`____________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`PFIZER, INC., and
`SAMSUNG BIOEPIS CO., LTD.,1
`Petitioners,
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`v.
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`GENENTECH, INC.,
`Patent Owner.
`____________
`
`Case IPR2017-01489
`Patent 6,407,213
`____________
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`
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`PETITIONERS’ RESPONSES TO PATENT OWNER’S OBSERVATIONS
`ON CROSS-EXAMINATION OF JEFFERSON FOOTE, PH.D.2
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`1 Samsung Bioepis Co. Ltd.’s IPR2017-02140 has been joined with this
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`proceeding. (IPR2017-02140, Paper 40.)
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`2 All emphases within are added.
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`IPR2017-01489: Petitioners’ Responses to Observations on Cross-Examination
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`Pursuant to the Joint Notice of Stipulation to Revise Schedule (Paper 51),
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`Petitioners submit the following responses to Patent Owner’s (PO’s) observations
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`on cross-examination of Jefferson Foote, Ph.D. (“Observations,” Paper 61).
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`Responses to Foote (Ex. 2059) Observations
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`Response to Observation 1: Observation 1 is misleading and irrelevant. The
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`observation is irrelevant because Petitioners and Dr. Foote do not rely on the
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`Riechmann 1988 paper (Ex. 1569) as anticipating or rendering obvious the
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`challenged claims of the ’213 patent, but rather as forming part of the state of the art
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`prior to that patent. Indeed, as described in Dr. Foote’s opening and reply
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`declarations, and during his first deposition, the humanized CAMPATH antibody
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`described in Riechmann 1998 is an example of a prior art antibody in which murine
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`CDR residues were incorporated into a human framework region including, in the
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`case of the light chain, a human framework comprising a “consensus” sequence
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`derived from the Kabat 1983 reference, with framework regions substitutions made
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`back to the corresponding murine residue at several positions. Exs. 1503, ¶103;
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`1702, ¶¶12, 42-43, 82; 2039 (Foote Tr.) at 327:12–331:11. This reference is
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`therefore relevant because it refutes PO’s assertion that the so-called “consensus”
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`approach described in the ’213 patent was somehow novel and/or non-obvious. The
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`fact that Riechmann et al. substituted framework residues at positions not listed in
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`the ’213 patent claims is also irrelevant, as Petitioners rely on other prior art
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`1
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`IPR2017-01489: Petitioners’ Responses to Observations on Cross-Examination
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`references that indisputably disclose the same criteria to identify framework residues
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`to substitute as those in the ’213 patent, and identify many of the same residues listed
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`in the claims. See, e.g. Pet. at 11-14.
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`Response to Observation 2: Observation 2 is misleading and irrelevant. As
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`Dr. Foote explains in his opening and reply declarations, Queen 1989 discloses the
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`same criteria to identify framework residue to substitute as those in the ’213 patent.
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`See, e.g. Exs. 1503, ¶¶36-37; 118, 252-266; 1702, ¶¶45, 98-99. The fact that the
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`specific residues positions of the claims are not substituted in the anti-Tac antibody
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`the humanization of which is described in Queen 1989 is irrelevant. As Dr. Foote
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`explained in his reply declaration, and Dr. Presta confirmed at his deposition, the
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`first step after identifying candidate positions for framework substitution based on
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`any given criteria, including those in Queen 1989, is to determine whether the donor
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`mouse and human acceptor sequences differ at those positions. Exs. 1702, ¶15; 1699
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`(Presta Tr.) at 98:25–99:5.
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`Response to Observation 3: Observation 3 is misleading and irrelevant. As
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`Dr. Foote explains in his opening and reply declarations, Queen 1990 discloses the
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`same criteria to identify framework residues to substitute as those in the ’213 patent.
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`See, e.g. Exs. 1503, ¶¶34-35; 120, 179-182, 188; 1702, ¶¶4, 6, 100-103. The fact
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`that the specific residues positions of the claims are not substituted in the working
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`example of Queen 1990 is irrelevant. As Dr. Foote explained in his reply
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`2
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`IPR2017-01489: Petitioners’ Responses to Observations on Cross-Examination
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`declaration, and Dr. Presta confirmed at his deposition, the first step after identifying
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`candidate positions for framework substitution based on any given criteria, including
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`those in Queen 1990, is to determine whether the donor mouse and human acceptor
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`sequences differ at those positions. Exs. 1702, ¶15; 1699 (Presta Tr.) at 98:25–99:5.
