Paper No. 1
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`––––––––––––––––––
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`––––––––––––––––––
`
`ABS GLOBAL, INC.,
`Petitioner,
`
`v.
`
`CYTONOME/ST, LLC,
`Patent Owner.
`
`––––––––––––––––––
`Case No. IPR2017-02162
`Patent No. 9,446,912 B2
`Issued: September 20, 2016
`Filed: August 16, 2013
`
`Inventors: John R. Gilbert, Manish Deshpande, and Bernard Bunner
`
`Title: MULTILAYER HYDRODYNAMIC SHEATH FLOW STRUCTURE
`––––––––––––––––––
`
`PETITION FOR INTER PARTES REVIEW
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`––––––––––––––––––
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`––––––––––––––––––
`
`ABS GLOBAL, INC.,
`Petitioner,
`
`v.
`
`CYTONOME/ST, LLC,
`Patent Owner.
`
`––––––––––––––––––
`Case No. IPR2017-02162
`Patent No. 9,446,912 B2
`Issued: September 20, 2016
`Filed: August 16, 2013
`
`Inventors: John R. Gilbert, Manish Deshpande, and Bernard Bunner
`
`Title: MULTILAYER HYDRODYNAMIC SHEATH FLOW STRUCTURE
`––––––––––––––––––
`
`PETITION FOR INTER PARTES REVIEW
`
`
`
`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
`
`TABLE OF CONTENTS
`
`Exhibit List (Attachment B) ...................................................................................... vi
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`COMPLIANCE WITH REQUIREMENTS FOR A PETITION FOR INTER
`PARTES REVIEW ........................................................................................... 4
`
`A.
`
`B.
`
`Certification that the ’912 Patent May Be Contested by Petitioner ...... 4
`
`Fee for Inter Partes Review (37 CFR § 42.15(a)) ................................ 5
`
`C. Mandatory Notices (37 CFR § 42.8(b)) ................................................ 5
`
`i.
`
`ii.
`
`iii.
`
`iv.
`
`v.
`
`Real Party in Interest (§ 42.8(b)(1)) ............................................ 5
`
`Other Proceedings (§ 42.8(b)(2)) ................................................ 5
`
`Lead and Backup Lead Counsel (§ 42.8(b)(3)) .......................... 6
`
`Service on Petitioner (§ 42.8(b)(4)) ............................................ 6
`
`Proof of Service (37 CFR §§ 42.6(e) and 42.105(a)) ................. 6
`
`III. RELEVANT INFORMATION CONCERNING THE CONTESTED
`PATENT .......................................................................................................... 6
`
`A.
`
`B.
`
`Effective Filing Date of the ’912 Patent ............................................... 6
`
`Background of the Technology ............................................................. 7
`
`i.
`
`ii.
`
`Miyake (Ex. 1010) ...................................................................... 8
`
`Tashiro (Ex. 1011) ...................................................................... 9
`
`iii. Weigl (Ex. 1005) ....................................................................... 10
`
`iv.
`
`Nieuwenhuis 2001, 2002, and 2003 (Exs. 1012, 1013, 1014) .. 13
`
`v. Wada (Ex. 1006) ....................................................................... 17
`
`i
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`
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`vi. Haussecker (Ex. 1015) .............................................................. 18
`
`vii. Flow Cytometers Using Microfluidic Hydrodynamic Focusing
`Were Commercially Marketed Before 2003 ............................. 19
`
`C.
`
`Person of Ordinary Skill in the Art ..................................................... 23
`
`D. Overview of the ’912 Patent ................................................................ 24
`
`E.
`
`F.
`
`Identification of Claims Being Challenged ......................................... 25
`
`Construction of Terms Used in the Claims ......................................... 27
`
`i.
`
`ii.
`
`“Suspending” (Claims 2, 15) ..................................................... 28
`
`“Symmetrically introduced . . . with respect to a centerline of
`the primary flow channel” (Claim 21) ...................................... 29
`
`IV. PRECISE REASONS FOR RELIEF REQUESTED .................................... 30
`
`A. Wada Anticipates Claim 2 ................................................................... 30
`
`i.
