Amgen, Inc. v. F. Hoffman-La Roche Ltd.

Page 160

581 F.Supp.2d 160

AMGEN, INC., Plaintiff, v. F. HOFFMANN-LA ROCHE LTD., Roche Diagnostics GmbH, and Hoffmann-La Roche Inc., Defendants.

Civil Action No. 05-12237-WGY.

United States District Court, D. Massachusetts.

October 2, 2008.

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Aaron R. Hand, Adam Arthur Bier, Andy H. Chan, Berrie R. Goldman, Christian E. Mammen, Craig H. Casebeer, Darcy A. Paul, David M. Madrid, Deborah E. Fishman, Geoffrey M. Godfrey, Jon B. Dubrow, Katie J.L. Scott, Krista M. Carter, Lloyd R. Day, Jr., Mario Moore, Rebecca J. Wais, Renee Dubord Brown, Robert M. Galvin, Susan M. Krumplitsch, Lauren M. Papenhausen, Day Casebeer Madrid & Batchelder LLP, Cupertino, CA, Andrew Kumamoto, Firasat Ali, Mary Boyle, Michelle E. Moreland, Terrence P. McMahon, William G. Gaede, III, McDermott Will & Emery LLP, Palo Alto, CA, Bobby R. Burchfield, Jon B. Dubrow, Raymond A. Jacobsen, Richard W. Smith, McDermott Will & Emery, LLP, Washington, DC, Cullen N. Pendleton, Jennifer E. Flory, Jeremy D. Protas, Kevin M. Flowers, Mark Izraelewicz, Matthew C. Nielsen, Sandip H. Patel, Thomas I. Ross, Michael F. Borun, Marshall Gerstein & Borun LLP, Michael F. Borun, Marshall, O'Toole, Gerstein, Murray & Borun, Chicago, IL, D. Dennis Allegretti, Michael R. Gottfried, Christopher S. Kroon, Patricia R. Rich, Duane Morris LLP, Dana M. McSherry, Daniel A. Curto, James M. Fraser, Joshua A. Munn, Lauren M. Papenhausen, Michael Kendall, Nicole A. Longton, Peter M. Acton, McDermott, Will & Emery LLP, Boston, MA, Darrell G. Dotson, Erica S. Olson, Kimberlin L. Morely, Monique L. Corday, Sandip H. Patel, Wendy A. White-ford, Amgen Inc., Thousand Oaks, CA, William Diaz, McDermott Will & Emery LLP, Irvine, CA, for Plaintiff.

Aaron Stiefel, Alfred H. Heckel, Christopher T. Jagoe, Sr., Howard Suh, Jeanna Wacker, Krista M. Rycroft, Leora Ben-Ami, Manvin Mayell, Matthew McFarlane, Monica Contreras, Patricia A. Carson, Peter Fratangelo, Richard A. De Sevo, Thomas F. Fleming, Kaye Scholer LLP, New York, NY, Aton Arbisser, Julian Brew, Kaye Scholer LLP, Los Angeles, CA, David L. Cousineau, Mark S. Popofsky, Kaye Scholer LLP, Kathleen McDermott, Sonnenschein Nath & Rosenthal LLP, Washington, DC, George W. Johnston, Nancy Dilella, Patricia Rocha-Tramaloni, Hoffmann-La Roche Inc., Law Department, Nutley, NJ, Julia Huston, Robert L. Kann, Erik Paul Belt, Joel R. Leeman, Keith E. Toms, Kimberly J. Seluga, Lee C. Bromberg, Nicole A. Rizzo Smith, Robert M. Asher, Timothy M. Murphy, Bromberg & Sunstein LLP, Boston, MA, for Defendants.

MEMORANDUM AND ORDER

WILLIAM G. YOUNG, District Judge.

Amgen Inc. ("Amgen") sought declaratory relief to prevent F. Hoffmann-LaRoche Limited, Roche Diagnostics GmbH, and Hoffmann-La Roche Inc. (collectively, "Roche") from marketing a drug that infringes U.S. Patent Nos. 5,441,868, 5,547,933, 5,618,698, 5,621,080, 5,756,349, and 5,955,422. These patents relate to Amgen's recombinant erythropoietin ("EPO"), a naturally occurring protein that stimulates the production of red blood cells. Amgen, Inc. v. Hoechst Marion Roussel, Inc., 3 F.Supp.2d 104, 106 (D.Mass.1998). The jury found for Amgen across the board, upholding the validity of the claims-in-suit for the '422, '933, '868, '698, and '349 patents and finding that Roche literally infringed all of the claims-in-suit except for claim 12 of the '933 patent, which it found infringed by the doctrine of equivalents. Jury Verdict [Doc. No. 1542] at 2-3. The Court writes to explain its rulings on various pre-trial motions for summary judgment, specifically its findings and rulings that the Amgen patents survive Roche's obviousness-double patenting contentions, to resolve various post-trial motions, and to explain the decision to grant Amgen's request for a permanent injunction.

