On the 21 December 2000, Mr. Justice Neuberger, sitting in the Patent's Court of the High Court of Justice in England on a revocation action brought by Novo Nordisk A\\S, found a patent for the cloning and expression of microbial phytase invalid on the grounds of obviousness and insufficiency. The judgment affirms the view that in the era post the mid 1980's (when the first genes were isolated and cloned into expression systems) unless there was a particular difficulty associated with the process of cloning and expressing a particular gene, then a patent on a gene and expression system is going to be vulnerable to the same finding.
The patent described how the patentee (DSM) had purified the enzyme phytase from the fungus Aspergillus ficuum, partially sequenced fragments of the protein, produced oligonucleotide probes based on these sequences and, then used these to locate the gene encoding the phytase enzyme. The gene was then inserted into an expression system and over expressed so that it could be produced in sufficient amounts for commercial exploitation. Phytase is an enzyme that catalyses the release of phosphate from organic sources. Its use as a supplement in animal feed for certain animals (those that cannot do it for themselves because they lack the enzyme in their digestive systems e.g. pigs and chickens) reducing the need to add inorganic phosphate to their food which in turn reduces the amount of phosphorus that enters the water table. This helps to reduce the environmental pollution caused by excess phosphorus.
The claimant (Novo Nordisk A\\S) manufactured a version of the phytase enzyme and brought the UK action, along with a number of other parallel actions, as a pre-emptive strike to protect their market position in Europe. They challenged the patent on three grounds: (1) that it was obvious (over common general knowledge and four prior art citations), (2) that it was insufficient and, (3) that it contained added matter. The defendant resisted the case and in addition sought to assert a case of commercial success in order to defeat the case on obviousness. The latter was not pursued at trial. The patent had seventeen claims but the case would turn on the judge's finding on the first two claims, which were;
"A DNA Sequence encoding a fungal phytase which catalyses the liberation of at least one inorganic phosphate from a myinositol phosphate, said sequence being selected from the group consisting of ...
(c) DNA sequences hybridizing at low stringency conditions (6 x SSC; 50C; overnight; washing in 6 x SSC at room temperature) with a DNA fragment corresponding to a cDNA of the nucleotide sequence depicted in Figure 6 from position 210 to 1129"
A DNA sequence which is related to the DNA sequence of claim 1 by the degeneration of the genetic code."
The first claim had three parts the last of which was the subject of much of the argument. What it was aimed at claiming was taking a specified DNA probe and using it to find genes encoding phytase from other organisms. The second claim tried to cover any degenerate variation of the gene.
In order to get to a point where you can produce an enzyme on a large scale, one has to isolate the gene and insert enough copies of it into a host so that when the gene is expressed the host over-expresses the protein. However, first one has to find the gene! One way to do this is to take a sample of the purified enzyme, break it up using one of a number of techniques, take some of the fragments and then find their corresponding DNA sequences. Once one has these sequences it is possible to construct probes that enable you to fish out the gene of interest by attaching the probe to the corresponding sequence in the genome of the organism (in this particular case a fungus).
The claimant's case was that there were two main objections to this patent. Firstly, the defendant had simply taken a path known by all in the field. There was nothing new in what they had disclosed. Further, there was prior art that took the skilled addressee to the front door step of the invention and thereafter the exercise was one of basic laboratory graft, rather than patentable invention. The defendant's case was that the inventive step lay in the combination of the use of an unusual purification technique that they employed together with a novel use of a staining technique. This, they said, had led to the break through of producing a pure enough protein to produce the probes that were needed. The defendant's contended that the main prior art (the so called "Ullah" paper) was to be disregarded as it contained matter that would lead the skilled addressee to discard it altogether.
The second main aspect was the insufficiency case. What the claimant was able to show, with some experimental evidence, was that the conditions specified in the last part of claim 1 were so indiscriminate that the probe would bind to anything and everything, even genes that encoded unrelated proteins. The defendant's answer was to produce experiments of their own which they claimed showed that if the conditions were altered from those claimed, in a way that the skilled addressee would know how to do, the binding of the DNA became more specific and enable a skilled addressee to find DNA encoding phytase in other organisms.
