Trials@uspto.gov Paper No. 10
`571-272-7822
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` Entered: February 7, 2019
`
`
`
`
`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 IPR2018-01367
`Patent 8,835,113 B2
`____________
`
`Before ERICA A. FRANKLIN, MICHELLE N. ANKENBRAND, and
`JOHN E. SCHNEIDER, Administrative Patent Judges.
`
`FRANKLIN, Administrative Patent Judge.
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`571-272-7822
`
` Entered: February 7, 2019
`
`
`
`
`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 IPR2018-01367
`Patent 8,835,113 B2
`____________
`
`Before ERICA A. FRANKLIN, MICHELLE N. ANKENBRAND, and
`JOHN E. SCHNEIDER, Administrative Patent Judges.
`
`FRANKLIN, Administrative Patent Judge.
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`IPR2018-01367
`Patent 8,835,113 B2
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`
` INTRODUCTION
`Thermo Fisher Scientific, Inc. (“Petitioner”) filed a Petition requesting
`an inter partes review of claims 1, 3–5, 7, 20, 22, and 25–27 of U.S. Patent
`No. 8,835,113 B2 (Ex. 1001, “the ’113 patent”). Paper 1 (“Pet.”). The
`Regents of the University of California (“Patent Owner”) filed a Preliminary
`Response to the Petition. Paper 7 (“Prelim. Resp.”).
`We have authority under 35 U.S.C. § 314 to determine whether to
`institute an inter partes review. Upon considering the Petition and the
`Preliminary Response, along with the circumstances involved in this case,
`we determine that Petitioner has not shown a reasonable likelihood that it
`would prevail in showing the unpatentability of at least one challenged
`claim. Accordingly, we deny the Petition and decline to institute an inter
`partes review.
`
`Related Proceedings
`A.
`Petitioner and Patent Owner identify an ongoing district court
`proceeding involving the ’113 patent: The Regents of the University of
`California et al. v. Affymetrix, Inc. et al., No. 3:17-cv-01394 (CASD).
`Pet. 67; Paper 4, 2. The parties also note that Petitioner has concurrently
`filed a separate petition involving the ’113 patent (IPR2018-01368) and,
`shortly thereafter, filed two petitions involving a related patent, U.S. Patent
`No. 8,110,673 B2 (IPR2018-01369 and IPR2018-01370). Pet. 67; Paper 4,
`1–2.
`
`The ’113 Patent
`B.
`The ’113 patent relates to methods for assaying a sample for an
`aggregant using an aggregation sensor. Ex. 1001, 1:32–34. “An aggregant
`to be assayed may be a target biomolecule (e.g., a polysaccharide, a
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`polynucleotide, a peptide, a protein, etc.).” Id. at 15:55–58. “The
`aggregation sensor comprises a component that can bind to an aggregant or
`class of aggregants.” Id. at 10:10–12. The Specification explains that
`“[c]onjugated polymers have proven useful as light gathering molecules in a
`variety of settings.” Id. at 1:49–50. In particular, “[w]ater-soluble
`conjugated polymers such as cationic conjugated polymers (CCPs) have
`been used in bioassays to improve detection sensitivity and provide new
`routes of selectivity in analyzing biomolecules.” Id. at 1:51–55. The
`molecular structure of those molecules “allows for a collective response and,
`therefore, optical amplification of fluorescent signals.” Id. at 2:33–37.
`Specifically, “[t]he large number of optically active units along the polymer
`chain increases the probability of light absorption, relative to small molecule
`counterparts.” Id. at 2:37–39. The presence of target DNA in a sample may
`be detected upon delivery of excitations to fluorophores, using facile
`fluorescence resonance energy transfer (FRET). Id. at 2:39–42.
`The Specification explains that “[r]ecent studies indicate that energy
`transfer between segments in conjugated polymers may be substantially
`more important than along the backbone” and that external perturbations that
`decrease the elongation of the backbone or bring its segments closer together
`may be used to modify emissive properties of the polymer in solution. Id. at
`2:46–49. Based on that information, the Specification states that the
`inventors recognized “a small number of fluorescent units within a polymer
`sequence could be activated by structural changes that compressed or
`aggregated the polymer chains to ultimately change the emission color” and
`then designed a cationic conjugated polymer structure in accordance with
`that principle. Id. at 2:50–55. According to the Specification,
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`“[e]lectrostatic complexation with negatively charged DNA can be used to
`reduce the average intersegment distance. When combined with a
`fluorophore labeled peptide nucleic acid (PNA) strand, the polymer can be
`used to design a three color DNA detection assay.” Id. at 2:55–60.
