Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 1 of 26 PageID #: 559
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`)
`THE TRUSTEES OF COLUMBIA
`UNIVERSITY IN THE CITY OF NEW )
`YORK and
`)
`QIAGEN SCIENCES, LLC,
`)
`)
`
`Plaintiffs,
`
`v.
`
`ILLUMINA, INC.
`
`Defendant.
`
`Civil Action No. 19-1681-CFC
`
`JURY TRIAL DEMANDED
`
`)))
`
`
`)
`)
`)
`)
`)
`)
`
`AMENDED COMPLAINT FOR PATENT INFRINGEMENT
`
`Plaintiffs The Trustees of Columbia University in the City of New York (“Columbia
`
`University”) and QIAGEN Sciences, LLC (“QIAGEN”) (collectively “Plaintiffs”), by and
`
`through their undersigned counsel, for their Amended Complaint against Defendant Illumina,
`
`Inc. (“Illumina”), allege as follows:
`
`THE PARTIES
`
`1.
`
`Plaintiff Columbia University is one of the world’s leading institutions of higher
`
`education, located at 535 West 116th Street, New York, New York 10027. It is a non-profit
`
`educational corporation formed by special act of the Legislature of the State of New York.
`
`2.
`
`Plaintiff QIAGEN Sciences, LLC is a Delaware company having its principal
`
`place of business at 19300 Germantown Road, Germantown, MD 20874. QIAGEN Sciences,
`
`LLC is the successor-in-interest to QIAGEN Waltham, Inc. as a result of a merger effective
`
`December 31, 2017.
`
`Columbia Ex. 2029
`Illumina, Inc. v. The Trustees
`of Columbia University
`in the City of New York
`IPR2020-01177
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 1 of 26 PageID #: 559
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`)
`THE TRUSTEES OF COLUMBIA
`UNIVERSITY IN THE CITY OF NEW )
`YORK and
`)
`QIAGEN SCIENCES, LLC,
`)
`)
`
`Plaintiffs,
`
`v.
`
`ILLUMINA, INC.
`
`Defendant.
`
`Civil Action No. 19-1681-CFC
`
`JURY TRIAL DEMANDED
`
`)))
`
`
`)
`)
`)
`)
`)
`)
`
`AMENDED COMPLAINT FOR PATENT INFRINGEMENT
`
`Plaintiffs The Trustees of Columbia University in the City of New York (“Columbia
`
`University”) and QIAGEN Sciences, LLC (“QIAGEN”) (collectively “Plaintiffs”), by and
`
`through their undersigned counsel, for their Amended Complaint against Defendant Illumina,
`
`Inc. (“Illumina”), allege as follows:
`
`THE PARTIES
`
`1.
`
`Plaintiff Columbia University is one of the world’s leading institutions of higher
`
`education, located at 535 West 116th Street, New York, New York 10027. It is a non-profit
`
`educational corporation formed by special act of the Legislature of the State of New York.
`
`2.
`
`Plaintiff QIAGEN Sciences, LLC is a Delaware company having its principal
`
`place of business at 19300 Germantown Road, Germantown, MD 20874. QIAGEN Sciences,
`
`LLC is the successor-in-interest to QIAGEN Waltham, Inc. as a result of a merger effective
`
`December 31, 2017.
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 2 of 26 PageID #: 560
`
`3.
`
`Upon information and belief, Defendant Illumina, Inc. is a Delaware corporation
`
`having its principal place of business at 5200 Illumina Way, San Diego, California 92122.
`
`JURISDICTION AND VENUE
`
`4.
`
`This action arises under the Patent Laws of the United States of America, 35
`
`U.S.C. § 1 et seq.
`
`5.
`
`This Court has subject matter jurisdiction over this action under 28 U.S.C. § 1331
`
`and 28 U.S.C. § 1338(a) because this is a civil action arising under the Patent Act.
`
`6.
`
`This Court has personal jurisdiction over Illumina because Illumina is
`
`incorporated in the State of Delaware.
`
`7.
`
`Venue is proper in this District under 28 U.S.C. § 1400(b) because Illumina is
`
`incorporated in the State of Delaware and thus resides in this District.
`
`BACKGROUND
`
`The Patents-in-Suit
`
`8.
