Focus of the Patent:

The technology is essentially a biochemically defined scaffold that allows controlled and directed growth of specific types of stem cells. These cells can be used for various therapeutic purposes in regenerative medicine as well as investigative models to understand molecular signaling events.

Limited Technical Details:

At the core of the technology is a scaffold referred to as a semi-interpenetrating polymer network (SIPN). This comprises of a mesh of cross-linked polymers. Entangled in the mesh are linear polymers attached to specific ligands which contain the bioactive component that promotes stem cell growth, proliferation, self-renewal and differentiated function.
One tested application has been using peptide ligands containing the amino acid sequence Arg-Gly-Asp (RGD) present in many extracellular matrix proteins, which are responsible for the signaling that produces the earlier mentioned cellular responses. Scaffolds engineered to contain these ligands have been demonstrated to precisely control neural stem cells growth and development into neurons and other types of cells in vitro. The patent claims are however wide enough to include a variety of biological ligands containing many different active amino acid sequences to produce varied effects as well as an entire range of different stem cells.

Applications and Market Potential:

The primary market that this patent focuses on is regenerative medicine which is increasingly being developed to address diseases as diverse and widespread as diabetes, cardiac failure and stroke and the mostly untapped global market potential for tissue engineering and regenerative medicine products is projected to grow at a 16.2% compound annual rate approaching $3.2 billion by 2013. Regenerative medicine needs reliable and specific sources of stem cells to engineer tissue implants. A biochemically defined matrix that can be manipulated to specifically direct and regulate self-renewal and differentiation of a heterogeneous collection of harvested stem cells can greatly benefit the bioprocess of stem cell expansion used for tissue regeneration. An immediate application of this patent is the stem cell subset involving regeneration of neural tissue and the treatment of spinal-cord injury, stroke, multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. StemCells Inc., Geron Corporation and ReNeuron are some of the companies that are on the way to marketing therapies using neural stem cells. But the patent covers a variety of stem cells and biological ligands and the range of applications can be broadened in future.
Another area where this scaffold can be marketed is the stem cell research sector. A chemically defined and characterized matrix, free of animal products allows for an in vitro cell culture system that can be used to study of the basic processes and signaling events responsible for the stem cell behaviors that result in regeneration.

Past History of Inventors:

Kevin E. Healy has founded several companies to develop materials for applications in biotechnology and regenerative medicine and has authored or co-authored more than 200 published articles, abstracts, or book chapters which emphasize the relationship between materials and the tissues they contact. He is a named inventor on numerous issued United States and international patents relating to biomaterials. He is currently a Professor in the Departments of Bioengineering and Materials Science and Engineering at the University of California at Berkeley.
David Schaffer is a Professor at UC Berkeley and Krishanu Saha is a Postdoctoral Fellow at Whitehead Institute.

In our opinion:

In studying this patent application a couple of things stand out. The demand for stem cell technology and its potential impact on regenerative medicine is large. Patented stem cell technologies have been the genesis of several successful commercial enterprises such as Osiris, Geron, Vistagen and StemCells inc. Additionally, every major pharmaceutical company has an active stem cell program. Pfizer announced in November of 2008 that it would invest in regenerative medicine and that its research would include both adult and embryonic stem cell projects. Stem cells products are being commercially developed for diseases such as type 1 diabetes, acute spinal cord injury and inflammatory bowel disease and are being pursued for such forward applications as, heart injury, and osteoarthritis in academia and in partnership with biotechnology companies, thereby allowing for a fast growing market.
However what any stem cell needs is a place to grow and direct their development, like children need a good home. This technology is an important “infrastructure” invention that can direct the maturation of resident stem cells into regenerative therapeutics. The SIPN scaffold is similar to other patented technologies in that it precisely controls the geometry of the of the fibers and the presentation of chosen ligands, and in that way it can create molecular contexts that are relevant to human disease states. However the inventor Kevin Healy points out that what makes it unique is being able to independently tune the mechanical properties of the cross network and the biological properties of the ligands on the linear chains allowing for more control of the cellular behavior. The defined and precise nature of the matrix also sets it apart from commonly used materials such as Matrigel which are complex and tend to vary from batch to batch. Additionally the fact that this technology is amenable to combination with other approaches such as micro-patterning opens up more complex design possibilities and arrangements to better mimic the environments found in the human body and potentially leads to more effective stem cell therapies.