`Illustrative Claim
`C.
`Claim 1 of the ’113 patent, reproduced below, is the only independent
`claim, and is illustrative of the claimed subject matter.
`1. A method of assaying a sample for an aggregant, the
`method comprising:
`(a) combining the sample with an aggregation sensor
`comprising
`(i) a polymer comprising a plurality of first optically
` active units forming a conjugated system, having a
` first absorption wavelength at which the first optically
` active units absorb light to form an excited state that
` can emit light of a first emission wavelength, and a
` plurality of solubilizing functionalities; and
`
` (ii) one or more second optically active units that can
`
` receive energy from the excited state of the first optically
`
` active unit;
`
` wherein said aggregation sensor comprises at least three
`
` first optically active units per second optically active unit
`
` and the second optically active unit is grafted to the
`
` conjugated system;
` (b) contacting the sample with light of the first absorption
` wavelength; and
` (c) detecting the optical properties of the aggregation sensor
` to assay the sample for the aggregant.
`
`
`D.
`
`The Asserted Grounds of Unpatentability
`
`Petitioner challenges the patentability of claims 1, 3–5, 7, 20, 22, and
`25–27 of the ’113 patent on the following grounds:
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`Claim(s)
`1, 20, 22, 25, and 26
`
`1, 3–5, 7, and 27
`
`Basis
`§ 103(a)
`
`§ 103(a)
`
`References
`Hou1 and Inganas2
`
`Hou, Bazan,3 and the Handbook4
`
`Petitioner also relies upon the Declaration of Kirk S. Schanze, Ph.D.
`(Ex. 1002).5 Patent Owner relies upon the Declaration of Dwight Seferos,
`Ph.D. (Ex. 2008).
`
` 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
`partes review proceedings).6 Under that standard, and absent any special
`
`
`
` 1
`
` Hou et al., Novel red-emitting fluorene-based copolymers, 12 J. MATER.
`CHEM. 2887-2892 (2002) (“Hou”) (Ex. 1007).
`2 Inganas et al., WO 2003/096016 A1, published Nov. 20, 2003 (“Inganas”)
`(Ex. 1006).
`3 Bazan et al., WO 2004/001379 A2, published Dec. 31, 2003 (“Bazan”)
`(Ex. 1033).
`4 Haugland, HANDBOOK OF FLUORESCENT PROBES AND RESEARCH
`PRODUCTS, 9th ed., Molecular Probes (2002) (“the Handbook”) (Ex. 1005).
`5 Petitioner includes the letters “TFS” with its exhibit numbers. We do not
`adopt that practice in this decision.
`6 The Office recently changed the claim construction standard to be
`employed in an inter partes review. 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,
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`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); Trivascular, Inc. v. Samuels, 812 F.3d 1056, 1062 (Fed. Cir. 2016)
`(“Under a broadest reasonable interpretation, words of the claim must be
`given their plain meaning, unless such meaning is inconsistent with the
`specification and prosecution history.”).
`Petitioner proposes that we adopt certain district court claim
`constructions for a number of claim terms. Pet. 15–17. In doing so,
`Petitioner provides the proposed constructions without any discussion or
`reference to the Specification in support of them. In any event, we
`determine that construction of those claim terms is not necessary for purpose
`of this Decision. See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d
`795, 803 (Fed. Cir. 1999) (only terms that are in controversy need to be
`construed, and only to the extent necessary to resolve the controversy).
`B.
`Level of Ordinary Skill in the Art
`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)).
`
`
`
`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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`According to Petitioner, a person of ordinary skill in the art at the time
`of the invention would have had “knowledge of the scientific literature
`concerning methods of synthesizing fluorescent conjugated polymers and
`using these polymers in biosensors.” Pet. 7 (citing Ex. 1002 ¶ 11). In
`particular, Petitioner asserts,
`Here, a POSA would typically have had (i) a Ph.D. in Chemistry,
`or a related field in the chemical sciences, and have at least about
`two years of experience in chemical synthesis and application of
`fluorescent conjugated polymers; or (ii) a Master's degree in the
`same fields with at least about five years of the same experience.
