`
`
`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 No. RE46,817
`_____________________
`
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. RE46,817
`
`
`
`
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`

`

`Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`TABLE OF CONTENTS
`
`V. 
`
`VI. 
`
`Introduction ..................................................................................................... 1 
`I. 
`Standing (37 C.F.R. § 42.104(a)) ................................................................... 6 
`II. 
`Statement of the precise relief requested and the reasons therefore .............. 6 
`III. 
`IV.  Overview ......................................................................................................... 6 
`A. 
`The '817 patent disclosure and claims ................................................... 6 
`B. 
`Person of ordinary skill in the art ("POSA") ....................................... 10 
`C. 
`State of the art ...................................................................................... 10 
`Claim construction ........................................................................................ 15 
`A. 
`The Office has determined in a related patent that the term "direct
`excitation" is indefinite ........................................................................ 15 
`The District Court has limited the term "multichromophore system"
`in a related patent to a polycationic multichromophore system ......... 17 
`Identification of the challenge (37 C.F.R. § 42.104(b)) ............................... 19 
`A. 
`Claims 1 and 3 would have been obvious over Cardullo, McQuade,
`and LeClerc ......................................................................................... 21 
`1. 
`Claim 1 ..................................................................................... 21 
`2. 
`Claim 3 ..................................................................................... 45 
`Claims 1 and 3 would have been obvious over Cardullo, LeClerc,
`and Harrison ........................................................................................ 45 
`1. 
`Claim 1 ..................................................................................... 46 
`2. 
`Claim 3 ..................................................................................... 59 
`Secondary considerations do not favor patentability .......................... 60 
`C. 
`VII.  Patent Owner has waived any right to Sovereign Immunity ........................ 61 
`VIII.  Mandatory Notices (37 C.F.R. § 42.8(a)(1)) ................................................ 63 
`
`
`B. 
`
`B. 
`
`
`
`
`
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`- i -
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`

`

` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`
`EXHIBIT LIST
`
`Description
`
`Bazan et al,. "Methods and Compositions For Detection And
`Analysis of Polynucleotides Using Light Harvesting
`Multichromophores," U.S. Patent No. RE46,817, (filed March 29,
`2017; issued May 1, 2018)
`Declaration of Kirk S. Schanze, Ph.D.
`Cardullo, R., et al., "Detection of nucleic acid hybridization by
`nonradiative fluorescence resonance energy transfer" PNAS 85:
`8790-8794 (1988)
`LeClerc et al., "Detection of Negatively Charged Polymers Using
`Water-Soluble, Cationic, Polythiophene Derivatives," International
`Publication No. WO 02/081735, (filed April 5, 2002; published
`October 17, 2002)
`
`McQuade, D., et al., "Signal Amplification of a "Turn-On" Sensor:
`Harvesting the Light Captured by a Conjugated Polymer," J. Am.
`Chem. Soc. 122: 12389-12390 (2000)
`
`Harrison, B., et al., "Amplified Fluorescence Quenching in a
`Poly(p-phenylene)-Based Cationic Polyelectrolyte," J. Am. Chem.
`Soc. 122: 8561-8562 (2000)
`
`Bazan et al., "Methods and Compositions For Detection and
`Analysis of Polynucleotides Using Light Harvesting
`Multichromophores," U.S. Patent No. 9,085,799 (filed August 14,
`2014; issued July 21, 2015)
`
`File History of U.S. Application No. 14/460,245
`
`- ii -
`
`
`
`
`
`Thermo
`Fisher
`Exhibit #
`
`1001
`
`1002
`
`1003
`
`
`1004
`
`
`1005
`
`
`1006
`
`
`1007
`
`
`1008
`
`
`

