IP Library › Granted Patent US 12,331,128
Granted Patent B2
US 12,331,128 · App. 17/590,918 · Granted Jun 17, 2025

Therapeutic and diagnostic methods for cancer

Inventors: Richard Bourgon (South San Francisco, CA); David Fabrizio (Cambridge, MA); Gregg Fine (South San Francisco, CA); Garrett M. Frampton (Cambridge, MA); Priti Hegde (South San Francisco, CA); Sanjeev Mariathasan (South San Francisco, CA); Philip J. Stephens (Cambridge, MA); James Xin Sun (Cambridge, MA); Roman Yelensky (Newton, MA)
Assignees: Genentech, Inc.; Foundation Medicine, Inc.
C07K16/2896A61K39/3955C07K16/2818G16H50/30A61K2039/505A61K2039/577A61P35/00C07K2317/24C07K2317/76G16H20/10
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Quick Facts
Patent No.
US 12,331,128
App. No.
17/590,918
Granted
Jun 17, 2025
Kind
B2
Abstract

The present invention provides therapeutic and diagnostic methods and compositions for cancer, for example, bladder cancer. The invention provides methods of treating bladder cancer, methods of determining whether a patient suffering from bladder cancer is likely to respond to treatment comprising a PD-L1 axis binding antagonist, methods of predicting responsiveness of a patient suffering from bladder cancer to treatment comprising a PD-L1 axis binding antagonist, and methods of selecting a therapy for a patient suffering from bladder cancer, based on somatic mutation levels of genes of the invention (e.g., somatic mutation levels in a tumor sample obtained from the patient).

Claims (16)

1. A method of treating a patient suffering from a urothelial bladder cancer, the method comprising administering to the patient a therapeutically effective amount of a PD-L1 binding antagonist, wherein a tumor sample obtained from the patient has been determined to have an increased level of mutation load relative to a reference level of mutation load, wherein mutation load of the tumor sample reflects the level of somatic mutations in at least one-third of the genes set forth in Table 1, and wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody comprising a heavy chain comprising the hypervariable region (HVR)-H1 sequence of SEQ ID NO: 19, the HVR-H2 sequence of SEQ ID NO: 20, and the HVR-H3 sequence of SEQ ID NO: 21; and a light chain comprising the HVR-L1 sequence of SEQ ID NO: 22, the HVR-L2 sequence of SEQ ID NO: 23, and the HVR-L3 sequence of SEQ ID NO: 24.

2. The method of claim 1 , wherein the mutation load of the tumor sample reflects the level of somatic mutations in at least one-half, two-thirds, three-fourths, or all of the genes set forth in Table 1.

3. The method of claim 1 , wherein:

(i) the somatic mutations are substitutions, deletions, and/or insertions;

(ii) the somatic mutations of the at least one gene set forth in Table 1 are protein-altering somatic mutations; or

(iii) the substitutions, deletions, and/or insertions of (i) are in coding regions.

4. The method of claim 1 , wherein the tumor sample obtained from the patient has a whole-genome mutation load that is higher than a reference level whole-genome mutation load.

5. The method of claim 4 , wherein the reference level whole-genome mutation load is at least about 10 mutations per megabase (Mb).

6. The method of claim 1 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:4.

7. The method of claim 1 , further comprising administering to the patient an effective amount of a second therapeutic agent.

8. The method of claim 7 , wherein the second therapeutic agent is selected from the group consisting of a cytotoxic agent, a growth-inhibitory agent, a radiation therapy agent, an anti-angiogenic agent, and combinations thereof.

9. The method of claim 1 , wherein the urothelial bladder cancer is a locally advanced urothelial bladder cancer or a metastatic urothelial bladder cancer.

10. The method of claim 1 , wherein the patient is ineligible for treatment with a platinum-based chemotherapeutic agent and has not received prior treatment for locally advanced or metastatic urothelial bladder cancer.

11. The method of claim 1 , wherein the tumor sample is a formalin-fixed and paraffin-embedded (FFPE) tumor sample, an archival tumor sample, a fresh tumor sample, or a frozen tumor sample.

12. The method of claim 1 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:32 and a light chain comprising the amino acid sequence of SEQ ID NO: 33.

13. A method of treating a patient suffering from a locally advanced or metastatic urothelial carcinoma, the method comprising administering to the patient 1200 mg of an anti-PD-L1 antibody comprising a heavy chain comprising the hypervariable region (HVR)-H1 sequence of SEQ ID NO: 19, the HVR-H2 sequence of SEQ ID NO: 20, and the HVR-H3 sequence of SEQ ID NO: 21; and a light chain comprising the HVR-L1 sequence of SEQ ID NO: 22, the HVR-L2 sequence of SEQ ID NO: 23, and the HVR-L3 sequence of SEQ ID NO: 24 intravenously on Day 1 of each 21-day cycle, wherein the patient is ineligible for treatment with a platinum-based chemotherapeutic agent and has not received prior treatment for locally advanced or metastatic urothelial carcinoma, wherein a tumor sample obtained from the patient has been determined to have an increased level of mutation load relative to a reference level of mutation load, and wherein the mutation load of the tumor sample reflects the level of somatic mutations in at least one-third of the genes set forth in Table 1.