`
`Overview of Wada (Ex. 1006) .................................................. 30
`
`ii. Wada Anticipates Claim 2 ........................................................ 36
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Preamble ......................................................................... 36
`
`A Primary Flow Channel ................................................ 38
`
`A First Sheath Fluid Channel ......................................... 41
`
`A Second Sheath Fluid Channel ..................................... 43
`
`Second Sheath Fluid Introduction Region Downstream of
`
`the First Sheath Fluid Introduction Region .................... 46
`
`6.
`
`First Sheath Fluid Channel is One of a Symmetrical
`
`Pair .................................................................................. 47
`
`ii
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`
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`iii. Wada Anticipates Claim 15 ...................................................... 49
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`Preamble ......................................................................... 49
`
`A Primary Flow Channel ................................................ 49
`
`A First Sheath Fluid Channel ......................................... 50
`
`A Second Sheath Fluid Channel ..................................... 50
`
`Second Sheath Fluid Region Downstream of the First
`
`Sheath Fluid Region ....................................................... 51
`
`Sample Fluid Inlet .......................................................... 51
`
`Sheath Fluid Inlet ............................................................ 54
`
`Sample Fluid Inlet in Fluid Communication with Primary
`
`Flow Channel .................................................................. 55
`
`9.
`
`Sample Fluid Inlet and Sheath Fluid Inlet on Same
`
`Surface ............................................................................ 57
`
`iv. Wada Anticipates Claim 20 ...................................................... 58
`
`v. Wada Anticipates Claim 21 ...................................................... 59
`
`vi. Wada Anticipates Claim 22 ...................................................... 61
`
`vii. Wada Anticipates Claim 23 ...................................................... 63
`
`viii. Wada Anticipates Claim 24 ...................................................... 64
`
`ix. Wada Anticipates Claim 25 ...................................................... 65
`
`B.
`
`Claims 2, 15, and 20–25 Would Have Been Obvious to a Skilled
`Person in View of Wada in Combination with Micronics 2001 ......... 66
`
`iii
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`
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`C.
`
`Claim 18 Would Have Been Obvious to a Skilled Person in View of
`Wada in Combination with Nieuwenhuis 2002 .................................. 72
`
`V.
`
`CONCLUSION .............................................................................................. 77
`
`Certificate Of Compliance ....................................................................................... 78
`
`Certificate Of Service (Attachment A) .................................................................... 79
`
`
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`iv
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Great W. Casualty Co. v. Transpacific IP I Ltd.,
`IPR2015-01912, Paper 10 (P.T.A.B. Mar. 22, 2016) ......................................... 26
`Microsoft Corp. v. Parallel Networks Licensing, LLC,
`IPR2015-00486, Paper 10 (P.T.A.B. July 15, 2015) .......................................... 27
`Other Authorities
`35 U.S.C. § 102(a) ............................................................................................. 25, 31
`35 U.S.C. § 102(e) ............................................................................................. 25, 31
`35 U.S.C. § 103(a) ............................................................................................. 25, 26
`35 U.S.C. § 325(d) ................................................................................................... 26
`37 CFR § 42.6(e) ........................................................................................................ 6
`37 CFR § 42.8(b) ................................................................................................... 5, 6
`37 CFR § 42.15(a) ...................................................................................................... 5
`37 CFR § 42.100(b) ................................................................................................. 27
`37 CFR § 42.105(a) .................................................................................................... 6
`M.P.E.P. § 2111.01 .................................................................................................. 27
`
`
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`v
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`EXHIBIT LIST (ATTACHMENT B)
`
`Exhibit Description
`No.
`1001 U.S. Patent No. 9,446,912 (“’912 Patent”)
`1002 File History of U.S. Patent No. 9,446,912 (“’912 FH”)
`1003 Declaration of Dino Di Carlo, Ph.D.
`1004 Curriculum Vitae of Dino Di Carlo, Ph.D.
`1005 U.S. Patent No. 6,159,739 to Weigl et al. (“Weigl”)
`1006 U.S. Patent No. 6,506,609 to Wada et al. (“Wada”)
`1007 Comparison of Specifications in Wada and U.S. Application No.
