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`IPR2017-01374
`Petitioner’s Reply
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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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. IPR2017-01374
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`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
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`IPR2017-01374
`Petitioner’s Reply
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`I.
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`B.
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`Table of Contents
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`Patent Owner’s Attempts to Establish an Earlier Date of Invention for
`Claims 12, 42, 60, 65, 71, 73-74, and 79 Are Insufficient .................................. 3
`II. All Challenged Claims of the ’213 Patent are Anticipated by and/or
`Obvious Over Kurrle and/or Queen-1990, Optionally in Light of Furey,
`Chothia & Lesk, Chothia 1985, and/or Hudziak ................................................. 7
`A. A POSA Following the Teachings of the Prior Art Would Have
`Identified the Residues Listed in Claims 12, 42, 60, 65-67, and
`71-79 for Substitution ................................................................................ 7
`The Limitation “Which Bind [an Antigen]” in Claims 4, 33, 62,
`66-67, 69, 71-72, 75-76, and 78 Is Taught by the Prior Art ................... 12
`C. Queen-1990 Teaches the “Consensus” Sequence Limitation ................. 13
`D.
`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 ............................ 15
`The Limitations Related to Binding p185HER2 of Claims 30-31, 33,
`42, and 60 Was Taught By the Prior Art ................................................. 17
`III. Secondary Considerations of Non-Obviousness Do Not Render the
`Challenged Claims Nonobvious ........................................................................ 18
`A.
`The Use of a Consensus Sequence Would Not Have Been
`Unexpected .............................................................................................. 18
`PO Has Not Established that the Alleged Unexpected Results and
`Commercial Success Have a Nexus to the Challenged Claims .............. 19
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`E.
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`F.
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`B.
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`TABLE OF AUTHORITIES
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`IPR2017-01374
`Petitioner’s Reply
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` Page(s)
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`Cases
`Chiron Corp. v. Genentech Inc.,
`363 F.3d 1247 (Fed. Cir. 2004) ................................................................................ 6
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`Coleman v. Dines,
`754 F.2d 353 (Fed. Cir. 1985) .................................................................................. 4
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`Ecolochem, Inc. v. S. Cal. Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000) ................................................................................ 4
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`Ecolochem, Inc. v. S. Cal. Edison Co.,
`91 F.3d 169, 1996 WL 297601 (Fed. Cir. 1996) .................................................. 3, 8
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`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................................ 10
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`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009) .............................................................................. 13
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`Mahurkar v. C.R. Bard, Inc.,
`79 F.3d 1572 (Fed. Cir. 1996) .................................................................................. 4
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`Medichem, S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) ................................................................................ 4
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`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) .............................................................................. 19
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`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) .............................................................................. 11
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`Santarus, Inc. v. Par Pharm., Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) .............................................................................. 16
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`Ex Parte Takeshi Shimono,
`Appeal 2013–003410 (PTAB Apr. 29, 2015) ......................................................... 19
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`IPR2017-01374
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`IPR2017-01374
`Petitioner’s Reply
`Petitioner’ s Reply
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`Statutes
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`Statutes
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`35 U.S.C. §102(b) .......................................................................................................... 6
`35 U.S.C. §102(b) .......................................................................................................... 6
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`IPR2017-01374
`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, 20),
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`essentially conceding that their limitations did not constitute patentable distinctions
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`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, 1-5.) 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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`PROTECTIVE ORDER MATERIAL
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`IPR2017-01374
`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-1990 and Kurrle. 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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`IPR2017-01374
`Petitioner’s Reply
`applying the roadmap in Queen-1990 or Kurrle 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, 15
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`(“Because Kurrle and Queen 1990 teach overlapping, and potentially
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`complimentary, sets of candidate amino acids for mouse to human substitution, we
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`agree with Petitioner that an ordinary artisan would have had a reason to combine
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`the teachings of those references.”).) Since the claimed Markush groups merely
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`require “one or more” of the recited substitutions, this is sufficient to render them
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`obvious. See, e.g., Ecolochem, Inc. v. S. Cal. Edison Co., 91 F.3d 169, 1996 WL
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`297601, *2 (Fed. Cir. 1996) (“[I]f utilizing one element of the [Markush] group is
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`anticipated or obvious, the patentee is precluded from arguing that the claim is
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`valid.”).
