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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 REDACTED PUBLIC VERSION

DR. RONALD K. STRONG'S SUPPLEMENTAL DECLARATION IN SUPPORT OF PDL'S ANSWERING CLAIM CONSTRUCTION BRIEF

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 Paula B. Whitten 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 Original Filing Date: June 11, 2008 Redacted Filing Date: June 13, 2008 Attorneys for Plaintiff, PDL BioPharma, Inc.

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I. Introduction 1. I have been asked by the plaintiff, PDL Biopharma, Inc., to comment on the declarations submitted by Jefferson Foote, Ph.D. and Michael R. Clark, Ph.D. on behalf of Alexion Pharmaceuticals, Inc. I have thoroughly reviewed the declarations and exhibits and provide my comments below. II. Level of ordinary skill in the art. 2. The opinions of Drs. Foote and Clark as to the level of ordinary skill in the art in the period December 1988 through February 1989 are not correct. 3. Drs. Foote and Clark propose different definitions for one of ordinary skill in the art. Dr. Foote proposes that the level of ordinary skill in the art be one who "had familiarity with the fields of biochemistry, molecular biology, structural biology, and immunology, a high level training (for example an M.D. or Ph.D.), and had performed laboratory research in antibody engineering, protein structure or related discipline."1 To the extent that Dr. Foote's definition requires an M.D. or Ph.D. in biochemistry, molecular biology, structural biology, immunology, or a related discipline, that is not correct. 4. Dr. Clark proposes that the level of ordinary skill in the art be one who had a "high level of training in immunology, molecular biology, or a related discipline, and would have conducted significant research related to antibody structure or antibody humanization or protein structure. This definition would include, for example, a person with a Ph.D. (or comparable degree) and post doctoral experience in immunology, molecular biology, or antibody humanization."2 That is not correct. 5. Dr. Cary Queen, a named inventor on the patents-in-suit, would not be one of ordinary skill in the art under Dr. Foote's definition to the extent it requires an M.D. or Ph.D. in biochemistry, molecular biology, structural biology, immunology, or a related discipline, or under Dr. Clark's definition. During the relevant time period, Dr. Queen had a Ph.D. in Mathematics.3 He did not have a Ph.D. in antibody engineering, protein structure or related discipline, as Dr. Foote's definition requires. He also did not have a Ph.D. in immunology, molecular biology, or antibody humanization, as Dr. Clark's definition requires. 6. Dr. Queen is one of ordinary skill in the art under my definition. As I explained in my opening declaration, one of ordinary skill in the art included Ph.D. post-doctoral students/ researchers working in a laboratory headed by a person such as a principal investigator in a relevant discipline, including molecular biology, immunology, biophysics, and structural biology.4 During the relevant time period, Dr. Queen had been a post-doctoral student at the Massachusetts Institute of Technology in the research area immunoglobulin gene expression.5 7. In defining the level of ordinary skill in the art, I considered on the following factors: (1) the educational level of the inventor; (2) the type of problems encountered in the

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art; (3) prior art solutions to those problems; (4) rapidity with which innovations are made; (5) sophistication of the technology; and (6) educational level of active workers in the field. a. The educational level of the inventor, Dr. Queen, at the time of the invention was a Ph.D. post-doctoral student/researcher working in a laboratory headed by a person such as a principal investigator in a relevant discipline, including molecular biology, immunology, biophysics, and structural biology. Persons with a Ph.D. in a relevant discipline and principal investigators were above the level of ordinary skill in the art at the time as Dr. Queen would not have qualified as a person of ordinary skill in the art under that definition. b. Other active researchers in the field included Ph.D. candidates working towards a Ph.D. in a relevant discipline, and Ph.D. post-doctoral students/researchers working in a laboratory headed by a principal investigator. For example, Paul Dear, who is listed as the second author of Jones et al., was a Ph.D. candidate at the time his work in the field was published.6 Persons with a Ph.D. in a relevant discipline and principal investigators were above the level of ordinary skill in the art at the time as Dr. Dear would not have qualified as person of ordinary skill in the art under that definition. III. "Humanized immunoglobulin" in the asserted claims. 8. The opinion of Drs. Foote and Clark that one of ordinary skill would have understood "humanized immunoglobulin" in the asserted claims to require framework amino acid substitutions is not correct. 9. Dr. Foote states that the specification supports his definition of humanized immunoglobulin in that "it distinguishes the patented subject matter from the prior art."7 Dr. Clark states that "PDL's characterization of the prior art is also helpful in determining the meaning of the term `humanized immunoglobulin.'"8 Citing Verhoeyen and Winter, Drs. Foote and Clark take the positions that humanized antibodies with 65% homology and murine CDRs were already known in the art, and from this assertion conclude that "one of ordinary skill would have understood that PDL's patents did not include CDR-only humanized antibodies (i.e., without framework substitutions), even if such antibodies had the specified identity."9 That is not correct. a. As discussed in my opening declaration, consistent with the explicit definition, the term "humanized immunoglobulin" is frequently used in the specification to describe the work of prior researchers Jones, Verhoeyen, and Riechmann, each of which is incorporated by reference.10 To one of ordinary skill in the art, the passage Dr. Clark cites would have meant that "humanized immunoglobulin" includes immunoglobulins which do not have framework substitutions, because Jones and Verhoeyen, which the specification describes as creating "humanized immunoglobulins," did not have framework substitutions.11

