Granted Patent
B2
US 12,209,282 · App. 17/316,148 · Granted Jan 28, 2025
Monitoring health and disease status using clonotype profiles
Assignee:
Adaptive Biotechnologies Corporation
C12Q1/6881C12N15/1072C12Q1/6809C12Q1/6827C12Q1/6869C12Q1/6874C12Q1/6883C12Q1/6886C12Q2600/106C12Q2600/118C12Q2600/156C12Q2600/158C12Q2600/16Y02A90/10
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Abstract
There is a need for improved methods for determining the diagnosis and prognosis of patients with conditions, including autoimmune disease and cancer, especially lymphoid neoplasms, such as lymphomas and leukemias. Provided herein are methods for using DNA sequencing to identify personalized, or patient-specific biomarkers in patients with lymphoid neoplasms, autoimmune disease and other conditions. Identified biomarkers can be used to determine and/or monitor the disease state for a subject with an associated lymphoid disorder or autoimmune disease or other condition. In particular, the invention provides a sensitive method for monitoring lymphoid neoplasms that undergo clonal evolutions without the need to development alternative assays for the evolved or mutated clones serving as patient-specific biomarkers.
Claims (24)
1. A method of monitoring a cancer in a patient by one or more patient-specific clonotypes correlated with the cancer, the method comprising the steps of:
(a) amplifying in a multiplex polymerase chain reaction (PCR) recombined nucleic acids comprising complementary determining region 3 (CDR3) sequences from immunoglobulin genes or T cell receptor (TCR) genes from a sample of nucleic acids from B cells and/or T cells obtained from the patient, wherein the sample is from a tissue affected by the cancer;
(b) sequencing the amplified nucleic acids by high-throughput sequencing (HTS) to form a clonotype profile, wherein the clonotype profile comprises at least 10,000 clonotype sequences of 20 to 400 nucleotides in length;
(c) determining from the clonotype profile one or more patient-specific clonotypes correlated with the cancer; and
(d) monitoring a level of the one or more patient-specific clonotypes in one or more samples subsequently obtained from the patient.
2. The method according to claim 1 , wherein the cancer is lymphoid cancer.
3. The method according to claim 2 , wherein the lymphoid cancer is B-cell acute lymphoblastic leukemia (ALL).
4. The method according to claim 3 , wherein step (a) comprises amplifying recombined nucleic acids comprising CDR3 sequences from immunoglobulin genes from a sample comprising B cells obtained from the patient.
5. The method according to claim 4 , wherein the sample comprising B cells obtained from the patient comprises bone marrow.
6. The method according to claim 5 , wherein the recombined nucleic acids comprise VDJ rearrangements of IgH genes, DJ rearrangements of IgH genes, rearrangements of IgK genes, rearrangements of IgL genes, BCL1-IgH translocations, BCL2-IgH translocations, or any combination thereof.
7. The method according to claim 5 , wherein the one or more samples subsequently obtained from the patient comprise one or more bone marrow samples.
8. The method according to claim 5 , wherein the one or more samples subsequently obtained from the patient comprise one or more peripheral blood samples.
9. The method according to claim 2 , wherein the lymphoid cancer is multiple myeloma (MM).
10. The method according to claim 9 , wherein step (a) comprises amplifying recombined nucleic acids comprising CDR3 sequences from immunoglobulin genes from a sample comprising B cells obtained from the patient.
11. The method according to claim 10 , wherein the sample comprising B cells obtained from the patient comprises bone marrow.
12. The method according to claim 11 , wherein the recombined nucleic acids comprise VDJ rearrangements of IgH genes, DJ rearrangements of IgH genes, rearrangements of IgK genes, rearrangements of IgL genes, BCL1-IgH translocations, BCL2-IgH translocations, or any combination thereof.
13. The method according to claim 11 , wherein the one or more samples subsequently obtained from the patient comprise one or more bone marrow samples.
14. The method according to claim 11 , wherein the one or more samples subsequently obtained from the patient comprise one or more peripheral blood samples.
15. The method according to claim 2 , wherein the lymphoid cancer is chronic lymphocytic leukemia (CLL).
16. The method according to claim 15 , wherein step (a) comprises amplifying recombined nucleic acids comprising CDR3 sequences from immunoglobulin genes from a sample comprising B cells obtained from the patient.
17. The method according to claim 16 , wherein the sample comprising B cells obtained from the patient comprises peripheral blood or bone marrow.
18. The method according to claim 17 , wherein the recombined nucleic acids comprise VDJ rearrangements of IgH genes, DJ rearrangements of IgH genes, rearrangements of IgK genes, rearrangements of IgL genes, BCL1-IgH translocations, BCL2-IgH translocations, or any combination thereof.
19. The method according to claim 17 , wherein the one or more samples subsequently obtained from the patient comprise one or more bone marrow samples.
20. The method according to claim 17 , wherein the one or more samples subsequently obtained from the patient comprise one or more peripheral blood samples.
Assignments (2)
SECURITY INTEREST
Recorded Sep 15, 2022
From: ADAPTIVE BIOTECHNOLOGIES CORPORATION
To: ORBIMED ROYALTY & CREDIT OPPORTUNITIES IV, LP
Reel/Frame 061449/0689 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 31, 2021
From: FAHAM, MALEK; WILLIS, THOMAS
To: ADAPTIVE BIOTECHNOLOGIES CORPORATION
Reel/Frame 057343/0404 →
Continuity (13)
Provisional Application
61446822
· Feb 25, 2011
Provisional Application
61455743
· Oct 25, 2010
Provisional Application
61332175
· May 6, 2010
Provisional Application
61112693
· Nov 7, 2008
References Cited (400)
US 5213960A
· Chang
· 1993
[cited by applicant]
US 5296351A
· Morley
· 1994
[cited by applicant]
US 5298396A
· Kotzin et al.
· 1994
[cited by applicant]
US 5326696A
· Chang
· 1994
[cited by applicant]
US 5336598A
· Kotzin et al.
