Case 3:21-cv-04062 Document 1 Filed 05/27/21 Page 1 of 23
`
`
`
`
`Saul Perloff (Cal. Bar 157092)
`saul.perloff@nortonrosefulbright.com
`NORTON ROSE FULBRIGHT US LLP
`111 W. Houston Street, Suite 1800
`San Antonio, Texas 78205-3792
`Telephone
`(210) 224-5575
`Telecopier
`(210) 270-7205
`Attorneys for Plaintiff
`GUARDANT HEALTH, INC.
`
`UNITED STATES DISTRICT COURT
`NORTHERN DISTRICT OF CALIFORNIA
`
`Plaintiff,
`
`GUARDANT HEALTH, INC.,
`a Delaware corporation,
`
`
`
`vs.
`
`NATERA, INC.,
`a Delaware corporation,
`
`
`
`Defendant.
`
`Case No. 3:21-cv-04062
`
`ORIGINAL COMPLAINT
`
`JURY TRIAL DEMANDED
`
`Plaintiff Guardant Health, Inc. (“Guardant” or “Plaintiff”) files this Original Complaint
`against Defendant Natera, Inc. (“Natera” or “Defendant”) and in support thereof, alleges as
`follows:
`
`INTRODUCTION
`I.
`This case concerns Plaintiff’s Guardant Reveal™ (“Reveal”) liquid biopsy cancer
`1.
`assay for early-stage colorectal cancer (CRC) patients, and Defendant Natera’s campaign of false
`and misleading advertising directed at this important and innovative diagnostic product. As the
`world’s leading provider of comprehensive circulating tumor DNA (ctDNA) assays for clinical
`use, Guardant’s oncology platform—including its gold-standard Guardant360®, Guardant360®
`CDx, and GuardantOMNI® assays—have helped improve clinical outcomes, while lowering
`healthcare costs, for advanced stage cancer patients around the world.
`
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`Leveraging its patented technology, vast data sets, and advanced analytics,
`2.
`Guardant recently launched Reveal, a plasma-only liquid biopsy test that detects residual and
`recurrent CRC in about 7 days from a simple blood draw. For oncologists, Reveal improves the
`management of early-stage CRC patients by detecting ctDNA in plasma after surgery, enabling
`doctors to identify patients with residual CRC who may benefit from post-surgery chemotherapy
`(adjuvant chemotherapy), months earlier than current standard-of-care tests permit. Reveal is the
`first test for minimal residual disease (MRD) detection that detects ctDNA in the plasma of CRC
`patients following treatment without the need for a tissue sample and sequencing to determine
`the particular mutations that were present in the patient’s tumor. Reveal achieves outstanding
`sensitivity (91%) for predicting recurrence of CRC disease.
`With little or no concern for the CRC patients who could be harmed, Natera has
`3.
`undertaken a campaign of misinformation to convince customers and potential customers,
`including oncologists and other physicians, cancer researchers, health care institutions,
`biopharmaceutical companies, and genetic laboratories, to avoid using Reveal in favor of
`Natera’s own Signatera™ (“Signatera”), a tumor-dependent assay. In its commercial advertising
`and promotion, Natera makes literally false and misleading statements that disparage Guardant’s
`new assay, and falsely asserts that Signatera is superior to Reveal across a variety of metrics,
`including sensitivity,1 failure rate,2 negative predictive value (NPV),3 and Hazard Ratio,4 among
`other categories. These claims are false. Natera combines outright misrepresentations with
`scientifically unfounded comparisons based on cherry-picked metrics, data artifacts, and
`
`
`1 “Sensitivity” refers to the assay’s ability to identify which patients will develop recurrences
`based on MRD detection by ctDNA assay. A higher percentage indicates a test is more sensitive.
`2 “Failure rate” refers to the percentage of time a ctDNA assay fails to provide a result at all,
`whether positive or negative. For any test, a lower failure rate is more desirable.
`3 “NPV” refers to the assay’s ability to correctly predict which patients will subsequently not
`develop a recurrence of CRC (i.e., a “negative” test result means CRC will not recur).
`4 The “Hazard Ratio” refers to a comparison between the recurrence rate over time in CRC
`patients who tested positive for MRD by ctDNA assay, to the recurrence rate in CRC patients
`who tested negative for MRD by ctDNA. A larger hazard ratio suggests that the assay is
`potentially more useful in successfully distinguishing CRC patients whose cancers will or will
`not recur.
