Oxford Nanopore Technologies Inc v. Pacific Biosciences Of California Inc

1. Case Identification

• Case #: IPR2018-00789
• Patent #: 9,546,400
• Filed: March 15, 2018
• Petitioner(s): Oxford Nanopore Technologies, Inc.
• Patent Owner(s): Pacific Biosciences of California, Inc.
• Challenged Claims: 1-15

2. Patent Overview

• Title: Nanopore Sequencing Using N-mers
• Brief Description: The ’400 patent discloses methods for nanopore-based nucleic acid sequencing. The technology addresses the challenge that the measured electrical signal from a nanopore is influenced by multiple nucleotides (an "N-mer") simultaneously, requiring the signal to be deconvoluted by comparing it to pre-established "calibration information" generated from all 4^N possible N-mer sequences.

3. Grounds for Unpatentability

Ground 1: Obviousness over Winters-Hilt and Hibbs - Claims 1-3, 6-9, and 12-15 are obvious over Winters-Hilt in view of Hibbs.

• Prior Art Relied Upon: Winters-Hilt (a 2003 dissertation) and Hibbs (Patent 7,731,826).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that the combination teaches all limitations of the challenged claims. Winters-Hilt disclosed that nanopore sequencing signals are affected by multiple bases (N ≥ 3) simultaneously, requiring a difficult "base-deconvolution" task. It further taught that due to unpredictable effects and "device sensitivity," a POSITA would be motivated to measure all 4^N combinations to determine the feasibility of sequencing. Hibbs disclosed a method to determine a nucleic acid sequence by comparing a measured signal to "calibrated values" derived from empirical measurements on known polymer sequences, explicitly providing a methodology to deconvolute signals from multiple monomers.
  • Motivation to Combine: A POSITA would combine these references as they address the identical problem of deconvoluting signals from multiple bases in nanopore sequencing. Petitioner asserted a POSITA would implement the calibration methodology of Hibbs into the sequencing paradigm of Winters-Hilt. Specifically, a POSITA would be motivated by Winters-Hilt's teaching on the unpredictability of nanopore signals to extend Hibbs’s calibration method to measure all 4^N possible sequence combinations, rather than modeling some, to ensure accuracy.
  • Expectation of Success: The combination of two known nanopore sequencing techniques to solve a well-known problem in the field would have yielded predictable results.

Ground 2: Obviousness over Winters-Hilt, Hibbs, and Akeson - Claims 4 and 5 are obvious over Winters-Hilt and Hibbs in view of Akeson.

• Prior Art Relied Upon: Winters-Hilt (a 2003 dissertation), Hibbs (Patent 7,731,826), and Akeson (Application # 2006/0063171).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground builds on Ground 1 by adding teachings for dependent claims 4 and 5, which require controlling the nucleic acid translocation rate enzymatically. Akeson explicitly disclosed a working system for controlling the translocation rate through a nanopore using enzymes ("molecular motors"), including specific enzymes like polymerase and helicase. This directly addresses a problem that Hibbs suggested was not yet solved by enzyme-based methods.
  • Motivation to Combine: Petitioner argued a POSITA, recognizing the translocation control issue identified in Hibbs, would have been motivated to search for and incorporate known solutions. Akeson provided such a solution, teaching the use of enzymes to precisely control translocation for sequencing, making its combination with the base method of Winters-Hilt and Hibbs an obvious improvement.

Ground 5: Obviousness over Sigalov - Claims 1-3, 6, 7, and 12-15 are obvious over Sigalov.

• Prior Art Relied Upon: Sigalov (a 2007 Nano Letters article).

• Core Argument for this Ground:

  • Prior Art Mapping: Petitioner contended that Sigalov, a single reference, rendered the claims obvious. Sigalov disclosed a nanopore sequencing method where the measured electrical potential is affected by a "group of several consecutive nucleotides" (e.g., a triad where N=3), requiring a "deconvolution procedure." Sigalov taught that sequencing requires "careful design and calibration of the device" using known DNA homopolymers and copolymers. A POSITA would understand that calibrating for a signal attributed to a triad of nucleotides would entail measuring the signal for each of the 4^3 (64) possible triads to create the necessary calibration data. Sigalov also taught that some signals may be degenerate and that overlapping reads of successive triads could be used to eliminate impossible sequences.
  • Motivation to Combine (N/A for single reference): Not applicable.
  • Expectation of Success: Sigalov described a complete, albeit conceptual, sequencing system, and a POSITA would have had a reasonable expectation of success in implementing its teachings.

• Additional Grounds: Petitioner asserted additional obviousness challenges, including combinations of Sigalov with Akeson, Winters-Hilt, Sazegari, and Lee to address other dependent claims related to array-based sequencing (claim 8), specific sequencing algorithms (claim 9), and the use of lookup tables with statistical thresholds (claims 10-11).

4. Key Claim Construction Positions

• "calibration information produced by measuring such property for 4 to the N sequence combinations": Petitioner argued that, based on the patent’s prosecution history where the Patent Owner distinguished prior art, this phrase must be construed to mean "calibration information produced by measuring each of the 4^N sequence combinations, wherein N is the total number of bases within the pore that contribute to the signal." This construction was central to Petitioner's argument that prior art teaching the necessity of comprehensive empirical measurement rendered the claims obvious.

5. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under §325(d) would be inappropriate even though the Hibbs application was considered during prosecution of the ’400 patent. The primary reasons asserted were:
  • The examiner erred in allowing the claims because the Patent Owner inaccurately characterized Hibbs as teaching only 12 calibration measurements, when in fact Hibbs taught measuring all 16 combinations for N=2 and 40 of 64 combinations for N=3.
  • The primary prior art reference, Winters-Hilt, which provided the explicit motivation for measuring all 4^N combinations that the Patent Owner argued was missing from Hibbs, was never considered by the examiner.

6. Relief Requested

• Petitioner requested institution of an inter partes review and cancellation of claims 1-15 of the ’400 patent as unpatentable under 35 U.S.C. §103.