throbber
Paper 72
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` Entered: December 16, 2016
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`Trials@uspto.gov
`571-272-7822
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`KITE PHARMA, INC.,
`Petitioner,
`
`v.
`
`SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH,
`Patent Owner.
`____________
`
`Case IPR2015-01719
`Patent 7,446,190 B2
`____________
`
`
`
`Before RAMA G. ELLURU, TINA E. HULSE, and
`ELIZABETH A. LAVIER, Administrative Patent Judges.
`
`LAVIER, Administrative Patent Judge.
`
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
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`IPR2015-01719
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`INTRODUCTION
`I.
`Petitioner, Kite Pharma, Inc. (“Kite”), filed a Petition requesting an
`inter partes review of claims 1–13 of U.S. Patent No. 7,446,190 B2 (“the
`’190 patent”; Ex. 1001), all the claims in the patent. Paper 2 (“Pet.”). Patent
`Owner, Sloan Kettering Institute for Cancer Research (“Sloan”), filed a
`Preliminary Response. Paper 7 (“Prelim. Resp.”). We instituted an inter
`partes review of the challenged claims, on the three grounds of
`unpatentability set forth in the Petition. Paper 8 (“Dec. Inst.”). Sloan filed a
`Response to the Petition. Paper 20 (“PO Resp.”). Kite filed a Reply to the
`Response. Paper 31 (“Pet. Reply”).
`Both parties filed motions to exclude certain exhibits and testimony.
`Paper 46 (Kite); Paper 52 (Sloan). Both parties opposed the other’s motion
`to exclude. Paper 56 (Kite); Paper 57 (Sloan). And both parties filed reply
`briefs in support of their motions to exclude. Paper 58 (Sloan); Paper 59
`(Kite). Sloan also filed Motions for Observation on certain cross-
`examination testimony of Kite’s declarants (Papers 47–49), to which Kite
`filed Responses (Papers 60–62).
`An oral hearing occurred on October 20, 2016, a transcript of which
`has been entered in the record.1 Paper 71 (“Tr.”).
`
`
`1 Kite filed Objections to Sloan’s Demonstrative Exhibits. Paper 70. In this
`Final Written Decision, we rely directly on the arguments presented properly
`in the parties’ briefs and the evidence of record. The demonstrative exhibits
`are considered only to the extent they are consistent with those arguments
`and evidence.
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`We have jurisdiction under 35 U.S.C. § 6. This Final Written
`Decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
`For the reasons that follow, we determine that Kite has not shown by a
`preponderance of the evidence that claims 1–13 of the ’190 patent are
`unpatentable.
`
`A. The ’190 patent
`The ’190 patent is titled “Nucleic Acids Encoding Chimeric T Cell
`Receptors.” Ex. 1001, at [54]. The ’190 patent explains that genetic
`engineering of T lymphocytes “to express artificial TCRs [(T cell receptors)]
`that direct cytotoxicity toward tumor cells” is a promising approach for
`“enhanc[ing] immune recognition and elimination of cancer cells.” Ex.
`1001, 1:29–33. Specifically, the ’190 patent describes engineered (i.e.,
`chimeric) TCRs that are formed by combining, in a single molecule, an
`activation signaling region (from CD3ζ (also known as the TCR ζ-chain)), a
`costimulatory signaling region (from, e.g., CD28), and a binding element for
`specific interaction with a selected target. See id. at 2:14–18. The ’190
`patent identifies P28Z as a chimeric TCR “in accordance with the
`invention.” Id. at 5:28–29. P28Z is the second chimeric TCR from the left
`depicted in Figure 2 (annotated to highlight P28Z (solid line) and P28
`(dotted line)), shown below:
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`Annotated Figure 2 of the ’190 patent diagrams “a series of chimeric
`TCRs.”2 Id. at 2:42. P28, a control species, includes “the intracellular,
`transmembrane and much of the extracellular portions of CD28.” Id. at
`5:26–28. The CD28 portion of P28 can be amplified from nucleotides 336–
`660 of human CD28 cDNA using primers listed in the ’190 patent as SEQ
`ID NO: 4 and 5, to produce the full sequence SEQ ID NO: 6. See id. at
`4:21–28, 7:51–56; see also id., Certificate of Correction (correcting SEQ ID
`NO: 6). The ’190 patent states that its “most important finding” is that the
`“expression of P28z enables T cells to undergo repeated rounds of antigen-
`dependent stimulation and expansion.” Ex. 1001, 5:58–61.
