Trials@uspto.gov
`571-272-7822
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`Paper 10
` Entered: December 3, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`THERMO FISHER SCIENTIFIC INC.,
`Petitioner,
`
`v.
`
`THE REGENTS OF THE UNIVERSITY OF CALIFORNIA,
`Patent Owner.
`____________
`
`Case IPR2018-01156
`Patent RE46,817 E
`____________
`
`
`
`Before ERICA A. FRANKLIN, JAMES A. WORTH, and KRISTI L. R.
`SAWERT, Administrative Patent Judges.
`
`SAWERT, Administrative Patent Judge.
`
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`571-272-7822
`
`
`Paper 10
` Entered: December 3, 2018
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`THERMO FISHER SCIENTIFIC INC.,
`Petitioner,
`
`v.
`
`THE REGENTS OF THE UNIVERSITY OF CALIFORNIA,
`Patent Owner.
`____________
`
`Case IPR2018-01156
`Patent RE46,817 E
`____________
`
`
`
`Before ERICA A. FRANKLIN, JAMES A. WORTH, and KRISTI L. R.
`SAWERT, Administrative Patent Judges.
`
`SAWERT, Administrative Patent Judge.
`
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`IPR2018-01156
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`INTRODUCTION
`I.
`Thermo Fisher Scientific Inc. (“Petitioner”) filed a Petition for an
`inter partes review of claims 1 and 3 of U.S. Patent No. RE46,817 E (“the
`’817 reissue patent,” Ex. 1001). Paper 1 (“Pet.”). The Regents of the
`University of California (“Patent Owner”) filed a Preliminary Response.
`Paper 8 (“Prelim. Resp.”).
`We have authority to determine whether to institute an inter partes
`review. 35 U.S.C. § 314(b); 37 C.F.R. § 42.4(a). We may not institute an
`inter partes review “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).
`Applying those standards, and upon consideration of the information
`presented in the Petition and the Preliminary Response, we determine that
`Petitioner has not demonstrated a reasonable likelihood of success in
`proving that at least one claim of the ’817 reissue patent is unpatentable.
`Accordingly, we do not institute an inter partes review of the challenged
`claims (1 and 3) of the ’817 reissue patent.
`A. Related Proceeding
`Petitioner and Patent Owner identify The Regents of the University of
`California v. Affymetrix, Inc., Case No. 3:17-cv-01394 (CASD), as a related
`matter under 37 C.F.R. § 42.8(b)(2). Pet. 63. Patent Owner states that this
`civil action involves U.S. Patent 9,085,799. Paper 5, 1. According to Patent
`Owner, both the ’817 reissue patent and the U.S. Patent 9,085,799 claim
`priority to the same priority documents. Id.
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`B. Background
`Fluorescence resonance energy transfer (“FRET”)1 is a “quantum
`mechanical phenomenon” that occurs between a fluorescence donor
`molecule and a fluorescence acceptor molecule. Ex. 1018, 93. When the
`donor molecule is excited, it transfers its excitation energy to the acceptor
`molecule through dipole-dipole interaction. Ex. 1019, 1106. This energy
`transfer results in quenching of the donor molecule fluorescence, and in
`excitation of the acceptor molecule and increased fluorescence. Id.
`For FRET to occur, the donor molecule and acceptor molecule must
`be in close proximity—usually less than 100 Å apart. Ex. 1018, 93. In
`addition, the emission spectrum of the donor molecule must overlap with the
`excitation spectrum of the acceptor molecule. Ex. 1018, 93–94 (Figure 1A).
`The following diagram illustrates an energy transfer from an excited donor
`molecule to an acceptor molecule, once the molecules are in close proximity.
`
`
`Id. at 94 (Fig. 1B). On the left side of the diagram, the donor (“D”)
`molecule and the acceptor (“A”) molecule are not within FRET distance,
`and D’s excitation energy is not transferred to A. Id. On the right side of
`the diagram, however, D and A are within FRET distance. Id. Excitation of
`
`
`1 FRET also stands for “Förster resonance energy transfer,” named
`after Theodor Förster. Förster developed the theory of FRET in the late
`1940s. Ex. 1019, 1106.
