PATENTS

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.

Patents Describing T-Stim™ Cell Formulation and Usage

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.

Patents Involving Preparation and Delivery of T-Stim™ and AlloStim®

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.

Patents Describing AlloStim® Formulation and Usage

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.

Patents Involving Clinical Applications of AlloStim®

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.

International and Foreign Patents and Patent Applications

Immunovative Therapies, Ltd. also has an extensive portfolio of United States, international and foreign patents and pending patent applications:

Foreign Patents

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, 13 Japanese, 10 Canadian, 7 Chinese, 7 Hong Kong, 7 Indian, 6 Korean, 5 Australian, 5 Brazilian, 5 Philippine, 5 Taiwan, 4 Singapore, 4 Thailand, 1 Vietnamese, and 1 Indonesian.

Full List of Granted Patents

Serial Number Country Title Status Date Granted Patent No
11/069,010 US T-Cell Therapy Formulation Granted 22/07/08 7402431
10/838,454 US Compositions for Allogeneic Cell Therapy Granted 14/10/08 7435592
11/601,446 US Biodegradable T-Cell Activation Device and Method Granted 22/09/09 7592431
11/066,133 US Methods for Preparing T-Cells for Cell Therapy Granted 16/03/10 7678572
12/172,594 US A Method for Stimulating a Host Immune System by Granted 17/05/11 7943180
12/687,281 US Device for Enhancing Immunostimulatory Capabilities of T-Cells Granted 07/06/11 7956164
11/936,948 US Ablative Immunotherapy Granted 05/07/11 7972594
12/533,668 US Biodegradable T-Cell Activation Method Granted 06/09/11 8012750
12/817,512 US Methods for Preparing T-Cells for Cell Therapy Granted 06/12/11 8071374
12/173,330 US Method of Preparing a Treatment Effective Amount Granted 13/12/11 8076135
12/869,490 US A Method for Allogeneic Cell Therapy Granted 25/09/12 8273377
13/099,871 US Method for Stimulating a Therapeutic Immune Effect Granted 30/10/12 8298587
13/187,991 US Methods to Cause Differentiation of T-Cells Granted 20/11/12 8313944
12/909,517 US Allogeneic Cell Compositions that Elicit Type I Granted 15/01/13 8354276
13/596,142 US A Method for Allogeneic Cell Therapy Granted 25/03/14 8679841
13/099,867 US Method for Stimulating a Host Immune System Granted 20/05/14 8728534
12/887,054 US Composition of Activated CD4 Cells Granted 15/07/14 8778678
12/887,054 US Composition of Activated CD4 Cells Granted 15/07/14 8778678
12/887,039 US Method to Formulate T-Cells Granted 22/07/14 8785188
11/251,585 US Allogeneic Cellular Immunotherapy for Invasive Pulmonary Aspergillosis (IPA) Granted 21/10/14 8,865,224
13/077,347 US A Device for Enhancing Immunostimulatory Capabilities of T-Cells Granted 11/11/14 8883974
13/581745 US Induction of IL-12 using immunotherapy Granted 12/01/16 9233156
13/150,893 US Ablative Immunotherapy Granted 01/03/16 9272001
14/173,494 US Method for Allogeneic Cell Therapy Granted 05/04/16 9301977
13/796,171 US Ablative Immunotherapy Granted 26/04/16 9320794
14/206,785 US Method for Stimulating a Host Immune System Granted 31/05/16 9352001
14/301,700 US Method to Formulate T-Cells Granted 06/12/16 9511127
14/500,381 US Device for Enhancing Immunostimulatory Capabilities of T-Cells Granted 14/03/17 9593308
12/570,442 US Th 1 Vaccination Priming for Active Immunotherapy Granted 04/07/17 9695397
15/041642 US Method for Allogeneic Cell Therapy Granted 10/10/17 9782463
102107555  Taiwan Automated Device for A Biologic Drug Distrubtion Granted 11/01/18 I610861
12010502709 Philippines Chaperone Proteins and Allogeneic T-Cells Granted 09/05/17 1-2010-502709
1020107027043 Korea Chaperone Proteins and Allogeneic T-Cells Granted 19/12/16 10-1689210
2007-501882 Japan Cell Therapy Formulation Method and Composition Granted 30/11/12 5144250
2009-505345 Japan Allogeneic Cell Therapy for Treatment of Opportunistic Infection Granted 26/04/13 5254952
2009-536306 Japan Ablative Immunotherapy Granted 14/03/14 5498792
2011-236442 Japan Cell Therapy Formulation Method and Composition Granted 21/11/14 5649551
2011507708 Japan Chaperone Proteins and Allogeneic T-Cells Granted 13/03/15 5709264
