Case 1:20-cv-01644-RGA Document 1 Filed 12/03/20 Page 1 of 55 PageID #: 1
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`Ravgen, Inc.,
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`v.
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`Plaintiff,
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`Defendants.
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`Civil Action No.____________________
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`JURY TRIAL DEMANDED
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`Illumina, Inc. and Verinata Health, Inc.,
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`COMPLAINT FOR PATENT INFRINGEMENT
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`Plaintiff Ravgen, Inc. (“Ravgen”), for its Complaint against Defendants Illumina, Inc.
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`(“Illumina”) and Verinata Health, Inc. (“VHI”) (collectively “Defendants”), hereby alleges as
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`follows:
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`NATURE OF THE ACTION
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`1.
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`This is a civil action for infringement of United States Patent Nos. 7,727,720 (the
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`“’720 Patent”) and 7,332,277 (the “’277 Patent”) (collectively the “Patents-in-Suit”), arising under
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`the Patent Laws of the United States, 35 U.S.C. §§ 271 et seq.
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`THE PARTIES
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`2.
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`Plaintiff Ravgen is a Delaware corporation with its principal place of business at
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`9241 Rumsey Rd., Columbia, MD 21045. Ravgen is a pioneering diagnostics company that
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`focuses on non-invasive prenatal testing. Ravgen has spent millions of dollars researching and
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`developing novel methods for the detection of cell-free DNA to replace conventional, invasive
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`procedures. Ravgen’s innovative cell-free DNA technology has various applications, including
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`non-invasive prenatal and other genetic testing. Those efforts have resulted in the issuance of
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`several patents, including the Patents-in-Suit.
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`

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`3.
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`Defendant Illumina is a company organized and existing under the laws of the State
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`of Delaware, with its principal place of business at 5200 Illumina Way, San Diego, California,
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`92122. (Ex. 5 at 1 (Illumina Inc. Form 10-Q, September 27, 2020).) Illumina has appointed The
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`Corporation Trust Company, Corporation Trust Center 1209 Orange Street, Wilmington,
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`Delaware 19801 as its agent for service of process. (Ex. 6 (State of Delaware Entity Status for
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`Illumina Inc.).)
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`4.
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`Defendant VHI is a company organized and existing under the laws of the state of
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`Delaware, with its principal place of business at 5200 Illumina Way, San Diego, California 92122.
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`VHI has appointed The Corporation Trust Company, Corporation Trust Center 1209 Orange
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`Street, Wilmington, Delaware 19801 as its agent for service of process. (Ex. 7 (State of Delaware
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`Entity Status for Verinata Health, Inc.).) VHI is a wholly owned subsidiary of Illumina. (See,
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`e.g., Ex 8 at 116 (Illumina Inc. Form 10-K, 2019).)
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`5.
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`Defendants, themselves and/or through their subsidiaries and affiliates, make, use,
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`and commercialize noninvasive prenatal tests that utilize next-generation sequencing (NGS) of
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`circulating cell-free DNA (cfDNA) extracted from a maternal blood sample to screen for
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`aneuploidy of chromosomes marketed under the tradename “Verifi.”
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`6.
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`Defendants, themselves and/or through their subsidiaries and affiliates, make, use,
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`and commercialize genetic tests using cell-free DNA, including in vitro diagnostic tests intended
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`for use as sequencing‐based screening tests for the detection of fetal aneuploidies from maternal
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`peripheral whole blood samples in pregnant women of at least 10 weeks gestation marketed under
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`the tradename “VeriSeq.”
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`7.
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`Defendants, themselves and/or through their subsidiaries and affiliates, make, use,
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`and commercialize genetic tests using cell-free DNA, including tests intended for use as
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`2
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`sequencing‐based screening tests for the detection of somatic variations, including tumor
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`mutational burden and microsatellite instability, from peripheral whole blood samples under the
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`tradename “TruSight.”
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`8.
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`Defendants offer and market tests under the Verifi, VeriSeq, and TruSight
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`tradenames throughout the United States, including without limitation through the website,
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`www.illumina.com.
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`
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`(See
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`generally
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`Ex.
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`9
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`(https://www.illumina.com/clinical/illumina_clinical_laboratory/verifi-prenatal-tests.html); Ex.