Continuity (5)
Continuation 16115343 · Aug 28, 2018
Continuation PCTUS2017019682 · Feb 27, 2017
Provisional Application 62405190 · Oct 6, 2016
Provisional Application 62301595 · Feb 29, 2016
Related Publication 20220153861A1 · May 19, 2022
References Cited (391)
US 4366241A · Tom et al. · 1982 [cited by applicant]
US 4376110A · David et al. · 1983 [cited by applicant]
US 4517288A · Giegel et al. · 1985 [cited by applicant]
US 4816567A · Cabilly et al. · 1989 [cited by applicant]
US 4837168A · de Jaeger et al. · 1989 [cited by applicant]
US 4987071A · Cech et al. · 1991 [cited by applicant]
US 5093246A · Cech et al. · 1992 [cited by applicant]
US 5116742A · Cech et al. · 1992 [cited by applicant]
US 5223409A · Ladner et al. · 1993 [cited by applicant]
US 5225539A · Winter · 1993 [cited by applicant]
US 5491224A · Bittner et al. · 1996 [cited by applicant]
US 5547835A · Koster · 1996 [cited by applicant]
US 5585089A · Queen et al. · 1996 [cited by applicant]
US 5605798A · Koster · 1997 [cited by applicant]
US 5693761A · Queen et al. · 1997 [cited by applicant]
US 5693762A · Queen et al. · 1997 [cited by applicant]
US 6277569B1 · Bittner et al. · 2001 [cited by applicant]
US 6455258B2 · Bastian et al. · 2002 [cited by applicant]
US 7943743B2 · Korman et al. · 2011 [cited by applicant]
US 8008449B2 · Korman et al. · 2011 [cited by applicant]
US 8354509B2 · Carven et al. · 2013 [cited by applicant]
US 8609089B2 · Langermann et al. · 2013 [cited by applicant]
US 11066709B2 · Klijn et al. · 2021 [cited by applicant]
US 11279767B2 · Bourgon · 2022 [cited by examiner]
US 11300570B2 · Fabrizio et al. · 2022 [cited by applicant]
US 20030143204A1 · Lewis et al. · 2003 [cited by applicant]
US 20030166282A1 · Brown et al. · 2003 [cited by applicant]
US 20030224432A1 · Myers et al. · 2003 [cited by applicant]
US 20040038278A1 · Tzertzinis et al. · 2004 [cited by applicant]
US 20040086884A1 · Beach et al. · 2004 [cited by applicant]
US 20100028330A1 · Collins et al. · 2010 [cited by applicant]
US 20100029498A1 · Gnirke et al. · 2010 [cited by applicant]
US 20120039906A1 · Olive · 2012 [cited by applicant]
US 20120114649A1 · Langermann et al. · 2012 [cited by applicant]
US 20120208706A1 · Downing et al. · 2012 [cited by applicant]
US 20130309254A1 · Samuels et al. · 2013 [cited by applicant]
US 20140287937A1 · So et al. · 2014 [cited by applicant]
US 20140296081A1 · Diehn et al. · 2014 [cited by applicant]
US 20140336996A1 · Sun et al. · 2014 [cited by applicant]
US 20160009805A1 · Kowanetz et al. · 2016 [cited by applicant]
US 20170175197A1 · Gatalica et al. · 2017 [cited by applicant]
US 20170275689A1 · Maguire et al. · 2017 [cited by applicant]
US 20180045727A1 · Spetzler et al. · 2018 [cited by applicant]
US 20180231554A1 · Schatton et al. · 2018 [cited by applicant]
US 20180282417A1 · Higgs et al. · 2018 [cited by applicant]
US 20180291074A1 · Chan et al. · 2018 [cited by applicant]
US 20180363066A1 · Chalmers et al. · 2018 [cited by applicant]
US 20180371099A1 · Bourgon et al. · 2018 [cited by applicant]
US 20190025308A1 · Cummings et al. · 2019 [cited by applicant]
US 20190085403A1 · Frampton et al. · 2019 [cited by applicant]
US 20190218618A1 · Klijn et al. · 2019 [cited by applicant]
US 20190219586A1 · Fabrizio et al. · 2019 [cited by applicant]
US 20220056531A1 · Trabucco et al. · 2022 [cited by applicant]
US 20220090205A1 · Klijn et al. · 2022 [cited by applicant]
US 20220153861A1 · Bourgon et al. · 2022 [cited by applicant]
US 20220412981A1 · Fabrizio et al. · 2022 [cited by applicant]
CN 105209919A · 2015 [cited by applicant]
EP 430402B2 · 1991 [cited by applicant]
EP 519596A1 · 1992 [cited by applicant]
JP 2016520800A · 2016 [cited by applicant]
JP 2017537087A · 2017 [cited by applicant]
JP 2018502828A · 2018 [cited by applicant]
JP 2019535237A · 2019 [cited by applicant]
WO WO1986001533A1 · 1986 [cited by applicant]
WO WO1987002671A1 · 1987 [cited by applicant]
WO WO1988009810A1 · 1988 [cited by applicant]
WO WO1989010134A1 · 1989 [cited by applicant]
WO WO1990002809A1 · 1990 [cited by applicant]
WO WO1991000906A1 · 1991 [cited by applicant]
WO WO1991010741A1 · 1991 [cited by applicant]
WO WO1991017271A1 · 1991 [cited by applicant]
WO WO1992001047A1 · 1992 [cited by applicant]
WO WO1992003917A1 · 1992 [cited by applicant]
WO WO1992003918A1 · 1992 [cited by applicant]
WO WO1992009690A2 · 1992 [cited by applicant]
WO WO1992015679A1 · 1992 [cited by applicant]
WO WO1992018619A1 · 1992 [cited by applicant]
WO WO1992020791A1 · 1992 [cited by applicant]
WO WO1993001288A1 · 1993 [cited by applicant]
WO WO1994016101A2 · 1994 [cited by applicant]
WO WO1994021822A1 · 1994 [cited by applicant]
WO WO1996029431A2 · 1996 [cited by applicant]
WO WO2006121168A1 · 2006 [cited by applicant]
WO WO2007005874A2 · 2007 [cited by applicant]
WO WO2009101611A1 · 2009 [cited by applicant]
WO WO2009114335A2 · 2009 [cited by applicant]
WO WO2010077634A1 · 2010 [cited by applicant]
WO WO2012092426A1 · 2012 [cited by applicant]
WO WO2013070634A1 · 2013 [cited by applicant]
WO WO2014151006A2 · 2014 [cited by applicant]
WO WO2014183078A1 · 2014 [cited by applicant]
WO WO2015095423A2 · 2015 [cited by applicant]
WO WO2015103037A2 · 2015 [cited by applicant]
WO WO2015116868A2 · 2015 [cited by applicant]
WO WO2015164862A1 · 2015 [cited by applicant]
WO WO2016018481A2 · 2016 [cited by applicant]
WO WO2016077553A1 · 2016 [cited by applicant]
WO WO2016081947A2 · 2016 [cited by applicant]
WO WO2016089873A1 · 2016 [cited by applicant]
WO WO2017151502A1 · 2017 [cited by applicant]
WO WO2017151517A1 · 2017 [cited by applicant]
WO WO2017151524A1 · 2017 [cited by applicant]
WO WO2018068028A1 · 2018 [cited by applicant]
WO WO2019018757A1 · 2019 [cited by applicant]
Abernathy et al., “Two NF1 mutations: Frameshift in the GAP-related domain, and loss of two codons toward the 3′ end of the gene,” Hum Mutat. 3(4):347-352 (1994). [cited by applicant]
Aggarwal et al., “Baseline Plasma Tumor Mutation Burden Predicts Response to Pembrolizumab-based Therapy in Patients with Metastatic Non-Small Cell Lung Cancer,” Clinical Cancer Research. 26(10):2354-2361 (May 15, 2020)… [cited by applicant]
Albertson, “Localization of the ribosomal genes in Caenorhabditis elegans chromosomes by in situ hybridization using biotin-labeled probes,” The EMBO Journal. 3(6): 1227-1234 (1984) (8 pages). [cited by applicant]
Andersen et al., “A conserved alternative splice in the von Recklinghausen neurofibromatosis (NF1) gene produces two neurofibromin isoforms, both of which have GTPase-activating protein activity,” Molecular and Cellular… [cited by applicant]
Anonymous: “Wayback Machine—Caris Life Sciences—Total Mutational Load (TML)”,, Aug. 30, 2016 (Aug. 30, 2016), pp. 1-4, XP93031805, Retrieved from the Internet: URL:https://web.archive.org/web/20160830183217/http://www.c… [cited by applicant]
Anonymous: “Wayback Machine—Foundation One”, Sep. 27, 2016 (Sep. 27, 2016), pp. 1-29, XP93031809, Retrieved from the Internet: RL:https://web.archive.org/web/20160927005802/http://foundationone.com/learn.php#2 [retrieve… [cited by applicant]
Ars, et al., “Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1,” Human Molecular Genetics. 9(2): 237-247 (2000) (11 pages). [cited by applicant]
Balch et al., “Final Version of 2009 AJCC Melanoma Staging and Classification,” Journal of Clinical Oncology. 27(36): 6199-6206 (2009) (8 pages). [cited by applicant]
Baralle et al., “Different mutations in the NF1 gene are associated with Neurofibromatosis Noonan syndrome (NFNS),” Am J Med Genet. 119A(1):1-8 (2003). [cited by applicant]
