Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 1 of 15 PageID #: 584
`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 1 of 15 PageID #: 584
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`EXHIBIT 19
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`EXHIBIT 19
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`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 1 of 15 PageID #: 584
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`EXHIBIT 19
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`EXHIBIT 19
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`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 2 of 15 PageID #: 585
`U.S. Patent No. 10,801,063
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`1p
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`Infringement of U.S. Patent No. 10,801,063 by Foundation Medicine Inc.’s (FMI’s) Liquid Biopsy Platform12
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`Infringement Support
`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 detect and classify
`mutations in cell-free DNA. To the extent the preamble is considered limiting, the Clark Paper
`shows that FMI’s Foundation Platform involves a method for classifying consensus sequences
`generated from sequencing reads derived from double-stranded cell-free DNA (cfDNA)
`molecules from a sample of a human subject.
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`’063 Claim Language
`A method for classifying
`consensus sequences
`generated from
`sequencing reads derived
`from double-stranded
`cell-free
`deoxyribonucleic acid
`(cfDNA) molecules from
`a sample of a human
`subject, the method
`comprising:
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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 1-19 Filed 11/23/20 Page 3 of 15 PageID #: 586
`U.S. Patent No. 10,801,063
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`’063 Claim Language
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`Infringement Support
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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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`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 4 of 15 PageID #: 587
`U.S. Patent No. 10,801,063
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`’063 Claim Language
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`Infringement Support
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`Woodhouse Paper at Abstract
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`Exhibit 14 (“FDA Label”) is an FDA label indication for the FoundationONE® Liquid CDx
`product, which is the latest version of the Foundation Platform.
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`FDA Label at 1.
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`The Clark Paper explains that duplex (i.e. double-stranded) cell-free nucleic acid molecules are
`non-uniquely tagged with a population of 12 molecular barcodes, which is at least 2 and fewer
`than the number of double-stranded cfDNA molecules that map to a mappable base position in
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`non-uniquely tagging a
`population of double-
`stranded cfDNA
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`1a
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`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 5 of 15 PageID #: 588
`U.S. Patent No. 10,801,063
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`’063 Claim Language
`molecules from the
`sample with more than a
`10× molar excess of
`adapters comprising
`molecular barcodes,
`relative to the double-
`stranded cfDNA
`molecules in the
`population, to generate
`non-uniquely tagged
`parent polynucleotides,
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`wherein the double-
`stranded cfDNA
`molecules that map to a
`mappable base position
`of a reference sequence
`are tagged with a number
`of different molecular
`barcodes ranging from at
`least 2 to fewer than a
`number of double-
`stranded cfDNA
`molecules that map to the
`mappable base position,
`and
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`wherein at least 20% of
`the double-stranded
`cfDNA molecules are
`non-uniquely tagged with
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`Infringement Support
`the assay. Upon information and belief, the Foundation Platform utilizes at least a 10× molar
`excess of molecular barcodes relative to the population of cfDNA molecules.
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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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`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 6 of 15 PageID #: 589
`U.S. Patent No. 10,801,063
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`Infringement Support
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`’063 Claim Language
`the adapters comprising
`the molecular barcodes at
`both ends of a molecule
`of the double-stranded
`cfDNA molecules;
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`FDA Label at 30.
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`Based on the reported sensitivities, at least 20% of the double-stranded cfDNA molecules are
`non-uniquely tagged using a 10X molar excess of molecular barcodes in the Foundation
`Platform.
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`The Clark Paper explains that cfDNA library products are PCR amplified.
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`amplifying a plurality of
`the non-uniquely tagged
`parent polynucleotides to
`produce progeny
`polynucleotides;
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`enriching a plurality of
`the progeny
`polynucleotides for target
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`Clark Paper at 688.
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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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`1b
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`1c
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`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 7 of 15 PageID #: 590
`U.S. Patent No. 10,801,063
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`’063 Claim Language
`regions of interest to
`generate enriched
`progeny polynucleotides;
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`Infringement Support
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`FDA Label at 2-3.
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`Clark Paper at 688.
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`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 8 of 15 PageID #: 591
`U.S. Patent No. 10,801,063
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`’063 Claim Language
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`Infringement Support
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`Woodhouse Paper at 3
`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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`sequencing a plurality of
`the enriched progeny
`polynucleotides to
`produce a set of
`sequencing 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 maps the sequence reads of the set of
`sequence reads to one or more reference sequences from a human genome.
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`mapping a plurality of
`sequencing reads from
`the set of sequencing
`reads to the reference
`sequence;
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`1d
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`1e
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`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 9 of 15 PageID #: 592
`U.S. Patent No. 10,801,063
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`’063 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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`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 10 of 15 PageID #: 593
`U.S. Patent No. 10,801,063
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`1f
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`’063 Claim Language
`grouping a plurality of
`the mapped sequencing
`reads into families of
`mapped sequencing reads
`based at least on (i)
`sequence information
`from the molecular
`barcodes and (ii) a
`beginning base position
`and an ending base
`position of the mapped
`sequencing reads;
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`Infringement Support
`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.”
`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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`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 11 of 15 PageID #: 594
`U.S. Patent No. 10,801,063
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`’063 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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`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 12 of 15 PageID #: 595
`U.S. Patent No. 10,801,063
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`’063 Claim Language
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`Infringement Support
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`Woodhouse Paper at 3-4.
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`As discussed for claim 1f, the Foundation Platform groups families of sequence reads according
`to fragment barcode information. After grouping families, the Foundation Platform generates
`a consensus sequence for each family.
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`1g
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`generating a consensus
`sequence for each family
`from among one or more
`of the families to produce
`a set of consensus
`sequences; and
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`Woodhouse Paper at 3-4.
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`The Clark paper explains that a consensus sequence is determined by comparing sequence reads
`from within families of read pairs as well as comparing sequence reads from different families
`to determine individual fragment sequences, i.e. the consensus sequence for each family.
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`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 13 of 15 PageID #: 596
`U.S. Patent No. 10,801,063
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`’063 Claim Language
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`Infringement Support
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`classifying one or more
`consensus sequences
`from among the set of
`consensus sequences as
`(1) paired consensus
`sequences generated
`from sequencing reads
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`Clark paper at 688.
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`Upon information and belief, the Foundation Platform classifies consensus sequences as either
`paired consensus sequences or unpaired consensus sequences as a part of its read processing.
`Paired consensus sequences representing a Watson strand and a Crick strand have
`complementary sequence information. Likewise, barcodes binding to paired consensus
`sequences have complementary sequence information. To generate groups of sequence reads
`arising from the same fragment, the Foundation Platform matches the sequence of the fragment
`barcodes. Read pairs that have the same sequence start and stop but different (i.e.
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`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 14 of 15 PageID #: 597
`U.S. Patent No. 10,801,063
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`Infringement Support
`complementary) barcode sequences are segregated as arising from different fragments and thus
`are classified as paired consensus sequences. Thus, the Foundation Platform identifies and
`classifies consensus sequences as either being paired consensus sequences or unpaired
`consensus sequences.
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`’063 Claim Language
`representing a Watson
`strand and a Crick strand
`of a non-uniquely tagged
`parent polynucleotide or
`(2) unpaired consensus
`sequences generated
`from sequencing reads
`representing only one of
`either a Watson strand or
`a Crick strand of a non-
`uniquely tagged parent
`polynucleotide.
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`Clark Paper at 688.
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`Case 1:20-cv-01580-LPS Document 1-19 Filed 11/23/20 Page 15 of 15 PageID #: 598
`U.S. Patent No. 10,801,063
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