IP Library › Granted Patent US 10,392,421

Granted Patent B2

US 10,392,421 · App. 15/961,531 · Granted Aug 27, 2019

Cytotoxic peptides and conjugates thereof

Inventors: Bernhard Hubert Geierstanger (Solana Beach, CA); Jan Grunewald (San Diego, CA); Yunho Jin (San Diego, CA); Weijia Ou (San Diego, CA); Tetsuo Uno (San Diego, CA); Yongqin Wan (San Diego, CA); Xing Wang (San Diego, CA)

Assignee: Novartis AG

C07K5/0205 A61K47/6817 A61K47/6851 C07K7/02 C07K16/32

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Quick Facts

Patent No.: US 10,392,421
App. No.: 15/961,531
Granted: Aug 27, 2019
Kind: B2

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Abstract

Disclosed herein are novel cytotoxic peptides of formula (I) as described herein: and the use of such peptides in making immunoconjugates (i.e Antibody Drug Conjugates) Also described herein are immunoconjugates (i.e Antibody Drug Conjugates) comprising such novel cytotoxic peptide linked to an antigen binding moiety, such as an antibody; where such immunoconjugates are useful for treating cell proliferative disorders. The invention further provides pharmaceutical compositions comprising these immunoconjugates, compositions comprising the immunoconjugates with a therapeutic co-agent, and methods to use these immunoconjugates and compositions for treating cell proliferation disorders.

Claims (69)

1. An immunoconjugate of Formula (III):

wherein:

Ab represents an antigen binding moiety;

L is selected from -L 1 L 2 L 3 L 4 L 5 L 6 -, -L 6 L 5 L 4 L 3 L 2 L 1 -, -L 1 L 2 L 3 L 4 L 5 -, -L 5 L 4 L 3 L 2 L 1 -, -L 1 L 2 L 3 L 4 -, -L 4 L 3 L 2 L 1 - -L 1 L 2 L 3 -, -L 3 L 2 L 1 -, -L 1 L 2 -, -L 2 L 1 - and -L 1 ,

wherein

L 1 is selected from —(CH 2 ) m —, —C(═O)(CH 2 ) m —, —C(═O)X 1 X 2 C(═O)(CH 2 ) m —, —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)X 1 X 2 C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —, —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 12 C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 12 C(═O)((CH 2 ) m O) n (CH 2 ) m —, —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 12 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —C(═O)X 1 X 2 (CH 2 ) m X 3 (CH 2 ) m —, —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m —, —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m NR 12 C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —C(═O)X 1 X 2 (CH 2 ) m NR 12 ((CH 2 ) m O) n (CH 2 ) m —, —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 12 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)((CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m S(═O) 2 ((CH 2 ) m O n (CH 2 ) m —, —C(═O)(CH 2 ) m NR 12 (CH 2 ) m —, —C(═O)NR 12 (CH 2 ) m —, —C(═O)NR 12 (CH 2 ) m X 3 (CH 2 ) m —, —C(═O)NH(CH 2 ) m NR 12 C(═O)X 2 X 2 C(═O)(CH 2 ) m —, —C(═O)X 1 C(═O)NR 12 (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)X 1 C(═O)NR 12 (CH 2 ) m X 3 (CH 2 ) m —, —C(═O)NR 12 (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)NR 12 (CH 2 ) m NR 12 C(═O)(CH 2 ) m X 3 (CH 2 ) m —,

—(CH 2 ) m C(═O)NR 12 (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)—, —(CH 2 ) m C(═O)X 2 X 1 C(═O)—, —(CH 2 ) m X 3 (CH 2 ) m C(═O)X 2 X 1 C(═O)—, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NR 12 (CH 2 ) m —, —(CH 2 ) m NR 12 C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m (O(CH 2 ) m ) n C(═O)—, —(CH 2 ) m (O(CH 2 ) m ) n S(═O) 2 (CH 2 ) m —, —(CH 2 ) m NR 12 (CH 2 ) m C(═O)—, —(CH 2 ) m NR 12 C(═O)—, —(CH 2 ) m C(═O)X 2 X 1 C(═O)NR 12 (CH 2 ) m NHC(═O)—, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m NR 12 C(═O)X 1 —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m NR 12 C(═O)—,

