Free Claim Construction Opening Brief - District Court of Delaware - Delaware

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE __________________________________________ PDL BIOPHARMA, INC. ) ) Plaintiff, ) ) v. ) ) ALEXION PHARMACEUTICALS, INC., ) ) Defendant. ) __________________________________________)

C.A. No. 07-156 (JJF)

OPENING CLAIM CONSTRUCTION BRIEF OF PLAINTIFF PDL BIOPHARMA INC.

MORRIS, NICHOLS, ARSHT & TUNNELL LLP Jack B. Blumenfeld (#1014) Karen Jacobs Louden (#2881) 1201 N. Market Street P.O. Box 1347 Wilmington, DE 19899-1347 (302) 658-9200 [email protected] Of Counsel: Matthew D. Powers Vernon M. Winters WEIL, GOTSHAL & MANGES LLP Silicon Valley Office 201 Redwood Shores Parkway Redwood Shores, CA 94065 (650) 802-3000 Jennifer H. Wu Rebecca E. Fett WEIL, GOTSHAL & MANGES LLP New York Office 767 Fifth Avenue New York, NY 10153 (212) 310-8000 May 14, 2008 Attorneys for Plaintiff PDL BioPharma, Inc.

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TABLE OF CONTENTS Page I. II. III. NATURE AND STAGE OF THE PROCEEDINGS ........................................................ 1 SUMMARY OF ARGUMENT ......................................................................................... 2 STATEMENT OF FACTS ................................................................................................ 3 A. Background on Immunoglobulins ......................................................................... 3 1. Immunoglobulin Function and Structure ................................................... 3 2. Depicting and Comparing Immunoglobulin Amino Acid Sequences................................................................................................... 5 B. The Three Patents-in-Suit ...................................................................................... 7 1. The Problems the Inventors Were Trying to Solve ................................... 7 a. The Problems with Monoclonal Immunoglobulins and with Chimeric Immunoglobulins ........................................................... 7 b. Limitations of Prior `Reshaped' Antibodies ­ The Work of Jones, Verhoeyen, Winter, and Riechmann ................................... 7 2. The Specifications' Description of the Three Distinct Groups of Inventions in the Patents ............................................................................ 8 3. The Asserted Claims Relate Only to One Group of Inventions: Replacing the CDRs in a Human Acceptor Immunoglobulin and Using a Human Acceptor Framework that is 65%-70% Homologous to the Donor........................................................................ 10 ARGUMENT................................................................................................................... 10 A. "Humanized Immunoglobulin"............................................................................ 10 1. The Patents Expressly Define "Humanized Immunoglobulin," and that Express Definition Governs.............................................................. 11 2. The Claim Language is Consistent with the Express Definition ............. 12 3. The Specifications are Consistent with the Express Definition............... 14 4. The File Histories are Consistent with the Express Definition................ 17 B. "Donor Immunoglobulin" and "Human Acceptor Immunoglobulin" ................. 20 1. The Patents Expressly Define "Donor Immunoglobulin," "Human Acceptor Immunoglobulin," and "Acceptor Human Immunoglobulin," and Those Definitions Govern .................................. 21 2. The Claims are Consistent with the Express Definition .......................... 22 3. The Specifications are Consistent with the Express Definitions ............. 23 C. "Complementarity Determining Region (CDR)" and "Framework"................... 25 1. The Patents Expressly Define "Complementarity Determining Region (CDR)" and "Framework," and Those Definitions Govern ........ 25 2. The Patents' Specification is Consistent with the Express Definitions................................................................................................ 27 i

IV.

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TABLE OF CONTENTS (continued) Page 3. The File Histories are Consistent with the Express Definitions .............. 29 D. Claim Phrases that Consist Mainly of Other Construed Terms Joined Together ............................................................................................................... 30 1. "Heavy and Light Chain Variable Region Frameworks" / "Heavy and Light Chain Frameworks"................................................................. 30 2. "Humanized Heavy [Light] Chain Variable Region Framework" .......... 31 3. The "DNA Segment[s] Encoding" Claim Terms..................................... 32 4. "Is at least 65% [70%] Identical to the [Sequence of the] Donor Immunoglobulin Heavy [Light] Chain Variable Region Framework" ............................................................................................. 36 5. "Synthesizing a [the] DNA Segment Encoding a Humanized Heavy [Light] Chain Variable Region" ................................................... 38 CONCLUSION................................................................................................................ 40

V.

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TABLE OF AUTHORITIES Page(s) CASES Gaus v. Conair Corp., 363 F.3d 1284 (Fed. Cir. 2004)........................................................................................ Passim Hill-Rom Co., Inc. v. Kinetic Concepts, Inc., 209 F.3d 1337 (Fed. Cir. 2000)..........................................................................................14, 24 Intamin, Ltd. v. Magnetar Tech. Corp., 483 F.3d 1328 (Fed. Cir. 2007).............................................................................. 12-13, 16, 23 Kumar v. Ovonic Battery Co., Inc., 351 F.3d 1364 (Fed. Cir. 2003)..........................................................................................27, 33 Lucent Techs., Inc. v. Gateway, Inc., --- F.3d ----, 2008 WL 1970225 (Fed. Cir. May 8, 2008)............................................ 14-15, 24 Microsoft Corp. v. Multi-Tech Sys., Inc., 357 F.3d 1340 (Fed. Cir.), cert. denied, 125 S.Ct. 61 (2004) ................................15, 24, 37, 39 Moleculon Research Corp. v. CBS, Inc., 793 F.2d 1261, 229 USPQ 805 (Fed. Cir. 1986) .....................................................................14 Multiform Desiccants, Inc. v. Medzam, Ltd., 133 F.3d 1473 (Fed. Cir. 1998)................................................................................................12 Nazomi Communications, Inc. v. ARM Holdings, PLC, 403 F.3d 1364 (Fed.Cir.2005)..................................................................................................16 NTP, Inc. v. Research In Motion, Ltd., 418 F.3d 1282 (Fed. Cir. 2005)..............................................................................14, 19, 23, 38 Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1438 (Fed. Cir. 2007)................................................................................................12 Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) (en banc) ....................................................................... Passim Rhodia Chimie v. PPG Indus., Inc., 402 F.3d 1371 (Fed. Cir. 2005)................................................................................................19 Sinorgchem Co., Shandong v. Int'l Trade Comm'n, 511 F.3d 1132 (Fed. Cir. 2007)........................................................................................ Passim

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TABLE OF AUTHORITIES (continued) Page(s) SRI Int'l v. Matsushita Elec. Corp. of Am., 775 F.2d 1107 (Fed. Cir. 1985)................................................................................................16 Stryker Corp. v. Intermedics Orthopedics, Inc., 96 F.3d 1409, 40 USPQ2d 1065 (Fed. Cir. 1996) ...................................................................14 Sunrace Roots Enter. Co. v. SRAM Corp., 336 F.3d 1298 (Fed. Cir. 2003)..........................................................................................14, 23 United States Surgical Corp. v. Ethicon, Inc., 103 F.3d 1554, 41 USPQ2d 1225 (Fed. Cir. 1997) .................................................................14 Vivid Techs., Inc. v. American Science & Eng'g, Inc., 200 F.3d 795 (Fed. Cir. 1999)..................................................................................8, 25, 28, 34

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I.

