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Immunex Corp. v. Sandoz Inc.

United States District Court, D. New Jersey

August 9, 2019

IMMUNEX CORP., et al.,
v.
SANDOZ INC., et al.

          OPINION

          HON. CLAIRE C. CECCHI UNITED STATES 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")-1[1]("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 CHI, 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.

         (Image Omitted)

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.

         (Image Omitted)

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 at least two TNFRs expressed by the human body: p55 and p75 TNFR. PFOF ¶¶ 37-38; DFOF ¶ 2. In April 1990, researchers at Roche (the "Roche Inventors"[2]) published the complete amino acid sequences for the p55 TNFR and the cDNAs[3] encoding it. PFOF ¶ 39; DFOF ¶¶ 15, 16; JTX-21 at 1. In May 1990, Immunex published an article containing the complete amino acid sequence for p75 and therein stated that the researchers isolated a cDNA clone of the receptor. PFOF ¶ 40; Smith, C.A., et. al., A Receptor for Tumor Necrosis Factor Defines an Unusual Family of Cellular and Viral Proteins, Science 248: 1019-23 (1990) (JTX-24) ("Smith 1990"); DFOF ¶ 4. Several months later in July 1990, the Roche Inventors published the complete amino acid sequence for the p75 TNFR and part of its encoding cDNA. PFOF ¶ 39; Dembic, Z. et al., Two Human TNF Receptors Have Similar Extracellular, But Distinct Intracellular, Domain Sequences, Cytokine 2(4): 231-37 (1990) (JTX-23) ("Dembic 1990"); DFOF ¶ 30.

         Around the same time that the Roche Inventors were publishing studies on the amino acid sequences in p55 and p75 TNFR, they were also exploring the possibility of TNFR-Ig fusion proteins. PFOF ¶ 46. The Roche Inventors were ultimately successful in creating fusion proteins using both p55 and p75 TNFRs. Id. ¶ 49. The initial fusion protein used an IgG3 immunoglobulin, however the Roche Inventors' "pathway of experimental work leading to a TNFR fusion protein" also contemplated fusion proteins with IgG1 and IgG2 immunoglobulins. Id. ¶¶ 50, 58-68.

         On August 31, 1990, the Roche Inventors filed a patent application in Europe bearing Application No. 90116707 ("EP '707 Application") and on September 13, 1990, they filed a U.S. Patent with Application No. 07/580, 013 ('"013 Application"). Id. ¶ 51. The Patents-in-Suit claim the benefit of the '013 Application and priority to the European '707 Application. Id. The Patents-in-Suit, as well as the EP '707 Application and the '013 Application, encompass a p75 TNFR-IgG1 fusion protein, but because the parties differ in their assessments of the patent specifications and validity of the claimed invention, further details on the Patents-in-Suit will be discussed below. Id. ¶¶ 50-53; DFOF¶¶ 36-37.

         C. Patents-in-Suit and Relevant Prosecution History

         1. The'182 Patent

         The' 182 Patent, entitled "Human TNF Receptor Fusion Protein," issued on November 22, 2011 and expires on November 22, 2028. PFOF ¶ 74; DFOF ¶ 83. The asserted claims "define a fusion protein consisting of parts of two different proteins: the extracellular region of p75 fused to all of the domains of the human IgG1 constant region other than the first domain." PFOF ¶¶ 74-76; see also '182 Patent (JTX-1) col. 39:60-67, 42:26-34.

         The initial '013 Application was abandoned, and U.S. Application No. 08/965, 640 ('"640 Application") was filed on July 21, 1993 as a continuation. PFOF ¶ 57; DFOF ¶¶ 38-39. The '640 Application was subject to a restriction requirement by the United States Patent and Trademark Office ("USPTO") and in response Roche elected to pursue claims related to the p55 fusion protein, which issued as U.S. Patent No. 5, 610, 279 ('"279 Patent") on March 11, 1997. PFOF ¶ 57; DFOF ¶¶ 39-40; ECF No. 688 at 6 ¶ 9. As a result of the restriction, Roche then filed two divisional applications on May 19, 1995: U.S. Application No. 08/444, 790 ('"790 Application"), which issued as the '182 Patent, and U.S. Application No. 08/444, 791 (the '791 Application"), which issued as the '522 Patent. See PFOF ¶ 57; DFOF ¶ 41.

