US6004555A — Methods for the specific coagulation of vasculatu…

Claim 1

Independent Claim 102 words

A method for delivering a coagulant to tumor-associated vasculature, comprising administering to an animal with a vascularized tumor, a pharmaceutical composition comprising an amount of a binding ligand effective to promote blood coagulation in the tumor-associated vasculature, the binding ligand comprising: (a) a first binding region that binds to a surface-expressed, surface-accessible or surface-localized component of a tumor cell, intratumoral vasculature or tumor-associated stroma, the first binding region operatively linked to (b) a coagulation factor or a second binding region that binds to a coagulation factor; wherein said second binding region comprises an antibody or an antigen binding region of an antibody.

Claim 2

Independent Claim 102 words

A method for delivering a coagulant to tumor-associated vasculature, comprising administering to an animal with a vascularized tumor, a pharmaceutical composition comprising an amount of a binding ligand effective to promote blood coagulation in the tumor-associated vasculature, the binding ligand comprising: (a) a first binding region that binds to a surface-expressed, surface-accessible or surface-localized component of a tumor cell, intratumoral vasculature or tumor-associated stroma, the first binding region operatively linked to (b) a coagulation factor or a second binding region that binds to a coagulation factor; wherein said second binding region comprises an antibody or an antigen binding region of an antibody.

Claim 3

Dependent Claim 21 words

The method of claim 1, wherein said first binding region comprises an antibody or an antigen binding region of an antibody.

Claim 4

Dependent Claim 23 words

The method of claim 2, wherein said first binding region comprises a monoclonal antibody or an antigen binding region of a monoclonal antibody.

Claim 5

Dependent Claim 33 words

The method of claim 2, wherein said first binding region comprises an antibody or an antigen binding region of an antibody that binds to a surface-expressed, surface-accessible or surface-localized component of intratumoral vasculature.

Claim 6

Dependent Claim 20 words

The method of claim 1, wherein said binding ligand comprises a first binding region operatively linked to a coagulation factor.

Claim 7

Dependent Claim 27 words

The method of claim 1, wherein said binding ligand comprises a first binding region operatively linked to a second binding region that binds to a coagulation factor.

Claim 8

Dependent Claim 24 words

The method of claim 1, wherein said second binding region comprises an antigen binding region of an antibody that binds to a coagulation factor.

Claim 9

Dependent Claim 31 words

The method of claim 1, wherein said first binding region is an antigen binding region of an antibody and said second binding region is an antigen binding region of an antibody.

Claim 10

Dependent Claim 36 words

The method of claim 1, wherein an exogenous coagulation factor is delivered to said tumor-associated vasculature by administering to said animal a binding ligand that comprises a first binding region covalently linked to a coagulation factor.

Claim 11

Dependent Claim 45 words

The method of claim 1, wherein an exogenous coagulation factor is delivered to said tumor-associated vasculature by administering to said animal a binding ligand that comprises a first binding region covalently linked to a second binding region that is non-covalently bound to a coagulation factor.

Claim 12

Dependent Claim 57 words

The method of claim 1, wherein an endogenous coagulation factor is delivered to said tumor-associated vasculature by administering to said animal a binding ligand that comprises a first binding region covalently linked to a second binding region that binds to an endogenous coagulation factor, said binding ligand thereby concentrating said endogenous coagulation factor at said tumor-associated vasculature.

Claim 13

Dependent Claim 16 words

The method of claim 1, wherein said tumor-associated vasculature is associated with a benign vascularized tumor.

Claim 14

Dependent Claim 16 words

The method of claim 1, wherein said tumor-associated vasculature is associated with a malignant vascularized tumor.

Claim 15

Dependent Claim 23 words

The method of claim 1, wherein said binding ligand comprises the vitamin K-dependent coagulation Factor II/IIa, Factor VIINVIIa, Factor IX/IXa or Factor X/Xa.

Claim 16

Dependent Claim 19 words

The method of claim 1, wherein said binding ligand comprises a vitamin K-dependent coagulation factor lacking the Gla modification.

