Trials@uspto.gov
`571.272.7822
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` Paper No. 13
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` Entered: October 23, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ARAGEN BIOSCIENCE, INC.
`AND
`TRANSPOSAGEN BIOPHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`KYOWA HAKKO KIRIN CO., LTD.,
`Patent Owner.
`____________
`
`Case IPR2017-01252
`Patent 6,946,292 B2
`____________
`
`
`Before JAMES T. MOORE, ERICA A. FRANKLIN, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`571.272.7822
`
`
`
`
`
`
`
`
`
`
` Paper No. 13
`
` Entered: October 23, 2017
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ARAGEN BIOSCIENCE, INC.
`AND
`TRANSPOSAGEN BIOPHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`KYOWA HAKKO KIRIN CO., LTD.,
`Patent Owner.
`____________
`
`Case IPR2017-01252
`Patent 6,946,292 B2
`____________
`
`
`Before JAMES T. MOORE, ERICA A. FRANKLIN, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`IPR2017-01252
`Patent 6,946,292 B2
`
`
`
`
`
`INTRODUCTION
`
`Aragen Bioscience, Inc. and Transposagen Biopharmaceuticals, Inc.
`
`(“Petitioner”)1 filed a Petition requesting an inter partes review of claims 1–
`
`12 of U.S. Patent No. 6,946,292 B2 (Ex. 1001, “the ’292 Patent”). Paper 1
`
`(“Pet.”). Kyowa Hakko Kirin Co., Ltd. (“Patent Owner”) filed a Preliminary
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`Response to the Petition. Paper 10 (“Prelim. Resp.”).
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`Institution of an inter partes review is authorized by statute when “the
`
`information presented in the petition . . . and any response . . . shows that
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`there is a reasonable likelihood that the petitioner would prevail with respect
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`to at least 1 of the claims challenged in the petition.” 35 U.S.C. § 314; see
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`37 C.F.R. §§ 42.4, 42.108. Upon considering the Petition and the
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`Preliminary Response, we determine that Petitioner has not shown a
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`reasonable likelihood that it would prevail in showing the unpatentability of
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`at least one challenged claim. Accordingly, we decline to institute an inter
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`partes review of the ’292 Patent.
`
`A.
`
`Related Applications and Proceedings
`
`The ’292 Patent shares substantially the same specification with U.S.
`
`Patent Nos. 8,067,232 B2 (“the ’232 Patent), 7,425,446 B2 (“the ’446
`
`Patent”), and 7,737,325 B2 (“the ’325 Patent”), which are related as follows.
`
`The ’232 Patent issued from Application No. 12/048,348 (“the ’348
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`Application”), which is a continuation of Application No. 11/131,212 (now
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`the ’325 Patent), which is a divisional of Application No. 09/971,773 (now
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`the ’292 Patent). This chain of continuations and divisionals was first filed
`
`
`
`1 Petitioner further identifies GVK Biosciences, Private Limited and GVK
`Davix Technologies Private Limited as real parties-in-interest. Pet. 55.
`
`2
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`
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`IPR2017-01252
`Patent 6,946,292 B2
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`
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`on October 9, 2001, and each patent in the family claims benefit of
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`provisional Application No. 60/268,916, filed February 16, 2001, as well as
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`foreign applications PCT/JP01/08804 and JP 2000-308526, filed October 5,
`
`2001, and October 6, 2000, respectively.
`
`In addition to the instant Petition challenging claims 1–12 of the ’292
`
`Patent, Petitioner has submitted Petitions challenging claims of the ’446
`
`Patent (IPR2017-01262), and the ’232 Patent (IPR2017-01254). Petitioner
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`does not presently challenge the ’325 Patent.
`
`According to the parties, the ’292 Patent is at issue in Kyowa Hakko
`
`Kirin Co., v. Aragen Bioscience, Inc., Case No. 3-16-cv-05993-JD (N.D.
`
`Cal.) (“the copending district court litigation”). Pet. 56; Paper 5.
`
`B.
`
`The ’292 Patent and Relevant Background
`
`The ’292 Patent relates to the development of host cells for the
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`production of antibody molecules that enhance antibody-dependent
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`cytotoxicity (ADCC). See Ex. 1001, 5:35–43, Title. As explained by
`
`Petitioner, ADCC is an inflammatory response mediated by NK (natural
`
`killer) cells that can result in the killing of tumor cells. See Pet. 3–4 (citing
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`Ex. 10262 ¶¶ 21–24).
