IP Library › Granted Patent US 12,274,699
Granted Patent B2
US 12,274,699 · App. 18/346,029 · Granted Apr 15, 2025

Methods of treating cholangiocarcinoma

Inventors: Siraj Mahamed Ali (Cambridge, MA); Matthew J. Hawryluk (Newton, MA); Jie He (Newton, MA); Doron Lipson (Chestnut Hill, MA); Vincent A. Miller (West Orange, NJ); Jeffrey S. Ross (Lebanon Springs, NY); Philip James Stephens (Lexington, MA)
Assignee: Foundation Medicine, Inc.
A61K31/5025A61K31/404A61K31/435A61K31/4412A61K31/4439A61K31/47A61K31/496A61K31/498A61K31/506A61K31/517A61K31/519A61K31/53A61K31/5383A61K31/553A61K45/06C07K14/705C07K14/71C07K16/40C12N9/12C12N15/1137C12Q1/6883C12Q1/6886C12Y207/10001G01N33/573C07K2319/00C12N2310/11C12N2310/12C12N2310/14C12Q2600/156C12Q2600/158G01N2333/912G01N2500/04
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Quick Facts
Patent No.
US 12,274,699
App. No.
18/346,029
Granted
Apr 15, 2025
Kind
B2
Abstract

Methods and compositions for treating cholangiocarcinoma.

Claims (57)

1. A method of determining presence of a fibroblast growth factor receptor (FGFR) gene fusion or a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, comprising:

detecting an FGFR or NTRK gene fusion in an FGFR or NTRK nucleic acid molecule or polypeptide in a sample obtained from a subject that has or is at risk of having a cholangiocarcinoma, thereby determining that the FGFR or NTRK gene fusion is present in the sample; and

responsive to the determination of the presence of the FGFR or NTRK gene fusion in the sample, generating a report comprising one or more therapeutic options comprising a therapeutic agent that antagonizes or inhibits an FGFR gene or gene product or an NTRK gene or gene product.

2. The method of claim 1 , further comprising administering to the subject an effective amount of the therapeutic agent.

3. The method of claim 1 , wherein said therapeutic agent comprises one or more of:

a kinase inhibitor;

a tyrosine kinase inhibitor;

a pan-FGFR2 inhibitor;

a pan-TRK inhibitor;

a multi-specific kinase inhibitor;

an FGF receptor inhibitor;

a reversible or an irreversible FGFR2 inhibitor;

a small molecule that binds to the FGFR2 gene product or the NTRK1 gene product;

an antibody molecule against the FGFR2 gene product or the NTRK1 gene product;

a kinase inhibitor that is selective for the FGFR2 gene product or the NTRK1 gene product; and

a siRNA, antisense RNA, or other nucleic acid based inhibitor of the FGFR2 gene or gene product or the NTRK1 gene or gene product.

4. The method of claim 1 , wherein said therapeutic agent comprises one or more of AZD-2171, AZD-4547, BGJ398, BIBF1120, Brivanib, Cediranib, Dovitinib, ENMD-2076, JNJ 42756493, Masitinib, Lenvatinib, LY2874455, Ponatinib, Pazopanib, R406, Regorafenib, PD173074, PD-173955, Danusertib, Dovitinib Dilactic Acid, TSU-68, Tyrphostin AG 1296, MK-2461, Brivanib Alaninate, Lestaurtinib, PHA-848125, K252a, AZ-23, Oxindole-3, AV369b, ACTB1003, Volasertib, R1530, Loxo-101, ARRY-470, ARRY-786, RXDX-101, RXDX-102, axitinib, bosutinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, neratinib, nilotinib, semaxanib, sunitinib, toceranib, vandetanib, vatalanib, sorafenib, PCI-32765, AC220, dovitinib lactate, BIBW 2992, SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib, OSI-930, MM-121, XL-184, XL-647, and XL228.

5. The method of claim 1 , wherein the cholangiocarcinoma is an intrahepatic cholangiocarcinoma (ICC).

6. The method of claim 1 , wherein the cholangiocarcinoma is an extrahepatic cholangiocarcinoma.

7. The method of claim 1 , wherein the cholangiocarcinoma is a metastatic cholangiocarcinoma.

8. The method of claim 1 , further comprising acquiring the sample from the subject.

9. The method of claim 1 , wherein the sample comprises genomic DNA, cDNA, or RNA.

10. The method of claim 1 , wherein the sample comprises cancerous tissue, whole blood, serum, plasma, buccal scrape, sputum, saliva, cerebrospinal fluid, urine, stool, circulating tumor cells, circulating nucleic acids, or bone marrow.

11. The method of claim 10 , wherein the sample is a tissue biopsy sample.

12. The method of claim 10 , wherein the sample comprises circulating tumor cells or circulating nucleic acids.

13. The method of claim 1 , further comprising, prior to acquiring the sequence, enriching the sample for an FGFR or NTRK nucleic acid molecule.

14. The method of claim 1 , wherein the FGFR gene fusion is an FGFR1, FGFR2, or FGFR3 gene fusion.

15. The method of claim 1 , wherein the NTRK gene fusion is an NTRK1 gene fusion.

16. The method of claim 1 , wherein detecting the FGFR or NTRK gene fusion comprises sequencing at least nucleic acid molecule that comprises the FGFR or NTRK gene fusion.

