DCT
1:20-cv-01646
Ravgen Inc v. Ariosa Diagnostics Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Ravgen, Inc. (Delaware)
- Defendant: Ariosa Diagnostics, Inc.; Roche Sequencing Solutions, Inc.; Roche Molecular Systems, Inc.; and Foundation Medicine, Inc. (all Delaware)
- Plaintiff’s Counsel: Farnan LLP; Desmarais LLP
- Case Identification: 1:20-cv-01646, D. Del., 04/19/2021
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because all Defendant entities are organized under the laws of Delaware, reside in the state for venue purposes, and conduct business in the district.
- Core Dispute: Plaintiff alleges that Defendants’ non-invasive prenatal and liquid biopsy genetic tests, along with their associated blood collection tubes, infringe patents related to methods for preparing and analyzing cell-free DNA samples.
- Technical Context: The technology at issue involves methods to improve the detection of cell-free DNA (cfDNA)—such as fetal DNA in a mother's bloodstream or circulating tumor DNA—by preventing other cells in a blood sample from breaking down and contaminating the sample with their own DNA.
- Key Procedural History: The complaint alleges an extensive history of Defendants’ awareness of the patents-in-suit, citing their citation during the prosecution of Defendants' own patents, their use in inter partes review (IPR) and reexamination proceedings initiated by Defendants against other patents, and direct pre-suit communications between the inventor and executives who later joined or founded the defendant companies.
Case Timeline
| Date | Event |
|---|---|
| 2002-05-08 | Priority Date for ’277 and ’720 Patents |
| 2008-02-19 | U.S. Patent No. 7,332,277 Issues |
| 2010-06-01 | U.S. Patent No. 7,727,720 Issues |
| 2012-01-01 | Accused Harmony Prenatal Test Launched by Ariosa |
| 2016-05-03 | Accused FoundationACT Test Launched by FMI |
| 2018-09-24 | Accused FoundationOne Liquid Test Launched by FMI |
| 2020-08-28 | Accused FoundationOne Liquid CDx Test Launched by FMI |
| 2021-04-19 | Second Amended Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 7,727,720 - “Methods for Detection of Genetic Disorders,” issued June 1, 2010.
The Invention Explained
- Problem Addressed: The patent addresses the difficulty of detecting the small amount of fetal DNA present in a sample of a pregnant mother’s blood (Compl. ¶¶ 18, 33). The vast majority of DNA in such a sample is maternal, which can obscure the fetal DNA signal, and maternal cells in the blood sample can break down (lyse) after collection, further contaminating the sample with maternal DNA (’720 Patent, col. 33:31-46).
- The Patented Solution: The invention introduces a method to increase the relative percentage of fetal DNA by adding an agent to the blood sample that inhibits or impedes the lysis of maternal cells (’720 Patent, col. 33:36-46). By stabilizing the maternal cells and preventing them from releasing their DNA, the existing cell-free fetal DNA becomes easier to detect and analyze for genetic abnormalities (Compl. ¶¶ 19, 34).
- Technical Importance: This sample preparation technique was described as a foundational improvement for developing accurate, non-invasive genetic diagnostic tests, offering an alternative to invasive procedures that carry a risk of pregnancy loss (Compl. ¶¶ 16, 22).
Key Claims at a Glance
- The complaint asserts infringement of at least Claim 1 (Compl. ¶135).
- Independent Claim 1 requires:
- A method for detecting a free nucleic acid
- Comprising the step of (a) isolating free nucleic acid from a non-cellular fraction of a sample
- Wherein the sample comprises an agent that impedes cell lysis, if cells are present
- Wherein the agent is selected from the group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor
- And comprising the step of (b) detecting the presence or absence of the free nucleic acid
U.S. Patent No. 7,332,277 - “Methods For Detection Of Genetic Disorders,” issued February 19, 2008.
The Invention Explained
- Problem Addressed: Similar to its related patent, the ’277 Patent addresses the challenge that the low percentage of fetal DNA in maternal plasma makes genotyping the fetus difficult (’277 Patent, col. 32:24-30). The background highlights the need for a non-invasive, accurate prenatal diagnostic test to replace existing invasive methods (Compl. ¶¶ 16-18).
- The Patented Solution: The patent discloses methods to improve the detection of genetic disorders from cell-free DNA. A central innovation, recited in the asserted exemplary claim, is a method for preparing a sample for analysis by including an agent that inhibits cell lysis (’277 Patent, col. 473:52-474:10). This prevents maternal cells from degrading and releasing their DNA, thereby increasing the relative concentration of fetal DNA in the cell-free fraction of the sample (Compl. ¶33).
- Technical Importance: The method provided a more reliable way to prepare blood samples for non-invasive genetic analysis, which was recognized as "an important step in improving detection of cell-free DNA" (Compl. ¶36).
Key Claims at a Glance
- The complaint asserts infringement of at least exemplary Claim 81 (Compl. ¶124).
- Independent Claim 81 requires:
- A method for preparing a sample for analysis
- Comprising isolating free fetal nucleic acid from the sample
- Wherein the sample comprises an agent that inhibits lysis of cells, if cells are present
- And wherein the agent is selected from the group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor
III. The Accused Instrumentality
Product Identification
The accused instrumentalities are genetic testing services and their associated collection materials (Compl. ¶¶ 7-9). They include:
- The Harmony Prenatal Test, a non-invasive test for fetal chromosomal abnormalities (Compl. ¶54).
- The Foundation Liquid Biopsy Tests (FoundationACT, FoundationOne Liquid, and FoundationOne Liquid CDx), which analyze circulating tumor DNA for cancer genomic profiling (Compl. ¶69).
