Trials@uspto.gov
`571-272-7822
`
`
`
` Paper 5
` Entered: March 15, 2017
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`FLUIDIGM, CORP.,
`Petitioner,
`
`v.
`
`THE BOARD OF TRUSTEES OF
`THE LELAND STANFORD JUNIOR UNIVERSITY,
`Patent Owner.
`____________
`
`Case IPR2017-00014
`Patent 7,695,926 B2
`____________
`
`Before ERICA A. FRANKLIN, GEORGIANNA W. BRADEN, and
`ZHENYU YANG, Administrative Patent Judges.
`
`FRANKLIN, Administrative Patent Judge.
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`

`

`IPR2017-00014
`Patent 7,695,926 B2
`
`
`INTRODUCTION
`
`Fluidigm Corporation (“Petitioner”) filed a Petition requesting an
`inter partes review of claims 1–9 and 11–12 of U.S. Patent No. 7,695,926
`B2 (Ex. 1001, “the ’926 patent”). Paper 1 (“Pet.”). The Board of Trustees
`of the Leland Stanford Junior University (“Patent Owner”) did not file a
`Preliminary Response to the Petition.1
`We have jurisdiction under 35 U.S.C. § 314, which provides that an
`inter partes review may not be instituted “unless . . . there is a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.” 35 U.S.C. § 314(a). Upon considering
`the Petition, we determine that Petitioner has shown a reasonable likelihood
`that it would prevail in showing the unpatentability of claims 1–9 and 11–12.
`Accordingly, we institute an inter partes review of those claims.
`Related Proceedings
`A.
`Petitioner and Patent Owner affirm that they are not aware of any
`judicial proceeding involving the ’926 patent. Pet 3, Paper 4, 1.
`The ’926 Patent
`B.
`The claims of the’926 patent are directed to a kit comprising first and
`second activation state-specific antibody, wherein each of those antibodies
`binds to an activation form of respective first and second proteins within one
`
`
` 1
`
`
`
` Although Patent Owner did not file a Preliminary Response, the burden
`remains on Petitioner to demonstrate unpatentability. See Dynamic
`Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d 1375, 1378 (Fed.
`Cir. 2015) (citing Tech. Licensing Corp. v. Videotek, Inc., 545 F.3d 1316,
`1326–27 (Fed. Cir. 2008)) (discussing the burden of proof in inter partes
`review).
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`IPR2017-00014
`Patent 7,695,926 B2
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`of the recited signaling pathways, i.e., MAPK, AKT, NFkB, STAT, or
`WNT. Ex. 1001, 51:20–33. Additionally, the kit comprises instructions for
`using those antibodies. Id. at 51:21–22. In some embodiments, claims 6–9,
`the antibodies are uniquely labeled. Id. at 52:44–55. In other embodiments,
`claims 11–12, the antibodies are immobilized in a solid surface. Id. at
`52:58–63.
`
`Illustrative Claim
`C.
`Claim 1 of the ’926 patent is the only independent claim and it is
`reproduced below:
`1. A kit comprising a first activation-state specific antibody
`and a second activation-state specific antibody and instructions
`for use of the antibodies, wherein at least one of the
`antibodies is specific for a phosphorylation site, wherein said
`first activation state-specific antibody binds to an activation
`form of a first protein within the MAPK (mitogen activated
`protein kinase), AKT (homolog of V-akt murine thymoma
`viral oncogene), NFkB (nuclear factor kappa B), PKC (protein
`kinase C), STAT (signal transducers and activators of
`transcription) or WNT (Win gless/Int) signaling pathways,
`and said second activation state-specific antibody binds to an
`activation form of a second protein within the MAPK, AKT,
`NFkB, PKC, STAT or WNT signaling pathways, and wherein
`said first and second proteins are different proteins.
`
`
`Ex. 1001, 51:20–33.
`
`
`The Asserted Grounds of Unpatentability
`D.
