Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 1 of 39 PageID #: 659
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`
`
`
`C.A. No. 24-687-RGA
`
`JURY TRIAL DEMANDED
`
`)
`)
`)
`)
`)
`)
`)
`)
`)
`
`GUARDANT HEALTH, INC.,
`
`
`
`
`
`TEMPUS AI, INC.,
`
`
`
`
`Plaintiff,
`
`
`
`v.
`
`
`
`Defendant.
`
`
`
`PLAINTIFF’S FIRST AMENDED COMPLAINT FOR PATENT INFRINGEMENT
`
`Plaintiff Guardant Health, Inc. (“Guardant”) files this First Amended Complaint for Patent
`
`Infringement against Defendant Tempus AI, Inc. (“Tempus”) and alleges as follows:
`
`OVERVIEW OF THE ACTION
`
`1.
`
`This action is necessitated by Tempus’s unauthorized use of Guardant’s
`
`groundbreaking, patented innovations in the field of cancer diagnostics. Specifically, this is an
`
`action against Tempus for infringement of Guardant’s U.S. Patent Nos. 11,149,306 (the “’306
`
`Patent”), 9,902,992 (the “’992 Patent”), 10,501,810 (the “’810 Patent”), 10,793,916 (the “’916
`
`Patent”), and 11,643,693 (the “’693 Patent”) (collectively, the “Patents-in-Suit”). Tempus’s
`
`infringement of the Patents-in-Suit has caused and is causing ongoing harm to Guardant. Guardant
`
`brings this suit to stop Tempus’s infringement and enjoin Tempus from practicing Guardant’s
`
`patented inventions. And Tempus must compensate Guardant for the infringement and injury that
`
`has already occurred.
`
`2.
`
`Guardant is a leading precision oncology company dedicated to helping conquer
`
`cancer with data obtained through its proprietary blood tests. Guardant was founded over a decade
`
`ago by Helmy Eltoukhy, Ph.D., and AmirAli Talasaz, Ph.D., pioneers in DNA sequencing and
`
`cancer diagnostics. Since its inception, Guardant has focused its expertise on the development of
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 2 of 39 PageID #: 660
`
`groundbreaking liquid biopsy cancer tests, including Guardant360® CDx, the first FDA-approved
`
`liquid biopsy test. To date, over 500,000 patient samples have been analyzed using Guardant’s
`
`tests.
`
`3.
`
`A liquid biopsy is the sampling and analysis of non-solid biological tissues, such
`
`as a patient’s blood. It is distinct from a conventional biopsy, which involves the removal of tissue
`
`for examination and is often conducted surgically. All cells in the human body contain DNA.
`
`When a person’s organ or tissues suffer from disease such as cancer, the DNA in the cells making
`
`up the organ or tissue may contain biomarkers that indicate the presence of the disease.
`
`Traditionally, a biopsy would need to extract cells from a particular organ or tissues of interest.
`
`The DNA from those cells would then be analyzed for biomarkers.
`
`4.
`
`But pieces of DNA originating from cells in many different organs and tissues also
`
`circulate freely in the human bloodstream. These DNA fragments circulating in the bloodstream
`
`are known as “cell-free DNA” or “cfDNA.” A simple, non-invasive blood draw can capture cell-
`
`free DNA originating from cells in many different organs and tissues all at once. That DNA can
`
`then be analyzed for relevant biomarkers indicating the presence of disease. But using cell-free
`
`DNA in the bloodstream to look for biomarkers raises substantial complexity and problems. A
`
`traditional biopsy provides a very large sample of DNA from a particular type of cell. With cell-
`
`free DNA, very small numbers of DNA fragments originating from the cells of interest may be
`
`present, mixed in with very large numbers of DNA fragments from many other cells.
`
`5.