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`noncomparable clinical studies to exaggerate the purported benefits of Signatera while
`inaccurately denigrating Reveal. In truth, Reveal has important clinical advantages over
`Signatera—including its superior landmark sensitivity, its availability for patients from whom
`tumor samples are unavailable, and its faster initial turnaround time from sample collection to
`assay results—all of which Natera ignores.
`Guardant seeks to enjoin Natera from continuing to make or disseminate false and
`4.
`misleading statements about the performance of Reveal and Signatera; to require Natera to
`retract, remove, and correct these false and misleading advertising claims; and to recover
`damages and other relief for the harm that Natera has inflicted on Guardant.
`PARTIES
`II.
`Plaintiff Guardant is a Delaware corporation having its principal place of business
`5.
`at 505 Penobscot Dr., Redwood City, California 94063.
`Guardant was founded in 2012 by pioneers in DNA sequencing and cancer
`6.
`diagnostics. Since its inception, Guardant has focused its expertise on the development of liquid
`biopsy assays for cancer. It was the first company to develop and commercialize a
`comprehensive liquid biopsy assay to identify genomic biomarkers for advanced solid tumors
`using cell-free ctDNA, from simple, non-invasive blood draws.
`Today, Guardant is a leading precision oncology company focused on helping
`7.
`conquer cancer globally through the use of its proprietary blood tests, vast data sets, and
`advanced analytics. The Guardant oncology platform leverages its capabilities to drive
`commercial adoption, improve patient clinical outcomes, and lower healthcare costs across all
`stages of the cancer care continuum. Guardant Health has commercially launched the liquid
`biopsy-based Guardant360®, Guardant360® CDx, and GuardantOMNI® tests for advanced
`stage cancer patients, and recently launched its Reveal test for early-stage CRC patients.
`Defendant Natera is a Delaware corporation having its principal place of business
`8.
`at 13011 McCallen Pass, Building A, Suite 100 Austin, Texas 78753, and offices at 201
`Industrial Rd., San Carlos, California 94070. Natera may be served with process by serving a
`copy of this Complaint on its Registered Agent: National Registered Agents, Inc., 1209 Orange
`
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`Street, Wilmington, Delaware 19801.
`Natera markets and sells Signatera, a product it describes as a “personalized,
`9.
`tumor-informed assay optimized to detect circulating tumor DNA (ctDNA) for molecular
`residual disease (MRD) assessment and recurrence monitoring for patients previously diagnosed
`with cancer.” Signatera competes with Reveal in the market for ctDNA assays that can be used
`after surgery on CRC patients, to detect recurrences and evaluate the need for adjuvant
`chemotherapy.
`
`JURISDICTION AND VENUE
`III.
`This is an action for false advertising under Section 43(a) of the Lanham Act, 15
`10.
`U.S.C. § 1125(a); for false advertising in violation of Cal. Bus. & Prof. Code § 17500 et seq.; for
`unlawful trade practices in violation of Cal. Bus. & Prof. Code § 17200 et seq.; and for unfair
`competition in violation of the common law of California and other states in which Defendant is
`conducting its activities.
`This Court has subject matter jurisdiction over this action pursuant to 28 U.S.C.
`11.
`§§ 1331 and 1338 and 15 U.S.C. §§ 1051, et seq.
`This Court has jurisdiction over Plaintiff’s state law claims pursuant to 28 U.S.C.
`12.
`§ 1367 and the doctrine of supplemental jurisdiction.
`The exercise of personal jurisdiction in California is proper both because of
`13.
`Defendant’s ongoing and systematic contact with California and the Northern District of
`California, including its maintenance of a regular place of business in the District, and because
`acts giving rise to Plaintiff’s causes of action have occurred in the Northern District of
`California. Specifically, Natera markets, promotes, advertises, offers for sale, sells, and/or
`distributes Signatera to customers including oncologists and other physicians, cancer researchers,
`health care institutions, biopharmaceutical companies, genetic laboratories, and/or others
`throughout the United States, including in the Northern District of California. Defendant has
`purposefully and voluntarily placed Signatera into the stream of commerce with the expectation
`that this product will be purchased by customers in the Northern District of California.
`Furthermore, Natera falsely and misleadingly advertises Signatera to customers, including
`
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`institutions, pharmaceutical
`oncologists, pathologists, additional physicians, health care
`companies, and/or others throughout the United States, including in the Northern District of
`California.
`14.
`§ 1391.
`
`Venue is proper in the Northern District of California pursuant to 28 U.S.C.
`
`A.
