists aimed at creating improved treatments for anemia. The U.S. Patent Office (PTO) recognized Roche's achievement in 2003, awarding Roche U.S. Patent No. 6,882,272. The MIRCERATM that Roche plans to sell in the U.S. will be manufactured in
1

During the July 17, 2007 summary judgment hearing, the Court asked Amgen's counsel "what is the structure of human erythopoietin?" Amgen has yet to respond to that question in this case. However, just days ago, in the HMR/TKT case, in which Amgen is attempting to narrow the meaning of claim 1 of the `422 patent in order to avoid invalidating prior art, Amgen ascribes inter alia, specific structural distinctions purportedly possessed by human erythropoietin "purified from mammalian cells grown in culture." (Amgen's Brief on Remand Concerning Whether Goldwasser Anticipates `422 Claim 1, Document 863, Amgen Inc. v. Hoechst Marion Roussel, Inc., Civil Action No. 97-10814-WG4). Amgen has provided no evidence whatsoever that MIRCERATM has any of these structural characteristics.

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Europe. MIRCERATM has not yet been approved for sale in the United States, although the FDA issued an "approvable" letter in May 2007.2 The European Commission approved the sale of MIRCERA in Europe in July 2007. The active ingredient in MIRCERATM is CERA -- an acronym for Continuous Erythropoiesis Receptor Activator. CERA is an erythropoiesis stimulating agent (ESA) that is synthesized by chemically reacting two starting materials: a specific activated polyethylene glycol reagent and Epoetin beta.3 Roche makes Epoetin beta by fermenting cells that are genetically altered with DNA that codes for the 193 amino acid residues that make up pre-erythropoietin. The cells Roche uses were originally created by a process known as "protoplast fusion." Bacteria transformed with plasmids containing DNA coding for the pre-erythropoietin amino acid sequence were "smushed" with mammalian cells so that DNA from the bacteria was introduced into the mammalian cells without isolation. The resulting cells are grown up in fermentation tanks under controlled conditions. The cells express various proteins, including a 166 amino acid residue glycoprotein which the cells proteolytically cleave to yield a 165 amino acid glycoprotein. Roche then harvests (separates from the cells) a crude isolate containing a heterogeneous collection of proteins, impurities and byproducts. That therapeutically useless mixture is

transformed into Epoetin beta via a patented process which includes five distinct
2

Roche has produced substantial evidence that MIRCERATM is not being used for any purposes that fall outside the exemption provided by 271(e)(1). Therefore, in addition to the non-infringement grounds detailed herein, Roche does not infringe any of the asserted claims because all of Roche's activities with CERA are protected from infringement by the safe harbor exemption. 35 U.S.C. §271(e)(1). Recombinant human erythropoietins are known as "epoetins." denominated Epoetin alfa. Amgen's product is

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chromatography steps.

Although erythropoietin molecules found in the crude isolate from

mammalian host cells ordinarily exist as fourteen different charged forms (isoforms) of erythropoietin, Roche's purification process yields a product having predominantly only six isoforms. That product is Epoetin beta. Roche synthesizes CERA by reacting Epoetin beta with an activated PEG reagent -- Nhydroxysuccinimidyl ester of methoxy poly(ethylene glycol)-butanoic acid (mPEG-SBA). A covalent bond forms between the mPEG-SBA and a free amino group on Epoetin beta. Hydrogen is removed from Epoetin beta and N-hydroxysuccinimide is released. The mPEGSBA reacts productively with the Epoetin beta at any one of nine locations on the Epoetin beta molecule and, following chromotography, yields a heterogeneous preparation of CERA. The chemical reaction changes either an internal lysine residue to a PEG-amido-2-aminocaproic acid (PEG-AACA) residue or the N-terminal alanine to a PEG-amido propionic acid (PEG-APA) residue. CERA is a new chemical entity which is a substantially different molecule from the Epoetin beta and mPEG-SBA starting materials. For example: · · · · · · The molecular weight of CERA is approximately double (60kDa) that of Epoetin beta (30kDa). The binding affinity of CERA to the EPO receptor on cell surfaces is 50- to 100-fold lower than the binding affinity of Epoetin beta to the EPO receptor. CERA has been found to be metabolized by cells more quickly than Epoetin alpha. CERA has a substantially longer half-life in vivo than Epoetin beta. CERA exhibits substantially greater potency than Epoetin beta both in vitro and in vivo. CERA and Epoetin beta have demonstrated different intracellular signaling properties.