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`D results in a transfer of energy to A (illustrated as lightning). Id. The
`amount of light emitted from A is concomitant with the decrease in the
`amount of light emitted from D. Id.
`
`FRET may be measured in terms of the efficiency of energy transfer
`(E) from the donor molecule to the acceptor molecule. Ex. 1019, 1106–07.
`E “is defined as the number of quanta transferred to the acceptor, divided by
`the number of quanta absorbed by the donor,” and is described by the
`expression:
`
`
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`E = (R0/R)6/1 + (R0/R)6
`where R is the distance (in Å) between the donor and acceptor, and R0 is the
`distance (in Å) at which energy transfer is 50% efficient. Id. at 1107.
`Generally, the efficiency of energy transfer rapidly declines to zero at
`distances greater than the 50% efficiency distance. Id.
`C. The ’817 reissue patent
`The ’817 reissue patent relates to a light-harvesting multichromophore
`system that utilizes FRET for detecting polynucleotides in a sample.
`Ex. 1001, Abstract. The system is made up of at least two components: “(a)
`a cationic multichromophore, and (b) a ‘sensor polynucleotide’ (Oligo-C*)
`comprising an anionic polynucleotide conjugated to a signaling
`chromophore.” Id. at 4:25–27. The ’817 reissue patent states that “the
`optical amplification provided by a water soluble multichromophore[,] such
`as a conjugated polymer[,] can be used to detect polynucleotide
`hybridization to a sensor polynucleotide.” Id. at 4:28–31. According to the
`Specification, the system is “useful for any assay in which a sample can be
`interrogated regarding a target polynucleotide. Typical assays involve
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`determining the presence of a target polynucleotide in the sample or its
`relative amount.” Id. at 4:48–52.
`The ’817 reissue patent states that light-harvesting multichromophore
`systems are “efficient light absorbers by virtue of the multiple chromophores
`they comprise,” and can “efficiently transfer energy to nearby luminescent
`species,” called “signaling chromophores.” Id. at 10:66–11:1, 11:14–15.
`The ’817 reissue patent states that “[t]he multichromophores used in the
`present invention are polycationic and can interact with a sensor
`polynucleotide electrostatically.” Id. at 11:54–56.
`In a preferred embodiment, the multichromophore is a conjugated
`polymer. Id. at 12:1–2. Conjugated polymers are “characterized by a
`delocalized electronic structure and can be used as highly responsive optical
`reporters for chemical and biological targets.” Id. at 11:34–38. The ’817
`reissue patent states that “the backbone” of the conjugated polymer
`“contains a large number of conjugated segments in close proximity,” and
`thus, is efficient for FRET. Id. at 11:38–42.
`The sensor polynucleotide is an anionic polynucleotide
`complementary to the target polynucleotide to be assayed. Id. at 12:60–62.
`The ’817 reissue patent states that it may be conjugated to a signaling
`chromophore using any chemical method known in the art. Id. at 12:66–67.
`Signaling chromophores “include any substance which can absorb energy
`from a polycationic multichromophore in an appropriate solution and emit
`light,” such as fluorophores. Id. at 13:5–11.
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`D. Challenged Claims
`Petitioner challenges claims 1 and 3 of the ’817 reissue patent.
`Pet. 19. Claim 1 is independent, and claim 3 depends from claim 1.
`1. A light harvesting multichromophore system, the
`system comprising:
`a) a signaling chromophore in solution; and
`b) a water-soluble multichromophore conjugated polymer
`in solution comprising a delocalized electronic
`structure, wherein
`the polymer
`is
`in energy
`transferring proximity to the signaling chromophore
`and upon excitation transfers energy from its excited
`state to the signaling chromophore to provide a
`greater than 4 fold increase in fluorescence emission
`from the signaling chromophore than can be achieved
`by direct excitation.
`
`
`
`3. The light harvesting multichromophore system of claim
`1, wherein the signaling chromophore comprises a fluorescent
`dye.
`Ex. 1001, 23:2–13, 19–21.