`Petitioner challenges the patentability of claims 1–9 and 11–12 of the
`’926 patent on the following grounds:
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`IPR2017-00014
`Patent 7,695,926 B2
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`
`Claims
`1–5 and 11–12
`
`1–9
`
`1–9
`
`Basis
`§ 1022
`
`References
`Shen3
`
`§ 103(a)
`
`Fleisher4
`
`§ 103(a)
`
`Darzynkiewicz5 and Yen6
`
`
`Petitioner also relies upon the Declaration of Tom Huxford, Ph.D.
`(Ex. 1002).
`
`
`
`ANALYSIS
`Claim Construction
`A.
`In an inter partes review, the Board interprets claim terms in an
`unexpired patent according to the 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, 2142 (2016)
`(affirming applicability of broadest reasonable construction standard to inter
`
`
` 2
`
` Petitioner asserts that Shen is prior art under pre-AIA 35 U.S.C. § 102(a) or
`§ 102(b). Pet. 18.
`3 Patent Application Publication No. WO 01/27624 A2 by
`Li Shen et al., published Apr. 19, 2001 (Ex. 1016) (“Shen”).
`4 Thomas A. Fleisher et al., Detection of Intracellular Phosphorylated
`STAT-1 by Flow Cytometry, 90 CLINICAL IMMUNOLOGY 425–430 (1999)
`(Ex. 1004) (“Fleisher”).
`5 Patent Application Publication No. WO 99/44067 A1 by
`Zbigniew Darzynkiewicz et al., published Sep. 2, 1999 (Ex. 1005)
`(“Darzynkiewicz”).
`6 Andrew Yen et al., Retinoic Acid Induced Mitogen-activated Protein
`(MAP)/Extracellular Signal-regulated Kinase (ERK) Kinase-dependent
`MAP Kinase Activation Needed to Elicit HL-60 Cell Differentiation and
`Growth Arrest, 58 CANCER RESEARCH 3163–3172 (1998) (Ex. 1006)
`(“Yen”).
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`partes review proceedings). Under that standard, and absent any special
`definitions, we give claim terms their ordinary and customary meaning, as
`would be understood by one of ordinary skill in the art at the time of the
`invention. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir.
`2007). Any special definitions for claim terms must be set forth with
`reasonable clarity, deliberateness, and precision. In re Paulsen, 30 F.3d
`1475, 1480 (Fed. Cir. 1994).
`The Specification explains, “the term ‘activation state-specific
`antibody’ or ‘activation state antibody’ or grammatical equivalents thereof,
`refer to an antibody that specifically binds to a corresponding and specific
`antigen.” Ex. 1001, 26:55–58. Petitioner recognizes that definition as the
`broadest reasonable construction of the claim term. Pet. 6–7. Petitioner also
`asserts, however, that definition encompasses “virtually any antibody, as all
`antibodies bind to a specific antigen.” Id. at 7. Based on that reasoning,
`Petitioner proposes to construe the term more narrowly to mean “an
`antibody that specifically binds to a corresponding and specific isoform of
`an activatable protein.” Id. (citing Ex. 1002 ¶¶ 54–55).
`Petitioner makes the point that, based on the disclosure of the
`Specification, a person of ordinary skill in the art at the time of the invention
`would consider an “activation state-specific antibody” as referring to an
`“antibody that specifically binds to a corresponding and specific isoform of
`an activatable protein.” Id. We decline, however, to substitute that
`construction for the definition expressly provided by the Specification, as it
`is set forth with reasonable clarity, deliberateness, and precision. See In re
`Paulsen, 30 F.3d at 1480. Moreover, independent claim 1 further describes
`an “activation state-specific antibody” in a manner that identifies such
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`antibody as one that binds to an activation form of a protein within a specific
`signaling pathway. Ex. 1001, 51:6–32.
`Level of Ordinary Skill in the Art
`B.
`The level of skill in the art is a factual determination that provides a
`primary guarantee of objectivity in an obviousness analysis. Al-Site Corp. v.