         (Image Omitted)

         In 2004, prior to issuance of the '182 Patent, Amgen and Immunex acquired the exclusive right to prosecute the Patents-in-Suit, among other rights, from Roche pursuant to an Accord and Satisfaction between non-party Amgen Inc., Immunex, and Roche. JTX-12 at 4-6, Article 3, ¶¶ 3.1-3.6; see also PFOF ¶ 34; DFOF ¶¶ 54, 58, 62. Those rights were later consolidated in Immunex by a separate agreement. JTX-14. In 2005, Immunex amended the '790 Application in response to a USPTO office action requiring the '790 Application to come into consonance with the restriction requirement. PFOF ¶ 285; DFOF ¶ 73. The '790 Application was again amended in 2006. PFOF ¶ 144; DFOF ¶ 74. Despite the amendments, the '790 Application was rejected "for failing to comply with the written description requirement and as obvious over the applied prior art," and the rejection was appealed to the Board of Patent Appeals and Interferences ("BPAI"). Plaintiffs' Trial Exhibit ("PTX")-6.456 ("BPAI Opinion"). The BPAI reversed the examiner's rejection. PTX-6.456 at 9 (BPAI Opinion reversing rejection by examiner). The '182 Patent then issued on November 22, 2011. See generally ' 182 Patent (JTX-1).

         2. The '522 Patent

         The '522 Patent, entitled "Human TNF Receptor," issued on April 24, 2012 and expires on April 24, 2029. PFOF ¶ 74; DFOF ¶ 83. The asserted claims "define a method of producing [the] fusion protein" defined in the '182 Patent. '522 Patent (JTX-2) at 47-48 (claims 3, 8, 10); PFOF ¶ 75. The '522 Patent issued from the '791 Application, which was filed on May 19, 1995 as a divisional of the '640 Application, along with the '790 Application which issued as the' 182 Patent. PFOF ¶ 57; DFOF ¶ 48.

         Prior to the '522 Patent's issuance, Amgen and Immunex amended the '791 Application in 2004, 2007, and 2010 to include several references related to the full amino acid sequence for p75. See, e.g., '522 Patent (JTX-2) col. 3:1-3, Fig. 5; DFOF¶¶ 78-80. Like the amendments to the '182 Patent, these amendments were triggered by two USPTO actions, which rejected the '791 application for obviousness and insufficient written description. PTX-7.351. Despite the amendments, the '791 Application was still rejected, and that rejection was eventually overcome by citing the '790 Application BPAI Opinion which dealt with similar issues. PFOF ¶ 323; JTX-4 at 4952-53. The '522 Patent then issued on April 24, 2012. See generally '522 Patent (JTX-2).

         II. ISSUES TO BE DECIDED

         Prior to the commencement of trial, Defendants advised that they did not contest infringement of the Patents-in-Suit. ECF No. 619. As discussed above, the parties also stipulated that the term "all of the domains of the constant region of a human immunoglobulin IgG[1] heavy chain other than the first domain of said constant region" is construed as meaning "the exon-encoded 'hinge-CH2-CH3' region of human [IgG/IgG1]." ECF No. 688 at 20 ¶ 68. Accordingly, the question before this Court is whether the' 182 and '522 Patents are invalid due to lack of written description and enablement, obviousness, and obviousness-type double patenting.

         III. DISCUSSION

         Issued patents are presumed valid. See 35 U.S.C. § 282(a). To rebut this presumption, Defendants bear the burden of proving invalidity by clear and convincing evidence. Titan Tire Corp. v. Case New Holland, Inc., 566 F.3d 1372, 1376 (Fed. Cir. 2009) ("Because of this presumption, an alleged infringer who raises invalidity as an affirmative defense has the ultimate burden of persuasion to prove invalidity by clear and convincing evidence, as well as the initial burden of going forward with evidence to support its invalidity allegation.").

         A. Written Description and Enablement (35 U.S.C. § 112)

         A patent specification "shall contain a written description of the invention." 35 U.S.C. § 112. The specification must "reasonably convey[] to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Pharm. Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010). The test for written description "requires an objective inquiry into the four corners of the specification from the perspective of a person of ordinary skill in the art."[4] Id. "[W]hether a patent complies with the written description requirement will necessarily vary depending on the context. Specifically, the level of detail required . . . varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology." Id. (citation omitted). When reviewing the patent according to these principles, "[w]ritten description is a question of fact, judged from the perspective of [a POSA] as of the relevant filing date." Falko-Gunter Falkner v. Inglis, 448 F.3d 1357, 1363 (Fed. Cir. 2006) (citing Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64 (Fed. Cir. 1991)).

         Additionally, as to enablement, a patent specification must describe "the manner and process of making and using [the invention], in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains ... to make and use the same ...." 35 U.S.C. § 112. Moreover, enablement requires that the specification teach a POSA "how to make and use the full scope of the claimed invention without undue experimentation." Martek Bioscis. Corp. v. Nutrinova, Inc., 579 F.3d 1363, 1378 (Fed. Cir. 2009) (citation omitted). A patentee need not "include in the specification that which is already known and available to [a POSA]" and "not every last detail is to be described, else patent specifications would turn into production specifications, which they were never intended to be." Koito Mfg. Co. v. Turn-Key-Tech, LLC, 381 F.3d 1142, 1156 (Fed. Cir. 2004) (citation omitted). "Enablement is a question of law involving underlying factual inquiries." Falkner, 448 F.3d at 1363 (citing Genentech, Inc. v. NovoNordiskA/S, 108 F.3d 1361, 1365 (Fed. Cir. 1997), In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988)).