-((CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m (O(CH 2 ) m ) n -, —(CH 2 ) m (O(CH 2 ) m ) n X 3 (CH 2 ) m —, —(CH 2 ) m X 3 ((CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(═O)—, —C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n C(═O)—, —C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m C(═O)—, —C(═O)(CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)(CH 2 ) m NR 12 C(═O)O(CH 2 ) m —, —(CH 2 ) m OC(═O)NR 12 (CH 2 ) m C(═O)—, —S(═O) 2 (CH 2 ) m NR 12 C(═O)O(CH 2 ) m —, —(CH 2 ) m OC(═O)NR 12 (CH 2 ) m S(═O) 2 —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m (O(CH 2 ) m ) n C(═O)—, —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m C(═O)NR 12 (CH 2 ) m —, —(CH 2 ) m NR 12 C(═O)(CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)NR 12 (CH 2 ) m NR 12 C(═O)—, —(CH 2 ) m S(CH 2 ) m —, —NR 12 C(═O)(CH 2 ) m —, —NR 12 C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NR 12 —, —(CH 2 ) m C(═O)NR 12 —, —(CH 2 ) m NR 12 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m —, —((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n -, —NR 12 (CH 2 ) m —, —NR 12 C(R 12 ) 2 (CH 2 ) m —, —(CH 2 ) m C(R 12 ) 2 NR 12 —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m NR 12 —, —NR 12 (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —NR 12 C(R 12 ) 2 (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m C(R 12 ) 2 NR 12 —, —NR 12 (CH 2 ) m X 3 (CH 2 ) m —, —NR 12 C(R 12 ) 2 (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(R 12 ) 2 NR 12 —, —NR 12 C(R 12 ) 2 (CH 2 ) m OC(═O)NR 12 (CH 2 ) m —, —(CH 2 ) m NR 12 C(═O)O(CH 2 ) m C(R 12 ) 2 NR 12 —, —NR 12 C(R 12 ) 2 (CH 2 ) m OC(═O)NR 12 (CH 2 ) m X 3 (CH 2 ) m —, —NR 12 (CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n NR 12 —, —NR 12 (CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m (O(CH 2 ) m ) n NR 12 —, —NR 12 (CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m NR 12 C(═O)O(CH 2 ) m C(R 12 ) 2 NR 12 —, —NR 12 C(R 12 ) 2 (CH 2 ) m OC(═O)NR 12 ((CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m (O(CH 2 ) m ) n NR 12 C(═O)O(CH 2 ) m C(R 12 ) 2 NR 12 —, —NR 12 C(R 12 ) 2 (CH 2 ) m OC(═O)NR 12 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n NR 12 C(═O)O(CH 2 ) m C(R 12 ) 2 NR 12 —, —(CH 2 ) m X 3 (CH 2 ) m NR 12 —, —NR 12 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n NR 12 —, —(CH 2 ) m NR 12 —, —NR 12 ((CH 2 ) m O) n (CH 2 ) m —, —NR 12 ((CH 2 ) m O) n (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m (O(CH 2 ) m ) n NR 12 —, —(CH 2 ) m (O(CH 2 ) m ) n NR 12 —, —(C(R 12 ) 2 ) m —, —(CH 2 CH 2 O) n —, —(OCH 2 CH 2 ) n —, —(CH 2 ) m O(CH 2 ) m —, —S(═O) 2 (CH 2 ) m —, —(CH 2 ) m S(═O) 2 —, —S(═O) 2 (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m S(═O) 2 —, —S(═O) 2 (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m S(═O) 2 —, —(CH 2 ) m X 2 X 1 C(═O)—, —C(═O)X 2 X 1 (CH 2 ) m —, —(CH 2 ) m (O(CH 2 ) m ) n C(═O)X 2 X 1 C(═O)—, —C(═O)X 1 X 2 C(═O)( (CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m (O(CH 2 ) m ) n X 2 X 1 C(═O)—, —(CH 2 ) m X 3 (CH 2 ) m X 2 X 1 C(═O)—, —C(═O)X 2 X 1 (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n X 2 X 1 C(═O)—, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NR 12 (CH 2 ) m NR 12 C(═O)—, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NR 12 (CH 2 ) m C(═O)—, —C(═O)(CH 2 ) m NR 12 C(═O(CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NR 12 (CH 2 ) m (O(CH 2 ) m ) n C(═O)—, —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 12 C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m NR 12 C(═O)X 1 X 2 C(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)X 2 X 1 C(═O)NR 12 (CH 2 ) m —, —X 4 X 1 X 2 C(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)X 2 X 1 X 4 —, —X 1 C(═O)(CH 2 ) m NHC(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)NH(CH 2 ) m C(═O)X 1 —, —C(═O)CHR aa NR 12 —, —CHR aa C(═O)—, —C(═O)NR 12 —, —C(═O)O—, —S—, —SCH 2 (C═O)NR 12 —, —NR 12 C(═O)CH 2 S—, —S(═O) 2 CH 2 CH 2 S—, —SCH 2 CH 2 S(═O) 2 —, —(CH 2 ) 2 S(═O) 2 CH 2 CH 2 S—, —SCH 2 CH 2 S(═O) 2 CH 2 CH 2 —, —NR 12 C(═S)—, —(CH 2 ) m X 3 (O(CH 2 ) m ) n C(═O)—, —C(═O)((CH 2 ) m O) n X 3 (CH 2 ) m —, —(CH 2 ) m NR 12 C(═O)((CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m (O(CH 2 ) m ) n C(═O)NR 12 (CH 2 ) m —, —(CH 2 ) m NR 12 C(═O)NR 12 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m NR 12 C(═O)—, —C(═O)NR 12 (CH 2 ) m X 3 (CH 2 ) m —, —NR 12 S(═O) 2 (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m S(═O) 2 NR 12 —,