`Also, a POSA may have worked as part of a multidisciplinary
`team and drawn upon not only his/her own skills, but of others
`on the team, e.g., to solve a given problem. For example, a
`biochemist, molecular biologist and a clinician specializing in
`detection of biological molecules may have been part of a team.
`
`
`Id. (citing Ex. 1002 ¶ 12).
` Patent Owner asserts that a person of ordinary skill in the art “would
`possess a Ph.D. in chemistry or related fields and some experience with
`fluorescence or, alternatively, a master’s degree in chemistry or related
`fields and industry experience in the field of biological detection systems
`and/or the use and design of fluorescent dyes.” Prelim. Resp. 4–5.
`We note that those descriptions are fairly the same, except for
`Petitioner’s description additionally recognizing a member of an unspecified
`multidisciplinary team as a person of ordinary skill in the art. Insofar as that
`additional description is vague, we decline to adopt it. Instead, for purposes
`of this Decision, we determine that the remaining portion of Petitioner’s
`description of the level of ordinary skill in the art is sufficiently detailed and
`one that the current record supports. Thus, we recognize, for purposes of
`this Decision, a person of ordinary skill in the art as one having either a
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`Ph.D. in Chemistry, or a related field in the chemical sciences, and having at
`least about two years of experience in chemical synthesis and application of
`fluorescent conjugated polymers, or a Master's degree in the same fields
`with at least about five years of the same experience.
`Moreover, we have reviewed the credentials of Drs. Schanze
`(Ex. 1027) and Seferos (Ex. 2009) and, at this stage in the proceeding,
`consider them to be qualified to provide their opinions 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).
`C. Obviousness over Hou and Inganas
`Petitioner asserts that claims 1, 20, 22, 25, and 26 would have been
`obvious over the combination of Hou and Inganas. Pet. 18–46. Patent
`Owner disagrees. Prelim. Resp. 5–51.
`1. Hou
`Hou is a journal article discussing the synthesis of a series of novel
`red-emitting fluorene-based conjugated copolymers. Ex. 1007. Hou
`explains that “electrolumine[s]cent polymers have attracted great attention
`due to their possible utilization in flat panel displays.” Id. at 2887.7 In
`particular, Hou notes that polyfluorenes are “promising new materials for
`
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`
` We refer to the original page numbering provided in each reference for
`citations to our statements. However, when setting forth Petitioner’s
`arguments and citations, we quote the page numbering in the manner
`Petitioner cites, which, for the most part, refers to page numbers that
`Petitioner added to the references.
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`light-emitting diodes because of their thermal and chemical stability and
`exceptionally high fluorescence quantum yields [] in thin solid films.” Id.
`Although polyfluorene homopolymers have large bandgaps and emit blue
`light, Hou explains that emission color can be desirably “tuned over the
`entire visible region by incorporating narrow band-gap comonomers into the
`polyfluorene backbone.” Id. According to Hou, it is expected that “the
`narrow band-gap unit functions as an exciton trap which allows efficient
`intramolecular energy transfer from the fluorene segment to the DBT unit,”
`giving rise to red light emission. Id. at 2887, 2889.
`
`Hou describes preparing the copolymers from 2,7-dibromo-9,9-
`dioctylfluorene (DOF), 2,7-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-
`9,9-dioctylfluorene and narrow band gap comonomer 4,7-bis(5-bromo-2-
`thienyl)-2,1,3-benzothiadiazole (DBT) using palladium catalyzed Suzuki
`coupling methods. Id. at 2888. Hou explains that the “n-octyl substituents
`in the 9-position of fluorine were employed to improve the solubility of the
`resulting copolymers.” Id. The resulting polymers were readily soluble in
`conventional organic solvents, e.g., toluene, chloroform, and tetrahydro-
`furan. Id. The photoluminescent (PL) spectra of the polymers in thin films
`and in CHCl3 solution, produced by excitation, were analyzed. Id. at 2889.
`Electroluminescent properties from a single layer device fabricated with
`copolymer with 15% DBT content were also determined. Id. at 2891. Hou
`concludes that “[t]he efficient energy transfer due to exciton trapping on
`narrow band-gap DBT sites has been observed. Polyfluorene fluorescence is
`quenched completely at DBT concentrations as low as 1% in the solid state
`film. All of the copolymers emit saturated red color.” Id. Hou “notes also
`that both PL (in solution and in solid films) and EL [electroluminescence]
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`emission are red-shifted with increasing DBT content in polymer chains.”
`Id.