`
`Guardant is a pioneer in the field and solved many of the problems critical to
`
`unlocking the use of cell-free DNA to detect cancer and other disease in the blood. For example,
`
`Guardant was one of the first companies to commercialize a comprehensive liquid biopsy test to
`
`identify genomic biomarkers. Guardant’s liquid biopsy technology enables patients, including
`
`2
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 3 of 39 PageID #: 661
`
`those who are ineligible for traditional tissue biopsies, to obtain detailed genomic information
`
`about their cancer. Guardant’s technology also allows patients to be screened for a large number
`
`of potential cancers or diseases that may be present in different parts of the body, all with a simple
`
`blood draw.
`
`6.
`
`For example, the Guardant360® CDx test is a liquid biopsy test that provides
`
`clinically actionable information from a routine blood draw taken from cancer patients. From the
`
`extracted cell-free DNA, the test sequences a panel of genes commonly mutated in cancer and
`
`detects genetic aberrations such as single nucleotide variants, indels (insertions or deletions of
`
`nucleotides), gene fusions, and copy number variants.
`
`7.
`
`In addition to the FDA-approved Guardant360® CDx test, Guardant currently offers
`
`six other tests: the Guardant360® laboratory developed test (LDT), the Guardant360 Response™,
`
`Guardant360 TissueNext™, Guardant Infinity™, Guardant Reveal™, and Shield™ tests. These tests
`
`span the cancer care continuum, including early cancer screening, treatment selection, and residual
`
`disease and recurrence monitoring.
`
`8.
`
`Guardant’s liquid biopsy technology has several additional advantages when
`
`compared to traditional tissue biopsies. Traditional tumor-based genotyping tests are limited in
`
`the number of genes interrogated, require invasive biopsies, and often take upwards of 15 days
`
`before results are generated. Guardant’s liquid biopsies are less painful and do not require hospital
`
`services. This technology is also less expensive and generates results in a shorter period of time,
`
`often in less than a week. Further, cfDNA samples allow for the detection of mutations that may
`
`be missed by a tissue biopsy sample.
`
`9.
`
`Guardant’s technology is built on a series of cutting-edge innovations that
`
`Guardant’s scientists developed over many years and at great cost through an extensive research
`
`3
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 4 of 39 PageID #: 662
`
`and development program. Those innovations are protected by over 95 patents issued by the
`
`United States Patent and Trademark Office, including the Patents-in-Suit. These patents were
`
`issued in recognition of the novelty and usefulness of Guardant’s patents.
`
`10.
`
`Tempus was founded in 2015. Since its inception, Tempus has capitalized on
`
`Guardant’s pioneering efforts to develop copy-cat cell-free DNA liquid biopsy tests. Tempus was
`
`formerly known as Tempus Labs, Inc.
`
`11.
`
`Tempus makes, markets, and uses liquid biopsy panels in ways that practice
`
`Guardant’s Patents-In-Suit. One such category of liquid biopsy panels includes products known
`
`as Tempus xF, Tempus xF+, and Tempus xM Monitor. These panels, and others that may function
`
`in relevantly similar ways, will be referred to as the “Accused xF Tests.” More recently, Tempus
`
`has developed a second generation of liquid tests known as Tempus xM MRD. The Tempus xM
`
`MRD will be referred to as the “Accused xM Tests.” Together, the Accused xF Tests and the
`
`Accused xM Tests will be referred to collectively as the “Accused Tests.”
`
`12.