`09/569,747
`(Reserved)
`1008
`1009 Random House Webster’s Unabridged Dictionary (2d ed. 2001)
`1010 Miyake et al., “A Development of Micro Sheath Flow Chamber,” in
`Proceedings of the IEEE Micro Electro Mechanical Systems Workshop
`1991, 265–270 (Jan. 1991) (“Miyake”)
`1011 Tashiro et al., “Design and Simulation of Particles and Biomolecules
`Handling Micro Flow Cells with Three-Dimensional Sheath Flow,” in
`Proceedings of the μTAS 2000 Symposium, 209–212 (May 14, 2000)
`(“Tashiro”)
`1012 Nieuwenhuis et al., “Particle-Shape Sensing-Elements for Integrated
`Flow Cytometer,” in Proceedings of the μTAS 2001 Symposium, 357–
`358 (Oct. 21, 2001) (“Nieuwenhuis 2001”)
`1013 Nieuwenhuis et al. “Virtual Flow Channel: A Novel Micro-fluidics
`System with Orthogonal, Dynamic Control of Sample Flow
`Dimensions,” in Proceedings of the μTAS 2002 Symposium, Vol. 1,
`103–105 (Nov. 3, 2002) (“Nieuwenhuis 2002”)
`1014 Nieuwenhuis et al., “Integrated flow-cells for novel adjustable sheath
`flows,” Lab Chip 3:56–61 (Mar. 2003) (“Nieuwenhuis 2003”)
`1015 U.S. Publication No. 2004/0043506 (“Haussecker”)
`1016 File History of U.S. Application No. 10/232,170 (“Haussecker FH”)
`
`vi
`
`
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`1017 Weigl et al., “Design and Rapid Prototyping of Thin-Film Laminate-
`Based Microfluidic,” Biomedical Microdevices 3(4):267–274 (2001)
`(“Micronics 2001”)
`1018 File History of U.S. Patent No. 6,506,609 (“Wada FH”)
`1019 Shapiro, Practical Flow Cytometry, 55-57, 166–169 (4th ed. 2003)
`1020 Altendorf et al., “Results Obtained Using a Prototype Microfluidics-
`Based Hematology Analyzer,” in Proceedings of the μTAS 1998
`Symposium, 73–76 (Oct. 1998) (“Micronics 1998”)
`1021 Shapiro, Practical Flow Cytometry, 15–17, 133–135 (3d ed. 1995)
`1022
`(Reserved)
`1023
`(Reserved)
`1024 Di Carlo et al., “Enhanced Velocity Gradients Within Microfluidics For
`Cellular Manipulation,” in Proceedings of the μTAS 2002 Symposium,
`Vol. 2, 799–801 (Nov. 3, 2002)
`
`
`
`vii
`
`
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
`
`I.
`
`INTRODUCTION
`
`The ’912 Patent generally concerns techniques used for controlling the flow
`
`of particles and fluids, techniques that have particular utility, for example, in
`
`analyzing samples using flow cytometers. Flow cytometers function by passing
`
`individual particles, such as cells, within a stream of fluid past a detector, which
`
`measures certain characteristics of each particle and takes actions based on that
`
`evaluation. To do that, the flow cytometer must regulate the flow of the sample so
`
`that the particles in the sample move into a substantially single-file particle stream,
`
`which enables each particle to be measured individually by the detector.
`
`The process by which particles in a sample are moved into this particle
`
`stream is generally referred to as “hydrodynamically focusing” the sample or
`
`particles. Ex. 1003 (Di Carlo Declaration) ¶¶ 43–48. It involves introducing a
`
`sample into a stream of fluid that carries the sample through a physical channel (a
`
`“flow chamber”) leading to the detector. An illustration of hydrodynamic focusing
`
`in a flow cytometer is provided in Miyake. See Ex. 1010 (“Miyake”); Ex. 1003
`
`¶ 50. Miyake shows in Figure 1 a stream of particles within a sample being
`
`narrowly focused within the flow chamber, which allows the light source and
`
`scattered light detector in the flow cytometer to interrogate each particle in the
`
`stream individually:
`
`1
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`
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`
`
`Ex. 1010, Fig. 1; Ex. 1003 ¶ 50. The introduced fluid that surrounds, moves, and
`
`positions the sample is typically referred to as “sheath fluid.”
`
`“Sheath flow” refers to a particular type of fluid flow in which one layer of
`
`fluid (e.g., the sheath layer, which contains sheath fluid) surrounds another layer of
`
`fluid (e.g., the sample layer, which contains particles) on more than one side. Ex.
