Claims for Patent: 6,083,698

Summary for Patent: 6,083,698

Title:	Cancer susceptibility mutations of BRCA1
Abstract:	New mutations have been found in the BRCA1 gene. The mutations are located at nucleotide numbers 421-2, 815, 903, 926, 1506, 2034, 2428, 3888, 3904, 4164, 4643, 5053, 5150, 5210, or 5396+40 of the gene sequence of BRCA1. A process for identifying a sequence variation in a BRCA1 polynucleotide sequence is disclosed. The identification process includes allele specific sequence-based assays of known sequence variations. The methods can be used for efficient, and accurate detection of a mutation in a test BRCA1 gene sample.
Inventor(s):	Olson; Sheri Jon (Falls Church, VA), Angelly; Tracy Staton (Gaithersburg, MD), Lawrence; Tammy (Laurel, MD), Lescallett; Jennifer Lee (Great Falls, VA), Murphy; Patricia Davis (Slingerlands, NY), Allen; Antonette Preisinger (Severn, MD), Thurber; Denise Bernadette (Silver Spring, MD), White; Marga Belle (Frederick, MD), Zeng; Bin (Indianapolis, IN), Sadzewicz; Lisa K. (Laurel, MD)
Assignee:	Oncormed, Inc. (Gaithersburg, MD)
Application Number:	08/988,706
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,083,698
Patent Claims:	1. An isolated oligonucleotide that hybridizes to either a normal or a mutant BRCA1 gene selected from the group consisting of: a first oligonucleotide for detecting a deletion of a nucleotide in intron 6 at nucleotide number 421-2 of a BRCA1 gene sequence, wherein said first oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 421-2 of the BRCA1 gene, a second oligonucleotide for detecting a deletion of two nucleotides at nucleotide number 815 of a BRCA1 gene sequence, wherein said second oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 815 of the BRCA1 gene, a third oligonucleotide for detecting an insertion of 10 nucleotides at nucleotide number 926 of a BRCA1 gene sequence, wherein said third oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 926 of the BRCA1 gene, a fourth oligonucleotide for detecting a deletion of one nucleotide at nucleotide number 1506 of a BRCA1 gene sequence, wherein said fourth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 1506 of the BRCA1 gene, a fifth oligonucleotide for detecting a mutation of one nucleotide at nucleotide number 2034 of a BRCA1 gene sequence, wherein said fifth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 2034 of the BRCA1 gene, a sixth oligonucleotide for detecting an amino acid change from serine to a stop codon at codon 770 of a BRCA1 gene sequence, wherein said sixth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 2428 of the BRCA1 gene, a seventh oligonucleotide for detecting an amino acid change from tryptophan to a stop codon at codon 1508 of a BRCA1 gene sequence, wherein said seventh oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 4643 of the BRCA1 gene, an eighth oligonucleotide for detecting a deletion of one nucleotide at nucleotide number 5053 of a BRCA1 gene sequence, wherein said eighth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 5053 of the BRCA1 gene, an ninth oligonucleotide for detecting a deletion of one nucleotide at nucleotide number 5210 of a BRCA1 gene sequence, wherein said ninth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 5210 of the BRCA1 gene, a tenth oligonucleotide for detecting an insertion of 12 nucleotides at nucleotide number 5396+40 in intron 20 of a BRCA1 gene sequence, wherein said tenth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 5396+40 of the BRCA1 gene, an eleventh oligonucleotide for detecting a deletion of one nucleotide at nucleotide number 5150 of a BRCA1 gene sequence, wherein said eleventh oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 5150 of the BRCA1 gene, a twelfth oligonucleotide for detecting an amino acid change