`
`On information and belief, Tempus has been monitoring Guardant’s intellectual
`
`property portfolio while making the Accused Tests. For example, in Tempus’s S-1 filing dated
`
`May 20, 2024,1 Tempus stated the following:
`
`the next generation
`in
`landscape
`intellectual property
`The
`sequencing, generative AI, and other fields in which we operate
`continues to evolve in ways that may impact our business. For
`example, we are aware of patent litigation involving certain
`disciplines in which we operate, such as liquid biopsy sequencing
`methods and minimal residual disease testing methods. While we
`are not a party to these suits, many of our competitors are or have
`been, including Guardant Health, Inc., Haystack Oncology, Inc.,
`Invitae Corp.,
`Illumina,
`Inc., Natera,
`Inc., NeoGenomics
`Laboratories, Inc., Personalis, Inc., TwinStrand Biosciences, Inc.,
`and others, and, as a result, we have monitored and continue to
`
`1 Available at
`https://www.sec.gov/Archives/edgar/data/1717115/000119312524142956/d221145ds1.htm
`
`
`
`4
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 5 of 39 PageID #: 663
`
`monitor their developments and their potential impact on the
`Company. Given the uncertainty of outcomes of patent litigation
`disputes, we have not determined whether our products and services
`could be subject to potential claims of patent infringement based on
`the patents at issue in these or other cases, whether we may need to
`modify or change any existing or planned sequencing procedures, or
`whether any of the patents at issue are valid or enforceable against
`us. However, it is possible that we will be subject to claims of patent
`infringement and that we may need to either modify our existing or
`future sequencing methods or license intellectual property from
`third parties, both of which could be time consuming and expensive.
`
`13.
`
`As shown above, Tempus “monitored and continue[s] to monitor” patent litigation
`
`involving Guardant and the potential impact of Guardant’s patents on Tempus. Tempus also
`
`understands that because of Guardant’s intellectual property, Tempus may need to “modify [its]
`
`existing or future sequencing methods.”
`
`14.
`
`Tempus has achieved market success with its Accused Tests. But, as described
`
`below, that success derives from Tempus’s unauthorized use of Guardant’s pioneering inventions.
`
`THE PARTIES
`
`15.
`
`Guardant is a corporation organized and existing under the laws of the state of
`
`Delaware, having its principal place of business at 3100 Hanover Street, Palo Alto, CA 94034.
`
`16.
`
`Tempus is a corporation organized and existing under the laws of the state of
`
`Delaware. Its principal place of business is 600 West Chicago Avenue, Suite 510, Chicago, Illinois
`
`60654.
`
`JURISDICTION AND VENUE
`
`17.
`
`This civil action arises under the patent laws of the United States, 35 U.S.C. § 1 et
`
`seq., including without limitation 35 U.S.C. §§ 271, 281, 283, 284, and 285. Accordingly, this
`
`Court has subject matter jurisdiction under, inter alia, 28 U.S.C. §§ 1331, 1338(a), 2201 and 2202.
`
`This Court has personal jurisdiction over Tempus because Tempus is subject to general and
`
`5
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 6 of 39 PageID #: 664
`
`specific jurisdiction in the state of Delaware. Tempus is subject to personal jurisdiction at least
`
`because Tempus is a Delaware corporation and resides in this District. Tempus has made certain
`
`minimum contacts with Delaware such that the maintenance of this suit does not offend traditional
`
`notions of fair play and substantial justice.
`
`18.
`
`The exercise of personal jurisdiction comports with Tempus’s right to due process
`
`because, as described above, Tempus has purposefully availed itself of the privilege of Delaware
`
`corporate laws such that it should reasonably anticipate being haled into court here.
`
`19.
`
`Venue is proper in this District pursuant to 28 U.S.C. §§ 1391 and 1400(b) because,
`
`among other things, Tempus is incorporated in Delaware.
`
`THE GUARDANT PATENTS-IN-SUIT
`
`20.
`
`On October 19, 2021, the United States Patent and Trademark Office lawfully
`
`issued U.S. Patent No. 11,149,306, entitled “Methods and systems for detecting genetic variants.”
`
`A true and correct copy of the patent is attached hereto as Exhibit A. Guardant is the owner and
`
`assignee of all right, title, and interest in and to the ’306 Patent, including the right to assert all
`
`causes of action arising under the ’306 Patent and the right to sue and obtain any remedies for past,
`
`present, or future infringement.
`
`21.
`
`On February 27, 2018, the United States Patent and Trademark Office lawfully
`
`issued U.S. Patent No. 9,902,992, entitled “Systems and methods to detect rare mutations and copy
`
`number variation.” A true and correct copy of the patent is attached hereto as Exhibit B. Guardant
`
`is the owner and assignee of all right, title, and interest in and to the ’992 Patent, including the
`
`right to assert all causes of action arising under the ’992 Patent and the right to sue and obtain any
`
`remedies for past, present, or future infringement.
