Abstract
Synopsis
Baxalta sued Genentech, asserting that Genentech's Hemlibra (emicizumb-kxwh) product, used to treat the blood clotting disorder hemophilia, infringed Baxalta's patent. Genentech's product is a bispecific antibody, and as such has different heavy chains and/or different light chains, which allow the molecule to bind two different antigens. The patent claims are directed towards isolated antibodies and antibody fragments, and the outcome of the case hinged upon the proper interpretation of “antibody,” as that term is used in the claims. Baxalta argued that the term “antibody” encompasses synthetic antibodies that have different heavy and/or light chains, including bispecific antibodies like Hemlibra, while Genentech argued for an interpretation that would limit the term “antibody” to molecules having identical heavy and light chains. The district court sided with Genentech, based on what the court believed to be an explicit definition of “antibody” in the patent specification, which specified that antibodies “consist[] of large, identical heavy chains (H chains) and two light, also identical chains (L chains).” On appeal, the Federal Circuit reversed, holding that the discussion of “identical” heavy and light chains in the specification did not limit the claimed invention to antibodies having identical chains. The Federal Circuit found it particularly significant that the specification specifically disclosed antibodies having non-identical chains, including bispecific antibodies, and that a number of the patent claims allowed by the patent examiner explicitly recited non-identical antibodies.
Baxalta Inc. sued Genentech, Inc. and Chugai Pharmaceutical Co. Ltd., alleging infringement of claims 1, 4, 17, and 19 of U.S. Patent No. 7,033,590. On December 3, 2018, the United States District Court for the District of Delaware issued a claim construction order, construing the terms “antibody” and “antibody fragment.” Following the claim construction order, the parties stipulated to non-infringement of the asserted claims. The district court entered judgment based on its claim construction order and the parties' stipulation. Baxalta appeals the district court's judgment, arguing the district court's claim constructions were erroneous.
Because the district court erred in construing the terms “antibody” and “antibody fragment,” we vacate the district court's judgment of non-infringement and remand.
I. Background
Baxalta sued Genentech, asserting that Genentech's Hemlibra® (emicizumb-kxwh) product used to treat the blood clotting disorder hemophilia infringes claims 1, 4, 17, and 19 of the ’590 patent. Blood clotting occurs in the body through a series of enzymatic activations known as the “coagulation cascade.” ’590 patent at 1:7–10. One “key step” in the cascade is when an enzyme known as activated clotting factor VIII (FVIIIa) complexes with another enzyme known as activated clotting factor IX (FIXa) to form a complex that then activates factor X (FX). ’590 patent at 1:17–19. Hemophilia A is a particular form of hemophilia where the activity of factor VIII is functionally absent, thereby impeding the coagulation cascade. This can occur in some Hemophilia A patients because they develop factor VIII inhibitors (i.e., antibodies against factor VIII), which hinder the effectiveness of factor VIII preparations administered as treatments. ’590 patent at 1:24–32. The ’590 patent relates to preparations used to treat hemophilia patients who have developed factor VIII inhibitors. ’590 patent at 2:25–29. The preparations comprise antibodies or antibody fragments that bind to factor IX or factor IXa to increase procoagulant activity of factor IXa to compensate for the decreased factor VIII activity. See, e.g., ’590 patent at 2:29–34. Independent claim 1 and dependent claims 4 and 19 are illustrative and 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. 19. The antibody or antibody fragment according to claim 4, wherein the antibody is a humanized antibody.
The parties disputed the construction of the terms “antibody” and “antibody fragment,” among other terms not at issue on appeal. Generally, antibodies are Y-shaped structures comprising two heavy chains (H chains) and two light chains (L chains). An antibody that has two identical H chains and two identical L chains is called “monospecific” because each H-L chain pair binds the same antigen. Bispecific antibodies, like Genentech's product Hemlibra® (emicizumb-kxwh), have different heavy chains and/or different light chains, allowing them to bind two different antigens. Baxalta argued “antibody” should be construed as “[a] molecule having a specific amino acid sequence comprising two heavy chains (H chains) and two light chains (L chains).” Genentech argued “antibody” should instead be construed as “[a]n 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).”
The district court determined that “the term antibody standing alone without other structural terms can have different meanings to those skilled in the art,” and that both Baxalta's and Genentech's proposed constructions were acceptable definitions. Baxalta Inc. v. Genentech, Inc., No. 17-509, 2018 WL 6304351, at *4 (D. Del. Dec. 3, 2018). It determined, however, that the patentee “chose [Genentech's] narrower definition” by expressly defining antibodies in column 5 of the patent, which states:
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).