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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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`Patent Owner’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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`PROTECTIVE ORDER MATERIAL
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`IPR2017-01374
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`Petitioner’ 5 Reply
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`Here, the default date of invention is June 14, 1991. Ecolochem, Inc. v. S.
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`Cal. Edison C0., 227 F.3d 1361, 1371 (Fed. Cir. 2000). Ex. 1001. PO bears the
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`burden to establish an earlier invention date. Mahm'kar v. CR. Bard, Inc., 79 F.3d
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`1572, 1576-77 (Fed. Cir. 1996).
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`Evidence of conception must be corroborated by a non—inventor. Id. at 1577
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`(this “rule provides a bright line for both district courts and the PTO to follow in
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`addressing the difficult issues related to invention dates”). PO stresses the “rule of
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`reason,” but that “does not dispense with the requirement for some evidence of
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`independent corroboration.” Coleman v. Dines, 754 F.2d 353, 360 (Fed. Cir. 1985).
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`Testimony of one co—inventor cannot be used to help corroborate the testimony of
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`another.” Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1171-72 (Fed. Cir.
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`2006)
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`IPR2017-01374
`Petitioner’s Reply
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`IPR2017-01374
`Petitioner’s Reply
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`Additionally, PO has not established that claims 12, 42, 60, 65, 71, 73-74,
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`and 79 are entitled to priority to the ’272 application. The only examples in the
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`’272 application are the eight variants of the humanized 4D5 antibody. (Ex. 2032,
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`93.) These claims, however, are not limited to these variants. If these claims are
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`not rendered obvious by Queen-1989 and the PDB, the examples from a single
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`humanization project do not disclose to a POSA the applicability of these
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`substitutions to a different antibody. (Ex. 1143, ¶¶31-32; see also Ex. 1138,
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`143:20-144:24.) As a result, the ’272 application does not contain sufficient
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`written description for the full scope of the ’213 patent claims, and thus these
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`claims are not entitled to claim priority to the ’272 application, making Queen-
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`1990 and Kurrle prior art under 35 U.S.C. §102(b). See Chiron Corp. v.
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`Genentech Inc., 363 F.3d 1247, 1253 (Fed. Cir. 2004).
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`Thus, PO has not satisfied its burden to present corroborated evidence that
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`the inventors conceived the claimed subject matter and reduced it to practice prior
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`IPR2017-01374
`Petitioner’s Reply
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`to the publication of the Queen-1990 and Kurrle references.
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`II. All Challenged Claims of the ’213 Patent are Anticipated by and/or
`Obvious Over Kurrle and/or Queen-1990, Optionally in Light of Furey,
`Chothia & Lesk, Chothia 1985, and/or Hudziak
`A. A POSA Following the Teachings of the Prior Art Would Have
`Identified the Residues Listed in Claims 12, 42, 60, 65-67, and 71-79
`for Substitution
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`PO faults the Queen-1990 and Kurrle references as leading POSAs “to a
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`broad genus of potential framework substitutions,” and alleges incorrectly that
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`“Petitioner offers no reason . . . why a person of ordinary skill would have chosen
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`the specific framework substitutions recited in [the challenged] claims.” (POR, 50-
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`51.) PO does not deny that a POSA following the prior art would identify residues
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`in claims 12, 42, 60, 65-67, and 71-79 as candidates for substitution, only that a
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`POSA would not limit the candidates to those specific residues. But this does not
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`save the 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. 1143, ¶20.) While the patent
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`claims a laundry list of possible substitutions to try, the only guidance in the ’213
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`patent regarding how to select the specific substitutions that will work in mAbs
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`beyond the examples is, as Dr. Wilson acknowledged, remarkably similar to the
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`guidance in Queen-1990 and Kurrle. The patent requires a POSA to construct a
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`computer model, identify the residues that, because of their positions within the VH
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`and VL domains, could alter binding affinity, and then conduct trial-and-error
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`mutagenesis to see which of those substitutions improve binding. (Ex. 1138,
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`116:1-122:1; compare Ex. 1050, 12:17-17:24 with Ex.1001, 20:41-21:3; Ex. 1142,
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`76:19-80:13.) Dr. Wilson further conceded that it would have required nothing
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`more than routine skill and experimentation to use these methods to identify the
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`specific residue(s) that would work in a given humanization project. (Ex. 1138,
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`116:1-122:1; see also Ex. 1142, 97:14-98:22.)