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`10
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`(https://www.illumina.com/products/by-type/ivd-products/veriseq-nipt.html);
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`Ex.
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`11
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`(https://www.illumina.com/products/trusight-panels.html).)
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`JURISDICTION AND VENUE
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`Ravgen incorporates by reference paragraphs 1–8.
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`This action arises under the patent laws of the United States, including 35 U.S.C.
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`9.
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`10.
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`§§ 271 et seq. The jurisdiction of this Court over the subject matter of this action is proper under
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`28 U.S.C. §§ 1331 and 1338(a).
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`11.
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`Venue is proper in this District pursuant to 28 U.S.C. §§ 1391(b), (c), and 1400(b).
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`Defendants are entities organized under the laws of Delaware and reside in Delaware for purposes
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`of venue under 28 U.S.C. § 1400(b). Defendants conduct business in Delaware, at least by offering
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`for sale and selling products and services through their websites, which are accessible in Delaware.
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`Defendants have also committed and continue to commit acts of infringement in this District.
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`12.
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`This Court has personal jurisdiction over Defendants because Defendants conduct
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`business in Delaware by at least offering for sale or selling products and services through their
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`websites, which are accessible in Delaware, and because infringement has occurred and continues
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`to occur in Delaware.
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`3
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`13.
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`Personal jurisdiction also exists over Defendants because they are entities
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`organized under the laws of Delaware.
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`BACKGROUND OF THE INVENTION
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`14.
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`Dr. Ravinder S. Dhallan is the founder of Ravgen, Inc. and the inventor of several
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`patents in the field of detection of genetic disorders, including chromosomal abnormalities and
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`mutations. Ravgen’s mission is to provide state of the art genetic testing that will enrich the lives
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`of its patients. For example, through the use of its novel techniques in non-invasive prenatal
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`diagnostic testing, Ravgen gives patients the knowledge they need to prepare for their pregnancies
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`and treat diseases at an early stage.
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`15.
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`Prior to founding Ravgen, Dr. Dhallan was a board-certified emergency room
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`physician. Between starting medical school at Johns Hopkins University and shortly after his
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`residency at Mass General (Harvard University School of Medicine), Dr. Dhallan and his wife
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`suffered three miscarriages. At that time, the prenatal diagnostic testing procedures available
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`included (a) non-invasive techniques with low sensitivity and specificity, and (b) tests with higher
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`sensitivity and specificity that were highly invasive and therefore associated with a risk for loss of
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`pregnancy. After discovering the limitations on the available techniques for prenatal testing, Dr.
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`Dhallan made it his mission to invent an improved prenatal diagnostic exam—one that was both
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`non-invasive and accurate. In September of 2000, Dr. Dhallan founded Ravgen (which stands for
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`“Rapid Analysis of Variations in the GENome”) to pursue that goal.
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`16.
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`Prior to Ravgen’s inventions, scientists had recognized the need for a genetic testing
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`technique that used “cell-free” or “free” fetal DNA circulating in maternal blood. A technique that
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`relied on circulating free fetal DNA would require only a simple blood draw from the mother and
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`would therefore be an improvement over invasive diagnostic tests.
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`4
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`17.
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`However, at that time, the use of free fetal DNA for detecting chromosomal
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`abnormalities was limited by the low percentage of free fetal DNA that could be recovered from a
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`sample of maternal blood using existing techniques. (See, e.g., Ex. 12 (Y.M. Dennis Lo et al.,
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`Presence of Fetal DNA in Maternal Plasma and Serum, 350 THE LANCET 768-75 (1997),
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`https://doi.org/10.1016/S0140-6736(97)02174-0).) Dr. Dhallan recognized that a method that
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`could increase the percentage of free fetal DNA relative to the free maternal DNA in a sample was
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`necessary to the development of an accurate, non-invasive prenatal diagnostic test.
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`18.
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`After substantial research, Dr. Dhallan conceived that including an agent that
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`impedes cell lysis (disruption of the cell membrane) if cells are present during sample collection,
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`shipping, handling, and processing would permit the recovery of a larger percentage of cell-free
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`fetal DNA (relative to the cell-free maternal DNA in a sample). Dr. Dhallan hypothesized that
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`this new approach would decrease the amount of maternal cell lysis and therefore lower the amount
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`of cell-free maternal DNA in the sample, thereby increasing the percentage of cell-free fetal DNA.
