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Baxalta Inc. v. Genentech, Inc.

United States District Court, D. Delaware

December 3, 2018

BAXALTA INCORPORATED and BAXALTA GMBH, Plaintiffs,
v.
GENENTECH, INC. and CHUGAI PHARMACEUTICAL CO., LTD., Defendants,

          OPINION & ORDER

          HONORABLE TIMOTHY B. DYK, UNITED STATES CIRCUIT JUDGE

         On May 4, 2017, Baxalta Inc. and Baxalta GmbH (together, "Baxalta") filed suit against Genentech, Inc. and Chugai Pharmaceutical Co., Ltd. alleging infringement of claims 1, 4, 17, and 19 of U.S. Patent No. 7, 033, 590 patent ("the '590 patent").[1] Chugai was voluntarily dismissed from this lawsuit pursuant to a stipulation of the parties on September 19, 2018. Order Dismissing Chugai, ECF No. 293.

         The alleged infringement is the manufacture, use, sale, offer to sell, and importation of an antibody used to treat hemophilia A and known as emicizumab, or ACE910, and marketed under the brand name Hemlibra (hereinafter, "Hemlibra"). Now before this court is the claim construction of six terms of the '590 patent: antibody, antibody fragment, bispecific antibody, isolated, binds Factor IX or Factor IXa and increases, and increases the procoagulant activity of Factor Ixa.

         This court held a Markman hearing on October 16, 2018, and received expert testimony and argument regarding the construction of the six terms. At an earlier preliminary injunction hearing on June 13 and 14, 2018, the court also received testimony and argument on construction of the terms antibody and antibody fragment.

         In terms of the factual record, the court will consider oral testimony given by experts at the Markman hearing, testimony offered at the preliminary injunction hearing, and the deposition testimony and reports and declarations of any of those experts, but the court declines to consider the declarations of experts who have not been subject to cross-examination at either hearing.[2]Whether or not such declarations are considered makes no difference to the constructions adopted by the court here.

         BACKGROUND

         I. Procedural History

         On May 4, 2017, Baxalta filed its complaint alleging infringement of the '590 patent. Compl. ¶¶ 37-51, ECF No. 1. On June 30, Genentech answered, denying Baxalta's allegations and counterclaiming for declaratory judgment of noninfringement and invalidity. Answer & Countercl. ¶¶ 37-51, 120-49, ECF No. 9.

         On December 14, 2017, Baxalta moved for a preliminary injunction. Mot. Prelim. Inj. 2, ECF No. 41; Prop. Prelim. Inj. Order 1, ECF No. 42-1. After an evidentiary hearing on August 7, 2018, this court denied Baxalta's preliminary injunction motion. Prelim. Inj. Order at 29, ECF No. 262. In that connection, the court declined to construe antibody and antibody fragment, concluding that the parties had presented "substantial arguments" on both sides. Id. at 13. Baxalta did not appeal the denial of the preliminary injunction. Discovery has been ongoing. Fact discovery is set to close on December 14, 2018, and expert discovery is set to close on April 19, 2019. Stip. & Order Amend. Sched. 1, ECF No. 325.

         At the Markman hearing, the parties presented expert testimony and argued construction of six terms: antibody, antibody fragment, bispecific antibody, isolated, binds Factor IX or Factor IXa and increases, and increases the procoagulant activity of Factor IXa. All these terms appear in claims 1 and 4 of the '590 patent, which recite

1. An isolated antibody or antibody fragment thereof that binds Factor IX or Factor IXa and increases the procoagulant activity of Factor IXa.
* * *
4. The antibody or antibody fragment according to claim 1, wherein said antibody or antibody fragment is selected from the group consisting of a monoclonal antibody, a chimeric antibody, a humanized antibody, a single chain antibody, a bispecific antibody, a diabody, and di-, oligo- or multimers thereof.

