WISTA APRIL 2009

From the Desk of Chairman IPR Biotechnology : Part 8 - 56

RNA splicing is the process in which introns, or intervening sequences within a gene, are removed from RNA prior to translation of RNA into protein. RNA splicing takes place in the nucleus of a cell where DNA transcription occurs. There are many types of splicing mechanisms, one of them involves the splicesome, an array of proteins that function to splice out introns. The proteins serve to initiate, stabilize, and break the RNA-RNA interactions forming during the process. The splicing pattern determines the delivery of genetic information and the nature of the final protein product. The information could be used to predict the genetic mutations potentially responsible for causing disease. The Special Feature in the current issue of WISTA:IPR Biotechnology deals with RNA splicing, its mechanism and clinical significance. It also briefly describes some of the recent patents on RNA splicing and related aspects in the field. 'On to Excellence' profiles Acrongenomics Inc, Geneva, a publicly traded research and development nanotechnology company, pioneering the development of uniquely advanced nano-molecular diagnostics for life sciences. It offers innovative and realistic concepts capable of creating viable, low cost and portable point-of-care diagnostic devices for medical testing. Arsenic is a highly toxic element and may pose health risk to humans. However, some microorganisms can tolerate relatively high concentrations of the metalloid. Researchers have found an algae that detoxifies arsenic, thus potentially discovering a possible way for cleaning up underground water, particularly in such affected areas as parts of West Bengal and Bangladesh. The 'Perspective' covers the algae capable of detoxifying arsenic. Other features covered in this issue are: Scan Around the Globe; Watch-Out IPR; In Focus; Strategic Alliances; Clinical Trials; Awards; and Legal Scene. We welcome comments and suggestions. Dr K V Swaminathan

CONTENTS RESEARCH & ANALYSIS TEAM • From the Desk of Chairman [P 2 ] Dr Shelley Lahiri Consultant • Scan Around the Globe: Bionic Eye (Australia); New Biologics Pilot Plant (Belgium); Hepavax-Gene (China); Marketing Authorisation for Valdoxan (France); Innovation Mr B K Wadhawan Director Award for Narion (Germany); Brain's Reserve Cells (Sweden); Stiffening Arteries (USA) [P 3 - 4] Mr S S Kalra Director • Watch-Out IPR: Antibody-Based Therapeuties; ATPace Formulation Patent; Japanese Patent for Invisicare; Monoclonal Antibody; Patents on AtherOx® Technology; This publication aims at Recombinant Protein Process. [P 5 - 6] disseminating information on pertinent developments in its • Perspective: Aglae Detoxifies Arsenic. [P 7] specific field of coverage. The • In Focus: Culturing HEK 293 Cells; Drugs Using New Biosensor; GenNext Cancer information published does not, Treatment; Nanoparticles Light Up Tumors; Stem Cells Control Knobs; Stem-Cell Niche therefore, imply endorsement of Model. [P 8 - 9] any product/process/producer or • Strategic Alliances: Agreementm on Vaccines for HIV and Malaria; Antibody technology by WITT. Optimization Collaboration; Business Merger Agreement; License for Asthma Discovery; Licensing Tie-Up; Ligand and Rockefeller Settle Dispute; Vaccine Adjuvant Editor : Dr K V Swaminathan R & D Collaboration; Zinc Finger Nucleases. [P 10 - 11] Printed and Published by • On To Excellence: Acrongenomics, Inc. [ P 12 ] Dr K V Swaminathan, on behalf of Waterfalls Institute of Technology • Special Feature: RNA Splicing. [P 13 - 15] Transfer, J-29 South Extension Part I, • Clinical Trials: BETAS Safety Trial Results; Phase II Trial of Tb-402. [P 16] New Delhi - 110 049. • Awards: Novo Nordisk Prize; Top Research Partner Award. [P 16] • Fine Tuning: Diseases vs Bactrial Genes. [P 17] Printed at Sagar Printers, 1880 Udaichand Marg, • Legal Scene: Fosrenal Lawsuit; Illumina Suit Against DNAPrint; Infringement Action; Legislation to Boost Clinical Trials; Skelaxin Patent Invalidated; Suit Against Kotla Mubarakpur, Teva; Warner Chilcott Infringement Lawsuit. [P 18 - 19] New Delhi -110 003.

VOL 10 ISSUE 10 1 IPR BIOTECHNOLOGY SEC 2 WISTA APRIL 2009

for its biological compounds under development, SCAN AROUND THE GLOBE extending its knowledge and competencies in this field. (Belgium - UCB, Inc., Feb 19, 2009) Bionic Eye Hepavax-Gene Australian consortium announced that tens of thousands of people with severe vision loss are The Chief Executive Officer (CEO) of Chinese set to benefit after the formation of a landmark company, Crucell N V, announced that the Chinese partnership of world-leading Australian research authorities have released Hepavax-Gene®, institutes. Bionic Vision Australia will pursue the a recombinant hepatitis B vaccine, for registration development of the most technologically advanced and quality control in China. According to the CEO, bionic eye to improve the sight of people with the launch of Hepavax-Gene® is a significant degenerative or inherited retinal disease. advancement in the expansion of Crucell’s business in the highly strategic Chinese vaccine market. This Bionic Vision Australia’s members include the hepatitis B vaccine will contribute significantly to the University of Melbourne, the University of New sustainability of Chinese operations. The Chinese South Wales, the Bionic Ear Institute, Centre for Eye hepatitis B vaccine market is the world’s biggest Research Australia and the Victoria Research market with approximately 100 million doses Laboratory of NICTA. administered yearly. According to the chairman of the Bionic Vision According to the company, the prospects for Australia, their research team is well placed to Hepavax-Gene® in the Chinese private market are undertake the critical research required to deliver an excellent. Hepavax-Gene® will be positioned in the advanced Bionic Eye, which would improve quality high-end private market segment with a particular of life for patients suffering from common causes focus on young adults. Hepavax-Gene® possesses of severe loss of vision and blindness. two decisive advantages: its production is based on Crucell’s hansenula polymorpha patented technology A bionic eye will assist in restoring patient and it is 100% free of thiomersal. Thiomersal is a mobility by effectively replacing the function of mercury based compound which, in several countries, damaged light-sensing cells in the eye. While the clarity is being phased out from vaccines given to children and definition of vision will not be equal to normal to avoid potentially adverse effects. sight, the device will allow patients to move around, detect large objects and, in time, read text and (China-Crucell N V, Dec 10, 2008) recognise faces and emotions. Marketing Authorisation for Valdoxan (Australia - Bionity.Com, Nov 14, 2008) France’s leading independent pharmaceutical company. Servier, discovered and developed New Biologics Pilot Plant Valdoxan (R)/ Thymanx (R), the first melatonergic UCB Inc., Brussels, Belgium, is a biopharmaceutical antidepressant for the treatment of adult patients company dedicated to research, development with major depressive episodes. The European and commercialization of innovative medicines with a Commission has granted marketing authorization focus on the fields of central nervous system and for Servier’s Valdoxan. immunology disorders. The company announced its The European approval of Valdoxan is based on plans to build a biologics pilot plant on its site in both short and long-term results from a large Braine-1’Alleud, Belgium. Company’s pilot plant comprehensive, international development programme is expected to become operational early 2012. including almost 6,000 adult patients with The biologics pilot plant will allow UCB depression. The results demonstrate the superior to further optimise the bio-manufacturing processes efficacy of Valdoxan.

