Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 1 of 17 PageID #: 526
`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 1 of 17 PageID #: 526
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`EXHIBIT 15
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`EXHIBIT 15
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`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 1 of 17 PageID #: 526
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`EXHIBIT 15
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`EXHIBIT 15
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`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 2 of 17 PageID #: 527
`U.S. Patent No. 10,501,810
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`1p
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`Infringement of U.S. Patent No. 10,501,810 by Foundation Medicine Inc.’s (FMI’s) Liquid Biopsy Platform12
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`’810 Claim Language
`A method for detecting
`somatic genetic variants
`of cell-free
`deoxyribonucleic acid
`(DNA) in a human
`subject, the method
`comprising:
`
`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 further explains that
`the Foundation Platform is a method for detecting rare mutations in cell free DNA. 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.” 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 1-15 Filed 11/23/20 Page 3 of 17 PageID #: 528
`U.S. Patent No. 10,501,810
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`’810 Claim Language
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`Infringement Support
`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 1-15 Filed 11/23/20 Page 4 of 17 PageID #: 529
`U.S. Patent No. 10,501,810
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`’810 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 10 to 100 nanograms of cell free DNA
`molecules from a blood sample.
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`3
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`obtaining 10 to 100
`nanograms (ng) of
`double-stranded cell-free
`DNA from a blood
`sample from the human
`subject;
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`1a
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`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 5 of 17 PageID #: 530
`U.S. Patent No. 10,501,810
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`’810 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 1-15 Filed 11/23/20 Page 6 of 17 PageID #: 531
`U.S. Patent No. 10,501,810
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`’810 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 generates a population of non-uniquely
`tagged parent polynucleotides, by ligating an identifier sequence, or barcode, onto the cfDNA
`molecule. It further explains that a set of 12 adaptors are used, each with a length of 6
`nucleotides.
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`5
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`ligating adapters
`comprising molecular
`barcodes to ends of a
`plurality of molecules of
`the double-stranded cell-
`free DNA to produce
`tagged parent
`polynucleotides, wherein
`the molecular barcodes
`together constitute a set
`of 5-100 molecular
`barcodes from 5-20
`nucleotides in length;
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`1b
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`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 7 of 17 PageID #: 532
`U.S. Patent No. 10,501,810
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`’810 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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`The Clark Paper explains that cfDNA library products are PCR amplified to produce progeny
`polynucleotides.
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`6
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`amplifying a plurality of
`the tagged parent
`polynucleotides to
`produce progeny
`polynucleotides with
`associated molecular
`barcodes;
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`1c
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`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 8 of 17 PageID #: 533
`U.S. Patent No. 10,501,810
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`’810 Claim Language
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`Infringement Support
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`Clark Paper at 6688.
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`The Foundation Platform selectively enriches progeny polynucleotides for target regions
`associated with cancer by utilizing hybrid capture of sequences associated with cancer-related
`genes.
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`1d
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`selectively enriching the
`progeny polynucleotides
`for target regions
`associated with cancer,
`whereby enriched
`progeny polynucleotides
`are generated;
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`FDA Label at 2-3.
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`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 9 of 17 PageID #: 534
`U.S. Patent No. 10,501,810
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`’810 Claim Language
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`Infringement Support
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`Clark Paper at 688.
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`sequencing a portion of
`the enriched progeny
`polynucleotides to
`produce sequencing reads
`of the progeny
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`1e
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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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`8
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`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 10 of 17 PageID #: 535
`U.S. Patent No. 10,501,810
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`’810 Claim Language
`polynucleotides with
`associated molecular
`barcodes;
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`Infringement Support
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`Clark Paper at 688.
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`The FDA Label further confirms that the Foundation Platform sequences hybrid-capture
`selected libraries.
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`FDA Label at 2-3.
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`Accordingly, the Foundation Platform sequences the population of amplified progeny
`polynucleotides to produce a set of sequence reads.
`After sequence reads are generated in the Foundation Platform, they are aligned to a human
`reference genome.
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`aligning mappable
`portions of the
`sequencing reads to a
`human reference genome
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`9
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`1f
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`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 11 of 17 PageID #: 536
`U.S. Patent No. 10,501,810
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`’810 Claim Language
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`Infringement Support
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`Clark paper at 688.
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`The Foundation Platform groups sequence reads into families based on the sequence
`information of the barcodes and the beginning and end base positions of the mapped portions
`of the progeny polynucleotides.
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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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`10
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`grouping a plurality of
`the sequencing reads into
`families based on the
`sequence information of
`the molecular barcodes
`and the beginning and
`end base positions of the
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`1g
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`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 12 of 17 PageID #: 537
`U.S. Patent No. 10,501,810
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`’810 Claim Language
`mapped portion of the
`progeny polynucleotides;
`and
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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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`11
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`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 13 of 17 PageID #: 538
`U.S. Patent No. 10,501,810
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`’810 Claim Language
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`Infringement Support
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`Clark paper at 688.
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`The Woodhouse Paper further 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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`12
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`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 14 of 17 PageID #: 539
`U.S. Patent No. 10,501,810
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`’810 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 Foundation Platform detects the presence or absence of genetic variants, including single
`nucleotide variants (base substitutions), copy number variations, and small insertions/deletions.
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`Clark Paper at Abstract.
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`13
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`detecting, from among a
`plurality of the families,
`the presence or absence
`of one or more somatic
`genetic variants
`comprising a single
`nucleotide variant
`(SNV), a copy number
`variation (CNV), an
`insertion or deletion
`(indel), a gene fusion, or
`any combination thereof
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`1h
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`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 15 of 17 PageID #: 540
`U.S. Patent No. 10,501,810
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`’810 Claim Language
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`Infringement Support
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`FDA Label at 1.
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`The Clark Paper explains that, to detect variants, “a set of 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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`Clark Paper at 688.
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`14
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`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 16 of 17 PageID #: 541
`U.S. Patent No. 10,501,810
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`’810 Claim Language
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`Infringement Support
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`Clark Paper at 691.
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`The Woodhouse Paper further identifies the algorithms used by the Foundation Platform to
`detect SNV, CNV, indel, or gene fusions from the plurality of the set of sequencing reads.
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`15
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`Case 1:20-cv-01580-LPS Document 1-15 Filed 11/23/20 Page 17 of 17 PageID #: 542
`U.S. Patent No. 10,501,810
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`’810 Claim Language
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`Infringement Support
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`Woodhouse Paper at 3-4.
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`16
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