IPR2017-01373
`Petitioner’s Reply
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`Celltrion, Inc.
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`Petitioner,
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`v.
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`Genentech, Inc.
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`Patent Owner
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`Patent No. 6,407,213
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`Inter Partes Review No. IPR2017-01373
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`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
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`IPR2017-01373
`Petitioner’s Reply
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`2.
`3.
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`4.
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`5.
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`6.
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`B.
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`C.
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`Table of Contents
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`All Challenged Claims Would Have Been Obvious over Queen-1989 or
`Queen-1990 and the PDB Database, Optionally in Light of Tramontano
`and/or Kabat-1987 and/or Hudziak ..................................................................... 4
`A.
`Claims 12, 42, 60, 65-67, and 71-79 are Obvious Over Queen-1989
`or Queen-1990, in Combination with the PDB ......................................... 4
`1.
`A POSA Following the Teachings of the Prior Art Would Have
`Identified the Claimed Residues for Substitution ........................... 4
`A POSA Would Have Used The PDB As Dr. Riechmann Did ...... 7
`A POSA Would Have Expected the Resulting Humanized mAb
`to Bind the Target Antigen ............................................................. 8
`Holding the Challenged Claims Invalid Would Not Have
`“Sweeping Consequences” ........................................................... 10
`Petitioner’s Arguments Regarding Queen-1989 Do Not Rely
`on Queen-1990 .............................................................................. 10
`Queen-1990 and Tramontano Further Support Petitioner’s
`Position .......................................................................................... 11
`The Consensus Sequence Limitation of Claims 4, 33, 62, 64, and 69
`Was Taught By the Prior Art ................................................................... 12
`The “Up to 3-Fold More Binding Affinity” Limitation of Claim 65
`Was Taught By the Prior Art ................................................................... 15
`The “Lack Immunogenicity Compared to a Non-Human Parent”
`Limitation of Claim 63 Was Taught By the Prior Art ............................ 16
`The Limitations Related to Binding p185HER2 of Claims 30-31, 33,
`42, and 60 Was Taught By the Prior Art ................................................. 17
`PO’s Attempts to Establish an Earlier Date of Invention for Claims 12, 42,
`60, 65, 71, 73-74, and 79 Are Insufficient ......................................................... 18
`Secondary Considerations of Non-Obviousness Do Not Render the
`Challenged Claims Nonobvious ........................................................................ 21
`A.
`The Use of a Consensus Sequence Would Not Have Been
`Unexpected .............................................................................................. 21
`PO Has Not Established that the Alleged Unexpected Results and
`Commercial Success Have a Nexus to the Challenged Claims .............. 22
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`i
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`D.
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`E.
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`B.
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`I.
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`II.
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`III.
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`TABLE OF AUTHORITIES
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`IPR2017-01373
`Petitioner’s Reply
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` Page(s)
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`Cases
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) .............................................................................. 14
`
`Chiron Corp. v. Genentech Inc.,
`363 F.3d 1247 (Fed. Cir. 2004) .............................................................................. 20
`
`Coleman v. Dines,
`754 F.2d 353 (Fed. Cir. 1985) ................................................................................ 18
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`Ecolochem, Inc. v. S. Cal. Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000) .............................................................................. 18
`
`Ecolochem, Inc. v. S. Cal. Edison Co.,
`91 F.3d 169, 1996 WL 297601 (Fed. Cir. 1996) .................................................. 3, 5
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`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .................................................................................................. 6
`
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009) ................................................................................ 9
`
`Mahurkar v. C.R. Bard, Inc.,
`79 F.3d 1572 (Fed. Cir. 1996) ................................................................................ 18
`
`Medichem, S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) .............................................................................. 18
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`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) .............................................................................. 22
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ................................................................................ 7
`
`Santarus, Inc. v. Par Pharm., Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) .............................................................................. 16
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`ii
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`IPR2017-01373
`Petitioner’s Reply
`St. Jude Med., Cardiology Division, Inc. v. Board of Regents of the Univ.