NATURE AND STAGE OF THE PROCEEDINGS The patentee plaintiff, PDL BioPharma, Inc., filed this lawsuit against Alexion

Pharmaceuticals, Inc. ("defendant") for infringement of three groundbreaking U.S. patents that claim antibody humanization technologies, after the U.S. Food and Drug Administration approved defendant's humanized antibody, Soliris, for use against paroxysmal nocturnal hemoglobinuria ("PNH"), a potentially life-threatening disease of the blood. D.I. 1. PNH sufferers pay $389,000 (three hundred and eighty-nine thousand dollars) per year for it. D.I. 1. PDL asserts certain claims of U.S. Patent Nos. 5,693,761, 5,693,762, and 6,180,370. D.I. 1. PDL has accused defendant of infringing only certain claims. D.I. 62. Almost a year after the parties' respective answers, counterclaims, and replies, D.I. 11 & 14, defendant alleged for the first time invalidity of patent claims that PDL was not asserting. D.I. 45. PDL accordingly moved to dismiss those claims; the Court heard and took that motion under submission on April 11, 2008. D.I. 67; D.I. 69; D.I. 77; D.I. 83. In February 2008, the parties exchanged claim terms for construction. PDL proposed construction of five claim terms. Wu Decl. Ex. 1; defendant proposed twenty-four, Wu Decl. Ex. 2, including seven from the unasserted clams, id. at Ex. 2. Later, defendant added another claim term from an unasserted claim (and withdrew others). Wu Decl. Ex. 3. PDL is prepared to file a Covenant Not to Sue on the unasserted claims, which would moot the case or controversy (had there been one) on the unasserted claims, and has provided a draft of it to Alexion. A claim construction hearing is set for July 1, 2008 at 3:00 pm. D.I. 76. Document discovery closes on July 10, 2008, willfulness discovery closes on August 1, 2008, fact discovery closes on October 2, 2008, expert reports for the parties with the burden of proof are due 30 days after the issuance of the Court's claim construction decision, and casedispositive motions are due in January 2009. D.I. 76; D.I. 89. This is PDL's opening claim construction brief.

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II.

SUMMARY OF ARGUMENT In Phillips v. AWH, the Federal Circuit, sitting en banc, re-confirmed the correct

methodology for construing patent claims. The Federal Circuit affirmed that when a patentee acts as his own lexicographer in the specification, that definition governs. Absent an express definition, the Court counseled that the construction that stays true to the claim language and most naturally aligns with the patent's description of the invention will be, in the end, the correct construction. It also emphasized that although a specification often describes very specific embodiments of the invention, it has repeatedly warned against confining the claims to those embodiments. It disapproved of an approach that went against its precedent counseling against importing limitations into the claims. The parties' claim constructions must be assessed against such principles. For example, the parties offer different constructions of "humanized immunoglobulin" ­ a term that appears in all of the asserted claims. The patents expressly define that phrase in the Detailed Description of the Invention, which, "[i]n order that the invention may be more completely understood," set forth "several definitions." One of the several definitions is of humanized immunoglobulin: "[a]s used herein, the term `humanized' immunoglobulin refers to an immunoglobulin comprising a human framework region and one or more CDR's from a nonhuman (usually a mouse or rat) immunoglobulin." Nothing in that definition requires amino acid substitutions ­ or, for that matter, excludes them. Defendant, however, seeks to re-write most of the disputed claim terms to require framework amino acid substitutions. But the Abstract, Summary of the Invention, and Detailed Description of the Invention of the patents describe framework amino acid substitutions as "possible," "optional," and "another embodiment" of the invention ­ a distinction that is reflected in the claims. There are other claims that expressly require framework amino acid substitutions. When the claims so require, they so state. The asserted claims are not those claims. This is just one example. For term after term, PDL proposes definitions that are, or are based on, express definitions in the patents, and, when there is no express definition, that stay true to the claims and most naturally align with the patent's description of the invention. 2

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Defendant, however, consistently seeks constructions that conflict with the patents' express definitions, the claim language, and the file histories. Patentee plaintiff PDL asks that the Court confirm all of its claim constructions. III. STATEMENT OF FACTS A. Background on Immunoglobulins The patents are directed to "humanized" immunoglobulins and methods of, and biological materials used in, making them. To assist in understanding the patents and the claim terms that defendant disputes, some brief background on immunoglobulins is provided below. More detailed information is found in the Declaration of Roland K. Strong, Ph.D., submitted with this brief ("Strong Decl."). 1. Immunoglobulin Function and Structure

Immunoglobulins are made up of proteins ­ that is, sequences of amino acids. Immunoglobulins are produced by the mammalian immune system, and they bind to substances, called "antigens," that are foreign to those mammals. Strong Decl. § II, ¶¶ A(1)-(3). The binding of an immunoglobulin to an antigen can have numerous biological effects, including, importantly, to neutralize or eliminate the target antigen. Binding between an immunoglobulin and an antigen may result in the recruitment of other parts of the immune system that are capable of destroying the antigen. Alternatively, when bound to an antigen that is a protein, an immunoglobulin may also block biochemical processes. For example, the antibody may function as a physical obstruction that prevents an interaction between two proteins involved in a disease. Strong Decl. § II, ¶¶ A(1). The immunoglobulin must form a sufficiently strong bond with the antigen if the immunoglobulin is to have a biological effect. The strength of the bond between an immunoglobulin and an antigen is called the "affinity"; it is a measure of the relative strength of the bond between an immunoglobulin and a particular antigen. The degree of affinity is determined by the physical and chemical complementarity between the amino acids in the antigen binding site of the immunoglobulin and the molecules on the surface of the antigen. Immunoglobulins with a relatively strong bond are called high-affinity immunoglobulins; those 3

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with a relatively weak bond, low-affinity immunoglobulins. This can be represented as:

Strong Decl. § II, ¶¶ A(2). A related concept is "specificity," which is the degree to which an immunoglobulin will bind to a particular antigen as opposed to other antigens. The immunoglobulin's amino acid sequence determines both the degree of affinity and specificity to a particular antigen. Given the large number of antigens that can invade a mammal, the immune system can produce extraordinarily large numbers of immunoglobulins: in the billions. See, e.g., Strong Decl. § II, ¶¶ A(1). Amino acids are the building blocks of all proteins, including immunoglobulins. A particular protein is defined by the length and sequence of the amino acids that comprise it. The divergent chemical properties of the different amino acids in a polypeptide drive the polypeptide to fold up into a specific compact shape, or structure. The structure of a protein, encompassing this defined three-dimensional shape and the chemical properties of its surface, defines the function of a particular protein. Strong Decl. § II, ¶¶ B(1)-(2). Although an oversimplification, immunoglobulins can be represented by a twodimensional Y-shaped molecule.

