Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 1 of 18 PageID #: 543
`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 1 of 18 PageID #: 543
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`EXHIBIT 16
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`EXHIBIT 16
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 1 of 18 PageID #: 543
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`EXHIBIT 16
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`EXHIBIT 16
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`1p
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 2 of 18 PageID #: 544
`U.S. Patent No. 10,704,085
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`Infringement of U.S. Patent No. 10,704,085 by Foundation Medicine Inc.’s (FMI’s) Liquid Biopsy Platform12
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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. This label explains that the
`Foundation Platform is a method for generating genetic profiles of a tumor from cell free DNA
`of a subject having cancer or suspected of having cancer.
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`’085 Claim Language
`A method for generating
`a genetic profile of a
`tumor from a blood
`sample of double-
`stranded cell-free
`deoxyribonucleic acids
`(cfDNA) molecules from
`a subject having cancer
`or suspected of having a
`cancer, the method
`comprising:
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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.” To the extent the preamble is considered limiting, the Clark Paper shows that FMI’s
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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 1-16 Filed 11/23/20 Page 3 of 18 PageID #: 545
`U.S. Patent No. 10,704,085
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`’085 Claim Language
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`Infringement Support
`Foundation Platform involves a method for detecting genetic variants in cell free DNA
`(cfDNA) extracted from the blood of a subject.
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`The genetic variants 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 generating genetic profiles of tumors using the
`FoundationONE Liquid CDx assay.
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`2
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 4 of 18 PageID #: 546
`U.S. Patent No. 10,704,085
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`’085 Claim Language
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`Infringement Support
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`Woodhouse Paper at Abstract
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`The Clark paper provides a method for obtaining cell free DNA molecules from a blood sample.
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`1a
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`obtaining a population
`comprising the double-
`stranded cfDNA
`molecules from the blood
`sample from the subject;
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`3
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 5 of 18 PageID #: 547
`U.S. Patent No. 10,704,085
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`’085 Claim Language
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`Infringement Support
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`Clark Paper at 687.
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`The FDA label indicates that FoundationONE® Liquid CDx uses cell-free DNA isolated from
`plasma from whole blood.
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`4
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 6 of 18 PageID #: 548
`U.S. Patent No. 10,704,085
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`’085 Claim Language
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`Infringement Support
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`FDA Label at 1.
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`Accordingly, the Foundation Platform provides a population of cell free DNA ("cfDNA")
`molecules obtained from a bodily sample from a subject.
`The Clark Paper explains that the Foundation Platform converts cfDNA into a population of
`non-uniquely tagged parent polynucleotides, by ligating an identifier sequence, or barcode,
`onto the cfDNA molecule. The Clark Paper explains that a set of 12 adapters, comprising 6 bp
`sequences, are used in the ligation. Based upon the reported sensitivites, the Foundation
`Platform utilizes more than a 30× molar excess of molecular barcodes relative to the double-
`stranded cfDNA, yielding at least 20% barcoded cfDNA.
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`5
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`ligating a set of
`molecular barcodes to
`both ends of a plurality
`of the double-stranded
`cfDNA molecules using
`more than a 30× molar
`excess of molecular
`barcodes relative to the
`double-stranded cfDNA
`molecules to produce
`tagged parent
`polynucleotides, wherein
`a given molecular
`barcode is a member of a
`set of molecular barcodes
`comprising 2 to
`1,000,000 different
`molecular barcode
`sequences,
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`1b
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 7 of 18 PageID #: 549
`U.S. Patent No. 10,704,085
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`Infringement Support
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`’085 Claim Language
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`wherein at least 20% of
`the double-stranded
`cfDNA molecules from
`the population of cfDNA
`molecules are attached to
`molecular barcodes
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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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`The Clark Paper explains that cfDNA library products are PCR amplified.
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`amplifying a plurality of
`the tagged parent
`polynucleotides to
`produce progeny
`polynucleotides with
`associated molecular
`barcodes;
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`6
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`1c
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 8 of 18 PageID #: 550
`U.S. Patent No. 10,704,085
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`1d
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`’085 Claim Language
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`selectively enriching a
`subset of the progeny
`polynucleotides for target
`regions associated with
`cancer, whereby enriched
`progeny polynucleotides
`are generated
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`Infringement Support
`Clark Paper at 6688.
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`The Foundation Platform selectively enriches progeny polynucleotides for target regions
`associated with cancer by utilizing hybridization-based capture of sequences associated with
`cancer-related genes.
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`FDA Label at 2-3.
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 9 of 18 PageID #: 551
`U.S. Patent No. 10,704,085
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`’085 Claim Language
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`Infringement Support
`Clark Paper at 688.
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`sequencing a portion of
`the enriched progeny
`polynucleotides to
`produce sequencing reads
`of the progeny
`polynucleotides with
`associated molecular
`barcodes;
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`aligning a plurality of the
`sequencing reads to a
`reference sequence;
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`1e
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`1f
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`Woodhouse Paper at 3
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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.
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`Clark Paper at 688.
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`Accordingly, the Foundation Platform sequences the population of amplified progeny
`polynucleotides to produce a set of sequence reads.
`The Clark Paper illustrates that the Foundation Platform aligns the sequence reads of the set of
`sequence reads to one or more reference sequences from a human genome.