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Most humanized immunoglobulins that have been previously described (Jones et al., op. cit.; Verhoeyen et al., op. cit.; Riechmann et al., op. cit.) have comprised a framework that is identical to the framework of a particular human immunoglobulin chain, the acceptor, and three CDR's from a non-human donor immunoglobulin chain [ ] The present invention includes criteria by which a limited number of amino acids in the framework of a humanized immunoglobulin are chosen to be the same as the amino acids at those positions in the donor rather than in the acceptor. b. The specifications do not distinguish the prior art only on the basis of requiring framework substitutions. The specifications do not suggest that Winter and Verhoeyen disclosed 65% homology, and in fact one of ordinary skill would not have understood that either publication teaches the use of a homologous framework. However, the specification teaches that a novel principle of the patented subject matter is to use a homologous human acceptor. As the patents explain, to avoid the problems of the prior art:12 The present invention uses one or more of the following principles for designing humanized immunoglobulins. Also, the criteria may be used singly, or when necessary in combination, to achieve the desired affinity or other characteristics. A principle is that as acceptor, a framework is used from a particular human immunoglobulin that is particularly homologous to the donor immunoglobulin...By choosing as the acceptor immunoglobulin one of the human heavy (respectively light) chain variable regions that is most homologous to the heavy (respectively light) chain variable regions of the donor immunoglobulin, fewer amino acids will be changed in going from the donor immunoglobulin to the humanized immunoglobulin. 10. Dr. Foote's opinion that "one of skill in the art would understand from the teachings of the patents-in-suit that a humanized immunoglobulin with a 65% homology between the donor and the acceptor would bind effectively (i.e., it would only work) if it also contained framework substitutions" is not correct.13 In light of the explicit definition and other portions of the specification, one of ordinary skill in the art would not have understood framework substitutions to be required from a single experimental example in which framework substitutions were not made and high affinity was not achieved. a. The experimental example which did not include framework substitutions is consistently described in the specification as a "humanized immunoglobulin." 3

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This is consistent with my opinion that the meaning of "humanized immunoglobulin" is not limited to immunoglobulins which include framework substitutions. One of ordinary skill would not have considered the success of this experiment when determining the meaning of the term. b. One of ordinary skill would not have interpreted the examples to override the explicit statements in the specification that framework substitutions are optional, not required (as I explained in my opening declaration).14 The patents state that the "examples are offered by way of illustration, not by limitation."15 c. A number of researchers have followed the teaching of the patents to create high affinity humanized immunoglobulins that have homologous frameworks and do not have framework substitutions. Dr. Queen identified a number of publications describing such experiments in his declaration to the Patent Office:16

d. Gorman et.al. and Routledge et al. followed the teaching of the patents by selecting a homologous human acceptor to create a humanized antibody with high affinity, and they did so without incorporating framework amino acid substitutions.17 e. Dr. Clark is listed as an author on both Gorman et al. and Routledge et al. Both publications describe the antibodies that were produced as "humanized" antibodies. This supports my opinion that one of ordinary skill in the art would have understood that a "humanized" antibody does not necessarily include framework substitutions. f. A further example is Soliris, the humanized immunoglobulin produced by Alexion. According to the definition of "CDR" that Drs. Clark and Foote 18 Yet it provides propose,

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an example of a high-affinity humanized immunoglobulin that employs the patent's teaching of using a high-homology framework. 11. One of ordinary skill would not have understood the file histories to define "humanized antibodies" to require framework amino acid substitutions. Dr. Foote opines that the file histories support his opinion because "besides characterizing its invention as requiring framework substitutions in addition to CDR substitutions, PDL made clear that frameworks substitutions are necessary to avoid the prior art."19 That is not correct. a. One of ordinary skill in the art would not interpret "humanized immunoglobulins" in the asserted claims on the basis of the difference between the patented invention and the prior art, because the specification uses "humanized immunoglobulins" to describe antibodies reported in the prior art. For example, in a paper entitled "Detailed Discussion of Most Closely Related References," PDL stated that "Riechmann reported the construction of a humanized immunoglobulin" and "Winter reported a general method of producing humanized immunoglobulins."20 b. It is not correct that, during prosecution, PDL characterized all claims in the patents-in-suit as requiring framework substitutions in order to avoid the prior art. As I explained in my opening report, PDL made the opposite argument in the prosecution of the `762 patent, in order to overcome a rejection on the basis of Huston et al. PDL argued that the claims of the `762 patent do not require framework substitutions and that the disclosures of Huston et al. are not relevant to claims that do not require framework substitutions. The Patent Office agreed and allowed the claims, thus concluding that Queen's high-homology approach worked. c. The prosecution history reflects that the Patent Office specifically considered Verhoeyen and Winter. During prosecution of the `762 patent, the publications were described in depth in a "Detailed Discussion of Most Closely Related References."21 The patent office determined that Winter and Verhoeyen did not disclose the subject matter of the claims, concluding that PDL's claims were "free of the prior art."22 12. Drs. Clark and Foote state that PDL characterized its invention as requiring framework substitutions in prosecuting U.S. Patent Application No. 07/290,975.23 That is not correct. a. PDL abandoned the `975 application, and the pending claims in that abandoned application lacked the term "humanized immunoglobulin." 24 One of ordinary skill would not have understood statements made in the `975 application to override the explicit definition of "humanized immunoglobulin" in the patents-insuit.

