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Last Updated: March 28, 2024

Claims for Patent: 7,052,837


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Summary for Patent: 7,052,837
Title:Histoplasma capsulatum catalase sequences and their use in the detection of Histoplamsa capsulatum and histoplasmosis
Abstract: The present invention describes Histoplasmosis capsulatum catalase A and catalase P nucleic acid and protein sequences as reagents for the detection of H. capsulatum infection. Specifically, the invention describes intron sequences from the H. capsulatum catalase A (CATA) and catalase P (CATP) genes which can be used for hybridization and PCR based detection of H. capsulatum infection. In another embodiment, assays for H. capsulatum catalase P or catalase A polypeptides are used as diagnostic tests for H. capsulatum infection and histoplasmosis, respectively. Also described is the differentiation of H. capsulatum from Blastomyces dermititidis based on a H. capsulatum catalase P PCR based assay.
Inventor(s): Johnson; Clayton H. (Little Rock, AR), York; J. Lyndal (Little Rock, AR), McEwen; Joan E. (Little Rock, AR)
Assignee: The Board of Trustees of the University of Arkansas (Little Rock, AR)
Application Number:10/099,352
Patent Claims:1. An isolated nucleic acid molecule for detection of H. capsulatum selected from the group consisting of: (a) a nucleic acid molecule comprising the sequence of SEQ ID NO: 7 or the complement of SEQ ID NO: 7; (b) a fragment of SEQ ID NO: 7 consisting of 20 or more consecutive nucleotides of SEQ ID NO. 7, or the complement thereof; and (c) a nucleic acid molecule of up to 25 nucleotides in length that comprises 20 or more consecutive nucleotides of SEQ ID NO: 7 or the complement thereof; wherein the isolated nucleic acid molecule hybridizes to intron 1 of the H. capsulatum catalase A gene.

2. The isolated nucleic acid molecule of claim 1, wherein the fragment consists of SEQ ID NO: 12 or SEQ ID NO: 13.

3. An isolated nucleic acid molecule for detection of H. capsulatum selected from the group consisting of: (a) a nucleic acid molecule comprising the sequence of SEQ ID NO: 8 or the complement of SEQ ID NO: 8; (b) a fragment of SEQ ID NO: 8 consisting of 20 or more consecutive nucleotides of SEQ ID NO: 8 or the complement thereof; and (c) a nucleic acid molecule of up to 25 nucleotides in length that comprises 20 or more consecutive nucleotides of SEQ ID NO: 8 or the complement thereof; wherein the isolated nucleic acid molecule hybridizes to intron 2 of the H. capsulatum catalase A gene.

4. The isolated nucleic acid molecule of claim 3, wherein the fragment consists of SEQ ID NO: 15.

5. An isolated nucleic acid molecule for detection of H. capsulatum selected from the group consisting of: (a) a nucleic acid molecule comprising the sequence of SEQ ID NO: 7 or the complement thereof or SEQ ID NO: 8 or the complement thereof; (b) a fragment of SEQ ID NO: 7 consisting of 20 or more consecutive nucleotides of SEQ ID NO. 7 or the complement thereof; (c) a fragment of SEQ ID NO: 8 consisting of 20 or more consecutive nucleotides of SEQ ID NO: 8 or the complement thereof; and (d) an oligonucleotide selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 15.

6. A method for detecting H. capsulatum in a sample comprising the steps of: (a) exposing the sample to at least one isolated nucleic acid molecule that hybridizes to H. capsulatum intron 1 comprising SEQ ID NO: 7 or the complement thereof, or to H. capsulatum intron 2 comprising SEQ ID NO: 8 or the complement thereof of the H. capsulatum catalase A gene (CATA); and (b) determining whether there is hybridization of the isolated nucleic acid molecule to the sample, wherein a sample comprising H. capsulatum exhibits detectable hybridization and a sample lacking H. capsulatum does not exhibit hybridization, and wherein the isolated nucleic acid molecule is selected from the group consisting of: (i) a nucleic acid molecule comprising the sequence of SEQ ID NO: 7 or the complement thereof, SEQ ID NO: 8 or the complement thereof; (ii) a fragment of SEQ ID NO: 7 consisting of 20 or more consecutive nucleotides of SEQ ID NO. 7 or the complement thereof, a fragment of SEQ ID NO: 8 consisting of 20 or more consecutive nucleotides of SEQ ID NO: 8 or the complement thereof; (iii) a nucleic acid molecule of up to 25 nucleotides in length that comprises 20 or more consecutive nucleotides of SEQ ID NO: 7 or the complement thereof, a nucleic acid molecule of up to 25 nucleotides in length that comprises 20 or more consecutive nucleotides of SEQ ID NO: 8 or the complement thereof; and (iv) an oligonucleotide selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15 and SEQ ID NO: 16.