`
`6
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 7 of 39 PageID #: 665
`
`22.
`
`On December 10, 2019, the United States Patent and Trademark Office lawfully
`
`issued U.S. Patent No. 10,501,810, entitled “Systems and methods to detect rare mutations and
`
`copy number variation.” A true and correct copy of the patent is attached hereto as Exhibit C.
`
`Guardant is the owner and assignee of all right, title, and interest in and to the ’810 Patent,
`
`including the right to assert all causes of action arising under the ’810 Patent and the right to sue
`
`and obtain any remedies for past, present, or future infringement.
`
`23.
`
`On October 6, 2020, the United States Patent and Trademark Office lawfully issued
`
`U.S. Patent No. 10,793,916, entitled “Methods and systems for detecting genetic variants.” A true
`
`and correct copy of the patent is attached hereto as Exhibit D. Guardant is the owner and assignee
`
`of all right, title, and interest in and to the ’916 Patent, including the right to assert all causes of
`
`action arising under the ’916 Patent and the right to sue and obtain any remedies for past, present,
`
`or future infringement.
`
`24.
`
`On May 9, 2023, the United States Patent and Trademark Office lawfully issued
`
`U.S. Patent No. 11,643,693, entitled “Compositions and methods for isolating cell-free DNA.” A
`
`true and correct copy of the patent is attached hereto as Exhibit E. Guardant is the owner and
`
`assignee of all right, title, and interest in and to the ’693 Patent, including the right to assert all
`
`causes of action arising under the ’693 Patent and the right to sue and obtain any remedies for past,
`
`present, or future infringement.
`
`TEMPUS’S INFRINGEMENT OF GUARDANT’S PATENTS-IN-SUIT
`
`25.
`
`In or around September 14, 2018, Tempus announced the release of its Tempus xF
`
`liquid biopsy test, describing it as “a non-invasive genomic sequencing panel” that “analyzes 77
`
`genes.” Press Release titled “Tempus Adds Tempus xF, a Liquid Biopsy Assay, to Sequencing
`
`Capabilities press release,” https://www.tempus.com/news/pr/tempus-adds-tempus-xf-a-liquid-
`
`7
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 8 of 39 PageID #: 666
`
`biopsy-assay-to-sequencing-capabilities/ (last visited October 25, 2024). On or around July 12,
`
`2021, Tempus published a press release announcing the results of a validation study purporting to
`
`demonstrate “the reliable analytical performance of the Tempus xF liquid biopsy.” Press release
`
`titled “Tempus xF Liquid Biopsy Assay Demonstrates Extensive Analytical and Clinical Validity
`
`in npj Precision Oncology Study,” https://www.tempus.com/news/pr/tempus-xf-liquid-biopsy-
`
`assay-demonstrates-extensive-analytical-and-clinical-validity-in-npj-precision-oncology-study/
`
`(last visited October 25, 2024).
`
`26.
`
`The validation study for Tempus xF was authored by scientists affiliated with
`
`Tempus, including J. Finkle, and is titled “Validation of a liquid biopsy assay with molecular and
`
`clinical profiling of circulating tumor DNA.” It was published in the Journal of Precision
`
`Oncology on July 2, 2021. On information and belief, this paper describes the methodology that
`
`Tempus uses in its Tempus xF liquid biopsy test. This paper will be referred to as “Finkle” and
`
`attached as Exhibit F.
`
`27.