· 1994
[cited by applicant]
US 5418134A
· Morley
· 1995
[cited by applicant]
US 5627037A
· Ward
· 1997
[cited by applicant]
US 5635354A
· Kourilsky et al.
· 1997
[cited by applicant]
US 5635400A
· Brenner
· 1997
[cited by applicant]
US 5667967A
· Steinman et al.
· 1997
[cited by applicant]
US 5741676A
· Fuller
· 1998
[cited by applicant]
US 5776708A
· Kotzin et al.
· 1998
[cited by applicant]
US 5776737A
· Dunn
· 1998
[cited by applicant]
US 5837447A
· Gorski
· 1998
[cited by applicant]
US 5846719A
· Brenner et al.
· 1998
[cited by applicant]
US 5925517A
· Tyagi et al.
· 1999
[cited by applicant]
US 5935793A
· Wong
· 1999
[cited by applicant]
US 5981176A
· Wallace
· 1999
[cited by applicant]
US 6087096A
· Dau et al.
· 2000
[cited by applicant]
US 6091000A
· Haynes
· 2000
[cited by applicant]
US 6172214B1
· Brenner
· 2001
[cited by applicant]
US 6258568B1
· Nyren
· 2001
[cited by applicant]
US 6300070B1
· Boles et al.
· 2001
[cited by applicant]
US 6312690B1
· Edelman et al.
· 2001
[cited by applicant]
US 6416948B1
· Pilarski et al.
· 2002
[cited by applicant]
US 6440706B1
· Vogelstein et al.
· 2002
[cited by applicant]
US 6458530B1
· Morris et al.
· 2002
[cited by applicant]
US 6489103B1
· Griffiths et al.
· 2002
[cited by applicant]
US 6524829B1
· Seegar
· 2003
[cited by applicant]
US 6569627B2
· Wittwer et al.
· 2003
[cited by applicant]
US 6596492B2
· Avery et al.
· 2003
[cited by applicant]
US 6753147B2
· Vogelstein et al.
· 2004
[cited by applicant]
US 6787308B2
· Balasubramanian et al.
· 2004
[cited by applicant]
US 6964850B2
· Bevilacqua
· 2005
[cited by applicant]
US 7068874B2
· Wang et al.
· 2006
[cited by applicant]
US 7112423B2
· Van Ness et al.
· 2006
[cited by applicant]
US 7115400B1
· Adessi et al.
· 2006
[cited by applicant]
US 7157228B2
· Hashmi et al.
· 2007
[cited by applicant]
US 7157274B2
· Bohm et al.
· 2007
[cited by applicant]
US 7208795B2
· Carver et al.
· 2007
[cited by applicant]
US 7232653B1
· Austrup et al.
· 2007
[cited by applicant]
US 7306906B2
· Maruyama et al.
· 2007
[cited by applicant]
US 7313308B2
· Turner et al.
· 2007
[cited by applicant]
US 7323305B2
· Leamon et al.
· 2008
[cited by applicant]
US 7329731B2
· Jakobsen et al.
· 2008
[cited by applicant]
US 7351578B2
· Cheo et al.
· 2008
[cited by applicant]
US 7365179B2
· Brenner
· 2008
[cited by applicant]
US 7371519B2
· Wolber
· 2008
[cited by applicant]
US 7375211B2
· Kou
· 2008
[cited by applicant]
US 7393665B2
· Brenner
· 2008
[cited by applicant]
US 7432084B2
· Shoemaker
· 2008
[cited by applicant]
US 7537897B2
· Brenner et al.
· 2009
[cited by applicant]
US 7544473B2
· Brenner
· 2009
[cited by applicant]
US 8628927B2
· Faham
· 2014
[cited by examiner]
US 8691510B2
· Faham
· 2014
[cited by applicant]
US 8748103B2
· Faham
· 2014
[cited by examiner]
US 8795970B2
· Faham
· 2014
[cited by applicant]
US 9181590B2
· Robins et al.
· 2015
[cited by applicant]
US 9217176B2
· Faham et al.
· 2015
[cited by applicant]
US 9228232B2
· Faham et al.
· 2016
[cited by applicant]
US 9279159B2
· Robins et al.
· 2016
[cited by applicant]
US 9416420B2
· Faham et al.
· 2016
[cited by applicant]
US 9512487B2
· Faham et al.
· 2016
[cited by applicant]
US 9809813B2
· Robins et al.
· 2017
[cited by applicant]
US 20020110807A1
· Pilarski et al.
· 2002
[cited by applicant]
US 20030096277A1
· Chen
· 2003
[cited by applicant]
US 20030120061A1
· Zhang
· 2003
[cited by applicant]
US 20030162197A1
· Morley et al.
· 2003
[cited by applicant]
US 20030207300A1
· Matray et al.
· 2003
[cited by applicant]
US 20040033490A1
· Laird et al.
· 2004
[cited by applicant]
US 20040132050A1
· Monforte
· 2004
[cited by applicant]
US 20040146901A1
· Morris et al.
· 2004
[cited by applicant]
US 20040170977A1
· Laird
· 2004
[cited by applicant]
US 20040248172A1
· Samoszuk et al.
· 2004
[cited by applicant]
US 20050037356A1
· Gullberg et al.
· 2005
[cited by applicant]
US 20050064421A1
· Gehrmann et al.
· 2005
[cited by applicant]
US 20050142577A1
· Jones et al.
· 2005
[cited by applicant]
US 20050250147A1
· Macevicz
· 2005
[cited by applicant]
US 20050255482A1
· Morley et al.
· 2005
[cited by applicant]
US 20050260570A1
· Mao et al.
· 2005
[cited by applicant]
US 20060019304A1
· Hardenbol et al.
· 2006
[cited by applicant]
US 20060020397A1
· Kermani
· 2006
[cited by applicant]
US 20060046258A1
· Lapidus et al.
· 2006
[cited by applicant]
US 20060085139A1
· Collette et al.
· 2006
[cited by applicant]
US 20060088876A1
· Bauer
· 2006
[cited by applicant]
US 20060134125A1
· Luxembourg et al.
· 2006
[cited by applicant]
US 20060147925A1
· Morley et al.
