Granted Patent
B2
US 12,448,366 · App. 18/000,168 · Granted Oct 21, 2025
Solid forms of pralsetinib
Inventors:
Joshua Waetzig (Cambridge, MA); Gordon D. Wilkie (Cambridge, MA); Lauren MacEachern (Halifax, CA); Kimberly Jean Miller (Halifax, CA)
Assignee:
Rigel Pharmaceuticals, Inc.
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Abstract
The compound cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4 methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexanecarboxamide can be prepared as a free base in various crystalline solid forms, and in various salt forms each having one or more solid forms.
Claims (121)
1. A crystalline Solid Form A of the free base of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4 methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexanecarboxamide.
2. The solid form of claim 1 characterized by an X-ray powder diffraction (XRPD) pattern having diffractions at angles (2 theta±0.2) of 5.0°, 9.7°, 12.7°, 13.6°, and 16.1°.
3. The solid form of claim 2 , characterized by an X-ray Powder Diffraction (XRPD) pattern having additional diffractions at angles (2 theta±0.2) of 6.8, 19.2, 19.5, and 23.5.
4. The solid form of claim 1 characterized by an X-ray Powder Diffraction (XRPD) pattern having peaks at the same or substantially the same angles (2 theta±0.2) and corresponding d-spacing (A±0.2) of:
2-theta
d-Spacing
Relative
(deg)
(ang.)
Intensity
4.95
17.82
62
6.80
12.98
16
9.74
9.07
29
12.71
6.96
48
13.62
6.50
100
14.82
5.97
9
16.06
5.52
39
17.18
5.16
5
17.83
4.97
8
19.22
4.62
20
19.52
4.54
35
20.50
4.33
5
21.56
4.12
6
23.09
3.85
14
23.51
3.78
16
24.77
3.59
5
25.59
3.48
10
25.97
3.43
9
27.86
3.20
7
29.41
3.03
7.
5. The solid form of claim 1 , further characterized by one or more of:
a differential scanning calorimetry (DSC) thermogram with an endothermic event observed at about 205° C.; and
a reversible mass change of about 10% by DVS between 2-95% relative humidity.
6. A crystalline Solid Form B of the free base of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4 methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexanecarboxamide.
7. The solid form of claim 6 , characterized by an X-ray powder diffraction (XRPD) pattern having diffractions at angles (2 theta±0.2) of 5.9°, 8.8°, 11.6°, 14.7°, and 19.5°.
8. The solid form of claim 7 , characterized by an X-ray Powder Diffraction (XRPD) pattern having additional diffractions at angles (2 theta±0.2) of 17.0, 17.6 and 22.2.
9. The solid form of claim 6 , characterized by an X-ray Powder Diffraction (XRPD) pattern having peaks at the same or substantially the same angles (2 theta±0.2) and corresponding d-spacing (A±0.2) of:
2-theta
d-Spacing
Relative
(deg)
(ang.)
Intensity
5.89
14.99
100
8.81
10.03
28
11.58
7.64
33
14.73
6.01
23
17.01
5.21
11
17.63
5.03
8
19.45
4.56
13
22.21
4.00
5.
10. The solid form of claim 6 , further characterized by one or more of:
a differential scanning calorimetry (DSC) thermogram with an endothermic event observed at about 205° C.; and
a reversible mass change of about 10% by DVS between 2-95% relative humidity.
11. A crystalline Solid Form C of the free base of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4 methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexanecarboxamide.
12. A Solid Form 5-A of crystalline hydrochloride salt of pralsetinib.
13. A Solid Form 5-B of crystalline hydrochloride salt of pralsetinib.
14. The solid form of claim 13 characterized by one or more of the following:
a XRPD pattern comprising characteristic diffraction peaks at 2-theta angles at approximately (±0.2 degrees) 6.1°, 8.9, 9.5°, 15.0°, 16.6°; and
A TGA/DSC thermogram characterized by an initial mass loss of 3.4 wt. % associated with a broad endotherm with an onset of 88.7° C. (±0.2 degrees) and a second mass loss event of 6.7 wt. % was observed from the end of the first broad endotherm to the end of the melt which had an onset of 244.2° C. (±0.2 degrees.
15. A Solid Form 5-C of crystalline hydrochloride salt of pralsetinib.
16. The solid form of claim 15 characterized by XRPD pattern 5-C.
17. The solid form of claim 11 , characterized by an X-ray powder diffraction (XRPD) pattern having diffractions at angles (2 theta±0.2) of 5.8°, 8.7°, 11.0°, 13.6°, and 20.2°.
18. The solid form of claim 12 characterized by a XRPD pattern having diffractions at angles (2 theta±0.2) of 5.0°, 6.1°, 91°, 9.9°, and 14.7°.
19. The solid form of claim 15 characterized by a XRPD pattern having diffractions at angles (2 theta±0.2) of 6.4°, 8.5°, 8.9°, 9.6°, and 17.3°.
Assignments (8)
SECURITY INTEREST
Recorded May 8, 2026
From: RIGEL PHARMACEUTICALS, INC.
To: MIDCAP FUNDING IV TRUST
Reel/Frame 075576/0880 →
RELEASE OF SECURITY INTEREST (REEL/FRAME 064748/0552)
Recorded Jul 24, 2025
From: TAO TALENTS, LLC
To: BLUEPRINT MEDICINES CORPORATION
Reel/Frame 072249/0280 →
SECURITY INTEREST
Recorded May 23, 2024
From: RIGEL PHARMACEUTICALS, INC.
To: MIDCAP FINANCIAL TRUST
Reel/Frame 067509/0146 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Apr 25, 2024
From: SOLID STATE PHARMA INC.