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As depicted in the simplified picture above, a full immunoglobulin molecule has two identical sets of chains: two heavy chains on the interior, and two light chains on the exterior. The variable region of both the heavy and the light chain consists of a "constant region" and a "variable region." The constant region contains amino acid sequences that are constant within a class of immunoglobulins (although it may vary from the sequence of immunoglobulins in other classes). The variable region contains amino acid sequences that vary both within and across immunoglobulin classes. Strong Decl. § II, ¶¶ C(1). Within each variable domain, there are discrete regions (called "complementarity determining regions," or "CDRs") in which the variability of the amino acid is particularly high. The portion of the variable region that is not the CDR is called the "framework." Binding between an immunoglobulin and an antigen occurs in the variable region, at the two distal tips of the "Y." See, e.g., Strong Decl. § II, ¶¶ B(2). 2. Depicting and Comparing Immunoglobulin Amino Acid Sequences

There are twenty different amino acids, and these are usually represented by three-letter abbreviations (Leu for Leucine, Val for Valine), or single letter abbreviations (C for Cysteine or H for Histidine). Different amino acids are linked together into a linear chain, or polymer, to form a polypeptide. An entire amino acid sequence can be represented by a string

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of letters, with each letter (or three-letter abbreviation) representing a particular amino acid. Strong Decl. § II, ¶¶ B(1)-(2). Because amino acid sequences can be represented by a string of letters or threeletter abbreviations, the extent to which amino acid sequences are the same can be determined. The degree of sameness is called "homology." If both proteins have the same amino acid at the same sequence position, this is a match. A measure of the degree of matching is the "percent identity," defined as the total number of matches divided by the total length of the polypeptides being compared. To determine which sequence positions correspond in order to count up matches, the two or more sequences must be "aligned." The task of alignment is facilitated by systems for numbering of amino acid residues. Appropriate alignment of protein sequences can be a difficult task, particularly when comparing sequences that may have small sections deleted or added. For antibodies, the task of aligning sequences has been much simplified by the work of Kabat et al. ("Kabat"). Strong Decl. § II, ¶¶ D(2)-(4). In 1970, Kabat first established an immunoglobulin amino acid sequence database; in it, the amino acids in each sequence were numbered according to a convention that, even by the time the patents were filed, had become known as "Kabat numbering." The Kabat sequence database has since been published in print in more than five editions and online and spans over five million light and heavy chain sequences. It is a standard reference in the fields

of immunology, structural biology, and related fields. In the December 1988 ­ February 1989 timeframe when the patents were filed (and even today), the amino acid numbering system established by Kabat was, and is currently, the default in the field of immunology. Strong Decl. § II, ¶¶ D(3)-(4). Kabat determined that differences between immunoglobulin sequences were not evenly distributed along the sequence, but clustered into regions. Kabat determined that variability increased greatly in three regions on each chain; these regions are called "complementarity determining regions" or "CDRs." See, e.g., Strong Decl. § II, ¶¶ D(3). At the time that the patents were filed, and today, researchers could use sequence 6

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databases and search tools to identify proteins that shared a specified percentage identity with a particular amino acid sequence (i.e., protein) of interest. Then, as now, there are a variety of publicly available databases that include millions of protein (i.e., amino acid) or DNA sequences. GenBank, maintained by the National Institutes of Health, is a frequently used database and can be accessed online. There are also a variety of publicly available search tools that perform algorithms to analyze the sequences in the databases. One can enter a particular amino acid sequence or DNA sequence into a search tool, and the tool will search a chosen database and identify the amino acid or DNA sequences with the greatest percentage of sequence identity to the sequence of interest. Strong Decl. § II, ¶¶ D(5). B. The Three Patents-in-Suit The three patents that PDL asserts share a common specification, and derive from the same parent application. Hence their figures and text are essentially identical, although located in slightly different columns and lines. For convenience this brief generally refers to the specification of the `761 patent when illustrating a point (for example, that the patents define a term expressly in their specifications). 1. The Problems the Inventors Were Trying to Solve a. The Problems with Monoclonal Immunoglobulins and with Chimeric Immunoglobulins

As the patents note, two kinds of previous man-made antibodies (so-called `monoclonal antibodies' and `chimeric antibodies') suffered from the same fundamental problem: they provoked an immune response when injected into a human. As Dr. Strong explains, because the human body's immune system would recognize a monoclonal or chimeric antibody as "foreign," the monoclonal or chimeric antibody, instead of serving as a therapeutic, would create another immune response which may simply render it ineffective or could possibly generate harmful responses. Strong Decl. § II, ¶¶ E(3)-(5). b. Limitations of Prior `Reshaped' Antibodies ­ The Work of Jones, Verhoeyen, Winter, and Riechmann

The patents discuss the work of prior researchers in the area of "reshaped" or "humanized" antibodies, citing those publications and incorporating them by reference. The 7

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patents acknowledge the problems with and limits of that prior work. One significant problem was loss of affinity, in some cases to the extent of a loss of all biological activity: "However, a major problem with present humanization procedures has been a loss of affinity for the antigen (Jones et al., Nature, 321, 522-525 (1986)), in some instances as much as 10-fold or more, especially when the antigen is a protein (Verhoeyen et al., Science, 239, 1534-1536 (1988)). Loss of any affinity is, of course, highly undesirable. At the least, it means that more of the humanized antibody will have to be injected into the patient, at higher cost and greater risk of adverse effects. Even more critically, an antibody with reduced affinity may have poorer biological functions, . . . (see, Riechmann et al., Nature, 332, 323-327 (1988); Table 1)." `761 Patent, Col. 2:12-21; see also Strong Decl. § III, ¶¶ A(3)(a)-(b). Another important problem was the unpredictability of results: "Similarly, utilizing recombinant DNA technology to produce so-called `reshaped' or `humanized' antibodies (see, e.g., Riechmann et al., Nature 332, 323 (1988) and EPO Publication No. 0239400 [Winter EP]), provides uncertain results, in part due to unpredictable binding affinities." `761 Patent, Col. 21:62-67; see also Strong Decl. § III, ¶¶ A(3)(c). 2. The Specifications' Description of the Three Distinct Groups of Inventions in the Patents

As is clear from the face of the patents' specifications, and as Dr. Strong explains, one of ordinary skill at the time would have understood that in their specification the patents, broadly speaking, classify three distinct inventions, and that the claims are based on those distinctions. The first group involves the claims at issue and therefore the subject of the claim construction proceedings in this case. This group involves replacing the CDRs in the human acceptor immunoglobulin with those from the donor immunoglobulin, using as the human acceptor an immunoglobulin whose framework region is at least 65%-70% identical to the donor framework. The Summary of the Invention states that "[t]o form the humanized variable region, amino acids in the human acceptor sequence will be replaced by the corresponding amino acids from the donor sequence if they are in the category: (1) the amino acid is in a CDR." `761 8

