Immunex Corp. v. Sandoz Inc.

• Decision Date: 09 August 2019
• Docket Number: Civil Action No.: 16-1118 (CCC)
• Parties: IMMUNEX CORP., et al., v. SANDOZ INC., et al.
• Court: U.S. District Court — District of New Jersey

395 F.Supp.3d 366

IMMUNEX CORP., et al.,

v.SANDOZ INC., et al.

Civil Action No.: 16-1118 (CCC)

United States District Court, D. New Jersey.

Signed August 9, 2019

Liza M. Walsh, Christine Intromasso Gannon, Colleen M. Maker, Eleonore Ofosu-Antwi, Marc D. Haefner, Walsh Pizzi O'Reilly Falanga LLP, Charles H. Chevalier, David E. Delorenzi, Christine A. Gaddis, Gibbons PC, Newark, NJ, for Immunex Corp., et al.

Eric I. Abraham, Yevgenia Shtilman Kleiner, Hill Wallack, LLP, Princeton, NJ, James S. Richter, Midlige Richter LLC, Basking Ridge, NJ, Christina Lynn Saveriano, Mullica Hill, NJ, for Sandoz Inc., et al.

CECCHI, District Judge.

This patent case was brought by Plaintiffs Immunex Corporation ("Immunex"), Amgen Manufacturing, Limited ("Amgen"), and Hoffman-La Roche, Inc. ("Roche") (collectively, "Plaintiffs") against Defendants Sandoz Inc., Sandoz International GmbH and Sandoz GmbH (collectively, "Defendants"). Specifically, this action relates to the validity of claims 11-12 and 35-36 of U.S. Patent No. 8,063,182, which covers the fusion protein etanercept

, the active ingredient in Immunex's product Enbrel ® (Joint Trial Exhibit ("JTX")-1¹ ("the '182 Patent")), and claims 3, 8, and 10 of U.S. Patent No. 8,163,522, which covers Enbrel ®'s method of manufacture (JTX-2 ("the '522 Patent")) (collectively, the asserted claims of the "Patents-in-Suit"). See ECF No. 18 ¶ 9. Enbrel ® is a brand name biologic drug primarily used to treat rheumatoid arthritis. Id. ¶¶ 43, 45; ECF No. 688 at 11 ¶ 38.

The Court held a two-week bench trial in this matter that began on September 11, 2018 and concluded on September 25, 2018. ECF Nos. 621-622, 627, 629-635. The parties submitted post-trial briefing and proposed findings of fact and conclusions of law through early November 2018. ECF Nos. 648 (corrected at 651-2 ("PFOF")), 647 (corrected at 649-2 and subsequently corrected at 650-1 ("DFOF")), 645 (corrected at 651-1 ("Pls. Br.")), 646 (corrected at 649-1 and subsequently corrected at 650-2 ("Defs. Br.")). On November 6, 2018, the parties submitted response briefs. ECF Nos. 653 ("Pls. Reply Br."), 652 ("Defs. Reply Br."). Closing arguments were held on November 19, 2018. ECF No. 656.

Enbrel

® is the first U.S. Food and Drug Administration ("FDA") approved fusion protein, approved in November 1998. PFOF ¶¶ 8, 10; DFOF ¶ 12. In August 2016, the FDA approved Defendants' biosimilar version of Enbrel ®, called Erelzi™. PFOF ¶ 11; ECF No. 688 at 11 ¶¶ 41-43. Defendants do not contest infringement of the '182 Patent or the '522 Patent. ECF No. 619; PFOF ¶ 16. Therefore, the issue left for this Court to decide is whether the Patents-in-Suit are invalid based on the following legal principles: (1) lack of written description and enablement; (2) obviousness; and (3) obviousness-type double patenting.

This Opinion constitutes the Court's findings of fact and conclusions of law pursuant to Federal Rule of Civil Procedure 52(a). The findings of fact are based on the Court's observations and credibility determinations of the witnesses who testified, and a thorough review of all the evidence admitted at trial. While the Court has reviewed all of the evidence presented, given the length of the trial record, the Court includes references only to the evidence most pertinent to its analysis. For the reasons set forth below, the Court finds that the Patents-in-Suit are not invalid.

I. BACKGROUND

A. Parties

Plaintiff Roche was the first to file the patent applications that eventually issued as the Patents-in-Suit. PFOF ¶ 51. Thereafter, Plaintiffs Amgen and Immunex obtained certain rights from Roche pertaining to the Patents-in-Suit, pursuant to an agreement called the Accord and Satisfaction, which included the right to take over the prosecution of the relevant patent applications and the right to commence an infringement action. JTX-12. Plaintiff Roche is a New Jersey corporation with its principal place of business in New Jersey. ECF No. 18 ¶ 3. Plaintiff Immunex is a Washington corporation with its principal place of business in California and is a wholly owned subsidiary of non-party Amgen Inc. Id. ¶ 1. Plaintiff Amgen is a corporation of the Territory of Bermuda with its principal place of business in Puerto Rico and is also a wholly owned subsidiary of non-party Amgen Inc. Id. ¶ 2.