7. The method of claim 6, wherein the sample is obtained from a human.

8. The method of claim 7, further comprising the steps of: (a) conducting polymerase chain reaction (PCR) amplification using the at least one nucleic acid molecule that hybridizes to intron 1 or intron 2 of the H. capsulatum catalase A gene (CATA) as an amplification primer; and (b) determining the presence or absence of the PCR product resulting from the amplification.

9. The method of claim 8, wherein the primers comprise at least one oligonucleotide molecule selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15 and SEQ ID NO: 16.

10. The method of claim 8, further comprising PCR amplification conditions that result in detection of a PCR product comprising a H. capulatum intron DNA sequence in a sample comprising H. capsulatum but not in a sample that does not contain H. capsulatum.

11. An isolated nucleic acid molecule for detection of H. capsulatum selected from the group consisting of: (a) a nucleic acid molecule comprising the sequence of SEQ ID NO: 9 or the complement of SEQ ID NO: 9; (b) a fragment of SEQ ID NO: 9 consisting of 19 or more consecutive nucleotides of SEQ ID NO. 9, or the complement thereof; and (c) a nucleic acid molecule of up to 25 nucleotides in length that comprises 19 or more consecutive nucleotides of SEQ ID NO: 9 or the complement thereof; wherein the isolated nucleic acid molecule hybridizes to intron 1 of the H. capsulatum catalase P gene.

12. The isolated nucleic acid molecule of claim 11, wherein the fragment consists of SEQ ID NO: 18 or SEQ ID NO: 19.

13. An isolated nucleic acid molecule for detection of H. capsulatum selected from the group consisting of: (a) a nucleic acid molecule comprising the sequence of SEQ ID NO: 10 or the complement of SEQ ID NO: 10; (b) a fragment of SEQ ID NO: 10 consisting of 20 or more consecutive nucleotides of SEQ ID NO. 10, or the complement thereof; (c) a nucleic acid molecule of up to 25 nucleotides in length that comprises 20 or more consecutive nucleotides of SEQ ID NO: 10 or the complement thereof; wherein the isolated nucleic acid molecule hybridizes to intron 2 of the H. capsulatum catalase P gene.

14. The isolated nucleic acid molecule of claim 13, wherein the fragment consists of SEQ ID NO: 20 or SEQ ID NO: 23.

15. An isolated nucleic acid molecule for detection of H. capsulatum selected from the group consisting of: (a) a nucleic acid molecule comprising the sequence of SEQ ID NO: 11 or the complement of SEQ ID NO: 11; (b) a fragment of SEQ ID NO: 11, consisting of 19 or more consecutive nucleotides of SEQ ID NO: 11 or the complement thereof; and (c) a nucleic acid molecule of up to 25 nucleotides in length that comprises 19 or more consecutive nucleotides of SEQ ID NO: 11 or the complement thereof; wherein the isolated nucleic acid hybridizes to intron 3 of the H. capsulatum catalase P gene.

16. The isolated nucleic acid molecule of claim 15, wherein the fragment consists of SEQ ID NO: 21 or SEQ ID NO: 22.

17. An isolated nucleic acid molecule for detection of H. capsulatum selected from the group consisting of: (a) a nucleic acid molecule comprising the sequence of SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11, or the complement of SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11; (b) a fragment of SEQ ID NO: 9 consisting of 19 or more consecutive nucleotides of SEQ ID NO. 9 or the complement thereof, a fragment of SEQ ID NO: 10 consisting of 20 or more consecutive nucleotides of SEQ ID NO. 10 or the complement thereof, a fragment of SEQ ID NO: 11 consisting of 19 or more consecutive nucleotides of SEQ ID NO: 11 or the complement thereof; and (c) an oligonucleotide selected from the group consisting of SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23.

