Baxalta Incorporated et al v. Genentech, Inc. et al
Filing
330
OPINION AND ORDER. Signed by Judge Timothy Belcher Dyk on 12/3/2018. (nmg)
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE
BAXALTA INCORPORATED and
BAXALTA GMBH.
Plaintiffs,
v.
Civil Action No. 17-509-TBD
GENENTECH, INC. and CHUGAI
PHARMACEUTICAL CO., LTD.,
Defendants.
OPINION & ORDER
On May 4,2017. Ba.xalta 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”).’
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 ACE9IO, 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, antiboth’ fragment, bispecic antibody,
isolated, binds Factor IX or Factor IXa and increases, and increases the procoagidant activity of
Factor LYa.
Baxalta also initially asserted infringement of claim 15 of the ‘590 patent, but dropped this
claim during the Markman hearing. See First Am. Compl. 9, ECF No. 239; Markman Yr.
235:11—13, ECF No. 320.
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 antibodyfragment.
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
1.
PROCEDURAL HISTORY
On May 4, 2017, Baxalta filed its complaint alleging infringement of the ‘590 patent.
Compl.
fi 37—5 1,
ECF No. 1. On June 30, Genentech answered, denying Baxalta’s allegations
and counterclaiming for declaratory judgment of noninfringement and invalidity. Answer &
Countercl.
¶J 37—5 1,
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
2
Baxalta initially presented Dr. Anthony A. Kossiakoffs declaration in support of its claim
construction positions. See Kossiakoff Reb. Dccl., ECF No. 126. I postponed the date of this
Markman hearing three times and made clear to the parties that the hearing was their opportunity
to present expert witness testimony in support of their claim construction positions. See May 14,
2018 Minute Entry; Sept. 12, 2018 Oral Order; Sept. 25, 2018 Oral Order. Nonetheless, Baxalta
failed to offer testimony from Dr. Kossiakoff at the Markman hearing, and Genentech
accordingly objected to reliance on Dr. Kossiakoffs declaration. Markman Tr. 46:1—22, 53:12—
54:11. I sustained this objection and do not consider Dr. Kossiakoffs declaration for the
purposes of claim construction. Markman Tr. 54:12—55:3.
As noted, the Kossiakoff
Declaration, even if considered, would make no difference in the outcome.
2
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: anilbody. antibody fragment, bispeeffic antibody, isolated, binds Factor LI or
Factor IXa and increases, and increases the procoagidant activity of Factor LIa. All these terms
appear in claims I 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 chimedc antibody, a humanized antibody, a single chain antibody,
a bispecific antibody, a diabody, and di-, oligo- or multimers thereof
‘590 patent. col. 101, II. 43—45. 5 1—56 (underlining added).3
Claims 17 and 19 of the ‘590 patent, also at issue here, are as follows:
17. A method of obtaining an antibody that interacts with Factor IX or Factor IXa
and increases the procoagulant activity of Factor IXa, comprising the steps
of:
Immunizing an immunocompetent mouse with an antigen selected from the
group consisting of FIX, FlXaa, FIXa or fragments thereof,
isolating spleen cells of the immunized mouse,
producing hybridoma cells,
screening the hybridoma cell supematants for an increase in the procoagulant
activity of Factor IXa, isolating and purifying the antibody from a
supematant from the hybridoma cells which exhibit an increase in the
procoagulant activity of Factor IXa.
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 DecI.
¶ 22,
ECF No. 112; accord Almagro DecI.
¶
33, ECF No. 49.
Structurally,
antibodies are Y-shaped, with two arms that are connected by disulfide bonds. Almagro DecI,
34; Strohl DecI.
¶ 22.
¶
Each arm of the Y contains two polypeptide chains known as the heavy
(“H”) chain and the light (“L”) chain.4 Almagro DecI.
¶
34; Strohl DecI.
¶ 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 DecI.
¶
34; Strohl DecI.
portions of the antibody are made up of constant regions. Almagro DecI.
¶ 23.
¶ 34;
The remaining
Strohl Decl.
¶ 23.
Within each variable domain, the antigen binding sequence of the antibody is divided into
three regions called complementarity-determining regions (“CDRs”).
Strohl DecI.
¶ 25.
Almagro Decl.
35;
The three CDRs in each variable region—designated CDRI, CDR2, and
CDR3—determine the binding specificity of the antibody. Almagro DecI.
¶ 25.
¶
¶
35; Strohl Dccl.
The CDR3 region of the heavy chain variable domain is “primarily responsible for antigen
binding specificity.” Strohl Dccl.
¶ 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
19. The antibody or antibody fragment according to claim 4, wherein the antibody
is a humanized antibody.
‘590 patent, col. 103, I. 3—col. 104, I. 6.
Though the basic unit of an antibody is a Y-shaped structure with two L chains and two H
chains, certain types of antibodies are more complex and can have up to ten light and ten heavy
chains. Markman Tr. 67:4—2 1.
‘
4
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 DecI.
¶ 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. lnj. Order 3—4. Relevant here is one particular step of
the clotting cascade involving Factor Villa and Factor lXa, 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 Aledon DecI.
DecI.
¶ 42.
C
14; Sheehan
This hinders the coagulation cascade by limiting the body’s ability to activate Factor
X. Aledort Dccl.
¶
14; Sheehan Decl.
C
42.
Genentech’s drug. Hemlibra, is directed to this step of the coagulation cascade and
functions by replacing Factor VIlla. See KHshnaswamy Dccl.
61. ECF No. 47. Kemlibra does
not have both identical light and identical heavy chains. See Strohl Dccl. a 38, 53; see also
Krishnaswamy Dccl.
1 55.
60. It is a bispecific antibody. The parties agree that in this patent a
bispecifle azitibody 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 DecI.
¶ 55.
60; Strohl DecI.