`
`1003 ¶¶ 44–45. For example, the sheath layer may form a concentric layer of fluid
`
`around a sample layer, surrounding the sample layer on all sides. Ex. 1003 ¶¶ 44–
`
`45. Figure 1 of Weigl illustrates this well-known concept. See Ex. 1005
`
`(“Weigl”), 2:1–5; Ex. 1003 ¶¶ 44–45. It provides a cross-sectional depiction of a
`
`flow channel in which a particle within a central sample layer is suspended in a
`
`sheath fluid layer and surrounded on all sides by sheath fluid:
`2
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`
`
`Ex. 1005, Fig. 1 (annotated to include red circles); Ex. 1003 ¶¶ 44–45.
`
`As Weigl explains, the sample was placed into the sheath flow “by injecting,
`
`via a needle or other concentric opening, a center fluid (41) containing a sample
`
`with particles (42) into a sheath fluid . . . .” Ex. 1005, 1:37–42; Ex. 1003 ¶ 45.
`
`The sheath of fluid (40) around the particles (42) in the sample (41) prevents the
`
`particles from contacting the sides of the flow channel. See Ex. 1005, 1:18–37,
`
`2:1–14; Ex. 1003 ¶ 45. This prevents clogging, protects particles (such as live
`
`cells), and produces more uniform velocity and transit times through detectors.
`
`See Ex. 1005, 2:5–14; Ex. 1003 ¶ 45.
`
`The purported invention of the ’912 Patent—a flow structure for suspending
`
`a particle in a sheath fluid—is squarely within the prior art. Long before the ’912
`
`Patent was filed, flow structures far more sophisticated than those claimed in the
`
`’912 Patent had been described in a number of publications and patents. Ex. 1003
`
`¶¶ 44–45, 49–105.
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`3
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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` One such system and its use in providing hydrodynamic focusing in flow
`
`cytometry applications was described in U.S. Patent No. 6,506,609 to Wada et al.
`
`(“Wada”). Wada—filed more than four years before the earliest priority date of
`
`the ’912 Patent—described advanced microfluidic systems that employ one or
`
`more inlets to hydrodynamically focus samples and particles within the samples.
`
`As discussed in detail below in section IV, Wada anticipates or would have
`
`rendered obvious systems and methods meeting each and every limitation of the
`
`challenged claims. As each of the challenged claims of the ’912 Patent is
`
`unpatentable, the Board should institute trial on the basis of this petition and cancel
`
`these claims.
`
`As discussed in detail below, Wada anticipates or would have rendered
`
`obvious flow structures meeting each and every limitation of the challenged
`
`claims. As the challenged claims of the ’912 Patent are unpatentable, the Board
`
`should institute trial on the basis of this petition and cancel these claims.
`
`II. COMPLIANCE WITH REQUIREMENTS FOR A PETITION FOR
`INTER PARTES REVIEW
`A. Certification that the ’912 Patent May Be Contested by Petitioner
`
`ABS Global, Inc. (“Petitioner”) certifies it is not barred or estopped from
`
`requesting inter partes review of U.S. Patent No. 9,446,912 (“’912 Patent”) (Ex.
`
`1001). Neither Petitioner, nor any party in privity with Petitioner, (i) has filed a
`
`civil action challenging the validity of any claim of the ’912 Patent; or (ii) has been
`4
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`served a complaint alleging infringement of the ’912 Patent more than a year prior
`
`to the present date. Also, the ’912 Patent has not been the subject of a prior inter
`
`partes review or a finally concluded district court litigation involving Petitioner.
`
`Petitioner therefore certifies that the ’912 Patent is available for inter partes
`
`review.
`
`B.
`
`Fee for Inter Partes Review (37 CFR § 42.15(a))
`
`The Director is authorized to charge the fee specified by 37 CFR § 42.15(a)
`
`to Deposit Account No. 50-1597.
`
`C. Mandatory Notices (37 CFR § 42.8(b))
`
`i.
`
`Real Party in Interest (§ 42.8(b)(1))
`
`The real parties-in-interest in this petition are (1) ABS Global, Inc., located
`
`at 1525 River Rd., DeForest, WI 53532; and (2) Genus plc, located at Belvedere
`
`House, Basing View, Basingstoke, Hampshire RG21 4DZ, UK.
