Although the patenting of genes has becomeacceptable to patent authorities in many coun-tries, the idea is still unpopular in certain quar-ters. First, it is necessary to distinguish betweenpatents on full-length genes and potentialpatents on gene fragments of unknown biolog-ical function. Many US authors1,2 haveaddressed the difficult question of patentinggene fragments as “research tools.” But thepatenting of novel genes the function of whichis revealed in the inventor’s patent application,although it might be thought easier to accept,is still disputed by many.

Those who oppose patents on genes usu-ally give four main reasons for their position:(1) Genes exist in nature and therefore, as ournatural heritage, they should not be “owned”by any individual or group. (2) Genes are dis-coveries and not inventions. (3) Because oftheir existence in nature, genes cannot be“new.” (4) Gene isolation and cloning is nowsuch a well-established technique that it is nolonger inventive to do it.

The objections consideredEven if the objection that genes should not be“owned” because they exist in nature werewell founded, it is really a philosophical onethat cannot be fitted easily into the groundsavailable for refusing a patent. It is also basedon a false conception of what a patent confersin terms of “ownership.”

The second claim—that genes are discover-ies—may seem to have weight. How can any-one invent a gene? In the US, the claims in genepatents usually recite “an isolated (or purified)DNA” of defined function or specific sequence.This ties the legal protection to a product ofhuman technical intervention, thus excludingthe gene in its natural habitat. Moreover, theclaimed DNA is often not genomic DNA butcDNA, a totally artificial construct.

Judging from previous US court cases onDNA patents, it is unlikely that US patent lawwill dismiss genes as unpatentable discover-ies. In Europe, the final answer to this objec-tion, and the previous one, is provided by aDirective to EU Member States3, whichdeclares that biological material is not auto-matically excluded from patentability justbecause it has preexisted in nature.

The objection that DNA is found innature or that DNA sequences are present in

gene banks has not succeeded with the officialpatent authorities, because the claimed mate-rials are dwarfed with so much else that theyare not “available to the public” in the sense inwhich this term is used in patent law. TheBiogen α-interferon case decided by theEuropean Patent Office (EPO) TechnicalBoard of Appeal4 illustrates this distinction. Ithad been argued against Biogen that theinterferon genes could not have been novelsince they must have been present in a certainwell-known gene bank. But the board heldthat the gene bank did not make the claimedDNA molecules sufficiently accessible to thepublic to be part of the state of the art. Theboard observed that “the situation resemblesthat prevailing with natural substances ... andis rather like the isolation of a component orbacterium from soil where the same exists inadmixture with other useless materials. Thusthe idea that the gene bank itself would onceand for all anticipate an invention relating toa nucleotide sequence which may be con-tained therein cannot be sustained.”

For the objection that gene isolation andcloning is now routine and therefore notinventive, important case law has arisen fromlitigation on some of the patents that wereapplied for in the late 1970s and early 1980swhen gene cloning was relatively new. Twocommercially important examples of this arethe tissue plasminogen activator (TPA)patents and the erythropoietin gene patent.

Rather exceptionally, the UK nationalpatent for recombinant TPA (first applicationfiled May 1982) was revoked by an Englishcourt for lack of inventiveness. The claims inthe TPA patent UK 2,119,804 were mainlydirected to the recombinant protein per se andto a process of making it. There were alsoclaims to recombinant cloning and expressionvectors containing the DNA, but there was noclaim to the naked DNA coding for TPA. Sothis patent was not a pure gene patent as such.Therefore, the reasoning of the English courtwas not specifically aimed at claims to thegene. The corresponding European patent EP93619 was mainly drawn in terms of claims tothe process technology. In contrast, the corre-sponding US patent 4,766,075 concentrateson claims to the DNA sequence.

The English Court of Appeal decided5 notto sustain the patent because, at the relevantdate, the objective to produce the known pro-tein TPA by recombinant DNA technologywas seen as practicable, and was being pur-sued by a number of rival teams in parallel;

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also because the method of isolating the TPAgene from a cDNA library by the use of probesbased on known parts of the protein sequencefollowed standard textbook general method-ology. The court did address the discoveryissue, but focused mainly on the “reach-through” claim directed to second-generationproducts, i.e., derivatives and analogs of TPA,which might be produced by protein engi-neering based on knowledge of the sequenceof natural TPA. This particular claim wasallowed by the EPO but is not present in theUS patent. But neither the EPO nor the USPatent Office followed the line of the Englishcourt on the inventiveness or obviousness ofthe recombinant approach to TPA itself.

In the case of the erythropoietin genepatent, as background to Amgen’s US patent4,703,008 claiming “A purified and isolatedDNA sequence consisting essentially of a DNAsequence encoding human erythropoietin,”there was relatively little sequence informationavailable when the Amgen inventor startedwork. The inventor had prepared a large num-ber of probes for small known parts of thesequence and used these to probe a genomiclibrary. This method was considered uncon-ventional and highly ingenious by the US Courtof Appeals for the Federal Circuit (CAFC)6 and,because it led to the isolation of the gene for thefirst time, it justified the claim to the DNA itself(and not only the method of cloning it).Neither of the parties to the dispute raised anyobjection to the claiming of the DNA itself.

It was the Amgen case that gave the CAFCthe opportunity to state that “[a] gene is achemical compound, albeit a complex one….”In a later case of interference7 between threepatent applications (Fiers, Sugano, Revel), theCAFC held that “conception of a DNA, likeconception of any chemical substance, requiresa definition of that substance other than by itsfunctional utility.” This case showed theimportance of sequence information in a pri-ority contest between rival applicants. A morerecent third case8 also showed the importanceof sequence information to support a claim toa specific cDNA. In that case, the claim to arecombinant plasmid containing the cDNAcoding for human insulin was held invalid forlack of human sequence information (only therat cDNA sequence was disclosed).