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Patent, Col. 2:61-65. These claims require that the human acceptor immunoglobulin framework amino acid sequence have a minimum level of identity with the donor acceptor immunoglobulin framework amino acid sequence: "The human immunoglobulin framework sequence will typically have about 65 to 70% homology or more to the donor immunoglobulin framework sequences." `761 Patent, Col. 2:51-54; see also Strong Decl. § III, ¶¶ B(1)(a). The second group, not at issue in this case, involves replacing the CDRs in the human acceptor with the donor CDRs, and then making optional further amino acid substitutions in the human framework. In the Summary of the Invention, the patents state: "[t]o form the humanized variable region, amino acids in the human acceptor sequence will be replaced by the corresponding amino acids from the donor sequence if they are in the category: (1) the amino acid is in a CDR. [¶] In another embodiment of the present invention, either in conjunction with the above comparison step or separately, additional amino acids in the acceptor immunoglobulin chain may be replaced with amino acids from the CDR-donor immunoglobulin chain" in specified circumstances. `761 Patent, Col. 2:61 ­ Col. 3:3; see also Strong Decl. § III, ¶¶ B(1)(b).1 The third group of inventions, also not in the asserted claims, involves replacing the CDRs in the human acceptor with the donor CDRs, and using a consensus framework as the human acceptor framework. A consensus sequence is an "[i]dealized or `typical' sequence (nucleic acid or protein) in which each position is the nucleotide or amino acid residue found most frequently when many actual sequences are compared." Rosen, Dictionary of Immunology (1989) at 52; see also Strong Decl. § III, ¶¶ B(1)(c). As the patents explain in the Detailed Description of the Invention, rather than using a human acceptor framework that is 65%-70% homologous to the donor framework, one could use a "consensus" sequence. `761 Patent, Col. 13:5-8; see also Strong Decl. § III, ¶¶ B(1)(c).

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Emphasis in quotations from cases or other sources has been supplied unless otherwise noted. 9

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3.

The Asserted Claims Relate Only to One Group of Inventions: Replacing the CDRs in a Human Acceptor Immunoglobulin and Using a Human Acceptor Framework that is 65%-70% Homologous to the Donor

As Dr. Strong explains, "in terms of the three groupings above, one of ordinary skill at the time would have understood that all of the asserted are in the first category: Replace the CDRs in the human acceptor with those from the donor, and use a human acceptor framework that is 65%-70% homologous to the donor framework. One of ordinary skill would have also understood that none of the asserted claims are within the second category: Replace the CDRs in the human acceptor with the donor CDRs, and then make optional further amino acid substitutions in the human framework." Strong Decl. § III, ¶¶ C(1). In particular, claims in the second category require framework amino acid substitutions; but the claims in the first category do not. IV. ARGUMENT As explained below, for term after term, PDL proposes definitions that are, or are based on, explicit definitions in the patents; and, when the patents contain no definition, that stay true to the claims and most naturally align with the patents' description of the invention. Defendant takes a different approach in its effort to obtain its desired result: it would have this Court import, into almost every term for construction, a limitation from the specification ­ framework amino acid substitutions. In the Abstract, Summary of the Invention, and Detailed Description of the Invention, the patents consistently describe framework amino acid substitutions as "possible," "optional," and "another embodiment" of the invention ­ a distinction that is reflected in the claims. When the claims require framework amino acid substitutions, they say so. The asserted claims are not those claims. We begin with a fundamental claim term, present in all of the asserted claims: "humanized immunoglobulin." A. "Humanized Immunoglobulin" The parties agree that a humanized immunoglobulin must be an immunoglobulin comprising a human framework region and one or more CDRs from a non-human immunoglobulin. As it does with many other claim terms, defendant, however, would import 10

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from the specification a limitation not present in this claim term. Hence: The Claim Term and the Parties' Dispute Claim Term "Humanized immunoglobulin" PDL's Construction "An immunoglobulin comprising a human framework region and one or more CDR's from a non-human (usually a mouse or rat) immunoglobulin." Framework amino acid substitutions are optional. Alexion's Position An immunoglobulin comprising a framework region from a human acceptor immunoglobulin and one or more CDRs from a nonhuman donor immunoglobulin wherein at least one amino acid of the framework of the humanized immunoglobulin is the same as the corresponding amino acid in the donor immunoglobulin rather than that of the human acceptor immunoglobulin.

The express definition of this term controls. Even if it did not, the language of the claims, the specification, and the file history all point firmly away from defendant's position. 1. The Patents Expressly Define "Humanized Immunoglobulin," and that Express Definition Governs.

Phillips instructs that "the specification may reveal a special definition given to a claim term," and that "[i]n such cases, the inventor's lexicography governs." Phillips v. AWH Corp., 415 F.3d 1303, 1317 (Fed. Cir. 2005) (en banc). defines this claim term. In the Detailed Description of the Invention teaches that "[i]n order that the invention may be more completely understood, several definitions are set forth." `761 Patent, Col. 11:4-5. The patents first expressly define `immunoglobulin,' making it clear that an "immunoglobulin" could be a full molecule, a fragment, or a single chain: "As used herein, the term `immunoglobulin' refers to a protein consisting of one or more polypeptides substantially encoded by immunoglobulin genes. . . . One form of immunoglobulin constitutes the basic structural unit of an antibody. . . . In addition to antibodies, immunoglobulins may exist in a variety of other forms including, for example, Fv, Fab, and (Fab')2, as well as bifunctional hybrid antibodies . . . and in single chains." Id. at Col. 11:5-34 (citations omitted). The patents then This is such a case: the specification

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define a "humanized" immunoglobulin: "As used herein, the term `humanized' immunoglobulin refers to an immunoglobulin comprising a human framework region and one or more CDR's from a non-human (usually a mouse or rat) immunoglobulin." Id. at Col. 12:1-4. Those definitions are unambiguous, and are complete. Nothing in those definitions requires framework amino acid substitutions ­ and, correlatively, nothing excludes framework amino acid substitutions, either. That definition is PDL's construction. One of ordinary skill would have regarded that definition as conclusive. Strong Decl. Opinion 3, ¶¶ C(1)(a)-(c). The definitions are also conclusive as a matter of law. "When the specification explains and defines a term used in the claims, without ambiguity or incompleteness, there is no need to search further for the meaning of the term." Sinorgchem Co., Shandong v. Int'l Trade Comm'n, 511 F.3d 1132, 1138 (Fed. Cir. 2007) (citing Multiform Desiccants, Inc. v. Medzam, Ltd., 133 F.3d 1473, 1477 (Fed. Cir. 1998)). Were one to search further, one would find that the claim language, specification, and file history do not conflict with the explicit definition, i.e., with PDL's construction ­ they support it.2 2. The Claim Language is Consistent with the Express Definition.

