Filed September 10, 2018
`
`
`On behalf of:
`
`Patent Owner The Regents of the University of California
`By: Kerry S. Taylor
`
`Ryan E. Melnick
`
`Maria V. Stout
`
`KNOBBE, MARTENS, OLSON & BEAR, LLP
`
`2040 Main Street, 14th Floor
`
`Irvine, CA 92614
`
`Tel.: (949) 760-0404 Fax: (949) 760-9502
`
`Email: BoxUC@knobbe.com
`
`
`
`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 No. IPR2018-01156
`U.S. Patent RE46,817
`__________________________________
`
`PATENT OWNER PRELIMINARY RESPONSE TO PETITION
`
`
`
`
`
`On behalf of:
`
`Patent Owner The Regents of the University of California
`By: Kerry S. Taylor
`
`Ryan E. Melnick
`
`Maria V. Stout
`
`KNOBBE, MARTENS, OLSON & BEAR, LLP
`
`2040 Main Street, 14th Floor
`
`Irvine, CA 92614
`
`Tel.: (949) 760-0404 Fax: (949) 760-9502
`
`Email: BoxUC@knobbe.com
`
`
`
`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 No. IPR2018-01156
`U.S. Patent RE46,817
`__________________________________
`
`PATENT OWNER PRELIMINARY RESPONSE TO PETITION
`
`
`
`
`TABLE OF CONTENTS
`
`Page No.
`
`INTRODUCTION ........................................................................................... 1
`I.
`II. THE PERSON OF ORDINARY SKILL ........................................................ 4
`III. CLAIM CONSTRUCTION ............................................................................ 4
`A.
`“direct excitation” .................................................................................. 4
`B.
`“multichromophore system” ................................................................. 6
`IV. RESPONSE TO GROUND 1: CARDULLO IN COMBINATION
`WITH MCQUADE AND LECLERC DOES NOT RENDER
`INDEPENDENT CLAIMS 1 AND 3 OBVIOUS ........................................... 7
`A.
`Introduction to Cardullo, McQuade, and LeClerc ................................ 8
`B.
`There was no motivation to combine Cardullo with McQuade
`and and LeClerc .................................................................................. 13
`1.
`A POSA would not have replaced the small-molecule
`acridine orange in Cardullo System C with McQuade’s
`PPE polymer ............................................................................. 14
`a)
`Thermo falsely characterizes Cardullo by
`asserting that System C has a much higher
`energy transfer than System B ........................................ 14
`A POSA would not have replaced a DNA
`intercalator with a large rigid polymer ........................... 16
`Thermo distorts the meaning of Cardullo’s
`“antenna effect” in an attempt to equate it to
`delocalized electronic structures ..................................... 24
`Thermo fails to explain how McQuade’s PPE
`would distinguish between single-stranded and
`double-stranded DNA ..................................................... 29
`
`b)
`
`c)
`
`d)
`
`-i-
`
`
`
`TABLE OF CONTENTS
`(Cont’d)
`
`Page No.
`
`c)
`
`3.
`
`2. McQuade’s teachings regarding its dry thin-film pH
`sensor does not provide a motivation to combine
`McQuade with Cardullo’s solution-based DNA system .......... 32
`a) McQuade only teaches measuring FRET
`between dry films and never in solution ......................... 32
`b) McQuade’s PPE polymer would be expected to
`exhibit quenching of fluorescence in aqueous
`solution ........................................................................... 34
`The high FRET transfer efficiency observed in
`McQuade was due to a combination of features
`in its thin-film sensor, and not the mere presence
`of PPE polymer ............................................................... 37
`LeClerc does not provide a motivation to use
`McQuade’s PPE polymer in Cardullo’s System C ................... 40
`a)
`LeClerc does not utilize the principle of FRET ............. 40
`b)
`LeClerc teaches that interaction between its
`conjugated polymer and DNA decreases
`fluorescence .................................................................... 41
`Contrary to Thermo’s assertions, LeClerc
`teaches that its aggregation is detrimental ...................... 43
`LeClerc’s teachings belie Thermo’s error in
`relying on the delocalized electronic structure of
`conjugated polymers as a motivation to combine .......... 43
`
`c)
`
`d)
`
`
`
`-ii-
`
`
`
`TABLE OF CONTENTS
`(Cont’d)
`
`Page No.
`
`2.
`
`C.