17. The method of claim 16 , wherein the sequencing is next-generation sequencing (NGS).

18. The method of claim 1 , wherein the sequencing comprises:

(a) hybridizing an oligonucleotide specific for the FGFR or NTRK gene fusion to the FGFR or NTRK nucleic acid molecule;

(b) hybridizing a primer that amplifies a region comprising the fusion junction of the FGFR or NTRK gene fusion to the FGFR or NTRK nucleic acid molecule;

(c) amplifying the region comprising the fusion junction of the FGFR or NTRK gene fusion;

(d) attaching an adapter oligonucleotide to one end of a nucleic acid that comprises the fusion junction of the FGFR or NTRK gene fusion;

(e) generating a signal specific to the presence of the fusion junction of the FGFR or NTRK gene fusion; and/or

(f) incorporating a nucleotide into an oligonucleotide that is hybridized to a nucleic acid that contains the fusion junction of the FGFR or NTRK gene fusion.

19. The method of claim 1 , wherein the FGFR or NTRK gene fusion is:

(a) an FGFR2-TACC3 gene fusion comprising exons 1-16 of SEQ ID NO: 1 and exons 11-16 of SEQ ID NO: 3;

(b) an FGFR2-KIAA1598 gene fusion comprising exons 1-16 of SEQ ID NO: 1 and exons 7-17 of SEQ ID NO: 5;

(c) a BICC1-FGFR2 gene fusion comprising exons 1-2 of SEQ ID NO: 7 and exon 17 of SEQ ID NO: 1;

(d) an FGFR2-BICC1 gene fusion comprising exons 1-16 of SEQ ID NO: 1 and exons 18-21 of SEQ ID NO: 7;

(e) a PARK2-FGFR2 gene fusion comprising exons 1-9 of SEQ ID NO: 9 and exon 18 of SEQ ID NO: 11;

(f) an FGFR2-NOL4 gene fusion comprising exons 1-17 of SEQ ID NO: 11 and exons 7-11 of SEQ ID NO: 13;

(g) a ZDHHC6-FGFR2 gene fusion comprising exons 1-5 of SEQ ID NO: 15 and exon 18 of SEQ ID NO: 11; or

(h) a RABGAP1L-NTRK1 gene fusion.

20. The method of claim 1 , wherein the report is in electronic, web-based, or paper form.

21. The method of claim 1 , further comprising providing the report to the patient or to a caregiver, physician, oncologist, hospital, clinic, third-party payor, insurance company, or government office.

22. The method of claim 1 , wherein the report further comprises information on likely effectiveness of a therapeutic option, acceptability of a therapeutic option, advisability of applying the therapeutic option to a patient, information or a recommendation on administration of the therapeutic agent at a preselected dosage or in a preselected treatment regimen, information or a recommendation on administration of the therapeutic agent in combination with another drug, or information on the role of an FGFR or NTRK gene fusion or a wild-type FGFR or NTRK gene sequence in disease.

23. A method of stratifying a subject that has or is at risk of having a cholangiocarcinoma for treatment, comprising:

detecting presence or absence of a fibroblast growth factor receptor (FGFR) gene fusion or a neurotrophic tyrosine receptor kinase (NTRK) gene fusion in an FGFR or NTRK nucleic acid molecule or polypeptide in a sample obtained from the subject;

responsive to a determination of the presence of the FGFR or NTRK gene fusion in the sample, classifying the subject as a candidate to receive a treatment comprising a therapeutic agent that antagonizes or inhibits an FGFR gene or gene product or an NTRK gene or gene product; and

responsive to a determination of the absence of the FGFR or NTRK gene fusion in the sample, classifying the subject as a candidate to receive a treatment other than a therapeutic agent that antagonizes or inhibits an FGFR gene or gene product or an NTRK gene or gene product.

24. A method of identifying a subject that has or is at risk of having a cholangiocarcinoma as likely or unlikely to respond to a treatment, comprising:

detecting presence or absence of a fibroblast growth factor receptor (FGFR) gene fusion or a neurotrophic tyrosine receptor kinase (NTRK) gene fusion in an FGFR or NTRK nucleic acid molecule or polypeptide in a sample obtained from the subject;

responsive to a determination of the presence of the FGFR or NTRK gene fusion in the sample, identifying the subject as likely to respond to a treatment comprising a therapeutic agent that antagonizes or inhibits an FGFR gene or gene product or an NTRK gene or gene product; and