Barbas et al., “Assembly of combinatorial antibody libraries on phage surfaces: the gene III site,” PNAS. 88(18): 7978-7982 (1991) (5 pages). [cited by applicant]
Barringer et al., “Blunt-end and single-strand ligations by [cited by applicant]
Bartel et al., “Isolation of New Ribozymes from a Large Pool of Random Sequences,” Science. 261(5127): 1411-1418 (1993) (8 pages). [cited by applicant]
Beidler et al., “Cloning and high level expression of a chimeric antibody with specificity for human carcinoembryonic antigen,” The Journal of Immunology. 141(11): 4053-4060 (1988) (9 pages). [cited by applicant]
Ben-Salem et al., “The mutation spectrum of the NF1 gene in neurofibromatosis type I patients from UAE,” Child's Nerv Syst. 30(7): 1183-1189 (2014) (7 pages). [cited by applicant]
Bernards et al., “Complete Human NF1 cDNA Sequence: Two Alternatively Spliced mRNAs and Absence of Expression in a Neuroblastoma Line,” DNA and Cell Biology. 11(10): 727-734 (1992) (8 pages). [cited by applicant]
Bertola et al., “Neurofibromatosis-Noonan syndrome: Molecular evidence of the concurrence of both disorders in a patient,” American Journal of Medical Genetics. 136A(3):242-245 (2005) (4 pages). [cited by applicant]
Bettegowda et al., “Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies,” available in PMC May 12, 2014, published in final edited form as: Sci Transl Med. 6(224): 224ra24 (2014) (25 pages). [cited by applicant]
Better et al., “ [cited by applicant]
Billy et al., “Specific interference with gene expression induced by long, double-stranded RNA in mouse embryonal teratocarcinoma cell lines,” PNAS. 98(25): 14428-14433 (2001) (6 pages). [cited by applicant]
Boulandet et al., “NF1 gene analysis focused on CpG-rich exons in a cohort of 93 patients with neurofibromatosis type 1,” Human Mutation. 16(3): 274-275 (2000) (7 pages). [cited by applicant]
Breslow, “Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma,” Annals of Surgery. 172(5): 902-908 (1970) (7 pages). [cited by applicant]
Brüggemann et al., “Designer mice: the production of human antibody repertoires in transgenic animals,” Year Immunol. 7:33-40 (1993) (8 pages). [cited by applicant]
Brüggemann et al., “Human antibody production in transgenic mice: expression from 100 kb of the human IgH locus,” Eur J Immunol. 21(5): 1323-1326 (1991). [cited by applicant]
Butler et al., “Allpaths: De novo assembly of whole-genome shotgun microreads,” Genome Research. 18(5):810-820 (2008) (11 pages). [cited by applicant]
Cancer Genome Atlas Network, “Genomic Classification of Cutaneous Melanoma,” Cell. 161 (7):1681-1696 (2015) (17 pages). [cited by applicant]
Cancer Genome Atlas Research Network, “Comprehensive molecular characterization of urothelial bladder carcinoma,” Nature. 507(7492):315-22 (2014) (8 pages). [cited by applicant]
Carell et al., “A Novel Procedure for the Synthesis of Libraries Containing Small Organic Molecules,” Angew Chem Int Ed Engl. 33(20):2059-2061 (1994) (3 pages). [cited by applicant]
Carell et al., “A Solution-Phase Screening Procedure for the Isolation of Active Compounds from a Library of Molecules,” Angew Chem Int Ed in Engl. 33(20):2061-2064 (1994) (4 pages). [cited by applicant]
Casey et al., “MYC regulates the antitumor immune response through CD47 and PD-L 1,” Science. 352(6282):227-231 (Mar. 2016) (5 pages). [cited by applicant]
Cawthon et al., “A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations,” Cell. 62(1):193-201 (1990) (9 pages). [cited by applicant]
Chae et al., “Clinical Implications of Circulating Tumor DNA Tumor Mutational Burden (ctDNA TMB) in Non-Small Cell Lung Cancer,” The Oncologist. 24(6):820-28. (2019). [cited by applicant]
Champiat et al., “Exomics and immunogenics: Bridging mutational load and immune checkpoints efficacy” OncoImmunology. 3(1):e27817 (2014) (6 pages). [cited by applicant]
Chen et al., “Effect of Combined Immune Checkpoint Inhibition vs Best Supportive Care Alone in Patients with Advanced Colorectal Cancer: The Canadian Cancer Trials Group CO.26 Study,” JAMA Oncol. 6(6):831-838 (May 2020). [cited by applicant]
Cho et al., “An Unnatural Biopolymer,” Science. 261(5126):1303-1305 (1993) (3 pages). [cited by applicant]
Clackson et al., “Making antibody fragments using phage display libraries,” Nature. 352(6336):624-628 (1991) (5 pages). [cited by applicant]
Clemens et al., “Use of double-stranded RNA interference in [cited by applicant]
Cohen et al., Chapter 3: Emerging Technologies for Sequencing Antisense Oligonucleotides: Capillary Electrophoresis and Mass Spectrometry. Advances in Chromatography, vol. 36. Phyllis R. Brown and Eli Grushka, 127-162 (… [cited by applicant]
Cronin et al., “Measurement of Gene Expression in Archival Paraffin-Embedded Tissues: Development and Performance of a 92-Gene Reverse Transcriptase-Polymerase Chain Reaction Assay,” Am J Pathol. 164(1): 35-42 (2004). [cited by applicant]
Cull et al., “Screening for receptor ligands using large libraries of peptides linked to the C terminus of the lac repressor,” PNAS 89(5):1865-1869 (1992). [cited by applicant]
Cwirla et al., Peptides on phage: a vast library of peptides for identifying ligands, Proc Natl Acad Sci. 87(16):6378-6382 (1990). [cited by applicant]
Davis et al., “Comparison of tumor mutational burden (TMB) across tumor tissue and circulating tumor DNA (ctDNA),” J of Clin Oncol. 35(15 suppl): e23028-e23028 (May 30, 2017) (2 pages). [cited by applicant]
De Luca et al., “NF1 gene analysis based on DHPLC,” Hum Mutat. 21(2):171-172 (2003) (8 pages). [cited by applicant]
De Luca et al., “NF1 Gene Mutations Represent the Major Molecular Event Underlying Neurofibromatosis-Noonan Syndrome,” Am J Hum Genet. 77(6):1092-1101 (2005). [cited by applicant]
De Luca et al., “Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1,” Hum Mutat. 23(6):629 (2004) (14 pages). [cited by applicant]
Devlin et al., “Random Peptide Libraries: a Source of Specific Protein Binding Molecules,” Science. 249(4967):404-406 (1990). [cited by applicant]
Dewitt et al., “‘Diversomers’: an approach to nonpeptide, nonoligomeric chemical diversity,” Proc Natl Acad Sci. 90(15):6909-6913 (1993). [cited by applicant]
Eisenhauer et al., “New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1),” Eur J Cancer. 45(2):228-247 (2009). [cited by applicant]
Elbashir et al., “Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells,” Nature. 411(6836): 494-498 (2001). [cited by applicant]
Erb et al., “Recursive deconvolution of combinatorial chemical libraries,” Proc Natl Acad Sci. 91(24):11422-11426 (1994). [cited by applicant]
Fahsold et al., “Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain,” Am J Hum Genet. 66(3):790-818 (2000). [cited by applicant]
Faria et al., “Phosphoramidate oligonucleotides as potent antisense molecules in cells and in vivo,” Nat Biotechnol. 19:40-44 (2001). [cited by applicant]
Felici et al., “Selection of antibody ligands from a large library of oligopeptides expressed on a multivalent exposition vector,” J Mol Biol. 222(2):301-310 (1991). [cited by applicant]
Ferner et al., “Neurofibromatous neuropathy in neurofibromatosis 1 (NF1)” J Med Genet. 41: 837-841 (2004). [cited by applicant]
Finger et al., “The human PD-1 gene: complete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors” Gene. 197(1-2):177-87 (1997). [cited by applicant]
Fodor et al., “Multiplexed biochemical assays with biological chips,” Nature. 364:555-556 (1993). [cited by applicant]
