US5354557A — Osteogenic devices

Claim 1

Independent Claim 120 words

In an osteogenic device for implantation in a mammal, the device comprising: osteogenic protein dispersed within a biocompatible, in vivo biodegradeable matrix defining pores of a dimension sufficient to permit influx, differentiation, and proliferation of migratory progenitor cells from the body of said mammal, the improvement wherein said osteogenic protein comprises a pair of unglycosylated protein chains disulfide bonded to produce a dimeric species having a conformation such that said pair of unglycosylated polypeptide chains is capable of inducing endochondral bone formation in said mammal when disposed in said matrix and accessible to said cells, said osteogenic protein being substantially pure, and comprising at least one of the following amino acid sequences: a) Ala-Cys-Cys-Val-Pro-Thr-Glu-Leu-Ser-Ala-Ile Ser-Met-Leu-Tyr-Leu-Asp-Glu-Asn-Glu-Lys, b) Val-Pro-Lys-Pro, and c) Ala-Pro-Thr.

Claim 2

Dependent Claim 120 words

In an osteogenic device for implantation in a mammal, the device comprising: osteogenic protein dispersed within a biocompatible, in vivo biodegradeable matrix defining pores of a dimension sufficient to permit influx, differentiation, and proliferation of migratory progenitor cells from the body of said mammal, the improvement wherein said osteogenic protein comprises a pair of unglycosylated protein chains disulfide bonded to produce a dimeric species having a conformation such that said pair of unglycosylated polypeptide chains is capable of inducing endochondral bone formation in said mammal when disposed in said matrix and accessible to said cells, said osteogenic protein being substantially pure, and comprising at least one of the following amino acid sequences: a) Ala-Cys-Cys-Val-Pro-Thr-Glu-Leu-Ser-Ala-Ile Ser-Met-Leu-Tyr-Leu-Asp-Glu-Asn-Glu-Lys, b) Val-Pro-Lys-Pro, and c) Ala-Pro-Thr.

Claim 3

Dependent Claim 22 words

The device of claim 1 wherein said matrix comprises close-packed particulate matter having a particle size within the range of 70-850 μm.

Claim 4

Dependent Claim 19 words

The device of claim 2 wherein said particulate matter has a particle size within the range of 70-420 μm.

Claim 5

Dependent Claim 14 words

The device of claim 1 wherein said matrix comprises demineralized, protein-extracted, particulate, allogenic bone.

Claim 6

Dependent Claim 40 words

The device of claim 1 wherein said matrix comprises a material selected from the group consisting of collagen, hydroxyapatite, tricalcium phosphate, polymers comprising lactic acid monomer units, polymers comprising glycolic acid monomer units, demineralized, guanidine-extracted allogenic bone, and mixtures thereof.

Claim 7

Dependent Claim 18 words

The device of claim 1 wherein said matrix is shaped to span a non-union fracture in said mammal.

Claim 8

Dependent Claim 13 words

The device of claim 1 disposed within the marrow cavity of allogenic bone.

Claim 9

Dependent Claim 32 words

The device of claim 1 wherein said osteogenic protein has an apparent molecular weight of about 27 kDa when oxidized as determined by comparison to molecular weight standards in SDS-polyacrylamide gel electrophoresis.

Claim 10

Dependent Claim 49 words

The device of claim 1 wherein one of said pair of polypeptide chains has an apparent molecular weight of about 14 kDa and the other has an apparent molecular weight of about 16 kDa, both as determined after reduction by comparison to molecular weight standards in SDS-polyacrylamide gel electrophoresis.

