US4495278A
Expired / Lapsed
US
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Process for making novel blood clotting enzyme compositions
Assignee: Baxter International Inc
•
Filing: 1981-04-27
•
Granted: 1985-01-22
•
Expires: 2001-04-27
Abstract
Abstract Viruses, particularly hepatitis viruses, in blood clotting enzyme compositions are inactivated with little enzyme activity loss by heating the compositions in the dry state. The novel products which result are therapeutically and diagnostically useful.
Inventors
- 👤 William R. Thomas
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-05 11:26
CPC Classifications
C; C12; C12N; C12N7/00; A; A61; A61K; A61K31/00; A61K31/13; A61K31/14; A61K35/00; A61K35/12; A61K35/14; A61K38/00; A61K38/16; A61K38/43; A61K38/46; A61K38/48; A61K39/00; A61K39/12; A61K39/29; A61L; A61L2/00; A61L2/02; A61L2/04; C12N9/00; C12N9/14; C12N9/48; C12N9/50; C12N9/64; C12N9/6421; C12N9/6424; C12N9/6429; C12N9/647; C12Q; C12Q1/00; C12Q1/56; C12Y; C12Y304/00; C12Y304/21; C12Y304/21005; A61L2103/00; A61L2103/05; A61L2103/09; C12N2770/00; C12N2770/00011; C12N2770/32011; C12N2770/32411; C12N2770/32461; G; G01; G01N; G01N2333/00; G01N2333/90; G01N2333/914; G01N2333/948; G01N2333/974; Y; Y02; Y02A; Y02A50/00; Y02A50/30
Claims Analysis
Total Claims: 103
Claim 1
Independent Claim
52 words
A method for inactivating virus in a blood clotting enzyme composition suspected to contain such virus, which method for inactivating consists essentially of heating the composition in the dry state until the composition is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 2
Independent Claim
52 words
A method for inactivating virus in a blood clotting enzyme composition suspected to contain such virus, which method for inactivating consists essentially of heating the composition in the dry state until the composition is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 3
Dependent Claim
15 words
The method of claim 1 wherein the virus is hepatitis A, B or non-A, non-B.
Claim 4
Dependent Claim
16 words
The method of claim 2 wherein the composition contains up to about 5% water by weight.
Claim 5
Dependent Claim
14 words
The method of claim 3 wherein the composition contains about 1% water by weight.
Claim 6
Dependent Claim
10 words
The method of claim 2 wherein the enzyme is prothrombin.
Claim 7
Dependent Claim
11 words
The method of claim 2 wherein the enzyme is factor VII.
Claim 8
Dependent Claim
11 words
The method of claim 2 wherein the enzyme is factor IX.
Claim 9
Dependent Claim
11 words
The method of claim 2 wherein the enzyme is factor X.
Claim 10
Dependent Claim
11 words
The method of claim 2 wherein the enzyme is factor XI.
Claim 11
Dependent Claim
11 words
The method of claim 2 wherein the enzyme is Hageman factor.
Claim 12
Dependent Claim
12 words
The method of claim 2 wherein the enzyme is activated factor VII.
Claim 13
Dependent Claim
12 words
The method of claim 2 wherein the enzyme is activated factor IX.
Claim 14
Dependent Claim
12 words
The method of claim 2 wherein the enzyme is activated factor X.
Claim 15
Dependent Claim
12 words
The method of claim 2 wherein the enzyme is activated factor XI.
Claim 16
Dependent Claim
12 words
The method of claim 2 wherein the enzyme is activated Hageman factor.
Claim 17
Dependent Claim
13 words
The method of claim 2 wherein the composition consists essentially of factor IX.
Claim 18
Dependent Claim
13 words
The method of claim 2 wherein the composition is substantially free of thrombin.
Claim 19
Dependent Claim
13 words
The method of claim 2 wherein the composition is substantially free of plasminogen.
Claim 20
Dependent Claim
13 words
The method of claim 2 wherein the composition is substantially free of prothrombin.
Claim 21
Dependent Claim
13 words
The method of claim 2 wherein the composition is substantially free of fibrinogen.