`
`On September 10, 2019, the United States Patent and Trademark Office
`
`(“USPTO”) duly issued United States Patent No. 10,407,458 (“the ’458 Patent”), entitled
`
`“Massive Parallel Method for Decoding DNA and RNA,” in the names of inventors Jingyue Ju,
`
`Zengmin Li, John Robert Edwards, and Yasuhiro Itagaki. A true and correct copy of the ’458
`
`Patent is attached hereto as Exhibit 1.
`
`9.
`
`On September 10, 2019, the USPTO duly issued United States Patent No.
`
`10,407,459 (“the ’459 Patent”), entitled “Massive Parallel Method for Decoding DNA and
`
`RNA,” in the names of inventors Jingyue Ju, Zengmin Li, John Robert Edwards, and Yasuhiro
`
`Itagaki. A true and correct copy of the ’459 Patent is attached hereto as Exhibit 2.
`
`10.
`
`On October 1, 2019, the USPTO duly issued United States Patent No. 10,428,380
`
`(“the ’380 Patent”), entitled “Massive Parallel Method for Decoding DNA and RNA,” in the
`- 2 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 3 of 26 PageID #: 561
`
`names of inventors Jingyue Ju, Zengmin Li, John Robert Edwards, and Yasuhiro Itagaki. A true
`
`and correct copy of the ’380 Patent is attached hereto as Exhibit 3.
`
`11.
`
`On October 8, 2019, the USPTO duly issued United States Patent No. 10,435,742
`
`(“the ’742 Patent”), entitled “Massive Parallel Method for Decoding DNA and RNA,” in the
`
`names of inventors Jingyue Ju, Zengmin Li, John Robert Edwards, and Yasuhiro Itagaki. A true
`
`and correct copy of the ’742 Patent is attached hereto as Exhibit 4.
`
`12.
`
`On October 29, 2019, the USPTO duly issued United States Patent No.
`
`10,457,984 (“the ’984 Patent”), entitled “Massive Parallel Method for Decoding DNA and
`
`RNA,” in the names of inventors Jingyue Ju, Zengmin Li, John Robert Edwards, and Yasuhiro
`
`Itagaki. A true and correct copy of the ’984 Patent is attached hereto as Exhibit 5.
`
`13.
`
`Columbia University owns by assignment all right, title, and interest in and to the
`
`’458 Patent, the ’459 Patent, the ’380 Patent, the ’742 Patent, and the ’984 Patent (collectively
`
`“the Patents-in-Suit”).
`
`14.
`
`15.
`
`QIAGEN is the exclusive licensee of the Patents-in-Suit.
`
`On January 31, 2019, the applications that issued as the ’458 Patent, the ’380
`
`Patent, and the ’742 Patent published as US2019/0031704, US2019/0031706, and
`
`US2019/0031705, respectively.
`
`16.
`
`On March 21, 2019, the applications that issued as the ’459 Patent and the ’984
`
`Patent published as US2019/0085014 and US2019/0085015 (collectively with US2019/0031704,
`
`US2019/0031706, and US2019/0031705, “the Published Applications”).
`
`17.
`
`The inventions as claimed in the Patents-in-Suit are identical to the inventions as
`
`claimed in the Published Applications.
`
`18.
`
`Illumina is a large and sophisticated company that has been a party to patent
`
`- 3 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 4 of 26 PageID #: 562
`
`litigation with Columbia University and QIAGEN, and thus, on information and belief, Illumina
`
`monitors patent applications involving DNA sequencing technology and was aware of the
`
`content of each of the claims of the ’458 Patent, the ’380 Patent, and the ’742 Patent on or after
`
`they were published on January 31, 2019, and the content of each of the claims of the ’459 Patent
`
`and the ’984 Patent on or after they were published on March 21, 2019.
`
`Nucleotides and DNA Sequencing
`
`19.
`
`The Patents-in-Suit relate to modified versions of nucleotides (known as
`
`“nucleotide analogues”) and methods of using such nucleotide analogues for sequencing DNA
`
`(deoxyribonucleic acid). DNA encodes the genetic information of living organisms. DNA
`
`consists of smaller building blocks called nucleotides; the sequence of the nucleotides determines
`
`hereditary traits in living organisms. DNA sequencing—i.e., determining the order of the
`
`nucleotides in a DNA strand—is of enormous importance for a wide variety of applications in
`
`medicine, biotechnology, and other fields. For example, by sequencing the DNA of individuals
`
`with a particular disease or the DNA in tumor cells, medical researchers and physicians may
`
`learn the genetic basis for the disease or tumor and may design or provide therapies specifically
`
`targeted to it.
