10X Genomics Inc v. Bruker Spatial Biology Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiffs: 10X Genomics, Inc. (Delaware) and President and Fellows of Harvard College (Massachusetts)
  • Defendant: NanoString Technologies, Inc. (Delaware)
  • Plaintiffs’ Counsel: Morris, Nichols, Arsht & Tunnell LLP; Morris James LLP
• Case Identification: 1:22-cv-00261, D. Del., 03/01/2023
• Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant NanoString Technologies, Inc. is a Delaware corporation and thus resides in the district.
• Core Dispute: Plaintiffs allege that Defendant’s CosMx Spatial Molecular Imager platform, which performs in situ analysis of biological samples, infringes six U.S. patents related to compositions and methods for detecting and imaging biological analytes.
• Technical Context: The technology at issue involves spatial genomics, a field that allows researchers to map the location and activity of genes and other molecules directly within tissue samples, providing crucial context for understanding complex biological systems.
• Key Procedural History: This action is a Second Amended Complaint. The complaint alleges that Defendant was on notice of infringement of U.S. Patent Nos. 10,227,639 and 11,021,737 since the filing of the original complaint on February 28, 2022. Notice for U.S. Patent Nos. 11,293,051, 11,293,052, and 11,293,054 is alleged to have been provided with the First Amended Complaint on May 12, 2022. Notice for U.S. Patent No. 11,542,554 is alleged to have occurred by February 2, 2023.

Case Timeline

Date	Event
2011-12-22	Earliest Priority Date for ’639, ’737, ’051, ’052, ’054 Patents
2015-11-03	Earliest Priority Date for ’554 Patent
2019-03-12	U.S. Patent No. 10,227,639 Issued
2021-03-01	NanoString launches CosMx SMI Technology Access Program
2021-06-01	U.S. Patent No. 11,021,737 Issued
2021-11-09	NanoString announces commercially-branded CosMx Spatial Molecular Imager
2022-02-28	Plaintiffs file original complaint, providing notice of ’639 and ’737 Patents
2022-04-05	U.S. Patent Nos. 11,293,051, 11,293,052, and 11,293,054 Issued
2022-05-12	Plaintiffs file First Amended Complaint, providing notice of ’051, ’052, ’054 Patents
2022-12-06	NanoString announces commercial shipments of Accused Instrumentalities
2023-01-03	U.S. Patent No. 11,542,554 Issued
2023-02-02	NanoString allegedly put on notice of ’554 Patent
2023-03-01	Second Amended Complaint Filed

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 10,227,639 - "Compositions and Methods for Analyte Detection"

• Patent Identification: U.S. Patent No. 10,227,639, "Compositions and Methods for Analyte Detection," issued March 12, 2019.

The Invention Explained

• Problem Addressed: The patent's background section describes the technical challenge of "multiplexing" in biological assays, where the ability to detect many different target molecules (analytes) in a single sample is limited by the small number of available fluorescent colors, typically four or five. (’639 Patent, col. 1:44-50). Probing a sample repeatedly with different sets of colored probes is a potential workaround but can cause the sample to degrade. (’639 Patent, col. 2:1-11).
• The Patented Solution: The invention proposes a method that avoids the "color" limitation by using detection reagents that combine a probe (e.g., an antibody that binds to a specific protein) with a nucleic acid "label." This label contains one or more pre-determined DNA or RNA subsequences that act as a unique identifier, similar to a barcode. The identity of the analyte is determined not by a single color, but by decoding this barcode in a "temporally-sequential manner," for example, by sequentially washing the sample with fluorescent "decoder probes" that bind to the subsequences and generate a time-ordered sequence of signals. (’639 Patent, Abstract; col. 2:20-27; Fig. 1).
• Technical Importance: This approach allows for the multiplexing of "many more labeled species in the same procedure than conventional methods" by breaking the dependency on the limited number of available colors. (’639 Patent, Abstract).