`
`ii.
`
`Other Proceedings (§ 42.8(b)(2))
`
`The ’912 Patent is the subject of litigation in the United States District Court
`
`for the District of Wisconsin (Civil Action Case No. 3:17-cv-446), which names
`
`ABS Global, Inc. and Genus plc, among others, as defendants.
`
`Petitions for inter partes review of certain claims of U.S. Patent Nos.
`
`8,529,161, 7,611,309, and 7,311,476, which each share a common specification
`
`5
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`
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`with the ’912 Patent, are also filed concurrently in Case Nos. IPR2017-02097,
`
`IPR2017-02161, and IPR2017-02163, respectively.
`
`iii.
`
`Lead and Backup Lead Counsel (§ 42.8(b)(3))
`
`Lead Counsel
`
`Jeffrey P. Kushan
`Reg. No. 43,401
`jkushan@sidley.com
`(202) 736-8914
`
`Backup Lead Counsel
`
`Lisa A. Schneider
`Reg. No. 43,907
`lschneider@sidley.com
`(312) 853-7567
`
`Paul J. Zegger
`Reg. No. 33,821
`pzegger@sidley.com
`(213) 896-6000
`
`iv.
`
`Service on Petitioner (§ 42.8(b)(4))
`
`
`
`Service on Petitioner may be made by e-mail (IPRNotices@sidley.com),
`
`mail, or hand delivery to: Sidley Austin LLP, 1501 K Street, N.W., Washington,
`
`D.C. 20005. The fax number for Lead and Backup Counsel is (202) 736-8711.
`
`v.
`
`Proof of Service (37 CFR §§ 42.6(e) and 42.105(a))
`
`Proof of service is provided in Attachment A.
`
`III. RELEVANT INFORMATION CONCERNING THE CONTESTED
`PATENT
`
`A. Effective Filing Date of the ’912 Patent
`
`The application that led to the ’912 Patent claims priority to a provisional
`
`application that was filed on October 30, 2003. While Petitioner does not believe
`
`that the ’912 Patent claims are entitled to that effective filing date, the prior art
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`6
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`
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`used in this petition is dated substantially earlier than October 30, 2003. It is thus
`
`unnecessary for the Board to determine whether the claims are entitled to their
`
`claimed priority date.
`
`B.
`
`Background of the Technology
`
`A wide variety of flow structures for hydrodynamically focusing fluids and
`
`particles were known before the effective filing date of the ’912 Patent. Ex. 1003 ¶
`
`48. These structures used a variety of configurations and methods for
`
`hydrodynamic focusing, all of which achieved the same goal as achieved by the
`
`disclosure of the ’912 Patent: suspending particles in sheath fluid. See generally
`
`Ex. 1005, 1006, 1010–1015, 1017; Ex. 1003 ¶¶ 48–105. All of these prior art
`
`systems and techniques have particular value in flow cytometry applications
`
`because they all enable the precise positioning of particles in a sample within a
`
`flow channel. Ex. 1003 ¶¶ 43, 60–64; see also Ex. 1005, 1:18–22, 2:5–7 (“Sheath
`
`flow is useful because it positions particles with respect to illuminating light, e.g., a
`
`laser beam . . . .”). To obtain accurate measurements in such a setting, “particles
`
`are arranged in single file, typically by hydrodynamic focusing within a sheath
`
`fluid . . . .” Ex. 1005, 1:24–27; Ex. 1003 ¶¶ 60–62.
`
`A brief summary of some of these prior art systems is provided below. This
`
`summary shows that a skilled person prior to the earliest effective filing date of the
`
`’912 Patent would have understood that sheath flow structures suspending a
`
`7
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`particle in sheath fluid could be made using microfluidic designs that employed
`
`one or more sheath fluid inlets along a flow channel. With the exception of Wada
`
`and Weigl, none of the prior art references discussed below in subsections (i)–
`
`(vii) were cited during prosecution of the ’912 Patent.
`
`i.
`
`Miyake (Ex. 1010)
`
`Miyake et al. described a two-layer channel design to achieve three-
`
`dimensional focusing in a flow cytometer system. See Ex. 1010 (“Miyake”); Ex.