`
`
`2 For reference, each of the four chimeric TCRs depicted in Figure 2
`includes an scFV (single-chain variable fragment) specific for PSMA
`(prostate-specific membrane antigen). See Ex. 1001, 5:21–23, 7:43–45.
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`B. Illustrative Claim
`Claim 1 is the only independent claim of the challenged claims, and is
`illustrative of the claimed subject matter:
`1. A nucleic acid polymer encoding a chimeric T cell receptor,
`said chimeric T cell receptor comprising
`(a) a zeta chain portion comprising the intracellular domain of
`human CD3 ζ chain,
`(b) a costimulatory signaling region, and
`(c) a binding element that specifically interacts with a selected
`target,
`wherein the costimulatory signaling region comprises the amino
`acid sequence encoded by SEQ ID NO:6.
`Ex. 1001, 25:30–38 (some formatting added).
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`C. Grounds of Unpatentability Instituted for Trial
`We instituted trial based on the following grounds of unpatentability:
`
`Ground Claims
`
`1–3, 6–9, 12, 13
`
`4, 10
`
`5, 11
`
`1
`
`2
`
`3
`
`
`
`References
`Basis
`§ 103(a)3 Krause,4 Finney,5 and
`Aruffo6
`Krause, Finney, Aruffo,
`and Gong7
`Krause, Finney, Aruffo,
`and Bejcek8
`
`§ 103(a)
`
`§ 103(a)
`
`
`3 The relevant sections of the Leahy-Smith America Invents Act (“AIA”),
`Pub. L. No. 112–29, took effect on March 16, 2013. Because the application
`from which the ’190 patent issued was filed before that date, our citations to
`Title 35 are to its pre-AIA version.
`4 Krause et al., Antigen-dependent CD28 Signaling Selectively Enhances
`Survival and Proliferation in Genetically Modified Activated Human
`Primary T Lymphocytes, 188 J. EXP. MED. 619–26 (1998) (Ex. 1002).
`5 Finney et al., Chimeric Receptors Providing Both Primary and
`Costimulatory Signaling in T Cells from a Single Gene Product, 161 J.
`IMMUNOL. 2791–97 (1998) (Ex. 1003).
`6 Aruffo & Seed, Molecular Cloning of a CD28 cDNA by a High-Efficiency
`COS Cell Expression System, 84 PNAS USA IMMUNOL. 8573–88 (1987)
`(Ex. 1012).
`7 Gong et al., Cancer Patient T Cells Genetically Targeted to Prostate-
`Specific Membrane Antigen Specifically Lyse Prostate Cancer Cells and
`Release Cytokines in Response to Prostate-Specific Membrane Antigen, 1
`NEOPLASIA 123–27 (1999) (Ex. 1004).
`8 Bejcek et al., Development and Characterization of Three Recombinant
`Single Chain Antibody Fragments (scFvs) Directed against the CD19
`Antigen, 55 CANCER RES. 2346–51 (1995) (Ex. 1016).
`6
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`CLAIM CONSTRUCTION
`II.
`In our decision instituting inter partes review, we determined it was
`not necessary to construe expressly any of the claim terms. Dec. Inst. 6.
`Upon consideration of the full record, express construction remains
`unnecessary. See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795,
`803 (Fed. Cir. 1999) (noting claim terms require construction “only to the
`extent necessary to resolve the controversy”). Indeed, neither the Response
`nor the Reply directly addresses claim construction, and the parties did not
`focus on claim construction issues during the oral hearing.
`
`III. OBVIOUSNESS
`A claim is unpatentable for obviousness if, to one of ordinary skill in
`the pertinent art, “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.” 35 U.S.C. § 103(a)
`(2006); see also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406–07 (2007).