`
`20.
`
`A nucleotide consists of a sugar, a base, and one or more phosphate groups, as
`
`shown below. Nucleotides are identified by their bases, which form the genetic code of DNA.
`
`There are four different nucleotide bases—an adenine (“A”), a guanine (“G”), a cytosine (“C”),
`
`and a thymine (“T”). A and G are known as “purine” bases, while C and T are “pyrimidine”
`
`bases. The sugar in the nucleotide contains five carbon atoms, conventionally numbered 1′
`
`through 5′. When the nucleotide is found in isolation, a hydroxyl group (OH) is attached at the 3′
`
`position and is referred to as the 3′-OH group (circled below). The nucleotide depicted below is
`
`called a deoxyribonucleotide triphosphate.
`
`- 4 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 5 of 26 PageID #: 563
`
`Ba~
`
`( __t J:
`
`Phosphate(s)
`
`0
`0
`0
`II
`II
`11
`HO-P-O-P-O-P-0
`I
`I
`I
`o·
`o·
`o·
`
`3'- 0H Group
`
`N
`
`Sugar
`
`5'
`
`N
`
`NH2
`
`21.
`
`DNA consists of a chain of nucleotides, held together by bonds between a
`
`phosphate group of one nucleotide and a 3′-OH group of another nucleotide. In nature, two such
`
`chains of nucleotides form a double helix structure (forming a DNA double helix). Bonds
`
`between complementary base pairs hold the chains together, and base pairs always bond in the
`
`same way: A always pairs with T; C always pairs with G. These bonds between complementary
`
`base pairs form the “cross-bars” in the DNA double helix while the bonds between the phosphate
`
`group of one nucleotide and the 3′-OH group of the adjacent nucleotide form the “backbone” of
`
`the DNA double helix.
`
`22.
`
`To duplicate, or “synthesize,” DNA, the two strands of the DNA double helix are
`
`first unwound and separated. Each strand of nucleotides can then serve as the template for the
`
`production (or copying) of a complementary strand. Synthesis of DNA typically begins with the
`
`use of a short strand of nucleotides, called a primer, which is designed to match, and therefore
`
`bind to, the corresponding nucleotides at the beginning of the template strand to be copied, as
`
`shown below. An enzyme called a polymerase extends the primer along the template by adding
`
`nucleotides with bases that are complementary to the nucleotides of the template being copied
`
`via the base-pairing rules: A-T and C-G. For example, if the next nucleotide in the template to
`
`be copied has a G base, the polymerase would incorporate into the growing primer chain a
`
`- 5 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 6 of 26 PageID #: 564
`
`nucleotide with a complementary C base.
`
`PRJ:\.ll:R
`
`T
`
`A
`
`C
`
`A
`
`POLY\IrR.\SE
`
`23.
`
`As shown above, each letter in a square is a nucleotide. The polymerase also
`
`facilitates the formation of a bond between a phosphate group at the 5′-position of a free
`
`nucleotide and the 3′-OH group of the last nucleotide incorporated into the growing copy, thus
`
`adding the next nucleotide to the growing strand.
`
`24.
`
`This reaction can only occur when the last nucleotide in the growing strand has a
`
`3′-OH group available for linking to a phosphate group of an incoming nucleotide, as shown
`
`below.
`
`T
`
`·o-
`
`o·
`I
`r- o g
`
`s·
`
`3'
`
`0 I
`·o-r-o
`II
`0
`
`3'
`OH
`\
`
`Polymerase
`
`T T\.. ,-
`·o-r-O- P- O- P- 0
`II
`II
`II
`0
`0
`0
`
`s·
`
`0
`
`Columbia University’s Patents-in-Suit
`
`25.
`
`The Patents-in-Suit disclose and claim nucleotide analogues that are useful in a
`
`- 6 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 7 of 26 PageID #: 565
`
`type of “next generation sequencing” (or “NGS”) technology called “sequencing by synthesis”
`
`(“SBS”). NGS technologies are used in a variety of medical and research applications,
`
`including identifying genes and polymorphisms associated with disease and with individual
`
`variability in drug response, and are important to genomics research and discovery,
`
`particularly in the emerging field of personalized precision medicine, which seeks to use a
`
`patient’s own genomic DNA sequence information as the basis for individualized healthcare.