Claim 22
Dependent Claim
14 words
The method of claim 2 wherein the composition is substantially free of antihemophilic factor.
Claim 23
Dependent Claim
13 words
The method of claim 2 wherein the composition is substantially free of albumin.
Claim 24
Dependent Claim
13 words
The method of claim 2 wherein the composition is substantially free of plasminogen.
Claim 25
Dependent Claim
14 words
The method of claim 2 wherein the composition is substantially free of factor XIII.
Claim 26
Dependent Claim
14 words
The method of claim 2 wherein the composition is substantially free of antithrombin III.
Claim 27
Dependent Claim
13 words
The method of claim 2 wherein the composition is substantially free of plasmin.
Claim 28
Dependent Claim
14 words
The method of claim 2 wherein the composition is substantially free of gamma globulin.
Claim 29
Dependent Claim
17 words
The method of claim 2 wherein the composition contains about from 1 to 3% albumin by weight.
Claim 30
Dependent Claim
16 words
The method of claim 2 wherein the composition includes a stabilizing amount of an amino acid.
Claim 31
Dependent Claim
13 words
The method of claim 29 wherein the amino acid is glycine or proline.
Claim 32
Dependent Claim
20 words
The method of claim 2 wherein the composition includes a stabilizing amount of a non-reducing monosaccharide, oligosaccharide or sugar alcohol.
Claim 33
Dependent Claim
12 words
The method of claim 31 wherein the composition includes a sugar alcohol.
Claim 34
Dependent Claim
13 words
The method of claim 31 wherein the sugar alcohol is mannitol or sorbitol.
Claim 35
Dependent Claim
27 words
The method of claim 2 wherein the composition contains less than 1.0 mole/l of amino acid and less than 20% w/w non-reducing monosaccharide, oligosaccharide or sugar alcohol.
Claim 36
Dependent Claim
17 words
The method of claim 2 wherein the composition has a pH of about from 6.0 to 8.0.
Claim 37
Dependent Claim
12 words
The method of claim 2 wherein the composition is activated prothrombin complex.
Claim 38
Dependent Claim
13 words
The method of claim 2 wherein the composition is substantially unactivated prothrombin complex.
Claim 39
Dependent Claim
20 words
The method of claim 2 wherein the composition contains factor IX and is substantially free of other blood clotting enzymes.
Claim 40
Dependent Claim
62 words
The method of claim 2 wherein the composition contains the following blood clotting enzymes, in units/ml: prothrombin, about from 1-10; total factor VII, about from 37-190; activated factor VII, about from 8-80; total factor IX, about from 15-112; factor IX precursor, about from 0-30; total factor X, about from 1-30; activated factor X, about from 1-20; and thrombin, less than about 0.003.
Claim 41
Dependent Claim
23 words
The method of claim 2 wherein the composition is filtered through a sterile filter to remove cellular microorganisms before the composition is heated.
Claim 42
Dependent Claim
17 words
The method of claim 2 wherein the composition is heated at about from 40 to 80° C.
Claim 43
Dependent Claim
17 words
The method of claim 41 wherein the composition is heated at about from 50 to 70° C.
Claim 44
Dependent Claim
17 words
The method of claim 41 wherein the composition is heated at about from 5 to 200 hours.
Claim 45
Dependent Claim
16 words
The method of claim 2 wherein the composition consists essentially of activated and unactivated factor VII.
Claim 46
Dependent Claim
22 words
The method of claim 1 wherein the composition is heated by infrared radiation, a convection oven, or a sand or water bath.
Claim 47
Dependent Claim
14 words
The method of claim 45 wherein the composition is heated by a water bath.