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II.

AMGEN CANNOT MEET ITS BURDEN OF PROVING THAT ROCHE INFRINGES THE ASSERTED CLAIMS4 A. Amgen's Burden Of Proving Infringement

As patentee, Amgen has the "burden of proving infringement by a preponderance of the evidence." Centricut, LLC v. Esab Group, Inc., 390 F.3d 1361, 1367 (Fed. Cir. 2004). "If the accused product meets each of the limitations contained in a claim" as properly construed, "then the product literally infringes that claim. If, however, even one limitation is not met, then the product does not literally infringe." Amgen, Inc. v. Hoechst Marion Roussel, Inc., 126 F. Supp. 2d 69, 117 (D. Mass. 2001) ("Amgen I"). A product "which does not infringe a patent claim literally may still infringe the claim under the doctrine of equivalents if each and every limitation of the claim is literally or equivalently presented." Id. As this Court explained: "A claim limitation is equivalently present in an accused product if there are only `insubstantial differences' between the limitation and the corresponding aspects of the product. `The usual test of the substantiality of the differences is whether the element in the accused composition performs substantially the same function in substantially the same way to obtain substantially the same result as the claimed element.'" Id. (citations omitted). The Court further observed that "application of infringement by equivalents . . . is limited by the doctrine of prosecution history estoppel." Id. According to the Federal Circuit "[t]he doctrine of prosecution history estoppel acts as a `legal limitation on the doctrine of equivalents.'

4

The "asserted claims" refers to claims 1 and 2 of the `868 Patent; claims 4-9 of the `698 Patent; claim 7 of the `349 Patent; claim 1 of the `422 Patent; and claims 3, 7-9, 11-12 and 14 of the `933 Patent. By letter from R. Day to L. Ben-Ami, dated August 2, 2007, Amgen represented that it would not assert claims 4 and 5 of the `698 patent at trial. Nonetheless, Roche maintains its invalidity counterclaims with respect to those claims.

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`[P]rosecution history estoppel limits the range of equivalents available to a patentee by preventing recapture of subject matter surrendered during prosecution of the patent.'" Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., 2007 WL 1932269, *6 (Fed. Cir. 2007). The Supreme Court has "made clear that a `presumption' of prosecution history estoppel arises when an amendment is made to secure the patent and the amendment narrows its scope." Amgen, Inc. v. Hoechst Marion Roussel, Inc., 287 F. Supp. 2d 126, 131 (D. Mass. 2003) ("Amgen III") (citing Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., 535 U.S. 722, 736 (2002)). "The inventor can overcome the `presumption' by showing that the amendment does not surrender the particular equivalent in question." Id. B. Amgen Cannot Prove That Roche Will Infringe Any Of The Asserted Claims of the `933 Patent 1. The Asserted Claims Of The `933 Patent.

Amgen asserts claims 3, 7, 8, 9, 11, 12 and 14 of the `933 patent in this action. Claim 3 is an independent product-by-process claim directed to a non-naturally occurring glycoprotein product: "A non-naturally occurring glycoprotein product of the expression in a mammalian host cell of an exogenous DNA sequence comprising a DNA sequence encoding human erythropoietin said product possessing the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells." Claims 7 and 8 also are product-by-process claims directed to non-naturally occurring glycoprotein products. Both are dependent on claim 3 (among other claims) and further limit the mammalian host cell of that claim: 7. The glycoprotein product according to Claim 3, 4, 5 or 6 wherein the host cell is a non-human mammalian cell. 8. The glycoprotein product of claim 7 wherein the non-human mammalian cell is a CHO cell. 5