`
`26.
`
`Generally speaking, SBS involves the use of modified nucleotides that take
`
`advantage of the foregoing reaction used to grow a DNA strand. The method uses modified
`
`nucleotides with removable “caps” (also called “protecting groups,” or “blocking groups”)
`
`attached to the 3′-OH group on the sugar portion of the nucleotide. The modified nucleotides
`
`also have detectable labels attached to them, to signal whether the nucleotides are an A, C, T, or
`
`G. When a polymerase incorporates such a nucleotide into a growing chain, the synthesis stops
`
`because the 3′-OH group—where the polymerase would otherwise be used to join with the
`
`phosphate group of the next nucleotide—is blocked by the cap. Once the process is stopped, the
`
`label on the nucleotide is detected to identify which base was incorporated. After the label is
`
`detected, the label and the cap are removed (or “cleaved”), allowing the polymerase to add
`
`another labeled nucleotide to the chain for continuous DNA sequencing.
`
`27.
`
`The Patents-in-Suit teach nucleotide analogues that use a small cleavable
`
`chemical moiety with certain structural features to cap the 3′-OH group of the deoxyribose, along
`
`with cleavable labels attached to the base of each nucleotide. They further teach that the
`
`cleavable chemical cap “is stable during the polymerase reaction” and “does not interfere with
`
`the recognition of the nucleotide analogue by polymerase as a substrate,” and that “the growing
`
`strand of DNA should survive the . . . cleavage process[] . . . .”
`
`- 7 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 8 of 26 PageID #: 566
`
`28.
`
`In addition to teaching the use of small chemically cleavable capping groups, the
`
`Patents-in-Suit also exclude certain chemical groups for use as caps in this SBS method. For
`
`example, the Patents-in-Suit claim that the “OR” of the nucleotide is not a methoxy or an ester
`
`group, and the “R” of the nucleotide does not contain a ketone group. Similarly, certain claims
`
`of the Patents-in-Suit recite that the “R” group (i.e., the cap) is not a –CH2CH=CH2 group, and
`
`certain claims of the Patents-in-Suit recite that the “OR” group is not an allyl ether group.
`
`29.
`
`For example, claim 1 of the ’459 Patent recites:
`
`1. An adenine deoxyribonucleotide analogue having the structure:
`
`0
`0
`0
`II
`II
`II
`o·-P-O-P-0-P-O
`I
`I
`I
`o·
`o·
`o ·
`
`OR
`
`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, (c) is stable during a DNA polymerase reaction, (d)
`does not contain a ketone group, and (e) is not a –CH2CH=CH2
`group;
`
`wherein OR is not a methoxy group or an ester group;
`
`wherein the covalent bond between the 3′-oxygen and R is stable
`during a DNA polymerase reaction;
`
`wherein tag represents a detectable fluorescent moiety;
`
`wherein Y represents a chemically cleavable, chemical linker
`which (a) does not interfere with recognition of the analogue as
`
`- 8 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 9 of 26 PageID #: 567
`
`a substrate by a DNA polymerase and (b) is stable during a
`DNA polymerase reaction; and
`
`wherein the adenine deoxyribonucleotide analogue:
`
`i) is recognized as a substrate by a DNA polymerase,
`
`ii) is incorporated at the end of a growing strand of DNA during
`a DNA polymerase reaction,
`
`iii) produces a 3′-OH group on the deoxyribose upon cleavage
`of R,
`
`iv) no longer includes a tag on the base upon cleavage of Y,
`and
`
`v) is capable of forming hydrogen bonds with thymine or a
`thymine nucleotide analogue.
`
`Illumina Makes, Uses, and Sells Nucleotide Analogues that Infringe the Patents-in-Suit
`
`30.
`
`Illumina manufactures, uses, imports and/or sells DNA sequencing instruments
`
`that infringe the Patents-in-Suit (the “Accused Instruments”). These Accused Instruments
`
`include, but are not limited to, at least the following:
`
`a. HiSeq X Ten system, HiSeq X Five system, HiSeq 2500 system, HiSeq
`
`3000 system, HiSeq 4000 system, MiSeq system, MiSeqDx system, and MiSeq FGx system
`
`(collectively “4-Channel Accused Instruments”),
`
`b. MiniSeq system, NextSeq 500 system, NextSeq 550 system, NextSeq
`
`550Dx system, NovaSeq 5000 system, and NovaSeq 6000 system (collectively “2-Channel
`
`Accused Instruments”), and
`
`c.