¶ 53.
By
During the Markman hearing, Dr. Almagro testified that “there were some examples [of
bispecific antibodies] before 1999 with identical light chains and identical heavy chains.”
Markman Tr. 109:16—18, ECF No. 320. Nonetheless, the parties have agreed that the bispecific
antibodies in the ‘590 patent are outside the scope of the column 5 definition of antibody. Id.
108:11—15, 109:19—110:8 (Almagro testimony).
5
doing so, Hemlibra allows Factor IX to activate Factor X. See Krishnaswamy Dccl.
¶ 61,
Strohl
DecI. ¶J 178—79.
ANALYSIS
I. 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 immunogiobulin 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. In].
Yr. 9:15—24, ECF No. 214—15; Markman Yr. 109:23—110:8. Hemlibra is not an antibody under
Genentech’s definition.
a.
The Meaning of the Tern, Anti body in the Patent as Originally Drafled
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
6
A secondary dispute is whether an antibody must bind only to an antigen that induced its
synthesis or very similar antigens. While the broader definition of antibody would not imply
such a requirement, I find that, since the column 5 definition includes this limitation, it is part of
the definition of the term antibody in the claims. See ‘590 patent, col. 5, II. 56—60. It is not clear
that this makes any difference with respect to infringement or invalidity.
6
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. lnj. 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 DecI.
¶ 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 [pjatent.” Strohl Cl. Const. Dccl. ¶JJ4l42, ECFNo. 161; accord itt, ¶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., lilMuNoLooY 72 (5th ed. 1998),
Strohl Dccl. Ex. F, ECF No. 112-6. And the Harlow and Lane reference says that “[e]ach Y
7
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 DecI. 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. Strohi’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, 11. 56—63. The Federal Circuit has recognized that use of the verb “is” may
“signify that a patentee is serving as its own lexicographer.” Sinorgchern Co. v. Int’l Trade
Corn,,,
‘ii,
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
‘
Even the expert declaration from Dr. Kossiakoff that Baxalta initially offered in support of its
construction, but which I have excluded from consideration, does not elaborate on why a person
skilled in the art would have understood the term antibody to have the broader meaning offered
by Baxalta. See KossiakoffReb. DecI. ¶J 21—52. Dr. Kossiakoffs only statement to this effect
is that “a POSITA reviewing the intrinsic record would have understood that the term ‘antibody’
has a plain and ordinary meaning in the art and would not need to be construed,” but that “to the
extent a construction is required, it is my opinion that Baxalta’s straightforward construction
should be adopted.” Id. ¶ 22.
8
term “is.” Here, the specification unequivocally states what “[a]ntibodies are.” ‘590 patent, col.
5. II. 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, I. 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, II. 1—5; Id. col. 7, 11. 32—35;
Id. col. 101, II. 5 1—56 (claim 4). Baxalta also points to the inclusion of 1gM antibodies and IgA
antibodies in claims 3 and 20 as well as throughout the specification. ‘590 patent, col. 6, II. 35—
38; Id. col, 12, II. 25—26; Id. col. 14,1. 22—col. 15, 1.4 (Example 4); Id. col. 30,1. 1 1—col. 31, I. 10
(Example 13); Id col. 101, II. 49—50 (claim 3); Id. col. 104, II. 6—7 (claim 20).
1gM 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. Bixalta 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 tent
antibody derivative.
9
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. Echosrar 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 clew lexicography
(alterations and emphasis in original) (quoting C. R. Ban!,
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. lnj. Yr. 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
10
“derived” from other antibodies.8 Almagro Dee!.
¶ 54
n. 5,
¶ 87
n. I 7; 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 bispeciuic 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 term9: (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. Ii. 3—7; (2) in the body of Example ii, where the patent includes in a list of
examples of antibody derivatives “scFv, Fab, etc.,” id. col. 20, I. 36; and (3) again in Example
13, where the patent refers to “antibody derivatives such as Fab, F(ab)2. scFv, etc.,” id. cot. 30, It.
16—17. See also MarkmanTr. 13:19—15:6.
These uses make clear that Fab. F(ab)2, and scFv are all antibody derivatives. As Dr.
Almagro and Dr. Strohi 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
In a similar vein, Dr. Strohl testified that “a chimeric antibody would be derived and be a
derivative.” Markman Tr. 172:8—9.
The specification also provides that “antibody derivatives may
be prepared by means of
methods known from the prior art, e.g. by molecular modeling.” ‘590 patent, col. 9, 1!. 5—7. This
use of antibody derivative, however, does not assist in understanding the tent.
...
11
such. Markman Tr. at 117:7—14 (Dr. Almagro), 155:19—23 (Dr. Strohi). 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[J 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.
153:11 (Dr. Slrohl); accord Strohl DecI.
¶ 32
Markman Tr. 152:25—
& 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. DecI.
4; accord Almagro Deel.
¶
¶ 33
& Fig.
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 the dependent claims and the column 5 definition of
antibody.
12
b.
The Prosecution History’s Exclusion of Antibody Derivatives Confinns the
Spec jflcation ‘s Definition of Antibody
During prosecution the Examiner found various categories of derivatives other than
antibody fragments not enabled.
The applicants disclaimed antibody derivatives including
bispecific antibodies, except antibody fragments.
Initially, the patent specification and the accompanying claims repeatedly referred to
“antibodies and antibody derivatives”; the patent did not refer to “antibody fragments.” See U.S.
Patent App. No. 09/661,992, Strohl DecI. Ex. D, ECF No. 112-4. In an office action dated
January 2, 2004, the Examiner rejected claims 1—14, 16, 18—19, 23, and 27 of the ‘590 patent for
lack of enablement. Jan. 2, 2004 Rejection, Strohl DecI. Ex. K, at 4, ECF No. 112-11. The
Examiner again rejected these claims for near-identical reasons on September 13, 2004. Sept.