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`He developed a novel method for processing cell-free fetal DNA that involved the addition of an
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`agent that impedes cell lysis—for example, a membrane stabilizer, a cross-linker, and/or a cell
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`lysis inhibitor—to maternal blood samples coupled with careful processing protocols. With that
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`novel method, Dr. Dhallan was able to increase the relative percentage of cell-free fetal DNA in
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`the processed sample.
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`19.
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`Having successfully increased the relative percentage of cell-free fetal DNA
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`recovered, Dr. Dhallan next addressed the challenge of distinguishing between the cell-free
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`maternal and cell-free fetal DNA in a sample in order to determine whether a chromosomal
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`abnormality is present in the fetal DNA. Prior to Ravgen’s inventions, known methods for
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`detecting fetal chromosomal abnormalities were time-consuming and burdensome. Many required
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`5
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`amplification of the entire sequence of a gene, or quantification of the total amount of a particular
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`gene product in a sample. Dr. Dhallan developed an alternate method that greatly increased the
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`efficiency of this process by taking advantage of the variation of base sequences among different
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`individuals (including a mother and fetus) (“alleles”) at particular positions (“loci”) on
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`chromosomes. The term “allele” refers to an alternate form of a gene, or a non-coding region of
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`DNA that occurs at a particular locus on a chromosome. The alleles present at certain loci on
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`chromosomes (including, for example, “single nucleotide polymorphisms” or “SNPs”) vary
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`between different individuals. At such a locus, a fetus may therefore inherit an allele from its
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`father that differs from the alleles present at that locus on its mother’s chromosome. Dr. Dhallan
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`developed a novel method for quantifying the allelic ratio at such a locus (or loci) of interest in a
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`sample comprising maternal and fetal cell-free DNA in order to detect whether a fetal
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`chromosomal abnormality was present in the fetal DNA of the sample, without requiring physical
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`separation of the fetal from the maternal cell-free DNA.
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`20.
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`Dr. Dhallan understood that his breakthroughs laid the foundation for the
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`development of accurate non-invasive prenatal diagnostic tests. For example, he published a paper
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`in the Journal of the American Medical Association (JAMA) in 2004, explaining that “the methods
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`described herein for increasing the percentage of cell-free fetal DNA provide a solid foundation
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`for the development of a noninvasive prenatal diagnostic test.” (Ex. 13 at 1119 (R. Dhallan et al.,
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`Methods to Increase the Percentage of Free Fetal DNA Recovered from the Maternal Circulation,
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`291 JAMA 1114–19 (2004), https://doi.org/10.1001/jama.291.9.1114).)
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`21.
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`JAMA also ran an editorial alongside Dr. Dhallan’s article in 2004, recognizing the
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`significance of his inventions to applications in prenatal genetic diagnosis and cancer detection
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`and surveillance:
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`6
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`In this issue of THE JOURNAL, the findings reported in the study
`by Dhallan and colleagues on enhancing recovery of cell-free DNA
`in maternal blood have major clinical implications. Developing a
`reliable, transportable technology for cell-free DNA analysis
`impacts 2 crucial areas—prenatal genetic diagnosis and cancer
`detection and surveillance. In prenatal genetic diagnosis, detecting
`a fetal abnormality without an invasive procedure (or with fewer
`invasive procedures) is a major advantage. Likewise in cancer
`surveillance (eg, in patients with leukemia), monitoring treatment
`without having to perform a bone marrow aspiration for karyotype
`also would be of great benefit.
`
`* * *
`With prospective studies focusing on clinical applications of these
`findings, profound clinical implications could emerge for prenatal
`diagnosis and cancer surveillance.
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`(Ex. 14 at 1135, 1137 (J.L. Simpson & F. Bischoff, Cell-Free Fetal DNA in Maternal Blood:
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`Evolving
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`Clinical
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`Applications,
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`291
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`JAMA
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`1135–37
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`(2004),
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`https://doi.org/10.1001/jama.291.9.1135).)
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`22.