responsive to a determination of the absence of the FGFR or NTRK gene fusion in the sample, identifying the subject as unlikely to respond to a treatment comprising a therapeutic agent that antagonizes or inhibits an FGFR gene or gene product or an NTRK gene or gene product.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 16, 2023
From: ALI, SIRAJ MAHAMED; HAWRYLUK, MATTHEW J.; HE, JIE; LIPSON, DORON; MILLER, VINCENT A.; ROSS, JEFFREY S.; STEPHENS, PHILIP JAMES
To: FOUNDATION MEDICINE, INC.
Reel/Frame 064607/0974 →
Continuity (5)
Continuation 17204830 · Mar 17, 2021
Division 14761518
Provisional Application 61756372 · Jan 24, 2013
Provisional Application 61754509 · Jan 18, 2013
Related Publication 20230372338A1 · Nov 23, 2023
References Cited (400)
US 3687808A · Merigan et al. · 1972 [cited by applicant]
US 3773919A · Boswell et al. · 1973 [cited by applicant]
US 4366241A · Tom et al. · 1982 [cited by applicant]
US 4376110A · David et al. · 1983 [cited by applicant]
US 4458066A · Caruthers et al. · 1984 [cited by applicant]
US 4469863A · Ts'o et al. · 1984 [cited by applicant]
US 4476301A · Imbach et al. · 1984 [cited by applicant]
US 4517288A · Giegel et al. · 1985 [cited by applicant]
US 4676980A · Segal et al. · 1987 [cited by applicant]
US 4816567A · Cabilly et al. · 1989 [cited by applicant]
US 4837168A · de Jaeger et al. · 1989 [cited by applicant]
US 4845205A · Dinh et al. · 1989 [cited by applicant]
US 4868103A · Stavrianopoulos et al. · 1989 [cited by applicant]
US 4873316A · Meade et al. · 1989 [cited by applicant]
US 4981957A · Lebleu et al. · 1991 [cited by applicant]
US 4987071A · Cech et al. · 1991 [cited by applicant]
US 5023243A · Tullis · 1991 [cited by applicant]
US 5034506A · Summerton 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 5118800A · Smith et al. · 1992 [cited by applicant]
US 5134066A · Rogers et al. · 1992 [cited by applicant]
US 5166315A · Summerton et al. · 1992 [cited by applicant]
US 5175273A · Bischofberger et al. · 1992 [cited by applicant]
US 5177195A · Gregory et al. · 1993 [cited by applicant]
US 5185444A · Summerton et al. · 1993 [cited by applicant]
US 5188897A · Suhadolnik et al. · 1993 [cited by applicant]
US 5214134A · Weis et al. · 1993 [cited by applicant]
US 5216141A · Benner · 1993 [cited by applicant]
US 5223409A · Ladner et al. · 1993 [cited by applicant]
US 5225539A · Winter · 1993 [cited by applicant]
US 5235033A · Summerton et al. · 1993 [cited by applicant]
US 5264423A · Cohen et al. · 1993 [cited by applicant]
US 5264564A · Matteucci · 1993 [cited by applicant]
US 5276019A · Cohen et al. · 1994 [cited by applicant]
US 5278302A · Caruthers et al. · 1994 [cited by applicant]
US 5286717A · Cohen et al. · 1994 [cited by applicant]
US 5319080A · Leumann et al. · 1994 [cited by applicant]
US 5321131A · Agrawal et al. · 1994 [cited by applicant]
US 5359044A · Cook et al. · 1994 [cited by applicant]
US 5367066A · Urdea et al. · 1994 [cited by applicant]
US 5393878A · Leumann et al. · 1995 [cited by applicant]
US 5399676A · Froehler · 1995 [cited by applicant]
US 5405938A · Summerton et al. · 1995 [cited by applicant]
US 5405939A · Suhadolnik et al. · 1995 [cited by applicant]
US 5432272A · Benner · 1995 [cited by applicant]
US 5434257A · Matteucci et al. · 1995 [cited by applicant]
US 5446137A · Maag et al. · 1995 [cited by applicant]
US 5453496A · Caruthers et al. · 1995 [cited by applicant]
US 5455233A · Spielvogel et al. · 1995 [cited by applicant]
US 5457187A · Gmeiner et al. · 1995 [cited by applicant]
US 5459255A · Cook et al. · 1995 [cited by applicant]
US 5466677A · Baxter et al. · 1995 [cited by applicant]
US 5466786A · Buhr et al. · 1995 [cited by applicant]
US 5470967A · Huie et al. · 1995 [cited by applicant]
US 5476925A · Letsinger et al. · 1995 [cited by applicant]
US 5484908A · Froehler et al. · 1996 [cited by applicant]
US 5489677A · Sanghvi et al. · 1996 [cited by applicant]
US 5491224A · Bittner et al. · 1996 [cited by applicant]
US 5500362A · Robinson et al. · 1996 [cited by applicant]
US 5502177A · Matteucci et al. · 1996 [cited by applicant]
US 5514785A · Van Ness et al. · 1996 [cited by applicant]
US 5519126A · Hecht · 1996 [cited by applicant]
US 5519134A · Acevedo et al. · 1996 [cited by applicant]
US 5525711A · Hawkins et al. · 1996 [cited by applicant]
US 5536821A · Agrawal et al. · 1996 [cited by applicant]
US 5539082A · Nielsen et al. · 1996 [cited by applicant]
US 5541307A · Cook et al. · 1996 [cited by applicant]
US 5541316A · Engelskirchen et al. · 1996 [cited by applicant]
US 5545806A · Lonberg et al. · 1996 [cited by applicant]
US 5547835A · Koster · 1996 [cited by applicant]
US 5550111A · Suhadolnik et al. · 1996 [cited by applicant]
US 5552540A · Haralambidis · 1996 [cited by applicant]
US 5561225A · Maddry et al. · 1996 [cited by applicant]