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Following approval from the European so-called Notch signaling pathway, which inhibits Commission, Valdoxan is expected to become the creation of new nerve cells. commercially available in European countries. (Sweden - Karolinska Instetutet, Feb 24, (France- PRNewswire, Jan 24, 2009) 2009) Innovation Award for Nanion Stiffening Arteries Nanion is a well known organized company. Scientists across Cornell are involved in the effort According to CTO of Nanion, to remain a profitable to combat heart disease and stroke in a variety of and leading provider of advanced and high ways, from investigating its causes and contributing quality ion channel drug screening system, the factors to testing possible pathways for treatments. company constantly seeks new inventions and Like skin that loses elasticity, blood vessels lose solutions that are attractive to industrial and their pliability and stiffen with age. In more than half academic institutions. of the US population over 65, this stiffening of the blood vessels is accompanied by a buildup of plaque The German Industry’s Innovation Award, also inside arterial walls - atherosclerosis - which can lead the world’s first innovation award, has since 1980 to blood vessel obstruction, increased stress on the annually nominated and rewarded the nation’s most heart and the risk of a heart attack. Researchers important scientific and technical innovations. Nanion have long known that factors like smoking and is one of the five remaining candidates for the award. high cholesterol intake contribute to the disease. But Nanion was nominated for an innovation award, Cynthia Reinhart-King, assistant professor of due to its impressive product portfolio of automated biomedical engineering at Cornell, is investigating patch clamp systems. Nanion is finalist in the category atherosclerosis from a different perspective, with “start-up companies.” hopes of finding new ways to treat it. (Germany - bionity.com, Jan 23, 2009) To study the relationship, Reinhart-King, who is supported in part by an American Heart Association Brain’s Reserve Cells (AHA) Young Investigators grant, is observing how Scientists at the Swedish medical university endothelial cells behave when attached to hard and Karolinska Institutet have found a way of activating soft surfaces. Specifically, she studies whether simply the neuronal reserves in the brains of mice by switching being attached to a stiffening artery, instead of a off the signal that inhibits the formation of new young, supple one, makes endothelial cells more nerve cells. susceptible to the buildup of plaque. Her preliminary findings indicate that being attached to a stiffer blood New nerve cells are formed from stem cells in specific areas of the human brain. This process vessel appears to reduce how tightly the cells that increases after a stroke, something that might line the vessels attach to each other, which could explain the recovery that is often observed in make it easier for plaque deposits to form. In a system patients, particularly in the first year following the onset adapted in her lab that mimics condition inside a of illness. In the study, the scientists have blood vessel (without the dozens of confounding demonstrated how a type of cell that does not give variables that exist in the body) Renihart-King rise to new cells in the healthy brain is activated in grows endothelial cells on polymer surfaces that laboratory animals after a stroke. match the elasticities of a healthy or diseased artery wall. Using a technique called traction force In addition to the stem cells that are normally microscopy, which measures the cells’ response to active, there is, therefore, also a kind of reserve stock the substrate, she then looks for differences in of cells that can be activated when demand increases. the way the cells adhere to the polymer, how they The team have identified the molecular mechanisms arrange themselves in response to blood flow, and that control the activation of these cells, and shown how tightly they bind to each other. that it is possible to increase the formation of new nerve cells in healthy mice by switching off the (USA-Cornell, Mar 2, 2009)

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ATPace is being developed as a therapeutic drug for the WATCH-OUT IPR acute management of paroxysmal supraventricular tachycardia (PSVT) as well as a diagnostic test for Antibody-Based Therapeutics Patent the identification of patients with bradycardic (slow heart rate) syncope who may benefit from Stromedix Inc, a biotechnology company pacemaker therapy. Injectable formulations of ATP, focused on innovative therapies for fibrosis and similar to ATPace, have been approved and marketed fibrotic organ failure, was awarded the US patent in Europe for over 50 years as safe and efficacious 7,465,449 which broadly covers monoclonal pharmaceutical treatments for PSVT. antibodies to integrin ávâ6, including compositions related to its lead product, STX-100. Cordex has recently announced the submission to the FDA of an amended Phase 3 clinical trial This patent provides Stromedix with strong protocol with ATPace as an antiarrhythmic drug for intellectual property protection for antibody-based the conversion of PSVT to normal sinus rhythm. therapeutics directed against ávâ6 through at The FDA is currently reviewing this protocol through least 2023. the Special Protocol Assessment procedure.

Stromedix holds a significant patent portfolio A stable liquid formulation of ATP is a prerequisite relating to development and commercialization of for ATPace’s marketing and clinical superiority monoclonal antibodies to integrin ávâ6. The new over adenosine, the only approved competition in the patent covers high-affinity monoclonal antibodies and US. The maintenance of intact ATP molecules in antigen-binding fragments that block the function of the solution is critical for the unique bradycardic effects integrin ávâ6, which is an important regulator of of ATP, in particular its blockade of atrio-ventricular fibrosis and tissue injury. It covers specific monoclonal (AV) nodal conduction. Specifically, ATP is believed antibody compositions including compositions to have dual inhibitory action, one mediated by relating to Stromedix’s lead drug candidate, STX-100. adenosine, the product of its rapid degradation in the In addition it provides Stromedix with strong blood vasculature by ecto-enzymes, and the other a protection from potential competitors. rapid and potent ATP-triggered vagal reflex. The latter mechanism of action is believed to be responsible for (Stromedix Inc, Jan 26, 2009) its superior efficacy over adenosine, which does not trigger a vagal reflex in the heart. Physical vagal ATPace Formulation Patent maneuvers aimed at enhancing vagal input to the heart, PSVT (Paroxysmal supraventricular tachycardia) and thereby suppressing atrio-ventricular nodal is an episodic, rapid, regular heart rate originating in conduction, have been clinically used to terminate the atria. The heart rate in PSVT can range from tachycardia in certain cases. 150 to 250 beats per minute. (Cordex Pharma, Inc., Mar 5, 2009)

Patients with PSVT may report palpitations, Japanese Patent for Invisicare pounding in the chest, chest pressure or pain, weakness, shortness of breath, or dizziness. Unless it Skinvisible, Inc. was granted a Japanese patent self-terminates, PSVT patients need to seek medical for Invisicare, a product-enhancing polymer delivery intervention to terminate the arrhythmia. system for topical dermatology products. The patent protects Invisicare in the areas of 'Topical Cordex Pharma, Inc. has announced that it has Composition','Topical Composition Precursor', and filed a formulation patent covering its lead product, 'Methods for Manufacturing and Using'. ATPace. Skinvisible's strong intellectual property protection ATPace is a stable liquid formulation of adenosine is often the key catalyst for a company to license triposphate (ATP) for in travenous administration. products formulated with Invisicare. Skinvisible's