· 2006
[cited by applicant]
US 20060275752A1
· Sindhi
· 2006
[cited by applicant]
US 20060199210A1
· Weichselbaum et al.
· 2006
[cited by applicant]
US 20060211030A1
· Brenner
· 2006
[cited by applicant]
US 20060216737A1
· Bodeau
· 2006
[cited by applicant]
US 20060228350A1
· Wu et al.
· 2006
[cited by applicant]
US 20060233812A1
· Burnie et al.
· 2006
[cited by applicant]
US 20060234234A1
· Van Dongen et al.
· 2006
[cited by applicant]
US 20060259248A1
· Collette et al.
· 2006
[cited by applicant]
US 20060263789A1
· Kincaid
· 2006
[cited by applicant]
US 20070020640A1
· McCloskey et al.
· 2007
[cited by applicant]
US 20070020670A1
· Loken et al.
· 2007
[cited by applicant]
US 20070105105A1
· Clelland et al.
· 2007
[cited by applicant]
US 20070117134A1
· Kou
· 2007
[cited by applicant]
US 20070160994A1
· Lim et al.
· 2007
[cited by applicant]
US 20070161001A1
· Leshkowitz
· 2007
[cited by applicant]
US 20070172873A1
· Brenner et al.
· 2007
[cited by applicant]
US 20070238099A1
· Cohen et al.
· 2007
[cited by applicant]
US 20070243564A1
· Lawson et al.
· 2007
[cited by applicant]
US 20070286849A1
· Chaturvedi
· 2007
[cited by applicant]
US 20080050780A1
· Lee et al.
· 2008
[cited by applicant]
US 20080069770A1
· Hercend et al.
· 2008
[cited by applicant]
US 20080108509A1
· Haupl et al.
· 2008
[cited by applicant]
US 20080166704A1
· Marche et al.
· 2008
[cited by applicant]
US 20080166718A1
· Lim et al.
· 2008
[cited by applicant]
US 20080199916A1
· Zheng et al.
· 2008
[cited by applicant]
US 20080248484A1
· Bauer
· 2008
[cited by applicant]
US 20080274904A1
· Gormley et al.
· 2008
[cited by applicant]
US 20090197257A1
· Harris
· 2009
[cited by applicant]
US 20090253581A1
· Van Eijk et al.
· 2009
[cited by applicant]
US 20100151471A1
· Faham et al.
· 2010
[cited by applicant]
US 20140194295A1
· Robins et al.
· 2014
[cited by applicant]
US 20140206548A1
· Robins et al.
· 2014
[cited by applicant]
US 20140206549A1
· Robins et al.
· 2014
[cited by applicant]
US 20140213463A1
· Robins et al.
· 2014
[cited by applicant]
US 20140221220A1
· Robins et al.
· 2014
[cited by applicant]
US 20140256567A1
· Robins et al.
· 2014
[cited by applicant]
US 20150299785A1
· Livingston et al.
· 2015
[cited by applicant]
US 20170335386A1
· Livingston et al.
· 2017
[cited by applicant]
US 20180023143A9
· Faham et al.
· 2018
[cited by applicant]
CN 101225441A
· 2008
[cited by applicant]
CN 102272327A
· 2011
[cited by applicant]
EP 0303459A2
· 1989
[cited by applicant]
EP 0799897A1
· 1997
[cited by applicant]
EP 1544308A1
· 2005
[cited by applicant]
EP 1549764B1
· 2005
[cited by applicant]
EP 0972081B1
· 2007
[cited by applicant]
EP 2062982A1
· 2009
[cited by applicant]
EP 2088205A1
· 2009
[cited by applicant]
EP 2364368B1
· 2014
[cited by applicant]
JP 4262799A
· 1992
[cited by applicant]
JP 2002503954A
· 2001
[cited by applicant]
JP 2005245381A
· 2005
[cited by applicant]
JP 2006501842A
· 2006
[cited by applicant]
JP 2007515955A
· 2007
[cited by applicant]
JP 2007536939A
· 2007
[cited by applicant]
JP 2008099588A
· 2008
[cited by applicant]
WO WO1993001838A1
· 1993
[cited by applicant]
WO WO1995028481A1
· 1995
[cited by applicant]
WO WO1997013868A1
· 1997
[cited by applicant]
WO WO1997013877A1
· 1997
[cited by applicant]
WO WO1997018330A1
· 1997
[cited by applicant]
WO WO1997046706A1
· 1997
[cited by applicant]
WO WO1998001738A2
· 1998
[cited by applicant]
WO WO1998044151A1
· 1998
[cited by applicant]
WO WO1999019717A1
· 1999
[cited by applicant]
WO WO1999020798A1
· 1999
[cited by applicant]
WO WO2002024322A2
· 2002
[cited by applicant]
WO WO2003008624A2
· 2003
[cited by applicant]
WO WO2003044225A2
· 2003
[cited by applicant]
WO WO2003052101A1
· 2003
[cited by applicant]
WO WO2003059155A2
· 2003
[cited by applicant]
WO WO2004003820A2
· 2004
[cited by applicant]
WO WO2004033728A2
· 2004
[cited by applicant]
WO WO2004034031A2
· 2004
[cited by applicant]
WO WO2004044209A1
· 2004
[cited by applicant]
WO WO2004046098A2
· 2004
[cited by applicant]
WO WO2004063706A2
· 2004
[cited by applicant]
WO WO2004096985A2
· 2004
[cited by applicant]
WO WO2005003375A2
· 2005
[cited by applicant]
WO WO2005005651A2
· 2005
[cited by applicant]
WO WO2005042774A2
· 2005
[cited by applicant]
WO WO2005053603A2
· 2005
[cited by applicant]
WO WO2005056828A1
· 2005
[cited by applicant]
WO WO2005059176A1
· 2005
[cited by applicant]
WO WO2005056828
· 2005
[cited by examiner]
WO WO2005084134A2
· 2005
[cited by applicant]
WO WO2005111242A2
· 2005
[cited by applicant]
WO WO2005113803A1
· 2005
[cited by applicant]
WO WO2006076025A2
· 2006
[cited by applicant]
WO WO2006076205A2
· 2006
[cited by applicant]
WO WO2006110855A2
· 2006
[cited by applicant]
WO WO2006116155A2
· 2006
[cited by applicant]
WO WO2006138284A2
· 2006
[cited by applicant]
WO WO2007134220A2
· 2007
[cited by applicant]
WO WO2008026927A2
· 2008
[cited by applicant]
WO WO2008039694A2
· 2008
[cited by applicant]
WO WO2008108803A2
· 2008
[cited by applicant]
WO WO2009095567A2
· 2009
[cited by applicant]
WO WO2010053587A2
· 2010
[cited by applicant]
WO WO2010151416A1
· 2010
[cited by applicant]
WO WO2011106738A2
· 2011
[cited by applicant]
WO WO2011139371A1
· 2011
[cited by applicant]
WO WO2011139372A1
· 2011
[cited by applicant]
Campana, (2003) “Determination of Minimal Residual Disease in Leukaemia Patients.” British Journal of Haematology, vol. 121, No. 6, pp. 823-838.