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`In ADCC, the Fc portions of IgG-type antibodies decorating a target
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`cell (e.g., a tumor cell) are recognized by Fc receptors (e.g., FcγRIII or
`
`CD16) on the NK cell surface. Id. The interaction between target cell-
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`specific antibodies and Fc receptors activates the NK cell, which then kills
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`the target cell. Id. at 4. According to the Specification, the Fc region of
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`IgG-type antibodies contains two complex-type, N-glycoside-linked (“N-
`
`
`
`2 Declaration of Dr. Royston Jefferis.
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`3
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`IPR2017-01252
`Patent 6,946,292 B2
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`linked”) oligosaccharide (sugar) chains, which are known to greatly
`
`influence ADCC activity. See generally Ex. 1001, 1:40–5:32. Despite prior
`
`art attempts to explore this structure-function relationship, the inventors of
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`the ’292 Patent assert that, “a truly important sugar chain structure has not
`
`been specified yet.” Id. at 2:9–37, 5:18–32; see also, id. at 2:34–37 (stating
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`that, whereas “structures of sugar chains [on IgG-type antibodies] are
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`various and complex, and it cannot be said that an actual important structure
`
`for the effector function was identified”).
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`N-linked oligosaccharide chains comprise a common core structure
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`illustrated in formula (I) of the ’292 Patent, reproduced below.
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`Id. at 2:50–55. Formula (I) shows the common core structure of N-linked
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`oligosaccharide chains comprising a branched arrangement of mannose
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`sugars (Man) and two N-acetyl glucosamine moieties (GlcNAc). The
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`mannose end of the core is referred to as the “non-reducing end,” and the
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`terminal GlcNAc end the “reducing end.” At the non-reducing end,
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`enzymatic attachment and modification of additional sugars moieties result
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`high mannose-, hybrid-, or complex-type sugar chains, depending on the
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`number and type of residues added. See generally, id. at 2:38–3:2; see also
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`Prelim. Resp., 5–6 (illustrating hig mannose-, hybrid, and complex-type
`
`sugar chains). At the reducing end, the terminal GlcNAc is linked to the
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`amino acid asparagine (“N” or “Asn”) of a polypeptide chain. Id. In the Fc
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`region of an antibody, a terminal GlcNAc at the reducing end of a complex-
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`type oligosaccharide chain is attached to each of the two antibody heavy
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`4
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`IPR2017-01252
`Patent 6,946,292 B2
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`chains; the 6 position of the terminal GlcNAc may bear a fucose moiety
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`added by α1,6-fucosyltransferase. See id. at 3:2–4:6, 20:37–46, 23:22–26,
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`23:34–24:11.
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`According to the Specification, reducing or eliminating the addition of
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`fucose at the reducing end of N-linked oligosaccharide chains of the Fc
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`region significantly improves the ADCC response. See generally, Ex. 1001,
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`5:35–67, 7:6–8:13. The Specification also discloses the design and testing
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`of a mammalian host cell line for producing antibodies where the FUT8
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`gene—the gene encoding α1,6-fucosyltransferase—was disrupted, thereby
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`reducing or eliminating α1,6-fucosyltransferase activity. Id.; see generally,
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`Ex. 1001, 7:15–43, 98:25–111:46; see, e.g., 111:43–45 (“ADCC activity of
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`produced antibodies can be improved by disrupting the FUT8 allele in host
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`cells”); Ex. 10373, 89:16–22.
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`In particular, Example 12 of the Specification details the cloning of
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`exon 2 of a mammalian FUT 8 gene using a Fut8 cDNA probe.4 Ex. 1001,
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`98:25–99:37. In Example 13, the genomic DNA was then used to “knock
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`out” or create a deletion in the α1,6-fucosyltransferase gene of mammalian
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`cells. Id. at 99:38–111:45. Antibodies produced in cells bearing the
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`disrupted α1,6-fucosyltransferase gene “showed a significantly more potent
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`ADCC activity than the antibody produced by the strain . . . before gene
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`disruption.” Id. at 111:31–42, Fig. 42.
`
`
`
`3 Transcript of Dr. Brian Van Ness Deposition taken in the copending
`district court litigation.