'590 patent, col. 101, ll. 43-45, 51-56 (underlining added).[3]

         II. Coagulation & Hemophilia A

         In general, the term antibody is used to describe glycoproteins that are "characterized by their ability to bind both to antigens and to specialized cells or proteins of the immune system." Strohl Decl. ¶22, ECF No. 112; accord Almagro Decl. ¶ 33, ECF No. 49. Structurally, antibodies are T-shaped, with two arms that are connected by disulfide bonds. Almagro Decl. ¶ 34; Strohl Decl. ¶ 22. Each arm of the Y contains two polypeptide chains known as the heavy ("H") chain and the light ("L") chain.[4] Almagro Decl. ¶ 34; Strohl Decl. ¶ 22. The portions of the heavy chain and light chain that are responsible for binding an antigen are called variable domains, VH and VL respectively. Almagro Decl. ¶ 34; Strohl Decl. ¶23. The remaining portions of the antibody are made up of constant regions. Almagro Decl. ¶ 34; Strohl Decl. ¶ 23.

         Within each variable domain, the antigen binding sequence of the antibody is divided into three regions called complementarity-determining regions ("CDRs"). Almagro Decl. ¶ 35; Strohl Decl. ¶ 25. The three CDRs in each variable region-designated CDR1, CDR2, and CDR3-determine the binding specificity of the antibody, Almagro Decl. ¶ 35; Strohl Decl. ¶25. The CDR3 region of the heavy chain variable domain is "primarily responsible for antigen binding specificity." Strohl Decl. ¶ 25; accord Almagro Decl. ¶ 38.

         While the parties agree as to these characteristics of an antibody, they disagree in at least one critical respect. Genentech contends that, as used in the patent, the term antibody standing alone has two heavy chains that are identical and the two light chains that are identical. Genentech Op. Br. 6-8, ECF No. 160; Strohl Decl. ¶ 50. Baxalta, in contrast, argues that the heavy chains are not necessarily identical to one another and the light chains are also not necessarily identical to one another. Baxalta Op. Br. 4-5, ECF No. 158. The resolution of this difference appears to be determinative of infringement.

         Hemophilia A and the process of blood coagulation are described at length in the preliminary injunction order. See Prelim. Inj. Order 3-4. Relevant here is one particular step of the clotting cascade involving Factor Villa and Factor IXa. See Aledort Decl. ¶ 13, ECF No. 46. In healthy individuals, Factor Villa and Factor IXa form a complex, which allows Factor IXa to activate Factor X. See id.; Sheehan Decl. ¶36, ECF No. 111. In patients afflicted with hemophilia A, Factor VIII is reduced, defective, or absent. See Aledort Decl. ¶ 14; Sheehan Decl. ¶ 42. This hinders the coagulation cascade by limiting the body's ability to activate Factor X. Aledort Decl. ¶ 14; Sheehan Decl. ¶ 42.

         Genentech's drug, Hemlibra, is directed to this step of the coagulation cascade and functions by replacing Factor Villa. See Krishnaswamy Decl. ¶ 61, ECF No. 47. Hemlibra does not have both identical light and identical heavy chains. See Strohl Decl. ¶¶ 38, 53; see also Krishnaswamy Decl. ¶¶ 55, 60. It is a bispecific antibody. The parties agree that in this patent a bispecific antibody has non-identical light chains, or non-identical heavy chains, or both.[5]Markman Tr. 38:5-21, ECF No. 320. One arm of the Hemlibra antibody binds to Factor IX (or IXa) and the other binds to Factor X. See Krishnaswamy Decl. ¶¶ 55, 60; Strohl Decl. ¶ 53. By doing so, Hemlibra allows Factor IX to activate Factor X. See Krishnaswamy Decl. ¶ 61, Strohl Decl.¶¶ 178-79.

         ANALYSIS

         1. antibody

         Baxalta's proposed construction: A molecule having a specific amino acid sequence comprising two heavy chains (H chains) and two light chains (L chains).

         Genentech's proposed construction: An immunoglobulin molecule, having a specific amino acid sequence that only binds to the antigen that induced its synthesis or very similar antigens, consisting of two identical heavy chains (H chains) and two identical light chains (L chains).