[cited by applicant]
Cavé et al., (1994) “Prospective Monitoring and Quantitation of Residual Blasts in Childhood Acute Lymphoblastic Leukemia by Polymerase Chain Reaction Study of δ and γ T-cell Receptor Genes.” Blood, vol. 83, No. 7, pp. …
[cited by applicant]
Haynes, (2010) “Move Over, GA: Illumina's HiSeq 2000 Increases Output to 200 GB Per Run.” 5 pages.
[cited by applicant]
Karow, (2010) “Illumina Demonstrates 350 GB Run on HiSeq 2000; Shows Sequencing Apps for New Instrument.” 6 pages.
[cited by applicant]
Ley et al., (2008) “DNA Sequencing of a Cytogenetically Normal Acute Myeloid Leukaemia Genome.” Nature, vol. 456, No. 7218, pp. 66-72.
[cited by applicant]
Morley et al., (2009) “Sensitive and Specific Measurement of Minimal Residual Disease in Acute Lymphoblastic Leukemia.” The Journal of Molecular Diagnostics, vol. 11, No. 3, pp. 201-210.
[cited by applicant]
Mortazavi et al., (2008) “Mapping and Quantifying Mammalian Transcriptomes by RNA-Seq.” Nature Methods, vol. 5, No. 7, pp. 621-628.
[cited by applicant]
Nakao et al., (2000) “Rapid and Reliable Quantification of Minimal Residual Disease in Acute Lymphoblastic Leukemia Using Rearranged Immunoglobulin and T-Cell Receptor Loci by Lightcycler Technology.” Cancer Research, v…
[cited by applicant]
Pickrell et al., (2010) “Understanding Mechanisms Underlying Human Gene Expression Variation with RNA Sequencing.” Nature, vol. 464, No. 7289, pp. 768-772.
[cited by applicant]
Pongers-Willemse et al., (1999) “Primers and Protocols for Standardized Detection of Minimal Residual Disease in Acute Lymphoblastic Leukemia Using Immunoglobulin and T Cell Receptor Gene Rearrangements and TAL1 Deletio…
[cited by applicant]
Wilhelm et al., (2008) “Dynamic Repertoire of a Eukaryotic Transcriptome Surveyed at Single-Nucleotide Resolution.” Nature, vol. 453, No. 7199, pp. 1239-1243.
[cited by applicant]
Abbott, et al. “Design and use of signature primers to detect carry-over of amplified material”,
[cited by applicant]
Ahmadzadeh et al. “FOXP3 expression accurately defines the population of intratumoral regulatory T cells that selectively accumulate in metastatic melanoma lesions”,
[cited by applicant]
Akatsuka, Y. et al., “Rapid screening of T-cell receptor (TCR) variable gene usage by multiplex PCR: Application for assessment of clonal composition”,
[cited by applicant]
Alatrakchi et al. “T-cell clonal expansion in patients with B-cell lymphoproliferative disorders”,
[cited by applicant]
Alexandre, D. et al. “
[cited by applicant]
Alexandre, D. et al. “
[cited by applicant]
Andreasson, et al. “The human IgE-encoding transcriptome to assess antibody repertoires and repertoire evolution”,
[cited by applicant]
Arstila, T.P., et al., “A direct estimate of the human αβ T cell receptor diversity,” Science, 286(5441): 958-961 (1999).
[cited by applicant]
Aslanzadeh. “Preventing PCR amplification carryover contamination in a clinical laboratory”,
[cited by applicant]
Assaf, et al. “High Detection Rate of T-Cell Receptor Beta Chain Rearrangements in T-Cell Lymphoproliferations by Family Specific Polymerase Chain Reaction in Combination with the Genescan Technique and DNA Sequencing”,
[cited by applicant]
Bagnara, et al. “IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemia”,
[cited by applicant]
Barker, et al. “A second type II restriction endonuclease from Thermus aquaticus with an unusual sequence specificity”, Nucleic Acids Res., 12(14): 5567-5581 (1984).
[cited by applicant]
Baum and McCune et al. “Direct measurement of T-cell receptor repertoire diversity with AmpliCot”,
[cited by applicant]
Becton-Dickinson T-Cell Research Tools, “Novel multicolor flow cytometry tools for the study of CD4+ T-cell differentiation and plasticity”, 16 pages (2009).
[cited by applicant]
Beishuizen, et al. “Analysis of Ig and T-cell receptor genes in 40 childhood acute lymphoblastic leukemias at diagnosis and subsequent relapse: implications for the detection of minimal residual disease by polymerase ch…
[cited by applicant]
Béné and Kaeda, “How and why minimal residual disease studies are necessary in leukemia: a review from WP10 and WP12 of the European LeukaemiaNet”,
[cited by applicant]
Berger, et al. “The clonotypic T cell receptor is a source of tumor-associated antigens in cutaneous T cell lymphoma”,
[cited by applicant]
Bernard et al. “Color multiplexing hybridization probes using the apolipoprotein E locus as a model system for genotyping”, Anal Biochem., 273(2):221-228 (1999).