The claim language also undercuts defendant's position ­ and supports PDL's. "A patentee may draft different claims to cover different embodiments," Intamin, Ltd. v. Magnetar Tech. Corp., 483 F.3d 1328, 1337 (Fed. Cir. 2007), and that is what PDL did here. The asserted claims do not, on their face, require framework amino acid substitutions. One of ordinary skill at the time would have noticed that, by contrast, a number of other claims (not asserted by PDL) do. For example, in the '761 patent, claim 10 requires "donor amino acids substitute for corresponding amino acids in the acceptor immunoglobulin heavy chain
2

The principle that the "definition given to a claim term by the patentee . . . governs" applies even when that definition "differs from the meaning it would otherwise possess," Phillips, 415 F.3d at 1317, and even when the explicit definition is technically incorrect, Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1438, 1454 (Fed. Cir. 2007) ("We recognize that hydrochloride and hydrobromide are not technically anions. However, since the patentee chose to be his own lexicographer, we will refer to these two acids as anions for purposes of this opinion."). This is an easier case in which to apply the principle. 12

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framework." `761 Patent, Col. 163:52-54. Claim 11 requires amino acids from the donor immunoglobulin heavy chain framework that "substitute for the corresponding amino acids in the acceptor immunoglobulin heavy chain framework." Id. at Col. 164:5-8. Claim 28 requires that the "donor amino acids substitute for the corresponding amino acids in the acceptor immunoglobulin light chain framework." Id. at Col. 165:59-61. Claim 32 requires that an amino acid from the donor immunoglobulin heavy chain framework "substitutes for the corresponding amino acid in the acceptor immunoglobulin heavy chain framework." Id. at Col. 166:27-29. Claim 37 requires "donor amino acids substitute for corresponding amino acids in the acceptor immunoglobulin heavy chain framework." Id. at Col. 167:10 ­ Col. 168:2. From this contrast, one of ordinary skill would have concluded that when claims require framework amino acid substitutions, they say so ­ and when they do not, they do not. Strong Decl. Opinion 3, ¶¶ C(5)(a)(i) ­ (iii). Indeed, not only is defendant's position inconsistent with how one of ordinary skill would understand the claims, defendant's position violates the doctrine of claim differentiation. "Differences among claims can also be a useful guide in understanding the meaning of particular claim terms. For example, the presence of a dependent claim that adds a particular limitation gives rise to a presumption that the limitation in question is not present in the independent claim." Phillips, 415 F.3d at 1314-15. Claim 32 of the `761 patent, which depends from claim 1, provides in its entirety: First and second polynucleotides according to claim 1 or 7, wherein said humanized immunoglobulin heavy chain further comprises an amino acid from the donor immunoglobulin heavy chain framework outside the Kabat and Chothia CDRs that substitutes for the corresponding amino acid in the acceptor immunoglobulin heavy chain framework, wherein said amino acid is typical for its position in human immunoglobulin sequences and said corresponding amino acid in the acceptor immunoglobulin is rare for its position in human immunoglobulin sequences. `761 Patent, Col. 166:23-33. If defendant's construction were correct, there would have been no need for this unasserted claim to specify (as it does) the humanized immunoglobulin heavy chain "further comprises an amino acid for the donor." Under defendant's construction, that

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limitation was already present. The presumption of claim differentiation "is especially strong when," as here, "the limitation in dispute is the only meaningful difference between an independent and dependent claim." Sunrace Roots Enter. Co. v. SRAM Corp., 336 F.3d 1298, 1302-03 (Fed. Cir. 2003). Claim terms are normally interpreted "consistently throughout the patent." Phillips, 415 F.3d at 1314. Moreover, where (as here) "patents all derive from the same parent application and share many common terms, we must interpret the claims consistently across all asserted patents." NTP, Inc. v. Research In Motion, Ltd., 418 F.3d 1282, 1293 (Fed. Cir. 2005) (citations omitted). Accordingly, "humanized immunoglobulin" means the same thing in all the claims: an immunoglobulin comprising a human framework region and one or more CDRs from a non-human (usually a mouse or rat) immunoglobulin. Framework amino acid substitutions are optional. 3. The Specifications are Consistent with the Express Definition.

As the Federal Circuit explained, even before Phillips, "[w]e have frequently looked to the abstract to determine the scope of the invention, see, e.g., United States Surgical Corp. v. Ethicon, Inc., 103 F.3d 1554, 1560, 41 USPQ2d 1225, 1230 (Fed. Cir. 1997); Stryker Corp. v. Intermedics Orthopedics, Inc., 96 F.3d 1409, 1412, 40 USPQ2d 1065, 1066 (Fed. Cir. 1996); Moleculon Research Corp. v. CBS, Inc., 793 F.2d 1261, 1269, 229 USPQ 805, 810 (Fed. Cir. 1986)." Hill-Rom Co., Inc. v. Kinetic Concepts, Inc., 209 F.3d 1337, 1341 n.1 (Fed. Cir. 2000). Post-Phillips, that remains the law. See, e.g., Lucent Techs., Inc. v. Gateway, Inc., --F.3d ----, 2008 WL 1970225, at *4-5 (Fed. Cir. May 8, 2008) (looking to the Abstract to determine scope of the invention). The Abstracts disclose that "[n]ovel methods for producing, and compositions of, humanized immunoglobulins having one or more complementarity determining regions (CDR's) and possible additional amino acids from a donor immunoglobulin and a framework region from an accepting human immunoglobulin are provided. Each humanized immunoglobulin chain will usually comprise, in addition to the CDR's, amino acids from the

