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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`Celltrion, Inc.
`Petitioner,
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`v.
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`Genentech, Inc.
`Patent Owner
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`Patent No. 6,407,213
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`Inter Partes Review No. IPR2017-01374
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`PETITIONER CELLTRION’S OPPOSITION TO PATENT OWNER’S
`MOTION FOR OBSERVATIONS ON CROSS EXAMINATION OF
`DR. LUTZ RIECHMANN
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`IPR2017-01374
`Petitioner’s Opposition to Motion for Observations
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`Response to Observation 1: Dr. Riechmann’s statements that residues
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`identified for back mutation would vary based on the antibody selected for
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`humanization is consistent with his statements in his second declaration. (Ex. 1143
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`at ¶¶ 26-27.) As Dr. Riechmann discussed in his first declaration, the Queen
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`references provide a method of humanization that a POSA could apply to any
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`given project, rather than a list of residue substitutions common to all
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`humanization projects. (Ex. 1003 at ¶¶ 119, 121-26.) Nothing in Dr. Riechmann’s
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`testimony suggests that a POSA would not have a reasonable expectation of
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`success in humanizing an antibody. His testimony that there are additional,
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`unclaimed, back mutations that a POSA could identify for use in a particular
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`antibody project, if appropriate, does not make the selection of the claimed
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`residues any less obvious. The ’213 patent provides a laundry list of potential
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`substitutions, but does not provide any information regarding which specific
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`substitutions will work for a given antibody other than the handful of examples in
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`the specification. (Paper 52 (Petitioner’s Reply) at 2, 11.)
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`Response to Observation 2: Dr. Riechmann’s statements that the residues
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`identified in the Queen references are not listed in the claims of the ’213 patent are
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`not relevant because the Queen references teach a method of humanization, which
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`when applied to a given humanization project would result in substitutions that
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`meet the requirements of the challenged claims. (Ex. 1003 at ¶¶ 119, 121-26.)
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`1
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`Further, Patent Owner’s argument that these statements contradict Petitioner’s
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`argument that “the prior art teaches humanized antibodies with the recited
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`substitutions that bind antigen” is misplaced. (Paper 65 (Motion for Observations)
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`at 2.) The specific residues will vary based on the antibody to be humanized, but
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`that does not change the fact that a POSA would have expected to be able to use
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`prior art teachings regarding antibody humanizations to arrive at an antibody that
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`binds an antigen.
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`Response to Observation 3: Patent Owner takes Dr. Riechmann’s
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`statements in paragraph 25 of his second declaration out of context. (Paper 65
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`(Motion for Observations) at 2.) Chothia 1985 identified the importance of residue
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`93H for antibody structure. (Ex. 1063 at 660.) A POSA, therefore, would have
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`been motivated to consider back mutation at 93H, based on the teachings of
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`Chothia 1985, in combination with the Queen references. (Ex. 1003 at ¶¶ 138,
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`227, 228.) As such, Dr. Riechmann’s testimony that Chothia 1985 does not relate
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`to a humanized antibody is irrelevant.
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`Response to Observation 4: Patent Owner takes Dr. Riechmann’s
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`statements in paragraph 25 of his second declaration out of context. (Paper 65
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`(Motion for Observations) at 4.) Chothia & Lesk identified the importance of
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`residue 78H as a residue that affected the framework structure and thus the
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`topology of the binding site. (Ex. 1063 at 906.) A POSA, therefore, would have
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`2
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`been motivated to consider back mutation at 78H, based on the teachings of
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`Chothia & Lesk, in combination with the Queen references. (Ex. 1003 at ¶¶ 104,
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`231-233.) As such, Dr. Riechmann’s testimony that Chothia & Lesk does not
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`relate to a humanized antibody is irrelevant. Petitioner does not object to the
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`correction that Dr. Riechmann made on the record regarding the table in paragraph
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`25 of his second declaration. (Ex. 2064 at 11:2-9.)
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`Response to Observation 5: As described in paragraphs 21 and 22 of
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`Dr. Riechmann’s second declaration, a POSA would have had a reasonable
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`expectation that Kurrle’s BMA-EUCIV4 would bind an antigen, because the other
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`Kurrle antibodies that contained back mutations bound antigens. (Ex. 1071 at
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`9:26-31; Ex. 1143, ¶¶ 21-22.) Dr. Riechmann’s statements at deposition are
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`consistent with that position. (Ex. 2064 at 50:15-22 (“The Kurrle reference has
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`binding data for CIV-3, which show that CIV-3 binds well, and CIV-4 . . . is a
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`mutant form of CIV-3, which further back mutations were made to improve the --
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`with the aim to improve the antibody affinity even more. So CIV-3 binds well and
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`CIV-4 is expected to bind or the aim is that CIV-4 would bind hopefully better
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`than CIV-3.”); 66:8-12 (“Q. Right. But as we discussed earlier, the Kurrle
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`reference doesn’t say what the binding affinity of CIV-4 is; right? A. No. You
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`would expect it to bind better than the best mutant, but it isn’t shown.”))
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`Response to Observation 6: Patent Owner takes Dr. Riechmann’s
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`statements in paragraph 25 of his second declaration out of context. (Paper 65
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`(Motion for Observations) at 4.) Chothia 1989 identified the importance of residue
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`71H for maintaining conformation of immunoglobulin hypervariable regions.
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`(Ex. 1003 at ¶ 143; Ex. 1049 at 877.) A POSA, therefore, would have been
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`motivated to consider back mutation at 71H, based on the teachings of Chothia
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`1989, in combination with the Queen references. (Ex. 1003 at ¶ 138.) As such,
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`Dr. Riechmann’s testimony that Chothia 1989 does not relate to a humanized
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`antibody is irrelevant.