R 20 is H or Me, and R 30 is H, —CH 3 or phenyl;

R 21 is

each R 25 is independently selected from H or C 1-4 alkyl;

R aa is a side chain of an amino acid selected from glycine, alanine, tryptophan, tyrosine, phenylalanine, leucine, isoleucine, valine, asparagine, glutamic acid, glutamine, aspatic acid, histidine, arginine, lysine, cysteine, methionine, serine, threonine, phenylglycine and t-butylglycine;

R 32 is independently selected from H, C 1-4 alkyl, phenyl, pyrimidine and pyridine;

R 33 is independently selected from

R 34 is independently selected from H, C 1-4 alkyl, and C 1-6 haloalkyl;

X 1 is self immolative spacer selected from

X 2 is dipeptide selected from

X 3 is

and

X 4 is

and L 2 , L 3 , L 4 , L 5 , and L 6 are each independently selected from a bond and L 1 ;

y is an integer from 1 to 16;

R 1 is a 6 membered heterocycloalkyl containing 1-2 N heteroatoms and a C 1 -C 2 alkylene bridge, wherein the 6 membered heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from R 5 and R 6 ;

or R 1 is a 5-8 membered fused bicyclic heterocycloalkyl containing 1-2 N heteroatoms, wherein the 5-8 membered fused bicyclic heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from R 5 and R 6 ;

R 2 is —C 1 -C 6 alkyl;

R 3 is

R 5 is C 1 -C 6 alkyl, —C(═O)R 11 , —(CH 2 ) m OH, —C(═O)(CH 2 ) m OH,—C(═O)((CH 2 ) m O) n R 12 , —((CH 2 ) m O) n R 12 , or C 1 -C 6 alkyl which is optionally substituted with —CN, —C(═O)NH 2 or 1 to 5 hydroxyl;

R 6 is halo, oxo, OH, C 1 -C 6 alkyl, —N(R 14 ) 2 , —R 16 and —NR 12 C(═O)R 11 ;

R 11 is C 1 -C 6 alkyly or C 1 -C 6 alkyl which is optionally substituted with 1 to 5 hydroxyl;

each R 12 is independently selected from H and C 1 -C 6 alkyly;

each R 14 is independently selected from H and C 1 -C 6 alkyly;

R 16 is an N-linked 4-8 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N and O;

R 17 is a bond, —NH—, —NHS(═O) 2 —,

R 18 is a bond,

R 19 is H or C 1 -C 6 alkyly ;

each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10,

and

each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17 and 18.

