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 IPR No. IPR2018-01795
`U.S. Patent No. 9,678,056
`
`
`
`
`
`PATENT OWNER PACIFIC BIOSCIENCES OF CALIFORNIA, INC.’S
`PRELIMINARY RESPONSE
`
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
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`
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`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`OXFORD NANOPORE TECHNOLOGIES, INC.,
`Petitioner,
`v.
`PACIFIC BIOSCIENCES OF CALIFORNIA, INC.
`Patent Owner
`
`Case IPR No. IPR2018-01795
`U.S. Patent No. 9,678,056
`
`
`
`
`
`PATENT OWNER PACIFIC BIOSCIENCES OF CALIFORNIA, INC.’S
`PRELIMINARY RESPONSE
`
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`
`
`
`
`
`
`I.
`
`II.
`
`TABLE OF CONTENTS
`
`Page
`
`INTRODUCTION .......................................................................................... 1
`
`THE BOARD SHOULD EXERCISE ITS DISCRETION TO DENY
`INSTITUTION PURSUANT TO §§ 314(A) AND 324(A) ............................ 5
`
`A.
`
`B.
`
`C.
`
`Petitioner’s Delay in Filing the Petition ................................................ 6
`
`Status of District Court Litigation ......................................................... 7
`
`The Board Has Broad Discretion to Deny Institution Under 35
`U.S.C. §§ 314(a) and 324(a) ................................................................. 7
`
`III. BACKGROUND ........................................................................................... 10
`
`A. Nanopore Sequencing Overview ......................................................... 10
`
`B.
`
`C.
`
`Overview Of The ’056 Patent ............................................................. 12
`
`Overview Of The Cited Prior Art ........................................................ 16
`
`1.
`
`2.
`
`U.S. Patent Publication 2006/0063171 (“Akeson”) ................. 16
`
`U.S. Patent Publication 2007/0196846 (“Hanzel”) .................. 18
`
`3. Mechanochemistry Of T7 DNA Helicase (“Liao”) .................. 22
`
`4. Mechanochemistry Of Transcription Termination Factor
`Rho (“Adelman”) ...................................................................... 24
`
`IV. CLAIM CONSTRUCTION .......................................................................... 26
`
`V.
`
`REASONS WHY THE PETITION SHOULD BE DENIED ....................... 26
`
`A.
`
`The Petition Is Based On Expert Testimony That Is Entitled To
`No Weight ........................................................................................... 27
`
`B.
`
`Ground 1: Inherent Anticipation by Akeson ...................................... 30
`
`
`
`i
`
`
`
`C.
`
`Ground 2: Obviousness Based On Akeson And Hanzel ..................... 36
`
`1.
`
`2.
`
`The Combination Of Akeson And Hanzel Does Not Teach
`Selecting An Enzyme And Reaction Conditions Such That
`The Enzyme Exhibits Two Kinetic Steps ................................. 36
`
`Petitioner Fails To Establish A Motivation To Combine
`And Reasonable Expectation Of Success ................................. 41
`
`D. Ground 3: Obviousness Based On Akeson And Liao ......................... 45
`
`1.
`
`2.
`
`The Combination Of Akeson And Liao Does Not Teach
`Selecting An Enzyme And Reaction Conditions Such That
`The Enzyme Exhibits Two Kinetic Steps ................................. 45
`
`Petitioner Fails To Establish A Motivation To Combine Or
`Reasonable Expectation Of Success ......................................... 49
`
`E.
`
`Ground 4: Obviousness Based On Akeson And Adelman ................. 51
`
`1.
`
`2.