Forbes et al., “Cosmic: exploring the world's knowledge of somatic mutations in human cancer,” Nucl Acids Res. 43(01):D805-D811 (2015). [cited by applicant]
Francisco et al., “Chapter 4: Melanoma Genetics: From Susceptibility to Progression” Melanoma—From Early Detection to Treatment. IntechOpen, 83-136 (Jan. 2013). [cited by applicant]
Fuchs et al., “Targeting Recombinant Antibodies to the Surface of [cited by applicant]
Gallop et al., “Applications of Combinatorial Technologies to Drug Discovery. 1. Background and Peptide Combinatorial Libraries,” J Med Chem. 37(9):1233-1251 (1994). [cited by applicant]
Garon et al., “Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer,” N Engl J Med. 372(21): 2018-2028 (2015). [cited by applicant]
Garrard et al., “FAB Assembly and Enrichment in a Monovalent Phage Display System,” Biotechnology (N Y). 9(12):1373-1377 (1991). [cited by applicant]
Gasparini et al., “Scanning the first part of the neurofibromatosis type 1 gene by RNA-SSCP: Identification of three novel mutations and of two new polymorphisms,” Hum Genet. 97: 492-495 (1996). [cited by applicant]
Gautier et al., “Alpha-DNA. IV: Alpha-anomeric and beta-anomeric tetrathymidylates covalently linked to intercalating oxazolopyridocarbazole. Synthesis, physicochemical properties and poly (rA) binding,” Nucl Acid Res. … [cited by applicant]
Gerlinger et al., “Ultra-deep T cell receptor sequencing reveals the complexity an intratumour heterogeneity of T cell clones in renal cell carcinomas,” J Pathol. 231(4):424-432 (2013). [cited by applicant]
Ginzinger et al., “Measurement of DNA Copy Number at Microsatellite Loci Using Quantitative PCR Analysis,” Cancer Res. 60(19):5405-5409 (2000) (6 pages). [cited by applicant]
Gnirke et al., “Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing,” avaliable in PMC Aug. 1, 2009, published in final edited form as: Nat Biotechnol. 27(2):182-189 (20… [cited by applicant]
Gram et al., “In vitro selection and affinity maturation of antibodies from a native combinatorial immunoglobulin library,” Proc Natl Acad Sci. U S A 89(8):3576-3580 (1992). [cited by applicant]
Green et al., “Antigen-specific human monoclonal antibodies from mice engineered with human Ig heavy and light chain YACs,” Nat Genet. 7(1):13-21 (1994). [cited by applicant]
Griffin et al., “DNA sequencing. Recent innovations and future trends,” App Biochem Biotechnol. 38(1-2):147-159 (1993). [cited by applicant]
Griffiths et al., “Human anti-self antibodies with high specificity from phage display libraries,” EMBO J. 12(2):725-734 (1993). [cited by applicant]
Guatelli et al., “Isothermal, in vitro amplification of nucleic acids by a multienzyme reaction modeled after retroviral replication,” Proc Natl Acad Sci. 87(5):1874-1878 (1990). [cited by applicant]
Gubin et al., “Cancer. The odds of immunotherapy success,” Science. 350(6257):158-9 (2015) (3 pages). [cited by applicant]
Gubin et al., “The odds of immunotherapy success,” Science. 350(6257):158-9 (2015) (3 pages). [cited by applicant]
Hamid et al., “Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma,” N Engl J Med. 369(2):134-144 (2013). [cited by applicant]
Han et al., “Evaluation of denaturing high performance liquid chromatography (DHPLC) for the mutational analysis of the neurofibromatosis type 1 (NF1) gene,” Hum Genet. 109(5):487-497 (2001). [cited by applicant]
Hansen et al., “PD-L1 Testing in Cancer: Challenges in Companion Diagnostic Development,” JAMA Oncology. 2(1):15-16 (Jan. 2016) (3 pages). [cited by applicant]
Haselhoff et. al., “Simple RNA enzymes with new and highly specific endoribonuclease activites,” Nature. 334(6183):585-591 (1988) (6 pages). [cited by applicant]
Hawkins et al., “Selection of phage antibodies by binding affinity. Mimicking affinity maturation,” J Mol Biol. 226(3):889-96 (1992). [cited by applicant]
Hay et al., “Bacteriophage cloing and [cited by applicant]
Helene et al., “Control of gene expression by triple helix-forming oligonucleotides. The antigene strategy,” Annals of the New York Academy of Sciences. 660:27-36 (1992). [cited by applicant]
Helene et al., “The anti-gene strategy: control of gene expression by triplex-forming-oligonucleotides,” Anti-cancer Drug Design. 6(6):569-584 (1991). [cited by applicant]
Herbst et al., “Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients,” Nature. 515(7528):563-7 (2014) (18 pages). [cited by applicant]
Hodis et al., “A Landscape of Driver Mutations in Melanoma,” available in PMC Jul. 20, 2013, published in final edited form as: Cell. 150(2):251-263 (2012) (24 pages). [cited by applicant]
Hoogenboom et al., “Multi-subunit proteins on the surface of filamentous phage: methodologies for displaying antibody (Fab) heavy and light chains,” Nucleic Acids Research, 19(15):4133-4137 (1991). [cited by applicant]
Houghten et al., “The use of synthetic peptide combinatorial libraries for the identification of bioactive peptides,” Biotechniques. 13(3):412-21 (1992). [cited by applicant]
Hudson et al., “Novel and recurrent mutations in the neurofibromatosis type 1 (NF1) gene,” Hum Mutat. 9(4):366-367 (1997). [cited by applicant]
Hugo et al., “Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma,” Cell. 165(1):35-44 (Mar. 2016) (14 pages). [cited by applicant]
Huse et al., “Generation of a large combinatorial library of the immunoglobulin repertoire in phage lambda,” Science. 246(4935):1275-81 (1989) (5 pages). [cited by applicant]
Hyrup et al., “Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma,” available in PMC Mar. 24, 2017, published in final edited form as: Cell. 165(1):35-44 (1996) (21 pages). [cited by applicant]
Hyrup et al., “Peptide Nucleic Acids (PNA): Synthesis, properties and potential applications,” Bioorganic & Medicinal Chemistry. 4(1):5-23 (1996). [cited by applicant]
Inoue et al., “Sequence-dependent hydrolysis of RNA using modified oligonucelotide splints and RNase H,” FEBS Letters. 215(2):327-330 (1987). [cited by applicant]
Inoue et al., “Synthesis and hybridization studies on two complementary nona(2′-O-methyl)ribonucleotides,” Nucleic Acid Research. 15(15):6131-6148 (1987). [cited by applicant]
Johnson et al., “Clinical Activity of Ipilimumab in Arcal Melanoma: A Retrospective Review,” The Oncologist. 20(6):648-652 (2015). [cited by applicant]
Johnson et al., “Impact of NRAS Mutations for Patients with Advance Melanoma Treated with Immune Therapies,” available in PMC Mar. 1, 2016, published in final edited form as: Cancer Immunol Res. 3(3):288-295 (2015) (17 … [cited by applicant]
Jones et al., “Replacing the complementarity-determining regions in a human antibody with those from a mouse,” Nature. 321(6069):522-5 (1986). [cited by applicant]
Kallioniemi et al., “ERBB2 amplification in breast cancer analyzed by fluorescence in situ hybridization,” PNAS. 89(12)5321-5325 (1992). [cited by applicant]
Kaufmann et al., “Spinal neurofibromatosis without cafe-au-lait macules in two families with null mutations of the NF1 gene,” Am J Hum Genet . . . 69(6):1395-1400 (2001). [cited by applicant]
Kei A Sato et al., “Individualized Mutation Detection in Circulating Tumor DNA for Monitoring Colorectal Tumor Burden Using a Cancer-Associated Gene Sequencing Panel,” PLoS One. Jan. 4, 2016;11(1): e0146275 .doi:10.1371… [cited by applicant]
Klose et al., “Selective Disactiviation of Neurofibromin GAP Activity in Neurofibromatosis Type 1 (NF1),” Human Molecular Genetics, 7(8): 1261-1268 (1998). [cited by applicant]
Kluwe et al., “Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas,” J Med Genet, 40(2):109-114 (2003). [cited by applicant]