`4 According to the Specification, the process involved designing PCR
`primers based on “a mouse FUT8 cDNA sequence (GenBank, AB025198).”
`Id. at 98:34–38.
`
`5
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`IPR2017-01252
`Patent 6,946,292 B2
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`C.
`
`Representative Claims
`
`Petitioner challenges claims 1–12, of which claims 1 and 7 are
`
`independent:
`
`1. An isolated fucosyltransferase knock-out host cell wherein
`when a gene encoding an antibody molecule is introduced in to
`said host cell, said host cell produces an antibody composition
`comprising the antibody molecule,
`
`said host cell being a mammalian cell,
`
`said antibody molecule comprising a Fc region comprising
`complex N-glycoside-linked sugar chains bound to the Fc
`region,
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`said sugar chain comprising a reducing end which contains an N-
`acetylglucosamine, wherein the sugar chains do not contain
`fucose bound to the 6 position of N-acetylglucosamine in the
`reducing end of the sugar chains.
`
`Ex. 1001, 183:26–39.
`
`7. An isolated fucosyltransferase knock-out host cell comprising
`a gene encoding an antibody molecule, wherein said host cell
`produces an antibody composition comprising the antibody
`molecule,
`
`said host cell being a mammalian cell,
`
`said antibody molecule comprising a Fc region comprising
`complex N-glycoside-linked sugar chains bound to the Fc
`region,
`
`said sugar chain comprising a reducing end which contains an N-
`acetylglucosamine, wherein the sugar chains do not contain
`fucose bound to the 6 position of N-acetylglucosamine in the
`reducing end of the sugar chains.
`
`Ex. 1001, 184:25–37.
`
`Dependent claims 2–5 and 8–11 limit the host cell types of the
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`independent claims (Ex. 1001, 183:40–47, 184:38–45); dependent claims 6
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`6
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`IPR2017-01252
`Patent 6,946,292 B2
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`and 12 specify that the antibody molecule is an IgG antibody (Ex. 1001,
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`183:48–49, 184:46–47).
`
`D.
`
`The Asserted Prior art and Grounds of Unpatentability
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`Petitioner asserts the following grounds of unpatentability (Pet. 17–
`
`18):
`
`Ground Reference(s)
`
`Basis
`
` Claims
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Rothman,5 Umaña,6 knowledge
`of POSA
`Harris,7 Umaña, knowledge of
`POSA
`
`§ 103
`
` 1–12
`
`§ 103
`
`1–12
`
`Rothman, Umaña, Malý,8
`knowledge of POSA
`
`Harris, Umaña, Malý,
`knowledge of POSA
`
`Rothman, Umaña, Gao,9
`knowledge of POSA
`
`Harris, Umaña, Gao,
`knowledge of POSA
`
`§ 103
`
`1–12
`
`§ 103
`
`§ 103
`
`§ 103
`
`1–12
`
`5 and 11
`
`5 and 11
`
`
`
`5 Rothman et al., Antibody-dependent cytotoxicity mediated by natural killer
`cells is enhanced by castanospermine-induced alterations of IgG
`glycosylation, 26(12) MOLEC. IMMUNOL. 1113–23 (1989). Ex. 1002.
`6 WO 99/54342, published Oct. 28, 1999. Ex. 1004.
`7 Harris et al., Refined structure of an intact IgG2a monoclonal antibody, 36
`Biochemistry 1581–97 (1997). Ex. 1003.
`8 Malý et al., The α(1,3)fucosyltransferase Fuc-TVII controls leukocyte
`trafficking through an essential role in L-, E-, and P-selectin ligand
`biosynthesis, 86 CELL 643–53 (1996). Ex. 1005.
`9 Gao et al., Characterization of YB2/0 cell line by counterflow
`centrifugation elutriation, 44 Exp. Toxic. Pathol. 435–38 (1992). Ex. 1006.
`
`7
`
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`IPR2017-01252
`Patent 6,946,292 B2
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`Petitioner also relies on the Declarations of Dr. Brian G. Van Ness
`
`(Ex. 1007) and Dr. Royston Jefferis (Ex. 1026). Petitioner further relies on
`
`the June 22, 2017, transcript of the deposition testimony of Dr. Brian
`
`Van Ness taken in the copending district court litigation (Exhibit 1037), and
`
`a supplemental paper relating to that testimony (Paper 11), both of which
`
`were entered in this case subject to the Board’s Order of August 9, 2017
`
`(Paper 9).
