US5750657A — Methods and compositions using fibrin monomer to …

Claim 1

Independent Claim 51 words

A method of making a fibrin sealant, which sealant comprises a fibrin polymer, comprising the steps of: (a) contacting a desired site with a composition which contains nondynamic fibrin monomer; and (b) converting said nondynamic fibrin monomer to a fibrin polymer concurrently with said contacting step, thereby forming a fibrin sealant.

Claim 2

Independent Claim 51 words

A method of making a fibrin sealant, which sealant comprises a fibrin polymer, comprising the steps of: (a) contacting a desired site with a composition which contains nondynamic fibrin monomer; and (b) converting said nondynamic fibrin monomer to a fibrin polymer concurrently with said contacting step, thereby forming a fibrin sealant.

Claim 3

Dependent Claim 26 words

The method of claim 1 wherein said fibrin monomer is selected from the group consisting of noncrosslinked fibrin I, des BB fibrin and noncrosslinked fibrin II.

Claim 4

Dependent Claim 12 words

The method of claim 2 wherein said fibrin monomer is fibrin I.

Claim 5

Dependent Claim 13 words

The method of claim 1 wherein said fibrin polymer is fibrin II polymer.

Claim 6

Dependent Claim 11 words

The method of claim 1 wherein said fibrin polymer is crosslinked.

Claim 7

Dependent Claim 27 words

The method of claim 1 wherein the composition containing nondynamic fibrin monomer is substantially free of any exogenous enzyme which catalyzes the formation of fibrin from fibrinogen.

Claim 8

Dependent Claim 28 words

The method of claim 1 wherein said composition is formed from a source selected from the group consisting of blood, recombinant fibrinogen and cell cultures that secrete fibrinogen.

Claim 9

Dependent Claim 10 words

The method of claim 7 wherein said source is blood.

Claim 10

Dependent Claim 21 words

The method of claim 8 wherein the composition containing nondynamic fibrin monomer further comprises prothrombin, activators of prothrombin and factor XIII.

Claim 11

Dependent Claim 11 words

The method of claim 7 wherein said blood is autologous blood.

Claim 12

Dependent Claim 27 words

The method of claim 1 wherein said rendering step is carried out by means of an alkaline buffer or distilled water being added to said fibrin monomer.

Claim 13

Dependent Claim 19 words

The method of claim 11 wherein said alkaline buffer or distilled water further comprises a source of calcium ions.

Claim 14

Dependent Claim 38 words

The method of claim 11 wherein said alkaline buffer is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, bicarbonate buffers, tri-metal salts of citric acid, salts of acetic acid and salts of sulfuric acid.

Claim 15

Dependent Claim 74 words

The method of claim 11 wherein said alkaline buffer is selected from the group consisting of 0.5-0.75M Sodium carbonate/bicarbonate pH 10-10.5, 0.5-0.75M Sodium bicarbonate/NaOH pH 10.0, 1.5M Glycine/NaOH pH 10.0, 0.5-1.0M Bis hydroxyethylaminoethane sulphonic acid (BES) pH 7.5, 1M Hydroxyethylpiperazine propane sulphonic acid (EPPS) pH 8.5, 0.5M Tricine pH 8.5, 1M Morpholino propane sulphonic acid (MOPS) pH 8.0, 1M Trishydoroxymethyl aminoethane sulphonic acid (TES) pH 8.0 and 0.5M Cyclohexylaminoethane sulphonic acid (CHES) pH 10.0.

Claim 16

Dependent Claim 46 words

The method of claim 11 wherein said alkaline buffer is selected from the group consisting of 0.5-0.75M Sodium carbonate/bicarbonate pH 10-10.5, 0.5-1.0M Bis hydroxeythylaminoethane sulphonic acid (BES) pH 7.5, 1M Hydroxyethylpiperazine propane sulphonic acid (EPPS) pH 8.5 and 1M Trishydroxymethyl aminoethane sulphonic acid (TES) pH 8.0.

Claim 17

Dependent Claim 35 words

The method of claim 11 wherein said contacting step is carried out by means of a double-barrelled syringe, wherein one barrel contains said composition and the other barrel contains said alkaline buffer or distilled water.

Claim 18

Dependent Claim 38 words

The method of claim 1 wherein said composition is an aqueous composition wherein said aqueous composition further comprises (a) an acid buffer that has a pH of from about 1 to about 5 or (b) a chaotropic agent.