from serine to a stop codon at codon 1262 of a BRCA1 gene sequence, wherein said twelfth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 3904 of the BRCA1 gene, a thirteenth oligonucleotide for detecting an amino acid change from tyrosine to stop at nucleotide number 903 of a BRCA1 gene sequence, wherein said thirteenth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 903 of the BRCA1 gene, and a fourteenth oligonucleotide for detecting a detecting an amino acid change from threonine to proline at nucleotide number 4164 of a BRCA1 gene sequence, wherein said fourteenth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 4164 of the BRCA1 gene. 2. The isolated oligonucleotide according to claim 1 wherein the oligonucleotide detects the presence or absence of an A at nucleotide number 421-2 by specifically hybridizing to the region encompassing nucleotide number 421-2 of the BRCA1 gene. 3. An isolated wild type allele specific oligonucleotide according to claim 2 having the sequence 5'TAT TTT ACA GAT GCA AA 3', SEQ ID NO:3, or the sequence complementary thereto. 4. An isolated mutant allele specific oligonucleotide according to claim 2 having the sequence 5'TAT TTT ACG ATG CAA AC 3', SEQ ID NO:4, or the sequence complementary thereto. 5. The isolated oligonucleotide according to claim 1 wherein the oligonucleotide detects the presence or absence of a TG at nucleotide number 815 by specifically hybridizing to the region encompassing the nucleotide number 815 of the BRCA1 gene. 6. An isolated wild type allele specific oligonucleotide according to claim 5 having the sequence 5'GAC GGA TGT AAC AAA TA 3', SEQ ID NO:7, or the sequence complementary thereto. 7. An isolated mutant allele specific oligonucleotide according to claim 5 having the sequence 5'GAG ACG GAT AAC AAA TA 3', SEQ ID NO:8, or the sequence complementary thereto. 8. The isolated oligonucleotide according to claim 1 wherein the oligonucleotide detects the presence or absence of an insertion at nucleotide number 926 by specifically hybridizing to the region encompassing the nucleotide number 926 of the BRCA1 gene. 9. An isolated wild type allele specific oligonucleotide according to claim 8 having the sequence SEQ ID NO:9, or the sequence complementary thereto. 10. An isolated mutant allele specific oligonucleotide according to claim 8 having the sequence SEQ ID NO:10, or the sequence complementary thereto. 11. The isolated oligonucleotide according to claim 1 wherein the oligonucleotide detects the presence or absence of an A at nucleotide number 1506 by specifically hybridizing to the region encompassing the nucleotide number 1506 of the BRCA1 gene. 12. An isolated wild type allele specific oligonucleotide according to claim 11 having the sequence SEQ ID NO:13, or the sequence complementary thereto. 13. An isolated mutant allele specific oligonucleotide according to claim 11 having the sequence SEQ ID NO:14, or the sequence complementary thereto. 14. The isolated oligonucleotide according to claim 1 wherein the oligonucleotide detects the presence or absence of a nucleotide change at nucleotide number 2034 by specifically hybridizing to the region encompassing the nucleotide number 2034 of the BRCA1 gene. 15. An isolated wild type allele specific oligonucleotide according to claim 14 having the sequence SEQ ID NO:17, or the sequence complementary thereto. 16. An isolated mutant allele specific oligonucleotide according to claim 14 having the sequence SEQ ID NO:18, or the sequence complementary thereto. 17. The isolated oligonucleotide according to claim 1 wherein the oligonucleotide detects the presence or absence of a nucleotide change at nucleotide number 2428 by specifically hybridizing to the region encompassing the nucleotide number 2428 of the BRCA1 gene. 18. An isolated wild type allele specific oligonucleotide according to claim 17 having the sequence SEQ ID NO:20, or the sequence complementary thereto. 