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donor immunoglobulin framework . . . ." `761 Patent, Abstract. The Abstracts teach that framework amino acid substitutions are "possible" and even "usual" ­ but not required. Likewise, the Summary of the Invention supports PDL's construction ­ and contradicts defendant's. It explains that "[t]he present invention provides novel methods for preparing humanized immunoglobulin chains having generally [1] one or more complementarity determining regions (CDR's) from a donor immunoglobulin and a [2] framework region from a human immunoglobulin." Id. at Col. 2:37-41 (brackets supplied). It further explains that in the human acceptor variable region, the CDRs will be replaced with CDRs from the non-human donor ("[t]o form the humanized variable region, amino acids in the human acceptor sequence will be replaced by the corresponding amino acids from the donor sequence if they are in the category: (1) the amino acid is in a CDR," id. at Col. 2:61-65) and that, in a first embodiment of the invention, a high-homology framework will be used ("[t]he human immunoglobulin framework sequence will typically have about 65 to 70% homology or more to the donor immunoglobulin framework sequences," id. at Col. 2:51-54). But, in the immediately following section, the Summary of the Invention states that framework amino acid substitutions are "another embodiment" of the invention that can be done "separately" or "in conjunction with the first embodiment": In another embodiment of the present invention, either in conjunction with the above comparison step or separately, additional amino acids in the acceptor immunoglobulin chain may be replaced with amino acids from the CDR-donor immunoglobulin chain. More specifically, further optional substitutions of a human framework amino acid of the acceptor immunoglobulin with the corresponding amino acid from a donor immunoglobulin will be made at positions which fall in one or more of the following categories [listing categories]. Id. at Col. 2:66 ­ Col. 3:7. Such statements are definitional. See, e.g., Microsoft Corp. v. Multi-Tech Sys., Inc., 357 F.3d 1340, 1348 (Fed. Cir.), cert. denied, 125 S.Ct. 61 (2004) (statements in the "`Summary of the Invention' portion of the specification, are not limited to describing a preferred embodiment, but more broadly describe the overall inventions."); Gaus v. Conair Corp., 363 F.3d 1284, 1290 (Fed. Cir. 2004) (phrase "according to the present invention"

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is definitional). By drawing a clear distinction between one embodiment (donor CDRs in a high-homology human acceptor framework) and another (requiring framework amino acid substitutions), the specification confirms the explicit definition set forth in the patents, which does not require framework amino acid substitutions. Defendant's argument here ­ that because the specification discloses a specific embodiment requiring framework amino acid substitutions, all claims must require framework amino acid substitutions ­ is the kind of argument that the Federal Circuit has repeatedly warned against, as it explained in Phillips: although the specification often describes very specific embodiments of the invention, we have repeatedly warned against confining the claims to those embodiments. See, e.g., Nazomi Communications, Inc. v. ARM Holdings, PLC, 403 F.3d 1364, 1369 (Fed.Cir.2005) (claims may embrace "different subject matter than is illustrated in the specific embodiments in the specification"); Liebel-Flarsheim, 358 F.3d at 906-08; Teleflex, 299 F.3d at 1327; SRI Int'l v. Matsushita Elec. Corp. of Am., 775 F.2d 1107, 1121 (Fed. Cir. 1985). 415 F.3d at 1323. The Federal Circuit further has "expressly rejected the contention that if a patent describes only a single embodiment, the claims of the patent must be construed as being limited to that embodiment." Id.; see also Intamin,, 483 F.3d at 1337 ("[a] patentee may draft different claims to cover different embodiments," and "a claim need not cover all embodiments."). PDL drafted different claims to cover different embodiments. When the claims require framework amino acid substitutions, they say so. Defendant's argument is also like the argument the Federal Circuit rejected in Sinorgchem, 511 F.3d 1132. There, as here, the patent's specification had an explicit definition of the disputed claim term ("controlled amount") ­ in fact, there the definition was less explicitly identified as a definition. The trumping definition of "controlled amount" in Sinorgchem did not appear (as here) in a section that states that definitions are set forth; was not accompanied (as here) by language such as "in the present invention"; and did not (as here) appear in the Abstract. Instead, in Sinorgchem, the specification simply provided that "a `controlled amount' of protic material is . . . ." The Federal Circuit concluded that that bland usage provided a "clear[],

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deliberate[], and precise[] defin[ition]," Sinorgchem, 511 F.3d at 1136, that overrode other indications in the specification, id. at 1137. This is an easier case: the definition is labeled as such, and is corroborated in the Abstract and other parts of the specification. It is also consistent with the file histories, as next explained. 4. The File Histories are Consistent with the Express Definition.

Finally, although recognizing that "because the prosecution history represents an ongoing negotiation between the PTO and the applicant, rather than the final product of that negotiation, it often lacks the clarity of the specification and thus is less useful for claim construction purposes," Phillips, 415 F.3d at 1317 (emphasis added), it is also true that the prosecution history can "inform the meaning of the claim language . . . ." Id. Here, there is no such lack of clarity. The prosecution history, particularly of the `762 patent, is clear and does not support requiring framework amino acid substitutions as defendant contends. As explained above, none of the claims of the `762 patent contain, on their face, the limitation that defendant seeks to import: required framework amino acid substitutions. The PTO considered and rejected during prosecution of the `762 patent precisely the construction that defendant now proffers. Specifically, during prosecution PDL presented amended claims that were generally the same as the issued claims; then-pending draft claim 86 was identical to issued claim 1. `762 FH at PDL-A 0000315 & following. The PTO rejected those claims, asserting that they were "anticipated by over Huston et al.," which the PTO characterized as disclosing the "altering of two residues outside the CDR region in the humanization of the antibody":

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`762 FH at PDL-A 0003046. In response, in Paper No. 18, PDL explained that although the pending `761 application (which contained a few such claims), the `762 application did not contain any claims that required framework amino acid substitutions, and that the disclosures of Huston et al. were not even relevant to claims that did not require framework amino acid

substitutions: `762 FH at PDL-A 0003055-63. The PTO's subsequent Interview Summary states that agreement "was reached," and that the "claims are in condition for allowance" based on PDL's explanation that the claims did not require framework amino acid substitutions: `762 FH at PDL-A 0003388. "[T]he prosecution history can often inform the meaning of the claim language by 18

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demonstrating how the inventor understood the invention . . . ." Phillips, 415 F.3d at 1417. This is such a case. PDL understood the claims of the `762 patent not to require framework amino acid substitutions. So did the PTO, and the PTO said so in its Interview Summary. Given that file history, the interpretation that defendant advances cannot be correct as a matter of law. Cf. Rhodia Chimie v. PPG Indus., Inc., 402 F.3d 1371, 1384 (Fed. Cir. 2005) ( "The purpose of consulting the prosecution history in construing a claim is to `exclude any interpretation that was disclaimed during prosecution.'") (citation omitted). Nor is it correct from the perspective of one of ordinary skill at the time. Such a person, reviewing that patent prosecution record, would have concluded that "humanized immunoglobulin" as used in the patents does not require framework amino acid substitutions ­ that such substitutions were, to be sure, optional, but they were not required. Strong Decl. Opinion 3, ¶¶ C(5)(c). ***** The patents' claims, the explicit definition, the specification, and the file histories all align to point ­ firmly ­ away from defendant's argument: that the asserted claims somehow require framework amino acid substitutions. This is not a case where "the distinction between using the specification to interpret the meaning of a claim and importing limitations from the specification into the claim can be a difficult one to apply in practice." Phillips, 415 F.3d at 1323. Rather, this is a case where "the line between construing terms and importing limitations can be discerned with reasonable certainty and predictability if the court's focus remains on understanding how a person of ordinary skill in the art would understand the claim terms." Id. It is important to understand that almost all of the claim terms into which defendant seeks to import the framework amino acid substitution requirement ­ the requirement that the PTO specifically rejected ­ appear in the asserted `762 patent claims. Given the `762 patent's file history and the law that where (as here) "patents all derive from the same parent application and share many common terms, we must interpret the claims consistently across all asserted patents," NTP, Inc., 418 F.3d at 1293 (citations omitted), because 19

