DCT
1:19-cv-00970
Complete Genomics Inc v. Illumina Inc
Key Events
Amended Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Complete Genomics, Inc. (Delaware)
- Defendant: Illumina, Inc. (Delaware)
- Plaintiff’s Counsel: Quinn Emanuel Urquhart & Sullivan, LLP; Young Conaway Stargatt & Taylor, LLP
- Case Identification: 1:19-cv-00970, D. Del., 07/01/2020
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because the defendant, Illumina, Inc., is a Delaware corporation and therefore resides in the district.
- Core Dispute: Plaintiff alleges that Defendant’s "two-channel" DNA sequencing systems, and associated reagents, infringe patents related to methods for efficiently determining nucleotide sequences using a reduced number of fluorescent labels.
- Technical Context: The case concerns high-throughput DNA sequencing, a foundational technology in modern genomics that enables large-scale genetic research, clinical diagnostics, and personalized medicine.
- Key Procedural History: The complaint is a Second Amended Complaint, adding allegations of infringement for the recently issued ’473 Patent. The complaint alleges that Illumina had pre-suit knowledge of the ’132 Patent because its application was cited and substantively discussed during the prosecution of one of Illumina’s own patent applications before the ’132 Patent issued.
Case Timeline
| Date | Event |
|---|---|
| 2008-01-28 | Earliest Priority Date for ’132 and ’473 Patents |
| 2015-11-04 | ’132 Patent application allegedly cited during prosecution of an Illumina patent |
| 2015-12-29 | U.S. Patent No. 9,222,132 Issues |
| 2020-05-26 | U.S. Patent No. 10,662,473 Issues |
| 2020-06-03 | Plaintiff’s counsel allegedly informs Defendant’s counsel of the ’473 Patent |
| 2020-07-01 | Second Amended Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 9,222,132 - "Methods and Compositions for Efficient Base Calling in Sequencing Reactions"
- Patent Identification: U.S. Patent No. 9,222,132, "Methods and Compositions for Efficient Base Calling in Sequencing Reactions," issued December 29, 2015 (the "’132 Patent").
The Invention Explained
- Problem Addressed: The patent describes conventional DNA sequencing methods as being limited by factors such as signal degradation over sequencing cycles and signal-to-noise ratios, which constrain the efficiency and feasibility of single-molecule sequencing (’132 Patent, col. 1:33-43). The underlying problem is the need for lower-cost, higher-throughput sequencing approaches.
- The Patented Solution: The invention provides a method to determine the identity of all four DNA bases (A, T, G, C) using fewer than four distinct labels, such as a system with only two fluorescent signals (’132 Patent, Abstract). For example, one base is identified by a first signal, a second base by a second signal, a third base by the presence of both signals, and a fourth base by the absence of any signal (’132 Patent, col. 2:20-33). This approach simplifies the instrumentation and data processing required for sequencing.
- Technical Importance: By reducing the number of unique fluorescent signals required to identify all four nucleotides, this method can increase the speed, reduce the complexity of optical detection systems, and lower the cost of high-throughput DNA sequencing (’132 Patent, Abstract).
Key Claims at a Glance
- The complaint asserts independent claim 1 and dependent claims 2-4 (Compl. ¶26).
- Independent Claim 1 recites a method with the following essential elements:
- Providing an array of single-stranded nucleic acid templates on a surface.
- Performing multiple cycles of a sequencing-by-extension reaction for each template.
- Each cycle comprises binding a complementary nucleotide and detecting fluorescent signals.
- The identity of the nucleotide is determined by a specific four-part decoding scheme based on the presence or absence of a "first fluorescent signal" and a "second fluorescent signal."
- Deducing the identity of the nucleotide in the original template based on the identity of the complementary nucleotide that was detected.
U.S. Patent No. 10,662,473 - "Methods and Compositions for Efficient Base Calling in Sequencing Reactions"
- Patent Identification: U.S. Patent No. 10,662,473, "Methods and Compositions for Efficient Base Calling in Sequencing Reactions," issued May 26, 2020 (the "’473 Patent").
The Invention Explained
- Problem Addressed: Similar to the ’132 Patent, the ’473 Patent addresses the need to increase the efficiency of sequencing reactions and the assembly of complete sequences from shorter reads (’473 Patent, col. 1:42-46).
- The Patented Solution: The invention describes a specific method for two-channel sequencing where the four bases are distinguished not only by color but also by signal intensity (’473 Patent, col. 6:59-63). The claimed method uses a pool of nucleotides where one is attached to a first dye, a second is attached to a second dye, a third is attached to both dyes, and a fourth has no dye. Critically, the method relies on detecting "different fluorescent intensities" at each of the two wavelengths to distinguish the nucleotides (’473 Patent, Abstract; Claim 1).
- Technical Importance: This approach provides a specific chemical and analytical framework for implementing a two-color sequencing system, enabling high-throughput sequencing by using differences in both emission wavelength and signal intensity to encode the identity of each nucleotide (’473 Patent, col. 1:47-51).
