DCT
1:20-cv-01644
Ravgen Inc v. Illumina Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Ravgen, Inc. (Delaware)
- Defendant: Illumina, Inc. (Delaware) and Verinata Health, Inc. (Delaware)
- Plaintiff’s Counsel: Farnan LLP
- Case Identification: 1:20-cv-01644, D. Del., 12/03/2020
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because both defendants are Delaware corporations and are therefore deemed to reside in the district. The complaint also alleges they conduct business in Delaware through their websites.
- Core Dispute: Plaintiff alleges that Defendant’s non-invasive prenatal and oncology genetic testing services infringe patents related to methods for preparing and analyzing cell-free DNA from blood samples.
- Technical Context: The technology at issue involves non-invasive diagnostic methods that analyze small fragments of cell-free DNA (cfDNA) circulating in a patient's blood to detect fetal chromosomal abnormalities or cancer biomarkers.
- Key Procedural History: The complaint alleges an extensive history of Defendants’ awareness of the patents-in-suit. This includes citations to the patents during the prosecution of Defendants’ own patent applications, Defendants’ participation in inter partes review (IPR) and reexamination proceedings involving the patents, and direct licensing discussions between the parties and their predecessors dating back to 2009.
Case Timeline
| Date | Event |
|---|---|
| 2002-05-08 | Earliest Priority Date for ’277 and ’720 Patents |
| 2008-02-19 | ’277 Patent Issue Date |
| 2009-01-21 | Defendant VHI's predecessor, Artemis Health, allegedly contacts Ravgen |
| 2010-06-01 | ’720 Patent Issue Date |
| 2011-04-26 | Artemis Health becomes Defendant Verinata Health, Inc. (VHI) |
| 2012-03-06 | VHI launches the accused Verifi® Prenatal Test |
| 2013-01-07 | Illumina announces acquisition of VHI |
| 2016-05-03 | Ravgen's advisor allegedly contacts Illumina to discuss patent portfolio |
| 2016-11-07 | Illumina launches the accused TruSight® Tumor 170 test |
| 2017-04-01 | Illumina launches the accused VeriSeq™ NIPT Solution |
| 2019-06-01 | Illumina launches the accused VeriSeq™ NIPT Solution v2 |
| 2019-11-05 | Illumina launches the accused TruSight™ Oncology 500 ctDNA test |
| 2020-12-03 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 7,727,720 - "Methods for Detection of Genetic Disorders" (June 1, 2010)
The Invention Explained
- Problem Addressed: The patent's background section describes the challenge of using cell-free fetal DNA from a maternal blood sample for prenatal diagnosis. The primary difficulty is that the vast majority of cell-free DNA in the sample is maternal, which dilutes the fetal DNA signal and "makes using the DNA for genotyping the fetus difficult" (’720 Patent, col. 33:31-35; Compl. ¶32). This creates a low signal-to-noise ratio for the target fetal DNA.
- The Patented Solution: The invention claims to solve this problem by introducing a method of sample preparation. It involves adding an agent to the initial blood sample that "impedes cell lysis," meaning it prevents maternal blood cells from breaking open and releasing their DNA into the plasma (’720 Patent, Abstract). By stabilizing the maternal cells, the method reduces the amount of contaminating maternal DNA, thereby increasing the relative percentage of fetal DNA in the sample available for analysis (’720 Patent, col. 33:38-46).
- Technical Importance: This sample preparation technique was presented as a key step toward making non-invasive prenatal testing more accurate and reliable by improving the quality of the genetic material to be analyzed (Compl. ¶¶18, 32).
Key Claims at a Glance
- The complaint asserts infringement of at least independent claim 1 (Compl. ¶117).
- The essential elements of Claim 1 are:
- A method for detecting a free nucleic acid, comprising:
- (a) isolating free nucleic acid from a non-cellular fraction of a sample, wherein said sample comprises an agent that impedes cell lysis, if cells are present, and wherein said agent is selected from the group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor; and
- (b) detecting the presence or absence of the free nucleic acid.
- The complaint reserves the right to assert other claims (Compl. ¶116).
U.S. Patent No. 7,332,277 - "Methods for Detection of Genetic Disorders" (February 19, 2008)
The Invention Explained
- Problem Addressed: The patent identifies the same core problem as its continuation, the ’720 patent: the low percentage of fetal DNA in maternal blood makes non-invasive prenatal diagnosis difficult (’277 Patent, col. 32:24-28). The patent also notes that prior methods for detecting fetal chromosomal abnormalities were often "costly, time-consuming, and burdensome" because they required complex steps like amplifying an entire gene sequence (’277 Patent, col. 66:14-20).
