IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`C.A. No. 19-1681-CFC
`
`The Trustees of Columbia University in the City
`of New York and QIAGEN Sciences, LLC
`v.
`Illumina, Inc.
`
`Plaintiffs’ Claim Construction Presentation
`
`September 2, 2020
`
`1
`
`Illumina Ex. 1162
`Illumina v. Columbia
`IPR2020-01177
`
`

`

`
`
`
`
`
`CompositionCompositositosittit nnionti
`
`
`
`
`Patentststs-ss--innninin-nnnn--Suit
`
`Nucleotide ucleotid
`
`base
`
`Amended Complaint
`
`Cite
`
`G
`
`A
`
`T
`
`C
`
`U.S. Patent No. 10,407,458
`(“’458 Patent”)
`
`U.S. Patent No. 10,407,459
`(“’459 Patent”)
`
`U.S. Patent No. 10,435,742
`(“’742 Patent”)
`
`U.S. Patent No. 10,457,984
`(“’984 Patent”)
`
`Method
`Patent-in-Suit
`
`U.S. Patent No. 10,428,380
`(“’380 Patent”)
`
`Count I
`
`Count II
`
`Count IV
`
`Count V
`
`JA0001-21
`(excerpts)
`D.I. 36-1
`
`D.I. 36-2
`
`D.I. 36-3
`
`D.I. 36-4
`
`Amended Complaint
`
`Cite
`
`Count III
`
`JA0022-27
`(excerpts)
`D.I. 36-5
`
`2
`
`

`

`Technology Background
`
`3
`
`

`

`Double Stranded DNA, Made From Nucleotides
`
`A
`
`T
`
`PRIMER
`G
`
`T
`
`GROWING COPYY
`
`
`T
`C
`
`C
`
`A
`
`A
`TEMPLATE
`
`G
`
`
`
`GG
`
`
`
`CC
`
`
`
`GG
`
`
`
`TT
`
`T
`
`A
`
`POLYMERASE
`
`Source: Left image (demonstrative based on public information); right image (enhanced figure from Joint Claim Construction Br., p. 15).Source: Le
`
`
`4
`
`GC
`GC
`
`C
`C
`
`G
`G
`
`TA
`TA
`
`CCCCCCCCCCCC
`C
`G
`G
`
`
`GG
`CCCCCCCCCC
`C
`
`G C
`G C
`
`T
`T
`
`AAAAAAAAA
`A
`
`GGGGGGGGGGGGGGGGGGGG
`C
`
`G C
`
`BASE PAIR
`
`

`

`Modified Nucleotides and Sequencingngngngng-gggg--bybybbybybybbbbb -yyyyyyyy--Synthesis (“SBS”)
`
`G
`
`T
`
`T
`
`CG
`
`PRIMER
`G
`
`C
`
`T
`
`A
`
`GROWING COPY
`T
`C
`
`G
`
`A
`TEMPLATE
`
`CLEAVABLE
`FLUORESCENT DYE
`
`CLEAVABLE
`CAP
`
`GROWING COPY
`T
`C
`
`G
`
`C
`
`G
`
`T
`
`T
`
`A
`TEMPLATE
`
`PRIMER
`G
`
`C
`
`T
`
`A
`
`Source: Demonstrative based on description of SBS in Joint Claim Construction Br., pp. 10-11, 16.
`
`5
`
`

`

`Modified Nucleotide for SBS
`
`Nucleotide
`
`Modified Nucleotide for SBS
`
`OH
`
`OR
`
`Source: JA0020 (modified nucleotide).
`
`6
`
`