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`Response to Observation 4: Observation 4 is misleading and irrelevant, and
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`takes Dr. Foote’s testimony out of context. What Dr. Foote actually testified is that
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`“Queen articulates principles of humanizing an antibody, Queen ’90 and Queen ’89.
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`And those teachings about homology, proximity to the CDRs through sequence or
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`through space, one using those would end up changing — well, may or may not, but
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`very likely would end up substituting some of the claimed residues in ’213. But I
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`didn’t give a specific example of how that would happen if that’s what you were
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`asking.” Ex. 2059 (Foote Tr.) at 32:22-33:9. He further clarified that he “didn’t
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`create a specific hypothetical example with sequence” and “didn’t do an illustrative
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`example the way someone might do as an example in a patent specification.” Id. at
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`33:19-22. What he did do, however, in both his opening and reply declarations, is
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`explain in detail how Queen 1989 and Queen 1990 disclose and/or render obvious
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`the limitations of the ’213 patent claims, and indeed how one skilled in the art
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`following Queen’s teachings would be led to the claimed invention of the ’213 patent
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`as a matter of course. Exs. 1503, ¶¶125-137; 155-349; 1702, ¶¶98-103, 122-181.
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`Response to Observation 5: Observation 5 is misleading and irrelevant. As
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`3
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`IPR2017-01489: Petitioners’ Responses to Observations on Cross-Examination
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`Dr. Foote explained in his reply declaration and at his deposition, the humanized
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`anti-Tac antibody described in Queen 1989 was later shown through a fluorescence
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`assay to have essentially the same binding affinity as the native murine antibody,
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`with Queen 1990 reporting that it could have up to four-fold more binding affinity.
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`Exs. 2059 (Foote Tr.) at 42:5-46:19; 1702, ¶¶103, 176. Moreover, PO does not
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`explain how the fact that Queen 1989 “does not disclose a humanized antibody with
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`better binding affinity than the original murine antibody from which it was made” is
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`any way relevant to the validity issues in this IPR, including with respect to claim
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`65. Moreover, this observation is irrelevant because Petitioners rely on different
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`references, Dr. Foote’s expert opinion, the admissions of PO’s own expert Dr.
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`Wilson, and the admissions regarding the state of the art in the ’213 patent, as
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`showing that achieving “up to 3-fold more” binding affinity than the parent with
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`humanized antibodies as required by claim 65 was either disclosed in, or obvious
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`over, the prior art. See Pet. at 51-52; Reply at 20-22; see also Response to
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`Observation 6, infra.
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`Response to Observation 6: Observation 6 is misleading and irrelevant. As
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`Dr. Foote explained at his deposition, Queen 1990 presents testing showing that the
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`binding affinity of the humanized anti-Tac antibody and its murine parent were
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`“about the same, within a factor of three and four” and that “that could be on either
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`side, less or more.” Ex. 2059 (Foote Tr.) at 46:7-19. This testimony is consistent
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`4
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`IPR2017-01489: Petitioners’ Responses to Observations on Cross-Examination
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`with the opinions in his declarations that, following prior art procedures including
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`those in Queen 1990, one skilled in the art would expect to be able to achieve around
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`the same binding affinity as the parent, including a moderate improvement in
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`affinity, which would meet the “up to 3-fold more” binding affinity limitation
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`of claim 65 of the ’213 patent, which sets no lower limit. Exs. 1503, ¶¶247-251;
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`306-310; 1702, ¶¶176-178. That is also consistent with the testimony of PO’s
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`expert Dr. Wilson that it was known from the prior art that “using the humanization
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`techniques that were known prior to the ’213 patent invention,” a POSITA “could
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`achieve about the same binding affinity as the parent” and that “in achieving around
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`about the same binding affinity as the parent, that might include a little bit more or
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`a little bit less.” Ex. 1697 (Wilson Tr.) at 104:12-105:5.
