`
`
`
`11111111111111111111111111111111111)1!1J111101,1111141101j1111111111111111111111111111111111
`
`(19) United States
`(12) Patent Application Publication
`Korman et al.
`
`(10) Pub. No.: US 2009/0217401 Al
`Aug. 27, 2009
`(43) Pub. Date:
`
`(54) HUMAN MONOCLONAL ANTIBODIES TO
`PROGRAMMED DEATH 1(PD-1) AND
`METHODS FOR TREATING CANCER USING
`ANTI-PD-1 ANTIBODIES ALONE OR IN
`COMBINATION WITH OTHER
`IMMUNOTHERAPEUTICS
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/679,466, filed on May
`9, 2005, provisional application No. 60/738,434, filed
`on Nov. 21, 2005, provisional application No. 60/748,
`919, filed on Dec. 8, 2005.
`Publication Classification
`
`(75)
`
`Inventors:
`
`Alan J. Korman, Piedmont, CA
`(US); Mohan Srinivasan, San Jose,
`CA (US); Changyu Wang,
`Fremont, CA (US); Mark J. Selby,
`San Francisco, CA (US); Bing
`Chen, Alameda, CA (US);
`Josephine M. Cardarelli, San
`Carlos, CA (US)
`
`Correspondence Address:
`BAKER BOTTS L.L.P.
`30 ROCKEFELLER PLAZA, 44th Floor
`NEW YORK, NY 10112-4498 (US)
`
`(73) Assignee:
`
`MEDAREX, INC, Princeton, NJ
`(US)
`
`(21) Appl. No.:
`
`11/913,217
`
`(22) PCT Filed:
`
`May 2, 2006
`
`(86) PCT No.:
`
`PCT/JP2006/309606
`
`§ 371 (c)(1),
`(2), (4) Date:
`
`Jan. 29, 2009
`
`Int. Cl.
`A 01K 67/027
`A61K 39/395
`CO7H 21/00
`C12N 15/74
`C12N 5/10
`C12N 5/16
`CO7K 16/18
`A61P 35/00
`U.S. Cl.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`800/18; 530/388.15; 424/142.1;
`536/23 .53; 435/320.1; 435/325; 435/326;
`530/402
`
`(57)
`
`ABSTRACT
`
`The present invention provides isolated monoclonal antibod-
`ies, particularly human monoclonal antibodies, that specifi-
`cally bind to PD-1 with high affinity. Nucleic acid molecules
`encoding the antibodies of the invention, expression vectors,
`host cells and methods for expressing the antibodies of the
`invention are also provided. Immunoconjugates, bispecific
`molecules and pharmaceutical compositions comprising the
`antibodies of the invention are also provided. The invention
`also provides methods for detecting PD-1, as well as methods
`for treating various diseases, including cancer and infectious
`diseases, using anti-PD-1 antibodies. The present invention
`further provides methods for using a combination immuno-
`therapy, such as the combination of anti-CTLA-4 and anti-
`PD-1 antibodies, to treat hyperproliferative disease, such as
`cancer. The invention also provides methods for altering
`adverse events related to treatment with such antibodies indi-
`vidually.
`
`Genome Ex. 1003
`Page 1 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 1 of 58
`
`US 2009/0217401 Al
`
`Anti-PD1 17D8 VII
`
`V segment: 3-33
`D segment: unknown
`J segment: JH4b
`
`Q V Q L V E S G G D V V Q P G G S L
`1 CAG GTG CAG CTG GTG GAG TCT GGG GGA GAC GTG GTC CAG CCT GGG GGG TCC CTG
`
`CDRI
`
`R L S C A A S G V A F S N Y G M H W
`55 AGA CTC TCC TGT GCA GCG TCT GGA GTC GCC TTC AGT AAC TAT GGC ATG CAC TGG
`
`CDR2
`
`3 R Q A P G K G L E W V A V I W
`Y D
`109 GTC CGC CAG GCT CCC GGC AAG GGG CTG GAG TGG GTG GCA GTT ATC TGG TAT GAT
`
`CDR2
`
`G S N K Y Y A D S V K G R F T I S R
`163 GGA AGT AAT AAA TAC TAT GCA GAC TCC GTG AAG GGC CGG TTC ACC ATC TCC AGA
`
`N S K N M L Y L Q M N S L R A E D
`D
`217 GAC AAT TCC AAG AAC ATG CTC TAT CTG CAA ATG AAC AGC CTG AGA GCC GAG GAC
`
`CDR3
`
`L
`T
`G
`Q
`G
`W
`Y
`D
`D
`N
`R
`A
`C
`Y
`Y
`M
`A
`T
`271 ACG GCT ATG TAT TAC TGT GCG AGG AAC GAT GAC TAC TGG GGC CAG GGA ACC CTG
`
`3 T V S S
`325 GTC ACC GTC TCC TCA
`
`1.1114b
`
`Figure 1A
`
`Genome Ex. 1003
`Page 2 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 2 of 58
`
`US 2009/0217401 Al
`
`Anti-PD1 17D8 VK
`
`V segment: L6
`J segment: JK4
`
`R
`E
`G
`P
`S
`L
`S
`L
`T
`P A
`S
`V
`Q
`T
`L
`I
`E
`GAA ATT GTG TTG ACA CAG TCT CCA GCC ACC CTG TCT TTG TCT CCA GGG GAA AGA
`
`1
`
`CDR1
`
`Y
`W
`A
`L
`Y
`S'
`S
`V
`S
`Q
`S
`A
`R
`C
`S
`L
`T
`A
`55 GCC ACC CTC TCC TGC AGG GCC AGT CAG AGT GTT AGC AGC TAC TTA GCC TGG TAC
`
`CDR2
`
`R
`N
`S
`A
`D
`Y
`L
`I
`R
`P
`A
`I
`Q
`G
`P
`K
`Q
`Q
`CAA CAG AAA CCT GGC CAG GCT CCC AGG CTC ATC ATC TAT GAT GCA TCC AAC AGG
`
`109
`
`CDR2
`
`T
`F
`D
`T
`G
`S
`G
`S
`G
`S
`F
`R
`A
`P
`I
`G
`T
`A
`163 GCC ACT GGC ATC CCA GCC AGG TTC AGT GGC AGT GGG TCT GGG ACA GAC TTC ACT
`
`CDR3
`
`Q
`Q
`C
`Y
`Y
`V
`A
`F
`D
`E
`P
`E
`L
`S
`S
`I
`T
`L
`CTC ACC ATC AGC AGC CTA GAG CCT GAA GAT TTT GCA GTT TAT TAC TGT CAG CAG
`
`217
`
`CDR3
`
`K
`I
`E
`V
`K
`T
`G
`G
`G
`F
`T
`L
`P
`W
`N
`S
`R
`CGT AGC AAC TGG CCT CTC ACT TTC GGC GGA GGG ACC AAG GTG GAG ATC AAA
`
`271
`
`Figure 1B
`
`Genome Ex. 1003
`Page 3 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 3 of 58
`
`US 2009/0217401 Al
`
`Anti-PD-1 2D3 VFI
`
`V segment: 3-33
`D segment: 7-27
`J segment: JH4b
`
`Q
`V
`V
`D
`G
`G
`S
`P
`E
`V
`R
`G
`L
`Q
`L
`S
`V
`Q
`CAG GTG CAG CTG GTG GAA TCT GGG GGA GAC GTG GTC CAG CCT GGG AGG TCC CTG
`
`1
`
`CDR1
`
`R
`F
`G
`Y
`N
`T
`T
`L
`G
`S
`C
`S
`L
`H
`F
`W
`A
`A
`55 AGA CTC TCC TGT GCA GCG TCT GGA TTA ACC TTC ACT AAC TAT GGC TTC CAC TGG
`
`CDR2
`
`3
`Q
`R
`I
`V
`A
`V
`W
`E
`L
`G
`K
`G
`P
`A
`D
`Y
`W
`109 GTC CGC CAG GCT CCA GGC AAG GGG CTG GAG TGG GTG GCT GTT ATA TGG TAT GAT
`
`CDR2
`
`S
`G
`S V
`D
`A
`K
`K
`R
`S
`I
`T
`F
`R
`G
`K
`Y
`Y
`163 GGA AGT AAG AAA TAT TAT GCA GAC TCC GTG AAG GGC CGA TTC ACC RTC TCC AGA
`
`217
`
`Y
`L
`T
`N
`K
`S
`N
`D
`D
`E
`A
`R
`L
`N
`N
`M
`Q
`L
`GAC AAT TCC AAG AAC ACG CTG TAT CTG CAA ATG AAC AAC CTG AGA GCC GAG GAC
`
`CDR3
`
`G
`C
`Y
`V
`A
`T
`L
`T
`G
`Q
`G
`W
`Y
`D
`D
`T
`A
`Y
`271 ACG GCT GTG TAT TAC TGT GCG ACT GGG GAT GAC TAC TGG GGC CAG GGA ACC CTG
`
`3 T
`S
`S
`V
`325 GTC ACC GTC TCC TCA
`
`Figure 2A
`
`Genome Ex. 1003
`Page 4 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 4 of 58
`
`US 2009/0217401 Al
`
`Anti-PD-1 2D3 VK
`
`V segment: L6
`J segment: JK4
`
`E I V L T Q S P A T L S L S P
`G E
`R
`1 GAA ATT GTG TTG ACA CAG TCT CCA GCC ACC CTG TCT TTG TCT CCA GGG GAA AGA
`
`CDR1
`
`A T L S C R A S Q S V S S Y L A W Y
`55 GCC ACC CTG TCC TGC AGG GCC AGT CAG AGT GTT AGC AGO TAC TTA GCC TGG TAC
`
`Q
`A
`Q
`G
`P
`K
`Q
`L
`L
`R
`P
`I
`D
`Y
`S
`T
`R
`N
`109 CAA CAG AAA CCT GGC CAG GCT CCC AGG CTC CTC ATC TAT GAT ACA TCC AAC AGG
`
`CDR2
`
`A T G I P A R F S G S G S G T
`D F T
`163 GCC ACT GGC ATC CCA GCC AGG TTC AGT GGC AGT GGG TCT GGG ACA GAC TTC ACT
`
`CDR2
`
`S
`I
`T
`L
`E
`P
`E
`L
`S
`V
`A
`F
`D
`Q
`C
`y
`y
`Q
`217 CTC ACC ATC AGC AGC CTA GAG CCT GAA GAT TTT GCA GTT TAT TAC TGT CAG CAG
`
`CDR3
`
`L
`P
`W
`N
`S
`R
`G
`G
`E
`T
`G
`K
`T
`E
`V
`K
`I
`271 CGT AGC AAC TGG CCG CTC ACT TTC GGC GGA GGG ACC AAG GTG GAG ATC AAA
`
`CDR3
`
`Figure 2B
`
`Genome Ex. 1003
`Page 5 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 5 of 58
`
`US 2009/0217401 Al
`
`Anti-PD-1 4H1 VH
`
`V segment: 3-33
`D segment: undetermined
`J segment: JH4b
`
`Q
`V
`G
`P
`V
`G
`G
`R
`G
`L
`S
`S
`E
`V
`L
`Y
`V
`Q
`1 CAG GTG TAC TTG GTA GAG TCT GGG GGA GGC GTG GTC CAG CCT GGG AGG TCC CTG