`

`Claim Construction
`
`Claim Construction
`
`7
`
`

`

`Disputedd Term
`
`Plaintiffs’ Proposed Construction
`
`Defendant’s Proposed Construction
`
`“Y”
`
`“Small”
`
`“R . . . is stable
`during a DNA
`polymerase
`reaction”
`
`“A method for
`sequencing a
`nucleic acid”
`
`“Represents a part of the nucleotide analogue,
`attaching the base of the nucleotide analogue to
`a tag, as depicted in the illustration of the
`nucleotide analogue in the claim”
`
`“A chemical group that has a diameter, i.e.,
`width, that is less than 3.7Å”
`
`“A single linker that directly connects the base to
`the label”
`
`“A chemical group that fits within the rat DNA
`polymerase active site shown in Fig. 1 of the
`patent, i.e. has a longest dimension less than
`3.7Å, including the 3ʹ oxygen”
`
`“R remains bonded to 3’ oxygen during a DNA
`polymerase reaction”
`
`“R has at least the stability of a MOM ether
`(-CH2OCH3) or allyl (-CH2CH=CH2) group”
`
`“A method for detecting the identity and
`sequence of a strand of nucleotides”
`
`Preamble is not limiting
`
`“Y”, “Small”, and “R . . . is stable during a DNA polymerase reaction” terms are from the ’458 Patent (Claims 1, 2), the ’459 Patent (Claims 1, 2),
`the ’742 Patent (Claims 1, 2), the ’984 Patent (Claims 1, 2), and the ’380 Patent (Claims 1, 3). “A method for sequencing a nucleic acid” term is
`from the ’380 Patent (Claims 1, 3).
`Source: JA0101-112 (Disputed Claim Terms and Proposed Constructions).
`
`8
`
`

`

`“Y”
`
`9
`
`

`

`“Y”
`
`Plaintiffs’ Proposed Construction
`
`Defendant’s Proposed Construction
`
`“Represents a part of the nucleotide analogue,
`attaching the base of the nucleotide analogue
`to a tag, as depicted in the illustration of the
`nucleotide analogue in the claim”
`
`“A single linker that directly connects the base
`to the label”
`
`Source: JA0020; JA0026.
`
`10
`
`

`

`“Y”
`Claims and Written Description of Patents-in-Suit Show “Y” as a “Linker” Made From
`Multiple Linkers
`
`Figures 7, 8
`
`Base
`
`Alkynylamino
`Linker
`
`Tag
`
`Photocleavable
`Linker
`
`Y
`
`Source: JA0004-5 (’458 Patent Fig. 7 (2nd nucleotide from the bottom), Fig. 8 (bottom nucleotide)) (annotations added);
`JA0019 (’458 Patent 23:50-59 (referring to Fig. 7 as containing a “linker”)); see also JA0033-34 (’458 Patent File History) (directing Examiner to Figs. 7 and 8 and prior art).
`
`11
`
`

`

`“Y”
`In Its Patent Related to Same Technology, Illumina Refers to Its “Linker” in Same Way as
`Columbia’s “Y”
`’537 Patent
`
`’458 Patent
`
`Base
`
`Base
`
`Source: JA0119 (’537 Patent Fig. 1) (annotation added); JA0020 (’458 Patent Claim 1) (annotation added).
`
`12
`
`

`

`“Y”
`In Illumina’s Patent Related to Same Technology, Its “Linker” Is Made Up of Two Linkers
`
`’537 Patent
`
`Example 1
`
`Base
`
`Disulfide
`Linker
`
`Alkynylamino
`Linker
`
`Base
`
`Source: JA0119 (’537 Patent Fig. 1) (annotation added); JA0126 (’537 Patent) (annotations added).
`
`13
`
`

`

`“Small”
`
`“Small”
`
`14
`
`

`

`“Small”
`
`wherein R (a) represents a small, chemically cleavable, chemical group
`capping the oxygen at the 3' position of the deoxyribose of the
`deoxyribonucleotide analogue, (b) does not interfere with recognition
`of the analogue as a substrate by a DNA polymerase….
`
`Plaintiffs’ Proposed Construction
`
`Defendant’s Proposed Construction
`
`“A chemical group that has a diameter, i.e., width,
`that is less than 3.7Å”
`
`“A chemical group that fits within the rat DNA
`polymerase active site shown in Fig. 1 of the patent,
`i.e. has a longest dimension less than 3.7Å,
`including the 3ʹ oxygen”
`
`Both sides agree that “small” means “less than 3.7Å”
`The first dispute is whether “small” means less than 3.7Å in width or longest dimension
`Second dispute is whether limited to rat DNA polymerase
`
`Source: JA0020; JA0026.
`
`15
`
`