`
`FACTUAL BACKGROUND
`IV.
`Early Identification of At-Risk Patients is a Key to Preventing Recurrence of
`Colorectal Cancer and Prolonging Survival
`
`Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the
`15.
`second leading cause of cancer death in the United States in both men and women. While a
`majority of patients are diagnosed with early-stage disease, nearly a third of patients whose CRC
`spreads into adjacent tissues and lymph nodes will die from their disease within five years.
`Surgery alone is often curative for early-stage CRC, and in later-stage cases,
`16.
`adjuvant chemotherapy after surgery can reduce the risk of recurrence. However, clinicians have
`had very limited means of identifying patients that require adjuvant chemotherapy. Thus, the
`development of effective clinical tests to identify CRC patients with MRD—i.e., a small number
`of CRC cells remaining in the body that can later multiply and cause recurrence of the disease—
`after surgery has long been recognized as a need, to help doctors both identify patients who may
`benefit from additional therapy, and avoid administering unnecessary and toxic treatment to
`patients who will not benefit from it.
`Because residual cancer cells that remain in the body following treatment
`17.
`typically cause no physical signs or symptoms and are present at very low levels that are
`undetectable with standard techniques, detecting and monitoring MRD has required development
`of advanced and highly sophisticated technologies with the requisite precision and sensitivity for
`clinical decision-making. Reveal provides that sophisticated technology.
`B.
`Liquid Biopsy Technology Allows Assessment of MRD by Detecting Circulating
`Tumor DNA in Blood
`
`18.
`
`Human blood contains fragments of DNA that are shed into the bloodstream by
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`dying cells in tissues—including cancers. Such fragments derived from tumor cells are known as
`circulating tumor DNA (ctDNA). This phenomenon led to the development of so-called “liquid
`biopsies” a game-changing technology capable of detecting the presence of cancer in patients by
`detecting ctDNA in their blood, and eventually led to liquid biopsies specifically designed to
`assess MRD following treatment of CRC. Liquid biopsies using simple blood draws offer major
`advantages for identifying MRD, because they are quick, convenient, and minimally invasive,
`and can be easily repeated to monitor for the presence of ctDNA over time.
`However, detecting and characterizing the very low concentrations of ctDNA
`19.
`present in the blood of patients with MRD, and using that information to stratify CRC patients as
`high- or low-risk for recurrence, requires an assay that is both highly sensitive and specific.
`Recognizing this need, Guardant expended substantial resources and time to develop Reveal,
`a clinical blood-based assay to evaluate ctDNA in blood using advanced DNA sequencing
`methods. Launched in February 2021, Reveal is the first commercially available plasma-only
`ctDNA assay, capable of detecting MRD in post-operative CRC patients without the need for
`prior sampling and sequencing of tumor tissue or the time needed to create a new, customized
`test for each new patient.
`20. Most important, Reveal works: Peer-reviewed data published by Parikh et al. in
`the journal Clinical Cancer Research shows that Reveal offers 91% recurrence sensitivity (i.e.,
`ability to identify which patients will recur based on ctDNA detection) and 100% positive
`predictive value5 for recurrence (i.e., all patients Reveal identified as having a “positive” ctDNA
`test result later recurred).
`Natera offers a liquid biopsy MRD assay it calls Signatera, which it launched
`21.
`commercially in 2019. Natera advertises, promotes, markets, and sells Signatera to oncologists
`and other physicians, cancer researchers, health care institutions, biopharmaceutical companies,
`genetic laboratories, and others nationwide, including in California. Unlike Reveal, Signatera is a
`
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`5 Positive predictive value (PPV) refers to the assay’s ability to correctly predict which patients
`will subsequently develop a recurrence of CRC (i.e., “positive” test result means CRC will
`recur).
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`“tumor-informed” (tumor-dependent) assay. It requires initial genomic profiling of tumor tissue
`taken from the individual patient. Information from the tumor tissue is then used to identify a
`panel of tumor-derived mutations specific to that patient, which then can be monitored through
`testing of blood samples collected throughout the patient’s disease course.
`Tumor-dependent assays like Signatera have meaningful drawbacks. Specifically,
`22.