19. An isolated mutant allele specific oligonucleotide according to claim 17 having the sequence SEQ ID NO:21, or the sequence complementary thereto. 20. The isolated oligonucleotide according to claim 1 wherein the oligonucleotide detects the presence or absence of a nucleotide change at nucleotide number 4643 by specifically hybridizing to the region encompassing the nucleotide number 4643 of the BRCA1 gene. 21. An isolated wild type allele specific oligonucleotide according to claim 20 having the sequence SEQ ID NO:24, or the sequence complementary thereto. 22. An isolated mutant allele specific oligonucleotide according to claim 20 having the sequence SEQ ID NO:25, or the sequence complementary thereto. 23. The isolated oligonucleotide according to claim 1 wherein the oligonucleotide detects the presence or absence of a G at nucleotide number 5053 by specifically hybridizing to the region encompassing the nucleotide number 5053 of the BRCA1 gene. 24. An isolated wild type allele specific oligonucleotide according to claim 23 having the sequence SEQ ID NO:28, or the sequence complementary thereto. 25. An isolated mutant allele specific oligonucleotide according to claim 23 having the sequence SEQ ID NO:29, or the sequence complementary thereto. 26. The isolated oligonucleotide according to claim 1 wherein the oligonucleotide detects the presence or absence of a T at nucleotide number 5210 by specifically hybridizing to the region encompassing the nucleotide number 5210 of the BRCA1 gene. 27. An isolated wild type allele specific oligonucleotide according to claim 26 having the sequence SEQ ID NO:32, or the sequence complementary thereto. 28. An isolated mutant allele specific oligonucleotide according to claim 26 having the sequence SEQ ID NO:33, or the sequence complementary thereto. 29. The isolated oligonucleotide according to claim 1 wherein the oligonucleotide detects the presence or absence of an insertion at nucleotide number 5396+40 by specifically hybridizing to the region encompassing the nucleotide number 5396+40 of the BRCA1 gene. 30. An isolated wild type allele specific oligonucleotide according to claim 29 having the sequence SEQ ID NO:36, or the sequence complementary thereto. 31. An isolated mutant allele specific oligonucleotide according to claim 29 having the sequence SEQ ID NO:37, or the sequence complementary thereto. 32. The isolated oligonucleotide according to claim 1 wherein the oligonucleotide detects the presence or absence of a deletion at nucleotide number 5150 by specifically hybridizing to the region encompassing the nucleotide number 5150 of the BRCA1 gene. 33. An isolated wild type allele specific oligonucleotide according to claim 32 having the sequence SEQ ID NO:40, or the sequence complementary thereto. 34. An isolated mutant allele specific oligonucleotide according to claim 32 having the sequence SEQ ID NO:41, or the sequence complementary thereto. 35. The isolated oligonucleotide according to claim 1 wherein the oligonucleotide detects the presence or absence of a deletion at nucleotide number 3904 by specifically hybridizing to the region encompassing the nucleotide number 3904 of the BRCA1 gene. 36. An isolated wild type allele specific oligonucleotide according to claim 35 having the sequence SEQ ID NO:44, or the sequence complementary thereto. 37. An isolated mutant allele specific oligonucleotide according to claim 35 having the sequence SEQ ID NO:45, or the sequence complementary thereto. 