`

` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`
`Description
`
`File History of U.S. Application No. 15/473,316
`
`Plaintiff's Opening Claim Construction Brief, The Regents of The
`University of California, and Becton, Dickinson and Company v.
`Affymetrix, Inc. and Life Technologies Corp., Case No. 17-01394
`(S.D. Cal., dated February 23, 2018)
`
`Declaration of Timothy M. Swager, Ph.D. in support of Plaintiff
`Becton Dickenson and Company's Motion for Preliminary
`Injunction, The Regents of The University of California, and Becton,
`Dickinson and Company v. Affymetrix, Inc. and Life Technologies
`Corp., Case No. 17-01394 (S.D. Cal., dated January 26, 2018)
`
`Claim Construction Order for the '799 Patent, the '673 Patent, and
`the '113 Patent, The Regents of The University of California, and
`Becton, Dickinson and Company v. Affymetrix, Inc. and Life
`Technologies Corp., Civil Action No. 17-01394 (S.D. Cal., dated
`March 26, 2018)
`
`Burgess et al., "Through Bond Energy Transfer In Fluorescent Dyes
`For Labelling Biological Molecules," U.S. Patent No. 6,340,750
`(filed December 14, 1999; issued January 22, 2002)
`
`Reppy et al., "Method For Detecting An Analyte By Fluorescence,"
`International Publication No. WO 01/71317 (filed March 20, 2001;
`published September 27, 2001)
`
`Kool, "Fluorescent Nucleoside Analogs and Combinatorial
`Fluorophore Arrays Comprising Same," International Publication
`No. WO 01/044220 (filed December 13, 2000; published June 21,
`2001)
`
`Kang, T., et al., "Photoluminescence properties of various
`polythiophene derivatives," Synthetic Metals 69: 377-378 (1995)
`
`Thermo
`Fisher
`Exhibit #
`
`1009
`
`
`1010
`
`
`1011
`
`
`1012
`
`
`1013
`
`
`1014
`
`
`1015
`
`
`1016
`
`
`
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`- iii -
`
`

`

` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`
`Description
`
`Glazer et al., "Dyes Designed For High Sensitivity
`Detection of Double-Stranded DNA," U.S. Patent No. 5,783,687
`(filed September 5, 1996; issued July 21, 1998)
`
`De Angelis, D., "Why FRET over genomics?" Physiological
`Genomics 1: 93-99 (1999)
`
`Didenko, V., "DNA Probes Using Fluorescence Resonance Energy
`Transfer (FRET): Designs and Applications," Biotechniques 31:
`1106–1121 (2001)
`
`LeClerc, M., "Optical and Electrochemical Transducers
`Based on Functionalized Conjugated Polymers," Adv. Mater. 11:
`1491 – 1498 (1999)
`
`Wang, J., et al., "Photoluminescence of Water-Soluble Conjugated
`Polymers: Origin of Enhanced Quenching by Charge Transfer,"
`Macromolecules 33: 5153-5158 (2000)
`
`Liu, B., et al., "Synthesis of a novel cationic water-soluble efficient
`blue photoluminescent conjugated polymer," Chem. Comm. 551-552
`(2000)
`
`Gaylord, B., et al., "DNA detection using water-soluble conjugated
`polymers and peptide nucleic acid probes," PNAS 99: 10954-10957
`(2002)
`
`The Nobel Prize in Chemistry 2000, Conductive Polymers, The
`Royal Swedish Academy of Sciences
`
`Chen, L., et al., "Highly sensitive biological and chemical sensors
`based on reversible fluorescence quenching in a conjugated
`polymer," PNAS 96: 12287-12292 (1999)
`
`Thermo
`Fisher
`Exhibit #
`
`1017
`
`
`1018
`
`
`1019
`
`
`1020
`
`1021
`
`
`1022
`
`
`1023
`
`1024
`
`1025
`
`
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`- iv -
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`

