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Also inside: Tumour detection, torque, aviation safety and more

The latest innovations, collaborations and technology transfer

Issue 67 Spring 12

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24
Information
03. Newsflash 05. The Portfolio

Issue 67

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Contents

No-hands navigation
Autonomous vehicles for land and sea

18
Invention

Cardiology focus
Drug discovery, treatment and remote monitoring

The latest news from Isis

12. Stiff challenge

Torque measurement and control

04. Enterprising Consultancy

Insights from Oxford University Consulting and Isis Enterprise

14. Breaking down barriers 16. Pressure point

Brain tumour detection and treatment

Investment and spin-out news

Reinventing pressure regulation

Innovation
06. Kuraray
Oxford Innovation Society (OIS) member profile

18. Compelling rhythms

Safe antiarrhythmic drug discovery

19. Confronting cardio disease

Prevention and treatment

08. From droplets to tissues

20. Stethoscope solution

The synthetic biology research of OIS speaker Professor Hagan Bayley

Remote monitoring of the heart

21. Bacterial breakthrough 22. Let there be light

10. Patenting value

Gene-based bacterial identification

OIS speaker Dr Lee Chapman, of J.A. Kemp & Co, discusses patenting

Improved bandwidth for optical wires

Inspiration
24. No-hands navigation
Oxford University Consulting and the Oxford Mobile Robotics Group

26. Optimising IP Portfolios

Isis Enterprise and the Kennedy Trust

Ii is produced by Isis Innovation Ltd, the technology transfer company owned by the University of Oxford. Isis Innovation Ltd 2012 For authorisation to reproduce extracts from this publication please contact Isis. To receive your free copy of Ii, email innovation@isis.ox.ac.uk www.isis-innovation.com

Isis Innovation: Information 2

News

flash
Successes from Oxford
Spin-out companies from Isis continue to make the headlines. Yasa Motors, formed in 2009, is supplying electric motors to the recently launched Lola-Drayson Formula 1 racer (pictured below), which functions as a technology demonstration platform showing the potential of an electric vehicle. 2005 spin-out Oxford Nanopore announced its game changing and truly disruptive MinION DNA sequencer to enthusiastic media response. The size of a USB memory stick, it is expected to retail at less than $900 and is set to revolutionise the industry. Featured on the cover of this edition is a fully autonomous road vehicle, based on a Bowler Wildcat, being used by the Mobile Robotics Group to demonstrate the futuristic concept of infrastructure-free navigation. Oxford University Consulting, part of Isis, is providing access to the information engineering expertise of this group for terrestrial and maritime applications (see page 24).

Information

Isis is a research and technology commercialisation company owned by the University of Oxford. Research funding fuels innovation
Innovation comes in many forms, but almost always as a result of original research. In the last financial year the University of Oxford received more than 500m in research funding more than any other UK institution which supports the breadth and depth of research activity at Oxford. It is of course the results of this research which are commercialised for the benefit of society by Isis. So it should be no surprise that the University is also ranked first amongst UK institutions in terms of the number of mature patents it has filed over recent years according to a recent report by consultancies PatAnalyse and TechnologiCa. Responding to an invitation from the Science and Technology Commons Select Committee, Isis contributed to a governmental study on improving the commercialisation of research. We applaud any initiative to support fledgling businesses, we hope to see greater encouragement for businesses and people investing for the long term, and we look forward to sectors such as healthcare and defence in the UK enthusiastically adopting new technologies.

Early successes from the Isis Software Incubator

After just a year the Isis Software Incubator already has two successful start-up companies to its name Pilio (highlighted in Isis Insights 66) and TheySay, a powerful Sentiment Analysis tool which launched in February to widespread interest. Further successful exits will be announced over the coming months.

International expansion
Following the establishment of Isis offices in China and Spain, we have now opened an office in Japan. Headed by Kenji Aiba OBE, the office in Kyoto is a focal point of Isis activity to strengthen business relationships with industry, investors and academia in Japan.

Photo: Jakob Ebrey Photography

Isis Innovation: Information 3

Enterprising Consultancy
News from Oxford University Consulting and Isis Enterprise
Consulting: the challenges
While Oxford University Consulting (OUC) has yet to manage the impossible, it did recently prove it could manage the near impossible. In consultancy terms, it was the perfect storm: a request for urgent help from a client just before Christmas and the University closing imminently for the holidays; the academic consultant due to go on annual leave immediately after the Christmas break; a client needing the deliverables yesterday; an 8 hour time difference to hamper discussions; and a language barrier which obscured nuances in the scope of work. condense out into the fuel during flight. The Photonics Research Group at Aston University has addressed this market need by developing a test based on optical fibre technology, with consultancy support from Isis Enterprise. The fibre is immersed into a fuel-water mixture and the signal from the fibre changes in the presence of water. The effect can be measured using a simple optical setup and the water concentration can be measured within minutes. Only available test for dissolved water Quantitative measurement Reusable and repeatable Working closely with Isis office in China, OUC managed to clarify the clients precise requirements and a good working relationship with the academic consultant along with a subtle, but effective, negotiation meant contracts were exchanged and work started in record time, demonstrating that miracles, albeit small ones, do indeed happen at Christmas time. Commercial sensitivity precludes discussion of project details, but what the story demonstrates is that OUC is well versed in handling tricky, multicultural, time-sensitive negotiations in a manner that does not compromise the expectations of the client, protects the interests of the academic consultant and respects the processes of the University.