         Defendants argue that the Patents-in-Suit are invalid because their specifications (1) lack a sufficient written description of the invention and (2) do not enable a POSA to make or use the invention. Defs. Br. at 20-35. By contrast, Plaintiffs contend that the specifications are adequate, and that Defendants failed to prove their written description or enablement claims by clear and convincing evidence. Pls. Br. at 12-21.

         In support of their arguments, the parties relied heavily on the testimony of the following four witnesses: (1) Defendants' expert Daniel Capon, Ph.D., (2) Defendants' expert Carl P. Blobel, M.D., Ph.D., (3) Plaintiffs' expert James Naismith, Ph.D, and (4) Plaintiffs' expert Hansruedi Loetscher, Ph.D.[5] For the reasons set forth below, the Court finds that Defendants failed to prove invalidity based on the written description and enablement requirements by clear and convincing evidence, and therefore the Patents-in-Suit are not invalid under 35 U.S.C. § 112.

         1. The Specifications Meet the Written Description Requirement

         Defendants argue that the specifications are deficient because they neither sufficiently describe etanercept nor convey that the Roche Inventors had possession of etanercept, and that further, the specifications in conjunction with the claims do not direct a POSA to the specific embodiment of etanercept. Defs. Br. at 20-32. Plaintiffs counter that the necessary elements of the claimed invention are adequately described throughout the specifications, were known and available prior to August of 1990, and that the specifications adequately describe the novel combination of those elements to create etanercept. Pls. Br. at 13-21. Therefore, Plaintiffs contend that the specifications demonstrate possession and the patents properly direct a POSA to etanercept. Id.

         The '182 Patent claims a fusion protein consisting of the extracellular portion of the p75, as well as the exon-encoded hinge, CH2 and CH3 domains of human IgG1, while the '522 Patent claims the method of making the fusion protein.' 182 Patent (JTX-1) col. 39:14- 42:34; 9/18 AM (Naismith) Tr. at 89:2-12, 91:8-14; '522 Patent (JTX-2) col. 45:44-48:4. The patent specifications of the '182 and '522 Patents identify soluble fragments of p75 TNFR as one of two TNF binding proteins, i.e. p55 and p75, used in TNFR-IgG fusion proteins and include both figures and examples that are referenced in the parties' arguments. There are multiple figures in the Patents-in-Suit that provide nucleotide sequences for the TNF binding protein. See generally ' 182 Patent (JTX-1); '522 Patent (JTX-2). In analyzing the specifications, it appears mat Figure 1 of the specifications relates to a p55 TNFR and Figure 4 relates to a p75 TNFR.[6] Figure 4 is a "[n]ucleotide sequence... and deduced amino acid sequence... for cDNA clones derived from" a p75 TNFR, which consists of a long combination of letters representing those amino acids and related cDNA combinations. '182 Patent (JTX-1) col. 2:60-62, Fig. 4. The specifications additionally include multiple examples pertaining to a TNFR-IgG fusion protein. In the examples, both the '182 and '522 Patents notably discuss and disclose two nucleotide sequences for portions of p75-SEQ ID NO: 10 (N-terminus) and SEQ ID NO: 7 (C-terminus).

         The Patents-in-Suit disclose using "especially preferred vectors" pCD4-Hγl (DSM 5314, deposited on Apr. 21, 1989) and pCD4-Hγ3 (DSM 5523, deposited on Sept. 14, 1989) "[f]or the expression of proteins which consist of a soluble fragment of non-soluble TNF-BP [binding protein] and an immunoglobulin fragment, i.e. all domains except the first of the constant region of the heavy chain." '182 Patent (JTX-1) col. 8:56-9:8. The specifications further state that "the present invention embraces not only allelic variants, but also those DNA sequences which result from deletions, substitutions and additions from one or more nucleotides of the sequences given in FIG. 1 or FIG. 4" and yield TNF-binding proteins. '182 Patent (JTX-1) col. 5:17-22; '522 Patent (JTX-2) col. 5:29-34. The Patents-in-Suit also reference the Smith 1990 article-the Immunex publication that includes the complete amino acid sequence for p75.' 182 Patent (JTX- 1) col. 5:22-24; '522 Patent (JTX-2) col. 5:34-37.

         a) The Requisite Components of the Fusion Protein Were Disclosed in the Specifications and Known Prior to Aueust 1990

