`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
`
`OXFORD NANOPORE TECHNOLOGIES, INC.
`
`Petitioner
`
`v.
`
`PACIFIC BIOSCIENCES OF CALIFORNIA, INC.
`
`Patent Owner
`
`____________
`
`Case No. Unassigned
`
`Patent 9,678,056
`
`____________
`
`PETITION FOR INTER PARTES REVIEW OF CLAIMS 1-16
`
`OF U.S. PATENT NO. 9,678,056
`
`
`
`
`
`
`
`
`
`
`
`- i -
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ............................................................................................ 1
`
`A. Summary of Unpatentability Grounds ............................................................... 1
`
`II. MANDATORY NOTICES, STANDING AND FEES .................................. 1
`
`A. Mandatory Notices ............................................................................................. 1
`
`B. Certification of Grounds for Standing ............................................................... 2
`
`C. Fees .................................................................................................................... 2
`
`III. STATE OF THE ART ..................................................................................... 3
`
`A. Sequencing Nucleic Acids using Nanopores and Molecular Motors ................ 3
`
`B. Kinetics of Molecular Motors ............................................................................ 6
`
`IV. OVERVIEW OF THE ’056 PATENT ........................................................... 6
`
`A. Overview of the Subject Matter of the ’056 Patent ........................................... 6
`
`B. Overview of the Prosecution History ................................................................. 8
`
`V. LEVEL OF ORDINARY SKILL IN THE ART ......................................... 12
`
`VI. SUMMARY OF PRIOR ART ...................................................................... 12
`
`A. Nanopore Sequencing using Molecular Motors was Known in the Art Prior to
`
`the Earliest Priority Date Claimed by the ’056 Patent ............................................. 12
`
`B.
`
`It Was Well Known That Polymerases and Helicases Exhibit At Least Two
`
`Kinetic Steps with Ratios of 10:1 to 1:10 ................................................................ 14
`
`
`
`
`- ii -
`
`
`
`
`
`
`
`VII. CLAIM CONSTRUCTION .......................................................................... 18
`
`VIII. THERE IS A REASONABLE LIKELIHOOD THAT THE
`
`CHALLENGED CLAIMS ARE UNPATENTABLE ......................................... 21
`
`A. Ground 1: Claims 1-5, 10-12 and 15-16 are anticipated by Akeson ............... 21
`
`B. Ground 2: Claims 1-2, 4 and 8-16 are obvious over Akeson and Hanzel ....... 32
`
`C. Ground 3: Claims 1-3 and 5-16 are obvious over Akeson and Liao ............... 41
`
`D. Ground 4: Claims 1-3, 5-10, and 12-16 are obvious over Akeson and
`
`Adelman ................................................................................................................... 52
`
`IX. CONCLUSION .............................................................................................. 62
`
`
`
`
`
`
`- iii -
`
`
`
`
`
`
`
`
`
`
`LIST OF EXHIBITS
`
`Exhibit No.
`
`Description
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`U.S. Patent No. 9,678,056
`
`Expert Declaration of Dr. Teakjip Ha
`
`Curriculum Vitae of Dr. Teakjip Ha
`
`U.S. Patent Application Publication No. 2006/0063171
`
`(“Akeson”)
`
`U.S. Patent Application Publication No. 2007/0196846 (“Hanzel”)
`
`Liao et al., Journal of Molecular Biology 350:452-475 (2005)
`
`(“Liao”)
`
`Declaration of Dr. Sylvia Hall-Ellis
`
`Second Declaration of Dr. Sylvia Hall-Ellis
`
`U.S. Patent No. 5,795,782 to Church et al. (“Church”)
`
`Prosecution History of U.S. Patent No. 9,678,056
`
`Prosecution History of U.S. Patent No. 8,133,672
`
`U.S. Patent No. 8,133,672
`
`Adelman et al., “Mechanochemistry of Transcription Termination
`
`Factor Rho,” Mol. Cell 22:611-612 (“Adelman”)
`
`- iv -
`
`
`
`
`
`
`
`I. INTRODUCTION
`
`Oxford Nanopore Technologies, Inc. (“Oxford” or “Petitioner”) requests
`
`inter partes review (“IPR”) under 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42.100 et
`
`seq. of Claims 1-16 of U.S. Patent No. 9,678,056 (“the ’056 Patent”).
`
`Petitioner asserts that there is a reasonable likelihood that the challenged
`
`claims are unpatentable and requests review of, and cancellation of, the challenged
`
`claims under 35 U.S.C. § 102 or 35 U.S.C. § 103 as outlined herein.