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Claims 9 and 12 of the `933 patent are directed to pharmaceutical compositions that include, as an active ingredient, the glycoprotein product of claims 3 and 7: 9. A pharmaceutical composition comprising an effective amount of a glycoprotein product for erythropoietin therapy according to claim 1, 2, 3, 4, 5 or 6 and a pharmaceutically acceptable diluent, adjuvant or carrier. 12. A pharmaceutical composition comprising an effective amount of a glycoprotein product effective for erythropoietin therapy according to claim 7 and a pharmaceutically acceptable diluent, adjuvant or carrier. Claims 11 and 14 are method of treatment claims which depend from claims 9 and 12, respectively: 11. A method for treating a kidney dialysis patient which comprises administering a pharmaceutical composition of claim 9 in an amount effective to increase the hematocrit level of said patient. 14. A method for treating a kidney dialysis patient which comprises administering a pharmaceutical composition of claim 12 in an amount effective to increase the hematocrit level of said product. Thus, the asserted claims of the `933 patent include, directly or by dependence, reference to "non-naturally occurring glycoprotein" products which are the "product of the expression in a mammalian host cell of an exogenous DNA sequence comprising a DNA sequence encoding human erythropoietin." 2. "Product Of The Expression In A Mammalian Host Cell."

In June 1989, during prosecution of the `933 patent, Amgen asserted that the claims of the application were "product-by-process claims" which define each of the claimed products "by the process by which it is produced," i.e., "expression in a mammalian cell." (`178 Application File History 116, Paper 11, Amendment Under Rule 116 at 3-4). This Court has construed the

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term "expression" to mean that "the glycoprotein was produced in a cell and recovered from the cell culture." (Mem. and Order, 7/3/07 at p. 32 n.3). Plainly, Roche's CERA is literally non-infringing because it is not a "product of . . . expression in a mammalian host cell," even under the broadest interpretation of a product-byprocess claim. See Scripps Clinic & Research Found. v. Genenech, Inc., 927 F.2d 1565, 1583 (Fed. Cir. 1991) ("the correct reading of product-by-process claims is that they are not limited to product prepared by the process set forth in the claims"). Rather, CERA is a chemically synthesized compound that is created in the laboratory. CERA is not and cannot be produced by living cells and is substantially different in structure and function from a product of the recited process. CERA is distinct from the Epoetin beta and mPEG-SBA starting materials and CERA cannot be broken down into the starting materials. CERA differs from an erythropoietin

glycoprotein product of a mammalian host cell not only in its structure but also in its resulting physiochemical, biological and clinical properties.5 Nor does Roche infringe under the doctrine of equivalents. As referenced above, during prosecution of the application for the `933 patent, the applicant added a claim which recited a "glycoprotein product of the expression of an exogenous DNA sequence" and represented to the PTO: "All product claims in the subject application are now product-by-process claims. . . . These product-by-process claims are presented. . . . to further define the product of the subject invention since the recombinant erythropoietin claim cannot be precisely defined except by the process by which it is produced." (`178 Application File History, paper 11, 6/2/89 Amendment
5

While the initial step in producing Epoetin beta involves expression in a mammalian host cell, Epoetin beta is made and used by Roche only outside of the United States in synthesizing CERA. Thus, Roche does not make, use, sell or offer to sell Epoetin beta in the United States.

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at 1, 3-4).

Having thus narrowed its claims by introducing the phrase "product of the

expression," Amgen should be estopped, under the Supreme Court's decision in Festo, from arguing that the term is satisfied under the doctrine of equivalents. In any event, CERA is not the equivalent of a "product of . . . expression in a mammalian host cell." Indeed, as cited above, there are profound physical and biological differences

between Epoetin beta, the purified therapeutically active protein extracted through a series of steps from material expressed by a mammalian host cell, and CERA. Furthermore, during prosecution Amgen argued to the PTO that human erythropoietin is an "obligate glycoprotein," a term Amgen coined to mean that EPO must be properly glycosylated to possess in vivo activity. (`179 Application File History, Paper 8, 5/24/88 Second Preliminary Amendment at 6.) Amgen stated that the claimed processes were "believed to constitute one of the first instances (if not the first instance) of recombinant production of an in vivo biologically active obligate human glycoprotein." Id. (emphasis in original). By contrast, experimental data indicates that CERA is not an "obligate glycoprotein" in that its in vivo biological activity persists even after N-deglycosylation. These differences reflect that CERA is structurally very different from human EPO and interacts with the body's EPO receptors in a substantially different way than does EPO to effect an increase in hemoglobin. As a practical matter, CERA and EPO yield different results in patients in that CERA requires less frequent dosing than Epoetin beta. Hence, even if

infringement under the doctrine of equivalents were not barred by prosecution history estoppel, CERA is not the equivalent of a "product of . . . expression in a mammalian cell." 3. "Non-Naturally Occurring Glycoprotein."