Although the district court recognized that the ’590 patent claims and discloses “bispecific antibodies, which do not have identical heavy and light chains,” and IgM and IgA antibodies, which “can have more than two heavy chains and more than two light chains,” it determined that these claimed embodiments were “antibody derivatives” rather than “antibodies.” Id. at *5–6. The district court likewise dismissed the “inconsisten[cy]” between Genentech's definition of “antibody” and “at least dependent claims 4 and 19” as insufficient to overcome what it considered to be the definitional language of column 5. Id. at *11. The district court therefore adopted Genentech's construction, construing “antibody” as “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).” Id. at *12.
To support its construction, the district court cited an amendment Baxalta made during prosecution of the ’590 patent. Original claim 1 recited “[a]n antibody or antibody derivative against factor IX/factor IXa which increases the procoagulant activity of FIXa.” Original dependent claim 4 recited a list of “antibod[ies] or antibody derivative[s] according to claim 1” including “chimeric antibodies, humanized antibodies, single chain antibodies, bispecific antibodies, diabodies and di-, oligo- or multimers thereof.” During prosecution, the patent examiner rejected the term “antibody derivatives” as not enabled for “any antibody derivative against factor IX/factor IXa which increases the procoagulant activity of FIXa in claim 1” or any one of the enumerated list in dependent claim 4. Based on the examiner's suggestion, the patentee amended the claims to recite “antibody fragment” in place of “antibody derivative” and the examiner removed the enablement rejection. The district court determined that this amendment amounted to a disclaimer of antibody derivatives “including bispecific antibodies, except antibody fragments.” Baxalta, 2018 WL 6304351, at *7–8 (emphasis in original).
The parties also disputed the construction of “antibody fragment.” Baxalta proposed that the term be construed as “[a] portion of a molecule having a specific amino acid sequence comprising two heavy chains (H chains) and two light chains (L chains).” Id. at *12. Genentech argued it should instead be construed as “[a] fragment of an antibody which partially or completely lacks the constant region; the term ‘antibody fragment’ excludes all other forms of antibody derivatives.” Id. The district court, relying on a portion of the written description reciting that “antibody fragments … partially or completely lack the constant region” and identifying examples of fragments (Fv, Fab, Fab’ [and] F(ab)’2), construed “antibody fragment” as “a fragment of an antibody which partially or completely lacks the constant region; the term ‘antibody fragment’ excludes bispecific antibodies.” Id. at *12–13 (citing ’590 patent at 6:20–21).
Based on the district court's constructions, the parties stipulated to non-infringement of the asserted claims of the ’590 patent. The district court entered final judgment of non-infringement of claims 1, 4, 17, and 19. Baxalta appeals, arguing that the district court erroneously construed the terms “antibody” and “antibody fragment.”
II. Discussion
A. “Antibody”
i. The claims of the ’590 patent
Claim 1 of the ’590 patent recites “[a]n isolated antibody or antibody fragment thereof that binds Factor IX or Factor IXa and increases the procoagulant activity of Factor IXa.” Therefore, contrary to the district court's construction, nothing in the plain language of claim 1 limits the term “antibody” to a specific antibody consisting of two identical heavy chains and two identical light chains or an antibody that only binds the antigen that induced its synthesis or very similar antigens.
The dependent claims confirm that “antibody” is not so limited. For example, dependent claim 4, recites “[t]he antibody or antibody fragment according to claim 1, wherein said antibody or antibody fragment is selected from the group consisting of … a chimeric antibody, a humanized antibody, … [and] a bispecific antibody.” Each of these claimed “antibodies” falls outside of the district court's construction because each does not “only bind[ ] to the antigen that induced its synthesis or very similar antigens.” 1 A “bispecific antibody” also does not satisfy the district court's construction of “antibody” because a bispecific antibody does not consist of two identical H chains and two identical L chains. Dependent claim 19 further limits claims 1 and 4 by claiming that the “antibody is a humanized antibody,” which again does not fall within the district court's construction of “antibody.”
The district court's construction which excludes these explicitly claimed embodiments is inconsistent with the plain language of the claims. See Intellectual Ventures I LLC v. T-Mobile USA, Inc., 902 F.3d 1372, 1378 (Fed. Cir. 2018); see also Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358, 1362 (Fed. Cir. 2008) (rejecting a construction that would “render several dependent claims meaningless”).