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 10 of 18 PageID #: 552
`U.S. Patent No. 10,704,085
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`’085 Claim Language
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`Infringement Support
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`Clark Paper at 688.
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`Clark Paper at 691.
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`Accordingly, the Foundation Platform maps sequence reads of the set of sequence reads to one
`or more reference sequences from a human genome.
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`The Clark Paper explains that “Fragment barcodes are used to identify multiple reads
`originating from the same unique input cfDNA fragment for subsequent error detection.”
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`9
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`grouping a plurality of
`the sequencing reads into
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`1g
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 11 of 18 PageID #: 553
`U.S. Patent No. 10,704,085
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`’085 Claim Language
`a plurality of families
`based at least on
`sequence information of
`the molecular barcodes, a
`start base position of a
`given sequencing read
`from among the
`sequencing reads at
`which the given
`sequencing read is
`determined to start
`aligning to the reference
`sequence, and a stop base
`position of the given
`sequencing read at which
`the given sequencing
`read is determined to stop
`aligning to the reference
`sequence, wherein a
`family of the plurality of
`families is representative
`of a cell-free nucleic acid
`molecule in the sample;
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`Infringement Support
`Figure 1 of the Clark Paper that each of the families includes sequence reads amplified from
`the same-tagged parent polynucleotide.
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`Clark Paper at 691.
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`10
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 12 of 18 PageID #: 554
`U.S. Patent No. 10,704,085
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`’085 Claim Language
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`Infringement Support
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`Clark paper at 688.
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`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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`11
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 13 of 18 PageID #: 555
`U.S. Patent No. 10,704,085
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`’085 Claim Language
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`Infringement Support
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`Woodhouse Paper at 3-4.
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`Accordingly, the Foundation Platform groups the sequence reads into families, each of the
`families comprising sequence reads comprising the same identifier sequence and having the
`same start and stop positions, whereby each of the families comprises sequence reads amplified
`from the same tagged parent polynucleotide.
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`The Clark Paper explains that “candidate variants was generated by parsing all alignments
`found in the consensus representation of the sequences determined for each fragment, avoiding
`sections marked as containing errors”.
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`1h
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`detecting, from among
`the families, the presence
`or absence of somatic
`genetic variants; and
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`Clark Paper at 688.
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`12
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 14 of 18 PageID #: 556
`U.S. Patent No. 10,704,085
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`’085 Claim Language
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`Infringement Support
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`Clark Paper at 691.
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`To the extent FMI contends that the Foundation Platform does not directly infringe this
`limitation, because it does not yield a base call at every locus of a reference sequence, it
`nevertheless infringes through doctrine of equivalents. The purpose of making a base call is to
`determine whether a mutation exists at any particular loci. The Foundation Platform performs
`this same function in substantially the same way, to achieve the same result, because it makes
`a “variant call” at a genetic loci to determine whether a mutation exists. To the extent the
`Foundation Platform does not perform a base call at some loci, those loci are not used in the
`analysis nor do they affect the Foundation method for making other base calls.
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`The Foundation Platform quantifies the plurality of genetic variants present to generate a
`genetic profile.
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`The FDA label, for instance, presents validation data for the performance of the Foundation
`Platform in quantifying genetic variants. In one example, the FDA label describes the use of
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`13
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`quantifying a plurality of
`somatic genetic variants
`detected as present to
`generate the genetic
`profile of the tumor.
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`1i
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 15 of 18 PageID #: 557
`U.S. Patent No. 10,704,085
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`’085 Claim Language
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`Infringement Support
`FoundationONE Liquid CDx to quantify BRCA 1 and BRCA 2 mutations in patients with
`prostate cancer.
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`FDA Label at 31.
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`In another study cited by the FDA label, FoundationONE Liquid CDx was used to quantify
`EGFR Exon 19 deletion and EGFR Exon 21 L858R alteration.
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`14
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 16 of 18 PageID #: 558
`U.S. Patent No. 10,704,085
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`’085 Claim Language
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`Infringement Support
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`FDA Label at 33.
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`The Clark Paper further shows that the Foundation Platform quantifies genetic variants. It
`explains, “the number of error-containing fragments [were] identified” using “the probability
`of observing the obtained number of fragments supporting the variant.”
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`15
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 17 of 18 PageID #: 559
`U.S. Patent No. 10,704,085
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`’085 Claim Language
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`Infringement Support
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`Clark paper at 688.
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`The Woodhouse Paper explains how somatic genetic variants are quantified. For example, to
`detect copy number variations, it explains that the Foundation Platform normalizes the number
`of sequence reads across all regions examined, and compares that to a process matched control.
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`Woodhouse Paper at 3.
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`Likewise, to detect tumor mutational burden, it explains that the Foundation Platform counts
`synonymous and non-synonymous variants above a certain allele frequency, and processing to
`determine the number of actionable mutations over the total region counted.
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`16
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`Case 1:20-cv-01580-LPS Document 1-16 Filed 11/23/20 Page 18 of 18 PageID #: 560
`U.S. Patent No. 10,704,085
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`’085 Claim Language
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`Infringement Support
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`Woodhouse Paper at 3-4.
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`Accordingly, the Foundation Platform quantifies genetic variants to generate a genetic profile
`of a tumor.
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