13, 2004 Rejection, Strohl DecI. Ex. M, at 2—3, ECF No. 112-13. To respond to those rejections,
the term antibody derivatives was deleted by an amendment to the claims, and the term antibody
fragment was added. Compare U.S. Patent App. No. 09/661,992 with ‘590 patent.
It is useful to describe how these amendments came about. Considering the prosecution
history as a whole, save for the failure to conform the language of certain dependent claims
(discussed below), it is apparent that the applicants and the Examiner continued to view the term
antibody as having its original meaning from the specification, but that antibody derivatives
(except antibody fragments) were now excluded from the scope of the claims. As noted, during
prosecution, the claims were initially rejected by the Examiner as not enabled. Jan. 2, 2004
Rejection, at 4. The Examiner found enabled certain antibody derivatives “wherein the variable
region of said antibody derivative comprises” specific portions of certain amino acid sequences
(SEQ ID NOs 82, 84, and 86) disclosed in the patent. Id. But the Examiner found not enabled
antibody derivatives comprising different portions of the same amino acid sequences.
13
Id.
Among the antibody derivatives the Examiner found not enabled were those comprising
“chimeric antibodies, humanized antibodies, single chain antibodies, bispecific antibodies,
diabodies and di-, oligo- or multimers thereof in claim 4.” Id. Based on this lack of enablement.
the claims were rejected.
Dr. Strohl explained during the Markman hearing that the portions of SEQ ID NOs 82,
84, and 86
found enabled by the Examiner comprised excised portions of already-existing
antibodies as defined in the specification, that is, antibody fragments. See Markman Tr. 200:5—
201:22; Id. at 203:5—205:16. The portions found not enabled were engineered artificial linker
sequences—i.e., human-engineered, synthetic peptides. Id. 203:5—205:16; see also Strohl DecI.
¶ 30 (discussing the composition of scFvs).
The applicants responded to the Examiner’s rejection on July 2, 2004, and argued that the
disclosed “antibodies and antibody derivatives” were all enabled because the specification
“provides extensive discussion regarding methods of preparing claimed antibodies” and
“provides the complete sequence scFvs, variable domains and CDRs, and provides guidance on
what regions can be mutated.” July 2, 2004 Amendment & Remarks, Strohl Decl. Ex. L, at 12,
ECF No. 112-12.
On September 13, 2004, the Examiner again rejected the same claims for lack of
enablement in an almost identical manner.
Sept. 13, 2004 Rejection, at 2.
The primary
difference between the first and second rejection was that the Examiner now referred to the
enabled portions of the scFvs embodied by SEQ ID NOs 82, 84, and 86 as “antibody fragments”
rather than “antibody derivatives.”
Id.
The Examiner maintained his rejection of antibody
derh’atives comprising “chimeric antibodies, humanized antibodies, single chain antibodies,
bispecific antibodies, diabodies and di-, oligo- or multimers thereof in claim 4.” Id.
14
On October 16, 2004, the Examiner conducted a telephonic interview with the applicant.
Oct. 16, 2004 Interview Summary. Strohi Dccl. Ex. N, ECF No. F 12-14. During that interview
the Examiner “suggested that the claims be amended to recite antibody fragment thereof to
substitute antibody derivative.” Id. at 1. Thereafter, the applicants amended their claims to
implement the changes proposed in the interview by, among other things, revising the claims to
recite antibody fragments instead of antibody derivatives. Dec. 13, 2004 Amendment, Strohi
DecI. Ex. 0. ECFNo. 112-15.
Thus, antibody derivatives except for antibody fragments were disclaimed from the scope
of the claims. As was made clear by the January 2 and September 13 rejections, the Examiner
found enabled antibody fragments, that is, fragments of antibodies as defined in the specification.
By way of example, in the case of the scFvs described by SEQ ID NOs 82, 84, and 86, the
Examiner found enabled only the pieces of those scFvs that are naturally occurring—i.e., the V1.1
and VL regions—and found not enabled the pieces of scFvs that contained an engineered
peptide—i.e.. the linker sequence.
Moreover, the Examiner maintained his rejection of
derivatives comprising, for example, chimeric antibodies, humanized antibodies, and bispecific
antibodies. As is the case with an entire scFv. each of these structures, while possibly derived
from an antibody as detned in column 5 of the specification, would have been understood, in
view of the ‘590 patent, to involve some form of alteration to a naturally occurring antibody. See
Markman 167:10—168:9 (Dr. StrohD; Prelim. Inj. Tr. 276:10—11 (Dr. Krishnaswamy testifying
that “[a]nything you do to the antibody creates a derivative”). Thus, antibody derivatives as
originally understood—i.e., everything derived from an antibody other than antibody
fragments—were disclaimed from the claims, and the narrower antibody fragments were claimed
15
instead.
On the face of the prosecution history, it therefore appears that the disclaimer of
antibody derivatives included b/specific antibodies.
Not surprisingly, the parties agree that antibody derivatives were disclaimed from the
scope of the ‘590 patent. Markman Tr. 10:4—21 (parties agreeing with the court that there is
“agreement that there was a disclaimer in the prosecution as to derivatives, but there’s no
agreement as to what a derivative is”). But they disagree on what that term encompasses. Id. At
the preliminary injunction stage. Baxalta was unable to provide any meaningful guidance as to
what, in fact, was disclaimed. Prelim. Inj. Tr. 32:2—23, 33:23—35:15. During the preliminary
injunction hearing, Baxalta stated only that while derivatives may very well have been
disclaimed during prosecution, the specification and prosecution history “tell[] us very little of
the meaning.” Id. at 33:23—34:5.
At the Markman hearing, Baxalta finally addressed the issue directly, arguing that the
disclaimer was very limited and that only two minor embodiments were surrendered, a
suggestion not appearing in its earlier briefing. Ba.xalta’s arguments related to two amendments
made during prosecution.