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the limitation that defendant seeks to import cannot be present in any of the limitations of the asserted `762 patent claims, they cannot be present in the corresponding `761 or `370 asserted claim terms, either. Nonetheless, defendant makes that attempt. It attempts to import framework amino acid substitutions into "donor immunoglobulin," "human acceptor immunoglobulin," "acceptor human immunoglobulin," "framework," "framework region," "variable region framework," "heavy and light chain variable region frameworks," "heavy and light chain frameworks," "humanized immunoglobulin heavy [light] chain variable region framework," "DNA segment encoding a [the] humanized heavy [light] chain variable region framework," "DNA segments encoding the humanized heavy and light chains," "DNA segments encoding humanized light and heavy chain variable regions," and "DNA segments encoding humanized light and heavy chain variable regions" ­ in short, every disputed claim term except for "complementarity determining region (CDR)." We turn, first, to two sides of the same coin: "donor immunoglobulin" and "human acceptor immunoglobulin." B. "Donor Immunoglobulin" and "Human Acceptor Immunoglobulin" The parties agree that the "donor immunoglobulin" in the asserted claims is the non-human immunoglobulin providing the CDRs in the acceptor human immunoglobulin/human acceptor immunoglobulin. The parties also agree that "human acceptor immunoglobulin" and "acceptor human immunoglobulin" are synonymous in the asserted claims, and that both are the human immunoglobulin that provides the framework for the CDRs from the donor immunoglobulin. The disputes (defendant's positions) are whether "donor immunoglobulin" "human acceptor immunoglobulin," and "acceptor human immunoglobulin" also require that the non-human donor immunoglobulin provide additional amino acid substitutions that the human acceptor immunoglobulin must accept. Hence:

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The Claim Term and the Parties' Dispute Claim Term "Donor immunoglobulin" PDL's Construction "The non-human immunoglobulin providing the CDRs." Framework amino acid substitutions are optional. Defendant's Position A non-human immunoglobulin that donates at least one CDR and at least one framework amino acid to a human acceptor immunoglobulin." Framework amino acid substitutions are required. A human immunoglobulin that accepts at least one CDR and at least one framework amino acid from a donor immunoglobulin." Framework amino acid substitutions are required.

"Human acceptor immunoglobulin" / "acceptor human immunoglobulin"

"The human immunoglobulin providing the framework for the CDRs." Framework amino acid substitutions are optional.

1.

The Patents Expressly Define "Donor Immunoglobulin," "Human Acceptor Immunoglobulin," and "Acceptor Human Immunoglobulin," and Those Definitions Govern.

As with "human immunoglobulin," the disputes about "donor immunoglobulin," "human acceptor immunoglobulin," and "acceptor human immunoglobulin" are ones in which "the inventor's lexicography governs" because "the specification . . . reveal[s] a special definition given to a claim term." Phillips, 415 F.3d at 1317. In the same part of the Detailed Description of the Invention that expressly defines "humanized immunoglobulin," the specification also expressly defines "donor immunoglobulin" and the "human acceptor immunoglobulin"/"acceptor human immunoglobulin": "[a]s used herein, the term `humanized' immunoglobulin refers to an immunoglobulin comprising a human framework region and one or more CDR's from a nonhuman (usually a mouse or rat) immunoglobulin. The non-human immunoglobulin providing the CDR's is called the `donor' and the human immunoglobulin providing the framework is called the `acceptor.'" `761 Patent Col. 12:1-7. Nothing in those definitions requires framework amino acid substitutions ­ and, correlatively, nothing excludes them, either. Those definitions are unambiguous and complete. One of ordinary skill would have regarded them as conclusive. Strong Decl. Opinion 4, ¶¶

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C(3)(a)-(c), Strong Decl. Opinion 5, ¶¶ C(3)(a)-(c). They are, again, PDL's constructions. Defendant resists them. In light of these express definitions, the principle that "[w]hen the specification explains and defines a term used in the claims, without ambiguity or incompleteness, there is no need to search further for the meaning of the term," Sinorgchem, 511 F.3d at 1138, also applies to this claim term. But, as with "humanized immunoglobulin," such a search would confirm that the claim language, specification, and file history are consistent with those explicit definitions, i.e., they support PDL's construction, and they undercut defendant's. 2. The Claims are Consistent with the Express Definition.

In the `761 patent, for example, claim 1 does not on its face require that the donor immunoglobulin must supply amino acids for framework substitutions that the human acceptor framework must accept. Claims 10 and 37, however, do. They requires that "the donor amino acids substitute for corresponding amino acids in the acceptor immunoglobulin heavy chain framework." `761 Patent, Col. 163:52-54; id. at Col. 167:10 ­ 168:2. Claim 11 requires amino acids from the donor immunoglobulin heavy chain framework that "substitute for the corresponding amino acids in the acceptor immunoglobulin heavy chain framework." Id. at Col. 164:5-7. Claim 28 requires that the "donor amino acids substitute for corresponding amino acids in the acceptor immunoglobulin light chain framework." `761 Patent, Col. 165:59-61. Claim 32 requires that an amino acid from the donor immunoglobulin heavy chain framework "substitutes for the corresponding amino acid in the acceptor immunoglobulin heavy chain framework." Id. at Col. 166:27-29. As is discussed in this brief, supra, the `762 patent does not contain any claims that on their face require framework amino acid substitutions. The `370 patent, however, contains such claims; they require that specified donor amino acids `replace' amino acids in the acceptor human framework (all of these claims are unasserted). See, e.g., `370 Patent, Col. 166:26-29 (claim 3); id. at Col. 166:51-53 (claim 4); id. at Col. 167:61-67 (claim 7); id. at Col. 168:19-23 (claim 8); and id. at Col. 168:37-42 (claim 9).