Kluwe et al., “NF1 mutations in neurofibromatosis 1 patients with plexiform neurofibromas,” Human Mutation. 19(3):309 (2002) (5 pages). [cited by applicant]
Krauthammer et al., “Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanoma,” available in PMC Jun. 22, 2016, published in final edited form as: Nat Genet. 47(9):996-1002 (201… [cited by applicant]
Krauthammer et al., “Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma,” avaliable in PMC Mar. 1, 2013, published in final edited form as: Nat Genet. 44(9):1006-1014 (2012) (30 pages). [cited by applicant]
Krkljus et al., “Analysis of CpG C-to-T mutations in neurofibromatosis type 1,” Human Mutation, 11(5):411 (11 pages) (1998). [cited by applicant]
Kwoh et al., “Transcription-based amplification system and detection of amplified human immunodeficiency virus type 1 with a bead-based sandwich hybridization format,” Proc Natl Acad Sci U S A. 86(4):1173-7 (1989). [cited by applicant]
Lam et al., “A new type of synthetic peptide library for identifying ligand-binding activity,” Nature. 354(6348):82-84 (1991). [cited by applicant]
Lam, “Application of combinatorial library methods in cancer research and drug discovery,” Anticancer Drug Des. 12(3):145-67 (1997). [cited by applicant]
Landegren et al., “A ligase-mediated gene detection technique,” Science. 241(4869):1077-80 (1988). [cited by applicant]
Larkin et al., “Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma,” available in PMC Nov. 22, 2017, published in final edited form as: N Engl J Med. 373(1):23-34 (2015) (18 pages). [cited by applicant]
Lemaitre et al., “Specific antiviral activity of a poly(L-lysine)-conjugated oligodeoxyribonucleotide sequence complementary to vesicular stomatitis virus N protein mRNA initiation site,” PNAS. 84(3):648-652 (1987). [cited by applicant]
Letsinger et al., (1989). “Cholesteryl-conjugated oligonucleotides: synthesis, properties, and activity as inhibitors of replication of human immunodeficiency virus in cell culture,” PNAS, 86(17):6553-6556. [cited by applicant]
Li et al., “Genomic organization of the neurofibromatosis 1 gene (NF1 ),” Genomics. 25(1):9-18 (1995). [cited by applicant]
Li et al., “Somatic mutations in the neurofibromatosis 1 gene in human tumors,” Cell. 69(2):275-281 (1992). [cited by applicant]
Liu et al., “Chimeric mouse-human IgG1 antibody that can mediate lysis of cancer cells,” Proc Natl Acad Sci USA. 84(10):3439-43 (1987). [cited by applicant]
Liu et al., “Genomic Organization of a New Candidate Tumor Suppressor Gene, LRP1 B,” Genomics. 69(2):271-274 (2000). [cited by applicant]
Liu et al., “LRP-DIT, a Putative Endocytic Receptor Gene, Is Frequently Inactivated in Non-Small Cell Lung Cancer Cell Lines,” Cancer Research. 60(7):1961-1967 (2000) (9 pages). [cited by applicant]
Liu et al., “Production of a mouse-human chimeric monoclonal antibody to CD20 with potent Fc-dependent biologic activity,” J Immunol. 139(10):3521-26 (1987). [cited by applicant]
Lonberg et al., “Antigen-specific human antibodies from mice comprising four distinct genetic modifications,” Nature. 368(6474): 856-859 (1994). [cited by applicant]
Luke et al., “Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and Univer… [cited by applicant]
Maher, L.J., “DNA triple-helix formation: an approach to artificial gene repressors?,” Bioessays. 14( 12) :807-815 (1992). [cited by applicant]
Marchuk et al., “cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product,” Genomics. 11 (4): 931-940 (1991). [cited by applicant]
Martin et al., “The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21,” Cell. 63(4):843-849 (1990). [cited by applicant]
Masuda et al., “Analysis of chemical modification of RNA from formalin-fixed samples and optimization of molecular biology applications for such samples,” Nucleic Acids Research. 27(22):4436-4443 (1999). [cited by applicant]
Mattocks et al., “Automated comparative sequence analysis identifies mutations in 89% of NF1 patients and confirms a mutation cluster in exons 11-17 distinct from the GAP related domain,” Journal of Medical Genetics. 41… [cited by applicant]
Maxam et al., “A new method for sequencing DNA,” Proc Natl Acad Sci U.S.A. 74(2):560-4 (1977). [cited by applicant]
Maynard et al., “Characterization and significance of nine novel mutations in exon 16 of the neurofibromatosis type 1 (NF1) gene,” Human Genetics. 99(5):674-6 (1997). [cited by applicant]
Messiaen et al., “Exon 10b of the NF1 gene represents a mutational hotspot and harbors a recurrent missense mutation Y489C associated with aberrant splicing,” Genetics in Medicine. 1 (6):248-253 (1999). [cited by applicant]
Metzker, “Sequencing technologies—the next generation,” Nature Reviews Genetics. 11 (1 ):31-46 (2010). [cited by applicant]
Morrison et al., “Chimeric human antibody molecules: Mouse antigen-binding domains with human constant region domains,” Proc Natl Acad Sci U S A. 81(21):6851-5 (1984). [cited by applicant]
Morrison, “Transfectomas provide novel chimeric antibodies,” Science. 229(4719):1202-7 (1985). [cited by applicant]
Naeve et al., “Accuracy of automated DNA sequencing: a multi-laboratory comparison of sequencing results,” Biotechniques 19(3):448-53 (1995). [cited by applicant]
Nath et al., “Fluorescence in situ hybridization (FISH): DNA probe production and hybridization criteria,” Biotechnic & Histochemistry. 73(1 ):6-22 (1998) (18 pages). [cited by applicant]
Nemethova et al., “Thirty-nine novel neurofibromatosis 1 (NF1) gene mutations identified in Slovak patients,” Annals of Human Genetics. 77(5):364-379 (2013). [cited by applicant]
Nikolaev et al., “Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma,” Nature Genetics. 44(2):133-139 (2011) (9 pages). [cited by applicant]
Nishi et al., “Differential expression of two types of the neurofibromatosis type 1 (NF1) gene transcripts related to neuronal differentiation,” Oncogene. 6(9):1555-1559 (1991). [cited by applicant]
Nishimura et al., “Recombinant human-mouse chimeric monoclonal antibody specific for common acute lymphocytic leukemia antigen,” Cancer Research. 47(4):999-1005 (1987). [cited by applicant]
Nissan et al., “Loss of NF1 in Cutaneous Melanoma Is Associated with RAS Activation and MEK Dependence,” available in PMC Apr. 15, 2015, published in final edited form as: Cancer Research. 74(8):2340-2350 (2014) (18 pag… [cited by applicant]
Nyström et al., “Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1 ,” Clinical Genetics. 76(6):524-534 (2009). [cited by applicant]
Oi et al., “Chimeric Antibodies,” BioTechniques. 4(3):214-221 (1986) (8 pages). [cited by applicant]
Paz-Ares, et al., “Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer” The New England Journal of Medicine. 379:21 (2018) (12 pages). [cited by applicant]
Perry-O'Keefe et al., “Peptide nucleic acid pre-gel hybridization: an alternative to southern hybridization,” PNAS. 93(25): 14670-14675 (1996) . . . . [cited by applicant]
Peters et al., “A novel mutation L 1425p in the GAP-region of the NF1 gene detected by temperature gradient gel electrophoresis (TGGE),” Human Mutation. 13(4):337 (1999) (5 pages). [cited by applicant]
Peters et al., “Atezolizumab versus chemotherapy in advanced or metastatic NSCLC with high blood-based tumor mutational burden: primary analysis of BFAST cohort C randomized phase 3 trial,” Nat Med. 28(9):1831-1839 (202… [cited by applicant]
Pinkel et al., “Fluorescence in situ hybridization with human chromosome-specific libraries: detection of trisomy 21 and translocations of chromosome 4,” Proc Natl Acad Sci U S A. 85(23):9138-42 (1988). [cited by applicant]