`

` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`
`Description
`
`Wang, S., et al., "Fluorescein Provides a Resonance Gate for FRET
`from Conjugated Polymers to DNA Intercalated Dyes," J. Am.
`Chem. Soc., 126:5446-5451 (2004)
`
`Curriculum Vitae for Kirk S. Schanze, Ph.D.
`
`Swager, T. "Fluorescence Studies of Poly(p-
`phenyleneethyny1ene)s: The Effect of Anthracene Substitution," J.
`Phys. Chem. 99, 4886-4893 (1995)
`
`Chen et al., "Method For Detecting Biological Agents," U.S. Patent
`Application Publication No. 2004/0023272 (filed April 10, 2003;
`published February 5, 2004)
`
`Swager, T. "The Molecular Wire Approach to Sensory Signal
`Amplification," Ace. Chem. Res. 31:201-207 (1998)
`
`Gruber, H., et al., "Biotin-Fluorophore Conjugates with
`Poly(ethylene glycol) Spacers Retain Intense Fluorescence after
`Binding to Avidin and Streptavidin," Bioconjugate Chem. 8: 552-
`559 (1997)
`
`Haugland, R., "Section 6.4 – Phycobiliproteins" in Handbook of
`Fluorescent Probes and Research Products, 9th Ed., Molecular
`Probes, Inc. (2002)
`
`Haugland, R., "Section 6.4 – Phycobiliproteins" in Handbook of
`Fluorescent Probes and Research Products, 8th Ed., Molecular
`Probes, Inc. (2001)
`
`Pinto, M. and Schanze, K., "Conjugated Polyelectrolytes: Synthesis
`and Applications," Synthesis 9: 1293 - 1309 (2002)
`Alberts, Molecular Biology of the Cell, 2nd ed., Garland Publishing,
`Inc. (1989)
`
`Thermo
`Fisher
`Exhibit #
`
`1026
`
`
`1027
`
`1028
`
`
`1029
`
`
`1030
`
`
`1031
`
`
`1032
`
`
`1033
`
`
`1034
`
`
`1035
`
`
`
`
`- v -
`
`

`

` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`
`Description
`
`Swager et al., "Emissive Polymers And Devices Incorporating
`These Polymers," International Publication No. WO 99/57222 (filed
`May 5, 1999; published November 11, 1999)
`
`Hancock et al., "Luminescent Polymer Particles," U.S. Patent
`Application Publication No. 2003/0134959 (filed November 30,
`2001; published July 17, 2003)
`
`Complaint, The Regents of The University of California, and
`Becton, Dickinson and Company v. Affymetrix, Inc. and Life
`Technologies Corp., Case No. 17-01394 (S.D. Cal., dated July 10,
`2017)
`
`
`
`- vi -
`
`Thermo
`Fisher
`Exhibit #
`
`1036
`
`
`1037
`
`
`
`1038
`
`
`
`
`
`

`

` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`Thermo Fisher Scientific Inc. petitions for inter partes review, seeking
`
`cancellation of claims 1 and 3 of U.S. Pat. No. RE46,817 (TFS1001) as
`
`unpatentable under 35 U.S.C. § 103(a).
`
`I.
`
`Introduction
`
`The '817 patent claims a light harvesting chromophore system that
`
`comprises a signaling chromophore and a multichromophore conjugated polymer,
`
`both in solution, wherein the polymer is in energy-transferring proximity to the
`
`chromophore so that, upon excitation, the polymer transfers energy to the
`
`chromophore to provide a greater than 4-fold increase in fluorescence emission
`
`from the chromophore. TFS1001, 23:1-12. Dependent claim 3 specifies that the
`
`chromophore is a fluorescent dye. TFS1001, 23:19-21.
`
`Simply put, the '817 patent claims an optical detection system based on a
`
`well-known and widely-utilized principle of Förster Resonance Energy Transfer
`
`(FRET) between two fluorescent molecules (chromophores). TFS1002, ¶¶13-18,
`
`67-79. The energy donor in the claimed system is a fluorescent conjugated
`
`polymer—old molecules, known for their ability to amplify energy transfer to
`
`chromophores via an "antenna effect." TFS1006, 3:1:1; TFS1030, 2:2:1; TFS1028,
`
`8:1:2; TFS1003, 6:1:3-2:1, 5:1:2; TFS1002, ¶¶30-34. The energy acceptor is any
`
`standard chromophore, also well-known and widely-used in the field. TFS1013,
`
`9:36-45; TFS1003, Abstract; TFS1005, 3:2:1; TFS1014, Tables 1 and 2; TFS1015,
`
`
`
`- 1 -
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`

