N 246

was difficult, different temperatures being obtained by change of solvent. In this way we were able to develop the new method for a wide range of volatile fatty acids and bases and to investigate the relation- ship between chemical structure and chromatographic behaviour. By using sta- tionary phases of sufficiently different structure to change the nature of the solute-solvent interaction, we showed how a study of the chromatographic behaviour of an unknown substance could elucidate most if not all of its constituent groups.

The way was now open to make the technique applicable to all volatile com- pounds by the development of a ne~i detec- tor capable of responding to any sub- stance. N. H. Ray of I.C.I. visited us at this time and though we suggested that he investigate infra-red detectors he, prob- ably wisely, preferred to use the catharo- meter, a well known device of reasonable simplicity. This resulted in the first paper describing the application of gas-liquid chromatography to compounds other than acids and bases. A. J. P. Martin disliked the inherent flow sensitivity of the catharo- meter and we preferred to try to develop a highly sensitive constant load micro- balance on whose pan the vapours emerg- ing from the column were to be condensed. After eighteen months work we gave it up because of the many difficulties with quan- titative condensation and instability of the quartz microbalance.

We now turned to a device that had been at the back of Martin’s mind for some years -the gas density balance. Recalcula- tion of its possible sensitivity showed this to be of the correct magnitude. A hasty construction of a glass model showed it to work, a brass half scale model followed and then a full-scale copper detector was constructed together with vapour heating jacket. The device, as expected, proved to be virtually flow sensitive and the best overall detector at that time. We quickly investigated the separation of saturated and unsaturated hydrocarbons, alcohols, ketones, etc. and showed, as had N. H. Ray, the great power of the new separation technique.

Although we were always slow and discriminatory in publication, the word rapidly spread and the take up and further development of the technique was safe in the hands of Desty, Scott and many others. A. T. James is the head of the Biosciences Division at Unilever Research Laboratories, Colnorth House, Sharnbrook. Bedfordshire, (1. K.

Figs I and 2 taken,f+om British Biochemistry Past and Present edited b.v T. W. Goodwin published by Aca- demic Press and reproduced b_v permission qf the Bio- chemical Society, London, U.K.

TIBS - November 1977

Patents and recombinant DNA G.S.A. Szabo

The possibility of combining genetic mate- rial from one source with DNA from an- other has opened new areas for scientific exploration and for inventive ingenuity. It follows that in the future patents may be granted in this new field of recom- binant DNA research and the question arises as to what these might cover. Whether research is financed by industry or through public funds, there is naturally a strong interest to recover expenses and to support further research from the profits of commercial activities operating under the protection of a temporary monopoly provided by patent rights.

It is generally agreed that the purpose of the patent system is to encourage inter- est and investment in research and scien- tific and technical progress. Whilst discov- eries are not patentable in themselves, certain applications of such discoveries which are profitable to industrial and trade activities, may well be suitable sub- jects for protection. Patentable inventions can take the form of either a tangible new entity, or a process providing an im- proved or entirely new effect, which has an economic potential in commerce, and they must of course also satisfy the usual cri- teria of novelty and non-obviousness. The patent disclosure must be adequate and the invention reproducible without undue ex- perimentation. Other scientists must be

Berry’s World

“What’s all the big fuss about genetic research?”

able to check the alleged merits of the invention, and should also have an oppor- tunity of improving the results by making further inventions, since these are funda- mental principles of the patent system.

What then may be patented in this new field of activity? Perhaps one should men- tion first that the equipment and safety measures used in the experiments includ- ing novel mechanical and electronic de- vices and instrumentation could be patent- able. New processes of industrial signiti- cance and their improved end-products are, of course, more important: When it comes to patentable inventions in micro- biology, there have been many examples relating to live vaccines, the use of cell lines, the modification of bacteria, and significantly, the hybridisation of viruses. What may be the lirst patent application in the field of DNA recombination, has been filed by Stanford University in Cali- fornia and presumably relates to the splic- ing and recombination of DNA segments and to the ways in which the bacteria can be used.

Using enfeebled bacterial cells, incap- able of living outside the laboratory, as hosts for recombinant DNA material is a recommended safety measure and current- ly The Research Corporation (an Ameri- can non-profitmaking organisation that helps universities take out patents) and the Department of Health, Education and Welfare are attempting to patent and licence such ‘fail safe’ forms of Eschrrichia co/i, developed by Roy Curtiss at the Uni- versity of Alabama Medical Center, Birm- ingham, Alabama.

It remains yet to be seen what the granted patents will cover, but it should be remembered that the product of a patent: able process must have a utility, recognised by the inventor and reproducible by others. In the past mere research interest or the possibility ofsome speculative applications was not accepted by the Courts in the U.S.A. as qualifying for a patent. In all probability, therefore, such patents will only be relevant to some commercial ex- ploitation of the method or the product.

