Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 1 of 16 PageID #: 617
`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 1 of 16 PageID #: 617
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`EXHIBIT 21
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`EXHIBIT 21
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`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 1 of 16 PageID #: 617
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`EXHIBIT 21
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`EXHIBIT 21
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`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 2 of 16 PageID #: 618
`U.S. Patent No. 9,834,822
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`1p
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`Infringement of U.S. Patent No. 9,834,822 by Foundation Medicine Inc.’s (FMI’s) Liquid Biopsy Platform12
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`’822 Claim Language
`A 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. 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
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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 1-21 Filed 11/23/20 Page 3 of 16 PageID #: 619
`U.S. Patent No. 9,834,822
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`’822 Claim Language
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`Infringement Support
`DNA.” To the extent the preamble is considered limiting, the Clark Paper shows that 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
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`2
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`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 4 of 16 PageID #: 620
`U.S. Patent No. 9,834,822
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`’822 Claim Language
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`Infringement Support
`explanation of FMI’s methods for detecting tumor mutational burden and microsatellite
`instability using the FoundationONE Liquid CDx assay.
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`Woodhouse Paper at Abstract
`The Clark paper provides a method for obtaining cell free DNA molecules from a bodily
`sample, namely blood.
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`1a
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`providing a population of
`cell free DNA
`(“cfDNA”) molecules
`obtained from a bodily
`sample from a subject;
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`3
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`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 5 of 16 PageID #: 621
`U.S. Patent No. 9,834,822
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`’822 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 1-21 Filed 11/23/20 Page 6 of 16 PageID #: 622
`U.S. Patent No. 9,834,822
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`’822 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.
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`5
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`converting the population
`of cfDNA molecules into
`a population of non-
`uniquely tagged parent
`polynucleotides, wherein
`each of the non-uniquely
`tagged parent
`polynucleotides
`comprises
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`(i) a sequence from a
`cfDNA molecule of
`the population of
`cfDNA molecules,
`and
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`(ii) an identifier
`sequence comprising
`one or more
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`1b
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`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 7 of 16 PageID #: 623
`U.S. Patent No. 9,834,822
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`’822 Claim Language
`polynucleotide
`barcodes;
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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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`6
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`amplifying the
`population of non-
`uniquely tagged parent
`polynucleotides to
`produce a corresponding
`population of amplified
`progeny polynucleotides;
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`1c
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`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 8 of 16 PageID #: 624
`U.S. Patent No. 9,834,822
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`1d
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`’822 Claim Language
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`sequencing the
`population of amplified
`progeny polynucleotides
`to produce a set of
`sequence 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 a set of sequence reads. In particular, the Clark paper
`explains that the progeny polynucleotides are sequenced to produce “2x176 bp paired end”
`sequencing reads.
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`Clark Paper at 688.
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`The FDA Label further confirms that the Foundation Platform utilizes sequencing.
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`FDA Label at 1.
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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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`7
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`mapping sequence reads
`of the set of sequence
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`1e
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`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 9 of 16 PageID #: 625
`U.S. Patent No. 9,834,822
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`’822 Claim Language
`reads to one or more
`reference sequences from
`a human genome;
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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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`8
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`grouping the sequence
`reads into families, each
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`1f
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`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 10 of 16 PageID #: 626
`U.S. Patent No. 9,834,822
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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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`’822 Claim Language
`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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`Clark Paper at 691.
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`9
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`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 11 of 16 PageID #: 627
`U.S. Patent No. 9,834,822
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`’822 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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`10
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`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 12 of 16 PageID #: 628
`U.S. Patent No. 9,834,822
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`’822 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 variantswas 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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`11
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`at each genetic locus of a
`plurality of genetic loci
`in the one or more
`reference sequences,
`collapsing sequence
`reads in each family to
`yield a base call for each
`family at the genetic
`locus; and
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`1g
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`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 13 of 16 PageID #: 629
`U.S. Patent No. 9,834,822
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`’822 Claim Language
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`Infringement Support
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`Clark Paper at 691.
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`The Woodhouse Paper explains that, for calling CNV, family base calls are obtained at all
`exons and SNPs and compared to a process matched control to determine allele frequency.
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`Woodhouse Paper at 4.
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`Accordingly, at each genetic locus of a plurality of genetic loci in the one or more reference
`sequences, the Foundation Platform collapses the sequence reads in each family to yield a base
`call for each family at the genetic locus.
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`12
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`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 14 of 16 PageID #: 630
`U.S. Patent No. 9,834,822
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`1h
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`’822 Claim Language
`determining a frequency
`of one or more bases
`called at the locus from
`among the families.
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`Infringement Support
`The Clark Paper specifically explains that “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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`Clark paper at 688.
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`The Woodhouse Paper explains that, for calling CNV, family base calls are obtained at all
`exons and SNPs and compared to a process matched control to determine allele frequency.
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`Woodhouse Paper at 4.
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`13
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`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 15 of 16 PageID #: 631
`U.S. Patent No. 9,834,822
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`’822 Claim Language
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`12
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`The method of claim 1,
`wherein the population of
`polynucleotides is tagged
`with n different unique
`identifiers, wherein n is
`no more than 100*z,
`wherein z is a mean of an
`expected number of
`duplicate molecules
`having the same start and
`stop positions in the
`sample.
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`Infringement Support
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`Accordingly, the Foundation Platform determines a frequency of one or more bases called at
`the locus from among the families.
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`The Foundation Platform utilizes no more than 100*z identifiers, where z is a mean of an
`expected number of duplicate molecules having the same start and stop positions. The
`Foundation Platform utilizes a set of 12 fragment-level indexed adapters that are 6bp each,
`yielding 4096 possible unique combinations of identifiers.
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`The Foundation Platform, on the other hand, generates at least 50 million sequence reads using
`short read sequencing, generating at least 25,000x coverage. Thus, the expected number of
`duplicate molecules having the same start and stop position is greater than a z of 41
`(corresponding to 4100 unique identifiers).
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`Clark Paper at 687-688.
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`14
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`Case 1:20-cv-01580-LPS Document 1-21 Filed 11/23/20 Page 16 of 16 PageID #: 632
`U.S. Patent No. 9,834,822
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`’822 Claim Language
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`Infringement Support
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`Clark Paper at 691.
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`15
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