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`In 2007, Dr. Dhallan published a second journal article in The Lancet that presented
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`a study showcasing Ravgen’s ability to use its novel technology to detect Down’s syndrome using
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`free fetal DNA in a maternal blood sample. (Ex. 15 (R. Dhallan et al., A Non-Invasive Test for
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`Prenatal Diagnosis Based on Fetal DNA Present in Maternal Blood: A Preliminary Study, 369
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`THE LANCET 474–81 (2007), https://doi.org/10.1016/S0140-6736(07)60115-9).) Dr. Dhallan’s
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`peers at The Lancet also recognized that his innovative test “opens a new era in prenatal screening.”
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`(See Ex. 16 (A. Benachi & J.M. Costa, Non-Invasive Prenatal Diagnosis of Fetal Aneuploidies,
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`369 THE LANCET 440–42 (2007), https://doi.org/10.1016/S0140-6736(07)60116-0).)
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`23.
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`Dr. Dhallan’s publications received worldwide press coverage, from outlets such
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`as CNN, BBC, and Washington Post. (See Ex. 17 (L. Palmer, A Better Prenatal Test?, CNN
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`MONEY
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`(Sept. 12, 2007), https://money.cnn.com/2007/09/07/smbusiness/amniocentesis
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`.fsb/index.htm); Ex. 18 (Hope for Safe Prenatal Gene Test, BBC NEWS, Feb 2, 2007,
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`7
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`http://news.bbc.co.uk/2/hi/health/6320273.stm); Ex. 19 (A. Gardner, Experimental Prenatal Test
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`Helps Spot Birth Defects, WASH. POST (Feb. 2, 2007), https://www.washingtonpost.com/wp-
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`dyn/content/article/2007/02/02/AR2007020200914.html).)
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`24.
`
`The Patents-in-Suit resulted from Dr. Dhallan’s years-long research at Ravgen to
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`develop these innovative new methods for detecting genetic disorders.
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`PATENTS-IN-SUIT
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`Ravgen incorporates by reference paragraphs 1–24.
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`The ’277 Patent, entitled “Methods For Detection Of Genetic Disorders,” was duly
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`25.
`
`26.
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`and legally issued by the United States Patent and Trademark Office on February 19, 2008. The
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`inventor of the patent is Ravinder S. Dhallan, and the patent is assigned to Ravgen. A copy of the
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`’277 Patent is attached hereto as Exhibit 1.
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`27.
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`Ravgen is the exclusive owner of all rights, title, and interest in the ’277 Patent, and
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`has the right to bring this suit to recover damages for any current or past infringement of the ’277
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`Patent. (See Ex. 3.)
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`28.
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`The ’720 Patent, entitled “Methods For Detection Of Genetic Disorders,” was duly
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`and legally issued by the United States Patent and Trademark Office on June 1, 2010. The inventor
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`of the patent is Ravinder S. Dhallan, and the patent is assigned to Ravgen. A copy of the ’720
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`Patent is attached hereto as Exhibit 2.
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`29.
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`Ravgen is the exclusive owner of all rights, title, and interest in the ’720 Patent, and
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`has the right to bring this suit to recover damages for any current or past infringement of the ’720
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`Patent. (See Ex. 4.)
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`30.
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`The ’277 Patent is directed to, among other things, novel methods used in the
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`detection of genetic disorders. For example, claim 81 of the ’277 Patent recites:
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`8
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`A method for preparing a sample for analysis comprising isolating
`free fetal nucleic acid from a the sample, wherein said sample
`comprises an agent that inhibits lysis of cells, if cells are present,
`and wherein said agent is selected from the group consisting of
`membrane stabilizer, cross-linker, and cell lysis inhibitor.
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`31.
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`The ’720 Patent is directed to novel methods for detecting a free nucleic acid in a
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`sample. For example, claim 1 of the ’720 Patent recites:
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`A method for detecting a free nucleic acid, wherein said method
`comprises: (a) isolating free nucleic acid from a non-cellular
`fraction of a sample, wherein said sample comprises an agent that
`impedes cell lysis, if cells are present, and wherein said agent is
`selected from the group consisting of membrane stabilizer, cross-
`linker, and cell lysis inhibitor; and (b) detecting the presence or
`absence of the free nucleic acid.
`
`32.