To: BLUEPRINT MEDICINES CORPORATION
Reel/Frame 067228/0211 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Apr 25, 2024
From: WAETZIG, JOSHUA; WILKIE, GORDON D.
To: BLUEPRINT MEDICINES CORPORATION
Reel/Frame 067228/0350 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Apr 25, 2024
From: MACEACHERN, LAUREN; MILLER, KIMBERLY JEAN
To: SOLID STATE PHARMA INC.
Reel/Frame 067228/0301 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 8, 2024
From: BLUEPRINT MEDICINES CORPORATION
To: RIGEL PHARMACEUTICALS, INC.
Reel/Frame 066703/0974 →
SECURITY INTEREST
Recorded Aug 29, 2023
From: BLUEPRINT MEDICINES CORPORATION
To: TAO TALENTS, LLC
Reel/Frame 064748/0552 →
Continuity (3)
Provisional Application
63047353
· Jul 2, 2020
Provisional Application
63032121
· May 29, 2020
References Cited (300)
US 8088806B2
· Zhang et al.
· 2012
[cited by applicant]
US 8802697B2
· Bifulco, Jr.
· 2014
[cited by applicant]
US 9126951B2
· Bifulco, Jr.
· 2015
[cited by applicant]
US 9187475B2
· Kawamura et al.
· 2015
[cited by applicant]
US 9200002B2
· Hodous et al.
· 2015
[cited by applicant]
US 9216172B2
· Kohno et al.
· 2015
[cited by applicant]
US 9297011B2
· Downing et al.
· 2016
[cited by applicant]
US 9334263B2
· Hodous et al.
· 2016
[cited by applicant]
US 9340514B2
· Bifulco, Jr.
· 2016
[cited by applicant]
US 9434700B2
· Bifulco, Jr.
· 2016
[cited by applicant]
US 9499522B2
· DiPietro et al.
· 2016
[cited by applicant]
US 9688680B2
· Hodous
· 2017
[cited by applicant]
US 9695165B2
· Bifulco, Jr.
· 2017
[cited by applicant]
US 9884861B2
· Hodous et al.
· 2018
[cited by applicant]
US 9944651B2
· Hodous et al.
· 2018
[cited by applicant]
US 9994552B2
· DiPietro et al.
· 2018
[cited by applicant]
US 9994575B2
· Hodous et al.
· 2018
[cited by applicant]
US 20120316137A1
· Huang et al.
· 2012
[cited by applicant]
US 20130096136A1
· Hata et al.
· 2013
[cited by applicant]
US 20130115313A1
· Charrier et al.
· 2013
[cited by applicant]
US 20140187559A1
· Miduturu
· 2014
[cited by applicant]
US 20140221404A1
· Kohno et al.
· 2014
[cited by applicant]
US 20140243357A1
· Dar et al.
· 2014
[cited by applicant]
US 20140272951A1
· Chakravarti et al.
· 2014
[cited by applicant]
US 20150057335A1
· Kohno et al.
· 2015
[cited by applicant]
US 20150177246A1
· Shibata et al.
· 2015
[cited by applicant]
US 20170066812A1
· Bifulco, Jr.
· 2017
[cited by applicant]
US 20190192522A1
· Hagel et al.
· 2019
[cited by applicant]
US 20210100795A1
· Evans Raab et al.
· 2021
[cited by applicant]
US 20210308134A1
· Hata et al.
· 2021
[cited by applicant]
US 20220315560A1
· Brubaker et al.
· 2022
[cited by applicant]
US 20230203009A1
· Waetzig et al.
· 2023
[cited by applicant]
US 20240059672A1
· Waetzig et al.
· 2024
[cited by applicant]
CN 104844567A
· 2015
[cited by applicant]
CN 105255927A
· 2016
[cited by applicant]
CN 107980784A
· 2018
[cited by applicant]
CN 108341782A
· 2018
[cited by applicant]
CN 111362923A
· 2020
[cited by applicant]
CN 111440151A
· 2020
[cited by applicant]
EP 3037547A1
· 2016
[cited by applicant]
JP 2015109806A
· 2015
[cited by applicant]
WO WO2001060816A1
· 2001
[cited by applicant]
WO WO2004009087A1
· 2004
[cited by applicant]
WO WO2005062795A2
· 2005
[cited by applicant]
WO WO2007023382A2
· 2007
[cited by applicant]
WO WO2007087245A2
· 2007
[cited by applicant]
WO WO2007124221A1
· 2007
[cited by applicant]
WO WO2007136103A1
· 2007
[cited by applicant]
WO WO2008061201A1
· 2008
[cited by applicant]
WO WO2009003136A1
· 2008
[cited by applicant]
WO WO2009007748A2
· 2009
[cited by applicant]
WO WO2009014637A2
· 2009
[cited by applicant]
WO 2009018415A1
· 2009
[cited by applicant]
WO WO2009100536A1
· 2009
[cited by applicant]
WO WO2010006432A1
· 2010
[cited by applicant]
WO WO2010111056A1
· 2010
[cited by applicant]
WO WO2010144359A1
· 2010
[cited by applicant]
WO WO2010144394A1
· 2010
[cited by applicant]
WO WO2011060295A1
· 2011
[cited by applicant]
WO WO2013077921A2
· 2013
[cited by applicant]
WO WO2013133367A1
· 2013
[cited by applicant]
WO WO2013170159A1
· 2013
[cited by applicant]
WO WO2014039971A1
· 2014
[cited by applicant]
WO WO2014050781A1
· 2014
[cited by applicant]
WO WO2014072220A1
· 2014
[cited by applicant]
WO WO2014130810A1
· 2014
