Ravgen Inc v. PerkinElmer Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Ravgen, Inc. (Delaware)
  • Defendant: PerkinElmer, Inc. (Massachusetts); PerkinElmer Genetics, Inc. (Pennsylvania); and Bioo Scientific Corporation (Texas)
  • Plaintiff’s Counsel: Desmarais LLP; The Dacus Firm, P.C.
• Case Identification: 6:20-cv-452, W.D. Tex., 06/01/2020
• Venue Allegations: Plaintiff alleges venue is proper in the Western District of Texas because Defendants maintain a "permanent and continuous presence" and "regular and established places of business" in the district, including facilities in Austin, Texas. The complaint further asserts that Defendant Bioo Scientific Corporation is a Texas corporation that resides in the district and that all defendants operate as a single corporate family.
• Core Dispute: Plaintiff alleges that Defendants’ non-invasive prenatal testing (NIPT) systems and cell-free DNA (cfDNA) extraction kits infringe patents related to methods for preserving and analyzing cell-free nucleic acid from biological samples.
• Technical Context: The technology relates to non-invasive prenatal genetic testing, which analyzes trace amounts of cell-free fetal DNA circulating in a pregnant mother's blood to screen for chromosomal abnormalities, offering a safer alternative to invasive procedures.
• Key Procedural History: The complaint alleges that on May 15, 2020, Plaintiff sent a letter to Defendants identifying the patents-in-suit and providing notice of alleged infringement. During the prosecution of the ’720 patent, the applicant argued to the USPTO that the addition of a cell lysis inhibitor to a sample to increase the proportion of free nucleic acid was a "significant[] and unexpected[]" improvement over the prior art.

Case Timeline

Date	Event
2002-05-08	Earliest Priority Date for ’277 and ’720 Patents
2008-02-19	’277 Patent Issued
2009-06-02	Plaintiff's Response to Office Action during ’720 Patent prosecution
2010-06-01	’720 Patent Issued
2015-02-01	Bioo Scientific launched NextPrep-Mag™ and NEXTflex® Kits (approximate)
2016-01-01	PerkinElmer began commercializing chemagic™ cfDNA 5k Kits (approximate)
2018-01-01	PerkinElmer launched the Vanadis® NIPT Assay (approximate)
2020-05-15	Plaintiff sent notice letter to Defendants regarding alleged infringement
2020-06-01	Complaint Filed

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

U.S. Patent No. 7,332,277 - “Methods For Detection Of Genetic Disorders”

• Issued: February 19, 2008

The Invention Explained

• Problem Addressed: The patent addresses the difficulty of using cell-free fetal DNA for genetic testing due to its low concentration in maternal blood plasma (U.S. Patent No. 7,332,277, col. 32:24-28). The small amount of fetal DNA is often overwhelmed by a much larger amount of maternal DNA released from maternal blood cells that break open (lyse) during sample collection, handling, and processing (Compl. ¶41; ’277 Patent, col. 32:36-39).
• The Patented Solution: The invention proposes a method to increase the relative percentage of fetal DNA in a sample by adding a specific agent to the maternal blood sample before processing (Compl. ¶54). This agent is selected from a group that includes cell membrane stabilizers, cross-linkers (like formaldehyde), and cell lysis inhibitors, which function to prevent maternal cells from breaking and releasing their DNA into the plasma ('277 Patent, col. 32:33-39). By inhibiting the lysis of the abundant maternal cells while preserving the already free fetal DNA, the method improves the signal-to-noise ratio for subsequent genetic analysis (Compl. ¶55).
• Technical Importance: This method provided a foundational technique for making non-invasive prenatal tests more accurate and reliable, facilitating their development as an alternative to riskier, invasive procedures (Compl. ¶42).

Key Claims at a Glance

• The complaint asserts infringement of at least exemplary independent claim 81 (Compl. ¶88).
• Claim 81 includes the following essential elements:
  • A method for preparing a sample for analysis comprising isolating free fetal nucleic acid from 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 alleges infringement of "one or more claims," suggesting the right to assert other claims is reserved (Compl. ¶87).

