Claims for Patent: 6,165,713

Summary for Patent: 6,165,713

Title:	Composition 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:	Oregon Health Sciences University (Portland, OR) Dana-Farber Cancer Institute (Boston, MA)
Application Number:	08/961,810
Patent Claims:	1. A method of diagnosing cancer susceptibility in a subject comprising detecting a mutation in a mutL homolog gene or gene product in a tissue of the subject, and diagnosing cancer susceptibility in the subject based on the detected mutation. 2. A method of determining whether a person has a mutation in a DNA mismatch repair gene comprising determining a sample sequence of at least a segment of a mutL homolog gene from the person, and comparing the sample sequence to a wild type sequence of at least a segment of any one of SEQ ID NOS: 6-24 and 132. 3. The method of claim 2 further comprising sequencing hMLH1 or a fragment thereof. 4. The method of claim 2 further comprising sequencing hPMS1 or a fragment thereof. 5. The method of claim 2 further comprising a step of ascertaining whether any difference between the sample sequence and the wild type sequence is a polymorphism. 6. The method of claim 2 further comprising a step of ascertaining whether any difference between the sample sequence and the wild type sequence results in a defective gene product. 7. The method of claim 2 wherein the determining step includes the step of collecting and sequencing a DNA sample from the person. 8. The method of claim 2 wherein the determining step includes the step of collecting and sequencing an RNA sample from the person. 9. The method of claim 2 further comprising collecting a sample containing hMLH1 or a fragment thereof from the person. 10. The method of claim 2 further comprising collecting a sample containing hPMS1 or a fragment thereof from the person. 11. The method of claim 2 wherein the person is suspected to be at increased risk of developing cancer based on family history, further comprising collecting the sample sequence from phenotypically normal tissue of the person. 12. The method of claim 2 wherein the person has been diagnosed as having cancer, further comprising collecting a sample from a tumor in the person. 13. A method of determining whether a person has a mutation in a DNA mismatch repair gene comprising determining a sample sequence of at least a segment of a mutL homolog gene from the person, and comparing the sample sequence to a wild type sequence of at least a segment of SEC ID NOS: 26 and 27. 14. A method of determining whether a person has a mutation in a DNA mismatch repair gene comprising determining a sample sequence of at least a segment of a mutL homolog gene from the person, and comparing the sample sequence to a wild type sequence of at least a segment of the nucleotide sequence shown in SEQ ID NOS: 26-43. 15. A method of determining whether there is an alteration in a mammalian DNA mismatch repair pathway comprising (a) isolating a biological specimen from a mammal, (b) testing the specimen for an alteration in a mutL homolog nucleotide sequence or its expression product, and (c) comparing the results obtained in step (b) with the results obtained from a wild-type control. 16. The method of claim 15 wherein the biological specimen is selected from the group consisting of blood, tissue, serum, stool, urine, sputum, cerebrospinal fluid, supernatant from cell lysate and a mammalian cell sample. 17. The method of claim 15 wherein the mammal is a human. 18. The method of claim 15 wherein the mammal is a mouse. 19. The method of claim 15 wherein an alteration is indicative of a predisposition to malignant growth of cells in the mammal. 20. The method of claim 15 wherein the nucleotide sequence is a gene. 21. The method of claim 20 wherein the gene is hMLH1. 22. The method of claim 20 wherein the gene is hPMS1. 23. The method of claim 15 wherein the expression product is mRMA. 24. The method of claim 15 wherein the speciment is tested for an alteration in the expression product and the expression product is a protein. 25. The method of claim 15 wherein the alteration in the pathway is in the nucleotide sequence of the DNA. 26. The method of claim 25 wherein the alteration is detected using a method of DNA amplification. 27. The method of claim 26 wherein the method of DNA amplification detects an alteration in at least one intron or exon. 28. The method of claim 27 wherein the alteration is detected in the hMLH1 gene using a pair of oligonucleotide primers. 29. The method of claim 28 wherein the oligonucleotide primers are selected from the group consisting of SEQ ID NOS: 44-122. 30. A pair of oligonucleotide primers selected from the group consisting of SEQ ID NOS: 44-122. 