Safe flying
Water in fuel is a serious problem, especially in aviation where the water can freeze and block the flow of fuel to the engine. This was the cause of the crash of BA38, a Boeing 777, on its approach to Heathrow from Beijing in January 2008, according to the UK Air Accidents Investigations Branch. Fortunately no one was killed. The accident was caused by normal levels of dissolved water condensing out into the fuel to form an emulsion, as the bulk fuel temperature dropped at high altitude. Ice crystals formed and blocked the fuel filters. The aviation industry has been aware of the water in fuel problem since the 1950s and has addressed this with several technologies including a test for undissolved water in aviation fuel. Tests are typically made on fuel prior to fuelling the aircraft, and no subsequent tests are made on the fuel in the airframe. To date, there is no standard test to determine the amount of water in aviation fuel and there exists an opportunity to measure the amount of dissolved water in fuel to determine when and how much water will

For more information, please contact: Dr Roger Welch Senior Consultant Isis Enterprise T +44 (0)1865 280854 E roger.welch@isis.ox.ac.uk

For more information, please contact: Gurinder Punn Project Manager Oxford University Consulting T +44 (0)1865 280826 E gurinder.punn@isis.ox.ac.uk

Isis Innovation: Information 4

The portfolio
The latest spin-out and investment news
The backstory and eclectic applications of a potential spinout with magnetic appeal
Low power magnetic field receivers fitted to badgers (coupled with magnetic fields above ground) allowed a researcher from Oxfords Department of Computer Science to track the animals in 3D. Dr Andrew Markham exploited the unique feature of magnetic fields to penetrate soil and rock and, in doing so, he unearthed groundbreaking applications for Location Based Services (LBS). Potential commercial applications for this technology exist in both the enterprise and consumer markets. For example, the capacity to penetrate soil and rock means that the technology could be invaluable to the mining industry. An emergency event, such as a rock burst or collapse, can isolate portions of underground tunnels, severing wired communication links and preventing radio communication. Low frequency magnetic fields can penetrate horizontally and vertically regardless of the tunnel structure and be used both to establish communication and localise trapped miners. Recent mining disasters have highlighted the need for this type of application. The technology also has wide ranging applications in the indoor navigation consumer market with its unique ability to penetrate walls and to avoid the multipath signal effect hampering some current indoor location technologies. End users could access this technology through a smartphone equipped with specialised magnetic field receivers (magnetometers). Basic magnetometers are already used in some smartphones, as sensors for an electronic compass, for example. The indoor navigation market is the next LBS frontier, driven by the increasing ownership of smartphones and the Location Based Advertising (LBA) market. In 2015

global smartphone sales are predicted to reach one billion units and by 2017 it is said that the global LBA market will be worth $12.8 billion. Taking advantage of this trend, the technology could be used to develop indoor navigation applications to locate people, places and products in venues such as airports, shopping centres, supermarkets, department stores, museums, exhibition centres, sports stadiums, overground and underground train stations and skyscrapers. This magnetic technology and its LBS market potential has been successfully presented to the University Challenge Seed Fund for the financial support of a commercial prototype.

The location technology, with its solution based applications, creates strong opportunities in multiple growth markets. This, combined with its global appeal, all add up to a spin-out with profitable prospects and boundless opportunities. Isis is now looking for potential investors to support in the commercialisation of this technology.

For more information, please contact: Andrea Alunni Seed Investment Manager Isis Innovation T +44 (0)1865 280843 E andrea.alunni@isis.ox.ac.uk

Isis Innovation: Information 5

Kuraray
Oxford Innovation Society member Kuraray is a chemicals company with particular expertise in polymerisation and synthetic chemistry. Kikuo Arimoto, from the R&D division, showcases the product range and plans for the future.

Kuraray is opening new fields of business using pioneering technology and contributing to an improved natural environment and quality of life. Its range of highly original products, from a solid technological base, are in demand in various fields including the sectors involved in chemicals, resins, high performance materials, fibres, and medical products.

the thermoplastic elastomer SEPTON and industrial cleaning agents, and pharmaceutical intermediates using isoprene. Our heat-resistant polyamide resin GENESTAR exhibits excellent resistance to abrasion as well as superior chemical resistance properties and is used in electronic and automotive components. Demand for GENESTAR has also grown in LED reflector applications used in TVs equipped with LEDs in the backlighting device.

Chemicals and resins

The synthetic resin POVAL/Mowiol, polyvinyl alcohol (PVA), is used in a wide range of products, from fibre sizing agents to polarised films for liquid crystal displays. The PVB polyvinyl butyral resin made from PVA has adhesive strength and transparency and is used for glass interlayers, encapsulation of solar cell modules and more. The EVOH (ethylene vinyl alcohol copolymer) resin EVAL boasts superior gas-barrier properties and is used for food packaging and automobile fuel tanks. Methacrylic resin, used for optical components and construction materials. Kuraray has also developed

Fibres
PVA fibre KURALON has a high level of strength, low elongation, hydrophilic properties, excellent durability and is used in various industrial applications. Man-made leather CLARINO holds the top place in the world market, and is in high demand for shoes, bags and sporting goods. In addition, the full-scale operation of a mass-production, environmentally friendly man-made leather production system started in 2009.

Diversity
Kuraray also has a water treatment business, which is expanding, and is

Isis Innovation: Information 6

Kuraray believes its technological innovations can provide unique and effective contributions for resolving issues threatening our planet and the living environment.
working on waste reduction and the reuse of valuable materials. Other business areas for Kuraray include the manufacture and sale of dental repair materials. leveraging its technical and market knowledge and harnessing the value creation potential of the entire group. In response to the effects of the global economic crisis Kuraray has instigated an action plan known as GS-Twins to firmly establish Kuraray as a profitable specialty company. The plan combines two main concepts: Green & Safety and Growth & Sustainability, and has three key initiatives: improving profit structure creation and expansion of new business acceleration of global strategy for core businesses By adopting and executing this plan Kuraray is preparing a foundation for sustainable growth, while contributing to the resolution of issues that threaten our planet and the environment. Image: Polarised LM of liquid crystals

The Oxford Innovation Society (OIS) is a network which exists to encourage Open Innovation between academia, industry and business. Many of the worlds leading companies are, or have been, members. Introductions and networking opportunities are provided for members to meet leading academics and other business leaders, and Isis provides early access to new technology available to license. Members can promote their products and services to each other and to the Oxford ecosystem through various channels, including articles such as this one.