         The Court finds that the specifications of the Patents-in-Suit sufficiently describe the components of etanercept. A patent must include sufficient details such that a POSA could understand the subject invention and recognize that the inventor possessed it. Ariad, 598 F.3d at 1351. However, this requirement does not necessarily mean that the specification of the patent must include every nuanced detail.[7] Indeed, "[a] patent need not teach, and preferably omits, what is well known in the art." Falkner, 448 F.3d at 1365 (quoting Spectra-Physics, Inc. v. Coherent, Inc., 827 F.2d 1524, 1534 (Fed. Cir. 1987)); see also Capon v. Eshhar, 418 F.3d 1349, 1357-58 (Fed. Cir. 2005) (holding that a patent's specifications do not need to reiterate the structure, formula, or chemical name of a claimed invention to satisfy the written description requirement when that information is already known in the field). The Court will first analyze the sufficiency of the description of p75, followed by the sufficiency of the description of the IgG1 portion of the fusion protein.

         i. p75 Is Adequately Described

         Analyzing the Patents-in-Suit, the Court finds that p75 is sufficiently described. The specifications of the Patents-in-Suit identify two TNF receptors, p55 and p75, and further note that the invention embraces allelic variants and DNA sequences resulting from deletions, substitutions, and additions of one or more nucleotides of the sequences provided in Figure 1 and/or Figure 4. '182 Patent (JTX-1) col. 4:1-5:24. Sequence identification numbers, which correspond to p75, are mentioned throughout the specification (including the examples therein) and in the claims, and Example 6 explains that the inventors isolated the p75 TNFR. Id. col. 15:31-39.

         Furthermore, the prior art demonstrates that the p75 amino acid sequence was well known to a POSA at the time of the invention. The Court may look to prior art and trial testimony when determining what a POSA would have known at the time of the invention. See, e.g., Ariad, 598 F.3d at 1351 (relying on expert testimony and examples of prior art to make written description determination); Falkner, 448 F.3d at 1365-66. The parties agreed that by August 1990, the p75 TNFR was well known to a POSA. PFOF ¶¶ 86-87; DFOF ¶ 2. Both the Immunex Smith article and the Roche Dembic article, which were published in May 1990 and July 1990 respectively, contain a full recitation of the p75 amino acid sequence. PFOF ¶¶ 89-91; Smith 1990 (JTX-24) at 3-4, Fig. 3B; Dembic 1990 (JTX-23) at 1-2. The Smith 1990 article, expressly referenced in the Patents-in-Suit, also notes that "[t]he entire nucleotide sequence is available upon request and has been deposited with GenBank, accession number M32315." Smith 1990 (JTX-24) at 3-4, Fig. 3B. GenBank is an amino acid repository which can match partial amino acid sequences with full corresponding sequences that have been deposited with GenBank. See 9/18 AM (Naismith) Tr. at 62:7-16. Sequences are provided to GenBank as "an information deposit" in which the DNA sequence letters are submitted and an "accession number" is the particular identification number assigned to each submitted sequence. Id. at 73:17-74:1. Similarly, the Dembic 1990 article contains the entire p75 amino acid sequence.[8] See Dembic 1990 (JTX-23) at Fig. 1. Ultimately, neither party contests that the prior art "definitively identified two TNF receptors: the p55 and the p75" by August 1990. Defs. Br. at 21; PFOF¶¶ 36-38. The parties further agree that Immunex scientists in May 1990 and later the Roche Inventors in July 1990 published the full-length p75 TNFR before the related European priority patent application was filed in August 1990.[9] DFOF ¶ 2; PFOF ¶¶ 39-41.

         Defendants, however, argue that because the specifications refer to Smith 1990 as an example of a "deletion" when compared to Figure 4 (when it was instead the complete sequence of Figure 4), a POSA would not have considered using the Smith 1990 sequence. Defs. Br. at 25. Upon review of the disclosure, the Court does not believe a POSA would have been deterred from looking to Smith 1990 for use in the fusion protein due to the term "deletion." Just prior to that language in the specification, the invention embraces not only deletions but also all allelic variants including "substitutions and additions." '182 Patent (JTX-1) col. 5:17-24. In fact, a POSA may have been encouraged to look to an outside reference, such as the Smith 1990 article, that was expressly called out by name in the specification. 9/18 PM (Naismith) Tr. at 52:23-53:8. At trial, Plaintiffs' expert Dr. Naismith credibly testified that the Smith 1990 reference would have communicated to the ordinary artisan that "[i]f you hadn't read the paper, go and read it. They'd think it was a landmark paper."[10] Id. Thus, the Court agrees with Plaintiffs that despite the word "deletion," a POSA would have been directed to Smith 1990 and therefore the full p75 protein.