- Associated Cell-Free DNA Collection Tubes sold by Roche and Foundation Medicine (Compl. ¶¶ 9, 56, 72).
Functionality and Market Context
- The accused tests analyze cell-free DNA (fetal or tumor) from a patient's blood sample to provide diagnostic information (Compl. ¶¶ 57, 66). A critical component of these testing services is the blood collection process. The complaint alleges that Defendants instruct healthcare providers to use specific collection tubes, such as the Roche Cell-Free DNA Collection Tube or the FoundationOne Liquid CDx cfDNA Blood Collection Tube (Compl. ¶¶ 58, 73).
- These tubes are alleged to contain a "proprietary solution," "preservative," or agent that "prevents cell lysis" or "suppress[es]... white blood cell lysis," thereby preserving the integrity of the cell-free DNA for analysis (Compl. ¶¶ 61, 74, 75). A product description for Roche’s tube states its “Proprietary solution prevents cell lysis to enable greater detection of cfDNA” (Compl. p. 21). The complaint alleges these tests are significant commercial products that generate substantial revenue (Compl. ¶120).
IV. Analysis of Infringement Allegations
U.S. Patent No. 7,727,720 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 Harmony and Foundation tests require isolating cfDNA from a plasma fraction of a whole blood sample. | ¶135.a; ¶140.a | col. 11:1-12 |
| ...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 blood samples are collected in Defendants' specialized tubes, which allegedly contain a preservative or proprietary solution that prevents or minimizes the lysis of maternal or nucleated blood cells. A product description for the FoundationOne tube describes its contents as including "a cell preservative" that "prevents lysis of nucleated blood cells" (Compl. p. 27). | ¶135.b; ¶140.b | col. 10:40-52 |
| ...and (b) detecting the presence or absence of the free nucleic acid. | After isolation, the cfDNA is analyzed using methods such as targeted amplification (Harmony) or whole-genome sequencing (Foundation) to detect genetic information and abnormalities. | ¶135.c; ¶140.c | col. 11:13-16 |
U.S. Patent No. 7,332,277 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 Harmony Prenatal Test involves isolating cell-free fetal DNA from a maternal blood sample. | ¶124.a | col. 473:52-54 |
| ...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 method requires collecting the maternal blood sample in a Roche Cell-Free DNA Collection Tube or equivalent, which contains an agent that prevents maternal blood cells from lysing and contaminating the sample. | ¶124.b | col. 473:55-60 |
- Identified Points of Contention:
- Scope Questions: A central issue may be whether the specific chemical agents used as "preservatives" in Defendants' collection tubes fall within the scope of the claimed Markush group "membrane stabilizer, cross-linker, and cell lysis inhibitor." The analysis will question whether a general-purpose "cell preservative" performs the specific function claimed in the patents.
- Technical Questions: The infringement theory depends on the function of the additives in the accused collection tubes. A key factual question will be what evidence demonstrates that these additives actively "inhibit" or "impede" cell lysis, as required by the claims, and whether this function is distinct from general sample preservation.
V. Key Claim Terms for Construction
- The Term: "agent that impedes cell lysis" (’720 Patent) / "agent that inhibits lysis of cells" (’277 Patent).
- Context and Importance: This term is the core of the asserted claims. The outcome of the infringement analysis will depend heavily on whether the chemical solutions in Defendants' blood collection tubes are determined to be such an "agent." Practitioners may focus on this term because the complaint alleges that general-purpose "preservatives" meet this limitation, a characterization Defendants may contest.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specifications provide extensive lists of potential agents, including aldehydes (formaldehyde, glutaraldehyde), various cross-linkers, and agents that stabilize cell membranes such as vitamins, cholesterol, and certain drugs (’720 Patent, col. 31:36–32:27; Table XXIII). This variety suggests the inventor contemplated a broad range of substances capable of performing the claimed function.
- Evidence for a Narrower Interpretation: The specifications also describe preferred embodiments, such as the use of formaldehyde at specific concentrations (’720 Patent, col. 5:44-52). A defendant may argue that the term should be limited by these more specific examples or that it implies an agent whose primary purpose and effect is cell stabilization for cfDNA analysis, not merely general preservation.
VI. Other Allegations
- Indirect Infringement: The complaint alleges induced infringement under 35 U.S.C. § 271(b). The basis for this allegation is that Defendants supply the Harmony and Foundation Liquid Biopsy tests, including the specialized collection tubes and instructional materials, with the knowledge and intent that their customers (e.g., healthcare providers, laboratories) will use them to perform the patented methods (Compl. ¶¶ 127, 138, 142).
- Willful Infringement: The complaint alleges that Defendants' infringement has been and continues to be willful. It supports this allegation with claims of both pre- and post-suit knowledge, including: Defendants' citation of the patents-in-suit during their own patent prosecution; Defendants' involvement in prior PTAB proceedings concerning the patents; direct communications between the inventor and individuals who became principals at Ariosa; and discussions between Ravgen and Roche executives (Compl. ¶¶ 77, 79-107, 130, 145).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of definitional scope: Will the claim term "agent that inhibits lysis of cells" be construed broadly to encompass the specific chemical "preservatives" used in Defendants' blood collection tubes, or will it be limited to a narrower set of compounds explicitly disclosed or primarily known for that specific function?
- A second key question will be one of willfulness and damages: Given the extensive pre-suit interactions and knowledge alleged in the complaint, the case may focus significantly on whether Defendants acted in an objectively reckless manner, which could expose them to the risk of enhanced damages if infringement is found.