`
`2. Inganas
`Inganas is a PCT Application directed to “methods for detection of
`biomolecular interactions through the detection of alterations of the intra-
`and inter-chain processes in materials based on zwitterionic conjugated
`polyelectrolytes.” Ex. 1006, 1:6–8. Inganas explains that conjugated
`polymers such as poly(thiophene) and poly(pyrrole) are useful as biosensors
`because they are “sensitive to very minor perturbations, due to amplification
`by a collective system response.” Id. at 1:15–18. Inganas states that such
`use of conjugated polymers requires that they are “compatible with aqueous
`environment.” Id. at 1:20–21. Inganas explains that this may be
`accomplished by making conjugated polyelectrolytes. Id. at 1:21–23.
`“[T]he polyelectrolyte comprises copolymers or homopolymers of
`thiophene, pyrrole, aniline, furan, phenylene, vinylene or their substituted
`forms, and preferably the conjugated polyelectrolyte has one or more
`zwitterionic side chain functionalities.” Id. at 3:1–4.
`3. Analysis
`“An obviousness determination requires that a skilled artisan would
`have perceived a reasonable expectation of success in making the invention
`in light of the prior art.” Amgen, Inc. v. F. Hoffman–La Roche Ltd., 580
`F.3d 1340, 1362 (Fed. Cir. 2009). “The reasonable expectation of success
`requirement refers to the likelihood of success in combining references to
`meet the limitations of the claimed invention.” Intelligent Bio-Sys, Inc. v.
`Illumina Cambridge Ltd., 821 F.3d 1359, 1367 (Fed. Cir. 2016). “[O]ne
`must have a motivation to combine accompanied by a reasonable
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`expectation of achieving what is claimed in the patent-at-issue.” Id.
`Petitioner asserts that “Hou and Inganas teach all the elements of
`claim 1.” Pet. 18. In particular, we focus on Petitioner’s reliance on the
`combined teachings of Hou and Inganas to yield the elements of the
`“aggregation sensor” recited in claim 1.
`Petitioner relies on Hou as disclosing a conjugated polymer with a
`plurality of first units, 9,9-dictylfluorene (fluorene), and one or more second
`units, 4,7-di-2-thienyl-2,1,3-benzothiadiazole (DBT). Id. at 19. Petitioner
`relies on Inganas as disclosing the use of conjugated polymers to detect
`interactions between biomolecules by an optical change in the polymer upon
`binding an analyte, wherein the spectral change could be mediated by
`“separation or aggregation of [polymer] chains.” Id. at 22. Specifically,
`Petitioner asserts that Inganas discloses forming conjugated polyelectrolytes
`by appending zwitterionic side-chains to the conjugated polymer. Id. at 21–
`22 (citing Ex. 1002 ¶¶ 67, 70; Ex. 1006, 4:1–4). Petitioner asserts that
`Inganas teaches that the “‘zwitterionic polyelectrolyte[s]’ could
`electrostatically associate with a ‘receptor’ moiety (e.g., antibody or DNA),
`which ‘act[ed] as the recognition site for analytes.” Id. at 22 (citing
`Ex. 1006, 6:16–7:3; Ex. 1002 ¶¶ 67, 74). Petitioner asserts that “Inganas
`taught that this polymer-receptor ‘complex’ would act as a ‘biosensor… for
`detection of molecular interactions’ through a spectral change.” Id. at 22
`(citing Ex. 1006, 9:7–28; Ex. 1002 ¶ 75). Petitioner states that “Inganas
`notes that the ‘the possibility to use [conjugated polymers] as detecting
`elements for biological molecules requires that polymer are [made]
`compatible with aqueous environment,’ via addition of ‘one or more
`zwitterionic side chain functionalities’ (i.e., a plurality of solubilizing
`
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`functionalities) to the polymer.” Id. at 28 (citing Ex. 1002 ¶¶ 67, 91;
`Ex. 1006, 2:19–21, 4:1–4).
`According to Petitioner and Dr. Schanze, although Hou’s polyfluorene
`copolymers were developed for use in LED devices, a person of skill in the
`art would have had a reason “to use Hou’s conjugated copolymers in
`Inganas’ biosensor” because Hou’s copolymers “showed a color change
`upon aggregation (a concentration increase), just as Inganas wanted.” Pet.