`VSI Int’l Inc., 174 F.3d 1308, 1324 (Fed. Cir. 1999) (citing Graham v. John
`Deere Co., 383 U.S. 1, 17–18 (1966); Ryko Mfg. Co. v. Nu-Star, Inc., 950
`F.2d 714, 718 (Fed. Cir. 1991)).
`According to Petitioner, a person of ordinary skill in the art at the time
`of the invention would have had “a Ph.D. in the areas of chemistry,
`biochemistry, cell biology or molecular biology including five or more years
`of experience in dealing with antibodies, protein labeling, protein
`interaction, and protein detection.” Pet. 17 (citing Ex. 1002 ¶¶ 12–13).
`At this stage in the proceeding, we determine that Petitioner’s
`description of the level of ordinary skill in the art is accurate and supported
`by the current record. Moreover, we have reviewed Dr. Huxford’s
`credentials (Ex. 1003) and, at this stage in the proceeding, we consider him
`to be qualified to provide his opinion on the level of skill and the knowledge
`of a person of ordinary skill in the art at the time of the invention. We also
`note that the applied prior art reflects the appropriate level of skill at the time
`of the claimed invention. See Okajima v. Bourdeau, 261 F.3d 1350, 1355
`(Fed. Cir. 2001).
`
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`
`Anticipation by Shen
`C.
`Petitioner asserts that claims 1–5 and 11–12 are unpatentable as
`anticipated by Shen. Pet. 18–28.
`
`1. Shen
`Shen discloses a method for detecting protein modification in a
`sample. Ex. 1016, 1:10–11. Specifically, Shen describes simultaneously
`assessing the protein modification status of a plurality of target proteins “by
`contacting the plurality of target proteins with an immobilized capture
`molecule, or a plurality of immobilized capture molecules, simultaneously”
`on a solid support. Id. at 1:15–16, 19:24–27. Shen explains that the protein
`modification can be a phosphorylation, and the capture molecules can be
`antibodies. Id. at 51. Further, Shen explains that the antibody array may be
`produced on any suitable solid surface, including in the form of beads,
`silicon chips, microplates, and a variety of membranes. Id. at 40:11–16.
`Shen also discloses kits of the invention comprising “a solid support
`of 2 or more capture molecules immobilized on the solid support, each of
`which can specifically bind a target protein that is capable of a subject
`protein modification,” as well as “a detection molecule specific for the
`subject protein modification in order to detect whether or not a captured
`target protein comprises the subject protein modification,” and instructions
`for using the kit. Id. at 50:22–26.
`2. Analysis
`“A claim is anticipated only if each and every element as set forth in
`the claim is found, either expressly or inherently described, in a single prior
`art reference.” Verdegaal Bros., Inc. v. Union Oil Co. of Cal., 814 F.2d 628,
`631 (Fed. Cir. 1987).
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`
`Independent claim 1 is directed to a kit comprising a first and a
`different second activation state-specific antibody, along with instructions
`for using the antibodies, wherein those antibodies respectively bind to an
`activated form of a first and a second protein within one of the recited
`signaling pathways. Petitioner asserts that Shen anticipates the claimed
`invention. Pet. 19–28. Based on the information presented at this stage of
`the proceeding, as discussed below, we determine that Petitioner has
`sufficiently established a reasonable likelihood of prevailing in that regard.
`Petitioner describes how Shen discloses each limitation of the claimed
`invention. Id. For example, Petitioner refers to Shen’s disclosure of a kit
`comprising “2 or more capture molecules immobilized on a solid support,
`each of which can specifically bind a target protein that is capable of a
`subject protein modification; . . . and instructions for use of the kit.” Id. at
`20 (quoting Ex. 1016, 50:21–28). Petitioner refers also to Shen’s disclosure
`that “[t]he capture molecules on the solid support can be antibodies,” and
`“[t]he subject protein modification on the solid support can be a
`phosphorylation.” Id. (quoting Ex. 1016, 51:21–22, 13–15).