`a significant number of CRC patients—particularly those treated with chemotherapy prior to
`surgery—may not have sufficient samples of tumor tissue to allow initial genomic profiling of
`the tumor. For these patients, a plasma-only ctDNA assay like Reveal provides the only option
`for MRD detection using ctDNA. Furthermore, acquiring sufficient tissue specimens can be
`painful, dangerous, time consuming and create significant delays in MRD testing turnaround
`time. Reveal reduces the time spent waiting for results needed to decide whether high-risk
`patients require adjuvant chemotherapy from approximately three weeks to 7 days. For patients
`with a potentially lethal disease, this reduction in wait time is critical for both outcomes (earlier
`initiation of chemotherapy has been associated with improved outcomes) and for peace of mind.
`Natera’s Advertising Falsely Claims that Signatera is Superior to Reveal, and that
`C.
`Reveal is Unproven and Insensitive
`Fearful that Signatera cannot compete with Reveal and Guardant on the merits,
`23.
`Natera falsely and misleadingly advertises and promotes Signatera in comparison to Reveal. In
`its advertising, Natera deceptively characterizes Reveal as unproven, insensitive, and
`consequently and unfoundedly “detrimental to patients,” while touting Signatera’s supposed
`superiority.
`Natera’s advertising is based on irrelevant metrics, misrepresented data artifacts,
`24.
`and misleading and inapt comparisons, presented in disregard of the actual scientific evidence
`supporting Reveal’s substantial benefits for oncologists and their patients. Carefully timed to
`coincide with the very launch of Reveal, Natera’s false and misleading comparisons of Reveal
`and Signatera have harmed Guardant, and will continue to cause Guardant irreparable harm if
`not stopped.
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`1.
`
`Natera’s Advertising Falsely Claims Signatera Is Superior to Reveal
`
`Shortly after Reveal’s commercial launch in February 2021, Natera began
`25.
`contacting both its and Guardant’s current and potential customers, including leading cancer
`centers like the Mayo Clinic, expressing supposed “concern” about “other laboratories rushing
`into the clinical MRD market and making potentially misleading claims” that Natera asserted
`“may be detrimental to patients.” In a “Dear Colleague” advertisement dated March 2, 2021,
`which, on information and belief, Natera widely emailed to both its and Guardant’s customers
`and potential customers, Natera stated:
`
`Natera is committed to the science and precision of molecular residual disease
`(MRD) testing for improving patient care. We are proud that Signatera data has
`been published or presented from over 2,000 patients across 30+ tumor
`histologies. As this exciting field gains momentum, especially in early-stage
`CRC, there is concern about other laboratories rushing into the clinical MRD
`market and making potentially misleading claims with no peer-reviewed
`evidence, which may be detrimental to patients. As you review the evidence for
`any new MRD test, please keep in mind several minimum requirements for MRD
`product performance and clinical validation
`
`(emphasis in original).
`In the same promotional email, Natera sent these customers and potential
`26.
`customers a slide presentation entitled “Evidence Review: Tumor-informed vs. tumor-naïve
`MRD.” Though not identifying Reveal by name, Natera’s presentation expressly references data
`presented by “Parikh, A. et al.” at the 2020 European Society for Medical Oncology (ESMO)
`conference—a study specifically concerning Reveal. Moreover, Reveal is the only “tumor-naïve”
`(that is, plasma-only) ctDNA assay for detecting MRD in CRC patients available on the market,
`and is also the only ctDNA assay for MRD introduced at or around the time Natera sent this
`presentation.
`
`Natera’s “Evidence Review” falsely criticizes “tumor-naïve methods,” that is,
`27.
`Reveal, as unsupported by “peer-reviewed evidence.” In fact, interim data from the very study
`cited by Natera—Parikh et al.—was peer-reviewed before being published, first as abstract-
`presentations at three separate prestigious scientific meetings (ASCO 2019, ESMO 2019, and
`ESMO 2020), and later as an article in the April 29, 2021 issue of the journal Clinical Cancer
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`Research.
`Natera further erroneously claims that, while Signatera’s “test performance” is
`28.
`“unsurpassed,” Reveal is not only inferior to Signatera, but has “unknown” performance with
`respect to sensitivity and hazard ratios for two of three “time points” that “matter”:
`
`
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`These statements too are false, as explained below. But rather than correcting its
`29.
`falsehoods, Natera repeated and amplified them—repeatedly.
`Shortly after Natera distributed its “Evidence Review,” Parikh et al.’s previously
`30.
`presented data supporting the clinical performance of Reveal, derived from plasma specimens
`from 84 CRC patients undergoing curative intent surgery, was published in the peer-reviewed
`journal Clinical Cancer Research. Nonetheless, Natera renewed and repeated its previous
`criticisms of Reveal on its website, including in a broadly misleading “white paper to learn how
`our
`tumor-informed approach stacks up against a
`tumor naïve assay”
`found at
`https://www.natera.com/wp-content/uploads/2021/05/SGN_WP_Solar_20210503_NAT-
`9000052_FINAL_DWNLD.pdf.