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13. Drs. Clark and Foote also cite amendments from the prosecution of U.S. Patent No. 5,530,101, which is not one of the patents-in-suit. Dr. Clark states that "PDL relied on framework substitutions to distinguish its claimed inventions from the prior art."25 Dr. Foote states that "the patentees again emphasized the necessity of framework substitutions."26 That is not correct. One of ordinary skill in the art would not have understood the statements that Dr. Clark and Dr. Foote cited to override the explicit definition of "humanized immunoglobulin" in the specifications of the patents-in-suit. In any event, the amendment that Dr. Clark cited to specifically refers to the patent's definition of "humanized immunoglobulin": "Moreover, the claim terms "humanized immunoglobulin" and "humanized framework region" are defined terms (see, e.g: Specification page 27, line 28-ff and page 27, lines 7-13, respectively)."27 The referenced definition of "humanized immunoglobulin" did not require framework substitutions:28

14. Dr. Foote also refers to statements "regarding the importance of framework substitutions" made by PDL "while prosecuting the European counterparts to the patents-in-suit."29 One of ordinary skill would not have interpreted such statements to override the explicit definition of "humanized immunoglobulin" because claims of European Patent 451216 expressly require framework substitutions whereas the asserted claims of the patents-in-suit do not. i. All the claims of the `216 European patent require framework substitutions.30 1. Independent claim 1 requires framework substitutions.31

2. Claim 7 requires framework substitutions.32

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3. The remaining claims 2-6 and 8-21 depend from claims 1 and 7 and also require framework substitutions.33 IV. "Donor immunoglobulin" in the asserted claims. 15. Drs. Clark and Foote propose that one of ordinary skill would have understood "donor immunoglobulin" to mean a non-human immunoglobulin that provides at least one CDR and at least one framework amino acid to a human acceptor immunoglobulin. That is not correct. 16. Dr. Foote states that "PDL required its claimed humanized immunoglobulins to have at least one amino acid from the donor's framework regions."34 Dr. Clark states that "PDL's invention must include framework substitutions of the human acceptor with mouse framework amino acids."35 These statements are not correct. As I explained in my opening declaration, the specifications and file histories make it clear that amino acid substitutions were optional, not required.36 17. Dr. Foote also states that limiting the claims to immunoglobulins having framework substitutions "was necessary to get around the work of Dr. Winter's group."37 PDL did not distinguish the work of Dr. Winter's group only on the basis of framework substitutions. The specification teaches that a novel principle of the patented subject matter is to use a homologous human acceptor. The patents explain that to avoid the problems of the prior art:38 The present invention uses one or more of the following principles for designing humanized immunoglobulins. Also, the criteria may be used singly, or when necessary in combination, to achieve the desired affinity or other characteristics. A principle is that as acceptor, a framework is used from a particular human immunoglobulin that is particularly homologous to the donor immunoglobulin...By choosing as the acceptor immunoglobulin one of the human heavy (respectively light) chain variable regions that is most 7

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homologous to the heavy (respectively light) chain variable regions of the donor immunoglobulin, fewer amino acids will be changed in going from the donor immunoglobulin to the humanized immunoglobulin. 18. As I explained in my opening declaration, during prosecution of the patents, PDL did not argue that the claims all required framework substitutions. PDL explicitly made the opposite argument in the prosecution of the `762 patent, in order to overcome a rejection on the basis of Huston et al. PDL argued that the claims of the `762 patent do not require framework substitutions and that the disclosures of Huston et al. are not relevant to claims that do not require framework substitutions. The Patent Office agreed and allowed the claims. 19. Dr. Foote further states that the patents taught that without framework substitutions, a humanized immunoglobulin "did not work."39 This is not correct and does not support Dr. Foote's proposed definition of "donor." In light of the explicit definition and other portions of the specification, one of ordinary skill in the art would not have understood framework substitutions to be required from a single experimental example in which framework substitutions were not made and high affinity was not achieved. a. One of ordinary skill would not have interpreted the examples to override the explicit definition of "donor immunoglobulin" and specific statements in the specification that framework substitutions are optional, not required. The patents state that the "examples are offered by way of illustration, not by limitation."40 b. A number of researchers have followed the teaching of the patents to create high affinity humanized immunoglobulins that have homologous frameworks and do not have framework substitutions. Dr. Queen identified a number of publications describing such experiments in his declaration to the Patent Office:41

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c. Gorman et.al. and Routledge et al. followed the teaching of the patents by selecting a homologous human acceptor to create a humanized antibody with high affinity, and they did so without incorporating framework amino acid substitutions.42 d. Dr. Clark is listed as an author on both Gorman et al. and Routledge et al. Both publications describe the antibodies that were produced as "humanized" antibodies. This supports my opinion that one of ordinary skill in the art would have understood that a "humanized" antibody does not necessarily include framework substitutions. e. A further example is Soliris, the humanized immunoglobulin produced by Alexion. According to the definition of "CDR" that Drs. Clark and Foote 43 Yet it provides propose, an example of a high-affinity humanized immunoglobulin that employs the patent's teaching of using a high-homology framework. 20. One of ordinary skill in the art would not have understood the definition of "donor immunoglobulin" in the asserted claims to include a requirement of framework substitutions. V. "Human acceptor immunoglobulin" and "acceptor human immunoglobulin" in the asserted claims. 21. Drs. Foote and Clark's opinions that one of ordinary skill would have understood "human acceptor immunoglobulin" and "acceptor human immunoglobulin" in the asserted claims to require framework amino acid substitutions are not correct. 22. Dr. Foote states that "the patent makes clear that the acceptor must also receive at least one amino acid from the donor framework in order to make a high affinity