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`Response to Observation 7: As Dr. Riechmann explained in his first
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`declaration, Tramontano taught that “the major determinant of the position of H2 is
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`the size of the residue at site 71, a site that is in the conserved framework of the
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`VH domain” and that “[u]nderstanding the relationship between the residue at
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`position 71 and the position and conformation of H2 has applications to the
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`prediction and engineering of antigen binding sites of immunoglobulins.”
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`(Ex. 1003 at ¶ 132; Ex. 1051 at Abstract.) A POSA, therefore, would have been
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`motivated to consider back mutation at 71H, based on the teachings of Tramontano
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`with the Queen references. (Ex. 1003 at ¶¶ 132, 281.) Dr. Riechmann’s statements
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`regarding Jones and whether there was back mutation at 71H in that reference are
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`not relevant to what Tramantano plainly taught.
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`Response to Observation 8: As Dr. Riechmann explained in his first
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`4
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`declaration, Tramontano taught that “the major determinant of the position of H2 is
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`the size of the residue at site 71, a site that is in the conserved framework of the
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`VH domain” and that “[u]nderstanding the relationship between the residue at
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`position 71 and the position and conformation of H2 has applications to the
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`prediction and engineering of antigen binding sites of immunoglobulins.”
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`(Ex. 1003 at ¶ 132; Ex. 1051 at Abstract.) A POSA, therefore, would have been
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`motivated to consider back mutation at 71H, based on the teachings of Tramontano
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`with the Queen references. (Ex. 1003 at ¶¶ 132, 281.) Dr. Riechmann’s statements
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`regarding Verhoeyen and whether there was back mutation at 71H in that reference
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`are not relevant to what Tramantano plainly taught.
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`Response to Observation 9: As Dr. Riechmann explained in his first
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`declaration, Tramontano taught that “the major determinant of the position of H2 is
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`the size of the residue at site 71, a site that is in the conserved framework of the
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`VH domain” and that “[u]nderstanding the relationship between the residue at
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`position 71 and the position and conformation of H2 has applications to the
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`prediction and engineering of antigen binding sites of immunoglobulins.”
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`(Ex. 1003 at ¶ 132; Ex. 1051 at Abstract.) A POSA, therefore, would have been
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`motivated to consider back mutation at 71H, based on the teachings of
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`Tramontano, in combination with the Queen references. (Ex. 1003 at ¶¶ 132, 281.)
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`Dr. Riechmann’s statements regarding Riechmann 1988 and whether there was
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`5
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`back mutation at 71H in that reference are not relevant to what Tramantano plainly
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`teaches.
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`Response to Observation 10: As Dr. Riechmann stated in his second
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`declaration, a POSA could have used routine mutagenesis and back-mutation to
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`arrive at an optimized antibody with better binding than the murine antibody. (Ex.
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`1143 at ¶ 20.) The claim language states “up to 3-fold more binding affinity,”
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`which means that any improvement would fall within the claim language. (Paper
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`52 (Petitioner’s Reply) at 15.) A POSA would have known that routine
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`optimization could lead to some degree of improvement; therefore, Dr.
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`Riechmann’s testimony is not relevant.
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`Response to Observation 11: Dr. Riechmann testified that he was qualified
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`to render an opinion regarding paragraph 34 of his second declaration, which
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`relates to the fact that Herceptin® does not use a consensus sequence. (Ex. 1143 at
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`¶ 34; Ex. 2064 at 87:11-15 (“Q. Do you believe you're qualified to render the
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`opinion expressed in paragraph 34? . . . A. Yes.”). As such, the portion of Dr.
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`Riechmann’s testimony referred to by Patent Owner is taken out of context.
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`Dated: July 6, 2018
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`Respectfully submitted,
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`/Cynthia Lambert Hardman/
`Cynthia Lambert Hardman (Reg. No. 53,179)
`Elizabeth J. Holland (Reg. No. 47,657)
`Robert V. Cerwinski (admitted pro hac vice)
`6
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`Linnea P. Cipriano (Reg. No. 67,729)
`GOODWIN PROCTER LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018
`(212) 813-8800 (telephone)
`(212) 355-3333 (facsimile)
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`Sarah J. Fischer (Reg. No. 74,104)
`GOODWIN PROCTER LLP
`100 Northern Avenue
`Boston, MA, 02210
`(617) 570-3908 (telephone)
`(617) 801-8991 (facsimile)
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`Counsel for Petitioner
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`7
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`CERTIFICATE OF SERVICE
`Pursuant to 37 C.F.R. § 42.6(e), I certify that on this 22th day of June, 2018, I
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`caused a copy of this PETITIONER CELLTRION’S OPPOSITION TO PATENT
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`OWNER’S MOTION FOR OBSERVATIONS ON CROSS EXAMINATION OF
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`DR. LUTZ RIECHMANN by email on the lead and back up counsel for Patent
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`Owners at:
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`David Cavanaugh (David.Cavanaugh@wilmerhale.com)
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`Lauren V. Blakely (lauren.blakely@wilmerhale.com)
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`Robert Gunther (Robert.Gunther@wilmerhale.com)
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`Adam Brausa (abrausa@durietangri.com)
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`Daralyn Durie (ddurie@durietangri.com)
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`Andrew Danford (Andrew.Danford@wilmerhale.com)
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`Lisa Pirozzolo (Lisa.Pirozzolo@wilmerhale.com)
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`Kevin Prussia (Kevin.Prussia@wilmerhale.com)
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`By: /Cynthia Lambert Hardman/
`Cynthia Lambert Hardman (Reg. No. 53,179)
`GOODWIN PROCTER LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018
`(212) 813-8800 (telephone)
`(212) 355-3333 (facsimile)
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