10X Genomics Inc v. NanoString Technologies Inc

1. Case Identification

• Case #: IPR2023-01298
• Patent #: 11,377,689
• Filed: August 16, 2023
• Petitioner(s): 10X Genomics, Inc.
• Patent Owner(s): NanoString Technologies, Inc.
• Challenged Claims: 1-30

2. Patent Overview

• Title: Spatially Resolved Analytes
• Brief Description: The ’689 patent relates to methods for spatially detecting and quantifying target analytes, such as proteins or nucleic acids, within a tissue sample. The methods involve using nucleic acid probes that bind to the analytes, collecting the probes or portions thereof, and sequencing them to determine their spatial origin.

3. Grounds for Unpatentability

Ground 1: Anticipation of Claims 1-8, 11-23, and 26-30 under 35 U.S.C. §102

• Prior Art Relied Upon: So-456 (WO 2017/019456)
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that So-456, a patent publication by Illumina, discloses every limitation of the challenged claims. So-456 described a spatial analysis technique using an array of immobilized oligonucleotide "capture probes," each having a unique spatial address. The method involved placing a tissue sample on the array, contacting it with pairs of primary probes that bind to a target analyte (e.g., genomic DNA), ligating the primary probes together in situ, and then releasing and capturing the ligated product on the array. Petitioner asserted that So-456’s subsequent steps of performing a bi-directional extension reaction to incorporate the spatial barcode into the captured product, followed by sequencing to decode the spatial information, directly map to the extension and identification steps of independent claims 1 and 16. Petitioner further contended that So-456 disclosed the specific limitations of the dependent claims, such as using formalin-fixed paraffin-embedded (FFPE) tissue samples immobilized on a microscope slide.

Ground 2: Obviousness of Claims 9-10 and 24-25 over So-456 in view of Stahl

• Prior Art Relied Upon: So-456 (WO 2017/019456) and Stahl (a 2016 article in Science)
• Core Argument for this Ground:
  • Prior Art Mapping: This ground addressed claims 9-10 and 24-25, which require the nucleic acid sequence identifying the analyte's location to comprise a "unique molecular identifier" (UMI). Petitioner argued that while So-456 taught the spatial barcode, Stahl explicitly disclosed incorporating UMIs into surface probes on spatially barcoded arrays. Stahl’s method used UMIs to identify and remove duplicate molecules arising from amplification, thereby enabling more accurate quantitative gene expression data.
  • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA) would combine Stahl's well-known UMI technique with So-456's spatial analysis method to improve its accuracy and robustness. The motivation was to distinguish true biological signals from amplification artifacts, a known challenge in sequencing-based methods. So-456 itself suggested its embodiments could be modified and taught including UMIs in other contexts, making the combination straightforward.
  • Expectation of Success: A POSA would have had a high expectation of success. Incorporating UMIs into oligonucleotide probes was a routine and predictable technique at the time, and Stahl demonstrated its successful application in a nearly identical spatial transcriptomics context.

Ground 3: Anticipation of Claims 1-30 under 35 U.S.C. §102 over Chell

• Prior Art Relied Upon: Chell (WO 2021/133849)

• Core Argument for this Ground:

  • Prior Art Mapping: Petitioner first argued that the ’689 patent was not entitled to its claimed priority date of February 12, 2018. This was based on a lack of written description support in the priority applications for the full scope of the claims, specifically for (1) collecting whole probes instead of only cleaved portions of probes, and (2) performing on-analyte ligation of primary probe pairs. Petitioner contended the priority applications only described cleaving a portion of a probe and performing ligation off-analyte. Therefore, the effective filing date should be September 16, 2021, making Chell (published July 1, 2021) intervening prior art.
  • Petitioner then argued Chell anticipated all claims. Chell disclosed methods for spatial gene expression analysis using RNA-templated ligation. The method involved contacting an FFPE tissue sample with pairs of primary probes, ligating the probes while hybridized to the target mRNA, releasing the ligated product, capturing it on a spatially-barcoded array, performing a bi-directional extension reaction to incorporate the spatial barcode, and sequencing the resulting products to identify the analyte's location. This workflow allegedly disclosed every step of claims 1 and 16 and the dependent claims.

• Additional Grounds: Petitioner asserted that claims 1-30 are obvious over So-456 alone (Ground 2 in the petition). This argument contended that even if So-456 did not explicitly disclose the claimed extension steps, it would have been obvious for a POSA to perform such steps to prepare a sequencing library for analysis using the well-known Illumina sequencing-by-synthesis (SBS) platform.

4. Key Claim Construction Positions

• For the purposes of this inter partes review (IPR), Petitioner adopted Patent Owner's proposed constructions from concurrent litigation.
• A key term highlighted was "collecting the [] probes, or portions thereof." Petitioner argued that under Patent Owner’s broad interpretation, this step encompassed the diffusion and capture of whole ligation products across the entire tissue sample, a process Petitioner contended was taught by the prior art references So-456 and Chell.

5. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial would be inappropriate under both 35 U.S.C. §325(d) and §314(a).
• §325(d): The primary references (So-456, Stahl, and Chell) were not before the Examiner during prosecution. Furthermore, the Examiner allegedly erred by failing to recognize the lack of written description support for the challenged claims in the priority applications.
• §314(a) (Fintiv): The parallel district court litigation was in its early stages. The scheduled trial date (December 9, 2024) was approximately two months before a Final Written Decision would be reached in the IPR, suggesting the IPR could be completed before trial. Petitioner also asserted that the petition presents a compelling, unrebutted challenge to patentability.

6. Relief Requested

• Petitioner requests institution of IPR and cancellation of claims 1-30 of Patent 11,377,689 as unpatentable.