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humanized immunoglobulin."44 Dr. Clark states that "this term has particularized meaning because the humanized immunoglobulin of PDL's invention must include framework substitutions of the human acceptor with mouse framework amino acids."45 These statements are not correct. As I explained in my opening declaration, the specifications and file histories make it clear that amino acid substitutions are optional, not required.46 23. Dr. Foote states that "Alexion's definition is also supported by the prosecution histories and proceedings on related patents before the European Patent Office. In sum, these show that PDL represented that its invention required the human acceptor immunoglobulin to receive at least one amino acid from the donor.47 The prosecution histories also show that PDL characterized its humanized immunoglobulins that way in order to avoid the prior art work of Dr Winter's group."48 Dr. Clark states that "my opinion on the construction of this term takes into account PDL's assertions during prosecution that framework substitutions in the human acceptor immunoglobulin are essential to PDL's invention."49 These statements are not correct. 24. PDL did not distinguish the work of Dr Winter's group only on the basis of framework substitutions. The specification teaches that a novel principle of the patented subject matter is to use a homologous human acceptor. The patents explain that to avoid the problems of the prior art:50 The present invention uses one or more of the following principles for designing humanized immunoglobulins. Also, the criteria may be used singly, or when necessary in combination, to achieve the desired affinity or other characteristics. A principle is that as acceptor, a framework is used from a particular human immunoglobulin that is particularly homologous to the donor immunoglobulin...By choosing as the acceptor immunoglobulin one of the human heavy (respectively light) chain variable regions that is most homologous to the heavy (respectively light) chain variable regions of the donor immunoglobulin, fewer amino acids will be changed in going from the donor immunoglobulin to the humanized immunoglobulin. 25. As I explained in my opening declaration, during prosecution of the patents, PDL did not represent that the asserted claims require framework substitutions. PDL explicitly made the opposite argument in the prosecution of the `762 patent, in order to overcome a rejection on the basis of Huston et al. PDL argued that the claims of the `762 patent do not require framework substitutions and that the disclosures of Huston et al. are not relevant to claims that do not require framework substitutions. The Patent Office agreed and allowed the claims.

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26. One of ordinary skill in the art would not have understood the definition of "human acceptor immunoglobulin" in the asserted claims to include a requirement of framework substitutions. IX. "Humanized immunoglobulin heavy [light] chain variable region framework" in the asserted claims. 27. Drs. Foote and Clark's opinions that one of ordinary skill in the art would have understood the term to mean a "heavy [light] chain variable region framework of a humanized immunoglobulin wherein one or more amino acids of the human acceptor framework of the humanized immunoglobulin have been replaced by the corresponding amino acid(s) of the donor immunoglobulin" are not correct.51 28. Dr. Foote relies upon "PDL's requirement that the claimed humanized immunoglobulins include at least one amino acid from the donor's framework substituted into the acceptor."52 Dr. Clark states that "my opinion on the construction of these terms takes into account that PDL's purported invention requires the humanized immunoglobulin of the claims to have a framework substitution of at least one amino acid of the human acceptor immunoglobulin with at least amino acid of the donor immunoglobulin."53 This is not correct. As I explained in my opening declaration and elsewhere in this declaration, one of ordinary skill would not have read "humanized immunoglobulin" or "variable region framework" to require framework substitutions. That discussion applies here too. It is clear from the claim language, the specifications, and the file histories that there is no requirement of framework substitutions in the asserted claims.54 VI. "Complementarity determining region" ("CDR") in the asserted claims. 29. Drs. Foote and Clark's opinions that the definition of CDR is "a hybrid of Kabat CDRs plus Chothia CDRs" or CDR comprises "both Kabat and Chothia hypervariable regions" are not correct.55 30. One of ordinary skill would not have understood the passages in the specification cited by Drs. Foote and Clark to override the specific definition of CDRs as delineated by the Kabat methodology (as explained in my opening declaration at Opinion 6, ¶¶ C(2)). a. Dr. Foote cites a passage in the specification that "Chothia and Lesk define CDRs differently from Kabat et al. Notably [Chothia] CDR1 is defined as including residues 26-32."56 b. The passage cited by Dr. Foote acknowledges the existence of the Chothia approach and incorporates it. This acknowledgement does not override the explicit definition of CDR in the specification as delineated by the Kabat methodology (as explained in my opening declaration at Opinion 6, ¶¶ C(2)).

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c. Dr. Clark cites a passage in the specification that "The chain all exhibit the same general structure of relatively conserved framework regions joined by three hypervariable regions, also called Complementarity Determining Regions or CDR's (see, "Sequence of Proteins of Immunological Interest," Kabat, E. et al., U.S. Department of Health and Human Services, (1983); and Chothia and Lesk, J. Mol. Biol., 196, 901-917 (1987), which are incorporated herein by reference)."57 d. The passage cited by Dr. Clark appears once in the specification, twelve columns after the definitions sections begins, and is in a discussion of specific anti-IL-2 receptor antibodies, an embodiment of claims that are not asserted. Given the specification's explicit definition, and the fact that the cited passage does not appear in the discussion of the other disclosed embodiments, it is not correct to opine that one of ordinary skill in the art would have concluded that this isolated passage provides an all-encompassing definition of "CDR" that applies to the asserted claims. In addition, as discussed in my opening declaration at Opinion 5, ¶ C(4), even though the patents' successful disclosed embodiments are directed to claims requiring framework substitutions that are not asserted, each of the successful disclosed examples define CDR by the Kabat methodology. To one of ordinary skill in the art, the fact that each of these examples uses the Kabat definition for CDRs would have meant that the cited passage is not a definition that overrides the explicit definition and other portions of the specification. e. As discussed in my opening declaration at Opinion 6, ¶¶ C(9), the patents' discussion of the prior art consistently uses the Kabat methodology. i. The patents state that "[t]he 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), notably at positions . . . 26-30, . . . of the heavy chain (numbering according to Kabat, op. cit.), . . ." `762 Patent Col. 15:16-23. Amino acids at those positions are outside of the CDRs (i.e., are "in the framework . . . known to be capable of interacting with the CDRs") only if CDR is defined by the Kabat methodology. If "CDR" is defined as Drs. Foote and Clark propose, ,then those amino acid positions are in the CDR; that is, they are not "in the framework . . . known to be capable of interacting with the CDRs." ii. As discussed in my opening declaration, Riechmann defined CDR by the Kabat methodology, as discussed in my opening declaration (Opinion 6, ¶¶ C(5)(b)(i)). Jones also applied the Kabat methodology to determine the boundaries of the CDRs (Opinion 6, ¶¶ C(5)(b)(ii)). Similarly, Verhoeyen applied the Kabat methodology to determine the boundaries of the CDRs (Opinion 6, ¶¶ C(5)(b)(ii)). Amit and Tramontano also apply the Kabat

