Spatially encoded biological assays

Patent No. US11001878 (titled "Spatially encoded biological assays") on Jan 8, 2021. The application was issued on May 11, 2021.

’878 is related to the field of spatially encoded biological assays and high-resolution molecular mapping. It addresses the technical challenge of simultaneously measuring the abundance and distribution of numerous biological targets, such as nucleic acids and proteins, within a solid tissue sample while preserving the original spatial context of those molecules.

The underlying idea behind ’878 is to utilize spatially-defined coding tags that act as digital proxies for the location of biological targets. By delivering reagents in specific patterns and coupling them to target-specific probes, the invention converts spatial information into a sequence-based format, allowing complex tissue architecture to be reconstructed from a pooled digital readout.

The claims of ’878 focus on a method for determining the presence or abundance of a target molecule at a specific region of interest within a tissue sample. This process involves delivering probes consisting of a capture agent conjugated to an oligonucleotide, separating the bound probes from the unbound population, and subsequently identifying the oligonucleotide through a targeted hybridization event.

In practice, the invention functions by affixing a sample to a support and applying probes that recognize specific biomarkers. The critical mechanism involves removing the conjugated oligonucleotides from the region of interest and determining their identity using a labeled detection probe that is 100% complementary to the tag, thereby linking the molecular signal back to its physical origin.

This approach differentiates itself from prior methods like laser capture microdissection or standard in situ hybridization by enabling high-level multiplexing without the need for laborious physical isolation of tissue segments. By shifting the burden of spatial resolution from physical separation to a digital decoding scheme, the system achieves the throughput of next-generation sequencing while maintaining the localized detail of histology.

How does this patent fit in bigger picture?

Technical Landscape

In the early 2010s when ’878 was filed, comprehensive gene expression and protein analysis were typically implemented using microarrays, in situ hybridization, or laser capture microdissection. At a time when systems commonly relied on the physical transference of tissue into wells or the manual isolation of small sample areas to preserve spatial information, hardware and software constraints made the simultaneous measurement of high-plex biological targets across large-scale spatial distributions non-trivial. Consequently, standard engineering practices forced a trade-off between the number of targets analyzed and the maintenance of high-resolution spatial context within a single biological sample.

Prosecution Position

The disclosed invention represents a meaningful technical advancement through the integration of a spatial encoding scheme with high-throughput digital sequencing to map biological activity. The architectural shift involves delivering encoded probes to a sample in a known spatial pattern, where each probe contains a coding tag that identifies its specific delivery location. This structural solution enables the simultaneous detection of thousands of targets across multiple sites by pooling the probes for parallel sequencing and then computationally associating the digital readout back to the original spatial coordinates. This capability overcomes the technical constraint of low spatial resolution in multiplexed assays, allowing for the generation of high-resolution spatial maps of gene or protein expression without the need for physical microdissection or limited-access well formats.

Claims

This patent contains a total of 28 claims, with claim 1 being the sole independent claim. The independent claim focuses on a method for determining the presence or abundance of target biological molecules within a specific region of a tissue sample by using probes consisting of capture agents conjugated to oligonucleotides, which are subsequently separated, removed, and sequenced via hybridization with labeled complementary probes. The dependent claims serve to further specify the technical parameters of the process, including the use of imaging to identify regions of interest, the specific types of target molecules such as mRNA or proteins, the nature of the capture agents like antibodies or aptamers, and the methods for detecting labels or analyzing differential expression across multiple tissue regions.

Key Claim Terms New

Definitions of key terms used in the patent claims.

Term (Source)	Support for Specification	Interpretation
Capture agent (Claim 1)	In some aspects, the probe regions of the encoded probes comprise antibodies, aptamers or small molecules. In some aspects, the probe regions of the encoded probes are proteins and the separating step is accomplished by encoded probes that interact with the biological targets being captured by an affinity capture agent.	A molecule, such as a protein, antibody, aptamer, or small molecule, that is designed to specifically bind to a target biological molecule within a sample.
Hybridization (Claim 1)	In these aspects involving nucleic acid agents, any methods of sequence determination can be used, e.g., sequencing, hybridization and the like. The melting temperature is the temperature at which a population of double-stranded nucleic acid molecules becomes half dissociated into single strands.	The process of a labeled probe binding to a complementary portion of the oligonucleotide to determine its sequence for identification and quantification.
Oligonucleotide (Claim 1)	In some aspects, the multiple biological targets comprise proteins, the probe regions of the encoding probes are proteins and the coding tags comprise oligonucleotides. Each encoded probe comprises a probe region that may interact with the biological targets and a coding tag that identifies a location of the site to which the encoded probe was delivered.	A nucleic acid sequence conjugated to a capture agent that serves as a coding tag to identify the target molecule and/or the spatial location of the site where the probe interacted.
Region of interest (Claim 1)	The assay systems of the invention detect the presence or absence and relative amount of a biological target or biological activity indicative of a biological target, as well as the location of the biological target or activity in a biological sample, e.g., a tissue section. In some aspects, the known spatial pattern is determined by histological features of the sample.	A specific spatial location or site within a tissue sample, often defined by histological features or a known spatial pattern, where biological targets are measured.
Target biological molecule (Claim 1)	The biological molecules to be detected can be any biological molecules such as proteins, nucleic acids, lipids, carbohydrates, ions, or multicomponent complexes containing any of the above. In particular aspects of the invention the biological targets comprise nucleic acids and the encoded probes are oligonucleotides.	The specific analyte of interest in the tissue sample, which may include nucleic acids, proteins, enzymes, lipids, carbohydrates, or multicomponent complexes.

Litigation Cases New

US Latest litigation cases involving this patent.

Case Number	Filing Date	Title
1:23-cv-01375	Dec 1, 2023	10X Genomics, Inc. V. Curio Bioscience, Inc.

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US11001878

Application Number: US17144965A
Filing Date: Jan 8, 2021
Publication Date: May 11, 2021
External Links: Slate, USPTO , Google Patents

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