Key Claims at a Glance

• The complaint asserts independent claim 1 (via dependent claim 20) (’639 Patent, Claims 1, 20; Compl. ¶37).
• The essential elements of independent claim 1 are:
  • Contacting a sample with a plurality of detection reagents, where different reagents target different analytes.
  • Each detection reagent comprises at least one probe reagent conjugated to at least one nucleic acid label.
  • The nucleic acid label contains pre-determined subsequences that form a unique identifier for the probe.
  • Detecting the plurality of pre-determined subsequences in a "temporally-sequential manner."
  • This detection generates a temporal order of "signal signatures."
  • This temporal order of signal signatures identifies the subpopulation of detection reagents, and thus the analyte.
• The complaint also asserts dependent claim 20, which specifies that the analyte is an antigen and the probe is an antibody, and reserves the right to assert additional claims. (Compl. ¶37).

U.S. Patent No. 11,021,737 - "Compositions and Methods for Analyte Detection"

• Patent Identification: U.S. Patent No. 11,021,737, "Compositions and Methods for Analyte Detection," issued June 1, 2021.

The Invention Explained

• Problem Addressed: As a continuation-in-part of the ’639 Patent, the ’737 Patent addresses the same fundamental problem of limited multiplexing in biological assays due to the small number of available fluorescent labels. (’737 Patent, col. 1:53-58).
• The Patented Solution: The ’737 Patent claims a method for identifying an analyte at a specific location within a cell or tissue sample. The method involves binding a detection reagent (comprising a probe and a nucleic acid label with pre-determined subsequences) to an analyte and then detecting a "temporal order of signal signatures" associated with those subsequences to identify the analyte at that location. (’737 Patent, Claim 16). This method is designed for in situ analysis, where preserving spatial information is critical.
• Technical Importance: This method allows for highly multiplexed analysis directly within the spatial context of a cell or tissue, linking molecular identity to physical location. (’737 Patent, col. 1:45-52).

Key Claims at a Glance

• The complaint asserts independent claim 16 and dependent claims 4, 18, 21, and 47. (Compl. ¶45).
• The essential elements of independent claim 16 are:
  • Providing a cell or tissue sample comprising an analyte at a location.
  • Binding a detection reagent to the analyte at that location, the reagent comprising a probe and one or more pre-determined subsequences.
  • Detecting a temporal order of signal signatures associated with the subsequences.
  • Using the temporal order of signal signatures to identify the analyte at that location.
• The complaint also asserts dependent claims that add further limitations, such as the sample being immobilized on a solid support (Claim 4) and the probe being an antibody (Claim 18), and reserves the right to assert additional claims. (Compl. ¶45).

Multi-Patent Capsule: U.S. Patent No. 11,293,051 - "Compositions and Methods for Analyte Detection"

• Patent Identification: U.S. Patent No. 11,293,051, "Compositions and Methods for Analyte Detection," issued April 5, 2022.
• Technology Synopsis: This patent, part of the same family as the ’639 and ’737 patents, describes methods for identifying analytes in a biological sample. It addresses the problem of limited multiplexing in conventional assays by teaching the use of detection reagents with nucleic acid labels that can be decoded sequentially over time.
• Asserted Claims: The complaint asserts claims 3, 26, 48, 53, 66, 77, 85, and 96. (Compl. ¶53).
• Accused Features: The complaint alleges that NanoString's CosMx SMI platform, which performs in situ analysis of biological samples, infringes the ’051 Patent. (Compl. ¶53).

Multi-Patent Capsule: U.S. Patent No. 11,293,052 - "Compositions and Methods for Analyte Detection"

• Patent Identification: U.S. Patent No. 11,293,052, "Compositions and Methods for Analyte Detection," issued April 5, 2022.
• Technology Synopsis: Continuing the same family of inventions, this patent covers methods for analyte detection using probes conjugated to nucleic acid labels. The invention allows for highly multiplexed analysis by generating a unique temporal "barcode" for each analyte through sequential detection of subsequences on the nucleic acid label.
• Asserted Claims: The complaint asserts claims 26, 35, 65, 73, and 75. (Compl. ¶61).
• Accused Features: The infringement allegations target the functionality of the CosMx SMI platform, including its instruments, reagents, and software used for spatial molecular imaging. (Compl. ¶61).