Amgen also cannot prove the "non-naturally occurring glycoprotein" element which, directly or by dependence, is a requirement of each of the asserted claims of the `933 patent. 8

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This Court has construed the words "non-naturally occurring" to mean "not occurring in nature." (Mem. and Order, 7/3/07 at 32). Thus, in order to prevail on infringement, Amgen has to prove that the allegedly infringing glycoprotein has structure that is different than the erythropoietin glycoproteins that occur in nature. In the course of prosecution, the applicant introduced the "non-naturally occurring" limitation in what issued as claim 3 in order to "distinguish the subject matter claimed from all prior art reference relating to erythropoietin isolates." (12/20/95 Second Preliminary

Amendment, Ser. No. 08/487,774, p. 7.) The applicant stated that in a PTO interview with the examiner "it was agreed that the negative limitation `non-naturally occurring' would, when combined with the notation of glycosylation differences in [what became claims 1 and 5], meet Section 112 specificity requirements." (Id. at p. 6). In order to overcome the prior art and distinguish the claimed glycoproteins from any that occur in nature, the addition of the term "non-naturally occurring" to the claims of the `933 patent had to reflect a physical difference. Stated otherwise, a protein that is not distinguishable from naturally occurring proteins is not a protein that does not occur in nature -- whatever the source. Indeed, the examiner's rejections which gave rise to the amendment (8/16/94 Office Action, pp. 6-9; 5/16/95 Office Action, pp. 4-6) had cited In re Brown, 459 F.2d 531, 535 (C.C.P.A. 1972), where the court stated that "the lack of physical description in a product-byprocess claim makes determination of the patentability of the claim more difficult, since . . . it is the patentability of the product claimed and not of the recited process steps which must be established." (Emphasis added). In Amgen, Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1354 (Fed. Cir. 2003) (Amgen II), the Federal Circuit similarly stated that "a claimed product shown to be present in the prior art cannot be rendered patentable solely by the addition

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of source or process limitations." See also General Electric Co. v. Wabash Appliance Corp., 304 U.S. 364, 373 (1938) ("a patentee who does not distinguish his product from what is old except by reference, express or constructive, to the process by which he produced it, cannot secure a monopoly on the product by whatever means produced"). The only supposed physical distinction between naturally occurring EPO glycoproteins and the EPO glycoproteins described in the specification of the `933 patent is their glycosylation: Novel glycoprotein products of the invention include those having a primary structural conformation sufficiently duplicative of that of a naturally-occurring (e.g., human) erythropoietin to allow possession of one or more of the biological properties thereof and having an average carbohydrate composition which differs from that of naturally-occurring (e.g., human) erythropoietin. (`933 patent, col. 10: 29-40). Given that the Court has already held that the glycosylation of naturally occurring EPO is so variable as to be an "unascertainable" standard, Amgen cannot prove -- as it erroneously attempts to do -- that the glycosylation of Epoetin beta is structurally distinct from the glycosylation of naturally occurring EPO.6 In other words, Amgen cannot show that Epoetin
6

Amgen is foreclosed, under the doctrine of collateral estoppel, from relitigating of whether the glycosylation of naturally occurring EPO is a definite standard. In patent cases, the Federal Circuit applies the issue preclusion law of the regional circuit. Vardon Golf Co. v. Karsten Mfg. Corp., 294 F.3d 1330, 1332 (Fed. Cir. 2002). In the First Circuit, courts look for five essential elements in applying collateral estoppel: "(1) the issue sought to be precluded must be the same as that involved in the prior action; (2) the issues must have been actually litigated; (3) the issue must have been determined by a valid and binding final judgment; and, (4) the determination of the issue must have been essential to the judgment; and (5) the party to the second action must be the same as or in privity with the parties in the first action." Boston Sci. Corp. v. SciMed Life Sys., Inc., 983 F. Supp. 245, 255 (D. Mass. 1997). Here, all of the requirements of issue preclusion are met: Whether glycosylation would allow a potential infringer to distinguish between naturally occurring and non-naturally occurring EPO was actually at issue in the prior Amgen litigation. That question was fully litigated by Amgen in the district court and the indefiniteness holding was essential to the final judgment holding claims 1, 2 and 9 of the `933 patent invalid. The judgment was affirmed on appeal.

