Kirin-Amgen v Hoechst Marion Roussel Ltd
|LORD HOFFMANN,LORD HOPE OF CRAIGHEAD,LORD RODGER OF EARLSFERRY,LORD WALKER OF GESTINGTHORPE,LORD BROWN OF EATON-UNDER HEYWOOD
|21 October 2004
| UKHL 46
|21 October 2004
|House of Lords
 UKHL 46
The Appellate Committee comprised:
Lord Hope of Craighead
Lord Rodger of Earlsferry
Lord Walker of Gestingthorpe
Lord Brown of Eaton-under-Heywood
HOUSE OF LORDS
Kirin-Amgen Inc ("Amgen"), a Californian pharmaceutical company, is the proprietor of a European patent (EP 0148605B2) relating to the production of erythropoietin ("EPO") by recombinant DNA technology. EPO is a hormone made in the kidney which stimulates the production of red blood cells by the bone marrow. The discovery by Amgen of a method of making EPO artificially for use as a drug was a significant advance in the treatment of anaemia, particularly when associated with kidney failure. Amgen market it under the name Epogen and the patent (which will expire on 11 December 2004) has been very profitable.
These appeals arise out of a dispute concerning both the validity and infringement of the patent between Amgen and two other pharmaceutical companies. Transkaryotic Therapies Inc ("TKT") is a Massachusetts corporation. It has also developed a method of making EPO, which it markets under the name Dynepo. It uses a process which it calls "gene activation" and the product been referred to in this appeal as "GA-EPO". Hoechst Marion Roussel Ltd ("Hoechst") is the English subsidiary of a well-known multinational pharmaceutical company which has been proposing to import GA-EPO into the United Kingdom. In three consolidated actions, Amgen claims that GA-EPO infringes the claims of the patent in suit and TKT and Hoechst claim a declaration of non-infringement and revocation of the patent. I shall for convenience refer to both Hoechst and TKT as "TKT" but it should be borne in mind that the only allegations of infringement in the United Kingdom arise out of the importation of the drug by Hoechst.
The science upon which recombinant DNA technology is based has been described in a number of judgments, not least in the admirable account given by Neuberger J in this case, much of which was reproduced verbatim by the Court of Appeal. I do not propose to repeat these passages but gratefully adopt them and will largely take them as read.
The race for EPO
The technology for manufacturing proteins ("polypeptides") by the expression of recombinant DNA developed rapidly after the mid-1970s. The speed of development is illustrated by the decision of your Lordships' House in , in which a recombinant method of making the antigens of a hepatitis virus was patented with a priority date of 22 December 1978 but was conceded to have been obvious by 21 December 1979. Pharmaceutical companies competed to be the first to plant the flag on some desirable protein.
EPO was a particularly elusive goal in the early 1980s because it was difficult to get hold of enough of the natural product to do the necessary research. To design the probes to find the gene, whether in a genomic or cDNA library, you first had to know the amino acid sequence of at least a part of the natural polypeptide. But the kidney makes such minuscule quantities that purified natural EPO was virtually unobtainable. In 1977 a team including Dr Takaji Miyake and Dr Eugene Goldwasser developed and published a protocol for purifying milligrams of EPO from large quantities of urine laboriously collected from patients suffering from aplastic anaemia: see Miyake et al, . Dr Goldwasser made some of this urinary EPO ("uEPO") available to Dr Rodney Hewick of Cal Tech, who tried to sequence 26 residues at the N terminus. (The protein has 165 residues). This information was published by Sue and Sytkowski in 80 PNAS USA, pp 3651-3655 (1983) but two of the residues were incorrectly identified.
The Amgen team trying to sequence the EPO gene was headed by (indeed, consisted largely of) Dr Fu-Kuen Lin. Dr Goldwasser was engaged as a consultant. He was able to make some uEPO available to Dr Lin, who designed a set of fully degenerate probes to hybridise with the DNA coding for two regions of the protein. As the kidney makes so little EPO, there was little prospect of obtaining mRNA for a cDNA library. So Dr Lin used his probes on the vast array of genes in a genomic library. Against the odds, he obtained three positives which enabled him to locate the EPO gene in the fall of 1983. He was then able by patient but conventional methods to identify the whole of its structural region, its introns, exons and splicing sites and a fair amount of the upstream and downstream sequences as well. He thus established the correct sequence of the amino acid residues which formed the protein and its leader sequence.