38. The isolated oligonucleotide according to claim 1 wherein the oligonucleotide detects the presence or absence of a G at nucleotide number 903 by specifically hybridizing to the region encompassing the nucleotide number 903 of the BRCA1 gene. 39. An isolated wild type allele specific oligonucleotide according to claim 38 having the sequence SEQ ID NO:50, or the sequence complementary thereto. 40. An isolated mutant allele specific oligonucleotide according to claim 38 having the sequence SEQ ID NO:51, or the sequence complementary thereto. 41. The isolated oligonucleotide according to claim 1 wherein the oligonucleotide detects the presence or absence of a C at nucleotide number 4164 by specifically hybridizing to the region encompassing the nucleotide number 4164 of the BRCA1 gene. 42. An isolated wild type allele specific oligonucleotide according to claim 41 having the sequence SEQ ID NO:54, or the sequence complementary thereto. 43. An isolated mutant allele specific oligonucleotide according to claim 41 having the sequence SEQ ID NO:55, or the sequence complementary thereto. 44. The isolated oligonucleotide according to claim 1 further comprising a label bound thereto. 45. The isolated oligonucleotide according to claim 44 wherein the label is selected from the group consisting of a radiolabel, a fluorescent label a bioluminescent label, a chemiluminescent label, an enzyme label and a ligand label. 46. An isolated oligonucleotide primer which specifically hybridizes to the BRCA1 gene wherein said primer is selected from the group consisting of: 5'CCA AGG TGT ATG AAG TAT GT 3', SEQ ID NO:5, 5'GTT ATG TTG GCT CCT TGC T 3', SEQ ID NO:6, ' ACT GTT AGG TTC TGA TGA CT 3', SEQ ID NO:11, 5'ATC ATT TCA GGA GTC TTT TG 3', SEQ ID NO:12, 5'GTG TAG AAC GTG CAG GAT TG 3', SEQ ID NO:38, 5'TCG CCT CAT GTG GTT TTA 3', SEQ ID NO:39, 5'GAA GTA ATT GTA AGC ATC CT 3'SEQ ID NO:42, 5'CAT TTT GTT TCC TCA CTA AG 3'SEQ ID NO:43, 5'CTA AGA ACA CAG AGG AGA A 3', SEQ ID NO:52, and 5'CTA GCT GTG TGA AGG ACT 3', SEQ ID NO:53. 47. An isolated oligonucleotide primer according to claim 46 which is a forward primer comprising the sequence BRCA-1-11F: (SEQ ID NO:5). 48. An isolated oligonucleotide primer according to claim 46 which is a reverse primer comprising the sequence BRCA-1-11R: (SEQ ID NO:6). 49. An isolated oligonucleotide primer according to claim 46 which is a forward primer comprising the sequence BRCA-1-11F: (SEQ ID NO:11). 50. An isolated oligonucleotide primer according to claim 46 which is a reverse primer comprising the sequence BRCA-1-11R: (SEQ ID NO:12). 51. An isolated oligonucleotide primer according to claim 46 which is a forward primer comprising the sequence BRCA-1-17F: (SEQ ID NO:38). 52. An isolated oligonucleotide primer according to claim 46 which is a reverse primer comprising the sequence BRCA-1-17R: (SEQ ID NO:39). 53. An isolated oligonucleotide primer according to claim 46 which is a forward primer comprising the sequence BRCA-1-11F: (SEQ ID NO:42). 54. An isolated oligonucleotide primer according to claim 46 which is a reverse primer comprising the sequence BRCA-1-11R: (SEQ ID NO:43). 55. A pair of isolated oligonucleotide primers which specifically hybridize to the BRCA1 gene, wherein the pair is: a primer having the sequence BRCA-1-11F: (SEQ ID NO:5) and a primer having the sequence BRCA-1-11R: (SEQ ID NO:6); a primer having the sequence BRCA-1-11F: (SEQ ID NO:11) and a primer having the sequence BRCA-1-11R: (SEQ ID NO:12); a primer having the sequence BRCA-1-17F: (SEQ ID NO:38) and a primer having the sequence BRCA-1-17R: (SEQ ID NO:39); a primer having the sequence BRCA-1-11F: (SEQ ID NO:42) and a primer having the sequence BRCA-1-11R: (SEQ ID NO:43); or a primer having the sequence BRCA-1-11F: (SEQ ID NO:52) and a primer having the sequence BRCA-1-11R: (SEQ ID NO:53). 56. The pair of primers according to claim 55 wherein said pair comprises a primer having the sequence BRCA-1-11F: (SEQ ID NO:5) and a primer comprising the sequence BRCA-1-11R: (SEQ ID NO:6). 