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patents provide a guaranteed period of market European patent # EP 1 548-436 B1 was issued exclusivity to licensees. Skinvisible's research and November 19, 2008. The patent is also a method development team works with companies offering life patent providing additional European protection to cycle management for their products coming off patent. the components and assay procedure used to Additionally, Invisicare offers unique attributes to measure AtherOx complexes in biological samples. topical products including the ability to hold active ingredients on the skin for extended periods of time and The latest patents add to previous US patents providing a controlled, fast or slow release of the (#5,900,359 issued May 4, 1999, 'Method for active ingredient. Determination of Oxidized Lipoproteins and Use Thereof'; # 7,160,733 issued January 9, 2007, (skinvisible.com, Mar 11, 2009) 'Ligand Specific to B2-glycoprotein I and Use Thereof'; and # 7,422,864 issued September Monoclonal Antibody 9, 2008, 'Method for Measuring Oxidized LDL-CRP BIOTECTID GmbH has been awarded an Complex and Measurement Kit'). These patents European patent for the new diagnostic EP1645 used describe the specific interaction of B2-LDL. The in the in vivo analysis of distribution patterns of human most recent patent provides additional coverage to CD4 presenting cell populations. immunoassays for the detection of the oxLDL/B2GPI complexes which is the basis for Corgenix EP 1645 is fragment of a monoclonal antibody AtherOx test kits. which binds selectively to the CD4 molecule on the surface of specific inflammatory cells. One of the (Corgenix Medical Corporation, Jan 20, 2009) areas of indication is the control and optimization of the use of biopharmaceuticals in the treatment Recombinant Protein Process of rheumatoid arthritis. Bone Biologics Inc. has received a US Patent (BIOTECTID, Feb 16, 2009) Office Notice of Allowance of patent claims which protect a method of production for the UCB-1 (NELL-1) recombinant protein that Bone Biologics Patents on AtherOx® Technology uses in the bone repair/regeneration technology in its lead product. Corgenix Medical Corporation, a worldwide developer and marketer of diagnostic test kits, has Bone Biologics has been developing the protein received notification of two new patents for as platform technology since 2004, leveraging the technology to which Corgenix holds exclusive previous ten years of research in the lab performed worldwide licensing rights outside of Japan. The by the company’s founding scientists at UCLA. technology is incorporated in the company’s The mechanism of action is not only identified as to AtherOx® product group, a next-generation how it works, but why, through this exhaustive technology to identify individuals at risk for research effort. This platform technology is combined developing atherosclerotic cardiovascular disease. with DBX(R) demineralized bone matrix to promote bone growth in spinal fusion. US Patent # 7,455,976 was issued November 25, 2008. The patent 'Method of Measuring The patent broadly protects the manufacturing Oxidized LDL/B2-Glycoprotein I Complex method for theUCB-1 (NELL-1) protein. The UCB-1 Occurring in the Living Body' incorporates newer (NELL-1) protein is currently utilized with a carrie immunochemical characteristics for the interaction (scaffold) of DBX(R) demineralized bone matrix between oxLDL and B2GPI to form oxLDL/B2GPI which is produced by the Musculoskeletal (AtherOx complexes) and their use as a standard for Transplant Foundation (MTF). more accurate measuring of this complex in biological samples such as serum or plasma. (Bone Biologics Inc., Feb 25, 2009)

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or dimethylarsinic adid (DMA). Prokaryotes can also PERSPECTIVE produce volatile methylated arsines, which remove arsenic from the local environment by forming it into a gaseous compound. An alternative strategy used by Algae Detoxifies Arsenic bacteria and yeast is based upon the “ArsC” arsenate Arsenic is a metalloid. It occurs in virtually all reductase protein. environmental metal matrices. The inorganic arsenic Researchers have stumbled on an algae that forms of As (III) and As (V) are toxic. It may pose a detoxifies arsenic, potentially opening the way for health risk to human population. Although exposure cleaning up underground water reservoirs in West of arsenic can occur in various settings, ingestion of Bengal and Bangladesh contaminated with the contaminated ground water is more widespread. The toxicity of arsenic is dependent to a large extent poison. Environmental science professor of Montana on its bioavailability or its ability to be liberated State University studied on the simple, single-celled from various matrices and be internalized in the algae called cyanidioschyzon also thrives in extremely target organs of the host. toxic conditions and chemically modifies arsenic that occurs naturally. The scientists cloned genes from the Although arsenic is highly toxic to humans, algae, then studied the enzymes to figure out how they and indeed most other forms of life, some transformed arsenic. They learned that the algae microorganisms have evolved to tolerate relatively oxidizes, reduces and converts arsenic to several high concentrations of the metalloid, while specialist forms that are less toxic than the original. Over the examples even thrive on the element, using it as a years, he noticed thick algae mats that were so lush source of energy for growth. This surprising array and green in December that they looked like of microbial processes, together with inorganic and Astro-Turf. By June, they were practically gone. physical processes, constitutes the global arsenic While investigating the change, scientist team learned cycle. Even at the low concentrations found in about cyanidiales algae and its ability to reduce seawater and freshwater, microorganism can accumulate arsenic to a less dangerous form. arsenic, often to concentrations many times those encountered in the environment they inhabit. The key The cyanidioschyzon algae grow all over to generating energy from arsenic lies in its redox Yellowstone, but the Montana-researcher concentrated on the Norris Geyser Basin. The algae chemistry, which is characterised by at least four thrives in water up to 55oC with a very acidic pH oxidation states. Energy is made available to support factor ranging from 0.5 to 3.5. microbial life from the oxidation of As3+ to As5+, (oxidation state of arsenic). Although the above two Scientists said that cyanidioschyzon could some day help reclaim arsenic-laden mine waste and oxidation states of arsenic dominate in most aid in everything from space exploration to creating terrestrial environments, the biogeochemical cycle of arsenic is rather more complicated. This is because safer foods and herbicides. in many environments one must consider not only There remains an urgent need for a better direct microbially catalysed redox transformations understanding of arsenic release into groundwaters, of arsenic, but also other environmental factors especially how the biochemical reactions within the that may exert critical controls on arsenic speciation. microbial cell drive the local chemistry at the These include the geochemical (aqueous) matrix of microbe-mineral interface to result in arsenic the system and the underpinning mineralogy, mobilistion. It is also important to define the especially if there are mineral phases that may environmental factors that drive the mobilisation of potentially host arsenic. arsenic into groundwater, and here a better The poisonous nature of arsenic has been known understanding of the source and role of organic matter from many years, but the mode of toxicity depends in the sediments is important. There is considerable very much on the chemical form of the metalloid. interest in developing methods to remediate Microorganisms have evolved multiple strategies to arsenic-contaminated groundwater, and again, protect themselves from arsenic. For example, fungi biotechnology could be employed to reverse the can use methylation as detoxification strategy, anaerobic, arsenic-mobilising, microbial activies that producing monomethylarsonic and acid (MMA) seem to be at the heart of this human catastrophe.

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This makes it possible to analyse the features of the IN FOCUS proteins, which are normally sensitive and unstable outside their natural environment. Culturing HEK293 Cells The colour changes can be attributed to the local HEK 293 cells are used by biotechnology and chemical environment on the nanostructured metal biopharmaceutical companies to produce human surface and provide information about different therapeutics. processes in which the proteins being studied are involved. A recent breakthrough was published in the scientific journal In Vitro Cellular & Developmental The colour phenomenon arises due to what are Biology, showing the benefit of using recombinant known as plasmons-heat wave movement that arises lactoferrin (Lacromin) to promote growth of HEK 293 when light induces electrons to move in a fixed rhythm cells using a serum-free and animal-free media. on metal surface. The strong colours generated by Lactoferrin is a protein derived from colostrum and plasmons have been utilized by people for thousands has been made using recombinant techniques in an of years. animal-free system by In Vitria. (bionity.com, Dec 11, 2008) In a study it was shown that recombinant GenNext Cancer Treatments lactoferrin (Lacromin) was used as a serum-free and A precious metal which has never before been animal-free media component to enhance the growth of used in a clinical setting is being developed as an anti- a variety of cell lines, including HEK cell lines. cancer agent by the researchers of Chemistry Using recombinant human lactoferrin (Lacromin), Department at the University of Warwick. The metal, viable cell growth was considerably higher when osmium, is closely related to platinum, which is widely compared to using recombinant or native human used to treat cancers in the form of the drug cisplatin. transferrin. The study also showed that recombinant The researchers worked closely with Warwick human lactoferrin (Lacromin) was capable of Ventures the University’s technology transfer office, promoting HEK 293 cell growth faster than human to seek partners to help develop the potential of transferrin, leading to faster doubling times. osmium through more extensive biological tests. (In Vitro Cellular & Developmental Biology, Nov Osmium, with its special chemical properties, offers 4, 2008) a new potential solution to an unmet clinical need. Drugs Using New Biosensor It has shown huge promise in treating several Chalmers researcher Andreas Dahlin has different types of cancer cell, including ovarian and developed a biosensor with an artificial membrane, colon cancers which have been developed and tested which means that membrane-bound proteins can in the laboratory. The metal also has another advantage retain their natural structure and function. The in that it is much cheaper alternative to platinum. method facilitates the study of the function of the (University of Warwick, Dec 10, 2008) proteins, which could be of major significance in the search for new drug. One-third of all our Nanoparticles Light Up Tumors proteins have the cell membrane as their According to research at Memorial Sloan-Kettering natural environment, where they perform several of Cancer Center (MSKCC), Cornell dots, also known the most basic life-preserving biological processes. as C dots, are biologically safe and stable and small Approximately half of the most common drugs are enough to be easily transported across the body’s directed at membrane receptor proteins. Understanding structure and efficiently passed through the kidneys and membrane proteins is therefore vital in modern drug. out in urine. The biosensor is based on nanostructures which A single dot consists of several dye molecules comprise holes in thin metal films where different types encased in a silica shell that can be as small as 5 of membrane with membrane proteins can be formed. nanometers in diameter. The silica shell, essentially

