Chemistry: molecular biology and microbiology – Virus or bacteriophage – except for viral vector or... – Inactivation or attenuation; producing viral subunits
Reexamination Certificate
1999-01-15
2001-07-31
Lankford, Jr., Leon B. (Department: 1651)
Chemistry: molecular biology and microbiology
Virus or bacteriophage, except for viral vector or...
Inactivation or attenuation; producing viral subunits
C435S001100, C435S002000, C435S173300, C435S235100, C422S021000
Reexamination Certificate
active
06268200
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to biotherapeutics and, more particularly, to viral attenuation in biotherapeutics.
BACKGROUND OF THE INVENTION
Biotherapy refers to the treatment of diseases with materials produced by living organisms. These materials are referred to as “biotherapeutics.” Exemplary biotherapeutics can include components derived from the fractionation of blood plasma which are then administered to a patient. Factor VIII is a well known biotherapeutic for treating patients with Hemophilia A. However, because such biotherapeutics are collected from living organisms, such as humans, transgenic animals, plants or immortalized cells, there is risk of contamination by viruses and other nucleic acid-based pathogens.
A virus is any of a large group of infectious submicroscopic agents ranging from about 10 nanometers to about 250 nanometers in diameter and composed of a protein sheath surrounding a nucleic acid core. Viruses are capable of infecting animals, plants and bacteria and are characterized by a total dependence on living cells for reproduction and by a lack of independent metabolism. Exemplary viruses transmissible by biotherapeutics such as blood products include, but are not limited to, Hepatitis A; Hepatitis B; Hepatitis C; Hepatitis D; Human immunodeficiency virus; and Parvovirus.
Viral control strategies include various procedures to screen biotherapeutics or their respective source materials for viruses and to remove or attenuate viruses (both known and unknown) contained therein. Known methods for attenuating viruses include filtration, chemical treatment, heat treatment, and photodynamic treatment. Filtration involves the use of membranes having the ability to selectively remove materials from fluids based on size. The separation and capture of a virus from a biotherapeutic may be accomplished by passing the biotherapeutic in a liquid state through a membrane. A large virus (e.g., Hepatitis A) can be separated from a small protein (e.g., Antithrombin III, 68,000 M.V.) by a process referred to as nanofiltration if there is no specific interaction of the viruses with the individual therapeutic protein. Specific absorption of the biotherapeutic by the membrane materials can also preclude the use of nanofiltration.
Unfortunately, small viruses, such as Parvovirus and Hepatitis G, have sizes similar to that of certain proteins and are, therefore, difficult to separate from these proteins via filtration. For example, human Parvovirus has a diameter of about 260 angstroms and contains a nucleic acid of about 5,600 base pairs and capsid protein. Fibrinogen is a high-molecular weight plasma protein with significant molecular asymmetry which possesses a hydrodynamic size which can approach the size of Parvovirus and, thus, preclude removal by filtration. Similarly, factor VIII-von Willebrand factor complex is quite large which can make the separation from small viruses by nanofiltration difficult.
Chemical treatment of biotherapeutics involves subjecting a virus contained within a biotherapeutic to a chemical or combination of chemicals. For example, solvent/detergent may be used to disrupt the lipid envelope surrounding the nucleic acid core of viruses. Unfortunately, not all viruses are lipid enveloped. Parvovirus is an example of a virus that is not lipid enveloped. Accordingly, chemical treatment with solvent and detergent is an ineffective viral attenuation method for viruses like Parvovirus and Hepatitis A. Another disadvantage of chemical treatment is that the chemicals, or resultant derivatives thereof, generally need to be removed during the manufacturing process, or demonstrated by pre-clinical and clinical studies to be innocuous, before a biotherapeutic can be administered to a patient.
Photodynamic treatment involves the use of dyes and light. A disadvantage of photodynamic treatment is it may be difficult to find a dye that is reasonably non-toxic and that has a suitable absorption spectrum. Furthermore, as with chemical treatment, the dye and photolytic products generally need to be removed from a biotherapeutic during the manufacturing process, or demonstrated by pre-clinical and clinical studies to be innocuous, before the biotherapeutic can be administered to a patient.
Heat treatment of biotherapeutics for viral attenuation is a useful, if somewhat limited, approach to viral attenuation. Heat treatment can be advantageous over chemical treatment because there are no residual chemicals to be removed. Application of heat to a biotherapeutic in the liquid state, generally referred to as pasteurization, has been applied to albumin and plasma protein fractions with considerable success. Unfortunately, biotherapeutics are often prepared and packaged in a dry (lyophilized) state. Heat treatment for viral attenuation relies on a differential effect of heat on the virus as opposed to protein. While there is limited success with heat treatment in the solid state, there are some situations where heat may be ineffective. For example, many viruses (such as Parvovirus) can withstand rather high temperatures. The temperatures at which viruses such as Parvovirus can be attenuated may also damage or kill a biotherapeutic.
Methods for heating biological materials for various reasons with single frequency microwave energy are known. For example, U.S. Pat. No. 4,250,139 to Luck et al. discloses a method of exposing dried protein to a lethal dose of single frequency microwave radiation for a time sufficient to provide a desired degree of decontamination. U.S. Pat. No. 5,073,167 to Carr et al. discloses a method of uniformly heating liquid blood and other intravenous fluids using single frequency microwave energy.
Unfortunately, it is difficult to achieve uniform distribution of microwave energy within a microwave furnace using single frequency microwave radiation. Hot spots may develop within a microwave furnace cavity which can damage a biotherapeutic being processed. In addition, repeatability of treatment time and results may not be achievable using single frequency microwave radiation without positioning a biotherapeutic in the same position and orientation within a microwave furnace cavity.
SUMMARY OF THE INVENTION
It is, therefore, an object of the present invention to provide a viral attenuation method that produces no contamination and that can be performed on a biotherapeutic in a dry (e.g., lyophilized) state.
It is another object of the present invention to provide a viral attenuation method that can be performed on a biotherapeutic within a final packaged state without requiring additional processing or packaging steps to provide a lyophilized virus-free biotherapeutic.
It is another object of the present invention to provide a viral attenuation method that can be performed on a biotherapeutic without damaging the biotherapeutic or components thereof.
It is another object of the present invention to provide a viral attenuation method that can be used to treat large quantities of a biotherapeutic simultaneously.
It is another object of the present invention to provide a viral attenuation method that can effectively irradicate Parvovirus, Hepatitis G, Hepatitis B, and other viruses, known and unknown.
These and other objects of the present invention are provided by a method of attenuating a virus contained within a dried (e.g., lyophilized) biotherapeutic, such as a blood product, sealed within a microwave permeable container without harming the biotherapeutic and without exposing the biotherapeutic to additional viruses, by subjecting the container and biotherapeutic therewithin to variable frequency microwave energy. The container and biotherapeutic therewithin are preferably swept with at least one range of microwave frequencies. Each range of microwave frequencies has a central frequency selected to disrupt a virus without harming the biotherapeutic. Disruption may include breaking a strand of a nucleic acid helix, separating multiple strands of a nucleic acid helix, and other types of damage that may be inflicted upon
Kingdon Henry Shannon
Lundblad Roger Lauren
Reisner Howard M.
Tucker Denise A.
Lambda Technologies Inc.
Lankford , Jr. Leon B.
Myers Bigel & Sibley & Sajovec
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