The first amendment related to original claims 5 and 6, which read:
5. An antibody derivative according to claim 1, wherein said antibody derivative
comprises a complement [sic] determining region (CDR) peptide.
6. An antibody derivative according to claim 5, wherein said CDR peptide is a
CDR3 peptide.
U.S. Patent App. No. 09/661,992, at 62. The Examiner rejected these claims as not enabled
because the “specification provides no direction or guidance regarding how to produce such
antibodies.” Jan. 2, 2004 Rejection, at 5. The Examiner explained that because “each of the
heavy and light chain CDRs are critical in maintaining the antigen binding specificity and
16
affinity which is characteristic of the parent immunoglobulin” “[ijt is unlikely that antibody
derivatives as defined by the claims which may contain less than the full complement of
CDRs
.
.
.
have the required binding function.” Id. In response, and following an interview with
the Examiner in which he requested that the applicants add two dependent claims regarding the
CDR3 peptide, Oct. 16, 2004 Interview Summary, the applicants deleted original claims 5 and 6,
and added current claims 21 and 22, which are as follows:
21. The antibody or antibody fragment of claim I, wherein the antibody fragment
comprises a CDR3 peptide.
22. The antibody or antibody fragment of claim I, wherein the antibody fragment
is a CDR3 peptide.
Dec. 13, 2004 Amendment, at 7 (numbered 30. and 31. in amendment); ‘590 patent. col. 104,11.
9—12.
At the Markman hearing Baxalta was unable to explain why these amendments defined
the scope of the disclaimer of antibody derivatives. Earlier the Examiner had expressed concern
that the original claims’ reference to CDRI and CDR2 peptides was not enabled, and Baxalta
opined that “the examiner wanted to be assured that that which is critical to antigen binding, the
CDR3, was included in the claim,” Markman Tr. at 36:5—Il.
But this sheds no light on the
meaning of the term antibody derivative or the scope of the disclaimer. All three binding sites
(CDRI, CDR2, and CDR3) exist in antibodies as defined in the specification and under the
broader definition of antibody.
Referring specifically to the CDR3 binding sites in two
dependent claims is perfectly consistent with the narrower definition of antibody. In short, while
Baxalta agrees that there was a disclaimer of antibody derivatives it is unable to show that the
term was somehow limited by, or defined by, the addition of the reference to the CDR3 binding
site in the dependent claim.
17
The second amendment on which Baxalta focused was that made to original claim 7,
which provided
7. An antibody derivative according to claim 6, wherein said CDR3 peptide
comprises an amino acid sequence selected from the group consisting of:
Tyr-Gly-Asn-Ser-Pro-Lys-Gly-Phc-Ala-Tyr;
Cys-X-X-Tyr-Gly-Asn-Ser-Pro-Lys-GlyPhe-A1a-Tyr-X-X-Cys
Wherein
X may be any desired amino acid;
Tyr-Gly-Asn-Ser-Pro-Lys-Gly-Phe-Ala-Tyr;
Asp-Gly-Gly-His-Gly-Tyr-Gly-Ser-Ser-Phe-Asp-Tyr; and
Phe-Arg-Asn-Arg-Gly-Met-Thr-Ala-Leu-Leu-Lys-Val-Ser-Ser-Cys-Asp.
Strohl Deci. Ex. D, at 2—3. The claim language on its face does not identify a specific amino
acid, or set of amino acids, that can be substituted for the variable ‘cx,” and provides only that “X
may be any desired amino acid.” Id. The Examiner rejected this claim as not enabled because
he reasoned that “it is unpredictable if any functional activity will be shared by two antibodies
having less than 100% identity over their CDR3 region.” Jan. 2, 2004 Rejection, at 5; accord
Sept. 13, 2004 Rejection, at 3. Again following an interview with the Examiner in which “the
antibody derivative and CDR3 peptide” were discussed, Oct. 16, 2004 Interview Summary, the
applicants amended claim 7 (now claim 5) to address the Examiner’s concern with variability in
the CDR3. Claim 5 now provides
5. A CDR3 peptide of the antibody or antibody fragment according to claim 1
consisting of an amino acid sequence selected from the group consisting of:
Tyr-GIy-Asn-Ser-Pro-Lys-Gly-Phe-AIa-Tyr (SEQ ID NO:5); and
Asp-Gly-Gly-His-Gly-Tyr-Gly-Ser-Ser-Phe-Asp-Tyr (SEQ ID NO:6).
Dec. 13, 2004 Amendment, at 4—5; ‘590 patent, col. 101, 11. 57—63.
During the Markman hearing Baxalta argued that this amendment disclaimed “antibody
derivatives comprising CDR3 peptides with variable or random amino acids as originally
claimed in 7.”
Markman Tr. at 36:21—37:9.
But again, as was the case with the other
amendment, this amendment sheds no light on the meaning of the disclaimed antibody
18
derivatives. It is entirely possible that there are antibodies and antibody fragments, as those
terms are defined by the court, that contain a CDR3 region comprising what was claimed in both
original claim 7 and amended claim 7.
The specification and amended claims are perfectly
consistent with the specification’s definition of antibody.
Given Baxalta’s failure to offer a plausible alternative definition of the disclaimer, the
court concludes that the obvious definition—a disclaimer of antibodies altered in some
significant way—should govern.
c.
The Language of tire Dependent Claims as Issued Does Not Require That the Term
Antibodies Standing Alone be Defined to Include Bispecj/lc Antibodies
Baxalta’s primary argument is that adopting the narrow construction of antibodies is
impermissible because, after the reference to antibody derivatives was deleted during
prosecution, certain dependent claims covered structures that would be excluded under the
narrower construction of the term antibody. In other words, Baxalta argues that including such
dependent claims after the amendment (which deleted antibody derivatives from the claims)
effectively redefines the term antibody. The language of the allowed claims is set forth above.