`
`CDR1
`
`M
`G
`Y
`N
`S
`F
`W
`H
`T
`F
`G
`S
`S
`A
`A
`C
`L
`R
`55 AGA CTC TCC TGT GCA GCG TCT GGA TTC ACC TTC AGT AAC TAT GGC ATG CAC TGG
`
`CDR2
`
`D
`Y
`W
`I
`L
`A
`V
`W
`E
`L
`G
`3
`K
`G
`P
`A
`Q
`R
`109 GTC CGC CAG GCT CCA GGC AAG GGG CTG GAG TGG GTG GCA CTT ATA TGG TAT GAT
`
`CDR2
`
`R
`S
`I
`T
`F
`R
`G
`K
`S V
`D
`A
`Y
`Y
`K
`N
`S
`G
`GGA AGT AAT AAA TAC TAT GCA GAC TCC GTG AAG GGC CGA TTC ACC ATC TCC AGA
`
`163
`
`D
`E
`V
`R
`L
`S
`T
`M
`Q
`L
`Y
`L
`T
`N
`K
`S
`N
`D
`GAC ART TCC AAG AAC ACG CTG TAT CTG CAA ATG ACC AGT CTG AGA GTC GAG GAC
`
`217
`
`CDR3
`
`L
`T
`G
`Q
`G
`W
`H
`D
`V
`N
`S
`A
`C
`Y
`Y
`V
`A
`T
`271 ACG GCT GTG TAT TAT TGT GCG AGC AAC GTT GAC CAT TGG GGC CAG GGA ACC CTG
`
`S
`3 T
`S
`V
`325 GTC ACC GTC TCC TCA
`
`3A
`
`Genome Ex. 1003
`Page 6 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 6 of 58
`
`US 2009/0217401 Al
`
`Anti -PD-1 4H1 VK
`
`V segment: L6
`J segment: JK1
`
`L
`S
`L
`T
`A
`P
`S
`E R.
`G
`P
`S
`Q
`T
`L
`V
`I
`E
`1 GAA ATT GTG TTG ACA CAG TCT CCA GCC ACC CTG TCT TTG TCT CCA GGG GAA AGA
`
`CDR1
`
`A T L S C R A S Q S V S S Y L A W Y
`55 GCC ACC CTC TCC TGC AGG GCC AGT CAG AGT GTT AGT AGT TAC TTA GCC TGG TAC
`
`CDR2
`
`Q Q K P G Q A P R L L I Y D A S N
`R
`109 CAA CAG AAA CCT GGC CAG GCT CCC AGG CTC CTC ATC TAT GAT GCA TCC AAC AGG
`
`CDR2
`
`T D F T
`A T G I P A R F S G S G S G
`163 GCC ACT GGC ATC CCA GCC AGG TTC AGT GGC AGT GGG TCT GGG ACA GAC TTC ACT
`
`CDR3
`
`L T I S S L E P E D F A V Y Y C Q Q
`217 CTC ACC ATC AGC AGC CTA GAG CCT GAA GAT TTT GCA GTT TAT TAC TGT CAG CAG
`
`CDR3
`
`S S N W P R T F G Q G T K V E I K
`271 AGT AGC AAC TGG CCT CGG ACG TTC GGC CAA GGG ACC AAG GTG GAA ATC AAA
`
`Figure 3B
`
`Genome Ex. 1003
`Page 7 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 7 of 58
`
`US 2009/0217401 Al
`
`Anti -PD1 5C4 VFi
`
`V segment: 3-33
`D segment: unknown
`J segment: JH4b
`
`Q V Q L V E S G G G V V Q P G R S L
`1 CAG GTG CAG CTG GTG GAG TCT GGG GGA GGC GTG GTC CAG CCT GGG AGG TCC CTG
`
`CDR1
`
`T
`I
`G
`S
`A
`K
`C
`D
`L
`R
`S
`F
`S
`N
`M
`G
`W
`H
`55 AGA CTC GAC TGT AAA GCG TCT GGA ATC ACC TTC AGT AAC TCT GGC ATG CAC TGG
`
`3 R
`L
`G
`P
`A
`Q
`W
`E
`K
`G
`A
`V
`W
`V
`D
`Y
`I
`109 GTC CGC CAG GCT CCA GGC AAG GGG CTG GAG TGG GTG GCA GTT ATT TGG TAT GAT
`
`CDR2
`
`163
`
`Y
`R
`K
`S
`G
`S V
`D
`A
`Y
`G
`K
`F
`R
`R
`S
`T
`I
`GGA AGT AAA AGA TAC TAT GCA GAC TCC GTG AAG GGC CGA TTC ACC ATC TCC AGA
`
`CDR2
`
`217
`
`N
`S
`N
`D
`Q
`L
`F
`L
`T
`K
`M
`L
`S
`N
`D
`E
`A
`R
`GAC AAT TCC AAG AAC ACG CTG TTT CTG CAA ATG AAC AGC CTG AGA GCC GAG GAC
`
`CDR3
`
`V
`A
`T
`N
`T
`A
`C
`Y
`Y
`Y
`D
`D
`G
`W
`G
`Q
`L
`T
`271 ACG GCT GTG TAT TAC TGT GCG ACA AAC GAC GAC TAC TGG GGC CAG GGA ACC CTG
`
`3 T
`S
`S
`V
`325 GTC ACC GTC TCC TCA
`
`JH4b
`
`Figure 4A
`
`Genome Ex. 1003
`Page 8 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 8 of 58
`
`US 2009/0217401 Al
`
`Anti -PD1 5C4 VK
`
`V segment: L6
`J segment: JK1
`
`E I V L T Q S P A T L S L S P G E R
`1 GAA ATT GTG TTG ACA CAG TCT CCA GCC ACC CTG TCT TTG TCT CCA GGG GAA AGA
`
`CDR1
`
`A T L S C R A S Q S V S S Y L A W Y
`55 GCC ACC CTC TCC TGC AGG GCC AGT CAG AGT GTT AGT AGT TAC TTA GCC TGG TAC
`
`CDR2
`
`P
`A
`Q
`G
`P
`K
`Q
`Q
`R
`N
`S
`A
`D
`Y
`I
`L
`L
`R
`109 CAA CAG AAA CCT GGC CAG GCT CCC AGG CTC CTC ATC TAT GAT GCA TCC AAC AGG
`
`CDR2
`
`G
`T
`A
`G
`S
`G
`S
`G
`S
`F
`R
`A
`P
`I
`T
`F
`D
`T
`163 GCC ACT GGC ATC CCA GCC AGG TTC AGT GGC AGT GGG TCT GGG ACA GAC TTC ACT
`
`CDR3
`
`L T I S S L E P E D F A V Y Y C Q Q
`217 CTC ACC ATC AGC AGC CTA GAG CCT GAA GAT TTT GCA GTT TAT TAC TGT CAG CAG
`
`CDR3
`
`W P R T F G Q G T K V E I K
`S S N
`271 AGT AGC AAC TGG CCT CGG ACG TTC GGC CAA GGG ACC AAG GTG GAA ATC AAA
`
`L
`
`Figure 4B
`
`Genome Ex. 1003
`Page 9 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 9 of 58
`
`US 2009/0217401 Al
`
`Anti-PD-1 4A11 VH
`
`V segment: 4-39
`D segment: 3-9
`J segment: JR4b
`
`1
`
`Q L Q L Q E S G P G L V K P S E T L
`CAG CTG CAG CTG CAG GAG TCG GGC CCA GGA CTG GTG AAG CCT TCG GAG ACC CTG
`
`CDR1
`
`55
`
`S L T C T V S G G S L S R S S F F W
`TCC CTC ACC TGC ACT GTC TCT GGT GGC TCC CTC AGC AGG AGT AGT TTC TTC TGG
`
`CDR1
`
`CDR2
`
`109
`
`G W I R Q P P
`GGC TGG ATC CGT CAG CCC CCA
`
`G
`K
`W
`E
`L
`S
`G
`I
`Y
`I
`AAG GGA CTG GAG TGG ATT GGG AGT ATC TAT
`
`CDR2
`
`163
`
`Y S G S T Y Y N P S L K S R V T I S
`TAT AGT GGG AGC ACC TAC TAC AAC CCG TCC CTC AAG AGT CGA GTC ACC ATA TCC
`
`217
`
`3
`D
`Q
`N
`K
`S
`T
`V
`S
`S
`L
`K
`L
`G
`F
`A
`A
`T
`GTA GAC ACG TCC AAG AAC CAG TTC TCC CTG AAG CTG AGC TCT GTG ACC GCC GCA
`
`271
`
`D T A V Y Y C V R D Y D I L T G
`D E
`GAC ACG GCT GTG TAT TAC TGT GTG AGA GAT TAC GAT ATT TTG ACT GGC GAC GAG
`
`CDR3
`
`CDR3
`
`325
`
`D Y W G Q G T L V T V S S
`GAC TAC TGG GGC CAG GGA ACC CTG GTC ACC GTG TCC TCA
`
`Figure 5A
`
`Genome Ex. 1003
`Page 10 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 10 of 58
`
`US 2009/0217401 Al
`
`Anti-PD-1 4A11 VK
`
`V segment: L15
`J segment: JK1
`
`1
`
`A
`S
`L
`S
`S
`R
`S
`Q
`S
`T
`M
`Q
`I
`D
`V
`R
`D
`G
`GAC ATC CAG ATG ACC CAG TCT CCA TCC TCA CTG TCT GCA TCT GTG GGA GAC AGA
`
`CDR1
`
`55
`
`3 S I T C R A S Q G I S S W L A W Y
`GTC TCC ATC ACT TGT CGG GCG AGT CAG GGT ATT AGC AGC TGG TTA GCC TGG TAT
`
`CDR2
`
`109
`
`Q Q K P E K A P K S L I Y A A S N L
`CAG CAG AAA CCA GAG AAA GCC CCT AAG TCC CTG ATC TAT GCT GCA TCC AAT TTA
`
`CDR2
`
`163
`
`R S G V P S R F S G S G S G T
`D F T
`CGA AGT GGG GTC CCA TCA AGG TTC AGC GGC AGT GGA TCT GGG ACA GAT TTC ACT
`
`217
`
`L T I S S L Q P E D F A T Y Y C Q Q
`CTC ACC ATC AGC AGC CTG CAG CCT GAA GAT TTT GCA ACT TAT TAC TGC CAA CAG
`
`CDR3
`
`271
`
`G
`F
`T
`R
`P
`Y
`S
`Y
`Y
`K
`I
`E
`V
`K
`T
`G
`Q
`TAT TAT AGT TAC CCT AGG ACG TTC GGC CAA GGG ACC AAG GTG GAA ATC AAA
`
`CDR3
`
`Figure 5B
`
`Genome Ex. 1003
`Page 11 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 11 of 58
`
`US 2009/0217401 Al
`
`Anti-PD-1 7D3 VH
`
`V segment: 3-33
`D segment: 7-27
`J segment: JH4b
`
`1
`
`Q V Q L V E S G G G V V Q P G R S L
`CAG GTG CAG CTG GTG GAG TCT GGG GGA GGC GTG GTC CAG CCT GGG AGG TCC CTG
`
`CDR1
`
`55
`
`R L S C T T S G I
`T F S S Y G F H W
`AGA CTC TCC TGT ACA ACG TCT GGA ATC ACC TTC AGT AGC TAT GGC TTT CAC TGG
`
`CDR2
`
`109
`
`3
`W
`E
`L
`G
`R
`I
`V
`A
`V
`K
`G
`P
`A
`Q
`D
`Y
`W
`GTC CGC CAG GCT CCA GGC RAG GGG CTG GAG TGG GTG GCA GTG ATA TGG TAT GAT
`
`CDR2
`
`163
`
`V
`S
`R
`S
`L
`T
`F
`R
`G
`K
`D
`A
`Y
`Y
`K
`K
`S
`G
`GGA AGT AAA AAA TAC TAT GCA GAC TCC GTG AAG GGC CGA TTC ACC CTC TCC AGA
`
`217
`
`D S K N T L Y L Q M N S L R A E D
`D
`GAC GAT TCC AAG AAC ACG CTG TAT CTG CAA ATG AAC AGC CTG AGA GCC GAG GAC
`
`cDR3
`
`271
`
`T A V Y Y C V T G D D Y N G Q G T L
`ACG GCT GTG TAT TAC TGT GTT ACT GGG GAT GAC TAC TGG GGC CAG GGA ACC CTG
`
`325
`
`3 T V S S
`GTC ACC GTC TCC TCA
`
`Figure 6A
`
`Genome Ex. 1003
`Page 12 of 128
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`

