Inventing a new diagnostic test for vaginal infectionBMJ 1994; 309 doi: https://doi.org/10.1136/bmj.309.6946.40 (Published 02 July 1994) Cite this as: BMJ 1994;309:40
- T C O'Dowd,
- N Bourne
- Department of Community Health and General Practice, Trinity College, Dublin 2, Republic of Ireland University of Wales College of Cardiff, Cardiff CF1 3XA.
- Accepted 3 March 1994
Bacterial vaginosis, which is underdiagnosed in clinical practice, has a characteristic fishy smell because of production of diamines. This smell is the basis of a visual rapid diagnostic test that is technically simple to perform. The test has been patented in Europe and America, and a licence agreement has been negotiated. This paper describes the process from idea to invention to patenting and licensing. The combined costs of research and patenting were met by a multinational company in return for rights to exploit the patented invention. The process has taken nine years and has needed clinical, scientific, legal, and commercial input to get the test to the marketplace.
About 5000 patents a year are registered by British inventors, but the Japanese company Hitachi registers 20 000 patents a year. Yet Japanese research shows that in the past few decades half the economically valuable inventions around the world originated in Britain.1 Since the withdrawal of the British Technology Group's monopoly of exploiting university research in 1986 many universities have accepted the responsibility of exploiting their own intellectual property. They now realise the commercial value of their intellectual property, and most have established offices of technology transfer, which focus on opportunities for industrial exploitation. The government's recent white paper on science and technology Realising our Potential further emphasises the importance of developing new technologies and discusses the various methods by which industry and academia might collaborate for the benefit of the economy.2 It is becoming more common for university research to lead to commercial products that have been exploited through the establishment of license agreements or have formed the basis for a new company. In this paper we describe our experience of inventing a rapid diagnostic test in response to a clinical need and taking it to the market.
The diagnostic test Clinical need for test
Vaginal symptoms are a common and recurring problem that affects about one in 10 women who present to a general practitioner. Vaginal symptoms are often assumed to be due to thrush, but bacterial vaginosis has been found to be associated with up to half of patients with vaginal symptoms.3 Bacterial vaginosis has the clinical features of a grey homogeneous malodorous vaginal discharge with higher than normal pH of 5.0-5.5 and minimal inflammation.4 There is increasing evidence of the virulence of bacterial vaginosis: it has been associated with pelvic inflammatory disease after abortion,5 endometritis after caesarean section,6 amniotic fluid infections,7 and preterm or low birth weight delivery.8,9
Despite this, bacterial vaginosis is not commonly diagnosed. The clinical history gives useful pointers, and diagnosis can be made by means of microscopy because of the presence of “clue cells,” which are vaginal epithelial cells dotted with coccobacilli. Microscopy is, however, a rare skill in clinical practice. Thus bacterial vaginosis is a common condition that is underdiagnosed partly because a diagnostic test does not exist.
Scientific rationale for the test
Bacterial vaginosis produces a fishy odour due to the presence of diamines, cadaverine, and putrescine, and these amines are known to be associated with the clinical symptoms of bacterial vaginosis.10 Attempts have been made to use the diamines to assist diagnosis by eletrophoresis or gas chromatography, but these techniques require specialised laboratory equipment and skilled personnel.11,12
Our aim was to convert the fishy odour into a diagnostic test. We realised that a general practitioner or office based specialist would need such a test to be accurate, fast, visually detectable, and technically simple so that it could be performed by a doctor, nurse, or even the patient herself. We learnt that the simpler we made the test the more complicated the basic science became. However, within seven months of starting laboratory work we had a visual diagnostic test that worked in one minute. We used selected diamine oxidases to react with the diamines produced, and this reaction caused a colour change in a suitable chromogenic system.13,14
Deciding to patent
The normal recourse for academic researchers would be to disseminate their findings by publication. However, a patent search carried out in the Patent Office satisfied us that we had made a discovery with an “inventive step.” Because bacterial vaginosis was becoming increasingly important we thought that our test had commercial potential, and we decided to pursue a patent as a priority and to publish our results at a later date.
Requirements of a patent
A patent confers an exclusive right to the use of an invention and a legal right to prevent others exploiting the invention without prior consent. For a patent to be granted the invention must be new — that is, never have been the subject of a non-confidential disclosure before the time of filing the patent application. A non-confidential disclosure means a disclosure to the public in any way, whether written or oral, anywhere in the world. The invention must also include an inventive step or an improvement over current knowledge that would not be obvious to a person skilled in that field, and it must be capable of industrial application.
The inventive step — Our test included an inventive step because, before our invention there was no simple diagnostic method available and established diagnostic procedures took some days to complete. In addition, our invention encompassed a diagnostic kit that allowed the test to be routinely carried out without the use of laboratory facilities.
The patenting system British patents
The Patent Office produces a number of helpful and explanatory publications.15 An invention must first be described in a patent specification, which is submitted to the Patent Office in accordance with the formal requirements of the British Patents Act.16 The description must be in sufficient detail for the invention to be understood by a suitably qualified person reading the application and contain at least one “claim,” which defines why patent protection is being sought. The services of a registered patent agent, most of whom are members of the Chartered Institute of Patent Agents, may be employed to assess the suitability of the invention in the first instance, to prepare a patent specification, and to comply with the formal procedures.