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methodology to define the boundaries of CDR (Opinion 6, ¶¶ C(5)(b)(iii),(iv)). 31. One of ordinary skill at the time would not have understood the sections of the file histories for the patents-in-suit cited Drs. Foote and Clark to override the specific definition of CDRs as delineated by the Kabat methodology (as explained in my opening declaration at Opinion 6, ¶¶ C(2)). a. Dr. Foote cites Dr. Queen's declaration discussing the Riechmann prior art and stating that "the final humanized antibody of Riechmann, et al. contains the Kabat CDRs and the Chothia CDR H1 from the mouse antibody, but no other mouse amino acids. Hence, the method of humanization utilized in Riechmann et al. can be stated as: transfer the Kabat CDRs plus the one Chothia CDR that contains extra amino acids (H1) to a pre-determined human framework."58 Dr. Clark cites to the same portion of Dr. Queen's declaration.59 One of ordinary skill at the time would not have understood those portions of the file histories to override the explicit definition of CDRs in the specifications of the patents-in-suit. i. In the specification, Dr. Queen and his co-inventors acknowledged the existence of the Chothia approach. This acknowledgement does not override the explicit definition of CDR in the specification as delineated by the Kabat methodology (as explained in my opening declaration at Opinion 6, ¶¶ C(2)). ii. Dr. Queen's declaration, read as a whole, does not suggest that he was trying to distinguish the asserted claims over the prior art. If anything, one of ordinary skill in the art would have known from reading that declaration that Dr. Queen was not talking about the asserted homology claims when discussing Riechmann. The paragraph cited by Drs. Foote and Clark discusses a "second method" of humanizing antibodies.60 Two paragraphs later, Dr. Queen discusses a "third method" of humanizing antibodies using "a human framework highly homologous to the mouse antibody."61 To one of ordinary skill, this would have suggested that Dr. Queen's discussion of CDRs in the "second method" is not directed to the asserted homology claims which are the subject of the "third method." Dr. Foote's opinion that "PDL disclaimed Kabat CDRs alone as the proper CDR definition in order to distinguish its invention from Riechmann" is not correct with respect to the asserted claims.62 iii. In addition, Dr. Queen's declaration emphasized the "pre-determined human framework," as contrasted to the use of a high-homology framework. The homology claims teach the use of a framework with a specified high homology ­ something lacking in the prior art. b. Dr. Clark also cites PDL's statement in the prosecution history of the `101 patent that "The position 27 and 30 modifications of Riechmann et al. were in fact

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within the Chothia-Lesk H1 CDR, rather than outside this CDR. Moreover, Riechmann et al. provided no suggestion or guidance as to which if any non-CDR positions to substitute, or which amino acids should be put in those positions (see paragraph 26 of the accompanying Queen declaration)." This statement does not override the explicit definition of CDR in the specifications of the patents-in-suit. i. The specification points out that Riechmann made amino acid substitutions in the framework, not the CDRs, which is consistent with the explicit definition as CDR as delineated by the Kabat methodology:63 Most humanized immunoglobulins that have been previously described (Jones et al., op. cit.; Verhoeyen et al., op. cit.; Riechmann et al., op. cit.) have comprised a framework that is identical to the framework of a particular human immunoglobulin chain, the acceptor, and three CDR's from a non-human donor immunoglobulin chain. In one case (Riechmann et al., op. cit.), two additional amino acids in the framework were changed to be the same as amino acids in other human framework regions. ii. In light of the specification, the passage from the `101 prosecution history cited by Dr. Clark distinguishes Riechmann on the grounds that it provided no suggestion or guidance as to [1] which if any non-CDR positions to substitute, or [2] which amino acids should be put in those positions provided. iii. The passage's observation that the two amino acid substitutions that Riechmann made were in the Chothia H1 CDR was technically accurate. In light of the specification's statement that that Riechmann made amino acid substitutions in the framework, one of ordinary skill would not have understood this passage to override the explicit definition of CDR in the specifications of the patents-in-suit as delineated by the Kabat methodology. c. Dr. Clark cites additional PDL statements that "the invention was directed to framework substitutions outside the regions as defined by Chothia and Kabat." He points to a statement that "Riechmann did not teach the importance of changing framework residues outside of the CDR loops . . . as is clearly provided in Applicants' presently pending claims" and another statement that "the contribution [of the invention] involves one or more amino acid substitutions in framework amino acid positions from the non-human donor antibody, which positions are outside the CDRs as defined by Kabat and Chothia."64 As Dr. Clark opines, the statements are directed to the framework substitution claims, and not to the asserted homology claims. This statement does not override the explicit definition of the CDR in the specifications of the patents-in-suit as delineated by the Kabat methodology.