`
`iSeq 100 (“1-Channel Accused Instrument”).
`
`31.
`
`Illumina manufactures, uses, imports, and/or sells a number of reagent kits
`
`containing nucleotide analogues that are sold for use with the Accused Instruments and infringe
`
`the Patents-in-Suit (the “Accused Kits”). These Accused Kits include, but are not limited to, at
`
`- 9 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 10 of 26 PageID #: 568
`
`least the following:
`
`a. HiSeq 3000/4000 SBS Kit, HiSeq Rapid SBS Kit v2, HiSeq SBS Kit v4,
`
`HiSeq X Reagent Kits, MiSeq FGx Reagent Kit, MiSeq Reagent Kit v3, MiSeq Reagent Kits v2,
`
`MiSeq Cystic Fibrosis 139-Variant Assay, MiSeq Cystic Fibrosis Clinical Sequencing Assay,
`
`MiSeq Universal Kit, VeriSeq PGS Kit, TruSight Cardio Sequencing Kit, TruSight One
`
`Sequencing Panels, TruSight Inherited Disease Sequencing Panel, Extended RAS Panel, TruSeq
`
`Rapid SBS Kits (200 Cycle and 50 Cycle) – HS, TruSeq SBS Kit v3-HS, and TruSeq SBS Kit
`
`v5-GA (collectively “4-Channel Accused Kits”),
`
`b. MiniSeq Reagent Kit, NextSeq 500/550 v2 and v2.1 Kits, NextSeq
`
`500/550 v2.5 Kits, NextSeq 550Dx Reagents, and NovaSeq Reagent Kits (collectively “2-
`
`Channel Accused Kits”), and
`
`c.
`
`iSeq 100 Reagents (“1-Channel Accused Kit”).
`
`32.
`
`Illumina also offers DNA sequencing services, including Illumina FastTrack
`
`Sequencing Services, Illumina Clinical Sequencing Services, and Verifi Prenatal Test
`
`(collectively “Accused Services”), in which it tests samples for a fee, on information and belief
`
`using the Accused Kits and Accused Instruments to do so. For example, as Illumina states on its
`
`website, “Illumina offers a diverse portfolio of array and next-generation sequencing (NGS)
`
`services to support a broad range of genomic applications. . . . Armed with proven Illumina NGS
`
`and array technologies and a network of scientific experts, customers are increasingly
`
`empowered to accelerate opportunities for discovery.” See
`
`https://www.illumina.com/services.html (emphasis added) (attached as Exhibit 6).
`
`33.
`
`On November 6, 2008, authors from Illumina and others published an article in
`
`Nature titled “Accurate Whole Human Genome Sequencing using Reversible Terminator
`
`- 10 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 11 of 26 PageID #: 569
`
`Chemistry” (“Bentley article”). A true and correct copy of the Bentley article is attached hereto
`
`as Exhibit 7. Along with the Bentley article, Nature also published “Supplementary
`
`Information” that provides more detail regarding Illumina’s sequencing methods that Illumina
`
`published in the Bentley article. A true and correct copy of the Supplementary Information is
`
`attached hereto as Exhibit 8.
`
`34.
`
`Illumina states in the Bentley article that the sequencing methods shown in the
`
`article are “the basis for the standard protocols now available from Illumina, Inc.” Ex. 7 at 58.
`
`Accordingly, on information and belief, the nucleotide analogues described in the Bentley article
`
`and Supplementary Information are the same as (or substantially the same as) the nucleotide
`
`analogues contained in the Accused Kits.
`
`35.
`
`Illumina’s disclosures in the Bentley article and its Supplementary Information
`
`confirm that Illumina uses the claimed deoxyribonucleotide analogues in Illumina’s sequencing
`
`technology. For example, the Bentley article provides that “[t]o ensure base-by-base nucleotide
`
`incorporation in a stepwise manner, [Illumina uses] a set of four reversible terminators, 3ʹ-O-
`
`azidomethyl 2ʹ-deoxynucleoside triphosphates (A, C, G and T), each labelled with a different
`
`removable fluorophore (Supplementary Fig. 1a).” Ex. 7 at 53. Fig. 1a from the Supplementary
`
`Information provides the “[s]tructure of the reversible terminator 3ʼ-O-azidomethyl 2ʼ-
`
`deoxythymine triphosphate (T) labelled with a removable fluorophore.” Ex. 8 at 14, Fig. S1.a.