`
`E. Overview of the Asserted References
`
`i. Rothman (Ex. 1002)
`
`Rothman describes the functional analysis of monoclonal IgG
`
`antibodies (“mAbs”) produced in culture in the presence of various
`
`glycosylation inhibitors. See, eg., Ex. 1002, Abstract, 1121.10 Rothman
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`reports that, although oligosaccharide modification did not significantly
`
`influence antigen binding to target cells, “a correlation was observed
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`between the efficiency of promoting ADCC and the glycosylation phenotype
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`of the mAb.” Id. at 1121. In particular, ADCC was enhanced when the IgG
`
`oligosaccharides were metabolically modified by exposure to
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`castanospermine (Cs) and certain other inhibitors. See, e.g., id at Abstract,
`
`1121. Rothman suggests that “absence of core fucosylation itself would
`
`appear to be a likely candidate as a structural feature necessary for
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`enhancement of NK cell-mediated ADCC.” Id. at 1122; see also id. (“[I]t is
`
`tempting to speculate that polyclonal variability in the expression of core
`
`fucosylation may confer a functional advantage to host defense by
`
`diversifying the effector activity of IgG.”).
`
`
`
`10 Where possible, we refer to the native page numbers of the exhibits.
`
`8
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`IPR2017-01252
`Patent 6,946,292 B2
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`ii. Harris (Ex. 1003)
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`Harris describes the crystal structure (including oligosaccharide
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`components) of an IgG-type monoclonal antibody directed against a canine
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`lymphoma. See Ex. 1003, Abstract; 1591–92. In comparing the Fc region
`
`of the canine antibody against that of a human antibody, Harris states that,
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`the principal differences lie in the orientation and placement of
`Fuc2 and of the branch ends Gal7 and Nag9 (Figure 10).11 The
`fucose residue may be of particular interest. In both this
`antibody and the human Fc it interacts with Tyr313 [of the IgG
`heavy chain], but the interactions are quite different in the two
`cases. This fucose is also near the Fcγ receptor binding site and
`could influence binding by the receptor.
`
`Id. at 1592. With respect to effector function, Harris further states:
`
`No direct evidence, that we know of, suggests that the
`oligosaccharides form part of any effector binding site.
`Degradation or modification of the carbohydrate has, however,
`been clearly shown to eliminate or reduce effector functions
`such as . . . binding to Fc receptors . . . .
`
`Id. at 1593–94.
`
`iii. Umaña (Ex. 1004)
`
`Umaña is directed to the production of antibodies and other proteins
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`having altered glycosylation patterns that provide improved therapeutic
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`properties. Ex. 1004, Abstract, 2. In particular, Umaña states that,
`
`the present invention is directed to a method for producing
`altered glycoforms of proteins having improved therapeutic
`values, e.g., an antibody which has an enhanced antibody
`dependent cellular cytotoxicity (ADCC), in a host cell. The
`invention provides host cells which harbor a nucleic acid
`
`
`
`11 We understand Fuc2, Gal7, and Nag9 to refer to specifically numbered
`sugar moieties (fucose, galactose, and N-acetyl glucosamine, respectively)
`of the IgG oligosaccharide chains.
`
`9
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`IPR2017-01252
`Patent 6,946,292 B2
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`
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`encoding the protein of interest, e.g., an antibody, and at least
`one nucleic acid encoding a glycoprotein-modifying glycosyl
`transferase.
`
`Id. at 3:6–11. Among the techniques taught by Umaña, are “the use of gene
`
`knockout technologies . . . to tailor the host cell’s glycosyl transferase
`
`and/or glycosidase expression levels.” Id. at 15:20–22.
`
`iv. Malý (Ex. 1005)
`
`According to Malý, five genes (Fuc-TVII, Fuc-TIII, V, VI, and TIV)
`
`encode α(1,3)fucosyltransferases in humans. Ex. 1005, 649; see id. at 643.
`
`Malý discloses the targeted disruption of the mouse homolog of Fuc-TVII,
`
`and the generation of mice homozygous for the knockout of this gene.
`
`Ex. 1005, 644.
