UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PFIZER, INC., and
`SAMSUNG BIOEPIS CO., LTD.,1
`Petitioners,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________
`
`Case IPR2017-01488
`Patent 6,407,213
`____________
`
`
`
`PETITIONERS’ RESPONSES TO PATENT OWNER’S OBSERVATIONS
`ON CROSS-EXAMINATION OF JEFFERSON FOOTE, PH.D.2
`
`
`
`
`
`
`1 Samsung Bioepis Co. Ltd.’s IPR2017-02139 has been joined with this
`
`proceeding. (IPR2017-02139, Paper 42.)
`
`2 All emphases within are added.
`
`
`
`
`
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PFIZER, INC., and
`SAMSUNG BIOEPIS CO., LTD.,1
`Petitioners,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________
`
`Case IPR2017-01488
`Patent 6,407,213
`____________
`
`
`
`PETITIONERS’ RESPONSES TO PATENT OWNER’S OBSERVATIONS
`ON CROSS-EXAMINATION OF JEFFERSON FOOTE, PH.D.2
`
`
`
`
`
`
`1 Samsung Bioepis Co. Ltd.’s IPR2017-02139 has been joined with this
`
`proceeding. (IPR2017-02139, Paper 42.)
`
`2 All emphases within are added.
`
`
`
`
`
`
`
`IPR2017-01488: Petitioners’ Responses to Observations on Cross-Examination
`
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`Pursuant to the Joint Notice of Stipulation to Revise Schedule (Paper 53),
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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 64).
`
`Responses to Foote (Ex. 2059) Observations
`
`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. 1069) 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. 1003, ¶103;
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`1202, ¶¶12, 42-43, 82; 2039 (Foote Tr.) at 327:12–331:11. This reference is
`
`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
`
`
`
`1
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`
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`IPR2017-01488: Petitioners’ Responses to Observations on Cross-Examination
`
`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.1 at 11-13.
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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 1990 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. 1003, ¶¶34-35; 120, 179-182, 188; 1202, ¶¶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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`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. 1202, ¶15; 1199 (Presta Tr.) at 98:25–99:5.
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`Response to Observation 3: Observation 3 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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`
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`2
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`
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`IPR2017-01488: Petitioners’ Responses to Observations on Cross-Examination
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`asking.” Ex. 2059 (Foote Tr.) at 32:22-33:9. He further clarified that he “didn’t
`
`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. 1003, ¶¶125-137; 155-349; 1202, ¶¶98-103, 122-181.
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`Response to Observation 4: Observation 4 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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`with the opinions in his declarations that, following prior art procedures including
`
`those in Queen 1990, one skilled in the art would expect to be able to achieve around
`
`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 of
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`claim 65 of the ’213 patent, which sets no lower limit. Exs. 1003, ¶¶247-251; 306-
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`310; 1202, ¶¶176-178. That is also consistent with the testimony of PO’s expert Dr.
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`Wilson that it was known from the prior art that “using the humanization techniques
`
`
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`3
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`
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`IPR2017-01488: Petitioners’ Responses to Observations on Cross-Examination
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`that were known prior to the ’213 patent invention,” a POSITA “could achieve about
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`the same binding affinity as the parent” and that “in achieving around about the same
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`binding affinity as the parent, that might include a little bit more or a little bit less.”
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`Ex. 1197 (Wilson Tr.) at 104:12-105:5.
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`Response to Observation 5: Observation 5 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
`
`admissions of PO’s own expert Dr. Wilson, and the admissions regarding the state
`
`of the art in the ’213 patent, as showing that achieving “up to 3-fold more” binding
`
`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 55-56; Reply at 21-23; see also Response to
`
`Observation 4, supra.
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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, Kurrle discloses at least one humanized
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`
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`4
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`
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`IPR2017-01488: Petitioners’ Responses to Observations on Cross-Examination
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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
`
`declarations that, following prior art procedures including those in Kurrle, one
`
`skilled in the art would expect to be able to achieve around the same binding affinity
`
`as the parent, including a moderate improvement in affinity, which would meet the
`
`“up to 3-fold more” binding affinity limitation of claim 65 of the ’213 patent, which
`
`sets no lower limit. Exs. 2059 (Foote Tr.) at 77:6-12; 1202, ¶¶127, 130, 176-178.