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`Response to Observation 7: Observation 7 is misleading and irrelevant. Dr.
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`Foote testified that “binding affinity is not a standard kind of entry when you submit
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`a new crystal structure to the database” but that “each entry in the Protein Data Bank
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`-- the main point of the entry is to give the [3D] coordinates, but they have subsidiary
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`information -- including references which may give binding -- those would be
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`literature references.” Ex. 2059 (Foote Tr.) at 50:10-51:11. Moreover, PO does not
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`identify the relevance of whether the PDB lists binding affinity to the validity issues
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`in this IPR, including with respect to claim 65. Indeed, this observation is irrelevant
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`because Petitioners rely on different references, Dr. Foote’s expert opinion, the
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`5
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`IPR2017-01489: Petitioners’ Responses to Observations on Cross-Examination
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`admissions of PO’s own expert Dr. Wilson, and the admissions regarding the state
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`of the art in the ’213 patent, as showing that achieving “up to 3-fold more” binding
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`affinity than the parent as required by claim 65 was either disclosed in, or obvious
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`over, the prior art. See Pet. at 51-52; Reply at 20-22; see also Response to
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`Observation 6, supra.
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`Response to Observation 8: Observation 8 is misleading and irrelevant. As
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`Dr. Foote explained at his deposition, Kurrle discloses at least one humanized
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`antibody that was able to achieve approximately the same binding affinity as the
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`native murine antibody. Ex. 2059 (Foote Tr.) at 74:2-17. His testimony that there
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`was “no clear evidence that it’s better” is consistent with the opinions in his
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`declarations that, following prior art procedures including those in Kurrle, one
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`skilled in the art would expect to be able to achieve around the same binding affinity
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`as the parent, including a moderate improvement in affinity, which would meet the
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`“up to 3-fold more” binding affinity limitation of claim 65 of the ’213 patent, which
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`sets no lower limit. Exs. 2059 (Foote Tr.) at 77:6-12; 1702, ¶¶127, 130, 176-178.
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`Moreover, this observation is irrelevant because Petitioners rely on different
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`references, Dr. Foote’s expert opinion, and the admissions of PO’s own expert Dr.
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`Wilson, as showing that achieving “up to 3-fold more” binding affinity than the
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`parent as required by claim 65 was either disclosed in, or obvious over, the prior art.
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`See Pet. at 51-52; Reply at 20-22; see also Response to Observation 6, supra.
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`6
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`IPR2017-01489: Petitioners’ Responses to Observations on Cross-Examination
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`Response to Observation 9: Observation 9 is misleading and irrelevant. Dr.
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`Foote testified that binding affinity is “not one of the parameters [Kabat 1987]
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`routinely reported, but it does give references to the sources of the sequences which
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`are usually papers that may have characterization that include[s] affinities,” and that
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`Kabat 1987 therefore reports binding affinities “in that indirect way.” Ex. 2059
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`(Foote Tr.) at 81:9-82:11. Moreover, PO does not explain how the fact that Kabat
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`1987 does not list any humanized antibodies or binding affinities is in any way
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`relevant to the validity issues in this IPR, including with respect to claim 65. This
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`observation is irrelevant because Petitioners rely on different references, Dr. Foote’s
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`expert opinion, the admissions of PO’s own expert Dr. Wilson, and the admissions
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`regarding the state of the art in the ’213 patent, as showing that achieving “up to 3-
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`fold more” binding affinity than the parent with humanized antibodies as required
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`by claim 65 was either disclosed in, or obvious over, the prior art. See Pet. at 51-52;
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`Reply at 20-22; see also Response to Observation 6, supra.
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`Response to Observation 10: Observation 10 is misleading and irrelevant.
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`This observation is irrelevant because Petitioners and Dr. Foote do not rely on
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`Chothia 1985 as describing humanized antibodies, but rather as identifying
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`framework positions that were known in the prior art to be important for antibody
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`conformation and binding, and therefore that would have been considered as
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`candidates for substitution in humanization of a murine antibody. Pet. at 25, 54-56;
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`7
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`IPR2017-01489: Petitioners’ Responses to Observations on Cross-Examination Exs.