Future developments of additional tech- niques may of course generate further patents, each appropriately limited by its novel features. As the recombination methodology becomes standard and can be reproduced routinely, patentability on

J.S.A. Szabo is a Chartered Patent Agent and manager of the Patent Department in the Well- come Foundation Ltd., London, U.K.

N 248

this count may diminish and protection on the basis of unexpected properties of a specific product would probably become the central issue.

Microbiological organisms have already been the subject of patent coverage. Inter- estingly (because E.coli is central to much recombinant research), the first patent in the U.K. to claim a bacterial strain per se (B.P. 1090 754)related toan E.cofivariant. New strains and cultures of yeasts have also been patented in Britain and cultures of modified bacteria and cell lines have been claimed in a number of countries. There is no reason to believe that the same would not apply to new vectors or to re- combinants themselves with or without the host cell, provided again there is a testable utility and provided that the materials themselves are adequately identified. New, non-obvious properties might appear after modification and purification. One cannot cover Nature, as it is, in patents, on the other hand, an artificial modification of what is available in Nature could well be covered. Thus new restriction endonu- cleases or ligases- the cutting and stitching enzymes of recombinant DNA work - may be discovered, and the patentability of such substances may depend on their pos- sessing some qualification distinguishing them from their natural state such as a degree of purity or a combination with other agents or carriers, which characterise the conditions of their usage. Whilst pro- tection of genetic manipulations may not be possible in many instances, perhaps be- cause of inadequate reproducibility or the absence of direct economic relevance, the new microbiological ‘factories’ of hor- mones, antigens, medicaments, and partic- ularly the formulations or usage of such materials, are primary candidates for patents.

0Q be considered to be better spent elsewhere where the outcome of the exercise may be

FOREIGN DNA more easily assessed. The Department of Health Education

and Welfare in the U.S.A. has recognised CLEAVAGE WITH RESTRICTION ENDONUCLEASES ] the need to lit DNA recombination pro-

1 t jects into its system of Institutional Patent Agreements with universities and non- profit making institutions, and such or-

FRAGMENTS ganisations may retain their right to exer- -- cise an option on the ownership of the

patent, for instance under certain condi- tions regarding licenses. Alternatively, the licensing would be done by the Depart- ment, or the invention may be dedicated to the public. The same authority is an- xious to transfer inventions quickly ‘from the bench to the market place’ and patents can obviously facilitate that, but there have been references to the possibility of adverse effects of patent claims.

ENFEEBLED HOST

Ecoli chromosome

/

E.COLI+NEW PLASMID

Simplified outline of recombinant DNA methodology.

European Patent Convention, but a new International Treaty has also been signed recently by a number of important coun- tries, including the U.K., Germany and the U.S.A., which will require a single deposi- tion in a depository institution authorised under the Treaty, for all countries con- cerned (‘Budapest Union’, under the World Intellectual Property Organisa- tion).

To satisfy the conditions for the experi- How can the monopoly of microbio- mental reproduction of the invention dur- logical inventions by patents be justified? ing the life of the patent and to ensure Unless the reward for inventive effort go the possibility of free commercial exploi- to those who invest in research and equip- tation after expiry or lapse of patent rights, ment to create new technologies, the publi- a deposition of the microorganism carry- cation of the results in the form of a patent ing the recombinant will be required, un- specification or the release of new recom- less the recombination and incorporation binant strains, would not be acceptable. steps are themselves satisfactorily repro- Not only is monopoly in consideration of ducible. Such deposition will take place in the disclosure, but the same is true the a culture collection capable of handling the other way round. If patent protection be- organism, usually before the first applica- comes inadequate or unenforceable, com- tion is filed providing priority rights under mercial research has only one alternative the International Convention on patents. and that is to restrict investment to investi- The release of the sample to third parties gations where the know-how and the re- would normally, however, only arise when sults may be kept secret for a reason- the application or patent is laid open to able time. Such a recourse to secrecy would public inspection or is granted. This can be a retrograde step and clearly contrary be expected to occur usually 18 months to the need for a wide dissemination of re- after the patent application is first filed. sults. Without adequate safeguards to en-

Conditions for such deposition and re- sure a reasonable lead in the market place lease are subject to national law, or the with new technologies, the expenditure in-

TIBS - November 1977

vested in research in risky new areas might

It appears that-there is a fear in some quarters that purely scientific methods may be covered by patents or that because of commercial pressures the results of re- search would not be communicated to fel- low scientists as rapidly as possible. A view has also been expressed that patent filings could create substantial delay in publication and that some granted rights may prevent the free availability of some DNA materials for research [ 11.

However, the reproduction of the inven- tion for purely scientific and experimental purposes would certainly not be construed as an infringement anywhere. On the other hand, the same activity on a commercial scale may be an infringement. A moditica- tion of an invention by others may not necessarily be independent of an earlier patent, even if it is patentable itself, when it comes to commercial exploitation.