`

` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`55: Example 8; TFS1016, Abstract; TFS1017, Table 1; TFS1002, ¶¶19-22. The
`
`claimed characteristic of the system is the ability of the conjugated polymer to
`
`transfer energy to the chromophore and increase the emission from the
`
`chromophore by more than 4-fold. But this effect is also not new: the field was
`
`utilizing "'amplified' sensing of chemical and biological analytes" with conjugated
`
`polymers for several years prior to the alleged invention of the '817 patent.
`
`TFS1005, 3:1:1, 3:2:2, 4:1:3; TFS1006, 3:1:1; TFS1002, ¶¶56-64. All the inventors
`
`of the '817 patent did, was to put a known conjugated polymer-based detection
`
`system in a format for detecting DNA hybridization. TFS1002, ¶¶67-79. But
`
`FRET-based DNA hybridization assays had been known for many years prior to
`
`the alleged invention. See, generally, TFS1015; TFS1014; TFS1003; TFS1004;
`
`TFS1013; TFS1002, ¶¶47-55. Thus, as this Petition, which is supported by an
`
`expert testimony of Dr. Schanze, will show in detail, nothing claimed in claims 1
`
`and 3 of the '817 patent is patentable.
`
`Claims 1 and 3 would have been obvious over Cardullo (TFS1003),
`
`McQuade (TFS1005), and LeClerc (TFS1004). Cardullo teaches a "powerful"
`
`optical biosensor system for detecting nucleic acid hybridization (i.e., double-
`
`stranded DNA) in solution. TFS1003, Abstract, 2:2:3, 6:2:2; TFS1002, ¶97. In
`
`Cardullo' s system, DNA hybridization brings donor and acceptor dyes in energy-
`
`transferring proximity to each other: the donor binds to an acceptor-labeled duplex
`
`
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`- 2 -
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`

`

` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`DNA and, upon excitation, transfers energy to the acceptor. TFS1003, Abstract,
`
`2:1:1, 6:2:2; TFS1002, ¶92-94. Fluorescent signal from the acceptor is what,
`
`therefore, detects DNA hybridization. Cardullo demonstrates that when multiple
`
`donor chromophores (acridine orange dyes) are bound to duplex DNA, the signal is
`
`amplified due to the "antenna effect" of multiple donors, which gives "a high
`
`degree of transfer efficiency." TFS1003, 6:1:3-2:1, 5:1:2; TFS1002, ¶95-96.
`
`Both McQuade and LeClerc teach optical detection systems based on
`
`multichromophore conjugated polymers. McQuade's system comprises a water-
`
`soluble, polycationic, conjugated polymer and a signaling chromophore, wherein
`
`the polymer, once excited, transfers energy to the chromophore. TFS1005, 3:2:2;
`
`TFS1002, ¶¶103-104. McQuade's chemosensor "substantially amplif[ies]" the
`
`output of the chromophore using "energy harvested from a conjugated polymer"—
`
`an "approximate 10-fold increase" compared to direct excitation of the
`
`chromophore. TFS1005, 3:1:1, 3:2:2, 4:1:3; TFS1002, ¶¶103-105, 116. A POSA
`
`would have known that this amplification was achieved because of the robust
`
`"antenna" effect that is characteristic of conjugated polymers. TFS1025, 3:2:1;
`
`TFS1028, 8:1:1; TFS1030, 2:2:1 ; TFS1006, 3:1:1; TFS1005, 3:1:1; TFS1002,
`
`¶¶119-121.
`
`LeClerc teaches that "any" water-soluble, polycationic, conjugated polymer
`
`could "make strong complexes with" double-stranded DNA in solution. TFS1004,
`
`
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`

`

` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`4:24-25, 10:6-7, 15:6-10, 15:13-16, 11:19-24; TFS1002, ¶129. LeClerc further
`
`teaches that its water-soluble, polycationic, conjugated polymers are fluorescent
`
`when bound to duplex DNA. TFS1004, 4:24-29, 11:19-29, 15:6-19, 15:Scheme 6,
`
`28:4-11, 28:Example 8, 55:Figure 7; TFS1002, ¶163.
`
`A person of ordinary skill in the art ("POSA") would have had reason to
`
`substitute the multiple acridine orange dyes in Cardullo's system for the
`
`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. TFS1002,
`
`¶119. And a POSA would have had a reasonable expectation of success in doing so
`
`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. TFS1002, ¶129. Further, a POSA would
`
`have reasonably expected to achieve 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. TFS1005, 4:1:3; TFS1002, ¶134.
`
`Claims 1 and 3 would have also been obvious over Cardullo (TFS1003),
`
`LeClerc (TFS1004), and Harrison (TFS1006). In addition to the teachings of
`
`Cardullo and LeClerc discussed above, Harrison teaches that a water-soluble,
`
`
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`- 4 -
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`