`
`A. Summary of Unpatentability Grounds
`
`Ground
`
`Summary
`
`1
`
` 2
`
`3
`
`4
`
`Claims 1-5, 10-12, and 15-16 are anticipated by Akeson
`
`Claims 1-2, 4 and 8-16 are obvious over Akeson and Hanzel
`
`Claims 1-3 and 5-16 are obvious over Akeson and Liao
`
`Claims 1-3, 5-10 and 12-16 are obvious over Akeson and Adelman
`
`
`II. MANDATORY NOTICES, STANDING AND FEES
`
`A. Mandatory Notices
`
`Real Party in Interest: The real party in interest is Oxford Nanopore
`
`Technologies, Inc. Out of an abundance of caution, Petitioner also identifies
`
`Oxford Nanopore Technologies, Ltd., the parent company of Oxford Nanopore
`
`Technologies, Inc., and Metrichor Ltd., a corporate affiliate of Oxford Nanopore
`
`Technologies, Inc., as parties of interest.
`- 1 -
`
`
`
`
`
`
`
`
`
`Related Matters: The ’056 Patent is subject to a pending lawsuit entitled
`
`Pacific Biosciences of California, Inc., v. Oxford Nanopore Technologies, Inc.,
`
`which was consolidated into actions 1:17-cv-00275-LPS, 1:17-cv-01353-LPS (D.
`
`Del.), in which Petitioner Oxford Nanopore Technologies, Inc. is a defendant.
`
`Lead Counsel: Lead Counsel is Steven Lendaris (Reg. No. 53,202) and
`
`Back-up Counsel is Carolyn Pirraglia (Reg. No. 75,365), each of Baker Botts
`
`L.L.P.
`
`Service Information: Baker Botts L.L.P., 30 Rockefeller Plaza, 45th Floor,
`
`New York, NY 10112; Tel. (212) 408-2500; Fax (212) 408-2501. Petitioners
`
`consent to service by electronic mail at Oxford056IPR@bakerbotts.com. Powers
`
`of Attorney are filed concurrently herewith under 37 C.F.R. § 42.10(b).
`
`B. Certification of Grounds for Standing
`
`Petitioner certifies that the ’056 Patent is available for IPR. Petitioner is not
`
`barred or estopped from requesting IPR of the ’056 Patent.
`
`C.
`
`Fees
`
`The Office is authorized to charge any fees that become due in connection
`
`with this Petition to Deposit Account No. 02-0384, Ref. No. 078288.0147, as well
`
`as any additional fees that might be due in connection with this Petition.
`
`
`
`
`- 2 -
`
`
`
`
`
`
`
`III. STATE OF THE ART
`A.
`Sequencing Nucleic Acids using Nanopores and Molecular Motors
`One of the techniques used for sequencing of nucleic acids is nanopore
`
`sequencing. A nanopore sequencing system is illustrated in Figure 1 of U.S. Patent
`
`No. 5,795,782 to Church et al. (“Church”; Ex. 1009), which issued on August 18,
`
`1998, and is § 102(b) prior art:
`
`
`
`Ex. 1009, Figure 1.
`
`In such a system, two chambers are connected through a nanopore—a hole with a
`
`diameter on the order of one nanometer—embedded in a substrate. Id., 1:40-2:58,
`
`Figure 1; see also Ex. 1004, Figure 2. As illustrated in the figure, a nucleic acid,
`
`e.g., a single-stranded DNA (ssDNA), is added to one chamber and an electric field
`
`is applied across the substrate. Ex. 1009, Figure 1. As DNA is negatively charged,
`
`
`
`
`- 3 -
`
`
`
`
`
`
`
`the electric field pulls the DNA strand through the nanopore towards the side of the
`
`substrate with a positive potential. Id. As the strand passes through the nanopore,
`
`an electrical signal that varies based on the composition of the DNA strand in the
`
`pore is measured. Id., 6:14-22, Figure 3. Often, the signal that is measured is the
`
`conductance of ions through the pore. Id. Because each nucleotide has different
`
`properties such as size and shape, they each block the pore, and consequently alter
`
`the flow of ions through the pore, to a differing degree. Id. Church provided a
`
`schematic of the conductance levels that may be observed as a DNA strand passes
`
`through the pore if only a single base contributed to the channel current:
`
`
`
`Id., Figure 3.