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beta has glycosylation that physically distinguishes it as a product having a structure that does not occur in nature. Although the accused product here is CERA, not the Epoetin beta starting material Amgen ignores the significant differences between the two products and bases most of its evidence on the features of Epoetin beta. Nor can Amgen show that CERA satisfies the "non-naturally occurring" term under the doctrine of equivalents. Given that Amgen added the words "non-naturally occurring" to the claims of the `933 patent to overcome prior art, Amgen should be estopped, pursuant to Festo, from arguing that the term "non-naturally occurring" can somehow be satisfied under the doctrine of equivalents. 4. Amgen Cannot Show That Roche Induces Infringement Of Claims 11 And 14.

Claims 11 and 14 of the `933 patent recite methods for treating kidney dialysis patients with the pharmaceutical compositions of claims 9 and 12, respectively. Even assuming, contrary to fact, that Roche does infringe claims 9 and 12, it does not infringe claims 11 and 14. Given that Roche sells -- but does not administer -- pharmaceuticals, Roche indisputably does not directly infringe claims 11 and 14 under 35 U.S.C. § 271. See Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348, 1363 n. 7 (Fed. Cir. 2003) ("[P]harmaceutical companies do not generally treat diseases; rather, they sell drugs to wholesalers or pharmacists, who in turn sell the drugs to patients possessing prescriptions from physicians. Pharmaceutical companies also

occasionally give samples of drugs to doctors and hospitals. In none of these cases, however, does the company itself treat the diseases"). Roche also does not induce infringement by others, under 35 U.S.C. § 271(b), because Roche lacks the requisite specific intent. As explained by the Federal Circuit: "`It must be established that the defendant possessed specific intent to encourage another's infringement and

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not merely that the defendant had knowledge of the acts alleged to constitute inducement.'. . . . Accordingly, inducement requires evidence of culpable conduct, directed to encouraging another's infringement, not merely that the inducer had knowledge of the direct infringer's activities." DSU Med. Corp. v. JMS Co., 471 F.3d 1293, 1306 (Fed. Cir. 2006). In DSU, the court upheld a jury verdict of no inducement, where the record contained evidence that the party accused of inducing infringement "did not believe its [product] infringed. Therefore, it had no intent to infringe." Id. at 1307. Here, Roche is proceeding with a good faith belief that treating patients with MIRCERATM is non-infringing. infringement. C. Amgen Cannot Prove That Roche Will Infringe The Asserted Claims Of The `868 Patent 1. The Asserted Claims Of The `868 Patent. Consequently, Roche lacks the intent necessary to induce

Amgen alleges that Roche infringes claims 1 and 2 of the `868 patent which claim processes for producing a glycosylated erythropoietin polypeptide as follows: 1. A process for the production of a glycosylated erythropoietin polypeptide having the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells comprising the steps of: (a) growing, under suitable nutrient conditions, mammalian host cells transformed or transfected with an isolated DNA sequence encoding human erythropoietin; and (b) isolating said glycosylated erythropoietin polypeptide therefrom. 2. The process according to claim 1 wherein said host cells are CHO cells.

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2.

Roche Does Not Practice The Claimed Process In The United States.

The asserted claims of the `868 patent describe processes for producing "a glycosylated erythropoietin polypeptide" using mammalian host cells which are "transformed or transfected with an isolated DNA sequence encoding human erythropoietin." Given that Roche makes MIRCERATM in Europe, Roche plainly does not practice the process claims of the `868 patent "within the United States," per 35 U.S.C. § 271(a). Process claims are only infringed if the entire process is carried out in the U.S. 3. "Cells Transformed Or Transfected With An Isolated DNA Sequence."