`
`V. RESPONSE TO GROUND 2: CARDULLO IN COMBINATION
`WITH LECLERC AND HARRISON DOES NOT RENDER
`INDEPENDENT CLAIMS 1 AND 3 OBVIOUS ......................................... 45
`A.
`Introduction to Harrison ...................................................................... 45
`B.
`The combination of Cardullo, LeClerc, and Harrison does not
`teach or suggest all limitations of Claim 1 or Claim 3 ........................ 47
`1.
`None of the references relied on by Thermo for
`Ground 2 disclose a greater than 4-fold increase in
`fluorescence emission ............................................................... 47
`The cases cited by Thermo regarding routine
`optimization are inapplicable .................................................... 49
`There was no motivation to combine Cardullo with LeClerc
`and Harrison ........................................................................................ 54
`1.
`A POSA would not have combined LeClerc with
`Cardullo ..................................................................................... 54
`A POSA would not have replaced the small-molecule
`acridine orange in Cardullo System C with LeClerc’s
`polythiophene polymers ............................................................ 55
`LeClerc teaches that interaction between its conjugated
`polymer and DNA decreases fluorescence ............................... 58
`LeClerc’s polythiophene polymers have low quantum
`yield in solution ......................................................................... 59
`Thermo’s assertions regarding LeClerc’s
`discrimination between ssDNA and dsDNA are not
`relevant to FRET ....................................................................... 59
`
`2.
`
`3.
`
`4.
`
`5.
`
`-iii-
`
`
`
`TABLE OF CONTENTS
`(Cont’d)
`
`Page No.
`
`6.
`
`7.
`
`Thermo has not established that LeClerc’s
`polythiophene polymers would exhibit Cardullo’s
`antenna effect ............................................................................ 60
`Harrison does not provide a motivation to use
`LeClerc’s polythiophene polymers in Cardullo
`System C ................................................................................... 62
`VI. CONCLUSION .............................................................................................. 63
`
`
`
`-iv-
`
`
`
`TABLE OF AUTHORITIES
`
`Page No(s).
`
`In re Aller
`220 F.2d 454 (CCPA 1955) ................................................................................ 51
`In re Antonie
`559 F.2d 618 (CCPA 1977) ................................................................................ 52
`In re Boesch
`617 F.2d. 272 (CCPA 1980) ............................................................................... 50
`In re Gordon
`733 F.2d 900 (Fed. Cir. 1984) ........................................................................... 31
`
`In re Peterson
`315 F.3d 1325 (Fed. Cir. 2003) .......................................................................... 50
`
`In re Ratti
`270 F.2d 810 (CCPA 1959) ............................................................................... 32
`OTHER AUTHORITIES
`35 U.S.C. § 311 ...................................................................................................... 5, 6
`
`
`
`-v-
`
`
`
`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
`
`For the reasons that follow, Patent Owner The Regents of the University of
`
`California (hereinafter “UC”) submits that the Petition fails to show that there is a
`
`reasonable likelihood that the Petitioner (hereinafter “Thermo”) would prevail with
`
`respect to at least 1 of the claims of U.S. Patent RE46,817 (“the ’817 patent”)
`
`challenged in the Petition. Therefore, the Petition should be denied.
`
`I. INTRODUCTION
`
`The ’817 patent is the result of years of work and innovation by scientists at
`
`the University of California at Santa Barbara (“UCSB”) in the field of analyte
`
`detection. UCSB then licensed this technology to Becton, Dickinson and Company
`
`(“BD”), a leading manufacturer of research reagents used in biological assays. BD
`
`has leveraged UCSB’s invention to offer a powerful flow cytometry platform. BD’s
`
`customers range from academic institutions conducting basic research to innovator
`
`biopharma companies engaged in clinical development of new medical therapies.
`
`Unable to develop a viable alternative, Thermo chose to copy UCSB’s fluorescent
`
`dye system in its own flow cytometry platform. Instead of acknowledging this
`
`innovation, Thermo now attempts to avoid liability by alleging that Claims 1 and 3
`
`of the ’817 patent are unpatentable.
`
`In its Petition, Thermo cobbles together disclosures from unrelated
`
`technologies to construct a system unlike any previously conceived. As its primary
`
`reference for both asserted grounds, Thermo relies on Cardullo and its teaching
`
`- 1 -
`
`
`
`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
`
`regarding a small-molecule dye that intercalates into double-stranded DNA
`
`(“dsDNA”). Thermo makes the untenable assertion that a person of ordinary skill
`
`(“POSA”) would replace such a dye with large conjugated polymers that do not
`
`intercalate into dsDNA. Thermo never addresses the significant structural and
`
`functional differences between Cardullo’s small-molecule intercalators and large
`
`conjugated polymers. Instead, Thermo concocts a motivation absent from any
`
`evidence and based solely on hindsight. In fact, a plain reading of the references
`
`shows that there is ample reason not to combine the references.