Key Claims at a Glance
- The complaint asserts independent claim 1 and dependent claims 2, 3, and 5 (Compl. ¶105).
- Independent Claim 1 recites a sequencing-by-extension method with the following essential elements:
- Providing a nucleic acid array and annealing primers.
- Extending the primers using a pool of nucleotides comprising:
- A first nucleotide with a first dye (first wavelength).
- A second nucleotide with a second dye (second wavelength).
- A third nucleotide comprising two types, one with the first dye and one with the second dye, that produce "different fluorescent intensities" compared to the first and second nucleotides.
- A fourth nucleotide with no dye.
- Illuminating the array and measuring fluorescence intensity at both wavelengths.
- Determining the incorporated nucleotide based on a specific four-part decoding scheme.
- Repeating for multiple cycles.
III. The Accused Instrumentality
Product Identification
The accused instrumentalities are Illumina’s "two-channel" DNA sequencing systems, including the NovaSeq 6000 system, the NextSeq 500/550 and 1000/2000 Series systems, and the MiniSeq system (Compl. ¶14). The complaint also accuses the use of these systems in combination with Illumina’s "Library Preparation Kits" and "Cluster Generation and Sequencing Kits" (Compl. ¶12).
Functionality and Market Context
The accused systems perform high-throughput DNA sequencing using a method Illumina calls "sequencing by synthesis" (SBS) (Compl. ¶35). The complaint alleges the NovaSeq 6000 system is Illumina's "most powerful, simple, scalable, and reliable" platform (Compl. ¶35).
The core accused functionality is "two-channel sequencing," which allegedly uses only two images—one from a red channel and one from a green channel—to determine the identity of all four DNA bases in each sequencing cycle (Compl. ¶51). The complaint includes a table from an Illumina guide illustrating how different combinations of red and green signals correspond to bases A, C, G, and T (Compl. ¶53). This table from the NovaSeq 6000 Sequencing System Guide shows base calls derived from red and green channel intensity (Compl. ¶53). The complaint also provides a visualization of the cluster intensities that generate these calls (Compl. ¶142).
IV. Analysis of Infringement Allegations
’132 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method for determining identities of nucleotides...by performing sequencing-by-extension reactions... | The accused systems use a method Illumina describes as "sequencing by synthesis" (SBS), which is another name for sequencing-by-extension. | ¶34, ¶35 | col. 1:44-48 |
| (a) providing an array comprising single-stranded nucleic acid templates disposed at positions on a surface; | The accused systems use a flow cell, which is a glass substrate containing billions of "nanowells" where clusters of single-stranded DNA templates are generated and fixed to the surface. | ¶36, ¶37 | col. 2:54-56 |
| ii) detecting...the presence or absence of fluorescent signal(s)...wherein 1) detecting a first fluorescent signal and not a second...2) detecting the second...and not the first...3) detecting both...and 4) detecting neither... | The accused systems detect signals in two channels (red and green). C is identified by red only; T by green only; A by both red and green; and G by neither signal. | ¶51, ¶54, ¶55, ¶56, ¶57 | col. 2:20-33 |
| iii) deducing the identity of the nucleotide at the detection position in the nucleic acid template based on the identity of the complementary nucleotide. | The systems determine the incorporated nucleotide's identity from the signal, which necessarily implies the identity of its complement in the template strand. This deduction is also allegedly performed when generating a reverse-complement sequence for alignment to a reference genome. | ¶58, ¶60, ¶62 | col. 2:5-7 |
Identified Points of Contention
- Scope Questions: A central issue may be the scope of the "deducing" step. The complaint alleges this is met not only by the direct chemical complementarity but also by the subsequent bioinformatic process of calculating a sequence's reverse-complement for alignment against a reference genome (Compl. ¶62, ¶65). The question for the court will be whether this post-detection data processing step falls within the scope of the claimed sequencing method itself.
- Technical Questions: The infringement theory rests on a direct mapping of the accused two-channel (red/green) detection to the claimed "first signal/second signal" decoding scheme. The complaint provides documentation from the defendant that appears to support this mapping (Compl. ¶53). The factual dispute may center on whether the accused system's operation contains any nuances that deviate from the specific four-part logic required by the claim.
’473 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| said pool of nucleotides comprises (i) a first nucleotide comprising a first fluorescent dye... (ii) a second... a second fluorescent dye... (iii) a third... a fluorescent dye that emits light detectable at the first wavelength and...at the second wavelength... (iv) a fourth nucleotide that does not comprise a fluorescent dye; | Illumina's systems allegedly use Cytosine labeled with a red dye (first), Thymine with a green dye (second), Adenine with both red and green dyes (third), and Guanine that is "permanently dark" and has no dye (fourth). | ¶136, ¶138, ¶140, ¶150 | col. 35:25-45 |
| wherein the first nucleotide and the first type of the third nucleotide have different fluorescent intensities at the first wavelength... and the second nucleotide and the second type of the third nucleotide have different fluorescent intensities at the second wavelength... | The complaint alleges, on information and belief, that the intensity of the red signal for Adenine is different from that for Cytosine, and the intensity of the green signal for Adenine is different from that for Thymine, citing Illumina's patent filings and technical data as evidence. | ¶145, ¶146, ¶148 | col. 6:59-63 |
| (3) measuring the intensity of a fluorescence signal at the first wavelength and the intensity of a fluorescence signal at the second wavelength at each of the plurality of spatially discrete sites to determine which...nucleotide is incorporated... | The accused systems' base calling process allegedly determines the base for each cluster by extracting and comparing intensities from red and green images, resulting in four distinct populations corresponding to the four bases. | ¶167, ¶168 | col. 36:1-12 |
Identified Points of Contention
- Scope Questions: Claim 1 recites a "third nucleotide" that comprises "a first type...that comprises a [first] fluorescent dye...and a second type...that comprises a [second] fluorescent dye." The question will be whether Illumina's practice of labeling Adenine with both red and green fluorophores meets this specific "first type" and "second type" language, or if Illumina uses a single molecular species that is differently labeled.