`of Mich., IPR2013-00041, Paper 69 (PTAB May 1, 2014) .................................... 24
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`Ex Parte Takeshi Shimono,
`Appeal 2013–003410 (PTAB Apr. 29, 2015) ......................................................... 22
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`Statutes
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`35 U.S.C. §102(b) ........................................................................................................ 20
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`IPR2017-01373
`Petitioner’s Reply
`After the Board considered the prior art cited by Petitioner and granted
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`institution, PO abandoned its defense of claims 1, 2, 25, 29, 80, and 81 (POR, 18-
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`22), essentially conceding that their limitations did not constitute patentable
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`distinctions over the work of others.1
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`Having made this concession, PO falls back to the position that certain
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`elements distinguish a handful of remaining claims from the prior art: (1) the use
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`of a “human consensus sequence” as the human framework (claims 4, 33, 62, 64
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`and 69), (2) “lack of immunogenicity as compared to a non-human parent
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`antibody” (claim 63), (3) “up to 3-fold more” binding affinity than the parent
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`antibody (claim 65), and (4) binding to p185HER2 (claim 30). (POR, 1-4.) PO also
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`alleges that even if some of the claimed substitutions were explicitly disclosed in
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`the prior art, not all of them were. (POR, 3-4.) These elements do not make the
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`otherwise-obvious claims patentable, however.
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`Elements (1)-(4) above affect only a small number of claims. PO’s
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`arguments do not change the fact that each element was explicitly disclosed in, or
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`obvious from, the prior art.
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`PO’s allegation that not all of the claimed residues are explicitly disclosed in
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`the prior art ignores all that the prior art teaches, as well as the limitations of what
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`1 Therefore, this Reply addresses the remaining challenged claims: 4, 12, 30, 31, 33,
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`42, 60, 62-67, 69, and 71-79.
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`IPR2017-01373
`Petitioner’s Reply
`the patent teaches. The patent does not teach that all of the claimed substitutions
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`and possible combinations thereof will work to improve the binding of all of the
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`huge number of antibodies that could fall within the claims. Indeed, as the patent
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`and prior art make clear, the substitutions needed to optimize antigen binding will
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`vary from mAb to mAb. In fact, the patent does not teach that any specific
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`substitution will work in any specific mAb falling within the claims, other than the
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`handful of examples provided. Instead, the patent teaches that a POSA must
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`conduct extensive modeling to determine which of the claimed substitutions might
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`possibly improve binding in a given project, and then use serial mutagenesis—
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`making mAbs with different substitutions and then testing them—to confirm which
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`precise combination of possibilities optimizes that binding. But there is no
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`material difference between this method and the humanization roadmap laid out in
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`Queen-1989 and -1990. PO’s expert Dr. Wilson conceded that each of the steps
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`required would have been routine to a POSA, and thus PO cannot credibly dispute
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`that a POSA would have been able to identify the claimed substitutions when
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`developing humanized mAbs that require them for optimal binding affinity. In
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`fact, if this is not the case, the claims are not enabled.
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`In addition, PO misconstrues the law when it comes to the laundry lists of
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`substitutions recited in the Markush groups of claims 4, 12, 30, 31, 33, 42, 60, 62,
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`63, 65-67, 69, and 71-78. As the Board found in its institution decision, a POSA
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`IPR2017-01373
`Petitioner’s Reply
`applying the roadmap in Queen-1989 or -1990 would have identified at least some
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`of the residues in each of claims 4, 30, 31, 33, 62, 63, 64 65, 66, 67, 69, and 78 as
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`likely candidates for substitution during humanization. (Institution Decision, 16)
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`(A POSA “would have identified nine positions in the light chain and eleven in the
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`heavy chain as candidates for substitution, including those recited in the challenged
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`claims.”). Since the claimed Markush groups merely require “one or more” of the
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`recited substitutions, this is sufficient to render them obvious. See, e.g.,
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`Ecolochem, Inc. v. S. Cal. Edison Co., 91 F.3d 169, 1996 WL 297601, *2 (Fed.