`In its white paper, which Natera publishes on its website to influence customers
`31.
`and potential customers to purchase Signatera rather than Reveal, Natera purports to compare
`“Signatera (tumor informed assay)” to a “Tumor-naïve assay,” that is, plasma-only Reveal, citing
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`data that appear to show—again, falsely—that Reveal is “not validated,” or that Signatera
`significantly outperforms Reveal on every referenced metric, including “Hazard ratios” and
`“Negative predictive value (NPV)”:
`
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`Natera’s white paper further asserts that: “Without the genomic information for
`32.
`each primary tumor, tumor naïve assays are unable to filter out background biological noise from
`CHIP or to avoid tracking driver mutations that may be subjected to selection pressure from
`treatment . . . .” 6 But this is false; Reveal can and does filter out CHIP background noise
`bioinformatically. In fact, data publicly presented in 2018 on a prototype of the Reveal assay
`showed 100% specificity with incorporation of the CHIP filter.
`In May 2021, Natera also published on its public-facing website advertising
`33.
`entitled “Investor presentation,” which purports to compare “Signatera vs. Reveal performance”:
`
`6 “CHIP” refers to clonal hematopoiesis of indeterminate potential—mutations from blood cells
`that can lead to false positive results when testing for MRD.
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`Shortly after posting the May 2021 performance comparison on its website,
`34.
`Natera began disseminating it—repeatedly—to the same customers and potential customers in
`order to tout Signatera’s supposed superiority over Reveal.
`
`Similar to its “Evidence Review” and white paper advertising, Natera’s May 2021
`35.
`performance comparison claims to demonstrate quantitatively that Signatera is superior to
`Reveal across a wide-ranging set of metrics. Here, these metrics purportedly include “pre-
`surgical sensitivity,” “failure rate,” “diagnostic lead time,” 7 “post-surgical” and “serial
`longitudinal” negative predictive value (NPV), and “Hazard Ratio,” among other categories. All
`of this is false and misleading.
`Natera’s Advertising is False and Misleading
`2.
`36.
`In reality, each of Natera’s promotional claims of superiority, including the
`express and implied claims contained in its “Evidence Review,” white paper, and the “Signatera
`vs. Reveal performance comparison” are false and misleading. They also either deceived or are
`likely to deceive oncologists and other physicians, cancer researchers, health care institutions,
`biopharmaceutical companies, and genetic laboratories, and other customers and potential
`
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`7 “Diagnostic lead time” refers to the time between the first MRD detection by ctDNA assay and
`the first confirmation of CRC recurrence by standard radiographic imaging methods. A longer
`diagnostic lead time is generally observed with higher sensitivity tests.
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`customers into believing that Reveal is untested, inaccurate, insensitive, and inferior to Signatera.
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`Any valid comparison between diagnostic tests, including ctDNA assays for
`37.
`detecting MRD in CRC patients—and specifically including Signatera and Reveal—must be
`supported by properly designed, head-to-head studies that directly compare the two assays using
`the same test procedures and protocols in the same patient population. Cross-test comparisons,
`especially where the purpose and methodology of the underlying studies differ significantly,
`and/or where the studies are conducted in different patient populations, necessarily lead to a
`misleading apples-to-oranges result that cannot legitimately be used to claim that one test is
`superior to the other.
`To date, no such head-to-head studies involving Signatera and Reveal and using
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`the same test protocol and study population are available. Instead, Natera’s purported
`comparisons of the “performance” of Signatera vs. Reveal largely rely on data published by
`Parikh et al. concerning Reveal, and data published by Reinert et al. for Signatera. These
`different studies used very different test protocols and analysis methods, and examined very
`different patient populations. Consequently, Natera’s claims of superiority based on these
`improper comparisons are false, misleading, and deceptive.
`In fact, many of Natera’s cherry-picked comparison metrics are unrelated to assay
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`“performance” at all. While Natera touts the number of “patients analyzed” in “published or
`presented studies,” which Natera claims is more than two thousand for Signatera, those numbers
`do not prove the superiority of the clinical performance of one ctDNA assay over another.
`Moreover, the “>2,000” number reported for Signatera is inflated. It double-counts some patients
`whose data were used in more than one published study, and it includes patient populations
`presenting with cancers other than CRC for which Reveal is neither validated nor intended to be
`used.