The main focus of the patent

The invention selectively delivers anticancer drugs to cancerous tissue at high enough concentrations to be effective without exposing the rest of the body to sustained high levels of the drug.

Limited technical details

The technology consists of two sequential steps that result in localized high concentrations of the drug at the tumor site.

The first step involves either choosing an enzyme that is produced exclusively by the tumor (or at least at concentrations many fold higher than non-tumor tissue). If this is not possible, then an enzyme can be coupled with a monoclonal antibody directed against the tumor to locally concentrate it at that site.

The second step requires creating a water soluble radioactive low molecular weight prodrug molecule that is a substrate for the earlier mentioned enzyme and administering it. Ordinarily this would not enter the cells on account of their water solubility and will be cleared from the body in an expected timeframe. However, due to the high concentration of the enzyme in the immediate environment of the cancer cells in the primary tumor and metastases, the prodrug gets broken down in those sites precipitating the water insoluble drug which gets trapped locally and exerts its action selectively on the tumor.

As a result, the drug is concentrated in the tumor at high enough levels to be effective while simultaneously being present in much lower concentration in the systemic circulation.

Implications/applications and sectors that are addressed by patent/technology

The basic principle of this technology is simple yet extremely versatile. The first step allows a choice of a large number of different enzymes that are known to be over expressed in various tumors. Additionally it also covers a wider scope of artificially creating a local high concentration of any enzyme at the tumor site by targeting via monoclonal antibodies (or modifying gene expression in animals). The second step is determined by the final objective and can involve coupling either a gamma ray emitting radiolabel if one wishes to image the tumor in a diagnostic application or an alpha or beta particle emitting particle if the purpose is to treat the tumor by radiotherapy.  As a result, this technology can find wide ranging applications in the field of cancer diagnostics and radiotherapy of solid cancers.

The overall market for cancer treatments is one of the largest and fastest growing areas in the pharmaceutical industry and it is estimated that accrued sales of antineoplastic monoclonal antibodies amass the largest market share of 34.1% (~ $11.3bn in 2007). So a technology that combines monoclonal antibodies with radiotherapeutic or diagnostic agents holds particular promise.

History of the Inventors

Amin I. Kassis is a professor of radiology in the Department of Radiology, Harvard Medical School and the director of the Radiobiology and Experimental Radionuclide Therapy Section of the Laboratory for Experimental Nuclear Medicine. He has published nearly 180 peer-reviewed articles, 30 book chapters/reviews, and holds 34 US and world patents. This particular technology was featured on the cover of a recent issue of the prestigious Cancer Research journal.

Ravi S.Harapanhalli is currently a principal consultant at Parexel Consulting dealing with leads for late stage Product development. He was formerly the chief of the division of premarketing assessment and manufacturing science in the Office of New Drug Quality Assessment at theFDA.

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Patentgo’s opinion:

Cancer remains a top therapeutic area both in terms of overall size as well as growth rate. Worldwide market for cancer treatment is anticipated to exceed US$ 78 Billion by 2012. Due to the high toxicity of existing anti-cancer agents, there is a focused effort to develop therapies that are effective while minimizing the collateral damage to healthy cells. Approaches to specifically target tumor cells include combining drugs with monoclonal antibodies, recombinant adenovirus vectors, hormones whose receptors known to be over expressed in the tumors etc. This technology of this patent has combines two different approaches – tumor cell selectivity achieved by either monoclonal antibodies or a substrate that tumor specific along with a prodrug that gets activated locally. This ensures that the activity is specific to the tumor region, thereby theoretically increasing the specificity of localized tumor site action further.

The invention is a glucose measurement system that can continuously measure and monitor the blood sugar levels.

Limited technical details

The technology involves development of a polymer film that is compatible with the body does not cause any kind of harmful reaction and is loaded with an enzyme that changes color in response to a change in the concentration of glucose in the blood. This film can now act as a sensor and is fixed to a tiny implant under the skin and connected to a watch-like reader on the wrist that can provide a continuous display of the blood sugar levels.  The reader can be either used by the patients to monitor their blood glucose or be connected to an insulin pump for automatic administration of the hormone when the sugar rises beyond a point. The invention specifically uses polyaniline nanofibers as optical biosensors to detect the presence and concentration of target analytes and can be extended beyond detection of just glucose.