This information, first discovered by Dr Lin, was essential to any process for making EPO, whether by Amgen's method or TKT's. As one of the principal issues in the case is whether TKT's GA-EPO (which is chemically exactly the same as Amgen's Epogen) falls outside the claims of the patent in suit because of the difference in the way it is made, I shall at once describe in bare outline the two methods. There are some details on which special arguments were founded and I shall come back to these later. For the moment, however, a sketch will do.
The two methods of making EPO
Once the sequence of the EPO gene had been discovered, it was possible to make it by methods of recombinant DNA technology which were well known in 1983. These are succinctly described in the specification of the patent in suit:
"Simply put, a gene that specifies the structure of a desired polypeptide product is either isolated from a 'donor' organism or chemically synthesised and then stably introduced into another organism which is preferably a self-replicating unicellular organism such as bacteria, yeast or mammalian cells in culture. Once this is done, the existing machinery for gene expression in the 'transformed' or 'transfected' microbial host cells operates to construct the desired product, using the exogenous DNA as a template for transcription of mRNA which is then translated into a continuous sequence of amino acid residues."
That is the way the patent in suit teaches how to make EPO. Dr Lin isolated the gene which coded for human EPO from a human donor cell and then introduced it into a mammalian cell in culture which had been derived from the ovary of a Chinese hamster (a "CHO cell"). As part of the hamster DNA, it expressed EPO. Of course it was not as simple as that. To get it into the DNA of the CHO cell, it had first to be incorporated into a bacterial plasmid vector. To improve the chances of expression, the gene's natural promoter was removed and a more powerful viral promoter substituted. To increase the rate of expression, cells in which the gene had been multiplied ("amplified") were selected by a technique which involved treating them with methotrexate. Indeed, the CHO cell had been chosen as host because it had a gene mutation which made it particularly suitable for amplification by methotrexate. But these were all tricks of the trade well known among practitioners of the art. The essence of the technique was that described in the passage from the specification which I have quoted, namely, the introduction of an exogenous DNA sequence coding for EPO into a host cell in which it would be expressed.
In TKT's gene activation method, the EPO is expressed in a human cell by an endogenous gene naturally present or by cells derived by replication from such a cell. Ordinarily, such a gene would not express EPO. Almost all human cells contain the full complement of DNA coding for all the proteins needed by the body ("the human genome") but each cell will express only those proteins which its particular tissue requires. The rest remain inactive, disabled by the absence of a suitable regulator which is needed to promote expression. The TKT technique involves introducing the necessary control sequence upstream of the EPO gene. The control sequence is accompanied by other bits of machinery (for example, to allow for amplification by methotrexate treatment) which it is for the moment unnecessary to describe. All this exogenous DNA has to be inserted into the human DNA at exactly the right point upstream of the EPO gene. This could not have been done at the time of the patent but can now be done by using a phenomenon called "homologous recombination". It is fully described by Neuberger J and I need say no more than that it enables TKT to activate or "switch on" the EPO gene in a human cell which would not ordinarily express that protein and then to select for commercial use those descendants of the manipulated cells in which the relevant genes have been amplified to produce a high level of expression.
The essential difference between Epogen and GA-EPO is that the former is made by an exogenous DNA sequence coding for EPO which has been introduced into an host cell and the latter is made by an endogenous DNA sequence coding for EPO in a human cell into which an exogenous upstream control sequence has been inserted.
With that introduction, we can now look at the patent. The specification explains the relevant science, the nature of EPO and the difficulties which stood in the way of identifying the gene. It then describes the methods which Dr Lin used to find the gene in the DNA of monkeys and humans and sets out the full sequences for both species in Tables V and VI respectively. In a series of 12 examples it describes what Dr Lin was able to do with this information,...
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