`
`On or around June 3, 2022, Tempus published a press release announcing the
`
`launch of Tempus xF+, which it described as “a new non-invasive, liquid biopsy panel of 523
`
`genes, focused on pathogenic mutations in cell-free DNA (cfDNA).” Press release titled “Tempus
`
`to
`
`Launch
`
`Largest
`
`Clinically
`
`Available
`
`Liquid
`
`Biopsy
`
`Panel,
`
`xF+,”
`
`https://www.tempus.com/news/pr/tempus-to-launch-largest-clinically-available-liquid-biopsy-
`
`panel-xf/ (last visited October 25, 2024). In this same press release, Tempus stated that it “expects
`
`that the xF+ panel will be the largest clinically available liquid biopsy panel on the market,
`
`covering more genes with single nucleotide variants and indels reported in all genes, plus expanded
`
`coverage of translocations/gene rearrangements, and copy number variants.” On information and
`
`8
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 9 of 39 PageID #: 667
`
`belief, Tempus xF+ and Tempus xF operate in a substantially similar manner, with the largest
`
`difference being the number of genes targeted by each product.
`
`28.
`
`Tempus’s xF liquid biopsy test detects cell-free DNA in blood specimens of
`
`patients with advanced solid tumors. The test is capable of detecting mutations in 105 genes,
`
`including Single Nucleotide Variants (SNVs) and insertions and deletions (INDELs), as well as
`
`Copy Number Gains (CNGs) in 6 genes, and gene rearrangements in 7 genes. The test covers
`
`recurrent hotspot mutations in 70 genes. Microsatellite Instability High (MSI-H) status is also
`
`reported when detected. Blood Tumor Mutational Burden (bTMB) status is also reported when
`
`detected.
`
` See, e.g., Tempus xF Validation specifications document, available at
`
`https://www.tempus.com/wp-content/uploads/2024/03/Tempus-xF_Validation.pdf.
`
`29.
`
`Tempus’s xF+ test covers clinically relevant exons and select non-coding regions
`
`in 523 genes and is capable of detecting mutations in four variant classes: single nucleotide variants
`
`(SNVs) and insertion-deletions (INDELs) in 523 genes; copy number gains (CNGs) in 7 genes;
`
`and gene rearrangements in 10 genes. Blood Tumor Mutational Burden (bTMB) as well as detected
`
`Microsatellite Instability High (MSI-H) will be reported by the test. See, e.g., Tempus xF+
`
`Validation
`
`specifications
`
`document,
`
`available
`
`at
`
`https://www.tempus.com/wp-
`
`content/uploads/2024/02/Tempus-xFPlus_Validation.pdf.
`
`30.
`
`On or around November 3, 2023, Tempus published a press release announcing the
`
`launch of Tempus xM Monitor (formerly xF Monitor), which it described as “detect[ing] and
`
`monitor[ing] changes in circulating tumor fraction to determine early response to immunotherapy
`
`for patients with advanced cancers.” Press release titled “Tempus Announces New ctDNA Assay,
`
`xM Monitor,” https://www.tempus.com/news/tempus-announces-new-ctdna-assay-xm-monitor/
`
`(last visited October 25, 2024). In this same press release, Tempus stated that “xM Monitor is now
`
`9
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 10 of 39 PageID #: 668
`
`available for research use only for both Tempus’ 105-gene liquid test, xF, and Tempus’ 523-gene
`
`liquid assay, xF+.” The Tempus xM Monitor uses the Tempus xF+ and Tempus xF Tests as inputs.
`
`31.
`
`On information and belief, Tempus performs the xF and xF+ tests at facilities in
`
`the United States on a regular basis. See, e.g., Tempus xF Validation specifications document,
`
`available at https://www.tempus.com/wp-content/uploads/2024/03/Tempus-xF_Validation.pdf.
`
`When using the Accused xF Tests, Tempus obtains samples of cell-free DNA from subjects. The
`
`cell-free DNA is ligated to adapters, including ligating unique molecular identifiers (UMIs) to the
`
`ends of each cell-free DNA fragment, with these UMIs including 96 different pairs of barcodes.
`
`On information and belief, Tempus uses a quantity of adapters having a number of moles more
`
`than ten times the number of moles of cell-free DNA in the sample, and these adapters are ligated
`
`to the cell-free DNA with an efficiency of 20 percent or more.
`
`32.