Even outside of the U.S., Roche does not transform or transfect cells with what the claims pointedly describe as "an isolated DNA sequence encoding human erythropoietin." (Emphasis added). This Court has construed the claims to recite "cells that have been genetically modified with isolated DNA containing genetic instructions for human erythropoietin or later generations of these cells that have inherited those instructions." At the time of the application, DNAmediated gene transfer techniques, such as calcium phosphate precipitation, electroporation and, microinjection, were available for transferring isolated and purified DNA fragments into host cells. In fact, the specification of the Amgen patents discloses several examples of host cell transformation and transfection with an isolated DNA sequence, including introduction of purified and isolated DNA into COS cells (Examples 6 and 7), CHO cells (Example 8) and E. Coli (Example 12) via DNA mediated gene transfer. As explained above, however, the

protoplast fusion method used to create Roche's production cell bank, in which cells are "smushed" together, does not involve the transfer of isolated DNA. Simply stated, Roche's cells are not themselves, nor are they later generations of cells, that were transformed or transfected

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with an "isolated" DNA sequence, as required by the claims, or even with an insubstantially different equivalent thereof. Furthermore, infringement under the doctrine of equivalents of the phrase "transformed or transfected with an isolated DNA sequence encoding human erythropoietin" is barred by the doctrine of prosecution history estoppel. During prosecution of U.S. Patent No. 4,703,008 (the `008 patent) -- the parent of the `868 patent -- the applicant distinguished over the prior art Sugimoto patent (U.S. Pat. No. 4,377,513), telling the PTO that "[u]nder no circumstances can the claims be urged to `read on' non-isolated DNA" of the Sugimoto reference. (`298

Application File History, Paper 12, 10/2/86 Amendment and Reply at 13). Therefore, the claims cannot cover non-isolated DNA by equivalence. Moreover, because literal infringement is a predicate for liability under 271(g), Genentech, Inc. v. Boehringer Mannheim GmbH, 47 F. Supp. 2d 91, 107 (D. Mass. 1999), the doctrine of equivalents is irrelevant with respect to Roche's manufacture of CERA outside the U.S. 4. "Isolating Said Glycosylated Polypeptide."

The concluding step of the processes of the claims of the `868 patent is "isolating said glycosylated erythropoietin polypeptide" from the cells which produce the protein. In securing its patents in the PTO, Amgen asserted that the term "isolating" means "nothing more than separating the expressed product from the cell," flatly denying that the step of "isolating" includes "purification." (Interf. No. 102,097, Brief for the Senior Party Lin at 48, 58). At the Markman hearing in this case, the Court acknowledged the binding effect of Amgen's statements and held that the term "isolating said glycosylated erythropoietin polypeptide" means separating said glycosylated erythropoietin polypeptide. Hence, the final product of the process recited in the claims, which ends with isolation, is the "crude isolate" -- the unpurified expression product that is "isolated" from the cells. Amgen has no evidence at all, however, that Roche's crude 14

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isolate -- in contrast to CERA or purified Epoetin beta -- has "the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells." Because Amgen cannot prove that the unpurified product of Roche's process has the in vivo biological activity recited in the `868 patent claims, Amgen cannot prevail on the issue of literal infringement. 5. Roche Does Not Infringe Under 35 U.S.C. § 271(g) Because The Isolated Glycoprotein Is "Materially Changed."

Even assuming, arguendo, that Roche practices the claims of the `868 patent outside of the United States, Amgen can establish infringement of the claims of the `868 patent, under 35 U.S.C. § 271(g) if, but only if, it demonstrates that Roche imports the product of the claimed process without it having been "materially changed by subsequent processes." In Eli Lilly & Co. v. American Cyanamid Co., 82 F.3d 1568 (Fed. Cir. 1996), the Federal Circuit stated that § 271(g) "permits the importation of an item that is derived from a product made by a patented process as long as that product is `materially changed' in the course of its conversion into the imported item." Id. at 1572. The court explained that the issue under § 271(g) is "the substantiality of the change between the product of the patented process and the product that is being imported." Id. at 1573. "In the chemical context, a `material' change in a compound is most naturally viewed as a significant change in the compound's structure and properties." Id. The patentee "bears the burden of proof on the issue of material change" under § 271(g). Genentech, 47 F. Supp. 2d at 108. The Lilly case concerned a claim to a method for making an intermediate compound that the defendants there used in synthesizing the antibiotic cefaclor which they, in turn, imported into the United States. Both the intermediate and cefaclor had the same nucleus, but the intermediate had to be changed at three positions to create cefaclor. In denying a motion for a