`
`The Combination Of Akeson And Adelman Does Not
`Teach Selecting An Enzyme And Reaction Conditions
`Such That The Enzyme Exhibits Two Kinetic Steps ................ 51
`
`Petitioner Fails To Establish A Motivation To Combine Or
`Reasonable Expectation Of Success ......................................... 54
`
`VI. CONCLUSION ............................................................................................ 55
`
`
`
`
`
`
`
`
`ii
`
`
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Cases
`Alphonso, Inc. v. Free Stream Media, Corp.,
`IPR2017-01731, 2018 WL 566832 (PTAB Jan. 25, 2018) ................................. 42
`Apotex Inc. and Apotex Corp., v. Abraxis Bioscience, LLC,
`IPR2018-00153, Paper 11 (PTAB May 8, 2018) ................................................. 32
`Arctic Cat Inc. v. Bombardier Recreational Prod. Inc.,
`876 F.3d 1350 (Fed. Cir. 2017) ............................................................... 41, 50, 55
`Avaya Inc., et al., v. Network-1 Security Solutions Inc.,
`IPR2013-00071, Paper 103 (PTAB May 22, 2014) ............................................. 35
`Carlson v. Bioremedi Therapeutic Sys.,
`822 F.3d 194 (5th Cir. 2016)................................................................................ 30
`Cheese Sys., Inc. v. Tetra Pak Cheese & Powder Sys.,
`725 F.3d 1341 (Fed. Cir. 2013) ............................................................................ 41
`Compass Bank v. Intellectual Ventures II,
`IPR2014-00786, Paper 46 (PTAB Sept. 23, 2015) ....................................... 33, 45
`
`Corning Inc. v. DSM IP Assets,
`IPR2013-00050, Paper 77 (PTAB May 1, 2014) .......................................... 33, 45
`General Plastic Indus. Co., Ltd. v. Canon Kabushiki Kaisha,
`Case IPR2016-01357, Paper 19 (PTAB Sept. 6, 2017) ......................................... 6
`Helifix Ltd. v. Blok-Lok, Ltd.,
`208 F.3d 1339 (Fed. Cir. 2000) ............................................................................ 29
`In re Oelrich,
`666 F.2d 578 (CCPA 1981) ................................................................................. 31
`
`Initiative for Medicines, Access & Knowledge (I-MAK), Inc., v. Gilead
`Pharmasset LLC,
`IPR2018-00211, Paper 7 (PTAB June 20, 2018) ................................................. 50
`
`
`
`iii
`
`
`
`Institut Pasteur v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) ............................................................................ 42
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc.
`688 F.3d 1342 (Fed. Cir. 2012) ............................................................................ 41
`
`KSR Intern. Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007) ...................................................................................... 41, 43
`Kumho Tire Co. v. Carmichael,
`526 U.S. 137 (1999) ............................................................................................. 30
`L’Oréal USA Inc. v. Liqwd, Inc.,
`PGR2018-00023, Paper 9 (PTAB Aug. 10, 2018) .............................................. 30
`MEHL/Biophile Int’l Corp. v. Milgraum,
`192 F.3d 1362 (Fed. Cir. 1999) ............................................................................ 31
`Microsoft Corp. v. Enfish, LLC,
`662 Fed. Appx. 981 (Fed. Cir. 2016) ................................................................... 42
`Microsoft Corp. v. Koninkijke Philips N.V.,
`Case IPR2018-00277, Paper 10 (PTAB June 8, 2018) .......................................... 6
`
`NHK Spring Co. Ltd. v. Intri-Plex Techs., Inc.,
`Case IPR2018-00752, Paper 8 (PTAB Sept. 12, 2018) .......................... 6, 8, 9, 10
`Ortho-McNeil Pharm., Inc. v. Mylan Labs, Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) ............................................................... 43, 50, 55
`Outdry Techs. Corp. v. Geox S.p.A.,
`859 F.3d 1364 (Fed. Cir. 2017) ............................................................................ 43
`Sciele Pharma Inc. v. Lupin Ltd.,
