a2) United States Patent
`US 11,591,393 B2
`(0) Patent No.:
`*Feb. 28, 2023
`(45) Date of Patent:
`Diaz et al.
`
`US011591393B2
`
`CHECKPOINT BLOCKADE AND
`MICROSATELLITE INSTABILITY
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`Primary Examiner — Lisa V Cook
`(74) Attorney, Agent, or Firm — Fish & Richardson P.C.
`
`(57)
`
`ABSTRACT
`
`Blockade of immunecheckpoints such as cytotoxic T-lym-
`phocyte antigen-4 (CTLA-4) and programmed death-1 (PD-
`1) shows promise in patients with cancer. Inhibitory anti-
`bodies directed at these receptors have been shownto break
`immunetolerance and promote anti-tumor immunity. These
`agents work particularly well
`in patients with a certain
`category of tumor. Such tumors maybe particularly suscep-
`tible to treatment because of the multitude of neoantigens
`which they produce.
`
`42 Claims, 13 Drawing Sheets
`
`JHU 2301
`Merck Sharp v. Johns Hopkins
`IPR2024-00648
`
`(54)
`
`(71)
`
`(72)
`
`Applicant: The Johns Hopkins University,
`Baltimore, MD (US)
`
`Inventors: Luis Diaz, Ellicot City, MD (US); Bert
`Vogelstein, Baltimore, MD (US);
`Kenneth W. Kinzler, Baltimore, MD
`(US); Nickolas Papadopoulos, Towson,
`MD (US); Dung Le, Lutherville, MD
`(US); Drew M. Pardoll, Brookville,
`MD (US); Suzanne L. Topalian,
`Brookville, MD (US)
`
`(73)
`
`Assignee: The Johns Hopkins University,
`Baltimore, MD (US)
`
`Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21)
`
`Appl. No.: 17/465,101
`
`(22)
`
`Filed:
`
`Sep. 2, 2021
`
`(65)
`
`(63)
`
`Prior Publication Data
`
`US 2021/0395365 Al
`
`Dec. 23, 2021
`
`Related U.S. Application Data
`
`Continuation of application No. 17/131,339, filed on
`Dec. 22, 2020, which is a continuation of application
`No. 16/144,549, filed on Sep. 27, 2018, now Pat. No.
`10,934,356, which is a continuation of application
`No.
`15/523,451,
`filed
`as
`application No.
`PCT/US2015/060331
`on Nov.
`12,
`2015,
`now
`abandoned.
`
`(60)
`
`Provisional application No. 62/190,977, filed on Jul.
`10, 2015, provisional application No. 62/079,357,
`filed on Nov. 13, 2014.
`
`(51)
`
`Int. Cl.
`
`GOIN 31/00
`GOIN 33/53
`CO7K 16/28
`C120 1/6886
`CO7K 16/30
`CO7K 16/40
`A6IK 39/00
`U.S. Cl.
`
`(52)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2018.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`CPC...... C07K 16/2803 (2013.01); CO7K 16/2818
`(2013.01); CO7K 16/2827 (2013.01); CO7K
`16/30 (2013.01); CO7K 16/40 (2013.01); C12Q
`1/6886 (2013.01); C12¥ 113/11052 (2013.01);
`AGOIK 2039/505 (2013.01); A6IK 2039/55
`(2013.01); CO7K 2317/00 (2013.01); CO7K
`2317/24 (2013.01); CO7K 2317/76 (2013.01);
`C120 2600/106 (2013.01); C120 2600/156
`(2013.01)
`
`JHU 2301
`Merck Sharp v. Johns Hopkins
`IPR2024-00648
`
`1
`
`

`

`US 11,591,393 B2
`Page 2
`
`Clinical Trials Identifier: NCT2060188, “A Phase 2 Clinical Trial of
`Nivolumab
`and Nivolumab Plus Ipilimumab in Recurrent and
`Metastatic Microsatellite
`High (MSI-H) Colon Cancer”, Version 16,
`Oct. 13, 20
`14, 12 pages.