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d. Drs. Foote and Clark also cite PDL's statement in the prosecution history of the `101 parent application that "Riechmann et al. made changes only within the heavy chain CDR loop (Chothia CDR H1), and did not modify or replace any framework residues outside the loop. Riechmann et al. shows only the CDR loop itself, and does not show any so-called packing interactions between the loop and framework residues outside the loop. Thus, Riechmann et al. does not teach the importance, as Appellants have invented, of changing framework residues outside the CDR loops in order to maintain the shape of the CDRs."65 e. One of ordinary skill would have read PDL's statement as referring to different claims that explicitly required amino acid substitutions outside of the Kabat and Chothia regions. This statement does not override the explicit definition of CDR in the specifications of the patents-in-suit as delineated by the Kabat methodology. 32. One of ordinary skill would not have understood the phrase "CDRs" to include the Chothia methodology. As discussed in my opening declaration at Opinion 6, ¶¶ C(7), the Chothia methodology failed to settle on one, clear definition of CDR boundaries and failed to supplant the Kabat definition. The concept that a "CDR" might also include the Chothia methodology was not reflected in contemporaneous dictionaries such as Rosen (1989) and Rosen (1993).66 33. One of ordinary skill would not have understood the sections of the opposition proceedings from the European Patent Office to override the specific definition of CDRs as delineated by the Kabat methodology (as explained in my opening declaration at Opinion 6, ¶¶ C(2)). a. Dr. Foote describes Alexion's proposed construction of CDR as Kabat plus Chothia to be "the same definition of `CDR' that PDL adopted in the European Patent Office."67 b. Dr. Clark states that it "is my recollection that in the prosecution of its European patents, PDL took the position that the term CDRs meant Kabat together with Chothia, which is the opposite definition that it proposes in this litigation. This litigation is confirmed by a review of the file history of PDL European patent EP 451216."68 c. Drs. Foote and Clark's discussions of these sections draws an incorrect conclusion. The claims and specifications of the `216 patent are different than the claims and specifications of the patents-in-suit. One of ordinary skill would not have understood PDL's statements to the European Patent Office as to the `216 patent to override the specific definition of CDRs as delineated by the Kabat methodology. i. The asserted claims of the patents-in-suit are different from the claims of the `216 European patent.

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1. None of the asserted claims define CDR as Kabat together with Chothia. By contrast, claim 1 of the `216 patent expressly defines CDRs as Kabat together with Chothia:69

2. None of the asserted claims require framework substitutions. By contrast, all the claims of the `216 European patent require framework substitutions.70 a. Independent claim 1 requires framework substitutions.71

b. Claim 7 requires framework substitutions.72

c. The remaining claims 2-6 and 8-21 depend from claims 1 and 7 and also require framework substitutions.73 ii. The specifications of the patents-in-suit are different from the claims of the specification of the `216 European patent.

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1. As discussed in my opening declaration, the specifications of the patents-in-suit explicitly define CDR according to Kabat.74

2. By contrast, the specification of the `216 patent explicitly defines CDR according to Kabat together with Chothia on page 3, lines 2932.75

iii. Aside from the differences in claims and specifications between the `216 patent and the patents-in-suit, the explicit definition in the '216 patent does not inform the meaning of the "CDR" because the definition was introduced on August 26, 1994 in the '216 patent application, which is after the relevant time period for the patents-in-suit.76

34. Dr. Clark relies on PDL's statements to the EPO, including "representations to the EPO that each of [PDL's] four experts would interpret the term CDRs as meaning Kabat CDRs together with the regions of Chothia."77 One of ordinary skill would not have understood these statements to override the specific definition of CDRs as

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delineated by the Kabat methodology (as explained in my opening declaration at Opinion 6, ¶¶ C(2)). a. PDL's experts were referring the meaning of the term CDRs in the claims of the `216 patent, which, as discussed above, were different than the asserted claims of the patents-suit. As discussed above, the specification of the `216 patent is also different from the specifications of the patents-in-suit. In light of those differences, PDL's statements in the `216 patent proceedings do not override the explicit definition of "CDR" in the specifications of the patents-in-suit. 35. Dr. Clark refers to the European opposition proceedings relating to EP 0 682 040 A1.78 However, he does not point to any statements in the those proceedings which support his position. One of ordinary skill would not have understood anything in these proceedings or the specification of the `040 patent79 to override the specific definition of CDRs as delineated by the Kabat methodology (as explained in my opening declaration at Opinion 6, ¶¶ C(2)). X. "Hypervariable Regions" 36. My opinions are limited to what I have been informed are the asserted claims. I understand that the term "hypervariable regions" does not appear in the asserted claims. I have not been asked to give, and have not reached, any opinion about the meaning of this term. VI. "Synthesizing a [the] DNA segment encoding a humanized heavy [light] chain variable region" 37. Drs. Clark and Foote propose that one of skill in the art would define the term "Synthesizing a [the] DNA segment encoding the humanized heavy [light] chain variable region" to mean "producing a polynucleotide encoding the entire humanized heavy [light] chain variable region by synthesizing de novo and ligating oligonucleotides."80 That is not correct. 38. Drs. Clark and Foote did not identify any claim language that supports their proposed definition. The claims do not distinguish between different methods of producing polynucleotides encoding humanized immunoglobulins. The claims use the phrases "synthesizing the DNA segment" and "providing a cell containing DNA segments." However, one of ordinary skill would have understood that these phrases describe separate steps in the production of humanized immunoglobulins, not separate methods. This is shown in claim 1 of the 370 patent, which requires both steps: 1. A method of producing a humanized immunoglobulin which specifically binds to an antigen, the method comprising: providing a cell containing DNA segments encoding humanized light and heavy chain variable regions; and

