Genzyme Corp. v. Zydus Pharms. (Usa) Inc., Civil Action No. 16-540 (KAJ)

• Court: United States District Courts. 3th Circuit. United States District Court (Delaware)
• Writing for the Court: JORDAN, Circuit Judge sitting by designation
• Parties: GENZYME CORPORATION, and SANOFI-AVETIS U.S. LLC Plaintiffs and Counter-Defendants v. ZYDUS PHARMACEUTICALS (USA) INC. Defendant and Counter-Claimant.
• Docket Number: Civil Action No. 16-540 (KAJ)
• Decision Date: 08 August 2018

GENZYME CORPORATION, and SANOFI-AVETIS U.S. LLC Plaintiffs and Counter-Defendants
v.
ZYDUS PHARMACEUTICALS (USA) INC. Defendant and Counter-Claimant.

Civil Action No. 16-540 (KAJ)

UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE

August 8, 2018

FILED UNDER SEAL

POST-TRIAL FINDINGS OF FACT AND CONCLUSIONS OF LAW

Jeffrey B. Bove, Karen R. Poppel, RatnerPrestia, 1007 Orange Street, Ste. 205, Wilmington, DE 19801, Counsel for Plaintiffs
Of Counsel: Paul H. Berghoff, Paula S. Fritsch, Jeremy E. Noe, Alison J. Baldwin, Kurt W. Rohde, James L. Lovsin, Nicole E. Grimm, Nathaniel P. Chongsiriwatana, Daniel F. Gelwicks, McDonnell Boehnen Hulbert & Berghoff LLP, 300 S. Wacker Drive, Chicago, IL 60606

Dominick T. Gattuso, Heyman Enerio Gattuso & Hirzel LLP, 300 Delaware Avenue, Ste. 200, Wilmington, DE 19801, Counsel for Defendant
Of Counsel: Chad A. Landmon, Edward M. Mathias, David K. Ludwig, Axinn, Veltrop & Hardkrider LLP, 90 State House Square, 9^th Fl., Hartford, Connecticut 06103
James T. Evans, Dan Feng Mei, Axinn, Veltrop & Harkrider LLP, 114 W. 47^th Street, 22^nd Fl., New York, NY 10036

August 8, 2018
Wilmington, Delaware

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JORDAN, Circuit Judge sitting by designation

I. INTRODUCTION

This is a patent infringement case. More particularly, it is a case about the validity of two patents. Genzyme Corporation ("Genzyme") and sanofi-aventis US LLC ("Sanofi," and together with Genzyme, "Plaintiffs") have sued Zydus Pharmaceuticals (USA) Inc. ("Zydus"), in connection with Zydus's Abbreviated New Drug Application ("ANDA") and, upon FDA approval, Zydus's planned commercial manufacture, importation, use, offer to sell, or sale of its generic version of MOZOBIL^®. MOZOBIL^® is a 20 mg/mL plerixafor solution for subcutaneous injection indicated for use in combination with granulocyte-colony stimulating factor ("G-CSF") to mobilize hematopoietic stem cells. (Docket Index ("D.I.") 71, App. A at ¶¶ 26-27.) Plaintiffs allege infringement of U.S. Patent No. 6,987,102 ("the '102 Patent") and U.S. Patent No. 7,897,590 ("the '590 Patent"), both entitled "Methods to Mobilize Progenitor/Stem Cells," and seek a declaratory judgment of infringement of those patents. Zydus stipulates to infringement, but responds in counterclaims that the asserted claims of the patents-in-suit are invalid. A four-day bench trial was held on March 26-27, 2018, and April 10-11, 2018. The following, issued pursuant to Federal Rule of Civil Procedure 52(a), are my findings of fact and conclusions of law on the issues of the validity of the patents-in-suit and attorney's fees.¹

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For the reasons that follow, I conclude that Zydus has infringed the asserted claims of the patents-in-suit and that those claims are valid. I also conclude that Plaintiffs have not carried their burden of establishing entitlement to attorney's fees.

II. FINDINGS OF FACT²

A. The Parties

1. Genzyme is a corporation organized and existing under the laws of the Commonwealth of Massachusetts, having its principal place of business at 500 Kendall Street, Cambridge, Massachusetts 02142. (D.I. 71, App. A at ¶ 1.) Though not a party, AnorMED is a company that played a critical role in the development of the pharmaceutical technology at issue in this case. Genzyme acquired AnorMED in 2006. (D.I. 82 at 371:15-23.) Sanofi is a limited liability company organized and existing under the laws of the State of Delaware with its principal place of business at 55 Corporate Drive, Bridgewater, New Jersey 08807. (D.I. 71, App. A at ¶ 2.) Zydus is a corporation organized and existing under the laws of the State of New Jersey, with a principal place of business at 73 Route 31 North, Pennington, New Jersey 08534. (D.I. 71, App. A at ¶ 3.)

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B. Plerixafor

2. 1,1'-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane is the chemical name for plerixafor, and is pretty hard to spell. (D.I. 71, App. A at ¶ 20.) It has the following chemical structure:

Image materials not available for display.

(D.I. 71, App. A at ¶ 21.) Cyclam (1,4,8,11-tetraazacyclotetradecane) is a macrocyclic compound having the following chemical structure:

Image materials not available for display.

