Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-12-11
2004-02-24
Kemmerer, Elizabeth (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C435S069600, C435S325000, C435S252300, C435S320100, C530S397000, C530S399000, C536S023500, C424S085100
Reexamination Certificate
active
06696411
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to recombinant canine erythropoietin and its use in methods for providing erythropoietin therapy to a dog or cat.
BACKGROUND OF THE INVENTION
Erythropoietin is a glycosylated protein that stimulates red blood cell production. It is produced by interstitial and capillary endothelial cells in the renal cortex and transported in the blood to the bone marrow. Koury et al., “Localization of Erythropoietin Synthesizing Cells in Murine Kidneys by in situ Hybridization,”
Blood
, 71:524-527 (1988); Eschbach, “The Anemia of Chronic Renal Failure: Pathophysiology and the Effects of Recombinant Erythropoietin,”
Kidneys Int
., 35:134-148(1989). The hormone's biological activity involves a direct receptor-mediated stimulation of the maturation and replication of late erythroid progenitor cells, proerythroblasts, and erythroblasts. Mufson et al., “Binding and Internalization of Recombinant Human Erythropoietin in Murine Erythroid Precursor Cells,”
Blood
, 69:1485-1490 (1987); Krantz et al., “Specific Binding of Erythropoietin to Spleen Cells Infected with the Anemia Strain of Friend Virus,”
Proc. Natl. Acad. Sci. USA
, 81:7574-7578 (1984). Synthesis of erythropoietin is stimulated in response to tissue hypoxia mediated by intracellular aerobic metabolism. Erslev, “Physiologic Controls of Red Cell Production,”
Blood
, 10:954-959 (1955). The primary protein structure of human erythropoietin includes a 27 amino acid signal peptide and a 166 amino acid mature protein. Lin et al., “Cloning and Expression of the Human Erythropoietin Gene,”
Proc. Natl. Acad. Sci. USA
, 82:7580-7584 (1985). Predicted molecular weight of 18.4 kDa is substantially less than the 32-34 kDa observed when erythropoietin is purified directly from blood or urine. The difference is due to glycosylation, three N-linked sugar chains at Asn 24, 38, and 83, and an O-linked mucin-like moiety at Ser 126. Lai et al., “Structural Characterization of Human Erythropoietin,”
J. Biol. Chem
., 261:3116-3121 (1986). Compared to human, the amino acid sequences of mouse and monkey erytlhropoietin are 80 and 92% identical, respectively. McDonald et al., “Cloning, Sequencing, and Evolutionary Analysis of the Mouse Erythropoietin Gene,”
Molecular and Cellular Biology
, 6:842-848 (1986): Shoemaker et al., “Murine Erythropoietin Gene: Cloning, Expression, and Human Gene Homology,”
Molecular and Cellular Biology
, 6:849-858 (1986); Lin et al., “Monkey Erythropoietin Gene: Cloning, Expression and Comparison with the Human Erythropoietin Gene,”
Gene
, 44:201-209 (1986). The basic erythropoietin gene structure, five exons and four introns, is conserved.
Recombinant human erythropoietin (rhEPO) synthesized in Chinese Hamster Ovary (CHO) cells is produced commercially (Epogen®, Amgen. Inc. Thousand Oaks, Calif.) and widely used to support red blood cell production in people suffering from anemia secondary to chronic renal disease. Eschbach, “The Anemia of Chronic Renal Failure: Pathophysiology and the Effects of Recombinant Erythropoietin.”
Kidney Int
., 35:134-148 (1989); Eschbach et al., “Treatment of the Anemia of Progressive Renal Failure with Recombinant Human Erythropoietin,”
N. Engl. J. Med
., 321:158-163 (1989). Although the pathogenesis of the anemia is multifactorial, compensatory failure by the bone marrow to replace red blood cells largely involves a loss of functional renal tissue and a drop in endogenous erythropoietin production. Eschbach, “The Anemia of Chronic Renal Failure: Pathophysiology and the Effects of Recombinant Erythropoietin,”
Kidney Int
., 35:134-148 (1989); King et al., “Anemia of Chronic Renal Failure in Dogs,”
J. Vet. Int. Med
., 6:264-270 (1992). Synthesis of rhEPO for clinical use is restricted to eukaryotic cells due to the requirement of post-translational glycosylation for in vivo stability and bioactivity of the hormone. Takeuchi et al., “Structures and Functional Roles of the Sugar Chains of Human Erythropoietins,”
Glycobiology
, 1:337-346 (1991). Devoid of sugars or even the terminal sialic acid residues, erythropoietin is rapidly cleared and metabolized by the liver. Spivak et al., “The in vivo Metabolism of Recombinant Human Erythropoietin in the Rat,”
Blood
, 73:90-99 (1989).