Claim 48
Independent Claim
58 words
a method for inactivating hepatitis A virus in a blood clotting enzyme composition suspected to contain hepatitis A virus, which method for inactivating hepatitis A virus consists essentially of heating the composition in the dry state until the composition is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 49
Independent Claim
58 words
a method for inactivating hepatitis A virus in a blood clotting enzyme composition suspected to contain hepatitis A virus, which method for inactivating hepatitis A virus consists essentially of heating the composition in the dry state until the composition is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 50
Independent Claim
57 words
A method for inactivating hepatitis B virus in a blood clotting enzyme composition suspected to contain hepatitis B virus, which method for inactivating hepatitis virus consists essentially of heating the composition in the dry state until the composition is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 51
Independent Claim
57 words
A method for inactivating hepatitis B virus in a blood clotting enzyme composition suspected to contain hepatitis B virus, which method for inactivating hepatitis virus consists essentially of heating the composition in the dry state until the composition is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 52
Independent Claim
61 words
A method for inactivating non-A, non-B hepatitis virus in a blood clotting enzyme composition suspected to contain non-A, non-B hepatitis virus, which method for inactivating non-A, non-B hepatitis virus consists essentially of heating the composition in the dry state until the composition is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 53
Independent Claim
61 words
A method for inactivating non-A, non-B hepatitis virus in a blood clotting enzyme composition suspected to contain non-A, non-B hepatitis virus, which method for inactivating non-A, non-B hepatitis virus consists essentially of heating the composition in the dry state until the composition is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 54
Independent Claim
54 words
A method for making a control or standard from blood plasma containing an infective virus, comprising removing substantially all reducing sugars from the plasma, lyophilizing the plasma and heating the lyophilized plasma until the plasma is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 55
Independent Claim
54 words
A method for making a control or standard from blood plasma containing an infective virus, comprising removing substantially all reducing sugars from the plasma, lyophilizing the plasma and heating the lyophilized plasma until the plasma is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 56
Dependent Claim
18 words
The method of claim 48 wherein reducing sugar is added to the plasma after the virus is inactivated.
Claim 57
Dependent Claim
9 words
The product produced by the method of claim 48.
Claim 58
Independent Claim
64 words
A method for inactivating virus in a composition which contains antihemophilic factor and at least one blood clotting enzyme, and which is suspected to contain an infective virus, which method for inactivating consists essentially of heating the composition in the dry state until the composition is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 59
Independent Claim
64 words
A method for inactivating virus in a composition which contains antihemophilic factor and at least one blood clotting enzyme, and which is suspected to contain an infective virus, which method for inactivating consists essentially of heating the composition in the dry state until the composition is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 60
Independent Claim
68 words
A method for treating a dry composition containing a blood clotting enzyme purified about from 3 to 50 fold over the concentration of such enzyme in normal human plasma. and suspected to contain an infective virus, which method comprises heating the composition in the dry state until the composition is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 61
Independent Claim
68 words
A method for treating a dry composition containing a blood clotting enzyme purified about from 3 to 50 fold over the concentration of such enzyme in normal human plasma. and suspected to contain an infective virus, which method comprises heating the composition in the dry state until the composition is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 62
Dependent Claim
15 words
The method of claim 54 wherein the virus is hepatitis A, B or non-A, non-B.
Claim 63
Independent Claim
24 words
The method of claims 53 or 54 wherein the composition includes a stabilizing amount of a non-reducing monosaccharide, oligosaccharide, sugar alcohol or amino acid.
Claim 64
Dependent Claim
60 words
In a method wherein a therapeutically effective amount of a blood clotting enzyme is infused into a patient, the improvement comprising infusing into said patient a composition containing noninfectious virus and a therapeutically effective amount of said enzyme, which composition is substantially free of said virus in the infectious form and substantially free of said enzyme in the denatured form.
Claim 65
Dependent Claim
60 words
In a method wherein a therapeutically effective amount of a blood clotting enzyme is infused into a patient, the improvement comprising infusing into said patient a composition containing noninfectious virus and a therapeutically effective amount of said enzyme, which composition is substantially free of said virus in the infectious form and substantially free of said enzyme in the denatured form.
Claim 66
Independent Claim
52 words
A method for inactivating virus in a composition comprising at least one blood clotting enzyme in a therapeutically effective amount, which method comprises heating the composition in the dry state until the composition is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 67
Independent Claim
52 words
A method for inactivating virus in a composition comprising at least one blood clotting enzyme in a therapeutically effective amount, which method comprises heating the composition in the dry state until the composition is substantially free of said virus in the infectious form and said blood clotting enzyme in the denatured form.
