# US 11,299,783 B2 · Methods and systems for genetic analysis

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- Number: US 11,299,783 B2
- Document ID: US11299783B2
- Status: Granted
- Kind: B2
- Application number: 17/235,776
- Filed: 2021-04-20
- Published: 2021-08-05
- Granted: 2022-04-12
- Earliest claimed: 2016-05-27
- Assignees: Personalis, Inc.
- Applicants: Personalis, Inc.
- Inventors: John West; Christian Haudenschild; Richard Chen
- Web page: https://patentgrep.com/patent/US11299783B2

## CPC

- C12Q 1/6874: involving nucleic acid arrays, e.g. sequencing by hybridisation
- C12Q 1/6806: Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay (C12Q1/6804 takes precedence)
- G16B 20/00: ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
- G16B 20/10: Ploidy or copy number detection
- G16B 20/20: Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
- G16B 30/00: ICT specially adapted for sequence analysis involving nucleotides or amino acids
- G16B 35/10: Design of libraries
- G16B 99/00: Subject matter not provided for in other groups of this subclass
- C12Q 1/6869: Methods for sequencing
- G16B 35/00: ICT specially adapted for in silico combinatorial libraries of nucleic acids, proteins or peptides
- G16C 20/60: In silico combinatorial chemistry
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G16B: BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16C: COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE

## Abstract

This disclosure provides systems and methods for sample processing and data analysis. Sample processing may include nucleic acid sample processing and subsequent sequencing. Some or all of a nucleic acid sample may be sequenced to provide sequence information, which may be stored or otherwise maintained in an electronic storage location. The sequence information may be analyzed with the aid of a computer processor, and the analyzed sequence information may be stored in an electronic storage location that may include a pool or collection of sequence information and analyzed sequence information generated from the nucleic acid sample. Methods and systems of the present disclosure can be used, for example, for the analysis of a nucleic acid sample, for producing one or more libraries, and for producing biomedical reports. Methods and systems of the disclosure can aid in the diagnosis, monitoring, treatment, and prevention of one or more diseases and conditions.

## Claims

### Claim 1

A method for personalized genetic testing, comprising:
(a) obtaining a personalized probe set for a subject, which personalized probe set comprises a plurality of nucleic acid probe molecules having a plurality of nucleic acid sequences or complements thereof, wherein said plurality of nucleic acid probe molecules are configured to selectively enrich or amplify sequences comprising a set of one or more genetic variants over other sequences in at least one biological sample of said subject, wherein said set of genetic variants are identified in sequence data for said at least one biological sample, further wherein said personalized probe set comprises nucleic acid probe molecules having oligonucleotide-directed genomic content comprising: (i) at least one variable portion from a result of said sequence data and (ii) at least one fixed portion independent of said result of said sequencing data
(b) using said personalized probe set to selectively enrich or amplify sequences comprising said set of genetic variants over other sequences in at least an additional biological sample from said subject, to generate a sequencing library;
(c) subjecting said sequencing library to sequencing to identify a presence or absence of at least a subset of said set of genetic variants in at least said additional biological sample from said subject, wherein a sequencing footprint of said sequencing of (c) is less than a sequencing footprint of said sequence data of (a); and
(d) generating a report identifying (i) a presence or absence of a health condition or disease of the subject in said additional biological sample based on said identified at least a subset of (c) and (ii) genetic variants which inform a therapy choice or a change in therapy for the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein said at least one biological sample comprises a plurality of biological samples.

### Claim 3 (depends on 2)

The method of claim 2, wherein said plurality of biological samples comprises a tissue sample and a plasma sample.

### Claim 4 (depends on 2)

The method of claim 2, wherein the plurality of biological samples comprise: (i) cell-free deoxyribonucleic acid molecules (cfDNA), (ii) cell-free ribonucleic acid molecules (cfRNA), (iii) DNA or RNA from circulating tumor cells, or (iv) RNA or DNA from a tumor metastasis.

### Claim 5 (depends on 2)

The method of claim 2, further comprising generating said sequence data of (a) from the plurality of biological samples.

### Claim 6 (depends on 1)

The method of claim 1, wherein said sequence data of (a) comprises sequence information for at least an exome, a panel of genes, or a whole genome.