`
`1003 ¶ 50. This was done by squeezing the sample fluid entering through an inlet
`
`(“nozzle”) in a shorter channel with sheath fluid entering from both sides in taller
`
`channels, as shown below:
`
`
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`8
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`
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`Ex. 1010, Fig. 4; Ex. 1003 ¶ 51. Miyake explained that its microfluidic system
`
`induced a flow that “envelope[d] the sample fluid from all sides.” Ex. 1010, 267;
`
`Ex. 1003 ¶¶ 52–53. As a result of the sheath fluid entering the primary flow
`
`channel from two opposed inlets, particles within the sample fluid were focused at
`
`the center of the flow channel (“capillary tube”). Ex. 1010, Fig. 13; Ex. 1003 ¶ 52.
`
`ii.
`
`Tashiro (Ex. 1011)
`
`Tashiro et al. also described use of a multilayer design to produce three-
`
`dimensional focusing. Ex. 1011 (“Tashiro”). In this design, sheath fluid entered at
`
`a wider inlet (“Carrier Inlet”) upstream of a sample inlet, shown below, to produce
`
`“[p]articles and cell handling micro fluidic devices . . . using laminar behavior in
`
`microfabricated flow channels”:
`
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`9
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`Ex. 1011, 209, Fig. 2; Ex. 1003 ¶ 54. The sheath fluid (“carrier flow”) is shown
`
`flowing downstream, where it surrounds the sample flow from three sides. Ex.
`
`1011, 209, Fig. 2; Ex. 1003 ¶ 55. A second inlet (“Carrier Inlet”) further
`
`downstream of the first sheath fluid inlet and the sample inlet introduced additional
`
`sheath fluid to surround the sheath flow from a fourth side. Ex. 1011, 209, Fig. 2;
`
`Ex. 1003 ¶ 55. The fluid introduced through these inlets hydrodynamically
`
`focused the sample in three dimensions, as illustrated below:
`
`
`
`Ex. 1011, Fig. 1(b); Ex. 1003 ¶ 55.
`
`iii.
`
`Weigl (Ex. 1005)
`
`
`
`Weigl illustrated a multiple inlet design that provides three-dimensional
`
`hydrodynamic focusing of a sample in a flow channel. Its design (below) showed
`
`use of both sheath fluid inlets and flow channel geometry to achieve hydrodynamic
`
`focusing:
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`10
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`
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`Ex. 1005 (“Weigl”), Fig. 5A; Ex. 1003 ¶¶ 56–57. Sheath fluid from a first sheath
`
`fluid inlet (10b) surrounded a sample entering the flow channel (8b) through a
`
`narrower, downstream sample injection inlet (20b) at inlet junction (21b). Ex.
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`1005, Fig. 5A; id., 11:62–12:15 and 12:42–50; Ex. 1003 ¶ 57. The sheath fluid
`
`surrounded the sample on three sides (focusing the sample away from the top, left,
`
`and right sides of the flow channel) and narrowed the sample stream within the
`
`flow channel. Ex. 1005, 11:62–12:15 and 12:42–50; Ex. 1003 ¶ 57. Sheath fluid
`
`from a second sheath fluid inlet (40) downstream of the sample inlet surrounded
`
`the sample on a fourth side (focusing the sample away from the bottom of the flow
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`channel) at inlet junction (41). This concentrically surrounded the sample with
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`sheath fluid and further narrowed the sample stream. Ex. 1005, Fig. 5A; id.,
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`11:62–12:15 and 12:42–50; Ex. 1003 ¶ 58.
`
`Weigl also shows use of tapered flow channel geometry downstream of the
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`sheath fluid inlets to further focus the sample horizontally and/or vertically. Ex.
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`11
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`1003 ¶ 59; see Ex. 1005, Fig. 5B. This is depicted, for example, at region 26b in
`
`Figure 5B, copied below:
`
`
`
`Ex. 1005, Fig. 5B.