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glass, is chemically inert. Coating the dots with high levels of extracellular potassium ions or to polyethylene glycol, a process called PEGylation, ouabain, a compound that blocks the transfer of ions further protects them from being recognized by the in and out of cells. Both treatments disrupted the body as foreign substances, giving them more time to normal increase in negative voltage that occurs find targeted tumors. during differentiation and suppressed fat and bone The outside of the shell can be coated with cell differentiation markers. organic molecules that will attach to such desired In contrast, treatment with hyperpolarizing targets as tumor surfaces or even locations within reagents up-regulated bone cell markers, indicating tumors. The cluster of dye molecules in a single dot that voltage changes are not merely permissive for fluoresces under near-infrared light much more differentiation but can act as instructive signal to brightly than single dye molecules, and the fluorescence either induce or inhibit differentiation. will identify malignant cells, showing a surgeon (Bionity.Com News, Dec 5, 2008) exactly what needs to be cut out and helping ensure that all malignant cells are found. According to MSKCC Stem-Cell Niche Model researchers, the technology also can show the extent Scientists at the Stanford University School of of a tumor’s blood vessels, cell death, treatment Medicine are making efforts to learn more about stem response and invasive or metastatic spread to lymph cells development, and have taken a significant step nodes and distant organs. forward by devising a way to recreate the cells’ lair, a (MSKCC, Feb 20, 2009) micro-environment called a niche, in an adult animal. Stem Cells Control Knobs The research marks the first time that scientists have successfully recreated a functional stem-cell Tufts University scientists have identified ‘control niche for further study. The scientists plan to knobs’ for stem cells. Natural changes in voltage that use the model system to determine how the niche occur across the membrane of adult human stem cells environment interacts with the blood stem cells to are a powerful controlling factor in the process affect their development and fate, and how by which these stem cells differentiate according leukemias respond to these niches. They will also to the scientists. investigate the bone and cartilage healing capacity of these cells. Harnessing the potential of stem cells for applications such as wound healing and tissue regeneration is a Blood-forming stem cells typically reside in the tantalizing yet daunting task. Although many studies bone marrow. The researchers found that a specific indicate that electrophysiology plays a crucial role in subset of fetal mouse bone cells could not only take cell proliferation and differentiation, its functional up residence and produce bone when injected role in stem cell biology is poorly understood. near the kidney of an adult animal, but they also generated bone marrow cavity that sheltered The Tufts researchers studied the changes in host-derived blood stem cells. In contrast, other membrane potential shown by human mesenchymal subsets of fetal bone cells generated only bone. stem cells (hMSCs) obtained from donor bone marrow as the hMSCs were differentiating into fat Suppressing the expression of factors involved and bone cells. They found that hyperpolarization in a specialized bone-building process, called (increased difference between the voltage in the endochondrial ossification in the host mouse, stopped interior and exterior of a cell) was characteristic the formation of the marrow cavity and the of differentiated cells compared with recruitment of host stem cells. Using similar fetal bone undifferentiated cells and that hMSCs showed cells from parts of the skeleton that do not undergo different membrane potential profiles during bone the process, such as the skull and the jaw, also blocks vs fat differentiation. cavity formation. The findings suggest that endochondrial ossification is a necessary step in To determine whether hyperpolarization was setting up house for stem cells. functionally required for differentiation, the scientists depolarized the hMSCs by exposing them either to (BUSINESS WIRE, Dec 10, 2008)

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Business Merger Agreement STRATEGIC ALLIANCES GPC Biotech AG and Agennix, Incorporated announced that the two oncology-focused Agreement on Vaccines for HIV and Malaria biotechnology companies have signed a Business Combination Agreement under which they propose ImmunoVaccine Technologies Inc. (IVT), a vaccine to merge their businesses. In the transaction, GPC development company, has signed a collaborative Biotech is to be merged into a new German company, agreement with the National Institute of Allergy and which will hold all of the shares of Agennix and a •15 Infectious Diseases (NIAID) at the National Institutes million cash contribution by dievini Hopp BioTech of Health (NIH), in Maryland, USA, that involves Holding GmbH & Co KG, an investment company formulating NIAID antigens in DepoVax(TM), IVT’s of Dietmar Hopp, co-founder of SAP, and one of vaccine enhancement system, and exploring potential the largest shareholders of GPC Biotech. The merger vaccines for HIV and malaria. combines GPC Biotech’s and Agennix’s oncology pipelines, including Agennix’s Phase 3 novel oncology There are currently a limited number of vaccine therapy, talactoferrin, with the clinical development formulations capable of inducing potent and durable and financial resources of GPC Biotech and dievini T-cell responses. Several vaccines in development, Hopp BioTech holding. based on replication-defective adenovirus, are limited in their ability to be used repeatedly. There is an The merger agreement between GPC Biotech and urgent need to develop protein vaccines that can the new company will be subject to further closing induce antibody and T-cell responses, and be used conditions, including any necessary anti-trust in combination with other vaccines. The goal of clearances. The merger is expected to be completed by this pre-clinical research collaboration is to establish the end of 2009. whether a novel vaccine formulation, in which (GPC Biotech AG and Agennix, Feb 20, 2009) a specified protein is formulated in DepoVax(TM), will induce stronger T-cell responses compared to License for Major Asthma Discovery other protein-based formulations. A major asthma discovery by a researcher at the (PR Newswire, Feb 25, 2009) La Jolla Institute for Allergy & Immunology has been licensed by Medlmmune, a leading innovation- Antibody Optimization Collaboration focused biotechnology company and wholly owned Xencor, Inc., an antibody discovery and subsidiary of AstraZeneca Plc. MedImmune licensed development company, announced that it has entered the discovery to explore its use in the development into an antibody optimization collaboration with of a potential biologics drug for treating asthma. CLS, Ltd. The collaboration will provide CSL with Under the agreement, Medlmmune was granted access to Xencor's XmAb® technology platform to exclusive intellectual property rights to the discovery, enhance the ADCC effector function of its which demonstrated the pivotal role of a protein called therapeutic antibodies. the OX40 ligand in asthma. The finding was made by During the research phase of the collaboration, the laboratory of La Jolla Institute scientist Michael Xencor will provide CSL with the opportunity to Croft and marked a major milestone in asthma research. utilize the technology broadly across its antibody Asthma is chronic disease of the airways that can candidate pipeline. Xencor has granted CSL several cause wheezing, coughing and difficulty in breathing. It is commerical licenses to move product candidates into the most common serious chronic disease of more development and ultimately commercialization which than 30 million Americans (or 11.2 percent of the incorporate Xencor's XmAb® technology. In addition population) reported having a history of asthma in to an upfront payment, CSL will pay Xencor 2005, including nine million children, according to development milestone payments and product royalties the US Centers for Disease Control and Prevention. for each produt commercialized that incorpoates the More than 20 million Americans said they currently have the disease. The National Institutes of Health Xencor technology. (NIH) estimates asthma-related healthcare costs (Xencor Inc., Feb 23, 2009) at US $ 14 billion annually.