`The question of obviousness is resolved on the basis of 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.
`Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966).
`If all the claimed elements are present in the prior art references, the
`obviousness inquiry turns to the combination of those references:
`[P]roper analysis under § 103 requires, inter alia, consideration
`of two factors: (1) whether the prior art would have suggested to
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`those of ordinary skill in the art that they should make the
`claimed composition or device, or carry out the claimed process;
`and (2) whether the prior art would also have revealed that in so
`making or carrying out, those of ordinary skill would have a
`reasonable expectation of success.
`Par Pharm., Inc. v. TWI Pharms., Inc., 773 F.3d 1186, 1196 (Fed. Cir. 2014)
`(quoting Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1164 (Fed. Cir.
`2006)).
`
`A. Level of Ordinary Skill in the Art
`The parties generally agree9 that one of ordinary skill in the art at the
`time of the invention10 would have had an advanced degree in immunology,
`cell biology, biochemistry, molecular biology, or a related discipline, along
`with knowledge and experience in the field of T cell research, including
`laboratory techniques. See Pet. 33–34 (citing Ex. 100811 ¶ 12); PO Resp. 9
`(citing Ex. 202212 ¶ 25; Ex. 1008 ¶ 12). In light of the parties’ general
`agreement on this point, we adopt that description of the level of ordinary
`
`
`9 However, Sloan disputes (see PO Resp. 9) Kite’s assertion that one of
`ordinary skill in the art would have “taken advantage of certain specialized
`skills” while working as part of a team (Pet. 34). As these specialties (see
`Pet. 34 (“[f]or example, an immunologist, a cell biologist, and a clinical
`oncologist”)) are in disciplines within the ambit of the relevant art of T cell
`research, we discern no meaningful distinction in the parties’ positions on
`this issue.
`10 The application leading to the ’190 patent was filed on May 28, 2003. Ex.
`1001, at [22].
`11 Declaration of Professor Hinrich Abken, M.D. (Ex. 1008).
`12 Declaration of Professor Thomas Brocker, Ph.D. (Ex. 2022).
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`skill in the art. In our analysis, we consider the applied prior art as
`representative of the level of ordinary skill. See Okajima v. Bourdeau,
`261 F.3d 1350, 1355 (Fed. Cir. 2001).
`
`B. Overview of Cited Art
`Each of the three grounds of unpatentability upon which we instituted
`this review relies on a combination of Krause, Finney, and Aruffo. See Pet.
`16. Kite adds Gong and Bejcek for Grounds 2 and 3, respectively. See id.
`
`1. Krause
`Krause describes a chimeric CD28 construct specific for GD2, a
`molecule overexpressed on the surface neuroblastoma and other human
`tumor cells. Ex. 1002, 619. Krause shows that this construct, called 3G6-
`CD28, “provides CD28 signaling upon specific recognition of the GD2
`antigen on tumor cells,” and further demonstrates selective expansion of
`CD8+ lymphocytes expressing 3G6-CD28 “when cultured with cells
`expressing allogeneic major histocompatibility complex [(MHC)] class I
`together with GD2.” Id. Thus, Krause focuses on inducing the CD28-
`mediated costimulatory signal. See id. at 619–620, 624. Krause does not
`indicate that the 3G6-CD28 construct contains CD3ζ specifically, or any
`other TCR complex-related sequence. Rather, for the primary T-cell
`activation signal, Krause relies on co-culturing its 3G6-CD28-expressing
`cells with “cells expressing MHC class I together with GD2.” Id. at 620.
`For its construct, Krause uses “the portion of the CD28 comprising
`part of the extracellular, the transmembrane, and the cytoplasmic domains.”
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`Id. at 620. More specifically, Krause provides primers for amplifying the
`CD28 coding sequence from isolated RNA using reverse transcription PCR,
`and states that the amplified region runs from nucleotides 336 to 663 of
`human CD28. See id. Notably, the ’190 patent cites Krause (as well as
`another paper with the same primary author) as describing the portion of
`CD28 used in the P28 and P28Z constructs. See Ex. 1001, 7:51–56.