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`Cir. 1996) (“[I]f utilizing one element of the [Markush] group is anticipated or
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`obvious, the patentee is precluded from arguing that the claim is valid.”). In
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`addition, as the Board found, a POSA would have identified all of the substitutions
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`in claims 12, 42, 60 and 71-79 (Institution Decision, 16), which means they, too,
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`are invalid.
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`PO’s attempt to avoid invalidity through antedating also fails. The evidence
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`of record is not corroborated and does not satisfy PO’s burden to prove an earlier
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`invention date. Moreover, PO only attempts to establish an earlier invention date
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`of claims 12, 42, 60, 65, 71, 73-74, and 79, and therefore concedes that it cannot
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`antedate Petitioner’s prior art for claims 4, 30-31, 33, 62-64, 66-67, 69, 72, and 75-
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`78.
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`I.
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`IPR2017-01373
`Petitioner’s Reply
`All Challenged Claims Would Have Been Obvious over Queen-1989 or
`Queen-1990 and the PDB Database, Optionally in Light of Tramontano
`and/or Kabat-1987 and/or Hudziak
`A. Claims 12, 42, 60, 65-67, and 71-79 are Obvious Over Queen-1989 or
`Queen-1990, in Combination with the PDB
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`1.
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`A POSA Following the Teachings of the Prior Art Would Have
`Identified the Claimed Residues for Substitution
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`PO faults the Queen references as leading POSAs “to a broad genus of
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`potential framework substitutions,” and alleges incorrectly that “Petitioner has
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`provided no reason why a skilled artisan would have selected the specific
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`framework substitutions recited in the challenged claims.” (POR, 46.) PO does
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`not deny that a POSA following the prior art would identify the residues in claims
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`12, 42, 60, 65-67, and 71-79 as candidates for substitution, only that a POSA
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`would not limit the candidates to those specific residues. But this does not save the
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`claims.
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`The ’213 patent purports to identify a laundry list of murine framework
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`residues that can be substituted for the corresponding human framework residues
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`to improve binding affinity. However, the patent does not tell a POSA which of
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`these residues to substitute in a specific humanized mAb project beyond
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`huMAb4D5, anti-CD3, and anti-CD18. (Ex. 1143, ¶4.) And as Figures 5-6 and
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`Table 3 of the patent make clear, each humanized mAb requires a different set of
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`substitutions to optimize binding affinity. (Ex. 1001; Ex. 1143, ¶20.) While the
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`IPR2017-01373
`Petitioner’s Reply
`patent claims a laundry list of possible substitutions to try, the only guidance in the
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`’213 patent concerning how to select specific substitutions that will work in mAbs
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`beyond the examples is, as PO’s expert Dr. Wilson acknowledged, remarkably
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`similar to the guidance in Queen-1989 and Queen-1990. The patent requires a
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`POSA to construct a computer model, identify the residues that, because of their
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`positions within the VH and VL domains, could alter binding affinity, and then
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`conduct trial-and-error mutagenesis to see which substitutions improve binding.
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`(Ex. 1138, 116:1-122:1; compare Ex. 1050, 12:17-17:24 with Ex. 1001, 20:41-
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`21:3; Ex. 1142, 76:19-80:13.) Dr. Wilson further conceded that it would have
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`required nothing more than routine skill and experimentation to use these methods
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`to identify specific residue(s) that would work in a given humanization project.
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`(Ex. 1138, 116:1-122:1; see also Ex. 1142, 97:14-98:22.)
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`As discussed in the Petition regarding Ground 1, a POSA following the
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`Queen-1989 roadmap and using the PDB would have identified the substitutions at
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`4L, 58L, 66L, 67L, 69L, 73L, 2H, 45H, and 69H using concededly routine skill.