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Such licensing arrangements are a central part of dates back to the 1992 license agreement, under the mission of research institutes to ensure that which Ligand licensed from Rockefeller certain discoveries stemming from private and publicly technology relating to cytokine-activated Signal funded research are put into direct use for improving Transducers and Activators of Transcription (STATs) human health. to control gene expression. (La Jolla Institute, Feb 25, 2009) (Business Wire, Feb 12, 2009) Vaccine Adjuvant R & D Collaboration Licensing Tie-Up Opsona Therapeutics, the biotechnology Romark Laboratories, a biopharmaceutical company focused on novel therapeutic and company in Florida, and Japan's Chugai preventive approaches to autoimmune and Pharmaceutical have entered into an exclusive license inflammatory diseases, announced that it has signed ageement for the development and commercialization a research development and collabration agreement of nitazoxanide as treatment of chronic hepatitis with the global specialty biopharmaceutical C in Japan. company CSL limited. The collaboration covers the identification of novel vaccine adjuvant Under the terms of the agreement, Chugai has formulation, based on Opsona's proprietary paid an upfront payment to Romark, and will make technology Opsovac TM which could traget additional payments based on the achievement of infectious diseases and certain cancers. certain clinical and regulatory milestones. Romark will Under the agreement, Opsona will receive participate in profits from produt sales in Japan undisclosed upfront payments and will be eligible through a supply agreement and royalties. for additional milestone and royalty payments should CSL elect to pursue formulations that result (BioSpectrum Bureau, Feb 18, 2009) from the collaboration. Ligand and Rockefeller Settle Dispute (Opsona Therapeutics, Feb 23, 2009) Ligand Pharmaceuticals Incorporated and The Zinc Finger Nucleases Rockefeller University ("Rockefeller") have entered Sangamo BioSciences, Inc. a leading developer of into a Settlement Agreement and Mutual release (the zinc finger DNA-binding proteins (ZFPs), announced "Settlement Agreement"), according to which the an agreement to provide Inc. with a worldwide, parties have resolved all disputes that have arisen non-exclusive license for the use of certain ZFP between them in litigation, including Rockefeller's Nuclease (ZFNs) reagents to permanently eliminate primary claim relating to the development of the Glutamine synthetase (GS) gene in Chinese PROMACT® (eltrombopag). In addition, the parties Hamster Ovary (CHO) cell lines and for the use of have agreed to jointly seek dismissal with prejudice of these ZFN-modified cells for clinical and commercial all claims and counter claims asserted in the ongoing production therapeutic proteins. litigation between the parties. Under the agreement, Sangamo will provide a Ligand and Rockefeller agreed to terminate worldwide, fully paid perpetual, royalty free, their 1992 license agrement. The termination of the non-exclusive, license for the use of certain ZFN license agreement will not negatively affect previously reagents for the elimination of the GS gene in Pfizer's granted sublicenses or conveyances of rights to any CHO cell lines and to use such ZFN-modified third party and under the license agreement, Ligand CHO cells for clinical and commercial production of does not believe that it requires a license from Rockefeller therapeutic protein products. Sangamo will receive an for its ongoing business activities, but Rockfeller has upfront payment of $3.0 million from Pfizer which granted Ligand and its sublicensees a covenant not to constitutes full and complete payment for the license. sue under any patents orknow-how that were the The license may not be sublicensed although Pfizer subject of the license agreement for any past, present or may transfer any GS ZFN-modified CHO cell line to future use of such patents or know-how. a contract mnufacturer to produce therapeutic proteins for Pfizer. This Settlement Agreement largely ends the relatonship between Ligand and Rockefeller that (Sangamo BioSciences, Inc, Dec 22, 2008)

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testing that will greatly extend the tools available to the ON TO EXCELLENCE medical community.

Acrongenomics, Inc. and Molecular Vision Ltd. ACRONGENOMICS, INC. announced the successful implementation of a fully functional, portable medical diagnostic demonstrator Acrongenomic, Inc. is a research and development Lab-on-a-Chip technology. The demonstrator oriented nanobiotechnology company, headquartered employs patented, organic semiconductor at Geneva, Switzerland. This company focuses on technology in a high sensitivity, handheld medical investing and commercializing revolutionary diagnostic device. technologies dealing with medical and life sciences industry. The company offers innovative but realistic The devices, being developed upon mutually set concepts which are both marketable and capable of milestones, will enable personalized on-the-spot being taken from the drawing board and used to analysis for: create viable customer orientated applications. - diabetes monitoring through albumin/creatinine With the rising global population, many of the detection in urine, world’s medical service providers are out searching for - detection of cardiac markers, new and better products and processes to deal with - detection of STD (sexually transmitted diseases), their increase in patient counts. Having high-tech and diagnostics systems available and improved methods for monitoring diseases is what Acrongenomics Inc. is - detection of substances of abuse. concentrating on. The company strives to stay relevant and at the forefront of the latest advances and Both the above companies were working towards revisions in order to maintain a global position in a generic research prototype to be delivered at the these emerging markets. beginning of 2007. Development steps include the design and fabrication of stand-alone product Products and Services models based on chemiluminescence detection. The products will comprise a microfluidic substrate, In the wake of global trend involving the an organic photodetector, a printed circuit board, a miniaturization of medical diagnostic devices, display and battery. Acrongenomics has been instrumental in leading the way in this technological revolution, Molecular Vision’s patented diagnostic chips incorporating diverse technologies like microeclronics, have the potential to become a de-facto standard for mechanics, optics, physics and molecular biology medical testing. They are based on a novel technology into its research and development strategies. platform that will allow the development of readily portable devices for broad range of applications. Alliances They incorporate two powerful technologies microfluidics and organic semiconductor devices (light Acrongenomics makes use of its extensive emitting diodes and photodetector). international network as well as its qualified management team in order to investigate and Acrongenomics maintains a stated goal of helping to potentially invest in dynamic research projects. Based advance the development of the medical diagnostics upon this strategy, Acrongenomics has established a industry while at the same time, accomplish atrategic alliance with the UK based company, Molecular industry-leading growth by establishing their exclusive Vision Ltd. On March 29, 2006, the two companies technology platform on a global market basis. sighed a Memorandum of Understanding (MOU) to Through innovative and advanced medical diagnostic embark on joint R & D to develop and commercialize a applications, Acrongenomics is aiming to provide the line of low-cost, easy-to-use and readily portable most efficient and sustainable means of delivering point-of-care (POC) diagnostic deviser for medical new value to the marketplace.