`
`2. Finney
`Finney describes chimeric receptors that feature “intracellular
`sequences comprising the signaling region of CD28 in series with the
`signaling region of the ζ-chain[13] from the TCR complex.” Ex. 1003, 2792.
`Finney states that “[t]hese constructs represent the first of a new generation
`of single gene multidomain chimeric receptors capable of mediating both
`primary and costimulatory signaling specifically from a single extracellular
`recognition event.” Id. at 2791. Finney’s experimental constructs feature
`sequences derived from an scFv extracellular antibody binding site, followed
`by one of two “spacer” sequences (“h.28” and “G1”), followed by a “linker,”
`followed by sequences derived from the intracellular domain of CD3ζ and
`the intracellular and transmembrane domains of CD28. Id. at 2792. In some
`constructs, the CD28 sequence is proximal to the cell membrane; in others,
`the CD3ζ sequence is proximal. See id.
`
`
`13 Unless quoting from Finney or another source, we use the “CD3ζ”
`nomenclature for consistency. The terms are interchangeable, as noted
`above.
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`Finney further reports that constructs containing the “h.28” spacer are
`more efficient than constructs with the “G1” spacer in mediating IL-2
`production in the same assays. See id. at 2791 (Abstract), 2794–95
`(discussing Figure 3). Both spacers include sequences from human IgG1
`hinge, but h.28 also includes “part of the extracellular region of human
`CD28.” Id. at 2793. In contrast, G1 includes human IgG1 as well as CH2
`and CH3 sequences (but not any sequence from CD28).14 Id.
`
`3. Aruffo
`Aruffo reports the successful cloning of human CD28 cDNA, and
`provides the nucleotide sequence. Ex. 1012 (see especially Fig. 2).
`
`4. Gong
`Gong discloses a chimeric TCR with a binding region specific for
`prostate-specific membrane antigen (PSMA), a glycoprotein expressed on
`prostate cancer cells and other tumor cells. Ex. 1004, 123 (Abstract). Gong
`reports that T cells transduced with Gong’s construct successfully lyse
`prostate cancer cells. Id.
`
`5. Bejcek
`Bejcek demonstrates cloning, expression, and binding of anti-CD19
`single chain antibody fragments. Ex. 1016, 2346 (Abstract).
`
`
`14 Immunoglobulin G1 (IgG1) is a subclass of antibodies found in humans.
`CH2 and CH3 are constant domains of the heavy chain of the antibody.
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`C. Ground 1
`Kite asserts that claims 1–3, 6–9, 12, and 13 are unpatentable because
`they would have been obvious over the combination of Krause, Finney, and
`Aruffo. Pet. 34–51. Sloan does not appear to dispute that the combination
`of cited references teaches each of the claim elements. Rather, Sloan argues
`Kite has not sufficiently established a rationale for combining the references,
`or that one of ordinary skill in the art would have had a reasonable
`expectation of success in doing so. See PO Resp. 9–43. Sloan also argues
`that the objective evidence of nonobviousness in this case is
`“overwhelming.” See id. at 48–61.
`Kite offers three alternative rationales for combining Krause, Finney,
`and Aruffo: (1) starting with Krause’s construct (with the CD28 sequence as
`provided in Aruffo), and adding Finney’s CD3ζ to it (see Pet. 38–40); (2)
`starting with Finney’s chimeric TCR, and replacing its CD28 region with
`Krause’s CD28 region (with the CD28 sequence as provided in Aruffo) (see
`id. at 40–45); and (3) routine optimization of Finney, with guidance from
`Krause and Aruffo (see id. at 45–46).
`As explained below, we find none of these rationales to be persuasive.
`Accordingly, we conclude that Kite has not carried its burden to prove, by a
`preponderance of the evidence, that claims 1–3, 6–9, 12, and 13 are
`unpatentable as obvious over Krause, Finney, and Aruffo.