[cited by applicant]
WO WO2014141187A1
· 2014
[cited by applicant]
WO WO2014147640A2
· 2014
[cited by applicant]
WO WO2015006875A1
· 2015
[cited by applicant]
WO WO2015079251A1
· 2015
[cited by applicant]
WO WO2016037578A1
· 2016
[cited by applicant]
WO WO2016038552A1
· 2016
[cited by applicant]
WO WO2016075224A1
· 2016
[cited by applicant]
WO WO2016127074A1
· 2016
[cited by applicant]
WO WO2017011776A1
· 2017
[cited by applicant]
WO WO2017079117A1
· 2017
[cited by applicant]
WO WO2017079121A2
· 2017
[cited by applicant]
WO WO2017079140A1
· 2017
[cited by applicant]
WO WO2017100642A1
· 2017
[cited by applicant]
WO WO2017145050A1
· 2017
[cited by applicant]
WO WO2017161269A1
· 2017
[cited by applicant]
WO WO2017178844A1
· 2017
[cited by applicant]
WO WO2017178845A1
· 2017
[cited by applicant]
WO WO2018017983A1
· 2018
[cited by applicant]
WO WO2018022761A1
· 2018
[cited by applicant]
WO WO2018049233A1
· 2018
[cited by applicant]
WO WO2018060714A1
· 2018
[cited by applicant]
WO WO2018064852A1
· 2018
[cited by applicant]
WO WO2018071447A1
· 2018
[cited by applicant]
WO WO2018071454A1
· 2018
[cited by applicant]
WO WO2018102455A1
· 2018
[cited by applicant]
WO WO2018136661A1
· 2018
[cited by applicant]
WO WO2018136663A1
· 2018
[cited by applicant]
WO WO2018183712A1
· 2018
[cited by applicant]
WO WO2018189553A1
· 2018
[cited by applicant]
WO WO2018213329A1
· 2018
[cited by applicant]
WO WO2018237134A1
· 2018
[cited by applicant]
WO WO2019001556A1
· 2019
[cited by applicant]
WO WO2019008172A1
· 2019
[cited by applicant]
WO WO2019126121A1
· 2019
[cited by applicant]
WO WO2019143977A1
· 2019
[cited by applicant]
WO WO2019143991A1
· 2019
[cited by applicant]
WO WO2019143994A1
· 2019
[cited by applicant]
WO WO2019195471A1
· 2019
[cited by applicant]
WO WO2020033838A2
· 2020
[cited by applicant]
WO WO2021243186A1
· 2021
[cited by applicant]
WO WO2021243192A1
· 2021
[cited by applicant]
WO WO2022120136A1
· 2022
[cited by applicant]
U.S. Appl. No. 18/606,346, RET Inhibitor for Use in Treating Cancer Having a RET Alteration, filed Mar. 15, 2024.
[cited by applicant]
U.S. Appl. No. 18/422,258, Inhibitors of RET , filed Jan. 25, 2024.
[cited by applicant]
Gainor et al., “Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study,” Lancet Oncology, 2021, 22(7), 959-969 (supplementary appendix) (218 pages).
[cited by applicant]
Gainor et al., “Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study,” Lancet Oncology, 2021, 22(7), 959-969.
[cited by applicant]
Konno, “Effect of polymers on stabilization of drugs in solid dispersions,” Pharmaceutics, 2011, 71(2), pp. 109-113.
[cited by applicant]
Pharmaceutical Dosage Forms: Tablets.—3rd ed., vol. 2 /edited by Larry L. Augsburger, Stephen W. Hoag, 2008, Chapter 6 (38 pages).
[cited by applicant]
Phase 1 Cancer Clinical Trials: A Practical Guide, Second Edition, Eds. E.A. Eisenhauer et al., Chapter 4, Basics of Phase I Design: First-in-Human Studies, Oxford University Press, 2015 (37 pages).
[cited by applicant]
Tanno et al., “Evaluation of Hypromellose Acetate Succinate (HPMCAS) as a Carrier in Solid Dispersions,” Drug Dev. Ind. Pharm., 2004, vol. 30, No. 1, pp. 9-17 (10 pages).
[cited by applicant]
U.S. Appl. No. 17/061,743 US 2021-0085680, RET Inhibitor for Use in Treating Cancer Having a RET Alteration, filed Oct. 2, 2020.
[cited by applicant]
U.S. Appl. No. 17/127,041 U.S. Pat. No. 11,273,160, RET Inhibitor for Use in Treating Cancer Having a RET Alteration, filed Dec. 18, 2020.
[cited by applicant]
U.S. Appl. No. 17/377,885 US 2022-0175773, RET Inhibitor for Use in Treating Cancer Having a RET Alteration, filed Jul. 16, 2021.
[cited by applicant]
U.S. Appl. No. 17/267,149 US 2021-0308134, Treatment of EGFR-Mutant Cancer, filed Feb. 9, 2021.
[cited by applicant]
U.S. Appl. No. 18/255,402, Method of Preparing Pralsetinib, filed Jun. 1, 2023.
[cited by applicant]
U.S. Appl. No. 18/000,166 US 2023-0203009, Pralsetinib Pharmaceutical Compositions, filed Nov. 29, 2022.
[cited by applicant]
U.S. Appl. No. 15/340,428 U.S. Pat. No. 10,030,005, Inhibitors of RET, filed Nov. 1, 2016.
[cited by applicant]
U.S. Appl. No. 16/041,719 U.S. Pat. No. 10,584,114, Inhibitors of RET, filed Jul. 20, 2018.