`Patent Application Publication Aug. 27, 2009 Sheet 12 of 58
`
`US 2009/0217401 Al
`
`Anti-PD-1 7D3 VK
`
`V segment: L6
`J segment: JK4
`
`1
`
`E I V L T Q S P A T L S L S P G E R
`GAA ATT GTG TTG ACA CAG TCT CCA GCC ACC CTG TCT TTG TCT CCA GGG GAA AGA
`
`CDR1
`
`55
`
`A T L S C R A S Q S V S S Y L A W Y
`GCC ACC CTC TCC TGC AGG GCC AGT CAG AGT GTT AGC AGC TAC TTA GCC TGG TAC
`
`CDR2
`
`109
`
`Q Q K P G Q A P R L L I Y D A S N
`R
`CAA CAG AAA CCT GGC CAG GCT CCC AGG CTC CTC ATC TAT GAT GCA TCC AAC AGG
`
`CDR2
`
`163
`
`A T G I P A R F S G S G S G T D
`F T
`GCC ACT GGC ATC CCA GCC AGG TTC AGT GGC AGT GGG TCT GGG ACA GAC TTC ACT
`
`217
`
`D
`E
`P
`E
`L
`S
`S
`I
`T
`L
`V
`A
`F
`Q
`Q
`C
`Y
`Y
`CTC ACC ATC AGC AGC CTA GAG CCT GAA GAT TTT GCA GTT TAT TAC TGT CAG CAG
`
`CDR3
`
`271
`
`W P L T F G G G T K V E I K
`R S N
`CGT AGC AAC TGG CCT CTC ACT TTC GGC GGA GGG ACC AAG GTG GAG ATC AAA
`
`CDR3
`
`Figure 6B
`
`Genome Ex. 1003
`Page 13 of 128
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`