Baxalta points, for example, to dependent claim 4, which claims “[ajn antibody or antibody
fragment according to claim 1, wherein said antibody or antibody fragment is selected from a
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, 11. 51—56. Baxalta contends that under the narrower construction of antibody,
the humanized antibodies, chimeric antibodies, and bispecific antibodies of claims 4 and 19
would be excluded from the scope of the claims, as would the 1gM and IgA antibodies of claims
3 and 20, and the artificial linker sequences of claims 7, 9, and 11. Baxalta
Op. Br. 4—5; Baxalta
Supp. Ltr. 1—3, ECF No. 202; Markman Tr. at 40:8—45:2 (citing Strohl Dep. Tr., Dadush DecI.
19
Ex. I, ECF. No. 234-2 at 99:23—100:13; Prelim. lnj. Tr. 61:4—7). Baxalta insists that “[lIt is
axiomatic that a dependent claim cannot be broader than the claim from which it depends.”
Alcon Research, Lid. v.Apotex Inc.. 687 F.3d 1362, 1367 (Fed. Cir. 2012); see also Baxalta
Op.
Br. 4—5; Baxalta Supp. Ltr. 1—3. It reasons that the independent claims, such as claim 1, must
encompass bispec(fic antibodies and that the term antibody must therefore include bispeqfic
antibodies.
I do not find Baxalta’s argument persuasive.
To be sure. Bixalta is correct, and
Genentech agrees, that at least dependent claims 4 and 19 are inconsistent with the narrower
definition of the term antibody)0 See Markman Tr. 143:2—19 (Genentech admission that claims
4 and 19’’ are inconsistent with the column 5 definition of antibody). The Federal Circuit has
recognized that adopting a construction that excludes dependent claims from the patent scope is
disfavored.
See AK Steel Corp. v. Sollac & Ugine, 344 F.3d 1234, 1242 (Fed. Cir. 2003)
(“Under the doctrine of claim differentiation, dependent claims are presumed to be of narrower
scope than the independent claims from which they depend.”). But the court has also made clear
that this rule of construction does not govern where the independent claims on their face are of
more limited scope. See Enw Biochem Inc v. Applera Corp.. 780 F.3d 1149, 1156—57 (Fed. Cir.
Other dependent claims alleged by Baxalta to be inconsistent with the narrower definition of
antibody may well be consistent with that definition. For example, even though 1gM and IgA
antibodies can have more than two identical light chains and two identical heavy chains, they can
also be understood as being composed of several monomers that have the structure identified in
column 5. See Markman Tr. 112:15—23 (Dr. Almagro agreeing that “an 1gM is a pentamer of a
module that has two identical heavy chains and two identical light chains” and “that module
meets the definition in column 5”); id. 114:17—23 (Dr. Almagro admitting that “some lgMs
circulate as monomers in serum”); id. 155:24—159:11 (Dr. Strohl confirming that 1gM and IgA
antibodies sometimes contain two identical light chains and two identical heavy chains).
It is apparent from context that Genentech’s counsel misspoke when he named claim 9, rather
than claim 19, as being inconsistent with the column 5 definition.
20
2015) (claim differentiation rejected as reason to broaden scope of independent claim contrary to
its plain meaning). That is the case here, for the reasons disclosed above.
In such situations, where the scope of the independent claims is clear, the Federal Circuit
has held that the failure of a patentee to conform dependent claims to the scope of the
independent claims results in invalidation of the inconsistent claims rather than an expansion of
the independent claim. See Regents Univ of Cal. v. Dakocytomarion Cat, Inc., 517 F.3d 1364,
1375—76 (Fed. Cir. 2008); Seachange Int’l, Inc. v. C-COR, Inc.. 413 F.3d 1361, 1369—75 (Fed.
Cir. 2005); N. Am. Vaccine, Inc. v. Am. qvanamid Co., 7 F.3d 1571, 1577—78 (Fed. Cir. 1993).
For instance, in Dakocytoniarion. the Federal Circuit rejected the appellants’ argument that the
district court’s claim construction, which excluded repetitive sequences, was “incorrect in light
of certain dependent claims requir[ing] inclusion of repetitive sequences.” 517 F.3d at 1375.
The court explained that, although there exists a presumption that dependent claims have
narrower scope than the independent claims from which they depend, “[p]resumptions are
rebuttable.” Id. Thus, “while it is true that dependent claims can aid in interpreting the scope of
claims from which they depend, they are only an aid to interpretation and are not conclusive.”
Id. (quoting N Am. Vaccine, 7 F.3d at 1577 (brackets omitted)). The Federal Circuit emphasized
that a contrary construction “dictated by the written description or the prosecution history” could
overcome the presumption. 1! (quoting Seachange, 413 F.3d at 1369).
I conclude that the presumption that the independent claim here is broader than the
dependent claim has been rebutted. The retention of inconsistent language in the dependent
claims does not suggest that the interpretation of independent claims should depart from the
original meaning of the term antibody as provided in column 5 of the ‘590 patent.
Dakocytomation, 517 F.3d at 1375—76 (“Here
21
.
.
.
See
the prosecution history overcomes the
presumption; the correct construction of ‘heterogeneous mixture’ is one that excludes repetitive
sequences, notwithstanding the presence of certain dependent claims that do not exclude them.”);
Seachange, 413 F.3d at 1375 (“The presumption attendant to claim differentiation doctrine is
rebutted. The phrase ‘network for data communications’ is limited to networks in which every
processor system is connected to every other processor system via direct, point-to-point, twoway channel interconnections.”); N. Am. Vaccine, 7 F.3d at 1577—78 (rejecting construction of
independent claim based on scope of dependent claims because “[t]he dependent claim tail
cannot wag the independent claim dog”). While the result of the court’s construction is that
certain embodiments in the specification are no longer covered by the claims, this is not
uncommon in disclaimer situations.