`

` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`polycationic, conjugated polymer can be used for "'amplified' sensing of chemical
`
`and biological analytes." TFS1006, 3:1:1; TFS1002, ¶¶148. Like Cardullo's
`
`system, Harrison's system also detects energy transfer from a donor (the
`
`conjugated polymer) to an acceptor (a fluorescent dye) in solution. TFS1006,
`
`3:1:1, 3:1:3-2:1, 4:2:2; TFS1002, ¶¶151-154. Notably, Harrison observes an
`
`approximately 2.5 fold increase in emission intensity from the acceptor when
`
`excited by the conjugated polymer—also due to the "antenna effect." TFS1006,
`
`3:1:1, 3:Figure 1(b); TFS1030, 2:2:2; TFS1028, 8:1:2; TFS1002, ¶¶155-158.
`
`A POSA would have had a reason to replace the multiple donor molecules of
`
`Cardullo with the multichromophore conjugated polymer of LeClerc to modify
`
`Cardullo's system to increase its sensitivity, in view of teachings of Harrison.
`
`TFS1002, ¶¶159-177. A POSA would have known that a higher efficiency of
`
`energy transfer—which Harrison achieves with a conjugated polymer—can lead to
`
`a higher sensitivity of detection of DNA hybridization. TFS1002, ¶146, 162-163.
`
`And a POSA would have selected LeClerc's conjugated polymers because the
`
`polymers retain their fluorescence when bound to duplex DNA, and thus are able
`
`to transfer energy to a signaling chromophore attached to DNA. TFS1004, 15:16-
`
`19, 28:Example 8, 55:Figure 7; TFS1002, ¶164. Further, a POSA would have
`
`routinely optimized Cardullo's system, to achieve a greater than 4-fold increase in
`
`fluorescence emission from the signaling chromophore in view of Harrison.
`
`
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`

`

` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`TFS1002, ¶¶169-177. A POSA would have had a reasonable expectation of
`
`success in doing so because of the "antenna effect" of LeClerc's conjugated
`
`polymers. TFS1006, 3:1:1; TFS1030, 2:2:1; TFS1028, 8:1:2; TFS1002, ¶¶184-185.
`
`II.
`
`Standing (37 C.F.R. § 42.104(a))
`
`Petitioners certify that the '817 patent is available for IPR and Petitioners are
`
`not barred or estopped from requesting IPR of any of the challenged claims.
`
`III. Statement of the precise relief requested and the reasons therefore
`
`The Office should institute IPR under 35 U.S.C. §§311-319, and 37 C.F.R.
`
`§§42.1-.80 and 42.100-42.123, and cancel claims 1 and 3 of the '817 patent as
`
`unpatentable under 35 U.S.C. § 103(a) for the reasons explained below. This
`
`petition is accompanied and supported by the declaration of Dr. Schanze
`
`(TFS1002), an expert in developing optical sensors containing fluorescent
`
`conjugated polymers and signaling chromophores, and using these sensors for
`
`detecting binding events. Petitioner's detailed, full statement of the reasons for
`
`relief requested is provided in §VI.
`
`IV. Overview
`A. The '817 patent disclosure and claims
`
`The '817 patent, entitled "Methods and Compositions for Detection and
`
`Analysis of Polynucleotides Using Light Harvesting Multichromophores," issued
`
`on May 1, 2018, from U.S. Appl. No. 15/473,316, which was filed on March 29,
`
`
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`