`

`Patent Application Publication Aug. 27, 2009 Sheet 13 of 58
`
`US 2009/0217401 Al
`
`Anti-PD-1 5F4 VFI
`
`V segment: 4-39
`D segment: 3-9
`J segment: JH4b
`
`1
`
`Q L Q L Q E S G P G L V K P S E T
`L
`CAG CTG CAG CTG CAG GAG TCG GGC CCA GGA CTG GTG AAG CCT TCG GAG ACC CTG
`
`CDR1
`
`55
`
`S L T C S V S G G S L S R S S Y F W
`TCC CTC ACC TGC TCT GTC TCT GGT GGC TCC CTC AGC AGG AGT AGT TAC TTC TGG
`
`CDR1
`
`CDR2
`
`109
`
`G W I R Q P P G K G L E W I A S I F
`GGC TGG ATC CGC CAG CCC CCA GGG AAG GGG CTG GAG TGG ATT GCG AGT ATC TTT
`
`CDR2
`
`163
`
`S
`R
`K
`S
`P
`N
`S
`Y
`I
`T
`V
`S
`L
`F
`Y
`E
`G
`T
`TAT AGT GGG GAA ACC TAC TTC AAT CCG TCC CTC AAG AGT CGA GTC ACC ATA TCC
`
`217
`
`3
`V
`S
`S
`L
`K
`L
`S
`F
`Q
`N
`R
`S
`T
`D
`A
`A
`T
`GTA GAC ACG TCC AGG AAC CAG TTC TCC CTG AAG CTG AGC TCT GTG ACC GCC GCA
`
`271
`
`D
`G
`D
`R
`E
`T
`L
`Y
`D
`A
`C
`Y
`Y
`V
`A
`D
`I
`T
`GAC ACG GCT GTG TAT TAC TGT GCG AGA GAT TAC GAT ATT TTG ACT GGC GAC GAG
`
`CDR3
`
`CDR3
`
`325
`
`T
`L V
`G
`Q
`G
`W
`Y
`D
`S
`S
`V
`T
`GAC TAC TGG GGC CAG GGA ACC CTG GTC ACC GTC TCC TCA
`
`Figure 7A
`
`Genome Ex. 1003
`Page 14 of 128
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`

`

`Patent Application Publication Aug. 27, 2009 Sheet 14 of 58
`
`US 2009/0217401 Al
`
`Anti -PD-1 5F4 VK
`
`V segment: L15
`J segment: JK1
`
`D I Q M T Q S P S S L S A S V G D R
`GAC ATC CAG ATG ACC CAG TCT CCA TCC TCA CTG TCT GCA TCT GTA GGA GAC AGA
`
`CDR1
`
`55
`
`3 T I T C R A S Q G I S S W L A W Y
`GTC ACC ATC ACT TGT CGG GCG AGT CAG GGT APT AGC AGC TGG PTA GCC TGG TAT
`
`CDR2
`
`109
`
`L
`S
`K
`P
`A
`K
`E
`P
`K
`Q
`Q
`A
`Y
`I
`S
`A
`L
`S
`CAG CAG AAA CCA GAG AAA GCC CCT AAG TCC CTG ATC TAT GCT GCA TCC AGT TTG
`
`CDR2
`
`163
`
`Q S G V P S R F S G S G S G T
`D F T
`CAA AGT GGG GTC CCA TCA AGG TTC AGC GGC AGT GGA TCT GGG ACA GAT TTC ACT
`
`217
`
`L T I S S L Q P
`CTC ACC ATC AGC AGC CTG CAG CCT
`
`D F A P Y Y C Q Q
`GAT TTT GCA ACT TAT TAC TGC CAA CAG
`
`CDR3
`
`271
`
`Y S Y P R T F G Q G T K V E I K
`Y
`TAT TAT AGT TAC CCT AGG ACG TTC GGC CAA GGG ACC AAG GTG GAA ATC AAA
`
`CDR3
`
`Figure 7B
`
`Genome Ex. 1003
`Page 15 of 128
`
`