[cited by applicant]
Bernardin, F. et al., “Estimate of the total number of CD8+ clonal expansions in healthy adults using a new DNA heteroduplex-tracking assay for CDR3 repertoire analysis”,
[cited by applicant]
Bertness, et al. “T-Cell Receptor Gene Rearrangements as Clinical Markers of Human T-Cell Lymphomas”,
[cited by applicant]
Biggerstaff, et al. “Enumeration of leukocyte infiltration in solid tumors by confocal laser scanning microscopy”,
[cited by applicant]
Bonarius, H.P.J. et al. “Monitoring the T-Cell Receptor Repertoire at Single-Clone Resolution”,
[cited by applicant]
Boria, et al. “Primer sets for cloning the human repertoire of T cell receptor variable regions”,
[cited by applicant]
Borst, et al. “False-positive results and contamination in nucleic acid amplification assays: suggestions for a prevent and destroy strategy”, Eur J Clin Microbiol Infect Dis., 23(4):289-299, Abstract Only (2004). Epub …
[cited by applicant]
Boudinot et al. “New perspectives for large-scale repertoire analysis of immune receptors”,
[cited by applicant]
Boyd, S.D. et al., “Measurement and Clinical Monitoring of Human Lymphocyte Clonality by Massively Parallel V-D-J Pyrosequencing,”
[cited by applicant]
Bradfield, et al. “Graft-versus-leukemia effect in acute lymphoblastic leukemia: the importance of tumor burden and early detection”, Leukemia, 18(6): 1156-1158 (2004).
[cited by applicant]
Brehm-Stecher and Johnson. “Single-cell microbiology: tools, technologies, and applications”,
[cited by applicant]
Brenan, C. et al., “High throughput, nanoliter quantitative PCR,”
[cited by applicant]
Brisco, et al. “Determining the repertoire of IGH gene rearrangements to develop molecular markers for minimal residual disease in B-lineage acute lymphoblastic leukemia”,
[cited by applicant]
Brisco, et al. “Outcome prediction in childhood acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction”,
[cited by applicant]
Brochet et al. “IMGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis”,
[cited by applicant]
Brüggemann, et al. “Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia”,
[cited by applicant]
Buüggemann, et al. “Rearranged T-cell receptor beta genes represent powerful targets for quantification of minimal residual disease in childhood and adult T-cell acute lymphoblastic leukemia”,
[cited by applicant]
Buccisano, et al. “Monitoring of minimal residual disease in acute myeloid leukemia”, Curr Opin Oncol., 21(6):582-588, Abstract Only (2009). doi: 10.1097/CCO.0b013e3283311856.
[cited by applicant]
Campana, et al. “Role of minimal residual disease monitoring in adult and pediatric acute lymphoblastic leukemia”,
[cited by applicant]
Campana. “Minimal residual disease in acute lymphoblastic leukemia”,
[cited by applicant]
Campana. “Role of Minimal Residual Disease Evaluation in Leukemia Therapy.” Current Hematologic Malignancy Reports (2008); 3: 155-160.
[cited by applicant]
Campbell et al. “Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing,”
[cited by applicant]
Carlotti, et al. “Transformation of follicular lymphoma to diffuse large B-cell lymphoma may occur by divergent evolution from a common progenitor cell or by direct evolution from the follicular lymphoma clone”,
[cited by applicant]
Casali, et al. “Human monoclonals from antigen-specific selection of B lymphocytes and transformation by EBV”,
[cited by applicant]
Catherwood, M.A. et al., “Improved clonality assessment in germinal centre/post germinal centre non-Hodgkin's lymphomas with high rates of somatic hypermutation”,
[cited by applicant]
Chen et al. “A novel approach for the analysis of T-cell reconstitution by using a T-cell receptor β-based oligonucleotide microarray in hematopoietic stem cell transplantation”,
[cited by applicant]
Chen, et al. “Microfluidic cell sorter with integrated piezoelectric actuator”,
[cited by applicant]
Chen, Y. et al., “T-cell receptor gene expression in tumour-infiltrating lymphocytes and peripheral blood lymphocytes of patients with nasopharyngeal carcinoma”,
[cited by applicant]
Chinese Patent Application No. 201510054401.X, Search Report dated Jul. 14, 2016, 2 pages.
[cited by applicant]
Choi, et al. “Clonal evolution in B-lineage acute lymphoblastic leukemia by contemporaneous V
[cited by applicant]
Choi, et al. “Relapse in children with acute lymphoblastic leukemia involving selection of a preexisting drug-resistant subclone”,
[cited by applicant]
Chothia, C. et al. “Canonical structures for the hypervariable regions of immunoglobulins,”
[cited by applicant]
Chothia, C. et al. “Conformations of immunoglobulin hypervariable regions,”
[cited by applicant]
Churchill and Waterman. “The Accuracy of DNA Sequences: Estimating Sequence Quality”,
[cited by applicant]
Chute, et al. “Detection of immunoglobulin heavy chain gene rearrangements in classic Hodgkin lymphoma using commercially available Biomed-2 primers”,
[cited by applicant]
Cleary, et al. “Production of complex nucleic acid libraries using highly parallel in situ oligonucleotide synthesis”,
[cited by applicant]
Craig et al. “Identification of genetic variants using bar-coded multiplex sequencing”,
[cited by applicant]
Cronn et al. “Multiplex sequencing of plant chloroplast genomes using Solexa sequencing-by-synthesis technology”,
[cited by applicant]
Curran et al. “Nucleotide sequencing of psoriatic arthritis tissue before and during methotrexate administration reveals a complex inflammatory T cell infiltrate with very few clones exhibiting features that suggest the…
[cited by applicant]
Curran-Everett, D., “Multiple comparisons: philosophies and illustrations”,
[cited by applicant]
Currier and Robinson. “Spectratype/immunoscope analysis of the expressed TCR repertoire”,
[cited by applicant]
Davi, et al. “Lymphocytic progenitor cell origin and clonal evolution of human B-lineage acute lymphoblastic leukemia”,
[cited by applicant]
Davis, et al. “Staining of cell surface human CD4 with 2′-F-pyrimidine-containing RNA aptamers for flow cytometry”,
[cited by applicant]
Dean, et al. “Rapid amplification of plasmid and phage DNA using Phi 29 DNA polymerase and multiply-primed rolling circle amplification”,
[cited by applicant]
Dedhia, et al. “Evaluation of DNA extraction methods and real time PCR optimization on formalin-fixed paraffin-embedded tissues”,
[cited by applicant]
Deng et al. “Gene profiling involved in immature CD4+ T lymphocyte responsible for systemic lupus erythematosus”,
[cited by applicant]
Dictor et al. “Resolving T-cell receptor clonality in two and genotype in four multiplex polymerase chain reactions”,
[cited by applicant]
Diederichsen, et al. “Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells”,
[cited by applicant]
Diehl, et al. “BEAMing: single-molecule PCR on microparticles in water-in-oil emulsions”,
[cited by applicant]
Diviacco, et al. “A novel procedure for quantitative polymerase chain reaction by coamplification of competitive templates”,
[cited by applicant]
Dohm, et al. “Substantial biases in ultra-short read data sets from high throughput DNA sequencing”,
[cited by applicant]
Dou, et al. “Analysis of T cell receptor V
[cited by applicant]
Dressman, et al. “Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations”, PNAS, 100(15):8817-8822 (2003). Epub Jul. 11, 2003.