These remarks of the CAFC put genes onthe same footing as other complex chemicalcompounds and show no hint of recognizingthe first three objections outlined above. It isalso clear that the intimate connection

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Patents on genes: clarifying the issuesThe debate on gene patenting, while still unresolved, can be simplified.R. Stephen Crespi

R.Stephen Crespi is a patent attorney based inWest Sussex, UK (R.S.Crespi@btinternet.com).

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between DNA and life processes is not a legalreason for excluding it from patent protec-tion. We can also conclude that the questionof inventiveness or “obviousness” of what thepatent or patent application claims is a mat-ter to be judged case by case and not by blan-ket prejudgment.

Incidentally, where rDNA technology isbeing applied to manufacture previouslyknown proteins, as in the two examples givenabove, official US and European patent prac-tice does not permit claims to the “recombi-nant protein” per se unless this can be shownto be different in some significant way fromthe wild-type material. So claims to the DNAcoding sequences or to methods of using theseto produce the recombinant protein may oftenbe the only types of claim allowable.

Different kinds of DNA patentsOne can distinguish at least two categories ofpatents in this field: (1) DNA coding for indus-trially useful expression products. Where aDNA coding sequence has been cloned andenables the commercial production of someimportant therapeutic protein, it is clear thatthis advance in pharmaceutical technology isan achievement deserving of legal protection,provided it meets standard criteria ofpatentability. The same can confidently besaid of the advances in plant biotechnologythat improve agricultural products, practice,and productivity. (2) Genes that control bio-logical pathways. The discovery of genesimplicated in the disease process seems to pre-sent another twist to this debate.

Research continues to identify receptorsand genes involved in biological pathways.Thus, knowledge of such a gene’s location mayallow researchers to correlate a malfunction inthe pathway with a mutation or loss of thisgene. The cDNA and the encoded polypeptidewould be considered targets for diagnosis and,hopefully, treatment. However, the immediateutility of this finding may not be proven andmay often require further research to confirmthat it has this potential. It is an open questionwhether these findings are ripe for patenting,but unless we try to patent them we will notknow the answer.

Genes implicated in major killer diseaseshave also been patented. These importantdevelopments typically involve the trackingdown and isolation of genes that, in the “nor-mal” allele, confer good health. The genescause disease when they mutate and eitherexpress the wrong product or are deleted andexpress none at all. How should one view apatent that claims the normal gene? In otherwords, what is the utility or industrial applica-bility of the normal gene and what are theprognostic or diagnostic consequences of hav-ing identified it?

The breast cancer genes that have beenpatented in the US are good examples of this

type of patent. US patent 5,747,282 coversBRCA1, the first of two breast cancer genesrecently discovered. As with other patentsderiving from academic institutionalresearch, the text of this patent stronglyresembles the kind of writing found in scien-tific publications. Thus, some of the patentexamples describe extensive backgroundresearch and genetic analysis of families orkindreds prone to breast cancer in the state ofUtah. These are not patent examples of thetype one would normally expect to find. Theleading two claims in this patent cover thenormal BRCA1 gene sequence. Another keyclaim covers the BRCA1 gene having specificmutations at four specified positions in thesequence. The claims that relate most directlyto the commercial realities resulting fromthis research are (1) one directed to a kit fordetecting mutations comprising a primerspecific for a mutation (unspecified), and (2)a related claim covering a kit comprising anallele-specific probe for a gene mutation(unspecified). There is also a claim to amethod of screening for cancer therapeuticsbased on the revealed genetic information.

These commercially important kit claimsare what one would expect to be presented bythe applicant for the patent in cases of thistype. An observer might wonder whether theclaim to the normal gene adds anything signif-icant to the legal protection given by the kitclaims. But cautious patent attorneys will pre-sent any claims that might be allowed by theofficial patent authorities. What harm iscaused by having such a claim is not apparent.

Patent exploitation policyWe need also to consider the way the holder ofany gene patent might choose to exploit it.Any attempt to suppress research on the basisof a claim to the gene itself is bound to attractopposition from a number of research groups,and not solely in academia or hospitals.Prominent US patent attorneys have alsojoined in this debate9,10. Ultimately, this maybe the real problem, rather than the grant ofthe patent itself. It would be much better toseek to solve this than to place restrictions onwhat can be patented.

1. Eisenberg, R.E. & Merges R.P. Am. Intell. Prop. L.Assn. Q. J. 1, 3–51 (1995).

2. Eisenberg, R.E. Nat. Genet. 15, 125–130 (1997).3. Directive 98/44/EC, Official Journal of the European

Communities, Article 3.2 (30 July 1998).4. Biogen Decision T 301/87, Official Journal of the

European Patent Office 8, 335 (1990).5. Genentech v. Wellcome Foundation, UK Court of

Appeal, Judgement, 1989 Reports of Patent Cases8, 147–203 and 9, 203–287, published by ThePatent Office, London.

6. Amgen Inc. v. Chugai Pharmaceutical, 13 USPQ 2d1737–1797 and 18 USPQ 2d 1017-1031 (1989, 1991).

7. Fiers v. Sugano, 25 USPQ 2d 1601–1607 (1993).8. Regents of the University of California v. Eli Lilly &

Co., 119 F.3d 1559,1566 (1997).9. Flores, M.A. Nat. Biotechnol. 17, 819–820 (1999).

10. Mays, T.D. Bio-Science Law Review 2, 56–66(1999/2000).

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