Biopatents: a sense of order

269

f OYUWl (e.g. a-CD3 x a-CD2) specific for lymphocyte receptor molecules simultaneously expressed by the et&tars have been produced. Applications have been tested in irr vitro models, maizdy in order to overcome the variation in susceptibility to cyeotoxic T-lymphocyte (CTL)-mediatcd lysis within individual tunlours. The cunclusicus are that the concurrent USCofdifferent bsmAbs to trigger may discrete activation pathways improve the general performance and may find practical application in cancer immu-lotherapy. Other apphcatlofic concern their use for intracellular routing and targeting of bsmAbs carrying toxins, while their USC to destroy ccl1 populations cxpressingtargct molcculcs (c.g. cells infected with HIV) appears highly promising. 1). M. Segal (NCI/NlH, Bethesda, MD, USA) rcvicwed the mechanisms involved in targeted cytolysis, emphasizing the secretion of factorsthat can biock the grow& of both tumor target cells and bystander tumor cells. The treatment of mice bearing intraperitor,eal human ovarian carcinoma with human T cells targeted with bsmAbs led to a rapid removal of most tumor cells from the peritoneum, and increased the survival of the mice. The efficacy of targeted T cells for treating humau cancer is currently being tested in clinical trials - preliminary results arc Promising. Melanoma immunotherapy with antiidiotypic mAb S. Ferrone (Vaihalla, NY, USA) reported the etfects irr t&o of the treatment of patients with a atrtiidiotypic mAb, whic!l bears the internal

image of HMW-MAA. The treatment induced an increase in the levels of anti-mouse antibodies iu nearIy all the patients w:th melanoma, but elicited anti-HMWMAA immunity in only about 6O’h of the immunized patients. The human HMW-MAA binding antibodies elicited upon mAb treatment arc Lath IgM and I&. Their titrcs arc markedly enhanced by the conjugation ofthe mAb with a carrier and the administration with an adjuvant, while the titres are not affected by the delivery of cytoxan. The conclusiou is that the induction of anti-HMWMAA immunity by immunizatiot~ with antiidiotypic m.\b is associated with a stati:;:ically significant survival prolongation in patients with melano1na.

may bc overcome a:ltibodics designed effector functions

by engineered with improved (i.c. incrcascd cotllpleIllcllt Fc-dcpcndcnr and c)-totoxicity) and to reducing to almost nil the imnlunogcnicity ofthc therapeutic antibody. (see also C. Cunningham and W. J. Harris, TIBT’ECH 10, 112-l 13, 1992.)

was more besides.. . also included besides awful weather - an updating on CD3 [by C. Tcrhorst (Harvard Medical School, Boston, MA, USA)], and on gene therapy mod& [R/1. D!arsc (NIH, Bcthcsda, MD, USA)/, satcllitc mectin~ (‘Molecular analysis of primary i~~~~~nunodcticio~cics’, ‘Cell and tissue engineering iI1 biomedicine’) and a round table on ‘Uiotcchnology in the EEC’. This the immune has been the seat of discussion of Reprogramming system with mAbs problems that are still burdcniug sciIt is known that immunosupence and rcscarch (elthcr in acadcnlic pressive drugs pcl?a!ize the wl~olc or in industrial organizations) in immune s-ystcIn for the misEurope. demeanors of only a sn~all proAnd finally, 1 note of optimism: portion of the lymphocytes. In the the data prcscntcd by the European attempt to overcome this problem, groups was original and of high quality, rctlccl;ing a slew wave of H. Waldmann (Cambridge, UK) basic science from Europe. Let us devised ways of inducing tolcrancc vow that this posit& trend may find to selected antigens (tolrrization). This was achieved iu mice by using further and turgctcd support by the Uiotcch proh?am that is to bc short couucs of mAb to CD4 and CD& which conferred tolerance to launched by dlc EEC soon. forcigu proteins, heart, skin alld bone marrow grafts. The tolerant state achieved at the price of a dcstructioo of a limited number of lymphocytes - was profound and rcsism?lt to the infusion of normal lyniphocytcs. This resistance was itselfmcdiatcd by host T cells that actively maintained the tolerizrd state. The iirnitatiour to this model to hunlans transferring There