`Petitioner asserts that Shen discloses that at least one of the antibodies
`is specific for a phosphorylation site by explaining that “[t]he subject protein
`modification on the solid support can be a phosphorylation and the
`phosphorylation can comprises [sic] tyrosine, serine or threonine
`phosphorylation.” Id. at 20–21 (alterations in original) (quoting Ex. 1016,
`51:13–15). Petitioner asserts also that Shen discloses that the antibodies are
`specific to 2 or more proteins within the MAPK or AKT signaling pathway
`by teaching that “the capture molecules [e.g., antibodies] are specific for 2
`or more phosphorylated proteins selected from the group consisting of
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`p44/42 MAP Kinase, MEK1/2, . . . Akt.” Id. at 22 (alteration in original)
`(quoting Ex. 1016, 53:12–17). Dr. Huxford explains that “P44/42 MAP
`Kinase, MEK 1/2, and AKT are different proteins activated by
`phosphorylation in the MAPK, MAPK and AKT signaling pathways,
`respectively.” Ex. 1002 ¶ 69.
`On the current record, we discern no deficiency in Petitioner’s
`characterization of Shen’s teachings. Thus, based on the information
`presented at this stage of the proceeding, Petitioner has shown sufficiently
`that there is a reasonable likelihood that it would prevail in showing the
`unpatentability of independent claim 1 as anticipated by Shen. We have
`considered also Petitioner’s arguments and evidence with respect to the
`challenged dependent claims. See Pet. 24–28. Based on the current record,
`we determine that Petitioner has made a sufficient showing that Shen
`discloses each element of those claims, as well. Accordingly, we institute an
`inter partes review of claims 1–5 and 11–12 of the ’926 patent as anticipated
`by Shen.
`
`D. Obviousness over Fleisher
`Petitioner asserts that claims 1–9 are unpatentable as obvious over
`Fleisher. Pet. 28–40.
`
`1. Fleisher
`Fleisher is a journal article discussing an investigation of interferon-γ
`
`activation of human monocytes using flow cytometry and monoclonal
`antibodies that distinguish between the native and phosphorylated forms of
`signal transducer and activator of transcription (1) proteins (“STAT-1”). Ex.
`1004, 425. Fleisher explains that its approach “enables rapid and
`quantitative assessment of STAT-1 phosphorylation on a discrete cell basis
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`and is both more sensitive and less time consuming than immunoblotting.”
`Id. In particular, Fleisher describes the method as follows:
` Peripheral blood mononuclear cells (PBMC) were . . .
`prepared in phosphate-buffered saline (PBS) with 2% fetal calf
`serum and 400 μl aliquots were cultured without or with
`interferon-γ (100 or 1000 IU/ml in the standard assay) at 37°C
`for the times indicated. Following incubation, the cells were
`either treated with specific antibodies or subjected to fixation
`and permeabilization before antibody addition . . . 100 μl of
`permeabilization medium . . . together with a specific antibody
`was added to each cell pellet followed by a 30-min incubation
`at room temperature. The tubes were then washed, incubated
`with the appropriate second antibody for 30 min at room
`temperature, and again washed before being resuspended in 200
`μl of PBS for flow cytometry. An augmented fixation and
`permeabilization method involved the addition of 3 ml of cold
`methanol while vortexing in between the addition of Reagents
`A and B (3). The tubes were held for 10 min at 4°C,
`centrifuged, washed
`in PBS,
`and
`resuspended
`in
`permeabilization medium (Reagent B) with antibody as
`described above.
`and
`fixed
` The precultured unmodified PBMC,
`permeabilized (F/P) PBMC, and fixed and permeabilized
`including methanol (F/P 1 MeOH) PBMC were incubated with
`1 μg of murine monoclonal anti-human STAT-1 cytoplasmic
`terminus (Transduction Laboratories, Lexington, KY), 1 μg of
`murine IgG2b, 0.1 μg of rabbit anti-human phosphorylated
`STAT-1 (New England Biolabs, Beverly, MA), or 0.1 μg of
`rabbit IgG for 30 min as above. The second antibody consisted
`of either 1 μg of FITC-conjugated F(ab′)2 goat anti-murine IgG
`(Caltag) or 1 μg of FITC conjugated F(ab′)2 goat anti-rabbit IgG
`(Caltag) with a 30-min incubation at room temperature as
`above. Following a final wash step, the cells were resuspended
`in 200 μl of PBS and analyzed with a flow cytometer.