`
`Subsequent to ligating the adapters to a cell-free DNA sample, Tempus amplifies
`
`and sequences the ligated cell-free DNA to generate sequence reads. Tempus maps the sequence
`
`reads to a reference sequence. Tempus groups these reads into families based on the barcodes
`
`(UMIs) as well as the alignment of the sequence reads to the reference sequence. Families are
`
`then collapsed into consensus sequences, each representing a unique sequence read corresponding
`
`to the sequence of an original cell-free DNA fragment. Reads failing to meet a set accuracy,
`
`quality score, or mapping score threshold are filtered out.
`
`33.
`
`The consensus sequence reads are then used to determine the presence of genetic
`
`variants including copy number variations (CNVs), rearrangements, insertions, deletions,
`
`microsatellite instabilities (MSIs), single nucleotide variations (SNV), and gene fusions.
`
`34.
`
`On or around January 18, 2024, Tempus published a press release announcing the
`
`launch of Tempus xM MRD, which it described as a process to “Assess Minimal Residual
`
`10
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 11 of 39 PageID #: 669
`
`Disease.” Press release titled “Tempus Introduces xM MRD to Assess Minimal Residual Disease
`
`(MRD)
`
`in Patients with Colorectal Cancer
`
`(CRC)
`
`for Research Use Only,”
`
`https://www.tempus.com/news/tempus-introduces-xm-to-assess-minimal-residual-disease-mrd-
`
`in-patients-with-colorectal-cancer-crc-for-research-use-only/ (last visited October 25, 2024). In
`
`this same press release, Tempus stated that the xM MRD “assay delivers a binary MRD assessment
`
`based on both methylation and genomic variant MRD classifiers+.” On information and belief,
`
`Tempus performs the xM MRD tests at facilities in the United States on a regular basis. On
`
`information and belief, when using the xM MRD Test, Tempus performs steps substantially similar
`
`to the steps performed with the tests used in the Tempus xF+ and Tempus xF Tests, and Tempus
`
`also analyses consensus sequences generated from the test to detect methylation profiles including
`
`at least the detection of methylation.
`
`FIRST COUNT
`(Infringement of ’306 Patent) (All Accused Tests)
`
`35.
`
`Guardant repeats and re-alleges the foregoing paragraphs as if set forth specifically
`
`herein.
`
`36.
`
`37.
`
`The claims of the ’306 Patent are valid and enforceable.
`
`The claims of the ’306 Patent are directed to patentable subject matter. The ’306
`
`Patent is directed to new techniques for detecting genetic variants such as copy number variations
`
`associated with a particular disease in cell free DNA for early disease detection. ’306 Patent at
`
`Abstract.
`
`38.
`
`Disorders that are caused by rare genetic mutations (e.g., sequence variations) or
`
`changes in epigenetic markers, such as cancer and partial or complete aneuploidy, may be detected
`
`or more accurately characterized with DNA sequence information. Id. at 1:26-30. Early detection
`
`and monitoring of genetic diseases are useful and needed to successfully treat or manage a disease.
`
`11
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 12 of 39 PageID #: 670
`
`In the prior art, methods were developed to estimate copy number variations, but those methods
`
`involve preparing a sample by converting the original nucleic acids into a sequenceable library,
`
`followed by massively parallel sequencing, and then conducting a bioinformatic analysis to
`
`estimate the copy number variation at one or more loci. Id. at 1:51–55. The ’306 patent states that
`
`although known methods for detecting cfDNA could reduce the errors introduced by the sample
`
`preparation and sequencing processes for the molecules that are converted and sequenced, these
`
`methods are not able to infer the counts of molecules that were converted, but not sequenced. Id.
`
`at 1:59–63. The ’306 patent states this inability to count converted but unsequenced molecules
`
`“can dramatically and adversely affect the sensitivity that can be achieved.” Id. at 1:63–67.
`
`39.
`
`The ’306 Patent claims solve these deficiencies in the prior art by describing an
`
`innovative technique for sequencing and analyzing cell free DNA samples, including a new
`
`technique for tagging physical DNA strands and estimating the number of unseen molecules using
`
`a specific number of different combinations of molecular barcodes for tagging and using a mean
`
`of an expected number of duplicate molecules in a sample population.