`Clinical Trials Identifier: NCT2060188, “A Phase 2 Clinical Trial of
`Nivolumab
`and Nivolumab Plus Ipilimumab in Recurrent and
`Metastatic Microsatellite
`High (MSI-H) Colon Cancer”, Version 17,
`Oct. 30, 20
`14, 12 pages.
`Clinical Tri
`als Identifier: NCT2060188, “A Phase 2 Clinical Trial of
`Nivolumab
`and Nivolumab Plus Ipilimumab in Recurrent and
`Metastatic Microsatellite
`High (MSI-H) Colon Cancer”, Version 18,
`Nov. 13, 2014, 12 pages.
`Clinical Tri
`als Identifier: NCT2060188, “A Phase 2 Clinical Trial of
`Nivolumab
`and Nivolumab Plus Ipilimumab in Recurrent and
`Metastatic Microsatellite
`High (MSI-H) Colon Cancer”, Version 19,
`Nov. 20, 2014, 12 pages.
`Clinical Tri
`als Identifier: NCT2060188, “A Phase 2 Clinical Trial of
`Nivolumab
`and Nivolumab Plus Ipilimumab in Recurrent and
`Metastatic Microsatellite
`High (MSI-H) Colon Cancer”, Version 2,
`pages.
`Mar. 25, 2014, 11
`Clinical Tri
`als Identifier: NCT2060188, “A Phase 2 Clinical Trial of
`Nivolumab
`and Nivolumab Plus Ipilimumab in Recurrent and
`Metastatic Microsatellite
`High (MSI-H) Colon Cancer”, Version 20,
`Dec. 5, 2014, 12 pages.
`Clinical Tri
`als Identifier: NCT2060188, “A Phase 2 Clinical Trial of
`Nivolumab
`and Nivolumab Plus Ipilimumab in Recurrent and
`Metastatic Microsatellite
`High (MSI-H) Colon Cancer”, Version 21,
`Dec. 31, 2014, 12 pages.
`Clinical Tri
`als Identifier: NCT2060188, “A Phase 2 Clinical Trial of
`Nivolumab
`and Nivolumab Plus Ipilimumab in Recurrent and
`Metastatic Microsatellite
`High (MSI-H) Colon Cancer”, Version 22,
`Jan. 27, 20
`15, 12 pages.
`Clinical Tri
`als Identifier: NCT2060188, “A Phase 2 Clinical Trial of
`Nivolumab
`and Nivolumab Plus Ipilimumab in Recurrent and
`Metastatic Microsatellite
`High (MSI-H) Colon Cancer”, Version 23,
`Feb. 6, 201
`5, 12 pages.
`Clinical Tri
`als Identifier: NCT2060188, “A Phase 2 Clinical Trial of
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`and Nivolumab Plus Ipilimumab in Recurrent and
`Metastatic Microsatellite
`High (MSI-H) Colon Cancer”, Version 24,
`pages.
`Feb. 19, 2015, 12
`Clinical Tri
`als Identifier: NCT2060188, “A Phase 2 Clinical Trial of
`Nivolumab
`and Nivolumab Plus Ipilimumab in Recurrent and
`Metastatic Microsatellite
`High (MSI-H) Colon Cancer”, Version 25,
`Mar. 5, 2015, 12 pages.
`Clinical Tri
`als Identifier: NCT2060188, “A Phase 2 Clinical Trial of
`Nivolumab
`and Nivolumab Plus Ipilimumab in Recurrent and
`Metastatic Microsatellite
`High (MSI-H) Colon Cancer”, Version 26,
`Mar. 23, 2015, 12 pages.
`Clinical Tri
`als Identifier: NCT2060188, “A Phase 2 Clinical Trial of
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`Metastatic Micros
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`High (MSI-H) Colon Cancer”, Version 27,
`pages.
`Apr. 13, 2015, 12
`Clinical Trials Identifier: NCT2060188, “A Phase 2 Clinical Trial of
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`High (MSI-H) Colon Cancer”, Version 28,
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`
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