`
`According to Malý, “mice deficient in α(1,3)fucosyltransferase Fuc-
`
`TVII exhibit a leukocyte adhesion deficiency characterized by absent
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`leukocyte E- and P-selectin ligand activity and deficient HEV12 L-selectin
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`ligand activity.” Id., Abstract. Malý indicates that “Fuc-TVII decorates the
`
`oligosaccharide components of these glycoproteins with α(1,3) fucose
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`residues essential to effective E- and P-selectin ligand activity.” Id. at 649.
`
`v. Gao (Ex. 1006)
`
`Gao describes the separation of YB2/0 cells into cell fractions
`
`according to cell cycle stages using counterflow centrifugal elutriation.
`
`Ex. 1006, 435. According to Gao, “[t]he YB2/0 plasmacytoma cell line is a
`
`highly efficient partner for the production of hybridomas.” Id. at 437.
`
`
`
`12 Short for high endothelial venules, cells which express specific adhesion
`molecules such as this ligand.
`
`10
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`IPR2017-01252
`Patent 6,946,292 B2
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`a.
`
`Principles of Law
`
`
`
`ANALYSIS
`
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
`
`between the subject matter sought to be patented and the prior art are such
`
`that the subject matter as a whole would have been obvious at the time the
`
`invention was made to a person having ordinary skill in the art to which that
`
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`
`(2007). The question of obviousness is resolved based on underlying factual
`
`determinations including: (1) the scope and content of the prior art; (2) any
`
`differences between the claimed subject matter and the prior art; (3) the level
`
`of ordinary skill in the art; and (4) objective evidence of nonobviousness, if
`
`present. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). Although
`
`the KSR test is flexible, we “must still be careful not to allow hindsight
`
`reconstruction of references . . . without any explanation as to how or why
`
`the references would be combined to produce the claimed invention.”
`
`TriVascular, Inc. v. Samuels, 812 F.3d 1056, 1066 (Fed. Cir. 2016) (citation
`
`omitted).
`
`“In an [inter partes review], the petitioner has the burden from the
`
`onset to show with particularity why the patent it challenges is
`
`unpatentable.” Harmonic Inc. v. Avid Tech., Inc., 815 F.3d 1356, 1363 (Fed.
`
`Cir. 2016) (citing 35 U.S.C. § 312(a)(3) (requiring inter partes review
`
`petitions to identify “with particularity . . . the evidence that supports the
`
`grounds for the challenge to each claim”)). This burden of persuasion never
`
`shifts to Patent Owner. See Dynamic Drinkware, LLC v. Nat’l Graphics,
`
`Inc., 800 F.3d 1375, 1378 (Fed. Cir. 2015) (discussing the burden of proof in
`
`inter partes review). “To satisfy its burden of proving obviousness, a
`
`11
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`IPR2017-01252
`Patent 6,946,292 B2
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`petitioner cannot employ mere conclusory statements. The petitioner must
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`instead articulate specific reasoning, based on evidence of record, to support
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`the legal conclusion of obviousness.” In re Magnum Oil Tools Int’l, Ltd.,
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`829 F.3d 1364, 1380 (Fed. Cir. 2016) (citing KSR, 550 U.S. at 418).
`
`We analyze the challenges presented in the Petition in accordance
`
`with the above-stated principles.
`
`A.
`
` Claim Construction
`
`In an inter partes review, claim terms in an unexpired patent are
`
`interpreted according to their broadest reasonable construction in light of the
`
`specification of the patent in which they appear. 37 C.F.R. § 42.100(b);
`
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016)
`
`(upholding the use of the broadest reasonable interpretation standard).
`
`Under that standard, we presume that a claim term carries its “ordinary and
`
`customary meaning,” which “is the meaning that the term would have to a
`
`person of ordinary skill in the art in question” at the time of the invention.
`
`In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007) (citation
`
`omitted).
`
`Petitioner proposes that we construe “knock-out” as used in
`
`independent claims 1 and 7 as “any gene deletion that results in reduced or
`
`removed gene expression.” Pet. 17 (citing Ex. 1007, ¶¶ 54–57; Ex. 1026 ¶¶
`
`48–52; Ex. 1036-B, Aug. 12, 2004 Amendment at 32–35). Patent Owner
`
`contends that construction of this term is unnecessary at this stage, but
`
`opposes Petitioner’s definition to the extent it “requires ‘gene deletion’ as
`
`the only means to knock-out the FUT8 gene.” Prelim. Resp. 23. For the
`
`purpose of this Decision, we agree with Patent Owner that it is unnecessary
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`12
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`to determine the scope of genetic techniques that may be used to create the
`
`claimed “knock-out host cell.” See Ex. 1001, 7:28–38.