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`Since claims 4, 12, 30, 31, 33, 42, 60, 62, 63, 65-67, 69, 71-75, and 78 each merely
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`require that “one or more” of the listed residues be selected for substitution, they
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`are invalid. See Ecolochem, 1996 WL 297601, *2 (“[I]f utilizing one element of
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`the [Markush] group is anticipated or obvious, the patentee is precluded from
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`IPR2017-01373
`Petitioner’s Reply
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`arguing that the claim is valid.”).2
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`PO’s complaint that POSAs would have been faced with a large list of
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`residues to choose from ignores that the patent likewise requires a POSA to choose
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`the particular substitutions needed for a given humanization project from the large
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`list of possibilities recited in the patent. PO has conceded that this kind of
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`selection would have involved nothing but routine skill, thus it does not weigh
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`against obviousness. See, e.g., KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416
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`(2007) (“The combination of familiar elements according to known methods is
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`likely to be obvious when it does no more than yield predictable results.”).
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`The fact that a POSA would have understood from the cited prior art
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`references that additional residues were also candidates for substitution is also
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`immaterial. A POSA would have understood that a given humanization project
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`may require substitutions not described in the patent, and thus that the list of
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`possible substitutions in the patent is incomplete. (Ex. 1143, ¶¶8-12.) Indeed,
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`Perjeta® (pertuzumab)—which PO states was made using methods disclosed in the
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`patent—contains substitutions not described in the patent. (Ex. 1138, 253:18-
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`254:21.) PO offers no rationale why the selection process required by the patent is
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`any less complex than the selection process disclosed in the prior art.
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`2 Dr. Wilson’s opinions applied an improper legal standard, requiring every recited
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`framework substitution to be obvious. (Ex. 1138, 91:3-92:14.)
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`IPR2017-01373
`Petitioner’s Reply
`Additionally, PO does not point to any evidence that the particular
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`substitutions listed in claims 12, 42, 60, 65-67, and 71-79 are critical to the claimed
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`invention. The prior art identified a range of potential residues to be substituted in
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`a humanization project, including the claimed residues. As a result, these residues
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`are prima facie obvious, and the patentee must establish “that the [claimed residue]
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`is critical, generally by showing that the claimed range achieves unexpected results
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`relative to the prior art range.” In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir.
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`2003) (quoting In re Geisler, 116 F.3d 1465, 1469-70 (Fed. Cir. 1997)). PO has
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`not made any such showing, and therefore, the selection of the residues listed in
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`claims 12, 42, 60, 65-67, and 71-79 would have been obvious. (Ex. 1143, ¶¶26-27;
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`Ex. 1001, Table 3; Ex. 1142, 131:10-132:5.)
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`2.
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`A POSA Would Have Used The PDB As Dr. Riechmann Did
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`PO incorrectly argues that “the Queen references do not teach using the PDB
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`database as Petitioner uses it.” (POR, 45.) PO does not dispute that the Queen
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`references teach the use of computer modeling to identify residues that influence
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`the conformations of the murine CDRs or interact directly with the antigen. (See
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`Ex. 1003, ¶¶249, 260; Ex. 1034, 10031; Ex. 1050, 14:32-36.) The prior art teaches
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`the use of the PDB data to do this. (See, e.g., Ex. 1050, 14:32-36; Ex. 1062, 902).
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`Indeed, a POSA would have had to use data like that contained in the PDB to
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`create an accurate molecular model. (Ex. 1143, ¶5.) Although PO points out that
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`IPR2017-01373
`Petitioner’s Reply
`the Queen references describe modeling the murine antibody versus the humanized
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`antibody, PO ignores that the modeling in Queen-1989 also considered “other
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`antibody V domains with known crystal structure” when constructing the model
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`(Ex. 1034, 10031), and Queen-1990 disclosed using “known antibody structures”
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`in the PDB as rough models (Ex. 1050, 16). PO also does not allege that this
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`distinction would alter the analysis in any respect, and a POSA would have
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`recognized that the Queen method is a reliable means of identifying framework
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`residue substitutions that would improve binding. (Ex. 1143, ¶¶6-7.)