[cited by applicant]
U.S. Appl. No. 16/775,646 U.S. Pat. No. 11,279,688, Inhibitors of RET, filed Jan. 29, 2020.
[cited by applicant]
U.S. Appl. No. 17/669,785 US 2022-0315560, Inhibitors of RET, filed Feb. 11, 2022.
[cited by applicant]
U.S. Appl. No. 15/548,925 U.S. Pat. No. 10,202,365, 2-(Pyridin-3-yl)-pyrimidine Derivatives as RET Inhibitors, filed Aug. 4, 2017.
[cited by applicant]
U.S. Appl. No. 16/228,381 U.S. Pat. No. 10,774,070, 2-(Pyridin-3-yl)-pyrimidine Derivatives as RET Inhibitors, filed Dec. 20, 2018.
[cited by applicant]
U.S. Appl. No. 15/462,255 U.S. Pat. No. 10,183,928, Inhibitors of RET, filed Mar. 17, 2017.
[cited by applicant]
U.S. Appl. No. 15/657,057 U.S. Pat. No. 10,227,329, Compounds Useful for Treating Disorders Related to RET, filed Jul. 21, 2017.
[cited by applicant]
U.S. Appl. No. 15/660,840 U.S. Pat. No. 10,035,789, Compounds Useful for Treating Disorders Related to RET, filed Jul. 26, 2017.
[cited by applicant]
Abdel-Rahman, O. and M. Fouad (2014) “Risk of cardiovascular toxicities in patients with solid tumors treated with sunitinib, axitinib, cediranib or regorafenib: an updated systematic review and comparative meta-analysi…
[cited by applicant]
Ahn M. et al. “OA 09.03 TATTON Ph Ib Expansion Cohort: Osimertinib plus Savolitinib for Pts with EGFR-Mutant MET-Amplified NSCLC after Progression on Prior EGFR-TKI.” J Thorac Oncol. 12(11) S1768, 2017.
[cited by applicant]
Anonymous “BLU-667 Targets RET-Altered Cancers” Cancer Discovery, vol. 8, No. 6, OF8, Jun. 2018 (Jun. 2018), p. 5pp, XP002792436, Retrieved from the Internet: URL:http://cancerdiscovery.aacrjournals.org/content/8/6/OF8.…
[cited by applicant]
Anonymous “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers”, Guidance for Industry, Jul. 1, 2005 (Jul. 1, 2005), pp. 1-30, XP093000005, Retrieved from th…
[cited by applicant]
Anonymous, “Phase 1 Study of the Highly-selective RET Inhibitor BLU-667 in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors,” ClinicalTrials.org Internet Citation, Feb. 7, 2020, …
[cited by applicant]
Anonymous: “Phase 1 Study of the Highly-selective RET Inhibitor BLU-667 in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors,” Internet Citation, Apr. 21, 2017, Retrieved from the…
[cited by applicant]
Antonescu, C.R. et al. (Jul. 2015) “Molecular Characterization of Inflammatory Myofibroblastic Tumors with Frequent ALK and ROS1 Fusions and Rare Novel RET Gene Rearrangement” Am J Surg Pathol, 39(7):957-967. HHS Public…
[cited by applicant]
Arighi, E. et al. (2005) “RET tyrosine kinase signaling in development and cancer” Cytokine & Growth Factor Reviews, 16:441-467.
[cited by applicant]
Baselga, J. et al. (2005) “Phase II and Tumor Pharmacodynamic Study of Gefitinib in Patients with Advanced Breast Cancer” J Clin Oncol, 23(23):5323-5333.
[cited by applicant]
Bentzien, F. et al. (2013) “In Vitro and in Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer” Thyroid, 23(12):1569-1577.
[cited by applicant]
Brandt, W. et al. (2010) “Inhibitors of the RET tyrosine kinase based on a 2-(alkylsulfanyl)-4-(3-thienyl) nicotinonitrile scaffold” Eur J Med Chem, 45:2919-2927.
[cited by applicant]
Brown et al. (1984) “Heterocyclic Amplifiers of Phleomycin. IV Pyrimidinylpurines, Phenylpyrimidines and Related Systems with Basic Side Chains,” Aust. J. Chem., 37:2093-101.
[cited by applicant]
Caira (1998) “Crystalline Polymorphism of Organic Compounds,” Topics in Current Chemistry 198:163-208.
[cited by applicant]
Caprelsa (vandetanib) “Full Prescribing Information” Reference ID: 3964956, Cambridge, MA: Sanofi Genzyme; 2016.
[cited by applicant]
Carlomagno, F et al. (Feb. 1995) “Point Mutation of the Ret Proto-oncogene in the TT Human Medullary Thyroid Carcinoma Cell Line” Biochem Biophys Res Common, 207(3):1022-1028.
[cited by applicant]
Cascone, T. et al., “Significant Systemic and CNS Activity of RET Inhibitor Vandetanib Combined with mTOR Inhibitor Everolimus in Patients with Advanced NSCLC with RET Fusion”, J. of Clinical Oncology 34, No. 15, 2 page…
[cited by applicant]
Ceccherini, I. et al. (1997) “Somatic in frame deletions not involving juxtamembranous cysteine residues strongly activate the RET proto-oncogene” Oncogene, 14:2609-2612.
[cited by applicant]
Chalice Software Technical Guide, Horizon CombinatoRx Inc., Cambridge, MA, USA (downloaded Jul. 2018).
[cited by applicant]
Chen, M-H et al. (2014) “Antitumor activity of the combination of a HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma,” Oncotarget, 5(8):2372-2389.