Looking ahead
Kuraray has a 10-Year Corporate Vision which guides the long-term direction in which the Kuraray Group is heading. It presents a clear image for growth with the goal of achieving one trillion Japanese Yen ($12.6 billion) in net sales as a cornerstone for establishing Kurarays global presence as a specialty chemical company. Kuraray also believes its technological innovations can provide unique and effective contributions for resolving issues threatening our planet and the living environment. The company works to achieve harmony with all of its corporate activities, the environment and society. Kuraray is placing emphasis on new energy-related business, aqua and environmentally friendly materials. The group believes that these perspectives on its role and the contributions it can make to society are what will make it possible for Kuraray to achieve long-term sustainable growth. It plans to maximize growth capabilities by

For more information, please contact: Kikuo Arimoto Research and Development Kuraray Europe GmbH Hoechst Industrial Park, 65926 Frankfurt, Germany T +49 69 305 85906 E kikuo.arimoto@kuraray.eu www.kuraray.co.jp/en/

Isis Innovation: Information 7

From Droplets to Tissues

Professor Hagan Bayley, of the Department of Chemistry, delved into the world of multisomes and synthetic biology in his presentation to the Oxford Innovation Society in December.
Hagan Bayley is Professor of Chemical Biology in the Department of Chemistry at Oxford University. After starting his academic career in Oxford, he moved to work at Harvard, MIT, Columbia and Texas A&M Universities, before returning to Oxford in 2003. His lab focuses on the science of membrane proteins, how they function and how they can be used and manipulated to move polymers from one side of a cell membrane to the other. This multidisciplinary work, spanning the interface of chemistry with biology and physics, was the foundation for the Oxford University spinout company Oxford Nanopore, formed in 2005, which is using membrane pore technology to develop a sensing platform for next generation DNA sequencing. However, in his talk at the December Oxford Innovation Society meeting, Professor Bayley explored a new and exciting area of research in his lab that of multisomes. Multisomes hold particular promise for synthetic biology, building artificial prototissues for medical applications. They are assemblies of lipid-encapsulated droplets formed by introducing water droplets into a solution of lipid in oil. Due to the amphipathic properties of lipid molecules, they form monolayers around the water droplets, and bringing these lipid-coated droplets together forms an artificial lipid bilayer between them which mimics cell membranes. Proteins can then be inserted into the bilayer. By incorporating different types of membrane proteins, for example pumps, channels or pores, which can be engineered as required, these droplets can communicate and interact with each other, forming functional networks to either mimic the functioning of real cell membranes or introduce new properties. These droplets can therefore be used as building blocks, generating complexes of multiple droplets known as multisomes. Although this research is still at an early stage, it has potential applications in a wide variety of fields. The type of proteins inserted determine the properties of the network and what they could be used for. Using particular configurations of ion selective pores allows you to build miniature electrical circuits with electrical current flowing through the network carried by ions such as sodium or potassium and even miniature biobatteries generating electrical current, providing an internal power source for these networks. The Bayley lab has also experimented with engineered pump proteins that respond to light. Inserting these light-sensitive proteins, such as bacteriorhodopsin, into the network

Multisomes hold particular promise for synthetic biology, building artificial prototissues for medical applications.
Isis Innovation: Invention 8

allows you to switch on an electrical circuit simply by shining light on it. The recent work from the Bayley lab stabilising these multisomes and placing them in an aqueous environment means that they can now be used in biological and physiological settings. Suspending or encapsulating these droplets in gels or aqueous matrices means that they could be used to build 2D and 3D artificial cell-like networks a prototissue where the multicompartment framework of multisomes mimics a simple synthetic tissue. These could then be used in drug-testing of watersoluble therapeutics or drug-release systems triggered by external stimuli (such as temperature or pH). Multisomes could also potentially be developed as vehicles for binary drug delivery, with different molecules contained in different compartments such as a prodrug and an enzyme that activates it. This could be particularly useful for compounds that you simply cannot keep in a pill as they have very short lifetimes of only a few seconds, yet are very powerful effectors in the body. Microfluidics techniques allow you to produce well controlled multisomes with many compartments suitable for medical applications. Material consisting of these complex multisomes could act like a synthetic tissue in many respects and potentially

The prototissues could be used in drug-testing of watersoluble therapeutics or drug-release systems triggered by external stimuli.
interface with living tissues, with the idea of repairing organs or enhancing their properties.

Further reading:
Villar G, Heron AJ & Bayley H (2011) Nature Nanotechnology 6(12):803-8. Formation of droplet networks that function in aqueous environments. Needham D (2011) Nature Nanotechnology 6(12):761-2. Lipid structures: a brief history of multisomes.

For more information, please contact: Professor Hagan Bayley Department of Chemistry University of Oxford T +44 (0)1865 285101 E hagan.bayley@chem.ox.ac.uk

Isis Innovation: Invention 9

Patenting Value
Dr Lee Chapman of J.A. Kemp & Co. introduced some of the key patenting issues to consider when he spoke at the Oxford Innovation Society Meeting
What is a patent?
As a starting point, it is worth bearing in mind the purpose of a patent and how one is obtained. A patent is a deal between you and the state: you get a limited monopoly (that typically lasts for 20 years) in exchange for disclosing your invention to the world (all patents will be published). The monopoly means that you can stop others from using the invention. The claims in the patent define the patented invention and thereby what others cannot do. A patent will only be granted for an invention that is new, involves an inventive step, and is disclosed in a manner sufficiently clear to be reproduced by a person skilled in the art. undertaken by one of our clients, Oxford Nanopore Technologies Limited (www. nanoporetech.com). Oxford Nanopore was founded in 2005 on the science of Professor Hagan Bayley during his time at Texas A&M University. The company has since expanded its external IP to include collaborations with a range of institutions including the University of Oxford, Harvard and University of California Santa Cruz (UCSC), to complement its internally generated IP. Oxford Nanopores platform technology, GridION, has been developed for the single molecule analysis of many types of analyte including DNA, RNA and proteins, but the company is best known for its development of two new techniques for DNA sequencing using nanopores: strand sequencing and exonuclease sequencing. Oxford Nanopore has broad patent coverage in many countries: it has at least 10 of its own international (PCT) applications and licences or owns more than 300 patents and patent applications, including several families from collaborators such as Isis Innovation, Harvard and UCSC. Importantly, this broad coverage crosses all of Oxford Nanopores technology, including fundamental nanopore sensing techniques and chemistry, novel chemistries, novel electronics and engineering and novel data analysis techniques. It also includes future generations of nanopore technologies such as nanopores fabricated in synthetic materials like graphene.

