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Last Updated: March 29, 2024

Claims for Patent: 5,447,838


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Summary for Patent: 5,447,838
Title: Protein-dye conjugate for confirmation of correct dilution of calibrators
Abstract:The present invention has multiple aspects that include an intermediate composition (i.e., a marked stock calibrator solution) for preparing diluted calibrator solutions that are marked in proportion to the amount of calibrator contained therein; a diluted (i.e., working) calibrator solution made therefrom, a series of diluted calibrator solutions that are visually colored in proportion to the concentration of calibrator therein; a method for performing a diagnostic assay that employs a series of marked calibrator solutions; a method for confirming that a stock solution of calibrator has been diluted correctly; and a method for indirectly confirming the concentration of calibrator in a working calibrator solution.
Inventor(s): Meiklejohn; Bruce (San Diego, CA), Chiapetta; Michael (San Marcos, CA)
Assignee: Hybritech Incorporated (San Diego, CA)
Application Number:07/925,513
Patent Claims:1. A composition for facilitating a determination that a stock solution containing a calibration or control material ("calibrator") dissolved therein has been diluted correctly, said composition comprising, a solution having dissolved therein:

a) a first compound ("calibrator") designated for use in calibrating an assay for an analyte of interest over a working concentration range, said calibrator being the same or substantially the same as the analyte of interest, said calibrator being present in said solution at a concentration that is substantially above the working concentration range of said analyte of interest; and

b) an identifiably effective and non-interfering amount of a second compound ("marker") dissolved therein substantially for identifying the dilution level of said stock solution over the working concentration range of said calibrator, said marker being a dye conjugated to a carrier protein, said marker having a concentration that is proportional to the concentration of said calibrator, said marker neither participating as a reactant nor as a label on a reactant in said assay for said analyte of interest.

2. The composition of claim 1 wherein the stock solution is an aqueous based solution.

3. The composition of claim 1 wherein the calibrator is a ligand or an antiligand.

4. The composition of claim 3 wherein the ratio of dye to carrier protein is within the range of about 1:1 to about 15:1.

5. The composition of claim 4 wherein the carrier protein is a mammalian serum protein.

6. The composition of claim 5 wherein the mammalian serum protein is selected from the group consisting of bovine serum albumin, human serum albumin, porcine serum albumin, sheep serum albumin, murine serum albumin, goat serum albumin, and guinea pig serum albumin.

7. The composition of claim 6 wherein the mammalian serum protein is bovine serum albumin.

8. The composition of claim 7 wherein the dye absorbs light in the visible spectrum.

9. The composition of claim 8 wherein the calibrator is selected from the group consisting of prostate specific antigen, human bone alkaline phosphatase antigen, human chorionic gonadotropin, follicle stimulating hormone, human leutenizing hormone, creatine phosphokinase MB isoenzyme, ferritin, carcinoembryonic antigen, CA-549, hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antigen, hepatitis B core antibody, hepatitis A virus antibody, hepatitis C virus antibody, the p41 antigen of HIV II, the gp120 antigen of HIV I, the p66 antigen of HIV I, the p41 antigen of HIV I, the p31 antigen of HIV I, the p24 antigen of HIV I, the p17 antigen of HIV I, and an antiligand to any one of said aforementioned antigens.

10. The composition of claims 1 or 8 wherein the dye is selected from the group consisting of Malachite Green, fluorescein, eosin, tetramethylrhodamine, phenolphthalein and erythrosin.

11. The composition of claim 10 wherein the dye is Malachite Green.

12. The composition of claim 11 wherein the ratio of dye to carrier protein is within the range from about 2.8:1 to about 7:1.