Claim 68
Dependent Claim
15 words
The method of claim 54, 57 or 58 wherein the composition also contains antihemophilic factor.
Claim 69
Dependent Claim
71 words
A composition containing noninfectious virus and at least one human blood clotting enzyme, said virus having been made noninfectious by a method consisting essentially of heating the virus until the virus is inactivated, which composition is substantially free of said virus in the infectious form, is substantially free of said blood clotting enzyme in the denatured form and which contains viral residues which are partially immunologically cross-reactive with the infectious virus.
Claim 70
Dependent Claim
71 words
A composition containing noninfectious virus and at least one human blood clotting enzyme, said virus having been made noninfectious by a method consisting essentially of heating the virus until the virus is inactivated, which composition is substantially free of said virus in the infectious form, is substantially free of said blood clotting enzyme in the denatured form and which contains viral residues which are partially immunologically cross-reactive with the infectious virus.
Claim 71
Dependent Claim
15 words
The composition of claim 60 wherein the virus is hepatitis A, B or non-A, non-B.
Claim 72
Dependent Claim
10 words
The composition of claim 61 wherein the enzyme is prothrombin.
Claim 73
Dependent Claim
11 words
The composition of claim 61 wherein the enzyme is factor VII.
Claim 74
Dependent Claim
11 words
The composition of claim 61 wherein the enzyme is factor IX.
Claim 75
Dependent Claim
11 words
The composition of claim 61 wherein the enzyme is factor X.
Claim 76
Dependent Claim
11 words
The composition of claim 61 wherein the enzyme is factor XI.
Claim 77
Dependent Claim
11 words
The composition of claim 61 wherein the enzyme is Hageman factor.
Claim 78
Dependent Claim
12 words
The composition of claim 61 wherein the enzyme is activated factor VII.
Claim 79
Dependent Claim
12 words
The composition of claim 61 wherein the enzyme is activated factor IX.
Claim 80
Dependent Claim
12 words
The composition of claim 61 wherein the enzyme is activated factor X.
Claim 81
Dependent Claim
12 words
The composition of claim 61 wherein the enzyme is activated factor XI.
Claim 82
Dependent Claim
12 words
The composition of claim 61 wherein the enzyme is activated Hageman factor.
Claim 83
Dependent Claim
20 words
The composition of claim 61 wherein the composition contains factor IX and is substantially free of other blood clotting enzymes.
Claim 84
Dependent Claim
13 words
The composition of claim 61 wherein the composition is substantially unactivated prothrombin complex.
Claim 85
Dependent Claim
12 words
The composition of claim 61 wherein the composition is activated prothrombin complex.
Claim 86
Dependent Claim
8 words
The composition of claim 61 which is sterile.
Claim 87
Dependent Claim
11 words
The composition of claim 61 which is in the dry state.
Claim 88
Dependent Claim
64 words
A composition containing noninfectious hepatitis A virus having been made noninfectious by a method consisting essentially of heating the virus until the virus is inactivated, which composition is substantially free of said virus in the infectious form, is substantially free of said blood clotting enzyme in the denatured form and which contains viral residues which are partially immunologically cross-reactive with hepatitis A infectious virus.
Claim 89
Dependent Claim
64 words
A composition containing noninfectious hepatitis A virus having been made noninfectious by a method consisting essentially of heating the virus until the virus is inactivated, which composition is substantially free of said virus in the infectious form, is substantially free of said blood clotting enzyme in the denatured form and which contains viral residues which are partially immunologically cross-reactive with hepatitis A infectious virus.
Claim 90
Dependent Claim
73 words
A composition containing noninfectious hepatitis B virus and at least one blood clotting enzyme, said virus having been made noninfectious by a method consisting essentially of heating the virus until the virus is inactivated, which composition is substantially free of said virus in the infectious form, is substantially free of said blood clotting enzyme in the denatured form and which contains viral residues which are partially immunologically cross-reactive with hepatitis B infectious virus.