Finally, even with the narrowing amendment to delete antibody derivative, the narrower
definition of antibody does not exclude any disclosed embodiments actually made by the
inventors from the scope of the claims. As Genentech established through its expert, Dr. Strohi’s
testimony, which I credit, and through cross-examination of Dr. Almagro, the patent does not
disclose that the inventors of the ‘590 patent ever made a bispecific antibody, a humanized
antibody, or a chimeric antibody.
Markman Tr. at 110:12—20 (Dr. Almagro regarding
humanized and bispecific antibodies); id. at 179:23—180:25 (Dr. Strohl testifying that Example
13 of the ‘590 patent is prophetic and therefore does not show that the inventors created a
chimeric antibody within the scope of the claims). Rather, as Dr. Almagro admitted, “all of the
antibodies that Baxalta made in performing the experiments set forth in [the ‘590] patent would
fall within the definition of column 5.” Markman Tr. 105:15—21.
Based on the foregoing, I conclude that the term antibody means an immunoglobulin
molecule, having a specific amino acid sequence that only binds to the antigen that induced its
22
synthesis or very similar antigens, consisting of two identical heavy chains (H chains) and two
identical light chains (L chains). Baxalta concedes that Hemlibra does not infringe the ‘590
patent under the court’s construction of antibody. Prelim. Inj. Tr. 9:15—24.
2. antibody fragment
Baxalta’s proposed construction: A portion of a molecule having a specific amino acid
sequence comprising two heavy chains (H chains) and two light chains (L chains).
Genentech’s proposed construction: A fragment of an antibody which partially or completely
lacks the constant region; the term “antibody fragment” excludes all other forms of antibody
derivatives.
Court’s construction: A fragment of an antibody which partially or completely lacks the
constant region; the term “antibody fragment” excludes bispecific antibodies.
Though substitution of the word fragments for derivatives preserved the applicant’s claim
to derivatives that are fragments, there is no assertion here that the term fragments included
bispecific antibodies, or expanded the defined meaning of the temi antibody. Nor is there any
contention that Hemlibra is a &agment.
“[T]here is no dispute between the parties that
[Hemlibra]. the accused product, is not a fragment. It’s a full-length antibody.” Prelim. lnj. Tr.
79:10—15;
accord
Markman Tr. 122:13—21 (Dr. Almagro agreeing that Hemlibra “is a bispeeific
antibody,” “not a Fab” and “not a fragment”). And as Bixalta conceded during the preliminary
injunction hearing, “the inclusion of the word ‘fragment’ wouldn’t expand the meaning of the
term ‘antibody.” Prelim. Inj. Tr. 35:23—36:2.
Baxalta argues that under the court’s definition of antibody any piece of an antibody can
be considered an antibody fragment. Genentech argues instead that the term antibody fragment
includes only “the sort of canonical antibody fragments that [a person of skilli talks about when
[that person] talks about a fragment.”
Markman Tr. 11:11—12.
23
In light of the prosecution
histonc Genentech contends that this sort of antibody fragment comprises a portion of an
antibody which partially or completely lacks its constant region.
The specification expressly states that “antibody fragments
.
.
.
partially or completely
lack the constant region.” ‘590 patent, col. 6, II. 20—2 1. The examples of fragments listed in the
specification—”Fv, Fab, Fab’ [andj F(ab)’2”—all support this limitation. Id.; see also supra at
11—12.
In summary, the court rejects Baxalta’s proposed construction of antibody fragment. The
Baxalta definition is unduly broad because it would include something as small as three amino
acids, which Dr. Almagro agreed would not be understood by a person skilled in the art to
constitute an antibody fragment. When asked if you “cut the last three amino acids off the
constant region” and ask an antibody scientist in 1993 whether that is an antibody fragment, Dr.
Almagro agreed that “[sjhe’d say ‘No, that’s three amino acids.” Markman Tr. 117:19—118:4.
Therefore, the court finds that antibody fragment comprises a fragment of an antibody
which partially or completely lacks the constant region; the term “antibody fragment” excludes
bispecific antibodies.
3. bispecjJlc antibody
Baxalta’s proposed construction: An antibody that is a macromolecular, heterobifunctional
cross-linker having two different binding specificities within one single molecule.
Genentech’s proposed construction; An antibody derivative that is an artificially engineered,
macromolecular. heterobifunctional cross-linker having two different binding specificities within
one single molecule; a bispecific antibody does not consist of two identical heavy chains and two
identical light chains.
Court’s construction: An artificially engineered, macromolecular, heterobiffinctional crosslinker having two different binding specificities within one single molecule; a bispecific antibody
does not consist of two identical heavy chains and two identical light chains.
24
The parties agree a bispeqfic antibody in the patent is a macromolecular.
heterobifunctional cross-linker having two binding specificities within one single molecule, and
does not consist of two identical heavy chains and two identical light chains.12 Markman Yr.
38:5—16. The court construes the term bispecflc antibody consistent with the parties’ agreement.
Therefore, a bispeci/Ic antibody is an artificially engineered, macromolecular, heterobifunctional
cross-linker having two different binding specificities within one single molecule; a bispecffic
antibody does not consist of two identical heavy chains and two identical light chains.
4. isolated
Baxalta’s proposed construction: Essentially free from other antibodies or antibody fragments
that do not bind Factor IX or Factor lXa.
Genentech’s proposed construction: Free of molecularly non-identical antibodies or antibody
fragments; all antibody molecules or antibody fragment molecules in the claimed composition
are identical.
Court’s construction: All antibody molecules or antibody fragment molecules in the claimed
composition have identical amino acid sequences except for any post-translational modifications.
