Claims for Patent: 6,191,268

Summary for Patent: 6,191,268

Title:	Compositions and methods relating to DNA mismatch repair genes
Abstract:	Genomic sequences of human mismatch repair genes are described, as are methods of detecting mutations and/or polymorphisms in those genes. Also described are methods of diagnosing cancer susceptibility in a subject, and methods of identifying and classifying mismatch-repair-defective tumors. In particular, sequences and methods relating to human mutL homologs, hMLH1 and hPMS1 genes are provided.
Inventor(s):	Liskay; Robert M. (Lake Oswego, OR), Bronner; C. Eric (Portland, OR), Baker; Sean M. (Portland, OR), Bollag; Roni J. (Martinez, GA), Kolodner; Richard D. (Jamaica Plain, MA)
Assignee:	Dana-Farber Cancer Institute (Boston, MA) Oregon Health Sciences University (Portland, OR)
Application Number:	08/352,902
Patent Claims:	1. An isolated nucleic acid molecule including a segment having a sequence selected from the group consisting of SEQ ID NOS: 6-24. 2. An isolated nucleic acid molecule including a segment having a sequence selected from the group consisting of SEQ ID NOS: 25-43. 3.A unique fragment of the nucleic acid molecule of claim 1 or claim 2. 4. An isolated polynucleotide including a unique segment of a human mutL homolog gene, wherein the mutL homolog gene is hMLH1, or hPMS1. 5. The polynucleotide of claim 4 wherein the segment is homologous to the DNA sequence between the two sets of underlined bases in FIG. 3. 6. An isolated human nucleic acid molecule comprising a segment of at least 13 nucleotides the same as any 13 nucleotide sequence in any one of SEQ ID NOS: 6-24. 7. An isolated polynucleotide comprising a segment of at least 13 nucleotides the same as any 13 nucleotide sequence in SEQ ID NO: 145. 8. An isolated polynucleotide comprising a segment of at least 13 nucleotides the same as any 13 nucleotide sequence in any one of SEQ ID NOS: 7-24. 9. An isolated polynucleotide comprising a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in any one of SEQ ID NOS: 26-43. 10. A composition comprising isolated nucleic acid molecules containing a human sequence encoding hMLH1, wherein said hMLH1 sequence is selected from the group consisting of: (a) SEQ ID NOS: 6-24, (b) nucleic acid sequences complementary to (a), and (c) nucleic acid sequences containing a segment of at least 13 nucleotides the same as any 13 nucleotide sequence in (a) or (b). 11. An isolated nucleotide sequence encoding an hMLH1 protein having an amino acid sequence as set forth in SEQ ID NO: 5. 12. An isolated polynucleotide comprising a segment having the same nucleotide sequence as shown in SEQ ID NO: 4 between nucleotide numbers 135-312. 13. The nucleic acid molecule of claim 6 further comprising a detectable label-moiety attached to the sequence. 14. The nucleic acid molecule of claim 13, wherein the label-moiety has a property selected from the group consisting of fluorescent, radioactive and chemiluminescent. 15. The polynucleotide of claim 4, comprising a segment of at least 13 nucleotides the same as any 13 nucleotide sequence in any one of SEQ ID NOS: 6-24. 16. The polynucleotide of claim 4, comprising a segment of at least 13 nucleotides the same as any 13 nucleotide sequence in SEQ ID NO: 145. 17. The polynucleotide of claim 4, comprising a segment of at least 13 nucleotides the same as any 13 nucleotide sequence in any one of SEQ ID NOS: 7-24. 18. The polynucleotide of claim 4, comprising a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in any one of SEQ ID NOS: 26-43. 19. The polynucleotide of claim 4, comprising a sequence encoding an HMLH1 protein having an amino acid sequences as set forth in SEQ ID NO: 5. 20. The polynucleotide of claim 4, comprising a segment having the same nucleotide sequences shown in SEQ ID NO: 4 between nucleotide numbers 135-312. 21. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 25. 22. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 26. 23. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 27. 24. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 28. 25. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 29. 26. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 30. 27. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 31. 28. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 32. 29. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 33. 30. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 34. 31. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 35. 32. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 36. 33. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 37. 34. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 38. 35. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 39. 36. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 40. 37. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 41. 38. An isolated polynucleotide comprising a segment having the nucleotide sequence of SEQ ID NO: 42. 39. The molecule of claim 6, wherein the molecule includes at least two separate segments, each segment having a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in any one of SEQ ID NOS: 6-24, wherein the sequences of the segments can be used to design a pair of oligonucleotide primers for amplifying specifically at least a portion of hMLH1. 40. The polynucleotide of claim 7, wherein the polynucleotide includes at least two separate segments, each segment having a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in SEQ ID NO: 145, wherein the sequences of the segments can be used to design a pair of oligonucleotide primers for amplifying specifically at least a portion of hMLH1. 41. The polynucleotide of claim 8, wherein the polynucleotide includes at least two separate segments, each segment having a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in any one of SEQ ID NOS: 7-24, wherein the sequences of the segments can be used to design a pair of oligonucleotide primers for amplifying specifically at least a portion of hMLH1. 42. The polynucleotide of claim 9, wherein the polynucleotide includes at least two separate segments, each segment having a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in any one of SEQ ID NOS: 26-43, wherein the sequences of the segments can be used to design a pair of oligonucleotide primers for amplifying specifically at least a portion of hMLH1. 43. The composition of claim 10, wherein the hMLH1 sequence includes at least two separate segments, each segment having a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in (a) or (b), wherein the sequences of the segments can be used to design a pair of oligonucleotide primers for amplifying specifically at least a portion of hMLH1. 44. The polynucleotide of claim 12, wherein the polynucleotide includes at least two separate segments, each segment having a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in SEQ ID NO: 4 between nucleotide numbers 135-312, wherein the sequences of the segments can be used to design a pair of oligonucleotide primers for amplifying specifically at least a portion of hMLH1. 45. The polynucleotide of claim 15, wherein the polynucleotide includes at least two separate segments, each segment having a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in any one of SEQ ID NOS: 6-24, wherein the sequences of the segments can be used to design a pair of oligonucleotide primers for amplifying specifically at least a portion of hMLH1. 46. The polynucleotide of claim 16, wherein the polynucleotide includes at least two separate segments, each segment having a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in SEQ ID NO: 145, wherein the sequences of the segments can be used to design a pair of oligonucleotide primers for amplifying specifically at least a portion of hMLH1. 47. The polynucleotide of claim 17, wherein the polynucleotide includes at least two separate segments, each segment having a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in any one of SEQ ID NOS: 7-24, wherein the sequences of the segments can be used to design a pair of oligonucleotide primers for amplifying specifically at least a portion of hMLH1. 48. The polynucleotide of claim 18, wherein the polynucleotide includes at least two separate segments, each segment having a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in any one of SEQ ID NOS: 26-43, wherein the sequences of the segments can be used to design a pair of oligonucleotide primers for amplifying specifically at least a portion of hMLH1. 49. Copies of a DNA sequence amplified from DNA or RNA, each copy comprising a segment of at least 13 nucleotides of hPMS1 as shown in SEQ ID NO: 132. 50. The polynucleotide of claim 4, wherein the segment has a sequence of at least 13 nucleotides of hPMS1 as shown in SEQ ID NO: 132. 51. The polynucleotide of claim 50 wherein the sequence has the nucleotide structure shown in SEQ ID NO: 132. 52. An isolated human gene comprising exons having a combined nucleotide sequence as shown in SEQ ID NO: 4, and introns intervening the exons. 53. Isolated DNA comprising a first strand containing a first segment of at least 13 nucleotides of hPMS1 cDNA as shown in SEQ ID NO: 132, and a second strand containing a second segment which is complementary to at least 13 nucleotides of hPMS1 cDNA as shown in SEQ ID NO: 132, wherein the sequences of the segments can be used to design a pair of oligonucleotide primers for amplifying specifically at least a portion of hPMS1. 