`

`“Small”
`Plaintiffs’ Construction Has Been Consistent
`
`April 3
`Plaintiffs’ initial construction
`(JA0296)
`Defendant’s initial construction
`(JA0299)
`
`April 14
`
`Defendant’s revised construction Defendan
`(JA0301)
`
`April 22
`
`“A chemical group that has a diameter less than 3.7Å”
`
`“Indefinite”
`
`“Indefinite” “A chemical group that has a longest dimension less than 3.7Å,
`including the 3’–O”
`
`Plaintiffs’ proposed d construction
`
`“A chemical group that has a diameter, i.e., width, that is less than 3.7Å”
`
`Defendant’s proposed construction
`
`“A chemical group that fits within the rat DNA polymerase active site shown in Fig.
`1 of the patent, i.e. has a longest dimension less than 3.7Å, including the 3ʹ oxygen”
`
`Source: JA0296 (Pls’ Prelim. Proposed Const.); JA0299 (Def.’s Prelim. Proposed Const.); JA0301 (04/14/20 C. Lavin Email); D.I. 36 (Joint Claim Const. Chart, Appx. B, pp. v-vi).
`
`16
`
`

`

`“Small”
`Prosecution History Reports “Diameter” of Several Capping Groups Smaller than 3.7Å;
`“Diameter” Measurements Match “Width” of the Capping Group, NOT “Longest Dimension”
`
`Width: 3.1Å
`
`Longest Dimension: 4.6Å
`
`Width: 2.1Å
`
`Longest Dimension: 4.4Å
`
`Width: 2.4Å
`Width: 2.1Å
`
`Longest Dimension: 4.9Å
`Longest Dimension: 4.9Å
`
`Source: JA0084 (’458 Patent File History, Dr. Ju’s Declaration, Ex. C); JA0063-64 (’458 Patent File History, Dr. Ju’s Declaration);
`JA0172 (Dr. Kuriyan’s Declaration); JA0156 (Illumina Preliminary Response in IPR2017-02172) (azidomethyl at least 5Å in length).
`
`17
`
`

`

`“Small”
`Defendant’s Expert Uses “Diameter” to Refer to Width in His Publications
`
`Deposition of Dr. Romesberg
`And “diameter” as used here is in reference to the width of the DNA duplex; correct?
`Q.
`It appears -- it says a helix diameter.
`That refers to the width of the helix; right?
`Well, it’s the diameter.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Which means the width. It’s not its length you’re referring to. You’re referring to its
`width; correct?
`We -- we say -- we say sorry, where is this? We say “diameter” but I think that in the
`common use of the word “width” that you’re describing, I think that would -- I don't
`think I would object to calling it that.
`
`Source: JA0346-347 (Romesberg Deposition at 136:17-137:8), referring to JA0353 (Romesberg Article, referring to helix width as “helix diameter”).
`
`18
`
`

`

`“Small”
`Diameter of a Cylinder Is Its Width
`
`D
`
`Source: JA0153 (enhanced).
`
`19
`
`

`

`“Small”
`Illumina’s Construction Is Incompatible with Written Description and Illumina’s Prior Positions
`
`
`
`Columbia’s written description provides two examples of “small” capping groups:Columbia s written description provides two examples of small capping groups:
`
`Other examples include analogues in which a small chemical moiety such as –CH2OCH3
`[MOM] or –CH2CH=CH2 [allyl] is used to cap the –OH group at the 3’-position of deoxyribose.
`
`
`
`Illumina previously admitted that one of them, -CH2CH=CH2 (the allyl), is “small”:usly admitted that one of them, -CH2CH=CH2 (th
`
`There is no dispute that allyl is small
`
`Under Illumina’s current construction, neither -CH2OCH3 nor -CH2CH=CH2 is “small” (< 3.7Å):
`= 4.4Å
`-CH2OCH3 longest dimension
`= 4.6Å
`-CH2CH=CH2 longest dimension
`Source: JA0013 (’458 Patent 8:24-27); JA0235 (IPR2018-00291 Oral Hearing); JA0049 (IPR2018-00291 Petition); JA0038 (IPR2018-00291 Final Written Decision);
`JA0172 (Dr. Kuriyan’s Declaration).
`
`20
`
`