Construction of isolated appears to be relevant to the question of patent validity. As to
the term isolated, the parties dispute the degree to which antibodies or antibody fragments that
are isolated must be identical.
The specification provides no apparent guidance as to the
meaning of the term. Isolated is only used twice in the body of the specification, and neither
reference illuminates what it means for an antibody or antibody fragment to be isolated. See
12
Although Dr. Almagro agreed that bispecific antibodies generally “don’t have two identical
heavy chains and two identical light chains,” he noted that “[tihere are some recent examples” to
the contrary. Markman Tr. 108:11—15. Genentech clarified, and Dr. Almagro confirmed, that
the recent examples Dr. Almagro referenced are bispecific antibodies developed by Genentech
that “in fact, have identical chains.” Id. 108:16—20. But the patent’s reference to bispecic
antibodies does not include these antibodies with identical chains.
25
‘590 patent, col. 32, 1. 37—38 (“clones were isolated”); Id. col. 32, II. 57—58 (“the gene of the
198/B 1 scFv was isolated from the plasmid”).
The prosecution history is also unhelpful. The Examiner added the term isolated to the
claims during prosecution but neither explained why the change was made, nor why the change
was necessary for allowance. See Dec. 21, 2004 Interview Summary, Cole DecI. Ex. 2, ECF No.
162-1; Notice of Allowance and Fees Due, U.S. Patent AppI. No. 09/661,992 (P.T.O. Dec. 29,
2004), ECF 202-1. Genentech argues that the term isolated was added to claim I of the ‘590
patent alongside the “inventors’ efforts to subclone mixed populations of hybridomas ‘to obtain
homogenous [sic] cell populations.” Genentech Op. Br. 14 (quoting ‘590 patent, col. 11, 1. 53).
Because such subcloning was performed until each hybridoma population “produce[d] the same
FIX/FIXa binding antibody,” ‘590 Patent. col. 12 1. 19—21, Genentech contends that antibodies
or antibody fragments which are isolated must be identical.
The sole expert testimony regarding this term comes from Genentech’s expert, Dr. Strohl.
Dr. Strohl explained that isolated in context of the specification’s description of dilution
subcloning would be understood to limit the antibodies and antibody fragments of claim 1 to
those that have an “identical amino acid sequence” but not necessarily an identical glycosylation
pattern. Strohi Claim Const. DecI.
¶J
124—27. Dr. Strohl also admitted that slight differences in
the amino acid sequences of antibodies may arise due to a process called post-translational
modification. Strohi Dep. Tr. 168:4—20, ECE No. 159-1.
Baxalta offers no testimony, evidence, or argument to the contrary. Based on the content
of the specification, Baxalta contends only that the term isolated cannot require identicalness
because such a construction ignores the contrast between the terms isolated and puried in the
claims and specification of the patent. Baxalta Resp. Br. 2—4, ECF No. 234 (citing ‘590 Patent,
26
ci. 17; id. col. 91!. 11—15; Id. col. 13,11. 16—58). Baxalta argues that because the patent discusses
“purifying” an antibody after it is “isolated.” antibodies that are isolated cannot all possibly be
identical, because were that the case, purification would be unnecessary. Id. I disagree with this
understanding of the patent. Purification is meaningful even under Genentech’s interpretation
since the reference to purification in the patent describes a solution containing antibodies and the
cells from which they are derived (hybridomas), and purification eliminates those cells from the
final product. See, e.g., ‘590 patent, col. 13, Il. 16—42.
Baxalta further points to a case, Morphosys AG v. Janssen Biotech, Inc., No. 16-221 -LPS,
2017 WL 4769368, at *4 (D. Del. Oct. 23, 2017), in which isolated was construed to mean
“essentially free from antibodies that do not bind to CD38.”
The court’s construction in
Aforphosys is not relevant, as the case dealt with an entirely different patent. See Monsanto Co.
v Bayer Bioscience N. V. 363 F.3d 1235, 1244 (Fed. Cir. 2004) (stating that “similar terms can
have different meanings in different patents depending on the specifics of each patent”).
Thus. Genentech’s construction most clearly corresponds to how isolated was used in the
patent, taking into account the caveats raised by Dr. Strohl regarding glycosylation and posttranslational modification. Accordingly, I find that the term isolated requires that all antibody
molecules or antibody fragment molecules in the claimed composition have identical amino acid
sequences except for any post-translational modifications.
5. binds Factor IX or Factor IXa and increases
Baxalta’s proposed construction: “and” has its plain and ordinary meaning.
Genenteeh’s proposed construction: The increase in procoagulant activity of Factor IXa is
caused only by the binding of the antibody or antibody fragment to Factor IX/IXa.
Court’s construction:
procoagulant activity.
Binding to Factor IX need not be the sole cause of the increase in
27
This court’s construction of binds Factor IX or Factor IXa and increases appears to be
relevant to infringement.
to this term, the parties dispute only the degree of causation
required between the binding of the inventive antibodies or antibody fragments to Factor IX!JXa
and the resultant increase in procoagulant activity.
Genentech contends that the increase in
procoagulant activity must be caused only by the binding of the inventive antibodies or antibody
fragments with Factor IX/IXa. Genentech
Op.
Br. 17—19. Baxalta. on the other hand, argues
that sole causation is not required. Ba.xalta Op. Br. at 14—15.
Geneniech cites various portions of the specification in support of its construction. The
abstract provides “[am
antibody or antibody derivative against factor IX/activated factor IX
(FIXa) which increases the procoagulant activity of FIXa.” ‘590 patent, Abstract. The title of
the patent is “Factor IX/Factor IXa Activating Antibodies and Antibody Derivatives.” Id. col. 1.