Due to the sheer number, the Court will not be able to address every motion.¹ Therefore, all motions not already granted and not resolved herein are denied. After explaining the grant of summary judgment on the issue of obviousness-type double patenting, the Court will address post-trial motions in three groups: validity, infringement, and injunctive relief. Regarding validity, the Court will write to explain three decisions. Primarily, the Court concluded that the source "purified from mammalian cells grown in culture" limits claim 1 of the '422 patent. As shall be discussed, the undisputed record revealed that none of the prior art, including the Goldwasser study, satisfied this limitation. Second, sufficient evidence supported the jury's finding that the term "human erythro-poietin," found in claim 1 of the '422 patent and claims 3, 7, and 9 of the '933 patent, is not indefinite, even though the specifications do not specify whether the glycoprotein described therein would be 165 or 166 amino acids in length.

Next, the Court will write to explain its grant of summary judgment to Amgen with respect to infringement of claim 1 of the '422 patent, see Electronic Order August 28, 2007, and the decision to uphold the jury's finding that Roche literally infringed claim 3 of the '933 patent. See Jury Verdict at 2. As shall be discussed below, Amgen patented recombinant EPO by reference to a specific amino acid sequence. See Amgen, Inc. v. F. Hoffmann-La Roche Ltd., 494 F.Supp.2d 54, 63 (D.Mass.2007) [hereinafter "Amgen Markman"]. Pegylation—the chemical reaction that attaches PEG to EPO via a single bond to form CERA, the active ingredient in MIRCERA—does not alter EPO's amino acid sequence. See Trial Ex. 53, Roche's Biologic License Application at 00004027 [hereinafter "Roche BLA"]. The attachment of PEG to EPO does not place MIRCERA beyond the boundary of the claims because "the specification expressly contemplates that additional molecules may be attached to `human erythropoietin.'" Amgen Markman, 494 F.Supp.2d at 63 (emphasis omitted). Thus, any minor modification of EPO that does not alter the specific amino acid sequence—such as the displacement of a single hydrogen atom—is immaterial and does not preclude a finding of infringement.

Finally, Amgen has satisfied all four factors necessary for a permanent injunction set forth in eBay Inc. v. MercExchange, L.L.C., 547 U.S. 388, 126 S.Ct. 1837, 164 L.Ed.2d 641 (2006). Failure to issue a permanent injunction would cause irreparable, immeasurable harm, for which there is no adequate remedy at law. Given that Roche infringes Amgen's valid patents, and in light of the harms that will be discussed, the balance of hardships clearly favors Amgen. Moreover, the Court has concluded that "the public interest would not be disserved by a permanent injunction." Id. at 391, 126 S.Ct. 1837. The record compiled over the course of a four-day evidentiary proceeding reveals no benefit to patient health or the public coffers so great as to outweigh the public's interest in a robust patent system.

I. BACKGROUND

"Erythropoiesis, the production of red blood cells, occurs continuously throughout the human life span to offset cell destruction." '422 Patent col. 5 ll. 41-43. "EPO is a protein hormone" that regulates erythropoiesis. Lodish Decl. [Doc. No. 513] ¶ 13. Produced in the kidneys, EPO circulates in the blood stream, id. ¶ 15, and, "[l]ike a key in a lock," id. ¶ 14, binds with EPO receptors located on erythroid progenitor cells in the bone marrow, id. ¶ 17. When EPO binds to the EPO receptor it "initiate[s] the signaling pathway that ultimately leads to red blood cell production." Id. ¶ 24. Red blood cells, of course, contain hemoglobin, the body's vehicle for transporting oxygen. Id. ¶ 15. "In healthy humans, the amount of EPO in circulation in the bloodstream is exquisitely regulated to produce just the required numbers of red cells." Id. Diseases or disorders affecting the kidneys often result in an EPO deficit, which leads to a low level of red blood cells, a condition generally referred to as anemia. Amgen Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1321 (Fed.Cir.2003) [hereinafter "Amgen II"].²

For some time preceding the 1980s, the medical community believed that the introduction of additional EPO into a patient's bloodstream could combat the effects of anemia by stimulating the production of additional red blood cells. See id. Nevertheless, a generation of researchers grappled with how to introduce exogenous EPO into the bloodstream of anemic patients. Id. Some of America's most accomplished researchers believed they could isolate and purify EPO that had exited the body in urine. Id. Others attempted to obtain EPO from plasma. Id. These approaches proved "unsuccessful because such recovery employed techniques that were complicated, yet still resulted in a low-yield, high-impurity, or unstable EPO end product. Similar attempts using antibody techniques failed because of difficulty in providing for the large-scale isolation of quantities of EPO from mammalian sources sufficient for further analysis, clinical testing, or therapeutic use." Id. (internal citation omitted). As of 1984, mass production of erythropoietin from recombinant DNA was not possible. Amgen, Inc. v. Hoechst Marion Roussel, Inc., 457 F.3d 1293, 1303-04 (Fed.Cir.2006) (hereinafter "Amgen IV").

In this case, Roche's anticipation defense focused on a clinical study supervised by Dr. Eugene Goldwasser. Dr. Goldwasser's study, which began in 1979-1980, attempted to treat three anemic patients with EPO purified from human urine. Amgen, Inc. v. Hoechst Marion Roussel, Inc., 126 F.Supp.2d 69, 111 (D.Mass.2001) [hereinafter "Amgen I"]. The results of the Goldwasser study were mixed and are still a matter of dispute. While experts debate whether and to what extent an increase in reticulocyte count may be attributed to Dr. Goldwasser's urinary EPO, Dr. Goldwasser, who characterized the study as a failure, has admitted that the study did not actually increase patient hematocrit,...