`
`Weigl also discussed the practical utility of these systems for flow
`
`cytometry. See Ex. 1005 at 1:18–22; Ex. 1003 ¶ 60. Weigl noted that, in this
`
`setting, “[s]heath flow is useful because it positions particles with respect to
`
`illuminating light, e.g., a laser beam . . . .”). Ex. 1005 at 2:5–7; Ex. 1003 ¶ 61. For
`
`measurement in these systems, Weigl noted that “particles are arranged in single-
`
`file, typically by hydrodynamic focusing within a sheath fluid . . . .” Ex. 1005 at
`
`1:24–27; Ex. 1003 ¶ 62. To make the precise adjustments required for such
`
`focusing, “[f]low cytometers often use two concentric fluids to carry particles
`
`through the measurement zone,” which “facilitates the passage of the particles
`
`through the measurement zone in a single file fashion, and helps avoid clogging of
`
`the flow channel,” as exemplified in the microfluidic systems of Weigl. Ex. 1005
`
`at 1:27–33; Ex. 1003 ¶¶ 63–64.
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`12
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`iv.
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`Nieuwenhuis 2001, 2002, and 2003 (Exs. 1012, 1013, 1014)
`
`A series of papers from Nieuwenhuis et al. describe similar designs to
`
`achieve three-dimensional focusing using sheath fluid injected through a
`
`combination of sheath flow inlets. Ex. 1003 ¶¶ 67–79, 84–89.
`
`Nieuwenhuis 2001 shows use of two sheath fluid inlets—one upstream and
`
`one downstream relative to the sample inlet—to produce hydrodynamic focusing:
`
`
`
`Ex. 1012, Fig. 5; Ex. 1003 ¶ 67.
`
`In particular, the first sheath inlet (“Sheath inlet 1”) intersected the flow
`
`channel upstream of a narrower, downstream sample inlet (“Sample inlet”), and
`
`was used to inject sheath fluid into the flow channel. Ex. 1003 ¶ 68. The sample
`
`inlet entered the device from the bottom, and injected a sample (“Sample liquid”)
`
`upward through the sample inlet into the flow channel, where it met the sheath
`
`fluid from the first sheath inlet. Ex. 1003 ¶ 68. A first focusing step occurred at
`13
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`this point, where sheath fluid was focused around the sample on the left and right
`
`sides and the top of the sample. Ex. 1003 ¶ 69.
`
`The sheath fluid and sample then flowed down the channel until they
`
`encountered the second sheath inlet (“Sheath inlet 2”), which introduced additional
`
`sheath fluid into the flow channel from the bottom. Ex. 1003 ¶¶ 69–70. This
`
`provided a second focusing of the sample, moving sheath fluid around the bottom
`
`of the sample fluid flow. Ex. 1003 ¶ 71. After this point, the sample was
`
`surrounded on all sides (left, right, top, and bottom) by sheath fluid, and flowed
`
`through the remainder of the microfluidic system depicted in Figure 5. Ex. 1003
`
`¶ 71.
`
`Nieuwenhuis 2001 also explained how to adjust the position of the sample
`
`fluid (e.g., up or down) within the flow channel by manipulating the flow rates in
`
`the second sheath inlet, as in the three inset panels on the right-hand side of Figure
`
`5. Ex. 1003 ¶ 73. For example, the sample fluid could be focused into the center
`
`of the flow channel (middle panel); adjusted up, by increasing the flow through the
`
`second sheath inlet (top panel); or adjusted down by decreasing the flow through
`
`the second sheath inlet (bottom panel). See Ex. 1012, Fig. 5; Ex. 1003 ¶ 73.
`
`In Nieuwenhuis 2002, a similar design, shown below, provided additional
`
`horizontal control over the sample:
`
`14
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`
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`Ex. 1013, Fig. 1; Ex. 1003 ¶¶ 74–75. Horizontal control in this design was
`
`provided by a pair of horizontally opposed sheath fluid inlets (labeled “Control
`
`inlet[s]”) positioned downstream from the sample inlet, which enabled various
`
`adjustments of the dimensions and position of the sample flow in a lateral
`
`dimension. Ex. 1003 ¶ 76. Figure 5 shows before-and-after images demonstrating
`
`that introduction of sheath fluid through these sheath fluid inlets narrowed the
`
`sample stream by surrounding the sample on the left and right sides:
`
`
`
`
`
` (Before)
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`15
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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` (After)
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`Ex. 1013, Fig. 5 (annotated to include red circles and text annotations); Ex. 1003
`
`¶¶ 77–78.