What to patent
Patent claims are typically directed to (1) a product, (2) a method of manufacture or (3) a method of use. Not all products are patentable, for instance aesthetic creations (such as paintings) cannot be patented in Europe. Also, different countries have different laws concerning what can and cannot be patented. For instance, methods of therapeutic treatment can be patented in the US, whereas only products for use in therapeutic treatment can be patented in Europe. So what should be patented? The key questions to ask are: What is commercially interesting to you and your competitors both now and in the future? What is potentially patentable? What can be covered in the different countries of interest? By way of example, the above evaluation approach has been

Breadth of claims
Having decided what to patent, the next consideration is the breadth of the claims. The claims must cover your

Isis Innovation: Invention 10

current and future commercial interests and those of your competitors. However, it is necessary to balance monopoly with patentability. The scope of the claims determines what others cannot do, but broad claims will attract more prior art (i.e. are more likely to lack novelty or be obvious) and will cover more embodiments (that must be enabled by the patents disclosure).

Where can the patent be enforced? How much will it cost to file patent applications in the different countries of interest? The subject matter of the invention is important. Different countries have different laws. For instance, methods of diagnosis are not patentable in China irrespective of how they are performed. Also, it is important to be sensitive to local customs or beliefs, particularly if you wish to trade in a particular country. The aims of the company and the purpose of the patent application are interlinked. If you make and sell products and the purpose of the patent application(s) is to protect the product, then you should file the application(s) in those countries in which you make and sell the products. Patent applications should also be filed in those countries in which your competitors are based and trade if you wish to prevent them from using the invention or wish them to obtain a licence. If your aim is to attract investors and generate revenue from patent applications, then applications should be filed in the countries of most value. Such countries are invariably those countries in which you and your competitors are based and trade.

When to patent?
A patent application can be filed once you have at least one piece of experimental data supporting the invention. The more data the better, but it is worth bearing in mind that some countries allow you to file additional data in support of technical effects disclosed in the patent application later. It is also important to ensure that you do not shoot yourself in the foot by waiting for more data and accidentally disclosing the invention in a non-confidential manner before your application is filed because your own disclosure will be citable against your application in most countries.

Where to patent?
There are lots of issues to consider in relation to where to file a patent application. The key questions are: What is the subject matter of the invention? What are the aims of the company? What is the purpose of the patent application? Where are you based and where do you trade? Where are your competitors based and where do they trade?

For more information, please contact: Dr Lee Chapman J.A. Kemp & Co. T +44 (0)1865 406100 E lchapman@jakemp.com

Isis Innovation: Invention 11

Stiff challenge
Dr Andy Robertson introduces an approach to measuring shaft torque in low strain conditions which will provide improved measurement accuracy for the power generation sector and many other industries.
Monitoring the power delivered by a shaft is an important part of understanding its performance. From the initial validation that the system is operating as designed through to condition monitoring for improved reliability and efficiency, accurate measurements of shaft torque are vital. Unfortunately, this is easier said than done. In instances where the shaft must have high torsional rigidity, in particular, the standard approach of attaching strain gauges directly to the shaft is unreliable. The twist experienced by the strain gauge is simply too small perhaps as small as 0.001! Now, an Oxford inventor has found a solution to the problem of reliably measuring torque in low strain applications a mechanical shaft torque amplifier which offers a number of advantages over the traditional approach. It is expected that this new monitoring technique will be of interest to suppliers already active in the torque measurement field and to end user organisations working with low strain (i.e. high torsional stiffness) applications such as shafts that connect large industrial gas or steam turbines to electrical generators. These are designed to be very stiff to provide an extended life even if the shaft is exposed to increased stress. Improved torque measurement in this environment results in reduced risk of component failure and unscheduled downtime.

Amplifier advantages
By applying a strain amplifier technique, users of the Oxford invention can benefit from improved torque monitoring performance. Where conventional strain gauges with a gauge length in the range 3mm to 6mm may struggle to achieve 5% to 10% accuracy, strain amplification can achieve accuracies of the order of 0.1%. Furthermore, compact bolt-on packaging provides a retro-fit solution for existing installations and enables improved measurement without modifying the shaft or compromising its performance. In one configuration, the invention needs only 150mm of shaft length for installation and can be

In instances where the shaft must have high torsional rigidity the standard approach of attaching strain gauges directly to the shaft is unreliable.

Isis Innovation: Invention 12

Loosely speaking, torque is a measure of the turning force on an object.

fitted, replaced or removed in a matter of minutes without access to the ends of the shaft. With the amplifier, torque measuring equipment can be calibrated away from the shaft to minimise downtime. This lab-based calibration can be undertaken at lower torques using standard test equipment and can include temperature compensation if appropriate. Improved signal-tonoise ratio also makes measurement possible in environments where electrical noise sometimes prevents standard torque monitoring. Measurement accuracy will generally be improved where best practice noise reduction methods are also employed. The device can be integrated with signal conditioning and data transfer telemetry to provide a complete torque monitoring package. Depending on the application, the packaged solution can optionally contain an on-board power supply and thermocouple for operating temperature compensation. (Useful in the harsh environments encountered in a number of the target applications.)

Who needs this solution?

Whether measured torque is seen as a standalone performance characteristic or as an element in a comprehensive condition monitoring system, the amplifier provides a valuable addition to the users toolkit. Torque monitoring is used in a wide range of industries including power generation, marine, aerospace and automotive.

Patent protection
This work is the subject of a UK patent application and Isis welcomes interest from companies interested in licensing the technology.

Improved torque measurement in this environment results in reduced risk of component failure and unscheduled downtime.

For more information, please contact: Dr Andy Robertson Technology Transfer Manager Isis Innovation T +44 (0)1865 280931 E andy.robertson@isis.ox.ac.uk Ref: 7935

Isis Innovation: Invention 13

Breaking down barriers

Dr Martin Procter presents a method for delivering agents to detect and treat brain tumours through increasing the permeability of the blood-brain barrier.
Brain cancer is inherently serious and life-threatening. More than 9,000 people in the UK were diagnosed with brain or central nervous system tumours in 2008, causing more than 4,500 deaths. The brain is well protected by the skull and so detection usually only occurs in advanced stages when the presence of the tumour has caused unexplained symptoms. Now, Oxford researchers are hopeful that a new method will allow for earlier detection. once the tumour becomes significantly large to cause gross structural abnormalities to the barrier. Researchers at Oxford have uncovered a method that selectively increases the permeability of the blood-brain barrier at sites of secondary brain tumours. It has been discovered that a low dose of a cytokine called tumour necrosis factor-alpha (TNF) temporarily increases the permeability of the BBB, improving the delivery of agents that can detect brain tumours. The technology will serve as an important addition to the clinicians arsenal looking to treat these cancers as the method will also allow the dosing of drugs that cannot usually access the brain due to the blood-brain barrier.