`
`In asserting its motivation argument for Ground 1, Thermo makes false and
`
`misleading statements regarding the teachings of the asserted references. Thermo’s
`
`characterizations of Cardullo are either plainly false or a distortion. Thermo ignores
`
`that the secondary reference in Ground 1, McQuade, is directed to a thin-film system
`
`that is only used for FRET in a dry environment. It is never used for in-solution
`
`FRET measurements, as required by Cardullo. Moreover, Thermo failed to cite or
`
`address a highly relevant publication by Thermo’s own testifying witness that
`
`contradicts Thermo’s alleged motivation to combine McQuade with Cardullo.
`
`Thermo is not helped by its reliance on a third reference, LeClerc, to provide
`
`the missing motivation to combine. Thermo completely ignores that the teachings
`
`of LeClerc would actually discourage combination of McQuade with Cardullo.
`
`- 2 -
`
`
`
`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
`
`When the Petition is viewed as a whole, it is clear that Thermo repeatedly
`
`relied on hindsight bias in assembling motivations that are absent from any of the
`
`references. As such, the Petition fails to establish a reasonable likelihood of the
`
`claims being obvious under Ground 1.
`
`Thermo’s Ground 2 is insufficient on its face because the combined references
`
`of Ground 2 fail to teach or suggest all elements of the claims. Instead of relying on
`
`patents or printed publications for the claim elements, Thermo tries to rely on
`
`routine-optimization case law to fill in gaps missing in the references. However, the
`
`cases cited by Thermo are factually distinct and do not support Thermo’s theory. In
`
`fact, Thermo attempts to rely on a case that actually supports the non-obviousness
`
`of the claims. Ground 2 clearly fails to establish that all claim elements are in or
`
`suggested by the prior art, and, therefore, the Petition cannot establish a reasonable
`
`likelihood that the claims are unpatentable under Ground 2.
`
`In addition to failing to account for all claim limitations in Ground 2, Thermo
`
`also fails to establish a motivation to combine the references. Thermo once again
`
`relies on mischaracterizations of the references to find a motivation where there is
`
`none. Furthermore, Thermo ignores the teachings of LeClerc that would discourage
`
`combination with Cardullo.
`
`- 3 -
`
`
`
`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
`
`For all of these reasons, the Petition fails to establish a reasonable likelihood
`
`that the claims are obvious under Ground 1 or Ground 2. Accordingly, the Board
`
`should deny institution of Thermo’s Petition.
`
`II. THE PERSON OF ORDINARY SKILL
`
`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.
`
`III. CLAIM CONSTRUCTION
`
`Thermo proposes claim constructions of two terms. But Thermo never
`
`indicates how those constructions relate to the grounds asserted in the Petition. To
`
`the contrary, neither construction is required for the Board to evaluate Thermo’s
`
`grounds. Thermo’s proposed constructions are simply an invitation to the Board to
`
`issue advisory opinions on constructions of terms that might be helpful to Thermo
`
`in future proceedings. Neither construction is required for the Board to evaluate
`
`Thermo’s grounds. Nevertheless, because both of Thermo’s constructions are
`
`incorrect, UC provides the following comments.
`
`A.
`
`“direct excitation”
`
`Thermo alleges that the term “direct excitation” in Claim 1 is indefinite.
`
`Thermo asserts the term is indefinite because it “is unclear of what is directly excited
`
`- 4 -
`
`
`
`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
`
`and how.” Petition at 17. Indefiniteness is not a ground for inter partes review and
`
`the Board need not opine on Thermo’s assertion in order to reach its institution
`
`decision. 35 U.S.C. § 311(b).
`
`In any case, Claim 1 is clear on its face, reciting that the claimed polymer
`
`“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.” Ex-1001 at Claim 1
`
`(emphasis added). Thus, the referenced “direct excitation” is clearly direct
`
`excitation of the “signaling chromophore.”
