Patent US5504067A successfully refreshed from Google Patents.
US5504067A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Treatment of bleeding with modified tissue factor in combination with FVII
Assignee: Oklahoma Medical Research Foundation
•
Filing: 1994-10-12
•
Granted: 1996-04-02
•
Expires: 2014-10-12
Abstract
Abstract It has been discovered that it is possible to administer truncated tissue factor, not having the transmembrane region (tTF) in combination with factor VIIa (FVIIa) to treat bleeding disorders such as those resulting from hemophilia or cirrhosis of the liver. Preferably, the tTF is administered to produce up to 10 μg tTF/ml of plasma. The FVIIa is administered to produce levels of between 40 ng FVIIa/ml and 4 μg FVIIa/ml of plasma. The effective dosages of both tTF and FVIIa are significantly and surprisingly less than the administration of either alone to stop bleeding. Examples demonstrate safety and efficacy in normal and hemophilic dogs.
Inventors
- 👤 James H. Morrissey
- 👤 Philip C. Comp
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 12:12
CPC Classifications
A; A61; A61K; A61K38/00; A61K38/16; A61K38/43; A61K38/46; A61K38/48; A61K38/482; A61K38/4846; G; G01; G01N; G01N33/00; G01N33/48; G01N33/50; G01N33/68; G01N33/86; G01N2333/00; G01N2333/435; G01N2333/745; G01N2333/90; G01N2333/914; G01N2333/948; G01N2333/95; G01N2333/964; G01N2333/96425; G01N2333/96427; G01N2333/9643; G01N2333/96433; G01N2333/96441; G01N2333/96447; G01N2405/00; G01N2405/04
Claims Analysis
Total Claims: 26
Claim 1
Independent Claim
177 words
A method for treating a patient for excessive bleeding occurring at a site, comprising the step of: simultaneously administering an effective amount of a truncated tissue factor protein and an effective amount of Factor VIIa to a patient to effect clotting of said patient's blood at said site and subsequent reduction of said excessive bleeding, said truncated tissue factor protein having an amino acid sequence beginning at position 1 and terminating near position 219 of SEQ ID NO:2, said truncated tissue factor protein differing from that of native tissue factor in that transmembrane amino acids selected from the membrane spanning domain of native tissue factor which would be sufficient to bind said truncated tissue factor protein to phospholipid membranes are lacking from said truncated tissue factor protein so that said truncated tissue factor protein does not bind to phospholipid membranes, said truncated tissue factor protein further characterized in that it is soluble and that it fails to convert Factor VII to Factor VIIa yet retains catalytic activity in cleaving Factor X in the presence of Factor VIIa.
Claim 2
Independent Claim
177 words
A method for treating a patient for excessive bleeding occurring at a site, comprising the step of: simultaneously administering an effective amount of a truncated tissue factor protein and an effective amount of Factor VIIa to a patient to effect clotting of said patient's blood at said site and subsequent reduction of said excessive bleeding, said truncated tissue factor protein having an amino acid sequence beginning at position 1 and terminating near position 219 of SEQ ID NO:2, said truncated tissue factor protein differing from that of native tissue factor in that transmembrane amino acids selected from the membrane spanning domain of native tissue factor which would be sufficient to bind said truncated tissue factor protein to phospholipid membranes are lacking from said truncated tissue factor protein so that said truncated tissue factor protein does not bind to phospholipid membranes, said truncated tissue factor protein further characterized in that it is soluble and that it fails to convert Factor VII to Factor VIIa yet retains catalytic activity in cleaving Factor X in the presence of Factor VIIa.
Claim 3
Dependent Claim
72 words
The method of claim 1, wherein said effective amount of said truncated tissue factor protein is an amount sufficient to produce a level of from about 100 nanograms to about 50 micrograms said truncated tissue factor protein per milliliter of plasma and said effective amount of said Factor VIIa is an amount sufficient to produce a level of from about 20 nanograms to about 10 micrograms Factor VIIa per milliliter of plasma.
Claim 4
Dependent Claim
37 words
The method of claim 2, wherein said truncated tissue factor protein is in an amount sufficient to produce a level of from about 1 microgram to about 10 micrograms truncated tissue factor protein per milliliter of plasma.
Claim 5
Dependent Claim
30 words
A method according to claim 3, wherein said Factor VIIa is administered to produce a level of between about 40 nanograms and 4 micrograms Factor VIIa per milliliter of plasma.
Claim 6
Dependent Claim
30 words
A method for treating a patient to control bleeding according to claim 1 wherein said truncated tissue factor protein and said Factor VIIa are administered topically to a wound site.