57. The pair of primers according to claim 55 wherein said pair comprises a primer having the sequence BRCA-1-11F: (SEQ ID NO:11) and a primer comprising the sequence BRCA-1-11R: (SEQ ID NO:12). 58. The pair of primers according to claim 55 wherein said pair comprises a primer having the sequence BRCA-1-17F: (SEQ ID NO:38) and a primer comprising the sequence BRCA-1-17R: (SEQ ID NO:39). 59. The pair of primers according to claim 55 wherein said pair comprises a primer having the sequence BRCA-1-11F: (SEQ ID NO:42) and a primer comprising the sequence BRCA-1-11R: (SEQ ID NO:43). 60. The pair of primers according to claim 55 wherein said pair comprises a primer having the sequence BRCA-1-11F: (SEQ ID NO:52) and a primer comprising the sequence BRCA-1-11R: (SEQ ID NO:53). 61. The pair of isolated oligonucleotide primers according to claim 55, wherein each primer is bound to a label. 62. The pair of primers according to claim 61 wherein each of said labels is selected from the group consisting of a radiolabel, a fluorescent label a bioluminescent label a chemiluminescent label, an enzyme label and a ligand label. 63. The isolated oligonucleotide primer according to claim 46 bound to a label. 64. The primer according to claim 63 wherein said label is selected from the group consisting of a radiolabel, a fluorescent label a bioluminescent label a chemiluminescent label, an enzyme label and a ligand label. 65. A method for determining the presence or absence of a sequence variation in a BRCA2 gene sample, comprising: (a) performing an allele specific detection assay for the presence or absence of one or more predetermined sequence variations; and (b) determining the presence or absence of a predetermined sequence variation in the BRCA1 gene sample at nucleotide number 421-2, 815, 926, 1506, 2034, 2428, 4643, 5053, 5210, 5396+40, 5150, 3904, 903, 4164 or its complementary gene sequence. 66. The method according to claim 65 wherein the predetermined sequence variation is IVS6-2delA, 815delTG, 926ins10, 1506delA, T2034C, C2428A, G4643A, 5053delG, 5210delT, IVS20+40ins12, 5150delT, C3904A, T903G or A4164C. 67. The method of claim 65 wherein the allele specific detection assay is performed as part of a multiplex amplification assay format. 68. The method of claim 65 wherein the allele specific sequence-based assay is performed using a dot blot format, reverse dot blot format, a multiplex allele specific diagnostic assay format, or a chip array format. 69. The method according to claim 65 further comprising (c) performing an allele specific detection assay for the presence or absence of one or more reference sequences without the predetermined sequence variations. 70. The method according to claim 69 wherein said reference sequence is a BRCA1 coding sequence. 71. The method according to claim 69 wherein said reference sequence is a BRCA1 genomic sequence. 72. The method according to claim 69 wherein said reference sequence is one or more exons of the BRCA1 gene. 73. A chip array having "n" elements for performing allele specific sequence-based techniques comprising; a solid phase chip and oligonucleotides having "n" different nucleotide sequences, wherein "n" is an integer greater than one, p1 wherein said oligonucleotides are bound to said solid phase chip in a manner which permits said oligonucleotides to effectively hybridize to complementary oligonucleotides or polynucleotides, wherein oligonucleotides having different nucleotide sequence are bound to said solid phase chip at different locations so that a particular location on said solid phase chip exclusively binds oligonucleotides having a specific nucleotide sequence, and wherein at least one oligonucleotide is an oligonucleotide according to claim 1. 