`31 (citing Ex. 1002 ¶¶ 77, 97, 98–109). Further, Petitioner and Dr. Schanze
`assert that a person of skill in the art “would have had reason to render
`copolymers water-soluble in the manner taught by Inganas: by attaching
`solubilizing ‘zwitterionic side chain functionalities’ to Hou’s polymer.” Id.
`at 37 (citing Ex. 1006, 4:1–5; Ex. 1002 ¶ 107). Specifically, Petitioner and
`Dr. Schanze assert that the person of skill would have modified Hou’s
`copolymer because Inganas explained that the zwitterionic side-chains were
`“needed—not only did they make the polymer ‘compatible with aqueous
`environment,’ but also mediated formation of a polymer-receptor complex
`by ‘hydrogen bonding, electrostatic- and non-polar interactions’ with the
`receptor.” Pet. 37; Ex. 1002 ¶ 107.
`Significantly, Petitioner and Dr. Schanze assert that a person of
`ordinary skill in the art it would have had a reasonable expectation of
`success in appending Inganas’ zwitterionic side-chains onto Hou’s
`copolymers to provide conjugated polymers comprising a plurality
`solubilizing functionalities. Pet. 38–40; Ex. 1002 ¶¶ 108, 111–113.
`According to Petitioner and Dr. Schanze, “a POSA would have known how
`to attach two zwitterionic functionalities to each fluorene monomer of Hou’s
`copolymer at position 9 of fluorene.” Pet. 39 (citing Ex. 1002 ¶ 112).
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`Petitioner asserts that “a POSA would have known, given the general
`knowledge in the art, that the 9 position of fluorene is the common place for
`attachment of different functionalities to fluorene polymers.” Id.
`Additionally, Petitioner asserts that it was “standard in this field, according
`to Dr. Schanze, to start with fluorene monomers that are underivatized at
`position 9, and use standard chemical methods to append the desired
`functionalities.” Id. In support, Petitioner and Dr. Schanze refer to Wang8
`as teaching “how to append polycationic functionalities onto fluorene
`monomers at position 9.” Id. at 40 (citing Ex. 1002 ¶ 113; Ex. 1004, 3:2:3–
`4:1:1:1, 4:Scheme 2 (compound 2)). According to Petitioner and
`Dr. Schanze, “[t]he only difference would have been in the last step—
`instead of treating precursor fluorenes corresponding to compounds 11a-c of
`Wang with trimethylamine, a POSA would have treated them with N-t-
`BOC-L-serine.” Id. (citing Ex. 1002 ¶113; Ex. 1004, 4:1:1).
`
`Patent Owner asserts, among other things, that a person of skill in the
`art “would not have been motivated to modify Hou’s polymers as suggested
`by Thermo because such modification would not have been expected to be
`successful.” Prelim. Resp. 47. In particular, Patent Owner asserts that
`Petitioner’s “proposed mechanism for attaching Inganas’ [zwitterionic] side
`chain requires one to ‘start with fluorene monomers that are underivatized at
`position 9, and use standard chemical methods to append the desired
`functionalities.’” Id. at 44 (quoting Pet. 39) (emphasis added by Patent
`
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` Wang et al., Size-Specific Interactions Between Single-and Double-
`Stranded Oligonucleotides and Cationic Water-Soluble Oligofluorenes, 13
`ADV. FUNCT. MATER. 463–467 (2003) (“Wang”) (Ex. 1004).
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`Owner). According to Patent Owner, Petitioner has not demonstrated that a
`person of ordinary skill in the art would have had a reasonable expectation
`of successfully doing so “because Hou’s copolymers are not underivatized at
`position 9 and because Inganas, in fact, instructs a POSA to add side chains
`to the thiophene unit, not a fluorene unit like in Hou.” Id. at 44. In that
`regard, Patent Owner asserts that Petitioner has not explained sufficiently
`why a person of ordinary skill in the art would have chosen to add Inganas’
`zwitterionic side chains to the fluorene monomer of Hou’s copolymer and
`not the thiophene unit in the DBT unit of Hou’s copolymer, as suggested by
`Inganas. Id. at 46–47; Ex. 1006, 3:1–4.
`
`Having considered the arguments and evidence, we find Patent
`Owner’s arguments to have merit. In particular, we agree with Patent
`Owner that Petitioner has not adequately demonstrated that a person of
`ordinary skill in the art would have had a reasonable expectation of
`successfully modifying Hou in the manner Petitioner has proposed.