Pinkel et al., “High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays,” Nature Genetics. 20(2):207-11 (1998). [cited by applicant]
Ponti et al., “Clinico-pathological and biomolecular findings in Italian patients with multiple cutaneous neurofibromas,” Hereditary Cancer in Clinical Practive. 9(1):6 (2011) (9 pages). [cited by applicant]
Postow et al., “Ipilimumab for Patients With Advanced Mucosal Melanoma,” The Oncologist. 18(6):726-32 (2013). [cited by applicant]
Purandare et al., “Characterisation of inherited and sporadic mutations in neurofibromatosis type-1,” Hum Mol Genet. 3(7):1109-1115 (1994). [cited by applicant]
Redman et al., “Advances in immunotherapy for melanoma,” BMC Medicine. 14(1):20 (Dec. 2016) (11 pages). [cited by applicant]
Rizvi et al., “Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial,” availa… [cited by applicant]
Robert et al., “Nivolumab in Previously Untreated Melanoma without BRAF Mutation,” N Engl J Med. 372(4):320-30 (2015). [cited by applicant]
Robert et al., “Pembrolizumab versus Ipilimumab in Advanced Melanoma,” N Engl J Med. 372(26):2521-32 (2015). [cited by applicant]
Sanger et al., “DNA sequencing with chain-terminating inhibitors,” Proc Natl Acad Sci U.S.A. 74(12):5463-7 (1977). [cited by applicant]
Schrock et al., “Characterization of 298 Patients with Lung Cancer Harboring MET Exon 14 Skipping Alterations,” J Thorac Oncol. 11(9):1493-502 (Sep. 2016). [cited by applicant]
Schumacher et al., “Biomarkers in Cancer Immunotherapy,” Cancer Cell. 27(1):12-14 (2015). [cited by applicant]
Scott et al., “Searching for peptide ligands with an epitope library,” Science. 249(4967):386-390 (1990). [cited by applicant]
Shaw et al., “Mouse/human chimeric antibodies to a tumor-associated antigen: biologic activity of the four human IgG subclasses,” J Nat Canc Inst. 80(19):1553-1559 (1988). [cited by applicant]
Shen et al., “Neurofibromatosis type 1 (NF1 ): the search for mutations by PCR-heteroduplex analysis on Hydrolink gels,” Hum Mol Genet. 2(11):1861-1864 (1993). [cited by applicant]
Shen et al., “ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors,” Cancer Discov. 5(7):752-67 (2015) (17 pages). [cited by applicant]
Shen et al., “Molecular genetics of neurofibromatosis type 1 (NF1),” J Med Genet. 33(1):2-17 (1996). [cited by applicant]
Shinohara et al., “Structure and chromosomal localization of the human PD-1 gene (PDCD1 ),” Genomics. 23(3):704-706 (1994). [cited by applicant]
Siolas et al., “Synthetic shRNAs as potent RNAi triggers,” Nature Biotechnology. 23(2):227-31 (2005). [cited by applicant]
Sjöblom et al., “The Consensus Coding Sequences of Human Breast and Colorectal Cancers,” Science. 314(5797): 268-74 (2006) (8 pages). [cited by applicant]
Smith et al., “Common fragile sites, extremely large genes, neural development and cancer,” Cancer Lett. 232(1):48-57 (2006). [cited by applicant]
Snyder et al., “Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma,” N Engl J Med. 371(23):2189-2199 (2014). [cited by applicant]
Specht et al., “Quantitative Gene Expression Analysis in Microdissected Archival Formalin-Fixed and Paraffin-Embedded Tumor Tissue,” AJP. 158(2):419-29 (2001). [cited by applicant]
Spranger et al., “Melanoma-intrinsic beta-catenin signaling prevents anti-tumour immunity,” Nature. 523(7559): 231-235 (2015) (18 pages). [cited by applicant]
Sun et al., “Chimeric antibody with human constant regions and mouse variable regions directed against carcinoma-associated antigen 17-1A,” Proc Natl Acad Sci USA. 84(1):214-8 (1987). [cited by applicant]
Suzuki et al., “Brain tumors predominantly express the neurofibromatosis type 1 gene transcripts containing the 63 base insert in the region coding for GTPase activating protein-related domain,” Biochem Biophys Res Comm… [cited by applicant]
Suzuki et al., “Evidence for the Presence of Two Amino-Terminal Isoforms of Neurofibromin, a Gene Product Responsible for Neurofibromatosis Type 1,” Tohoku J Exp Med. 175(4):225-33. (1995). [cited by applicant]
Suzuki et al., “Molecular cloning of a cDNA coding for neurofibromatosis type 1 protein isoform lacking the domain related to ras GTPase-activating protein,” Biochem Biophys Res Commun. 187(2):984-990 (1992). [cited by applicant]
Tassabehji et al., “Tandem Duplication within a Neurofibromatosis Type I (NFI) Gene Exon in a Family with Features of Watson Syndrome and Noonan Syndrome,” Am J Hum Genet. 53(1):90-5 (1993). [cited by applicant]
Thomas et al., “Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas,” European Journal of Human Genetics. 20(4):411-9 (2012). [cited by applicant]
Topalian et al., “Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer,” N Engl J Med. 366(26):2443-54 (2012). [cited by applicant]
Toulme, “New candidates for true antisense,” Nat Biotechnol. 19(1):17-18 (2001). [cited by applicant]
Trapnell et al., “How to map billions of short reads onto genomes,” available in PMC May 1, 2010, published in final edited form as: Nat Biotechnol. 27(5):455-7 (2009) (9 pages). [cited by applicant]
Tuaillon et al., “Human immunoglobulin heavy-chain minilocus recombination in transgenic mice: Gene-segment use in mu and gamma transcripts,” Proc Natl Acad Sci USA. 90(8):3720-4 (1993). [cited by applicant]
Tumeh et al., “PD-1 blockade induces responses by inhibiting adaptive immune resistance,” available in PMC May 26, 2015, published in final edited form as: Nature. 515(7528):568-571 (2014) (24 pages). [cited by applicant]
Upadhyaya et al., “An Absence of Cutaneous Neurofibromas Associated with a 3-bp Inframe Deletion in Exon 17 of the NF1 Gene (c.2970-2972 delAAT): Evidence of a Clinically Significant NF1 Genotype-Phenotype Correlation,”… [cited by applicant]
Upadhyaya et al., “Analysis of mutations at the neurofibromatosis 1 (NF1) locus,” Hum Mol Genet. 1(9): 735-740 (1992). [cited by applicant]
Upadhyaya et al., “Characterisation of germline mutations in the neurofibromatosis type 1 (NF1) gene,” J Med Genet. 32(9):706-10 (1995). [cited by applicant]
Upadhyaya et al., “Molecular basis of neurofibromatosis type 1 (NF1): mutation analysis and polymorphisms in the NF1 gene,” Hum Mutat. 4(2): 83-101 (1994). [cited by applicant]
Upadhyaya et al., “Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene,” Hum Genet. 99(1):88-92 (1997). [cited by applicant]
Upadhyaya et al.; “Six novel mutations in the neurofibromatosis type 1 (NF1) gene,” Human Mutation. 10(3):248-50 (1997). [cited by applicant]
Van der Krol et al., “Modulation of Eukaryotic Gene Expression by Complementary RNA or DNA Sequences,” BioTechniques. 6(10):958-76 (1988). [cited by applicant]
Verhoeyen et al., “Reshaping Human Antibodies: Grafting an Antilysozyme Activity,” Science. 239(4847):1534-6 (1988). [cited by applicant]
Wallace et al., “Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients,” Science. 249(4965): 181-186 (1990) (7 pages). [cited by applicant]
Wang et al., “Assessment of Blood Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Patients With Non-Small Cell Lung Cancer With Use of a Next-Generation Sequencing Cancer Gene Panel,” Jama Oncology… [cited by applicant]
Wang et al., “Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type,” Hum Genet. 112(2):117-123 (2003). [cited by applicant]
Warren et al., “Assembling millions of short DNA sequences using SSAKE,” Bioinformatics 23(4): 500-1 (2007). [cited by applicant]
Weber et al., “Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial,” Lancet Oncol. 16(4):375-8… [cited by applicant]