Claim 19

Dependent Claim 77 words

The method of claim 17 wherein said acid buffer is selected from the group consisting of acetic acid, salts of acetic acid, succinic acid, salts of succinic acid, glucuronic acid, salts of glucuronic acid, cysteic acid, salts of cysteic acid, crotonic acid, salts of crotonic acid itaconic acid, salts of itaconic acid, glutamic acid, salts of glutamic acid, formic acid, salts of formic acid, aspartic acid, salts of aspartic acid, adipic acid, and salts of adipic acid.

Claim 20

Dependent Claim 27 words

The method of claim 18 wherein said acid buffer is selected from the group consisting of succinic acid, aspartic acid, adipic acid and salts of acetic acid.

Claim 21

Dependent Claim 12 words

The method of claim 19 wherein said acid buffer is sodium acetate.

Claim 22

Dependent Claim 19 words

The method of claim 18 wherein the concentration of said acid buffer is from about 0.02M to about 1M.

Claim 23

Dependent Claim 15 words

The method of claim 21 wherein said concentration is from about 0.1M to about 0.3M.

Claim 24

Dependent Claim 27 words

The method of claim 17 wherein said chaotropic agent is selected from the group consisting of urea, sodium bromide, guanidine hydrochloride, KCNS, potassium iodide and potassium bromide.

Claim 25

Dependent Claim 19 words

The method of claim 23 wherein the concentration of said chaotropic agent is from about 0.2M to about 6.0M.

Claim 26

Dependent Claim 15 words

The method of claim 24 wherein said concentration is from about 3.5M to about 5.0M.

Claim 27

Dependent Claim 24 words

The method of claim 17 wherein the concentration of fibrin monomer in said aqueous solution is from about 10 mg/ml to about 200 mg/ml.

Claim 28

Dependent Claim 17 words

The method of claim 26 wherein said concentration is from about 20 mg/ml to about 100 mg/ml.

Claim 29

Dependent Claim 16 words

The method of claim 17 wherein said aqueous composition further comprises a source of calcium ions.

Claim 30

Dependent Claim 13 words

The method of claim 1 wherein the desired site is on a mammal.

Claim 31

Dependent Claim 11 words

The method of claim 29 wherein said mammal is a human.

Claim 32

Dependent Claim 40 words

The method of claim 30 wherein the desired site is selected from the group consisting of skin, cardiovascular system, lymphatic system, pulmonary system, ear, nose, throat, eye, liver, spleen, cranial, spinal, maxillo-facial, bone, tendon, pancreas, genito-urinary tract and alimentary tract.

Claim 33

Independent Claim 45 words

A method of making a fibrin sealant which comprises: (a) contacting a desired site with a composition which contains nondynamic noncrosslinked fibrin; and (b) rendering said noncrosslinked fibrin dynamic concurrently with said contacting step such that said noncrosslinked fibrin is converted to said fibrin sealant.

Claim 34

Independent Claim 45 words

A method of making a fibrin sealant which comprises: (a) contacting a desired site with a composition which contains nondynamic noncrosslinked fibrin; and (b) rendering said noncrosslinked fibrin dynamic concurrently with said contacting step such that said noncrosslinked fibrin is converted to said fibrin sealant.

Claim 35

Dependent Claim 26 words

The method of claim 32 wherein said noncrosslinked fibrin is selected from the group consisting of noncrosslinked fibrin I, des BB fibrin and noncrosslinked fibrin II.

Claim 36

Dependent Claim 12 words

The method of claim 33 wherein said noncrosslinked fibrin is fibrin I.

Claim 37

Dependent Claim 19 words

The method of claim 32 wherein said composition is formed from blood, recombinant fibrinogen and cells that secrete fibrinogen.

Claim 38

Dependent Claim 11 words

The method of claim 35 wherein said blood is autologous blood.

Claim 39

Dependent Claim 22 words

The method of claim 32 wherein said rendering step is carried out by contacting said composition with a source of calcium ions.

Claim 40

Dependent Claim 38 words

An aqueous composition comprising noncrosslinked fibrin monomer wherein the concentration of said fibrin monomer is greater than 10 mg/ml and up to about 200 mg/ml and said composition has a pH of from about 1 to about 5.

Claim 41

Dependent Claim 38 words

An aqueous composition comprising noncrosslinked fibrin monomer wherein the concentration of said fibrin monomer is greater than 10 mg/ml and up to about 200 mg/ml and said composition has a pH of from about 1 to about 5.

Claim 42

Dependent Claim 18 words

The aqueous composition of claim 38 wherein said concentration is from about 20 mg/ml to about 100 mg/ml.