`684 F.3d 1253 (Fed. Cir. 2012) ............................................................................ 29
`Spansion, Inc. v. Macronix Int’l Co., Ltd.,
`IPR2014-01118, Paper 16 (PTAB Jan. 21, 2015) ................................................ 33
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) ............................................................... 43, 50, 55
`
`
`
`iv
`
`
`
`Titex International, Ltd., v. Precision Fabrics Group, Inc.,
`IPR2014-01248, Paper 39 (PTAB Jan. 27, 2016) ................................................ 35
`
`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
`200 F.3d 795 (Fed. Cir. 1999) .............................................................................. 26
`ZTE Corp. v. ContentGuard Holdings, Inc.,
`IPR2013-00137, Paper 58 (PTAB July 1, 2014) ................................................. 35
`Statutes and Regulations
`35 U.S.C. § 314(a) ............................................................................................ 5, 7, 8
`35 U.S.C. § 316(b) ..................................................................................................... 7
`35 U.S.C. § 326(b) ..................................................................................................... 7
`35. U.S.C. § 324(a) ................................................................................................5, 7
`37 C.F.R. § 42.65(a) ................................................................................................. 44
`Legislative Authority
`H.R. Rep. No. 112-98, pt. 1 (2011)........................................................................6, 8
`
`
`
`
`
`
`v
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`EXHIBIT LIST
`
`Ex. 2002
`
`Ex. 2003
`
`Ex. 2004
`
`Description
`Exhibit #
`Ex. 2001 Excerpt from Brown, Clive, KeyGene Nanopore Seminar, April
`2016 “Petitioner’s Technical Presentation”
`Deposition Excerpts of Taekjip Ha, Ph.D., dated October 29,
`2018, Pacific Biosciences of California, Inc. v. Oxford Nanopore
`Technologies, Inc., Case Nos. 1:17-cv-00275 (D. Del.) and 1:17-
`cv-01353 (D. Del.)
`Complaint for Patent Infringement arising under U.S. Patent No.
`9,546,400, Pacific Biosciences of California, Inc. v. Oxford
`Nanopore Technologies, Inc., Case No. 1:17-cv-00275 (D. Del.),
`Docket No. 1
`Complaint for Patent Infringement arising under U.S. Patent No.
`9,678,056, Pacific Biosciences of California, Inc. v. Oxford
`Nanopore Technologies, Inc., Case No. 1:17-cv-01353 (D. Del.),
`Docket No. 1
`Oxford Nanopore Technologies, Inc.’s Initial Invalidity
`Contentions, Pacific Biosciences of California, Inc. v. Oxford
`Nanopore Technologies, Inc., Case Nos. 1:17-cv-00275 (D. Del.)
`and 1:17-cv-01353 (D. Del.)
`Docket text for Oral Order Rescheduling Markman Hearing,
`Pacific Biosciences of California, Inc. v. Oxford Nanopore
`Technologies, Inc., Case Nos. 1:17-cv-00275 (D. Del.) and 1:17-
`cv-01353 (D. Del.)
`Scheduling Order, Pacific Biosciences of California, Inc. v. Oxford
`Nanopore Technologies, Inc., Case No. 1:17-cv-01353 (D. Del.),
`Docket No. 35
`Declaration of Taekjip Ha, Ph.D., Pacific Biosciences of
`California, Inc. v. Oxford Nanopore Technologies, Inc., Case Nos.
`1:17-cv-00275 (D. Del.) and 1:17-cv-01353 (D. Del.), Docket No.
`95
`
`Ex. 2005
`
`Ex. 2006
`
`Ex. 2007
`
`Ex. 2008
`
`vi
`
`
`
`
`
`I.
`
`INTRODUCTION
`Patent Owner, Pacific Biosciences of California, Inc. submits this Preliminary
`
`Response to Petition For Inter Partes Review of U.S. Patent No. 9,678,056 (“the
`
`Petition”). As explained in this Response, the Board should not institute review.
`
`This IPR is the third in a sequence of IPRs that Petitioner has filed against
`
`Patent Owner’s nanopore sequencing patents. Petitioner’s first IPR request was
`
`directed to a patent that overcame a long-standing resolution problem in nanopore
`
`sequencing by inter alia tackling signal analysis in a clever new way. The Board
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`denied institution of Petitioner’s first IPR request. See Paper No. 8, IPR2018-00789.