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`Likewise, Natera claims that Signatera requires only two “blood tubes,” while
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`Reveal requires four. But again, this is not a “performance” metric at all. But even there,
`Natera’s representation that Reveal “requires” 4 tubes is false. Reveal, like Signatera, only
`requires 2 tubes of blood. Unlike Natera, Guardant’s Reveal kit collects 2 additional tubes of
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`blood to provide redundancy in the rare event of an assay failure on the first 2 blood tubes;
`thereby protecting patients from having to provide another blood sample and saving valuable
`time.
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`Finally, “quantitation of ctDNA for monitoring purposes” is an assay feature, not
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`an appropriate measure of assay performance. Natera’s assertions that quantitation, i.e.,
`“quantitative results,” is necessary to achieve good assay performance, or is an “MRD assay
`requirement,” are misleading. This is particularly so in light of the intended use of both the
`Signatera and Reveal assays: to identify CRC patients at increased risk for recurrence of the
`disease. All available evidence shows that the presence of ctDNA—regardless of the quantity—
`indicates a high likelihood of recurrence. As such, the clinical utility of ctDNA quantitation in
`the context of the intended use of the assay is unclear, at best. Natera’s assertion that
`“quantitation is essential for monitoring tumor response during the patient’s treatment,” is
`unsupported by any studies showing that an improvement in patient outcome is achieved by
`knowing or acting on changes in ctDNA quantity during treatment. Because it is wholly
`unsupported, Natera’s claim is false. Signatera’s practice of reporting a “mean tumor molecules
`per mL” value, and Reveal’s choice not to do so, does not represent a performance advantage for
`one over the other.
`is Natera’s
`it
`these false and misleading claims are harmful,
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`misrepresentations concerning Reveal’s actual performance metrics that are the most damaging
`to Guardant and its new assay.
`Failure rate: Natera’s comparison of “failure rate in CRC,” and its claim of
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`Signatera’s superiority over Reveal, are false. As the article published by Parikh et al. in the
`April 29, 2021 issue of Clinical Cancer Research states, this study—which Natera cites as proof
`that Reveal has a “12-14%” failure rate (vs. a “< 3%” rate for Signatera)—relied on banked
`plasma or cell free DNA samples that had input amounts substantially less than recommended.
`Indeed, as Parikh et al. stated explicitly in the cited publication, “the extracted ctDNA quantity or
`quality was below the recommended and optimal input levels for the assay” and “may have
`affected overall performance characteristics.” In point of fact, the actual failure rate of Reveal in
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`patient care testing is less than 1%, better than Signatera’s claimed failure rate of less than 3%.
`Pre-surgical sensitivity: Natera’s claims of Signatera’s superior “pre-surgical
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`sensitivity” (“89-94%” vs. “47%”) is functionally meaningless and highly misleading. Reveal is
`not intended or indicated to be used as a diagnostic tool pre-surgery. And, as an assay that relies
`on the existence of surgically-excised tumor tissue, Signatera cannot be used as a pre-surgical
`diagnostic tool (meaning it has a real-world pre-surgical clinical sensitivity of 0%). Moreover,
`the study Natera cites as the source of this statistic—Parikh et al.—contains a population where
`nearly half (45%) of the study cohort had received chemotherapy prior to surgery and in which
`the pre-surgical sample volumes were far lower than recommended. Such pre-surgical treatment
`suppresses ctDNA, and thus necessarily lowers the ctDNA detection rate and low sample volume
`also can affect assay sensitivity.
`Post-surgical NPV/PPV: Natera’s further comparison of the 30-day post-
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`surgical negative and positive predictive value (NPV/PPV) for Signatera vs. Reveal, (i.e.,
`88%/100% vs. “not reported” or “not validated”), is similarly misleading. For many CRC
`patients, surgery to remove the tumor does not represent the end of the patient’s initial treatment
`regimen; many patients receive adjuvant chemotherapy. While—contrary to Natera’s claim—
`Parikh et al. did report data that could be used to calculate a 30-day post-surgical NPV and PPV
`for Reveal, they did not focus on—nor did they draw conclusions from—data from this
`timepoint. The 30-day post-surgical MRD timepoint is relevant for clinical MRD testing to assist
`with adjuvant therapy decisions during patient care. It is not the appropriate timepoint in an
`observational/retrospective research study to validate certain performance metrics, like PPV or
`NPV, of assays like Signatera or Reveal that are intended t