`
`The Patents-in-Suit are directed to unconventional, non-routine techniques for
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`preparing and analyzing extracellular circulatory DNA, including for the detection of genetic
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`disorders. The Patents-in-Suit explain that, inter alia, the inventions claimed therein overcame
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`problems in the field—for example, that the low percentage of fetal DNA in maternal plasma
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`makes using the DNA for genotyping the fetus difficult—with a novel and innovative solution—
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`the addition of cell lysis inhibitors, cell membrane stabilizers or cross-linkers to the maternal blood
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`sample, which increase the percentage of cell-free DNA available for detection and analysis:
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`The percentage of fetal DNA in maternal plasma is between 0.39-
`11.9% (Pertl, and Bianchi, Obstetrics and Gynecology 98: 483-490
`(2001)). The majority of the DNA in the plasma sample is
`maternal, which makes using the DNA for genotyping the fetus
`difficult. However, methods that increase the percentage of fetal
`DNA in the maternal plasma allow the sequence of the fetal DNA
`to be determined, and allow for the detection of genetic disorders
`including mutations,
`insertions, deletions, and chromosomal
`abnormalities. The addition of cell lysis inhibitors, cell membrane
`stabilizers or cross-linkers to the maternal blood sample can
`increase the relative percentage of fetal DNA. While lysis of both
`maternal and fetal cells is inhibited, the vast majority of cells are
`maternal, and thus by reducing the lysis of maternal cells, there is a
`relative increase in the percentage of free fetal DNA.
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`9
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`(Ex. 1 (’277 Patent) at 32:24–39; Ex. 2 (’720 Patent) at 33:31–46 (emphases added).)
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`33.
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`The Patents-in-Suit teach that the benefit of Dr. Dhallan’s discovery, an increase in
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`the relative percentage of cell-free DNA, is realized by performance of the claimed method,
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`including through the inclusion of an agent that inhibits the lysis of the cells in a sample:
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`An overall increase in fetal DNA was achieved by reducing the
`maternal cell lysis, and thus, reducing the amount of maternal DNA
`present in the sample. In this example, formaldehyde was used to
`prevent lysis of the cells, however any agent that prevents the lysis
`of cells or increases the structural integrity of the cells can be used.
`Two or more than two cell lysis inhibitors can be used. The increase
`in fetal DNA in the maternal plasma allows the sequence of the fetal
`DNA to be determined, and provides for the rapid detection of
`abnormal DNA sequences or chromosomal abnormalities including
`but not limited to point mutation, reading frame shift, transition,
`transversion, addition, insertion, deletion, addition-deletion, frame-
`shift, missense, reverse mutation, and microsatellite alteration,
`trisomy, monosomy,
`other
`aneuploidies,
`amplification,
`rearrangement,
`translocation,
`transversion, deletion, addition,
`amplification, fragment, translocation, and rearrangement.
`
`(Ex. 1 (’277 Patent) at 91:44–60; Ex. 2 (’720 Patent) at 92:10–26.)
`
`34.
`
`For example, during the prosecution of the ’720 Patent at the Patent and Trademark
`
`Office, Ravgen explained that the innovative concept of using agents that inhibit cell lysis during
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`cell-free DNA detection and analysis is recited by the claimed methods of the ’720 Patent,
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`including in claim 1:
`
`Applicant has discovered that the addition of a cell lysis inhibitor to
`a sample prior to detecting the presence of free nucleic acid can
`significantly and unexpectedly increase the proportion of free
`nucleic acid obtained from the non-cellular fraction of a sample.
`
`* * *
`The methods disclosed in claims 1-8, 21-23, and 26 serve a long-felt
`need in the medical community, and provide unexpected results, and
`are therefore non-obvious.
`
`(Ex. 20 (’720 File History, June 2, 2009 Response to Office Action) at 12, 14 (emphasis added).)
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`10
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`35.
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`The inventive concept of the Patents-in-Suit of including an agent that inhibits cell
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`lysis—for example, a membrane stabilizer, a cross-linker, and/or a cell lysis inhibitor—with a
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`sample represented a significant improvement in the preparation of samples used for non-invasive
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`testing, including non-invasive prenatal testing to unmask previously undetectable fetal genetic
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`traits. At the time of the invention, it would not have been routine or conventional to add an agent
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`that inhibits cell lysis to a sample to increase the proportion of free nucleic acid obtained from the
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`non-cellular fraction of a sample. In fact, as described above, that inventive concept was
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`recognized by Dr. Dhallan’s peers as “an important step in improving detection of cell-free DNA.”