         In further support of Plaintiffs' arguments, Example 7 contains the N-terminus sequence designated SEQ ID NO: 10. '182 Patent (JTX-1) col. 16:22-30. SEQ ID NO: 10 matches the first 18 amino acids at the N-terminus of the known p75 as published in Smith 1990. Id.; Smith 1990 (JTX-24) at 3, Fig. 3B. The Patents-in-Suit also include the 18 amino acid sequences close to the C-terminus of the known p75 protein designated SEQ ID NO: 7. These two disclosed nucleotide sequences for p75 would have, in addition to Figure 4 and the Smith 1990 reference, directed a POSA to the full p75 sequence at the time of the invention. See '182 Patent (JTX-1) col. 39:13-42:34 (claims of the '182 Patent specifically requiring the use of the protein that "comprises the amino acid sequence ... (SEQ ID NO: 10)"), col. 4:18-20, 16:36-38 (identifying SEQ ID NO:7 as a partial amino acid sequence that makes up a preferred protein); '522 Patent (JTX-2) col. 45:44-48:4 (claims of the '522 Patent specifying the amino acid described in SEQ ED NO: 10), col. 4:31-32, 16:57-58 (listing SEQ ID NO:7 as an example of a partial amino acid sequence to be used in a preferred protein); see also '182 Patent (JTX-1) col. 5:17-22. With respect to the sequence identification numbers for SEQ ID NO: 10 and SEQ ID NO: 7, Plaintiffs' expert Dr. Naismith credibly testified that there was less than a one-in-a-million chance that the wrong protein would be produced by GenBank if an inquiry was made to retrieve the complete p75 sequence corresponding to one of the sequence identification numbers.[11] See 9/18 AM (Naismith) Tr. at 68:13-16. Moreover, Dr. Naismith testified that there was "zero chance" that any other protein would be returned by GenBank if the request included both SEQ ID NO: 10 and SEQ ID NO: 7 at that time. Id. at 68:17-25; see also 9/12 PM (Blobel) Tr. at 14:6-12 (Defendants' expert Dr. Blobel also testifying "if you took a sequence of this receptor, you would presumably get this receptor back. That's how it works.").[12] Accordingly, the Patents-in-Suit sufficiently describe the subject fusion protein using the known full p75 sequence.

         ii. IgG1 and the Fusion Protein are Adequately Described

         The disclosure of the second necessary part of etanercept was also adequate because the specification clearly refers to use of deposited vectors (including "pCD4-Hγ1") that contain DNA sequences encoding the exon-defined hinge-CH2-CH3 region of a human IgG1 heavy chain as confirmed by the declaration of Defendants' expert, Jeffery Kittendorf, Ph.D., an expert in biochemistry and a Research Assistant Scientist at the University of Michigan Life Sciences Institute. ECF No. 688 at 132 ¶ 47; JTX-16 at 32-34; see also 9/17 (Loetscher) Tr. at 57:4-58:25.

         Example 11 then provides a recipe to fuse a soluble TNF-binding fragment directly to that exon-encoded hinge-CH2-CH3 region of an IgG heavy chain, thereby providing a POSA with the full fusion protein. '182 Patent (JTX-1) col. 9:3-8; 9/17 (Loetscher) Tr. at 56:10-57:13, 58:18-59:5; 9/18 AM (Naismith) Tr. at 54:16-21, 90:10-91:7, 92:21-93:8. This example illustrates utilizing a cDNA fragment that encodes the extracellular region of a TNF-binding protein, and describes the process generally using a p55 TNFR as an illustration. 9/17 (Loetscher) Tr. at 56:5-58:24. A POSA would have followed that example and used p75 to create etanercept based on the claims in the Patents-in-Suit and the specification.[13] See 9/12 PM (Blobel) Tr. at 8:5-10:2, 14:6-12; 9/17 (Loetscher) Tr. at 56:5-58:24; 9/18 AM (Naismith) Tr. at 67:14-68:25, 72:15-73:1, 73:17-74:8, 94:10-14, 94:20-95:6.

         Moreover, the parties agree that the IgG1 hinge-CH2-CH3 was also known in the prior art as of August 1990. DFOF ¶ 167; PFOF ¶¶ 99-100. Thus, because the p75 TNFR sequence and the IgG1 sequence were well known and accessible to a POSA, a reproduction of the known sequences was not required to be explicitly included in the Patents-in-Suit in order to claim a novel combination of those sequences. See Falkner, 448 F.3d at 1368 (holding that genes and their nucleotide sequences must not be recited or incorporated by reference where "accessible literature sources ... as of the relevant date" contain such information, because "forced recitation of known sequences in patent disclosures would only add unnecessary bulk to the specification").

         b) The Patents-in-Suit Demonstrate Possession

         To the extent Defendants assert that Roche[14] never made the claimed p75-IgG1 fusion protein, such contention is legally insignificant. Ariad holds that "the written description requirement does not demand either examples or an actual reduction to practice; a constructive reduction to practice that in a definite way identifies the claimed invention can satisfy the written description requirement." 598 F.3d at 1352 (citing Falkner, 448 F.3d at 1366-67). Here, as discussed, the claim language identifies the requisite elements of the subject invention-the p75 fusion protein combined with the hinge-CH2-CH3 domains of IgG1-and, in conjunction with the specification, provides support of possession. Many of the examples in the Patents-in-Suit further demonstrate that the Roche Inventors had possession.[15] Accordingly, the Court is persuaded that the Roche Inventors had possession of the invention based on the specifications of the Patents-in- Suit, including the examples within the specifications, and the claims.