(D.I. 71, App. A at ¶ 22.) Plerixafor, sometimes referred to as AMD-3100,³ is known as a "bicyclam" because it consists of two cyclams connected by a linker.⁴ (D.I. 71, App. A

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at ¶¶ 23, 25.) It is not a naturally occurring compound (JTX-004 at 12; PTX-211; D.I. 82 at 307:3-308:14), and it was not invented by AnorMED (D.I. 82 at 307:10-13; D.I. 89 at ¶ 4; D.I. 98 at 1). It had been synthesized previously by an academic group, which published its findings in 1987. (PTX211; D.I. 82 at 307:10-308:14; D.I. 89 at ¶ 4; D.I. 98 at 1.) However, that publication did not describe the biological activity of plerixafor. (PTX211; D.I. 82 at 308:15-22.) I find that plerixafor is the active ingredient in a pharmaceutical composition with the anti-human immunodeficiency virus ("HIV") activity claimed in U.S. Patent No. 5,583,131 ("the '131 Patent"), which issued on December 10, 1996, and is currently owned by Plaintiffs. (PTX008 at 11; D.I. 89 at ¶ 7; D.I. 98 at ¶ 7.)

C. Stem Cells and Stem Cell Transplantation

3. The pharmaceutical technology at issue in this case has applications in the field of stem cell transplantation. (JTX-002 at 1; JTX-004 at 5.) Stem cells are undifferentiated and primitive cells in the blood system that give rise to all the other cells that develop later and form the body's blood. (D.I. 81 at 68:24-69:2.) Progenitor cells are slightly more mature and more differentiated cells that have a specialized function. (D.I. 81 at 69:3-19.) However, for purposes of this case, the parties agree that the term "stem cells" includes both stem cells and progenitor cells. (D.I. 81 at 11:18-21, 37:23-38:4, 69:20-22; D.I. 82 at 320:13-321:3.)

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4. Stem cells normally reside in the bone marrow, but can be mobilized from the bone marrow into the peripheral blood stream. (D.I. 81 at 79:17-80:2, 170:16-23.) Stem cells express CD34 receptors, which are specific "site[s] or structure[s]" on stem cells that "combine[] with a drug or other biological to produce a specific alteration of cell function." Receptor, McGraw-Hill Dictionary of Scientific and Technical Terms (6th ed. 2003); (D.I. 81 at 82:14-83:5.) The presence of stem cells in the blood can be determined by testing for the CD34 marker that is present on the surface of the stem cells. (D.I. 81 at 82:22-24.)

5. Stem cell transplantation is a procedure used in the treatment of patients having certain blood cancers, such as non-Hodgkin's lymphoma and multiple myeloma. (D.I. 81 at 78:3-79:13.) Since before September 2000, the procedure has been used to help cancer patients (D.I. 81 at 82:8-10), and it can alleviate the negative side effects they experience due to intense chemotherapy and radiation therapy (D.I. 81 at 78:22-82:7). It involves "harvesting" stem cells from a cancer patient before a chemo- or radiation therapy session and then transplanting those cells back into the patient's blood stream after therapy. (D.I. 81 at 78:22-82:7.) "Mobilizing" stem cells from the bone marrow into the peripheral blood and then collecting or harvesting them from the body for future use is key to the success of the procedure. (D.I. 81 at 79:17-80:19, 170:16-23; D.I. 83 at 607:2-4.) Mobilizing regimens, which are combinations of chemical agents that can induce stem cell mobilization, are used to increase the number of stem cells in the blood to an amount sufficient to conduct a stem cell transplantation procedure. (D.I. 95 at

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DDX-008; DTX-214 at 5; D.I. 81 at 90:20-93:10; D.I. 83 at 647:18-25; see also, e.g., JTX-009 at 2.)

6. Harvested stem cells are stored while the patient undergoes chemotherapy or radiation therapy that simultaneously destroys both cancerous cells and healthy cells. (D.I. 81 at 80:20-81:6.) As just noted, after the therapy is completed, the harvested stem cells are then transplanted back into the patient, where they repopulate the bone marrow with healthy cells. (D.I. 81 at 81:7-82:7.) During stem cell transplantation, the stem cells "home" from the peripheral blood back to the bone marrow, and, ideally, they then "engraft" in the marrow by interacting with the bone marrow cells, proliferating, and producing progeny. (D.I. 81 at 81:7-22, 173:6-9.) Engraftment is essential to reconstituting the hematopoietic and immune systems in patients after transplantation. (D.I. 81 at 81:7-82:7, 112:24-113:17, 157:17-25; D.I. 83 at 753:11-19.) But if not enough stem cells are mobilized or harvested, stem cell transplantation cannot be performed on a patient. (D.I. 83 at 647:18-25, 649:12-20.) A successful stem cell transplantation requires successful mobilization, successful homing, and successful engraftment. (D.I. 84 at 743:11-744:11.)⁵

7. By September 2000, harvesting stem cells was a conventional procedure. (D.I. 81 at 80:5-19, 82:11-13; D.I. 83 at 628:23-629:13; D.I. 88 at ¶ 169; D.I. 100 at 37.) One method of harvesting them is known as apheresis. (D.I. 81 at 80:3-19.) During apheresis, the patient's blood is processed through a machine that concentrates the stem

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cells and separates them from the other blood cells. (D.I. 81 at 80:3-19.) The non-stem cell fraction is reinfused into the patient, while the stem cells are retained outside the body. (D.I. 81 at 80:3-19.) The process of apheresis was known before September 2000. (D.I. 81 at 82:11-13.)

8. By September 2000, people researching in the field of blood chemistry had reported that the migration of stem cells out of (i.e., mobilization) and into (i.e., homing) the bone marrow might involve similar chemical actors. (DTX-214; D.I. 81 at 86:13-88:6.) Specifically, a person of ordinary skill in the art in September 2000 would have known of the theory that stem cell mobilization and homing "are likely to be 'mirror images' of each other, differentially utilizing similar classes of molecules and...