The conferz:lce

Biopatmts: a sense of order

Since the discovery of fire, it scc~lls, mankind has worried about the implications of ‘inventiveness’. What can the inventor do with the discovery? Even worse, what could someone else do with it?! Should discoveries bc put to use for the benefit of all, or for the profit of a ft-w? Who should decide what is to bc done - and how can the decisions be enforced? C’1992, Elsebier Science Publishers CM [UK)

Mul~lan invcntivencss has rewltcd in a constant tlow oi new products, atli of new applicaGcnr f&r evicting products. With the uvolutiou of the various disciplines of science and technology, so too arose the nrrd hr some sort of regulation with reg‘trd to recognition and/or profit t)om an individual’s own work, The patcnting system has devclopcd ro fill that need. Tccl~~~olo~~, generally,

ic ‘patentable if utile’ (Ii. 13izlcy. Hepworth, Laurence ,~nd fiizlcy, IHarlow. UK). Uiotcclmolo~~ is not quite so simple Where patents arc concerned, life and life-derived products pre+z!lt a special challcngr, and may bc subjcrt to certain exclusion clauses. tlowever, since 1980 it cau no longer bc said that something is not pnrent;tble just because it i?: Iwing. Patent protcctiou t6r a limited rang’- of living matter has already bcc13 granted, a13d biotechnolo~~~ 11.1~ advanced so rapidly in recwt years tht tllcic is :BTECH AOGUST 1992WL

10)

now virtually no life form which does not have potcntiaiasthe subject ofa pateI;: application. Patenting life, with ail its attendent ethical and legal qucrtiom was addressed at a rcccnt meeting*, whose participants were a rich mix of rsprcscntativss ironi the sceiningly disparate worlds ofscience and law. 1~. Bizlcy, in his introduction, defined patents AS ‘economic and ownership factors . . they are not responsible for the science but simply give out party a monopoly, for a limited time, on the use of his/ her particular product. proccsz or application’. This allows the patent holder to exclude other pxtics from copying their tcchnolobT without Thuc, consent. their csprcrrcd patents will mcourdgc progms by otTming protection for rhc rrtults of invcstnicnt by their ow~irrs.

Rights that can be licensed Patcntsare not the only type of right that can bc licensed to give an inventor some form of protection. M. Turner (Denton Hall, Burgin 81 Warrens, Loudon, UK) outlined the other rights involved in hccnsing biotechnological inventions including the intellcccual property of ‘know-how’ (contidcntiahty undcrtakings may also bc required to give added protection), copyright, and the physical owumhip of biological materials (if the ownership of tmnsferrcd materials can be rctaincd. this can give extra prntcction). In addition, thcrc arc the cstablishcd l’lant Breeder’s Rights (see below). Parenring life - the procedure To be granted patent protection, H. Austin (Urquhart-Dykcs &I Lord, SwaIl.wa, explained, any UK) process, product or use of product must he: (1) novel’, (2) innovative (non-obvious) (see A. Nixon, pp. 272-273 in this issue of TIBTECH), (3) utile, (4~ :io: in an ‘cscludcd’ category, and (5) dcscribcd in sufficient detail as to enable a skilled worker to follow the prom@. This last stipuIntion may provide problems for patents that involve the use of living m~~zrinl. ID. Wood (The IJatcnt

Otice, Newport, UK) cspiored cm: of the ways chat this problem has brcll addressed, i.e. the deposit of microorganism in a recognized dcpositary, on the understanding that a third party, upon fulfilling certain conditions, 11lay obtain a sample. Howcvcr, deposition may prcscnt ‘new problems. For csamplc, if the patent application is unsuccessful, or is withdrawn, uniimitcd access to the material would then be available to competitors. There is a need, thercfore, for safeguards to bc built into the systcrn. Information sources in biotechnology use of on-line ‘I’he increasing infornmion sources, uccc~sitatcd by the vast amounts of data being gcncrated in the f&t-moving discipline of biotcchl?oloby, could have both conmlcrcial and Icgal implicationa. 13. W,&,h (The Royal Society of Chemistry, Cmbridgc, UK) camtncntcd upon the logistics of disscminatiug this growing bmk of infortnntioll in a field with roots as divcrsc as chemistry, biology, medicine. agricuiturc, food scicncc and chcmical cngineaing. Hc suggcstcd that the way forward may bc a payas-y~:~-t~sc system of on-lint datdbases I:Oprovide access to all who are intcrcsted. Howcvcr, there is some‘ da;:g:er hcrc that sonx information Inay bc disclosccl prior tn a patelx apphcat1on takm: c&t. Public acco:untability - some of the qucstious Tbc ethics ofpatcnting genetically manipt~lntcd organisms, and of actoidly producing thcw orgmisms cause major concern: what is being qucstiomd by the public, scientists and rcgulntors is the social and economic impact of the USC‘Sto which genetic engineering technologies arc being put. M. Lloyd-Evans (BioBridgr, Cambridge, UK) pointed out that all technologies can br abused. However, attempts to prcvcnt such nbusc must not stitlc innovation and thus prcvcnt potentially bcncticial advancc’s as well. Other concern:. over the cstcnsivc patenting ofgenetically n:o1;“-c IIICLI J !ivi~g organisms include concern for animal w&rc, the fear that big buxixss may profit greatly at the expense ofthc Third World, and the social implications of gene thcrapy. An adverse impact on biodivcrsity and the unknown etfccts of the rclcasc of genetically cnginccred organisms, such as those engineered