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`1503, ¶¶148-149, 239-243; 1702, ¶¶108, 172-175. Moreover, PO does not
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`explain how the fact that Chothia 1985 does not list any humanized antibodies or
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`binding affinities is in any way relevant to the validity issues in this IPR, including
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`with respect to claim 65. Additionally, this observation is irrelevant because
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`Petitioners rely on different references, Dr. Foote’s expert opinion, the admissions
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`of PO’s own expert Dr. Wilson, and the admissions regarding the state of the art in
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`the ’213 patent, as showing that achieving “up to 3-fold more” binding affinity than
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`the parent with humanized antibodies as required by claim 65 was either disclosed
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`in, or obvious over, the prior art. See Pet. at 51-52; Reply at 20-22; see also Response
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`to Observation 6, supra.
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`Response to Observation 11: Observation 11 is misleading and irrelevant.
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`Petitioners and Dr. Foote do not rely on Chothia & Lesk as describing humanized
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`antibodies, but rather as identifying framework positions that were known in the
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`prior art to be important for antibody conformation and binding, and therefore that
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`would have been considered as candidates for substitution in humanization of a
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`murine antibody. Pet. at 24-25, 28, 52-54, 62; Exs. 1503, ¶¶ 35, 49, 116, 151-152,
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`236-238, 242, 264, 349; 1702, ¶¶107, 172. Moreover, PO does not explain how the
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`fact that Chothia & Lesk does not list any humanized antibodies or binding affinities
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`is in any way relevant to the validity issues in this IPR, including with respect to
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`claim 65. Additionally, this observation is irrelevant because Petitioners rely on
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`8
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`IPR2017-01489: Petitioners’ Responses to Observations on Cross-Examination
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`different references, Dr. Foote’s expert opinion, the admissions of PO’s own expert
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`Dr. Wilson, and the admissions regarding the state of the art in the ’213 patent, as
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`showing that achieving “up to 3-fold more” binding affinity than the parent with
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`humanized antibodies as required by claim 65 was either disclosed in, or obvious
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`over, the prior art. See Pet. at 51-52; Reply at 20-22; see also Response to
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`Observation 6, supra.
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`Response to Observation 12: Observation 12 is misleading and irrelevant.
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`In fact, when asked whether PO’s counsel was “correct that Tramontano does not
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`disclose a humanized antibody which has better binding affinity than the parent
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`murine antibody from which it was made,” Dr. Foote testified that “there’s a
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`discussion at the end … and that whole section Applications to Antibody
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`Engineering … and they explain how they think affinity might be improved by
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`incorporating their ideas about residue position 71.” Ex. 2059 (Foote Tr.) at 87:8-
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`88:2. And with respect to one of the papers discussed in Tramontano, the Verhoeyen
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`1988 paper, “[t]here’s an implication that if Verhoeyen might change the [residue]
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`71, she would get better affinity, but they’re just recounting what was already in the
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`literature.” Id. at 93:21-94:17. Moreover, PO does not explain how the fact that
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`Tramontano does not report any “experimental results in which a humanized
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`antibody obtained better binding affinity that the parent from which it was made” is
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`any way relevant to the validity issues in this IPR, including with respect to claim
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`9
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`IPR2017-01489: Petitioners’ Responses to Observations on Cross-Examination
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`65. Additionally, this observation is irrelevant because Petitioners rely on different
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`references, Dr. Foote’s expert opinion, the admissions of PO’s own expert Dr.
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`Wilson, and the admissions regarding the state of the art in the ’213 patent, as
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`showing that achieving “up to 3-fold more” binding affinity than the parent with
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`humanized antibodies as required by claim 65 was either disclosed in, or obvious
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`over, the prior art. See Pet. at 51-52; Reply at 20-22; see also Response to
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`Observation 6, supra.
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`Response to Observation 13: Observation 13 is misleading and irrelevant.