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expressing the DNA segments in the cell to produce the humanized immunoglobulin; wherein the cell containing the DNA segments was produced by: (1) comparing the sequence of a donor immunoglobulin heavy chain variable region against a collection of sequences of human heavy chain variable regions; (2) selecting a human heavy chain variable region from the collection of human heavy chain variable regions to provide an acceptor heavy chain variable region, wherein the selected variable region framework is at least 65% identical to the donor immunoglobulin heavy chain variable region framework, wherein percentage sequence identity is determined by aligning amino acids in said frameworks by Kabat numbering; (3) synthesizing the DNA segment encoding the humanized heavy chain variable region, comprising complementarity determining regions (CDRs) from the donor immunoglobulin heavy chain variable region and a variable region framework from the selected acceptor heavy chain variable region; (4) introducing the DNA segment encoding the humanized immunoglobulin heavy chain variable region and the DNA segment encoding the humanized immunoglobulin light chain variable region into the cell, wherein the humanized immunoglobulin heavy chain variable region framework comprises at least 70 amino acid residues identical to those in the acceptor immunoglobulin heavy chain variable region framework. 39. Drs. Clark and Foote cite to the specification to support their position.81 They are not correct. One of ordinary skill would not have understood the specification to require "synthesizing de novo and ligating oligonucleotides." Drs. Clark and Foote quote the following statement in the specification:82 Once designed, the immunoglobulins, including binding fragments and other immunoglobulin forms, of the present invention may be produced readily by a variety of recombinant DNA or other techniques. Preferably, polynucleotides encoding the desired amino acid sequences are produced synthetically and by joining appropriate nucleic acid sequences, with ultimate expression in transfected cells.

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40. This statement makes it clear that the claims are not to be limited to "synthetic" production of DNA, because the specification states that it is only preferable to produce polynucleotides synthetically. 41. Drs. Clark and Foote equate "produced synthetically" with "synthesizing." This is contrary to the understanding of one of ordinary skill in the art at the time. Dr. Foote quotes language in the specification that distinguishes between producing polynucleotides synthetically and by other methods, and draws the conclusion that the specification therefore distinguishes "synthesizing" from other methods.83 That is not correct. One of ordinary skill in the art would have understood that "produced synthetically" and "synthesizing" differ substantially in meaning. One of ordinary skill would also have understood that "synthetic" implies an artificial means of production, whereas "synthesis" and "synthesizing" are broader and encompass artificial and biological processes. 42. Drs. Clark and Foote acknowledge that "synthesis of DNA" and "synthesizing (of DNA)" would have been understood to mean "building (i.e. polymerization manufacture) of a known sequence of nucleotides into a chain called an oligonucleotide . . . or DNA." Clark Decl. at ¶ 73; Foote Decl. at ¶ 72. This supports my opinion that one of ordinary skill in the art would have understood that "synthesizing" is synonymous with "producing" a polynucleotide and is not limited to "synthetic" production. 43. The definition proposed by Drs. Clark and Foote is also unlikely in that one of ordinary skill would not have known whether the entire DNA segment must be "synthesized de novo," or whether part may be produced by enzymatic extension, using another oligonucleotide as a template. If it is understood to mean that the entire DNA segment must be formed from oligonucleotides that are synthesized de novo and ligated (joined) together, then the definition does not describe the method employed in the specification, contrary to the opinion of Dr. Foote.84 The experimental section of the specification clearly shows that part of the complete polynucleotide encoding each humanized immunoglobulins is produced by an enzyme, DNA polymerase, that extends each oligonucleotide using another oligonucleotide as a template. 85 This is not "synthesizing de novo."

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44. Dr. Clark's declaration opines that the skilled artisan would have had no choice but to synthesize oligonucleotides de novo because, "at the time of the invention, the routine sequencing of DNA by polymerase chain reaction ("PCR") and other automated methods was just coming of age, and DNA or RNA sequences of antibody proteins were not commercially available."86 But PCR technique was known and in use at the time and the specifications of the patents-in-suit state that, using this technique, DNA segments encoding immunoglobulins could be readily obtained:

45. The inventors utilized this technique to obtain antibody DNA sequences in examples 3, 5, 6, 7, 8 and 9.87 Reading the specifications of the patents-in-suit, one of ordinary skill in the art would have understood that techniques and resources were available to produce polynucleotides by a variety of methods, and that producing polynucleotides was not limited to "synthesizing de novo."

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I declare under penalty of perjury of the laws of the United States that the foregoing is true and correct. Executed on June 11, 2008, at Seattle, Washington.

_______________________________ Roland K. Strong, Ph.D.
1 2 3 4 5 6

Foote Decl. at ¶ 15. Clark Decl. at ¶ 20. Queen resume at PDL-A 0001758 (Ex. 1). Strong Decl. at ¶¶ V-VI. Queen resume at PDL-A 0001758 (Ex. 1).

Paul H. Dear, "Techniques for manipulating large DNA," Ph.D. Thesis ­ University of Oxford (1989) at PDL-A 0243638-0243639 (Ex. 2).
7 8 9

Foote Decl. at ¶ 42. Clark Decl. at ¶ 46. Clark Decl. at ¶ 46. Strong Opening Decl. at pp. 15-16. 761 Patent, Col. 12:29-43 (Strong Opening Decl. Ex. 10). Id., Col. 13:1-9. Foote Decl. at ¶ 49. Strong Opening Decl. at pp. 19-21. 761 Patent, Col. 37:66-67 (Strong Opening Decl. Ex. 10). `101 Patent File History at PDL-A 0001739-0001778 (Ex. 3).

