Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 1 of 18 PageID #: 599
`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 1 of 18 PageID #: 599
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`EXHIBIT 20
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`EXHIBIT 20
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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 1 of 18 PageID #: 599
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`EXHIBIT 20
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`EXHIBIT 20
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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 2 of 18 PageID #: 600
`U.S. Patent No. 9,840,743
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`10p
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`Infringement of U.S. Patent No. 9,840,743 by Foundation Medicine Inc.’s (FMI’s) Liquid Biopsy Platform12
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`’743 Claim Language
`A method for detecting a
`rare mutation in a cell-
`free or substantially cell-
`free sample obtained
`from a subject,
`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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`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 1-20 Filed 11/23/20 Page 3 of 18 PageID #: 601
`U.S. Patent No. 9,840,743
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`’743 Claim Language
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`Infringement Support
`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 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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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 4 of 18 PageID #: 602
`U.S. Patent No. 9,840,743
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`’743 Claim Language
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`Infringement Support
`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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`Woodhouse Paper at Abstract
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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. The Clark Paper further explains
`that “2x176 bp paired-end” sequence reads are generated by the process. Therefore, the
`Foundation Platform produces a plurality of sequence reads for each of the tagged parent
`polynucleotides.
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`3
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`sequencing extracellular
`polynucleotides from a
`bodily sample from the
`subject, wherein each of
`the extracellular
`polynucleotides
`generates a plurality of
`sequence reads;
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`10a
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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 5 of 18 PageID #: 603
`U.S. Patent No. 9,840,743
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`’743 Claim Language
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`Infringement Support
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`Clark Paper at 688.
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`The FDA Label 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 plurality of sequence reads.
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`To the extent FMI contends that Foundation Platform does not directly infringe this limitation,
`for example that it does not generate a plurality of sequence reads from each and every parent,
`it nevertheless infringes through the doctrine of equivalents. A method that does not produce
`multiple sequence reads from literally every single parent polynucleotide would be
`insubstantially different from a technique that does and would perform the same function in
`substantially the same way to achieve substantially the same result as this claim element. The
`function of this claim elements is to produce a plurality of sequence reads from each of the
`tagged parent polynucleotides. To the extent there are some polynucleotides in the Foundation
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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 6 of 18 PageID #: 604
`U.S. Patent No. 9,840,743
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`’743 Claim Language
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`Infringement Support
`Platform that generate fewer than two sequence reads, the Foundation Platform nonetheless
`performs substantially the same function as the claim element. To the extent the Foundation
`Platform does not generate two or more sequence reads for each parent polynucleotide, it is
`simply because there was an inefficiency in the amplification process, not all of the parent
`polynucleotides are applied to the sequence, or there was a failure in the sequencing process.
`Even if the claim element is construed to not encompass processes that include normal
`inefficiencies such as these, the function the Foundation Platform is performing is nonetheless
`substantially the same because, to the extent possible, the Foundation Platform nonetheless
`aims to generate multiple sequence reads from each polynucleotide. This is supported by FMI’s
`own descriptions of its platforms. For example, in Figure 1, panel B of the Clark publication,
`parent polynucleotides are shown as redundantly sequenced:
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`Clark Paper at 691.
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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 7 of 18 PageID #: 605
`U.S. Patent No. 9,840,743
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`10b
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`’743 Claim Language
`filtering out reads that
`fail to meet a set
`accuracy, quality score,
`or mapping score
`threshold;
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`Infringement Support
`The Foundation Platform filters out sequence reads that fail to meet a set accuracy, quality
`score, or mapping score threshold. The Clark Paper, explains that sequence sections are marked
`with errors and are avoided.
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`Clark Paper at 688.
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`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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`10c
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`mapping sequence reads
`derived from the
`sequencing onto a
`reference sequence;
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`Clark Paper at 688.
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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 8 of 18 PageID #: 606
`U.S. Patent No. 9,840,743
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`’743 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 consensus sequences are aligned to the reference genome.
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`Woodhouse Paper at 3-4.
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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 1-20 Filed 11/23/20 Page 9 of 18 PageID #: 607
`U.S. Patent No. 9,840,743
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`10d
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`’743 Claim Language
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`determining unique
`sequence reads
`corresponding to the
`extracellular
`polynucleotides from
`among the sequence
`reads;
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`Infringement Support
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`The Foundation Platform determines unique sequence reads corresponding to parent
`extracellular polynucleotides. The Clark Paper explains, “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 1-20 Filed 11/23/20 Page 10 of 18 PageID #: 608
`U.S. Patent No. 9,840,743
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`’743 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 unique reads representing the consensus of the family of sequence
`reads.