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preliminary injunction, the court there held that the product of the claimed process was "likely to be found to have been `materially changed' in the process of its conversion into cefaclor" such that the importation or sale of the final product was "not likely to be held to infringe." Id. at 1578. Ultimately, the district court granted summary judgment finding a material change based, at least in part, on "ease of dosing," despite evidence presented that the product of the patented process had antibiotic utility like the imported product. Roche does not infringe under § 271(g) because, even if Roche practiced the process of claims 1 and 2 of the `868 patent outside of the U.S., the product of that process is "materially changed" before it is imported as MIRCERATM. Roche materially changes the crude isolate recovered from cells by performing a series of patented purification steps to remove potentially harmful chemicals. The purification process converts a therapeutically useless composition--the crude isolate--into a useful therapeutic product Epoetin beta. While EPO produced by a single mammalian cell can consist of a heterogeneous mixture of different isoforms having from zero to 14 sialic acid residues and, as a result, different electrical charges, Roche's purification method materially changes the recovered product by selecting out predominantly six isoforms. Amgen has made much of the fact that the isoform composition of EPO impacts its in vivo biological activity. Roche makes a further, more drastic, material change by chemically reacting the Epoetin beta with an activated polythylene glycol molecule to create CERA. As made clear above, CERA differs from the Epoetin beta starting material in terms of structure and function as well as in terms of pharmacodynamic and pharmacokinetic properties. This Court has pointed to the same sorts of differences between the imported product and the product of the patented process, in finding material change under § 271(g). Genentech, 47 F. Supp. 2d at 113-20.

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Amgen argues that the pegylation reaction between Epoetin beta and mPEG-SBA that yields CERA is a "conventional process" which, according to Amgen, does not effect a material change. However, as mentioned, pegylation is not the only material change that occurs in the process of transforming the crude isolate to make MIRCERATM. Prior to the pegylation reaction, the crude isolate is subjected to a patented purification process and after the pegylation reaction the CERA must be formulated to make MIRCERATM. Furthermore, in Lilly, the Federal Circuit concluded that there likely was a material change even though steps involved in changing the intermediate to the final cefaclor product were all "relatively routine chemical reactions." 82 F.3d at 1573. In any event, the pegylation of Epoetin beta was far from routine--particularly at the time of the priority date of the `868 patent in the early 1980s. Pegylation reactions are complex chemical reactions, requiring the evaluation of numerous variables and yielding new molecules with unpredictable physiochemical and biological properties. Pegylation procedures employed during the late 1970s and 1980s were plagued by difficulties, including restriction to PEGs with low molecular weights, relatively unstable activated PEGs and lack of selectivity in protein modification. As of 1992, the experience with pegylation technology was limited and rather unsatisfactory. When asked in this case about the predictability of pegylation, Amgen's

inventor, Dr. Lin, testified: "For any particular procedure, you had to do it yourself to see if the end product that you modified -- the way you did it -- would be active or not. You had to check it out experimentally. (Lin Tr. (3/28/07) at 100:18-22). The notion that pegylation of a particular protein was routine is at odds with the fact that (i) Roche's MIRCERA is the product of nearly a decade of research and experimentation toward the development of a new erythropoiesis stimulating agent; and (ii) between 1985 and 17

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approximately 2000, Amgen attempted unsuccessfully to develop a new product by reacting PEG and EPO. Amgen maintains that Roche has no commercially viable alternatives to the patented process. The evidence however, is to the contrary. A DNA sequence encoding an analog of erythropoietin with an amino acid other than arginine at position 166 is not a DNA sequence encoding human erythropoietin. Host cells transformed or transfected with such a DNA

sequence would ultimately produce a glycoprotein having the 165 amino acid residues of Epoetin beta because of the activity of cellular carboxypeptidases which leave the amino acid at position 166. In the alternative, the crude isolate from these cells could be purified and treated with a carboxypeptidase in vitro to remove the C-terminal amino acid. In this way one could make what is essentially the Epoetin beta starting material for CERA without practicing any of the claimed methods. Another example of a viable alternative would be to use non-mammalian host cells to produce the products of the claimed process. In sum, even if Roche were to practice the process of claims 1 and 2 of the `868 patent outside of the U.S., the MIRCERATM that Roche will be importing is materially changed from the product of the processes claimed in the `868 patent. Therefore, Roche does not infringe under 35 U.S.C. § 271(g). D. Amgen Cannot Prove That Roche Will Infringe The Asserted Claim Of The `698 Patent 1. The Asserted Claims Of The `698 Patent.