Claim 43

Dependent Claim 25 words

The aqueous composition of claim 38 wherein said fibrin monomer is selected from the group consisting of fibrin I, des BB fibrin and fibrin II.

Claim 44

Dependent Claim 13 words

The aqueous composition of claim 40 wherein said fibrin monomer is fibrin I.

Claim 45

Dependent Claim 22 words

An aqueous composition comprising fibrin monomer wherein the concentration of said fibrin monomer is from about 20 mg/ml to about 200 mg/ml.

Claim 46

Dependent Claim 22 words

An aqueous composition comprising fibrin monomer wherein the concentration of said fibrin monomer is from about 20 mg/ml to about 200 mg/ml.

Claim 47

Dependent Claim 18 words

The aqueous composition of claim 42 wherein said concentration is from about 20 mg/ml to about 100 mg/ml.

Claim 48

Dependent Claim 25 words

The aqueous composition of claim 42 wherein said fibrin monomer is selected from the group consisting of fibrin I, des BB fibrin and fibrin II.

Claim 49

Dependent Claim 13 words

The aqueous composition of claim 44 wherein said fibrin monomer is fibrin I.

Claim 50

Dependent Claim 47 words

An aqueous composition substantially free of an exogenous enzyme which catalyzes the cleavage of fibrinopeptides A and/or B from fibrinogen comprising: (a) fibrin monomer, and (b) a source of calcium ions, wherein the concentration of said calcium ions is from about 5 mM to about 200 mM.

Claim 51

Dependent Claim 47 words

An aqueous composition substantially free of an exogenous enzyme which catalyzes the cleavage of fibrinopeptides A and/or B from fibrinogen comprising: (a) fibrin monomer, and (b) a source of calcium ions, wherein the concentration of said calcium ions is from about 5 mM to about 200 mM.

Claim 52

Dependent Claim 102 words

In a method of preparing a fibrin sealant comprising a fibrin polymer for application to a desired site, which method comprises: subjecting a source of fibrinogen to an enzyme which catalyzes the cleavage of fibrinopeptide A and/or B from fibrinogen; providing conditions to cause the polymerization of the so-treated source of fibrinogen thereby forming said fibrin polymer; the improvement comprising: subjecting said source of fibrinogen to said enzyme prior to application to said desired site and thereafter applying the so-treated source of fibrinogen, substantially free of said enzyme, to said desired site under conditions to cause said polymerization to said fibrin polymer.

Claim 53

Dependent Claim 102 words

In a method of preparing a fibrin sealant comprising a fibrin polymer for application to a desired site, which method comprises: subjecting a source of fibrinogen to an enzyme which catalyzes the cleavage of fibrinopeptide A and/or B from fibrinogen; providing conditions to cause the polymerization of the so-treated source of fibrinogen thereby forming said fibrin polymer; the improvement comprising: subjecting said source of fibrinogen to said enzyme prior to application to said desired site and thereafter applying the so-treated source of fibrinogen, substantially free of said enzyme, to said desired site under conditions to cause said polymerization to said fibrin polymer.

Claim 54

Independent Claim 95 words

A method of making a fibrin sealant for application to a single patient, which sealant comprises a fibrin polymer, comprising the steps of subjecting a source of fibrinogen to an enzyme capable of catalyzing the cleavage of fibrinopeptide A and/or B from fibrinogen, which enzyme is exogenous to said patient; substantially separating said enzyme from the so-treated source of fibrinogen; and applying the so-treated fibrinogen to said patient under conditions to provide for the polymerization of the so-treated fibrinogen to a fibrin polymer whereby a fibrin sealant substantially free of said exogenous enzyme is provided.

Claim 55

Independent Claim 95 words

A method of making a fibrin sealant for application to a single patient, which sealant comprises a fibrin polymer, comprising the steps of subjecting a source of fibrinogen to an enzyme capable of catalyzing the cleavage of fibrinopeptide A and/or B from fibrinogen, which enzyme is exogenous to said patient; substantially separating said enzyme from the so-treated source of fibrinogen; and applying the so-treated fibrinogen to said patient under conditions to provide for the polymerization of the so-treated fibrinogen to a fibrin polymer whereby a fibrin sealant substantially free of said exogenous enzyme is provided.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	2001-05-11	2001-11-10	2002-05-12	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	2005-05-11	2005-11-10	2006-05-12	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2009-05-11	2009-11-10	2010-05-12	$7700.00	Window Closed / Lapsed

Methods and compositions using fibrin monomer to make a fibrin sealant

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