`

`“Small”
`Illumina Admits the Relevant Capping Groups Are Cylindrical, Not Spherical
`
`A.
`
`Deposition of Dr. Romesberg
`And in Dr. Kuriyan's structure, MOM is not a sphere?
`Q.
`It would look difficult -- it would -- same answer as -- as previously. Especially if you attach it to a
`carbon, it is looking to me if you wish to -- if you wish to ascribe a geometrical object, if you wish to use
`a geometrical object to describe these protecting groups, as you get longer, as your length gets longer,
`as one dimension gets increasingly long relative to the other two, I think it's common sense that that
`becomes a better -- that would be better described by a cylinder as opposed to a sphere by definition.
`
`Illumina’s Preliminary Response
`
`[T]he long and linear cylindrical shape of the azido group [portion of the azidomethyl capping group]
`would occupy a large amount of space and provides significant steric bulk that must be accommodated
`within a polymerase active site.
`
`Source: JA0331-332 (Dr. Romesberg Deposition at 54:25-55:14); JA0156 (Illumina Preliminary Response in IPR2017-02172).
`
`21
`
`

`

`“Small”
`Illumina Never Sought to Construe “DNA Polymerase” and Its Construction of “Small”
`Being Limited to Rat DNA Polymerase Is Incompatible with Claim and Written Description
`
`Columbia’s claim refers to a “DNA polymerase,” not a rat DNA polymerase
`
`JA0020 (’458 Patent Claim 1 (e.g., 33:49-50, 54)).JA0020 ( 458 Patent Claim 1 (e.g., 33:49 50, 54)).
`
`Columbia’s written description lists a variety of polymerases for use with the invention:
`“Possible DNA polymerases include Thermo Sequenase, Taq FS DNA polymerase, T7 DNA polymerase, and Vent
`(exo-) DNA polymerase.”
`
`Illumina’s construction improperly limits construction to rat DNA polymerase:
`“A chemical group that fits within the rat DNA polymerase active site shown in Fig. 1 of the patent, i.e. has a
`longest dimension less than 3.7Å, including the 3ʹ oxygen”
`
`Illumina’s expert testified that rat DNA polymerase was “a typical DNA polymerase”:
`“The crystal structure of a typical DNA polymerase was published in 1994 by Pelletier….Pelletier’s publication
`would have been relevant to the methods of Dower and Tsien.”
`
`
`
`Source: JA0018 (’458 Patent 21:23-25); JA0357 (IPR2020-00988 Ex. 1038).Source: JA0018 (’458 Patent 21:23-25); JA0357 (IPR2020-00988
`
`22
`
`

`

`“R . . . is stable during a DNA
`polymerase reaction”
`
`23
`
`

`

`“R . . . is stable during a DNA polymerase reaction”
`
`Agreed Upon Construction ofAgreed Upon Construction of
`
`“Y… is stable during a DNA polymerase reaction”
`
`“Y remains bonded to base and tag during a DNA
`polymerase reaction”
`
`Plaintiffs’ Proposed Construction
`
`Defendant’s Proposed Construction
`
`“R remains bonded to 3’ oxygen during a
`DNA polymerase reaction”
`
`“R has at least the stability of a MOM ether
`(-CH2OCH3) or allyl (-CH2CH=CH2) group”
`
`Source: JA0099 (Agreed-To Claim Construction).
`
`24
`
`

`

`“R . . . is stable during a DNA polymerase reaction”
`Plaintiffs’ Position is Consistent with Written Description
`
`Source: JA0014 (’458 Patent 10:13-19).
`
`25
`
`

`

`“A method for sequencing
`a nucleic acid”
`
`26
`
`

`

`“A method for sequencing a nucleic acid”
`
`Plaintiffs’ Proposed Construction
`
`Defendant’s Proposed Construction
`
`“A method for detecting the identity and
`sequence of a strand of nucleotides”
`
`Preamble is not limiting
`
`Source: JA0026
`
`27
`
`