`
`Id. at 425–426. Fleisher also describes using a FACScan, i.e., a fluorescent
`activated cell sorting (“FACS”) flow cytometer. Id. at 426. According to
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`Fleisher, the disclosed “technique should find applications in the study of
`multiple phosphorylation-dependent pathways such as those involving other
`Jak-STAT combinations, IKB, and MAP kinases.” Ex. 1004, 429. Further,
`Fleisher explains that its approach “should be valuable in studying any
`activation pathway for which antibody reagents exist that discriminate
`between a native and an activation modified protein.” Id.
`2. Analysis
`A conclusion that claimed subject matter is obvious must be supported
`by evidence, as shown by some objective teaching in the prior art or by
`knowledge generally available to one of ordinary skill in the art that would
`have led that individual to combine the relevant teachings of the references
`to arrive at the claimed invention. In re Fine, 837 F.2d 1071, 1074 (Fed.
`Cir. 1988).
`Petitioner asserts that a person of ordinary skill in the art would have
`found it obvious to provide the claimed kit comprising materials needed to
`carry out the methods taught by Fleisher. Pet. 28–40. Based on the
`information presented at this stage of the proceeding, as discussed below, we
`determine that Petitioner has sufficiently established a reasonable likelihood
`of prevailing in that regard.
`According to Petitioner, Fleisher teaches a method of detecting the
`activation state of a first activatable protein, i.e., STAT-1, in single cells
`using a labeled activation state-specific antibody that is specific for a STAT-
`1 phosphorylation site, wherein the antibody binds to an activation form of
`STAT-1. Pet. 29–31. Petitioner acknowledges that Fleisher does not
`expressly teach using a state-specific antibody to detect the activation state
`of a second activatable protein. Id. at 28. Petitioner asserts, however, that
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`Fleisher explains that its method may apply generally to evaluate other
`activatable signaling proteins, where activation state-specific antibodies
`exist. Id. (citing Ex. 1004, 425; Ex. 1002 ¶ 74).
`Further, Petitioner asserts that the following statement in Fleisher
`suggests other activatable proteins for evaluation: “This technique should
`find applications in the study of multiple phosphorylation-dependent
`pathways such as those involving other Jak-STAT combinations, IkB, and
`MAP kinases.” Id. at 28–29 (quoting Ex. 1004, 429). Based on that
`statement, Petitioner asserts that Fleisher teaches one of skill in the art that
`its method may be used to analyze multiple different activatable proteins.
`Id. at 29.
`Petitioner asserts also that Fleisher’s instruction that its “technique
`should find application in the study of multiple phosphorylation-dependent
`pathways,” along with its discussion that the technique may be applied to
`MAP kinases, would have provided a person of ordinary skill in the art a
`reason to perform Fleisher’s method using activation state-specific
`antibodies to detect MAP kinases (ERK1/2 and MEK1/2), in addition to
`using an activation state-specific antibody to detect the activated STAT-1.
`Pet. 30 (quoting Ex. 1004, 425, 429) (citing Ex. 1002 ¶¶ 80, 82). Petitioner
`asserts that Fleisher informed a skilled artisan that such a modification
`would have only required “the existence of an antibody specific to the
`activated form of the [additional] proteins of interest.” Id. (citing Ex. 1004,
`429; Ex. 1002 ¶ 79). Petitioner’s declarant, Dr. Huxford, explains that a
`person of skill in the art would have known that antibodies specific to the
`phosphorylated form of ERK1/2 and MEK1/2 were commercially available,
`e.g., anti-phospho-p44/42 MAPK (Thr202/Tyr204) known to detect
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`activated ERK 1/2, and anti-phospho-MEK1/2 (Ser217/221) known to detect
`activated MEK1/2. Ex. 1002 ¶¶ 22–24, 81, 83.