`
`Petitioner’s second IPR request is awaiting an institution decision, and is directed to
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`a patent that covers novel nucleic acid templates that can be used to further increase
`
`the accuracy of nanopore sequencing. Petitioner’s second IPR request is defective
`
`on several levels and should not be instituted either. See Paper No. 6, IPR2018-
`
`01792.
`
`The instant petition is directed to U.S. Patent No 9,678,056 (the “’056
`
`patent”), which covers improvements to yet another aspect of nanopore sequencing:
`
`the enzymatic motors that translocate DNA through a nanopore. The inventors
`
`recognized that by selecting a translocating enzyme and reaction conditions such
`
`that the enzyme exhibits two kinetic steps—those two kinetic steps having rate
`
`
`
`1
`
`
`
`
`
`constants within a 1:10 to 10:1 ratio—one can generate a cleaner and more robust
`
`signal from a nanopore device. See Ex. 1001 at Claim 1.
`
`Years after the inventors made this discovery, Petitioner adopted this same
`
`concept itself and has incorporated it into its products. This is apparent from the
`
`following side-by-side comparison of Fig. 33 from the ’056 patent with a figure from
`
`one of Petitioner’s recent technical presentations:
`
`
`Ex. 2001 [Petitioner’s Technical Presentation] at 2. As the figure shows, Petitioner
`
`has adopted the precise non-exponential kinetics that are taught in the ’056 patent,
`
`and has publicly portrayed this approach as a significant advance.
`
`Petitioner’s attempt to now attack the ’056 patent suffers from the same
`
`logical gaps and defects as Petitioner’s first two IPR requests and should be rejected.
`
`Just as in Petitioner’s first two IPR requests, the Petitioner makes bold claims that
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`the key concepts underlying the ’056 patent were well known in the art. According
`
`to the Petitioner’s expert, the “concept of using nanopores to sequence DNA has
`2
`
`
`
`
`
`
`
`been around for decades.” Ex. 1002 ¶ 32. Likewise, Petitioner’s expert states that
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`the “kinetic behavior of molecular motors, e.g., DNA polymerases and helicases, has
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`been studied for years.” Id. ¶ 37.
`
`One would think, then, that Petitioner would have at its fingertips a wealth of
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`prior art references expressly teaching the selection of a translocating enzyme
`
`exhibiting two kinetic steps within the prescribed ratio. Yet, just like Petitioner’s
`
`first two IPR requests, the prior art relied upon by Petitioner conspicuously fails to
`
`disclose the key aspects of the invention that were supposedly well-known and
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`obvious to the ordinary practitioner.
`
`Indeed, Petitioner’s primary argument is based not on express disclosure, but
`
`an alleged inherent disclosure in the Akeson reference. Akeson, however, makes no
`
`mention of any kinetic steps, much less selecting reaction conditions that would
`
`cause the enzyme to exhibit two kinetic steps with the recited ratio of rate constants.
`
`As documented herein, Petitioner’s inherency argument is based on nothing more
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`than unsupported argument from its expert.
`
`
`
`3
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`
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`
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`Here, the testimony of Petitioner’s expert should be given heightened scrutiny
`
`because Dr. Ha admitted in deposition1 that he did not even understand the scope of
`
`the claims:
`
`Q. Okay. So you offered opinions on the validity of the claims in the ’056
`Patent without understanding the scope of the claims of the ’056 Patent
`with reasonable certainty; is that correct?
`
`MR. HASH: Objection. Form.
`
`A. That's correct.
`
`Ex. 2002 [Ha CC Depo.] at 71:18-24. Dr. Ha further argued that a skilled artisan
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`could not have even understood what a “kinetic step” was. Id. at 61:24-62:2. Yet,
`
`Dr. Ha now claims that Akeson inherently discloses the claimed “kinetic steps,” and
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`he also seems to have identified them in three other references. This position defies
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`credulity and signals that the Petition is without merit.
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`Faced with these defects, Petitioner attempts to fill the gaps in Akeson by
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`combining it with three references broadly describing the kinetic behavior of various
`
`enzymes. None of Petitioner’s secondary references, however, disclose a
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`combination of enzyme and reaction conditions that will cause the enzyme to exhibit
`
`
`1 Although this is only a preliminary response, Petitioner’s expert has been
`questioned on some aspects of his opinions in this case in connection with claim
`construction proceedings in co-pending district court litigation. Some of his
`deposition testimony is presented herein.