`
`E. The Prior Art
`Petitioner advances the following references as prior art on which it
`relies for the asserted grounds challenging the claims of the ’817 reissue
`patent:
`1. Richard A. Cardullo et al., Detection of nucleic acid hybridization
`by nonradiative fluorescence resonance energy transfer, 85 PROC.
`NATL. ACAD. SCI. USA 8790–94 (1988) (“Cardullo,” Ex. 1003);
`
`2. Mario LeClerc et al., Int’l Publication No. WO 02/081735
`(Oct. 17, 2002) (“LeClerc,” Ex. 1004);
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`3. Q. Tyler McQuade et al., Signal Amplification of a “Turn-On”
`Sensor: Harvesting the Light Captured by a Conjugated Polymer,
`122 J. AM. CHEM. SOC. 12,389–390 (2000) (“McQuade,”
`Ex. 1005); and
`
`
`4. Benjamin S. Harrison et al., Amplified Fluorescence Quenching in
`a Poly(p-phenylene)-Based Cationic Polyelectrolyte, 122 J. AM.
`CHEM. SOC. 8561–62 (2000) (“Harrison,” Ex. 1006).
`F. Asserted Grounds of Unpatentability
`Petitioner challenges the patentability of claims 1 and 3 of the ’817
`reissue patent on the following grounds:
`References
`Claims
`Basis
`1 and 3
`35 U.S.C. § 103(a) Cardullo, McQuade, and LeClerc
`1 and 3
`35 U.S.C. § 103(a) Cardullo, LeClerc, and Harrison
`
`Pet. 19. Petitioner also relies on the Declaration of Kirk S. Schanze, Ph.D.
`(Ex. 1002). Id. at 6. Patent Owner disputes that Petitioner’s asserted
`grounds render the challenged claims unpatentable. See generally Prelim.
`Resp.
`
`II. ANALYSIS
`We address below whether the Petition meets the threshold showing
`for institution of an inter partes review under 35 U.S.C. § 314(a). We
`consider each ground of unpatentability in view of the understanding of a
`person of ordinary skill in the art. For the purpose of this decision, we find
`that the prior art itself is sufficient to demonstrate the level of ordinary skill
`in the art at the time of the invention. See Okajima v. Bourdeau, 261 F.3d
`1350, 1355 (Fed. Cir. 2001) (the prior art, itself, can reflect appropriate level
`of ordinary skill in art). Further, based on the information presented at this
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`stage of the proceeding, we consider Petitioner’s declarant—Dr. Schanze—
`qualified to opine from the perspective of an ordinary artisan at the time of
`the invention. See Ex. 1027 (curriculum vitae of Dr. Schanze).
`A. Claim Construction
`For an unexpired patent, the Board interprets claims using the
`“broadest reasonable construction in light of the specification of the patent.”
`37 C.F.R. § 42.300(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131,
`2144–46 (2016).2 Under the broadest reasonable construction standard, and
`absent any special definitions, we give claim terms their ordinary and
`customary meaning, as they 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). For this Decision, we determine that no claim
`term requires express construction to resolve any controversy in this
`proceeding. See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795,
`803 (Fed. Cir. 1999) (“[O]nly those terms need be construed that are in
`controversy, and only to the extent necessary to resolve the controversy.”).
`B. The Prior Art
`Before turning to Petitioner’s asserted grounds, we provide an
`overview of the asserted references.
`
`
`2 The claim construction standard to be employed in an inter partes
`review recently changed. See Changes to the Claim Construction Standard
`for Interpreting Claims in Trial Proceedings Before the Patent Trial and
`Appeal Board, 83 FED. REG. 51340 (October 11, 2018). However, based on
`the filing date of the Petition in this proceeding, the applicable claim
`construction standard remains as set forth in 37 C.F.R. § 42.100(b) (2016).
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`1. Cardullo
`Cardullo describes experiments using FRET to detect nucleic acid
`hybridization. Ex. 1003, 8790. Cardullo describes three FRET strategies,
`illustrated in Figure 1 (reproduced below). Id. at 8791 (Fig.1).
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`Figure 1 provides a schematic diagram of three FRET strategies
`disclosed in Cardullo. Ex. 1003, 8791 (Fig.1).
