Pacific Biosciences Of California Inc v. Chinese University Of Hong Kong

1. Case Identification

• Case #: IPR2024-00028
• Patent #: 11,091,794
• Filed: October 17, 2023
• Petitioner(s): Pacific Biosciences of California, Inc.
• Patent Owner(s): The Chinese University of Hong Kong
• Challenged Claims: 1-19

2. Patent Overview

• Title: Determination of Base Modifications of Nucleic Acids
• Brief Description: The ’794 patent discloses a method for detecting nucleotide modifications during single-molecule, real-time (SMRT) sequencing. The method involves receiving optical pulse data, creating an input data structure comprising nucleotide identity, position, pulse width (PW), and interpulse duration (IPD) for a "window" of nucleotides, and inputting this structure into a trained model to determine if a modification exists.

3. Grounds for Unpatentability

Ground 1: Claims 1-2, 7, 10-12, 14-15, and 17-19 are obvious over the Flusberg Publications in view of PacBio-BAM.

• Prior Art Relied Upon: The Flusberg Publications (a 2010 journal article and Patent 9,175,338) and PacBio-BAM (PacBio BAM Format Documentation, 2017).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that the combination of Flusberg and PacBio-BAM taught every limitation of the independent claim. The Flusberg Publications taught using polymerase kinetic data—specifically PW and IPD obtained from SMRT sequencing—to detect epigenetic modifications like methylation. Flusberg disclosed analyzing these metrics within a local sequence "context" or "window" and inputting them into analytical models. Petitioner contended that the key "input data structure" (comprising nucleotide identity, position, PW, and IPD), which the Patent Owner argued was novel during prosecution, was explicitly disclosed by PacBio-BAM. PacBio-BAM was the standard, publicly documented file format for storing SMRT sequencing data and expressly included fields for sequence, position, PW, and IPD, noting its suitability for downstream "base modification detection."
  • Motivation to Combine: A person of ordinary skill in the art (POSITA) would combine Flusberg's modification detection method with the PacBio-BAM data format because Flusberg's method relied on SMRT sequencing data, and PacBio-BAM was the conventional data structure provided by the SMRT sequencing platform for storing and accessing precisely that data. PacBio-BAM expressly suggested its use for modification detection, providing a clear motivation to use it as the input for the models described in Flusberg.
  • Expectation of Success: A POSITA would have had a high expectation of success, as the combination involved using a standard data format with its intended data types (kinetic parameters) for its stated purpose (modification detection) in a well-understood analytical framework.

Ground 2: Claims 3-6 and 9 are obvious over the Flusberg Publications, PacBio-BAM, and Clement.

• Prior Art Relied Upon: The Flusberg Publications, PacBio-BAM, and Clement (Application # 2016/0326593).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground built upon the base combination in Ground 1. While Flusberg noted an association between DNA methylation and cancer, Clement specifically taught methods for determining a cancer prognosis by evaluating epigenetic changes. Clement disclosed classifying cancer based on methylation patterns, such as identifying "discordant" methylation as an indicator of malignancy, and using a read depth cutoff to ensure statistical significance. This mapped to the claims’ limitations regarding classifying a disorder (cancer) and using a cutoff number.
  • Motivation to Combine: A POSITA, knowing from Flusberg that methylation patterns could be detected and were associated with cancer, would be motivated to apply the more specific diagnostic and classification methods of Clement. Combining the references would allow the SMRT-detected methylation data to be used for the clinically relevant purpose of assessing cancer prognosis, a natural and predictable application of the base technology.

Ground 3: Claims 8 and 15-16 are obvious over the Flusberg Publications, PacBio-BAM, and the PacBio Template Guide.

• Prior Art Relied Upon: The Flusberg Publications, PacBio-BAM, and the PacBio Template Guide (a 2015 guide).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground added the PacBio Template Guide to the base combination to address claims related to size-selection and filtering of nucleic acid molecules. The PacBio Template Guide described standard, routine laboratory procedures for preparing DNA templates for SMRT sequencing. It explicitly taught and "highly recommended" performing a size-selection step to filter the DNA molecules, for example, by removing fragments smaller than a specified cutoff size (e.g., 0.4 kb) to ensure data quality. This directly taught the claim limitations requiring molecules to be greater than a cutoff size or filtered to be within a specific size range.
  • Motivation to Combine: A POSITA seeking to implement the Flusberg detection method would have been motivated to use the standard, recommended sample preparation protocols from the PacBio Template Guide. Following these routine procedures, including the recommended size-selection step, was a necessary and conventional prerequisite for obtaining high-quality SMRT sequencing data for any downstream analysis, including modification detection.
• Additional Grounds: Petitioner asserted that claims 13 and 15-16 are obvious over the Flusberg Publications and PacBio-BAM in view of Tsai (Application # 2016/0208241). Tsai taught enriching nucleic acids by cutting DNA with a Cas9 complex and ligating hairpin adaptors to form circular DNA for SMRT sequencing, providing the basis for these claims.

4. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under §325(d) was not appropriate. The petition presented new prior art (PacBio-BAM, Clement, Template Guide, Tsai) that was not before the Examiner during prosecution. This new art was argued to be material and to directly address the alleged novelty of the "input data structure," which was the central basis for allowance. Petitioner claimed the patent was issued due to material error, as the Examiner was unaware of art that showed the supposedly novel feature was entirely conventional.
• Petitioner also argued that denial under Fintiv was not warranted because the co-pending district court litigation was in its early stages, a trial date had not been set, and a Final Written Decision in the IPR was expected well before any potential trial.

5. Relief Requested

• Petitioner requested the institution of an inter partes review and the cancellation of claims 1-19 of the ’794 patent as unpatentable under 35 U.S.C. §103.