Immunovative Therapies, Ltd.’s unique Mirror EffectTM is heavily protected by an extensive portfolio of multiple issued United States and foreign patents, with many more pending. The complex Mirror Effect TM technology was patent protected by breaking it down into key processes and then broadening the applications within each of these steps. Immunovative Therapies, Ltd. is exploring many additional uses of the unique Mirror EffectTM technology (such as use in HIV positive patients) and will promptly pursue patent protection for these new applications.
Goswitz and Sawicki, in their 2012 publication, describe how Immunovative Therapies, Ltd.’s patent portfolio may define an entirely new field of immune-based medicine leading to a new industry.
The Mirror EffectTM is a “Host-Versus-Graft” and subsequent “Host-Versus-Tumor” response that is precipitated by the infusion of AlloStim® cells that are differentiated, expanded, activated, and infused using proprietary methods.
AlloStim® cells are derived from immune cells purified normal blood donors. These immune cells are then incubated in bioreactors and caused to expand and change into an intermediate product called T-StimTM cells.
T-StimTM cells are uniquely prepared T-cells that await activation and infusion. T-StimTM is converted into AlloStim® in a final cell culture process. AlloStim® is the final activated T-cell product that is suspended in media suitable for human infusion and administered to a patient to produce the Mirror EffectTM.
The Mirror EffectTM’s broad patent protection is best conceptualized by dividing it into the following categories as defined by Goswitz and Sawicki
1) Patents involving T-StimTM
2) Patents involving preparation and delivery methods for T-StimTM and AlloStim®
3) Patents involving AlloStim®
Each of these three categories of patents has a “parent” application that defines the group and serves as the basis for subsequent patents within the group. Within each category, the additional patents introduce more claims that overlap with the parent application, thereby producing broader and much more extensive protection of the proprietary Mirror EffectTM technology. Additional patents involving clinical applications of AlloStim® are also described.
US Patent No. 7435592 – Compositions for allogeneic cell therapy - parent application that defines the unique T-StimTM production process. T-cells are isolated from normal donor blood. The T-cells are then cultured in the presence of anti-CD3 and anti-CD28 monoclonal antibodies (mAbs) that are conjugated to a biodegradable tissue-like matrix. During this 9-day culture process the mAbs supply the T-cells with maturation signals, thus transforming them into T-StimTM cells with unique immunomodulatory characteristics. The cultured T-StimTM cells are then divided into single doses and stored in liquid nitrogen. The final T-StimTM preparation can be widely distributed and stored for long periods.
US Patent No. 7943180 – Method for stimulating a host immune system by administering an allogeneic cell material- describes the administration of the T-StimTM preparation to an intentionally mismatched host that has not received prior immunosuppressive therapy. This unique process is the mirror opposite of the allogeneic bone marrow transplant, where a genetically matched host is given a foreign preparation after receiving immunosuppressive chemotherapy. This patent also further defines the phenotypic identity of the T-StimTM cells and the cytokines they express.
US Patent No. 8273377 – Method for allogeneic cell therapy - defines T-StimTM’s intended target patient population, namely those with hematologic malignancies, those with solid tumors and solid tumor metastases, or those with viral infections. This patent also defines the necessary degree of mismatch between T-StimTM donor and recipient (50%) as well as additional T-StimTM cell characteristics.
US Patent No. 8354276 – T-cell compositions that elicit type I cytokine response - characterizes the T-StimTM product as predominately CD4+ Th1 cells of a specific phenotype that are crosslinked via CD3/CD28 molecules, suspended in an infusion media, and stored in a syringe or collapsible container.
US Patent No. 8728534 – Method for stimulating a host immune system - describes the administration of previously defined T-StimTM cells to an immunocompetent host with a malignancy. The host immune system rejects the T-StimTM cells and in the process mounts an effective immune response.
US Patent No. 8298587 – Method for stimulating a therapeutic immune effect in a patient - further defines timing of T-StimTM activation prior to infusion into a patient, and the different routes of administration.
US Patent No. 9301977 – Method for allogeneic cell therapy- further characterizes the T-StimTM product as an allogeneic transplant into a host that provides anti-tumor effect without graft-versus-host-disease (GVHD) toxicity.