US 5563253A · Agrawal et al. · 1996 [cited by applicant]
US 5567811A · Misiura et al. · 1996 [cited by applicant]
US 5569825A · Lonberg et al. · 1996 [cited by applicant]
US 5571799A · Tkachuk et al. · 1996 [cited by applicant]
US 5571894A · Wels et al. · 1996 [cited by applicant]
US 5576427A · Cook et al. · 1996 [cited by applicant]
US 5587361A · Cook et al. · 1996 [cited by applicant]
US 5587458A · King et al. · 1996 [cited by applicant]
US 5587469A · Cook et al. · 1996 [cited by applicant]
US 5591722A · Montgomery et al. · 1997 [cited by applicant]
US 5594121A · Froehler et al. · 1997 [cited by applicant]
US 5596086A · Matteucci et al. · 1997 [cited by applicant]
US 5596091A · Switzer · 1997 [cited by applicant]
US 5597909A · Urdea et al. · 1997 [cited by applicant]
US 5602240A · De Mesmaeker et al. · 1997 [cited by applicant]
US 5605798A · Koster · 1997 [cited by applicant]
US 5608046A · Cook et al. · 1997 [cited by applicant]
US 5610289A · Cook et al. · 1997 [cited by applicant]
US 5610300A · Altmann et al. · 1997 [cited by applicant]
US 5614617A · Cook et al. · 1997 [cited by applicant]
US 5618704A · Sanghvi et al. · 1997 [cited by applicant]
US 5623070A · Cook et al. · 1997 [cited by applicant]
US 5624821A · Winter et al. · 1997 [cited by applicant]
US 5625050A · Beaton et al. · 1997 [cited by applicant]
US 5625126A · Lonberg et al. · 1997 [cited by applicant]
US 5627053A · Usman et al. · 1997 [cited by applicant]
US 5631169A · Lakowicz et al. · 1997 [cited by applicant]
US 5633360A · Bischofberger et al. · 1997 [cited by applicant]
US 5633425A · Lonberg et al. · 1997 [cited by applicant]
US 5639873A · Barascut et al. · 1997 [cited by applicant]
US 5646265A · McGee · 1997 [cited by applicant]
US 5648260A · Winter et al. · 1997 [cited by applicant]
US 5658873A · Bertsch-Frank et al. · 1997 [cited by applicant]
US 5661016A · Lonberg et al. · 1997 [cited by applicant]
US 5663312A · Chaturvedula · 1997 [cited by applicant]
US 5670633A · Cook et al. · 1997 [cited by applicant]
US 5677437A · Teng et al. · 1997 [cited by applicant]
US 5677439A · Weis et al. · 1997 [cited by applicant]
US 5681941A · Cook et al. · 1997 [cited by applicant]
US 5700920A · Altmann et al. · 1997 [cited by applicant]
US 5714331A · Buchardt et al. · 1998 [cited by applicant]
US 5719262A · Buchardt et al. · 1998 [cited by applicant]
US 5731168A · Carter et al. · 1998 [cited by applicant]
US 5750373A · Garrard et al. · 1998 [cited by applicant]
US 5750692A · Cook et al. · 1998 [cited by applicant]
US 5770429A · Lonberg et al. · 1998 [cited by applicant]
US 5776688A · Bittner et al. · 1998 [cited by applicant]
US 5821337A · Carter et al. · 1998 [cited by applicant]
US 5869046A · Presta et al. · 1999 [cited by applicant]
US 5876930A · Livak et al. · 1999 [cited by applicant]
US 6015886A · Dale et al. · 2000 [cited by applicant]
US 6028188A · Arnold et al. · 2000 [cited by applicant]
US 6075181A · Kucherlapati et al. · 2000 [cited by applicant]
US 6124445A · Imbach et al. · 2000 [cited by applicant]
US 6147200A · Manoharan et al. · 2000 [cited by applicant]
US 6150584A · Kucherlapati et al. · 2000 [cited by applicant]
US 6160109A · Just et al. · 2000 [cited by applicant]
US 6166197A · Cook et al. · 2000 [cited by applicant]
US 6169170B1 · Gryaznov et al. · 2001 [cited by applicant]
US 6172209B1 · Manoharan et al. · 2001 [cited by applicant]
US 6194551B1 · Idusogie et al. · 2001 [cited by applicant]
US 6222025B1 · Cook et al. · 2001 [cited by applicant]
US 6235887B1 · Froehler et al. · 2001 [cited by applicant]
US 6239265B1 · Cook · 2001 [cited by applicant]
US 6248516B1 · Winter et al. · 2001 [cited by applicant]
US 6268490B1 · Imanishi et al. · 2001 [cited by applicant]
US 6277569B1 · Bittner et al. · 2001 [cited by applicant]
US 6277603B1 · Cook · 2001 [cited by applicant]
US 6326199B1 · Cook et al. · 2001 [cited by applicant]
US 6346614B1 · Metelev et al. · 2002 [cited by applicant]
US 6380368B1 · Froehler et al. · 2002 [cited by applicant]
US 6444423B1 · Meade et al. · 2002 [cited by applicant]
US 6455258B2 · Bastian et al. · 2002 [cited by applicant]
US 6528640B1 · Beigelman et al. · 2003 [cited by applicant]
US 6531590B1 · Manoharan et al. · 2003 [cited by applicant]
US 6534639B1 · Manoharan et al. · 2003 [cited by applicant]
US 6602684B1 · Umaña et al. · 2003 [cited by applicant]
US 6608035B1 · Agrawal et al. · 2003 [cited by applicant]
US 6617438B1 · Beigelman et al. · 2003 [cited by applicant]
US 6639062B2 · Manoharan et al. · 2003 [cited by applicant]
US 6670461B1 · Wengel et al. · 2003 [cited by applicant]
US 6683167B2 · Metelev et al. · 2004 [cited by applicant]
US 6737056B1 · Presta · 2004 [cited by applicant]
US 6794499B2 · Wengel et al. · 2004 [cited by applicant]
US 6858715B2 · Ravikumar et al. · 2005 [cited by applicant]
US 6867294B1 · Sanghvi et al. · 2005 [cited by applicant]