for stress tolcrxncc or discasr rcsistmc~, me fimdamcntal cnuironmental concerns. While much effort is being direct4 at developing mod& fol estimating the risks, we cannot yet predict with certainty what the results ofrelease will be. That ‘Bioindustry mus: not bc allowed to work within a moral vacuum’ is a desirable goat for biozchnologists and public ‘alike, acd is not in dispute (M. Lloyd-Evans). Abandoning the prtcnt system and the commxci.J protection it provides for the inventor would not prevent the science whose ethics arc being qucstiotlcd from bring done, but would just drive it undcr~ground. Weakening patent laws would not help solve the problems mentioned above. nor those ofthr Third World. Creaking at the seams The Iaw cannot rpcIl out in detail cvcry instance of what can and what cannot bc patcntcd, and each application must be scparatcly considcrcd. What scicncc a11 achieve today was llot deemed possible cvcn when the relativeiy rcccnt patent laws in Europe and in the UK wc’rc conceived (in 1973)“, and this mc~ms that the system is now ‘crcaking at the s~‘ams’ in some respects (R. Bizlcy). The European Patent Convention (EPC), Articlc 53(b) specifically cscludcs from pntcntability: ‘. . any vnricty ofanimal or plant or rsscntially biological process for the producrion of an animal or plant, not being a microbiological process or the product of such d proccrs.’ It is very ditficuh to d&e accurat+ a ‘variety’ of nnima! or plant, or even a process that is ‘csscntia!ly biological’ as distinct from one that is &&ted significantly by the scientific intervention. Some limited csceptions have been made to this ruling. The procedure for patent appiications that involve living organisms, howcvcr, can take time and uncspcctd turns. The European granting oncoof a patent for the Harvard mousc3 in October 199i, is an esample of a gcncric claim that was grant& whereas the claim by Upjohn 011 sheep genetically enginecred for better wool production has IIO~ yet hccrl accepted. Even for the same ‘product’, applications made in different count& lnay be ditfcrcntly received (e.g. in the late

271

197c)s, an oil-eating microbe was granted patent prouxtion in the UK quiLe straightforwardly, but the application in the USA was granted only aficr an appeal to the Supreme Court). Killer tomatoes strike back The intcllrctual properr rights in plants were ably elucidated by K. Percy (British Technology Group, London, UK), who explained the tern1 ‘Plant Breeder’s Rights’, also known as Plant Variety Rights (from the Plant Variety and Seeds Acr, UK, 1964). that give the holder the csclusivc right to produce for salt rcproductive nlarcriai (i.e.‘-seeds or plant tissue for culture or g&in& of a protected variety. This offers limited protection (e.g. the liccnsor n~ay be rcstrictcd with regard to the uses for the seeds thus obtained), but the right is fairly narrow (e.g. one technical report on the Plant Breeder’s Right for the hybrid tea rose ‘Glenfiddich’, as an csan7ple, includrs no fewer than 65 dctincd charactcristics). In addition, hnners are exempt inasmuch as they tnay save seed from onr crop in order to plant another crop (but not to sell). At the present, a plant variety nnxt be Wstinct, Imifonn and xablc in propagation (DUS). Changes are afoot under the Union for new UPOV (International the Protccrion of New Varictics of Plants, Gcncva, 1991) Convention" &at considcm a detinidon ofthc tcnu ‘variety’ for plants as: ‘...a plant grouping within a single botanical taxon ofthc lowcst known rank, which grouping, irrcspcctive of whether the conditions for the grant. of brcrdcr’s rights arc fully rnct, can bc: - defined by the expression of thr characteristics fron-I 3 given genotype (or combination of genotypes); - distinguished from any other plane grouping by the expression of at lcast one of the said characrerisrics; and considered as a unit with regard to its suitability for bring propagated unchanged.’ (NB There is no rncntion of stabi1ity.j Patent applications pertaining only co the patenting of gent X, then, can clearly show that they arc not patcnting a plant ‘variety’, There are nlany interesting esatnplcs of granted %ursi_‘can uatents for the methods of culture ofplants,