Claim 7
Dependent Claim
83 words
A method for treating a patient to control bleeding according to claim 5 wherein a sufficient amount of said truncated tissue factor protein is administered to produce a local concentration in said wound site of from about 10 to about 50 micrograms truncated tissue factor protein per milliliter of plasma and a sufficient amount of said Factor VIIa is administered to produce a local concentration in said wound site of from about 1 to about 10 micrograms Factor VIIa per milliliter of plasma.
Claim 8
Independent Claim
179 words
A method for treating a patient for excessive bleeding occurring at a site, comprising the step of: sequentially administering an effective amount of a truncated tissue factor protein and an effective amount of Factor VIIa to a patient to effect clotting of said patient's blood at said site and subsequent reduction of said excessive bleeding, said truncated tissue factor protein having an amino acid sequence beginning at position 1 and terminating near position 219 of SEQ ID NO:2, said truncated tissue factor protein differing from that of native tissue factor protein in that transmembrane amino acids selected from the membrane spanning domain of native tissue factor protein which would be sufficient to bind said truncated tissue factor protein to phospholipid membranes are lacking from said truncated tissue factor protein so that said truncated tissue factor protein does not bind to phospholipid membranes, said truncated tissue factor protein further characterized in that it is soluble and that it fails to convert Factor VII to Factor VIIa yet retains catalytic activity in cleaving Factor X in the presence of Factor VIIa.
Claim 9
Independent Claim
179 words
A method for treating a patient for excessive bleeding occurring at a site, comprising the step of: sequentially administering an effective amount of a truncated tissue factor protein and an effective amount of Factor VIIa to a patient to effect clotting of said patient's blood at said site and subsequent reduction of said excessive bleeding, said truncated tissue factor protein having an amino acid sequence beginning at position 1 and terminating near position 219 of SEQ ID NO:2, said truncated tissue factor protein differing from that of native tissue factor protein in that transmembrane amino acids selected from the membrane spanning domain of native tissue factor protein which would be sufficient to bind said truncated tissue factor protein to phospholipid membranes are lacking from said truncated tissue factor protein so that said truncated tissue factor protein does not bind to phospholipid membranes, said truncated tissue factor protein further characterized in that it is soluble and that it fails to convert Factor VII to Factor VIIa yet retains catalytic activity in cleaving Factor X in the presence of Factor VIIa.
Claim 10
Dependent Claim
73 words
The method of claim 7, wherein said effective amount of said truncated tissue factor protein is an amount sufficient to produce a level of from about 100 nanograms to about 50 micrograms said truncated tissue factor protein per milliliter of plasma and said effective amount of said factor protein VIIa is an amount sufficient to produce a level of from about 20 nanograms to about 10 micrograms Factor VIIa per milliliter of plasma.
Claim 11
Dependent Claim
34 words
The method of claim 8, wherein said truncated tissue factor protein is added to produce a level of from about 1 microgram to about 10 micrograms truncated tissue factor protein per milliliter of plasma.
Claim 12
Dependent Claim
29 words
The method of claim 9, wherein said Factor VIIa is administered to produce a level of between about 40 nanograms and 4 micrograms Factor VIIa per milliliter of plasma.
Claim 13
Dependent Claim
30 words
A method for treating a patient to control bleeding according to claim 7 wherein said truncated tissue factor protein and said Factor VIIa are administered topically to a wound site.
Claim 14
Dependent Claim
83 words
A method for treating a patient to control bleeding according to claim 11 wherein a sufficient amount of said truncated tissue factor protein is administered to produce a local concentration in said wound site of from about 10 to about 50 micrograms truncated tissue factor protein per milliliter of plasma and a sufficient amount of said Factor VIIa is administered to produce a local concentration in said wound site of from about 1 to about 10 micrograms Factor VIIa per milliliter of plasma.
Claim 15
Dependent Claim
135 words
A pharmaceutical composition for treating excessive bleeding comprising a truncated tissue factor protein having an amino acid sequence beginning at position 1 and terminating near position 219 of SEQ ID NO:2, said truncated tissue factor protein differing from that of native tissue factor protein in that transmembrane amino acids selected from the membrane spanning domain of native tissue factor protein which would be sufficient to bind said truncated tissue factor protein to phospholipid membranes are lacking from said truncated tissue factor protein protein so that said truncated tissue factor protein does not bind to phospholipid membranes, said truncated tissue factor protein further characterized in that is soluble and that it fails to convert Factor VII to Factor VIIa yet retains catalytic activity in cleaving Factor X in the presence of Factor VIIa, and Factor VIIa.
