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 cancer progression monitoring.
• Brief Description: The ’596 patent discloses a method for monitoring cancer by first identifying patient-specific single nucleotide variant (SNV) mutations from a tumor biopsy. Subsequently, cell-free DNA (cfDNA) is isolated from the patient at different times and assayed by performing targeted multiplex PCR amplification on the loci of the identified SNVs, followed by high-throughput sequencing. The key limitation requires detecting an SNV present in less than or equal to 0.015% of the cfDNA.

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 foundational "tumor-informed" assay of claim 1: identifying mutations in a tumor and then monitoring those mutations in cfDNA over time using PCR and next-generation sequencing (NGS). Diaz explicitly identified the problem of low sensitivity due to sequencing errors and pointed to the Safe-SeqS method as a solution. Kinde 2013 disclosed an improved, widely-cited version of Safe-SeqS that used unique identifiers (UIDs) for error correction, was compatible with multiplex PCR, and demonstrated the ability to detect mutations at levels far below the claimed 0.015% threshold (e.g., 0.01%).
  • Motivation to Combine (for §103 grounds): A person of ordinary skill in the art (POSITA) reading Diaz would have been directly motivated to use the Safe-SeqS method taught by Kinde 2013 to address the known sensitivity problem that Diaz itself raised. The combination represented the application of a known solution to a known problem.
  • Expectation of Success (for §103 grounds): A POSITA would have had a high expectation of success, as Kinde 2013 provided a detailed, proven method for increasing sequencing sensitivity that was known to be applicable to cfDNA analysis.

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

• Prior Art Relied Upon: Diaz, Kinde 2013, and Rabinowitz (Application # 2012/0270212).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground builds on the combination of Diaz and Kinde 2013 by adding Rabinowitz to teach highly efficient multiplexing. Petitioner asserted that Rabinowitz, an application by the inventors of the ’596 patent, explicitly taught methods for highly multiplexed PCR (over 50 or 100 primers) on cfDNA. This reference provided specific primer design strategies to achieve accurate results when amplifying a large number of target loci (10-50, as required by claim 11) simultaneously.
  • Motivation to Combine (for §103 grounds): A POSITA, seeking to implement the tumor-informed assay from Diaz and Kinde 2013 with greater efficiency and throughput, would combine it with Rabinowitz’s teachings. Rabinowitz provided a clear path to scaling up the number of target loci in a single reaction, a known goal for improving the comprehensiveness of such assays.
  • Expectation of Success (for §103 grounds): Success was predictable because Rabinowitz provided detailed methods for designing primers for multiplex cfDNA amplification, addressing known challenges like primer-dimer formation to ensure a high percentage of sequencing reads map to the intended targets.

Ground 3: 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: This ground presented an alternative path to obviousness. Petitioner argued that Rabinowitz provided the multiplex PCR and NGS framework for analyzing cfDNA from cancer patients. Bettegowda taught applying a tumor-informed assay and using the Safe-SeqS error correction method to detect mutations in cfDNA from plasma. Critically, Bettegowda demonstrated that Safe-SeqS could detect one mutant template in DNA from 5 ml of plasma, which Petitioner’s expert calculated to be equivalent to a detection level of 0.0125%-0.00125%—well below the claimed 0.015% threshold.
  • Motivation to Combine (for §103 grounds): A POSITA looking to apply Rabinowitz's multiplex PCR methods for detecting cancer recurrence would naturally consult contemporary literature like Bettegowda. Bettegowda demonstrated the successful use of a multiplex-compatible, high-sensitivity method (Safe-SeqS) in the precise context of a tumor-informed assay, providing a clear motivation to incorporate its teachings.
  • Expectation of Success (for §103 grounds): A POSITA would reasonably expect to achieve the claimed sensitivity. Bettegowda showed that Safe-SeqS could detect mutations at levels comparable to or better than the claimed threshold in cfDNA, and Rabinowitz taught how to perform such multiplex assays efficiently.

• Additional Grounds: Petitioner asserted an additional obviousness challenge for claim 15 (bladder cancer) based on the combination of Diaz, Kinde 2013, and Fleischhacker, which specifically disclosed detecting SNVs in cfDNA of bladder cancer patients.

4. Arguments Regarding Discretionary Denial

• §325(d): Petitioner argued that discretionary denial is improper because the petition relies on art and arguments that are not the same or substantially the same as those before the Examiner. Four of the five key references (Diaz, Kinde 2013, Bettegowda, Fleischhacker) were never considered by the Examiner. Petitioner contended this new art is not cumulative because it directly addresses the specific limitation (0.015% detection with multiplexing) that the Examiner identified as the basis for allowance, and the Examiner’s failure to consider such art constituted a material error.
• Discretionary Denial under Fintiv: Petitioner argued that the Fintiv factors favor institution. The parallel district court litigation is in its early stages, with minimal investment to date. Petitioner asserted that the median time-to-trial in the district court (nearly a year after the FWD deadline) and the likelihood of a stay weigh against denial. Furthermore, Petitioner stipulated that it would not pursue the same invalidity grounds in the district court if the IPR is instituted. Finally, Petitioner argued the petition presents compelling merits that are highly likely to lead to cancellation.

5. Relief Requested

• Petitioner requests institution of inter partes review and cancellation of claims 1, 2, 5, and 10-18 as unpatentable.