54. The nucleic acid sequence of claim 50, further comprising a second segment of at least 13 nucleotides of hPMS1 as shown in SEQ ID NO: 132, wherein the sequences of the segments can be used to design a pair of oligonucleotide primers for amplifying specifically at least a portion of hPMS1. 55. An isolated human nucleic acid sequence comprising a segment of hPMS1 as shown in the first 500 bases listed in SEQ ID NO: 132. 56. An isolated human nucleic acid sequence comprising a segment of hPMS1 including bases 501 through 1000 as listed in SEQ ID NO: 132. 57. An isolated human nucleic acid sequence comprising a segment of hPMS1 including bases 1001 through 1500 as listed in SEQ ID NO: 132. 58. An isolated human nucleic acid sequence comprising a segment of hPMS1 including bases 1501 through 2000 as listed in SEQ ID NO: 132. 59. An isolated human nucleic acid sequence comprising a segment of hPMS1 including bases 2001 through 2687 as listed in SEQ ID NO: 132. 60. An isolated polynucleotide comprising a segment having a sequence as shown in SEQ ID NOS: 146 and 147. 61. An isolated polynucleotide comprising a first segment of at least 13 nucleotides the same as any 13 nucleotide sequence in SEQ ID NOS: 146 and 147. 62. The polynucleotide of claim 50, further comprising a second segment of at least 13 nucleotides the same as any 13 nucleotide sequence in SEQ ID NO: 132, wherein the sequences of the first and second segments can be used to design a pair of oligonucleotide primers for amplifying specifically at least a portion of hPMS1. 63. An isolated polynucleotide comprising a segment having a sequence as shown in SEQ ID NO: 149 or a unique fragment thereof. 64. An isolated polynucleotide comprising a first segment of at least 13 nucleotides the same as any 13 nucleotide sequence in SEQ ID NO: 149. 65. The polynucleotide of claim 64, further comprising a second segment of at least 13 nucleotides the same as any 13 nucleotide sequence in SEQ ID NO: 149, wherein the sequences of the first and second segments can be used to design a pair of oligonucleotide primers for amplifying specifically at least a portion of hPMS1. 66. The polynucleotide of claim 50, wherein the sequence is labeled. 67. An isolated human polynucleotide comprising a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in SEQ ID NO: 132, wherein the polynucleotide contains at least one mutation that increases a person's risk of developing cancer. 68. An isolated human polynucleotide comprising a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in SEQ ID NO: 4, wherein the polynucleotide contains at least one mutation that increases a person's risk of developing cancer. 69. An isolated human polynucleotide comprising a sequence of at least 13 nucleotides the same as any 13 nucleotide sequence in SEQ ID NO: 148, wherein the polynucleotide contains at least one mutation that increases a person's risk of developing cancer. 70. The polynucleotide of claim 69, wherein the mutation is a C to T substitution. 71. An isolated segment of a human gene, comprising an intron portion and an exon portion, the exon portion corresponding sequentially to a unique fragment of HMLH1 cDNA as shown in SEQ ID NO: 145. 72. The segment of claim 71, wherein the segment contains at least one mutation that increases a person's risk of developing cancer. 73. The nucleic acid molecule of claim 6 comprising a segment of at least 20 nucleotides the same as any 20 nucleotide sequence in any one of SEQ ID NOS: 6-24. 74. The polynucleotide of claim 7 comprising a segment of at least 20 nucleotides the same as any 20 nucleotide sequence in SEQ ID NO: 145. 75. The polynucleotide of claim 4 comprising a segment of at least 20 nucleotides the same as any 20 nucleotide sequence in SEQ ID NO: 145. 76. The polynucleotide of claim 4 comprising a segment of at least 20 nucleotides the same as any 20 nucleotide sequence in SEQ ID NO: 4. 77. The polynucleotide of claim 4 comprising a segment of at least 20 nucleotides the same as any 20 nucleotide sequence in SEQ ID NO: 146. 78. The polynucleotide of claim 4 comprising a segment of at least 20 nucleotides the same as any 20 nucleotide sequence in SEQ ID NO: 147. 79. The polynucleotide of claim 4 comprising a segment of at least 20 nucleotides the same as any 20 nucleotide sequence in SEQ ID NO: 132. 80. The segment of claim 72, wherein the mutation is located in the intron portion.

Details for Patent 6,191,268

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		2018-02-20
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2018-02-20
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2018-02-20