`

`Patent Application Publication
`
`8S Jo SI WIN 600Z `LZ 't nV
`
`TV IOVLIZO/600Z SR
`
`Anti-PD1 17D8, 2D3, 4H1, 5C4 and 7D3 VH region
`
`3-33 Germline:
`17D8 VH:
`2D3 VH:
`4H1 VH:
`5C4 VH:
`7D3 VH:
`
`3-33 Germline:
`17D8 VH:
`2D3 VH:
`4H1 VH:
`5C4 VH:
`7D3
`
`QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQ
`
` D
` G
` V A
`
` D
` L
`- - Y
`
`
`
` D K
` T T
`
`1
`I
`
`
`
`CDR1
`
`N
`T N
` N
`N S
`
`F
`
`F
`
`CDR2
`A P G K G L E W V A V I W Y D G S N K Y Y A D S V K G R F T I S R D N S K N T
`
`
`
` K R
`
`3-33 Germline:
`JH4b germline:
`• 17D8 VH:
`2D3 VH:
`4H1 VH:
`5C4 VH:
`7D3 VH:
`
`LYLQMNSLRAEDTAVYYCAR
`
`M
`
`N
`
`V
`
`- F
`
`CDR.
`
`DYWGQGTLVTVSS
`
` T G
` "S
`V H
` T N D
`VTGD
`
`(JH4b)
` (JH4b)
` (JH4b)
` (JH4b)
` (JH4b)
`
`Figure 8
`
`Genome Ex. 1003
`Page 16 of 128
`
`

`

`Patent Application Publication
`
`8S Jo 91 loollS 600Z `LZ toV
`
`Iv IOVLIZO/600Z SR
`
`Anti-PD-1 17D8, 2D3 and 7D3 Vic Region
`
`L6 germline: EIVLTQSPATLSLSPGERATLSCRASQSVSSYLA
`17D8 VK:
`2D3 VK:
`7D3 VK:
`
`CDR2
`
`L6 germline: WYQQKPGQAPRLLIYDASNRATGIPARFSGSGS
`17D8 VK:
`2D3 VK:
`7D3 VK:
`
`CDR1
`
`G
`
`CDR3
`
`L6 germline: T D F T L T I S S L E P E D F A V Y Y C Q Q R S N W P
`JK4 germline:
`LTFGGGT
`17D8 VK;
`2D3 VK:
`7D3 VK:
`
`JK4 germline:KVEIK
`17D8 VK:
`
` (JK4)
`2C3 VK:
`
` (JK4)
`7D3 VK:
`
` (JK4)
`
`Figure 9
`
`Genome Ex. 1003
`Page 17 of 128
`
`

`

`Patent Application Publication
`
`8S Jo LI WIN 600Z `LZ 't nV
`
`IV IOVLIZO/600Z SR
`
`Anti-PD-1 4H1 and 5C4 VK Region
`
`L6 germ4ne: EIVLTOSPATLSLSPGERATLSCRASQSVSSYLA
`4H1 VK:
`5C4 VK:
`
`
`
`CDR1
`
`
`CDR2
`L6 germ1ine: W Y Q Q K P G Q A P R L L I Y D A S N R ATGIPARFSGSGSG
`4H1 VK:
`5C4 VK:
`
`L6 germline: TDFTLTISSLEPEDFAVYYCQQRSNWP
`JK1 germline:
`
`4H1 VK:
`5C4 VK:
`
`CDR3
`
` 3
`
`WTFGQGT
`
`JK1 germline:KVEIK
`(JK1)
`4H1 VK:
`5C4 VK:
`(JK1)
`
`Figure 10
`
`Genome Ex. 1003
`Page 18 of 128
`
`

`

`Patent Application Publication
`
`8S Jo 81 WIN 600Z `LZ tilV
`
`IV IOVLIZO/600Z SR
`
`Anti-PD-1 4A11 and 5F4 VH regions
`
`4-39 germline:
`4A11 VH:
`5F4 VH:
`
`QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYW
`
`
`
` L R
` S-----L-R---F-
`
`F F -
`
`CDR1
`
`4-39 germ1ine:
`4A11 VH:
`5F4 VH:
`
`
`EWIRQFPGKGLEWIGSIYYSGSTYYNPSL
`
`CDR2
`
`K S R V T I S
`
`4-39 germline:
`4A11 VH:
`5F4 VH:
`
`VDTSKNHFSLKLSSVTAADTAVYYCAR
`
` Q
`R
`
`CDR3
`
` V -DYDILTGDE
` DYDILTGDE
`
`JH4b germ1ine:
`4A11 VH:
`5F4 VH:
`
`DYWGQGTLVTVSS
`
`
`
` (JH4b)
` (JH4b)
`
`Figure 11
`
`Genome Ex. 1003
`Page 19 of 128
`
`

`

`Patent Application Publication
`
`8S Jo 61 WIN 600Z `LZ tilV
`
`IV IOVLIZO/600Z SR
`
`Anti-PD-1 4A11 and 5F4 VK region
`
`L15 germline:
`4A11 VK:
`5F4 VK1:
`
`L15 germline:
`4A11 VK:
`5F4 VK1:
`
`L15 germline:
`4A11 VK:
`5F4
`
`
`CDR1
`D I Q M T Q S P S S L S A S V G D R V T I T C R A S Q G I S S
`
`CDR2
`WLAWYQQKPEKAPKSLIYAASSLQSGVPSRF
`
`
` N - R -
`
`SGSGSGTDFTLTISSLQPEDEATYYCQQINS
`
`CDR3
`
`L15 germ1ine:
`JK1 germline:
`4A11 VK:
`5F4 VKl:
`
`Y P
`
`T F G Q G T K V E I K
`R
` (JK1)
`R
` (JK1)
`
`Figure 12
`
`Genome Ex. 1003
`Page 20 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 20 of 58
`
`US 2009/0217401 Al
`
`00 10 102 103 104
`FITC
`
`Figure 13A
`
`• NM
`
`.I.
`
`J
`
`(
`
`:8
`
`00 10 102 03 104
`FITC
`
`Figure 13B
`
`Genome Ex. 1003
`Page 21 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 21 of 58
`
`US 2009/0217401 Al
`
`Binding specificity of HuMab anti-PD-1 antibodies to
`PD-1 ICOS, CTLA-4 and CD28
`
`.
`q.
`
`2.50
`
`2.00
`
`1.50
`
`too
`
`0.50
`
`0.00
`
`NI PD-1
`
`I COS
`
`0 CTLA-4
`
`1M CD28
`
`5C4.
`
`2D3
`
`17D8
`
`4A11
`
`4H1
`
`Control
`Ab
`
`Figure 14
`
`Genome Ex. 1003
`Page 22 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 22 of 58
`
`US 2009/0217401 Al
`
`Binding of HuMab anti-hPD-1 Abs to activated human T cells
`
`ii:
`
`500
`
`400-
`
`300-
`
`200-
`
`100-
`
`0
`-2
`
`•
`
`•
`
`•
`
`4H1
`
`5C4
`
`17D6
`
`• 2D3
`
`i
`0
`
`i
`1
`
`1
`2
`
`3
`
`Concentration [IM]
`
`gure 15A
`
`Binding of HuMab anti-hPD-1 Abs to activated cynomolgous monkey PBMC
`
`700
`
`600-
`
`500-
`
`400-
`
`300-
`
`200-
`
`100-
`
`a:
`m
`
`• 4H1
`
`A
`
`5C4
`
`•
`17D8
`• 2D3
`
`1
`o
`
`1
`1
`
`2
`
`3
`
`Concentration [nM]
`
`Figure 15B
`
`Genome Ex. 1003
`Page 23 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 23 of 58
`
`US 2009/0217401 Al
`
`Binding of HuMab anti-hPD-1 Abs to PD-1 expressing CHO cells
`
`1200
`
`800-
`
`400-
`
`T.
`E
`
`8
`
`v
`
`•
`
`4A11
`
`•
`
`O
`
`A
`
`4H1
`
`5C4
`
`17D8
`
`-1
`
`1
`0
`
`t
`1
`
`1
`2
`
`1
`3
`
`4
`
`Concentration [nrtil]
`
`Figure 15C
`
`Genome Ex. 1003
`Page 24 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 24 of 58
`
`US 2009/0217401 Al
`
`Anti-PD-1 Abs promote T cell proliferation in MLR
`
`60000
`
`50000
`
`40000
`
`30000
`
`20000
`
`10000
`
`U
`
`111] 25ug/ml
`2.5 ug/ml
`0.25ug/m1
`2 0.025ug/m1
`0 0.0025ug/m1
`
`No Ab
`
`control IgG
`
`5C4
`
`4H1
`
`17D8
`
`Figure 16A
`
`Anti-PD-1Abs on IFN-O secretion in MLR
`
`a 100 ug/ml
`um 10 ug/ml
`Ei 1 ug/ml
`0.1 ug/mi
`1=10.01 ug/ml
`um 0.001 ualn
`
`25000
`
`20000
`
`E 15000
`
`c 10000
`U-
`
`5000
`
`no Ab control A
`
`5C4
`
`2D3
`
`17D8
`
`4A11
`
`Antibodies
`
`Figure 16B
`
`Genome Ex. 1003
`Page 25 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 25 of 58
`
`US 2009/0217401 Al
`
`Anti-PD-1 Abs on IL-2 secretion in MLR
`
`• 100 ug/ml
`M3 10 ug/ml
`O 1 ug/m1
`00.1 ug/ml
` ®0.01 ug/ml
`0.001 ug/ml
`
`1 000
`
`800
`
`E 600
`
`
`
`CL
`
`CIA
`—1
`
`400
`
`200
`
`0
`
`no Ab control A
`
`5C4
`
`203
`Antibodies
`
`e 16C
`
`1708
`
`4A11
`
`Genome Ex. 1003
`Page 26 of 128
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`