Amgen alleges that Roche infringes claims 6-9 of the `698 patent7. Similar to the asserted claims of the `868 patent, claims 6-9 of the `698 patent recite processes for the
7

Amgen has indicated, by letter from R. Day to L. Ben-Ami, dated August 2, 2007, that it would not assert claims 4 and 5 at trial.

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production of a glycosylated erythropoietin polypeptide involving growing cells with DNA encoding "the mature erythropoietin amino acid sequence of FIG. 6" and "isolating said glycosylated erythropoietin polypeptide expressed by said cells." Independent claim 6 provides: 6. A process for the production of a glycosylated erythropoietin polypeptide having the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells comprising the steps of: a) growing, under suitable nutrient conditions, vertebrate cells comprising amplified DNA encoding the mature erythropoietin amino acid sequence of FIG. 6; and b) isolating said glycosylated expressed by said cells. (Emphasis added). 2. Roche Does Not Infringe Under § 271(a) Because Roche Does Not Make MIRCERATM In The U.S. erythropoietin polypeptide

As explained above in connection with the `868 patent, Roche does not make CERA or MIRCERATM in the United States and, therefore, does not infringe under 35 U.S.C. § 271(a). 3. Amgen Cannot Prove That Roche Practices The Patented Process.

As in the case of the `868 patent, the product of the claimed process is the crude isolate -the product of the process which concludes with "isolating said glycosylated erythropoietin polypeptide" expressed by said cells -- not purified Epoetin beta. The court decided that

"expressed" means produced by a cell and recovered from a cell. However, there is no evidence that Roche's crude isolate has the claimed "in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells." Additionally, the claims of the `698 patent require DNA encoding the mature erythropoietin amino acid sequence of Fig. 6 which as explained above Roche's cells do not have.

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4.

Roche Does Not Infringe Under § 271(g) Because The Crude Isolate Is "Materially Changed" Before Importation.

Even if Roche were to practice the claimed processes outside of the United States, Roche would not infringe, under 35 U.S.C. § 271(g), because, as detailed above, the crude isolate produced by Roche is materially changed in the course of being purified, reacted with mPEGSBA and then formulated into MIRCERATM before importation into the U.S. E. Amgen Cannot Prove That Roche Will Infringe The Asserted Claim Of The `349 Patent 1. The Asserted Claim Of The `349 Patent.

Amgen claims that Roche infringes one claim of the `349 patent -- claim 7 -- which states: "A process for producing erythropoietin comprising the step of culturing, under suitable nutrient conditions, vertebrate cells according to claim 1, 2, 3, 4, 5, or 6." According to Amgen, Roche infringes claim 7 by using cells according to claims 1, 2 and 3 of the patent. (Plaintiff's Supp. Resp. to Defs. First Set of Interrogs, Ex. A thereto, p. 21). Claims 1-3 read as follows: 1. Vertebrate cells which can be propagated in vitro and which are capable upon growth in culture of producing erythropoietin in the medium of their growth in excess of 100 U of erythropoietin per 106 cells in 48 hours as determined by radioimmunoassay, said cells comprising non-human DNA sequences which control transcription of DNA encoding human erythropoietin. 2. Vertebrate cells according to claim 1 capable of producing in excess of 500 U erythropoietin per 106 cells in 48 hours. 3. Vertebrate cells according to claim 1 capable of producing in excess of 1000 U erythropoietin per 106 cells in 48 hours.

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Thus, asserted claim 7 recites a process which employs vertebrate cells that are "capable of" producing 100, 500 and 1000 "U of erythropoietin per 106 cells in 48 hours as determined by radioimmunoassay." The term "U of erythropoietin" is not defined in the patent. 2. Roche Does Not Practice The Claimed Process In The U.S.

Again, Roche does not infringe, under 35 U.S.C. § 271(a), because claim 7 of the `349 patent is a process claim and Roche makes MIRCERATM outside of the U.S. 3. Roche Does Not Infringe Because The Product Of Roche's Cells Is "Materially Changed" Prior To Importation.

Even assuming, arguendo, that Roche does practice the claimed process abroad, Roche does not infringe, under 35 U.S.C. § 271(g