`
`Although Church hypothesized that each nucleotide provides a distinct
`
`signal, it was well recognized as of the priority date of the ’056 patent that multiple
`
`nucleotides contribute simultaneously to the measured signal and such a signal
`
`
`
`
`- 4 -
`
`
`
`
`
`
`
`must be deconvoluted to obtain the sequence of nucleotides that comprise the
`
`DNA. See also Ex. 1002, ¶ 33.
`
`As the conductance is characteristic of the nucleotides residing in the
`
`nanopore at a given time, the conductance data may be analyzed to determine the
`
`sequence of the DNA strand that passed through the pore. Ex. 1009, 6:14-22. That
`
`analysis involves comparing the experimental data to previously measured
`
`calibration information representative of the signal indicative of a specific
`
`nucleotide or group of nucleotides, e.g., data obtained for nucleic acids with known
`
`sequences.
`
`It was also well recognized as of the priority date of the ’056 patent that the
`
`rate of nucleic acid translocation through a nanopore could be controlled by
`
`incorporating a molecular motor. Ex. 1002, ¶ 35. In fact, the ’056 patent, itself,
`
`cites U.S. Patent Publication No. 2006/0063171 to Akeson et al. (“Akeson”) as
`
`disclosing nanopore systems incorporating molecular motors. Ex. 1001, 23:27-32.
`
`Akeson discloses that “one disadvantage of previous nanopore analysis techniques
`
`is controlling the rate at which the target polynucleotide is analyzed,” and teaches
`
`the use of a molecular motor to modify the rate of translocation of a nucleic acid
`
`through a nanopore to facilitate characterization of the nucleic acid. Ex. 1004, ¶¶
`
`[0007], [0019], [0036], [0081]; see also Ex. 1009, 4:11-30, Figure 2. Akeson also
`
`discloses that the molecular motor can be, for example, “a DNA polymerase, a
`
`
`
`
`- 5 -
`
`
`
`
`
`
`
`RNA polymerase, a ribosome, an exonuclease, or a helicase,” and that the intrinsic
`
`rate of such a molecular motor can be modified to alter, e.g., decrease, the rate of
`
`movement of the polynucleotide. Id., ¶¶ [0013], [0047]-[0051], [0083]; see also
`
`id., Figure 11. Thus, a POSA would not only be well aware of the use of
`
`molecular motors in connection with nanopore-based sequencing, but would also
`
`be aware of the types of proteins, e.g., polymerases and helicases, which would be
`
`useful to reduce the rate of nucleic acid translocation. Ex. 1002, ¶ 36.
`
`B. Kinetics of Molecular Motors
`The kinetic behavior of molecular motors, e.g., DNA polymerases and
`
`helicases, has been studied for years. Experiments, even certain experiments
`
`performed by Pacific Biosciences, have indicated that many molecular motors
`
`exhibit at least two kinetics steps, if not more, and that the ratios of the rates of
`
`those steps fall within 10:1 and 1:10. See Ex. 1005, Ex. 1006, Ex. 1013.
`
`IV. OVERVIEW OF THE ’056 PATENT
`
`A. Overview of the Subject Matter of the ’056 Patent
`
`The claims of the ’056 patent are directed to methods for nanopore-based
`
`sequencing and, in particular, to methods where a molecular motor is used to
`
`control the translocation of the DNA molecule through the pore. The claims also
`
`require that the rate constants of at least two of the reaction steps of the molecular
`
`
`
`
`- 6 -
`
`
`
`
`
`
`
`motor, result in particular ratios, e.g., ranging from 10:1 to 1:10. The ’056 patent
`
`includes 18 claims, with only claim 1 being independent.
`
`According to the ’056 patent, “[d]evices using nanopores to sequence DNA
`
`and RNA molecules have generally not been capable of reading sequence at a
`
`single-nucleotide resolution.” Ex. 1001, 1:58-60. The ’056 patent states that “[f]or
`
`the purposes of single molecule sequencing it can be advantageous to control the
`
`translocation of DNA through nanopore structures under applied voltage” and cites
`
`to Akeson before suggesting that “[p]rotein components on either the cis or trans
`
`side of the nanopore can be utilized to control the rate of the translocation through
`
`the nanopore...” Id., 23:29-34. The ’056 patent then includes a series of
`
`paragraphs incorporated into the specification via a preliminary amendment from
`
`U.S.S.N. 12/414,191 (“the ’191 application”).1 These paragraphs note that certain
`
`protein components, e.g., polymerases and other enzymes, can be useful in the
`
`context of sequencing in that “by providing two or more partially rate-limiting
`
`steps within a phase of an enzyme reaction, one improves the ability to monitor
`
`that reaction using optical detection systems.” Id., 24:46-49 (emphasis added).
