NeoGenomics Laboratories, Inc. v. Natera, Inc.

1. Case Identification

• Case #: IPR2025-00455
• Patent #: 11,319,596
• Filed: January 14, 2025
• Petitioner(s): NeoGenomics Laboratories, Inc.
• Patent Owner(s): Natera, Inc.
• Challenged Claims: 1, 2, 5, 10-18

2. Patent Overview

• Title: Method for Preparing Biological Samples for Monitoring Progression of Cancer
• Brief Description: The ’596 patent discloses methods for monitoring cancer progression by first sequencing a tumor biopsy to identify subject-specific single nucleotide variant (SNV) mutations. Subsequently, cell-free DNA (cfDNA) is isolated from the subject over time and assayed using targeted multiplex PCR and high-throughput sequencing to detect these specific SNVs, with a claimed detection sensitivity of 0.015% or less.

3. Grounds for Unpatentability

Ground 1: Obviousness over Diaz and Kinde 2013 - Claims 1, 2, 5, 10, 12-14, and 16-18 are obvious over Diaz in view of Kinde 2013.

• Prior Art Relied Upon: Diaz (a 2014 journal article on liquid biopsies) and Kinde 2013 (a 2013 journal article on error-corrected sequencing).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that Diaz taught the core framework of a tumor-informed assay: identifying tumor-specific mutations from a tissue sample and then monitoring for those mutations in cfDNA over time using PCR and next-generation sequencing. However, Diaz also acknowledged that polymerase errors create a technical limit on sensitivity. Petitioner contended that Kinde 2013 directly addressed this problem by disclosing an improved error-correction method (Safe-SeqS) using unique identifiers (UIDs) to distinguish true mutations from sequencing artifacts. Kinde 2013 demonstrated this method was compatible with multiplex PCR and capable of detecting mutations at levels well below the ’596 patent’s 0.015% limitation (e.g., at 0.01%).
  • Motivation to Combine: A person of ordinary skill in the art (POSITA) reading Diaz would be motivated to improve the sensitivity of the described cfDNA assay to detect rare mutations. Diaz itself pointed to the problem of sequencing errors and referenced an earlier version of Kinde's Safe-SeqS as a solution "aimed at increasing overall sensitivity." This created an express motivation to combine Diaz's tumor-informed assay with the improved Safe-SeqS method taught by Kinde 2013.
  • Expectation of Success: A POSITA would have a reasonable expectation of success because Kinde 2013 taught that its Safe-SeqS method was compatible with multiplex PCR. Furthermore, by 2014, Safe-SeqS had already been successfully applied to cfDNA samples to detect rare mutations, making its application to the cfDNA assay in Diaz a predictable implementation.

Ground 2: Obviousness over Rabinowitz and Bettegowda - Claims 1, 2, 10-13, and 15-18 are obvious over Rabinowitz in view of Bettegowda.

• Prior Art Relied Upon: Rabinowitz (Application # 2012/0270212) and Bettegowda (a 2014 journal article on ctDNA detection).

• Core Argument for this Ground:

  • Prior Art Mapping: Petitioner asserted that Rabinowitz taught methods for highly efficient, highly multiplexed targeted PCR to amplify cfDNA, followed by high-throughput sequencing. Bettegowda taught a tumor-informed assay where mutations are first identified in a tumor and then detected in plasma using the Safe-SeqS method. Bettegowda demonstrated that Safe-SeqS could detect a single mutant template in DNA purified from 5 ml of plasma, which Petitioner calculated corresponds to a detection level of 0.0125% to 0.00125%—well below the claimed 0.015% threshold.
  • Motivation to Combine: A POSITA seeking to apply Rabinowitz's multiplex PCR methods for cancer monitoring would be motivated to incorporate a method for highly sensitive detection of rare mutations. They would have looked to references like Bettegowda, which applied the well-known Safe-SeqS error correction method to tumor-informed cfDNA assays. Combining Bettegowda's proven high-sensitivity approach with Rabinowitz's efficient multiplexing was argued to be a straightforward optimization.
  • Expectation of Success: Success was reasonably expected because both references addressed cfDNA analysis for cancer mutations. Bettegowda taught that Safe-SeqS was compatible with multiplexing, and Rabinowitz taught that its primer design methods could incorporate molecular barcodes, which are the same technology as the UIDs used in Safe-SeqS. Therefore, combining the teachings was a predictable integration of known techniques.

• Additional Grounds: Petitioner asserted additional obviousness challenges, including:

  • Claims 1, 2, 5, 10-14, and 16-18 as obvious over Diaz and Kinde 2013 in further view of Rabinowitz, arguing Rabinowitz provided additional motivation for highly multiplexed PCR.
  • Claim 15 as obvious over Diaz and Kinde 2013 in further view of Fleischhacker (a 2007 review article), arguing Fleischhacker provided the specific context of applying the method to bladder cancer.

4. Key Claim Construction Positions

• For the purpose of the IPR proceeding, Petitioner adopted Patent Owner's proposed constructions but reserved the right to challenge them in district court. Key adopted constructions include:
  • "performing high-throughput sequencing of the amplified DNA" allows for intermediate steps between the multiplex amplification and the sequencing.
  • "the isolated cell-free DNA" includes cfDNA isolated from any of the plurality of biological samples obtained at different time points.
• Petitioner argued that because it adopted Patent Owner’s positions, the Board need not formally construe these terms.

5. Arguments Regarding Discretionary Denial

• §325(d) Denial: Petitioner argued denial under §325(d) is improper because the core prior art references (Diaz, Kinde 2013, Bettegowda, Fleischhacker) were never considered by the Examiner. While Rabinowitz was listed in a large IDS, it was never discussed or applied. Petitioner contended the new art is not cumulative because it fills the exact gap the Examiner identified for allowance: the lack of art showing detection at the 0.015% level that was compatible with multiplex amplification. The Examiner's failure to find and apply this art constituted a material error.
• Discretionary Denial under Fintiv: Petitioner argued against Fintiv denial, asserting that the factors favor institution. Key arguments included:
  • The district court (M.D.N.C.) tends to stay cases pending IPR.
  • The median time-to-trial in the district (30.5 months) suggests a trial would occur nearly a year after the statutory deadline for a Final Written Decision (FWD).
  • Investment in the parallel proceeding is minimal as it is in the early stages.
  • The petition presents compelling merits that are highly likely to lead to cancellation, as it provides the specific art the Examiner found missing during prosecution.

6. Relief Requested

• Petitioner requested institution of an inter partes review and cancellation of claims 1, 2, 5, and 10-18 of Patent 11,319,596 as unpatentable under 35 U.S.C. §103.