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`As discussed in the Petition regarding Ground 1, Kurrle explicitly disclosed
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`substitutions at 4L, 69H, 71H, 73H, and 76H. Claims 4, 30, 31, 33, 62-63, 65-67,
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`69, 71-72, 75, and 78 each require that “one or more” of the listed residues be
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`selected for substitution. Kurrle anticipates the Markush groups of residues in
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`these claims because it discloses “one or more” residues of the groups. See, e.g.,
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`Ecolochem, 1996 WL 297601, *2 (“[I]f utilizing one element of the [Markush]
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`group is anticipated or obvious, the patentee is precluded from arguing that the
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`claim is valid.”).2 Kurrle also anticipates the list of residues in claim 76, which
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`requires 71H and 73H to be substituted. (Ex. 1143, ¶25.) Similarly, as discussed
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`in the Petition regarding Ground 2, Queen-1990 explicitly disclosed substitutions
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`at 98L and 36H. Thus, it anticipates the Markush groups in claims 4, 62 and 63.
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`Queen-1990 also anticipates the framework substitution element of claim 64, since
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`it teaches that residues 98L and 36H are likely to, e.g., “interact with the CDR” as
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`required by the claim.
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`As discussed in the Petition regarding Ground 3, the residue lists in claims 4,
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`12, 30, 31, 33, 42, 60, 62-67, 69 and 71-79 also would have been obvious from
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`Queen-1990 in combination with Kurrle, since a POSA following the guidance in
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`those references would have identified “one or more” of the residues recited in
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`claims 12, 42, 60, 65-67, and 71-79, and all of the residues recited in claims 76-77
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`and 79, as candidates for substitution. A POSA also would have identified the
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`residues recited in claims 65, 73, 74, 77 and 79 following the guidance of those
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`references in combination with Chothia & Lesk and Chothia 1985.
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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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`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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`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 in fact 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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`Additionally, PO does not point to any evidence that the particular
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`substitutions listed in the above claims are critical to the claimed invention. The
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`prior art identified a range of potential residues to be substituted in a humanization
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`project, including the claimed residues. As a result, these residues are prima facie
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`obvious and the patentee must establish “that the [claimed residue] is critical,
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`generally by showing that the claimed range achieves unexpected results relative to
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`the prior art range.” In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003) (quoting
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`In re Geisler, 116 F.3d 1465, 1469-70 (Fed. Cir. 1997)). PO has not made any
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`such showing, and therefore, the selection of the residues listed in claims 12, 42,
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`60, 65-67, and 71-79 would have been obvious. (Ex. 1143, ¶¶26-27; Ex. 1001,
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`Table 3; Ex. 1142, 131:10-132:5.)
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`PO’s hyperbole that finding the challenged claims obvious over Queen-1990
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`and Kurrle would remove “patent protection for most if not all humanized
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`antibodies” is baseless. (POR, 55.) The challenged claims are not directed to the
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`primary sequences of the handful of specific humanized mAbs that the named
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`inventors allegedly created. And PO already obtained a patent covering the
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`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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`The Limitation “Which Bind [an Antigen]” in Claims 4, 33, 62, 66-
`67, 69, 71-72, 75-76, and 78 Is Taught by the Prior Art
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`B.
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`PO incorrectly argues that because Queen-1990 does not explicitly disclose
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`binding affinity data from a mAb with the claimed substitutions, and Kurrle does
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`not provide data regarding the binding properties of EUCIV4, neither of these
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`references, alone or in combination, would have led a POSA to expect that
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`following the prior art would lead to a mAb that binds an antigen. (POR, 44-45,
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`48-49.) The claim language “bind an antigen” encompasses binding to any degree.
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`PO’s expert admitted that in a humanization project “one approach to try to regain
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`the binding affinity . . . was to make additional substitutions back to mouse in the
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`human framework.” (Ex. 1138, 28:2-8.)