`
`We also agree with Patent Owner’s position that the
`
`“fucosyltransferase knock-out” of the instant claims, refers to a disruption of
`
`FUT8, the gene encoding α1,6-fucosyltransferase. See Prelim. Resp. 29; see
`
`id. at 2, fn.3. As indicated by the Specification, α1,6-fucosyltransferase is
`
`responsible for adding fucose at the 6 position of N-acetylglucosamine in the
`
`reducing ends of an antibody’s sugar chains, whereas disruption of the gene
`
`encoding this enzyme results in antibodies with more potent ADCC
`
`function. See id. at 3:60–4:1, 23:22–26, 111:31–45.
`
`Although Petitioner’s proposed construction does not expressly refer
`
`to α1,6-fucosyltransferase or the FUT 8 gene encoding it, Petitioner’s
`
`obviousness arguments are in accord with our interpretation of
`
`“fucosyltransferase knock-out.” In particular, Petitioner asserts that one of
`
`ordinary skill in the art would be motivated to obtain the host cells of the
`
`challenged claims “by ‘knocking-out’ the gene for the enzyme that adds the
`
`fucose to the sugar chain—α(1,6)fucosyltransferase.” See Pet. 19, 25, 32, 39
`
`(citations omitted); see also Ex. 1026 ¶ 45 (“The standard approach would
`
`have been to import the antibody genes into a host cell to express the
`
`antibody, and to genetically ‘knock out’ the enzyme that added α-1,6-fucose
`
`to the sugar chain (i.e., the α-1,6-fucosyltransferase enzyme).”). Further
`
`crystallizing this interpretation, Petitioner’s expert, Dr. Van Ness testified
`
`that, “the independent claims of the ’292 are directed to creating mammalian
`
`host cells—including those that are transfected with antibody genes—that
`
`have the cells’ α1,6-fucosyltransferase genes knocked out, in order to
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`express afucosylated antibodies with enhanced effector (ADCC) function.”
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`Ex. 1007 ¶ 45.
`
`In view of the above, we construe a “fucosyltransferase knock-out
`
`host cell” as a host cell in which FUT8, the gene encoding α1,6-
`
`fucosyltransferase, is disrupted.
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`At this stage of the proceeding, we find that no explicit construction
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`of any other claim term is necessary to determine whether to institute a trial
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`in this case. See Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361
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`(Fed. Cir. 2011) (“[C]laim terms need only be construed ‘to the extent
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`necessary to resolve the controversy.’” (quoting Vivid Techs., Inc. v. Am.
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`Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)).
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`B.
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`Person of Ordinary Skill in the Art.
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`According to Petitioner, one of ordinary skill in the art as of the
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`earliest possible filing date of the invention would have had A) “knowledge
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`of the scientific literature . . . concerning the means and methods for creating
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`cells in which the gene for the fucose-adding enzyme fucosyltransferase was
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`knocked out, resulting in a modified sugar chain giving improved
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`antibodies” and, B) “a doctorate in molecular immunology or biochemistry
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`of glycoproteins including antibodies, knowledge of routine genetic
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`procedures including gene ‘knock-outs,’ and a few years’ practical
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`experience working on the genetics of antibodies.” Pet. 15–16 (citing
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`Ex. 1026 ¶¶ 11–13; Ex. 1007 ¶¶ 18–20). Petitioner further directs us to the
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`level of skill in the art indicated by Applicants during prosecution. Id.
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`(citing Ex. 1036-B, Aug. 12, 2004 Amendment at 32–35) (indicating, for
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`example, that the state of the art with respect to genetic manipulation
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`techniques was “quite advanced”).
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`14
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`IPR2017-01252
`Patent 6,946,292 B2
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`Patent Owner does not propose an alternative definition. See Prelim.