`
`(Ex. 14 at 1137.)
`
`36.
`
`The ’277 Patent is further directed to an unconventional, non-routine method of
`
`detecting fetal chromosomal abnormalities which involves “quantitating a ratio of the relative
`
`amount of alleles in a mixture of maternal DNA and fetal DNA.” (Ex. 21 (’277 File History, May
`
`30, 2007 Response to Office Action) at 30.) For example, claim 1 of the ’277 Patent recites:
`
`A method for detecting the presence or absence of a fetal
`chromosomal abnormality, said method comprising: quantitating a
`ratio of the relative amounts of alleles at a heterozygous locus of
`interest in a mixture of template DNA, wherein said mixture
`comprises maternal DNA and fetal DNA, and wherein said mixture
`of maternal DNA and fetal DNA has been obtained from a sample
`from a pregnant female, and further wherein said heterozygous locus
`of interest has been identified by determining the sequence of alleles
`at the locus of interest, and wherein said ratio indicates the presence
`or absence of a fetal chromosomal abnormality.
`
`37.
`
`The ’277 Patent explains that this claimed method represented a significant
`
`improvement over prior art methods of detecting fetal chromosomal abnormalities, many of which
`
`were costly, time-consuming, and burdensome because they either required the amplification of
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`the entire sequence of a gene, or quantification of the total amount of a particular gene product.
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`(Ex. 1 at 66:14-20.) By contrast, the claimed “ratio” method of the ’277 Patent only requires
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`11
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`sequencing of discrete “loci of interest” (such as “single nucleotide polymorphisms,” or “SNPs”)
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`from the collected DNA sample. (Id. at 34:63-35:37 (“In fact, it is an advantage of the invention
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`that primers that copy an entire gene sequence need not be utilized. . . . There is no advantage to
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`sequencing the entire gene as this can increase cost and delay results. Sequencing only the desired
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`bases or loci of interest maximizes the overall efficiency of the method because it allows for the
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`sequence of the maximum number of loci of interest to be determined in the fastest amount of time
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`and with minimal cost.”); Id. at 35:28-37.)
`
`38.
`
`During the prosecution of the ’277 Patent at the Patent and Trademark Office,
`
`Ravgen gave the following example of an implementation of the claimed “ratio” method:
`
`Applicants have invented a method for detecting the presence or
`absence of a fetal chromosomal abnormality, wherein the method
`comprises, inter alia, quantitating a ratio of the relative amount of
`alleles in a mixture of maternal DNA and fetal DNA.
`
`***
`
`[R]atios were calculated at both chromosomes 13 and 21 in a
`heterogeneous mixture of 75% Down syndrome DNA and 25%
`maternal DNA. Single nucleotide polymorphisms were analyzed
`wherein the maternal genome was homozygous for one allele at a
`specific genetic site and
`the Down syndrome DNA was
`heterozygous at the same genetic site. If at a certain site, the
`maternal genome contains an adenine at both copies of chromosome
`13, and the Down syndrome genome is comprised of one
`chromosome with an adenine nucleotide and one chromosome with
`a guanine nucleotide, then the ratio of G:A is 0.60 (0.75 (Down
`syndrome G allele)/(0.75 Down syndrome A allele + 0.25 + 0.25
`maternal A alleles).
`
`On the other hand, if at a certain genetic site on chromosome 21, the
`maternal genome contains an adenine at both copies of chromosome
`21, and the Down syndrome genome is comprised of two
`chromosome with an adenine nucleotide and one chromosome with
`a guanine nucleotide, then the ratio of G:A is 0.375 (0.75 (Down
`syndrome G allele)/(0.75 Down syndrome A allele + 0.75 Down
`syndrome A allele + 0.25 + 0.25 (maternal A alleles). Thus, the
`methods described in the present application detect chromosomal
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`12
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`abnormalities using a method that comprises, inter alia, quantitating
`a ratio of alleles in a heterogeneous mixture of DNA, wherein the
`ratio represents alleles from more than one individual.