         Court's construction: An immunoglobulin molecule, having a specific amino acid sequence that only binds to the antigen that induced its synthesis or very similar antigens, consisting of two identical heavy chains (H chains) and two identical light chains (L chains).

         Construing the claims requires resolution of the parties' primary dispute that an antibody in the claims is required to have two identical heavy chains and two identical light chains.[6] The parties agree that the requirement that an antibody have two identical heavy chains and two identical light chains would exclude Hemlibra from the scope of the term antibody. Prelim. Inj. Tr. 9:15-24, ECF No. 214-15; Markman Tr. 109:23-110:8. Hemlibra is not an antibody under Genentech's definition.

         a. The Meaning of the Term Antibody in the Patent as Originally Drafted

         It is clear from the '590 patent's specification that, as originally drafted, the term antibody in the claims required identical heavy and identical light chains.

         Based on the evidence, I find that the term antibodies does not have a single fixed meaning in the art. The word antibody can denote different meanings to a person skilled in the art depending on the context in which it appears. For example, antibody standing alone may connote a different meaning than when it is part of a larger term that defines its structure-e.g., bispecific antibody.

         The parties agree that the term antibody standing alone without other structural terms can have different meanings to those skilled in the art. See Markman Tr. 174:21-175:24. One definition is Baxalta's definition (hereinafter the "broader" definition), requiring only a molecule with a specific amino acid sequence and comprising two heavy chains and two light chains. The other definition is Genentech's definition (hereinafter the "narrower" definition), requiring a pair of identical heavy chains and a pair of identical light chains. Baxalta argues that its broader definition should apply because it would have been utilized by persons of ordinary skill in the art. Baxalta Op. Br. 5. But in its opening preliminary injunction brief, Baxalta itself used the narrower definition, stating that "[a]n antibody comprises two identical heavy chains and two identical light chains." Baxalta Op. Prelim. Inj. Br. 13 n.7, ECF No. 42. Similarly, Dr. Almagro, Baxalta's expert, described an antibody in his declaration as "a glycoprotein that has a specific 'Y' shape" that "has two pairs of identical polypeptide chains, which are linked together by disulfide bonds." Almagro Decl. ¶ 34. Genentech's expert agreed that such a definition "represents the plain and ordinary meaning of 'antibody' and is consistent with standard textbook definitions of immunoglobulin molecules dating from prior to the 1999 priority date of the '590 [p]atent." Strohl CI. Const. Decl. ¶¶ 41-42, ECF No. 161; accord Id. ¶ 44.

         Various references cited on the face of the '590 patent use a similar definition. The Roitt reference describes an antibody as "a unit consisting of two identical light polypeptide chains and two identical heavy polypeptide chains." Ivan Roitt et al., Immunology 72 (5th ed. 1998), Strohl Decl. Ex. F, ECF No. 112-6. And the Harlow and Lane reference says that "[e]ach Y contains four polypeptides[:] [t]wo identical copies of a polypeptide known as the heavy chain and two identical copies of a polypeptide called the light chain." Ed Harlow & David Lane, Antibodies: A Laboratory Manual 7 (1988), Strohl Decl. Ex. E, ECF No. 112-5. Baxalta does not point to any references cited in the '590 patent that use a broader definition.

         Nonetheless the parties agree that Baxalta's broader definition was also known to those skilled in the art. See Markman Tr. 172:6-176:6. During the Markman hearing, Dr. Strohl, Genentech's expert testified that the broader definition was a "common language definition." Id. at 175:12-13. Baxalta only points to Dr. Strohl's testimony as evidence of the understanding of someone skilled in the art.[7]

         In the patent specification, the applicant chose the narrower definition. In relevant part, the summary of the invention provides that

Antibodies are immunoglobulin molecules having a specific amino acid sequence which only bind to antigens that induce their synthesis (or its immunogen, respectively) or to antigens (or immunogens) which are very similar to the former. Each immunoglobulin molecule consists of two types of polypeptide chains. Each molecule consists of large, identical heavy chains (H chains) and two light, also identical chains (L chains).