Multi-Patent Capsule: U.S. Patent No. 11,293,054 - "Compositions and Methods for Analyte Detection"

• Patent Identification: U.S. Patent No. 11,293,054, "Compositions and Methods for Analyte Detection," issued April 5, 2022.
• Technology Synopsis: This patent, also in the same family, describes methods for identifying an analyte at a specific location within a biological sample. The technology uses detection reagents with nucleic acid identifiers that are read out over time to overcome the limitations of color-based multiplexing in spatial analysis.
• Asserted Claims: The complaint asserts claim 18. (Compl. ¶69).
• Accused Features: The complaint accuses the CosMx SMI platform of infringement, alleging its in situ analysis methods practice the claimed invention. (Compl. ¶69).

Multi-Patent Capsule: U.S. Patent No. 11,542,554 - "Method and Apparatus for Volumetric Imaging"

• Patent Identification: U.S. Patent No. 11,542,554, "Method and Apparatus for Volumetric Imaging," issued January 3, 2023.
• Technology Synopsis: This patent relates to a system and apparatus for performing volumetric imaging. Unlike the other asserted patents that focus on the chemical compositions and methods, this patent appears directed at the hardware system used to perform the imaging and analysis, including components like a sample stage, fluidics system, and optical system.
• Asserted Claims: The complaint asserts claim 36. (Compl. ¶78).
• Accused Features: The complaint identifies the "CosMx Spatial Molecular Imager ('CosMx' or 'CosMx SMI') Systems, including instruments, components, and consumables" as the infringing products. (Compl. ¶77).

III. The Accused Instrumentality

Product Identification

• The accused instrumentalities are Defendant’s "CosMx Spatial Molecular Imaging ('CosMx SMI') platform" and associated products, components, and services, including instruments, software, reagents, and consumables. (Compl. ¶18, ¶20).

Functionality and Market Context

• The complaint alleges the CosMx SMI platform is designed for "high-plex in situ analysis," providing "spatially resolved mapping data and imaging for RNA and protein at a single-cell and subcellular resolution." (Compl. ¶18). NanoString allegedly markets the platform as capable of quantifying and visualizing up to 1,000 RNA and 100 validated protein analytes within their native tissue environment. (Compl. ¶18). The complaint notes that NanoString offers the platform as both a service (the "Technology Access Program") and as a system for sale to customers, with commercial shipments having begun in December 2022. (Compl. ¶18, ¶19). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint references exemplary infringement claim charts in Attachments A through F, but these attachments were not filed with the complaint. (Compl. ¶¶ 37, 45, 53, 61, 69, 78). Therefore, the infringement allegations are summarized below in prose based on the narrative descriptions in the complaint and the technology of the patents.

’639 Patent Infringement Allegations

The complaint alleges that the CosMx SMI platform infringes claim 20 of the ’639 Patent. (Compl. ¶37). This claim requires a method of contacting a sample with antibody-based detection reagents that are conjugated to nucleic acid labels containing identifier subsequences, and then detecting those subsequences in a temporally-sequential manner to generate a signal signature that identifies the target antigen. (Compl. ¶37; ’639 Patent, Claim 20). The complaint’s description of the CosMx platform performing "high-plex in situ analysis" to provide "spatially resolved mapping data and imaging for RNA and protein" suggests a process of identifying multiple specific analytes (antigens) within a tissue sample, which is the subject of the asserted claim. (Compl. ¶18).

’737 Patent Infringement Allegations

The complaint alleges the CosMx SMI platform infringes claim 16 of the ’737 Patent. (Compl. ¶45). This claim recites a method for identifying an analyte at a location in a cell or tissue sample by binding a detection reagent (probe plus nucleic acid identifier) and detecting a "temporal order of signal signatures" associated with that location. (’737 Patent, Claim 16). This aligns with the alleged function of the CosMx platform, which is described as providing "spatially resolved mapping data" and creating "spatial maps of gene expression in the original tissue." (Compl. ¶17, ¶18).