Claim 11

Dependent Claim 69 words

The device of claim 1 wherein said osteogenic protein has the approximate amino acid composition set forth below: ______________________________________ Amino acid Rel. no. Amino acid Rel no. residue res./molec. residue res./molec. ______________________________________ Asp/Asn 22 Tyr 11 Glu/Gln 24 Val 14 Ser 24 Met 3 Gly 29 Cys 16 His 5 Ile 15 Arg 13 Leu 15 Thr 11 Pro 14 Ala 18 Phe 7 Lys 12 Trp ND ______________________________________

Claim 12

Dependent Claim 73 words

The device of claim 1 further comprising an amino acid sequence selected from the group consisting of: fragment 1, (residues 93 to 109 of Seq. ID No. 20); fragment 2, (residues 121 to 134 of Seq. ID No. 22); fragment 4, (residues 153 to 165 of Seq. ID No. 22); fragment 5, (residues 137 to 151 of Seq. ID No. 22); and fragment 6, (residues 77 to 83 of Seq. ID No. 20).

Claim 13

Dependent Claim 36 words

A method of inducing local cartilage and bone formation in a mammal comprising the step of implanting the device of claim 1 in said mammal at a locus accessible to migratory progenitor cells of said mammal.

Claim 14

Dependent Claim 34 words

A method of inducing endochondral bone formation in a mammal comprising the step of implanting the device of claim 1 in said mammal at a locus accessible to migratory progenitor cells of said mammal.

Claim 15

Dependent Claim 30 words

A method of inducing endochondral bone formation in a non-union fracture in a mammal comprising the step of implanting in the fracture in said mammal the device of claim 6.

Claim 16

Dependent Claim 108 words

An osteogenic device for implantation in a mammal, the device comprising: a biocompatible matrix of mineral-free, delipidated Type I insoluble bone collagen particles, substantially depleted in noncollagenous protein; and a protein produced by the expression of recombinant DNA in a mammalian host cell, the protein comprising two oxidized subunits, the amino acid sequence of each subunit being sufficiently duplicative of the amino acid sequence described by residues 335 to 431 of Sequence Listing No. 1 (OPS) such that the dimeric species comprising said subunits has a conformation that is capable of inducing endochondral bone formation in a mammal when disposed within said matrix and implanted in said mammal.

Claim 17

Dependent Claim 108 words

An osteogenic device for implantation in a mammal, the device comprising: a biocompatible matrix of mineral-free, delipidated Type I insoluble bone collagen particles, substantially depleted in noncollagenous protein; and a protein produced by the expression of recombinant DNA in a mammalian host cell, the protein comprising two oxidized subunits, the amino acid sequence of each subunit being sufficiently duplicative of the amino acid sequence described by residues 335 to 431 of Sequence Listing No. 1 (OPS) such that the dimeric species comprising said subunits has a conformation that is capable of inducing endochondral bone formation in a mammal when disposed within said matrix and implanted in said mammal.

Claim 18

Dependent Claim 61 words

The device of claim 15 wherein each said subunit is independently selected and comprises at least the osteogenically active region of a protein selected from the group consisting of OP1-18Ser (residues 293-431 of Seq. ID. No. 1); mOP1-Ser (residues 292-430 of Seq. ID No. 24); mOP2-Ala (residues 261-399) of Seq. ID. No. 26); hOP2-Ala (residues 264-402 of Seq. ID No. 28).

Claim 19

Dependent Claim 128 words

An osteogenic device for implantation in a mammal, the device comprising: a biocompatible matrix of mineral-free, delipidated Type I insoluble bone collagen particles, substantially depleted in noncollagenous protein; and a protein produced by the expression of recombinant DNA in a mammalian host cell, the protein comprising two oxidized subunits, the amino acid sequence of each said subunit comprising a sequence independently selected from the group consisting of: residues 318 to 431 of Seq. ID No. 1 (OP1-16Val); residues 293 to 431 of Seq. ID No. 1 (OP1-18Ser); residues 300 to 431 of Seq. ID No. 1 (OP1-16Ser); residues 313 to 431 of Seq. ID No. 1 (OP1-16Leu); residues 315 to 431 of Seq. ID No. 1 (OP1-16Met); and residues 316 to 431 of Seq. ID No. 1 (OP1-16Ala).