18. A method for detecting H. capsulatum in a sample comprising the steps of: (a) exposing the sample to at least one isolated nucleic acid molecule that hybridizes to H. capsulatum intron 1 DNA comprising SEQ ID NO: 9 or the complement thereof, H. capsulatum intron 2 comprising SEQ ID NO: 10 or the complement thereof, or H. capsulatum intron 3 comprising SEQ ID NO: 11 or the complement thereof of the H. capsulatum catalase P gene (CATP); and (b) determining whether there is hybridization of the isolated nucleic acid molecule to the sample, wherein a sample comprising H. capsulatum exhibits detectable hybridization, and wherein the isolated nucleic acid molecule is selected from the group consisting of: (i) a nucleic acid molecule comprising the sequence of SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11, or the complements of SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11; (ii) a fragment of SEQ ID NO: 9 consisting of 19 or more consecutive nucleotides of SEQ ID NO. 9 or the complement thereof, a fragment of SEQ ID NO: 10 consisting of 20 or more consecutive nucleotides of SEQ ID NO. 10 or the complement thereof, a fragment of SEQ ID NO: 11 consisting of 19 or more consecutive nucleotides of SEQ ID NO: 11 or the complement thereof; (iii) a nucleic acid molecule of up to 25 nucleotides in length that comprises 19 or more consecutive nucleotides of SEQ ID NO: 9 or the complement thereof, a nucleic acid molecule of up to 25 nucleotides in length that comprises 20 or more consecutive nucleotides of SEQ ID NO: 10 or the complement thereof, a nucleic acid molecule of up to 25 nucleotides in length that comprises 19 or more consecutive nucleotides of SEQ ID NO: 11 or the complement thereof; and (iv) an oligonucleotide selected from the group consisting of SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23.

19. The method of claim 18, wherein the sample is obtained from a human.

20. The method of claim 18, further comprising the steps of: (a) conducting polymerase chain reaction (PCR) amplification using the at least one nucleic acid molecule that hybridizes to intron 1, intron 2, or intron 3 of the H. capsulatum catalase P gene (CATP) as an amplification primer; and (b) determining the presence or absence of the PCR product resulting from said amplification.

21. The method of claim 20, wherein the primers comprise at least one oligonucleotide molecule selected from the group consisting of SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22 and SEQ ID NO: 23.

22. The method of claim 20, further comprising PCR amplification conditions that result in detection of a PCR product in a sample comprising H. capsulatum but not in a sample that does not contain H. capsulatum.

23. A composition for the specific detection of an active case of histoplasmosis in a subject comprising an isolated nucleic acid molecule selected from the group consisting of: (a) a nucleic acid molecule comprising the sequence of SEQ ID NO: 24 or the complement of SEQ ID NO: 24; and (b) a fragment of SEQ ID NO: 24 consisting of 19 or more consecutive nucleotides of SEQ ID NO. 24 or the complement thereof.

24. A kit for detection of H. capsulatum comprising: (a) a container comprising an isolated nucleic acid molecule selected from the group consisting of: (i) a fragment of SEQ ID NO. 7 consisting of 20 or more consecutive nucleotides of SEQ ID NO. 7 or the complement thereof; (ii) a fragment of SEQ ID NO. 8 consisting of 20 or more consecutive nucleotides of SEQ ID NO. 8 or the complement thereof; (iii) a fragment of SEQ ID NO. 9 consisting of 19 or more consecutive nucleotides of SEQ ID NO. 9 or the complement thereof; (iv) a fragment of SEQ ID NO. 10 consisting of 20 or more consecutive nucleotides of SEQ ID NO. 10 or the complement thereof; (v) a fragment of SEQ ID NO. 11 consisting of 19 or more consecutive nucleotides of SEQ ID NO. 11 or the complement thereof; and (vi) at least one oligonucleotide selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23; wherein the isolated nucleic acid hybridizes to introns 1 or 2 of the H. capsulatum catalase A gene or introns 1, 2 or 3 of the H. capsulatum catalase P gene; and (b) at least one separate container comprising H. capsulatum DNA comprising at least one of catalase intron A or catalase P intron DNA individually or in combination, wherein the catalase A intron DNA comprises at least one of SEQ ID NO: 7 or the complement of SEQ ID NO: 7, or SEQ ID NO: 8 or the complement of SEQ ID NO: 8, and wherein the catalase P intron DNA comprises SEQ ID NO: 9 or the complement of SEQ ID NO: 9, SEQ ID NO: 10 or the complement of SEQ ID NO: 10, or SEQ ID NO: 11 or the complement of SEQ ID NO: 11.

25. The isolated nucleic acid molecule of claim 1, comprising SEQ ID NO: 7 or the complement of SEQ ID NO: 7.

26. The isolated nucleic acid molecule of claim 3, comprising SEQ ID NO: 8 or the complement of SEQ ID NO: 8.

27. The isolated nucleic acid molecule of claim 11, comprising SEQ ID NO: 9 or the complement of SEQ ID NO: 9.

28. The isolated nucleic acid molecule of claim 13, comprising SEQ ID NO: 10 or the complement of SEQ ID NO: 10.

29. The isolated nucleic acid molecule of claim 15, comprising SEQ ID NO: 11 or the complement of SEQ ID NO: 11.

Details for Patent 7,052,837

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 ⤷  Try a Trial 2021-03-13
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b For Injection 103132 ⤷  Try a Trial 2021-03-13
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b Injection 103132 ⤷  Try a Trial 2021-03-13
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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