[cited by applicant]
Droege, et al. “The Genome Sequencer FLX System—longer reads, more applications, straight forward bioinformatics and more complete data sets”,
[cited by applicant]
Droese, J., et al. “Validation of Biomed-2 multiplex PCR tubes for detection of TCRB gene rearrangements in T-cell malignancies,”
[cited by applicant]
Du et al. “TCR spectratyping revealed T lymphocytes associated with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation”,
[cited by applicant]
Dunn, et al. “Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human glioma”,
[cited by applicant]
Eason et al. “Characterization of synthetic DNA bar codes in
[cited by applicant]
Edd et al. “Controlled encapsulation of single cells into monodisperse picoliter drops”,
[cited by applicant]
Eichler, et al. “Haplotype and interspersion analysis of the FMR1 CGG repeat identifies two different mutational pathways for the origin of the fragile X syndrome”,
[cited by applicant]
Eichler, et al. “Length of uninterrupted CGG repeats determines instability in the FMR1 gene”,
[cited by applicant]
Eid et al. “Real-time DNA sequencing from single polymerase molecules”,
[cited by applicant]
Eis, et al. “An invasive cleavage assay for direct quantitation of specific RNAs”,
[cited by applicant]
Esendagli et al. “Malignant and non-malignant lung tissue areas are differentially populated by natural killer cells and regulatory T cells in non-small cell lung cancer”,
[cited by applicant]
European Application No. 09764927.1, European Opposition dated Oct. 15, 2014 (in French only).
[cited by applicant]
European Application No. 09764927.1, Notice of Opposition dated Oct. 14, 2014, Reference# 547-7.
[cited by applicant]
European Application No. 09764927.1, Notice of Opposition dated Oct. 14, 2014, Reference# BR0-0001EP.
[cited by applicant]
European Patent Application No. 09764927.1, EPO's Communication of Notices of Opposition, dated Nov. 21, 2014.
[cited by applicant]
European Patent Application No. 09764927.1, Opponent's Response to Submission of the Patentee dated Nov. 23, 2015.
[cited by applicant]
European Patent Application No. 09764927.1, Patentee's Observations/Response dated May 27, 2015.
[cited by applicant]
European Patent Application No. 11777704.5, European Search Report dated Jul. 26, 2013, 6 pages.
[cited by applicant]
European Patent Application No. 13195379.6, Extended European Search Report and Opinion dated Mar. 13, 2014, 6 pages.
[cited by applicant]
European Patent Application No. 16183402.3, Extended European Search Report dated Feb. 21, 2017, 8 pages.
[cited by applicant]
European Patent Application No. 18184843.3, Extended European Search Report dated Aug. 13, 2018, 10 pages.
[cited by applicant]
European Patent Application No. 18201137.9, Extended European Search Report dated Nov. 26, 9 pages.
[cited by applicant]
Faham, M. et al. “Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia”,
[cited by applicant]
Ferradini et al. “Analysis of T Cell Receptor Variability in Tumor-infiltrating Lymphocytes from a Human Regressive Melanoma”,
[cited by applicant]
Flohr, T., et al. “Minimal residual disease-directed risk stratification using real-time quantitative PCT analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-B…
[cited by applicant]
Födinger et al., “Multiplex PCR for rapid detection of T-cell receptor-gamma chain gene rearrangements in patients with lymphoproliferative diseases.” British Journal of Haematology (1996); 94(1): 136-139.
[cited by applicant]
Frank. “Barcrawl and Bartab: software tools for the design and implementation of barcoded primers for highly multiplexed DNA sequencing,”
[cited by applicant]
Frederiksson et al., “Multiplex amplification of all coding sequences within 10 cancer genes by Gene-Collector”, Nucleic Acids Research, 35(7): e47 (2007).