`

`Patent Application Publication Aug. 27, 2009 Sheet 26 of 58
`
`US 2009/0217401 Al
`
`HuMab anti-PD-1 Abs block binding of PD-1:1 to CHO/hPD-1 cells
`
`T.
`
`400-
`
`300-
`
`200-
`
`100-
`
`0
`
`10 -2
`
`10 -1
`
`10 0
`
`101
`
`102
`
`103
`
`Concentration [nM]
`
`Figure 17A
`
`HuMab anti-hPD-1 Abs block binding of
`PD-L2 to CHO/PD-1 cells
`
`■ 5C4
`♦
`4H1
`
`•
`
`•
`
`•
`
`a
`
`•
`
`4A 1 1
`
`4H1
`
`5C4
`
`17D8
`
`2D3
`
`Concentration [OM]
`
`Figure 17B
`
`Genome Ex. 1003
`Page 27 of 128
`
`M
`

`

`Patent Application Publication
`
`8S Jo LZ WIN 600Z `LZ 't nV
`
`TV IOVLIZO/600Z SR
`
`Genome Ex. 1003
`Page 28 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 28 of 58
`
`US 2009/0217401 Al
`
`--E—PBS
`Mouse IgG
`--g-- Hamster IgG
`—6 °CTLA-4 4F10
`' PD-1 (4H2.63)
`
`1 4 7 1013161922252831 343740
`AA AA
`
`Dosing
`
`Days
`
`Figure 20
`
`2000
`1800
`1600
`1400
`1200
`1000
`800
`600
`400
`200
`0
`
`Tumor volume (mm3)
`
`Genome Ex. 1003
`Page 29 of 128
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`

`

`Patent Application Publication Aug. 27, 2009 Sheet 29 of 58
`
`US 2009/0217401 Al
`
`mIgG1 @ 10 mq!kg
`
`anti-CTLA4 mAb @10mg/kg
`
`9000
`7003-
`GO CO-
`5000-
`4000-
`3000^
`2000-
`1000.
`0-
`
`3
`
`0
`
`10
`
`20
`
`.
`40
`
`50
`
`30
`days
`
`-
`
`84951
`84993
`.-41" 85232
`-4.-85245
`-4- 86052
`-a- 88063
`--r- 88066
`...F., 86072
`- 0- 860 83
`- 0- 87280
`
`▪
`
`84952
`-*-85233
`85246
`-4.-86053
`-4-66057
`-N--86064
`-A--86067
`-
`86073
`- 4,-86747
`-
`87261
`
`days
`
`Figure 21A
`
`Figure 21B
`
`anti-PD-1 mAb
`
`10 mgrkg
`
`WOO
`7000
`COCO
`9000
`4000
`3000
`
`h 2000
`a 1000
`0-
`0
`
`-ft-84955
`"* 05239
`-T.- 86055
`-.- 86060
`-4- 86070
`- s- 86081
`86750
`- 4,- 86760
`- 4.- 87264
`--4- 87268
`
`10
`
`20
`
`30
`days
`
`40
`
`fO
`
`6O
`
`anti-CTLA4 + anti-POI mAbs: each t§5 mg/kg
`00
`7
`
`84956
`-
`-m-85240
`-S-85058
`-4.-86062
`.4..86071
`88082
`- gr- 86751
`-T-86761
`+
`87265
`- 4-67287
`
`10
`
`20 W
`days
`
`40
`
`90
`
`GO
`
`Figure 21C
`
`Figure 21D
`
`Genome Ex. 1003
`Page 30 of 128
`
`