Cancer spread
Metastasis, where there is a spread of the cancer from one organ to another part of the body, is one of the greatest hurdles in cancer therapy. Between 20 and 40 percent of all cancer patients will suffer metastatic spread of the primary cancer to the brain. Unfortunately, our inability to diagnose brain metastasis (BM) early enough and to obtain an accurate measure of the number of metastases present is a major limitation in the treatment and management of cancer patients. Clinical diagnosis of BM is limited to larger, late-stage metastases (>5mm) and early detection (<5mm) had previously proved impossible.

Supporting data
Using cytokine-enhanced MRI, detection of BM of the order of 100m in diameter in preclinical models has been achieved. Translation of these findings into the clinical setting would equate to diagnosis several months earlier than conventional gadolinium-based MRI. Importantly, this approach would facilitate specific delivery of potential therapies and radiosensitisers to early stage tumours, to enhance and extend current treatment options. The research work at the University of Oxford has demonstrated that: TNF can be used as an adjunct therapy to temporarily and reversibly increase blood-brain barrier permeability, improving the delivery of imaging agents.

Diagnosis and treatment

The blood-brain barrier (BBB) is the primary reason why diagnosis and treatment of BM is so problematic. It has specifically evolved to restrict the diffusion of many molecules into the brain, which includes imaging agents and many drugs. Accordingly, contrast agents for MRI can only cross the BBB

Isis Innovation: Invention 14

A low dose of cytokine temporarily increases permeability, improving the delivery of agents that can detect brain tumours.

Secondary brain cancer, MRI scan

Cytokines only induce breakdown of the blood-brain barrier local to tumour sites. This enables these sites to be imaged by MRI with contrast agents that are normally excluded from the brain. There is no effect on normal vasculature, the effect being specific to tumour vasculature.

The patent application covering the invention has recently been published: WO2011/070358 Systemic administration of an agent that permeabilises tumour vasculature. Image: Breakdown of blood-brain barrier

Market readiness
The Oxford research findings have all been achieved at much lower systemic doses than previously used to treat peripheral tumours and the BBB returns to normal on discontinuation of cytokine treatment.

For more information, please contact: Dr Martin Procter, Senior Technology Transfer Manager Isis Innovation T +44 (0)1865 280919 E martin.procter@isis.ox.ac.uk Ref: 6855

Isis Innovation: Invention 15

Pressure point
Oxfords new In-line Flow Control Device will reduce costs, make installation dramatically easier and increase reliability in all pipework systems, as Evert Geurtsen explains.
Oxfords In-Line Flow Control Device is an elegant solution to a longstanding problem of complex, bulky and fragile valve installations. The patent pending design is now available to licence to product developers for any gas and fluid handling systems. Pressure regulators are used for fluid and gas flow control in pipe systems and conduits. Applications are numerous and include the control of shop air in industrial applications, process fluids in industrial plants, transmission pipelines carrying water, oil or gas, heating and refrigeration systems, and many more. With so many uses in industrial and domestic applications pressure regulators are manufactured and distributed in very high volumes worldwide. Despite their widespread use, the predominant design of most regulator valves has a number of deficiencies. Large protruding parts, which are exposed to the environment, make the assembly bulky and create installation challenges. The new design developed in the Thermo-fluids Lab of the University of Oxfords Engineering Department offers a valve that can be entirely contained inside the pipe carrying the gas or liquid that is being regulated. With only a single moving part this elegant design creates a decisive improvement over existing designs. Oxfords In-line Flow Control Device can be used as a pilot operated pressure regulator or as a pressure reducing flow device that maintains an output pressure to a specific fraction of the input pressure. The fields of application are numerous as the device is applicable to almost any mass flow rate and pressure from very low to

In application, Oxfords In-line Flow Control Device: can be retro-fitted into existing pipe-work without plant modifications fits inside the flow conduit, requiring no additional space or protrusions from the conduit does not require its own certified pressure housing when fitted inside the existing, already certified, pipe-work has very low manufacturing cost in comparison to conventional devices can be produced and supplied inside a standard length of pipe, further facilitating storage, supply and installation has only a single moving part and no deformable or elastic parts, resulting in high reliability and low maintenance costs is fully protected from the environment can cope with very high mass flows can control from low (Pa) to ultra high pressure (MPa) flows has good adjustment for mass flow rate changes or pressure drops is scalable to any size

Isis Innovation: Invention 16

A prototype has been built and has an excellent record of reliable operation over an extended period of time in a real world industrial application.

extremely high, e.g. from communal gas supply systems to deep sea oil exploration. The invention delivers better than order-of-magnitude cost savings in manufacture. A prototype has been built and has an excellent record of reliable operation over an extended period of time in a real world industrial application. The technology has been demonstrated to Technology Readiness Level 7 and a patent application has been filed. Oxfords Engineering Department have developed a numerical model that can predict the valves dynamic behaviour in use. For the producers of regulator valves this is a great opportunity to introduce a new product range with genuine differentiation and tangible advantages for installers and operators. Isis Innovation is interested in meeting with companies that wish to bid for opportunities to brand and commercialise this remarkable invention, with particular interest in companies able to offer a rapid route to market in high volume applications.

For more information, please contact: Evert Geurtsen Technology Transfer Team Leader Isis Innovation T +44 (0)1865 614424 E evert.geurtsen@isis.ox.ac.uk Ref: 4220

Isis Innovation: Invention 17

ar d fo io cu lo s gy

Compelling rhythms
Existing antiarrhythmic drugs have proved only moderately effective and can produce adverse, life-threatening effects. Oxfords U-turn Protocol reveals potentially dangerous arrhythmogenic regimes undetectable using traditional methods. By Dr Natasha Tian.
An Oxford invention, named the U-turn Protocol, uses nonlinear dynamical phenomena to investigate biological cell system instability, including cardiac cells. These phenomena are important initiators of electrical instabilities, therefore the method can reveal potentially dangerous arrhythmogenic regimes that are not detectable using traditional protocols. The invention can be practised with current heart arrhythmia equipment and is suitable for use in laboratory conditions for screening single cells to large numbers of cells or organs in vitro or in vivo, as well as in clinical settings.