'590 patent, col. 5, ll. 56-63. The Federal Circuit has recognized that use of the verb "is" may "signify that a patentee is serving as its own lexicographer." Sinorgchem Co. v. Int'l Trade Comm'n, 511 F.3d 1132, 1136 (Fed. Cir. 2007) (quoting Abbott Labs. v. Andrx Pharms., Inc., 473 F.3d 1196, 1210 (Fed. Cir. 2007)). The use of the term "are" here is the equivalent of the term "is." Here, the specification unequivocally states what "[a]ntibodies are." '590 patent, col. 5, ll. 56-63. This definition is also clearly defining the term antibodies covered by the claims of this patent because the definition immediately follows and immediately precedes references to "the inventive antibodies and antibody derivatives." '590 patent, col. 5, 1. 53; id col. 6, 1. 1. The fact that the applicants chose to include the narrower definition in the specification over a broader definition confirms that the applicants intended the narrow definition apply to the term antibody standing alone.

         Baxalta argues that the specification in other places uses the broader definition. Baxalta Op. Br. 6-7. For example, the specification and claims disclose bispecific antibodies, which do not have identical heavy and light chains. See id; '590 patent col. 6, ll.. 1-5; id. col. 7, ll.. 32-35; id. col. 101, ll.. 51-56 (claim 4). Baxalta also points to the inclusion of IgM antibodies and IgA antibodies in claims 3 and 20 as well as throughout the specification. '590 patent, col. 6, ll. 35-38; id. col. 12, ll.. 25-26; id col. 14, 1. 22-col. 15, 1.4 (Example 4); id. col. 30, 1. ll.-col. 31, 1. 10 (Example 13); id. col. 101, ll. 49-50 (claim 3); id. col. 104, ll.. 6-7 (claim 20). IgM and IgA antibodies can have more than two heavy chains and more than two light chains. Markman Tr. 71:11.-13, 156:12-159: 11. Baxalta thus contends that this limitation of the narrow definition of antibody is inappropriate in the context of the '590 patent. Baxalta Op. Br. 6-7. But all these embodiments were initially listed as falling within "antibodies or antibody derivatives." See, e.g., '590 patent, col. 5, 1. 51; U.S. Patent App. No. 09/661, 992, at 10-11, Strohl Decl. Ex. D, ECF No. 112-4. Thus, as originally drafted, the claims covered antibodies as more broadly defined, but not because they fell within the term antibody but because they fell within the term antibody derivative.

         Under such circumstances, the Federal Circuit has held that the specification's choice of definition governs. See Sinorgchem, 511 F.3d at 1136-40 ("Where, as here, multiple embodiments are disclosed, we have previously interpreted claims to exclude embodiments where those embodiments are inconsistent with unambiguous language in the patent's specification or prosecution history."); Irdeto Access, Inc. v. Echostar Satellite Corp., 383 F.3d 1295, 1300 (Fed. Cir. 2004) (concluding that the scope of the claim terms was controlled by the specification even in the absence of express definitions where applicant admitted to the examiner that the terms had "no accepted meaning in the art" and were "adequately described in the specification"). Indeed, given the specification's clarity, the definition included in column 5 of the '590 patent would govern even if it were contrary to an ordinary meaning of the term. See Thorner v. Sony Comp. Entmt. Am. LLC, 669 F.3d 1362, 1365-66 (Fed. Cir. 2012) ("[T]he inventor's written description of the invention, for example, is relevant and controlling insofar as it provides clear lexicography" (alterations and emphasis in original) (quoting C.R. Bard, Inc. v. U.S. Surgical Corp., 388 F.3d 858, 862 (Fed. Cir. 2004))).