13. A series of calibrator solutions, each calibrator solution in said series having therein a predetermined concentration of a non-visible calibrator and an identifiably effective and non-interfering amount of a visible marker, said marker being a colored dye conjugated to a carrier protein, the amount of visible marker in each calibrator solution being proportional to the concentration of said calibrator, said series of calibrator solutions spanning a predetermined range of calibrator concentrations and a corresponding range of marker concentrations, whereby each solution in said series of calibrator solutions has a color intensity in proportion to the concentration of calibrator therein.

14. The series of calibrator solutions of claim 13 wherein the calibrator is a ligand or an antiligand.

15. The series of calibrator solutions of claim 14 containing from 2 to 10 calibrator solutions.

16. The series of calibrator solutions of claim 15 wherein one or more calibrator solutions in said series are capable of functioning as control solutions in an assay.

17. The calibrator solution of claims 13 or 16 wherein the calibrator is selected from the group consisting of human bone alkaline phosphatase antigen, human chorionic gonadotropin, human leutenizing hormone, human follicle stimulating hormone, ferritin, carcinoembryonic antigen, prostate specific antigen, CA-549, creatine kinase MB isoenzyme, hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antigen, hepatitis B core antibody, hepatitis A virus antibody; hepatitis C virus antibody, the p41 antigen of HIV II, the gp120 antigen of HIV I, the p66 antigen of HIV I, the p41 antigen of HIV I, the p31 antigen of HIV I, the p24 antigen of HIV I, the p17 antigen of HIV I, and an antiligand to any one of said aforementioned antigens.

18. The series of calibrator solutions of claim 16 wherein the colored dye is selected from the group consisting of Malachite Green, eosin and erythrosin.

19. The series of calibrator solutions of claim 18 wherein the carrier protein is a mammalian serum protein.

20. The series of calibrator solutions of claim 19 wherein the mammalian serum protein is a mammalian serum albumin.

21. The series of calibrator solutions of claim 20 wherein the mammalian serum albumin is selected from the group consisting of bovine serum albumin, human serum albumin, procine serum albumin, sheep serum albumin, murine serum albumin, goat serum albumin and guinea pig serum albumin.

22. The series of calibrator solutions of claim 21 wherein the mammalian serum albumin is bovine serum albumin.

23. The series of calibrator solutions of claim 22 wherein the colored dye is Malachite Green.

24. The series of calibrator solutions of claim 23 wherein the ratio of dye to protein is within the range from about 2.8:1 to about 7:1.

25. A series of calibrator solutions for calibrating a diagnostic test kit, said series spanning a predetermined range of calibrator concentrations, each solution in said series having a predetermined concentration of calibrator therein and a second predetermined and non-interfering concentration of a colored marker therein, said marker being a colored dye conjugated to a carrier protein, said concentration of colored marker in each solution in said series being proportional to the concentration of calibrator therein, each solution in said series having a color intensity in proportion to the concentration of calibrator therein such that said series spans a range of color intensity in proportion to the range of calibrator concentrations therein.

26. The series of calibrator solutions of claim 25 wherein said working calibrator solutions are aqueous based.

27. The series of calibrator solutions of claim 26 wherein the calibrator is a ligand or an antiligand.

28. The series of calibrator solutions of claim 27 wherein the ratio of dye to carrier protein is within the range from about 1:1 to about 15:1.

29. The series of calibrator solutions of claim 28 wherein the carrier protein is a mammalian serum protein.

30. The series of calibrator solutions of claim 29 wherein the mammalian serum protein is selected from the group consisting of bovine serum albumin, human serum albumin, porcine serum albumin, sheep serum albumin, murine serum albumin, goat serum albumin, and guinea pig serum albumin.

31. The series of calibrator solutions of claims 23 or 25 wherein the calibrator is selected from the group consisting of prostate specific antigen, human bone alkaline phosphatase antigen, human chorionic gonadotropin, follicle stimulating hormone, leutenizing hormone, creatine phosphokinase MB isoenzyme, ferritin, carcinoembryonic antigen, CA-549, hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antigen, hepatitis B core antibody, hepatitis A virus antibody, hepatitis C virus antibody, the p41 antigen of HIV II, the gp120 antigen of HIV I, the p66 antigen of HIV I, the p41 antigen of HIV I, the p31 antigen of HIV I, the p24 antigen of HIV I, the p17 antigen of HIV I and an antiligand to any one of said aforementioned antigens.