`
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`1. Rationale 1: Add Finney’s CD3ζ to Krause’s Chimeric T Cell
`Receptor
`Kite first argues that an ordinarily skilled artisan focused on the GD2
`cancer target in Krause “would have been motivated to make a chimeric
`TCR that included the CD3ζ domain disclosed in Finney together with the
`binding element and CD28 region Krause teaches, to achieve a chimeric
`TCR with both a primary and a costimulatory domain in a single chimeric
`receptor.” Pet. 38 (citing Ex. 1008 ¶¶ 93–102). However, the purported
`advantages Kite asserts (see id. at 38–40) are all advantages taught by
`Finney alone (i.e., the advantages of a dual-signaling chimeric T cell
`receptor over using two separate constructs), as applied to a GD2 target. That
`is, Kite does not proffer any rationale for using Krause’s CD28 sequence
`rather than Finney’s. Using either CD28 sequence would yield the general
`advantages of a dual-signaling chimeric TCR noted in rationale (1) by Kite,
`but only the combination including Krause’s CD28 sequence, not Finney’s,
`would be within the scope of the challenged claims of the ’190 patent.
`Central to any allegation of obviousness is that the proponent must
`establish that the prior art renders the invention obvious as claimed. Cf.
`KSR, 550 U.S. at 418 (discussing various considerations important in
`determining “whether there was an apparent reason to combine the known
`elements in the fashion claimed by the patent at issue”). Here, Kite’s
`rationale (1), as presented in the Petition, does not distinguish expressly
`between the advantages of Krause’s CD28 sequence versus Finney’s, or
`explain why one of ordinary skill in the art, in developing a dual-signaling
`chimeric TCR to target GD2, would have been motivated to retain Krause’s
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`CD28 sequence over Finney’s when combining the two references.
`Accordingly, rationale (1) is deficient on its face. However, if we impute
`the alleged advantages of Krause’s CD28 sequence as discussed with respect
`to rationales (2) and (3) to rationale (1),15 then rationale (1) rises or falls
`with rationale (2).16
`
`2. Rationale 2: Replacement of Finney’s CD28 Sequence with Krause’s
`CD28 Sequence
`Second, Kite argues that an ordinarily skilled artisan focused on
`Finney’s CD33 cancer target “would have had a reason to replace Finney’s
`CD28 region[17] in Finney’s chimeric TCR with Krause’s CD28 region,
`which is longer than Finney’s,” specifically because they “would have
`expected Krause’s CD28 region to offer advantages with respect to signal
`transduction and cell surface expression levels.” Pet. 40 (citing Ex. 1003,
`2793, Fig. 2, 2794, Fig. 3A; Ex. 1008, ¶¶ 103–108). And although Kite’s
`proposed combination uses the CD28 region from Krause, not Finney, Kite
`
`
`15 Kite appears to take this approach in its Reply, discussing these
`advantages in the context of rationale (1). See Pet. Reply 11–14.
`16 As we discuss below, rationale (3) is not meaningfully distinct from
`rationale (2).
`17 The phrase “Finney’s CD28 region” is somewhat vague absent additional
`context because, as discussed above, Finney discloses constructs with one of
`two spacer sequences, only one of which (h.28) includes extracellular CD28
`sequence. By “Finney’s CD28 region,” we understand Kite to mean the
`extracellular CD28 sequence from the h.28 spacer plus the transmembrane
`and intracellular CD28 sequence from the CD28 cassette. See Ex. 1002,
`2793; Pet. 22; Pet. Reply 18 (Figure 4); Tr. 28:19–25.
`14
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`argues that Finney itself shows “the benefits of including additional
`extracellular CD28 sequence in a chimeric TCR,” because Finney’s
`construct with a “longer” CD28 region resulted in more cell surface
`expression and IL-2 production as compared to the construct with “less
`CD28 sequence.” Id. at 42.