`
`fl
`
`HNJ_ / '~,,l,o'-""o~O~
`Q
`0,;0__ ,,;:'.JJf
`lQJ :""':ye,
`. ~
`.
`
`0.............,.H1
`
`Although only the structure for the thymine (T) nucleotide is provided, the Bentley article
`
`- 11 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 12 of 26 PageID #: 570
`
`indicates that the A, C, and G nucleotides each have the same protecting group. Ex. 7 at 53.
`
`36.
`
`On information and belief, the adenine, cytosine, guanine, and thymine
`
`nucleotides contained in the 4-Channel Accused Kits, the adenine, cytosine, and thymine
`
`nucleotides contained in the 2-Channel Accused Kits, and the adenine and thymine nucleotides
`
`contained in the 1-Channel Accused Kit each have the same general structure as the nucleotide
`
`shown in paragraph 35 (i.e., an azidomethyl capping group attached to the 3’ oxygen and a
`
`fluorophore attached to the base via a cleavable linker). See Illumina CMOS Chip and One-
`
`Channel SBS Chemistry at p. 2 (attached as Exhibit 9).
`
`37.
`
`On information and belief, during the use of the 1-Channel Accused Kit in the 1-
`
`Channel Accused Instrument, the cytosine nucleotide has the same general structure as the
`
`nucleotide shown in paragraph 35 (i.e., an azidomethyl capping group attached to the 3’ oxygen
`
`and a fluorophore attached to the base via a cleavable linker). Ex. 9 at 2.
`
`38.
`
`To demonstrate how Illumina’s nucleotide analogues and/or their use in
`
`sequencing methods infringe the Patents-in-Suit, attached as Exhibits 10-14 are preliminary and
`
`exemplary claim charts. These charts are illustrative only and not intended to limit Plaintiffs’
`
`right to modify these charts or provide any other claim charts or allege that other Illumina
`
`nucleotide analogues infringe each of the Patents-in-Suit. Exhibits 10-14 are hereby
`
`incorporated by reference in their entirety.
`
`39.
`
`Each claim element in Exhibits 10-14 that is mapped to Illumina’s nucleotide
`
`analogues and/or Illumina’s sequencing methods shall be considered an allegation within the
`
`meaning of the Federal Rules of Civil Procedure and therefore a response to each allegation is
`
`required.
`
`40.
`
`On information and belief, Illumina directly and willfully infringes the claims of
`
`- 12 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 13 of 26 PageID #: 571
`
`each of the Patents-in-Suit pursuant to 35 U.S.C. § 271(a), literally or under the doctrine of
`
`equivalents, by making, using, offering for sale, selling, and/or importing into the United States
`
`the Accused Kits or by performing the Accused Services. Illumina also actively induces
`
`infringement of the Patents-in-Suit pursuant to 35 U.S.C. § 271(b).
`
`COUNT I
`
`Infringement of U.S. Patent No. 10,407,458
`
`41.
`
`Plaintiffs re-allege and incorporate by reference the allegations contained in
`
`paragraphs 1-40 above.
`
`42.
`
`Illumina directly infringes claims 1-2 of the ’458 Patent, literally or under the
`
`doctrine of equivalents, by making, using, offering for sale, selling, and/or importing into the
`
`United States the 4-Channel Accused Kits, and/or by using the 4-Channel Accused Kits to
`
`perform the Accused Services in the United States. Attached as Exhibit 10 is a claim chart
`
`showing specifically element-by-element how Illumina’s 4-Channel Accused Kits infringe
`
`claims 1-2 of the ’458 Patent.
`
`43.