[cited by applicant]
Freeman, et al. “Quantitative RT-PCR: Pitfalls and Potential”,
[cited by applicant]
Freeman, J.D., et al. “Profiling the T-Cell Receptor Beta-Chain Repertoire by Massively Parallel Sequencing”,
[cited by applicant]
Fritz et al. “Alterations in the spinal cord T cell repertoire during relapsing experimental autoimmune encephalomyelitis,”
[cited by applicant]
Fuller, et al. “The challenges of sequencing by synthesis”,
[cited by applicant]
García-Castillo and Nunez, et al. “Detection of clonal immunoglobulin and T-cell receptor gene recombination in hematological malignancies: monitoring minimal residual disease”,
[cited by applicant]
Gauss, et al. “Mechanistic constraints on diversity in human V(D)J recombination”,
[cited by applicant]
Germano, et al. “Clonality profile in relapsed precursor-B-ALL children by GeneScan and sequencing analyses. Consequences on minimal residual disease monitoring”,
[cited by applicant]
Gilbert, et al. “The isolation of nucleic acids from fixed, paraffin-embedded tissues-which methods are useful when?”,
[cited by applicant]
Giuggio, et al. “Evolution of the intrahepatic T cell repertoire during chronic hepatitis C virus infection”,
[cited by applicant]
Godelaine, et al. “Polyclonal CTL responses observed in melanoma patients vaccinated with dendritic cells pulsed with a MAGE-3.A1 peptide”,
[cited by applicant]
Golembowski, et al. “Clonal evolution in a primary cutaneous follicle center B cell lymphoma revealed by single cell analysis in sequential biopsies”,
[cited by applicant]
Gonzalez et al., “Incomplete DJH rearrangements as a novel tumor target for minimal residual disease quantitation in multiple myeloma using real-time PCR”, Leukemia, 17:1051-1057 (2003).
[cited by applicant]
Gonzalez, et al. “Incomplete DJH rearrangements of the IgH gene are frequent in multiple myeloma patients: immunobiological characteristics and clinical implications”,
[cited by applicant]
Gorski, et al. “Circulating T cell repertoire complexity in normal individuals and bone marrow recipients analyzed by CDR3 size spectratyping. Correlation with immune status”,
[cited by applicant]
Gottenberg, et al. “Markers of B-lymphocyte activation are elevated in patients with early rheumatoid arthritis and correlated with disease activity in the ESPOIR cohort”,
[cited by applicant]
Gratama and Kern. “Flow cytometric enumeration of antigen-specific T lymphocytes”,
[cited by applicant]
Gratama, et al. “Measuring antigen-specific immune responses”, 2008 update.
[cited by applicant]
Green, et al. “Clonal diversity of Ig and T-cell-receptor gene rearrangements identifies a subset of childhood B-precursor acute lymphoblastic leukemia with increased risk of relapse”,
[cited by applicant]
Greenberg, et al. “Profile of immunoglobulin heavy chain variable gene repertoires and highly selective detection of malignant clonotypes in acute lymphoblastic leukemia” J Leukoc Biol., 57(6):856-864 (1995).
[cited by applicant]
Greenman, et al. “Patterns of somatic mutation in human cancer genomes”,
[cited by applicant]
Gulliksen, et al. “Real-time nucleic acid sequence-based amplification in nanoliter volumes”,
[cited by applicant]
Gunderson et al. “Decoding Randomly Ordered DNA Arrays”,
[cited by applicant]
Guo, et al. “Sequence changes at the V-D junction of the V
[cited by applicant]
Gurrieri, et al. “Chronic lymphocytic leukemia B cells can undergo somatic hypermutation and intraclonal immunoglobulin V
[cited by applicant]
Hadrup, et al. “Parallel detection of antigen-specific T-cell responses by multidimensional encoding of MHC multimers”,
[cited by applicant]
Halldórsdóttir, et al. “Application of Biomed-2 clonality assays to formalin-fixed paraffin embedded follicular lymphoma specimens: superior performance of the IGK assays compared to IGH for suboptimal specimens”,
[cited by applicant]
Hamady, et al. “Error-correcting barcoded primers for pyrosequencing hundreds of samples in multiplex”,
[cited by applicant]
Han et al. “Immunorepertoire analysis by multiplex PCR amplification and high throughput sequencing”,
[cited by applicant]
Harismendy et al. “Evaluation of next generation sequencing platforms for population targeted sequencing studies”,
[cited by applicant]
Hawkins, et al. “Whole genome amplification—applications and advances”,
[cited by applicant]
Henegariu, O. et al., “Multiplex PCR: Critical Parameters and Step-By-Step Protocol,” Biotechniques, Informa HealthCare, 23(3):504-511 (1997).
[cited by applicant]
Hensel et al. “Simultaneous identification of bacterial virulence genes by negative selection”,
[cited by applicant]
Hill, et al. “Using ecological diversity measures with bacterial communities”,
[cited by applicant]
Hirohata, et al. “Regulation of human B cell function by sulfasalazine and its metabolites”,
[cited by applicant]
Hodges, E. et al. “Diagnostic role of tests for T cell receptor (TCR) genes”,
[cited by applicant]
Holt and Jones. “The new paradigm of flow cell sequencing”,
[cited by applicant]
Holt. “Q &A: BC cancer agency's Robert Holt on sequencing the immune repertoire in immune reconstitution,”
[cited by applicant]
Hoogenboom, et al. “Multi-subunit proteins on the surface of filamentous phage: methodologies for displaying antibody (Fab) heavy and light chains”,
[cited by applicant]
Hoogendoorn, et al. “Primary allogeneic T-cell responses against mantle cell lymphoma antigen-presenting cells for adoptive immunotherapy after stem cell transplantation”,
[cited by applicant]
Hosono, et al. “Unbiased whole-genome amplification directly from clinical samples”,
[cited by applicant]
Hoven, et al. “Detection and isolation of antigen-specific B cells by the fluorescence activated cell sorter (FACS)”,
[cited by applicant]
Howe, et al. “T cell receptor clonotype analysis of T cell responses: Diagnostic application of a clonotypic database”, Blood (2003); 102 (11): Abstract 3918, p. 54b, 1 page.
[cited by applicant]
Huh, et al. “Microfluidics for flow cytometric analysis of cells and particles”,
[cited by applicant]
Huse, et al. “Generation of a large combinatorial library of the immunoglobulin repertoire in phage lambda”,
[cited by applicant]
Hwang, H.Y. et al. “Identification of a Commonly used CDR3 Region of Infiltrating T Cells Expressing Vβ13 and Vβ15 Derived from Psoriasis Patients”,
[cited by applicant]
Illumina Systems & Software, Technology Spotlight, DNA Sequencing with Solexa® Technology, Illumina, Inc., Pub. No. 770-2007-002, 4 pages (2007).