         c) Amendments to the Prosecution File History Did Not Add New Material

         The Court will now consider two amendments to the Patents-in-Suit, both of which were approved by the USPTO. First, in 2006, Amgen and Immunex, with assistance from Roche, deposited a plasmid containing a p75 cDNA with American Tissue Culture Collection ("ATCC")[16], and gave it a designation of PTA 7942. PFOF ¶¶ 93-94; DFOF ¶ 75; see also JTX- 81 at 19-20 (Plaintiffs' witness Dr. Werner Lesslauer, one of the Roche Inventors involved in this project, testifying that Amgen deposited the p75 plasmid, Roche assisted in the deposit, and it was designated PTA 7942). That same year, Immunex amended the specification of the '790 application (which resulted in the '182 Patent) to include a reference to Immunex's PTA 7942 plasmid deposit. 9/13 AM (Capon) Tr. at 50:9-51:1; JTX-16 at 29-31. The cDNA for the PTA 7942 plasmid encodes the full-length p75 TNFR, which is identical to the sequence reported in Smith 1990. JTX-16 at 29-31. Second, in 2007, Immunex amended the specification of the '791 application (which resulted in the '522 Patent) to expressly incorporate the Smith 1990 protein by reference. Defs. Br. at 33. Immunex also inserted a new figure, Figure 5, that included the Smith 1990 sequence (in addition to the reference previously included). Id.

         Defendants assert that Immunex's decision to take over the prosecution and amend the specifications of the Patents-in-Suit is a clear indication that the original specifications as filed by Roche were deficient. Id. at 32-33. In addition, Defendants assert that the USPTO did not have complete information when it approved the amendments because the Plaintiffs informed the USPTO that the Smith 1990 protein was "99% identical" to Figure 4, when in fact Defendants contend the two proteins are meaningfully different. Id. at 33-34. Defendants argue that Plaintiffs' amendments added what amounts to "new matter" not previously included in the application, which is a ground for a patent rejection.[17] See 35 U.S.C. § 132 ("No amendment shall introduce new matter into the disclosure of the invention."); see also Defs. Reply Br. at 16 n.13.

         By contrast, Plaintiffs contend that each amendment did not contain new matter and that the USPTO properly approved the valid amendments. Pls. Br. at 16 n.2, 18 n.3; PFOF ¶¶ 11-14. Plaintiffs maintain that the amendment to include the PTA 7942 plasmid, which encodes the sequence reported in Smith 1990, complies with USPTO rules because the plasmid (1) contains p75 cDNA that was identified in the original specification as variants of a "DNA sequence[] encoding the 75/65 kD," (2) was made prior to August 1990, and (3) was properly deposited with the ATCC in 2006. Pls. Br. at 16 n.2; PFOF ¶¶ 11-14.

         The Court concludes that the deposited PTA 7942 plasmid was properly made part of the Patents-in-Suit and did not add new matter. The Federal Circuit has held that where information is properly deposited with an independent source, "[a]n accession number and deposit date add nothing to the written description of the invention" and are therefore, not considered new matter. In re Lundak, 773 F.2d 1216, 1223 (Fed. Cir. 1985). Further, the deposited plasmid was appropriately made part of the Patents-in-Suit as of their 1990 priority dates because as long as the plasmid was described in the application as-filed, it is not considered new and may be deposited at any time before issuance. See In re Lundak, 773 F.2d at 1222-23 ("Lundak's deposit with the ATCC, which was made after filing but prior to issuance of his patent, and which is referred to in his specification, meets the statutory requirements."); see also 37 C.F.R. § 1.804(a) (" . . . an original deposit . . . may be made . . . subject to § 1.809, during pendency of the application for patent.").[18] The Court agrees with the USPTO and finds that the properly deposited plasmid reflected one of these variants and did not add new matter. Accordingly, the Court finds that Plaintiffs' amendments adequately described the inventive concept at the time of the invention.

         As to the Smith 1990 incorporation, the Court does not find that Immunex's decision to amend is proof that me original specifications were deficient. As discussed above, the Court finds that the Smith 1990 protein was sufficiently described when it was originally referred to and did not need to be amended to expressly incorporate it by reference. See, e.g., Falkner, 448 F.3d at 1365 (finding that "the absence of incorporation by reference is not problematic"). The Court therefore finds that the amendments to the Patents-in-Suit were proper and do not alter the written description analysis.

         2. The Specification Enables Etanercept

         Finally, Defendants argue that the claims of the Patents-in-Suit are not enabled. DFOF ¶ 180; Defs. Br. at 35. Plaintiffs assert that Defendants' enablement challenge fails because the Patents-in-Suit identify both p75 TNFR and IgG1 (which were well-known), sufficiently describe how to combine them to enable a POSA to produce etanercept, and Defendants' own experts concede that a POSA could have produced the claimed fusion protein without undue experimentation by using known methods as of August 1990. See Pls. Br. at 2, 21-22; see also 9/12 PM (Blobel) Tr. at 53:19-56:13; 9/13 PM (Capon) Tr. at 61:22-62:16.