2. The immunoconjugate of claim 1 , wherein the immunoconjugate of Formula (Ill) is an immunoconjugate of Formula (IIIb) or Formula (IIIc):

3. The immunoconjugate of claim 2 , wherein R 1 is

4. The immunoconjugate of claim 3 , wherein

R 3 is

R 17 is—-NH—, —NHS(═O) 2 —,

R 18 is

and R 19 is H or —CH 3 .

5. The immunoconjugate of claim 4 , wherein R 5 is —CH 3 , —C(═O)CH 3 , —C(═O)((CH 2 ) 2 O) 12 R 12 , —C(═O)((CH 2 ) 2 O) 8 R 12 , or —C(═O)((CH 2 ) 2 O) 4 R 12 .

6. The immunoconjugate of claim 5 , wherein R 12 is H, —CH 3 or —CH 2 CH 3 .

7. The immunoconjugate of claim 6 , wherein R 2 is methyl, ethyl, isopropyl or sec-butyl.

8. The immunoconjugate of claim 7 , wherein:

L 1 is selected from —*C(═O)(CH 2 ) m —, —(CH 2 ) m —, —*(CH 2 ) m X 3 (CH 2 ) m —, —*(CH 2 ) m NHC(═O)X 1 X 2 C(═O)(CH 2 ) m —, —*X 4 X 1 X 2 C(═O)(CH 2 ) m —, —*X 1 C(═O)(CH 2 ) m NHC(═O)(CH 2 ) m —, —*(CH 2 ) m C(═O)NH(CH 2 ) m NHC(═O)(CH 2 ) m —, —*S(═O) 2 (CH 2 ) m X 3 (CH 2 ) m —,

—*C(═O)NH (CH 2 ) m —, —*C(═O)X 1 X 2 C(═O)(CH 2 ) m —, —*C(═O)((CH 2 ) m O) n (CH 2 ) m —, —*((CH 2 ) m O) n (CH 2 ) m —, —*(CH 2 ) m S(═O) 2 ((CH 2 ) m O) n (CH 2 ) m —, —*C(═O)(CH 2 ) m NR 12 (CH 2 ) m —, —*C(═O)(CH 2 ) m NH(CH 2 ) m —, —*(CH 2 ) m (O(CH 2 ) m ) n —, —*C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —*C(═O)NH(CH 2 ) m —, —*C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —*(CH 2 ) m NHC(═O)(CH 2 ) m —, —*C(═O)NH(CH 2 ) m NHC(═O)(CH 2 ) m —, —*C(═O)(CH 2 ) m NHC(═O)(CH 2 ) m —, —*C(═O)((CH 2 ) m O) n (CH 2 ) m NHC(═O)(CH 2 ) m —, —*((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m C(═O)NH (CH 2 ) m NHC(═O)(CH 2 ) m —, —*NHS(═O) 2 (CH 2 ) m X 3 (CH 2 ) m —, —*(CH 2 ) m NHC(═O)(CH 2 ) m NHC(═O)(CH 2 ) m — and —C(═O)NH(CH 2 ) m NHC(═O)—, wherein the * indicates the point of attachment to R 3 ;

L 2 is a bond,

—S—, —SCH 2 (C═O)NH—, —NHC(═O)CH 2 S—,

—S(═O) 2 CH 2 CH 2 S—, —SCH 2 CH 2 S(═O) 2 - ,

(CH 2 ) 2 S(═O) 2 CH 2 CH 2 S —or —SCH 2 CH 2 S(═O) 2 CH 2 CH 2 —, wherein the * indicates the point of attachment to L 1 ,

and L 3 , L 4 , L 5 and L 6 are a bond.