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`Queen-1990 discloses “human-like immunoglobulins . . . which have
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`binding affinities of at least about 108 M-1, and preferably 109 M-1 to 1010 M-1 or
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`stronger.” (Ex. 1050, 9:3-7.) While BMA-EUCIV1, a mAb with murine CDRs
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`but no framework substitutions, had little binding affinity, as Kurrle optimized the
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`mAb by making framework substitutions, affinity improved. (Ex. 1071, 9:26-31;
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`Ex. 1143, ¶21.) Further, Kurrle stated that BMA-EUCIV2 did “not bind well,”
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`which indicates it had at least some binding affinity. (Ex. 1143, ¶¶21-22.) Further,
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`Kurrle stated that BMA-EUCIV3 “does bind well.” (Ex. 1071, 9:26-31; Ex. 1143,
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`¶22.)
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`Moreover, PO’s argument ignores all of the prior art disclosing successful
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`humanization projects. For example, Kurrle teaches a humanized antibody with
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`substitutions at 71H, 73H, and 76H bound an antigen “well.” (Petition, 29-30, 46-
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`47.) Dr. Riechmann’s humanized CAMPATH mAb similarly had high binding
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`affinity. (Ex. 1069, 3.) A POSA using the methodology set forth in Queen-1990
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`would have understood that the prior art methods for humanization had been
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`successfully used to achieve mAbs with high binding affinity. (Ex. 1050, Abstract
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`(disclosed antibodies “retain the same affinity as the donor immunoglobulin to the
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`antigen”).) A POSA using prior art methods would have had a reasonable
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`expectation of achieving results at least as good as those disclosed in the prior art.
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`(Ex. 1138, 104:12-105:5.) Additionally, the binding affinity of any antibody made
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`according to the teachings of the prior art would be an inherent property of an
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`obvious combination and cannot impart patentability. In re Kubin, 561 F.3d 1351,
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`1357 (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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`C. Queen-1990 Teaches the “Consensus” Sequence Limitation
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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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`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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`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 each of the criteria may
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`be used separately. (Ex. 1050, 12:12-15 (“These criteria may be used singly, or
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`IPR2017-01374
`Petitioner’s Reply
`when necessary in combination, to achieve the desired affinity or other
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`characteristics.”); Ex. 1143, ¶16.)
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`D.
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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 that was slightly less or
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`slightly more than the parent. (E.g., Petition, 50-53.) A POSA also would have
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`known that mutagenesis could lead to improved binding. Indeed, as Table 3 of the
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`patent shows, one residue substitution can increase the binding affinity during
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`humanization. (Ex. 1001, Table 3; Ex. 1143, ¶26.) While the specific binding
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`properties of a humanized antibody can only be confirmed by testing, such
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`mutagenesis would have been a routine part of antibody humanization. (Ex. 2039,
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`271:15-17; Ex. 1142, 101:24-102:19; Ex. 1143, ¶20.)
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`E.
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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, 57-59.) But PO does not dispute the Board’s
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`IPR2017-01374
`Petitioner’s Reply
`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, 19 (emphasis added).) As Queen-1990 and Kurrle state,
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`the expectation that humanizing a murine mAb would reduce its immunogenicity
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`was the very reason why humanization was undertaken in the first place. (Ex.
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`1050, 4:3-8; Ex. 1071, 3:3-5; see also Ex. 1138, 102:23-103:5 (“the goal of
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`humanization is to retain binding affinity and reduce immunogenicity”);
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`) 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
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` Ex. 1143, ¶24.) Indeed, the patent does
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`not contain any immunogenicity data, which underscores that the named inventors
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`expected that the humanized mAbs would not be as immunogenic as the murine
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`parent mAbs. Moreover, merely testing the immunogenicity of an otherwise
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`obvious mAb does not render it patentable.3 See Santarus, Inc. v. Par Pharm.,
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`3 Similarly, merely testing the binding affinity of an otherwise obvious mAb does
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`PROTECTIVE ORDER MATERIAL
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`IPR2017-01374
`Petitioner’s Reply
`Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012) (“an obvious formulation cannot
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`become nonobvious simply by administering it to a patient and claiming the
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`resulting serum concentrations . . . To hold otherwise would allow any
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`formulation—no matter how obvious—to become patentable merely by testing and
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`claiming an inherent property.”) (quotation omitted).).