There seems to be no evidence that faster communication is required in this field, than is normal in chemistry, electronics or mechanical engineering. Pending and granted patent rights and temporary infor- mation containment may be an additional means of control to ensure that physical and biological containments proposed by authorities are fully implemented even in countries where there are no regulations or statutory measures yet in force.

It is very likely that the need for rapid communication arises more frequently with results of pure research rather than with applications of industrial potential and as in other fields, scientists and con- sultants should be aware of the additional problems and financial risks that can arise when commercial exploitation comes into play. In any case, patent matters can be sorted out fairly rapidly, if necessary, and analysis of the support and scope of a pro- ject could easily become beneficial to fur-

TIBS - November 1977 N 249

ther research. On the commercial front, the filing of patent applications not only allows but often also requires informative publications to create interest and facili- tate utilisation.

In addition to the legal steps, associated with patenting, instigated by research establishments there are of course safety measures being considered by Govern- mental organisations to protect the interest of the public. The Guidelines issued by the National Institutes of Health in the U.S.A. [2] and in the Williams’ Report in the U.K. [3] recommend physical and biological standards for containment and proce- dures, whereby proposals for research projects in the genetic recombination field would be assessed, and approved or pro- hibited, by appropriate committees within the N.I.H. or by the Genetic Manipula- tion Advisory Group (G.M.A.G.) in the U.K. Whilst the former has only power to control research sponsored from federal funds, the latter is intended to act as a supervisory authority to both academic and industrial research, on a voluntary basis for the time being. The scheme has the backing of the law under the Health and Safety at Work Act by which Govern- ments have already some power to enforce existing statutory controls on grounds of safety to the environment and to operators in employment. Industry, therefore, has hardly any option but to comply with the suggested standards and proposals. Indus- try would certainly be happier to co-oper- ate with the authorities if it could be con- fident that there would be no disclosure to competitors (and this may include University personnel), or to the public at large beyond that necessary on safety grounds, since this might be detrimental to the validity of any future patents on the subject or to the commercial position of a company.

The Williams’ Report suggests (6ii) that

newly developed varieties of disabled or- ganisms used as hosts for the new DNA recombinant material ‘should be made freely available to workers in the field’. Since many Governments have some stat- utory means for making vital inventions available to them or to others by compul- sory licensing, one would have thought that no restrictions could be imposed on their availability. It would be difficult to enforce an outright confiscation of new disabled organisms in many countries on constitutional grounds, and in any case the inventor would simply move the strain and the manufacture to another country.

International provisions such as have been described might certainly facilitate the availability of new and presumably established recombinants for research pur- poses. Although the N.I.H. Guidelines prohibit the release of recombinants into the ‘environment’, it is uncertain whether or not this would be interpreted as cover- ing depositary institutions and third parties, particularly if they have contain- ment facilities. (Non-availability of mate- rial would, of course, cast doubt on the validity of the patent, unless the whole recombination process could be repeated by others easily from the published infor- mation and using readily accessible mate- rial.)

A much more serious problem for in- dustry is the requirement of early and de- tailed disclosure, to the N.I.H., G.M.A.G. or a similar organisation, of intended work which may lead to a patentable invention. Under U.S. law, any disclosure to these bodies by the inventor would have no legal affect on a patent application in that country if it is filed within one year of the disclosure. In contrast, even oral disclo- sure to such organisation anywhere may be detrimental to a subsequent patent appli- cation in France. The same applies to a British application if the disclosure was

within the U.K., unless the information is communicated under a seal of confidence, enforceable under the law. Such a degree of confidentiality, however, is inconsistent with the aim of the advisory or approval procedure as participation by members representing public interest and a wide variety of disciplines is encouraged. This is also apparent from legislative proposals for the statutory control of such research in some States of the U.S.A., and in a Federal Bill, which is already in the draft stage. The supervision of standards and disclosure to the authorities would also in- volve advisory councils with wide public participation. The approval procedure it- self, however, would be secret according to the draft Federal Bill; the suggested pro- cedure before G.M.A.G. in Britain is still unclear in this respect. Of primary impor- tance, therefore, is the establishment of an effective system of experiment control ac- ceptable to industry and this can only be achieved if confidentiality is maintained in the suggested procedures. At the same time, the academics need to be reassured that the patent system will not deprive them of the right to carry out any experi- ment they wish, notwithstanding the rele- vance af patents to commercial activities. The more protection is given by the patent system to commercially oriented research the less likely is the growth of secret know- how not available to the scientific com- munity at large.

References

1 Kourilsky, P. (1977) Trends Biochem. Sri. 2. N 12 2 Department of Health, Education, and Welfare,

National Institutes of Health, Recombinant DNA Research, Guidelines (1976) Federal Regisrer, 41/131.27902-27943

3 Report of the Working Party on the Practice of Genetic Manipdlation, Prof. Sir R. Williams (1976) H.M. Stationary OffIce

drawn forilES

Paul staplet%