Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Blood
Reexamination Certificate
1999-06-25
2001-10-16
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Blood
C424S535000, C424S548000, C424S195110, C514S002600, C514S021800, C514S04400A
Reexamination Certificate
active
06303153
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an improved method of making a therapeutic composition, Product R
1
, as hereinafter defined, which contains peptides and nucleotides. The components of Product R have molecular weights not more than 14 kilodaltons (KDa).
Product R was used as synonyms of RETICULOSE in some literature. For the purpose of the present application, Product R and RETICULOSE represent two distinct products.
2 . Description of the Related Art
The concept of an antiviral agent composed of peptones, peptides, proteins and nucleic acid was originated in 1934. After some years of experimentation, such an antiviral agent was modified by using bovine serum albumin in combination with peptone, and ribonucleic acid to produce an antiviral biotic agent which is nontoxic, free from anaphylactogenic properties and is miscible with tissue fluids and blood sera. The agent used to be described as a “lipopeptide-nucleic acid compound”
2
and registered under trademark RETICULOSE® by Chemico Laboratories, Inc. Physician Desk Reference, p 651, 1960. RETICULOSE® was reported as an antiviral agent for treating a variety of human viral infections, such as influenza, herpes, hepatitis A and B. It was then assumed that RETICULOSE® acts as an antiviral agent at least by increasing leukogenesis, synthesis of antibodies and enhancing phagocytosis. RETICULOSE® was last sold in the United States in 1964.
The method of making RETICULOSE® had been kept as a trade secret by the manufacture until the issuance of U.S. Pat. No. 5,849,196, which discloses the method of making RETICULOSE®.
As disclosed in U.S. Pat. No. 5,849,196, the starting materials for making RETICULOSE® consist of, by weight, 40-50% of casein, 1-10% of blood albumin, 15-40% of beef peptone, 10-25% of RNA and 5-25% of sodium hydroxide. These starting materials are suspended in water which yields a ratio of proteins (casein, peptone and blood albumin) to water equals to about 4.3 to about 100 by weight. After an autoclaving treatment of the mixture of the starting materials, the resulting solution is filtered and pH is adjusted to approximately 8.5 and then to 7.8, after which the neutralized solution is filtered again. The pH is further adjusted to approximately 7.5 after the solution is diluted. Such process yields a mixture of peptides and nucleic acids having molecular weights in a range of approximately 1 to 25 KDa.
As taught by U.S. Pat. No. 5,849,196, the components over 15 KDa of the conventional composition of RETICULOSE® are more effective in treating viral diseases such as HIV, influenza virus, herpes simplex virus, etc. while the components in a range of approximately 1 to 15 KDa function as phagocytosis inhibitors.
However, the conventional methods suffers from several disadvantages: 1) the method does not ensure that each preparation produces the finished components having the same ratio, thereby the product is not reproducible; 2) the conventional method produces a wide range of the finished components, which makes the quality control of the preparation extremely difficult, if possible, because too many parameters need to be determined; 3) the presence of the higher molecular weight components, such as 25 KDa component, essentially peptides, increases the risk of hypersensitivity or immune reaction and renders the product less stable.
Therefore, it is desirable to have a product devoid of the deficiencies of conventional RETICULOSE® while maintaining its therapeutic properties.
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is directed to a novel therapeutic composition, Product R. Unlike RETICULOSE®, Product R is reproducible, highly stable and non-antigenic. Similar to RETICULOSE®, Product R is a wide range antiviral agent for treating viral infections such as infections of human immnunodeficiency virus (HIV), herpes simplex virus, adenovirus and papilloma virus. Surprisingly, Product R has been proven to be effective in stimulating the production of chemokines including interferon-gamma, interleukin-6 and interleukin-1 (J. Investig Med 1996; 44:347-351), the production of red blood cells (U.S. Pat. No. 5,807,839), treating basal cell carcinoma (U.S. Pat. No. 5,902,786) and treating canine distemper viral infections (U.S. Pat. No.
5,807,840).
Another object of the present invention is directed to an improved method for making the novel therapeutic composition Product R. Product R according to the present improved method comprises novel components that generate a novel UV absorption spectrum and a novel molecular weight profile. Particularly, Product R comprises molecules having molecular weights not more than 14 KDa.