Implications/applications and sectors that are addressed by patent/technology.

In the US the prevalence of diabetes is close to 24 million (about 8 percent of the population) with an economic estimated to be about 174 billion dollars. In addition to those with the disease, there are a much larger number of people who are classified as pre-diabetic and need careful monitoring. Such statistics push efforts to increase diagnosis of the undiagnosed diabetic population and achieve better blood sugar control in those with the disease, thereby expanding the market for glucose monitors which is currently assessed to be around $4-5 billion in the US and $8.8 billion worldwide.

The advantages of a continuous and accurate real-time glucose monitor are that it provides feedback for the user and ensures proper user care during critical hyper- or hypoglycemic events. The continuous monitoring ensures user compliance and eliminates repeated finger pricks each day. The optical sensor in a watch-like device worn over film eliminates the need for conductive wires found with conventional electrical sensors.

History of the Inventors

Arthur Epstein is a professor of Physics and Chemistry at the Ohio State University and founding director of the university’s Center for Materials Research. He is the holder of more than 30 patents or patents pending but has no prior experience of starting a company.

Louis Nemzer is a graduate student in Epstein’s group and works on developing polyaniline nanofibers as optical biosensors that can detect the presence and concentration of target analytes.

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US Patent 6475750 – Glucose biosensor

US Patent Application 20050137471 – Continuous glucose monitoring device

The invention deals with the development of a mutated gene for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein that can be administered to cystic fibrosis patients through gene therapy. The resulting altered protein is associated with an increase of chloride channel function thereby alleviating the symptoms of the disease.

Background and limited technical details

Cystic fibrosis is the most common genetic disease in the United States causing progressive disability and often, early death. It is caused by a defect in the gene coding for the CFTR protein resulting in an altered composition and viscosity of secretions in the pancreas and/or the lung. The blockage of the pancreatic duct by the thickened secretions in patients impairs digestion requiring external administration of the pancreatic enzymes to prevent malnutrition.  In the lung, the altered composition of the secreted fluid favors bacterial growth leading to frequent infections, and the thickness of the mucus prevents effective clearing from the airways causing destruction of lung tissue with loss of function.

Although the diseased gene in cystic fibrosis has long been identified as CFTR, initial therapy using the wildtype (normal) CFTR gene did not meet with the expected success due to inflammation caused by viral vectors used to deliver the gene. Alternate safer lipid-DNA complexes of the CFTR gene are of low efficiency and do not transfer the gene of interest into a sufficient number of cells required to alleviate symptoms of the disease.

The current invention involves development of a mutated CFTR gene that results in an altered CFTR protein with an increase in functionality (chloride channel function). As a result, a sufficient correction of the chloride defect can be achieved even with the low efficiency of the safer lipid-DNA complexes when the gene described in the invention is used for gene therapy.

Implications/applications and sectors that are addressed by patent/technology

Cystic fibrosis (CF) is the most common genetic disease of Caucasians in North America, affecting around 1 in 2000 live births in the US. It is ranked as one of the most widespread life-shortening genetic diseases. The U.S. market for the treatment of pulmonary symptoms of cystic fibrosis in 2007 was around $397 million.

History of the Inventors

John Teem was an Assistant Professor of Biology at Florida State University and is currently a Scientist at Florida Department of Agriculture and Consumer Services. He has not been involved in the startup of any prior companies.

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US Patent 6984487 – Cystic fibrosis gene

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Inventors and Affiliation – Hongming Chen (Director of Formulation, Transform Pharmaceuticals), Robert S Langer (Institute Professor, MIT).