`According to Petitioner, a person of ordinary skill in the art would have
`understood from Inganas that in order for Hou’s copolymers to be useful as
`aggregation sensors in the method Inganas discloses, Hou’s copolymers
`would need to be modified to include zwitterionic side chains. Pet. 37.
`Indeed, Petitioner asserts that Inganas teaches that inclusion of those side
`chains were “needed—not only did they make the polymer ‘compatible with
`aqueous environment,’ but also mediated formation of a polymer-receptor
`complex by ‘hydrogen bonding, electrostatic- and non-polar interactions’
`with the receptor.” Id.; Ex. 1002 ¶ 107. Thus, Petitioner’s combination of
`Hou and Inganas requires, at a minimum, a person of ordinary skill in the art
`to have had a reasonable expectation of successfully appending Inganas’
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`zwitterionic side chain functionalities to Hou’s copolymer.
`According to Petitioner and Dr. Schanze, such modification should be
`performed at position 9 of the fluorene unit. Pet. 39 (citing Ex. 1002 ¶ 112).
`As Patent Owner has demonstrated, Hou discloses that such position already
`includes two C8H17 dioctyl side chains. See Prelim. Resp. 45 (citing
`Ex. 1007, Scheme 1). In proposing its modification to Hou, Petitioner has
`not addressed the presence of those dioctyl side chains at position 9 of the
`fluorene unit in Hou’s copolymer, and thus has not provided any explanation
`regarding whether a person of ordinary skill would have removed and
`replaced those side chains with zwitterionic side chains, how the skilled
`artisan would have done so, and whether the skilled artisan would have had
`a reasonable expectation of success in doing so. See Intelligent Bio-Sys,
`Inc., 821 F.3d at 1367. Moreover, as Patent Owner asserts, Inganas teaches
`adding its zwitterionic functionalities to a thiopene unit. Prelim. Resp. 46–
`47; Ex. 1006, 3:1–4. In view of that teaching, and the presence of a thiopene
`unit in the DBT unit of Hou’s copolymer, the Petitioner has not explained
`persuasively why a person of skill in the art would have had a reasonable
`expectation of success modifying Hou’s copolymer in a different fashion,
`i.e., by appending the zwitterionic side chains instead to the fluorene unit of
`the copolymer. For at least those reasons, based on the information
`presented, we determine that Petitioner has not shown a reasonable
`likelihood of prevailing in showing the unpatentability of independent claim
`1, or dependent claims 20, 22, 25, and 26, over the proposed combination of
`Hou and Inganas.
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` D. Obviousness over Hou, Bazan, and the Handbook
`Petitioner asserts that claims 1, 3–5, 7, and 27 would have been
`obvious over the combination of Hou, Bazan, and the Handbook. Pet. 46–
`61. Patent Owner disagrees. Prelim. Resp. 51–58. We incorporate our
`discussion of Hou in Section II. C. here.
`1. Bazan
`Bazan is a PCT Application directed to methods and compositions for
`assaying a sample for a target polynucleotide using a polycationic
`multichromophore and a sensor peptide nucleic acid (PNA) complementary
`to the target polynucleotide. Ex. 1033, 2:13–16. Bazan teaches that
`“[b]ecause the target polynucleotide is negatively charged, the sensor PNA
`associates with the polycationic multichromophore, permitting energy
`transfer from the polycationic multichromophore to the signaling
`chromophore, for example via the Förster energy transfer mechanism.” Id.
`at 4:16–19. Bazan describes a preferred embodiment of the invention
`involving the use of a conjugated polymer as the polycationic
`multichromophore, for example poly((9,9-bis(6’-N,N,N-
`trimethylammonium)-hexyl)-fluorene phenylene) with iodide counteranions.
`Id. at 15:15–18. Bazan explains that the “specific molecular structure is not
`critical; any water soluble cationic conjugated polymer with relatively high
`luminescence quantum efficiency can be used.” Id. at 15:21–23.
`2. The Handbook
`Chapter 1 of the Handbook discusses fluorophores and their amine-
`reactive derivatives. Ex. 1005, Table of Contents. Section 1.2 of that
`chapter describes kits for labeling proteins and nucleic acids with a
`fluorescent dye. Id. at 14. In particular, the Handbook describes three
`
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`IPR2018-01367
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`nucleic acid labeling kits: ARES DNA Labeling Kits, Alexa Fluor
`Oligonucleotide Amine Labeling Kits, and ULYSIS Nucleic Acid Labeling
`Kits. Id. at 18.