Claim 91
Dependent Claim
73 words
A composition containing noninfectious hepatitis B virus and at least one blood clotting enzyme, said virus having been made noninfectious by a method consisting essentially of heating the virus until the virus is inactivated, which composition is substantially free of said virus in the infectious form, is substantially free of said blood clotting enzyme in the denatured form and which contains viral residues which are partially immunologically cross-reactive with hepatitis B infectious virus.
Claim 92
Dependent Claim
74 words
A composition containing noninfectious non-A, non-B hepatitis virus and at least one blood clotting enzyme, said virus having been made noninfectious by a method consisting essentially of heating the virus until the virus is inactivated, which composition is substantially free of said virus in the infectious form, is substantially free of said blood clotting enzyme in the denatured form and which contains viral residues which are partially immunologically cross-reactive with non-A, non-B hepatitis virus.
Claim 93
Dependent Claim
74 words
A composition containing noninfectious non-A, non-B hepatitis virus and at least one blood clotting enzyme, said virus having been made noninfectious by a method consisting essentially of heating the virus until the virus is inactivated, which composition is substantially free of said virus in the infectious form, is substantially free of said blood clotting enzyme in the denatured form and which contains viral residues which are partially immunologically cross-reactive with non-A, non-B hepatitis virus.
Claim 94
Dependent Claim
58 words
A composition containing noninfectious virus, antihemophilic factor and at least one blood clotting enzyme, said virus having been made noninfectious by a method consisting essentially of heating the virus until the virus is inactivated, which composition is substantially free of said virus in the infectious form and said blood clotting enzyme and antihemophilic factor in the denatured form.
Claim 95
Dependent Claim
58 words
A composition containing noninfectious virus, antihemophilic factor and at least one blood clotting enzyme, said virus having been made noninfectious by a method consisting essentially of heating the virus until the virus is inactivated, which composition is substantially free of said virus in the infectious form and said blood clotting enzyme and antihemophilic factor in the denatured form.
Claim 96
Dependent Claim
50 words
A composition containing noninfectious virus and at least one blood clotting enzyme in a purification of about from 3- to 50-fold over the concentration of such enzyme in normal human plasma, which composition is substantially free of said virus in the infectious form and said enzyme in the denatured form.
Claim 97
Dependent Claim
50 words
A composition containing noninfectious virus and at least one blood clotting enzyme in a purification of about from 3- to 50-fold over the concentration of such enzyme in normal human plasma, which composition is substantially free of said virus in the infectious form and said enzyme in the denatured form.
Claim 98
Dependent Claim
41 words
A composition comprising noninfectious virus and a therapeutically effective amount of at least one blood clotting enzyme, said composition being substantially free of said virus in the infectious form and substantially free of said blood clotting enzyme in the denatured form.
Claim 99
Dependent Claim
41 words
A composition comprising noninfectious virus and a therapeutically effective amount of at least one blood clotting enzyme, said composition being substantially free of said virus in the infectious form and substantially free of said blood clotting enzyme in the denatured form.
Claim 100
Dependent Claim
21 words
The composition of claim 60, wherein no more than about 10 mole percent of the total enzyme consists of denatured enzyme.
Claim 101
Dependent Claim
30 words
The composition of claims 60, 81, 82 or 83 containing no more than about 5 mole percent of denatured enzyme based on the total moles of denatured and active enzyme.
Claim 102
Dependent Claim
21 words
The composition of claims 60, 81, 82 or 83 containing viral residues which are partially immunologically cross-reactive with the infectious virus.
Claim 103
Dependent Claim
17 words
The composition of claims 60, 78, 80, 81, 82 or 83 which contains denatured viral epitopic sites.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1988-01-22 | 1988-07-23 | 1989-01-22 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1992-01-22 | 1992-07-23 | 1993-01-22 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1996-01-22 | 1996-07-23 | 1997-01-22 | $7700.00 | Window Closed / Lapsed |