Claim 17

Dependent Claim 17 words

The method of claim 1, wherein said binding ligand comprises Tissue Factor or a Tissue Factor derivative.

Claim 18

Dependent Claim 22 words

The method of claim 16, wherein said binding ligand comprises a mutant Tissue Factor deficient in the ability to activate Factor VII.

Claim 19

Dependent Claim 14 words

The method of claim 16, wherein said binding ligand comprises a truncated Tissue Factor.

Claim 20

Dependent Claim 15 words

The method of claim 16, wherein said binding ligand comprises a dimeric truncated Tissue Factor.

Claim 21

Dependent Claim 26 words

The method of claim 1, wherein said binding ligand comprises Russell's viper venom Factor X activator, thromboxane A 2 , thromboxane A 2 synthase or α2-antiplasmin.

Claim 22

Independent Claim 103 words

A method for treating cancer, comprising administering a pharmaceutical composition to an animal with a vascularized tumor in an amount effective to promote blood coagulation in the vasculature of said tumor, wherein the pharmaceutical composition comprises a coagulative binding ligand that comprises: (a) a first binding region that binds to a surface-expressed, surface-accessible or surface-localized component of a tumor cell, intratumoral vasculature or tumor-associated stroma, the first binding region operatively linked to (b) a coagulation factor or a second binding region that binds to a coagulation factor; wherein said second binding region comprises an antibody or an antigen binding region of an antibody.

Claim 23

Independent Claim 103 words

A method for treating cancer, comprising administering a pharmaceutical composition to an animal with a vascularized tumor in an amount effective to promote blood coagulation in the vasculature of said tumor, wherein the pharmaceutical composition comprises a coagulative binding ligand that comprises: (a) a first binding region that binds to a surface-expressed, surface-accessible or surface-localized component of a tumor cell, intratumoral vasculature or tumor-associated stroma, the first binding region operatively linked to (b) a coagulation factor or a second binding region that binds to a coagulation factor; wherein said second binding region comprises an antibody or an antigen binding region of an antibody.

Claim 24

Dependent Claim 26 words

The method of claim 21, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody.

Claim 25

Dependent Claim 28 words

The method of claim 22, wherein the first binding region of said coagulative binding ligand comprises a monoclonal antibody or an antigen binding region of a monoclonal antibody.

Claim 26

Dependent Claim 23 words

The method of claim 22, wherein the first binding region of said coagulative binding ligand comprises an IgG antibody or an IgM antibody.

Claim 27

Dependent Claim 28 words

The method of claim 22, wherein the first binding region of said coagulative binding ligand comprises an scFv, Fv, Fab', Fab or F(ab') 2 fragment of an antibody.

Claim 28

Dependent Claim 28 words

The method of claim 21, wherein the second binding region of said coagulative binding ligand comprises an scFv, Fv, Fab', Fab or F(ab') 2 fragment of an antibody.

Claim 29

Dependent Claim 37 words

The method of claim 22, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to a cell surface antigen of a tumor cell.

Claim 30

Dependent Claim 81 words

The method of claim 27, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to the tumor cell surface antigen p 185 HER2 , milk mucin core protein, TAG-72, Lewis a, carcinoembryonic antigen (CEA) or a tumor cell surface antigen that binds to an antibody selected from the group consisting of B3 (ATCC HB 10573), KS1/4 (NRRL B-18356), 260F9 (ATCC HB 8488), and D612 (ATCC HB 9796).

Claim 31

Dependent Claim 38 words

The method of claim 22, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to a surface-expressed, surface-accessible or surface-localized component of intratumoral vasculature.

Claim 32

Dependent Claim 47 words

The method of claim 29, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to a component of intratumoral vasculature that has little or no expression at the surface of normal endothelial cells.

Claim 33

Dependent Claim 36 words

The method of claim 22, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to an intratumoral vasculature endothelial cell surface molecule.