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from the late RNAs, as well as from the intervening SPECIAL FEATURE sequences (intros). Subsequent to the adenoviral discovery, introns were found in many other viral and eukaryotic genes, including those for hemoglobin RNA SPLICING and immunoglobulin (Darnell, 1978). Splicing of RNA transcripts were then observed in several in vitro Introduction systems derived from eukaryotic cells, including removal of introns from transfer RNA in yeast RNA splicing process has a very significant role cell-free extracts (Knapp et al, 1978). in human molecular mechanism. For most eukaryotic gene (and some prokaryotic ones), the initial RNA Splicing Signal that is transcribed from a gene’s DNA template must be processed before it becomes a mature An intron usually contains a clear signal for RAN (mRNA) that can direct the synthesis of protein. splicing (e.g., the beta globin gene). In some cases One of the steps in the processing, called RNA (e.g., the sex lethal gene of fruit fly), a splicing signal splicing, involves the removal or “splicing out” of may be masked by a regulatory protein, resulting certain sequences referred to as intervening in alternative splicing. In rare cases (e.g., HIV genes), sequences. Splice means to join two ends of DNA- a pre-mRAN may contain several ambiguous rope (here) by wearing the strands of one into the splicing signals, resulting in a few alternatively strands of the other. So RNA splicing (in molecular spliced mRANAs . genetics) is the process by which base pairs that Most introns start from the sequence GU and interrupt the continuity of genetic information in end with the sequence AG (in the 5’ to 3’ direction). deoxyribonucleic acid are removed (splicing out) They are referred to as the splice door and splice from the precursors of messenger ribonucleic acid acceptor site, respectively. However, the sequences and the subsequent pairing (splicing together) of exons at the two sites are not sufficient to signal the presence in the production of a mature RNA molecules. The of an itron. Another important sequence is called RNA splicing involves removal of nitrous, the the branch site located 20-50 bases upstream of non-coding elements present in RNA molecule. the acceptor site. The consensus sequence of the Most genes of higher eukaryotes contain non coding branch site is “CU(A/G)A(C/U)”, where A is intervening sequences or axons. The final mRNA conserved in all genes. then consists of the remaining sequences, called axons, which are connected to one another through Splicing Mechanism the splicing process. RNA splicing occurs in the nucleus of the cell RNA splicing was initially discovered in 1970s, where DNA transcription takes place. There are years of thought in the field of gene expression. several types of known splicing mechanisms one Gene regulation was first thoroughly studied in of which involves the spliceosome, an array of relatively simple bacterial systems. Most bacterial proteins that function to splice out introns. RNA transcripts do not undergo splicing. In 1977, The human spliceosome has been found to contain several groups of researchers who were working 44 different components. Another mechanism with adenoviruses that infect and replicate in involves excision of introns by the RNA mammalian cells obtained some surprising results. itself. Introns have also been shown to be removed These scientists identified a series of RNA molecules by tRNA. that they “mosaics,” each of which contained sequences from noncontiguous sites in the viral The spliceosome system is one of the most genome (Berget et al., 1997; Chow et al, 1977). widely understood splicing mechanisms. Five small These mosaics were found late in viral infection. nuclear RNAs (snRNAs) and more than 50 different Studies of early infection revealed long primary proteins comprise the splicing mechinery. snRNAs RNA transcripts that contained all of the sequences are essential splicing factors. Each snRNA aggregates

IPR BIOTECHNOLOGY 12 WISTA APRIL 2009

with various proteins to achieve five distinct small and U6. The genes encoding these snRNAs are nuclear ribonucleoprotein (snRNPs) complexes highly conserved in vertebrate and insects and are (U1, U2, U3, U4, U5). These snRNP complexes also found in yeasts and slime molds indicating and other protein splicing factors, collectively called their importance. the spliceosome, determine the exon-intron borders of the pre-processed mRNA. It is believed that the Analysis of a large number of mRNA genes has RNA (not the protein) are the active sites for the led to the indentification of highly conserved reaction. The proteins serve to initiate, stabilize, and consensus sequences at the 5' and 3' ends of essentially break the RNA-RNA interactions that form during all mRNA introns. this process. A set of enzymes cuts the intron from the RNA and joins the two ends or exons. The U1 RNA has sequences that are complimentary to sequences near the 5' end of the intron. The There are several different classes of reactions binding of U1 RNA distinguishes the GU at the 5' end involved in intron removal. The two most common of the intron from other randomly placed GU are the group I and group II intron. Group I introns sequences in mRNAs. The U2 RNA also recognizes are found in nuclear, mitochondrial and chloroplast sequences in the intron, in this case near the 3' end. rRNA genes, group II in mitochondrial and The addition of U4, U5 and U6 RNAs forms a chloroplast mRNA genes. Many of the group I complex identified as the spliceosome that then and group II introns are self-splicing, i.e. no additional removes the intron and joins the two exons together. protein factors are necessary for the intron to be accurately and efficiently spliced out. In comparing different tissues or developmental stages, the mRNA produced from the same gene Group I introns require an external guanosine may be different depending on how the RNA gets nucleotide as a cofactor. The 3-OH of the guanosine processed. Thus, for an identical gene, many different nucleotide acts as a nucleophile to attack the proteins can be produced. The process is called 5-phosphate of the 5 nucleotide of the intron. The alternative splicing and represents an important resultant 3-OH at the 3 end of the 5 exon then attacks principle in how the genetic message is determined. the 5 nucleotide of the 3 exon releasing the intron and It is not definitely determined at the stage when covalently attaching the two exons together. The 3 end the RNA is first synthesized. Instead, the splicing of the 5 exon is termed the splice donor site and the 5 pattern determines how the genetic information end of the 3 exon is termed the splice acceptor site. will be delivered and the nature of the final protein product. Group II introns are spliced similarly except that instead of an external nucleophile the 2-OH of an Patent Scenario adenine residue within the intron is the nucleophile. This residue attacks the 3 nucleotide of the 5 exon Upto March 31st 2009, there were twelve hundred forming an internal loop called a lariat structure. The 3 and sixty (1260) US patents on RNA splicing. Some end of the 5 exon then attacks the 5 end of the 3 exon of them are briefly mentioned below. as in group I splicing releasing the intron and covalently attaching the two exons together. • On March 31, 2009, USA scientists Crooke, Roseanne M et al won the US patent (7,511,131) The third class of introns is also the largest class entitled, Antisense modulation of apolipoprotein B found in nuclear mRNAs. This class of introns expression. In the invention, Antisense compounds, undergoes a splicing reaction similar to group II introns compositions and methods are provided for modulating in that an internal lariat structure is formed. However, the expression of apolipoprotein. The antisense the splicing is catalyzed by specialized RNA-protein compounds, particularly antisense oligonueleotides, complexes called small nuclear ribonucleoprotein targeted to nucleic acids encoding aplipoprotein B. particles (snRNPs, pronounced snurps). The RNAs Methods of using these compounds for modulation found in snRNPs are identified as U1, U2, U3, U4, U5 of apolipoprotein B expression and for treatment