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`Resp. 19–22. Patent Owner argues, however, that the cited references fail to
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`disclose “the FUT8 gene or any method of knocking out the FUT8 gene to
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`create the claimed fucosyltransferase knock-out host cell,” such that part A)
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`of Petitioner’s proposed definition is merely an attempt to “make up for the
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`missing elements and the missing motivation to combine in the prior art
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`references they cite” (id. at 2–3, 8–9, 20–22). In light of our construction of
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`“fucosyltransferase knock-out,” we agree with Patent Owner to the extent
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`that part A) of Petitioner’s proposed definition avoids the salient issue,
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`discussed in section II(C)(iii), below, of whether Petitioner has established
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`that the prior art discloses a mammalian α1,6-fucosyltransferase gene, or any
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`method of deleting or adding a mutation to the genomic α1,6-
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`fucosyltransferase gene, as required by the challenged claims.
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`Accordingly, on this record, we adopt part B) of Petitioner’s definition
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`of the level of ordinary skill in the art. Specifically – a person of ordinary
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`skill in the art would have had a doctorate level degree in a field concerned
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`with molecular immunology or biochemistry of glycoproteins including
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`antibodies, knowledge of routine generic genetic procedures including gene
`
`knock-outs, and a few years practical experience working on the genetics of
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`antibodies.
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`We further note that the prior art itself demonstrates the level of skill
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`in the art at the time of the invention. See Okajima v. Bourdeau, 261 F.3d
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`1350, 1355 (Fed. Cir. 2001) (explaining that specific findings regarding
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`ordinary skill level are not required “where the prior art itself reflects an
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`appropriate level and a need for testimony is not shown”) (quoting Litton
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`15
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`Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir.
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`1985)).
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`C.
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`Asserted Grounds
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`We next turn to the six grounds of invalidity asserted in the Petition:
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`whether the subject matter of claims 1–12 of the ’292 Patent would have
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`been obvious to a person of ordinary skill in the art at the time of the
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`invention over Rothman or Harris in view of Umaña (Grounds 1 and 2);
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`Umaña and Malý (Grounds 3 and 4) or, in the case of claims 5 and 11 only,
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`Umaña and Gao (Grounds 5 and 6). Pet. 17–18.
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`Briefly, Petitioner contends that Rothman and Harris each suggest a
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`link between removal of fucose and improved ADCC—and thus motivation
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`to obtain “fucosyltransferase knock-out” host cells producing antibodies that
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`“do not contain fucose bound to the 6 position of N-acetylglucosamine at the
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`reducing end of the sugar chains,” as required by the independent claims.
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`See Pet. 18–19, 31–32. Asserting that one of ordinary skill in the art “would
`
`achieve this result by ‘knocking out’ the gene for the enzyme that adds the
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`fucose to the sugar chain— α(1,6)fucosyltransferase,” Petitioner relies on
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`Umaña, as “teach[ing] the creation of mammalian host cells with modified
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`sugar-adding genes (including ‘knock-outs’) to create sugar-modified
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`antibodies with more efficient ADCC” properties.” See e.g., Pet. 18–19.
`
`Petitioner further asserts that “[t]he necessary steps for creating such a host
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`cell . . . were in the common knowledge.” See, e.g., id. at 19 (citing
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`Ex. 1007 ¶¶ 32–34, 39–42, 70–77). With respect to Grounds 3 and 4,
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`Petitioner further argues that one of ordinary skill in the art would have been
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`“emboldened . . . to pursue ‘knock-out’ of α1,6-fucosyltransferase” by
`
`16
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`IPR2017-01252
`Patent 6,946,292 B2
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`Malý’s “knockout of the gene for α(1,3)-fucosyltransferase in mouse
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`embryos.” Id. at 32, 39.13
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`Patent Owner responds that the challenged claims are not obvious
`
`because 1) neither Rothman nor Harris suggests a link between removal of
`
`fucose and improved ADCC and, 2) the Petition fails to provide a reasoned
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`explanation of how one of ordinary skill in the art would have combined the
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`asserted references to generate the “fucosyltransferase knock-out” having
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`the claimed properties, “especially given that none of the references mention
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`the gene encoding α1,6-fucosyltransferase (FUT8), let alone knocking out
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`the FUT8 gene to create a fucosyltransferase knock-out host cell.” Prelim.
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`Resp. 23–56.
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`We address these issues below.
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`i. Grounds 1, 3, and 5 (based on Rothman)
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`Petitioner relies on Rothman’s teachings regarding “a possible
`
`involvement of core fucosylation of IgG in NK cell-mediated ADCC,” and
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`the reference’s conclusion that the “absence of core fucosylation itself would
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`appear to be a likely candidate as a structural feature necessary for
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`enhancement of NK cell-mediated ADCC,” as providing motivation to target
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`the α1,6-fucosyltransferase gene for genetic knockout. See, e.g., Pet. 18–20.