`
`Moreover, this observation is irrelevant because Petitioners rely on different
`
`references, Dr. Foote’s expert opinion, and the admissions of PO’s own expert Dr.
`
`Wilson, as showing that achieving “up to 3-fold more” binding affinity than the
`
`parent as required by claim 65 was either disclosed in, or obvious over, the prior art.
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`See Pet. at 55-56; Reply at 21-23; see also Response to Observation 4, supra.
`
`Response to Observation 7: Observation 7 is misleading and irrelevant. Dr.
`
`Foote testified that binding affinity is “not one of the parameters [Kabat 1987]
`
`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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`5
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`
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`IPR2017-01488: Petitioners’ Responses to Observations on Cross-Examination
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`relevant to the validity issues in this IPR, including with respect to claim 65. This
`
`observation is irrelevant because Petitioners rely on different 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 showing that achieving “up to 3-
`
`fold more” binding affinity than the parent with humanized antibodies as required
`
`by claim 65 was either disclosed in, or obvious over, the prior art. See Pet. at 55-56;
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`Reply at 21-23; see also Response to Observation 4, supra.
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`Response to Observation 8: Observation 8 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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`Exs. 1003, ¶¶148-149, 239-243; 1202, ¶¶108, 172-175. Moreover, PO does not
`
`explain how the fact that Chothia 1985 does not list any humanized antibodies or
`
`binding affinities is in any way relevant to the validity issues in this IPR, including
`
`with respect to claim 65. Additionally, this observation is irrelevant because
`
`Petitioners rely on different 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 showing that achieving “up to 3-fold more” binding affinity than
`
`
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`6
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`
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`IPR2017-01488: Petitioners’ Responses to Observations on Cross-Examination
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`the parent with humanized antibodies as required by claim 65 was either disclosed
`
`in, or obvious over, the prior art. See Pet. at 55-56; Reply at 21-23; see also Response
`
`to Observation 4, supra.
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`Response to Observation 9: Observation 9 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. 1003, ¶¶ 35, 49, 116, 151-152,
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`236-238, 242, 264, 349; 1202, ¶¶107, 172. Moreover, PO does not explain how the
`
`fact that Chothia & Lesk does not list any humanized antibodies or binding affinities
`
`is in any way relevant to the validity issues in this IPR, including with respect to
`
`claim 65. Additionally, this observation is irrelevant because Petitioners rely on
`
`different 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
`
`showing that achieving “up to 3-fold more” binding affinity than the parent with
`
`humanized antibodies as required by claim 65 was either disclosed in, or obvious
`
`over, the prior art. See Pet. at 55-56; Reply at 21-23; see also Response to
`
`Observation 4, supra.
`
`Response to Observation 10: Observation 10 is misleading and irrelevant.
`
`
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`7
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`
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`IPR2017-01488: Petitioners’ Responses to Observations on Cross-Examination
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`In fact, when asked whether PO’s counsel was “correct that Tramontano does not
`
`disclose a humanized antibody which has better binding affinity than the parent
`
`murine antibody from which it was made,” Dr. Foote testified that “there’s a
`
`discussion at the end … and that whole section Applications to Antibody
`
`Engineering … and they explain how they think affinity might be improved by
`
`incorporating their ideas about residue position 71.” Ex. 2059 (Foote Tr.) at 87:8-
`
`88:2. And with respect to one of the papers discussed in Tramontano, the Verhoeyen
`
`1988 paper, “[t]here’s an implication that if Verhoeyen might change the [residue]
`
`71, she would get better affinity, but they’re just recounting what was already in the
`
`literature.” Id. at 93:21-94:17. Moreover, PO does not explain how the fact that
`
`Tramontano does not report any “experimental results in which a humanized
`
`antibody obtained better binding affinity that the parent from which it was made” is
`
`in any way relevant to the validity issues in this IPR, including with respect to claim
`
`65. Additionally, this observation is irrelevant because Petitioners rely on different
`
`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
`
`showing that achieving “up to 3-fold more” binding affinity than the parent with
`
`humanized antibodies as required by claim 65 was either disclosed in, or obvious
`
`over, the prior art. See Pet. at 55-56; Reply at 21-23; see also Response to
`
`Observation 4, supra.