32. The series of calibrator solutions of claim 30 wherein the mammalian serum protein is bovine serum albumin.

33. The series of calibrator solutions of claims 32 or 29 wherein the dye is selected from the group consisting of Malachite Green, fluorescein, eosin, phenolphthalein, tetramethylrhodamine, and erythrosin.

34. The series of calibrator solutions of claim 33 wherein the dye is Malachite Green.

35. The series of calibrator solutions of claim 34 wherein the ratio of dye to protein is within the range from about 2.8:1 to about 7:1.

36. A method for performing a diagnostic assay for an analyte of interest, the method comprising the steps of:

a. providing a series of calibrator solutions spanning a predetermined range of calibrator concentrations, each solution in said series having a predetermined concentration of calibrator therein, said calibrator being the same or substantially the same as the analyte of interest;

b. aligning the series of calibrator solutions in an ascending or descending order based upon the concentration of a calibrator material contained therein, each calibrator solution in said series being characterized in that it further contains a visible and non-interfering marker therein in proportion to the concentration of calibrator material contained therein, said marker being a colored dye conjugated to a carrier protein;

c. viewing the color of the aligned series of calibrator solutions for non-reversing ascent or descent to assure that the calibrator solutions are in proper alignment for pipetting and/or sampling;

whereby a reversal in the ascent or descent of the color in the aligned series of calibrator solutions would indicate misalignment in the assay; and

d. performing a diagnostic assay using said series of calibrator solutions.

37. A process for confirming the correct dilution of a stock solution containing a calibration or control material ("calibrator") comprising the steps of:

a. combining an identifiably effective and non-interfering amount of a marker and a predetermined quantity of a calibrator to form a marked stock calibrator solution having a first concentration of said marker and a second concentration of said calibrator, said marker being a dye conjugated to a carrier protein;

b. calculating a proportion between the concentration of the marker and the concentration of the calibrator in the marked stock calibrator solution;

c. diluting the marked stock calibrator solution or a portion thereof by a predetermined amount to produce a diluted calibrator solution wherein said proportion is substantially maintained, said diluted calibrator solution having a first expected concentration of said marker that is associated with a first expected physical parameter and further having a second expected concentration of said calibrator therein;

d. measuring an actual physical parameter of the diluted calibrator solution, the actual physical parameter being proportional to the actual concentration of the marker therein;

e. comparing the actual physical parameter or a derivative thereof to the first expected physical parameter or a derivative thereof respectively to confirm that the diluting step was performed correctly.

38. The process of claim 37 wherein the marked stock calibrator solution is an aqueous based solution.

39. The process of claim 38 wherein the calibrator is a ligand or an antiligand.

40. The process of claim 39 wherein the ratio of dye to carrier protein is within the range from about 1:1 to about 15:1.

41. The process of claim 40 wherein the carrier protein is a mammalian serum protein.

42. The process of claim 41 wherein the mammalian serum protein is selected from the group consisting of bovine serum albumin, human serum albumin, porcine serum albumin, sheep serum albumin, murine serum albumin, goat serum albumin, and guinea pig serum albumin.

43. The process of claims 39 or 42 wherein the calibrator is selected from the group consisting of prostate specific antigen, human bone alkaline phosphatase antigen, human chorionic gonadotropin, follicle stimulating hormone, human leutenizing hormone, creatine phosphokinase MB isoenzyme, ferritin, carcinoembryonic antigen, CA-549, hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antigen, hepatitis B core antibody, hepatitis A virus antibody, hepatitis C virus antibody, the p41 antigen of HIV II, the gp120 antigen of HIV I, the p66 antigen of HIV I, the p41 antigen of HIV I, the p31 antigen, the p24 antigen of HIV I, the p17 of HIV I, and an antiligand to any one of said aforementioned antigens.