`According to Petitioner and Dr. Huxford, a skilled artisan would have
`understood that applying Fleisher’s method in this manner would provide “a
`better understanding of the MAPK signaling pathway.” Pet. 31; Ex. 1002 ¶
`82. Petitioner asserts that goal is consistent with Fleisher’s statement
`describing a benefit of its technique as “permit[ting] dissection of a full
`range of cellular signaling pathways.” Pet. 32–33 (quoting Ex. 1004, 425,
`429).
`Moreover, Petitioner notes that Fleisher explains that its technique is
`“applicable in any setting where immunoblotting has already been useful to
`dissect intracellular signaling pathways.” Id. at 33 (quoting Ex. 1004, 425).
`Petitioner asserts that one of skill in the art would have been aware of
`“numerous immunoblot assays that detected multiple different intracellular
`signaling proteins at the [same time].” Id. Thus, we understand Petitioner
`explains that Fleisher’s teachings would have provided a skilled artisan with
`a reasonable expectation of successfully detecting multiple different
`activatable proteins by applying Fleisher’s method.
`Petitioner asserts that it would have been obvious to provide the
`necessary first and second activation state-specific antibodies, discussed
`supra, in a kit because doing so would beneficial in assisting practitioners
`who only occasionally need to perform an assay such as the one suggested
`by Fleisher, and providing a kit would likely increase the reliability and ease
`of performing the assay. Pet. 29 (citing Ex. 1002 ¶ 85).
`With respect to the claim recitation that the kit comprises “instructions
`for use of the antibodies,” Petitioner asserts that claim element should not be
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`given patentable weight as such “instructions” constitute printed matter. Id.
`at 30 (citing In re Ngai, 367 F.3d 1336, 1337–38 (Fed. Cir. 2004)
`(characterizing kit instructions as printed matter). Alternatively, Petitioner
`asserts that it would have been obvious for a person of ordinary skill in the
`art to include instructions with a kit comprising materials to perform
`Fleisher’s assay to provide a detailed protocol for the use of the included
`antibodies. Id. (citing Ex. 1002 ¶ 85).
`On the current record, we discern no deficiency in Petitioner’s
`characterization of the knowledge in the art at the time of the invention,
`Fleisher’s teachings, or in Petitioner’s assertions as to the reasonable
`inferences an ordinary artisan would make from Fleisher. Thus, based on
`the information presented at this stage of the proceeding, Petitioner has
`shown sufficiently that there is a reasonable likelihood that it would prevail
`in showing the unpatentability of independent claim 1 as obvious over
`Fleisher. We have considered also Petitioner’s arguments and evidence with
`respect to the challenged dependent claims. See Pet. 34–40. Based on the
`current record, we determine that Petitioner has made a sufficient showing
`as to those claims, as well. Accordingly, we institute an inter partes review
`of claims 1–9 of the ’926 patent as obvious over Fleisher.
`E. Obviousness over Darzynkiewicz and Yen
`Petitioner asserts that claims 1–9 are unpatentable as obvious over
`Darzynkiewicz and Yen. Pet. 40–54.
`1. Darzynkiewicz
`Darzynkiewicz is directed to methods, reagents and kits that “permit
`the concurrent and discriminable detection of discrete functional
`conformations of proteins within a single cell.” Ex. 1005, 7:2–6. The
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`invention focuses on the protein encoded by the retinoblastoma
`susceptibility gene (“pRB” or “pRb”) “which plays a pivotal role in the
`regulation of the cell cycle.” Id. at 2:23–26. pRB restrains cell cycle
`progression in a manner that allows tumor suppression. Id. at 2:26–30.