### Claim 7 (depends on 1)

The method of claim 1, wherein identifying said presence or absence of a health condition or disease is based on a frequency of a genetic variant from said set of genetic variants.

### Claim 8 (depends on 1)

The method of claim 1, wherein said additional biological sample of (c) is a blood sample.

### Claim 9 (depends on 1)

The method of claim 1, wherein said health condition or disease is cancer.

### Claim 10 (depends on 2)

The method of claim 2, wherein the plurality of samples are each identifiable based on a nucleic acid barcode sequence.

### Claim 11 (depends on 1)

The method of claim 1, further comprising repeating (a) on a second subject different from said subject to generate a second personalized probe set for said second subject.

### Claim 12 (depends on 11)

The method of claim 11, wherein said personalized probe set and said second personalized probe set are coupled to a same array.

### Claim 13 (depends on 1)

The method of claim 1, further comprising repeating (b) and (c) one or more times and generating one or more additional reports.

### Claim 14 (depends on 1)

The method of claim 1, wherein said at least one additional biological sample in (c) was obtained after said at least one biological sample in (a).

### Claim 15 (depends on 1)

The method of claim 1, wherein said additional biological sample is a blood sample comprising: (i) cfDNA, (ii) cfRNA, (iii) DNA or RNA from circulating tumor cells, or (iv) RNA or DNA from a tumor metastasis.

### Claim 16 (depends on 1)

The method of claim 1, wherein said additional biological sample and one or more subsequent biological samples are each blood samples comprising: (i) cfDNA, (ii) cfRNA, (iii) DNA or RNA from circulating tumor cells, or (iv) RNA or DNA from a tumor metastasis.

### Claim 17 (depends on 1)

The method of claim 1, wherein said at least one fixed portion comprises one or more known tumor variants.

### Claim 18 (depends on 1)

The method of claim 1, wherein said at least one fixed portion is selected from a group consisting of one or more of: (i) cancer driver genes, (ii) genes involved in the pharmacogenomics of cancer drugs, (iii) genes involved in Mendelian immunological diseases, (iv) genes related to inherited forms of cancer, (v) genes associated with tumor escape from a targeted or immune cancer therapy, (vi) HLA typing, (vii) variants common in the population and used by B-allele methods to detect structural variation, and any combination thereof.

### Claim 19 (depends on 1)

The method of claim 1, wherein said sequence data of (a) is derived from sequences of nucleic acids from said at least one biological sample, wherein said at least one biological sample comprises a tumor biopsy.

### Claim 20 (depends on 1)

The method of claim 1, wherein said enrichment comprises the depletion of locations or regions of the genome or portions thereof.

### Claim 21 (depends on 1)

The method of claim 1, wherein said set of one or more genetic variants comprise one or more members selected from the group consisting of: (i) a single nucleotide polymorphism, (ii) an insertion or deletion, (iii) a copy number variation, and (iv) structural variation.

### Claim 22 (depends on 1)

The method of claim 1, wherein said personalized probe set comprises hybrid capture probes.

### Claim 23 (depends on 1)

The method of claim 1, wherein said set of genetic variants identified in sequence data are determined with respect to a reference.

### Claim 24 (depends on 1)

The method of claim 1, further comprising, prior to (a), sequencing said least one biological sample to generate said sequencing data.

### Claim 25 (depends on 1)

The method of claim 1, further comprising generating said personalized probe set for said subject based on said set of genetic variants identified in said sequence data for said at least one biological sample.

### Claim 26 (depends on 1)

The method of claim 1, wherein (b) further comprises using said personalized probe set to selectively enrich or amplify sequences comprising said set of genetic variants over other sequences in a biological sample from another subject to generate said sequencing library.

### Claim 27 (depends on 1)

The method of claim 1, wherein (c) further comprises identifying levels of gene expression, sequencing read counts, or read depth.

### Claim 28 (depends on 1)

The method of claim 1, wherein said at least one additional biological sample comprises a plurality of additional samples obtained at different time points.

### Claim 29 (depends on 1)

The method of claim 1, wherein the report of (d) further comprises reporting biomedical information of said subject that is predictive, prognostic, or diagnostic of one or more biomedical features selected from the group consisting of a disease state, efficacy of a drug therapy, prediction of optimal drug dosage, a recommendation of one or more therapies, and a recommendation of a course of treatment of a disease.