patent specification must be construed with reference to the state of knowledge of those skilled in the art at
the time of the priority date of the patent in issue. Accordingly, in order to enable the court to construe the
specification properly, it must be instructed by expert witnesses as to the state of the art in the field of the
invention in order to place the court as near as may be possible to the position of those skilled members of
the public to whom it is addressed, as at the relevant date (see eg Sappi Fine Papers (Pty) Ltd v ICI Canada Inc
(formerly CIL INC) 1992 (3) SA 306 (A) at 318I319E).
Background
[10] For that purpose, two experts in the field were called to give evidence at the trial, namely, Prof Martyn Davies
on behalf of Bayer and Dr Peter Rue on behalf of Pharma. They were largely in agreement that the
addressees of the patent would be a broad interdisciplinary product formulation team of a pharmaceutical
company, led by an experienced scientist and including biological pharmacologists, toxicologists, clinicians and
so forth. For the sake of brevity, these addressees of the patent in suit were referred to at the trial and in
argument as "the skilled formulator". I propose to follow that example. Broadly speaking, the two experts
were also
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in agreement as to the state of the knowledge of that skilled formulator as at the priority date, ie 31 August
1999. In this way the following background had been established.
[11] An active pharmaceutical ingredient ("API") administered to humans orally, passes down the gastrointestinal
tract and is absorbed into the bloodstream. For present purposes we can concentrate on two parts of that
tract, to wit, the stomach and the small intestine. The stomach is highly acidic with a generally accepted pH
range of between 1 and 3. The stomach lining is not designed for absorption. The primary purpose of the
stomach is after all not to absorb, but to digest the ingested food. By contrast, the small intestine is less
acidic generally accepted as ranging from pH 5 to 7 and primarily designed for absorption into the
bloodstream. The API can only be absorbed into the bloodstream once it is in solution, ie once it has been
dissolved. The quantity of API absorbed into the bloodstream and eventually becoming available at the point
of the human body where it is required for treatment of the individual, is said to be bioavailable. Bioavailability
therefore describes the quantity of the drug, expressed as a percentage of the dose administered, that
becomes available for treatment.
[12] Because of the arrangement of the gastrointestinal tract, the API must pass through the highly acidic
conditions in the stomach before it reaches the small intestine where it can be absorbed, ie before it becomes
bioavailable. It stands to reason that the longer the API remains in the stomach, the more it will be affected
by those conditions. The skilled formulator would have been aware that the residence time of the API in the
stomach might vary substantially. With regard to a particular individual it would be influenced by a number of
factors, including whether the individual had eaten or fasted, the nature of the diet and so forth. Moreover,
apart from this intraindividual variability, there would be interindividual variability in residence time. All in all
stomach residence may vary between 30 minutes and 4,5 hours with a meantime of 90 minutes. If the API is
therefore immediately released once it reaches the stomach, it may spend anything between 30 minutes and
4,5 hours in that highly acidic condition.
[13] A formulator charged with a formulation for an API will invariably conduct formulation tests in the laboratory,
referred to as in vitro tests. These are, inter alia, aimed at establishing, among other things, the solubility of
the drug and its stability under acidic conditions. The rate of dissolution may be studied in vitro using standard
dissolution tests. Such tests are routinely used in the pharmaceutical industry. The "USP XXIII Paddle Method"
referred to in claim 1 of the 2004 patent to which I shall presently return is one of these standard methods
of testing the rate of dissolution, which any skilled formulator would understand.
[14] As drugs administered orally need to dissolve in the gastrointestinal tract in order to be effective, drug
candidates that exhibit poor solubility in vitro will be considered a risk for development as they may show poor
bioavailability in vivo, ie in the human body. The dissolution rate of a drug can, however, be increased. So, for
example, the particle size of the drug can be reduced known as micronisation or the drug can be dissolved
and sprayed onto the surface of inert carrier particles. Since these two
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methods of improving the rate of dissolution are expressly referred to in the 2004 patent, I shall return to
them in later discussion.
[15] If an API is unstable in acidic conditions, ie if it is acid labile, a significant portion of the drug may be degraded
or isomerised in the stomach, which would in turn reduce its bioavailability. This would of course be a
contraindication for increasing the dissolution rate of an API known to be acid labile. The reason for the "of
course" is that the sooner the drug dissolves in the acidic conditions of the stomach, the more severe the
influence of those conditions will probably be. Moreover, given the potential of both intra and inter individual
variability in stomach residence time, the formulator would have to produce a formulation that could cope with
the longest possible exposure to the acidic environment of the stomach.
[16] One way of overcoming the problem of isomerisation in the stomach is to increase the dosage of API
administered. That, however, could result in an overdose. The skilled formulator would have known that,
especially with reference to a drug which is used regularly, as in the case of a contraceptive, overdose could
be particularly detrimental to the user. Another way of resolving the problem of acid lability is to protect it from
the acidic environment in the stomach by means of an enteric coating. Enteric coatings act as an impermeable
barrier around the API and prevent the acid content of the stomach from coming into contact with the