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One of ordinary skill at the time, reading these claims, would understand that the absence of such requirements in the asserted claims of the patents signaled that such requirements were not present. Strong Decl. Opinion 4, ¶¶ C(5)(a). This is a case where the "patentee . . . draft[ed] different claims to cover different embodiments." Intamin, 483 F.3d at 1337. As with "humanized immunoglobulin," the doctrine of claim differentiation undercuts defendant's position. Claim 32 of the `761 patent, which depends from claim 1, provides in its entirety: First and second polynucleotides according to claim 1 or 7, wherein said humanized immunoglobulin heavy chain further comprises an amino acid from the donor immunoglobulin heavy chain framework outside the Kabat and Chothia CDRs that substitutes for the corresponding amino acid in the acceptor immunoglobulin heavy chain framework, wherein said amino acid is typical for its position in human immunoglobulin sequences and said corresponding amino acid in the acceptor immunoglobulin is rare for its position in human immunoglobulin sequences. `761 Patent, Col. 166:23-32. There would be no reason for claim 32 to specify framework amino acid substitutions if that requirement were present in claim 1. Hence, there is a strong presumption that the disputed claim terms, as used in claim 1 of the `761 patent, do not require that the donor immunoglobulin supply amino acids for framework amino acid substitutions that the human acceptor accept, because the presumption of claim differentiation "is especially strong when the limitation in dispute is the only meaningful difference between an independent and dependent claim." Sunrace Roots Enter. Co., 336 F.3d at 1302-03. Claim terms are normally interpreted "consistently throughout the patent." Phillips, 415 F.3d at 1314. And where (as here) "patents all derive from the same parent application and share many common terms, we must interpret the claims consistently across all asserted patents." NTP, Inc., 418 F.3d at 1293 (citations omitted). Under that precedent, these claim terms mean the same thing throughout the asserted claims. 3. The Specifications are Consistent with the Express Definitions.

Other portions of the specification point firmly away from the conclusion that the patent's express definitions somehow do not apply, and that a "donor immunoglobulin" must 23

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necessarily provide amino acids for framework substitutions in the "human acceptor immunoglobulin" or "acceptor human immunoglobulin." The Abstract defines such substitutions as "possible" and even "usual" ­ but not required: Novel methods for producing, and compositions of, humanized immunoglobulins having one or more complementarity determining regions (CDR's) and possible additional amino acids from a donor immunoglobulin and a framework region from an accepting human immunoglobulin are provided. Each humanized immunoglobulin chain will usually comprise, in addition to the CDR's, amino acids from the donor immunoglobulin framework . . .. `761 Patent, Abstract. Even before Phillips, "[w]e have frequently looked to the abstract to determine the scope of the invention," Hill-Rom Co., 209 F.3d at 1341 n.1, and the Federal Circuit continues to do so. Lucent Techs., 2008 WL 1970225, at *4-5. The Summary of the Invention describes the circumstances in which the donor immunoglobulin provides amino acids for substitutions in the human acceptor immunoglobulin and acceptor human immunoglobulin frameworks as "another embodiment' of the invention ­ "optional" but not required: In another embodiment of the present invention, either in conjunction with the above comparison step or separately, additional amino acids in the acceptor immunoglobulin chain may be replaced with amino acids from the CDR-donor immunoglobulin chain. More specifically, further optional substitutions of a human framework amino acid of the acceptor immunoglobulin with the corresponding amino acid from a donor immunoglobulin will be made at positions which fall in one or more of the following categories [defining categories]. `761 Patent, Col. 2:66 ­ Col. 3:7. Such statements are definitional, see, e.g., Microsoft Corp., supra, 357 F.3d at 1348 (statements in the "`Summary of the Invention' portion of the specification, are not limited to describing a preferred embodiment, but more broadly describe the overall inventions."); Gaus, supra, 363 F.3d at 1290 (phrase "according to the present invention" is definitional), and by drawing a clear distinction between one embodiment (donor CDRs in a high-homology human acceptor framework) and another (requiring framework amino acid substitutions), the specification confirms the patents' explicit definition, which does not require framework amino acid substitutions. 24

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***** We turn to another disputed claim term that the patents define ­ "complementarity determining region" or "CDR" ­ where, again, the patents expressly define the claim term in a manner inconsistent with defendant's position. C. "Complementarity Determining Region (CDR)" and "Framework" Here, as elsewhere, the parties agree in part. Defendant, however, seeks to disregard the patents' explicit definition and the other intrinsic evidence, and import a limitation into the claim ­ that "CDR" is defined by the aggregate of the Kabat and Chothia methodologies. Hence, the dispute:3 The Claim Terms and the Parties' Disputes Claim Term "Complementarity determining region (CDR)" PDL's Construction "Amino acid sequence in the variable region, the boundaries of which are defined by the Kabat methodology" "The amino acid sequence in the variable region of an immunoglobulin that is not a CDR (as defined by the Kabat methodology)" Defendant's Position A hypervariable region as defined by the aggregate of the Kabat methodology and the Chothia methodology Portion of the variable region of an immunoglobulin that is not a CDR (as defined by the aggregate of the Kabat methodology and by the Chothia methodology)

"Framework" / "framework region" / "variable region framework"

1.

The Patents Expressly Define "Complementarity Determining Region (CDR)" and "Framework," and Those Definitions Govern.

As with the prior claim terms, defendant's disputes about the meaning of "complementarity determining region (CDR)" and "framework" are ones in which "the inventor's lexicography governs" because "the specification . . . reveal[s] a special definition given to a claim term." Phillips, 415 F.3d at 1317.

3

Defendant also attempts to import "hypervariable regions" into this dispute. That claim term appears in unasserted claims. There is no dispute on the unasserted claims, and hence no need to construe "hypervariable regions." See, e.g., Vivid Techs., Inc. v. American Science & Eng'g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) ("only those terms need be construed that are in controversy, and only to the extent necessary to resolve the controversy."). 25

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In the same part of the Detailed Description of the Invention that defines the other claim terms discussed above, the specification defines "complementarity determining region (CDR)." Indeed, the specification notes that the boundaries had been "precisely defined" by a precise methodological reference (Kabat) that the specification expressly incorporates:

`761 Patent, Col. 10:54-56 & Col. 11:38-44. One of ordinary skill at the time would have regarded this definition as conclusive. Strong Decl. Opinion 6, ¶¶ C(2)(a). It is not until several pages later that the specification references and incorporates the Chothia paper that first set forth Chothia's methodology. `761 Patent Col. 15:21-26 ("The amino acids at several positions in the framework are known to be capable of interacting with the CDRs in many antibodies (Chothia and Lesk, J. Mol. Biol. 196, 901 (1987), Chothia et al., Nature 342, 877 (1989), and Tramontano et al., J. Mol. Biol. 215, 175 (1990) all of which are incorporated herein by reference)"); `761 Patent Col. 15:42-43 ("Chothia and Lesk (op. cit.) define the CDRs differently from Kabat et al. (op. cit.)"). Importantly, however, when the patent defined "CDR," it did so exclusively on the basis of the Kabat methodology ­ not the Chothia methodology. "Here, the drafter clearly, deliberately, and precisely defined the term," and that precise definition governs. Sinorgchem, 511 F.3d at 1136; see also Phillips, 415 F.3d at 1317 (en banc) (specification's express definitions "govern," even when different from accepted usage). In light of these express definitions, the principle that "[w]hen the specification explains and defines a term used in the claims, without ambiguity or incompleteness, there is no need to search further for the meaning of the term," Sinorgchem, 511 F.3d at 1138, applies to 26

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these claim terms. If one were to look further, the claims as a whole do not support defendant; the claim terms are neutral. Strong Decl. Opinion 6, ¶¶ C(8). The patents' descriptio