`Further, Kite asserts (see Pet. 40–42; see also Pet. Reply 15–20) that
`the extracellular CD28 sequence of Krause includes particularly
`advantageous features: the “MYPPPY” motif,18 and the adjacent “LDN”
`motif,19 neither of which is present in Finney’s extracellular CD28 sequence
`(see Ex. 1008 ¶¶ 74–75). Kite cites a study by Kariv et al.20 discussing the
`significance of the MYPPPY and LDN motifs to CD28 expression and IL-2
`
`
`18 “MYPPPY” is the sequence of single-letter amino acid codes representing
`Methionine-Tyrosine-Proline-Proline-Proline-Tyrosine. See Ex. 1010, 390.
`As Krause does not include full sequence data, Krause does not expressly
`mention the MYPPPY motif. Rather, Dr. Abken deduces the inclusion of
`the MYPPPY motif in Krause from Krause’s primers and the full CD28
`sequence disclosed in Aruffo. See Ex. 1008 ¶ 74. Sloan does not dispute
`that Krause’s CD28 region includes the MYPPPY motif.
`19 “LDN” is the sequence of single-letter amino acid codes representing
`Leucine-Aspartic acid-Asparagine. Cf. Ex. 1006, 32. As with the MYPPPY
`motif, Krause does not expressly mention the LDN motif, but Dr. Abken
`deduces its inclusion in Krause’s extracellular CD28 sequence from
`Krause’s primers and Aruffo’s sequence. See Ex. 1008 ¶ 74. Sloan does not
`dispute that Krause’s CD28 region includes the LDN motif adjacent to the
`MYPPPY motif.
`20 Kariv et al., Analysis of the Site of Interaction of CD28 with Its Counter-
`receptors CD80 and CD86 and Correlation with Function, 157 J. IMMUNOL.
`29–38 (1996) (Ex. 1006).
`
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`production. See Pet. 29–30 (citing Ex. 1006); see also id. at 40–42 (same).
`According to Kite, “the MYPPPY motif of CD28 was known to be highly
`conserved across many species, i.e., ‘virtually identical when compared
`among human, mouse, rat, and even chicken, indicating that it may have an
`important role in ligand binding and/or signal transduction.’” Id. at 29
`(quoting Ex. 1010,21 390 (emphasis added in Petition)). Kite notes that
`amino acids immediately adjacent to the MYPPPY motif, i.e., the LDN
`motif, were thought to be required for full surface-level expression of CD28.
`Id. at 30 (citing Ex. 1006, 36, Fig. 6; Ex. 1008 ¶ 75). Accordingly, Kite
`argues that one of ordinary skill in the art would have been motivated to
`replace Finney’s CD28 region with Krause’s (which has a longer
`extracellular domain, including the MYPPPY and LDN motifs) to improve
`both signal transduction and cell surface expression. Id. at 40–41; see also
`id. at 42 (discussing the benefit of “longer” CD28 regions).
`We do not find Kite’s analysis to be persuasive, for the reasons
`outlined below.
`
`a. Finney Does Not Teach or Suggest that “Longer” CD28 Sequences Are
`Better than “Shorter” Ones
`Kite’s thesis that “longer” CD28 regions would be considered
`advantageous over “shorter” ones is not supported by the cited prior art.
`Although Kite is correct that Finney’s chimeric TCR containing a “longer
`
`
`21 Greenfield et al., CD28/B7 Costimulation: A Review, 18 CRITICAL
`REVIEWS IN IMMUNOLOGY 389, 390 (1998) (Ex. 1010).
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`region of CD28” performed better than the chimeric TCR with “less CD28
`sequence” (Pet. 42), this statement ignores other differences between
`Finney’s constructs. As discussed above, Finney teaches constructs
`containing one of two spacers, h.28 or G1. Only the h.28 spacer includes
`extracellular CD28 sequence; the G1 spacer itself contains no CD28
`sequence at all. See Ex. 1003, 2792. However, the two spacers further
`differ from each other insofar as the G1 spacer includes human IgG1, CH2
`and CH3 sequences, but the h.28 spacer does not. Id. Ultimately, as Sloan
`points out, the G1 spacer is “218 amino acids longer than the h.28 spacer.”
`PO Resp. 13 (citing Ex. 1003, 2793; Ex. 2022 ¶¶ 114, 194; Ex. 2021,
`188:10–13).