Advantages of the U-turn Protocol

This new screening system promises new opportunities for discovering safe and antiarrhythmic drugs, offering more reliable prediction of potentially dangerous arrhythmogenic regimes, improved assessment and earlier prediction of the appearance of cardiac instabilities. In addition, the U-turn protocol may accelerate research and development of new drugs by revealing hidden proarrhythmic effects during early pre-clinical studies, thereby reducing drug discovery and development costs.

Patent position
A PCT patent application has been made (Publication No. WO 2011/121307), covering methods and apparatus that use nonlinear dynamics to assess the proarrhythmic effects of drugs and heart arrhythmogenicity. Isis would like to talk to companies that are interested in developing this technology.

U-Turn Protocol potential

The Oxford tool may: Enhance the effectiveness of antiarrhythmic drug therapy by discerning the underlying mechanism of arrhythmia, which may suggest a more suitable drug. Re-evaluate already-marketed drugs in terms of their effect on cardiac dynamics and also correct the dose medications. Aid decision-making efforts in the selection and development of new drugs and help to assess the risk/benefit ratio of a given drug.

For more information, please contact: Dr Natasha Tian Technology Transfer Manger Isis Innovation T +44 (0)1865 280844 E natasha.tian@isis.ox.ac.uk Ref: 4315

Isis Innovation: Invention 18

C y g lo io s d cu ar fo

Confronting cardio disease

Oxford researchers have developed methods for preventing and treating cardiovascular diseases by modestly increasing intracellular creatine in the heart, as Dr Natasha Tian explains.
Merely increasing dietary creatine without also modulating creatine transporter activity is ineffective in tackling cardiovascular diseases. Using a cell-based screening method, Oxford academics have now identified promising therapeutic compounds that upregulate the creatine transporter. This allows for the potential treatment or prevention of ischaemia, reperfusion injury, coronary heart disease, heart attacks and angina. to have an effect lasting for several months.

Supporting data
Therapeutic agent screens for small molecules that upregulate the creatine transporter have produced several leads that are being followed up and the academics have elucidated the precise mechanism of action through which creatine exerts its effects. Pre-clinical work is currently ongoing to determine the benefits of increasing intracellular creatine in heart failure in combination with other metabolic therapies.

Therapeutic potential
Treatment prior to cardiac surgery Treatment as secondary protection for patients at high risk of myocardial ischaemia and infarction Prolonged treatment of angina Treatment of heart failure, particularly in combination therapy Protection of donor hearts prior to transplant Treatment of analagous brain conditions

Patent protection
An international patent application has been made (Publication No: WO 2011/058364). Isis would like to talk to companies that are interested in developing this technology.

Ischaemic damage
Elevating intracellular creatine prevents ischaemic damage from occurring by boosting cardiac energy reserves. In contrast, current therapies aim to correct ischaemic damage after it has occurred. Raising creatine levels represents a new therapeutic strategy that can be used alone or in combination with existing drugs with very different mechanisms of action, such as altering blood flow or the frequency and force of contraction. A further advantage may be that short-term dosing is likely

For more information, please contact: Dr Natasha Tian Technology Transfer Manger Isis Innovation T +44 (0)1865 280844 E natasha.tian@isis.ox.ac.uk Ref: 4222

Isis Innovation: Invention 19

ar d fo io cu lo s gy

Stethoscope solution
Dr Bharti Ranavaya reveals a stethoscope and phone application which records phonocardiograms and enables remote monitoring of heart rates and murmurs.
Researchers from the University of Oxford have developed a portable digital stethoscope and a phone application (for low-spec and high-spec phones). It enables basically trained healthcare workers to capture high quality phonocardiograms (PCGs) and transmit them to a central server for analysis and diagnosis by a trained expert. The technology also offers signal quality feedback. Electronic stethoscopes available within the marketplace do not offer these advantages. alleviating some of these problems. Low cost, easy to use medical devices which allow for early, constant monitoring and analysis by a doctor hundreds of miles away are in global demand.

Early diagnosis
The device was initially developed to target tuberculosis pericarditis, which affects around 10% of all TB patients and has a high mortality rate (40%) because sufferers in developing countries struggle to reach a clinic before it is too late. The ability to pick up the early warning signs of this and many other conditions is made possible through the Oxford invention. In the future it could also be utilised for pulmonary auscultations and foetal heart sound examinations.

Remote healthcare
Within both developing and developed countries there is a growing requirement for effective remote monitoring of patients. Within the UK, for instance, the NHS faces major financial challenges and reform which will see healthcare delivery shifting into the local community to reduce hospital administration and the use of beds. In developing countries such as South Africa and India a large percentage of the population live within rural areas where constant monitoring and hospital access is difficult and expensive. Remote healthcare workers have been employed in such areas to aid in

Clinical trials
A clinical trial was conducted in Cape Town, South Africa. Data from this study has not yet been published. Isis would like to speak to companies interested in reviewing this data in order to license and/or develop this technology.

The PCGs can be transmitted to a central server for analysis and diagnosis by a trained expert.
Isis Innovation: Invention 20

For more information, please contact: Dr Bharti Ranavaya Technology Transfer Manager Isis Innovation T +44 (0)1865 280909 E bharti.ranavaya@isis.ox.ac.uk Ref: 7159

Bacterial breakthrough
Dr Matthew Carpenter reports on the first gene-based bacterial identification system that can identify all bacteria.

High-resolution bacterial characterisation is essential in microbiology, particularly for disease diagnosis, where rapid and precise identification is a high priority. Gene-based methods have become increasingly important in bacterial classification, complementing and to an extent replacing more traditional phenotypic methods. However, until now, there has been no single system which works for all bacteria. Scientists at the University of Oxford have developed a universal identification scheme based on ribosomal multilocus sequence typing (rMLST). This represents the first genotypic scheme that can provide both broad and accurate characterisation of bacteria at all phylogenetic levels. The system works through the identification and analysis of allelic variation within the ribosomal protein subunit (rps) genes, which are universal yet record a wide range of evolutionary diversity, to effect rapid and highly accurate phylogenetic identification.