The Summary of the Invention states that the “object of the present invention to provide a
preparation for the treatment of blood coagulation disorders” is “achieved through the use of
antibodies or antibody derivatives against factor IX/factor IXa which have factor Villa-cofactor
activity or factor IXa-activating activity and lead to an increase in the procoagulant activity of
factor IXa.” Id. col. 2. II. 25—33. The specification states that “hybridomas are selected with a
view to the fact that the antibodies and antibody derivatives in the supematants of the hybñdoma
cells bind to factor IX/factor IXa and cause an increase of the procoagulant activity of factor
IXa.” Id col. 8, Il. 18—21.
Though these portions of the specification certainly imply that
binding to Factor IX/IXa plays a role in causing an increase in procoagulant activity, they do not
suggest sole causation as Genentech contends.
28
Because nothing in the intrinsic record suggests otherwise, I find this term unambiguous
and conclude that and in the term binds Factor LY or Factor EVa and increases means that
binding to Factor IX need not be the sole cause of the increase in procoagulant activity.
6. the procoagulant activity of Factor IXa and increases the procoagidant activity of
Factor IXa
Baxalta’s proposed construction: The rate of clot formation promoted by Factor IXa.
Genentech’s proposed construction: The ability of Factor IXa to activate Factor X to Factor
Xa by any amount as determined by any assay used to measure Factor Vill-like activity.
Court’s construction: The ability of Factor IXa to activate Factor X to Factor Xa by any
amount as determined by any assay used to measure Factor Vill-like activity.
The court’s construction of this term appears to be relevant to the question of patent
validity. The parties’ final dispute relates to the term increases the procoagulant activity of
Factor IXa. This construction raises the question of how the patent claims instruct a person of
skill in the art to measure the procoagulant effect of the inventive antibodies and antibody
fragments. Baxalta proposes a construction that Limits the assessment of procoagulant activity to
tests that measure the rate of clot formation—e.g., by use of Activated Partial Thromboplastin
Time (“aPT]’”) assays, Baxalta Op. Br. at 16—19. Genentech, on the other hand, argues that any
prior art test for measuring Factor VIlI-like activity, including clotting-time and chromogenic
assays, can be used—e.g., aPT]’ assays and chromogenic assays like COATEST VI11(C) and
Immunochrom, Genentech Op. Br. at 16; Markman Tr. 223:6—15; id. at 224:14—17.
I conclude that the specification provides clear guidance that any prior art assay that can
measure Factor VIlI-like activity may be used.
The patent twice expressly states that any
method for determining Factor Vill-like activity may be used to measure procoagulant activity:
In column 8 the patent provides that “[tjhe increase in the procoagulant activity may, e.g., be
29
proven by assaying methods as known from the prior art for the measurement of factor Vu-like
activity, e.g. chromogenic assays.” ‘590 patent, coL 8, II. 2 1—25. And in column 9 the patent
states
The following methods may be used as the test methods to show that the
antibodies and antibody derivatives of the present invention bind to factor
IX/factor IXa, increase the procoagulant activity of factor IXa or have factor VIIIlike activity••. the one step coagulation test.
or the chromogenic tests, such as
COATEST VIJI:C® (Chromogenix) or Immunochrom (IMMUNO). In principle,
all the methods used for determining factor VIII activity may be used.
.
.
Id. at col. 9, 11. 14—23. The patent reiterates this point in Example 5, where the specification
states that “{1]actor VIII activity is usually determined with a chromogenic assay and/or an
APTT-based clotting assay” and that “[b]oth types of assays rely on FVIIIa/FJXa-mediated
factorXa generation.” Id. col. 15,11. 10—13.
There is no support for Baxalta’s contrary position that only clotting-time assays are
permissible.
Baxalta’s primary argument is that the ‘590 patent in certain places refers to
clotting time assays alone as a measure of procoagulant activity. For example, Baxalla points to
column 17 of the patent, which states that ‘[t]here is a clear dose-dependent reduction of the
clotting time in samples supplemented with antibody I 93/AD3” and that such “results imply that
[thej antibody.
.
.
is procoagulant in the presence of FIXa.” Id. col. 17, II. 35—38. Baxalta also
notes that column 29 of the patent states that a particular peptide “becomes procoagulant as
indicated by the reduced clotting time” and that column 23 similarly states that certain peptides
“did not give any reduction in the clotting time indicating that they lack procoagulant activity.”
Id. at col. 29, II. 36—40; Id. at col. 23, I. 66—col. 24, 1. 2. The patent’s reference to the use of
clotting-time assays to measure procoagulant activity hardly excludes other possible methods of
measurement, particularly where other parts of the specification state that “assaying methods as
known from the prior art” may be used. Id. at col. 8, I. 2 1—25.
30
Bixalta also relies on the statement in column 9 of the patent that the inventive antibodies
and antibody fragments “increase the procoagulant activity of factor IXa or have factor VIlI-like
activity.” Id. at col. 9, II. 17—18. It contends that the use of”or” implies a distinction between
procoagulant activity and Factor VIJI-like activity. Baxalta Resp. Br. at 8—12. Baxalta argues
that Example 9 illustrates the same distinction. See ‘590 patent, col. 18, II. 22—67. It follows.
says Baxalta, that the term “procoagulant activity” and “factor VIJI-like activity” are mutually
exclusive, so that the chrornogenic assay used to determine factor VIlE-like activity cannot be
used to determine procoagulant activity.
The premise of this argument is simply incorrect.
Procoagulant activity and Factor VIII-like activity are not distinct terms, but rather are
overlapping.
Accordingly, I conclude that the term increases the procoagulant activity’ of Factor LIa
means the ability of Factor IXa to activate Factor X to Factor Xa by any amount as determined
by any assay used to measure Factor Vlll-like activity.
IT IS SO ORDERED this
3
day of
December
,2018.
Honorable Timothy B. Dyk
United States Circuit Judge, sitting by designation
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