44. The process of claim 42 wherein the mammalian serum protein is bovine serum albumin.

45. The process of claims 37 or 44 wherein the dye is selected from the group consisting of Malachite Green, fluorescein, eosin, phenolphthalein, and erythrosin.

46. The process of claim 44 wherein the dye absorbs light in the visible spectrum.

47. The process of claim 46 wherein the dye is a triphenylmethyl type dye.

48. The process of claim 46 wherein the dye is Malachite Green.

49. A process for confirming that the actual concentration of a calibration or control material ("calibrator") is near its expected concentration in a solution that has been diluted from a stock solution comprising the steps of:

a. combining an identifiably effective and non-interfering amount of marker ("the marker") and a predetermined quantity of a calibrator to form a marked stock calibrator solution having a first concentration of the marker and a second concentration of the calibrator, said marker being a dye conjugated to a carrier protein;

b. calculating a proportion between the concentration of the marker and the concentration of the calibrator in the marked stock calibrator solution;

c. diluting the marked stock calibrator solution or a portion thereof by a predetermined amount to produce a diluted calibrator solution wherein the proportion is substantially maintained, the diluted calibrator having a first expected concentration of the marker that is associated with a first expected physical parameter and further having a second expected concentration of the calibrator therein;

d. measuring an actual physical parameter of the diluted calibrator solution, the actual physical parameter being proportional to the actual concentration of the marker therein;

e. confirming that the actual concentration of calibrator in the diluted calibrator solution, as calculated from said actual physical parameter, is substantially near its expected concentration.

50. The process of claim 49 wherein the stock solution is an aqueous based solution.

51. The process of claim 42 wherein the calibrator is a ligand or an antiligand.

52. The process of claim 51 wherein the calibrator is selected from the group consisting of prostate specific antigen, human bone alkaline phosphatase antigen, human chorionic gonadotropin, follicle stimulating hormone, human leutenizing hormone, creatine phosphokinase MB isoenzyme, ferritin, carcinoembryonic antigen, hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antigen, hepatitis B core antibody, hepatitis A virus antibody, hepatitis C virus antibody, the p41 antigen of HIV II, the gp120 antigen of HIV I, the p66 antigen of HIV I, the p41 antigen of HIV I, the p31 antigen of HIV I, the p24 antigen of HIV I, the p17 antigen of HIV I, and an antiligand to any one of said aforementioned antigens.

53. The process of claim 52 wherein the ratio of dye to carrier protein is within the range of from about 1:1 to about 15:1.

54. The process of claim 53 wherein the carrier protein is a mammalian serum protein.

55. The process of claims 49 or 54 wherein the mammalian serum protein is selected from the group consisting of bovine serum albumin, human serum albumin, porcine serum albumin, sheep serum albumin, murine serum albumin, goat serum albumin and guinea pig serum albumin.

56. The process of claim 55 wherein the mammalian serum protein is bovine serum albumin.

57. The process of claim 56 wherein the dye absorbs light in the visible spectrum.

58. The process of claim 57 wherein the dye is selected from the group consisting of Malachite Green, fluorescein, eosin, tetramethylrhodamine, and erythrosin.

59. The process of claim 58 wherein the dye is Malachite Green.

60. The process of claim 59 wherein the ratio of Malachite Green to bovine serum albumin is within the range from about 2.8:1 to about 7:1.

Details for Patent 5,447,838

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 01/15/1974 ⤷  Try a Trial 2040-01-28
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 12/27/1984 ⤷  Try a Trial 2040-01-28
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 02/15/1985 ⤷  Try a Trial 2040-01-28
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 02/16/1990 ⤷  Try a Trial 2040-01-28
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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