Case 1:20-cv-01580-LPS Document 1-17 Filed 11/23/20 Page 1 of 15 PageID #: 561
`Case 1:20-cv-01580-LPS Document 1-17 Filed 11/23/20 Page 1 of 15 PageID #: 561
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`EXHIBIT 17
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`EXHIBIT 17
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`Case 1:20-cv-01580-LPS Document 1-17 Filed 11/23/20 Page 1 of 15 PageID #: 561
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`EXHIBIT 17
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`EXHIBIT 17
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`1p
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`Case 1:20-cv-01580-LPS Document 1-17 Filed 11/23/20 Page 2 of 15 PageID #: 562
`U.S. Patent No. 10,704,086
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`Infringement of U.S. Patent No. 10,704,086 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 detecting genetic variants in cell free DNA.
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`’086 Claim Language
`A method for detecting a
`presence or absence of
`one or more somatic
`genetic variants in cell-
`free deoxyribonucleic
`acid (cfDNA) molecules
`from a bodily fluid
`sample of a subject,
`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
`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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`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 1-17 Filed 11/23/20 Page 3 of 15 PageID #: 563
`U.S. Patent No. 10,704,086
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`’086 Claim Language
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`Infringement Support
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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 1-17 Filed 11/23/20 Page 4 of 15 PageID #: 564
`U.S. Patent No. 10,704,086
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`’086 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 bodily
`sample, namely blood.
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`3
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`non-uniquely tagging a
`plurality of cfDNA
`molecules from a
`population of cfDNA
`molecules obtained from
`the bodily fluid sample
`with molecular barcodes
`from a set of molecular
`barcodes to produce non-
`uniquely tagged parent
`polynucleotides;
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`wherein the non-uniquely
`tagging comprises
`ligating molecular
`barcodes from the set of
`molecular barcodes to
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`1a
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`Case 1:20-cv-01580-LPS Document 1-17 Filed 11/23/20 Page 5 of 15 PageID #: 565
`U.S. Patent No. 10,704,086
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`’086 Claim Language
`both ends of a cfDNA
`molecule from the
`plurality of cfDNA
`molecules using more
`than a 10× molar excess
`of molecular barcodes
`relative to the population
`of cfDNA molecules,
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`wherein the cfDNA
`molecules that map to a
`mappable base position
`of a reference sequence
`are tagged with a number
`of diffrent molecular
`barcodes ranging from at
`least 2 and fewer than a
`number of cfDNA
`molecules that map to the
`mappable base position,
`and
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`wherein at least 20% of
`the cfDNA molecules
`from the population of
`cfDNA molecules are
`attached to molecular
`barcodes;
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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 1-17 Filed 11/23/20 Page 6 of 15 PageID #: 566
`U.S. Patent No. 10,704,086
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`’086 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 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 further explains that “a set of 12 fragment-level
`indexed adaptors with variable 6-bp DNA barcodes” are used. Based on the reported
`sensitivities, the Foundation Platform utilizes at least a 10× molar excess of molecular barcodes
`relative to the population of cfDNA molecules, such that at least 20% of the cfDNA molecules
`are attached to barcodes.
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`5
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`Case 1:20-cv-01580-LPS Document 1-17 Filed 11/23/20 Page 7 of 15 PageID #: 567
`U.S. Patent No. 10,704,086
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`’086 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.
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`amplifying a plurality of
`the non-uniquely tagged
`parent polynucleotides to
`produce progeny
`polynucleotides with
`associated molecular
`barcodes;
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`1b
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`Case 1:20-cv-01580-LPS Document 1-17 Filed 11/23/20 Page 8 of 15 PageID #: 568
`U.S. Patent No. 10,704,086
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`’086 Claim Language
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`sequencing a plurality of
`the progeny
`polynucleotides to
`produce sequencing reads
`of the progeny
`polynucleotides with
`associated molecular
`barcodes;
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`mapping a plurality of
`the sequencing reads to
`the reference sequence to
`generate mapped
`sequencing reads;
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`Infringement Support
`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 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 maps the sequence reads of the set of
`sequence reads to one or more reference sequences from a human genome.
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`Clark Paper at 688.
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`1c
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`1d
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`Case 1:20-cv-01580-LPS Document 1-17 Filed 11/23/20 Page 9 of 15 PageID #: 569
`U.S. Patent No. 10,704,086
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`’086 Claim Language
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`Infringement Support
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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 Foundation Platform groups sequence reads into families based on the sequence
`information of the barcodes and the start and/or stop 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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`grouping a plurality of
`the mapped sequencing
`reads into a plurality of
`families based on
`sequence information
`from the molecular
`barcodes and at least (1)
`a start base position of a
`given mapped
`sequencing read from
`among the mapped
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`1e
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`Case 1:20-cv-01580-LPS Document 1-17 Filed 11/23/20 Page 10 of 15 PageID #: 570
`U.S. Patent No. 10,704,086
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`’086 Claim Language
`sequencing reads at
`which the given mapped
`sequencing read is
`determined to start
`mapping to the reference
`sequence and/or (2) a
`stop base position of the
`given mapped
`sequencing read at which
`the given mapped
`sequencing read is
`determined to stop
`mapping to the reference
`sequence; and
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`Infringement Support
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`Clark Paper at 691.
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`Case 1:20-cv-01580-LPS Document 1-17 Filed 11/23/20 Page 11 of 15 PageID #: 571
`U.S. Patent No. 10,704,086
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`’086 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 1-17 Filed 11/23/20 Page 12 of 15 PageID #: 572
`U.S. Patent No. 10,704,086
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`’086 Claim Language
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`Infringement Support
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`detecting, from among
`the mapped sequencing
`reads in a plurality of the
`families, the presence or
`absence of the one or
`more somatic genetic
`variants.
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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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`11
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`1f
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`Case 1:20-cv-01580-LPS Document 1-17 Filed 11/23/20 Page 13 of 15 PageID #: 573
`U.S. Patent No. 10,704,086
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`’086 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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`12
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`Case 1:20-cv-01580-LPS Document 1-17 Filed 11/23/20 Page 14 of 15 PageID #: 574
`U.S. Patent No. 10,704,086
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`’086 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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`Case 1:20-cv-01580-LPS Document 1-17 Filed 11/23/20 Page 15 of 15 PageID #: 575
`U.S. Patent No. 10,704,086
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`’086 Claim Language
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`Infringement Support
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`Woodhouse Paper at 3-4.
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