`Darzynkiewicz explains that pRB activity is controlled by changes in
`phosphorylation. Id. at 3:4–5. For example, phosphorylated pRB discharges
`transcription factors, and those factors in turn activate transcription of genes
`coding for proteins regulating DNA replication and cell proliferation. Id. at
`3:13–16. The invention provides methods and materials for “the flow
`cytometric determination of multiple pRB phosphorylation states in
`individual cells” using anti-pRB antibodies that distinguish the
`phosphorylation state of pRB and that may be conjugated to fluorophores to
`allow concurrent detection of such functional conformations of pRB in
`single cells. Id. at 7:6–25.
`In addition to comprising contacting a cell with a first and a second
`antibody specific for two different phosphorylation conformations of pRB,
`id. at 9, Darzynkiewicz explains that the method may further comprise
`contacting the cell with a third antibody, wherein the third antibody is
`“specific for a second protein and [is] distinguishable from each of said first
`and second antibodies, and then detecting the concurrent binding of each of
`said antibodies to said cell,” id. at 10:8–13. Darzynkiewicz discloses
`preferred embodiments wherein “the second protein may be a cyclin, a
`cyclin dependent kinase, or a cyclin dependent kinase inhibitor.” Id. at
`10:13–16. Darzynkiewicz teaches that “multiparametric flow cytometric
`techniques permit more than two antibodies to be discriminably detected in a
`single assay.” Id. at 27:22–24. As an example, Darzynkiewicz explains that
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`its methods may be used, along with such antibodies, “to report,
`concurrently with the phosphorylation status of pRB, the concurrent levels
`of other proteins that participate in the regulation of the cell cycle.” Id. at
`27:28–33.
`
`2. Yen
`Yen is a journal article describing a study revealing that retinoic acid
`(“RA”) “augments MEK-dependent ERK2 activation that is needed for
`subsequent RB hypophosphorylation, cell differentiation, and G0 arrest.”
`Ex. 1006 Abstract. In the study, Western blotting of RB, MAPK, and
`activated MAPK was performed, wherein cell membranes were “probed
`with antibodies detecting the phosphorylated and unphosphorylated forms of
`RB, ERK2, and ERK1.” Id. at 3165.
`3. Analysis
`Petitioner asserts that a person of ordinary skill in the art would have
`found it obvious to provide the claimed kit comprising materials needed to
`carry out the methods taught or suggested by combined teachings of
`Darzynkiewicz and Yen. Pet. 40–47. Based on the information presented at
`this stage of the proceeding, as discussed below, we determine that
`Petitioner has sufficiently established a reasonable likelihood of prevailing
`in that regard.
`In particular, Petitioner asserts that Darzynkiewicz describes
`providing kits comprising materials needed to perform its assay. Pet. 42.
`Specifically, Petitioner refers to Darzynkiewicz’s explanation that “any one
`clinical laboratory may have only sporadic need to perform the assay [of the
`invention], and there is thus a need for compositions and kits that permit the
`assay readily to be performed on an as-needed basis,” and its description of
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`IPR2017-00014
`Patent 7,695,926 B2
`
`meeting that need, i.e., “the present invention provides reagents and kits that
`permit the assay readily to be performed on an as-needed basis.” Id. at 42–
`43 (quoting Ex. 1005, 39:28–40:2). With respect to the materials needed in
`the kit, Petitioner asserts that Darzynkiewicz teaches a method of detecting
`two different proteins in a single cell. Id. at 43 (citing Ex. 1005, 10:13–16).
`Petitioner acknowledges that Darzynkiewicz does not describe the second
`protein to be an activated isoform. Id. at 40. Petitioner, however, contends
`that a person of skill in the art would understand from Darzynkiewicz that its
`method of using distinguishable antibodies inclusively applies to using
`activation state-specific antibodies specific for an activated isoform of the
`second protein. Id. at 40–41 (citing Ex. 1002 ¶¶ 16–17). Further, according
`to Petitioner and Dr. Huxford, doing so would not require any change to
`Darzynkiewicz’s approach. Id. at 41 (citing Ex. 1002 ¶ 17).
