PTAB

IPR2019-00566

Bio-Rad Laboratories, Inc. v. 10X Genomics, Inc.

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1. Case Identification

2. Patent Overview

  • Title: Methods for Droplet-Based Sample Preparation
  • Brief Description: The ’468 patent describes methods for preparing nucleic acid samples for analysis by tagging them with oligonucleotide barcodes. The process involves encapsulating the sample and barcoded beads within droplets generated by a microfluidic device.

3. Grounds for Unpatentability

Ground 1: Claims 1-4, 6-9, 11, 12, 21, and 22 are obvious over Samuels in view of Hinz.

  • Prior Art Relied Upon: Samuels (Application # 2012/0220494) and Hinz (Application # 2010/0304982).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Samuels disclosed the fundamental method of claim 1: generating droplets containing nucleic acid analytes and oligonucleotide barcodes attached to beads. Samuels taught barcode libraries, attachment to beads (e.g., via biotin-streptavidin), and encapsulation in droplets for analysis. However, Samuels did not explicitly require the beads to be porous. Petitioner asserted that Hinz supplied this teaching, describing the construction and use of porous gel beads suitable for nucleic acid analysis. Hinz taught that porous beads, such as those made of polyacrylamide (addressing claim 6), allow for higher loading capacity of polynucleotides compared to non-porous beads. Hinz also taught that its beads are "gel particles" (addressing claim 7) and can be formed with cross-linking methods (addressing claim 22). Furthermore, Hinz disclosed that attached polynucleotides could be released via scissile or cleavable linkages, mapping to the "releasably attached" limitation of claim 1.
    • Motivation to Combine: A POSITA would combine Samuels with Hinz to solve a known problem. Samuels' method requires a sufficient number of barcode molecules to function effectively, and Hinz directly addressed this by teaching that porous beads increase loading capacity and help generate a sufficient signal for analysis. Given that both references operated in the same technical space of nucleic acid analysis using beads, a POSITA would have been motivated to substitute the conventional beads in Samuels with the improved, higher-capacity porous beads described in Hinz to achieve a more robust and predictable result.
    • Expectation of Success: Petitioner asserted a high expectation of success, as Hinz’s porous beads were designed for the exact same application: serving as a support for oligonucleotide molecules. The substitution was a simple one, and Hinz provided detailed examples of methods for preparing and functionalizing the bead supports with known chemistries, ensuring a high degree of predictability for a POSA implementing the combination.

Ground 2: Claims 1-4, 6-9, 11, 12, 21, and 22 are obvious over Samuels in view of Abate.

  • Prior Art Relied Upon: Samuels (Application # 2012/0220494) and Abate (Abate et al., Lab Chip, 9, 2628-2631 (2009)).
  • Core Argument for this Ground:
    • Prior Art Mapping: As in the first ground, Samuels provided the foundational barcoding-in-droplets method. Abate was introduced to teach the use of porous, "compliant gel particles" made from cross-linked polyacrylamide (addressing claims 6, 7, and 22). Abate described these beads as "useful substrates for chemical and biological applications" that can be functionalized with "DNA fragments, antibodies, and enzymes." Critically, Abate also taught a specific microfluidic device using two cross-channel junctions in series—a first to combine aqueous streams of particles and water, and a second to add oil to encapsulate the mixture. Petitioner argued this directly mapped to the claimed method of combining aqueous phases at a first junction and generating a droplet with an immiscible phase at a second junction.
    • Motivation to Combine: A POSITA would have been motivated to combine the teachings of Samuels and Abate to improve the bead-loading process and overall system efficiency. Abate taught a "simple, robust method to load a controllable number of particles into every drop," addressing a common challenge in microfluidics. A POSITA implementing Samuels's method would naturally look to a reference like Abate for its specific guidance on controlling droplet formation with beads for "biological assays" like "analyzing genetic material," the very focus of the '468 patent.
    • Expectation of Success: The combination was allegedly predictable and would have had a high expectation of success. Abate’s gel particles were used in the same context as Samuels' beads—as a support for biological molecules in microfluidic assays. Abate provided detailed methods for synthesizing its particles ("10% polyacrylamide with 10% cross-linker"), giving a POSITA a clear and predictable path for incorporating these superior beads into the Samuels framework.

4. Key Claim Construction Positions

  • "barcode": Petitioner adopted the construction agreed upon by the parties in a related ITC proceeding: "a label that may be attached to an analyte to convey identifying information about the analyte." This construction was central to framing the scope of the prior art search and analysis.
  • "releasably attached": Petitioner proposed that this term means "wherein said bead is configured to release said at least 1,000,000 oligonucleotide molecules." This construction was argued to be critical, as the petition asserted that prior art methods like thermal or chemical cleavage (e.g., of biotin-streptavidin or disulfide bonds) would meet this functional requirement, thereby rendering the claims obvious.
  • "gel": Petitioner proposed the construction "a cross-linked material...that exhibits no steady state flow." This definition was important for demonstrating that the polyacrylamide beads taught in the Hinz and Abate references, which are made from cross-linked polymers, fall within the scope of the claimed "gel bead" (claim 7).

5. Relief Requested

  • Petitioner requested institution of an inter partes review and cancellation of claims 1-4, 6-9, 11, 12, 21, and 22 of the ’468 patent as unpatentable.