`

`Patent Application Publication Aug. 27, 2009 Sheet 30 of 58
`
`US 2009/0217401 Al
`
`-m- I gG
`" —As " anti-CTLA4
`anti-PD1
`anti-CTLA4 + anti-PD1
`
`-IF- I gG
`anti-CTLA4
`anti-PD1
`-4- anti-CTLA4 + anti-PD1
`
`4000-
`
`3000-'
`
`s_ c,)
`° E 2000-
`E
`E
`
`
`
`1000-
`
`E
`
`0-
`0
`
`I
`5
`
`I
`10
`
`1
`I
`15
`20
`days
`
`1
`25
`
`30
`
`35
`
`Ficture 22
`
`E
`
`>
`O o eel
`E E
`• E
`•
`cts
`:5
`E
`
`3000-,
`
`2000-
`
`1000-
`
`0 -
`0
`
`10
`
`20
`days
`
`30
`
`40
`
`Figure 23
`
`Genome Ex. 1003
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`Patent Application Publication Aug. 27, 2009 Sheet 31 of 58
`
`US 2009/0217401 Al
`
`migal
`
`nli-CTLA4
`
`- 11- 88641
`-
`88652
`-
`9121 4
`- 0- 8063 0
`-0- 88648
`"-e••• 8930 5
`8863 9
`-0- 8864 5
`-0- 8931 8
`-0- 8931 7
`89309
`
`-
`91221
`-10-88643
`-
`8 8654
`-+-92059
`8 8632
`-
`-a- 88659
`-it- 8 8640
`-0- 90311
`-0- 8 8658
`-e- 91216
`-x- 8 931 6
`
`days
`
`Figure 24A
`
`Figure 24B
`
`arM41124
`
`anti -CT LA4P13-I
`
`--a- 92056
`88634
`8863 3
`-
`-4- 89308
`642
`8862 9
`9031 6
`-
`8865 6
`-e- 8956 2
`-0- 91215
`91315
`
`days
`
`Figure 24C
`
`Figure 24D
`
`▪
`88650
`--kr- 9122 0
`92057
`-0-9121 8
`-0- 91219
`-
`02060
`8 9320
`89560
`8 931 0
`88651
`9 0317
`
`-
`
`-
`
`3000
`ri am
`g 2000
`1500
`6- 1000
`500
`0
`
`3003
`ZOO
`2000
`1500
`1000
`SOO
`a
`
`nE
`
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`Patent Application Publication Aug. 27, 2009 Sheet 32 of 58
`
`US 2009/0217401 Al
`
`E
`>
`al 2
`E
`
`as
`
`1750
`
`1500
`
`1250
`
`1000
`
`750
`
`500
`
`250
`
`0
`
`g
`
`1750
`
`1500
`
`1250
`—0-
`t co 1000
`E E
`E 750
`
`63 •
`5:5
`a)
`
`500
`
`260
`0
`
`10
`days
`
`15
`
`20
`
`Figure 25
`
`mIgG1
`- 41E- anti-CTLA4
`anti-PD-1
`anti-CTLA4/PD-1
`
`-
`
`I gG1
`anti-CTLA4
`anti-PD-1
`anti-CTLA4/P D-1
`
`-
`
`10
`
`20
`days
`
`30
`
`40
`
`e 26
`
`Genome Ex. 1003
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`Patent Application Publication Aug. 27, 2009 Sheet 33 of 58
`
`US 2009/0217401 Al
`
`4501
`nnnn
`E301
`T
`
`F
`E
`E 2000
`3
`
`g 1500
`3
`8 1000
`E
`." 500
`
`Group AX2O
`
`J
`
`Group LI Pi 0 3C1 0
`
`-a- 91421
`-a-01409
`—,-91429
`-4- 91282
`-a-81307
`—F3— 0139a
`-r5-91415
`--7-01420
`-0- 01334
`-e- 012:39
`
`45001
`3503
`2563
`07 2590
`E
`E 203
`
`1504
`
`500
`
`0
`
`15
`days
`
`25
`
`0
`
`5
`
`10
`
`20
`
`25
`
`15
`class
`
`T
`
`•
`
`-N-Giace
`
`-a-914M
`-1-91428
`a-91334
`-0--g1230
`-A-91354
`-q-01411
`-0-01336
`-0-(31318
`30
`
`Figure 27A
`
`Figure 27B
`
`Group C CIOX10
`
`Group 0 CIO MO
`
`30301
`"i111'
`
`(7).
`S 2000
`2
`2 1500
`a
`1000
`E
`-P. 503
`
`0
`
`5
`
`10
`
`20
`
`15
`days
`
`-u-01417
`-A-01322
`1351
`-4.- 91279
`-4-91392
`-0--91397
`--*-91.935
`-v-91323
`-91273
`-0-01320
`
`-0- 91385
`—A— 91339
`-4- 91267
`-
`91424
`-
`91375
`-a- 91364
`▪
`91331
`91284
`-
`--0- 91315
`.43- 91268
`
`*Ix
`
`Figure 27C
`
`Figure 27D
`
`Genome Ex. 1003
`Page 34 of 128
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`

`Patent Application Publication Aug. 27, 2009 Sheet 34 of 58
`
`US 2009/0217401 Al
`
`Group E C3 P3
`
`Group F
` Cl P1
`
`2500
`
`12000
`
`1500
`
`F.• 1000
`
`570
`
`O
`
`5
`
`10
`
`15
`dugs
`
`20
`
`25
`
`3000
`2500
`
`E 20
`
`S 15
`3
`t 100'
`E
`
`500
`
`-4.- 91410
`-9- 91 338
`-
`91358
`-4- 91 276
`191324
`- 0- 91339
`-a- 91231
`-
`91 413
`-o- 91 311
`30 -0- 91239
`
`-N-- 91386
`81379
`-
`-lir- 91371
`-4.- 91353
`- 44.- 91378
`-a-- 91274
`-Li- 91350
`- 7- 91353
`-4- 91309
`-a-9130}
`
`0
`
`5
`
`10
`
`15
`days
`
`20
`
`25
`
`30
`
`Figure 27E
`
`Figure 27F
`
`Group G CieCioPioPio
`
`2500
`
`1000
`
`I
`
`500
`
`0
`
`O
`
`5
`
`10
`
`15
`claw
`
`20
`
`25
`
`som
`
`E 2030
`
`15:6
`3
`1E00
`
`V. sal
`
`0
`
`91349
`-a-91352
`-v-91359
`191310
`-4-91278
`-a- 91422
`-A-91357
`-v-91414
`-v-91418
`30 —o-91412
`
`Group H PiePioCioCio
`
`-N-131373
`-A-913E2
`1385
`-8-91379
`-8-91333
`-a- 9 1272
`-A-91337
`-8-91319
`-4-913,V
`-8-91303
`
`0
`
`5
`
`10
`
`15
`days
`
`20
`
`25
`
`30
`
`Figure 27G
`
`Figure 27H
`
`Genome Ex. 1003
`Page 35 of 128
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`Patent Application Publication Aug. 27, 2009 Sheet 35 of 58
`
`US 2009/0217401 Al
`
`1500-
`
`1500-
`
`1000-
`
`500-
`
`0
`
`0 >
`
`E E
`• E
`c
`ca
`a)
`E
`
`0
`
`---s— A
`—*— B
`• C
`
`—e— E
`—o— F
`G
`H
`
`--m— A
`
`D
`—*-- E
`—o— F
`G
`-V-H
`
`10
`days
`
`15
`
`20
`
`Figure 28
`
`ti
`
`
`
`•—•
`•
`
`10
`days
`
`15
`
`20
`
`Figure 29
`
`Genome Ex. 1003
`Page 36 of 128
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`

`

`Patent Application Publication Aug. 27, 2009 Sheet 36 of 58
`
`US 2009/0217401 Al
`
`Group A
`vehicle
`
`81292
`81307
`X81244
`81272
`81209
`81229
`81216
`81295
`••--81210
`
`10 13 16 19 22 25 28 31 34
`Days Post implantation
`
`Figure 30A
`
`Group B
`mouse IgG
`
`-
`
`81232
`81301
`81256
`-
`•• 81280
`-
`•
`81215
`—8— 81308
`•,ir 81220
` •
`81212
`.•40 . 81227
`81257
`
`10 13 16 19 22 25 28 31 34
`Days Post implantation
`
`Figure 30B
`
`2800
`
`2400
`
`2000
`
`1600
`
`1200
`
`800
`
`400
`
`0
`
`E
`
`w
`
`Tumor vo
`
`2800
`E 2400
`(I) 2000
`• 1600
`O
`> 1200
`8 800
`400
`•
`0
`
`Genome Ex. 1003
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`