`
`
`1 The ’191 application, which was filed on March 30, 2009, was issued as U.S.
`
`Patent No. 8,133,672 on March 13, 2012.
`
`
`
`
`- 7 -
`
`
`
`
`
`
`
`B. Overview of the Prosecution History
`U.S.S.N. 15/366,849, which matured into the ’056 patent, was filed on
`
`December 1, 2016, and included 28 claims. Ex. 1010, 67-69. On December 2,
`
`2016, a preliminary amendment was filed to incorporate disclosure from the ’191
`
`application. Id., 142-327. The sections of the ’191 application incorporated in the
`
`specification relate to the use of polymerases and reaction conditions that result in
`
`a polymerase reaction exhibiting two kinetically observable steps. Patent Owner
`
`represented that the basis for this amendment was the incorporation by reference of
`
`the ’191 application into the ’056 patent. Id., 306. See also Ex. 1001, 24:28-32.
`
`On February 13, 2017, a Restriction Requirement issued requiring an
`
`election of claims. Ex. 1010, 512-518. Patent Owner elected the method claims
`
`(claims 1-18) and canceled the system claims (claims 19-28). Id., 519.
`
`On April 13, 2017, a Non-Final Office Action issued rejecting the pending
`
`claims under 35 U.S.C. § 112 grounds. Id., 530-533. In addition, claims 1-4 and
`
`6-18 were rejected on the ground of nonstatutory double patenting as being
`
`unpatentable over claims 1-29 of U.S. Patent No. 8,133,672 (“the ’672 patent”) in
`
`view of Meller et al. (WO 2006/020775; “Meller”). Id., 533-537. The Examiner
`
`argued that “[b]oth sets of claims are drawn to the same steps of sequencing
`
`nucleic acids, two kinetic steps, enzymes, rates and rate ratios” and that Meller
`
`discloses nanopore sequencing. Id., 535-536. Claim 5 was also rejected on the
`
`
`
`
`- 8 -
`
`
`
`
`
`
`
`ground of nonstatutory double patenting as being unpatentable over claims 1-29 of
`
`the ’672 patent in view of Meller and in further view of Guo (U.S. Patent
`
`Publication No. 2005/0266416), with the Examiner contending that Guo teaches
`
`“the claimed functionally equivalent nanomotor [], which is used in nanopore
`
`based sequencing devices.” Id., 537. In response, Patent Owner filed a terminal
`
`disclaimer to the ’672 patent. Id., 624 and 648.
`
`As evidenced by the rejection of the claims on the ground of nonstatutory
`
`double patenting over the ’672 patent, which issued from the ’191 application, and
`
`the incorporation of disclosure from the ’191 application into the specification of
`
`the ’056 patent, the prosecution of the ’191 application is highly relevant to the
`
`claims of the ’056 patent.
`
`During the prosecution of the ’191 application, the Examiner rejected the
`
`pending claims as anticipated by Hanzel2 and Bakhtina et al., Biochemistry
`
`44:5177-518 (2005) (“Bakhtina”). Ex. 1011, 35-38. In addition to the anticipation
`
`rejections, the Examiner rejected the claims of the ’191 application as obvious over
`
`Hanzel in combination with Esteban et al., Biochemistry 31:350-359 (1992) and
`
`Rechkunova et al., Biochemistry (Moscow) 65:609-614 (2000). Id., 38-39. The
`
`Examiner asserted that Hanzel teaches a sequencing method where the polymerase
`
`reaction exhibits two kinetically observable steps within an observable phase of the
`
`
`2 Hanzel is assigned to Pacific Biosciences. Ex. 1005.
`- 9 -
`
`
`
`
`
`
`
`
`
`reaction, and the ratios of the product release rates and the branching rates of the
`
`polymerases disclosed in Hanzel fall between 10:1 and 1:10. Id., 38-39. Similarly,
`
`the Examiner argued that Bakhtina discloses a sequencing method where the
`
`polymerase reaction exhibits two kinetically observable steps within an observable
`
`phase of the reaction, and that Bakhtina discloses ratios of rate constants between
`
`10:1 to 1:10. Id., 35-37.