`Kite does not acknowledge these other differences between Finney’s
`spacers in the Petition, and this omission undercuts the persuasiveness of
`Kite’s argument. In its Reply, Kite includes a substantive discussion of the
`h.28 and G1 spacers, but relies almost exclusively on its experts’ analyses to
`brush aside the other distinctions, concluding that “a POSA would have
`viewed Finney’s constructs as differing essentially in only one way: the
`length of the CD28 sequence.” Pet. Reply 19 (citing Ex. 103222 ¶ 56; Ex.
`103323 ¶ 46). Also, Kite characterizes Sloan as allegedly “conced[ing] that
`the G1 spacer was ‘inert, [and] non-signaling.’” Pet. Reply 18 (quoting PO
`Resp. 23). But this misses Sloan’s point, which is that neither the h.28 nor
`
`
`22 Second Declaration of Dr. Abken (Ex. 1032).
`23 Declaration of Professor Jürgen Bajorath, Ph.D. (Ex. 1033).
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`the G1 spacer contains binding domains. Kite’s incomplete representation
`of Sloan’s position is clear when the quoted passage is considered in
`context:
`Skilled artisans also used spacer domains derived from CD8,
`CD7, and CD4, also found on T cells. See KIT1004, 124; Ex.
`2015, 102; Ex. 2030, 183; Ex. 2031, 1669; Ex. 2032, 720; Ex.
`2033, 412-413; Ex. 2023, 4319. None of these spacers contained
`the ligand-binding domain of the protein from which it derived,
`but rather comprised the inert, non-signaling portions of the
`protein’s constant-like domain. Ex. 2022, ¶160. Finney’s h.28
`and G1 spacers likewise contained no portion of the specific
`binding domains of CD28 or the IgG1, respectively. Ex. 1003,
`2792-93; Ex. 2022, ¶161. The CH2 and CH3 domains are inert
`constant regions within the immunoglobulin. Ex. 2022, ¶42.
`
`PO Resp. 23. In other words, Sloan argues that Finney’s spacers, like other
`spacers known in the art, were meant to be non-signaling and otherwise
`inert. Accordingly, Sloan’s argument is consistent with Finney’s stated
`purpose for its spacer sequences: “[s]pacers are used to distance the
`extracellular binding domain from the membrane” (Ex. 1003, 2792).
`To be sure, Finney reports superior results for constructs with the h.28
`spacer instead of the G1 spacer. See, e.g., id. at 2793 (“The presence of the
`CD28 extracellular spacer resulted in greater expression of the CD28-ζ
`signaling sequence than did the G1 spacer.”), 2795 (“Again the h.28 spacer
`was more efficient than the G2 spacer at mediating IL-2 production.”).
`However, as Sloan notes, Finney never “compar[es] the relative ‘lengths’ of
`CD28 regions or suggest[s] advantages of ‘longer’ CD28 regions.” PO
`Resp. 3. Thus, the ordinarily skilled artisan, reading Finney, would
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`appreciate that the h.28 spacer was superior to the G1 spacer, but would not
`have attributed that superiority to the presence of extracellular CD28
`sequence in the h.28 spacer. Further, we agree with Sloan (see PO Resp.
`15–16) that even if the ordinarily skilled artisan had attributed some value to
`the extracellular CD28 sequence in the h.28 spacer, there would have been
`no reason to expect that even more extracellular CD28 sequence would yield
`further improvements. As Finney includes only one spacer (h.28)
`comprising extracellular CD28 sequence, there is no trend from which one
`could extrapolate the relative value of differing extracellular CD28 lengths.
`Furthermore, to add more extracellular CD28 sequence would risk adding
`binding domains (as discussed further below), contrary to Finney’s stated
`purpose of the spacer to simply provide “distance” between the construct’s
`intended extracellular binding domain and the cell membrane.
`
`b. The Prior Art Does Not Teach or Suggest that Inclusion of the MYPPPY
`and/or LDN Motifs Would Have Been Advantageous
`We are also not persuaded that one of ordinary skill in the art would
`have considered the inclusion of more extracellular CD28 sequence,
`particularly the MYPPPY and LDN motifs, to be advantageous in designing
`a chimeric TCR.