US 6878805B2 · Manoharan et al. · 2005 [cited by applicant]
US 6982321B2 · Winter · 2006 [cited by applicant]
US 6998484B2 · Koch et al. · 2006 [cited by applicant]
US 7015315B1 · Cook et al. · 2006 [cited by applicant]
US 7041816B2 · Ravikumar et al. · 2006 [cited by applicant]
US 7041870B2 · Tomizuka et al. · 2006 [cited by applicant]
US 7045610B2 · Dempcy et al. · 2006 [cited by applicant]
US 7053207B2 · Wengel · 2006 [cited by applicant]
US 7084125B2 · Wengel · 2006 [cited by applicant]
US 7087409B2 · Barbas et al. · 2006 [cited by applicant]
US RE39464E · Cook et al. · 2007 [cited by applicant]
US 7189826B2 · Rodman · 2007 [cited by applicant]
US 7244567B2 · Chen et al. · 2007 [cited by applicant]
US 7273933B1 · Krotz et al. · 2007 [cited by applicant]
US 7321029B2 · Gryaznov et al. · 2008 [cited by applicant]
US 7332581B2 · Presta · 2008 [cited by applicant]
US 7371826B2 · Presta · 2008 [cited by applicant]
US 7399845B2 · Seth et al. · 2008 [cited by applicant]
US 7427672B2 · Imanishi et al. · 2008 [cited by applicant]
US 7495088B1 · Brakel et al. · 2009 [cited by applicant]
US 7521541B2 · Eigenbrot et al. · 2009 [cited by applicant]
US 7527791B2 · Adams et al. · 2009 [cited by applicant]
US 8377921B2 · Michellys et al. · 2013 [cited by applicant]
US 9340830B2 · Lipson et al. · 2016 [cited by applicant]
US 10000814B2 · Cronin et al. · 2018 [cited by applicant]
US 10980804B2 · Ali et al. · 2021 [cited by applicant]
US 11098368B2 · Cronin et al. · 2021 [cited by applicant]
US 11230589B2 · Lipson et al. · 2022 [cited by applicant]
US 11578372B2 · Hawryluk et al. · 2023 [cited by applicant]
US 20020164328A1 · Shinkawa et al. · 2002 [cited by applicant]
US 20020197679A1 · Tang et al. · 2002 [cited by applicant]
US 20030115614A1 · Kanda et al. · 2003 [cited by applicant]
US 20030143204A1 · Lewis et al. · 2003 [cited by applicant]
US 20030157108A1 · Presta · 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 20040093621A1 · Shitara et al. · 2004 [cited by applicant]
US 20040109865A1 · Niwa et al. · 2004 [cited by applicant]
US 20040110282A1 · Kanda et al. · 2004 [cited by applicant]
US 20040110704A1 · Yamane et al. · 2004 [cited by applicant]
US 20040132140A1 · Satoh et al. · 2004 [cited by applicant]
US 20050014934A1 · Hinton et al. · 2005 [cited by applicant]
US 20050079574A1 · Bond · 2005 [cited by applicant]
US 20050119455A1 · Fuh et al. · 2005 [cited by applicant]
US 20050123546A1 · Umana et al. · 2005 [cited by applicant]
US 20050266000A1 · Bond et al. · 2005 [cited by applicant]
US 20050287541A1 · Nakagawara et al. · 2005 [cited by applicant]
US 20060025576A1 · Miller et al. · 2006 [cited by applicant]
US 20060246497A1 · Huang et al. · 2006 [cited by applicant]
US 20060275779A1 · Li et al. · 2006 [cited by applicant]
US 20070010657A1 · Klocke et al. · 2007 [cited by applicant]
US 20070059710A1 · Luke et al. · 2007 [cited by applicant]
US 20070061900A1 · Murphy et al. · 2007 [cited by applicant]
US 20070087362A1 · Church et al. · 2007 [cited by applicant]
US 20070117126A1 · Sidhu et al. · 2007 [cited by applicant]
US 20070160598A1 · Dennis et al. · 2007 [cited by applicant]
US 20070194225A1 · Zorn · 2007 [cited by applicant]
US 20070237764A1 · Birtalan et al. · 2007 [cited by applicant]
US 20070248605A1 · Hestir et al. · 2007 [cited by applicant]
US 20070292936A1 · Barthelemy et al. · 2007 [cited by applicant]
US 20080051462A1 · Fritz et al. · 2008 [cited by applicant]
US 20080069820A1 · Fuh et al. · 2008 [cited by applicant]
US 20080131375A1 · Gordon et al. · 2008 [cited by applicant]
US 20080171689A1 · Williams · 2008 [cited by applicant]
US 20080226664A1 · Old et al. · 2008 [cited by applicant]
US 20090002360A1 · Chen et al. · 2009 [cited by applicant]
US 20090130101A1 · Cohen · 2009 [cited by applicant]
US 20090156475A1 · Rikova et al. · 2009 [cited by applicant]
US 20090209496A1 · Chaplin et al. · 2009 [cited by applicant]
US 20100029498A1 · Gnirke et al. · 2010 [cited by applicant]
US 20110118298A1 · Fritz et al. · 2011 [cited by applicant]
US 20110150893A1 · Cho et al. · 2011 [cited by applicant]
US 20110183924A1 · Mintz et al. · 2011 [cited by applicant]
US 20120039805A1 · Lisanti et al. · 2012 [cited by applicant]
US 20120208706A1 · Downing et al. · 2012 [cited by applicant]
US 20130034559A1 · Queva et al. · 2013 [cited by applicant]
US 20130096021A1 · Chinnaiyan et al. · 2013 [cited by applicant]
US 20140336236A1 · Cronin et al. · 2014 [cited by applicant]
US 20150073036A1 · Hawryluk et al. · 2015 [cited by applicant]
US 20150366866A1 · Ali et al. · 2015 [cited by applicant]
US 20160009785A1 · Lipson et al. · 2016 [cited by applicant]
US 20160010068A1 · Bastian et al. · 2016 [cited by applicant]
US 20160272725A1 · Stransky et al. · 2016 [cited by applicant]
US 20180030548A1 · Nanda et al. · 2018 [cited by applicant]