         To be enabling, "[t]he specification must 'enable one of ordinary skill in the art to practice the claimed invention without undue experimentation.'" Transocean Offshore Deepwater Drilling, Inc. v. Maersk Contractors USA, Inc., 617 F.3d 1296, 1305 (Fed. Cir. 2010) (quoting Nat'l Recovery Techs., Inc. v. Magnetic Separation Sys., Inc., 166 F.3d 1190, 1196 (Fed. Cir. 1999)). "Enablement is not precluded by the necessity for some experimentation such as routine screening." In re Wands, 858 F.2d at 736-37. However, the experimentation needed to practice the art must not be undue. Id. at 737. The test for undue experimentation "is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed." Id. To determine whether a disclosure would require undue experimentation, courts should consider the Wands factors, which include: (1) the quantity of experimentation necessary; (2) the amount of direction or guidance presented; (3) the presence or absence of working examples; (4) the nature of the invention; (5) the state of the prior art; (6) the relative skill of those in the art; (7) the predictability or unpredictability of the art; and (8) the breadth of the claims. Id.

         The Court finds that Defendants have failed to show by clear and convincing evidence that the Patents-in-Suit do not meet the enablement standard. Preliminarily, both parties agree to a POSA's relative skill in the art, and each party used nearly identical definitions and qualifications for their respective hypothetical POSA. Compare 9/11 PM (Blobel) Tr. at 30:24-32:5 with 9/20 AM (Wall) Tr. at 18:6-25.[19] Specifically, the parties' experts agreed that the p75 protein and the exon-encoded hinge-CH2-CH3 portion of the IgG1 immunoglobulin sequences were known before August of 1990, which is the initial date of the applications. 9/11 PM (Blobel) Tr. at 14:19-15:5 (Dr. Blobel noting that the claims in the '182 Patent were directed at "essentially etanercept"); 9/20 AM (Wall) Tr. at 19:2-12, 92:16-93:2 (Dr. Wall explaining that the components of etanercept were known by August 1990). Both of Defendants' experts, namely Dr. Blobel and Dr. Capon, agreed that a POSA in 1990 would have been able to produce a fusion protein that is similar to etanercept. 9/12 PM (Blobel) Tr. at 55:20-56:5 (Dr. Blobel testifying that a POSA would have been able to produce a fusion protein similar to etanercept using "ordinary and routine methods utilized in the art"); 9/13 PM (Capon) Tr. at 73:5-14 (Dr. Capon testifying to the same). These experts also testified that the claim scope is both limited to and covers etanercept. 9/11 PM (Blobel) Tr. at 14:19-15:5; 9/13 PM (Capon) Tr. at 82:22-83:3. Regarding the state of the art at the time of the invention, the parties explicitly agreed that technology relating to recombinant DNA was developed by 1990 and allowed for the creation of fusion proteins like etanercept. 9/12 PM (Blobel) Tr. at 54:13-56:13 (Dr. Blobel testifying regarding the state of the art in August 1990); see also ECF No. 688 at 65 ¶ 247.

         Furthermore, the Patents-in-Suit, and in particular the '522 Patent, provide a POSA with sufficient guidance on how to make etanercept. Specifically, both Patents-in-Suit explain to a POSA how to prepare a cDNA encoding the extracellular region of the known p75 protein.' 182 Patent (JTX-1) col. 16:22-48, 5:22-24, 7:24-46; 9/18 AM (Naismith) Tr. at 60:13-62:6; 9/18 PM (Naismith) Tr. at 53:12-54:6; 9/20 AM (Wall) Tr. at 93:14-94:16. The specifications also provide a POSA with information regarding how to prepare a cDNA encoding all of the domains of a human IgG1 constant region, except the first, including identifying a publicly accessible exemplary vector pCD4-Hγl. '182 Patent (JTX-1) col. 8:56-9:3; 9/20 AM (Wall) Tr. at 94:17-95:19.

         Finally, Plaintiffs' witnesses Dr. Naismith and Dr. Loetscher credibly testified that the' 182 Patent directs a POSA to follow the recipe set forth in Example 11 contained in the specification. 9/17 (Loetscher) Tr. at 56:5-9 (Dr. Loetscher noting that the example "describe[s] the process [of] how to make TNF receptor fusion proteins"); 9/18 AM (Naismith) Tr. at 53:22-54:2. Defendants' expert Dr. Capon even appeared to acknowledge that Example 11 in conjunction with the prior art would have enabled a POSA to construct etanercept. See 9/13 PM (Capon) Tr. at 72:3-73:14. Hence, as Plaintiffs submit, a POSA could have easily made the claimed fusion protein (i.e., a fusion protein that had the extracellular region of the p75 receptor with an exon-encoded hinge and the CH2-CH3 region of the IgG1 immunoglobulin) of the '182 Patent in or before August 1990 with only routine experimentation by adapting Example 11 to make the claimed fusion protein. 9/17 (Loetscher) Tr. at 58:18-59:5; 9/18 AM (Naismith) Tr. at 93:12-22 (Dr. Naismith explaining that a POSA would have been able to make Example 11 in August of 1990); 9/20 AM (Wall) Tr. at 95:17-19 (Dr. Wall testifying that a POSA would have "been able to adapt Example 11 to make the claimed fusion protein."); JTX-82 (Lesslauer Deposition) at 298:11-14, 17. The Court finds that based on this evidence, Defendants have not met their burden of proving by clear and convincing evidence that the Patents-in-Suit fail to meet the enablement standard.