[cited by applicant]
Chilean Search Report dated Jun. 27, 2022, in Chilean Patent Application No. 202002544, Chilean National Stage of International Patent Application No. PCT/US2019/025655, filed Apr. 3, 2019, by Blueprint Medicines Corp.
[cited by applicant]
Chilean Search Report dated Mar. 16, 2023, in Chilean Patent Application No. 202002544, Chilean National Stage of International Patent Application No. PCT/US2019/025655, filed Apr. 3, 2019, by Blueprint Medicines Corp.
[cited by applicant]
Cometriq (cabozantinib)“Full Prescribing Information” Reference ID: 3964956, South San Francisco, CA: Exelixix, Inc.; 2018.
[cited by applicant]
Drilon et al. (2018) “Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes,”
[cited by applicant]
Druker, B.J. et al. (2001) “Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia” New Engl J Med, 344(14):1031-1037.
[cited by applicant]
Eisenhauer, E.A. et al. (2009) “New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)” Eur J Cancer, 45:228-247.
[cited by applicant]
Elisei, R. et al. (2008) “Prognostic Significance of Somatic RET Oncogene Mutations in Sporadic Medullary Thyroid Cancer: A 10-Year Follow-Up Study” J Clin Endocrinol Metab, 93(3):682-687.
[cited by applicant]
Engelman J.A. et al. “MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling.” Science, 2007, 316 (5827), pp. 1039-1043.
[cited by applicant]
Evans, E. (May 1, 2016) “The Development of Potent and Selective RET Inhibitors” Slides presented at the 2016 Annual Meeting of the International Thyroid Oncology Group at the University of Colorado (19 pages).
[cited by applicant]
Fagin, J.A. et al. “Biologic and Clinical Perspectives on Thyroid Cancer.” N Engl J Med. 2016, 375 (11) pp. 1054-1067.
[cited by applicant]
Fang, P. et al. (Feb. 2016) “Detection of a novel RET gene fusion in a non-small cell lung cancer patient using AMP chemistry” J Thorac Oncol, 11.2:S21-S22.
[cited by applicant]
Ferrara et al. “Clinical and Translational Implications of RET Rearrangements in Non-Small Cell Lung Cancer,” Journal of Thoracic Oncology, 2018, 13, pp. 27-45.
[cited by applicant]
Gainor J.F. et al. “Dramatic Response to Combination Erlotinib and Crizotinib in a Patient with Advanced, EGFR-Mutant Lung Cancer Harboring De Novo MET Amplification.” J Thorac Oncol. 11(7) 2016, pp. e83-e85.
[cited by applicant]
Gautschi, O. et al. (2016) “Targeting RET in patients with RET-rearranged lung cancers: Results from a global registry” J Clin Oncol, 34(15S) (suppl; abstr 9014).
[cited by applicant]
Gild, M.L. et al. (Oct. 2013) “Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells” Endocr Re/at Cancer, 20(5):659-667. HHS Public Access Author Manuscript; available in PMC Mar. 27, 2015 (16 …
[cited by applicant]
Graham et al., 17 Bioorganic & Medicinal Chemistry, 5886-5893 (2007).
[cited by applicant]
Grubbs, E.G. et al. (Mar. 2015) “RET Fusion as a Novel Driver of Medullary Thyroid Carcinoma” J Clin Endocrinol Metab, 100:788-793.
[cited by applicant]
Halkova, T. et al. (2015) “A novel RET/PTC variant detected in a pediatric patient with papillary thyroid cancer without ionization history” Hum Pathol, 46:1962-1969.
[cited by applicant]
Hayashi, H. et al. (2000) “Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor” Oncogene, 19:4469-4475.
[cited by applicant]
Hilfiker et al. (2006) “Relevance of Solid-state Properties for Pharmaceutical Products,” Polymorphism in the Pharmaceutical Industry, XP002528052, 19 pages.
[cited by applicant]
Horiike, A. et al. (2016) “Sorafenib treatment for patients with RET fusion-positive non-small cell lung cancer” Lung Cancer, 93:43-46.
[cited by applicant]
Hughes (2021) “Review of Synthetic Routes and Crystalline Forms of the Oncology Drugs Capmatinib, Selpercatinib, and Pralsetinib,” Org. Process Res. Dev. 25:2192-2204.
[cited by applicant]
International Search Report and Written Opinion dated Apr. 29, 2016, in International Patent Application No. PCT/US2016/016808, filed Feb. 5, 2016, by Blueprint Medicines Corp. (8 pages).
[cited by applicant]
International Search Report and Written Opinion dated Aug. 16, 2021, in International Patent Application No. PCT/US2021/034823, filed May 28, 2021, by Blueprint Medicines Corp. (14 pages).
[cited by applicant]
International Search Report and Written Opinion dated Feb. 24, 2022, in International Patent Application No. PCT/US2021/061754, filed Dec. 3, 2021, by Blueprint Medicines Corp. (16 pages).
[cited by applicant]
International Search Report and Written Opinion dated Jan. 18, 2017, in International Patent Application No. PCT/US2016/059879, filed Nov. 1, 2016, by Blueprint Medicines Corp. (12 pages).
[cited by applicant]
International Search Report and Written Opinion dated Jun. 12, 2017, in International Patent Application No. PCT/US2017/022969, filed Mar. 17, 2017, by Blueprint Medicines Corp. (12 pages).
[cited by applicant]
International Search Report and Written Opinion dated May 11, 2021, in International Patent Application No. PCT/US2021/034811, filed May 28, 2021, by Blueprint Medicines Corp. (16 pages).