Supporting data
A web-accessible and expandable database comprising genome data from more than 2000 bacterial isolates has been generated. The variation of 53 rps genes is catalogued in this database, providing a means of defining the precise phylogenetic position of any bacterial sequence at the domain, phylum, class, order, family, genus, species and strain levels.

Applications
The data generated for the rMLST scheme could be used in combination with next generation sequencing to enable the rapid identification of bacterial isolates at the push of a button. Equally the database enables the development of PCR-based species or strain-specific diagnostic tests.

Applications include:
Population studies Epidemiological investigations Diagnostic tests

Benefits of the Oxford system

Reliable identification High resolution Results at push of a button One system for all bacteria

A web-accessible and expandable database comprising genome data from more than 2000 bacterial isolates has been generated.

For more information, please contact: Dr Matthew Carpenter Technology Transfer Manager Isis Innovation T +44 (0)1865 280970 E matthew.carpenter@isis.ox.ac.uk Ref: 7895

Isis Innovation: Invention 21

Let there be light

Dr Jon Carr looks at an inexpensive method for the fabrication of a microstructure which allows light to be efficiently coupled into or split out of the side of an optical fibre.
Sometimes known as optical wires, glass optical fibres are used for transmitting light over long distances with minimal loss, in much the same way as a metallic wire transmits electrons. Optical fibres are widely used in the telecommunication, sensor and laser design sectors and there is a market need to efficiently couple light into, or split light out of, these fibres. Oxford researchers have now conceived a solution. The working principle of the Oxford method to couple light into or out of the optical fibre is based on a simple notch coupler design (see diagram). A mirrored surface is fabricated at a 45 degree angle to the fibre axis and penetrates a desired distance into the fibre core. Virtually all of the light directed in at the mirrored surface from the side of the fibre is coupled into the fibre core. The method involves cutting an optical cable in half and cutting a notch at a certain angle in the corner of one of the exposed ends. Using a specific chemical process, aluminium is deposited just on this corner in order to create a discrete mirror. Reattaching the two cable ends creates an entrance and exit point in the optical fibre for light to be directed in or out. The academics have now perfected this low-cost and simple process to control the angle, cross-section area and mirror coating quality of the notch.

Advantages
Expands the range of fibre couplers and splitters to encompass any desired coupling/splitting ratio. Functions over a broad range of wavelengths, so bandwidth is improved in relation to couplers that only work at a particular wavelength. Efficient method to monitor laser spectroscopy equipment, by splitting out only a small percentage of the beam. Economical process to introduce a pump beam into fibre lasers.

Optical fibre technology

Despite their many advantages (capacity, unaffected by electromagnetic interference etc.) deployment of optical fibre technology has traditionally been held back by difficulties in achieving connections that are reliable, efficient and cost-effective. A wide variety of connector designs have been developed for different markets, most of which are substantially more complex than equivalents for cable and wire technology. Specialist splicing equipment required for connections in an optical cable can jeopardise the integrity of the original connection. The inexpensive and efficient method described here offers the potential for much simpler connections to tap signals into and out of optical fibre cables.

Isis Innovation: Invention 22

The academics have now perfected this low-cost and simple process to control the angle, crosssection area and mirror coating quality of the notch.
LIGHT IN

LIGHT OUT

Mirrored notch acting as both an input and output coupler.

Novel application
Fibre-loop cavity ring-down spectroscopy, developed for real-time detection in micro fluidics, demands high coupling efficiency. The Oxford method ensures nearly all of the light can be coupled into the fibre loop, with losses of less than a few percent. This represents an improvement of some magnitude over current technology.

The Oxford method ensures nearly all of the light can be coupled into the fibre loop, with losses of less than a few percent.

Optical fibres
An optical fibre typically consists of a doped silica core and cladding surrounded by a plastic buffer, which provides mechanical strength. The doping ratio is tuned so that the cladding has a lower refractive index than the core. Incident light is then trapped in the core by total internal reflection and the fibre acts as a waveguide.

Patent protection
This technology is now the subject of a patent application, and Isis would like to discuss with interested companies the licensing of the technology. Image: Bundle of optical fibres conducting light

For more information, please contact: Dr Jon Carr Technology Transfer Manager Isis Innovation T +44 (0)1865 280907 E jon.carr@isis.ox.ac.uk Ref: 7989

Isis Innovation: Invention 23

No-hands navigation
Andrew Goff, Head of Oxford University Consulting (OUC), introduces an exciting autonomous navigation innovation from the Oxford Mobile Robotics Group.
Researchers at Oxford are helping to build a future where autonomous vehicles will play an important part in all our lives and OUC is helping support the application of this research expertise by managing the consultancy of Professor Paul Newman and some of his colleagues in the Oxford Mobile Robotics Group. Robots will come in a variety of shapes and sizes and undertake a diverse set of tasks on our behalf, says Professor Newman. We will want them to carry things and transport us, labour for us and defend us. We shall want them to be flexible, reliable and safe. And they will need to work in a range of environments, sometimes hostile, and sometimes dynamically changing. Robots today already carry goods around factories, move stock around warehouses and manage our ports, but these are constrained, controlled

The Oxford approach allows computers in robots to interpret data from sensors like cameras, radars and lasers, aerial photos and on-the-fly internet queries.

Isis Innovation: Invention 24

and highly managed workspaces. In such environments the navigation task is made simple by installing reflective beacons or guide wires. However, Professor Newman and his co-workers are extending the reach of robot navigation to truly vast scales without the need for such expensive, awkward and inconvenient modifications of the environment. Their approach does not rely on GPS which, if available, does not offer the accuracy required for robots to make decisions about how and when to move safely. Even if it did, it would say nothing about what is situated around the robot, and that has a massive impact on autonomous decision-making. Instead, the Oxford approach is to use the mathematics of probability and estimation to allow computers in robots to interpret data from sensors like cameras, radars and lasers, aerial photos and on-the-fly internet queries. Professor Newman uses machine learning techniques to build and calibrate mathematical models which can explain the robots view of the world in terms of prior experience (training), prior knowledge (aerial images, road plans and semantics) and automatically generated web queries. His goal is to produce technology which allows robots to always know precisely where they are and what is around them. One of Professor Newmans most high profile projects to date is the Wildcat vehicle (see images), a fully autonomous road vehicle based on a Bowler Wildcat. With research supported by the Engineering and Physical Sciences Research Council (EPSRC), and in collaboration with BAE Systems and Nissan, it is among the first projects in the world to tackle the big challenges of creating an autonomous vehicle that can go anywhere and deal with all the situations it might encounter on the open road.