`4
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`
`
`
`
`
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`two kinetic steps with rate constants within the required ratio. Rather, each reference
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`merely discloses that rate constants for individual kinetic steps can be measured by
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`varying experimental conditions (and reaction conditions). Notably, Petitioner
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`ignores the claim language and points to disclosures in these references of kinetic
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`steps that would not even occur during the translocation of a single stranded portion
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`of DNA.
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`Petitioner does not establish a reasonable likelihood that it will prevail as to
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`at least one claim of the ’056 patent, which is an important invention being infringed
`
`by the Petitioner. The Board should not allow this IPR to proceed further.
`
`II. THE BOARD SHOULD EXERCISE ITS DISCRETION TO DENY
`INSTITUTION PURSUANT TO §§ 314(A) AND 324(A)
`While the Petition is substantively deficient, and institution should be denied
`
`on the merits, the Board should also exercise its discretion and deny this petition
`
`under 35 U.S.C. §§ 314(a) and 324(a) because it would be a waste of the Board’s
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`finite resources and fundamentally unfair to Patent Owner to institute a trial that
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`would result in a final written decision after the conclusion of the same validity
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`challenge in the related district court litigation.
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`The efficient resolution of patent challenges is foundational to the IPR system
`
`and the AIA generally. To this end, it is “an objective of the AIA . . . to provide an
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`effective and efficient alternative to district court litigation.” General Plastic Indus.
`
`
`
`5
`
`
`
`
`
`Co., Ltd. v. Canon Kabushiki Kaisha, Case IPR2016-01357, Paper 19 at 16-17
`
`(PTAB Sept. 6, 2017) (precedential); see also Microsoft Corp. v. Koninkijke Philips
`
`N.V., Case IPR2018-00277, Paper 10 at 7 (PTAB June 8, 2018) (explaining that
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`“AIA proceedings ‘are not to be used as tools for harassment or a means to prevent
`
`market entry through repeated litigation and administrative attacks on the validity of
`
`a patent. Doing so would frustrate the purpose of the section as providing quick and
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`cost effective alternatives to litigation’” (quoting H.R. Rep. No. 112-98, pt. 1, at 48
`
`(2011)).
`
`This purpose is frustrated when, as here, a party delays filing a Petition until
`
`such time that the IPR, if instituted, would result in a final written decision only after
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`the same validity issues have been resolved by a district court. See NHK Spring Co.
`
`Ltd. v. Intri-Plex Techs., Inc., Case IPR2018-00752, Paper 8 at 19-20 (PTAB Sept.
`
`12, 2018).
`
`A.
`Petitioner’s Delay in Filing the Petition
`Patent Owner filed suit against Petitioner in district court for infringement of
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`one of its nanopore sequencing patents, the ’400 Patent, on March 15, 2017. On
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`September 25, 2017, Patent Owner filed a second action asserting infringement of
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`the ’929 and ’056 Patents. Exs. 2003, 2004. The two litigations were subsequently
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`consolidated by the Court. On July 13, 2018, Petitioner served its invalidity
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`contentions for all of the asserted patents, alleging invalidity of the ’056 Patent based
`6
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`
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`on Akeson, Hanzel, and Liao, the primary reference and two of the three secondary
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`references at issue here. Ex. 2005 [Inv. Cont. Cover Doc]. Petitioner filed its first
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`IPR petition related to the patents in suit on March 15, 2018, more than six months
`
`before it filed the current petition. See IPR2018-00789 Paper 1.
`
`B.