`
`One of Thermo’s own cited references, McQuade, uses the exact same term
`
`in the exact same way. Ex-1005 at 12390, col. 1.1 Specifically, in discussing energy
`
`transfer from a donor polymer to an acceptor dye (FA) in a dry thin film, McQuade
`
`
`
`1 Throughout the Petition, Thermo uses a confusing, and often incorrect,
`
`method for citing to the references that requires the Board and UC to play
`
`archeologist with the record searching the entire reference for the cited text. For
`
`example, Thermo uses an unexplained “x:y:z” citation scheme for numerous
`
`references, and UC is unable to verify the accuracy of those indecipherable
`
`citations. Rather
`
`than adopt Thermo’s obtuse citation method, UC has
`
`independently cited the references according to standard conventions.
`
`- 5 -
`
`
`
`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
`
`notes that “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. (emphasis added). Thermo appears to understand this term when used by
`
`McQuade because Thermo repeatedly relies on this sentence throughout its Petition.
`
`See, e.g., Petition at 3, 4, 27, 35, and 41. As demonstrated by McQuade and
`
`Thermo’s reliance thereon, a POSA would have no difficulty in understanding the
`
`meaning of “direct excitation” in Claim 1.
`
`B.
`
`“multichromophore system”
`
`Thermo asserts that the term “multichromophore system” in Claim 1 should
`
`be construed as “a polycationic multichromophore.” Petition at 19. As a first matter,
`
`neither of Thermo’s grounds rely on this narrowing construction. Thus, there is no
`
`need for the Board to construe the term “multichromophore system” in reaching its
`
`institution decision.
`
`Furthermore, the proposed narrowing construction is unwarranted. The term
`
`“polycationic” is absent from Claim 1. Ex-1001 at Claim 1. Contrary to Thermo’s
`
`assertions, the specification of the ’817 patent does not equate a “multichromophore”
`
`with “a polycationic multichromophore.” Indeed, the specification provides several
`
`examples of “multichromophore systems,” including
`
`conjugated polymers, aggregates of conjugated molecules, luminescent
`dyes attached to saturated polymers, semiconductor quantum dots and
`dendritic structures.
`
`- 6 -
`
`
`
`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
`
`Id. at 11:1-5. None of these examples are restricted to being polycationic. With
`
`respect to conjugated polymers, the ’817 patent merely states that
`
`[c]onjugated polymers (CPs) are characterized by a delocalized
`electronic structure and can be used as highly responsive optical
`reporters for chemical and biological targets.
`
`Id. at 11:34-37. Thus, the specification does not imply that the claimed
`
`“multichromophore” must be polycationic, and Thermo’s importation of this
`
`limitation from one embodiment of the specification into the claims is
`
`impermissible.
`
`IV. RESPONSE TO GROUND 1: CARDULLO IN COMBINATION
`WITH MCQUADE AND LECLERC DOES NOT RENDER
`INDEPENDENT CLAIMS 1 AND 3 OBVIOUS
`
`In Ground 1, Thermo argues that Claims 1 and 3 would have been obvious
`
`over the combination of Cardullo with McQuade and LeClerc. Petition at 21.
`
`Specifically, Thermo argues that it would have been obvious to replace a small
`
`molecule intercalating dye in Cardullo with a large conjugated polymer disclosed in
`
`McQuade. Petition at 30. However, Thermo cannot credibly cite to anything in the
`
`references themselves that would have motivated a POSA to make this replacement.
`
`Instead, Thermo concocts a motivation from false and misleading characterizations
`
`of the asserted references, and Thermo ignores teachings in the asserted references,
`
`as well the work of its own witness, that would discourage attempting such a
`
`replacement.
`
`- 7 -
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`
`
`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
`
`A.
`
`Introduction to Cardullo, McQuade, and LeClerc
`
`Cardullo
`
`Cardullo is directed to using small molecule donor and acceptor fluorophores
`
`to study nucleic acid hybridization via “nonradiative fluorescence resonance energy
`
`transfer (FRET).” Ex-1003 at 8790, col. 1. FRET is transfer of “excited-state energy
`
`of the donor molecule” to the acceptor molecule by a “resonance dipole-induced
`
`dipole interaction.” Id. The result includes “an enhancement of acceptor [molecule]
`
`fluorescence intensity.” Id. Thus, when the donor molecule is excited by absorbing
`
`light the acceptor molecule fluoresces due to energy transfer from the donor.