US Patent No. 9352001 – Method for stimulating a host immune system - describes more specifically the cytotoxic action of the T-StimTM cells. T-StimTM activates and upregulates the cytotoxic activity of the host’s natural killer (NK) cells and generates tumor-associated-antigen (TAA) shedding by apoptosis of the tumors. The apoptosis is specifically induced by binding of Fas with FasL and by TRAIL ligand and TRAIL-R.
US Patent No. 7678572 – Methods for preparing T-cells for cell therapy - parent patent of the group - describes the specific crosslinking technique between biodegradable spheres and T-cells. This unique crosslinking method is a critical part of the 9-day process in which T-cells are activated and prompted to differentiate into T-StimTM cells. A first material (an antibody, such as polyclonal goat or sheep anti-mouse antibody) is applied to the surface of the biodegradable sphere. A second agent, also an antibody, is bound to the surface of the T-cells and crosslinks with the antibodies on the sphere. During a 9-day culture process, additional and different second agents (the second and third arrays) are sequentially added. These additional second agents also crosslink with the T-cells and guide the differentiation process. The characteristics of the activated T-cells can be manipulated based on which second agents are used.
US Patent No. 7592431 – Biodegradable T-cell activation device - describes the biodegradable sphere and first and second materials used in the activation process. The biodegradable sphere’s specific chemical composition is described. The first material is identified as a polyclonal or monoclonal antibody and is attached to the spheres with glutaraldehyde. The second linking agents include anti-CD3 and anti CD28 monoclonal antibodies which can bind to chemokine receptors and which are specific for one or more T-cell surface molecules.
US Patent No. 7956164 – Device for enhancing immunostimulatory capabilities of T-cells - more completely defines the materials or device used in the activation process. It characterizes the components of each successive array of second materials and indicates that they consist of antibodies that have specificity to a T-cell surface moiety. It also describes the first material as being an antibody, and the support as being a nontoxic biodegradable support, such as a microsphere, that degrades in 14 days or less. It also provides a list of antibodies from which the second agents are chosen. Lastly, it states that the first material may crosslink two or more arrays of multiple second materials, with each array being added at a later time in the T-cell response.
US Patent No. 8012750 – T-cell activation device - details more of the precise method of T-cell activation. It focuses on the attachment of the first agent to the biodegradable support. The first agent is bound to the support (biodegradable sphere) with glutaraldehyde and is attached prior to mixing the support with the T-cells. A blocking agent is also applied to the first material to prevent absorption of undesirable proteins.
US Patent No. 8071374 – Methods for preparing T-cells for cell therapy - further defines the T-cell activation method and states that the T-cells produced (T-StimTM cells) are to be used in cell therapy to either stimulate or suppress immunity. The patent focuses on the sequential application of the second agents, stating that the process of adding an array of second agents, along with the spheres coated with the first agent, is repeated multiple times – each time with a different second agent. Characteristics of the second agent are also further defined. The second agents include anti-chemokine receptors of the C-C and C-X-C categories with one or more of the following - CCR1, CCR2, CCR3, CCR4, CCR5 and CXCR3.
US Patent No. 8313944 – Methods to cause differentiation of T-cells for use in cell therapy - more specifically describes how sequential arrays of different antibodies (rather than “agents” or “materials”) are applied to the T-cells, along with the universal crosslinking agent. It also states that the described crosslinking technique is for the purpose of causing T-cell differentiation, and that the differentiated T-cells (T-StimTM cells) are to be used to either stimulate or suppress immunity.
US Patent No. 8883974 – Device for enhancing immunostimulatory capabilities of T-cells - builds upon patent #7956164. It similarly defines the materials or device used in the T-cell activation process, but includes a description of the anti-chemokine receptors as being of the C-C and C-X-C categories with one or more of the following - CCR1, CCR2, CCR3, CCR4, CCR5 and CXCR3.
US Patent No. 7402431 – T-cell therapy formulation - parent patent describing the concept of AlloStim® formulation. T-cells are prepared with a first agent (e.g., CD3 and CD28) that primes them for activation when crosslinked with a second agent (e.g. anti-CD3 and anti-CD28 mAbs). The prepared T-cells are, in practice, T-StimTM cells. The T-cells are then activated by exposure to the second agent attached to a biodegradable support. This formulation (T-StimTM cells + the biodegradable support), now AlloStim®, is suspended in an infusion solution in a concentration of at least 107 cells per mL. The AlloStim® is then packaged in a container suitable for infusion into a patient.