`
`
`
`8
`
`
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`IPR2017-01488: Petitioners’ Responses to Observations on Cross-Examination
`
`
`Response to Observation 11: Observation 11 is misleading and irrelevant.
`
`Petitioners and Dr. Foote do not rely on Furey as describing humanized antibodies,
`
`but rather as identifying framework positions that were known in the prior art to
`
`sufficiently proximate to the CDR residues to interact with them, thereby meeting
`
`the prior art criteria from the Queen and Kurrle references as candidates for
`
`substitution. Exs. 1003, ¶¶34, 115, 139, 233-234, 258, 280, 346-348; 1202, ¶¶109-
`
`111; Pet. at 23-24, 28, 51-52, 61-62; Reply at 17, n. 6. Moreover, PO does not
`
`explain how the fact that Furey does not list any humanized antibodies or binding
`
`affinities is in any way relevant to the validity issues in this IPR, including with
`
`respect to claim 65. Additionally, this observation is irrelevant because Petitioners
`
`rely on different 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 showing that achieving “up to 3-fold more” binding affinity than the parent with
`
`humanized antibodies as required by claim 65 was either disclosed in, or obvious
`
`over, the prior art. See Pet. at 55-56; Reply at 21-23; see also Response to
`
`Observation 4, supra.
`
`Response to Observation 12: Observation 12 is misleading and irrelevant.
`
`This observation is irrelevant because Petitioners and Dr. Foote do not rely on
`
`Hudziak as describing humanized antibodies, but rather as disclosing having
`
`“prepared [murine] monoclonal antibodies against the extracellular domain of
`
`
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`9
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`
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`IPR2017-01488: Petitioners’ Responses to Observations on Cross-Examination
`
`p185HER2 … [t]o further investigate the consequences of alteration in HER2/c-erbB-
`
`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
`
`proliferation of human breast tumor cells overexpressing p185HER2 and, furthermore,
`
`to increase the sensitivity of these cells to the cytotoxic effects of TNF-α,” and
`
`stating that “[m]onoclonal antibodies specific for p185HER2 may therefore be useful
`
`therapeutic agents for the treatment of human neoplasias, including certain
`
`mammary carcinomas, which are characterized by the overexpression of p185HER2.”
`
`Pet. at 25-28, 56-61; Reply at 23-24; Exs. 1003, ¶¶40, 147, 327-349; 1202, ¶¶56,
`
`112, 180-181. Hudziak is therefore relevant to the motivation of skilled artisans to
`
`humanize anti-HER2 antibodies, in particular 4D5. Id. PO does not identify how
`
`the fact that Hudziak does not disclose any humanized antibodies or anything
`
`comparing the binding affinity of a humanized antibody with a parent antibody is in
`
`any way relevant to the validity issues in this IPR, including with respect to claim
`
`65. Moreover, this observation is also irrelevant because Petitioners rely on different
`
`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
`
`showing that achieving “up to 3-fold more” binding affinity than the parent with
`
`humanized antibodies as required by claim 65 was either disclosed in, or obvious
`
`over, the prior art. See Pet. at 55-56; Reply at 21-23; see also Response to
`
`
`
`10
`
`
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`IPR2017-01488: Petitioners’ Responses to Observations on Cross-Examination
`
`Observation 4, supra.
`
` Date: July 3, 2018
`
`
`
`
`
`Respectfully submitted,
`
` /Amanda Hollis/
`Attorney For Petitioner Pfizer, Inc.
`
`11
`
`
`
`IPR2017-01488: Petitioners’ Responses to Observations on Cross-Examination
`
`
`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
`
`service on lead and back-up counsel:
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` /Amanda Hollis/
`Amanda Hollis
`
`12
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`
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