Defendant Sandoz Inc. is a Colorado corporation with its principal place of business in New Jersey. Id. ¶ 4. Defendant Sandoz International GmbH is a German corporation with its principal place of business in Germany. Defendant Sandoz GmbH is an Austrian corporation with its principal place of business in Austria and is a subsidiary of Sandoz International GmbH. Id. ¶¶ 6-7. Sandoz Inc. is the United States agent for Defendants Sandoz International GmbH and Sandoz GmbH. Id. ¶ 4. All parties are in the business of developing, manufacturing, marketing, and selling biopharmaceutical products. Id.

B. Background of the Invention

The active ingredient in the biopharmaceutical drug at issue in this case is a fusion protein known as etanercept

that is made by combining the extracellular region of a 75 kilodalton Human Tumor Necrosis Factor Receptor with a portion of an IgG1 immunoglobulin. This section will first provide the scientific background of the claimed invention, by explaining each component and its purpose. Next, the Court will provide the relevant research and patent history for the Patents-in-Suit.

1. Scientific Background

Rheumatoid arthritis

is an inflammatory auto-immune disease, i.e. a disease which occurs when "an overactive immune system attacks an individual's own body," and causes bone erosion, narrowing of joint space, and irreversible joint damage. PFOF ¶¶ 32-33. One way to treat rheumatoid arthritis is to "dampen the immune system" and to "inhibit inflammatory reactions." Id. ¶¶ 47-48. The immune system is made up of various cells and antibodies that protect the body from foreign invaders. Id. ¶ 23. Antibodies have two primary functions: to bind foreign substances known as antigens, and to recruit other immune system components to attack antigens. Id. There are many classes and subclasses of the antibody immunoglobulin or "Ig", of which IgG is one such class. Id. ¶¶ 99, 158. There are four subclasses of human IgG: IgG1, IgG2, IgG3, and IgG4. Id.

IgG is a protein, and proteins are made up of "amino acid residues connected in a strand called a ‘polypeptide,’ which folds into a three-dimensional shape that imparts certain structural and functional characteristics." Id. ¶ 20. Scientists can identify protein sequences based on the order of amino acids in the protein, with the beginning portion of the sequence referred to as the "N-terminus" and the end portion referred to as the "C-terminus." Id. ¶¶ 21-22.

Structurally, an IgG protein, pictured below, consists of two heavy chains and two light chains, and each chain contains variable and constant regions. Id. ¶ 24. The constant region is the portion that interacts with other components of the immune system to elicit a response. Id. The heavy chain constant region includes the CH1, the hinge, CH2, and CH3 domains while the light chain constant region consists of the CL domain. Id. The variable region of each chain, labeled here as VH and VL, is what binds to the antigen. Id.

DFOF ¶ 208.

Another component of the immune system, called a cytokine, is a messenger protein that has a wide variety of functions, including to initiate an immune response. PFOF ¶ 27. The body makes dozens of distinct cytokines, one of which is the Human Tumor Necrosis

Factor ("TNF"). Id. ¶¶ 27-29. TNF can be found in an insoluble (membrane-bound) or soluble (free-flowing) form. Id. ¶ 28. Originally discovered to kill tumor cells, TNF has many functions and by August 1990, scientists associated it with inflammatory diseases, such as rheumatoid arthritis. Id. ¶¶ 28-33.

TNF plays a significant role in auto-immune disorders. Id. TNF binds to certain proteins called TNF receptors ("TNFRs") that extend beyond the outer membrane of a cell. Id. ¶ 30. TNFRs have three regions: intracellular, transmembrane, and extracellular. Id. The extracellular portion of the TNFR, which is the portion that "protrudes outside the cell," can be split off to produce a "soluble" fragment of the TNFR that can bind to TNF. Id. ¶¶ 30, 76. Two types of TNFRs have been identified, one that has a molecular weight of approximately 55 kilodaltons ("p55 TNFR" or "p55") and one with a molecular weight of approximately 75 kilodaltons ("p75 TNFR" or "p75"). Id. ¶¶ 36-38.

Etanercept

, the active ingredient in the biopharmaceutical drug Enbrel ® at issue here, is a fusion protein that combines the extracellular region of a p75 TNFR with an IgG1. Id. ¶ 9. "A fusion protein is made by combining DNA sequences encoding parts of different proteins into one sequence, introducing that sequence into host cells, and using their natural internal machinery to produce the desired fusion protein." Id. ¶ 19. Specifically, etanercept is a "dimeric fusion protein consisting of the extracellular region of the p75 TNF receptor" which, as the parties have stipulated, is "fused to the exon-encoded ‘hinge-CH2-CH3’ of the constant region of a human IgG1 antibody heavy chain." Id. ¶ 9; DFOF ¶ 93; ECF No. 688 at 20 ¶ 68. Etanercept works by binding to and neutralizing excess TNF in patients with rheumatoid arthritis, thereby reducing the auto-immune inflammatory response. PFOF ¶ 244. The graphic below depicts images of a p75 TNFR and an IgG1 on the left-hand side and etanercept on the right-hand side. The Patents-in-Suit cover etanercept and the method of making etanercept. Id. ¶ 76.

DFOF ¶¶ 208, 214.

2. Research and Patent History

By 1990, "there was a high level of interest in studying TNF and investigating whether targeting TNF with a TNF-binding protein would provide a therapeutic benefit by inhibiting the binding of TNF to its cell-bound receptors." DFOF ¶¶ 1, 14. At that time, scientific evidence pointed to...