The technology installed in the Wildcat is set to remove the dependence on GPS, improve navigation precision, lower emissions, interpret local traffic conditions, track risks, and above all offer a hands-free experience to the driver. All this by interpreting a flood of data from sensors such as cameras, radars, and lasers mounted on the car itself. But the application of Oxford mobile robotics expertise is not only confined to terrestial environments. Guidance Navigation Limited (GNL), a leading developer and supplier of sophisticated navigation and position measurement technologies, is also working with Professor Newman to develop better dynamic positioning systems for offshore marine applications. GNLs aim is to increase the flexibility of marine vessel operation, helping to widen the weather operation window and improve safety. Lifelong infrastructure-free navigation lies at the heart of the agenda for The Oxford Mobile Robotics Group, says Professor Newman. This is an information engineering problem encompassing lifelong learning, multi sensor fusion, perception, control, planning, state estimation and software engineering. These skills may be available to organisations through OUC. Organisations looking to access such expertise are invited to contact Oxford University Consulting.

For more information, please contact: Andrew Goff Head of OUC Isis Innovation T +44 (0)1865 280866 E andrew.goff@isis.ox.ac.uk Ref: 7911

Isis Innovation: Invention 25

Optimising IP Portfolios
Gaurav Misra illustrates the importance of understanding return-on-investment from intellectual property within research organisations by looking at the work undertaken by Isis Enterprise for the Kennedy Trust.
Isis Enterprise recently undertook an extensive, seven month review of a portfolio of patents owned by the Kennedy Trust, an independent charity supporting research into the causes and treatment of rheumatic diseases. The Trust funds the Kennedy Institute one of the worlds leading research centres in rheumatology which has recently relocated to the University of Oxford. Isis Enterprise was chosen for this project on the basis of Isis Innovations impeccable track record of commercialising hundreds of patents in a cost effective manner over many years. As a patient-centric organisation operating in the fast-evolving field of biomedical research, the Trusts patents were filed at different points in time over the past ten years. Most comprised of method-of-treatment and process claims surrounding the use of tumour necrosis factor (TNF) inhibitors for new therapeutic indications and treatment settings.

Understanding the commercial landscape was key to unlocking the portfolio value.
The Trusts management believed that the patents held significant potential for translation into better clinical outcomes for patients, and wanted to

A major breakthrough in understanding autoimmune diseases occurred in the early 1990s, when immunologist Professor Sir Marc Feldmann of the Kennedy Institute in London, England, discovered that the key lay in molecules responsible for cell communication molecules known as cytokines. In the early 90s, tests in humanoid mice revealed that all the different cytokines could be stopped by blocking one kind namely Tumor Necrosis Factor (TNF)-alpha.

Soon after Professor Feldmann conducted the first series of successful trials with rheumatoid arthritis patients at the Kennedy Institute. During the test runs, patients received a TNF-alphaspecific monoclonal antibody known as cA2, later registered as infliximab. Subsequently this approach has revolutionised medical practice, in recognition of which Professor Sir Feldmann received the Lifetime Achievement Award from the EPO in 2007.

Isis Innovation: Invention 26

Isis Enterprise helps technology providers and seekers to source, develop and commercialise new innovations.
prioritise the portfolio on the basis of such clinical value. Further, we were to explore options for monetisation or collaborative R&D to increase the trusts research scope and budgets. A secondary objective was to reduce maintenance expenditure on these patent positions, where possible, without jeopardising their inherent therapeutic potential. Our task involved many challenges. The first was to gain a clear picture of the portfolio by tracing the legal status, approval timeline and litigation history for each patent. The second was to forecast the maintenance cost of the patent positions till expiry, so as to understand the financial needs and identify patent families with high resource utilisation. Through examining various patent databases and detailed communication with patent attorneys, these objectives were achieved. The next goal was to understand the scientific objectives of the inventor at the time the patent was first filed, and to assess whether the logic was still valid in the context of todays commercial realities. Key issues included the inventions industrial application, the clinical research needed to translate it into a product, along with the associated costs and probabilities. approach patent expiry, unleashing a wave of conflicting incentives across the industry. Original branded biologics are reliant on second generation method and process patents to extend market exclusivity, which biosimilar manufacturers are seeking to invalidate. Stakes are high because the foundational regulatory mechanisms for new-age biosimilar therapies will be decided on the case of TNF inhibitors. Any recommendations made to the Trust had to be mindful of the partnering landscape created by such industry events. The assessment of barriers to entry also uncovered interesting learning points. For example, a distinction often had to be made between the legal enforceability of a patent (i.e. an inventive step with industrial application) and its market enforceability (i.e. the ability to generate revenues based on the claims). The seven-month exercise enabled Isis Enterprise to prioritise the whole portfolio of over 100 patents and for further research and licensing. The resultant consolidation of the portfolio may even confer a significant cost-saving to the Trust, without compromising the therapeutic potential of the IP assets. Image: Monoclonal antibodies

An IP timeline
Patent portfolios of successful researchbased organisations grow with time. While an organisations strategy and priorities may change, the patent portfolio tends to accrue and can resemble a log book of the organisations research endeavours. Over time, shifts in the competitive landscape add value to some patents and devalue others, while the cost of maintaining large IP portfolios escalates sharply.

Blockbuster therapies
An understanding of the commercial landscape was the key to unlocking the value within the portfolio. The Institutes pioneering work had found global application via categoryleading blockbuster therapies such as infliximab, adalimumab, etanercept, and certolizumab. This group of TNF inhibitors are the first monoclonal antibody therapies to

For more information, please contact: Gaurav Misra Senior Consultant Isis Enterprise T +44(0)1865 280859 E gaurav.misra@isis.ox.ac.uk Ref: 8138

Isis Innovation: Invention 27

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