After registration at the Patent Office the invention is said to be “filed.” A “priority date” is established, which gives the applicant priority over subsequent applications for the same invention. Once the priority date has been established the invention can be published without invalidating the patent application (the application will customarily be published by the Patent Office 18 months after the date of initial filing anyway). However, commercial considerations may make early publication unwise. The published patent application can be studied by researchers from academic and commercial communities.
The Patent Office will examine the application in the light of published material to see if the invention is new. If any objections are raised at this stage the applicant has the opportunity to address these, but it is advisable that a patent agent is engaged to make such a rebuttal, especially when dealing with examiners in the United States or Japan.
The commercial potential of our test extended to foreign markets, and in order to obtain protection abroad it was necessary to extend the application to the appropriate countries. Most western European countries are party to the European Patent Convention, and for filing on a worldwide basis there is the Patent Cooperation Treaty, to which the United Kingdom (together with 31 other countries) is party. We chose to apply for a patent with the Patent Cooperation Treaty as we required international protection, and the filing of a single international application in English in accordance with one set of procedures was a great advantage.
Costs of patenting
The cost of patenting depends on the extent of the cover required. If the services of a patent agent are employed the costs range from about pounds sterling 1000 to prosecute a British application to over pounds sterling10 000 for a Patent Cooperation Treaty application. For example, the fees for filing in all 15 European states, America, and Japan could amount to pounds sterling 6500 to pounds sterling 7800. Additionally, prosecution fees would probably be pounds sterling 3000–6000 annually. The life of a patent is 20 years from the date of filing, and to maintain a patent in force an annual renewal fee must be paid for each territory (starting from the fourth anniversary from the filing date) at an average cost of about pounds sterling 200–300. Some of the initial expenses can be delayed for up to two years (such as by applying for a patent with the Patent Cooperation Treaty), allowing the applicant to undertake some market research in order to assess the value of the invention. Such a delay allows the applicant to identify a potential licensee who may be prepared to share the costs of patent protection (as happened in our case).
We were able to negotiate some return — from licence fees and minimum royalty fees — ahead of products actually being sold. The rights to our invention reside with our university employers, but, as the inventors, we are allowed a share of the royalties. The university licensors have been able to gain pounds sterling 60 000 in royalties, and the licensee has funded further research and met all the costs of prosecuting and maintaining extensive worldwide patent cover.
Licensing an invention Choosing a licensee
The choice of licensee is a crucial aspect of technology transfer and often requires a knowledge of the market, including the major industrial players, and it is advisable to seek expert advice at this stage. In general it is wise to offer licences of an exclusive nature to companies that have a worldwide market share as they are likely to have the sales network required for exploitation on a large scale. In some cases, however, it may be possible to offer a number of non-exclusive licences to more than one interested party. It is essential that any commercial arrangement is subject to a well written contract, and care should be taken that the rights of the licensor are upheld and that no onerous undertakings are imposed on the licensor.
Technology transfer arrangements such as those described for this project are subject to intellectual property law.17 Our invention was the product of a collaboration between two university institutions, neither in a position to exploit it commercially. It was necessary to collaborate with an industrial partner to develop the invention into a marketable product. Negotiations were pursued with interested parties through the Universities Research and Development Section, and six years after the filing of the initial patent application a license agreement was concluded with a multinational licensee for the rights to exploit the patented invention. This gives an indication of the time required to license successfully a potential technology from an initial idea. The various stages included applying for research funding, conducting a successful research programme (including clinical trials), marketing the technology, further evaluation of the technology by potential licensees, and the negotiation of commercial terms.
The licence agreement is a commercial arrangement that incorporates an element of risk for both parties. If it is to be successful it must be unambiguous from the outset. Important issues that need to be addressed include the actual transfer of the technology and how this will be implemented — provision should be included for the transfer of documentation, know how, and, if necessary, people. The level of technical support to be provided by the licensee and the rights to future developments also need to be addressed. Universities are usually well placed to generate ideas but not well able to provide technical back up if things go wrong with prototypes or end products.
The existence of a granted patent does not guarantee the successful exploitation of the invention, but there are a number of measures that safeguard rights. We included provision for the payment of minimum royalties, which at least indicated the licensee's commitment to the project regardless of the level of commercial success. We negotiated that the licensee share the costs past and present associated with the patent. In addition, the licensee is expected to demonstrate reasonable endeavours towards the exploitation of the licensed technology or, in the case of non-performance, be required to accept a reduction in rights.
The amount of royalties payable is negotiable but in practice will depend on the nature of the invention, the strength of the patent portfolio, and the type of licence being offered (exclusive, sole, or non-exclusive). Royalties are usually calculated on a percentage of the net sales of the licensed product or by a method that is readily accountable and that will stand up to independent audit anywhere in the world.
The idea of the test began in 1984, and it has taken nearly nine years to get it ready for the market. At the last minute, however, our multinational licensee has pulled out of the agreement as the company reorganises itself in response to economic problems. Commercial exploitation has added a rigour and depth to the project, and the partnership between commerce and academy needs the support of professional management. Universities are full of people whose ideas are a valuable asset, but researchers may give away such assets freely and naively in return for career advancement. If universities are to exploit their intellectual property it has to be given a value and treasured. A good patent and commercial licence portfolio will play its part in securing a sound future for its owners, and there is welcome evidence that universities are recognising the importance of patents in their research selectivity exercises.
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