U.S. Patent No. 7,727,720 - “Methods For Detection Of Genetic Disorders”

• Issued: June 1, 2010

The Invention Explained

• Problem Addressed: As a continuation of the application leading to the ’277 Patent, the ’720 Patent addresses the same technical challenge: the majority of DNA in a maternal plasma sample is maternal, which "makes using the DNA for genotyping the fetus difficult" (U.S. Patent No. 7,727,720, col. 33:31-36).
• The Patented Solution: The patent claims a method that builds upon the core concept of the ’277 Patent. It involves two main parts: first, isolating free nucleic acid from a sample that contains an agent to impede cell lysis (such as a stabilizer or cross-linker), and second, detecting the presence or absence of that isolated nucleic acid ('720 Patent, Abstract; Compl. ¶53). By coupling the sample preparation technique with a detection step, the patent claims a more complete diagnostic method.
• Technical Importance: The claimed method provides an end-to-end process for non-invasive genetic analysis that benefits from the increased relative percentage of fetal DNA achieved through cell stabilization (Compl. ¶55).

Key Claims at a Glance

• The complaint asserts infringement of at least exemplary independent claim 1 (Compl. ¶101).
• Claim 1 includes the following essential elements:
  • A method for detecting a free nucleic acid, comprising:
  • (a) isolating free nucleic acid from a non-cellular fraction of a sample,
  • wherein the sample comprises an agent that impedes cell lysis and is selected from the group of a membrane stabilizer, cross-linker, or cell lysis inhibitor; and
  • (b) detecting the presence or absence of the free nucleic acid.
• The complaint alleges infringement of "one or more claims," suggesting the right to assert other claims is reserved (Compl. ¶100).

III. The Accused Instrumentality

Product Identification

The complaint identifies two main categories of accused instrumentalities: (1) the Vanadis® NIPT Assay and associated system; and (2) various cfDNA Kits, including the chemagic™ cfDNA 5k Kits, the NextPrep-Mag™ cfDNA Automated Isolation Kits, and the NEXTflex® Cell-Free DNA-Seq Kits (Compl. ¶4, ¶59, ¶69).

Functionality and Market Context

• The Vanadis® NIPT Assay is a non-invasive prenatal test that analyzes circulating fetal DNA from a maternal blood sample to screen for chromosomal abnormalities like trisomy (Compl. ¶60, ¶67). The system automates the workflow, starting with cfDNA extraction from plasma, followed by capturing target DNA fragments, converting them into DNA circles, labeling them with chromosome-specific fluorescent tags, and finally counting the labeled molecules to calculate risk (Compl. ¶60-66). The complaint provides a diagram illustrating this workflow, from cfDNA extraction to analysis by a microplate scanner (Compl. p. 23, Ex. 34).
• The cfDNA Kits are used for extracting and processing cell-free DNA from samples for subsequent analysis (Compl. ¶75). The NextPrep-Mag™ and chemagic™ kits are designed for automated extraction of cfDNA from plasma, while the NEXTflex® kits are used to prepare the extracted DNA into "sequencing-ready libraries" (Compl. ¶70, ¶71, ¶79). The complaint includes a flowchart detailing an automated workflow using these kits for high-throughput cfDNA extraction and library preparation from plasma samples (Compl. p. 34, Ex. 55).
• A key allegation for all accused instrumentalities is their use with maternal blood samples collected in Streck Cell-Free DNA BCT® tubes, which allegedly contain a "unique preservative" that "limits the release of genomic DNA" by "limiting cell lysis" (Compl. ¶62, ¶63, ¶77).

IV. Analysis of Infringement Allegations

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 the sample,	Defendants' Vanadis Extract® platform and cfDNA kits (NextPrep-Mag™, chemagic™) are used to extract cell-free fetal DNA from maternal blood or plasma samples.	¶88a, ¶89a	col. 15:32-40
wherein said sample comprises an agent that inhibits lysis of cells, if cells are present,	The accused methods process blood samples that are collected and stored in Streck Cell-Free DNA BCT® tubes, which allegedly contain a preservative chemistry that limits cell lysis.	¶88b, ¶89b	col. 10:10-16
and wherein said agent is selected from the group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor.	The complaint alleges that the preservative in the Streck tubes functions as a cell lysis inhibitor, membrane stabilizer, or cross-linker as contemplated by the patent.	¶88b, ¶89b	col. 10:14-16

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 Vanadis Extract® platform and the accused cfDNA kits perform extraction of cfDNA from plasma, which is the non-cellular fraction of a blood sample.	¶101a, ¶102a	col. 12:13-21
wherein said sample comprises an agent that impedes cell lysis...selected from the group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor;	The process allegedly uses blood samples collected in Streck Cell-Free DNA BCT® tubes, which contain a preservative that limits cell lysis and falls within the claimed group of agents.	¶101b, ¶102b	col. 10:25-32
and (b) detecting the presence or absence of the free nucleic acid.	The Vanadis system detects the nucleic acid by labeling it with fluorophores and counting signals. The cfDNA kits enable detection by preparing the nucleic acid for sequencing or electrophoresis.	¶101c, ¶102c	col. 9:19-24