- The Patented Solution: The patent discloses a two-part solution. First, similar to the ’720 patent, it describes preparing the sample with an agent that inhibits maternal cell lysis to increase the relative concentration of fetal DNA (’277 Patent, col. 32:32-39). Second, it describes a method for analyzing the mixed DNA sample by "quantitating a ratio of the relative amounts of alleles at a heterozygous locus of interest" to determine if a fetal chromosomal abnormality is present (’277 Patent, Abstract; col. 66:22-28). An abnormal ratio can signal the presence of an extra chromosome, such as in Trisomy 21.
- Technical Importance: The combination of sample preparation and allelic ratio analysis provided a more efficient, non-invasive method for detecting fetal genetic disorders than prior techniques (Compl. ¶37).
Key Claims at a Glance
- The complaint asserts infringement of at least claim 81 as an example (Compl. ¶99).
- The essential elements of Claim 81 are:
- A method for preparing a sample for analysis comprising
- isolating free fetal nucleic acid from a the sample,
- wherein said sample comprises an agent that inhibits lysis of cells, if cells are present,
- and wherein said agent is selected from the group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor.
- The complaint reserves the right to assert other claims (Compl. ¶98).
III. The Accused Instrumentality
Product Identification
- The complaint accuses three families of genetic testing services and products offered by Illumina:
- The Verifi® Prenatal Test and Verifi® Plus Prenatal Test ("Verifi Tests") for non-invasive prenatal testing (NIPT) (Compl. ¶¶5, 40).
- The VeriSeq™ NIPT Solution and VeriSeq™ NIPT Solution v2 ("VeriSeq Tests"), which are automated NIPT systems (Compl. ¶¶6, 46).
- The TruSight™ Oncology 500 ctDNA and TruSight® Tumor 170 tests ("TruSight Tests") for liquid biopsy cancer testing (Compl. ¶¶7, 56-58).
Functionality and Market Context
- The accused tests are alleged to operate by analyzing cell-free DNA (cfDNA) extracted from a patient’s blood sample (Compl. ¶¶5-7). The Verifi and VeriSeq tests analyze cfDNA to detect fetal aneuploidies, while the TruSight tests analyze cfDNA to detect somatic variations related to cancer (Compl. ¶¶41, 47, 59).
- A central allegation is that all accused tests are designed to be used with, and their protocols require, blood samples collected in Streck Cell-Free DNA Blood Collection Tubes ("BCT") (Compl. ¶¶42, 49, 60). These tubes are alleged to contain a "unique preservative" that "limits the release of genomic DNA" from blood cells by "limiting cell lysis" (Compl. ¶44).
- A diagram in the complaint for the Verifi test illustrates a multi-step process beginning with cfDNA extraction and preparation, followed by DNA sequencing and algorithmic analysis to generate a test report (Compl. ¶45, p. 15). Another diagram for the VeriSeq test shows an automated workflow from sample collection to reporting using various hardware modules (Compl. ¶51, p. 19). A third diagram for the TruSight test depicts the process of extracting cell-free DNA from plasma to detect somatic variants from circulating tumor DNA (Compl. ¶62, p. 26).
- The complaint alleges that these tests are commercially significant, having generated "hundreds of millions of dollars in revenue" for the Defendants (Compl. ¶95).
