DCT

1:19-cv-01681

Trustees Of Columbia University In City Of New York v. Illumina Inc

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:19-cv-01681, D. Del., 09/10/2019
  • 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: Plaintiffs allege that Defendant’s DNA sequencing instruments, kits, and services infringe patents related to modified nucleotide analogues used in sequencing-by-synthesis methods.
  • Technical Context: The technology relates to next-generation DNA sequencing (NGS), a field critical for genomics research, personalized medicine, and diagnostics.
  • Key Procedural History: The complaint alleges that the parties have engaged in prior litigation involving a patent from the same family as the patents-in-suit, which commenced in July 2017. It also notes an Inter Partes Review (IPR) proceeding in which Plaintiffs allegedly informed Defendant of the patent applications that would issue as the patents-in-suit, a fact which may be relevant to the allegations of willful infringement.

Case Timeline

Date Event
2001-06-26 Priority Date for ’458 and ’459 Patents
2008-11-06 Publication of "Bentley article" describing Illumina's accused technology
2017-07-01 Plaintiffs initiated prior litigation against Illumina on a related patent
2019-01-31 U.S. Patent Application Publication for the ’458 Patent
2019-03-15 Plaintiffs allegedly notified Illumina of pending patent applications in an IPR
2019-03-21 U.S. Patent Application Publication for the ’459 Patent
2019-03-26 Illumina allegedly acknowledged knowledge of pending applications in an IPR filing
2019-09-10 Issue Date for ’458 and ’459 Patents
2019-09-10 Complaint Filing Date

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 10,407,458 - "Massive Parallel Method for Decoding DNA and RNA"

The Invention Explained

  • Problem Addressed: The patent's background section describes the limitations of then-current DNA sequencing technologies, such as electrophoresis-based methods, which were prone to errors in G-C rich regions and had throughput bottlenecks (’458 Patent, col. 2:5-20). It also notes that early "sequencing by synthesis" methods often used bulky chemical groups to "cap" the 3'-OH position of a nucleotide, which could interfere with the DNA polymerase enzyme's ability to incorporate it into a growing DNA strand (’458 Patent, col. 2:40-50).
  • The Patented Solution: The invention proposes a nucleotide analogue with two key features: (1) a "small cleavable chemical moiety" to cap the 3'-OH group on the deoxyribose, which temporarily terminates the synthesis reaction for one cycle; and (2) a unique, detectable label (e.g., a fluorescent dye) attached to the nucleotide's base via a separate, cleavable linker (’458 Patent, col. 3:7-14). This design allows a polymerase to efficiently incorporate the nucleotide, followed by detection of the label to identify the base, and then chemical cleavage of both the cap and the label to permit the next synthesis cycle to begin (’458 Patent, Fig. 2A).
  • Technical Importance: This two-part modification approach sought to improve the efficiency, accuracy, and read-length of sequencing-by-synthesis by solving the problem of polymerase intolerance to bulky 3'-OH caps (’458 Patent, col. 2:51-58).

Key Claims at a Glance

  • The complaint asserts independent claim 1 and dependent claim 2 (’458 Patent, col. 33:12-34:25; Compl. ¶39).
  • Essential elements of independent claim 1 include:
    • A guanine deoxyribonucleotide analogue with a specific chemical structure.
    • A "small, chemically cleavable, chemical group" (R) capping the 3' oxygen that does not interfere with polymerase recognition, is stable during the reaction, and is not a ketone or a –CH2CH=CH2 group.
    • The resulting OR group is not a methoxy or ester group.
    • A "detectable fluorescent moiety" (tag) attached to the base via a "chemically cleavable, chemical linker" (Y).
    • The analogue must be recognized as a substrate by DNA polymerase, be incorporated at the end of a growing DNA strand, and produce a 3'-OH group upon cleavage of R.