Claim 34

Dependent Claim 58 words

The method of claim 31, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to an MHC Class II protein, a VEGF/VPF receptor, an FGF receptor, a TGFβ receptor, a TIE, VCAM-1, ICAM-1, P-selectin, E-selectin, α v β 3 integrin, pleiotropin, endosialin or endoglin.

Claim 35

Dependent Claim 34 words

The method of claim 32, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to an MHC Class II protein.

Claim 36

Dependent Claim 32 words

The method of claim 32, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to a VEGF/VPF receptor.

Claim 37

Dependent Claim 30 words

The method of claim 32, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to VCAM-1.

Claim 38

Dependent Claim 30 words

The method of claim 32, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to ICAM-1.

Claim 39

Dependent Claim 30 words

The method of claim 32, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to P-selectin.

Claim 40

Dependent Claim 30 words

The method of claim 32, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to E-selectin.

Claim 41

Dependent Claim 30 words

The method of claim 32, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to endoglin.

Claim 42

Dependent Claim 53 words

The method of claim 39, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to the same epitope as the monoclonal antibody TEC-4 (ATCC HB 12312) or to the same epitope as the monoclonal antibody TEC-11 (ATCC HB 12311).

Claim 43

Dependent Claim 44 words

The method of claim 29, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to a ligand or growth factor that is bound to an intratumoral vasculature cell surface molecule.

Claim 44

Dependent Claim 54 words

The method of claim 41, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to FGF, TGFβ, a ligand that binds to a TIE, a tumor-associated fibronectin isoform, scatter factor/hepatocyte growth factor (HGF), platelet factor 4 (PF4), PDGF or TIMP.

Claim 45

Dependent Claim 53 words

The method of claim 41, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to the same epitope as the monoclonal antibody GV39 (ATCC HB 12450) or to the same epitope as the monoclonal antibody GV97 (ATCC HB 12451).

Claim 46

Dependent Claim 30 words

The method of claim 41, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to FGF.

Claim 47

Dependent Claim 30 words

The method of claim 41, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to TGFβ.

Claim 48

Dependent Claim 66 words

The method of claim 29, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to a ligand:receptor complex or a growth factor:receptor complex, but does not bind to the ligand or growth factor or to the receptor when the ligand or growth factor or the receptor is not in the ligand:receptor complex.

Claim 49

Dependent Claim 34 words

The method of claim 22, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to a component of tumor stroma.

Claim 50

Dependent Claim 49 words

The method of claim 47, wherein the first binding region of said coagulative binding ligand comprises an antibody or an antigen binding region of an antibody that binds to a basement membrane component, tenascin, an activated platelet or an antigen inducible on a basement membrane component or activated platelet.

Claim 51

Dependent Claim 38 words

The method of claim 21, wherein the first binding region of said coagulative binding ligand comprises a ligand or receptor that binds to a surface-expressed, surface-accessible or surface-localized component of a tumor cell, intratumoral vasculature or tumor-associated stroma.

Claim 52

Dependent Claim 51 words

The method of claim 49, wherein the first binding region of said coagulative binding ligand comprises VEGF/VPF, FGF, TGFβ, a ligand that binds to a TIE, a tumor-associated fibronectin isoform, scatter factor, hepatocyte growth factor (HGF), platelet factor 4 (PF4), PDGF, TIMP or a soluble binding domain of a VEGF/VPF receptor.

Claim 53

Dependent Claim 23 words

The method of claim 21, wherein said coagulative binding ligand comprises a first binding region that is operatively linked to a coagulation factor.

Claim 54

Dependent Claim 30 words

The method of claim 21, wherein said coagulative binding ligand comprises a first binding region that is operatively linked to a second binding region that binds to a coagulation factor.

Claim 55

Dependent Claim 14 words

The method of claim 51, wherein said coagulative binding ligand is a bispecific antibody.

Claim 56

Dependent Claim 24 words

The method of claim 21, wherein said coagulative binding ligand comprises the vitamin K-dependent coagulation Factor II/IIa, Factor VII/VIIa, Factor IX/IXa or Factor X/Xa.