`
`Cardullo describes three approaches using FRET to study nucleic acid
`
`hybridization. These three approaches are illustrated in Figure 1 of Cardullo, which
`
`is reproduced below with annotations:
`
`- 8 -
`
`
`
`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
`
`Non-hybridized DNA
`
`Hybridized DNA
`
`System A
`
`System B
`
`System C
`
`fluorescein
`
`rhodamine
`
`acridine
`orange
`
`Ex-1003 at 8791, col. 1 (annotated). These techniques will hereinafter be referred
`
`to as “Cardullo System A” (Fig. 1a), “Cardullo System B” (Fig. 1b), and “Cardullo
`
`System C” (Fig. 1c).2 In Cardullo System A, a donor fluorescein molecule was
`
`attached to the 5’ end of one oligodeoxynucleotide and an acceptor rhodamine
`
`
`
`2 To maintain consistency, Patent Owner uses the System “A”, “B”, and “C”
`
`nomenclature used by Thermo to refer to Cardullo’s Figure 1a, 1b, and 1c,
`
`respectively.
`
`- 9 -
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`
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`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
`
`molecule was attached to the 5’ end of a complementary oligodeoxynucleotide. Id.
`
`at 8790, col. 1, and 8791, col. 2. In Cardullo System B, three oligodeoxynucleotide
`
`strands were used. Two shorter strands were labeled with a donor fluorescein
`
`molecule at the 5’ end or an acceptor rhodamine molecule at the 3’ end. Id. at 8790,
`
`col. 1, and 8792, col. 2. A longer unlabeled complementary 29-mer was used as the
`
`third strand. Id. In Cardullo System C, two complementary oligodeoxynucleotide
`
`strands were used, one unlabeled and one labeled at the 5’ end with acceptor
`
`molecule rhodamine. Id. at 8790, col. 1, and 8792, col. 2 to 8793, col. 1. The
`
`intercalating dye acridine orange was used as a donor molecule. Id. Fluorescence
`
`measurements were made of each system to determine FRET transfer efficiency
`
`from donor
`
`to
`
`acceptor upon hybridization of
`
`the
`
`complementary
`
`oligodeoxynucleotide strands. Id. at 8791, col. 1 to 8793, col. 1.
`
`- 10 -
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`
`
`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
`
`McQuade
`
`McQuade is directed to a thin film pH sensor that is only used to detect
`
`fluorescence after drying of the thin film. Ex-1005 at 12390, col. 1.3 The thin films
`
`were constructed on glass slides by layer-by-layer deposition of a cationic poly(p-
`
`phenylene ethynylene) (“PPE”) polymer and an anionic polyacrylate polymer, which
`
`contained an appended fluoresceinamine dye. Id. at 12389, col. 1-2, and Ex-2001 at
`
`S-1. The constructed sensor was immersed in solutions of varying pH, completely
`
`dried after removal from solution, and then fluorescence was measured in dry air
`
`upon excitation of the PPE polymer at 420 nm. Id. at 12390, col. 1; Ex-2001 at S-1.
`
`No fluorescence was ever measured in solution.
`
`LeClerc
`
`LeClerc is directed to using polythiophene polymers with oligonucleotides in
`
`a “single reagent assay” that “does not require nucleic acid functionalization.” Ex-
`
`1004 at 4:14-15 and 11:24-25. None of LeClerc’s methods use the principle of
`
`
`
`3 Although Thermo provided a copy of McQuade as Ex-1005, it neglected to
`
`include the Supplementary Materials that are part of the McQuade reference.
`
`Accordingly, the Supplementary Materials of McQuade are provided as Ex-2001.
`
`These Supplementary Materials contain various experimental details omitted by
`
`Thermo in its Petition.
`
`- 11 -
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`
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`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
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`FRET. Only the “single reagent” of the polymer is present—none of LeClerc’s
`
`methods include a donor and acceptor molecule, as is required for FRET. LeClerc’s
`
`invention is “based on the different electrostatic interactions and conformational
`
`structural changes between single-stranded or double-stranded negatively-charged
`
`oligonucleotides or nucleic acid fragments, and cation electroactive and photo active
`
`poly(3-alkoxy-4-methylthiophene) derivatives.” Id. at 11:20-24.