2014-509383 Japan Methods for Handling Biological Drugs Containing Living Cells Granted 13/05/16 5934783
2014-266252 Japan Flexible Container or Syringe Granted 16/09/16 6006288
2010-232031 Japan Allogeneic Cell Therapy: Mirror Effect Granted 28/10/16 6030819
2013-241607 Japan Methods for Preparing T-Cells for Cell Therapy Granted 28/10/16 6031021
2011-530213 Japan Pre-Vaccinations in Active Immunotherapy Granted 20/12/16 6042065
2013-526060 Japan Cells Expressing TH1 Characteristics and Cytolytic Properties Allowed    
173405 Israel Compositions for Infusion Containing Ex-Vivo Prepared T-Cells  Granted 29/05/11 06/10/74
198782 Israel Biodegradable T-cell Activation Device and Methods Granted 03/01/13 198782
171850 Israel Allogeneic Cell Therapy: Mirror Effect Granted 28/05/14 171850
194667 Israel Allogeneic Cell Therapy for Treatment of Opportunistic Infection Granted 01/10/15 194667
198704 Israel Ablative Immunotherapy Granted 01/10/15 198704
212102 Israel Pre-Vaccinations in Active Immunotherapy Granted 01/10/16 212102
177404 Israel Methods for Preparing T-Cells for Cell Therapy Granted 30/03/17 177404
W-00201204692 Indonesia Methods and Compositions for Inhibiiton of Treg Cells Granted 30/03/16 IDP000040595
13111030.4 Hong Kong Methods and Compositions for Inhibition of Treg Cells Granted 29/01/16 HK1184362 
5724065.7 Europe Cell Therapy Formulation Method and Composition Granted 17/05/17 1749090
9818495.5 Europe Pre-Vaccinations in Active Immunotherapy Granted 31/05/17 2334309
12779413.9 Europe Methods for Handling Biological Drugs Containing Living Cells Granted 23/08/17 2704741
11818884.6 Europe Cells Expressing TH1 Characteristics and Cytolytic Properties Granted 22/11/17 2606125
12177732 EPO  Method for Preparing T-Cells for Cell Therapy Granted 11/05/16 2573166
6750196.5 EPO Allogeneic Cell Therapy for Treatment of Opportunistic Infection Granted 11/06/14 2003978
2009801477496 China Pre-Vaccinations in Active Immunotherapy Granted 25/03/15 ZL200980147749.6
201180019282 China Methods and Compositions for Inhibition of Treg Cells Granted 23/09/15 ZL201180019282.4
201510137977 China Th1 Vaccination Priming for Active Immunotherapy Granted 22/09/17 ZL201510137976.8
2555714 Canada Methods for Preparing T-Cells for Cell Therapy Granted 03/12/13 2555714
2530513 Canada Cell Therapy Formulation Method and Composition Granted 31/01/17 2530514
2649290 Canada Allogeneic Cell Therapy for Treatment of Opportunistic Infection Granted 04/04/17 2649290
2669315 Canada Therapeutic Compositions With Lysates and T-Cells for Tumors or Pathogen Infected Tissue Granted 12/12/17 2669315
2009242471 Australia Chaperone Proteins and Allogeneic T-Cells Granted 24/09/15 2009242471
2012250794 Australia Methods for Handling Biological Drugs Containing Living Cells Granted 18/02/16 2012250794
2011240752 Australia Methods and Compositions for Inhibition of Treg Cells Granted 10/11/16 2011240752
2011291477 Australia Cells Expressing TH1 Characteristics and Cytolytic Properties Granted 10/11/16 2011291477
2016231642 (Divisional of 2011240752) Australia Methods and Compositions for Inhibition of Treg Cells Granted 19/07/18 2016231642

SPECIALITY INFORMATION

patients


Treatment strategy designed to use the power of the human immune system to kill tumors and prevent their recurrence.
No requirement for a matched donor or chemotherapy/radiation conditioning prior to treatment.
Innovative technology – proven and non-toxic.
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Healthcare professionals


Therapeutic anti-tumor vaccine developed from core break-through technology called the "Mirror Effect™“ which opens a pathway to treating patients with metastatic cancer that have failed all available therapy options.
Elicits a GVT-like mechanism without the GVHD toxicity.
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Investors


Privately-held Israeli biopharmaceutical company spin out from Hadassah-Hebrew University Medical Center with headquarters in Jerusalem.

Over 200 individual private shareholders and grant support from the Israel Office of the Chief Scientist.
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