         Before turning to the prosecution history, it is important to ascertain the meaning of the term antibody derivative in the patent as initially drafted. The parties agree that antibody derivative is not a term that is commonly used in the art. Markman Tr. 119:21-120:3. But Dr. Almagro, Baxalta's expert, admitted during the preliminary injunction hearing, and again during the Markman hearing, that antibodies that have been altered in some significant way are "sometimes... called derivatives." Prelim. Inj. Tr. 413:4-15; accord Markman Tr. 120:6-11 (Dr. Almagro agreeing with previous testimony that "significant variants" of antibodies are "sometimes.. . called derivatives"). Also in support of this understanding, Dr. Almagro, a person of skill in the art, repeatedly described Hemlibra, a bispecific antibody, as being "derived" from other antibodies.[8] Almagro Decl. ¶ 54 n. 5, ¶ 87 n. 17; Markman Tr. 122:8-24; see also id 120:6-21 (Dr. Almagro agreeing that "[t]alking in plain English" Hemlibra" is "derived from a Factor IX antibody and a Factor X antibody"). This definition of antibody derivatives-an antibody that has been altered in some significant way-is consistent with the specification. First, the specification makes clear that the group consisting of antibodies and antibody derivatives includes bispecific antibodies and other structures that do not have identical light and heavy chains. Since bispecific antibodies are not within the definition of antibodies, they must be within the definition of antibody derivatives.

         This understanding is further supported by the uses of antibody derivative in those places in the patent specification where antibody derivative is used separately. Antibody derivative is used separately in three instances that inform the interpretation of the term[9]: (1) in Example 10, which is entitled "Structure and Procoagulant Activity of Antibody Derivatives Derived from Anti-FIX/FIXa-antibodies; Subcloning Antibody Variable Domains from Hybridoma Cell Lines," id. col. 19, ll.. 3-7; (2) in the body of Example 11, where the patent includes in a list of examples of antibody derivatives "scFv, Fab, etc.," id. col. 20, 1. 36; and (3) again in Example 13, where the patent refers to "antibody derivatives such as Fab, F(ab)2, scFv, etc.," id. col. 30, ll.. 16-17. See also Markman Tr. 13:19-15:6.

         These uses make clear that Fab, F(ab)2, and scFv are all antibody derivatives. As Dr. Almagro and Dr. Strohl agree, Fab and F(ab)2 are the sort of canonical antibody fragments (a subset of derivatives) that a person of skill in the art would unquestionably have understood as such. Markman Tr. at 117:7-14 (Dr. Almagro), 155:19-23 (Dr. Strohl). Each of these can be derived from an existing antibody as defined in the specification. A Fab comprises "the complete light chain[] paired with the full variable and a portion of the constant domain[] of the heavy chain[]" and can be excised from an existing antibody. See Strohl Claim Const. Decl. ¶ 31 & Fig. 2, ECF No. 161; accord Markman Tr. 151:18-152:24 (Dr. Strohl). A F(ab)2, comprises "two Fab fragments linked with disulfide bonds" and also "can be generated from an antibody by cleaving off the other portions" to leave the fragment remaining. Markman Tr. 152:25- 153:11 (Dr. Strohl); accord Strohl Decl. ¶ 32 & Fig. 3. Based on inclusion of Fab and F(ab)2 it is clear that antibody fragments are antibody derivatives.

         But the specification makes clear that an scFv is not an antibody fragment using the definition of antibody from the specification. Rather, it is called a single-chain variable fragment and is synthetically created by linking with a stretch of synthetic peptide "a truncated fragment comprising only the [variable heavy] domain" of an antibody with a truncated fragment comprising only the variable light region of an antibody. Strohl Claim Const. Decl. ¶ 33 & Fig. 4; accord Almagro Decl. ¶ 35; Markman Tr. 60:2-6, 201:17-22. Because of the reference to scFv as an antibody derivative, the term antibody derivative was clearly meant to include antibodies that have been altered in some significant way.

         Thus, I find that the term antibody derivative was used in the patent to denote antibodies within the column 5 definition that had been altered in some significant way. As initially drafted, there was no inconsistency between ...


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