[cited by applicant]
International Search Report and Written Opinion dated Oct. 12, 2017, in International Patent Application No. PCT/US2017/043964, filed Jul. 26, 2017, by Blueprint Medicines Corp. (13 pages).
[cited by applicant]
International Search Report and Written Opinion dated Oct. 25, 2017, in International Patent Application No. PCT/US2017/043340, filed Jul. 21, 2017, by Blueprint Medicines Corp. (14 pages).
[cited by applicant]
International Search Report and Written Opinion mailed Aug. 21, 2018, in International Patent Application No. PCT/US2018/032794, filed May 15, 2018, by Blueprint Medicines Corp. (18 pages).
[cited by applicant]
International Search Report and Written Opinion of the International Searching Authority for International Application No. PCT/US2019/025655 mailed Jul. 23, 2019 (16 pages).
[cited by applicant]
International Search Report and Written Opinion of the International Searching Authority for International Application No. PCT/US2019/045919 mailed Jan. 22, 2020 (11 pages).
[cited by applicant]
Jin, N. et al. (Oct. 15, 2011), “Synergistic Action of a RAF Inhibitor and a Dual PI3K/mTOR Inhibitor in Thyroid Cancer,” Clin Cancer Res, 17(20):6482-6489.
[cited by applicant]
Joung, J.Y. et al. (2016) “Diffuse sclerosing variant of papillary thyroid carcinoma: major genetic alterations and prognostic implications” Histopathology, 69:45-53.
[cited by applicant]
Jovanovic, R. et al. (2015) “Novel RET Mutations in Macedonian Patients with Medullary Thyroid Carcinoma: Genotype-Phenotype Correlations” Prilozi, 36(1):93-107.
[cited by applicant]
Kamil et al. “Dose estimation, conversion and translation from animal to human and human to animal for clinical and animal studies”, Int. J. Biol. Biotech., Jul. 1, 2017 (Jul. 1, 2017), pp. 311-317, XP093000013, Retriev…
[cited by applicant]
Kang et al., “Osimertinib and Cabozantinib Combinatorial Therapy in an EGFR-Mutant Lung Adenocarcinoma Patient with Multiple MET Secondary-Site Mutations after Resistance to Crizotinib,” Journal of Thoracic Oncology, Ap…
[cited by applicant]
Karrasch, T. et al. (2016) “How to Assess the Clinical Relevance of Novel RET Missense Variants in the Absence of Functional Studies?” Eur Thyroid J, 5:73-77.
[cited by applicant]
Kato, S. et al. (Apr. 15, 2017) “RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients” Clin Cancer Res, 23(8):1988-1997.
[cited by applicant]
Kim, S.H. et al. (2015) “A New Germline ALA641THR Variant in the Transmembrane Domain of the RET Gene Associated with Medullary Thyroid Cancer” Acta Endocrinologica (Buc), 11.2:189-194.
[cited by applicant]
Klempner et al. “Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI” Lung Cancer, Sep. 2015, vol. 89, No. 3,…
[cited by applicant]
Kohno et al. (2013) “RET fusion gene: Translation to personalized lung cancer therapy,” Cancer Sci 104(11):1396-1400.
[cited by applicant]
Krampitz, G.W. and J.A. Norton (2014) “RET Gene Mutations (Genotype and Phenotype) of Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma” Cancer, 120:1920-1931.
[cited by applicant]
Kuster, B. (Ed.) (2012)
[cited by applicant]
Latteyer, S. et al. (Mar. 2016) “A 6-Base Pair in Frame Germline Deletion in Exon 7 of RET Leads to Increased RET Phosphorylation, ERK Activation, and MEN2A” J Clin Endocrinol Metab, 101(3):1016-1022.
[cited by applicant]
Le Rolle, A. et al. (2015) “Identification and characterization of RET fusions in advanced colorectal cancer” Oncotarget, 6(30):28929-28937.
[cited by applicant]
Lee, M.S. et al. (2016) “Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models” Oncotarget, 7(26):39595-39608.
[cited by applicant]
Lehar, J. et al. (2009) “Synergistic drug combinations improve therapeutic selectivity” Nat Biotechnol, 27(7):659-666. HHS Public Access Author Manuscript; available in PMC Jan. 1, 2010 (23 pages).
[cited by applicant]
Lin, J.J. et al. (2016) “Clinical Activity of Alectinib in Advanced RET-Rearranged Non-Small Cell Lung Cancer” J Thorac Oncol, 11(11):2027-2032.
[cited by applicant]
Lipson, D. et al. (2012) “Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies” Nat Med, 18(3):382-384. HHS Public Access Author Manuscript; available in PMC Feb. 6, 2014 (7 pages).
[cited by applicant]
Machens, A. et al. (2003) “Early Malignant Progression of Hereditary Medullary Thyroid Cancer” New Engl J Med, 349:1517-1525.
[cited by applicant]
McMahon (2000) “VEGF Receptor Signaling in Tumor Angiogenesis,” The Oncologist 5(suppl 1):3-10.
[cited by applicant]
Mologni, L. et al. (2010) “Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors” Bioorg Med Chem, 18:1482-1496.
[cited by applicant]
Mologni, L. et al. (2013) “Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase” Mol Cell Endocrinol, 377:1-6.
[cited by applicant]
Mologni, L. et al. (2017) “RET kinase inhibitors: a review of recent patents (2012-2015)” Exp Opin Ther Patents, 27(1):91-99.
[cited by applicant]
Moura, M.M. et al. (2009) “Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas” Br J Cancer, 100:1777-1783.