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of diseases associated with exprcssion of acids this this this invention relates to compounds, apolipoprotein B are provided. particularly oligonucleotides, specifically hybridizable with nucleic acids encoding C-reactive protein. Such • A group of Texas’s (USA) scientists, Thorpe, compounds have been shown to modulate the expression et al won the US patent (No. 7,511,124) March of C-reactive protein. 31, 2009, entitled ‘Compositions comprising phosphatidylethanolamine-binding peptides linked • Texas’s scientists Fewell, Jason G et al on February to anti-viral agents’. The invention covers discoveries 17, 2009, were awarded the US patent (No. 7,491,537) concerning the role of anionic phospholipids and entitled ‘Nucleic acid formulations for gene delivery aminophospholipids in tumor vasculature. The invention and methods of use’. In the invention, a nucleic acid also provides a number of preferred antibody for use in formulation for use in gene delivery comprising a the safe and effective treatment of cancer, viral infections nucleic acid and anionic polymer is disclosed. and related diseases. • Ruben, et al of USA got the US patent • USA scientists Wei, et al were awarded the (No.7,482,442) on January 27, 2009, entitled US patent (No. 7,511,017, March 31, 2009) entitled ‘HEMCM42 nucleic acids’. The invention relates to ‘Methods of treatment with with TNFR5’. The novel human secreted proteins and isolated nucleic invention relates to a novel human gene encoding acids containing the coding regions of the genes a polypeptide which is a member of the TNF encoding such proteins. Also provided are vectors, receptor family, and has now been found to bind host cells, antibodies, and recombinant methods for TRAIL. The invention further relates to screening producing human secreted proteins. The invention methods for identifying agonists or antagonists of further relates to diagnostic and therapeutic methods TRAIL polypeptide activity. Also provided are useful for diagnosing and treating disorders related to diagnostic and therapeutic methods utilizing these novel human secreted proteins. such compositions. • Song, Xias-yu R et at were awarded US patent (No. • Maryland’s (USA) scientists Roschke et al obtained 7,497,479) on January 20, 2009) entitled ‘CNGH0010 the US patent (No. 7,501,123) on March 10, 2009, specific polynucleotides, polypeptides, antibodies, entitled on ‘Human G-protein chemokine receptor compositions methods and uses’. The invention relates (CCR5) HDGNR10’. The invention relates to a human to CNGH0010 polypeptides, variants, and fragments protein called Human G-protein Chemokine receptor thereof, and antibodies and anti-idiotype antibodies (CCR5) HDGNR10, and isolated polynucleotides specific therefor, as well as nucleic acids encoding encoding this protein. The invention further relates such CNGH0010 polypeptides, variants, fragments, to diagnostic and therapeutic methods useful for antibodies, complementary nucleic acids, vectors, diagnosing and treating diseases, disorders, and/or host cells, and methods of making and using thereof, conditions related to this human protein and these including diagnostic and therapeutic formulations, human antibodies. administration and devices.

• Kotkow, et al on 3rd March 2009, won the Conclusion US patent (No. 7,498,304), entitled ‘Angiogenesis- modulating compositions and uses’. The invention The existence of introns and differential splicing relates that hedgehog agonists and antagonists have helps explain how new genes are created during utility in modulating tissue repair and the treatment of evolution. Splicing makes genes more “modular,” many forms of cancer. allowing new combinations of exons to be created during evolution. Furthermore, new exons can be • On February 17, 2009, Crooke, et al of California inserted into old introns, creating new proteins were awarded the US patent (No. 7,491,815) entitled without disrupting the function of the old gene. ‘Antisense modulation of C-reactive protein expression’. Introns and splicing have clearly played a significant The invention provides compositions and methods for role in evolution, and scientists are only beginning to modulating the expression of C-reactive protein. In discover the nature of that role.

IPR BIOTECHNOLOGY 14 WISTA APRIL 2009

CLINICAL TRIALS AWARDS

BETAS Safety Trial Results Novo Nordisk Prize

The Canadian public biotechnology company, Action Pharma A/S, a Danish biotech company, Stem Cell Therapeutics Corp. focuses on the announced that Soren Nielsen, its CEO has been development and commercialization of drug-based awarded the Novo Nordisk Prize 2009. The Novo therapies to treat central nervous system Nordisk Prize was founded by the Novo Nordisk diseases. The company made poster presentation Foundation and is awarded in the Foundation’s at the International Stroke Conference, February name and from the Foundation’s funds. The prize is 19, 2009. The poster presentation was entitled awarded, without application, in recognition of unique “Safety of Beta-hCG and EPO in Acute Ischemic medical research or other research contributions that Stroke.” It was a presentation of the complete are of benefit to medical science. The prize is awarded positive results of the Phase IIa BETAS trial, and for a predominantly Danish contribution. comprehensive evaluation of the safety and efficacy The prize was awarded based on Soren Nielsen’s results of the completed Phase IIa BETAS trial. and his colleagues’ discoveries on the fundamental role of cell membrane water channels (aquaporins) in (Stem Cell Therapeutics Corp, Feb 19, 2009) water balance regulation and that dysregulation of aquaporins play pivotal roles in water balance Phase II Trial of TB-402 disorders, including acquired and inherited kidney diseases, heart failure and brain edema. ThromboGenics NV and co-development partner Biolnvent International announced that This work was performed in close collaboration the first patient has been enrolled in the Phase II with 2003 Noble Prize winner in Chemistry for the trial with their long-acting anticoagulant TB-402 discovery of aquaporia water channels. for the prophylaxis of Deep Vein Thrombosis (DVT) following orthopaedic surgery. TB-402, (Action Pharma A/C, Feb 16, 2009) which is given as a single injection post Top Research Partner Award surgery, could overcome the major drawbacks such as bleeding and the need for extensive HD Biosciences Co., Ltd. (HDB), a Shanghai- patient monitoring associated with current anti- based biotechnology company specializing in high value coagulant therapy. drug discovery contract research services, has been awarded the Pfezer Inc “2008 Top Research Service TB-402 is a recombinant human monoclonal Partner Award” in recognition of quality, productivity, antibody that targets Factor VIII, a key component and value that HD Biosciences brought to Pfizer over of the coagulation cascade. TB-402 is a novel the past year. anticoagulant agent. The award was presented to president and CEO The Phase II trial is an active (enoxaparin)- of HDB by Richard Connell, and Head of the External controlled, dose-escalating, multicenter, prospective, Research Solutions Center of Excellence in Pfizer. randomized, open label trial evaluating TB-402 HD Biosciences has been collaborating with for the prophylaxis of DVT after knee surgery. multiple Pfizer research sites to provide top quality biology discovery services ranging from assay (ThromboGenics NV, Biolnvent International, Feb development and validation, to plate based screening 24, 2009) in both cell-based and biochemical assay formats. (HD Biosciences Co., Feb 25, 2009)

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into something that can make one sick. The FINE TUNING finding has implications for how scientists identify and assign risk to emerging diseases in the environment. This section attempts to fine-tune some basic concepts on a subject of interest about which one The researchers found that bacteria can develop might have already heard of. The current issue into illness-causing pathogens by rewiring features “Diseases vs Bacterial Genes”. regulatory DNA, the genetic material that controls disease-causing genes in a body. Previously, disease Diseases vs Bacterial Genes evolution was thought to occur mainly through the addition or deletion of genes. Since long effort has been going on to detect how diseases evolve. A lot of diverse explanation According to Brian Coombes, assistant professor about the subject has been presented. Traditionally, of Biochemistry and Biomedical Sciences at evolutionary biologists have viewed mutations McMaster University, bacterial cells contain about within individual genes as the major source of 5,000 different genes, but only a fraction of them phenotypic variation leading to adaptation through are used at any given time, the difference being able natural selection, and ultimately generating diversity to cause disease or not cause disease, lies in among species. Although such processes must where, when and what genes in this collection are contribute to the initial development of gene turned on. The scientists have discovered how functions and their subsequent fine-tuning, changes bacteria evolve to turn on just the right combination in the genome whole through gene acquisition of genes in order to cause disease in a host. In view and functions, are the major events underlying of Coombes, above incidence is similar to playing the emergence and evolution of bacterial pathogens a musical instrument-one has to play the right keys and symbionts. Furthermore, pathogens and in the right order to make music. symbionts depend on similar mechanisms for interacting with hosts and show parallel trends in With infectious diseases on the rise, the genome evolution. McMaster finding has implications on how new pathogens are identified in the environment. Scientists Bacteria, tiny organisms, are typically present currently monitor the risk of new diseases by in almost every habitat on the planet. Even though assessing the gene content of bacteria found in they measure just a few micrometres, they prove water, food and animals. life-threatening. They are ubiquitous to soil, radioactive waste, water, biomass and even Bacteria display a wide diversity of specialized organic matter. Bacteria inhabit the bodies of interactions with eukaryotic hosts. A common way life forms, like plants and animals. They are to classify bacterial-eukaryote associations is much more in number than the human cells in along an axis from pathogenic to mutualistic. From the human body. Bacteria play a very vital role the host perspective, this distinction is central. But in recycling nutrients. While majority of bacteria for the bacteria themselves, pathogenesis and in the human body are encountered by the immune symbiosis present similar obstacles. Primary system, there are a few that are pathogenic among these is the invasion of host cells or tissues in nature. Pathogenic bacteria cause infectious in the face of generalized cellular and chemical diseases like leprosy, cholera, anthrax and defenses. Remarkably, studies during the past bubonic plague. decade of a number of phylogenetically diverse pathogens of plants and animals have shown Recently, researchers of the Michael G. DeGroote that host invasion often depends on a set of Institute of Infectious Disease Research have evolutionarily homologous genes that have been discovered a new way that bacteria evolve transferred among distinct bacterial lineages.