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`3.
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`A POSA Would Have Expected the Resulting Humanized mAb
`to Bind the Target Antigen
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`PO incorrectly argues that there is no evidence that a POSA would have
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`expected a humanized mAb to bind an antigen.3 The claim language “bind an
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`antigen” encompasses binding to any degree. PO’s expert admitted that in a
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`humanization project “one approach to try to regain the binding affinity . . . was to
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`make additional substitutions back to mouse in the human framework.” (Ex. 1138,
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`28:2-8.)
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`PO’s argument ignores all of the prior art discussing successful
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`3 PO makes similar arguments with respect to claims 4, 33, 62, and 69. (POR, 56-
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`57.) The arguments presented in this section apply with equal weight to those
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`claims.
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`IPR2017-01373
`Petitioner’s Reply
`humanization projects. For example, Queen-1989’s humanized anti-Tac mAb
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`bound the target antigen with high affinity. (Ex. 1034, 10029, 10033 (“The
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`resulting humanized antibody has a high affinity, 3 x 109 M-1, for its antigen.”).)
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`Dr. Riechmann’s humanized CAMPATH mAb similarly had high binding affinity.
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`(Ex. 1069, 3.) A POSA using the methodology set forth in Queen-1990 would
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`have understood that the prior art methods for humanization had been successfully
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`used to achieve mAbs with high binding affinity. (Ex. 1050, Abstract (disclosed
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`antibodies “retain the same affinity as the donor immunoglobulin to the antigen”).)
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`A POSA using prior art methods would have had a reasonable expectation of
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`achieving results at least as good as those disclosed in the prior art. (Ex. 1138,
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`104:12-105:5.) Additionally, the binding affinity of any antibody made according
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`to the teachings of the prior art would be an inherent property of an obvious
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`combination and cannot impart patentability. In re Kubin, 561 F.3d 1351, 1357
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`(Fed. Cir. 2009).
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`Furthermore, the ’213 patent provides no binding affinity data for most of
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`the residue substitutions identified in the claims, which indicates either that a
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`POSA would reasonably have expected antibodies with those substitutions to bind
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`the target antigens, or that the patent lacks sufficient written description.
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`IPR2017-01373
`Petitioner’s Reply
`Holding the Challenged Claims Invalid Would Not Have
`“Sweeping Consequences”
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`4.
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`PO’s hyperbole that finding the challenged claims obvious over the Queen
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`references and the PDR would remove “patent protection for most if not all
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`humanized antibodies” is baseless. (POR, 51.) The challenged claims are not
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`directed to the primary sequences of the handful of specific humanized mAbs that
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`the named inventors allegedly created. And PO already obtained a patent covering
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`the variable domain sequences of its humanized 4D5 mAb, but that patent expired.
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`(Ex. 1144, Claim 15; Ex. 1143, ¶29.) In this patent, PO is trying to reach far
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`beyond the humanized mAbs the named inventors actually made, to grasp
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`essentially huge numbers of mAbs made using basic prior-art humanization
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`techniques pioneered by others. There is no evidence of record to support PO’s
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`allegation that holding these over-reaching claims obvious would impact the
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`patentability of different claims to novel humanized mAbs. Regardless, the only
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`issue before the Board here is the invalidity of the challenged claims.
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`5.
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`Petitioner’s Arguments Regarding Queen-1989 Do Not Rely on
`Queen-1990
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`PO is incorrect that Petitioner’s arguments in Grounds 1, 3, and 6 rely on
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`Queen-1990 and not Queen-1989 because Dr. Riechmann used a 3.3 Å cutoff for
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`identifying residues in contact with one another. (POR, 44-45.) Queen-1989 states
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`that “a number of amino acid residues outside of the CDRs are in fact close enough
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`IPR2017-01373
`Petitioner’s Reply
`to them to either influence their conformation or interact directly with antigen.”