`
`Different conformational structures of the polymer in a “duplex” form
`
`(polymer bound
`
`to single-stranded oligonucleotide and having a “planar
`
`conformation”) and a “triplex” form (polymer bound
`
`to double-stranded
`
`oligonucleotide and having a “non-planar conformation”) result in different
`
`“colorimetric effects.” 4 Id. at 15:13 to 16:11. For example, in the absence of
`
`oligonucleotide, one of LeClerc’s polymers in solution was yellow in color. Id. at
`
`15:10-11. This color was associated with “a random coil conformation” of the
`
`polymer. Id. at 15:12-13. After addition of an oligonucleotide, the mixture became
`
`red due to the formation of a “duplex.” Id. at 15:13-16. After mixing
`
`complementary oligonucleotide, the solution became yellow again due to the
`
`
`
`4 A “colorimetric effect” (i.e., the observed color of the polymers) is a
`
`characteristic of an absorption spectrum.
`
`- 12 -
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`
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`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
`
`formation of a “triplex.” Id. at 15:16-19. The various conformations and complexes
`
`are depicted in Figure 6, reproduced below with annotations:
`
`ssDNA
`
`Polythiophene
`
`dsDNA
`
`
`
`Id. at Figure 6 (annotated).
`
`B.
`
`There was no motivation to combine Cardullo with McQuade and
`LeClerc
`
`Contrary to Thermo’s assertion, a POSA would have lacked motivation to
`
`combine the teachings of Cardullo with those of McQuade and LeClerc. First,
`
`Cardullo’s small-molecule acridine orange is drastically different in structure and
`
`function than McQuade’s PPE polymer, and there is no basis to consider these
`
`distinct compositions interchangeable with each other. Second, McQuade’s thin
`
`film sensor is designed for FRET measurement only in a dry environment, not in
`
`- 13 -
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`
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`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
`
`solution, and its fluorescent characteristics can be attributed to its unique thin film
`
`structure. Third, LeClerc does not supply the missing motivation, and would
`
`actually discourage a POSA from pursuing the proposed combination.
`
`1.
`
`A POSA would not have replaced the small-molecule acridine
`orange in Cardullo System C with McQuade’s PPE polymer
`
`Thermo argues that a POSA would have been motivated to replace the
`
`multiple intercalating dyes in Cardullo System C with the PPE polymer of McQuade.
`
`Petition at 30. Such a position is untenable. A plain reading of these references
`
`provides ample reason why a POSA would not have made this replacement.
`
`a)
`
`Thermo falsely characterizes Cardullo by asserting that
`System C has a much higher energy transfer than System B
`
`Thermo distorts the teachings of Cardullo by mischaracterizing the Cardullo
`
`FRET system that has the highest energy transfer, System B. Thermo states:
`
`A POSA would have had a reason to modify Cardullo’s FRET system
`“C” because a POSA would have understood that system “C” was
`simpler and more sensitive than the alternative “A” and “B” formats . .
`. . Indeed Cardullo showed that system “C” had a much higher energy
`transfer than “A” and “B”—“by a factor of ≈ 2.”
`
`Petition at 31. This is a plainly false characterization of Cardullo. In direct
`
`contradiction to Thermo, Cardullo repeatedly states that System B had a higher
`
`transfer efficiency than System C, including in the Abstract, the description of
`
`experimental results, and in Table 2. Cardullo observed that the “transfer efficiency”
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`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
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`from fluorescein to rhodamine in System B was “about 0.6.” Ex-1003 at 8792, col.
`
`2. In contrast, with System C, Cardullo observed a “transfer efficiency” of “0.52.”
`
`Id. at 8793, col. 1. These results are clearly presented in Table 2 of Cardullo,
`
`reproduced below with annotations:
`
`System B
`
`System C
`
`Transfer
`efficiency
`
`
`
`Id. at Table 2 (annotated). Yet, inexplicably, Thermo asserts that System C “had a
`
`much higher energy transfer than . . . ‘B’ . . . ” Petition at 31. Cardullo directly
`
`contradicts Thermo’s assertions—Cardullo System B exhibited a higher energy
`
`transfer than Cardullo System C.