`

` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`2017, which is a reissue of U.S. Patent No. 8,841,072, filed as a U.S. Appl. No.
`
`14/086,532, filed on November 21, 2013. TFS1001, face page. The '072 patent is a
`
`continuation of and claims priority to the following U.S. Appl. Nos.: 13/544,303,
`
`filed July 9, 2012, now USPN 8,617,814, which is a continuation of 12/632,734,
`
`filed Dec. 7, 2009, now 8,227,187, which is a continuation of 11/854,365, filed
`
`Sept. 12, 2007, now 7,629,448, which is a division of 10/648,945, filed Aug. 26,
`
`2003, now 7,270,956, which claims priority benefit to Prov. Appl. No. 60/406,266,
`
`filed Aug 26, 2002.
`
`The light-harvesting multichromophore system of the '817 patent has "at
`
`least two components; (a) a cationic multichromophore, and (b) a 'sensor
`
`polynucleotide' (Oligo-C*) comprising an anionic polynucleotide conjugated to a
`
`signaling chromophore." TFS1001, 4:24-27; see also 10:65-12:58 ("The
`
`Polycationic Multichromophore"); 12:59–13:3 ("The Sensor Polynucleotide"); and
`
`15:4-15:6 ("The Signaling Chromophore"). Together, these components are used to
`
`detect target polynucleotides in a sample. Id., 8:31-9:10 ("The Sample"). Dr.
`
`Schanze prepared the graphic below to illustrate the claimed multichromophore
`
`(A); and its application in a detection method (B), as a POSA would have
`
`understood it:
`
`
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`

`

` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`
`
`
`TFS1002, ¶¶73-79.
`
`As the graphic illustrates, the signaling chromophore (C*) can be attached to
`
`a sensor polynucleotide. TFS1001, e.g., 2:3-5; 3:28-35; 12:66-67. The sensor
`
`polynucleotide "is anionic," has a "predetermined sequence," and "is
`
`complementary to the target polynucleotide to be assayed." Id. 12:60-62.
`
`According to the '817 patent, the "multichromophores used in the present invention
`
`are polycationic and can interact with a sensor polynucleotide electrostatically." Id.
`
`11:54-56.
`
`
`
`When a target polynucleotide is present in a sample, the sensor
`
`polynucleotide hybridizes to the target polynucleotide, resulting in "an increase in
`
`
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`- 8 -
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`