`
`In response, Pacific Biosciences amended claim 1 of the ’191 application,
`
`the only independent claim, to recite:
`
`“each of which kinetically observable steps proceeds
`
`from an intermediate in which a nucleotide or a
`
`polyphosphate product is bound to the polymerase
`
`enzyme or each of which kinetically observable steps
`
`proceeds from an intermediate in which the nucleotide
`
`and the polyphosphate product are not bound to the
`
`polymerase enzyme.”
`
`Id., 46. Pacific Biosciences also acknowledged that Hanzel describes a system that
`
`includes two kinetic steps, a first kinetic step proceeding from an intermediate that
`
`is bound and a second kinetic step proceeding from an intermediate that is unbound
`
`and that Bakhtina discloses two kinetic steps, a single kinetically observable
`
`binding step (unbound phase) and a single kinetically observable chemistry step
`
`
`
`
`- 10 -
`
`
`
`
`
`
`
`(bound phase). Id., 49-51. Distinguishing Hanzel and Bakhtina in this fashion
`
`underscores the importance of the newly-added limitation, where both of the
`
`kinetic steps proceed from an intermediate “in which the nucleotide and the
`
`polyphosphate product are not bound to the polymerase enzyme” or “in which a
`
`nucleotide or a polyphosphate product is bound to the polymerase enzyme.” Id.
`
`Despite the materiality of the art cited by the Examiner during the
`
`prosecution of the ’191 application (e.g., Hanzel) to the ’056 patent’s claim
`
`limitations relating to enzyme kinetic steps, Pacific Biosciences failed to provide
`
`the cited references to the Examiner handling the ’056 patent. Similarly, the
`
`amendments made to claim 1 of the ’191 application, which were explicitly made
`
`to overcome Hanzel and Bakhtina, were not mentioned during prosecution of the
`
`’056 patent, let alone incorporated into the claims of the ’056 patent.
`
`A Notice of Allowance was mailed on May 2, 2017, which resulted in the
`
`issuance of the ‘056 patent. In the Notice of Allowance, the Examiner states that
`
`“while [Akeson] teach the use of the translocating enzyme polymerase, the
`
`manipulation of the reaction conditions to create the claimed ratio of rate constants
`
`is free and clear of the prior art.” Ex. 1010, 659. While this rationale for
`
`allowance is flawed in that ignores express teachings in Akeson (see infra Section
`
`VI.A.), it also highlights the materiality of the art withheld by Pacific Biosciences,
`
`
`
`
`- 11 -
`
`
`
`
`
`
`
`e.g., Hanzel, -- which teaches the exact limitation the Examiner alleged was
`
`missing from Akeson. See infra Sections VI.A.1, VI.B.1, VIII.
`
`V. LEVEL OF ORDINARY SKILL IN THE ART
`The level of ordinary skill in the art is evidenced by the references. See In re
`
`GPAC Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995). A person of ordinary skill in the
`
`art (POSA) for the ’056 Patent possesses a Ph.D. or an equivalent amount of
`
`experience in molecular biology, genetics, biochemistry or a related field. A
`
`POSA in the art area would have experience in DNA sequencing techniques
`
`including Maxam-Gilbert and Sanger sequencing, as well as other techniques
`
`available on or before the priority date of the ’056 Patent, such as Applied
`
`Biosystems/Life Technologies, Solexa/Illumina, Helicos and PacBio sequencing.
`
`Ex. 1002, ¶¶ 30-31.
`
`VI. SUMMARY OF PRIOR ART
`
`A. Nanopore Sequencing using Molecular Motors was Known in the
`Art Prior to the Earliest Priority Date Claimed by the ’056 Patent
`1.
`U.S. 2006/0063171 (“Akeson”)
`
`Akeson was filed as U.S. Application No. 11/088,140 on March 23, 2005
`
`and published on March 23, 2006 and is § 102(b) prior art (Ex. 1004).
`
`Akeson discloses methods for sequencing nucleic acids using a nanopore
`
`and a molecular motor (referred to as a “molecular motor” in Akeson). Ex. 1004,
`
`¶¶ [0008]-[0009]. For example, Akeson discloses the use of a molecular motor to
`
`
`
`
`- 12 -
`
`
`
`
`
`
`
`reduce the rate of translocation of a nucleic acid through a nanopore. Id., ¶¶
`
`[0019], [0081]. Akeson also discloses that the molecular motor can be a
`
`polymerase, a helicase, a ribosome or an exonuclease. Id., ¶¶ [0047]-[0051]. In
`
`particular, Akeson discloses that the polymerase can be a “Phi-29 DNA
`
`polymerase” and that the helicase can be a “E.coli bacteriophage T7 gp4A” or E.