The district court rejected this inconsistency, suggesting that the proper result here is “invalidation of the inconsistent claims rather than an expansion of the independent claims.” Baxalta, 2018 WL 6304351, at *11. Similarly, Genentech invites us to assume that the examiner simply overlooked at least these dependent claim limitations when he allowed the claims. Genentech argues that because the patent defines the term “antibody” in column 5, we should invalidate all dependent claims which would not be consistent with that definition such as claims 4 and 19. We do not agree. The plain language of these dependent claims weighs heavily in favor of adopting Baxalta's broader claim construction. And as in Intellectual Ventures I, we reject the district court's construction which renders dependent claims invalid. 902 F.3d at 1378.
ii. The written description of the ’590 patent
Under the heading “Antibodies and Antibody Derivatives,” the patentee explains:
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).
The district court determined that this portion of the written description defined the term “antibody.” While this is a plausible reading of the excerpt in isolation, claim construction requires that we “consider the specification as a whole, and [ ] read all portions of the written description, if possible, in a manner that renders the patent internally consistent.” Budde v. Harley-Davidson, Inc., 250 F.3d 1369, 1379–80 (Fed. Cir. 2001). When considered in the context of the remainder of the written description and the claims, we read the excerpt in column 5 as a generalized introduction to antibodies rather than as a definitional statement. We also note that these general statements do not include terms we have held to be limiting in other contexts such as “the present invention includes … ” or “the present invention is … ” or “all embodiments of the present invention are . … ” Luminara Worldwide, LLC v. Liown Elecs. Co., 814 F.3d 1343, 1353 (Fed. Cir. 2016).
Beyond this general description in column 5, the written description provides specific disclosures regarding bispecific, chimeric, and humanized antibodies and methods of production thereof, all of which do not comport with the district court's construction. For example, the written description explains that “[t]he inventive antibodies and antibody derivatives and organic compounds derived there from comprise … bispecific antibodies.” ’590 patent at 6:1–6. Both parties agree “bispecific antibodies” do not consist of two identical H chains and two identical L chains and thus fall outside the district court's construction. The written description further discloses that “antibodies and antibody derivatives may also include … ‘technically modified antibodies’ such as … chimeric or humanized antibodies . … In these technically modified antibodies, e.g., a part or parts of the light and/or heavy chain may be substituted.” ’590 patent at 6:15–24. And the written description explains that “[t]he antibodies of the present invention can be prepared by methods known from the prior art, e.g. by conventional hybridoma techniques, or by means of phage display gene libraries, immunoglobulin chain shuffling or humanizing techniques.” Id. at 7:65–8:3 (emphasis added). The written description, therefore, discloses synthetic techniques for preparing antibodies such as humanized or chimeric antibodies, which are inconsistent with the district court's claim construction requirement that the antibody “only binds to the antigen that induced its synthesis or very similar antigens.” Recognizing that these disclosed techniques for preparing the claimed antibodies would result in antibodies excluded by the district court's construction, Genentech's response was “I hesitate to say that that's a typo.” Baxalta, No. 19-1527 Oral Arg. at 37:02–38:26.
Genentech does not dispute that the written description discloses antibodies that fall outside the district court's construction, but rather argues that “there is no legal problem with a claim construction that excludes certain disclosed embodiments, where the specification otherwise supports that construction.” To adopt Genentech's construction, we would need to invalidate several dependent claims, which according to Genentech, the examiner overlooked in allowing, and to conclude that preparation techniques for the claimed antibodies included in the written description were disclosed in error. As discussed, column 5 is not definitional, and the remainder of the written description and claims do not support the district court's construction. The claim construction excluding these disclosed and claimed embodiments is therefore incorrect.
The parties agree that Baxalta's and Genentech's proposed constructions are recognized meanings of “antibody.” We hold that the district court erred in selecting the narrower construction, which is inconsistent with the written description and the plain language of the claim. Consistent with the claims and the written description, we instead construe “antibody” as “an immunoglobulin molecule having a specific amino acid sequence comprising two heavy chains (H chains) and two light chains (L chains).”
B. “Antibody fragment”
[omitted]
III. Conclusion
We have considered the parties' remaining arguments and do not find them persuasive. Because the district court erred in construing the terms “antibody” and “antibody fragment” and entered judgment of non-infringement based on its erroneous constructions, we vacate and remand for further proceedings consistent with the correct constructions of the terms.
VACATED AND REMANDED