• Identified Points of Contention:
  • Scope Questions: A primary question may be whether the "unique preservative" contained in the third-party Streck BCT® tubes meets the claim limitation of an "agent that inhibits lysis of cells...selected from the group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor." The analysis will likely depend on the chemical composition and mechanism of action of the agent in the Streck tubes, which is not detailed in the complaint.
  • Technical Questions: The infringement theory relies on Defendants using or instructing others to use samples that are pre-treated with a stabilizing agent. This raises the question of whether performing downstream processing on such a sample constitutes practicing the full claimed method, which may be interpreted to include the step of adding the agent.

V. Key Claim Terms for Construction

• The Term: "agent that inhibits lysis of cells" / "agent that impedes cell lysis"

• Context and Importance: This term is the central inventive concept of the patents-in-suit. The infringement case hinges on whether the preservative in the Streck tubes, which are used with the accused products, falls within the scope of this term. Practitioners may focus on this term because the accused products do not themselves contain the agent, but are allegedly designed for use with samples that do.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specifications provide extensive and non-limiting lists of potential agents, including "formaldehyde, and derivatives of formaldehyde, formaline, glutaraldehyde, and derivatives of glutaraldehyde," as well as dozens of chemical cross-linkers listed in a table ('277 Patent, col. 30:35-52, Table XXIII; '720 Patent, col. 31:39-55, Table XXIII). This breadth may support an interpretation that covers any chemical compound that performs the stated function of preventing cell lysis to increase the relative percentage of fetal DNA.
  • Evidence for a Narrower Interpretation: The specifications repeatedly emphasize the use of "formaldehyde" as a primary example ('277 Patent, col. 91:47-49; '720 Patent, col. 92:14-20). A defendant could argue that the term should be construed more narrowly in light of these specific embodiments or that it implies a particular level of efficacy in preventing lysis that must be demonstrated.

• The Term: "isolating"

• Context and Importance: This is the primary active step performed by the accused hardware and kits (e.g., the Vanadis Extract® instrument). The dispute may turn on whether the specific technical method of isolation used by Defendants (e.g., a "bead based protocol") is covered by the claims (Compl. ¶64).

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The patents describe "isolating" in general terms, such as separating plasma from blood via centrifugation and then extracting DNA from the plasma ('277 Patent, col. 15:32-40). The term is not explicitly limited to a single technique.
  • Evidence for a Narrower Interpretation: The patent examples reference using specific commercial kits for isolation, such as the "QIAGEN DNA Blood Mini Kit," which utilizes a silica-membrane-based method ('277 Patent, col. 31:47-49). It could be argued that the scope of "isolating" should be informed by these disclosed examples, potentially creating a distinction with the "bead based" methods allegedly used by Defendants.

VI. Other Allegations

• Indirect Infringement: The complaint alleges both induced and contributory infringement. It asserts that Defendants induce infringement by selling the Vanadis® Assay and cfDNA Kits with promotional materials, product manuals, and instructions that direct customers to use them in an infringing manner, specifically with blood samples collected in cell-stabilizing tubes (Compl. ¶91, ¶104). Contributory infringement is alleged on the basis that the accused products are a material part of the patented methods, are not staple articles of commerce, and are especially adapted for infringing use (Compl. ¶93, ¶106).
• Willful Infringement: The complaint alleges willful infringement based on Defendants' continued infringing activities after receiving a notice letter from Ravgen on May 15, 2020, which allegedly provided knowledge of the patents and the infringement (Compl. ¶95, ¶108).

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

• A core issue will be one of infringement by a third-party component: can Plaintiff prove that the unspecified preservative in the commercially available Streck BCT® tubes—a product not made by Defendants but allegedly used with the accused systems—meets the specific definitional requirements of an "agent that inhibits lysis of cells" as claimed in the patents?
• A second key question will be one of divided infringement and control: does Defendants' act of using, or instructing customers to use, a pre-stabilized blood sample constitute direct infringement of a method that includes sample preparation with a stabilizing agent? The outcome may depend on whether Defendants' control over the entire process, from sample collection instructions to final analysis, is sufficient to attribute all steps of the claimed method to them.