31. A method of diagnosing a DNA mismatch repair abnormality in a human subject, comprising the steps of collecting a sample from a human subject, and detecting whether there is an abnormal deficiency of a mutL homolog protein in the sample. 32. The method of claim 31, wherein the collecting step includes the step of obtaining a sample from a tumor in the human subject. 33. The method of claim 31, further comprising the step of determining whether there is an abnormal deficiency of hMLH1 protein in the sample. 34. The method of claim 31, wherein the detecting step includes the step of contacting a sample with an antibody that binds specifically to a mutL homolog protein. 35. The method of claim 31, wherein the detecting step includes the step of contacting a sample with a monoclonal antibody that binds specifically to a mutL homolog protein. 36. The method of claim 31, wherein the detecting step includes the step of contacting a sample with a polyclonal antibody that binds specifically to a mutL homolog protein. 37. The method of claim 31, wherein the detecting step includes the step of contacting a sample with an antibody that binds specifically to a protein selected from the group consisting of hMLH1 and hPMS1. 38. The method of claim 31, wherein the detecting step includes the step of contacting a sample with an antibody that binds specifically to a protein, at least a portion of which has a deduced amino acid sequence as shown in SEQ ID NOS: 26-43. 39. The method of claim 31, wherein the detecting step includes the step of contacting a sample with an antibody that binds specifically to a protein, at least a portion of which has a deduced amino acid sequence as shown in SEQ ID NOS: 26 and 27. 40. The method of claim 31, wherein the detecting step includes the step of contacting a sample with an antibody that is conjugated to a fluorescent compound. 41. A method of diagnosing a tumor associated with defective DNA mismatch repair in a human comprising isolating a tissue suspected of being a tumor from said human, and detecting an alteration in a mutL homolog gene or its expression product, wherein said alteration is indicative of a tumor associated with defective DNA mismatch repair. 42. The method of claim 41, wherein the tumor associated with defective DNA mismatch repair is selected from the group of tumors consisting of colorectal, ovarian, endometrial, gastric and breast. 43. A method of diagnosing cancer in an individual, comprising comparing a polynucleotide sequence of a mutL homolog gene from a cancer cell from an individual with a polynucleotide sequence of the mutL homolog gene from a non-cancer cell from the individual, and determining whether there is a difference between the polynucleotide sequence from the cancer cell in comparison to the polynucleotide sequence from the non-cancer cell. 44. A kit for performing an assay to determine whether an individual has a mutation in a DNA mismatch repair gene comprising a set of oligonucleotide primers which can be used to amplify specifically a portion of a mutL homolog gene. 45. The kit of claim 44, wherein the oligonucleotide primers can be used to amplify specifically at least a segment of a mutL homolog gene selected from the group consisting of hMLH1 and hPMS1. 46. The kit of claim 44, wherein the oligonucleotide primers can be used to amplify specifically at least a segment of SEQ ID NOS: 26-43. 47. The kit of claim 44, wherein the oligonucleotide primers can be used to amplify specifically at least a segment of SEQ ID NOS: 25-43. 48. The kit of claim 44, wherein the oligonucleotide primers can be used to amplify specifically at least a segment of SEQ ID NOS: 6-24. 49. The kit of claim 44, wherein the oligonucleotide primers are selected from the group consisting of SEQ ID NOS: 44-82. 50. A kit for performing an assay to determine whether a human subject has an abnormal deficiency of a protein involved in a DNA mismatch repair pathway comprising a purified antibody that binds specifically to a mutL homolog protein. 51. The kit of claim 50, wherein the antibody is a monoclonal antibody. 52. The kit of claim 50, wherein the antibody is a polyclonal antibody. 53. The kit of claim 50, wherein the antibody is conjugated to a fluorescent compound. 54. A kit for performing an assay to determine whether an individual has a mutation in a DNA mismatch repair gene comprising at least one or more allele-specific oligomer probe that is capable of detecting a mutant allele in a mutL homolog gene. 55. The kit of claim 54, wherein said at least one allele-specific oligomer probe is capable of detecting a mutant allele in a DNA mismatch repair gene selected from the group consisting of hMLH1 and hPMS1.

Details for Patent 6,165,713

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		2013-12-17
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2013-12-17
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2013-12-17