• Identified Points of Contention:
  • Scope Questions: The infringement analysis for the method patents (’639, ’737, ’051, ’052, ’054) may turn on the construction of "detecting in a temporally-sequential manner." A central question will be whether the specific series of imaging, washing, and chemical steps employed by the accused CosMx platform constitutes the "temporally-sequential" detection of "signal signatures" as contemplated by the patents.
  • Technical Questions: A key evidentiary question will be what specific technical process the accused platform uses to identify analytes. The complaint does not provide sufficient detail for analysis of how the CosMx reagents' unique identifiers are structured or how its imaging system decodes them over time, leaving open the question of whether this process functionally matches the claimed method of detecting a temporal order of signal signatures generated from pre-determined subsequences.

V. Key Claim Terms for Construction

• The Term: "detecting in a temporally-sequential manner"

• Context and Importance: This phrase appears in the independent claims of both the ’639 and ’737 patents and is foundational to the claimed method. The dispute may focus on whether this requires a specific, active process of creating a time-ordered signal (e.g., wash, probe, image, repeat) or if it can be read more broadly to cover other multi-step identification processes. Practitioners may focus on this term because it defines the core novelty over prior art methods that detect multiple signals simultaneously.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification states the detection can include "sequencing, e.g., which can be performed via any methods known in the art, including but not limited to, ligation, hybridization, synthesis, amplification, single-base extension," suggesting the term is not limited to a single specific technique. (’639 Patent, col. 3:42-49).
  • Evidence for a Narrower Interpretation: The embodiments and figures consistently illustrate a process where distinct sets of "decoder probes" are applied in discrete steps, imaged, and then removed or displaced before the next set is applied, creating a literal sequence of signals over time. (’639 Patent, Fig. 9; col. 9:18-34). This may support an interpretation requiring a series of discrete hybridization and imaging cycles.

• The Term: "signal signature"

• Context and Importance: This term defines what is being detected in the "temporally-sequential manner." The scope of this term will be critical to determining if the optical data generated by the accused CosMx platform meets this claim limitation.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification provides a broad definition, stating "Examples of optical signatures can include, without limitations, signatures of fluorescent color..., visible light, no-color or no-light, color..., Raman signatures, and any combinations thereof." (’639 Patent, col. 4:35-39). This language may support a construction covering a wide variety of detectable optical phenomena.
  • Evidence for a Narrower Interpretation: The detailed description and figures primarily describe the signal signature as the specific sequence of colors (or lack thereof) produced by hybridizing sequential sets of distinctly labeled decoder probes. (’639 Patent, Fig. 1, Fig. 5). This could be argued to limit the term to a specific type of optically-generated code.

VI. Other Allegations

• Indirect Infringement: The complaint alleges induced infringement, stating that Defendant intentionally encourages infringement by providing customers with instructions, user guides, training, and on-site support for using the CosMx platform in an infringing manner. (Compl. ¶¶ 38, 46). It also alleges contributory infringement, asserting that the CosMx platform components, particularly the instruments and reagents, were "designed specifically" for the infringing use, are a material part of the invention, and have no substantial non-infringing uses. (Compl. ¶¶ 39, 47).
• Willful Infringement: The complaint alleges willful infringement based on Defendant's alleged knowledge of the patents-in-suit since at least the filing dates of the original and first amended complaints (February 28, 2022, and May 12, 2022, respectively). (Compl. ¶¶ 40, 41, 48, 49). It is alleged that Defendant continued to market, sell, and commercially launch the accused platform despite this knowledge. (Compl. ¶35).

VII. Analyst’s Conclusion: Key Questions for the Case

• A core issue will be one of definitional scope: can the phrase "detecting in a temporally-sequential manner," which is described in the patents' embodiments as a series of discrete hybridization and imaging steps, be construed to cover the specific multi-cycle imaging and analysis workflow of the accused CosMx platform?
• A second central issue will be one of apparatus vs. method: while five of the asserted patents claim methods of analyte detection, the sixth (’554 patent) claims a "method and apparatus." The case may explore the boundary between infringement by practicing a method (what the CosMx user does) and infringement by making or selling a system (what NanoString does), particularly concerning the system claims of the ’554 patent.
• A key evidentiary question will be one of functional mapping: without the detailed claim charts, Plaintiffs will need to present evidence demonstrating how the accused platform's specific reagents, hardware, and software perform each step of the asserted method claims, raising the question of whether there is a direct correspondence or a fundamental mismatch in technical operation.