`
`A simple reading of Cardullo makes it abundantly clear that the statement
`
`regarding enhanced transfer efficiency “by a factor of ≈2,” which was misquoted by
`
`Thermo, is actually comparing System A with System C. Cardullo reports that
`
`System C showed a “transfer efficiency [of] 0.52,” while System A “gave a transfer
`
`efficiency of only 0.22.” Ex-1003 at 8793, col. 1. Cardullo concludes that System
`
`C enhanced “transfer efficiency by a factor of ≈2 in the 12-mer” compared to System
`
`A. Id. As detailed above, Cardullo’s System B showed the highest transfer
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`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
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`efficiency. Thus, Thermo’s statement that Cardullo’s System C had a much higher
`
`energy transfer efficiency than System B, by a factor of ≈2, is demonstrably false
`
`and a blatant misquotation of Cardullo. Rather, a POSA considering Cardullo would
`
`conclude that System B had the highest energy transfer and provided the most
`
`sensitive platform. Thus, if a POSA were to attempt improving upon the teachings
`
`of Cardullo, they would select the single-dye System B for modification, and not the
`
`multiple-dye System C as alleged by Thermo. And there would be no basis, and
`
`Thermo provides none, to modify System B with McQuade’s PPE polymer.
`
`b) A POSA would not have replaced a DNA intercalator with a
`large rigid polymer
`
`Even if a POSA would have selected the less-sensitive Cardullo System C for
`
`further modification, the POSA would not have been motivated to replace the small
`
`molecule intercalating acridine orange dye with the large PPE polymer of McQuade.
`
`The manner in which acridine orange interacts with DNA is unique and distinct from
`
`PPE, and the structure of acridine orange is completely different from PPE.
`
`Acridine orange works in Cardullo by intercalating into double-stranded
`
`nucleic acids. Ex-1003 at 8790, col. 1. DNA intercalators, such as acridine orange,
`
`preferentially bind with double-stranded DNA by stacking between base pairs of
`
`double-stranded DNA. Ex-2002 at 88 (“the planar chromophore is sandwiched in
`
`between the base pairs of the double helix”). This interaction is illustrated by the
`
`following molecular model:
`
`- 16 -
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`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
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`Acridine orange
`
`DNA base pairs
`
`
`
`Id. at Figure 4c (annotated) (determined using single crystal X-ray studies). Thus,
`
`acridine orange can be used to detect hybridization events by inserting into the
`
`double strand. This feature is illustrated by Figure 1c of Cardullo, reproduced below
`
`with annotations:
`
`Non-hybridized DNA
`
`Hybridized DNA
`
`Unbound
`acridine orange
`
`Rhodamine
`
`Base pair
`
`DNA strand
`
`Intercalated
`acridine orange
`
`
`
`Ex-1003 at Figure 1c (annotated). When mixed with non-hybridized (single-
`
`stranded) DNA, the donor acridine orange molecules move freely in solution and are
`
`- 17 -
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`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
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`not in close proximity to the acceptor rhodamine molecule (left diagram of Figure
`
`1c). Once the strands of DNA hybridize to form double-stranded DNA, the acridine
`
`orange molecules intercalate between the DNA base pairs, bringing at least some of
`
`the donor acridine orange molecules into close proximity to the rhodamine acceptor
`
`molecule (right diagram of Figure 1c). As Thermo acknowledges, this results in
`
`significant FRET transfer from a single acridine orange donor to the rhodamine
`
`acceptor, but only when the acridine orange intercalates. Petition at 40 (“Cardullo
`
`demonstrated that DNA hybridization brings donor and acceptor ‘sufficiently close
`
`to allow resonance energy transfer’ . . . . Indeed, under conditions that prevent DNA
`
`hybridization (high temperature), Cardullo did not observe significant energy
`
`transfer.”).
`
`Acridine orange has a molecular weight of 265.4 g/mol and the following
`
`chemical structure:
`
`
`
`This small molecule is of appropriate size to intercalate between DNA base pairs as
`
`illustrated above in Figure 4c of Ex-2002. In contrast, the PPE polymer described
`
`in McQuade would not similarly intercalate into double-stranded DNA due to its
`
`large size and rigid geometry.
`
`McQuade describes the synthesis of its PPE polymer in its Supplementary
`
`Materials. Ex-2001 at S-2 to S-3. The synthesized polymer had a number average
`
`- 18 -
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`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
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`molecular weight of 67,000 g/mol (“Mn=67,000”), over 250-fold higher than that of
`
`acridine orange. Id. at S-3. Thus, a typical single molecule of McQuade’s PPE has
`
`the structure shown below, extending across several pages.5
`
`
`
`5 The depicted structure contains 94 monomers having a molecule weight of
`
`710.71 g/mol each for a total molecular weight of 66,808.74 g/mol.
`
`- 19 -
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`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
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`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
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`- 21 -
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`
`
`
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`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
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`- 22 -
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`Thermo Fisher v. UC Regents
`Patent RE46,817 - IPR2018-01156
`
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