A further object of the present invention is to define the components of Product R based on chemical and physical methods.
Other objects and features of the present invention will become apparent from the following detailed description considered in conjunction with the accompanying drawings. It is to be understood, however, that the drawings are designed solely for purposes of illustration and not as a definition of the limits of the invention, for which reference should be made to the appended claims. It should be further understood that the drawings are not necessarily drawn to scale and that, unless otherwise indicated, they are merely intended to conceptually illustrate the structures and procedures described herein.
REFERENCES:
patent: 5807839 (1998-09-01), Hirschman
patent: 5807840 (1998-09-01), Hirschman
patent: 5849196 (1998-12-01), Kochel
patent: 5902786 (1999-05-01), Bregman
Cooke, Stanford B., Upper Respiratory Viral Manifestations, Clinical Symposium on Viral Diseases Demonstrating the Anti-viral Biotic Properties of the Drug Reticulose (Symposium), Sep., 1960, Miami Beach, Florida, pp. 25-32.
Kosaka, K and Shimada, Y., Infectious Hepatitis, Symposium, pp. 61-74, 1960.
Kuckku, Morris E., Herpetic Diseases, Symposium, pp. 7-13, 1960.
Medoff, Lawrence R., Infectious Mononucleosis, Symposium, pp. 33-37, 1960.
Plucinski, Stanisloff J., Suspected Viral Varieties, Symposium, pp. 53-59, 1960.
Reynolds, Margaret R., Generalized Vaccinia, Symposium, pp. 5-6, 1960.
Schaeffer, Oden A., Influenza, Symposium, pp. 15-21, 1960.
Seydel, Frank, Epidemic, Asian Influenza, Symposium, pp. 23-24, 1960.
Anderson, Robert H., Encephalitis, Symposium, pp. 39-52, 1960.
Anderson, Robert H. and Thompson, Ralph M., Treatment of Viral Syndrome with a Lipoprotein-Nucleic Acid Compound (Reticulose), A Report of Five Cases, Virginia Medical Monthly, 84: 347-353, 1957.
Reynolds, Margaret R., Generalized Vaccinia Successfully Treated With Lipoprotein-Nucleic Acid Complex (Reticulose), Archives of Pediatrics, 77:421-422, 1960.
Kozima, Fumio, Osawa, Mitsuo and Oyama, Mitsuko, Animal Tests on Reticulose (“Key”), Kensan Report No. Sho 43-22, Sep. 4, 1968.
Wegryn, Stanley P., Marks, Robert A. and Baugh, John R., Herpes Gestationis, A Report of 2 Cases, American Journal of Obstetrics and Gynecology, 79:812-814, 1960.
Catterall, R.A., Lumpur, Kuala, A New Treatment of Herpes Zoster, Vaccinia And Chicken Pox, J. Roy. Coll. Gen. Practit., 1970, 19, 182.
Chinnici, Angelo A., Reticulose in Treatment Aids patients, Personal Communication to William Bregman, Jul. 6, 1992.
Cott, Rafael A., Summary of 11 Cases of Viral Infections Treated with Reticulose, Private Communication with Advance Viral Research Corp., 1992?.
Cohen, Matthew, The Efficacy of a Peptide-Nucleic Acid Solution (Reticulose) for the Treatment of Hepatitis A and Hepatitis B—a Preliminary Controlled Human Clinical Trial, J. Roy. Soc. Health, Dec., 1992, 266-270.
Mundschenk, David D., In Vitro Antiviral Activity of Reticulose vs Influenaz A, Personal Communication with William Bregman, May 1, 1990.
Resnick, Lionel, Anti-HIV in Vitro Activitiy of Two Samples of Peptide-nucleic Acid Solution, Personal Communication with Dr. Bernard Friedland, Dec. 22, 1989.
Friedland, Bernard, In Vitro Antiviral Activity of a Peptide-Nucleic Acid Solution Against the Human Immunodeficiency Virus and I
Friedland Bernard
Hirschman Shalom Z.
Advanced Viral Research Corp.
Cohen & Pontani, Lieberman & Pavane
Witz Jean C.
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