`

` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`negative charge density along the DNA strand." Id. 3:65-66. Electrostatic
`
`interactions between the thus-formed negatively-charged duplex DNA and the
`
`positively-charged conjugated polymer bring the conjugated polymer into a close
`
`proximity to the signaling chromophore (C*). Id. 3:67–4:4. This close proximity
`
`results in energy transfer (labeled "FRET" in (B), which stands for "Forster
`
`Resonance Energy Transfer") from the conjugated polymer to the signaling
`
`chromophore (C*). Id. Emission of light from the excited chromophore indicates
`
`the presence of the target polynucleotide in the sample. Id. 4:14-19.
`
`The '817 patent claims. The '817 patent has twelve claims. Claim 1 is the
`
`only independent claim, and recites:
`
`1. A light harvesting multichromophore system, the system
`comprising:
`
`i) a signaling chromophore in solution; and
`
`ii) 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.
`
`TFS1001, 23:2-13.
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` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`B. Person of ordinary skill in the art ("POSA")
`
`A POSA is a hypothetical person who is presumed to be aware of all
`
`pertinent art, thinks along conventional wisdom in the art, and is a person of
`
`ordinary creativity. A POSA in the technical field of the '817 patent (conjugated
`
`polymer energy transfer detection systems) would have had knowledge of the
`
`scientific literature concerning methods of synthesizing fluorescent conjugated
`
`polymers and signaling chromophores, and using these polymers and
`
`chromophores for detecting binding events. TFS1002, ¶11.
`
`Here, a POSA would typically have had (i) a Ph.D. in Chemistry, or in 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 or 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., ¶12.
`
`C. State of the art
`
`By August 2002 researchers were regularly using sensing systems based on
`
`the theory of Förster resonance energy transfer (also called fluorescence resonance
`
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` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`energy transfer; "FRET") for the detection of analytes. TFS1019, 3; TFS1002,
`
`¶13. FRET involves energy transfer between two chromophores: a donor
`
`chromophore and an acceptor chromophore.
`
`In a FRET-based system, a donor chromophore is excited by light radiation
`
`at a certain wavelength. When an acceptor chromophore is in close proximity to
`
`the donor, the excited donor transfers energy to the acceptor through a dipole-
`
`dipole interaction. The excited acceptor then dissipates this excess energy either
`
`by a fluorescence emission of light or as heat. TFS1019, 3; TFS1002, ¶14. The
`
`figure below, which was prepared by Dr. Schanze, illustrates a POSA's
`
`understanding of a typical FRET-based system:
`
`Donor
`
`Acceptor
`
`
`
`In a FRET system, the donor chromophore and acceptor chromophore each
`
`have different spectra wavelengths at which each chromophore absorbs and emits
`
`radiation. TFS1002, ¶15. For FRET to occur, the emission spectrum of the donor
`
`must overlap with the absorption spectrum of the acceptor, as shown
`
`schematically below. When there is overlap, excitation within the donor
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` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`absorption spectrum causes a signal in the acceptor emission spectrum. TFS1018,
`
`4:1; TFS1019, 3; TFS1002, ¶16.
`
`
`
`TFS1002, ¶16. Thus, as Dr. Schanze confirms, a POSA in August 2002 would
`
`have known that a FRET-based system has only two basic requirements: (i) the
`
`donor and the acceptor are in close enough proximity to each other for energy
`
`transfer, and (ii) the donor emission spectrum overlaps with the acceptor
`
`absorption spectrum. TFS1002, ¶¶13-18.
`
`The field had described a variety of small-molecule fluorescent dyes, many
`
`of which were commercially available, for use in various FRET systems by
`
`August 2002. TFS1013, 9:36-45; TFS1003, Abstract; TFS1005, 3:2:1; TFS1014,
`
`Tables 1 and 2; TFS1015, 55: Example 8; TFS1016, Abstract; TFS1017, Table 1;
`
`TFS1002, ¶19. As Dr. Schanze explains, selection of donor and acceptor dyes was
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` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`routine well before 2002—all that was needed was an overlap between the
`
`acceptor emission spectrum and the donor absorption spectrum, and a
`
`physicochemical compatibility of the two (e.g., aqueous solubility). TFS1018,
`
`4:1:1; TFS1019, 3:2:1; TFS1002, ¶16-22. As a rule of thumb, in matching a donor
`
`to an acceptor, researchers looked to maximize overlap in emission/absorption
`
`spectra for best FRET signal. TFS1018, 4:1:1; TFS1019, 3:2:1; TFS1002, ¶¶16-
`
`22,123.
`
`In addition to small molecule dyes, fluorescent conjugated polymers were
`
`becoming increasingly popular as donors in FRET systems by August 2002.
`
`TFS1002, ¶27; see also, TFS1005, 3:1:1; TFS1004, 4:24-29; TFS1021, 4:1:1;
`
`TFS1006, 3:1:1; TFS1022, 3:1:1; and TFS1028, 8:1:1. Conjugated polymers are
`
`polymeric molecules composed of multiple monomeric subunits having
`
`alternating single and multiple bonds (i.e., double or triple bonds) that form a