[cited by applicant]
Mulligan, L.M. (Mar. 2014) “RET revisited: expanding the oncogenic portfolio” Nat Rev Cancer, 14:173-186.
[cited by applicant]
Mulligan, L.M. et al. (1995) “Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium” J Int Med, 238:343-346.
[cited by applicant]
Mulligan, L.M. et al. (Jun. 3, 1993) “Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A” Nature, 363:458-460.
[cited by applicant]
NCT03037385, entitled “Phase 1 Study of BLU-667 in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and OtherAdvanced Solid Tumors,” ClinicalTrials.gov, Jan. 17, 2018 (8 pages).
[cited by applicant]
NCT03037385, entitled “Phase 1 Study of BLU-667 in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and OtherAdvanced Solid Tumors,” ClinicalTrials.gov, Jan. 27, 2017 (7 pages).
[cited by applicant]
NCT03037385, entitled Phase 1/2 Study of the Highly-selective RET Inhibitor, Pralsetinib (BLU-667), in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors (ARROW) (13 pages).
[cited by applicant]
NCT04222972, entitled AcceleRET Lung Study of Pralsetinib for 1L Ret Fusion-positive, Metastatic NSCLC (11 pages).
[cited by applicant]
Neal et la., “Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlle…
[cited by applicant]
Oxnard, G.R. et al. “Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib.” JAMA Oncol. 2018, 4(11), pp. 1527-1534.
[cited by applicant]
Pinedo (2000) Translational Research: The Role of VEGF in Tumor Angiogenesis, The Oncologist 5(suppl 1):1-2.
[cited by applicant]
Piotrowska et al.(2018) “MA26.03 Activity of Osimertinib and the Selective RET Inhibitor BLU-667 in an EGFR-Mutant Patient with Acquired RET Rearrangement,” Journal of Thoracic Oncology—IASLC 19th World Conference on Lu…
[cited by applicant]
Piotrowska et al. (2018) “Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-677 for Acquired RET Fusion,” Cancer Di…
[cited by applicant]
Pirker, R. and M. Filipits (2015) “Alectinib in RET-rearranged non-small cell lung cancer—Another progress in precision medicine?” Transl Lung Cancer Res, 4(6):797-800.
[cited by applicant]
Plaza-Menacho, I. et al. (2014) “Mechanisms of RET signaling in cancer: Current and future implications for targeted therapy” Cellular Signalling, 26:1743-1752.
[cited by applicant]
Pound et al. “Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail”, J. Transl Med, Jan. 1, 2018 (Jan. 1, 2018), pp. 1-8, XP093000231, DOI: 10.1…
[cited by applicant]
Qi, X. et al. (2015) “RET mutation p.S891A in a Chinese family with familial medullary thyroid carcinoma and associated cutaneous amyloidosis binding OSMR variant p.G513D” Oncotarget, 6(32):33993-34003.
[cited by applicant]
Rahal, R. (Apr. 18, 2016) “The development of potent, selective RET inhibitors” Slides of a Presentation at the American Association for Cancer Research (AACR) Annual Meeting, Apr. 16-20, 2016, New Orleans (15 pages).
[cited by applicant]
Rahal, R. et al. “BLU-667 is a Potent and Highly Selective RET Inhibitor Being Developed for RET-Driven Cancers,” Poster B151, Blueprint Medicines Corporation (1 page).
[cited by applicant]
Rahal, R. et al. (2016) “The development of potent, selective RET inhibitors that target both wild-type RET and prospectively identified resistance mutations to multi-kinase inhibitors” Abstract submitted to the America…
[cited by applicant]
Ramalingam et al. “Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer” Journal Of Clinical Oncology, Mar. 20, 2018, vol. 36, No. 9, p. 841-849; abstract.
[cited by applicant]
Reagan-Shaw et al. (2007) “Dose translation from animal to human studies revisited” The FASEB Journal, 22:659-661.
[cited by applicant]
Reckamp et al. (2014) “Phase II trial of XL184 (cabozantinib) plus erlotinib in patients (pts) with advanced EGFR-mutant non-small cell lung cancer (NSCLC) with progressive disease (PD) on epidermal growth factor recept…
[cited by applicant]
Reckamp, K. L. et al. “Abstract 936: Analysis of cell-free DNA from 32,991 advanced cancers reveals novel co-occurring activating RET alterations and oncogenic signaling pathway aberrations.” Cancer Research. Pubished J…
[cited by applicant]
Robinett, R.G. et al. (2007) “The discovery of substituted 4-(3-hyroxyanilino)-quinolines as potent RET kinase inhibitors” Bioorg Med Chem Lett, 17:5886-5893.
[cited by applicant]
Robinson B. G. et al. “Vandetanib (100 mg) in Patients with Locally Advanced or Metastatic Hereditary Medullary Thyroid Cancer,” Journal of Clinical En doc ri no logy and Metabolism, vol. 95, No. 6, Jun. 1, 2010 (Jun. 1…
[cited by applicant]
Romei, C. et al. (Apr. 2016) “A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma” Nat Rev Endocrinol, 12:192-202.
[cited by applicant]
Russian Search Report dated Jan. 13, 2023, in Russian Patent Application No. 2020135917, Russian National Stage of International Patent Application No. PCT/US2019/025655, filed Apr. 3, 2019, by Blueprint Medicines Corp.
[cited by applicant]
Saito, M. et al. (Jun. 2016) “Gene aberrations for precision medicine against lung adenocarcinoma” Cancer Sci, 107(6):713-720.
[cited by applicant]
Sarker, D. and P. Workman (2007) “Pharmacodynamic Biomarkers for Molecular Cancer Therapeutics” Adv Cancer Res, 96:213-268.