`
`coli rho helicase. Id., ¶¶ [0048], [0051]. Akeson also highlights desirable
`
`enzymatic rates for such molecular motors in the context of nanopore sequencing.
`
`Id., ¶ [0082]. Akeson specifically discloses that “for a DNA polymerase, a
`
`desirable range is 75-1500Hz; and for ribosomes, helicases and exonucleases, a
`
`desirable range is 50-1500Hz.” Id. As discussed in detail below, such rates would
`
`only be achievable if the individual kinetic steps of the disclosed molecular motors
`
`fell within the ratios claimed in the ’056 patent. See infra Section VIII.A.1.
`
`Akeson was not cited as a prior art reference in a § 102 or § 103 rejection of
`
`the claims and only discussed in the Notice of Allowance of the ’056 patent. Ex.
`
`1010, 659. The Examiner’s characterization of the Akeson fails to contextualize
`
`the explicit disclosures in Akeson relevant to the claims of the ’056 patent. The
`
`Examiner failed to cite to Akeson’s disclosure that “[t]he intrinsic rate of
`
`movement of a particular molecular motor may be modified, e.g., by chemical
`
`modification of the motor, by changes in temperature, pH, ionic strength, the
`
`presence of necessary cofactors, substrates, inhibitors, agonists, or antagonists, by
`
`
`
`
`- 13 -
`
`
`
`
`
`
`
`the nature of the medium (e.g., the presence of nonaqueous solvents or the
`
`viscosity), by external fields (e.g., electric or magnetic fields), and hydrodynamic
`
`pressure … to start, stop, increase, decrease, or stabilize the rate of movement.”
`
`Ex. 1004, ¶ [0083]. The Examiner also failed to indicate that Akeson’s disclosure
`
`of desirable enzymatic rates could only be achievable if the enzymes operated
`
`within the ratios of rates claimed in the ’056 patent. See infra Section VIII.A.1.
`
`Moreover, the Notice of Allowance fails to address Akeson’s disclosure in
`
`light of Pacific Biosciences’ own art, e.g., Hanzel, and arguments submitted in
`
`connection with the prosecution of the ’191 application. For example, Pacific
`
`Biosciences conceded during the prosecution of the ’191 application that modified
`
`motors were known in the art, including in Hanzel, that satisfy the claimed ratios
`
`of rate constants. Ex. 1011, 46-51. Accordingly, reconsideration of the disclosure
`
`of Akeson is warranted, and should not be dismissed under 35 U.S.C. § 325(d),
`
`particularly in light of the Examiner’s failure to articulate all of the relevant aspects
`
`of Akeson as well as Pacific Biosciences’ knowledge of the state of the art at the
`
`time of filing in combination with their failure to bring such material information
`
`to the attention of the Examiner.
`
`B.
`
`It Was Well Known That Polymerases and Helicases Exhibit At
`Least Two Kinetic Steps with Ratios of 10:1 to 1:10
`1.
`U.S. 2007/0196846 (“Hanzel”)
`
`Hanzel was filed as U.S.S.N. 11/645,223 on December 21, 2006 and
`- 14 -
`
`
`
`
`
`
`
`
`
`published on August 23, 2007 and therefore qualifies as § 102(b) prior art (Ex.
`
`1005). Hanzel is assigned to Pacific Biosciences. Hanzel was not submitted to, or
`
`cited by, the Examiner or otherwise made of record during prosecution of the ’056
`
`Patent.
`
`Hanzel discloses polymerases that have been modified to alter their kinetic
`
`behavior. In particular, Hanzel discloses Phi29 DNA polymerases that can be
`
`modified “to slow [] the overall nucleotide incorporation speed of the polymerase
`
`(e.g., depending on
`
`the resolution of
`
`the equipment used
`
`to monitor
`
`incorporation).” Ex. 1005, ¶ [0092]; see also Ex. 1004, ¶ [0048]. Hanzel further
`
`discloses the modification of reaction conditions by manipulating nucleotide
`
`concentrations and the type of nucleotides, e.g., nucleotide analogs, to be used in
`
`the polymerase reaction. Ex. 1005, ¶ [0080], Table 5.