`
`(Ex. 21 (’277 File History, May 30, 2007 Response to Office Action) at 30.)
`
`DEFENDANTS’ INFRINGING ACTIVITIES
`
`39.
`
`Ravgen incorporates by reference paragraphs 1–38.
`
`A.
`
`The Accused Verifi Prenatal Tests
`
`40.
`
`On March 6, 2012, VHI launched the Verifi® Prenatal Test, a commercial non-
`
`invasive prenatal
`
`test for detecting fetal chromosomal abnormalities.
`
` (See Ex. 22
`
`(https://www.medgadget.com/2012/03/verinata-launches-prenatal-to-test-to-detect-down-
`
`syndrome.html).) On January 7, 2013, Illumina announced that it was acquiring VHI for access
`
`to VHI’s Verifi® Prenatal Test, and that the Verifi® Prenatal Test would continue to be offered
`
`through VHI’s CLIA-certified
`
`and CAP-accredited
`
`laboratory.
`
`
`
`(Ex.
`
`23
`
`(https://investor.illumina.com/news/press-release-details/2013/Illumina-Strengthens-Leadership-
`
`Position-in-Reproductive-Health-withAgreement-to-Acquire-Verinata-Health-Inc/default.aspx).)
`
`In 2017, Defendants began providing the Verifi® Plus Prenatal Test. (See Ex. 24 (Illumina, Inc.
`
`v. Natera, Inc., Case No. 3:18-cv-01662-SI, D.I. 63 at 5 (N.D. Cal. Sep. 6, 2018)).) The Verifi®
`
`Plus Prenatal Test contains everything in the Verifi® Prenatal Test and includes additional panels.
`
`(Ex.
`
`9
`
`(https://www.illumina.com/clinical/illumina_clinical_laboratory/verifi-prenatal-
`
`tests.html).) Defendants now offer both the Verifi® Prenatal Test and Verifi® Plus Prenatal Test
`
`(collectively the “Verifi Tests”). (Id.)
`
`41.
`
`The Verifi Tests offer “noninvasive prenatal testing (NIPT) based on cell-free DNA
`
`analysis
`
`from
`
`a
`
`maternal
`
`blood
`
`draw.”
`
`
`
`(Ex.
`
`9
`
`(https://www.illumina.com/clinical/illumina_clinical_laboratory/verifi-prenatal-tests.html).)
`
`
`
`13
`
`

`

`Case 1:20-cv-01644-RGA Document 1 Filed 12/03/20 Page 14 of 55 PageID #: 14
`
`42.
`
`The Verifi Tests require samples containing an agent that inhibits cell lysis. For
`
`example, providers of the Verifi Tests list “One Streck BCT tube” or “Streck Cell-Free DNA BCT”
`
`as
`
`the
`
`container
`
`for
`
`the
`
`test
`
`specimen
`
`requirements.
`
`
`
`(See,
`
`e.g., Ex. 25
`
`(https://nslijlab.testcatalog.org/show/VERIFI);
`
`Ex.
`
`26
`
`at
`
`2
`
`(https://www.ntd-
`
`eurofins.com/healthcare-providers/screening-options-overview/prenatal-screening/non-invasive-
`
`prenatal-screening/:http://www.ntd-eurofins.com/wp-content/uploads/2018/12/Verifi-Sample-
`
`Collection-and-Shipping-Instructions_LB-0010.pdf ); Ex. 27 (http://www.viapath.co.uk/news-
`
`and-press/leading-non-invasive-prenatal-test-now-available-through-viapath).)
`
`43.
`
`Illumina-funded scientific articles analyzing the Verifi Tests confirm the use of
`
`Streck Blood Collection Tubes (BCT™) tubes to collect samples for the Verifi Tests. (See, e.g.,
`
`Ex. 28 at 376 (Diana W. Bianchi, et al., Fetal Sex Chromosome Testing by Maternal Plasma DNA
`
`Sequencing: Clinical Laboratory Experience and Biology, 125.2 OBSTETRICS & GYENECOLOGY
`
`375, 376 (Feb. 2015), https://doi.org/10.1097/AOG.0000000000000637) (“All testing was
`
`performed on maternal whole blood samples in cell-free DNA BCT™ tubes received at Illumina
`
`within 5 days of the blood draw[.]”) (funded by Illumina)); Ex. 29 at 570 (Tracy Futch, et al.,
`
`Initial Clinical Laboratory Experience in Noninvasive Prenatal Testing for Fetal Aneuploidy from
`
`Maternal Plasma DNA Samples, 33 PRENATAL DIAGNOSTICS 569, 570
`
`(2013),
`
`https://doi.org/10.1002/pd.4123) (“All testing was performed on maternal whole‐blood samples
`
`received in cfDNA BCT™ tubes (Streck, Omaha, NE) received within 5 days from blood draw[.]”)