74. A method of detecting a predisposition or higher susceptibility to cancer in an individual, comprising: (a) digesting DNA from said individual with a restriction endonuclease; (b) separating DNA fragments obtained from said digestion; (c) detecting a DNA fragment containing a sequence variation at nucleotide number 421-2, 815, 926, 1506, 2034, 2428, 4643, 5053, 5210, 5396+40, 5150, 3904, 903 or 4164 of a BRCA1 gene sequence or the complementary sequence thereof by sequencing; (d) analyzing the DNA fragment sequence for the presence of a sequence variation at nucleotide number 421-2, 815, 926, 1506, 2034, 2428, 4643, 5053, 5210, 5396+40, 5150, 3904, 903 or 4164 of the BRCA1 gene sequence, wherein the presence of a sequence variation indicates a predisposition or higher susceptibility to cancer. 75. A method according to claim 74 further comprising amplifying said DNA fragments prior to sequencing. 76. A method according to claim 74 wherein the sequence variation is amplified prior to detection by sequencing with an oligonucleotide primer having a sequence comprising; 5'CAC AAC AAA GAG CAT ACA TAG GG 3', SEQ ID NO:1 5'TCG GGT TCA CTC TGT AGA AG 3', SEQ ID NO:2 5'CCA AGG TGT ATG AAG TAT GT 3', SEQ ID NO:5 5'GTT ATG TTG GCT CCT TGC T 3', SEQ ID NO:6 5'ACT GTT AGG TTC TGA TGA CT 3', SEQ ID NO:11 5'ATC ATT TCA GGA GTC TTT TG 3', SEQ ID NO:12 5'GTA TAA GCA ATA TGG AAC TCG A 3', SEQ ID NO:15 5'TTA AGT TCA CTG GTA TTT GAA CA 3', SEQ ID NO:16 5'TGG AAC AAC CAT GAA TTA GTC 3', SEQ ID NO:19 5'TGG CTG CCC AGG AAG TAT G 3', SEQ ID NO:22 5'AAC CAG AAT ATC TTT ATG TAG GA 3', SEQ ID NO:23 5'AAT TCT TAA CAG AGA CCA GAA C 3', SEQ ID NO:26 5'AAA ACT CTT TCC AGA ATG TTG T 3', SEQ ID NO:27 5'GGC TCT TTA GCT TCT TAG GAC 3', SEQ ID NO:30, 5'GAG ACC ATT TTC CCA GCA TC 3', SEQ ID NO:31, 5'ATA TGA CGT GTC TGC TCC AC 3', SEQ ID NO:34, 5'GGG AAT CCA AAT TAC ACA GC 3', SEQ ID NO:35, 5'GTG TAG AAC GTG CAG GAT TG 3', SEQ ID NO:38, 5'TCG CCT CAT GTG GTT TTA 3', SEQ ID NO:39, 5'GAA GTA ATT GTA AGC ATC CT 3', SEQ ID NO:42, 5'CAT TTT GTT TCC TCA CTA AG 3', SEQ ID NO:43, ' CTA AGA ACA CAG AGG AGA A 3', SEQ ID NO:52, or 5'CTA GCT GTG TGA AGG ACT 3', SEQ ID NO:53. 77. A method according to claim 76 wherein said oligonucleotide primer is labeled with a radiolabel, a fluorescent label a bioluminescent label, a chemiluminescent label, an enzyme label, or a ligand label. 78. A method of detecting a predisposition or higher susceptibility to cancer in an individual, comprising; (a) digesting DNA from said individual with a restriction endonuclease; (b) separating DNA fragments obtained from said digestion; (c) hybridizing a DNA fragment with an allele specific oligonucleotide having a nucleotide sequence capable of hybridizing to and identifying a sequence variation at nucleotide position 421-2, 815, 926, 1506, 2034, 2428, 4643, 5053, 5210, 5396+40, 5150, 3904, 903 or 4164 of the BRCA1 gene sequence or its complementary gene sequence, (d) correlating the presence or absence of said sequence variation with the respective presence or absence of the BRCA1 gene, thereby determining a predisposition or higher susceptibility to cancer. 79. A method according to claim 74 wherein said allele specific oligonucleotide is selected from the group consisting of: ' TAT TTT ACA GAT GCA AA 3', SEQ ID NO:3, 5'TAT TTT ACG ATG CAA AC 3', SEQ ID NO:4, 5'GAC GGA TGT AAC AAA TA 3', SEQ ID NO:7, 5'GAG ACG GAT AAC AAA TA 3', SEQ ID NO:8, 5'CAT GTG GAG CCA TGT GGC ACA AAT ACT 3', SEQ ID NO:9, 5'CAT GTG GAG CCA TGT GGA GCC ATG TGG 3', SEQ ID NO:10, 5'TAT TTG GGA AAA CCT AT 3', SEQ ID NO:13, 5'TAT TTG GGA AAC CTA TC 3', SEQ ID NO:14, 5'GTA CTG AAT TGC AAA TT 3', SEQ ID NO:17, 5'GTA CTG AAC TGC AAA TT 3', SEQ ID NO:18, 5'CAG TAT TTC ATT GGT AC 3', SEQ ID NO:20, 5'CAG TAT TTA ATT GGT AC 3', SEQ ID NO:21, 5'GAT AGG TGG TAC ATG CA 3', SEQ ID NO:24, 5'GAT AGG TGA