Key Words- Liposome, polymerized, lectin, vaccine, targeted delivery

The main focus of the patent

The patent describes a method to make micro vesicles called liposomes that are used to encapsulate drugs and vaccines for uptake by cells. Previously developed liposomes had to be administered by injection since they were destroyed by the harsh environment in the gastric tract when given orally. However the liposomes described in this patent have been chemically modified (by polymerization) to make the coating strong enough resist destruction by the gastric acid and intestinal enzymes. Additionally, carbohydrate molecules called lectins have been attached on their surface that help them bind to and be taken up by specific immune cells in the intestine. As a result, these vesicles can be designed to contain different vaccines, allergens and drugs and given orally without destruction and leakage of the agents before they reach and concentrate at the site of intended action.

Limited technical details

The drug delivery system patented comprises mainly of 3 components.

1. At the core is a drug or vaccine (in which case it comprises of an antigen to evoke the immune response and an adjuvant to facilitate it). These are typically hydrophobic and need to be encapsulated in a lipid bilayer in order to be taken up by cells.
2. The core is encapsulated in an envelope that has phospholipid molecules covalently bonded to each other at varying degrees thereby increasing its ability to withstand destruction by gastric acid and intestinal enzymes.
3. The targeting molecule may be, for example, a carbohydrate (lectin) attached to the surface of the capsule that is recognized and bound by specific cells (in this case immune cells in the Peyer’s patch of the intestine) thereby facilitating the uptake of these vesicles by them. Other targeting molecules can include various carbohydrates, monoclonal antibodies, antibody fragments, viral proteins, bacterial proteins and magnetic particles.

Implications/applications and sectors that are addressed by patent/technology

This technology offers a drug delivery system to target specific cell or organs as intact particles where they can release the drug/antigen after uptake by the cells. Based on a variety of agents that can serve as the core (different drugs, vaccines, antigens etc) and the possible modifications on the surface to target various cells or tissues, a wide variety of applications can be approached with this patent.  It will be specifically useful in offering orally or mucosally administrable alternatives in conditions where the agent needs to bypass gastric and intestinal destruction and targeted to specific cells. The patent describes the delivery of a wide variety of compounds, allergens and antigens, including, but not limited to insulin peptides, diphtheria toxin antigens and influenza antigens as well as chemotherapy agents for the treatment of cancer; cytokines, including interferon; and hormones including insulin, human growth hormone (HGH), fertility drugs, calcitonin, calcitriol and other bioactive steroids.

History of the Inventors:

Hongming Chen: Chen was involved in founding TransForm Pharmaceuticals, a company engaged in the development of pharmaceutical products and based in Lexington, MA  in 1999. Chen is currently the director  of formulation development at Transform (which is now a subsidiary of the Johnson & Johnson group of companies).

Robert Langer: Langer is an extremely successful inventor and holds more than 600 granted or pending patents. He has been involved in the creation of about 25 companies and serves as a director on the boards of Echo Therapeutics, Inc., a medical device and pharmaceutical company, Momenta Pharmaceuticals, Inc., a biotechnology company developing drugs based on sugar sequencing technology, Alseres, Inc., a company focused on research and development of therapeutic and diagnostic products, and Wyeth, a pharmaceutical and consumer healthcare products company.

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US Patent Application 20090162424: Compositions and methods for making and using multifunctional polymerized liposomes

US Patent 6187335: Polymerizable fatty acids, phospholipids and polymerized liposomes therefrom

US Patent 6350466: Targeted polymerized liposome diagnostic and treatment agents

Patentgo’s opinion:

Liposomes which are microscopic phospholipid bubbles are an innovative form of drug delivery to administer a wide range of drugs and vaccines that would otherwise be easily degraded in the blood. There is an attraction in developing orally administrable forms of liposomes that resist the gastric acid to avoid the necessity of parenteral administration. The current invention not only offers resistance to gastric acid, but also combines a targeting molecule to selectively concentrate the drug at specific cell types. However the applications tried by the inventors have only been partially successful and they need to explore alternate applications since the model of combining the liposome with different drugs in the core and targeting molecules on the surface offers a lot of possibilities. Simultaneously they would have to compete with alternate technologies such as chitosan coated liposomes, ganglioside containing liposomes and PEG coated liposomal preparations that are also designed for oral liposome delivery.