`
`40.
`
`The ’306 patent thus provides a new and unconventional way of sequencing and
`
`analyzing DNA samples not found in the prior art. For example, the ’306 patent describes tagging
`
`and counting both halves of double-stranded DNA and estimating the number of unseen molecules
`
`based on the number of pairs (i.e., molecules where both strands were identified) and singlets (i.e.,
`
`molecules where only one strand was identified) detected in a particular region. See id. at 2:1-18.
`
`41.
`
`The asserted claims describe innovations for reducing or tracking redundancy of
`
`sequence reads for genetic testing by, inter alia, an unconventional method involving non-unique
`
`duplex tagging to infer information about DNA. See, e.g., ’306 Patent at cls. 1-29.
`
`42.
`
`Independent Claim 1 of the ’306 Patent, for example, recites:
`
`12
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 13 of 39 PageID #: 671
`
`1. A method, comprising:
`
`(a) providing a population of cell-free deoxyribonucleic acid
`(cfDNA) molecules having first and second complementary strands;
`
`(b) tagging a plurality of the cfDNA molecules in the population
`with duplex tags comprising molecular barcodes to produce tagged
`parent polynucleotides, wherein the duplex tags are attached to both
`ends of a molecule of the plurality of the cfDNA molecules, wherein
`the plurality of the cfDNA molecules are tagged with n different
`combinations of molecular barcodes, wherein n is at least 2 and no
`more than 100,000*z, wherein z is a mean of an expected number of
`duplicate molecules in the population of cfDNA molecules that map
`to identical start and stop positions on a reference sequence;
`
`(c) amplifying a plurality of the tagged parent polynucleotides to
`produce amplified progeny polynucleotides;
`
`(d) sequencing at least a subset of the amplified progeny
`polynucleotides to produce a set of sequence reads; and
`
`(e) reducing or tracking redundancy of a plurality of sequence reads
`from the set of sequence reads using at least sequencing information
`from the molecular barcodes of the duplex tags to determine distinct
`cfDNA molecules from among the tagged parent polynucleotides,
`wherein the distinct cfDNA molecules are determined based on (i)
`paired reads corresponding to sequence reads generated from a first
`tagged strand and a second tagged complementary strand derived
`from cfDNA molecules
`from among
`the
`tagged parent
`polynucleotides, or (ii) unpaired reads corresponding to sequence
`reads generated from a first tagged strand having no second tagged
`complementary strand derived from cfDNA molecules from among
`the tagged parent polynucleotides, wherein reducing or tracking the
`redundancy of the plurality of sequence reads comprises mapping at
`least a subset of the plurality of sequence reads to the reference
`sequence.
`
`43.
`
`The innovations in the ’306 Patent claims were not conventional, well-understood,
`
`or routine. Indeed, the U.S. Patent and Trademark Office (“USPTO” or “Patent Office”) found
`
`the ’306 Patent claims patentable over certain prior art. Ex. L. As one example, the USPTO found
`
`the ’306 Patent’s innovations include the claim element found in claim 1 and its dependent claims
`
`2-16, 29:
`
`13
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 14 of 39 PageID #: 672
`
`tagging a plurality of cfDNA molecules with duplex tags comprising
`molecular barcodes to produce tagged parent polynucleotides,
`wherein the duplex tags are attached to both ends of a molecule of
`the cfDNA molecules.
`
`44.
`
`According to the USPTO, this claim element, in combination with other elements
`
`recited in the claims, was not present in the cited prior art. See id. at 15-16. It is thus
`
`unconventional, not routine, and not well-understood, including as shown by the USPTO’s
`
`decision.
`
`45.
`
`Furthermore, independent claim 1 and its dependent claims 2-16, 29 recite:
`
`wherein the plurality of the cfDNA molecules are tagged with n
`different combinations of molecular barcodes, wherein n is at least
`2 and no more than 100,000*z, wherein z is a mean of an expected
`number of duplicate molecules in the population of cfDNA
`molecules that map to identical start and stop positions on a
`reference sequence.