Wheeless et al., “Bladder Irrigation Specimens Assayed by Fluorescence In Situ Hybridization to Interphase Nuclei,” Cytometry. 17(4):319-26 (1994). [cited by applicant]
Wiesner et al., “NF1 Mutations are Common in Desmoplastic Melanoma,” available in PMC Oct. 1, 2016, published in final edited form as: Am J Surg Pathol. 39(10):1357-62 (2015) (14 pages). [cited by applicant]
Wikipedia, “Exome,” available online at <https://en.wikipedia.org/w/index.php?title=Exome&oldid=1010823778> (2021) (2 pages). [cited by applicant]
Wolchok, Jedd D., “PD-1 Blockers,” Cell. 162(5):937 (2015) (1 page). [cited by applicant]
Wood et al., “The synthesis and in vivo assembly of functional antibodies in yeast,” Nature. 314(6010): 446-449 (1985). [cited by applicant]
Woolf et al., “Specificity of antisense oligonucleotides in vivo,” Proc Natl Acad Sci USA. 89(16):7305-9 (1992). [cited by applicant]
Wu et al., “Neurofibromatosis type I gene mutation in a patient with features of Leopard syndrome,” Hum Mutat. 8(1): 51-56 (1996). [cited by applicant]
Wu et al., “The ligation amplification reaction (LAR)—amplification of specific DNA sequences using sequential rounds of template-dependent ligation,” Genomics. 4(4):560-9 (1989). [cited by applicant]
Xu et al., “The neurofibromatosis type 1 gene encodes a protein related to GAP,” Cell. 62(3): 599-608 (1990). [cited by applicant]
Yang et al., “Short RNA duplexes produced by hydrolysis with [cited by applicant]
Zatkova et al., “Disruption of Exonic Splicing Enhancer Elements Is the Principal Cause of Exon Skipping Associated With Seven Nonsense or Missense Alleles of NF1,” Hum Mutat. 24(6):491-501 (2004). [cited by applicant]
Zerbino et al., “Velvet: Algorithms for de novo short read assembly using de Bruijn graphs,” Genome Research. 18:821-829 (2008) (11 pages). [cited by applicant]
Zon, “Oligonucleotide analogues as potential chemotherapeutic agents,” Pharm Res. 5(9): 539-549 (1988). [cited by applicant]
Zuckermann et al., “Discovery of Nanomolar Ligands for 7-Transmembrane G-Protein-Coupled Receptors from a Diverse N-(Substituted)glycine Peptoid Library,” J Med Chem. 37(17):2678-2685 (1994). [cited by applicant]
Extended European Search Report for European Patent Application No. 22191450.0, dated Feb. 16, 2023 (7 pages). [cited by applicant]
“Exome,” Wikipedia. Retrieved from <https://en.wikipedia.org/w/index.php?title=Exome&oldid=1010823778> on Jun. 17, 2021 (6 pages). [cited by applicant]
Asmar et al., “Clinical utility of nivolumab in the treatment of advanced melanoma,” Ther Clin Risk Manag. 12:313-25 (2016). [cited by applicant]
Bahary et al., “Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with pancreatic ductal adenocarcinoma (PDA),” J Clin Oncol. 35(15):4128 (2017) (Abstract Only) (5 pages). [cited by applicant]
Bardoli et al., “The PD-1/PD-L1 axis in the pathogenesis of urothelial bladder cancer and evaluating its potential as a therapeutic target,” Future Oncol. 12(5):595-600 (2016). [cited by applicant]
Bidnur et al., “Inhibiting Immune Checkpoints for the Treatment of Bladder Cancer,” Bladder Cancer. 2(1): 15-25 (2016) (11 pages). [cited by applicant]
Campesato et al., “Comprehensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice,” Oncotarget. 6(33):34221-7 (2015) (7 pages). [cited by applicant]
Caris Life Sciences, “Total Mutational Load—Immune Checkpoint Inhibitors Response,” <https://www.carismolecularintelligence.com/wp-content/uploads/2016/12/TN0291-v1_Total-Mutational-Load-Immunotherapy-REVERSED-PAGES.pdf… [cited by applicant]
Castro et al., “Mismatch repair deficiency associate with complete remission to combination programmed cell death ligan immune therapy in a patient with sporadic urothelial carcinoma: immunotheranostic considerations,” … [cited by applicant]
Cazier et al., “Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden,” Nat Commun. 5:3756 (2014) (13 pages). [cited by applicant]
Chalmers et al., “Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden,” Genome Med. 9(1):34 (2017) (14 pages). [cited by applicant]
Champiat et al., “Exomics and immunogenics,” OncoImmunology. 3(1):e27817 (2014). [cited by applicant]
Choudhury et al., “Low T-cell Receptor Diversity, High Somatic Mutation Burden, and High Neoantigen Load as Predictors of Clinical Outcome in Muscle-invasive Bladder Cancer,” Eur Urol Focus. 2(4):445-452 (2015). [cited by applicant]
Dagogo-Jack et al., “Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with advanced non-small cell lung cancer (NSCLC),” J Clin Oncol. 35(15 suppl):9025 (2017) (5 pages). [cited by applicant]
Diaz et al., “Liquid Biopsies: Genotyping Circulating Tumor DNA,” J Clin Oncol. 32(6):579-586 (2014) (9 pages). [cited by applicant]
Fabbri et al., “Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation,” J Exp Med. 208(7):1389-401 (2011). [cited by applicant]
Fakhrejahani et al., “Immunotherapies for bladder cancer: a new hope,” Curr Opin Urol. 25(6):586-596 (2015). [cited by applicant]
FoundationOne, “Technical Information and Test Overview,” retrieved on Jan. 18, 2018 from <https://assets.contentful.com/vhribv12Imne/6YRrchSINOeSu48YwuesoY/caeec492925a7d569ce4e070866f709b/F1_-_Tech_Specs.pdf> (2 pages… [cited by applicant]
Frampton et al., “Assessment of tumor mutation burden from >60,000 clinical cancer patients using comprehensive genomic profiling,” J Clin Oncol. 34(15 suppl):11558 (2016) (5 pages). [cited by applicant]
Frampton et al., “Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing,” available in PMC Dec. 1, 2017, published in final edited form as: Nat Biotechnol. 31(… [cited by applicant]
Gabril et al., “Molecular Testing in Urothelial Tumors,” Springer. 301-17 (2014). [cited by applicant]
Gandara et al., “Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab,” Nat Med. 24(9):1441-8 (2018) (8 pages). [cited by applicant]
Gatalica et al., “Programmed Cell Death 1 (PD-1) and Its Ligand (PD-L1) in Common Cancers and Their Correlation with Molecular Cancer Type,” Cancer Epidemiol Biomarkers Prev. 23(12): 2965-2970 (2014). [cited by applicant]
Ghasemzadeh et al., “New Strategies in Bladder Cancer: A Second Coming for Immunotherapy,” Clin Cancer Res. 22(4):793-801 (2015). [cited by applicant]
Govindan et al., “Genomic landscape of non-small cell lung cancer in smokers and never-smokers,” Cell. 150(6):1121-34 and supplemental content (2012) (24 pages). [cited by applicant]
Gubin et al., “Checkpoint Blockade Cancer Immunotherapy Targets Tumour-Specific Mutant Antigens,” Nature. 515(7528):577-81 (2014). [cited by applicant]
Gui et al., “Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder,” Nat Genet. 43(9):875-8 (2011). [cited by applicant]
Henick et al., “The PD-1 pathway as a therapeutic target to overcome immune escape mechanisms in cancer,” Expert Opin Ther Targets. 18(12):1407-20 (2014) (14 pages). [cited by applicant]
Howitt et al., “Association of Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1,” JAMA Oncol. 1(9):131… [cited by applicant]
Jing et al., “PD-I/PD-LI blockades in non-small-cell lung cancer therapy,” Onco Targets Ther. 9:489-502 (2016). [cited by applicant]
Johnson et al., “Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade,” available in PMC Nov. 1, 2017, published in final edited form as: Cancer Immunol Res. 4(11):959-67 (2016) (17 pages). [cited by applicant]
Kates et al., “Immune checkpoint inhibitors: a new frontier in bladder cancer,” World J Urol. 34(1):49-55 (2016) (7 pages). [cited by applicant]
Kim et al., “Emerging immunotherapies for bladder cancer,” Curr Opin Oncol. 27(3):191-200 (2015). [cited by applicant]