IV. Analysis of Infringement Allegations
'720 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| (a) isolating free nucleic acid from a non-cellular fraction of a sample… | The accused tests are alleged to involve isolating cfDNA from a non-cellular plasma fraction of a maternal blood sample. | ¶117a | col. 27:32-37 |
| …wherein said sample comprises an agent that impedes cell lysis, if cells are present, and wherein said agent is selected from the group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor… | The accused tests allegedly require blood collection in Streck BCTs, which are said to contain a preservative that limits cell lysis. | ¶117b | col. 10:9-19 |
| (b) detecting the presence or absence of the free nucleic acid. | The accused tests are alleged to use whole-genome sequencing and proprietary algorithms to analyze the isolated cfDNA to detect genetic abnormalities. | ¶117c | col. 21:28-39 |
'277 Patent Infringement Allegations
| Claim Element (from Independent Claim 81) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method for preparing a sample for analysis comprising isolating free fetal nucleic acid from a the sample… | The accused tests are alleged to involve isolating cell-free fetal DNA from a maternal blood sample. | ¶99a | col. 26:27-40 |
| …wherein said sample comprises an agent that inhibits lysis of cells, if cells are present, and wherein said agent is selected from the group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor. | The accused tests allegedly require blood collection in Streck BCTs, which are said to contain a preservative that inhibits cell lysis. | ¶99b | col. 10:9-19 |
- Identified Points of Contention:
- Scope Questions: The claims are directed to a "method." The complaint alleges that Defendants infringe by "using" the tests themselves or by "directing and/or controlling the performance of the claimed steps by third-party laboratories" (Compl. ¶¶100, 118). This framing suggests a potential dispute over divided infringement, where different entities perform different steps of the claimed method. The resolution may depend on whether Illumina's control over its CLIA-certified lab (VHI) and its instructions to third-party users are sufficient to attribute all steps of the method to Illumina.
- Technical Questions: A key technical question is whether the preservative chemistry in the Streck BCTs, which the complaint alleges "limits cell lysis" (Compl. ¶44), meets the claim requirement of an "agent that impedes cell lysis... selected from the group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor." The analysis may require evidence on the specific mechanism of action of the Streck tube preservative and how that aligns with the technical definitions of the claimed agent categories.
V. Key Claim Terms for Construction
- The Term: "agent that impedes cell lysis" / "agent that inhibits lysis of cells"
- Context and Importance: This term is central to the claimed invention and the infringement allegations. The definition of this phrase will determine whether the preservative in the Streck BCTs used with the accused tests falls within the scope of the claims. Practitioners may focus on this term because the entire infringement theory rests on the function of the chemical in the blood collection tubes.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent specifications state that "any agent that prevents the lysis of cells or increases the structural integrity of the cells can be used" (’720 Patent, col. 92:13-16). The patents also provide extensive, non-limiting lists of exemplary agents, including aldehydes, formaldehyde, and various cross-linkers, suggesting the term should be construed functionally to cover any chemical that achieves the stated result (’720 Patent, Table XXIII).
- Evidence for a Narrower Interpretation: A party could argue that the term should be limited by the three specific categories recited in the claims: "membrane stabilizer, cross-linker, and cell lysis inhibitor." Interpretation may focus on whether the accused agent fits the established scientific definitions of those categories, potentially excluding agents that work through other mechanisms. The use of formaldehyde in the patent's working examples could also be cited to support a narrower construction limited to that class of chemicals (’720 Patent, col. 92:12-13).
VI. Other Allegations
- Indirect Infringement: The complaint alleges both induced and contributory infringement. The inducement theory is based on allegations that Defendants supply the tests and provide instructional materials, user manuals, and technical information that direct and encourage customers and third-party laboratories to perform the patented methods, including the use of collection tubes containing a cell lysis inhibitor (Compl. ¶¶101, 107-108, 119). Contributory infringement is alleged on the basis that the accused test kits and systems are a material part of the invention, are not staple articles of commerce, and are especially adapted for infringing use (Compl. ¶¶103, 109, 121).
- Willful Infringement: The complaint alleges that Defendants' infringement has been willful and deliberate since the launch of each accused product (Compl. ¶¶111, 134). The basis for this allegation is extensive pre-suit knowledge, allegedly arising from (1) Defendants' own patent prosecution, during which the patents-in-suit were cited as prior art; (2) Defendants' participation in IPR and reexamination proceedings concerning the patents-in-suit; and (3) direct communications and licensing discussions with Ravgen regarding its patent portfolio (Compl. ¶¶68-94).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of liability for method claims: where the initial step of sample collection in a specific tube may be performed by a clinician, can Ravgen establish that Illumina "uses" the entire claimed method by directing or controlling the entire end-to-end process, or will the case turn on the sufficiency of its indirect infringement allegations?
- A key technical question will be one of definitional scope: does the proprietary preservative in the accused Streck BCTs function in a way that falls within the patent's definition of an "agent that impedes cell lysis," and can it be properly categorized as a "membrane stabilizer, cross-linker, or cell lysis inhibitor" as required by the claims?
- Given the extensive history of alleged interactions detailed in the complaint, a central question for damages will be one of willfulness: does the evidence of Defendants' prior patent prosecution history, PTAB proceedings, and direct licensing discussions with Ravgen establish knowledge of infringement sufficient to support a finding of willful conduct?