`As shown in FRET strategy “A”3 of Figure 1, Cardullo attached donor
`(D) and acceptor (A) fluorophores—fluorescein and rhodamine,
`respectively—to the 5′ ends of short complementary oligonucleotides (i.e.,
`oligonucleotides comprising 8, 12, and 16 nucleotides) via covalent bonds.
`Id. at 8790–91. In the case of hybridization of the 8-mer oligonucleotide,
`
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`3 For consistency with the parties, we use “A,” “B,” and “C”
`nomenclature when referring to Cardullo’s Figure 1a, 1b, and 1c,
`respectively.
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`Cardullo detected energy transfer from fluorescein to rhodamine by
`measuring a decrease in fluorescein emission intensity and an increase in
`rhodamine emission intensity. Id. Cardullo calculated the transfer
`efficiency between fluorescein and rhodamine as about 0.5. Id. at 8791; see
`also id. at 92 (Table 1). In the case of the 12-mer and 16-mer
`oligonucleotides, Cardullo found that increasing chain length resulted in a
`decreased transfer efficiency. Specifically, transfer efficiency “decreased
`from about 0.5 to 0.22 to 0.04 as the distance between donor and acceptor
`fluorophores in the hybrid increased from 8 to 12 to 16 nucleotides.” Id. at
`8790; see also id. at 8792 (Table 1).
`As shown in FRET strategy “B” of Figure 1, Cardullo attached a
`donor (D) fluorophore (fluorescein) to the 5′ end of one oligonucleotide, and
`an acceptor (A) fluorophore (rhodamine) to the 3′ end of another
`oligonucleotide, via covalent bonds. Id. at 8791 (Fig. 1). The labeled
`oligonucleotides are complementary to distinct, but closely spaced,
`sequences of the longer, unlabeled strand of DNA. Id. Upon hybridization
`of the labeled oligonucleotides to the unlabeled oligonucleotide, Cardullo
`calculated a transfer efficiency of about 0.60 between the adjacent
`fluorophores. Id. at 8792.
`Finally, as shown in FRET strategy “C” of Figure 1, Cardullo utilized
`the fluorescent dye acridine orange (D) to detect hybridization between an
`unlabeled DNA sequence and its rhodamine-labeled (A) complementary
`oligonucleotide. Id.; see also id. at 8791 (Fig. 1). Acridine orange
`“intercalates into double-helical nucleic acids and can act as either a donor
`or acceptor molecule to an appropriate fluorophore covalently attached to a
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`hybridized” oligonucleotide sequence. Id.at 8790. Upon hybridization,
`Cardullo calculated a transfer efficiency of about 0.52. Id. According to
`Cardullo, “[t]he use of an intercalating dye allows a short separation distance
`between donor and acceptor molecules and, in the case of a helical structure,
`presents many dye molecules at different distances and orientations.” Id. at
`8794. “The result is an ‘antenna effect’ that gives a high degree of transfer
`efficiency.” Id.
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`2. LeClerc
`LeClerc describes methods “for the simple optical and
`electrochemical detection of double-stranded oligonucleotides” based on
`“electrostatic interactions between cationic poly (3-alkoxy-4-
`methylthiophene) derivatives and single-stranded or double-stranded
`(hybridized) oligonucleotides.” Ex. 1004, Abstract. LeClerc describes the
`polythiophene derivatives as water-soluble, cationic polymers that “can
`make strong complexes with negatively-charged oligomers.” Id. at 13:6–8.
`“This complexation results in the formation of complexes having specific
`optical properties.” Id. at 13:8–10.
`Specifically, LeClerc describes a random coil conformation of a
`cationic polythiophene derivative in aqueous solution as having yellow
`(λmax=397 nm) optical properties. Id. at 13:10–12. The addition of an
`oligonucleotide (single-stranded DNA probe) causes the formation of a
`“duplex” via electrostatic interaction between the polythiophene derivative
`and the oligonucleotide that results in a red solution (λmax = 527 nm), and the
`addition of a complementary oligonucleotide causes the formation of a
`“triplex” between the polythiophene derivative and the hybridized DNA
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`complex that results in a yellow solution (λmax = 421 nm). Id. at 13:12–19.