Claim 16
Dependent Claim
135 words
A pharmaceutical composition for treating excessive bleeding comprising a truncated tissue factor protein having an amino acid sequence beginning at position 1 and terminating near position 219 of SEQ ID NO:2, said truncated tissue factor protein differing from that of native tissue factor protein in that transmembrane amino acids selected from the membrane spanning domain of native tissue factor protein which would be sufficient to bind said truncated tissue factor protein to phospholipid membranes are lacking from said truncated tissue factor protein protein so that said truncated tissue factor protein does not bind to phospholipid membranes, said truncated tissue factor protein further characterized in that is soluble and that it fails to convert Factor VII to Factor VIIa yet retains catalytic activity in cleaving Factor X in the presence of Factor VIIa, and Factor VIIa.
Claim 17
Dependent Claim
14 words
The composition of claim 13, further comprising a pharmaceutically acceptable carrier for systemic administration.
Claim 18
Dependent Claim
14 words
The composition of claim 13, further comprising a pharmaceutically acceptable carrier for topical administration.
Claim 19
Dependent Claim
42 words
The composition of claim 15, wherein said composition comprises about 10 nanograms to about 50 micrograms of said truncated tissue factor protein per milliliter of said carrier and from about 1 to about 10 micrograms Factor VIIa per milliliter of said carrier.
Claim 20
Dependent Claim
31 words
A pharmaceutical composition according to claim 16 wherein said truncated tissue factor protein is present in a concentration of from about 10 to about 50 micrograms per milliliter of said carrier.
Claim 21
Independent Claim
100 words
A method for treating a patient for excessive bleeding occurring at a site, comprising the step of: simultaneously administering an effective amount of a truncated tissue factor protein and an effective amount of Factor VIIa to said patient to effect clotting of said patient's blood at said site and subsequent reduction of said excessive bleeding, said truncated tissue factor protein further characterized in that it does not bind to phospholipid membranes, that it is soluble and that it fails to convert Factor VII to Factor VIIa yet retains catalytic activity in cleaving Factor X in the presence of Factor VIIa.
Claim 22
Independent Claim
100 words
A method for treating a patient for excessive bleeding occurring at a site, comprising the step of: simultaneously administering an effective amount of a truncated tissue factor protein and an effective amount of Factor VIIa to said patient to effect clotting of said patient's blood at said site and subsequent reduction of said excessive bleeding, said truncated tissue factor protein further characterized in that it does not bind to phospholipid membranes, that it is soluble and that it fails to convert Factor VII to Factor VIIa yet retains catalytic activity in cleaving Factor X in the presence of Factor VIIa.
Claim 23
Independent Claim
100 words
A method for treating a patient for excessive bleeding occurring at a site, comprising the step of: sequentially administering an effective amount of a truncated tissue factor protein and an effective amount of Factor VIIa to said patient to effect clotting of said patient's blood at said site and subsequent reduction of said excessive bleeding, said truncated tissue factor protein further characterized in that it does not bind to phospholipid membranes, that it is soluble and that it fails to convert Factor VII to Factor VIIa yet retains catalytic activity in cleaving Factor X in the presence of Factor VIIa.
Claim 24
Independent Claim
100 words
A method for treating a patient for excessive bleeding occurring at a site, comprising the step of: sequentially administering an effective amount of a truncated tissue factor protein and an effective amount of Factor VIIa to said patient to effect clotting of said patient's blood at said site and subsequent reduction of said excessive bleeding, said truncated tissue factor protein further characterized in that it does not bind to phospholipid membranes, that it is soluble and that it fails to convert Factor VII to Factor VIIa yet retains catalytic activity in cleaving Factor X in the presence of Factor VIIa.
Claim 25
Dependent Claim
61 words
A pharmaceutical composition for treating excessive bleeding comprising a truncated tissue factor protein, said truncated tissue factor protein further characterized in that it does not bind to phospholipid membranes, that it is soluble and that it fails to convert Factor VII to Factor VIIa yet retains catalytic activity in cleaving Factor X in the presence of Factor VIIa, and Factor VIIa.
Claim 26
Dependent Claim
61 words
A pharmaceutical composition for treating excessive bleeding comprising a truncated tissue factor protein, said truncated tissue factor protein further characterized in that it does not bind to phospholipid membranes, that it is soluble and that it fails to convert Factor VII to Factor VIIa yet retains catalytic activity in cleaving Factor X in the presence of Factor VIIa, and Factor VIIa.
References Cited (Backward Citations)
US4479938A
Cited
EP0225160A2
Cited
US5180583A
Cited
EP0278776A2
Cited
WO1988007543A1
Cited
WO1988009817A1
Cited
US5298599A
Cited
US5346991A
Cited
WO1993023074A1
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1999-04-02 | 1999-10-02 | 2000-04-02 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2003-04-02 | 2003-10-02 | 2004-04-02 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2007-04-02 | 2007-10-02 | 2008-04-02 | $7700.00 | Window Closed / Lapsed |