US 20180045727A1 · Spetzler et al. · 2018 [cited by applicant]
US 20180346992A1 · Cronin et al. · 2018 [cited by applicant]
US 20190367613A1 · Harvey et al. · 2019 [cited by applicant]
US 20200299775A1 · Hawryluk et al. · 2020 [cited by applicant]
US 20210283134A1 · Ali et al. · 2021 [cited by applicant]
US 20220002818A1 · Cronin et al. · 2022 [cited by applicant]
US 20220169703A1 · Lipson et al. · 2022 [cited by applicant]
US 20220243280A1 · Darcy et al. · 2022 [cited by applicant]
CA 2880013A1 · 2014 [cited by applicant]
CN 113186287A · 2021 [cited by applicant]
EP 171496A2 · 1986 [cited by applicant]
EP 173494A2 · 1986 [cited by applicant]
EP 184187A2 · 1986 [cited by applicant]
EP 264166A1 · 1988 [cited by applicant]
EP 404097A2 · 1990 [cited by applicant]
EP 125023B1 · 1991 [cited by applicant]
EP 430402A2 · 1991 [cited by applicant]
EP 698096B1 · 1996 [cited by applicant]
EP 2057465A2 · 2009 [cited by applicant]
EP 2877854B1 · 2022 [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 WO1992001047A1 · 1991 [cited by applicant]
WO WO1991017271A1 · 1991 [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 WO1993001161A1 · 1993 [cited by applicant]
WO WO1993001288A1 · 1993 [cited by applicant]
WO WO1993008829A1 · 1993 [cited by applicant]
WO WO1993016185A2 · 1993 [cited by applicant]
WO WO1994016101A2 · 1994 [cited by applicant]
WO WO1994021822A1 · 1994 [cited by applicant]
WO WO1994026889A2 · 1994 [cited by applicant]
WO WO1994029351A2 · 1994 [cited by applicant]
WO WO1996029431A2 · 1996 [cited by applicant]
WO WO1997030087A1 · 1997 [cited by applicant]
WO WO1998058964A1 · 1998 [cited by applicant]
WO WO1999022764A1 · 1999 [cited by applicant]
WO WO1999051642A1 · 1999 [cited by applicant]
WO WO2000061739A1 · 2000 [cited by applicant]
WO WO2001027081A1 · 2001 [cited by applicant]
WO WO2001029246A1 · 2001 [cited by applicant]
WO WO2002031140A1 · 2002 [cited by applicant]
WO WO2003011878A2 · 2003 [cited by applicant]
WO WO2003031568A2 · 2003 [cited by applicant]
WO WO2003084570A1 · 2003 [cited by applicant]
WO WO2003085107A1 · 2003 [cited by applicant]
WO WO2003085119A1 · 2003 [cited by applicant]
WO WO2004013099A1 · 2004 [cited by applicant]
WO WO2004056312A2 · 2004 [cited by applicant]
WO WO2005016894A1 · 2005 [cited by applicant]
WO WO2005035586A1 · 2005 [cited by applicant]
WO WO2005035778A1 · 2005 [cited by applicant]
WO WO2005053742A1 · 2005 [cited by applicant]
WO WO2005100402A1 · 2005 [cited by applicant]
WO WO2006029879A2 · 2006 [cited by applicant]
WO WO2006121168A1 · 2006 [cited by applicant]
WO WO2007005874A2 · 2007 [cited by applicant]
WO WO2007060402A1 · 2007 [cited by applicant]
WO WO2008021290A2 · 2008 [cited by applicant]
WO WO2008077546A1 · 2008 [cited by applicant]
WO WO2009089004A1 · 2009 [cited by applicant]
WO WO2009101611A1 · 2009 [cited by applicant]
WO WO2009114335A2 · 2009 [cited by applicant]
WO WO2010027827A2 · 2010 [cited by applicant]
WO WO2010077634A1 · 2010 [cited by applicant]
WO WO2010081817A1 · 2010 [cited by applicant]
WO WO2011005861A1 · 2011 [cited by applicant]
WO WO2011066342A2 · 2011 [cited by applicant]
WO WO2011066389A1 · 2011 [cited by applicant]
WO WO2011135376A1 · 2011 [cited by applicant]
WO WO2012092426A1 · 2012 [cited by applicant]
WO WO2013059740A1 · 2013 [cited by applicant]
WO WO2013076186A1 · 2013 [cited by applicant]
WO WO2013087716A2 · 2013 [cited by applicant]
WO WO2014018673A2 · 2014 [cited by applicant]
WO WO2014036387A2 · 2014 [cited by applicant]
WO WO2014071358A2 · 2014 [cited by applicant]
WO WO2014071419A2 · 2014 [cited by applicant]
WO WO2014113729A2 · 2014 [cited by applicant]
WO WO2014130975A1 · 2014 [cited by applicant]
WO WO2015016718A1 · 2015 [cited by applicant]
WO WO2016196671A1 · 2016 [cited by applicant]
WO WO2019158512A1 · 2019 [cited by applicant]
Adnane et al., (1991). “BEK and FLG, two receptors to members of the FGF family, are amplified in subsets of human breast cancers,” Oncogene, 6(4):659-63. [cited by applicant]
Akslen et al., (2005). “BRAF and NRAS mutations are frequent in nodular melanoma but are not associated with tumor cell proliferation or patient survival,” J Invest Dermatol, 125(2):312-7. [cited by applicant]
Al-Ahmadie et al., (2011). “Somatic mutation of fibroblast growth factor receptor-3 (FGFR3) defines a 20 distinct morphological subtype of high-grade urothelial carcinoma,” J Pathol, 224(2):270-9, 20 pages. [cited by applicant]
Alazzouzi et al., (2005). “SMAD4 as a prognostic marker in colorectal cancer,” Clinical cancer research, 11(7):2606-11. [cited by applicant]
Albanese et al., (2010). “Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy”, Mol Cancer Ther 9(8):2243-54. [cited by applicant]
Alberti et al., (2003). “RET and NTRK1 proto-oncogenes in human diseases,” J Cell Physiol, 195:168-186. [cited by applicant]