Claim 57

Dependent Claim 20 words

The method of claim 21, wherein said coagulative binding ligand comprises a vitamin K-dependent coagulation factor lacking the Gla modification.

Claim 58

Dependent Claim 18 words

The method of claim 21, wherein said coagulative binding ligand comprises Tissue Factor or a Tissue Factor derivative.

Claim 59

Dependent Claim 23 words

The method of claim 56, wherein said coagulative binding ligand comprises a mutant Tissue Factor deficient in the ability to activate Factor VII.

Claim 60

Dependent Claim 32 words

The method of claim 57, wherein said coagulative binding ligand comprises a mutant Tissue Factor that includes a mutation in the amino acid region between about position 157 and about position 167.

Claim 61

Dependent Claim 62 words

The method of claim 58, wherein said coagulative binding ligand comprises a mutant Tissue Factor in which Trp at position 158 is changed to Arg; wherein Ser at position 162 is changed to Ala; wherein Gly at position 164 is changed to Ala; or wherein Trp at position 158 is changed to Arg and Ser at position 162 is changed to Ala.

Claim 62

Dependent Claim 15 words

The method of claim 56, wherein said coagulative binding ligand comprises a truncated Tissue Factor.

Claim 63

Dependent Claim 28 words

The method of claim 60, wherein said coagulative binding ligand comprises a truncated Tissue Factor that consists essentially of amino acids 1-219 of the mature Tissue Factor protein.

Claim 64

Dependent Claim 25 words

The method of claim 60, wherein said coagulative binding ligand comprises a truncated Tissue Factor that has the amino acid sequence of SEQ ID NO:23.

Claim 65

Dependent Claim 15 words

The method of claim 56, wherein said coagulative binding ligand comprises a dimeric Tissue Factor.

Claim 66

Dependent Claim 15 words

The method of claim 63, wherein said coagulative binding ligand comprises a polymeric Tissue Factor.

Claim 67

Dependent Claim 36 words

The method of claim 56, wherein said coagulative binding ligand comprises a Tissue Factor derivative with a hydrophobic membrane insertion moiety, said Tissue Factor derivative being linked to said first binding region via a biologically-releasable bond.

Claim 68

Dependent Claim 27 words

The method of claim 21, wherein said coagulative binding ligand comprises Russell's viper venom Factor X activator, thromboxane A 2 , thromboxane A 2 synthase or α2-antiplasmin.

Claim 69

Dependent Claim 25 words

The method of claim 22, wherein the first binding region of said coagulative binding ligand comprises a humanized antibody or an antigen binding region thereof.

Claim 70

Dependent Claim 14 words

The method of claim 21, wherein said coagulation factor is a human coagulation factor.

Claim 71

Dependent Claim 18 words

The method of claim 68, wherein said coagulation factor is a human Tissue Factor or Tissue Factor derivative.

Claim 72

Dependent Claim 30 words

The method of claim 21, wherein the first binding region of said coagulative binding ligand is operatively linked to said coagulation factor or said second binding region via a cross-linker.

Claim 73

Dependent Claim 56 words

The method of claim 21, wherein said coagulative binding ligand is a fusion protein prepared by expressing a recombinant vector in a host cell, wherein the vector comprises, in the same reading frame, a DNA segment encoding said first binding region operatively linked to a DNA segment encoding said coagulation factor or said second binding region.

Claim 74

Dependent Claim 40 words

The method of claim 21, wherein the second binding region is bound to an exogenous coagulation factor prior to administration to said animal and wherein said coagulative binding ligand delivers said exogenous coagulation factor to the vasculature of said tumor.

Claim 75

Dependent Claim 51 words

The method of claim 21, wherein the second binding region is not bound to a coagulation factor prior to administration to said animal and wherein said coagulative binding ligand binds to an endogenous coagulation factor and the binding ligand thereby delivers the endogenous coagulation factor to the vasculature of said tumor.

Claim 76

Dependent Claim 15 words

The method of claim 21, wherein said pharmaceutical composition is administered to said animal parenterally.