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`(Ex. 1034, 10031.) As explained by Dr. Riechmann,4 a POSA reading Queen-1989
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`would have known that the operative distance would be approximately twice the
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`interatomic distance—that is, approximately 3.3 Å for most protein atoms. (Ex.,
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`1003, ¶255 n.17; Ex. 1143, ¶23; Ex. 1145, 261.) PO’s expert agreed,
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`acknowledging that a POSA would have known that “Van der Waals and
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`hydrophobic interactions can occur at distances of 3.5 to 4 Angstroms.” (Ex. 2014,
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`¶184; Ex. 2045.)
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`6.
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`Queen-1990 and Tramontano Further Support Petitioner’s
`Position
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`PO wrongly states that Tramontano “never suggested that substitutions at
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`position 71H were desirable.” (POR, 15.) Tramontano explicitly disclosed that
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`residue 71H is likely a “major determinant of the conformation of” the H2 CDR,
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`thus it would have been obvious to a POSA to consider this residue for substitution
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`where the murine and human framework residues differed at this position.
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`(Petition, 7-8, 22, 50; Ex. 1003, ¶132; Ex. 1051, Abstract.)
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`4 PO’s arguments that Dr. Riechmann “simply adopted the opinions” of Dr. Padlan
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`are misplaced. (POR, 46-47.) Dr. Riechmann conducted his own thorough review
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`of the relevant art and the ’213 patent and formed his own opinions regarding the
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`’213 patent. (Ex. 1003, ¶10; Ex. 2039, 29:12-47:2; Ex. 1143, ¶36.)
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`IPR2017-01373
`Petitioner’s Reply
`The Consensus Sequence Limitation of Claims 4, 33, 62, 64, and 69
`Was Taught By the Prior Art
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`B.
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`As discussed in the Petition, Queen-1990 explicitly discloses the use of a
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`consensus sequence as the human framework in a humanization project. (Petition,
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`36-37.) In arguing that Queen-1990’s disclosure of using “many human
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`antibodies” to make a consensus is different than the claimed approach of using
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`“all human antibodies,” PO offers no evidence that Queen’s approach was any
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`different than
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` (Ex. 1142,
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`27:14-28:13, 32:17-20, 35:9-20.) Moreover, a POSA would have been motivated
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`to use as many different known antibody structures as possible, to make the
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`sequence as much of a consensus as possible. (Ex. 1143, ¶13-14.) A POSA would
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`not have understood Criterion I as instructing a POSA to consider only a subset of
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`human antibodies, since it does not explain what that subset is.
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`PO’s argument that the Queen-1990 consensus sequence is different than
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`that disclosed in the ’213 patent is also wrong. PO relies on a passage in Queen-
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`1990 regarding “a representative collection” of human heavy chains, but this
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`passage is taken out of context. This quote from Queen-1990 does not refer to the
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`consensus sequence human framework, but relates to the other potential framework
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`Queen-1990 describes. (Ex. 1050, 13:3-11; Ex. 1143, ¶15.)
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`IPR2017-01373
`Petitioner’s Reply
`PO is also incorrect that a POSA would have understood the “rare” amino
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`acids language in Criterion II of Queen-1990 as applying to the consensus
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`sequence in Criterion I. (POR, 53.) Queen-1990 is clear that each of the criteria
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`may be used separately. (Ex. 1050, 12:12-15 (“These criteria may be used singly,
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`or when necessary in combination, to achieve the desired affinity or other
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`characteristics.”); Ex. 1143, ¶16.)