`Petitioner asserts also that Darzynkiewicz applies its method to the
`human promyelocytic leukemic cell line, HL-60. Id. at 43; Ex. 1005, 24:15–
`16. According to Petitioner and Dr. Huxford, a person of skill in the art
`would have understood that the HL-60 cell line contains many different
`activatable and distinct proteins, including retinoblastoma, Ras, ERK1/2 and
`MEK1/2. Pet. 43 (citing Ex. 1002 ¶¶ 96–97). In further support of that
`contention, Petitioner refers to Yen’s discussion relating to detecting
`retinoblastoma in addition to activated ERK1/2, using an activation state-
`specific antibody specific for activated ERK1/2, to analyze the effect of
`those proteins on cell cycle regulation. Id. at 43–46 (citing Ex. 1006, 3163,
`3165).
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`IPR2017-00014
`Patent 7,695,926 B2
`
`
`Petitioner asserts also that Darzynkiewicz describes using
`“multiparametric flow cytometric techniques to permit more than two
`antibodies to be discriminably detected in a single assay.” Id. at 41–42
`(emphasis omitted) (quoting Ex. 1005, 27:22–24). Petitioner refers also to
`statement in Darzynkiewicz that “these further antibodies may, for example,
`be used to report, concurrently with the phosphorylation status of pRB, the
`concurrent levels of other proteins that participate in the regulation of the
`cell cycle.” Id. (quoting Ex. 1005, 27:29–33).
`According to Petitioner, the combined teachings of Darzynkiewicz
`and Yen would have motivated a person of ordinary skill in the art to
`analyze the effects of cell cycle regulation by concurrently analyzing the
`activated state of retinoblastoma protein, ERK1/2, MEK1/2, or RAS using
`the multiparametric flow cytometric method taught by Darzynkiewicz. Id. at
`42. Further, Petitioner asserts that, when providing the kit described by
`Darzynkiewicz for performing the assay, it would have been obvious to a
`person of ordinary skill in the art to include the required and known
`activation state-specific antibodies specific for the activated proteins of
`interest. Pet. 44. For example, Petitioner asserts that when analyzing
`ERK1/2 and MEK1/2, two proteins within the MAPK signaling pathway, it
`would have been obvious for a skilled artisan to select and include in the kit:
`(a) a first activation state-specific antibody, anti-phospho-p44/42 MAPK
`(Thr202/Tyr204) known to detect activated ERK 1/2, and (b) anti-phospho-
`MEK1/2 (Ser217/221) known to detect activated MEK1/2. Pet. 47 (citing
`Ex. 1002 ¶¶ 22–24, 99). Dr. Huxford explains that those antibodies, each
`specific for a phosphorylation site, were commercially available at the time
`of the invention. Ex. 1002 ¶¶ 22–24, 99.
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`IPR2017-00014
`Patent 7,695,926 B2
`
`
`With respect to the claim recitation that the kit comprises “instructions
`for use of the antibodies,” Petitioner asserts that claim element should not be
`given patentable weight as such “instructions” constitute printed matter. Pet.
`43 (citing In re Ngai, 367 F.3d 1337–38 (characterizing kit instructions as
`printed matter)). Alternatively, Petitioner asserts that it would have been
`obvious for a person of ordinary skill in the art to include instructions with
`Darzynkiewicz’s kit, as Darzynkiewicz explained the kit was being provided
`to assist practitioners who “only sporadically need to perform the assay.” Id.
`at 44 (citing Ex. 1005, 18:16–19; Ex. 1002 ¶ 100). According to Petitioner
`and Dr. Huxford, those practitioners who only sporadically perform the
`assay would likely benefit from instructions. Id.
`On the current record, we discern no deficiency in Petitioner’s
`characterization of the knowledge in the art at the time of the invention, the
`teachings of Darzynkiewicz and Yen, or in Petitioner’s assertions as to the
`reasonable inferences an ordinary artisan would draw from those combined
`teachings. Thus, based on the information presented at this stage of the
`proceeding, Petitioner has shown sufficiently that there is a reasonable
`likelihood that it would pr