Albertson (1984). “Localization of the ribosomal genes in Caenorhabditis elegans chromosomes by in situ hybridization using biotin-labeled probes,” EMBO J., 3:1227-1234. [cited by applicant]
Almagro et al., (2008). “Humanization of antibodies,” Front. Biosci., 13:1619-1633. [cited by applicant]
Alonso et al, (1994). “Biodegradable microspheres as controlled-release tetanus toxoid delivery systems,” Vaccine, 12(4):299-306. [cited by applicant]
Altorki et al., (2010). “Phase II Proof-of-Concept Study of Pazopanib Monotherapy in Treatment-Naive Patience With State I/II Respectable Non-Small-Cell Lung Cancer” Journal of Clinical Oncology, 28(19):3131-3137. [cited by applicant]
Altschul et al., (1990). “Basic local alignment search tool,” J. Mol Biol., 215:403-410. [cited by applicant]
Altschul et al., (1997). “Gapped BLAST and PSI-BLAST: a new generation of protein database search programs,” Nucleic Acids Res., 25(17):3389-3402. [cited by applicant]
Amatu et al., (2016). “NTRK gene fusions as novel targets of cancer therapy across multiple tumour types” ESMO Open, 1:e000023, 9 pages. [cited by applicant]
Andoniou et al., (1994). “Tumour induction by activated abl involves tyrosine phosphorylation of the product of the cbl oncogene,” EMBO J, 13(19):4515-23. [cited by applicant]
Arbitrario et al., (2010). “SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo,” Cancer Chemother Pharmacol., 65(4):707-717. Abstract Only. [cited by applicant]
Ardini et al., (2014). “The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition,” Mol Oncol., 8:1495-507. [cited by applicant]
Avet-Loiseau et al., (1998). “High Incidence of Translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in Patients with Plasma Cell Malignancies” Cancer Research, 58:5640-5645. [cited by applicant]
Baca et al., (1997). “Antibody humanization using monovalent phage display,” J. Biol. Chem., 272(16):10678-10684. [cited by applicant]
Bacher et al., (2010). “Mutations of the TET2 and CBL 20 genes: novel molecular markers in myeloid malignancies,” Ann Hematol, 89(7):643-52. [cited by applicant]
Bai et al., (2010). “GP369, an FGFR2-IIIb-Specific Antibody, Exhibits Potent antitumor Activity against Human Cancers Driven by Activated FGFR2 Signaling” Cancer Research, 70(19):7630-39. [cited by applicant]
Banerji et al., (1983). “A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes,” Cell, 33(3):729-740. [cited by applicant]
Baraniskin et al., (2011). “A Prognostic value of reduced SMAD4 expression in patients with metastatic colorectal cancer under oxaliplatin-containing chemotherapy: a translational study of the AIO colorectal study group… [cited by applicant]
Barringer et al., (1990). “Blunt-end and single-strand ligations by [cited by applicant]
Bartel et al., (1993). “Isolation of new ribozymes from a large pool of random sequences,” Science, 261(5127):1411-1418. [cited by applicant]
Beaucage et al., (1981). “Deoxynucleoside phosphoramidites—A new class of key intermediates for deoxypolynucleotide synthesis,” Tetrahedron Letters, 22(20):1859-1862. [cited by applicant]
Beidler et al., (1988). “Cloning and high level expression of a chimeric antibody with specificity for human carcinoembryonic antigen,” J. Immunol., 141(11):4053-4060. [cited by applicant]
Beimfohr et al., (1999). “NTRK1 re-arrangement in papillary thyroid carcinomas of children after the Chernobyl reactor accident,” Int J Cancer, 80(6):842-7. [cited by applicant]
Bender et al., (2019). “Refractory and metastatic infantile fibrosarcoma harboring LMNA-NTRK1 fusion shows complete and durable response to crizotinib,” Cold Spring Harb Mol Case Stud., 5:a00376, 9 pages. [cited by applicant]
Bernt et al., (2011). “A role for DOT1L in MLL-rearranged leukemias,” Epigenomics, 3(6):667-70. [cited by applicant]
Bernt et al., (2011). “MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L,” Cancer Cell, 20(1):66-78. [cited by applicant]
Better et al. (1988). “ [cited by applicant]
Bhatia et al., (2011). “Immunobiology of Merkel cell carcinoma: implications for immunotherapy of a polyomavirus-associated cancer,” Curr. Oncol. Rep., 13(6):488-497. [cited by applicant]
Billy et al., (2001). “Specific interference with gene expression induced by long, double-stranded RNA in mouse embryonal teratocarcinoma cell lines,” Proc. Natl. Sci. USA, 98(25):14428-14433. [cited by applicant]
Birch et al., (2011). “Chromosome 3 Anomalies Investigated by Genome Wide SNP Analysis of Benign, Low Malignant Potential and Low Grade Ovarian Serous Tumours,” PLoS One, 6:e28250, 20 pages. [cited by applicant]
Boerner et al., (1991). “Production of antigen-specific human monoclonal antibodies from in vitro-primed human splenocytes,” J. Immunol., 147(1):86-95. [cited by applicant]
Borrow et al., (1996). “The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative 25 acetyltransferase to the CREB-binding protein,” Nat Genet, 14(1):33-41. [cited by applicant]