`LeClerc states that “these colorimetric effects are made possible due to the
`different conformational structure of the conjugated polymer in the duplex
`(highly conjugated, planar conformation) compared to that observed in the
`triplex (less conjugated, non-planar conformation) and to a stronger affinity
`of the conjugated polymer for the double-stranded oligonucleotides . . . than
`that measured for single stranded oligonucleotides.” Id. at 14:6–11. Figure
`6 (reproduced below) provides a schematic diagram of these conformational
`transitions.
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`Figure 6 shows the formation of a duplex and a triplex between
`a polythiophene derivative and oligonucleotides. Ex. 1004,
`5:12–13.
`LeClerc also describes the “fluorometric detection of oligonucleotide
`
`hybridization . . . based on the difference in the fluorescence quantum yield
`of the positively-charged [polythiophene derivative] in the random coil (the
`isolated state) or in the aggregated state.” Id. at 16:20–23. LeClerc
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`describes the “fluorescent intensity of a ‘duplex’ (association between a
`positively charged polymer and an oligonucleotide capture probe)” as “weak
`or insignificant (practically zero) due to the fluorescent-quenching property
`of the aggregated form of the polymer.” Id. at 26:6–9. “When perfect
`hybridization does occur,” however, “the fluorescent signal becomes more
`significant.” Id. at 26:9–11. Figure 7 (reproduced below) shows a decrease
`in fluorescent intensity as the polythiophene derivative (“Poly 2”) interacts
`with an oligonucleotide probe.
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`Figure 7 shows the fluorescent intensity of (a) a polythiophene
`derivative in an isolated state; (b) an aggregated “duplex” state
`with an oligonucleotide probe; and (c) an aggregated “triplex”
`state with a hybridized DNA complex. Ex. 1004, 5:14–15.
`3. McQuade
`McQuade discloses a thin-film “chemosensor design” that
`“substantially amplif[ies] the output of a pH-sensitive fluorophore using
`energy harvested from a conjugated polymer.” Ex. 1005, 12389. McQuade
`constructed the thin film by depositing “a new water-soluble, cationic
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`poly(p-phenlyene ethynylene) (PPE)” and “an anionic polyacrylate” layer-
`by-layer onto a glass substrate. Id. PPE (structure 1) and the anionic
`polyacrylate (structure 2) have the following chemical structures:
`
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`Id.
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`McQuade teaches that the polyacrylate polymer comprises a
`fluoresceinamine (FA) dye, which when placed onto the glass substrate,
`exists “in close proximity to the conjugated polymer.” Id. The PPE polymer
`and the FA dye “were selected so that the polymer emission overlaps with
`the absorbance band of the dye.” Id. According to McQuade, “[t]his
`overlap encourages Fluorescence Resonance Energy Transfer (FRET)
`between the polymer and the dye.” Id.
`
`McQuade tested the thin-film systems in solutions of varying pH. Id.
`at 12390. After immersion in solution, the films were dried and selectively
`excited. Id. McQuade found that, for a bilayer system, greater than 90% of
`the conjugated polymer’s emission transferred to the dye at pH 11. Id. And
`“[a]t each pH, the measured excitation at 420 nm resulted in an approximate
`10-fold increase in the emission at 535 nm relative to that measured by
`direct excitation (500 nm) of the FA.” Id.
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`McQuade states that “[t]he combination of layer-by-layer deposition,
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`of pH-sensitive dye, and the transport properties of a conjugated polymer
`has produced a chemosensor displaying a dramatically brighter response.”
`Id. McQuade concludes that the “thin-film system represents a simple
`approach for creating different chemosensors in which an analyte sensitive
`dye is electrostatically bound to a cationic conjugated polymer.” Id.