`
`Hanzel discloses the rates of specific kinetic steps, e.g., the rates of product
`
`release and branching, for modified Phi29 DNA polymerases. These ratios fall
`
`within the ratio ranges claimed in the ’056 patent. Id., ¶¶ [0184], [0186]-[0187],
`
`Tables 6 and 7; see also infra Section VIII.B. The product release rate disclosed in
`
`Hanzel corresponds to step 112 (k5) of Figure 32 of the ’056 patent, which is the
`
`step where a product is released from the enzyme. Ex. 1002, ¶ 55. The branching
`
`rate, also known as the nucleotide dissociation rate, corresponds to step 104 (k-1) of
`
`
`
`
`- 15 -
`
`
`
`
`
`
`
`Figure 32 of the ’056 patent, which is the step where the nucleotide dissociates
`
`from the polymerase that is bound to the polynucleotide. Id.
`
` 2. Liao
`
`Liao et al., Journal of Molecular Biology 350:452-475 (2005) (Ex. 1006)
`
`was published online on May 23, 2005 and published in print on July 15, 2005, and
`
`therefore qualifies as § 102(b) prior art. See also Ex. 1007. Liao was not
`
`submitted to, or cited by, the Examiner or otherwise made of record during
`
`prosecution of the ’056 Patent.
`
`Liao discloses the kinetic analysis of the bacteriophage T7 DNA helicase.
`
`Ex. 1006, 452. Liao discloses that the helicase, which is one of the helicases
`
`expressly disclosed in Akeson as useful in connection with the nanopore detection
`
`systems disclosed therein, exhibits a variety of kinetic steps having rate constants
`
`that fall within the ratio ranges claimed in the ’056 patent. See infra Section
`
`VIII.C; see also Ex. 1004, ¶ [0051]. Scheme 1 of Liao discloses the kinetic steps
`
`that were analyzed, and the rate constants of such steps are provided in Table 1 of
`
`Liao. Ex. 1006, 457, 468; see also Ex. 1002, ¶¶ 57-60.
`
`Ex. 1006, Scheme 1 (460).
`
`
`
`
`
`
`- 16 -
`
`
`
`
`
`
`
` 3. Adelman
`
`Adelman et al., entitled “Mechanochemistry of Transcription Termination
`
`Factor Rho,” Mol. Cell 22:611-612 (Ex. 1013) was published in print on June 9,
`
`2006 and therefore qualifies as § 102(b) prior art. See also Ex. 1008. Adelman
`
`was not submitted to, or cited by, the Examiner or otherwise made of record during
`
`prosecution of the ’056 Patent.
`
`Adelman discloses the kinetic analysis of the E. coli rho helicase. Ex. 1013,
`
`611. Adelman discloses that the E. coli rho helicase, which is one of the helicases
`
`expressly disclosed in Akeson as useful in connection with the nanopore detection
`
`systems disclosed therein, exhibits a variety of kinetic steps that have rate
`
`constants that when compared have a ratio that falls within the ratio ranges claimed
`
`in the ’056 patent. See infra Section VIII.D; see also Ex. 1004, ¶ [0051]. Scheme
`
`1 of Adelman discloses the kinetic steps that were analyzed, and the rate constants
`
`of such steps are provided in Table 1. Ex. 1013, 615, 618; see also Ex. 1002, ¶¶
`
`62-65.
`
`Ex. 1013, Scheme 1 (615).
`
`
`
`
`
`
`- 17 -
`
`
`
`
`
`
`
`VII. CLAIM CONSTRUCTION
`
`In an IPR, claims are given their “broadest reasonable construction in light
`
`of the specification.” See 37 C.F.R. § 42.100(b); In re Cuozzo Speed Technologies,
`
`LLC, 793 F.3d 1268, 1275-78 (Fed. Cir. 2015).
`
`Claim 5 identifies two specific subtypes of translocating enzyme: (1) “a viral
`
`genome packaging motor”; and (2) “an ATP-dependent chromatin remodeling
`
`complex.” While neither term is specifically defined in the specification, they are
`
`included in a larger list of translocating enzyme alternatives, “[o]ptionally, the
`
`protein components can be chosen from a broad class of DNA translocation
`
`enzymes including DNA and RNA helicases, viral genome packaging motors, and
`
`chromatin remodeling ATPases.” Ex. 1001, 23:57-60. Given the identification in
`
`the specification of viral genome packaging motors and chromatin remodeling
`
`ATPases as alternatives to DNA and RNA helicases, the broadest reasonable
`
`construction of those terms cannot be coextensive in scope with DNA and RNA
`
`helicases. Id. This is true despite the fact that some viral genome packaging
`
`motors and chromatin remodeling ATPases may have helicase or helicase-like
`
`motifs. Ex. 1002, ¶ 67. Accordingly, the broadest reasonable construction for
`
`viral genome packaging motor is “a viral protein or complex of proteins having the
`
`functions of associating with a viral capsid and translocating viral DNA into a
`
`capsid shell.” Id. Similarly, the broadest reasonable construction for “chromatin
`
`
`
`
`- 18 -
`
`
`
`
`
`
`
`remodeling ATPase” is “a protein or complex of proteins having the function of
`
`coupling ATP hydrolysis to nucleosome translocation.” Id.