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`Patent Owner contends that Petitioner’s expert, Dr. Jefferis, fails to credit
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`Rothman (or Harris) with discovering a correlation between defucosylation
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`and enhanced ADCC in several review articles. Prelim. Resp. 54–56.
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`Patent Owner further argues that one of ordinary skill in the art would not
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`
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`13 Petitioner further references Gao, in Grounds 5 and 6, merely to highlight
`the applicability of cell line YB2/0 for production of hybridomas. Id. at 45–
`48.
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`17
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`Patent 6,946,292 B2
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`have read Rothman the way Petitioner urges based on a review article by
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`Wright and Morrison (Ex. 2004) published before the earliest possible filing
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`date of the ’292 Patent, which potentially contradicts a portion of Rothman’s
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`analysis. See id. at 51–53.
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`We do not find Patent Owner’s position persuasive on the current
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`record. Dr. Jefferis’s failure to mention Rothman in two review articles is
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`insufficient to overcome Rothman’s express teaching that the “absence of
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`core fucosylation itself would appear to be a likely candidate as a structural
`
`feature necessary for enhancement of NK cell-mediated ADCC.” See
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`Ex. 1002, 1122. And although we do not find Patent Owner’s arguments
`
`based on Wright and Morrison unreasonable, Patent Owner’s explanation of
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`how one of ordinary skill in the art would interpret Rothman in view of this
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`reference rests on attorney argument, which is entitled to little probative
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`value. See In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997).
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`Accordingly, on the present record, Petitioner has shown sufficiently that
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`Rothman provides a link between removal of fucose and improved ADCC
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`and, thus, motivation to generate IgG-type antibodies in cells lacking α1,6-
`
`fucosyltransferase activity. This determination does not, however, end our
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`inquiry with respect to Petitioner’s assertion of obviousness.
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`ii. Grounds 2, 4, and 6 (based on Harris)
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`With respect to Grounds 2, 4, and 6, Petitioner relies on Harris to
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`establish motivation to generate IgG-type antibodies in cells lacking α1,6-
`
`fucosyltransferase activity. In particular, Petitioner points to Harris’s
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`teaching that the fucose residue of an IgG-type antibody “may be of
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`particular interest” because it is “near the Fcγ receptor binding site and could
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`influence binding by the receptor.” See, e.g., Pet. 25–31 (quoting Ex. 1003,
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`18
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`IPR2017-01252
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`1592) (emphasis removed); see also Ex. 1026 ¶¶ 80, 124 (asserting that
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`Harris “describes the correlation between sugar chain modification—
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`including the removal of fucose, particularly—and improved ADCC”);
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`Ex. 1007 ¶¶ 87, 111 (same).
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`We do not find Petitioner’s arguments persuasive. Although Harris
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`draws attention to the proximity of the fucose moiety and the Fcγ receptor
`
`binding site, it merely hypothesizes that the fucose “could,” therefore,
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`“influence” Fcγ binding. See Ex. 1003, 1592. We do not read Harris as
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`suggesting that any such potential influence would have a positive effect on
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`ADCC. To the contrary, Harris’s teaching that “[d]egradation or
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`modification of the carbohydrate has . . . been clearly shown to eliminate or
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`reduce effector functions such as . . . binding to Fc receptors,” suggests that
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`any potential influence would more likely reduce, rather than enhance,
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`ADCC. Ex. 1003, 1593–94. Moreover, as Patent Owner points out, “Harris
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`does not mention removing fucose or improved ADCC, much less any
`
`causal relationship between the two. Rather, Harris suggests that the
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`presence of fucose is required for receptor binding since fucose interacts
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`with Tyr313 on the Fc region.” Prelim. Resp. 13–14.
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`For at least these reasons, the Petition fails to show sufficiently that
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`the subject matter of claims 1–12 would have been obvious over Harris, in
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`view of Umaña, Malý, and/or Gao. Accordingly, for at least these reasons,
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`we decline to institute trial with respect to Grounds 2, 4, and 6.
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`iii. A gene encoding α1,6-fucosyltransferase
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`Every challenged claim is directed to
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