Before approaching the issue of the validity of the claims, the judge started by considering the skilled addressee of the patent and the state of the common general knowledge. On the first of these both sides agreed that the project would require a protein chemist in order to purify the protein and then a molecular biologist to carry out the gene isolation.
On the issue of what was common general knowledge there was similarly a degree of agreement between the parties' expert witnesses. The judge found that it was known: (i) that their were a range of known protein purification techniques, (ii) that there were a range of known staining techniques, (iii) that proteins could be broken and sequenced, and that (iii) from such sequence one could design probes to isolate the gene of interest.
The defendant's evidence tried to show that the particular techniques that they used to purify the enzyme, "flat bed IEF", was not routinely used for this kind of purification work. It was more established as an analytical tool not a purification method. However, the judge rejected this line of evidence.
In essence the judge found that the patent was obvious over the common general knowledge. There was no invention, in this case, of using a well-known series of methods in combination with one another. The use of the particular technique that proved to be the successful one, although not the first choice, was similarly obvious as the skilled addressee would have turned to it as a matter of course.
The patent was also found invalid over the Ullah prior art. Ullah had published a paper where he had purified the phytase enzyme (using a different technique to the defendant), produced four protein fragments and then published the amino acid sequences together with his method. In theory all the skilled addressee had to do was take these and design probes based on one of these. In fact a subsequent team of workers (who published their work after the patent's priority date but did the work about the same time as the defendants) had done this with one of the peptides (called Peptide II during the trial) and succeeded.
The defendant's case on Ullah was two fold: (i) Peptide II could not be used as it contained an amino acid sequence that was so unusual that it would put off the skilled man, (ii) the other two peptides were from proteins later discovered to be contaminants, whilst the fourth, although from the phytase enzyme, was unsuitable to design probes. All of this meant the paper was unreliable and therefore should be ignored. This meant that the skilled addressee would have to start from scratch and then be faced with the purification problem referred to above with regard to obtaining a pure sample of the protein.
All the experts agreed that the sequence as a whole would be an ideal sequence to use, and in fact worked when used as a probe. The judge found that on the balance of the evidence the skilled addressee would have used the sequence and as a result would have succeeded in using it as a probe for the gene encoding phytase. The patent was therefore invalid over the Ullah paper as well.
On the allegation of insufficiency the court approached the question the court started by construing the claims and then turning to consider whether they were sufficient in the light of the construction that the court had come to. The question was, was claim 1 (c) claiming any gene (whether it encoded phytase or not) that bound under the conditions in the claim or was it, as the defendant's contended, limited to any gene encoding phytase and the conditions specified were to give the skilled addressee a start point from which to begin looking for the phytase gene in other organisms? In the absence of any indication to the contrary in the patent, the judge decided that the claimant's construction was to be preferred and the claim was to be read as covering any DNA sequences that bound to those conditions.
On the substantive issue of insufficiency the defendant's expert evidence contended that the skilled addressee would take the conditions given in the claim and modify them in order to produce a result that meant that the results were much more specific (i.e. showing clear bands). This then extended would then allow the skilled addressee to continue to the next stage of isolating the gene.
There were two difficulties with this: firstly this required the skilled addressee to modify the conditions specified by a strict reading of the claim and secondly, even on the defendant's experimental results, both sides experts agreed that the amount of work left to do in order to isolate the gene was still considerable. Faced with this evidence the judge ruled that the claim was insufficient.
There are two important points to take away from this case. Firstly, the judgement establishes the common general knowledge in this area in the United Kingdom and any patent that does no more than this is unlikely to survive judicial scrutiny. Secondly, biotech inventions that try to stake a claim on an area, as this one did, are likely to be insufficient where they do not provide information that aid the skilled addressee to find the alternatives within the whole area claimed.
First published in Patent World in March 2001.