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`Petitioners and Dr. Foote do not rely on Furey as describing humanized antibodies,
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`but rather as identifying framework positions that were known in the prior art to
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`sufficiently proximate to the CDR residues to interact with them, thereby meeting
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`the prior art criteria from the Queen and Kurrle references as candidates for
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`substitution. Exs. 1503, ¶¶34, 115, 139, 233-234, 258, 280, 346-348; 1702, ¶¶109-
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`111; Pet. at 23-24, 28, 51-52, 61-62; Reply at 20-22. Moreover, PO does not explain
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`how the fact that Furey does not list any humanized antibodies or binding affinities
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`is in any way relevant to the validity issues in this IPR, including with respect to
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`claim 65. Additionally, this observation is irrelevant because Petitioners rely on
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`different references, Dr. Foote’s expert opinion, the admissions of PO’s own expert
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`Dr. Wilson, and the admissions regarding the state of the art in the ’213 patent, as
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`showing that achieving “up to 3-fold more” binding affinity than the parent with
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`10
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`IPR2017-01489: Petitioners’ Responses to Observations on Cross-Examination
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`humanized antibodies as required by claim 65 was either disclosed in, or obvious
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`over, the prior art. See Pet. at 51-52; Reply at 20-22; see also Response to
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`Observation 6, supra.
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`Response to Observation 14: Observation 14 is misleading and irrelevant.
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`This observation is irrelevant because Petitioners and Dr. Foote do not rely on
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`Hudziak as describing humanized antibodies, but rather as disclosing having
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`“prepared [murine] monoclonal antibodies against the extracellular domain of
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`p185HER2 … [t]o further investigate the consequences of alteration in HER2/c-erbB-
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`2 gene expression in mammary gland neoplasia,” reporting that “[o]ne monoclonal
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`antibody (4D5) was characterized in more detail and was shown to inhibit in vitro
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`proliferation of human breast tumor cells overexpressing p185HER2 and, furthermore,
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`to increase the sensitivity of these cells to the cytotoxic effects of TNF-α,” and
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`stating that “[m]onoclonal antibodies specific for p185HER2 may therefore be useful
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`therapeutic agents for the treatment of human neoplasias, including certain
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`mammary carcinomas, which are characterized by the overexpression of p185HER2.”
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`Pet. at 27-29, 56-60; Reply at 23-24; Exs. 1503, ¶¶40, 147, 327-349; 1702, ¶¶56,
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`112, 180-181. Hudziak is therefore relevant to the motivation of skilled artisans to
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`humanize anti-HER2 antibodies, in particular 4D5. Id. PO does not identify how
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`the fact that Hudziak does not disclose any humanized antibodies or anything
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`comparing the binding affinity of a humanized antibody with a parent antibody is in
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`11
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`IPR2017-01489: Petitioners’ Responses to Observations on Cross-Examination
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`any way relevant to the validity issues in this IPR, including with respect to claim
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`65. Moreover, this observation is also irrelevant because Petitioners rely on different
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`references, Dr. Foote’s expert opinion, the admissions of PO’s own expert Dr.
`
`Wilson, and the admissions regarding the state of the art in the ’213 patent, as
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`showing that achieving “up to 3-fold more” binding affinity than the parent with
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`humanized antibodies as required by claim 65 was either disclosed in, or obvious
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`over, the prior art. See Pet. at 51-52; Reply at 20-22; see also Response to
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`Observation 6, supra.
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` Date: July 3, 2018
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`Respectfully submitted,
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` /Amanda Hollis/
`Attorney For Petitioner Pfizer, Inc.
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`12
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`IPR2017-01489: Petitioners’ Responses to Observations on Cross-Examination
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`CERTIFICATE OF SERVICE
`The undersigned hereby certifies that a copy of the foregoing Responses to
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`Observations on Cross-Examination were served on July 3, 2018, via electronic
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`service on lead and back-up counsel:
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`For Genentech:
`david.cavanaugh@wilmerhale.com
`lauren.blakely@wilmerhale.com
`robert.gunther@wilmerhale.com
`abrausa@durietangri.com
`ddurie@durietangri.com
`andrew.danford@wilmerhale.com
`kevin.prussia@wilmerhale.com
`lisa.pirozzolo@wilmerhale.com
`
`For Samsung Bioepis Co., Ltd.:
`ddrivas@whitecase.com
`sweingaertner@whitecase.com
`eric.majchrzak@whitecase.com
`athakore@whitecase.com
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`13
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` /Amanda Hollis/
`Amanda Hollis
`
`