`
`Illumina’s sale of 4-Channel Accused Instruments also actively induces, and
`
`continues to actively induce, infringement of claims 1-2 of the ’458 Patent in violation of 35
`
`U.S.C. § 271(b). Users of the 4-Channel Accused Kits, including Illumina’s customers, directly
`
`infringe claims 1-2 of the ’458 Patent when they use the 4-Channel Accused Kits with the 4-
`
`Channel Accused Instruments. Illumina knowingly induces the users of the 4-Channel Accused
`
`Kits to infringe by selling to such users the 4-Channel Accused Instruments with instructions
`
`(attached hereto as Exhibit 15) that the 4-Channel Accused Instruments can only be used with
`
`the 4-Channel Accused Kits. See, e.g., Ex. 15 at 9 (“The MiSeq Reagent Kit is a single-use
`
`reagent kit required to perform a sequencing run. It is available in different types and sizes. Each
`
`- 13 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 14 of 26 PageID #: 572
`
`type of MiSeq Reagent Kit includes a kit-specific flow cell type and all reagents required for
`
`performing a run.”). Based on the allegations in the Complaint (19-cv-1681, D.I. 1), this
`
`Amended Complaint, and the attached claim chart, Illumina has knowledge that use of the 4-
`
`Channel Accused Kits by its customers infringes claims 1-2 of the ’458 Patent.
`
`44.
`
`Illumina’s infringement of the ’458 Patent is damaging and will continue to
`
`damage Plaintiffs.
`
`45.
`
`Illumina’s continuing infringement of the ’458 Patent will irreparably harm
`
`Plaintiffs, and Illumina’s infringement will continue unless enjoined by this Court pursuant to 35
`
`U.S.C. § 283.
`
`46.
`
`Illumina is a large and sophisticated company that is highly experienced with
`
`patent litigation generally, and litigation involving Columbia University’s patents specifically.
`
`In July 2017, Plaintiffs sued Illumina on a patent from the same family as the Patents-in-Suit.
`
`See The Trustees of Columbia University in the City of New York and QIAGEN Sciences, LLC v.
`
`Illumina Inc., C.A. No. 17-973 (CFC) (D. Del.). In that action, Plaintiffs thereafter amended the
`
`complaint three times to assert additional issued patents from the same patent family as the
`
`current Patents-in-Suit. In addition, Columbia University and Illumina are parties to IPR2018-
`
`00291, wherein on March 15, 2019, Columbia University filed Supplemental Mandatory Notices
`
`informing Illumina that Columbia University was prosecuting ten patent applications, including
`
`U.S. Application No. 16/149,098, which published as US2019/0031704 and issued as the ’458
`
`Patent. The Trustees of Columbia University in the City of New York v. Illumina, Inc., IPR2018-
`
`00291, Paper No. 60 (March 15, 2019). The ’458 Patent claims are identical to those published
`
`in US2019/0031704. On March 26, 2019, Illumina acknowledged in a Paper filed in IPR2018-
`
`00291 that it had actual knowledge of the pending patent applications, which were published.
`
`- 14 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 15 of 26 PageID #: 573
`
`The Trustees of Columbia University in the City of New York v. Illumina, Inc., IPR2018-00291,
`
`Paper No. 63 at 3 (March 26, 2019) (“Columbia is prosecuting an additional 10 pending
`
`applications . . . [s]hould any of those issue, it is likely that the Parties will be back before the
`
`Board yet again[.]”). Thus, on information and belief, Illumina was monitoring the patent
`
`applications in the family of the Patents-in-Suit and, thus, aware of the content of claims 1-2 of
`
`the ’458 Patent on or soon after they were published on January 31, 2019.
`
`47.
`
`On information and belief, Illumina’s infringement of the ’458 Patent will be
`
`willful, justifying an award of increased damages and making this an exceptional case entitling
`
`Plaintiffs to reasonable attorneys’ fees pursuant to 35 U.S.C. § 285.
`
`COUNT II
`
`Infringement of U.S. Patent No. 10,407,459
`
`48.
`
`Plaintiffs re-allege and incorporate by reference the allegations contained in
`
`paragraphs 1-47 above.
`
`49.
`
`Illumina directly infringes claims 1-2 of the ’459 Patent, literally or under the
`
`doctrine of equivalents, by making, using, offering for sale, selling, and/or importing into the
`
`United States the Accused Kits, and/or by using the Accused Kits to perform the Accused
`
`Services in the United States. Attached as Exhibit 11 is a claim chart showing specifically
`
`element-by-element how Illumina’s Accused Kits infringe claims 1-2 of the ’459 Patent.
`
`50.
`
`Illumina’s sale of the Accused Instruments also actively induces, and continues to
`
`actively induce, infringement of claims 1-2 of the ’459 Patent in violation of 35 U.S.C. § 271(b).