`
`This element, in combination with the other elements of the claims, was not present in the prior
`
`art. The USPTO found this innovation is directed to solving a problem of ensuring enough tags to
`
`differentiate “cognates” (i.e., original cfDNA fragments with identical start and stop mappings)
`
`while still allowing use of non-unique tags. The technique of applying between 2 and 100,000*z
`
`different combinations of molecular barcodes for tagging and tracking cfDNA molecules was not
`
`taught in the prior art and improves the functionality of tagging for DNA fragments. See Ex. M
`
`(finding claim reciting similar limitation non-obvious in final written decision), vacated in part on
`
`other grounds sub nom. Guardant Health, Inc. v. Vidal, No. 2021-1104, 2023 U.S. App. LEXIS
`
`11037 (Fed. Cir. May 5, 2023) (vacating finding of obviousness for other claims). It is thus
`
`unconventional, not routine, and not well-understood, including as shown by the USPTO’s
`
`decision.
`
`14
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 15 of 39 PageID #: 673
`
`46.
`
`Even further, the innovations of the ’306 Patent claims involve determining paired
`
`and unpaired molecules. For example, independent claim 1 and its dependent claims 2-16 and 29
`
`involve:
`
`determin[ing] distinct cfDNA molecules from among the tagged
`parent polynucleotides, wherein the distinct cfDNA molecules are
`determined based on (i) paired reads corresponding to sequence
`reads generated from a first tagged strand and a second tagged
`complementary strand derived from cfDNA molecules from among
`the
`tagged parent polynucleotides, or (ii) unpaired reads
`corresponding to sequence reads generated from a first tagged strand
`having no second tagged complementary strand derived from
`cfDNA molecules from among the tagged parent polynucleotides.
`
`’306 Patent at cl. 1 (emphasis added). The claimed determining of paired and unpaired molecules
`
`is unconventional, not routine, and not well-understood in the art, including as shown by the
`
`prosecution history of the ‘306 patent.
`
`47.
`
`As another example, independent claim 17 of the ’306 Patent recites:
`
`17. A method, comprising:
`
`cell-free
`double-stranded
`of
`population
`a
`tagging
`(a)
`deoxyribonucleic acid (cfDNA) molecules obtained or derived from
`a sample of a subject with a set of tags comprising molecular
`barcodes to produce tagged parent polynucleotides;
`
`(b) amplifying a plurality of the tagged parent polynucleotides to
`produce amplified progeny polynucleotides;
`
`(c) sequencing at least a subset of the amplified progeny
`polynucleotides to produce a set of sequence reads; and
`
`(d) sorting a plurality of sequence reads from the set of sequence
`reads into (i) families comprising paired reads corresponding to
`sequence reads generated from a first tagged strand and a second
`tagged complementary strand derived from double-stranded cfDNA
`molecules from among the tagged parent polynucleotides, and (ii)
`families comprising unpaired reads corresponding to sequence
`reads generated from a first tagged strand having no second tagged
`complementary strand derived from double-stranded cfDNA
`molecules from among the tagged parent polynucleotides.
`
`15
`
`

`

`Case 1:24-cv-00687-RGA Document 21 Filed 11/04/24 Page 16 of 39 PageID #: 674
`
`Id. at cl. 17 (emphasis added). The claimed determining of paired and unpaired molecules is
`
`unconventional, not routine, and not well-understood in the art, including as shown by the
`
`prosecution history of the ’306 patent.
`
`48.
`
`Similarly, Claim 17 and its dependent claims 18-28 include the element:
`
`sorting a plurality of sequence reads from the set of sequence reads
`into (i) families comprising paired reads . . . and (ii) families
`comprising unpaired reads.
`
`Id. at 16.
`
`49.
`
`The Patent Office confirmed that detecting paired and unpaired molecules was a
`
`non-obvious technical improvement over the cited prior art. See Ex. L at 15-16, 27. T