Inventors and Affiliation – Batycky; Richard P. (Newton, MA), Edwards; David A. (Boston, MA), Lipp; Michael M. (Framingham, MA)

Key Words- Spray-dried, vaccine, pulmonary, powder, inhaler

The main focus of the patent

This patent describes a method to make pharmaceuticals and vaccines that were previously only administered by injection available by inhalation.  Specifically, the patent describes a method for creating hollow, collapsible drug micron size particles whose properties make them suitable for administration by inhalation.

Limited technical details

Physiochemical properties such as particle size, morphology, electrostatic charge interactions and moisture content are known to influence the overall stability, efficiency and delivery of dry particles used in inhalation therapies. The patents by Edwards et al. (U.S. Pat. No. 7,384,649 and 7182961) identify and list specific properties of particles that render them easily dispersible (mass median diameter of at least about 5 microns, surface area parameter greater than 2, tap density of less than 0.4 g/cm³, a median geometric diameter greater than 5 μm, and an external surface area greater than about 5 m²/g and being able to efficiently penetrate into the lungs when dispensed from a dry powder inhaler. The spray drying method described in the patent creates dry powder pharmaceutical compositions containing the active drug and the vehicle that are hollow, spherical collapsible particles having the above mentioned properties. The patent also goes on to describe specific spray drying conditions required to minimize the average wall thickness of the shells of these particles to less than 150 nanometers, a way to measure and collect particles having the required minimized average wall thickness and finally a method to administer them to the respiratory tract of a patient in need of the drug.

Implications/applications and sectors that are addressed by patent/technology

The patent can potentially have widespread applications in any of the forms inhalation therapy using metered-dose inhalers and nebulizers examples include, beta 2 receptor agonists (used in asthma), corticosteroids, antivirals, antibiotics, and cromolyn (used for preventing symptoms of asthma), the area which the inventors are immediately focusing  is its application to vaccines, which are traditionally administered by injection, but could be administered by inhalation.  Vaccines given by inhalation There are ongoing clinical trials using a spray dried form of the commonly used injectible Bacille Calmette Guerin  (BCG) tuberculosis vaccine as an aerosol.

Inhaled (Needle-free) vaccinations through mucosal surfaces such as nasal passages and lungs are not currently widespread but could represent an emerging market. These vaccines can potentially address shortcomings of conventional injection vaccines such as low acceptance rates (by virtue of being relatively easier and pain-free) and additionally avoid the problems of needle stick injury and contamination as well as the need for trained personnel. Another advantage that a spray dried powder formulation created by this technology can offer is stability at room temperature which would remove the need for refrigeration during storage and transport, a major barrier in developing countries where vaccines for diseases such as tuberculosis are used.  Early studies using the spray dried form of the BCG vaccine have demonstrated to be more effective in animal models than an injectable version

Market: In the specific instance of the tuberculosis vaccine, the worldwide incidence of the disease is about 8 million. However the main market is in the developing countries, especially Asia and sub Saharan Africa where immunization is still a major tool for preventing the disease. In the US, the BCG is not recommended as a means to control TB because of the unproven efficacy of the vaccine in its current form thereby making the development of a more effective alternative an attractive option.

History of the Inventors:

David Edwards, a biomedical engineering professor at Harvard University, he founded Advanced Inhalation Research, Inc., a company that made inhaled form of drugs such as growth hormone and epinephrine and was acquired by Alkermes in 1999. He also co-founded a company called Pulmatrix in 2003 which focuses on respiratory infectious disease. Their products inhibit the formation and transport of infectious aerosols within the lungs thereby decreasing both disease severity as well as spread. Both companies were funded and backed by Polaris Venture Partners.

For the current patent, Edwards, through an international nonprofit he established called Medicine in Need, or MEND has moved the first inhalable TB vaccine candidate into the clinical trial stage.

Richard P. Batycky  was the Vice President, Pulmonary Research and Development at Alkermes , Inc. and is currently the Chief Scientific Officer and Senior Vice President of Research and Development at Pulmatrix Inc.

Michael Lipp was the Director of Formulation Development at Alkermes , Inc.  and is currently Senior Director of Development at Pulmatrix Inc.

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PatentGO is staffed by a variety of writers who have worked at several large and small Pharma companies.  They have worked at Merck, Pfizer, Shire and others.  They also have experience working with University technology transfer offices through the own university patents and markteting those same patents to industry partners as well interested investors.