`
`(funded by VHI); Ex. 30 at 16 (Jay Stoerker, et al., On the Importance of Clinical Follow-up in
`
`The Establishment of Non-Invasive Prenatal Testing (NIPT) for Laboratory Developed Tests, MOJ
`
`PROTEOMICS & BIOINFORMATICS 14, 16 (2017), https://doi.org/10.15406/mojpb.2017.05.00147);
`
`Ex. 31 at 151 (Ioanna Kotsopoulou et al., Non-invasive Prenatal Testing (NIPT): Limitations on
`
`
`
`14
`
`

`

`Case 1:20-cv-01644-RGA Document 1 Filed 12/03/20 Page 15 of 55 PageID #: 15
`
`the Way to Become Diagnosis, 2 DE GRUYTER 141, https://doi.org/10.1515/dx-2015-0002
`
`(describing NIPT tests, including Verifi, as “usually performed on maternal blood drawn in
`
`specific [circulating cell-free fetal DNA] BCT tubes (Streck) because they have been proved [sic]
`
`to minimize increases in background DNA levels caused by temperature fluctuations or agitation
`
`that can occur during blood sample storage and shipping”).)
`
`44.
`
`The Streck Cell-Free DNA Blood Collection Tube (“BCT”) includes an agent that
`
`inhibits cell lysis. A Streck Cell-Free DNA BCT “stabilizes nucleated blood cells. The unique
`
`preservative limits the release of genomic DNA, allowing isolation of high-quality cell-free
`
`DNA. Cell-Free DNA BCT has also been demonstrated to minimize the degradation of circulating
`
`tumor cells (CTCs). By limiting cell lysis, the specialized chemistry provides sample integrity
`
`during storage, shipping and handling of blood samples. Cell-free DNA and gDNA are stable for
`
`up to 14 days at 6 °C to 37 °C. CTCs are stable for up to 7 days at 15 °C to 30 °C.” (Ex. 32 at 2
`
`(https://www.streck.com/products/stabilization/cell-free-dna-bct/#resources) (emphases added).)
`
`45.
`
`In processing the Verifi Tests, Defendants isolate cell-free DNA from a sample of
`
`maternal blood collected in a Streck Cell-Free DNA BCT and then analyze the isolated fetal cell-
`
`free
`
`DNA
`
`to
`
`detect
`
`chromosomal
`
`abnormalities
`
`as
`
`shown
`
`below:
`
`(Ex.
`
`33
`
`at
`
`6
`
`(https://www.illumina.com/content/dam/illumina-
`
`marketing/documents/clinical/rgh/nipt-verifi-prenatal-test-clinical-evidence-dossier-web.pdf);
`
`see also id. at 7 (“The test process involves [1] collection of blood at clinics and shipment of the
`
`
`
`15
`
`

`

`Case 1:20-cv-01644-RGA Document 1 Filed 12/03/20 Page 16 of 55 PageID #: 16
`
`blood to the testing site, [2] isolation of plasma before cfDNA extraction from the plasma, [3]
`
`preparation of DNA libraries, [4] cluster generation and multiplexed sequencing on an Illumina
`
`NGS machine, [5] processing of sequencing results, which involves sequence alignment to the
`
`human genome and counting of unique tags, [6] sample classification.”); Ex. 28 at 376 (“The data
`
`presented here were collected or generated as part of cell-free DNA testing for fetal aneuploidy in
`
`the Illumina (formerly Verinata Health, Redwood City, CA) noninvasive prenatal testing
`
`laboratory that is accredited by the College of American Pathology and certified by the Clinical
`
`Laboratory Improvements Amendments Act. Sex chromosome aneuploidy