`
`Claims 6 and 7 of the ’056 patent refer to five distinct kinetic steps: (1)
`
`“enzyme isomerization”; (2) “nucleotide incorporation”; (3) “product release”; (4)
`
`“template translocation”; and (5) “nucleotide binding.” The specification provides
`
`an example of each of these steps in the context of a nucleic acid polymerase, with
`
`reference to Figure 32:
`
`
`
`Ex. 1001, Figure 32.
`
`The specification makes clear, however, that “the scheme in FIG. 32 does not
`
`provide a unique representation of the process.” Id., 25:39-42. The specification
`
`goes on to note that the kinetic steps of the polymerase process may include “fewer
`
`
`
`
`- 19 -
`
`
`
`
`
`
`
`steps.”3 Id. Alternatively, it may include additional steps, if those steps are “slow,
`
`and thus limit the rate of reaction.” Id., 25:44-47. Thus, while Figure 32 may be a
`
`guide, it does not provide a comprehensive listing of all possible steps. Id., claims
`
`1-3, 5-18; Ex. 1002, ¶ 68.
`
`In view of the statements made in the specification, the broadest reasonable
`
`construction of “enzyme isomerization” as recited in claim 6 is “a step that
`
`involves a change in enzyme configuration.” Id., 25:59-64; see also Ex. 1002, ¶
`
`69.
`
`In view of the statements made in the specification, the broadest reasonable
`
`construction of “nucleotide incorporation” as recited in claim 6 is “a chemistry step
`
`where a nucleotide is incorporated into a growing strand.” Ex. 1001, 25:61-63; see
`
`also Ex. 1002, ¶ 70.
`
`In view of the statements made in the specification, the broadest reasonable
`
`construction of “product release” as recited in claim 6 is “a step where a product is
`
`released from the enzyme.” Ex. 1002, ¶ 71.
`
`3 There is no broad consensus as to the number and types of steps involved in an
`
`enzymatic process; indeed, different prior art publications define “steps”
`
`differently. The instant claims, however, require a specific ratio of the rate
`
`constants of any two “kinetic steps” in an enzymatic process, and that requirement
`
`is disclosed in the art.
`
`
`
`
`- 20 -
`
`
`
`
`
`
`
`In view of the statements made in the specification, the broadest reasonable
`
`construction of “template translocation” as recited in claim 7 is “a step where the
`
`enzyme translocates on the bound nucleic acid.” Ex. 1001, 25:66-67; see also Ex.
`
`1002, ¶ 72.
`
`In view of the statements made in the specification, the broadest reasonable
`
`construction of “nucleotide binding” as recited in claim 7 is “a step where a
`
`nucleotide forms initial interactions in the nucleotide binding pocket of the
`
`enzyme.” Ex. 1002, ¶ 73.
`
`VIII. THERE
`IS A REASONABLE LIKELIHOOD THAT THE
`CHALLENGED CLAIMS ARE UNPATENTABLE
`A. Ground 1: Claims 1-5, 10-12 and 15-16 are anticipated by Akeson
`1. Claim 1
`
`Claim 1[pre]. “A method for sequencing a nucleic acid template
`
`comprising:”
`
`Akeson discloses methods for the “analysis of a polynucleotide sequence” to
`
`identify the “number and composition of monomers that make up each individual
`
`polynucleotide, in sequential order.” Ex. 1004, ¶¶ [0019], [0079]. Accordingly, to
`
`the extent that the preamble is limiting, Akeson discloses a “method for sequencing
`
`a nucleic acid template,” as recited by the preamble of claim 1. Ex. 1002, ¶ 74.
`
`
`
`
`- 21 -
`
`
`
`
`
`
`
`Claim 1[a]. “providing a substrate having an upper solution above the
`
`substrate and a lower solution below the substrate, the substrate comprising a
`
`nanopore connecting the upper s
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