`

`“A method for sequencing a nucleic acid”
`Preamble Contains Essence of the Invention
`
`[Insert Preamble shorter]
`
`Plaintiffs’ Proposed Construction
`
`“A method for detecting the identity and sequence of
`a strand of nucleotides”
`
`Source: JA0026 (’380 Patent, e.g., Claim 1); JA0023 (’380 Patent 3:14-17, 4:45-48).
`
`28
`
`

`

`Supplemental Slides
`
`Supplemental Slides
`
`29
`
`

`

`“Small”
`
`Source: JA0020; JA0026.
`
`30
`
`

`

`“Small”
`POSA Would Know “Diameter” Is Width, Not Longest Dimension
`
`
`
`Source: JA0169 (Dr. Kuriyan’s Declaration). Source: JA0169 (Dr Kuriyan
`
`31
`
`

`

`“Small”
`POSA Would Know “Diameter” Is Width, Not Longest Dimension
`
`
`
`Source: JA0170 (Dr. Kuriyan’s Declaration). Source: JA0170 (Dr Kuriyan
`
`32
`
`

`

`“Small”
`
`“More recent work in the literature exploring DNA sequencing by a synthesis method is mostly focused on designing and
`synthesizing a photocleavable chemical moiety that is linked to a fluorescent dye to cap the 3′-OH group of deoxynucleoside
`triphosphates (dNTPs) (Welch et al. 1999). Limited success for the incorporation of the 3′-modified nucleotide by DNA polymerase
`is reported. The reason is that the 3′-position on the deoxyribose is very close to the amino acid residues in the active site of the
`polymerase, and the polymerase is therefore sensitive to modification in this area of the deoxyribose ring. On the other hand, it is
`known that modified DNA polymerases (Thermo Sequenase and Taq FS polymerase) are able to recognize nucleotides with
`extensive modifications with bulky groups such as energy transfer dyes at the 5-position of the pyrimidines (T and C) and at the
`7-position of purines (G and A) (Rosenblum et al. 1997, Zhu et al. 1994). The ternary complexes of rat DNA polymerase, a DNA
`template-primer, and dideoxycytidine triphosphate (ddCTP) have been determined (Pelletier et al. 1994) which supports this fact.
`As shown in FIG. 1, the 3-D structure indicates that the surrounding area of the 3′-position of the deoxyribose ring in ddCTP is
`very crowded, while there is ample space for modification on the 5-position the cytidine base.
`The approach disclosed in the present application is to make nucleotide analogues by linking a unique label such as a fluorescent
`dye or a mass tag through a cleavable linker to the nucleotide base or an analogue of the nucleotide base, such as to the 5-position of
`the pyrimidines (T and C) and to the 7-position of the purines (G and A), to use a small cleavable chemical moiety to cap the 3′-OH
`group of the deoxyribose to make it nonreactive, and to incorporate the nucleotide analogues into the growing DNA strand as
`terminators. Detection of the unique label will yield the sequence identity of the nucleotide. Upon removing the label and the 3′-OH
`capping group, the polymerase reaction will proceed to incorporate the next nucleotide analogue and detect the next base.”
`
`Source: JA0010-11 (’458 Patent 2:47-3:17).
`
`33
`
`

`

`“Small”
`Written Description Teaches that Area into Which the Capping Group Must Fit Is Crowded
`
`
`
`Source: JA0010-11 (’458 Patent 2:66-3:1); JA0064 (’458 Patent File History, Dr. Ju’s Declaration).(’ ) (’ l
`
`
`
`
`
`
`
`34
`
`

`

`“Small”
`Prosecution History Reports “Diameter” Measurements Showing Several Capping
`Groups Smaller than 3.7Å in Diameter
`
`Source: JA0084 (’458 Patent File History, Dr. Ju’s Declaration, Ex. C).
`
`35
`
`

`

`“Small”
`Examiner Agreed with Columbia’s Construction of Small
`
`Source: JA0144 (’480 Patent File History, 6/23/17 Notice of Allowability).
`
`36
`
`