`4. Harrison
`Harrison describes the “[a]pplication of fluorescent conjugated
`polymers to ‘amplified’ sensing of chemical and biological analytes” in an
`aqueous environment. Ex. 1006, 8561. Specifically, Harrison describes
`“fluorescence quenching of the water soluble, poly(p-phenylene)-based
`polycation, P-NEt3
`+ dibromide[,] by several anionic quenchers, including
`4- and Fe(CN)6
`+ has the
`4- in aqueous solution.” Id.4 P-NEt3
`Ru(phen′)3
`following chemical structure:
`
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`4 Harrison uses the term “phen′” as an abbreviation for 4,7-bis(4-
`sulfophenyl)-1,10-phenanthroline. Ex. 1006, 8561.
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`Id. Harrison found that “quenching of P-NEt3
`4- occurs via
`+ by Ru(phen′)3
`energy transfer by observing the metal complexes’ photoluminescence when
`the excitation light is absorbed mainly by the polymer.” Id. Harrison states
`4- “may be
`+ and Ru(phen′)3
`that “long-range energy transfer” between P-NEt3
`facilitated by dipole-dipole (Förster) coupling between the P-NEt3
`+ donor
`4- acceptor.” Id. at 8562. “Indeed,” Harrison notes, “a
`and the Ru(phen′)3
`computation based on the spectra and photophysical properties of the two
`chromophores indicates that the Förster transfer distance (R0) is ≈ 40 Å.” Id.
`C. Alleged Obviousness over Cardullo, McQuade, and LeClerc
`Petitioner argues that claims 1 and 3 are unpatentable as obvious over
`Cardullo, McQuade, and LeClerc. See Pet. 21–45. Petitioner argues that the
`combination of Cardullo, McQuade, and LeClerc teaches or suggests each
`limitation of claims 1 and 3. Id. at 21–29 (claim 1), 45 (claim 3). And,
`relying on the Declaration of Dr. Schanze, Petitioner argues that a person of
`ordinary skill in the art would have been motivated to combine the
`references, and would have had a reasonable expectation of success. Id. at
`30–45 (citing Ex. 1002 ¶¶ 56–64, 92, 93, 96, 99, 105, 108, 113–131, 136–
`143).
`Specifically, Petitioner argues that an ordinarily skilled artisan would
`have had a reason to substitute the multiple acridine orange dyes in
`Cardullo’s system for McQuade’s multichromophore conjugated polymer
`“because of the high efficiency of energy transfer achieved with McQuade’s
`polymer—a feature that would have been highly desirable in an optical
`biosensor, as evidenced by Cardullo.” Id. at 4 (citing Ex. 1002 ¶ 129).
`Petitioner also argues that the ordinarily skilled artisan would have had a
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`reasonable expectation of success in the substitution, “because LeClerc
`taught that water-soluble, polycationic polymers could bind DNA of any
`sequence, and thus be in energy-transferring proximity to an acceptor
`chromophore attached to duplex DNA.” Id. (citing Ex. 1002 ¶ 129).
`Petitioner also argues that the ordinarily skilled artisan would have expected
`the claimed “greater than 4-fold increase in emission” “because McQuade’s
`conjugated polymer actually amplified emission from the signaling
`chromophore by more than 10-fold compared to direct excitation.” Id.
`(citing Ex. 1005, 12390; Ex. 1002 ¶ 134).
`At this stage of the proceeding, Patent Owner does not challenge
`Petitioner’s assertion that each limitation of claims 1 and 3 is individually
`found in the prior art. See generally Prelim. Resp. 7–44. Patent Owner
`instead contends that a person of ordinary skill in the art would have had no
`motivation to combine Cardullo with McQuade and LeClerc. Id. at 13.
`Having considered the arguments and evidence before us, we find that
`the record does not establish a reasonable likelihood that Petitioner would
`prevail on its asserted ground of obviousness. Even “[i]f all elements of the
`claims are found in a combination of prior art references,” “the factfinder
`should further consider whether a person of ordinary skill in the art would
`[have been] motivated to combine those references, and whether in making
`that combination, a person of ordinary skill would have [had] a reasonable
`expectation of success.” Merck & Cie v. Gnosis S.P.A., 808 F.3d 829, 833
`(Fed. Cir. 2015). The “motivation to combine” and “reasonable expectation
`of success” factors are subsidiary requirements for obviousness subsumed
`within the Graham factors. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1361
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`(Fed. Cir. 2007). Here, for the reasons set forth below, we agree with Patent
`Owner that Petitioner’s obviousness challenge fails because it does not show
`sufficiently that an ordinarily skilled artisan would have had a reason to
`combine the teachings of Cardullo with those of McQuade and LeClerc.