Claim 20

Dependent Claim 128 words

An osteogenic device for implantation in a mammal, the device comprising: a biocompatible matrix of mineral-free, delipidated Type I insoluble bone collagen particles, substantially depleted in noncollagenous protein; and a protein produced by the expression of recombinant DNA in a mammalian host cell, the protein comprising two oxidized subunits, the amino acid sequence of each said subunit comprising a sequence independently selected from the group consisting of: residues 318 to 431 of Seq. ID No. 1 (OP1-16Val); residues 293 to 431 of Seq. ID No. 1 (OP1-18Ser); residues 300 to 431 of Seq. ID No. 1 (OP1-16Ser); residues 313 to 431 of Seq. ID No. 1 (OP1-16Leu); residues 315 to 431 of Seq. ID No. 1 (OP1-16Met); and residues 316 to 431 of Seq. ID No. 1 (OP1-16Ala).

Claim 21

Dependent Claim 28 words

The osteogenic device of claim 15 or 16, wherein said matrix is treated to increase the number of pores and micropits on said collagen particles at least 3-fold.

Claim 22

Dependent Claim 26 words

The osteogenic device of claim 18 wherein said matrix is treated to increase the number of pores and micropits on said collagen particles at least 10-fold.

Claim 23

Dependent Claim 30 words

The device of claim 15, 16 or 17 wherein said bone collagen particles comprise pores or micropits having a mean diameter within the range of 1 μm to 100 μm.

Claim 24

Dependent Claim 26 words

The device of claim 15, 16 or 17 wherein said bone collagen particles have a mean diameter within the range of 150 μm to 420 μm.

Claim 25

Dependent Claim 18 words

The device of claim 15, 16 or 17 wherein said matrix is substantially depleted in residual heavy metals.

Claim 26

Dependent Claim 41 words

The osteogenic device of claim 15, 16 or 17 wherein said matrix is treated with a hot aqueous medium having a temperature above about 37° C. in an amount and for a time sufficient to alter the morphology of said particles.

Claim 27

Dependent Claim 72 words

The device of claim 23 wherein said matrix is depleted in a component extractable from said matrix by said hot aqueous medium treatment, said component being characterized in inhibiting bone formation in implanted osteogenic devices and eluting at 24 minutes, as determined by absorbance at 214 nm, when said extract is fractionated through a C-18 HPLC column in the presence of 0.1% TFA and eluted at a flow rate of 25 ml/min.

Claim 28

Dependent Claim 27 words

The device of claim 23 wherein said matrix is treated with a hot aqueous medium having a temperature within the range of 37° C. to 65° C.

Claim 29

Dependent Claim 27 words

The device of claim 24 wherein said matrix is treated with a hot aqueous medium having a temperature within the range of 45° C. to 60° C.

Claim 30

Dependent Claim 18 words

The device of claim 23 wherein said hot aqueous medium has a pH value less than about 4.5.

Claim 31

Dependent Claim 18 words

The device of claim 27 wherein said pH value is within the range of about pH 2-pH 4.

Claim 32

Dependent Claim 12 words

The device of claim 28 wherein said pH value is about 3.

Claim 33

Dependent Claim 13 words

The device of claim 23 wherein said aqueous medium comprises 0.1% acetic acid.

Claim 34

Dependent Claim 33 words

A method of inducing endochondral bone formation in a non-union fracture in a mammal comprising the step of implanting in the fracture in said mammal the device of claim 15, 16 or 17.

Claim 35

Dependent Claim 36 words

A method of inducing cartilage or endochondral bone formation in a mammal comprising the step of implanting the device of claim 15, 16 or 17 in said mammal at a locus accessible to migratory progenitor cells.

Claim 36

Dependent Claim 21 words

The method of claim 32 wherein said locus is a mammalian jaw bone for use in periodontal or dental reconstructive procedures.