`Status of District Court Litigation
`Due to Petitioner’s delay in filing the current Petition, the District Court
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`litigation is at an advanced stage, and trial will conclude before a final written
`
`decision will issue in this proceeding. The District Court Markman hearing has been
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`held, wherein the Petitioner and its Expert argued positions directly at odds with its
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`arguments presented in this Petition. The Court’s claim construction order is likely
`
`to be issued prior to any institution decision in this proceeding. Ex. 2006 [Markman
`
`Scheduling Order]. Trial is set for five days starting on March 9, 2020. Ex. 2007
`
`[Scheduling Order]. Thus, the District Court will reach a verdict on the validity of
`
`the ’056 Patent based on the same prior art before the completion of this proceeding.
`
`C. The Board Has Broad Discretion to Deny Institution Under 35
`U.S.C. §§ 314(a) and 324(a)
`The Board has discretion under §§ 314(a) and 324(a) to deny institution of a
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`petition. This “discretion is informed by 35 U.S.C. §§ 316(b) and 326(b), which
`
`require the Director to ‘consider the effect of any such regulation [under this section]
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`on the economy, the integrity of the patent system, the efficient administration of the
`
`
`
`7
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`
`
`
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`Office, and the ability of the Office to timely complete proceedings instituted under
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`this chapter.’” August 2018 Update to the Office Patent Trial Practice Guide at 9
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`(Aug. 13, 2018) (“August 2018 Trial Practice Guide Update”). In discussing this
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`discretion, the August 2018 Trial Practice Guide Update recognizes that the “AIA
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`was ‘designed to establish a more efficient and streamlined patent system that will
`
`improve patent quality and limit unnecessary and counterproductive litigation
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`costs.’” Id. (citing H.R. Rep. No. 112-98, pt. 1 (2011).
`
`The Board has applied its discretion to deny institution under §§ 314(a) and
`
`324(a) on facts substantially identical to those presented here. See NHK Spring Co.,
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`Case IPR2018-00752, Paper 8. In NHK Spring, like the instant case, (1) the parties
`
`were engaged in District Court litigation on the same patent, (2) the petitioner was
`
`relying on the same prior art in the petition as in the litigation, and (3) the District
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`Court trial would conclude before the IPR. Id. at 19-20. The Board cited the
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`“advanced state of the district court proceeding[s]” and concluded that the “Patent
`
`Owner argues persuasively that instituting a trial under the facts and circumstances
`
`here would be an inefficient use of Board resources.” Id. at 20. In NHK Spring, the
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`Board noted that “[i]nstitution of an inter partes review under these circumstances
`
`would not be consistent with ‘an objective of the AIA . . . to provide an effective and
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`efficient alternative to district court litigation’” and denied institution. Id.
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`
`
`8
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`
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`
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`Here, the parties are currently engaged in District Court litigation on the same
`
`patent, and Petitioner relies on the same primary reference—Akeson—for invalidity.
`
`Moreover, a trial on the validity of the ’056 Patent in the District Court will be
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`complete before a final written decision would be issued if this proceeding were
`
`instituted. Ex. 2007 [Scheduling Order].
`
`The only distinction between NHK Spring and the instant case is that
`
`Petitioner has taken inconsistent claim construction positions between the District
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`Court litigation and this Petition, arguing that “kinetic step” is indefinite before the
`
`district court but that no construction is necessary here. Notably, however, these
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`competing claim construction positions will have no effect on the analysis of the
`
`references or the questions of anticipation or obviousness. If “kinetic step” is found
`
`to be indefinite, then the Petition is moot. If it is given its plain and ordinary
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`meaning, then there is no distinction between the District court litigation and this
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`Petition. Ultimately, this is a distinction without a difference.
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`Moreover, it is clear that Petitioner’s delay was tactically motivated. By
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`delaying as long as it has, Petitioner has avoided the possibility of any estoppel
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`pursuant to 35 U.S.C. § 315(e) applying to it. Because there will be no final written
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`decision until after the district court trial, Petitioner will be free to present a full
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`range of invalidity arguments against the ’056 patent to the jury. Indeed, Petitioner
`
`made clear in its co-pending IPR reply that its strategy was to have its cake and eat
`9
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`
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`it too, asserting that the Board should institute its delayed IPR so that if it wins here
`
`but loses with the jury it will be able to present a consolidated appeal to the Federal
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`Circuit or have the district court result “dismissed as moot.” See IPR2018-01792,
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`Paper No. 8 at 5. This, however, is directly contrary to the statutory scheme
`
`underlying IPR, which includes estoppel provisions specifically to avoid wasteful
`
`duplicate proceedings.
