underlying API. As at the priority date, the skilled operator would have known that there were a number of
different enteric coatings available for this purpose.
[17] Also wellknown, since at least the 1960s, was the fact that DSP in combination with EE could be used as a
contraceptive. In vitro tests had shown, however, that DSP has the two features that presented a particular
challenge to formulators, namely that it was both poorly soluble and acid labile. Moreover, because it was
destined for use as a contraceptive, excessive dosage was a potential problem, which indicated small
dosages. To add to the formulator's difficulty, a contraceptive has to be formulated so that it is a 100%
effective at inhibiting ovulation, given that the consequence of an ineffective dose could be an unwanted
pregnancy. This added demand does not present itself, for instance, with analgesics and antibiotics. With DSP
it was therefore necessary to establish a dosage which achieved this high degree of reliability. What the
formulator would have known in sum was that in all these circumstances, it was of cardinal importance to
ensure, not only that each tablet contained the right dosage at the point of administration, but also that as
little as possible of the dosage was not lost on its way to the site of absorption in the small intestine.
[18] The two experts who testified at the trial were generally in agreement that the results of in vitro tests in
themselves would have indicated a development of a small dosage of DSP with increased solubility also
described as rapid dissolution eg by way of micronisation, but protected from the acid in the stomach by an
enteric coating. The record of the in vitro tests carried out by Bayer in fact showed this. From here on, the two
experts, however, parted company. Dr Rue's view was that the skilled formulator would not have decided to
protect DSP with an enteric coating unless and until the results of the in vitro experiments had been confirmed
by in vivo tests on humans. Even with drugs known to be highly acid labile, so
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he said, in vivo tests are routinely conducted. The reason, he said, was the known fact that one cannot
accurately predict the in vivo bioavailability of the drug purely from in vitro experiments. Accordingly, he
concluded that despite the results of the in vitro tests, the skilled formulator would routinely have performed
an in vivo test with both enteric coated and uncoated DSP at an early stage of the development process. In
vivo tests would then have shown, as we now know with the experience of hindsight, that good bioavailability
could be attained with DSP unprotected by an enteric coating. Prof Davies, on the other hand, was of the view
that in the light of the in vitro results, the skilled formulator would have regarded in vivo tests with uncoated
DSP as wasteful of both time and money. This is particularly so, because in vivo tests, he said, are costly and
time consuming. A skilled formulator would therefore not embark on this road with no expectation of success
which was what the in vitro experiments predicted.
[19] How Bayer actually came to realise that DSP need not be protected by an enteric coating, emerges from the
"inventors" story" that derived from the documents referred to by both experts during their evidence at the
trial. In broad terms the story went as follows. During April 1983, Dr Johannes Tack, who later became the
Head of Pharmaceutical Development at Bayer but at that time, still a junior researcher was charged with
the task of developing an oral tablet formulation of one milligram DSP. Results of in vitro tests steered him in
the direction of an enteric coating. For the next four years scientists at Bayer thus conducted preformulation
experiments with enteric coated DSP exclusively. Results achieved by in vivo studies during this period, both
with dogs and humans, were encouraging to the formulation team. Of some concern to them, however, was
the intersubject variation in these results. To address the possibility that these variances could be caused by
the enteric coating that they used, they decided to do what was referred to in evidence as a three arm
bioavailability test, which was done during the first term of 1988.
[20] Broadly speaking, the three arm test compared the bioavailability of DSP when administered in three forms:
(a) intravenously where absorption plays no role; (b) through enteric coated tablets; and (c) through tablets
which were not enteric coated at all, and the DSP is thus immediately released in the stomach. Based on the
results of in vitro studies, the formulation team clearly had no anticipation of success for the uncoated
formulation. However, the surprise came when the bioavailability of the uncoated formulation proved to be
statistically no different from that of the enteric coated drug.
[21] What must also be borne in mind at this juncture is that, although enteric coatings perform the positive
function of protection against acid in the stomach, they had known disadvantages. First of these is that it
delays absorption until it is finally dissolved in the small intestine. Hence, it also delays the onset of action of
the drug. The second and related problem is that the period of delay would be the subject of inter and intra
patient variability which is coupled to the residence time of the protected drug in the stomach. This again is of
particular significance with a drug intended for contraception where it is undesirable to leave large gaps in the
sequence of administration. In the light of these known disadvantages of an
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enteric coating and consequent delayed release of the drug, skilled formulators of Bayer realised the benefits
of an immediate release of DSP. In consequence, the formulation team at Bayer subsequently redirected its
research and development from coated to uncoated DSP, which is the form in which its Yasmin product was
eventually marketed.
[22] In this light Prof Davies contended that the invention covered by the patent is the following (page 2 137):
"The very fact that against all expectations for a drug which is poorly soluble such as drospirenone and which is acid
labile, against all expectations that if you used a rapid dissolution, a formulation that achieves a rapid dissolution, as
per claim 1 of the 2004 specification . . . what you get is good bioavailability, in other words, good absorption in vivo.
That is against all expectation due to the acid lability of the drug. So that is the inventive step."
And at 2 504: