DCT
1:16-cv-01112
Esoterix Genetic Laboratories LLC v. Myriad Genetics Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Esoterix Genetic Laboratories, LLC (Delaware) and The Johns Hopkins University (Maryland)
- Defendant: Myriad Genetics, Inc. (Delaware) and Myriad Genetic Laboratories, Inc. (Delaware)
- Plaintiff’s Counsel: Kilpatrick Townsend & Stockton LLP; Ellis & Winters LLP; Baker & Hostetler LLP
- Case Identification: 1:16-cv-01112, M.D.N.C., 09/07/2016
- Venue Allegations: Venue is alleged to be proper in the Middle District of North Carolina because Defendant Myriad conducts substantial business in the district, offers for sale and sells the accused services to residents, maintains business relationships with local entities, and is registered to do business in the state.
- Core Dispute: Plaintiffs allege that Defendant’s myRisk® Hereditary Cancer test, a genetic testing service, infringes four patents related to a method for detecting and quantifying rare genetic sequences known as "digital amplification" or "digital PCR."
- Technical Context: The technology at issue, digital PCR, enables the highly sensitive detection of rare genetic mutations from a biological sample by digitally counting individual DNA molecules, a capability with significant applications in cancer diagnostics and monitoring.
- Key Procedural History: The patents-in-suit are owned by The Johns Hopkins University and exclusively licensed to Esoterix Genetic Laboratories. Three of the four asserted patents (the ’706, ’889, and ’015 patents) were previously asserted against a third party, Life Technologies, and subsequently survived reexamination proceedings at the USPTO, which confirmed their validity over the prior art presented.
Case Timeline
| Date | Event |
|---|---|
| 1999-08-02 | Priority Date for ’706, ’889, ’015, and ’206 Patents |
| 2002-08-27 | U.S. Patent No. 6,440,706 Issued |
| 2010-11-02 | U.S. Patent No. 7,824,889 Issued |
| 2011-03-29 | U.S. Patent No. 7,915,015 Issued |
| 2014-10-14 | U.S. Patent No. 8,859,206 Issued |
| 2014-10-23 | ’015 Patent Reexamination Certificate Issued |
| 2014-10-24 | ’706 Patent Reexamination Certificate Issued |
| 2014-10-31 | ’889 Patent Reexamination Certificate Issued |
| 2016-03-XX | Myriad Press Release referenced in complaint |
| 2016-09-07 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 6,440,706 - "Digital Amplification", Issued August 27, 2002
The Invention Explained
- Problem Addressed: The patent describes the difficulty of detecting a small number of mutant-containing cells within a large population of normal cells, noting that conventional methods like DNA sequencing are often not sensitive enough, while other sensitive techniques are difficult to quantify accurately (’706 Patent, col. 1:24-53).
- The Patented Solution: The invention transforms the exponential, analog signal of a polymerase chain reaction (PCR) into a linear, digital one by first diluting a DNA sample to the point that individual template molecules can be physically isolated in separate reaction vessels (e.g., wells of a plate) (’706 Patent, col. 2:5-18, Fig. 1A). Each isolated molecule is then amplified, resulting in a homogeneous population of molecules (either all mutant or all wild-type) in each vessel. This homogeneity allows for simple detection, and a quantitative result is obtained by counting the number of vessels containing the mutant sequence versus the wild-type sequence (’706 Patent, Abstract; col. 4:4-9).
- Technical Importance: This method provided a reliable and quantitative way to measure the proportion of variant sequences in a DNA sample, a critical advance for applications like early cancer detection from bodily fluids (’706 Patent, col. 1:31-43).
- Analogy: The process is analogous to finding counterfeit bills in a large stack of currency. Rather than examining the entire stack at once, the method separates the money into thousands of individual envelopes, each containing a single bill. A simple test on each envelope reveals which contain a counterfeit, and counting the positive envelopes gives an exact tally.
Key Claims at a Glance
- The complaint asserts independent claim 1 and a number of dependent claims (Compl. ¶30).
- The essential elements of independent claim 1 (as reexamined) are:
"diluting isolated nucleic acid template molecules isolated from a biological sample to form a set comprising a plurality of assay samples;""amplifying the template molecules within the assay samples to form a population of amplified molecules in the assay samples of the set;""analyzing the amplified molecules in the assay samples of the set to determine a first number of assay samples which contain the selected genetic sequence and a second number of assay samples which contain a reference genetic sequence;""comparing the first number to the second number to ascertain a ratio which reflects the composition of the biological sample."
- The complaint reserves the right to assert claims 2-3, 7-11, 15-16, 19, 20, 24, 27, 38-43, 47-48, 51-52, 56, and 59 (Compl. ¶30).
U.S. Patent No. 7,824,889 - "Digital Amplification", Issued November 2, 2010
The Invention Explained
- Problem Addressed: The patent addresses the technical challenge of quantitatively assessing "allelic status," particularly in distinguishing whether two observed genetic variants exist on the same allele or on separate alleles, an analysis that typically required cumbersome cloning of PCR products (’889 Patent, col. 5:15-22).
- The Patented Solution: The patent applies the digital amplification method to determine allelic imbalance by isolating, amplifying, and then counting individual DNA molecules from different sources within the genome (’889 Patent, claim 1). The method specifically claims analyzing sequences from a "first chromosome" and a "second chromosome" and comparing their respective counts to ascertain an imbalance, thereby providing a quantitative measure of their relative abundance without cloning (’889 Patent, col. 5:40-44).
- Technical Importance: The invention provides a direct, quantitative method for detecting allelic imbalances, which are hallmarks of certain diseases, thereby simplifying a complex diagnostic analysis (’889 Patent, col. 5:42-44).
Key Claims at a Glance
- The complaint asserts independent claim 1 (Compl. ¶35).
- The essential elements of independent claim 1 (as reexamined) are:
"distributing isolated nucleic acid template molecules to form a set comprising a plurality of assay samples...;""amplifying the template molecules within the set to form a population of amplified molecules in individual assay samples of the set;""analyzing the amplified molecules...to determine a first number of assay samples which contain a selected genetic sequence on a first chromosome and a second number...which contain a reference genetic sequence on a second chromosome, wherein between 0.1 and 0.9 of the assay samples yield an amplification product...;""comparing the first number...to the second number...to ascertain an allelic imbalance in the biological sample."
- The complaint reserves the right to assert claims 4-9 and 12-22 (Compl. ¶35).
U.S. Patent No. 7,915,015 - "Digital Amplification", Issued March 29, 2011
- Patent Identification: U.S. Patent No. 7,915,015, "Digital Amplification", Issued March 29, 2011 (Compl. ¶15).
- Technology Synopsis: This patent claims a method for determining an allelic imbalance in a biological sample using the digital amplification technique. The method involves amplifying template molecules within a set of assay samples and then analyzing the amplified products to determine the number of samples containing a "first allelic form of a marker" and a "second allelic form of the marker," then comparing these numbers to identify an imbalance (’015 Patent, claim 1; Compl. ¶¶40-41).
- Asserted Claims: Independent claim 1 and dependent claims 5-13, 16, and 18 are asserted (Compl. ¶40).
- Accused Features: The myRisk® Hereditary Cancer test is alleged to infringe by distributing DNA, amplifying it, and comparing the resulting numbers of different allelic forms to ascertain an allelic imbalance (Compl. ¶41).
U.S. Patent No. 8,859,206 - "Digital Amplification", Issued October 14, 2014
- Patent Identification: U.S. Patent No. 8,859,206, "Digital Amplification", Issued October 14, 2014 (Compl. ¶16).
- Technology Synopsis: This patent claims a method for detecting a rare genetic sequence in a mixed population of cell-free human genomic DNA, such as in a sample where the mutant allele fraction is less than 20%. The method requires distributing the DNA into at least fifteen assay samples, each with fewer than ten template molecules, and amplifying them to form homogeneous products. The nucleic acid sequences of these products are then determined to quantify the number of samples containing the wild-type versus the mutant sequence (’206 Patent, claim 1; Compl. ¶46).
- Asserted Claims: Independent claim 1 and dependent claims 1-19, 21-22, and 24-28 are asserted (Compl. ¶45).
- Accused Features: The myRisk® Hereditary Cancer test is alleged to infringe by distributing, amplifying, and sequencing cell-free DNA to detect and quantify mutations in a mixed population (Compl. ¶46).
III. The Accused Instrumentality
- Product Identification: Defendant Myriad's myRisk® Hereditary Cancer test and service (Compl. ¶22).
- Functionality and Market Context:
- The myRisk® test is a multi-gene panel that identifies an elevated risk for multiple types of cancer by using digital polymerase chain reaction ("dPCR") technology (Compl. ¶22). The complaint alleges the test operates by extracting genomic DNA from a biological sample (e.g., blood) and "dilutes or distributes" it into picoliter-sized aqueous droplets, which serve as assay samples (Compl. ¶¶24, 31). These isolated DNA molecules are then amplified using a PCR-based strategy, allegedly with a "ThunderStorm®" system from RainDance Technologies (Compl. ¶¶24-25). The amplified molecules are subsequently analyzed via massively-parallel NextGen sequencing, and the resulting data is processed with software to determine the relative number of different genetic sequences and thereby ascertain ratios or allelic imbalances (Compl. ¶31).
- The complaint alleges that Myriad is a diagnostic company and purports to process over 1,000 samples per day using its accused tests and services (Compl. ¶¶21, 23).
No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
U.S. Patent No. 6,440,706 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| diluting isolated nucleic acid template molecules isolated from a biological sample to form a set comprising a plurality of assay samples; | Myriad allegedly extracts DNA from blood or buccal samples and disperses the "fragmented DNA... into picoliter-sized aqueous droplets" that form the assay samples (Compl. ¶31). | ¶31 | col. 2:8-10 |
| amplifying the template molecules within the assay samples to form a population of amplified molecules in the assay samples of the set; | Myriad allegedly subjects the droplets to a "PCR-based target-enrichment strategy" in which the emulsion of microdroplets undergoes PCR amplification (Compl. ¶31). | ¶31 | col. 2:10-12 |
| analyzing the amplified molecules in the assay samples of the set to determine a first number of assay samples which contain the selected genetic sequence and a second number of assay samples which contain a reference genetic sequence; | Myriad allegedly uses a "massively-parallel NextGen" sequencing step to generate sequence data, which provides the "first and second numbers of assay samples" (Compl. ¶31). | ¶31 | col. 2:12-16 |
| comparing the first number to the second number to ascertain a ratio which reflects the composition of the biological sample. | Myriad allegedly uses software to analyze the sequencing data to perform "base-calling, alignment, variant identification" and "ascertain a ratio to reflect the composition of the sample" (Compl. ¶31). | ¶31 | col. 2:16-18 |
- Identified Points of Contention:
- Scope Questions: A primary question may be whether Myriad's process of "dispersing" DNA into picoliter droplets meets the claim limitation of "diluting." The defense may argue that "diluting" implies reducing concentration in a bulk solution, whereas Myriad's process partitions a sample. Further, it may be disputed whether a transient droplet in an emulsion constitutes an "assay sample" as contemplated by the patent, which was exemplified with multi-well plates.
U.S. Patent No. 7,824,889 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| distributing isolated nucleic acid template molecules to form a set comprising a plurality of assay samples...; | Myriad allegedly extracts DNA and disperses it "into picoliter-sized aqueous droplets that are merged with a dropletized Target Enrichment Primer Library" (Compl. ¶36). | ¶36 | col. 10:11-13 |
| amplifying the template molecules within the set to form a population of amplified molecules in individual assay samples of the set; | Myriad allegedly subjects the droplets to a "PCR-based target-enrichment strategy" and "PCR amplification" using a target-enrichment machine (Compl. ¶36). | ¶36 | col. 10:14-16 |
| analyzing the amplified molecules... to determine a first number of assay samples which contain a selected genetic sequence on a first chromosome and a second number... on a second chromosome...; | Myriad allegedly uses a NextGen sequencing step to provide sequence data, which allows for the determination of the first and second numbers (Compl. ¶36). | ¶36 | col. 10:19-25 |
| ...wherein between 0.1 and 0.9 of the assay samples yield an amplification product of at least one of the selected and reference genetic sequences; | The complaint alleges, "upon information and belief," that Myriad's process meets this specific efficiency range for amplification (Compl. ¶36). | ¶36 | col. 10:25-28 |
| comparing the first number... to the second number... to ascertain an allelic imbalance in the biological sample. | Myriad allegedly uses commercial and laboratory-developed software to analyze the sequencing data "to ascertain an allelic imbalance in the sample" (Compl. ¶36). | ¶36 | col. 10:28-31 |
- Identified Points of Contention:
- Evidentiary Questions: A key factual dispute will likely concern the allegation, made "upon information and belief," that Myriad's process meets the quantitative requirement that "between 0.1 and 0.9 of the assay samples yield an amplification product." Plaintiffs will need to substantiate this allegation through discovery.
- Technical Questions: The claim recites analyzing sequences on a "first chromosome" and a "second chromosome." A technical question is whether Myriad's test, which analyzes allelic markers that may reside on homologous chromosome pairs (i.e., the same chromosome number from maternal and paternal sources), satisfies this specific claim language.
V. Key Claim Terms for Construction
The Term:
"diluting"(from ’706 Patent, claim 1)- Context and Importance: This term is the first step in the claimed method and is foundational to the "digital" concept of isolating individual molecules. The complaint alleges that Myriad's process of "dispersing" DNA into droplets constitutes "diluting" (Compl. ¶31). Practitioners may focus on this term because its construction will determine whether droplet-based dPCR systems are encompassed by claims drafted in the era of well-plate-based PCR.
- Intrinsic Evidence for a Broader Interpretation: The stated purpose of the invention is to isolate single molecules for individual amplification (’706 Patent, Abstract). A party could argue that any technique that achieves this physical isolation, including partitioning into droplets, falls within the scope of the term as it is used to enable the core inventive concept.
- Intrinsic Evidence for a Narrower Interpretation: The specification consistently uses the term "dilution" in its conventional sense and exemplifies the invention with serial dilutions into multiwell plates (’706 Patent, col. 4:13-17). Figure 1A explicitly states, "DILUTE TO ~ 1/2 COPY/ WELL PCR," which could support an argument that the term requires a reduction in concentration in a solution before partitioning.
The Term:
"assay samples"(from ’706 and ’889 Patents, claim 1)- Context and Importance: This term defines the discrete units in which the individual amplification reactions occur. The complaint alleges these are "picoliter-sized aqueous droplets" (Compl. ¶¶31, 36). The construction of this term is critical to determining if the claims read on modern emulsion-based dPCR systems.
- Intrinsic Evidence for a Broader Interpretation: The claims use the general term "plurality of assay samples" without limiting them to a specific physical form. The core function is to provide discrete reaction environments, a function that droplets in an emulsion perform.
- Intrinsic Evidence for a Narrower Interpretation: The patent's working examples are exclusively described using 96-well and 384-well plates (e.g., "PCR was performed in 7 ul volumes in 96 well polypropylene PCR plates") (’706 Patent, col. 7:59-62). A party could argue that "assay samples" should be limited to such physically stable, pre-manufactured reaction vessels.
VI. Other Allegations
- Willful Infringement: The complaint does not contain a formal count for willful infringement. It alleges that Myriad has knowledge of the patents-in-suit "at least through the filing of this Complaint" (Compl. ¶28). This allegation may support a claim for enhanced damages for any infringement occurring post-filing but does not allege pre-suit knowledge, which is typically central to a willfulness claim. The prayer for relief requests that the case be declared "exceptional" under 35 U.S.C. § 285, which is a related but distinct request for attorneys' fees (Compl. p. 18, Prayer E).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of definitional scope: can patent claims drafted and exemplified in the context of multi-well plate PCR, using terms like "diluting" and "assay samples," be construed to cover modern digital PCR systems that "distribute" DNA into picoliter droplets within an emulsion? The outcome of this claim construction battle will be pivotal.
- A key evidentiary question will be one of functional proof: can Plaintiffs prove, beyond the "information and belief" pleading standard, that Myriad's accused myRisk® test meets the specific quantitative limitations recited in the claims, such as the requirement in the ’889 patent that "between 0.1 and 0.9 of the assay samples yield an amplification product"?
- A central dynamic of the litigation will be one of validity resilience: given that three of the four patents-in-suit have already survived USPTO reexamination proceedings initiated by a different accused infringer, the case raises the question of whether Myriad can mount a successful invalidity challenge based on new prior art or arguments not previously considered by the patent office.