Nonregenerative anemia, characterized by an inadequate production of new red blood cells, is a frequent and serious complication of kidney failure, certain types of cancer, and other chronic diseases in companion animals.
Chronic renal failure is a progressive and irreversible deterioration of kidney function that is a common and frustrating clinical problem in veterinary medicine. Although usually considered a disease of older animals, chronic renal failure is also encountered congenitally as familial renal disease (e.g., in the Norwegian elkhound, Cocker spaniel, Samoyed, Doberman pinscher, Lhasa apso, Shih Tzu, golden retriever) (Finco, “Congenital, Inherited and Familial Renal Diseases,” In:
Canine and Feline Nephrology and Urology
. Osborne et al., (eds.), Baltimore: Williams & Wilkins, pages 471-483 (1995)) and in other young animals through nephrotoxic or infectious mechanisms. Polzin et al., “Diseases of the Kidneys and Ureters,” In:
Textbook of Veterinary Internal Medicine
, Ettinger (ed), Philadelphia: WB Saunders Company. pp. 1962-2046 (1989): Krawiec. “Renal Failure in Immature Dogs.”
J. Amer. Anim. Hosp. Assoc
. 23:101-107 (1987). Despite a poor long-term prognosis, many dogs and cats with chronic renal failure are medically managed for years with special diets, phosphate binders, and antacids. Eventually, however, this conventional therapy fails to control the clinical signs of renal failure. Cowgill et al., “Veterinary Applications of Hemodialysis.” In:
Kirk's Current Veterinary Therapy
, 12th ed., Bonagura et al., (eds.), Philadelphia: W B Saunders, pages 975-977 (1995). For these animals, intermittent hemodialysis has improved survival by decreasing the uremic toxins that accumulate during renal failure. Operational dialysis units are already available in several veterinary centers across the country, and expanded use of hemodialysis in the management of renal failure in veterinary medicine is expected.
Nevertheless, even though dialysis ameliorates the uremia in canine and feline patients, lethargy, weakness, and inappetence resulting from the anemia of chronic renal failure persist. In fact, the anemia may even be compounded by blood loss in the dialyzer. Eschbach et al., “Iron Balance in Hemodialysis Patients,”
Ann. Int. Med
., 87:710-713 (1977). Erythropoietin treatment has become an essential component of the therapy for animals receiving hemodialysis. Even with the life-threatening risk of red cell aplasia, rhEPO is used because it represents the only erythropoietin-replacement option currently available.
Lymphosarcoma (also known as lymphoma or malignant lymphoma) is a common cancer in dogs. Although the exact cause is unknown, certain breeds including Boxer, Basset hound, St. Bernard, Scottish terrier, Airedale terrier, English bulldog, and Labrador retriever have a predisposition for development of this cancer. Nelson et al.,
Essentials of Small Animal Internal Medicine
. St. Louis: Mosby-Year Book. Inc, pages 861-870 (1992). Treatment of lymphosarcoma consists of various chemotherapy protocols (typically utilizing vincristine, cyclophosphamide, doxorubicin, and prednisone) that result in high remission rates and allow survival for approximately 6-12 months.
Nonregenerative anemia is a common hematologic finding in dogs with lymphosarcoma. Nelson et al.,
Essentials of Small Animal Internal Medicine
. St. Louis: Mosby-Year Book, Inc, pages 861-870 (1992); Lucroy, et al., “Anaemia Associated with Canine Lymphoma,”
Comp. Haematol. Int'l
8:1-6 (1998). The anemia may be encountered during the initial diagnostic evaluation, or may develop during chemotherapy. Similarly, human cancer patients are often anemic. Miller et al., “Decreased Erythropoietin Response in Patients with the Anemia of Cancer.”
N. Engl. J. Med
., 322:1689
Cornell Research Foundation Inc.
DeBerry Regina M.
Kemmerer Elizabeth
Nixon & Peabody LLP
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