[cited by applicant]
Ishii et al. “Isolation and expression profiling of genes upregulated in the peripheral blood cells of systemic lupus erythematosus patients,”
[cited by applicant]
Jacobi et al. “Activated memory B cell subsets correlate with disease activity in systemic lupus erythematosus: delineation by expression of CD27, IgD, and CD95”,
[cited by applicant]
Jacobi et al. “Correlation between circulating CD27
[cited by applicant]
Jaffe, et al. “Classification of lymphoid neoplasms: the microscope as a tool for disease discovery”,
[cited by applicant]
Jalla, et al. “Enumeration of lymphocyte subsets using flow cytometry: Effect of storage before and after staining in a developing country setting”,
[cited by applicant]
Jena, et al. “Amplification of genes, single transcripts and cDNA libraries from one cell and direct sequence analysis of amplified products derived from one molecule”,
[cited by applicant]
Jung, et al. “Unraveling V(D)J recombination; insights into gene regulation”,
[cited by applicant]
Jurkat, Clone 6-1 (ATCC TIB-152) Webpage retrievable from the ATCC under http:/ /www.lgcstandards-atcc.org/Products/ All MB-152. aspx#characteristics. Accessed Oct. 14, 2014.
[cited by applicant]
Kato et al. “Analysis of accumulated T cell clonotypes in patients with systemic lupus erythematosus,”
[cited by applicant]
Katz, S.C. et al. “T Cell Infiltrate Predicts Long-Term Survival Following Resection of Colorectal Cancer Liver Metastases,” Ann. Surg. Oncol., 16:2524-2530 (2009).
[cited by applicant]
Kedzierska, et al. “Tracking phenotypically and functionally distinct T cell subsets via T cell repertoire diversity”,
[cited by applicant]
Kiianitsa, et al., “Development of Tools for T-Cell Repertoire Analysis (TCRB Spectratyping) for the Canine Model of Hematopoietic Cell Transplantation”,
[cited by applicant]
Kim, et al. “An efficient and reliable DNA extraction method for preimplantation genetic diagnosis: a comparison of allele drop out and amplification rates using different single cell lysis methods”,
[cited by applicant]
Kim, et al. “Polony multiplex analysis of gene expression (PMAGE) in mouse hypertrophic cardiomyopathy”,
[cited by applicant]
Kircher, et al. “Improved base calling for the Illumina Genome Analyzer using machine learning strategies”,
[cited by applicant]
Kita, et al. “T cell receptor clonotypes in skin lesions from patients with systemic lupus erythematosus”,
[cited by applicant]
Klenerman, et al. “Tracking T cells with tetramers: new tales from new tools”,
[cited by applicant]
Kneba, et al. “Characterization of clone-specific rearrangement T-cell receptor gamma-chain genes in lymphomas and leukemias by the polymerase chain reaction and DNA sequencing”,
[cited by applicant]
Kneba, M., et al. “Analysis of Rearranged T-cell Receptor β-Chain Genes by Polymerase Chain Reaction (PCR) DNA Sequencing and Automated High Resolution PCR Fragment Analysis”,
[cited by applicant]
Kobari, et al. “T cells accumulating in the inflamed joints of a spontaneous murine model of rheumatoid arthritis become restricted to common clonotypes during disease progression”,
[cited by applicant]
Koboldt et al., “VarScan: variant detection in massively parallel sequencing of individual and pooled samples”, Bioinformatics, 25(17): 2283-2285 (2009).
[cited by applicant]
Koch, et al. “Tumor infiltrating T lymphocytes in colorectal cancer: Tumor-selective activation and cytotoxic activity in situ,”
[cited by applicant]
Kojima et al. “PCR amplification from single DNA molecules on magnetic beads in emulsion: application for high-throughput screening of transcription factor targets”,
[cited by applicant]
Kwak, et al. “Induction of immune responses in patients with B-cell lymphoma against the surface-immunoglobulin idiotype expressed by their tumors”,
[cited by applicant]
Kyu et al. “Frequencies of human influenza-specific antibody secreting cells or plasmablasts post vaccination from fresh and frozen peripheral blood mononuclear cells”,
[cited by applicant]
Ladetto, M. et al. “Real-time polymerase chain reaction in multiple myeloma: Quantitative analysis of tumor contamination of stem cell harvests”,
[cited by applicant]
Ladetto, M. et al. “Real-Time Polymerase Chain Reaction of Immunoglobulin Rearrangements for Quantitative Evaluation of Minimal Residual Disease in Multiple Myeloma”,
[cited by applicant]
Langerak, et al. “Immunoglobulin/T-cell receptor clonality diagnostics”,
[cited by applicant]
Langerak, et al. “Polymerase chain reaction-based clonality testing in tissue samples with reactive lymphoproliferations: usefulness and pitfalls. A report of the Biomed-2 Concerted Action BMH4-CT98-3936”,
[cited by applicant]
Laplaud et al. “Blood T-cell receptor β chain transcriptome in multiple sclerosis. Characterization of the T cells with altered CDR3 length distribution”,
[cited by applicant]
Laplaud et al. “Serial blood T cell repertoire alterations in multiple sclerosis patients; correlation with clinical and MRI parameters”,
[cited by applicant]
Lassmann, et al. “Application of Biomed-2 primers in fixed and decalcified bone marrow biopsies: analysis of immunoglobulin H receptor rearrangements in B-cell non-Hodgkin's lymphomas”,
[cited by applicant]
Lee, et al. “Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients”,
[cited by applicant]
Lee, et al. “Prognostic implications of type and density of tumour-infiltrating lymphocytes in gastric cancer”,
[cited by applicant]
Lefranc. “IMGT, the international ImMunoGeneTics database”,
[cited by applicant]
Leiden, J.M. et al. “The Complete Primary Structure of The T-Cell Receptor Genes From an Alloreactive Cytotoxic Human T-Lymphocyte Clone”, Immunogenetics, 24(1): 17-23 (1986).
[cited by applicant]
Leisner, et al. “One-pot, mix-and-read peptide-MHC tetramers”,
[cited by applicant]