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`Queen-1989 also teaches the use of a consensus sequence as the human
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`framework. Queen-1989 describes further humanizing a human antibody
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`framework by replacing residues that are “unusual” in human antibodies with
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`“residue[s] much more typical of human sequences . . . to make the antibody more
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`generically human.” (Ex. 1034, 10032.) A POSA following that teaching, and
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`informed by the sequence data in Kabat-1987 identifying the residues that are most
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`“typical” in human immunoglobulins of particular subclasses and subunits, would
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`have swapped out unusual residues with consensus residues until he or she ended
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`up with a human consensus framework. (Petition, 51-52; Ex. 1003, ¶310; Ex.
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`1143, ¶17-18.)
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`PO’s argument that Queen-1989 does not teach a POSA to start with a
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`consensus sequence is irrelevant. The ’213 patent claims do not require that a
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`particular method be used to obtain the human consensus sequence.
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`PO’s complaint that Queen-1989 replaces unusual human framework
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`residues with murine residues is also misplaced. Queen-1989 describes how
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`human antibodies exhibit “strong amino acid homology outside of the CDRs,” but
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`that there are occasionally atypical residues. (Ex. 1034, 10031-32.) During
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`humanization of anti-Tac, several atypical residues were identified, including 93H,
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`95H, 98H, 106H, 107H, 108H, and 110H, as well as 47L and 62L, which were
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`back-mutated to the murine residue. (Ex. 1034, 10032.) According to Queen-
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`1989, back mutation to the murine residue only occurs when the murine antibody
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`“has a residue much more typical of human sequences than does” the human
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`framework. (Ex. 1034, 10032.). This was not done, as PO suggests, to maintain
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`the confirmation of the murine CDRs, but instead “to make the antibody more
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`generically human.” (Ex. 1034, 10032.)
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`That Queen-1989 does not use the word “consensus” is irrelevant. Queen-
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`1989 renders obvious all that it teaches a POSA, regardless of the terminology
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`Queen et al. chose to use. See In re Applied Materials, Inc., 692 F.3d 1289, 1298
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`(Fed. Cir. 2012) (“A reference must be considered for everything that it teaches”).
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`Similarly, PO is incorrect that Kabat-1987 was only a reference to check the
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`veracity of a potential sequence. A POSA would have used the information in
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`Kabat-1987 to determine whether a particular residue was common. (Petition, 22-
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`23, 51-52; Ex. 1003, ¶309; Ex. 1143, ¶19; Ex. 1142, 30:5-13, 57:23-58:6, 178:18-
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`179:14; Ex. 1140, 60:3-12.)
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`Finally, PO ignores that prior to the earliest possible priority date of the
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`alleged invention, scientists had already created humanized antibodies using
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`consensus sequences. (Ex. 1193, 106; Ex. 1138, 196:5-197:6 (discussing
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`Genentech’s admission during EU patent proceedings that Dr. Riechmann used
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`Foote’s consensus sequence in humanizing CAMPATH).) This is compelling
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`evidence that it would have been obvious to use human consensus sequences in the
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`human framework.
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`C.
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`The “Up to 3-Fold More Binding Affinity” Limitation of Claim 65
`Was Taught By the Prior Art
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`The language “up to 3-fold more binding affinity” in claim 65 means just
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`that: any improvement up to 3-fold more binding affinity, no matter how small.
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`(Ex. 1138, 103:23-104:1; Ex. 1142, 118:8-17.) As explained in the Petition, a
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`POSA optimizing binding affinity through mutagenesis would reasonably have
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`expected to achieve a humanized antibody with an affinity around that of the
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`parent antibody, i.e., an affinity that was slightly less or slight more than the
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`parent. (E.g., Petition, 47-48.) A POSA also would have known that mutagenesis
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`could lead to improved binding. Indeed, as Table 3 of the patent shows, one
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`residue substitution can increase the binding affinity during humanization. (Ex.
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`1001, Table 3; Ex. 1143, ¶26). While the specific binding properties of a
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`humanized antibody can only be confirmed by testing, such mutagenesis would
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`have been a routine part of antibody humanization. (Ex. 2039, 271:15-17; Ex.