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`F.
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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 murine 4D5 downregulated p185HER2. (Ex. 1021, 1169; Ex.
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`1004, ¶14; Ex. 1140, 22:1-24:7; Ex. 1138, 19:23-20:25, 22:8-12.) This would have
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`motivated a POSA to use the humanization framework of Queen-1990 and apply
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`that framework to 4D5 to make a therapeutic agent that would downregulate
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`p185HER2. (Ex. 1004, ¶16; Ex. 1021; Ex. 1143, ¶28.) Dr. Leonard confirmed that a
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`POSA would have understood 4D5 to be a promising target for humanization, and
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`not render it patentable.
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`IPR2017-01374
`Petitioner’s Reply
`the prior art taught a POSA how to humanize the antibody to generate a potential
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`therapeutic agent that bound p185HER2. (Ex. 1004, ¶¶48-49.) As explained above,
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`the prior art humanization process would have identified the potential residue
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`substitutions identified in the ’213 patent, rending claims 30-31, 33, 42, and 60
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`obvious.
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`III. Secondary Considerations of Non-Obviousness Do Not Render the
`Challenged Claims Nonobvious
`A.
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`The Use of a Consensus Sequence Would Not Have Been Unexpected
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`PO incorrectly argues that before the ’213 patent, it would have been
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`unexpected that it was “even possible to develop a broadly-applicable platform that
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`could be used to humanize different antibodies from the same sequence.” (POR,
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`64.) Both Foote and Queen-1990 teach use of a consensus sequence in humanizing
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`antibodies. (Ex. 1003, ¶173; Ex. 1050, 12:17-20; Ex. 1143, ¶30; Ex. 1193, 106;
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`Ex. 1138, 196:5-197:6.) Given the previous success in humanizing CAMPATH
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`using Foote’s consensus sequence, there was nothing unexpected about the broad-
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`applicability of a consensus sequence. (Ex. 1143, ¶30.) Therefore, PO’s position
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`that a POSA would not have expected that a consensus sequence could be used to
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`humanize multiple antibodies is incorrect.
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`Additionally, PO has provided no data to support its claims of unexpectedly
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`superior properties from using a consensus sequence as defined in the patent, as
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`compared to other prior art humanization methods.
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`IPR2017-01374
`Petitioner’s Reply
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`Dr. Presta published an article stating “Dr. Queen’s best fit method has remained
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`the more popular method for designing the sequence of the humanized antibody
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`than the consensus method” and the two approaches “both may function well with
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`regard to acceptance by the human immune system with perhaps an occasional
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`aberration.” (Ex.1196, 319-20; Ex. 1142, 131:10-136:14.) PO provides no
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`evidence of any head-to-head comparison regarding the relative binding affinities
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`for the same antibody humanized using the consensus approach and the most
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`homologous approach. (Ex. 1138, 184:16-185:7.)
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`B.
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`PO Has Not Established that the Alleged Unexpected Results and
`Commercial Success Have a Nexus to the Challenged Claims
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`Even if PO could establish unexpected results or commercial success, there
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`is no evidence that these allegedly unexpected results have any nexus to the claims.
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`Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299, 1311–12 (Fed. Cir. 2006). To
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`the extent PO is relying on the consensus sequence element, this limits only claims
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`4, 33, 62, 64, and 69. Therefore, as a matter of law, this evidence can only apply to
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`these claims. See, e.g., Ex Parte Takeshi Shimono, Appeal 2013–003410 (PTAB
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`IPR2017-01374
`Petitioner’s Reply
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`Apr. 29, 2015).
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`Further, PO relies on data relating to Herceptin to support its claims of
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`enhanced binding and reduced immunogenicity, but PO has not established that
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`Herceptin is an embodiment of the claims. The ’213 patent defines a “consensus
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`human variable domain” as “a human variable domain which comprises the most
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`frequently occurring amino acid residues at each location in all human
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`immunoglobulins of any particular subclass or subunit structure.” (Ex 1001,
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`11:32-38.)
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`Moreover, the evidence of record indicates that the human framework of
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`Herceptin does not comprise the “most frequently-occurring amino residues at
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`each location in all human immunoglobulins.” Kabat-1991 added sequences to
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`those listed in Kabat-1987. Th
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