U.S. Patent No. 10,407,459 - "Massive Parallel Method for Decoding DNA and RNA"

The Invention Explained

  • The technology disclosed in the ’459 Patent is substantially identical to that of the ’458 Patent, as described above. The primary distinction in the asserted claims is the specific nucleotide base.

Key Claims at a Glance

  • The complaint asserts independent claim 1 and dependent claim 2 (’459 Patent, col. 33:12-34:25; Compl. ¶46).
  • Essential elements of independent claim 1, which covers an adenine deoxyribonucleotide analogue, are structurally parallel to claim 1 of the ’458 Patent. The complaint quotes this claim in its entirety (Compl. ¶26).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities include a wide range of Illumina's DNA sequencing systems (e.g., HiSeq, MiSeq, NextSeq, NovaSeq), associated reagent kits ("Accused Kits"), and sequencing services ("Accused Services") (Compl. ¶¶27-29).

Functionality and Market Context

  • The complaint alleges that Illumina’s sequencing technology relies on a "sequencing by synthesis" (SBS) method (Compl. ¶22). Central to this method are the nucleotide analogues contained in the Accused Kits. These analogues are alleged to have an "azidomethyl capping group attached to the 3' oxygen and a fluorophore attached to the base via a cleavable linker" (Compl. ¶33). The complaint provides a chemical structure diagram of an accused thymine nucleotide analogue to illustrate this configuration (Compl. ¶32, p. 11). The accused products are positioned as "proven Illumina NGS and array technologies" that support a "diverse portfolio of... genomic applications" (Compl. ¶29).

IV. Analysis of Infringement Allegations

The complaint incorporates by reference claim chart exhibits that were not attached to the publicly filed document. The following summary is based on the narrative allegations.

’458 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A guanine deoxyribonucleotide analogue... The complaint alleges Illumina uses, sells, or imports Accused Kits containing a guanine nucleotide analogue having the accused structure and functionality (Compl. ¶¶33, 39). ¶¶33, 39 col. 33:12-24
wherein R (a) represents a small, chemically cleavable, chemical group capping the oxygen at the 3' position... (b) does not interfere with recognition... Illumina’s nucleotide analogues allegedly use an "azidomethyl capping group attached to the 3' oxygen" which functions as a reversible terminator (Compl. ¶¶32-33). This group is alleged to be small and cleavable. ¶32-33 col. 33:45-50
wherein OR is not a methoxy group or an ester group; The accused capping group is an azidomethyl group, which is not a methoxy or ester group (Compl. ¶32). ¶32 col. 33:51-52
wherein tag represents a detectable fluorescent moiety; The accused analogues are allegedly "labelled with a different removable fluorophore" (Compl. ¶32). ¶32 col. 33:56-57
wherein Y represents a chemically cleavable, chemical linker... The fluorophore is allegedly attached to the base via a "cleavable linker" (Compl. ¶33). ¶33 col. 33:58-63
wherein the guanine deoxyribonucleotide analogue: i) is recognized as a substrate by a DNA polymerase, ii) is incorporated at the end of a growing strand of DNA... iii) produces a 3'-OH group... upon cleavage of R... The complaint alleges that Illumina's sequencing method involves incorporating these nucleotide analogues in a stepwise manner, which implies polymerase recognition, incorporation, and subsequent cleavage to permit further synthesis (Compl. ¶32). ¶32 col. 33:64-34:5
  • Identified Points of Contention:
    • Scope Questions: A central question may be whether Illumina's "azidomethyl" capping group falls within the scope of the claimed "small, chemically cleavable, chemical group." The claim includes negative limitations, excluding specific chemical groups (e.g., "not a –CH2CH=CH2 group"), but does not explicitly mention azidomethyl. The analysis will likely focus on whether the accused group is structurally and functionally consistent with the invention as described in the patent.
    • Technical Questions: The infringement analysis may turn on the functional properties of the accused azidomethyl cap. A key question for the court could be whether this group "does not interfere with recognition of the analogue as a substrate by a DNA polymerase" as required by the claim, which is a technical question that will likely require expert testimony.