US Patent No. 8076135 – Method of preparing a treatment effective amount of allogeneic T-cells - further defines the methods of AlloStim® packaging and routes of administration. This patent states that AlloStimTM is stored in a collapsible container, such as a syringe or IV infusion bag, and may be delivered subcutaneously, intramuscularly, intradermally, intravenously, or intra-arterially.
US Patent No. 8778678 – Composition of activated CD4 cells - more specifically characterizes the composition of AlloStim®. This patent specifies that the activated CD4 cells (T-StimTM cells) are Th1 cells. These cells are activated by crosslinking of CD3 and CD28 using anti-CD3 and anti-CD28 mAbs that are immobilized on biodegradable nano or micro particles less than 1 micron in diameter. Microspheres less than 1 micron across can be injected into the body by conventional means (e.g. intravenously).
US Patent No. 8785188 – Method to formulate T-cells - defines a particular solution and route of administration of AlloStim®. The AlloStim® cells are suspended in a PlasmaLyte A solution supplemented with human serum albumin and are stored in a syringe. The PlasmaLyte A/albumin formulation was found to minimize exposure of the AlloStim® to foreign proteins responsible for toxicity.
US Patent No. 8679841 – Allogeneic cell compositions with cross-linked CD3/CD28 - further defines AlloStim®‘s composition and packaging. AlloStim® is comprised of predominately Th1 CD4+ cells that have been activated by CD3/CD28 crosslinking. The composition is stored in a syringe or other collapsible container.
US Patent No. 8865224 – Allogeneic cellular immunotherapy for opportunistic infection - describes the use of AlloStim® to treat Invasive Aspergillosis in the immunocompromised host who has received a prior allogeneic bone marrow transplant. The AlloStim® administration results in a dominant Th1 immune response with enhanced dendritic cell IL-12 production. The AlloStim® cells are irradiated prior to administration in order to prevent a graft-vs-host response.
US Patent No. 7972594 – Ablative immunotherapy - outlines a technique where the patient is first primed with an intradermal or intravenous dose of AlloStim®. Then, an accessible tumor is ablated and the AlloStim® is injected into the necrotic lesion. This creates an accelerated response where host dendritic cells respond to the necrotic tissue, mature, and migrate to the lymphatic system to stimulate systemic immunity. Tumor ablation with subsequent AlloStim® infusion greatly enhances the anti-tumor response.
US Patent No. 9233156 – Induction of IL-12 using immunotherapy – describes materials and methods in which AlloStim® is administered to stimulate production of elevated but non-toxic levels of IL-12. Sequential doses of AlloStim® are administered intravenously, intratumorally, and/or intradermally until endogenous IL-12 levels reach at least 20,000 pg/ml. Patent also describes AlloStim® administration combined with tumor ablation to reach endogenous IL-12 levels of at least 8000 pg/ml.
US Patent No. 9272001 – Ablative immunotherapy– describes the composition of the material used in the previously described ablative immunotherapy technique. The material used is a combination of tumor antigens (generated by necrosis) and activated T-cells (AlloStim®). Further characterizes this material as a vaccine, since it stimulates a delayed-type hypersensitivity response to the allogeneic cells and thus acts as an adjuvant to the stimulation of systemic anti-tumor immunity.
US Patent No. 9320794 – Ablative immunotherapy – specifies ablative technique as cryoablation. Patent describes generated antigens as combinations of tumor antigens and heat shock proteins. Also characterizes allogeneic cells (AlloStim®) as expressing high levels of Type 1 cytokines as well as a high density of CD40L, TRAIL, and FasL combinations.
Immunovative Therapies, Ltd. also has an extensive portfolio of United States, international and foreign patents and pending patent applications:
5 Japanese, 3 Israeli, 1 Canadian, 1 Chinese, and 1 European.
United States, Foreign and International Patent Applications
20 United States, 14 International, 14 Israeli, 13 European, 12 Japanese, 11 Canadian, 7 Chinese, 7 Hong Kong, 7 Indian, 6 Korean, 5 Australian, 5 Brazilian, 5 Philippine, 4 Singapore, 4 Thailand, 4 Taiwan, 1 Vietnamese, and 1 Indonesian.