         B. Obviousness (35 U.S.C. § 103)

         To prove mat an asserted claim of a patent is invalid as obvious under 35 U.S.C. § 103, a patent challenger bears the burden of establishing by clear and convincing evidence that the "differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a [POSA]."[20] 35 U.S.C. § 103(a); see also Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1360-61 (Fed. Cir. 2007). Obviousness is a question of law that is predicated on several factual inquiries. See Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17 (1966). Specifically, there are four basic factual inquiries which concern: (1) the scope and content of the prior art; (2) the level of ordinary skill in the art;[21] (3) the differences between the claimed subject matter and the prior art; and (4) objective indicia (secondary considerations) of non-obviousness, including unexpected results, success and praise in the industry, long-felt but unsolved need, failure of others, and other indicia. See id.

         Defendants assert that the Patents-in-Suit are invalid because they are obvious in view of prior art that would have motivated a POSA to create etanercept prior to the relevant patent applications.[22] Defs. Br. at 35-43; see also Defs. Reply Br. at 19-22. At trial, Defendants asserted six obviousness combinations of prior art references, two of which disclose the protein sequence of, and the DNA sequence that encodes, the p75 extracellular region (Smith 1990 and Immunex's U.S. Patent No. 5, 395, 760 (JTX-65) (the "Smith '760 Patent")). PFOF ¶ 147. The other asserted prior art references disclose Ig fusion proteins, which combine a receptor protein with various portions of an Ig heavy chain. Id. Specifically, the first five (5) combinations are the Smith '760 in view of: (1) the Seed European Patent Application No. 0325262 ("Seed '262"); (2) Byrn, R. et al., Biological Properties of a CD4 Immunoadhesin, Nature 344: 667-70 (1990) ("Bryn 1990"); (3) Watson, S. et al., A Homing Receptor-IgG Chimera as a Probe for Adhesive Ligands of Lymph Node High Endothelial Venules, J. Cell. Bio. 110: 2221-2229 (1990) ("Watson 1990"); (4) the Karjalainen European Patent Application No. 0394827 ("Karjalainen '827"); and (5) the Capon U.S. Patent No. 5, 116, 964 ("Capon '964") in further view of Traunecker, A. et al, Highly Efficient Neutralization of HIV with Recombinant CD4-immunogloblin Molecules, Nature 339: 68-70 (1989) ("Traunecker 1989"). The sixth combination was Smith 1990 in view of Watson. Id. ¶ 147 n.3. Defendants' post-trial arguments regarding these prior art references focus on motivation. Defs. Br. at 35 ("[T]he only real dispute as to obviousness of the asserted claims concerned motivation."). The Court has examined the asserted prior art references both alone and in combination, as discussed below, to determine motivation and whether it would have been obvious to a POSA to create etanercept.

         In addition, Defendants argue that certain secondary considerations prove, rather than refute, that the Patents-in-Suit are invalid for obviousness. Id. at 44-50. In support of their obviousness arguments, Defendants primarily rely on (1) Dr. Blobel, introduced above; and (2) Arne Skerra, Ph.D, Chair of Biological Chemistry at the Technical University of Munich, Center of Life Sciences at Weihenstephan, Freising, Germany. ECF No. 688 at 131-32 ¶¶ 43, 49.[23]

         Plaintiffs contend that Defendants' obviousness arguments fail because a POSA would not have been motivated to create etanercept based on the prior art and, in fact, would have actually been dissuaded by the prior art to create a TNFR-Ig fusion protein to treat inflammation. Pls. Br. at 22-23. Further, Plaintiffs counter each of Defendants' secondary consideration arguments as set forth below and contend that the secondary considerations support nonobviousness. Id. at 33-39. Plaintiffs rely on (1) Randolph Wall, Ph.D., a Distinguished Professor in the Department of Microbiology, Immunology, and Molecular Genetics at the Molecular Institute, University of California at Los Angeles (UCLA) and the David Geffen School of Medicine at UCLA, as an expert on obviousness (ECF No. 688 at 122 ΒΆ 22); and (2) Warner C. Greene, M.D., Ph.D., the Founder and Director of the Gladstone Institute of ...


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