`
`Users of the Accused Kits, including Illumina’s customers, directly infringe claims 1-2 of the
`
`’459 Patent when they use the Accused Kits with the Accused Instruments. Illumina knowingly
`
`induces the users of the Accused Kits to infringe by selling to such users the Accused
`
`- 15 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 16 of 26 PageID #: 574
`
`Instruments with instructions (attached hereto as Exhibits 15-17) that the Accused Instruments
`
`can only be used with the Accused Kits. See, e.g., Ex. 15 at 9 (“The MiSeq Reagent Kit is a
`
`single-use reagent kit required to perform a sequencing run. It is available in different types and
`
`sizes. Each type of MiSeq Reagent Kit includes a kit-specific flow cell type and all reagents
`
`required for performing a run.”); Ex. 16 at 5 (“Performing a sequencing run on the MiniSeq
`
`System requires a single-use MiniSeq Kit. Each kit includes a flow cell and the reagents required
`
`for a sequencing run.”); Ex. 17 at 7 (“Performing a run on the iSeq 100 System requires one
`
`single-use iSeq 100 i1 Reagents kit.”) Based on the allegations in the Complaint (19-cv-1681,
`
`D.I. 1), this Amended Complaint, and the attached claim chart, Illumina has knowledge that use
`
`of the Accused Kits by its customers infringes claims 1-2 of the ’459 Patent.
`
`51.
`
`Illumina’s infringement of the ’459 Patent is damaging and will continue to
`
`damage Plaintiffs.
`
`52.
`
`Illumina’s continuing infringement of the ’459 Patent will irreparably harm
`
`Plaintiffs, and Illumina’s infringement will continue unless enjoined by this Court pursuant to 35
`
`U.S.C. § 283.
`
`53.
`
`Illumina is a large and sophisticated company that is highly experienced with
`
`patent litigation generally, and litigation involving Columbia University’s patents specifically.
`
`In July 2017, Plaintiffs sued Illumina on a patent from the same family as the Patents-in-Suit.
`
`See The Trustees of Columbia University in the City of New York and QIAGEN Sciences, LLC v.
`
`Illumina Inc., C.A. No. 17-973 (CFC) (D. Del.). In that action, Plaintiffs thereafter amended the
`
`complaint three times to assert additional issued patents from the same patent family as the
`
`current Patents-in-Suit. In addition, Columbia University and Illumina are parties to IPR2018-
`
`00291, wherein on March 15, 2019, Columbia University filed Supplemental Mandatory Notices
`
`- 16 -
`
`

`

`Case 1:19-cv-01681-CFC-SRF Document 12 Filed 10/29/19 Page 17 of 26 PageID #: 575
`
`informing Illumina that Columbia University was prosecuting ten patent applications, including
`
`U.S. Application No. 16/149,114, which published as US2019/0085014 and issued as the ’459
`
`Patent. The Trustees of Columbia University in the City of New York v. Illumina, Inc., IPR2018-
`
`00291, Paper No. 60 (March 15, 2019). The ’459 Patent claims are identical to those published
`
`in US2019/0085014. On March 26, 2019, Illumina acknowledged in a Paper filed in IPR2018-
`
`00291 that it had actual knowledge of the pending patent applications, which were published.
`
`The Trustees of Columbia University in the City of New York v. Illumina, Inc., IPR2018-00291,
`
`Paper No. 63 at 3 (March 26, 2019) (“Columbia is prosecuting an additional 10 pending
`
`applications . . . [s]hould any of those issue, it is likely that the Parties will be back before the
`
`Board yet again[.]”). Thus, on information and belief, Illumina was monitoring the patent
`
`applications in the family of the Patents-in-Suit and, thus, aware of the content of claims 1-2 of
`
`the ’459 Patent on or soon after they were published on March 21, 2019.
`
`54.
`
`On information and belief, Illumina’s infringement of the ’459 Patent will be
`
`willful, justifying an award of increased damages and making this an exceptional case entitling
`
`Plaintiffs to reasonable attorneys’ fees pursuant to 35 U.S.C. § 285.
`
`COUNT III
`
`Infringement of U.S. Patent No. 10,428,380
`
`55.
`
`Plaintiffs re-allege and incorporate by reference the allegations contained in
`
`paragraphs 1-54 above.
`
`56.
`
`Illumina directly infringes claims 1-4 of the ’380 Patent, literally or under the
`
`doctrine of equivalents, by using the Accused Instruments and Accused Kits, and by performing
`
`the Accused Services in the United States. Attached as Exhibit 12 is a claim chart showing
`
`speci