Claim 77

Dependent Claim 21 words

The method of claim 21, wherein said pharmaceutical composition is administered to said animal by injection into the vascularized tumor site.

Claim 78

Dependent Claim 12 words

The method of claim 21, wherein said animal is a human patient.

Claim 79

Independent Claim 110 words

A method for treating cancer, comprising administering a pharmaceutical composition to an animal with a vascularized tumor in an amount effective to promote specific blood coagulation in the vasculature of said tumor relative to the vasculature in non-tumor sites, wherein the pharmaceutical composition comprises a coagulative binding ligand that comprises: (a) a first antibody or antigen binding region of an antibody that binds to a surface-expressed, surface-accessible or surface-localized component of intratumoral vasculature or tumor-associated stroma; the first antibody or antigen binding region of an antibody operatively linked to (b) a coagulation factor or a second antibody or antigen binding region of an antibody that binds to a coagulation factor.

Claim 80

Independent Claim 110 words

A method for treating cancer, comprising administering a pharmaceutical composition to an animal with a vascularized tumor in an amount effective to promote specific blood coagulation in the vasculature of said tumor relative to the vasculature in non-tumor sites, wherein the pharmaceutical composition comprises a coagulative binding ligand that comprises: (a) a first antibody or antigen binding region of an antibody that binds to a surface-expressed, surface-accessible or surface-localized component of intratumoral vasculature or tumor-associated stroma; the first antibody or antigen binding region of an antibody operatively linked to (b) a coagulation factor or a second antibody or antigen binding region of an antibody that binds to a coagulation factor.

Claim 81

Dependent Claim 27 words

The method of claim 77, wherein said coagulative binding ligand comprises a first antibody or antigen binding region of an antibody operatively linked to a coagulation factor.

Claim 82

Dependent Claim 40 words

The method of claim 77, wherein said coagulative binding ligand comprises a first antibody or antigen binding region of an antibody operatively linked to a second antibody or antigen binding region of an antibody that binds to a coagulation factor.

Claim 83

Dependent Claim 38 words

The method of claim 77, wherein said coagulative binding ligand comprises a first antibody or antigen binding region of an antibody that binds to a surface-expressed, surface-accessible or surface-localized component of the intratumoral vasculature of a vascularized tumor.

Claim 84

Dependent Claim 18 words

The method of claim 77, wherein said coagulative binding ligand comprises Tissue Factor or a Tissue Factor derivative.

Claim 85

Dependent Claim 20 words

The method of claim 77, wherein said first binding region comprises a humanized antibody or an antigen binding region thereof.

Claim 86

Dependent Claim 14 words

The method of claim 77, wherein said coagulation factor is a human coagulation factor.

Claim 87

Independent Claim 90 words

A method for treating cancer, comprising administering a pharmaceutical composition to an animal with a vascularized tumor in an amount effective to promote blood coagulation in the vasculature of said tumor, wherein the pharmaceutical composition comprises a coagulative binding ligand that comprises: (a) a first binding region that binds to a surface-expressed, surface-accessible or surface-localized component of intratumoral blood vessels of a vascularized tumor; the first binding region operatively linked to (b) a coagulant or an antibody or an antigen binding region of an antibody that binds to a coagulant.

Claim 88

Independent Claim 90 words

A method for treating cancer, comprising administering a pharmaceutical composition to an animal with a vascularized tumor in an amount effective to promote blood coagulation in the vasculature of said tumor, wherein the pharmaceutical composition comprises a coagulative binding ligand that comprises: (a) a first binding region that binds to a surface-expressed, surface-accessible or surface-localized component of intratumoral blood vessels of a vascularized tumor; the first binding region operatively linked to (b) a coagulant or an antibody or an antigen binding region of an antibody that binds to a coagulant.