9. The immunoconjugate of claim 8 , wherein:

L 1 is selected from —*C(═O)(CH 2 ) m —, —(CH 2 ) m —, —*(CH 2 ) m X 3 (CH 2 ) m —, —*C(═O)X 1 X 2 C(═O)(CH 2 ) m —, —*((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —*(CH 2 ) m NHC(═O)X 1 X 2 C(═O)(CH 2 ) m —, —*X 4 X 1 X 2 C(═O)(CH 2 ) m —, —*X 1 C(═O)(CH 2 ) m NHC(═O)(CH 2 ) m —, —*(CH 2 ) m C(═O)NH(CH 2 ) m NHC(═O)(CH 2 ) m —, —*S(═O) 2 (CH 2 ) m X 3 (CH 2 ) m —,

*NHS(═O) 2 (CH 2 ) m X 3 (CH 2 ) m —, —*C(═O)((CH 2 ) m O) n (CH 2 ) m — and —*C(═O)NH(CH 2 ) m —, wherein the * indicates the point of attachment to R 3 ;

L 2 is

wherein the * indicates the point of attachment to L 1 ,

and L 3 , L 4 , L 5 and L 6 are a bond.

10. The immunoconjugate of claim 9 , wherein:

L 1 is selected from —*C(═O)(CH 2 ) m —, —(CH 2 ) m —, —*(CH 2 ) m X 3 (CH 2 ) m —, —*C(═O)X 1 X 2 C(═O)(CH 2 ) m —, —*((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —*S(═O) 2 (CH 2 ) m X 3 (CH 2 ) m —,

—*NHS(═O) 2 (CH 2 ) m X 3 (CH 2 ) m —, —*C(═O)((CH 2 ) m O) n (CH 2 ) m — and —*C(═O)NH(CH 2 ) m —, wherein the * indicates the point of attachment to R 3 ;

L 2 is

wherein the * indicates the point of attachment to L 1 , and L 3 , L 4 , L 5 and L 6 are a bond.

11. A pharmaceutical composition comprising an immunoconjugate of claim 1 , and one or more pharmaceutically acceptable carriers.

12. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of an immunoconjugate of claim 1 .

Assignments (6)

CORRECTIVE ASSIGNMENT TO CORRECT THE APPLICATION NUMBER 14961531 TO 15961531 PREVIOUSLY RECORDED AT REEL: 046474 FRAME: 0985. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Aug 27, 2018

From: NOVARTIS INTERNATIONAL PHARMACEUTICAL AG

To: NOVARTIS AG

Reel/Frame 047719/0865 →

CORRECTIVE ASSIGNMENT TO CORRECT THE SPELLING OF THE FOURTH LISTED INVENTOR'S NAME FROM "TERSUO" TO "TETSUO" PREVIOUSLY RECORDED ON REEL 046470 FRAME 0004. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT FROM INVENTORS TO NOVARTIS INSTITUTE FOR FUNCTIONAL GENOMICS, INC.. Recorded Jul 31, 2018

From: GEIERSTANGER, BERNHARD HUBERT; GRUNEWALD, JAN; OU, WEIJIA; UNO, TETSUO; WAN, YONGQIN; WANG, XING; JIN, YUNHO

To: NOVARTIS INSTITUTE FOR FUNCTIONAL GENOMICS, INC., DBA GENOMICS INSTITUTE OF THE NOVARTIS RESEARCH FOUNDATION

Reel/Frame 046709/0077 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 26, 2018

From: GEIERSTANGER, BERNHARD HUBERT; GRUNEWALD, JAN; OU, WEIJIA; UNO, TERSUO; WAN, YONGQIN; WANG, XING; JIN, YUNHO

To: NOVARTIS INSTITUTE FOR FUNCTIONAL GENOMICS, INC., DBA GENOMICS INSTITUTE OF THE NOVARTIS RESEARCH FOUNDATION

Reel/Frame 046470/0004 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 26, 2018

From: NOVARTIS INSTITUTE FOR FUNCTIONAL GENOMICS, INC., DBA GENOMICS INSTITUTE OF THE NOVARTIS RESEARCH FOUNDATION

To: IRM LLC

Reel/Frame 046474/0473 →

MERGER Recorded Jul 26, 2018

From: IRM LLC

To: NOVARTIS INTERNATIONAL PHARMACEUTICAL LTD.

Reel/Frame 046474/0484 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 26, 2018

From: NOVARTIS INTERNATIONAL PHARMACEUTICAL LTD.

To: NOVARTIS INTERNATIONAL PHARMACEUTICAL AG

Reel/Frame 046474/0994 →

Continuity (3)

Continuation 15104727

Provisional Application 61917293 · Dec 17, 2013

Related Publication 20180244717A1 · Aug 30, 2018