TAC ATG CA 3', SEQ ID NO:25, 5'ACA GAA AGG GTC AAC AA 3', SEQ ID NO:28, 5'ACA GAA AGG TCA ACA AA 3', SEQ ID NO:29, 5'GTT TGT GTG TGA ACG GA 3', SEQ ID NO:32, 5'GTT TGT GTG GAA CGG AC 3', SEQ ID NO:33, 5'CCA CTC TGT ATT CCA CTC CCC TTT GCA G 3', SEQ ID NO:36, 5'CCA CTC TGT ATT CCA CTC TGT ATT CCA C 3', SEQ ID NO:37, 5'CAC TTT AAC TAA TCT AA 3', SEQ ID NO:40, 5'CAC TTT AAC AAT CTA AT 3', SEQ ID NO:41, 5'TTA TTA TCA TTG AAG AA 3', SEQ ID NO:44, 5'TTA TTA TAA TTG AAG AA 3', SEQ ID NO:45, 5'GAA AAG TAT CAG GGT AG 3', SEQ ID NO:50 5'GAA AAG TAG CAG GGT AG 3', SEQ ID NO:51 5'AAG AGG AAC GGG CTT GG 3', SEQ ID NO:54 5'AAG AGG ACC GGG CTT GG 3', SEQ ID NO:55 and oligonucleotides complementary thereto. 80. A method according to claim 78 further comprising amplifying said DNA fragments prior to sequencing. 81. A method according to claim 78 wherein said oligonucleotide is labeled with a radiolabel, a fluorescent label a bioluminescent label, a chemiluminescent label, an enzyme label, or a ligand label. 82. A kit comprising a carrier means being compartmentalized to receive in close confinement one or more container means, and at least one container means, wherein at least one container means contains the oligonucleotide of claim 1. 83. The kit acording to claim 75 further comprising at least one container means containing the oligonucleotide primer of claim 50. 84. The kit according to claim 82 further comprising at least one container means containing the pair of oligonucleotide primers of claim 55. 85. A kit comprising a carrier means being compartmentalized to receive in close confinement one or more container means, and at least one container means, wherein at least one container means contains the oligonucleotide primer of claim 46. 86. A kit comprising a carrier means being compartmentalized to receive in close confinement one or more container means, and at least one container means, wherein at least one container means contains the pair of oligonucleotide primers of claim 55. 87. An isolated DNA sequence comprising DNA coding for or complementary to at least a part of a BRCA1 gene containing at least one mutation from the list: IVS6-2delA, 815delTG, 926ins10, 1506delA, T2034C, C2428A, G4643A, 5053delG, 5210delT, IVS20+40ins12, 5150delT, C3904A, T903G or A4164C. 88. A vector comprising the isolated DNA sequence according to claim 87 linked to a vector by at least one of the termini of the isolated DNA sequence. 89. An isolated DNA sequence according to claim 87, wherein the isolated DNA sequence contains the sequence of or a sequence complementary to at least one of the following: SEQ ID NO:4, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:14:, SEQ ID NO:18, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:29, SEQ ID NO:33, SEQ ID NO:37, SEQ ID NO:41, SEQ ID NO:45, SEQ ID NO:51, or SEQ ID NO:55. 90. A vector comprising the isolated DNA sequence according to claim 89 linked to a vector by at least one of the termini of the isolated DNA sequence. 91. A method of determining whether a mutation is present in a BRCA1 gene comprising sequencing at least a portion of the BRCA1 gene containing either: the sequence of or the sequence complementary to SEQ ID NO:4, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:14, SEQ ID NO:18, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:29, SEQ ID NO:33, SEQ ID NO:37, SEQ ID NO:41, SEQ ID NO:45, SEQ ID NO:51, SEQ ID NO:55 or at least one mutation from the list: IVS6-2delA, 815delTG, 926ins10, 1506delA, T2034C, C2428A, G4643A, 5053delG, 5210delT, IVS20+40ins12, 5150delT, C3904A, T903G and A4164C.

Details for Patent 6,083,698

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2015-09-25
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2015-09-25
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2015-09-25