Systems and methods to detect rare mutations and copy number variation
Patent No. US10501810 (titled "Systems and methods to detect rare mutations and copy number variation") on Feb 22, 2019. The application was issued on Dec 10, 2019.
What is this patent about?
’810 is related to the field of molecular diagnostics and bioinformatics, specifically focusing on the high-sensitivity detection of genetic aberrations in cell-free DNA (cfDNA). The technology addresses the challenge of identifying rare mutations and structural variations that are often masked by the inherent noise and distortion of standard next-generation sequencing workflows.
The underlying idea behind ’810 is to treat the sequencing process as a communication channel where the original DNA molecules are the message and sequencing artifacts are noise. By using a combination of molecular barcodes and the unique genomic coordinates (start/stop positions) of DNA fragments, the system can group sequencing reads into families derived from a single parent molecule, effectively collapsing them into high-fidelity consensus sequences.
The claims of ’810 focus on a method for detecting somatic genetic variants from a limited input of 10 to 100 ng of double-stranded cfDNA. The process involves ligating a specific set of 5–100 molecular barcodes to the fragments, followed by amplification and selective enrichment of cancer-associated target regions to ensure that rare signals are captured and distinguishable from background errors.
In practice, the invention functions by identifying unique parent molecules through their specific barcode and mapping coordinates, which allows the system to filter out PCR-induced errors and sequencing miscalls. This digital sequencing approach enables the detection of single nucleotide variants, indels, and copy number variations with a sensitivity as low as 0.1%, even when the mutant DNA is present in a vast excess of healthy germline DNA.
This method differs from prior approaches by significantly increasing conversion efficiency, ensuring that a higher percentage of the initial DNA fragments are successfully tagged and sequenced. By moving beyond simple quality filtering and instead utilizing a familial grouping strategy, the invention overcomes the traditional trade-off between breadth of genomic coverage and the depth required to identify clinically actionable somatic mutations.
How does this patent fit in bigger picture?
Technical Landscape
In the early 2010s when ’810 was filed, molecular diagnostic systems were increasingly utilized for genetic testing at a time when the detection of rare genetic alterations was typically implemented using high-throughput sequencing of fragmented nucleic acids. During this era, systems commonly relied on standard mapping and quantification protocols that were often limited by the inherent error rates of sequencing platforms, which made the identification of low-frequency variants non-trivial. Technical practices for analyzing cell-free DNA generally involved basic alignment to reference genomes, where hardware and software constraints necessitated specific filtering and normalization techniques to distinguish true biological signals from noise introduced during library preparation and amplification.
Prosecution Position
The disclosed invention addresses the technical problem of accurately detecting rare mutations and copy number variations in heterogeneous cell-free polynucleotide samples where the signal-to-noise ratio is extremely low. The architectural solution involves a multi-step integration of molecular tagging, sequence read collapsing into consensus sequences, and statistical normalization across predefined genomic regions. This approach enables a significant technical advancement by allowing for the identification of genetic variants at frequencies lower than the per-base sequencing error rate of the underlying hardware. The resulting capability allows for the simultaneous quantification of fractional copy number changes and rare sequence variants from a single bodily sample, overcoming the constraints of representational bias and amplification errors that previously limited the sensitivity of liquid biopsy diagnostics.
Claims
The patent contains a total of 28 claims, with claim 1 serving as the sole independent claim. This independent claim focuses on a method for detecting somatic genetic variants in a human subject by processing cell-free DNA through molecular barcode ligation, amplification, target enrichment, and sequencing read family grouping. The dependent claims serve to further define specific technical parameters such as ligation efficiency, barcode characteristics, targeted cancer genes, consensus sequence generation, and the production of clinical reports containing mutation profiles and treatment recommendations.
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US10501810
- Application Number
- US16283629A
- Filing Date
- Feb 22, 2019
- Publication Date
- Dec 10, 2019
- External Links
- Slate, USPTO , Google Patents