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`As in NHK Spring, the Board should exercise its discretion not to institute trial
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`here, as it would be a waste of both the Board’s and the Parties’ resources and
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`fundamentally at odds with Congress’s intent for IPR proceedings.
`
`III. BACKGROUND
`A. Nanopore Sequencing Overview
`Nanopore sequencing is a single-molecule sequencing technique that derives
`
`its name from the structures used in the sequencing process. In nanopore
`
`sequencing, a voltage is applied across a membrane embedded with “nanopores”—
`
`narrow channels through the membrane, which can be formed from membrane-
`
`embedded proteins. The voltage induces a current by virtue of the flow of ions
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`through the channel.
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`Individual DNA molecules that are placed on one side of the membrane can
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`be pulled through the channel, either by virtue of the voltage or through some other
`
`
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`10
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`
`
`
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`mechanism. The basic set up is shown in an early patent filing by George Church
`
`of Harvard University:
`
`
`
`Ex. 1009 [Church] at Fig. 1.
`
`As the single DNA molecule is pulled through the channel, the current is
`
`blocked by the presence of the DNA. The concept behind nanopore sequencing is
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`that the level of current blockage will be unique to the different nucleotide that is
`
`passing through the pore at a given point in time. As Church described it in his
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`patent filing, the “monomeric units of DNA (bases G, A, T, and C) interfere
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`differentially with the flow of ions through the pore, resulting in discrete
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`conductance levels that are characteristic of each base. The order of appearance of
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`the conductance levels sequentially identifies the monomers of the DNA.” Ex. 1009
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`[Church] at 6:17-20. Church outlined an ideal signal that could be measured from a
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`nanopore-sequencing apparatus to determine the sequence at Fig. 3:
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`11
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`B. Overview Of The ’056 Patent
`One of the primary challenges to nanopore sequencing is controlling the
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`passage, or translocation, of the polynucleotide as it passes through the nanopore.
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`As Church explains, “[s]ince the blockade durations we observed are in the
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`millisecond range, each nucleotide in a one or two thousand monomer-long
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`polynucleotide occupies the channel for just a few microseconds.” Ex. 1009
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`[Church] at 12:54-62.
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`Uncontrolled, passage of a polynucleotide through a nanopore occurs too
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`quickly for the nanopore system to resolve clear individual base pairs as depicted in
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`Church’s ideal figure. The rate in which a polynucleotide passes through the
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`nanopore is also highly variable, which further confounds the signal. Thus, control
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`of the polynucleotide through the nanopore is a central problem in nanopore
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`sequencing systems.
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`12
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`One method of controlling translocation of polynucleotides through a
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`nanopore that had been proposed was to use enzymes that interact with the
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`polynucleotide. As the ’056 patent explains, many classes of enzymes can be used
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`for this purpose, including DNA or RNA metabolizing enzymes, DNA or RNA
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`translocating enzymes, DNA or RNA binding proteins, among others. See Ex. 1001
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`[’056 Patent] at 23:45-60.
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`In seeking to control translocation, the inventors of the ’056 patent focused
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`not just on the overall function of the enzyme, but on the fact that translocating
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`enzymes were understood to act through a series of steps that were repeated for each
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`successive DNA nucleotide. Each step can be characterized by a rate constant, and
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`can thus be termed a “kinetic step.”
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`Prior art approaches to nanopore sequencing involved trial-and-error attempts
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`to modify the translocating enzyme so that the overall translocation rate of the
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`polynucleotide would be slowed. See Ex. 1004 ¶ [0083]. The inventors of the ’056
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`patent broke away from this paradigm by recognizing that it would be advantageous
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`to create enzymes that exhibited certain behavior at particular periods of action.