as well as for im3ovati.x methods, for example, for introducing genes into plants. A~WJhCtfTrif~lli f~:m$~ckm, a bacterium containing a tumourinducing plasmid (Ti) that can carry foreign DNA into some plants at the sitr of a wound, for csan~plc, providcs the basis for one such method. A patent for this method was granted in 1089 to Lubrizol Gcnctics Inc. (El’-B 122 791), and the claim included a plant grown from a plant cell transformed using the innovative method. Genetic cngineedng in plar3ts is still in its inf&cy, and will provide s&mists and patent lawyers alike with challenges for years to come. A harmonizing influence There is an obvious need for harmonization, and uniform interpretation throughout the world, of patents involving living matter. I<. S. Crespi (Bognor Rcgis, UK) outlined the European Comlnission (EC) Proposal for a Council Directive on the legal protection ofbiotcchnological inventionsJ. It is hoped that this will go some way towards rationalizing such anomalies as the fact that US and Japanese laws oft& ‘bcttcr’ protection than European laws for biotechnological inventions (WC lick. 3). Among other objccrivcs. rhc EC Directive: o seeks to secure harmony between the 12 EC countncs ,md the EPC, and uniform intcrprctation in its courts; 0 confirms patentability of living matter from the simplest to the nlore complex life forms; Q afirms patentability of natural lwoducts; 0 seeks to clarify the interprcra&w of the scope of patent for scltlreplicablc material or maI trial containing genetic inform,ltlon which permits multiplication or propag‘\tion and considers thz ‘exhaustion of rights’ doctrine (i.c. onw a product has been sold, :hc purchasers arc Free to deal wiGi it as they wish and the patclit cannot bc invoked tor a second time)” as applied to this type of marcrial. A ‘biopatcnt’ should extend beyond the firstgcncratjon. Opinions on chc EC Directive have recenrly been given by various commixecs of the European Pz-liammt. These rcquirc assessment and possible modification of the Directive before it can be adopted by the Council and made part of EC law.

Conclusion Patenting represents only a stnnll part ofa very colnples picture. Considering that fnrtnen have, for thousands of years, treated at3imals as items of commcrcc, and bred them selcctivcly for agriculturally desirable characteristics, I<. Bizlcy felt that the extent of the concern expressed by some public groups over life patents is surpri:,ing. The public imagination has been captured, in particular, by the idea ofgenctic rnginccring, often srnsationalizcd and n3isreprcscnted by the 3ncdia. Public concern can perhaps bc nllaycd, ill part, by the dissemination of as much ncctirntc information as possible, and not by shrouding dcvclopmcnts in sccrccy, as happcncd, for instance, in the nuclear industry. Tire patenting systcrn, it seems, has gonr: a long way to bring a scnsc of order to the process of inventions that involve living matter. There arc Intiny social, political and cthicrl hcstill to bc ton aotl t33any viewpoints

cotlsidcred, but the patcnting cystcm is ‘alive and well’ and doing its best to, keep up witll bioccchnology. Kcferences

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UK PATENT COSTS - 1992 Mystified by Patenting Costs P

Ttpinkingof Financiflg the Protection of Your Own invention? Managing Patent Budgets? This handy Guide provides a detailed breakdown of estimated costs per annum over a IO-year time scale for e&i Gage oi prosecution unuer the PCTsystem. Two filing strategies are featured: USA/Europe and USA/ Europe/Japan/Canada/ Australia.

COMMERCWANiilNTEUECNALPROPERTY hW'iAGEMEMlNTtlEBlOMEOlCALSClENCES

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TI6TECHAIJGUST 1992!VOLl@l