`Petitioner contends that an ordinarily skilled artisan “would have had
`a reason to replace the multiple intercalating dyes of Cardullo with the
`multichromophore conjugated polymer of McQuade to modify Cardullo’s
`system.” Pet. 30. Petitioner contends that substituting McQuade’s
`conjugated polymer for Cardullo’s multiple acridine orange dyes “would
`have been nothing but a ‘simple substitution of one known element for
`another’ to obtain predictable results.” Id. at 37 (quoting KSR Int’l Co. v.
`Teleflex Inc., 550 U.S. 398, 403 (2007)).
`Beginning with the teachings of Cardullo, Petitioner contends that an
`ordinarily skilled artisan would have started with FRET strategy “C.”
`Specifically, Petitioner contends that the skilled artisan “would have had a
`reason to modify Cardullo’s FRET system ‘C’” because that artisan “would
`have understood that system ‘C’ was simpler and more sensitive to the
`alternative ‘A’ and ‘B’ formats, which required pre-conjugation of the donor
`to a 5′ or 3′ terminus of a DNA molecule.” Id. at 31 (citing Ex. 1003, 8791
`(Fig. 1); Ex. 1002 ¶¶ 92–93). Petitioner contends that Cardullo’s strategy
`“C” has “a much higher energy transfer than ‘A’ and ‘B’—by a factor of
`≈2.” Id. (citing Ex. 1003, 8793–94 (quotation omitted); Ex. 1002 ¶ 96).
`Turning to McQuade, Petitioner next contends that an ordinarily
`skilled artisan would have had a reason to substitute McQuade’s conjugated
`polymer for Cardullo’s multiple acridine orange dyes. Id. at 31–38.
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`Specifically, Petitioner contends that Cardullo recognized and desired a
`“high FRET transfer efficiency” and “highly preferred a system in which
`multiple molecules of a donor dye are intimately associated with a DNA
`duplex within a short separation distance to the acceptor, since this close
`clustering of donors on the DNA duplex results in an ‘antenna effect’ that
`increased acceptor emission.” Id. at 31(citing Ex. 1003, 8791 (Fig. 1),
`8793–94 (quotation omitted); Ex. 1002 ¶ 115). Petitioner contends that the
`ordinarily skilled artisan would have recognized that McQuade’s conjugated
`polymer met those objectives for at least two reasons. Id. at 32.
`First, according to Petitioner, an ordinarily skilled artisan would have
`known that McQuade’s conjugated polymer “could achieve higher energy
`transfer than Cardullo’s own donors.” Id. (citing Ex. 1005, 12389–390; Ex.
`1002 ¶ 116). Second, Petitioner asserts that an ordinarily skilled artisan
`would have recognized that “McQuade’s conjugated polymer could better
`achieve Cardullo’s observed ‘antenna effect’ than Cardullo’s acridine orange
`donors” because LeClerc shows that a conjugated polymer can bind in an
`aggregated form to DNA (similarly to acridine orange), id. (citing Ex. 1004,
`26; Ex. 1002 ¶ 120), and ordinarily skilled artisans knew that conjugated
`polymers “possess powerful antenna-like properties, owing to their
`delocalized electronic structure and ultrafast exciton mobility along the
`conjugated polymer chain.” Id. at 32–33 (citing Ex. 1025, 12287; Ex. 1002
`¶ 120; Ex. 1028; Ex. 1030; Ex. 1006; Ex. 1005).
`For these reasons and others, see id. at 33–36, Petitioner concludes
`that an ordinarily skilled artisan “would have considered Cardullo’s acridine
`orange dyes to be interchangeable with McQuade’s polymer,” and
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`“[c]consequently, a [ordinarily skilled artisan] would have simply
`substituted one known element—a conjugated polymer—for another known
`element—acridine orange.” Id. at 37–38 (citing Ex. 1002 ¶ 125).