Claim 37

Dependent Claim 15 words

The device of claim 15 or 17 for use in cartilage repair in a mammal.

Claim 38

Dependent Claim 16 words

The device of claim 15, 16 or 17 for use in periodontal or dental reconstructive procedures.

Claim 39

Dependent Claim 14 words

The device of claim 15 or 17 for use in endochondral bone reconstructive procedures.

Claim 40

Dependent Claim 108 words

An osteogenic device for implantation in a mammal, the device comprising: a biocompatible, in vivo biodegradable matrix defining pores of a dimension sufficient to permit influx, differentiation, and proliferation of migratory progenitor cells from the body of said mammal, and a protein comprising a pair of oxidized subunits disulfide bonded to produce a dimeric species, each said subunit being independently selected and comprising at least the osteogenically active region of a protein selected from the group consisting of OP1-18Ser (residues 293-431 of Seq. ID. No. 1); mOP1-Ser (residues 292-430, Seq. ID No. 24); mOP2-Ala (residues 261-399 Seq. ID. No. 26); hOP2-Ala (residues 264-402 of Seq. ID No. 28).

Claim 41

Dependent Claim 108 words

An osteogenic device for implantation in a mammal, the device comprising: a biocompatible, in vivo biodegradable matrix defining pores of a dimension sufficient to permit influx, differentiation, and proliferation of migratory progenitor cells from the body of said mammal, and a protein comprising a pair of oxidized subunits disulfide bonded to produce a dimeric species, each said subunit being independently selected and comprising at least the osteogenically active region of a protein selected from the group consisting of OP1-18Ser (residues 293-431 of Seq. ID. No. 1); mOP1-Ser (residues 292-430, Seq. ID No. 24); mOP2-Ala (residues 261-399 Seq. ID. No. 26); hOP2-Ala (residues 264-402 of Seq. ID No. 28).

Claim 42

Dependent Claim 33 words

A method of inducing cartilage or endochondral bone formation in a mammal comprising the step of implanting the device of claim 37 in said mammal at a locus accessible to migratory progenitor cells.

Claim 43

Dependent Claim 33 words

A method of inducing cartilage or endochondral bone formation in a mammal comprising the step of implanting the device of claim 37 in said mammal at a locus accessible to migratory progenitor cells.

Claim 44

Dependent Claim 21 words

The method of claim 39 wherein said locus is a mammalian jaw bone for use in periodontal or dental reconstructive procedures.

Claim 45

Dependent Claim 30 words

A method of inducing endochondral bone formation in a non-union fracture in a mammal comprising the step of implanting in the fracture in said mammal the device of claim 37.

Claim 46

Dependent Claim 17 words

The device of claim 37 for use in inducing bone formation in periodontal or dental reconstructive procedures.

Claim 47

Dependent Claim 17 words

The device of claim 37 for use in inducing cartilage or bone formation in craniofacial reconstructive procedures.

Claim 48

Dependent Claim 40 words

The device of claim 37 wherein said matrix comprises a material selected from the group consisting of collagen, hydroxyapatite, tricalcium phosphate, polymers comprising lactic acid monomers, polymers comprising butyric acid monomers, polymers comprising glycolic acid monomer units, and mixtures thereof.

Claim 49

Dependent Claim 124 words

An osteogenic device for implantation in a mammal, the device comprising: an osteogenic protein expressed from recombinant DNA in a host cell, the protein comprising a pair of oxidized subunits disulfide bonded to produce a dimeric species, one of said subunits having an amino acid sequence sufficiently duplicative of the sequence comprising residues 335 to 431 of Seq. ID No. 1 (OPS), such that the disulfide bonded dimeric species comprising said subunit has a conformation capable of inducing cartilage and endochondral bone formation in a mammal when disposed within a matrix implanted in said mammal, and a biocompatible, in vivo biodegradable matrix defining pores of a dimension sufficient to permit influx, differentiation, and proliferation of migratory progenitor cells from the body of said mammal.