’459 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
An adenine deoxyribonucleotide analogue having the structure... The complaint alleges Illumina uses, sells, or imports Accused Kits containing an adenine nucleotide analogue having the accused structure and functionality (Compl. ¶¶26, 33, 46). ¶¶26, 33, 46 col. 33:12-24
wherein R (a) represents a small, chemically cleavable, chemical group capping the oxygen at the 3' position... (b) does not interfere with recognition... Illumina’s nucleotide analogues allegedly use an "azidomethyl capping group attached to the 3' oxygen" which functions as a reversible terminator (Compl. ¶¶32-33). The complaint provides a structural diagram of the claimed analogue (Compl. ¶26). ¶¶32-33 col. 33:45-50
wherein OR is not a methoxy group or an ester group; The accused capping group is an azidomethyl group, which is not a methoxy or ester group (Compl. ¶32). ¶32 col. 33:51-52
[Remaining elements are parallel to the ’458 Patent analysis above] [The alleged infringing functionality is parallel to the ’458 Patent analysis above] ¶¶32-33 col. 33:53-34:5

V. Key Claim Terms for Construction

  • The Term: "small" (referring to the chemical group R)

  • Context and Importance: The "small" nature of the 3'-OH capping group is a core element of the invention, intended to distinguish it from bulkier prior art caps that allegedly hindered polymerase function. The construction of this term will be critical, as Defendant's infringement may depend on whether its "azidomethyl" capping group is considered "small" in the context of the patent.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The patent specification does not provide a precise molecular weight or structural definition for "small," instead describing the invention functionally. This may support a construction where any capping group that does not unduly interfere with the polymerase is considered "small."
    • Evidence for a Narrower Interpretation: The specification discloses specific examples of capping groups, such as MOM (–CH2OCH3) and allyl (–CH2CH=CH2) (’458 Patent, col. 3:49-54). A party could argue that "small" should be construed as being limited to chemical groups of a similar size, structure, or chemical properties as these exemplars.

  • The Term: "does not interfere with recognition" (by a DNA polymerase)

  • Context and Importance: This functional language is central to the infringement analysis. Practitioners may focus on this term because the degree to which the accused azidomethyl cap affects polymerase efficiency will be a key factual dispute.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The plain language suggests that the group must not prevent recognition, which could be interpreted to allow for some reduction in efficiency as long as incorporation still occurs. The patent contrasts the invention with bulky prior art groups that presented a more significant obstacle (’458 Patent, col. 2:40-50).
    • Evidence for a Narrower Interpretation: An opposing argument could be that the term requires a high level of efficiency, close to that of an uncapped nucleotide, in order to solve the stated problem of the prior art. Any significant reduction in incorporation speed or fidelity could be characterized as "interference."

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement based on Defendant’s sale of Accused Instruments with instructions, which allegedly direct customers to use the Accused Kits in an infringing manner. It is also alleged that the instruments and kits are designed to be used together (Compl. ¶¶40, 47).
  • Willful Infringement: The claim for willfulness is based on alleged pre-suit knowledge of the patented technology. The complaint alleges that Defendant was aware of the patent applications that matured into the patents-in-suit due to prior litigation involving a patent from the same family and from monitoring those applications during a related IPR proceeding (Compl. ¶¶43-44, 50-51).

VII. Analyst’s Conclusion: Key Questions for the Case

  • A core issue will be one of functional equivalence: does the accused "azidomethyl" capping group, as used in Illumina's products, meet the functional requirements of being a "small" chemical group that "does not interfere" with polymerase recognition, as those terms are defined by the patent claims?
  • A central question of claim scope will be the interpretation of the claims' negative limitations (e.g., "is not a –CH2CH=CH2 group", "OR is not a methoxy group"). The case will likely require the court to determine whether the accused azidomethyl group, while not explicitly recited or excluded, is sufficiently different from the disclosed embodiments and excluded prior art to fall outside the scope of what the inventors claimed as their invention.