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`1142, 101:24-102:19; Ex. 1143, ¶20.)
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`D.
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`The “Lack Immunogenicity Compared to a Non-Human Parent”
`Limitation of Claim 63 Was Taught By the Prior Art
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`PO incorrectly implies that claim 63 requires that the humanized antibody
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`produce no immunogenic reaction, and uses an out-of-context quote from Dr.
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`Riechmann as support. (POR, 60-61.) But PO does not dispute the Board’s
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`construction that “lacks immunogenicity” refers to “a humanized antibody having
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`reduced immunogenicity in a human patient as compared to its non-humanized
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`parent antibody,” (POR, 18 (emphasis added).) As the Queen references state, the
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`expectation that humanizing a murine mAb would reduce its immunogenicity was
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`the very reason why humanization was undertaken in the first place. (Ex. 1034,
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`10029; Ex. 1050, Abstract; see also Ex. 1138, 102:23-103:5 (“the goal of
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`humanization is to retain binding affinity and reduce immunogenicity”); Ex. 1140,
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`82:22-83:4; Ex. 1142, 111:1-6 (“Q: And in order to make a human therapeutic
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`agent, the humanized antibody would need to lack immunogenicity compared to
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`the nonhuman parent, right? Otherwise, you would just use the mouse? A:
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`Agreed.”).) A POSA would thus have expected that making the antibody more
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`human would make the antibody less immunogenic. (Ex. 1142, 112:5-9, 112:16-
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`21 (“Q: So the fact that there were fewer mouse residues in the humanized variant
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`versus the parent led to an expectation that is would lack immunogenicity
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`compared to the parent, right? . . . A: Yes.”); Ex. 1143, ¶24.) Indeed, the patent
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`does not contain any immunogenicity data, which underscores that the named
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`inventors expected that the humanized mAbs would not be as immunogenic as the
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`murine parent mAbs. Moreover, merely testing the immunogenicity of an
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`otherwise obvious mAb does not render it patentable. See Santarus, Inc. v. Par
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`Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012).
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`E.
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`The Limitations Related to Binding p185HER2 of Claims 30-31, 33, 42,
`and 60 Was Taught By the Prior Art
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`PO argues, in essence, that because there is no disclosure in the prior art of a
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`humanized 4D5 mAb, such an antibody cannot be obvious. (POR, 62-63.) This
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`argument misapplies the law of obviousness. PO’s expert admitted that, prior to
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`the date of the alleged invention, it was known that overexpression of p185HER2 led
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`to a poor prognosis in cancer, and work had been done to identify antibodies that
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`would target p185HER2. (Ex. 1138, 19:7-20:1.) Also prior to the alleged invention,
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`Hudziak identified that the murine antibody 4D5 downregulated p185HER2. (Ex.
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`1021, 1169; Ex. 1004, ¶14; Ex. 1140, 22:1-24:7; Ex. 1138, 19:23-20:25, 22:8-12.)
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`This would have motivated a POSA to use the humanization framework of Queen-
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`1989 and apply that framework to 4D5 to make a therapeutic agent that would
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`downregulate p185HER2. (Ex. 1004, ¶16; Ex. 1021; Ex. 1143, ¶28.) Dr. Leonard
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`confirmed that a POSA would have understood 4D5 to be a promising target for
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`humanization, and the prior art taught a POSA how to humanize the antibody to
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`generate a potential therapeutic agent that bound p185HER2. (Ex. 1004, ¶¶48-49.)
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`As explained above, the prior art humanization process would have identified the
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`potential residue substitutions identified in the ’213 patent, rending claims 30-31,
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`33, 42, and 60 obvious.
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`II.
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`PO’s Attempts to Establish an Earlier Date of Invention for Claims 12,
`42, 60, 65, 71, 73-74, and 79 Are Insufficient
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`Here, the default date of invent