Claim 50

Dependent Claim 124 words

An osteogenic device for implantation in a mammal, the device comprising: an osteogenic protein expressed from recombinant DNA in a host cell, the protein comprising a pair of oxidized subunits disulfide bonded to produce a dimeric species, one of said subunits having an amino acid sequence sufficiently duplicative of the sequence comprising residues 335 to 431 of Seq. ID No. 1 (OPS), such that the disulfide bonded dimeric species comprising said subunit has a conformation capable of inducing cartilage and endochondral bone formation in a mammal when disposed within a matrix implanted in said mammal, and a biocompatible, in vivo biodegradable matrix defining pores of a dimension sufficient to permit influx, differentiation, and proliferation of migratory progenitor cells from the body of said mammal.

Claim 51

Dependent Claim 117 words

An osteogenic device for implantation in a mammal, the device comprising: osteogenic protein expressed from recombinant DNA in a host cell, the protein comprising a pair of oxidized subunits disulfide bonded to produce a dimeric species capable of inducing cartilage and endochondral bone formation in a mammal when disposed within a matrix implanted in said mammal, one of said subunits having an amino acid sequence encoded by a nucleic acid capable of hybridizing to a nucleic acid encoding residues 335 to 431 of Seq. ID No. 1 (OPS), and a biocompatible, in vivo biodegradable matrix defining pores of a dimension sufficient to permit influx, differentiation, and proliferation of migratory progenitor cells from the body of said mammal.

Claim 52

Dependent Claim 117 words

An osteogenic device for implantation in a mammal, the device comprising: osteogenic protein expressed from recombinant DNA in a host cell, the protein comprising a pair of oxidized subunits disulfide bonded to produce a dimeric species capable of inducing cartilage and endochondral bone formation in a mammal when disposed within a matrix implanted in said mammal, one of said subunits having an amino acid sequence encoded by a nucleic acid capable of hybridizing to a nucleic acid encoding residues 335 to 431 of Seq. ID No. 1 (OPS), and a biocompatible, in vivo biodegradable matrix defining pores of a dimension sufficient to permit influx, differentiation, and proliferation of migratory progenitor cells from the body of said mammal.

Claim 53

Dependent Claim 115 words

An osteogenic device for implantation in a mammal, the device of comprising: a biocompatible, in vivo biodegradable matrix defining pores of a dimension sufficient to permit influx, differentiation, and proliferation of migratory progenitor cells from the body of said mammal, and a protein comprising a pair of oxidized subunits disulfide bonded to produce a dimeric species, at least one subunit comprising a polypeptide chain having an amino acid sequence sharing greater than 74% identity with the sequence described by residues 264-402 of Seq. ID No. 28 (hOP2-Ala) such that the disulfide bonded dimeric species comprising said polypeptide chain is capable of inducing endochondral bone formation when implanted in a mammal in association with a matrix.

Claim 54

Dependent Claim 115 words

An osteogenic device for implantation in a mammal, the device of comprising: a biocompatible, in vivo biodegradable matrix defining pores of a dimension sufficient to permit influx, differentiation, and proliferation of migratory progenitor cells from the body of said mammal, and a protein comprising a pair of oxidized subunits disulfide bonded to produce a dimeric species, at least one subunit comprising a polypeptide chain having an amino acid sequence sharing greater than 74% identity with the sequence described by residues 264-402 of Seq. ID No. 28 (hOP2-Ala) such that the disulfide bonded dimeric species comprising said polypeptide chain is capable of inducing endochondral bone formation when implanted in a mammal in association with a matrix.

Claim 55

Dependent Claim 107 words

An osteogenic device for implantation in a mammal, the device of comprising: a biocompatible, in vivo biodegradable matrix defining pores of a dimension sufficient to permit influx, differentiation, and proliferation of migratory progenitor cells from the body of said mammal, and a protein comprising a pair of oxidized subunits disulfide bonded to produce a dimeric species, at least one subunit comprising a polypeptide chain having an amino acid sequence encoded by a nucleic acid capable of hybridizing to a nucleic acid encoding the pro region of mOP2-PP (res. 17-260 of Seq. ID No. 26) or hOP2-PP (res. 17-263 of Seq. ID No. 28) under stringent hybridization conditions.