- Technical Questions: Infringement hinges on whether there are, in fact, "different fluorescent intensities" between the single-color bases (C and T) and the dual-color base (A), as required by the claim. The complaint supports this with a cluster intensity plot from an Illumina guide (Compl. ¶142) and alleges this will be borne out in discovery, suggesting this will be a key factual and evidentiary battleground.
V. Key Claim Terms for Construction
For the ’132 Patent
- The Term: "deducing the identity of the nucleotide at the detection position in the nucleic acid template"
- Context and Importance: The construction of this term is critical because the plaintiff’s infringement theory relies in part on bioinformatic analysis (calculating a reverse-complement for sequence alignment) that occurs after the initial optical detection is complete (Compl. ¶¶61-65). A narrow construction limiting "deducing" to the immediate chemical interpretation of the signal could impact the infringement analysis.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent’s stated purpose is to provide methods for "acquiring nucleotide sequence information" ('132 Patent, Abstract). Because aligning reads to a reference genome is a necessary part of acquiring useful sequence information from short-read data, this purpose may support a construction that includes related data processing steps.
- Evidence for a Narrower Interpretation: Claim 1 places "deducing" as the final sub-part (iii) of a multi-part "determining" step that begins with "binding a complementary nucleotide" (i) and "detecting" a signal (ii). This structure suggests "deducing" is an immediate consequence of the detection within a given sequencing cycle, rather than a subsequent, separate data analysis workflow.
For the ’473 Patent
- The Term: "different fluorescent intensities"
- Context and Importance: This term is the central technical limitation that enables the four-base, two-color decoding scheme of claim 1. Whether the accused systems infringe will likely depend on whether the signal intensities generated by their chemistry are meaningfully "different" in the way required by the patent. Practitioners may focus on this term because the complaint relies on interpreting defendant's public data plots to allege this element is met (Compl. ¶¶142, 145).
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claim language does not quantify the required difference, suggesting any measurable, non-identical intensity could suffice. The specification supports this by describing a method where intensity is a basis for determining which nucleotide is present (’473 Patent, col. 6:59-63).
- Evidence for a Narrower Interpretation: The claim requires that the first and third nucleotides "have" different intensities, which could imply an inherent and designed-in property of the reagents, rather than incidental fluctuations in measurement. The abstract describes the method as improving "efficiency," which may suggest the intensity difference must be sufficiently robust to serve as a reliable basis for decoding.
VI. Other Allegations
- Indirect Infringement: The complaint alleges that Illumina induces infringement by selling its two-channel systems and associated kits with instructions, user guides, and software that direct customers to use them in an infringing manner (Compl. ¶¶88, 206). It further alleges contributory infringement on the basis that the kits are specialized components that are not staple articles of commerce and have no substantial non-infringing use with respect to the claimed methods (Compl. ¶¶92, 210).
- Willful Infringement: For the ’132 Patent, willfulness is alleged based on pre-suit knowledge dating back to at least the patent’s issue date of December 29, 2015. The complaint alleges this knowledge arises from the fact that the application that led to the ’132 Patent was cited and substantively discussed by Illumina during the prosecution of its own separate patent application (Compl. ¶89). For the ’473 Patent, willfulness is alleged based on knowledge since at least June 3, 2020, when plaintiff's counsel allegedly informed defendant's counsel of the patent's existence (Compl. ¶207).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of evidentiary proof: can the plaintiff demonstrate through discovery and expert testimony that Illumina’s accused sequencing chemistry generates the specific "different fluorescent intensities" required to distinguish nucleotides as claimed in the ’473 Patent, or will the evidence show a different technical mechanism or only incidental signal variation?
- A key question of claim scope will be whether the "deducing" step in the ’132 Patent is limited to the immediate interpretation of optical signals within a sequencing cycle, or if it can be construed more broadly to encompass subsequent bioinformatic data processing steps, such as calculating a reverse-complement for sequence alignment.
- A central issue for damages will be willfulness: can the plaintiff prove that a patent applicant's citation of a third party's patent application during prosecution establishes knowledge of the resulting patent from its date of issuance, sufficient to support a finding of willful infringement of the ’132 Patent?