`
`3. Analysis
`Petitioner asserts that Hou, Bazan, and the Handbook teach all of the
`elements of claim 1. Pet. 47. In particular, we focus on Petitioner’s reliance
`on the combined teachings to yield the elements of the “aggregation sensor”
`recited in claim 1.
`Petitioner asserts that “Hou’s conjugated copolymers meet all the
`requirements of the conjugated polymer included within the aggregation
`sensor of claim 1,” except that “Hou’s polymers are not used as an
`‘aggregation sensor’ to detect or analyze an aggregant.” Id. According to
`Petitioner, “Bazan used polyfluorene copolymers like Hou’s in exactly such
`[a] manner.” Id. Specifically, Petitioner asserts that “Bazan teaches
`solubilization of polyfluorene copolymers, like Hou’s with cationic side-
`chains, and use of these conjugated copolymers as FRET donors to detect
`DNA.” Id. Petitioner asserts that a person of ordinary skill in the art would
`have had a reason “to use Hou’s conjugated copolymer in Bazan’s FRET-
`based DNA detection assay, equipped with the Alexa Fluor®750
`fluorophore of the Handbook, and to add Bazan’s cationic side chains to
`Hou’s copolymer.” Id. at 49.
`Petitioner asserts that a skilled artisan would have modified Hou’s
`copolymer to include cationic side chains because “Bazan taught that the
`cationic functionalities on [its] polymer allowed it to bind to DNA and that
`the polymer should be ‘water-soluble’ in order to work properly in aqueous
`assays.” Id. at 52 (citing Ex. 1033, 17:3–6, 17:21–23); Ex. 1002 ¶ 147.
`
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`Therefore, Petitioner asserts that a skilled artisan “would have solubilized
`Hou’s copolymers with Bazan’s cationic functionalities” to render the
`copolymers useful for Bazan’s assay. Id. (citing Ex. 1002 ¶ 147).
`According to Petitioner and Dr. Schanze, doing so would have been routine
`to such artisans. Id. at 54 (citing Ex. 1002 ¶¶ 151–154). In support of that
`assertion, Petitioner and Dr. Schanze rely upon Bazan’s reference to Stork9
`for details on the synthesis of the copolymer. Id. at 55 (citing Ex. 1006,
`24:30). According to Petitioner and Dr. Schanze, Stork teaches a skilled
`artisan how to prepare “Hou’s copolymers with fluorine units comprising the
`solubilizing functionalities of Bazan.” Id. (citing Ex. 1002 ¶ 152).
`Patent Owner asserts that Petitioner and Dr. Schanze have “not
`presented a credible method for adding Bazan’s side chains to Hou’s
`fluorine units” because Hou’s copolymers already include dioctyl side
`chains at position 9 of the fluorene unit. Prelim. Resp. 58. Patent Owner
`asserts that Petitioner does not suggest “that a POSA would have been
`motivated to remove Hou’s dioctyl side chains to replace them with Bazan’s
`cationic side chains, nor does [Petitioner] explain how a POSA would
`accomplish this.” Id.
`Having considered the arguments and evidence, we find Patent
`Owner’s arguments to have merit. In particular, we agree with Patent
`Owner that Petitioner has not adequately demonstrated that a person of
`ordinary skill in the art would have had a reasonable expectation of
`
`
`
` 9
`
` Stork et al., Energy Transfer in Mixtures of Water-Soluble Oligomers:
`Effect of Charge, Aggregation, and Surfactant Complexation, 14 ADV.
`MATER. 361-366 (2002) (“Stork”) (Ex. 1081).
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`successfully modifying Hou to include cationic side chains in the manner
`disclosed in Bazan. According to Petitioner, a person of ordinary skill in the
`art would have understood from Bazan that in order for Hou’s copolymers to
`be useful as aggregation sensors in the method disclosed by Bazan, Hou’s
`copolymers would need to be modified to include cationic side chains. Pet.
`52. Indeed, Petitioner asserts that “Bazan taught that the cationic
`functionalities on [its] polymer allowed it to bind to DNA and that the
`polymer should be ‘water-soluble’ in order to work properly in aqueous
`assays.” Id. (citing Ex. 1033, 17:3–6, 17:21–23); Ex. 1002 ¶ 147. Thus, at a
`minimum, Petitioner’s combination of Hou and Bazan requires a person of
`ordinary skill in the art to have had a reasonable expectation of successfully
`modifying Hou’s cop
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