`Patent Application Publication Aug. 27, 2009 Sheet 37 of 58
`
`US 2009/0217401 Al
`
`Group C
`PD-1 10mg/kg
`
`2800
`E 2400
`2000
`
`CD
`• 1600
`1200
`8 800
`•
`400
`0
`7 10 13 16 19 22 25 28 31 34 37 40
`Days Post Implantation
`
`-1-- 81237
`81211
`81263
`-
`-4-- 81291
`
`81262
`- 8- 81264
`•-tr- 81223
`- 1P- 81236
`-0- 81285
`•
`81270
`
`Picture 30C
`
`Group D
`CTLA-4 (9D9) 10mg/kg
`
`2800
`E 2400
`2000
`E 1600
`1200
`O 800
`•
`400
`0
`7 10 13 16 19 22 25 28 31 34 37 40
`Days Post Implantation
`
`Figure 30D
`
`-10- 81297
`81304
`-T- 81239
`8 1 2 3 1
`-0- 81279
`-fia- 81287
`--att.- 81276
`-V- 81242
`--0- 81247
`-;-44-- 8-1284
`
`Genome Ex. 1003
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`Patent Application Publication Aug. 27, 2009 Sheet 38 of 58
`
`US 2009/0217401 Al
`
`Group E
`CTLA-4 (9D9) 0.2mg/kg
`
`81226
`81275
`—41-- 81224
`81288
`81294
`—6-- 81213
`—A— 81298
`81245
`—0— 81225
`—9-- 81302
`
`10 13 16 19 22 25 28 31 34
`Days Post Implantation
`
`Figure 30E
`
`2800
`E 2400
`2000
`1600
`C)> 1200
`
`L3
`
` 800
`H 400
`0
`
`Group F
`PD-1 10mg/kg / 9D9 0.2mg/kg
`
`- 4— 81273
`—or— 81228
`—Jr— 81267
`—4P— 81214
`81299
`-
`81246
`—6— 81234
`-
`81282
`—40— 81230
`81253
`-
`
`2800
`cer
`E 2400
`2000
`
`§ 1600
`0 > 1200
`8 800
`400
`
`0
`7 10 13 16 19 22 25 28 31 34 37 40
`Days Post Implantation
`
`Figure 30F
`
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`

`Patent Application Publication Aug. 27, 2009 Sheet 39 of 58
`
`US 2009/0217401 Al
`
`SAl/N (mean)
`
`--Vehicle
`mo. IgG
`-46- PD-1 10mg/kg
`-4-- CTLA-4 9D9 10mg/kg
`-416- CTLA-4 9D9 0.2mg/kg
`-GI- PD-1 10mg/kg & 9D9 0.2mg/kg
`
`2000—
`cl•—•
`1800-
`E 1600-
`E 1400-
`g 1200-
`z 1000-
`800-
`O▪ 600-
`E 400-
`=
`I-- 200-
`
`0
`
`0 3 6 9 12 15 18 21 24 27 30 33 36
`Ai AA
`= Dosing
`Days Post Implantation
`
`Figure 31
`
`SAVN (median)
`
`-6-Vehicle
`MO. IgG
`-
`PD-1 10mg/kg
`-
`--.-CTLA-4 9D9 10mg/kg
`CTLA-4 9D9 0.2mg/kg
`-
`PD-1 10mg/kg & 9D9 0.2mg/kg
`
`2000
`1800
`E 1600
`E 1400
`w 1200
`• 1000
`75 800
`6- 600
`E 400
`I— 20
`
`0 3 6 9 1215 8 21 24 27 30 33 36 39 42
`= Dosing
`
`Days Post Implantation
`
`Figure 32
`
`Genome Ex. 1003
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`

`Patent Application Publication Aug. 27, 2009 Sheet 40 of 58
`
`US 2009/0217401 Al
`
`Group A
`Vehicle
`
`2000
` 1800
`C)
`E 1600
`f.-- 1400
`g 1200
`= 1000
`o > 800
`8 600
`E 400
`=
`I— 200
`0
`6 9 12 15 18 21 24273033363942454851
`Days Post Implantation
`
`-111- 81399
`-911-- 81642
`-.- 81375
`-4- 81357
`-0- 81369
`-8- 81644
`-Al- 81407
`--,F- 81404
`
`Figure 33A
`
`Group B
`mo. IgG, 10 mg/kg
`
`2000
`cer' 1800
`
`E 1600
`1400
`E 1200
`= 1000
`o > 800
`8 600
`E 400
`=
`I— 200
`0
`6 9 12 15 18 21 24 27 0 33 36 39 42 45 48 51
`Days Post Implantation
`
`-ff- 81388
`A 81350
`1 81327
`-S- 81347
`-40- 81319
`-s- 81379
`-It,- 81320
`-C1- 81324
`
`e 33B
`
`Genome Ex. 1003
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`

`Patent Application Publication Aug. 27, 2009 Sheet 41 of 58
`
`US 2009/0217401 Al
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`Group C
`909, 0.25 mg/kg
`
`2000
`tr 1800
`E 1600
`1400
`g 1200
`= 1000
`> 800
`8 600
`E 400
`I- 200
`0
`6 9 12 15 18 21 24 27 0 33 36 39 42 45 48 51
`Days Post Implantation
`
`--11- 81374
`--111,- 81354
`81367
`-6- 81408
`-lb- 81386
`-El- 81342
`—Its— 81346
`-4" 81337
`
`Figure 33C
`
`Group D
`9D9, 0.5 mg/kg
`
`2000-
`co^ 1800-
`E 1600-
`E — 1400-
`g 1200-
`= 1000-
`o
`
`600-4
`400-
`1-- 200-
`0
`6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
`Days Post Implantation
`
`•sSo\‘..
`
`ti.,}••
`
`Figure 33D
`
`81385
`It". ` 81329
`-4g- 81378
`-
`81373
`81403
`-9- 81363
`-itt- 81321
`-IF- 81401
`
`Genome Ex. 1003
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`

`Patent Application Publication Aug. 27, 2009 Sheet 42 of 58
`
`US 2009/0217401 Al
`
`Group E
`9D9, 5 mg/kg
`
`2000
`0^ 1800
`E 1600
`—. 1400
`c) 1200
`m 1000
`> 800
`8
`600
`E
`= 400
`I— 200
`0
`6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
`Days Post Implantation
`
`-NI- 81637
`-1- 81362
`IP' 81643
`'
`---q--- 81361
`-41- 81366
`-0-- 81398
`Ate". 81353
`---V- 81381
`
`Figure 33E
`
`Group F
`PD-I, 3 mg/kg
`
`2000-
`v." 1800-
`E
`1600-
`E
`— 1400-
`o E 1200-
`= 1000-
`o > 800-
`8 600-
`E 400-
`I-- 200
`0
`6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
`Days Post Implantation
`
`-s- 81345
`-A- 81331
`T 81364
`-0- 81349
`-0- 81402
`-B- 81376
`--fr- 81328
`-56- 81339
`
`Figure 33F
`
`Genome Ex. 1003
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`

`

`Patent Application Publication Aug. 27, 2009 Sheet 43 of 58
`
`US 2009/0217401 Al
`
`Group G
`PD-I, 10 mg/kg
`
`2000
`cer 1800
`E 1600
`--- 1400
`E 1200
`• 1000
`800
`> •
`8 600
`400
`I— 200
`0
`6 9 121518 21 24 27 30 33 36 39 42 45 48 51
`Days Post Implantation
`
`81393
`-A- 81371
`-w- 81323
`81406
`-0- 81395
`'me— 81365
`—lir' 81359
`-CI- 81336
`
`Figure 33G
`
`Group H
`PD-1 9D9, 10+0.25 mg/kg
`
`2000
`0-7' 1800
`E 1600
`— 1400
`E 1200
`1000
`800
`o" SOO
`E 400
`I— 200
`0
`6 9 12 5 18 21 24 27 30 33 36 39 42 45 48 51
`Days Post Implantation
`
`-0- 81387
`-lir- 81344
`--496- 81330
`
` 81400
`81377
`-e- 81396
`-dr- 81325
`81397
`
`Figure 33H
`
`Genome Ex. 1003
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`

`Patent Application Publication Aug. 27, 2009 Sheet 44 of 58
`
`US 2009/0217401 Al
`
`Group I
`PD- +9D9, 10+0.5 mg/kg
`
`2000
`