`
`Nieuwenhuis 2003 showed another variation of this design that enabled
`
`adjustable, dynamic, three-dimensional focusing in both horizontal and vertical
`
`directions:
`
`
`
`Ex. 1014, Fig. 3; Ex. 1003 ¶ 84. The design shown in Nieuwenhuis 2003
`
`combined elements found in Nieuwenhuis 2001 and Nieuwenhuis 2002. It
`
`included a wider sheath flow inlet upstream of a narrower sample inlet, a
`
`downstream vertical position inlet, a tapered region, and a downstream horizontal
`
`16
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`control inlet to further position the sample stream, or core flow, within the flow
`
`channel by manipulating the flow of sheath fluid around the top, bottom, left, and
`
`right sides of the sample. Ex. 1003 ¶¶ 84–87. These elements allowed further
`
`manipulation of the flow of sheath fluid around the top, bottom, left, and right
`
`sides of the sample, and thus enabled a number of fine positional adjustments to
`
`the sample. Ex. 1014, Fig. 4; Ex. 1003 ¶¶ 87–89.
`
`v.
`
`Wada (Ex. 1006)
`
`Wada et al. described a design that used inlet microchannels to focus a
`
`particle-containing sample within a main flow channel. See Ex. 1006, 9:8–26; Ex.
`
`1003 ¶ 65. One embodiment of this design (depicted in Figure 1A) shows a cross-
`
`section of a microfabricated sheath flow structure that is designed to focus the
`
`particles in a sample into the center of the main channel by injecting fluid through
`
`two orthogonal inlet microchannels.
`
`
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`17
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`See Ex. 1006, Fig. 1A, 9:8–26; Ex. 1003 ¶ 65. Wada also showed other
`
`embodiments that incorporate additional inlet microchannels in a variety of
`
`configurations to provide further control over the position of particles within the
`
`main channel, as discussed below in Section IV. See, e.g., Ex. 1006, Figs. 22–23;
`
`Ex. 1003 ¶ 66.
`
`vi.
`
`Haussecker (Ex. 1015)
`
`Haussecker described designs similar to those shown in Wada, which it
`
`explained provide “multi-step (cascading), hydrodynamic fluid focusing,” as
`
`illustrated in Figure 2:
`
`
`
`Ex. 1015, Fig. 2 ¶¶ [0023]–[0027]; Ex. 1003 ¶ 80. In this design, at least “two
`
`focusing steps” were used. Ex. 1005 ¶ [0027]; Ex. 1003 ¶ 81. In a first step,
`
`sheath fluid was injected through microchannels 34 and 32 to focus the sample in a
`
`first circled region (36). Ex. 1003 ¶ 81. In a second step, sheath fluid was injected
`
`through microchannels 48 and 46 to further focus the sample in a second circled
`18
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`IPR2017-02162 Petition for Inter Partes Review of U.S. Patent No. 9,446,912 B2
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`region (44). Ex. 1003 ¶ 81. With each step, “the sample fluid (an outline of which
`
`is depicted by the continuous, dashed streamline within the center channel 30)”
`
`became more focused. Ex. 1015 ¶¶ [0024]–[0026]; Ex. 1003 ¶ 82. Optional,
`
`“additional focusing channels”—depicted on the right-hand side of the figure—
`
`were suggested to focus the sample further. Ex. 1015 ¶ [0027]; Ex. 1003 ¶ 82.
`
`The claims in Haussecker are very similar to the challenged claims of the
`
`’912 Patent. E.g., Ex. 1016 (“Haussecker FH”), 149, cl. 38; see also id., 144, cl. 1;
`
`145, cl. 13; 146, cl. 18; 147, cl. 21; 148, cl. 33. Notably, all of the Haussecker
`
`claims were rejected as anticipated by U.S. Patent No. 6,592,821 to Wada et
`
`al.—which shares a common specification with Wada—and thereafter
`
`abandoned. Ex. 1016, 1–9; Ex. 1003 ¶ 83.
`
`vii.
`
`Flow Cytometers Using Microfluidic Hydrodynamic Focusing
`Were Commercially Marketed Before 2003
`
`Flow cytometers incorporating microfluidic devices had been commercially
`
`marketed well before 2003. See, e.g., Ex. 1019, 167; Ex.
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