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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 11 of 18 PageID #: 609
`U.S. Patent No. 9,840,743
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`’743 Claim Language
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`Infringement Support
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`Woodhouse Paper at 3-4.
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`The Foundation Platform identifies unique sequence reads that include a variant. The Clark
`Paper explains that the Foundation Platform does this by applying a threshold of five
`unambiguous variant calls in order to identify real variants.
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`10e
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`identifying a subset of
`mapped unique sequence
`reads that include a
`variant as compared to
`the reference sequence at
`each mappable base
`position;
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`Clark paper at 688.
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`Furthermore, the Clark Paper identifies variants as compared to the reference sequence at each
`mappable base position. For example, called variants are compared to databases of known
`variants prior to reporting.
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`10
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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 12 of 18 PageID #: 610
`U.S. Patent No. 9,840,743
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`’743 Claim Language
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`Infringement Support
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`Clark Paper at 688.
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`The Foundation Platform determines genetic variants by calculating a probability of observing
`the obtained number of sequence reads supporting a variant call. This probability contains a
`ratio of the number of mapped unique sequence reads containing the variant to an expected
`value. In order to determine an expected value, the total number of sequence reads must be
`taken into account. Therefore, the Foundation Platform calculates a ratio of a number of
`mapped unique sequence reads that include a variant to a number of total unique sequence
`reads.
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`10f
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`for each mappable base
`position, calculating a
`ratio of (a) a number of
`mapped unique sequence
`reads that include a
`variant as compared to
`the reference sequence,
`to (b) a number of total
`unique sequence reads
`for each mappable base
`position; and
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`11
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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 13 of 18 PageID #: 611
`U.S. Patent No. 9,840,743
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`’743 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, for detecting copy number variation, the Foundation
`Platform quantifies the number of sequence reads corresponding to sequences at all candidate
`loci.
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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 14 of 18 PageID #: 612
`U.S. Patent No. 9,840,743
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`’743 Claim Language
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`Infringement Support
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`Woodhouse at 4.
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`The Foundation Platform can utilize this quantification to of genetic variants present to generate
`a genetic profile of tumors.
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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
`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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`13
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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 15 of 18 PageID #: 613
`U.S. Patent No. 9,840,743
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`’743 Claim Language
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`Infringement Support
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`FDA Label at 33.
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`The FDA Label further explains that the Foundation Platform is capable of detecting variants
`with varying levels of variant allele frequency, or VAF, representing the ratio of sequence reads
`containing the variant to the total number of sequence reads.
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`14
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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 16 of 18 PageID #: 614
`U.S. Patent No. 9,840,743
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`’743 Claim Language
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`10g
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`processing the ratio with
`a similarly derived
`number from a reference
`sample.
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`Infringement Support
`FDA Label at 10.
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`Accordingly, the Foundation Platform quantifies genetic variants to generate a genetic profile
`of a tumor.
`As discussed in claim 10f, above, the Foundation Platform processes the probability of
`determining a variant in part by comparing the number of sequence reads supporting a variant
`to an expected level for the variant.
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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 17 of 18 PageID #: 615
`U.S. Patent No. 9,840,743
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`’743 Claim Language
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`Infringement Support
`Clark Paper at 688.
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`Furthermore, the Clark Paper explains that reference cell line samples are used as comparisons
`for base substitution and indel variant calls. The Clark Paper explains that, using data generated
`by the reference cell lines, “final expected mutant allele frequencies (MAFs) were calculated
`on the actual mixing ratios using a linear regression of SNP alternate AFs in the pools.”
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`For copy number amplification variant calling, the Foundation Platform specifically matches
`samples against a “process-matched normal control sample.”
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`Case 1:20-cv-01580-LPS Document 1-20 Filed 11/23/20 Page 18 of 18 PageID #: 616
`U.S. Patent No. 9,840,743
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`’743 Claim Language
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`Infringement Support
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`Clark Paper at 689.
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`The Woodhouse Paper explains that, for detecting copy number variation, candidate mutations
`are matched against process matched controls.
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`Woodhouse at 4.
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