10 11 12 13 14 15 16 17

Gorman et al., "Reshaping a therapeutic CD4 antibody," Proc. Natl. Acad. Sci. 88:4181-4185 (1991) ("Gorman") at PDL-A 0020869-0020873 (Ex. 4); Routledge et al., "A humanized monovalent CD3 antibody which can activate homologous complement,"

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Eur. J. Immunol. 21: 2717-2725 (1991) ("Routledge") at PDL-A 0020683-0020691 (Ex. 5).
18

19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39

Foote Decl. at ¶ 48. `762 Patent File History at PDL-A 0002936 (Ex. 7). Id. at PDL-A 0002934-0002941. Id. at PDL-A 0003010. Foote Decl. at ¶ 47; Clark Decl. at ¶ 52. U.S. Patent Application No. 07/290,975 at PDL-A 0001153-56 (Ex. 13). Clark Decl. at ¶ 54. Foote Decl. at ¶ 47. `101 Patent File History at PDL-A 0001804-0001829 (Ex. 3). Id. at PDL-A 0001339. Foote Decl. at ¶ 50. European Patent No. 0 451 216 ("`216 Patent") at PDL-A 0016353-0016377 (Ex. 9). Id. at PDL-A 0016365. Id. at PDL-A 0016366. Id. at PDL-A 0016365-0016366. Foote Decl. at ¶ 54. Clark Decl. at ¶ 60. Opening Decl at pp. 19-21. Foote Decl. at ¶ 55 `761 Patent, Col. 13:1-9 (Strong Opening Decl. Ex. 10). Foote Decl. at ¶ 56

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40 41 42

`761 Patent, Col 37:66-67 (Strong Opening Decl. Ex. 10). `101 Patent File History at PDL-A 0001744 (Ex. 3).

Gorman at PDL-A 0020869-0020873 (Ex. 4); Routledge PDL-A 0020683-0020691 (Ex. 5).
43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

Foote Decl. at ¶ 59. Clark Decl. at ¶ 63. Strong Opening Decl. at pp. 19-21. See e.g., Foote Decl. Ex. J at p. 15. Foote Decl. at ¶ 60. Clark Decl. at ¶ 64. `761 Patent, Col. 13:1-9 (Strong Opening Decl. Ex. 10). Foote Decl. at ¶¶ 62-63; Clark Decl. at ¶ 65. Foote Decl. at ¶ 64. Clark Decl. at ¶ 66. Strong Opening Decl. at p 14, 18-22, 46-50. Foote Decl. at ¶ 33; Clark Decl. at ¶ 30. Foote Decl. at ¶ 33. Clark Decl. at ¶ 30. Foote Decl. at ¶ 36. Clark Decl. at ¶ 32. `101 Patent File History at PDL-A 0001742-0001743 (Ex. 3). Id. at PDL-A 0001744. Foote Decl. at ¶ 36.

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63 64 65 66

`762 Patent, Col. 12:29-37 (Strong Opening Decl. Ex. 12). Clark Decl. at ¶¶ 31-35. Foote Decl. at ¶ 36; Clark Decl. at ¶¶ 33.

F. Rosen, Dictionary of Immunology (1989) ("Rosen 1989") at PDL-A 02436300243632 (Ex. 10); F. Rosen, Dictionary of Immunology (1993) ("Rosen 1993") at PDL-A 0243635-0243637 (Ex. 11).
67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85

Foote Decl. at ¶ 37. Clark Decl. at ¶ 36. `216 Patent at PDL-A 0016365 (Ex. 9). Id. at PDL-A 0016353-0016377. Id. at PDL-A 0016365. Id. at PDL-A 0016366. Id. PDL-A 0016365-0016366. Strong Decl. at Opinion 6, ¶¶ C(2). `216 Patent at PDL-A 0016355 (Ex. 9). `216 Patent Application at PDL-A 0042540 (Ex. 12). Clark Decl. at ¶¶ 38, 39. Clark Decl. at ¶ 36. European Patent No. 0 682 040 at PDL-A 0016477-0016500 (Ex. 8). Foote Decl. at ¶ 69, Clark Decl. at ¶ 73. Foote Decl. at ¶ 73, Clark Decl. at ¶ 74. `762 Patent, Col. 3:44-50 (Strong Opening Decl. Ex. 12). Foote Decl. at ¶ 74. Foote Decl. at ¶¶ 73-76. `761 patent, Col. 39:34-49 (Strong Opening Decl. Ex. 10).

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86 87

Clark Decl. at ¶ 75.

`761 patent, Col. 43:43-52, Col. 50:57-67, Col. 53:51-65, Col. 58:51-60 (Strong Opening Decl. Ex. 10).

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CERTIFICATE OF SERVICE I, the undersigned, hereby certify that on June 13, 2008, I electronically filed the foregoing with the Clerk of the Court using CM/ECF, which will send notification of such filing(s) to the following: Josy W. Ingersoll I also certify that copies were caused to be served on June 13, 2008, upon the following in the manner indicated: BY HAND Josy W. Ingersoll Andrew A. Lundgren Young, Conaway, Stargatt & Taylor, LLP The Brandywine Building 1000 West Street, 17th Flr. Wilmington, DE 19801 BY EMAIL Gerald J. Flattmann, Jr. Christine Willgoos Gregory A. Morris Kirkland & Ellis 153 East 53rd Street New York, NY 10022-4611

/s/ Karen Jacobs Louden
___________________________ Karen Jacobs Louden

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