Case 1:20-cv-01580-LPS Document 1-18 Filed 11/23/20 Page 1 of 8 PageID #: 576
`Case 1:20-cv-01580-LPS Document 1-18 Filed 11/23/20 Page 1 of 8 PageID #: 576
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`EXHIBIT 18
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`EXHIBIT 18
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`Case 1:20-cv-01580-LPS Document 1-18 Filed 11/23/20 Page 1 of 8 PageID #: 576
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`EXHIBIT 18
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`EXHIBIT 18
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`Case 1:20-cv-01580-LPS Document 1-18 Filed 11/23/20 Page 2 of 8 PageID #: 577
`U.S. Patent No. 10,793,916
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`13p
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`Infringement of U.S. Patent No. 10,793,916 by Foundation Medicine Inc.’s (FMI’s) Liquid Biopsy Platform12
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`’916 Claim Language
`A method for detecting a
`genetic variation in one
`or more microsatellite
`regions in a sample of
`cell-free nucleic acid
`molecules from a subject
`having a cancer, the
`method comprising:
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`Infringement Support
`Exhibit 14 (“FDA Label”) is an FDA label indication for the FoundationONE® Liquid CDx
`product, which is the latest version of the Foundation Platform. In particular, the
`FoundationONE® Liquid CDx product provides detection for tumor mutational burden
`profiling.
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`FDA Label at 1.
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`Ex. 10 (the “Clark Paper”) is entitled “Analytical Validation of a Hybrid Capture Based Next-
`Generation Sequencing Clinical Assay for Genomic Profiling of Cell-Free Circulating Tumor
`DNA.” The Clark Paper explains the methods the FMI platform uses to measure mutations in
`cell-free DNA. To the extent the preamble is considered limiting, the Clark Paper shows that
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`1 The figures in this chart have been modified to include highlighting and red annotations that more clearly identify the individual
`claim elements.
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`2 As used herein, “Foundation Platform” refers to all processes, procedures and activities performed in utilizing FMI’s liquid biopsy
`assay for identifying genetic sequences of ctDNA fragments isolated from body samples, including but not limited to each version of
`“FoundationACT,” “FoundationONE® Liquid,” and “FoundationONE® Liquid CDx”
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`Case 1:20-cv-01580-LPS Document 1-18 Filed 11/23/20 Page 3 of 8 PageID #: 578
`U.S. Patent No. 10,793,916
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`’916 Claim Language
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`Infringement Support
`FMI’s Foundation Platform involves a method for detecting rare mutations in cell free DNA
`(cfDNA) extracted from the blood of a subject.
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`The rare mutations fall into one or more of four classes of genomic alterations in ctDNA, base
`substitutions, short
`insertions/deletions, genomic rearrangements, and copy number
`amplifications.
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`Clark Paper at Abstract
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`Ex. 13 (the “Woodhouse Paper”) is entitled “Clinical and analytical validation of
`FoundationOne Liquid CDx, a novel 324-Gene cfDNA-based comprehensive genomic
`profiling assay for cancers of solid tumor origin.” The Woodhouse Paper provides further
`explanation of FMI’s methods for detecting tumor mutational burden and microsatellite
`instability using the FoundationONE Liquid CDx assay.
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`2
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`Case 1:20-cv-01580-LPS Document 1-18 Filed 11/23/20 Page 4 of 8 PageID #: 579
`U.S. Patent No. 10,793,916
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`’916 Claim Language
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`Infringement Support
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`13a
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`ligating molecular
`barcodes from a set of
`molecular barcodes
`having 2 to 1,000,000
`different molecular
`barcode sequences to a
`plurality of the cell-free
`nucleic acid molecules
`from the sample to
`produce tagged parent
`polynucleotides;
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`Woodhouse Paper at Abstract
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`The Clark Paper explains that 6-bp DNA molecular barcodes are ligated to both ends of each
`cell-free nucleic acid molecule. The Clark Paper also explains that a set of 12 different barcode
`sequences are used.
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`Case 1:20-cv-01580-LPS Document 1-18 Filed 11/23/20 Page 5 of 8 PageID #: 580
`U.S. Patent No. 10,793,916
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`’916 Claim Language
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`Infringement Support
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`Clark Paper at 687-688.
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`Barcodes are used in the FoundationONE Liquid CDx product as indicated in the FDA Label.
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`FDA Label at 30.
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`Likewise, the Woodhouse Paper explains that fragment barcode sequences are utilized in the
`Foundation Platform to group families of sequence reads.
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`Case 1:20-cv-01580-LPS Document 1-18 Filed 11/23/20 Page 6 of 8 PageID #: 581
`U.S. Patent No. 10,793,916
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`’916 Claim Language
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`Infringement Support
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`amplifying a plurality of
`the tagged parent
`polynucleotides to
`produce amplified tagged
`progeny polynucleotides;
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`sequencing a plurality of
`the amplified tagged
`progeny polynucleotides
`to produce a set of
`sequencing reads; and
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`13b
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`13c
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`Woodhouse Paper at 3-4.
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`The Clark Paper explains that cfDNA library products are PCR amplified.
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`Clark Paper at 6688.
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`The Clark Paper explains that the Foundation Platform sequences the population of amplified
`progeny polynucleotides to produce a set of sequence reads using Illumina sequencers.
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`Clark Paper at 688.
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`5
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`Case 1:20-cv-01580-LPS Document 1-18 Filed 11/23/20 Page 7 of 8 PageID #: 582
`U.S. Patent No. 10,793,916
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`’916 Claim Language
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`13d
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`determining, from among
`a plurality of sequencing
`reads in the set of
`sequencing reads, a
`quantitative measure of
`polymorphic forms
`comprising microsatellite
`changes in the one or
`more microsatellite
`regions based at least on
`sequence information of
`the molecular barcodes,
`thereby detecting the
`genetic variation in the
`one or more
`microsatellite regions.
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`Infringement Support
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`Accordingly, the Foundation Platform sequences the population of amplified progeny
`polynucleotides to produce a set of sequence reads.
`The Foundation Platform determines microsatellite changes from the plurality of sequence
`reads. The Woodhouse Paper explains that the Foundation Platform groups sequence reads
`into families comprising sequence reads amplified from the same parent polynucleotide using
`“fragment barcodes (FBCs)”. In particular, the Woodhouse Paper notes that sequence reads
`that overlap are merged into single reads.
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`Woodhouse Paper at 3-4.
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`The Woodhouse Paper next explains that the Foundation Platform determines a quantitative
`measure of microsatellite (MSI) status by determining the quantity of “unstable” repetitive loci
`present in demultiplexed families of sequence reads. The Woodhouse Paper explains that the
`Foundation Platform identifies microsatellite changes by determining the fraction of “unstable”
`loci as a percentage of the total tagged parent polynucleotide sample. Because barcode
`sequences are utilized to generate consensus sequences from groups of sequence reads, and it
`is those consensus sequences that are measured to detect microsatellite instability, the
`Foundation Platform utilizes sequence information of the molecular barcodes at least in part to
`determine microsatellite changes.
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`6
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`Case 1:20-cv-01580-LPS Document 1-18 Filed 11/23/20 Page 8 of 8 PageID #: 583
`U.S. Patent No. 10,793,916
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`’916 Claim Language
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`Infringement Support
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`Woodhouse Paper at 4
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