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`system of connected atomic orbitals. TFS1002, ¶27. As Dr. Schanze explains, this
`
`arrangement allow electrons to be delocalized over the length of the polymers.
`
`TFS1002, ¶¶28-29. Because of the delocalized electronic structure and the
`
`presence of multiple chromophoric monomers, conjugated polymers are able to
`
`harvest light energy and transmit it along the length of the polymer. See, e.g.,
`
`TFS1028, 8:1:1; TFS1006, 3:1:1; TFS1024, 1-2; TFS1030, 2:2:2-3:1:2; TFS1002,
`
`¶¶27-29. If there is another chromophore in energy transferring proximity to an
`
`
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` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`excited conjugated polymer, the polymer can transfer the energy to the
`
`chromophore, e.g., via FRET. This energy transfer along the polymeric chain was
`
`known in the art as the "antenna effect" or "molecular wire effect." TFS1002,
`
`¶¶30-33.
`
`By August 2002, researchers had demonstrated that this "molecular wire
`
`effect" results in an amplified energy transfer between a conjugated polymer and
`
`another chromophore. TFS1006, 3:1:1; TFS1030, 2:2:1; TFS1028, 8:1:1;
`
`TFS1002, ¶56. What is more, it was known that when a conjugated polymer
`
`transfers energy to another chromophore, that chromophore's emission is
`
`increased compared to direct excitation of the chromophore. TFS1030, 2:2:2-
`
`3:1:2; TFS1002, ¶56. Indeed, the field had demonstrated the antenna effect in
`
`FRET systems prior to August 2002. For example, McQuade demonstrated a
`
`significant increase in acceptor fluorescence obtained by excitation of a
`
`conjugated polymer donor compared the fluorescence of the directly excited
`
`acceptor. TFS1005, 4:1:3; TFS1002¶¶59-60. Harrison also demonstrated a
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`significant increase in acceptor fluorescence following excitation of a conjugated
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`polymer donor. TFS1006, 3:1:1; TFS1002, ¶¶61-63.
`
`As the signal obtained from FRET is highly dependent on the distance
`
`between the donor and acceptor, researchers recognized the usefulness of FRET in
`
`detecting the binding of biological molecules in the 1970s and began using FRET
`
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` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`for studying protein-protein interactions. TFS1019, 3; TFS1002, ¶18. Developing
`
`on the protein-protein systems, researchers began to use FRET to measure nucleic
`
`acid binding (i.e., hybridization) in the mid-1980s. TFS1019, 5-15; TFS1002, ¶18.
`
`By August 2002, biosensing FRET systems had been developed for
`
`detection of various biological molecules, including nucleic acids. TFS1002, ¶¶18,
`
`47-55; see also, TFS1015, 3:2; TFS1014, 2:7-10; TFS1003, Abstract; TFS1004,
`
`3:6-10; TFS1013, 1:20-23. These biosensing FRET systems comprised energy
`
`transfer from dye to dye (TFS1003, 2:2:2, Figure 1; TFS1013, Figure 1, 8:39-
`
`9:47, TFS1015, 4, Example 8 ), from conjugated polymer to dye (TFS1014,
`
`Example 2; TFS1015, Example 10) or from conjugated polymer to quencher
`
`(TFS1025, Abstract, Figure 2; TFS1029, Examples 1, 4 and 5).
`
`V. Claim construction
`
`Except for the constructions set forth below, the terms of the '817 patent
`
`claims are to be given their plain and ordinary meaning as understood by a POSA.
`
`A. The Office has determined in a related patent that the term
`"direct excitation" is indefinite
`
`Every claim of the '817 patent requires that the conjugated polymer transfer
`
`energy 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." TFS1001; 23:2-13. But, during prosecution of the related '799
`
`patent (TFS1007), the Office rejected the following claim for being indefinite:
`
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` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`
`21. A method comprising:
`
`(a) contacting a sample with light harvesting multichromophore
`system, the system comprising:
`
`i) a signaling chromophore; and
`
`ii) a water-soluble conjugated polymer comprising a
`delocalized electronic structure, wherein the polymer can
`transfer 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;
`
`(b) applying a light source to the sample; and
`
`(c) detecting whether light is emitted from the signaling
`chromophore.
`
`TFS1008, 3, 113 (emphasis added). The Examiner stated that the claim is "vague
`
`and indefinite because it is unclear what the phrase "direct excitation" means. It is
`
`unclear of what is directly excited and how." Id., 113 In response, Patent Owner
`
`did not argue that a POSA could have deciphered a plain and ordinary meaning of
`
`the phrase "direct excitation." Id., 125. Instead, Patent Owner amended the claim to
`
`specify "direct excitation of the signaling chromophore in the absence of a
`
`polymer." Id., 123 (emphasis in original). After the amendment, the Examiner
`
`withdrew the rejection. Id., 140. Thus, the Office previously determined that the
`
`claim reciting "direct excitation," without more explanation, is indefinite.
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` Petition for Inter Partes
`Review of U.S. Patent No. RE46,817
`Patent Owner knew that the Office considered the claim term "direct
`
`excitation" indefinite when it filed the rei