Bouhana et al., (2012). “Abstract 1798: Identification of pan-Trk inhibitors for the treatment of Trk-driven cancers,” Cancer Res, 72(8 Suppl):1798, 2 pages. [cited by applicant]
Bown, (2001). “Neuroblastoma tumour genetics: clinical and biological aspects,” J Clin Pathol, 54(12):897-910. [cited by applicant]
Brambilla et al., (2001). “The new World Health Organization classification of lung tumours,” Eur Respir J, 18:1059-1068. [cited by applicant]
Branton et al., (2008). “The potential and challenges of nanopore sequencing,” Nat Biotechnol., 26(10):1146-1153. [cited by applicant]
Brave et al., (2011). “Assessing the Activity of Cediranib, a VEGFR-2/3 Tyrosine Kinase Inhibitor, against VEGFR-1 and Members of the Structurally Related PDGFR Family” Molecular Cancer Therapeutics, 10(5):861-873. [cited by applicant]
Brennan et al., (1985). “Preparation of bispecific antibodies by chemical recombination of monoclonal immunoglobulin G1 fragments,” Science, 229(4708):81-83. [cited by applicant]
Brenner et al., (2011). “Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer,” Cancer Cell, 19(5):664-78. [cited by applicant]
Brodeur et al., (2009). “Trk receptor expression and inhibition in neuroblastomas,” Clin Cancer Res, 15(10):3244-50. [cited by applicant]
Bruggemann et al., (1987). “Comparison of the effector functions of human immunoglobulins using a matched set of chimeric antibodies,” J. Exp. Meet., 166(5):1351-1361. [cited by applicant]
Butler et al., (2008). “ALLPATHS: de novo assembly of whole-genome shotgun microreads,” Genome Res., 18(5):810-820. [cited by applicant]
Butti et al., (1995). “A sequence 10 analysis of the genomic regions involved in the rearrangements between TPM3 and NTRK1 genes producing TRK oncogenes in papillary thyroid carcinomas,” Genomics, 28(1):15-24. [cited by applicant]
Byrne et al., (1989). “Multiplex gene regulation: a two-tiered approach to transgene regulation in transgenic mice,” Proc. Natl. Acad Sci. USA, 86(14):5473-5477. [cited by applicant]
Byron et al., (2008). “Inhibition of Activated Fibroblast Growth Factor Receptor 2 in Endometrial Cancer Cells Induces Cell Death Despite PTEN Abrogation” Cancer Research, 68(17):6902-10005. [cited by applicant]
Calame et al., (1988). “Transcriptional controlling elements in the immunoglobulin and T cell receptor loci,” Adv. Immunol., 43:235-275. [cited by applicant]
Camidge et al., (2010). “Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment,” Clin Cancer Res, 16(22):5581-55… [cited by applicant]
Camper et al., (1989). “Postnatal repression of the alpha-fetoprotein gene is enhancer independent,” Genes Dev., 3(4):537-546. [cited by applicant]
Caneiro et al., (2015). “FGFR3-TACC3: A novel gene fusion in cervical cancer,” Gynecologic Oncology Reports, 13:53-56. [cited by applicant]
Capelletti et al., (2014). “Identification of Recurrent FGFR3-TACC3 Fusion Oncogenes from Lung Adenocarcinoma,” Clin Cancer Res, 20:6551-6558. [cited by applicant]
Cappellen et al., (1999). “Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas,” Nature Genetics, 23:18-20. [cited by applicant]
Carboni et al., (2009). “BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR,” Mol Cancer Ther., 8(12):3341-3349. [cited by applicant]
Carell et al., (1994). “A Solution-Phase Screening Procedure for the Isolation of Active Compounds from a Library of Molecules,” Angew. Chem. Int. Ed. Engl., 33(20):2061-2064. [cited by applicant]
Carrell et al., (1994). “A Novel Procedure for the Synthesis of Libraries Containing Small Organic Molecules,” Angew. Chem. Int. Ed. Engl., 33(20):2059-2061. [cited by applicant]
Carrillo de Santa Pau et al., (2009). “Prognostic significance of the expression of vascular endothelial growth factors A, B, C, and D and their receptors R1, R2, and R3 in patients with nonsmall cell lung cancer,” Canc… [cited by applicant]
Carter et al., (1992). “Humanization of an anti-p185HER2 antibody for human cancer therapy,” Proc. Natl. Acad. Sci. USA, 89(10):4285-4289. [cited by applicant]
Carver et al., (2009). “Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate,” Nat Genet, 41(5):619-24, 14 pages. [cited by applicant]
Chan et al., (2008). “A phase I trial of CEP-701 + gemcitabine in patients with advanced adenocarcinoma of the pancreas,” Invest New Drugs, 26(3):241-7. [cited by applicant]
Chase et al., (2012). “Ponatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome,” Haematologica, 98:103-6. [cited by applicant]
Chen et al., (2005). “FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies,” Oncogene, 24:8259-8267. [cited by applicant]
Chen et al., (1999). “Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen,” J Mol Biol., 293(4):865-881. [cited by applicant]
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