`As discussed above, none of Finney’s constructs includes the
`MYPPPY or LDN motifs. Krause’s construct does, but Krause does not
`emphasize (or even acknowledge) this fact. As Sloan points out, “[n]either
`Krause nor Finney even suggested a signaling role for any extracellular
`CD28 portion.” PO Resp. 18 (citing Ex. 1003, 2792; Ex. 1002, 623).
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`Rather, Krause characterizes its data as “strongly suggest[ing]” that the
`costimulatory signal is “dependent on the cytoplasmic domain of CD28”
`(Ex. 1002, 623), i.e., not the extracellular domain.
`Kariv, on which Kite relies, calls the MYPPPY motif a “key site of
`common and selective recognition” for CD28. Ex. 1006, Abstract. More
`specifically, Kariv reports that “the majority of substitutions and deletions in
`the MYPPPY motif abrogate binding to both receptors, while retaining cell
`surface reception,” and also notes that the adjacent LDN residues “also
`contribute to this site of interaction.” Ex. 1006, 35. Kite argues that Kariv
`supports the motivation to include the MYPPPY and LDN motifs in a
`chimeric TCR construct because Kariv’s studies show that mutations in the
`MYPPPY motif “dramatically reduced the CD28 protein’s ability to signal
`the release of IL-2 by T cells” and that mutations in the LDN motif
`“decreased CD28 expression on the cell surface of T cells, indicating that
`this adjacent region is required for full protein expression.” Pet. 29–30
`(citing Ex. 1006, 36–37, Figs. 6, 7; Ex. 1008 ¶¶ 74–75). But these
`arguments only serve to support the general importance of the MYPPPY
`motif to CD28 function; they do not provide specific support for the
`proposition that the MYPPPY motif is important in signal transduction. Put
`differently, we agree with Sloan and credit the testimony of Dr. Brocker that
`Kariv’s mutational analyses do not indicate whether the MYPPPY and/or
`LDN motifs would have been important for signal transduction decoupled
`from binding to a natural ligand, i.e., in the case of a chimeric TCR with an
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`artificial binding domain not reliant on natural ligand binding to CD28. See
`PO Resp. 20; Ex. 2022 ¶¶ 82, 134–44.
`Kite’s reliance on Greenfield suffers from the same problem, insofar
`as Greenfield addresses the importance of the MYPPPY motif “in ligand
`binding and/or signal transduction” (Pet. 29 (quoting Ex. 1010, 390
`(emphasis added in Petition))), and its cross-species conservation (id.). The
`“and/or” in Greenfield’s sentence indicates that the MYPPPY motif was
`thought to have been important for ligand binding or signal transduction or
`both. Greenfield thus stands for the proposition that the MYPPPY motif is
`important for endogenous CD28 function; it is silent as to the potential role,
`if any, of the MYPPPY motif in the absence of natural ligand binding to
`CD28.
`In sum, the prior art references cited by Kite in the Petition that
`expressly address the MYPPPY and/or LDN motifs, i.e., Kariv and
`Greenfield, show that these sequences are important to CD28 function
`generally. Further, Kariv provides evidence that the MYPPPY and LDN
`motifs are important for ligand binding. However, these references shed no
`light upon what role the MYPPPY and/or LDN motifs would play if natural
`CD28 ligand binding is bypassed, as would be the case in a dual-signaling
`chimeric TCR. Accordingly, Kite’s argument, that one of ordinary skill in
`the art would have been motivated to include more extracellular CD28
`sequence including the MYPPPY and LDN motifs in designing a chimeric
`TCR, is not supported sufficiently by Kariv or Greenfield.
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`c. The Prior Art Teaches Away from Inclusion of the MYPPPY Motif in a
`Chimeric TCR
`The foregoing subsections provide a sufficient basis on which to
`conclude that Kite has not carried its burden of persuasion as to Ground 1.
`However, there is an additional, related reason that further supports this
`conclusion, namely that

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