Claim 56

Dependent Claim 107 words

An osteogenic device for implantation in a mammal, the device of comprising: a biocompatible, in vivo biodegradable matrix defining pores of a dimension sufficient to permit influx, differentiation, and proliferation of migratory progenitor cells from the body of said mammal, and a protein comprising a pair of oxidized subunits disulfide bonded to produce a dimeric species, at least one subunit comprising a polypeptide chain having an amino acid sequence encoded by a nucleic acid capable of hybridizing to a nucleic acid encoding the pro region of mOP2-PP (res. 17-260 of Seq. ID No. 26) or hOP2-PP (res. 17-263 of Seq. ID No. 28) under stringent hybridization conditions.

Claim 57

Independent Claim 64 words

The device of claims 47 or 48 wherein at least one said subunit comprises an amino acid sequence selected from the group consisting of: mOP2-Ala (residues 261-399 Seq. ID No. 26); hOP2-Ala (residues 264-402 of Seq. ID No. 28); hOP2-Pro (residues 267-402 of Seq. ID No. 28); hOP2-Arg (residues 270-402 of Seq. ID No. 28); and hOP2-Ser (residues 243-402 of Seq. ID No. 28).

Claim 58

Independent Claim 22 words

The device of claims 37, 45, 46, 47 or 48 wherein said matrix is treated to increase the porosity of said matrix.

Claim 59

Independent Claim 44 words

The device of claims 45, 46, 47 or 48 wherein said matrix comprises a material selected from the group consisting of collagen, hydroxyapatite, tricalcium phosphate, polymers comprising lactic acid monomers, polymers comprising butyric acid monomers, polymers comprising glycolic acid monomer units, and mixtures thereof.

Claim 60

Independent Claim 60 words

The device of claims 37, 45, 46, 47 or 48 wherein said matrix comprises a biocompatible matrix of mineral-free, dilipidated Type I insoluble bone collagen particles, substantially depleted in non-collagenous protein and treated with a hot aqueous medium having a temperature above about 37° C. in an amount and for a time sufficient to alter the morphology of said particles.

Claim 61

Dependent Claim 28 words

The device of claim 52 wherein said aqueous medium has a temperature within the range of 45° C. to 60° C. and a pH value of about 3.

Claim 62

Dependent Claim 72 words

The device of claim 52 wherein said matrix is depleted in a component extractable from said matrix by said hot aqueous medium treatment, said component being characterized in inhibiting bone formation in implanted osteogenic devices and eluting at 24 minutes, as determined by absorbance at 214 nm, when said extract is fractionated through a C-18 HPLC column in the presence of 0.1% TFA and eluted at a flow rate of 25 ml/min.

Claim 63

Independent Claim 18 words

The device of claims 37, 45, 46, 47 or 48 for use in cartilage repair in said mammal.

Claim 64

Independent Claim 18 words

The device of claims 37, 45, 46, 47 or 48 disposed within the marrow cavity of allogenic bone.

Claim 65

Independent Claim 18 words

The device of claims 37, 45, 46, 47 or 48 wherein said matrix comprises allogenic bone or muscle.

Claim 66

Dependent Claim 38 words

A method of accelerating allograft repair in a mammal, comprising the step of implanting at a locus in need of replacement bone the device of claim 37, 45, 46, 47 or 48, wherein said matrix comprises allogenic bone.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1997-10-10	1998-04-11	1998-10-11	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	2001-10-10	2002-04-11	2002-10-11	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2005-10-10	2006-04-11	2006-10-11	$7700.00	Window Closed / Lapsed

Osteogenic devices

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