Kim, “Immune checkpoint blockade therapy for bladder cancer treatment,” Investig Clin Urol. 57 Suppl 1(Suppl 1):S98-S105 (2016). [cited by applicant]
Knowles et al., “Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity,” Nat Rev Cancer. 15(1):25-41 (2015). [cited by applicant]
Kowanetz et al., “Tumor Mutation Burden (TMB) is Associated with Improved Efficacy of Atezolizumab in 1L and 2L+ NSCLC Patients,” J Thorac Oncol. 12(1):S321-2 OA20.01 (Abstract) (2017). [cited by applicant]
Kurtoglu et al., “Elevating the Horizon: Emerging Molecular and Genomic Targets in the Treatment of Advanced Urothelial Carcinoma,” Clin Genitourin Cancer. 13(5):410-20 (2015). [cited by applicant]
Le et al., “PD-1 Blockade in Tumors with Mismatch-Repair Deficiency,” N Engl J Med. 372(26):2509-2520 (2015). [cited by applicant]
Llosa et al., “The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer Is Balanced by Multiple Counter-Inhibitory Checkpoints,” Cancer Discov. 5(1):43-51 (2015). [cited by applicant]
Maby et al., “Correlation between Density of CD8 [cited by applicant]
Marcq et al., “Targeting immune checkpoints: New opportunity for mesothelioma treatment?” Cancer Treat Rev. 41(10):914-24 (2015) (11 pages). [cited by applicant]
Melero et al., “Evolving synergistic combinations of targeted immunotherapies to combat cancer,” Nat Rev Cancer. 15(8):457-72 (2015) (16 pages). [cited by applicant]
Meng et al., “Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy,” Cancer Treat Rev. 41(10):868-76 (2015). [cited by applicant]
Millis et al., “Molecular Profiling of Infiltrating Urothelial Carcinoma of Bladder and Nonbladder Origin,” Clin Genitourin Cancer. 13(1):e37-49 (2015). [cited by applicant]
Morse et al., “Elevated tumor mutational burden and prolonged clinical response to anti-PD-L1 antibody in platinum-resistant recurrent ovarian cancer,” Gynecol Oncol Rep. 21:78-80 (2017). [cited by applicant]
Powles et al., “MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer,” Nature. 515(7528): 558-62 (includes supplemental content) (2014) (12 pages). [cited by applicant]
Rizvi et al., “Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer,” Science. 348(6230):124-8 and supplementary materials (2015) (37 pages). [cited by applicant]
Rooney et al., “Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity,” Cell. 160(1-2):48-61 (2015). [cited by applicant]
Rosenberg et al., “Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial,” … [cited by applicant]
Rosenberg et al., “Supplement to: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single arm, phase 2 trial,… [cited by applicant]
Schumacher et al., “Neoantigens in cancer immunotherapy,” Science. 348(6230):69-74 (2015). [cited by applicant]
Stephens et al., “Analytic validation of a clinical circulating tumor DNA assay for patients with solid tumors,” Ann Oncol. 27(Suppl. 6):vi401-vi406 (2016) (Abstract Only) (1 page). [cited by applicant]
Strickland et al., “Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer,” On… [cited by applicant]
Tamborero et al., “OncodriveCLUST: exploiting the positional clustering of somatic mutations to identify cancer genes,” Bioinformatics. 29(18):2238-44 (2013). [cited by applicant]
The Cancer Genome Atlas Research Network, “Comprehensive molecular characterization of urothelial bladder carcinoma,” Nature. 507:315-22 (2014). [cited by applicant]
Vaish et al., “Microsatellite instability as prognostic marker in bladder tumors: a clinical significance,” BMC Urol. 5:2 (2005) (7 pages). [cited by applicant]
Van Allen et al., “Genomic correlates of response to CTLA-4 blockade in metastatic melanoma,” Science. 350(6257):207-211 (2015) (5 pages). [cited by applicant]
Van Buuren et al., “High sensitivity of cancer exome-based CD8 T cell neo-antigen identification,” OncoImmunology. 3:e28836 (2014) (7 pages). [cited by applicant]
Vansteenkiste et al., “Prospects and progress of atezolizumab in non-small cell lung cancer,” Expert Opin Biol Ther. 17(6):781-9 (2017) (10 pages). [cited by applicant]
Yamamoto et al., “Microsatellite instability: an update,” Arch Toxicol. 89(6):899-921 (2015). [cited by applicant]
Yap et al., “Whole-Exome Sequencing of Muscle-Invasive Bladder Cancer Identifies Recurrent Mutations of UNC5C and Prognostic Importance of DNA Repair Gene Mutations on Survival,” Clin Cancer Res. 20(24):6605-17 (2014). [cited by applicant]
Decision of Rejection for Japanese Patent Application No. 2018-545157, issued May 12, 2020 (10 pages). [cited by applicant]
Examination Report for Australian Patent Application No. 2017225854, dated Nov. 29, 2019 (3 pages). [cited by applicant]
First Office Action and Search Report for Chinese Application No. 201780024162.0, dated Sep. 25, 2020 (11 pages). [cited by applicant]
International Preliminary Report on Patentability for International Patent Application No. PCT/US2017/019682, issued Sep. 4, 2018 (8 pages). [cited by applicant]
International Preliminary Report on Patentability for International Patent Application No. PCT/US2017/019763, issued Sep. 4, 2018 (19 pages). [cited by applicant]
International Search Report and Written Opinion for International Patent Application No. PCT/US2017/019682, mailed Apr. 24, 2017 (17 pages). [cited by applicant]
International Search Report and Written Opinion for International Patent Application No. PCT/US2017/019763, mailed Aug. 2, 2017 (25 pages). [cited by applicant]
International Search Report and Written Opinion for International Patent Application No. PCT/US2017/055669, mailed Jan. 8, 2018 (21 pages). [cited by applicant]
International Search Report and Written Opinion for International Patent Application No. PCT/US2018/043074, mailed Oct. 29, 2018 (17 pages). [cited by applicant]
Notice of Preliminary Rejection for Korean Patent Application No. 10-2018-7027973, dated Oct. 16, 2019 (11 pages). [cited by applicant]
Notice of Preliminary Rejection for Korean Patent Application No. 10-2018-7027973, dated Oct. 26, 2020 (6 pages). [cited by applicant]
Notice of Preliminary Rejection for Korean Patent Application No. 10-2021-7032039, dated Jan. 17, 2022 (8 pages). [cited by applicant]
Notice of Reasons for Rejection for Japanese Patent Application No. 2018-545157, dated Sep. 24, 2019 (12 pages). [cited by applicant]
Office Action for Canadian Patent Application No. 3,015,528, dated Jul. 22, 2020 (4 pages). [cited by applicant]
Office Action for Canadian Patent Application No. 3,015,528, dated Jun. 27, 2019 (4 pages). [cited by applicant]
Second Office Action for Chinese Application No. 201780024162.0, dated Jan. 11, 2021 (9 pages). [cited by applicant]
Borch et al., “Reorienting the immune system in the treatment of cancer by using anti-PD-1 and anti-PD-L1 antibodies,” Drug Discovery Today. 20(9):12 pages (2015). [cited by applicant]
Powles et al., “Immune biomarkers associated with clinical benefit from atezolizumab (MPDL3280a; anti-PD-L1) in advanced urothelial bladder cancer (UBC),” Journal for ImmunoTherapy of Cancer. 3(Suppl 2):P83 (2015). [cited by applicant]
Sherry et al., “dbSNP: the NCBI database of genetic variation,” Nucleic Acids Research. 29(1): 308-311 (2001). [cited by applicant]
Shien et al., “Predictive biomarkers of response to PD-1/PD-L1 immune checkpoint inhibitors in non-small cell lung cancer,” Lung Cancer. 99(1): 79-87 (Jun. 21, 2016). [cited by applicant]
Shukuya et al., “Predictive Markers for the Efficacy of Anti-PD-1/PD-L1 Antibodies in Lung Cancer,” J. Thorac. Oncol. 11(7): 976-988 (Mar. 1, 2016). [cited by applicant]