IP Verse

Methods And Systems For Analyzing Nucleic Acid Molecules

Patent No. US12312634 (titled "Methods And Systems For Analyzing Nucleic Acid Molecules") was filed by Guardant Health Inc on Jul 11, 2024.

What is this patent about?

’634 is related to the field of molecular diagnostics, specifically methods for analyzing nucleic acid populations to detect diseases like cancer. The background involves the challenge of analyzing cell-free nucleic acids (cfNAs) in bodily fluids, which are often present in low amounts and are heterogeneous in form (DNA, RNA, single-stranded, double-stranded, modified, protein-bound). Existing methods struggle to maintain sensitivity and preserve epigenetic information, such as methylation patterns, which are crucial for early cancer detection.

The underlying idea behind ’634 is to improve the sensitivity and accuracy of liquid biopsy assays by combining genetic and epigenetic analysis of cfNAs. This is achieved by fractionating the nucleic acid population based on characteristics like methylation status or strandedness, then differentially tagging the fractions with unique molecular identifiers (UMIs). This allows for parallel processing and sequencing of multiple forms of nucleic acids while preserving information about their original state, enabling a more comprehensive analysis of genetic and epigenetic variations.

The claims of ’634 focus on methods for monitoring residual disease or recurrence of cancer by analyzing cell-free DNA (cfDNA). Specifically, the method involves splitting a cfDNA sample into two aliquots. One aliquot is sequenced to identify SNVs, indels, and gene fusions, irrespective of methylation state. The other aliquot is sequenced to determine the methylation state of the cfDNA. Both aliquots undergo target capture to enrich for specific sequences of interest before sequencing. The sequence data from both aliquots are then analyzed to monitor for residual disease or recurrence.

In practice, the invention involves several key steps. First, cfDNA is extracted from a bodily fluid sample. Then, the cfDNA is fractionated based on characteristics like methylation status using a methyl-binding domain (MBD) protein. Each fraction is then tagged with a unique molecular barcode. The tagged fractions are pooled, amplified, and then subjected to target enrichment to focus on specific genomic regions. Finally, the enriched DNA is sequenced, and the sequence data is analyzed to identify genetic and epigenetic variations, allowing for a more sensitive and accurate assessment of disease status.

The invention differentiates itself from prior approaches by combining genetic and epigenetic analysis in a single assay, which improves sensitivity and reduces the amount of sample required. Traditional methods often analyze genetic and epigenetic markers separately, requiring more sample material and potentially missing crucial correlations between the two. By using molecular tagging and fractionation, ’634 allows for a more comprehensive and efficient analysis of cfNAs, leading to improved detection and monitoring of diseases like cancer. The use of hairpin adapters and bisulfite sequencing further enhances the ability to analyze modified cytosine residues, providing valuable epigenetic information.

How does this patent fit in bigger picture?

Technical landscape at the time

In the mid-2010s when ’634 was filed, next-generation sequencing was becoming increasingly prevalent in genomic analysis, at a time when assays commonly relied on PCR amplification to increase the amount of nucleic acid available for sequencing. At this time, methods for analyzing cell-free nucleic acids were being developed, when hardware or software constraints made it non-trivial to accurately quantify and distinguish between different forms or modifications of nucleic acids in complex biological samples.

Novelty and Inventive Step

The claims were rejected as being indefinite under 35 U.S.C. 112(b). The examiner stated that the claims were free of prior art but were rejected for reasons of indefiniteness. The examiner indicated that the closest prior art was Lo et al. (US 2014/0080715) and Talasaz (US 2015/0299812). The prosecution record does NOT describe the technical reasoning or specific claim changes that led to allowance.

Claims

This patent contains 20 claims, with claim 1 being the only independent claim. Independent claim 1 is directed to a method of monitoring residual disease or recurrence of cancer by analyzing cell-free DNA (cfDNA) through sequencing and methylation analysis. The dependent claims generally elaborate on and refine the method of independent claim 1, specifying details such as target capture techniques, sample tagging, sequencing depth, bodily fluid sources, bisulfite sequencing, sequence coverage, variant detection, therapy selection, cancer types, and remission status.

Key Claim Terms New

Definitions of key terms used in the patent claims.

Term (Source)Support for SpecificationInterpretation
Cell-free DNA (cfDNA)
(Claim 1)		“Cancers are often detected by biopsies of tumors followed by analysis of cells, markers or DNA extracted from cells. But more recently it has been proposed that cancers can also be detected from cell-free nucleic acids in body fluids, such as blood or urine. In some embodiments, the nucleic acid population is a cell free nucleic acid population.”DNA circulating freely in the blood or other bodily fluids, not contained within cells. It is used as a template for sequencing.
Methylation state
(Claim 1)		“The DNA can be methylated at cytosine such as in CpG dinucleotide regions. DNA methylation along with histone complexes may influence DNA packaging into chromatin as well epigenetic regulation of gene expression. Based on DNA methylation status, the nucleic acid molecules in a sample can be fractionated into different groups that can enrich nucleic acid molecules with similar methylation status using experimental procedures.”The extent to which cytosine bases in the cfDNA are modified by the addition of a methyl group.
SNVs, indels and/or gene fusions
(Claim 1)		“Sequence information may be analyzed to determine genetic variations, including, for example, single nucleotide variants, copy number variations, indels, or fusions. In any of the above methods, the sequence data can indicate presence of a somatic or germline variant, or a copy number variation or a single nucleotide variation, or an indel or gene fusion.”Specific types of genetic variations that are analyzed in the first aliquot. SNVs are single nucleotide variations, indels are insertions or deletions of nucleotides, and gene fusions are abnormal joining of two genes.
Target capture
(Claim 1)		“The disclosure further provides a method for analyzing a nucleic acid population in which at least some of the nucleic acids include one or more modified cytosine residues. The method comprises linking capture moieties, e.g., biotin, to nucleic acids in the population to serve as templates for amplification; performing an amplification reaction to produce amplification products from the templates; separating the templates linked to capture moieties from amplification products; assaying sequence data of the templates linked to capture moieties by bisulfite sequencing; and assaying sequence data of the amplification products.”A process where specific nucleic acid sequences of interest are selectively isolated from a sample for further analysis.

Litigation Cases New

US Latest litigation cases involving this patent.

Case NumberFiling DateTitle
1:25-cv-01013Aug 12, 2025Guardant Health, Inc. V. Tempus Ai, Inc.

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US12312634

GUARDANT HEALTH INC
Application Number
US18770271
Filing Date
Jul 11, 2024
Status
Granted
Expiry Date
Dec 22, 2037
External Links
Slate, USPTO, Google Patents