[cited by applicant]
Schrock, A.B. et al. “Receptor Tyrosine Kinase Fusions and BRAF Kinase Fusions are Rare but Actionable Resistance Mechanisms to EGFR Tyrosine Kinase Inhibitors.” Translational Oncology, 2018, 13 (9) pp. 1312-1323.
[cited by applicant]
Scollo, C. et al. (2016) “A novel RET gene mutation in a patient with apparently sporadic pheochromocytoma” Endocr J, 63(1):87-91.
[cited by applicant]
Sentürk et al. (2020) “Quantitative bioanalytical assay for the selective RET inhibitors selpercatinib and pralsetinib in mouse plasma and tissue homogenates using liquid chromatography-tandem mass spectrometry,” Journa…
[cited by applicant]
Silva, A.L. et al. (2015) “Identification and characterization of two novel germline RET variants associated with medullary thyroid carcinoma” Endocrine, 49:366-372.
[cited by applicant]
Singapore Written Opinion dated Dec. 13, 2021, in Singapore Patent Application No. 11202009681Y, Singapore National Stage of International Patent Application No. PCT/US2019/025655, filed Apr. 3, 2019, by Blueprint Medic…
[cited by applicant]
Smith et al., “Role of ERBB signaling in RET-rearranged lung cancer and contribution of EGFR amplification to cabozantinib resistance,” Journal of Clinical Oncology, 2017, vol. 35, No. 15_suppl, Abstract No. 11583.
[cited by applicant]
Stransky, N. et al. (2014) “The landscape of kinase fusions in cancer” Nat Commun, 5:4846 (10 pages).
[cited by applicant]
Subbiah et al. “Clinical activity and safety of the RET inhibitor pralsetinib in patients with RET fusion-positive solid tumours: update from the ARROW trial”, ASCO, Jun. 4, 2021 (Jun. 4, 2021), pp. 1-1, XP093000210, Re…
[cited by applicant]
Subbiah et al. Abstract CT043 “Highly potent and selective RET inhibitor, BLU-667, achieves proof of concept in a phase I study of advanced, RET-altered solid tumors,” Cancer Research vol. 78, No. 13, Supplement Jul. 1,…
[cited by applicant]
Subbiah V. et al. “Precision Targeted Therapy with BLU-667 for RET-Driven Cancers,” Cancer Discovery, vol. 8, No. 7, Apr. 15, 2018 (pp. 836-849).
[cited by applicant]
Subbiah, V. et al. (Jul. 2015) “Systemic and CNS activity of the RET inhibitor vandetanib combined with the mTOR inhibitor everolimus in KIF5B-RET re-arranged Non-Small Cell Lung Cancer with brain metastases” Lung Cance…
[cited by applicant]
Suehara, Y. et al. (Dec. 15, 2012) “Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions” Clin Cancer Res, 18(24): 6599-6608. HH…
[cited by applicant]
Suzuki, M. et al. (Jul. 2013) “Identification of a lung adenocarcinoma cell line with CCDC6-RET fusion gene and the effect of RET inhibitors in vitro and in vivo” Cancer Sci, 104(7):896-903.
[cited by applicant]
Takeuchi, K. et al. (Mar. 2012) “RET, ROS1 and ALK fusions in lung cancer” Nat Med, 18(3):378-381.
[cited by applicant]
Tan, D.S. et al. (2009) “Biomarker-Driven Early Clinical Trials in Oncology” Cancer J, 15(5):406-420.
[cited by applicant]
Thackaberry et al. (2012) “Non-clinical toxicological considerations for pharmaceutical salt selection,” Expert Opin. Drug Metab. Toxicol. 8(11):1419-1433.
[cited by applicant]
Touat, M. et al. (2015) “Targeting FGFR Signaling in Cancer” Clin Cancer Res, 21(12):2684-2694.
[cited by applicant]
U.S. Nat'l Library of Med., A Phase 1 Trial of Vandetanib (a Multi-kinase Inhibitor of EGFR, VEGFR and RET Inhibitor) in Combination With Everolimus (an mTOR Inhibitor) in Advanced Cancer, ClinicalTrials.gov,https://cli…
[cited by applicant]
U.S. Nat'l Library of Med., Phase 1 Study of the Highly-selective RET Inhibitor BLU-667 in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors, ClinicalTrials.gov, https://clinicalt…
[cited by applicant]
Wakelee et al. (2017) “A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer,” Cancer Chemother Pharmacol 79:923-932.
[cited by applicant]
Wang et al., “Abstract 4110: Combinatory approaches targeting EGFR, HER2 and c-MET in recurrent SCCHN,” Cancer Res, 2017, vol. 77, No. 13_Supplement, Abstract No. 4110.
[cited by applicant]
Wang, L. et al. (2012) “Identification of a Novel, Recurrent HEY1-NCOA2 Fusion in Mesenchymal Chondrosarcoma based on a Genome-wide Screen of Exon-level Expression Data” Genes Chromosomes Cancer, 51(2):127-139. HHS Publ…
[cited by applicant]
Wang, R. et al. (Dec. 10, 2012) “RET Fusions Define a Unique Molecular and Clinicopathologic Subtype of Non-Small-Cell Lung Cancer” J Clin Oncol, 30(35):4352-4359.
[cited by applicant]
Wells, S.A. et al. (2015) “Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma” Thyroid, 25(6):567-610.
[cited by applicant]
Zhang et al., “Activation of the AXL kinases causes resistance to EGFR-targeted therapy in lung cancer,” Nature Genetics, 2012, vol. 44, No. 8, pp. 852-860.
[cited by applicant]