IPR BIOTECHNOLOGY 16 WISTA APRIL 2009

DNAPrint Genomics for genotyping kits and DNA LEGAL SCENE analysis kits that it ordered from Illumina and didn’t pay for, as stipulated under a contract between the firms in April 2007. Fosrenol Lawsuit Between December 2006 and June 2008, Shire plc announced that it has filed a lawsuit in DNAPrint entered into nine separate purchase order the US District Court of the Southern District of contacts with Illumina. The suit alleges that although New York against Inc, Mylan Pharmaceuticals Illumina provided all of the products under the Inc and Matrix Laboratories Limited (collectively agreements, DNAPrint never made payments “Mylan”) for infringement of Shire’s US patent No. on the products. 5,968,976 (“976 Patent”). Illumina has demanded a jury trial seeking The lawsuit was filed in response to an payment of the full amount due, plus interest and the Abbreviated New Drug Application (“ANDA”) award of attorneys’ fees. filed by Mylan seeking FDA approval to market and sell generic versions of Shire’s 500 (GenomeWeb Daily News, Mar 16, 2009) mg, 750mg, and 1g FOSRENOL® (lanthanum carbonate) products. Infringement Action

Under the Hatch-Waxman Act, because Shire Cook Incorporated announced that as part of filed its patent infringement lawsuit within 45 days its global effort to protect its extensive intellectual of receiving Mylan’s Paragraph IV notification letter, property portfolio, it will appeal promptly an initial the FDA must refrain from approving Mylan’s ruling by the District Court of Dusseldorf, Germany ANDA for 30 months, or until a District Court denying the company’s claim that Edwards decision finding that the patent is invalid or not Lifesciences is infringing Cook’s German patent infringed, whichever occurs earlier. The stay on for transcatheter valve technology. generic approval will expire on April 26, 2012 unless terminated earlier. Cook filed the action in February 2008, claiming that the Sapien THV valve made by Edwards Shire has asserted the ‘976 patent based upon infringes Cook’s German patent. Despite the information provided to it by Mylan. Shire will decision , the company remains convinced that the continue to evaluate the situation throughout the Edwards product infringes Cook’s. In addition, Cook litigation and will take all necessary actions to legal counsel stressed that the company is protect its rights to the fullest extent possible. Shire committed to establishing and defending its patent has a robust patent estate and is confident that it rights in this growing field of medical technology will protect the FOSRENOL franchise. on a global basis. (Shire plc, Mar 20, 2009) Cook Medical was one of he first companies to Illumina Suit Against DNAPrint help popularize intervention medicine, pioneering many of the devices now commonly used worldwide Illumina has filed a lawsuit against DANPrint to perform minimally invasive medical procedures. Genomics and its Ellipsis Biotherapeutics subsidiary Today, the campany integrates minimally seeking payment for products Illumina shipped to the invasivemedical device design, biophrma, gene and firm in 2007-2008. cell therapy and biotech to enhance patient safety and improve clinical outcome in the fields of aortic According to the suit filed in the US District intervention; interventional cardiology. Court for the Southern District of California, Illumina is seeking nearly $275,000 in payments from (Business Wire, Mar 19, 2009)

17 IPR BIOTECHNOLOGY WISTA APRIL 2009

Legislation to Boost Clinical Trials The company announced that it has filed two lawsuit in US District Court in Delaware against A Senate Bill 39, mandated that healthcare Teva Pharmaceuticals USA, Inc. (“Teva”) and plans continue to pay routine medical care costs Mylan Pharmaceuticals, Inc. (“Mylan”) for for patients with life threatening illnesses who enroll infringement of US Patent No. 5,747,498, US Patent in clinical trials in Texas. According to the No. 6,900,221 and US Patent No. 7,087,613. All proponents of the bill, it would help Texas health- three patents are associated with Tarceva® (erlotinib). care and bioscience landscapes. The proposed mandate would remove a financial barrier from The lawsuits are based on Abbreviated New clinical-trials patients. Drug Applications (ANDs) filed by Teva and Mylan seeking permission to manufacture and market a (Austin Business Journal, Mar 27, 2009) generic version of Tarceva before the expiration of the three patents. The filing of these lawsuits restricts Skelaxin Patent Invalidated the FDA from approving Teva and Mylan’s ANDAs until May 18, 2012 (the statutory stay period), , Inc. reported that the US unless an adverse adverse court ruling occurs District Court for the Eastern District of New York in prior to such time. the case of King Pharmaceuticals, Inc., et al. v. Eon Labs Inc., issued an Order invalidating United OSI plans to vigorously protect and enforce the States patent Nos. 6,407,128 and 6,686,102, two intellectual property rights of Tarceva. patents relating to SKELAXIN® (metaxalone). (Business Wire, Mar 20, 2009)

The company plans to appeal the order, which Warner Chilcott Infringement Lawsuit was issued in response to Eon's motion for summary judgment without the benefit of a hearing. Warner Chilcott is a leading specialty Furthermore, the order is unrelated to the company's pharmaceutical company currently focued on the pending litigation against Sandoz, Inc., successor to women's healthcare and dermatology segments of Eon, in the US District Court for the District of the US pharmaceuticals market. The company is a New Jersey regarding Unted States Patent fully integrated company with internal resources No. 7,122,566, an additional patent relating to dedicated to the development, manufacture and SKELAXIN® which is listed in the US Food and promotion of its products. Drug Administration' s Approved Drug Products with Therapeutic Equivalence Evaluation (the The company announced that one of its "Orange Book"). Importantly, Sandoz does not subsidiaries and Mayne Pharma International Pty. currently have an Abbreviated New Drug Ltd. ("Mayne") have filed lawsuit aganist Application approved by the US Food and Drug Elizabeth LLC ("Actavis") in the District Court for Administration to market a generic version of the District of New Jersey for infringement of SKELAXIN®. Mayne's US Patent No. 6,958,161 (the "161 Patent") which covers DORYX, a tetracycline-class oral (Business Wire, Jan 22, 2009) antibiotic. Warner Chilcott markets and sells DORYX delayed-release tablets in 150,100 and Suit Against Teva 75 mg strengths under a license agreement with Mayne. Warner Chilcott has previously announced OSI Pharmaceuticals is committed to “shaping the filing of similar lawsuits aginst each of medicine and changing lives” by discovering, Mutual Pharmaceutical Company, Inc., Mylan developing and commercializing high-quality, novel Pharmaceuticals Inc., Impax Laboratories, Inc. and and differentiated personalized medicines designed Sanzon Inc. to extend life and improve the quality of life for patients with cancer and diabetes/obesity. (Warner Chilcott Limited, Jan 30, 2009)

IPR BIOTECHNOLOGY 18