Claim 89

Independent Claim 108 words

A method for treating cancer, comprising administering a pharmaceutical composition to an animal with a vascularized tumor in an amount effective to promote specific blood coagulation in the vasculature of said tumor relative to the vasculature in non-tumor sites, wherein the pharmaceutical composition comprises a coagulative binding ligand that comprises: (a) a first antibody or antigen binding region of an antibody that binds to a surface-expressed, surface-accessible or surface-localized component of intratumoral blood vessels of a vascularized tumor; the first antibody or antigen binding region thereof operatively linked to (b) a coagulant or a second antibody or antigen binding region of an antibody that binds to a coagulant.

Claim 90

Independent Claim 108 words

A method for treating cancer, comprising administering a pharmaceutical composition to an animal with a vascularized tumor in an amount effective to promote specific blood coagulation in the vasculature of said tumor relative to the vasculature in non-tumor sites, wherein the pharmaceutical composition comprises a coagulative binding ligand that comprises: (a) a first antibody or antigen binding region of an antibody that binds to a surface-expressed, surface-accessible or surface-localized component of intratumoral blood vessels of a vascularized tumor; the first antibody or antigen binding region thereof operatively linked to (b) a coagulant or a second antibody or antigen binding region of an antibody that binds to a coagulant.

Claim 91

Independent Claim 121 words

A method for treating cancer, comprising administering a pharmaceutical composition to an animal with a vascularized tumor in an amount effective to promote specific blood coagulation in the vasculature of said tumor relative to the vasculature in non-tumor sites, wherein the pharmaceutical composition comprises a coagulative binding ligand that comprises: (a) a first antibody or antigen binding region of an antibody that binds to a surface-expressed, surface-accessible or surface-localized component of intratumoral blood vessels of a vascularized tumor; the first antibody or antigen binding region thereof operatively linked to (b) a human Tissue Factor or human Tissue Factor derivative or to a second antibody or antigen binding region of an antibody that binds to a human Tissue Factor or derivative thereof.

Claim 92

Independent Claim 121 words

A method for treating cancer, comprising administering a pharmaceutical composition to an animal with a vascularized tumor in an amount effective to promote specific blood coagulation in the vasculature of said tumor relative to the vasculature in non-tumor sites, wherein the pharmaceutical composition comprises a coagulative binding ligand that comprises: (a) a first antibody or antigen binding region of an antibody that binds to a surface-expressed, surface-accessible or surface-localized component of intratumoral blood vessels of a vascularized tumor; the first antibody or antigen binding region thereof operatively linked to (b) a human Tissue Factor or human Tissue Factor derivative or to a second antibody or antigen binding region of an antibody that binds to a human Tissue Factor or derivative thereof.

Claim 93

Independent Claim 110 words

A method for treating cancer, comprising administering a pharmaceutical composition to an animal with a vascularized tumor in an amount effective to promote specific blood coagulation in the vasculature of said tumor relative to the vasculature in non-tumor sites, wherein the pharmaceutical composition comprises a coagulative binding ligand that comprises: (a) a first antibody or antigen binding region of an antibody that binds to a surface-expressed, surface-accessible or surface-localized component of intratumoral blood vessels of a vascularized tumor; the first antibody or antigen binding region thereof operatively linked to (b) a second antibody or antigen binding region of an antibody that binds to a human Tissue Factor or derivative thereof.

Claim 94

Independent Claim 110 words

A method for treating cancer, comprising administering a pharmaceutical composition to an animal with a vascularized tumor in an amount effective to promote specific blood coagulation in the vasculature of said tumor relative to the vasculature in non-tumor sites, wherein the pharmaceutical composition comprises a coagulative binding ligand that comprises: (a) a first antibody or antigen binding region of an antibody that binds to a surface-expressed, surface-accessible or surface-localized component of intratumoral blood vessels of a vascularized tumor; the first antibody or antigen binding region thereof operatively linked to (b) a second antibody or antigen binding region of an antibody that binds to a human Tissue Factor or derivative thereof.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	2002-12-20	2003-06-21	2003-12-21	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	2006-12-20	2007-06-21	2007-12-21	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2010-12-20	2011-06-21	2011-12-21	$7700.00	Window Closed / Lapsed

Methods for the specific coagulation of vasculature

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