Laboratory Corp Of America Holdings v. Ravgen Inc

1. Case Identification

• Case #: IPR2021-00902
• Patent #: 7,332,277
• Filed: May 3, 2021
• Petitioner(s): Laboratory Corporation of America Holdings
• Patent Owner(s): Ravgen, Inc.
• Challenged Claims: 81-96 and 133

2. Patent Overview

• Title: Methods for Detection of Genetic Disorders
• Brief Description: The ’277 patent discloses methods for preparing biological samples to detect genetic disorders by isolating cell-free fetal nucleic acid from a maternal sample. The core of the claimed invention is the inclusion of an agent that inhibits cell lysis (e.g., a membrane stabilizer, cross-linker, or cell lysis inhibitor) to prevent the release of maternal DNA, which would otherwise increase background interference and complicate the detection of the fetal DNA.

3. Grounds for Unpatentability

Ground 1: Claims 81-91, 94-96, and 133 are obvious over Chiu and Bianchi

• Prior Art Relied Upon: Chiu (a 2001 article in Clinical Chemistry) and Bianchi (Patent 5,648,220).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that the combination of Chiu and Bianchi taught all limitations of the challenged claims. Chiu described methods for isolating and quantifying cell-free fetal DNA from maternal plasma, recognizing that contamination from lysed maternal cells was a problem that could be partially addressed by centrifugation protocols. However, Chiu suggested that processing samples within two hours was necessary, implying the method was insufficient for longer storage. Bianchi addressed a similar problem by teaching the use of cell-stabilizing agents, such as paraformaldehyde, to fix and permeabilize fetal cells from maternal blood while keeping their membranes intact. This process inherently inhibits cell lysis.
  • Motivation to Combine: A Person of Ordinary Skill in the Art (POSITA) studying Chiu's methods would have recognized the problem of maternal cell lysis, especially after the two-hour window Chiu suggested. A POSITA would combine Bianchi's well-known cell stabilization technique with Chiu's fetal DNA isolation protocol to solve this known problem. The motivation was to improve the stability of the sample for storage or transport and to reduce the background noise from maternal DNA, thereby increasing the accuracy and reliability of the fetal DNA analysis.
  • Expectation of Success: A POSITA would have a reasonable expectation of success in this combination. It was well-understood that stabilizing agents like formaldehyde prevent cell lysis. Applying this known technique to the maternal blood samples in Chiu’s protocol would predictably result in less maternal DNA contamination and a cleaner sample for fetal DNA analysis.

Ground 2: Claims 92 and 93 are obvious over Chiu, Bianchi, and Granger

• Prior Art Relied Upon: Chiu (a 2001 article in Clinical Chemistry), Bianchi (Patent 5,648,220), and Granger (WO 95/01796).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground builds upon the combination of Chiu and Bianchi to address the specific formalin concentration ranges recited in claims 92 and 93. While Bianchi taught using paraformaldehyde (2% to 8%), Granger disclosed methods for stabilizing leukocytes in whole blood using lower concentrations of aldehydes like formaldehyde, specifically in the range of 0.1% to 0.5%. The concentration ranges claimed in the ’277 patent substantially overlap with or are very close to those taught by Granger.
  • Motivation to Combine: A POSITA, having decided to use a stabilizing agent as taught by Bianchi, would be motivated to consult a reference like Granger to optimize the concentration. The motivation would be to use the lowest effective concentration of formaldehyde to achieve the desired cell stabilization while minimizing any potential damage to the sample or dealing with the known toxicity of the chemical. This type of optimization was a routine aspect of laboratory practice.
  • Expectation of Success: A POSITA would expect success in using the lower concentrations taught by Granger, as Granger demonstrated their effectiveness for stabilizing blood cells. Fine-tuning concentrations for a specific application is a predictable and standard experimental step.

Ground 3: Claims 81-96 and 133 are obvious over Chiu and Rao

• Prior Art Relied Upon: Chiu (a 2001 article in Clinical Chemistry) and Rao (WO 03/018757).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground presented an alternative combination to prove the obviousness of the claims. As in Ground 1, Chiu provided the foundational method for isolating fetal DNA and identified the problem of maternal cell lysis. Rao provided an alternative solution to Bianchi, disclosing methods for stabilizing rare cells (such as circulating tumor cells, which are analogous to fetal cells in maternal blood) in a biological specimen. Rao explicitly taught adding a stabilizing agent, such as an aldehyde or a formaldehyde donor, to a blood collection tube prior to the blood draw to prevent cell degradation and the formation of interfering debris during processing and storage.
  • Motivation to Combine: The motivation to combine Chiu and Rao was strong and direct. A POSITA seeking to improve upon Chiu's method, particularly for samples requiring storage or transport, would look for ways to stabilize the sample at the point of collection. Rao taught exactly that: adding a stabilizer to the collection tube to preserve rare cells. Rao even identified pregnancy as an example of a condition involving rare cells in a biological specimen, making the connection to Chiu’s work explicit.
  • Expectation of Success: A POSITA would have a high expectation of success. Rao’s stabilizers were designed for the express purpose of preserving rare cells and preventing the formation of cellular debris in blood samples, which directly addressed the challenge of maternal cell lysis in Chiu's protocol. The combination represented the application of a known solution (Rao) to a known problem (identified in Chiu).

4. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under the Fintiv factors was not warranted. It contended that the parallel litigation in the Western District of Texas was in its nascent stages, with no definitive trial date, no claim construction, and minimal discovery. Furthermore, Petitioner filed a stipulation agreeing not to pursue in district court the same invalidity grounds or prior art combinations raised in the IPR petition, thereby avoiding duplicative efforts and conserving judicial resources.

5. Relief Requested

• Petitioner requested the institution of an inter partes review and the cancellation of claims 81-96 and 133 of Patent 7,332,277 as unpatentable under 35 U.S.C. §103.