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`Rather than simply trying to slow down the enzyme, the inventors pursued an
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`approach focused on providing a more reliable and steady detection period. The
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`inventors discovered that, by modifying the enzyme and the reaction conditions
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`together to cause the enzyme to exhibit two kinetic steps with rate constants with a
`13
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`ratio between 1:10 to 10:1 (preferably 1:1), one could achieve a more reliable
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`detection period. See Ex. 1001 [’056 Patent] at 24:46-49; id. at 26:22-26
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`(“controlling the reaction such that the reaction exhibits two or more kinetically
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`observable, or slow steps can produce a nucleic acid polymerization reaction in
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`which the incorporation of the nucleotides can be observed more accurately”); see
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`also id. at 28:17-20.
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`The behavior of enzymes that exhibit one or two kinetic steps is depicted in
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`Fig. 33 of the ’056 patent:
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`14
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`The figure above shows the probability that a detectable intermediate that can be
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`observed during enzymatic DNA translocation will have a particular “residence
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`time,” or lifetime. When the enzyme is characterized by only a single step, the curve
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`may be characterized by a single exponential function that rapidly decays.
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`On the other hand, when the enzyme can be characterized by “two limiting
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`steps,” which the patent also calls “two kinetically observable steps,” the probable
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`“residence time” curve corresponds to a peaked function that may be characterized
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`by the sum of two exponentials: y=A0e-k1t-B0-k2t, where k1 and k2 represent the rate
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`constants of the two kinetic steps that must fall within a ration from 10:1 to 1:10.
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`See Ex. 1001 [’056 Patent] at 28:44-51. Because the peak probability that the
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`intermediate can be detected is shifted away from time T=0 to a time that is greater
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`than the minimum detection time of the sequencing instrument, Tmin, the detection
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`process is made more reliable. See id. at 24:41-49.
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`Importantly, to exhibit such two-step kinetics, it is not enough that any two
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`steps in the mechanistic process of an enzyme have a ratio of rate constants from
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`10:1 to 1:10. Indeed, multiple kinetic steps may proceed at so fast a rate that they
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`do not impact the exhibited kinetics of the enzyme. Thus, to exhibit the claimed
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`two-step kinetics, it must be the rate limiting steps, which actually impact the
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`kinetics, that have the claimed ratio of rate constants.
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`15
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`Claim 1 of the ’056 patent is representative, and includes limitations directed
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`to an enzyme that exhibits two kinetic steps wherein the ratio of kinetic steps being
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`from 10:1 to 1:10:
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`1. A method for sequencing a nucleic acid template comprising:
`[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 solution and lower solution, the nanopore sized to
`pass a single strand of a nucleic acid;
`[b] providing a voltage across the nanopore to produce a measurable current
`flow through the nanopore;
`[c] controlling the rate of translocation of a single stranded portion of the
`nucleic acid template through the nanopore with a translocating enzyme
`that is associated with the nucleic acid template under reaction conditions
`whereby the translocating enzyme and the reaction conditions are selected
`such that the translocating enzyme exhibits two kinetic steps wherein each
`of the kinetic steps has a rate constant, and the ratio of the rate constants
`of the kinetic steps is from 10:1 to 1:10;
`[d] measuring the current through the nanopore over time as the nucleic acid
`template is translated through the nanopore; and
`[e] determining the sequence of a portion of the nucleic acid template as it
`translates through the nanopore using the measured current over time.
`C. Overview Of The Cited Prior Art
`1.
`U.S. Patent Publication 2006/0063171 (“Akeson”)
`Akeson is directed to a generic nanopore sequencing system. It describes the
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`components of a nanopore sequencing system, including the membranes and
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`nanopore apertures through which the DNA traverses the nanopore. See, e.g., Ex.
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`1004 [Akeson] at Abstract.
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`16
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`Akeson teaches the use of a “molecular motor” to “substantially reduce” the
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`rate of polynucleotide translocation through the nanopore during sequencing. Id. at
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`[0007]-[0009]. Akeson only teaches that a molecular motor should be chosen so
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`that the target polynucleotide “move[s] with respect to the nanopore
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