`We are not persuaded that Petitioner establishes a reasonable
`likelihood that the subject matter of claims 1 and 3 would have been obvious
`over Cardullo, McQuade, and LeClerc, because Petitioner has not
`adequately supported its contentions. As an initial matter, we agree with
`Patent Owner that Petitioner has placed undue reliance on the teachings of
`Cardullo to support its argument that the ordinarily skilled artisan would
`have had a reason to modify FRET strategy “C.” See Prelim. Resp. 14–16.
`First, the Petition does not direct us to evidence supporting
`Petitioner’s allegation that FRET strategy ‘C’ is necessarily “simpler” than
`FRET strategies “A” and “B.” See Pet. at 31. The paragraphs of
`Dr. Schanze’s Declaration that Petitioner cites make no mention of the
`simplicity of “C” as compared to FRET strategies “A” and “B.” Ex. 1002
`¶¶ 92–93. And, although FRET strategy “C” does not require pre-
`conjugation of a donor molecule to DNA, Cardullo describes the fluorescent
`probes as “easily attached to a[n oligodeoxynucleotide].” Ex. 1003, 8793.
`For these reasons, Petitioner has failed to show adequately for institution
`that an ordinarily skilled artisan would have been drawn to Cardullo’s FRET
`strategy “C” over “A” and “B” for “C’s” alleged simplicity.
`Second, we find that, contrary to Petitioner’s assertions, Cardullo’s
`FRET strategy “C” did not have the highest energy transfer of all the
`disclosed FRET strategies. See Pet. 31. Cardullo expressly states that FRET
`strategy “B” had a transfer efficiency (Et) from fluorescein to rhodamine of
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`“about 0.6.” Ex. 1003, 8792. This transfer efficiency is higher than that
`Cardullo observed between acridine orange and rhodamine in FRET strategy
`“C”—i.e., an Et of 0.52. Id. at 8790. These results are shown in Table 2 of
`Cardullo:
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`Id. at 8793. Line A in Table 2 represents FRET strategy “B” (i.e., “two 12-
`mers attached to a 29-mer”), and Line B represents FRET strategy “C” (i.e.,
`“two hybridized 12-mers in the presence of acridine orange”). Compare id.
`at 8793 (Table 2), with id. at 8791 (Figure 1).
`Petitioner also cites to Dr. Schanze’s Declaration for supporting its
`argument that strategy “C” showed the highest energy transfer. See Pet. 31
`(citing Ex. 1002 ¶ 96). But Dr. Schanze merely repeats Cardullo’s statement
`that strategy “C” showed superior energy transfer over “single donor dye
`systems”—i.e., those systems “‘where single donor and acceptor molecules
`were covalently linked to [oligodeoxynucleotides].’” Ex. 1002 ¶ 96 (quoting
`Ex. 1003, 8793). Even though both FRET strategies “A” and “B” are
`technically “single donor dye systems,” we find that the systems to which
`Cardullo refers on page 8793 can only be those based on FRET strategy
`“A”—not strategy “B.” Prelim. Resp. 15–16.
`Specifically, Cardullo measured a transfer efficiency of 0.22 with
`FRET strategy “A,” and, as described above, Cardullo measured a transfer
`efficiency of 0.52 with FRET strategy “C.” Ex. 1003, 8793. Thus, when
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`Cardullo reports that strategy “C” enhanced “transfer efficiency by a factor
`of ≈2,” Cardullo is describing the difference in transfer efficiency between
`strategies “A” and “C.” The converse (i.e., that FRET strategy “C” also
`experienced enhanced transfer efficiency over strategy “B” by a factor of
`≈2) cannot be reconciled with Cardullo’s own data. As explained above,
`FRET strategy “B” shows a higher transfer efficiency (Et of 0.60) than
`strategy “C” (Et of 0.52). Id. at 8793. Thus, FRET strategy “C” could not
`have shown an enhanced “transfer efficiency by a factor of ≈2” over “B” as
`Petitioner contends.
`In sum, we agree with Patent Owner, see Prelim. Resp. 16, that
`Petitioner’s contention that strategy “C” “had a
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