[NO.

5] COURT OF APPEAL

IN THE COURT OF APPEAL

Before: LORD JUSTICE SIMON BROWN

LORD JUSTICE ALDOUS
LORD JUSTICE SEDLEY

July 27, 20001

AMERICAN HOME PRODUCTS CORPORATION V. NOVARTIS

PHARMACEUTICALS UK LTD

[2001] R.P.C. 8

HI PatentInfringementPreliminary issueValidityConstruction of claim

Rapamycin as immunosuppressantWhether derivatives within scope of
protection if none identifiedSufficiencyPatent held infringed and
sufficientAppeal.

H2 Patents Act 1977, ss 4(2), 60(l)(c), 72(l)(c)

H3 Claim 1 of the patent in suit claimed "Use of rapamycin for the preparation of a
medicament for inhibiting organ or tissue transplant rejection in a mammal in
need thereof" Rapamycin was known as an antifungal antibiotic and the claims
of the patent were thus in "second use" form. The alleged infringement was a
derivative of rapamycin in which the hydroxyl group at position 40 had been
O-alkylated with a 2-hydroxyethyl group. This derivative was referred to as SDZ
RAD.
H4 The defendants contended that derivatives of rapamycin did not fall within the
ambit of the claims and that, if they did, the patent was invalid as it was insufficient
in that there was no disclosure in the specification of how to make or select
derivatives of rapamycin to prepare a medicament "suitable for inhibiting organ
or tissue transplant rejection in a mammal" as required by claim 1. The judge
heard the issues of construction and sufficiency was a preliminary issue. The
judge construed the word "rapamycin " in claim 1 as including derivatives with the
result that the functional words in the claim limited it to rapamycin and its
derivatives which were suitable for preparation of a medicament which was
suitable for treating organ transplant rejection. He rejected the insufficiency
attack and found in favour of the patentee.2 The defendants appealed.
H5 The patentee contended that claim 1 should be read as meaning "rapamycin
itself and derivatives thereof which exhibit the same type of inhibition to organ
rejection as rapamycin and which are suitable for the preparation of a
medicament for inhibiting organ or tissue transplant rejection in a mammal". In
relation to infringement, the patentee contended that as the claim only covered
1
Paragraph numbers in this judgment are as assigned by the court.
2
[2000] R.P.C. 547.

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variants which were suitable for producing a medicament which had to be

suitable for inhibiting rejection, the variants could not have a material effect on
the way the invention worked and further that the functional limitation would be
answered in the affirmative as it would be obvious that the variant would work in
the same way.
H6 By a respondent's notice, the patentee contended that SDZ RAD infringed
claim 1 even if, on its true construction, it was limited to the use of rapamycin
itself. It contended that claim 1 was a process claim and that the defendants had
manufactured SDZ RAD using rapamycin as the starting material and that it had
imported a product (SDZ RAD) obtained by means of the process of claim 1 in
that they had used rapamycin for the preparation of a medicament which was
suitable for inhibiting transplant rejection.
H7
Held, construing the claim as excluding derivatives of rapamycin and, on such
construction, rejecting the attack on insufficiency, allowing the appeal and
making a declaration of non-infringement:
H8 (1) Throughout the specification the word "rapamycin " was used to denote the
molecule rapamycin. The only references to derivatives were in the title and in a
passage which drew a distinction between rapamycin and derivatives. The
specification did not identify a single derivative which had been shown to work,
(para. 20)
H9 (2) Applying the "Protocol questions",3 the invention was the discovery of a
second medical use for rapamycin and the variation was the class of compounds
called derivatives of rapamycin with the actual variant in issue being SDZ RAD.
(para. 22)
H10 (3) The patentee's approach to infringement was fallacious and would always
result in the first two Protocol questions being answered in its favour if a claim
was limited to variants which would work and obviously work. (para. 24)
HI 1 (4) There was no basis in the specification to enable the skilled person to decide
whether a particular derivative had rapamycin-like effect other than the
requirement of the functional part of the claim. The variant was not, as the
patentee contended, a derivative which had rapamycin-like effect or was a
derivative which complied with the functional limitation in the claim. The variant
was either all derivatives of rapamycin or the particular derivative SDZ-RAD.
(paras 25 and 27)
H12 (5) Although the judge had not made a specific finding as to the equivalence of
SDZ-RAD to rapamycin, there was evidence that the use of SDZ-RAD would not
materially affect the way the invention worked. The answer to the first Protocol
question would be assumed to be in favour of the patentee, (para. 26)
H13 (6) It was fair to the patentee to include within the claim immaterial variants
and to exclude material variants: hence the first Protocol question. However, third
parties had to be taken into account and the second Protocol question was
designed for that purpose because it excluded variants unless third parties should
have realised they were immaterial. For there to be reasonable certainty, those
were variants which were obviously or clearly immaterial, (para. 29)
H14 (7) The judge had found that at the date of the patent there was a strong
probability that some derivatives of rapamycin would work but it was impossible
to predict with certainty whether any particular one would. It might be that
1
Previously referred to as "the Improver questions" but re-named in Wheatley (Davina) v. Drillsafe
Ltd, [2001] R.P.C. 7.

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SDZ-RAD was a good candidate to try but it was not obvious that it would work
as an immunosuppressant. The same was true in relation to other derivatives.
Accordingly, the answer to the second Protocol question was "no ". (paras 28,29)
H15 (8) The answer to the third Protocol question was "yes". Throughout the
specification the word "rapamycin" was used to designate the molecule rapamy-
cin and derivatives were referred to as such. It was not to be expected that a
different nomenclature would be used in the claims. Further a claim to rapamycin
and rapamycin derivatives or rapamycin-like derivatives would not have been
allowed by the European Patent Office as it lacked support and would have been
speculative, (para. 31)
H16 (9) There was a difference between a specification which required the skilled
person to use his skill and application to perform the invention and one which
required him to go to the expense and bihour of trying to escertain whether some
product had the required properties, ii..: 1 " carrying out the former, the skilled
person was trying to perform the invention, whereas the latter required him to go
further and to carry out research to ascertain how the invention was to be
performed. If the latter was required the specification would appear to be
insufficient, (para. 40)
HI 7 (10) The duty upon the patentee was to provide a description wh ich enabled the
skilled person to perform the invention across the breadth of the claim; it was not
to supply a starting point for a research programme. If the claim was to be
construed so as to include derivatives of rapamycin, an enabling description of
such derivatives was needed so that the products of the claim could be ascertained,
(para. 43)
H18 (11) Once it was appreciated that a claim which encompassed derivatives had
to be sufficient across its breadth, the extent of the research task to find out which
derivatives would work became apparent. The number of derivatives was vast
and the task of ascertaining which would satisfy the functional part of the claim
would also be vast and correspondingly burdensome, (para. 44)
H19 (12) Claim 1 if construed so as to cover derivatives of rapamycin would be
invalid for insufficiency, (para. 47)
H20 (13) Claim 1 was a Swiss-type claim and the specification made it clear that the
medicament which provided the inhibition was rapamycin. The word "medic-
ament" should not be construed so as to mean any product whether or not it
contained rapamycin as that would render the claim invalid. Accordingly SDZ
RAD was not a medicament within the meaning of claim 1 and the use of
rapamycin to produce it did not amount to infringement, (paras 52 and 56)
H21 The following cases were referred to in the judgment:
Biogen Inc. v. Medeva Pic [1997] R.P.C. 1.
Mentor Corporation v. Hollister Inc. [1993] R.P.C. 7.
Wheatley (Davina) v. Drillsafe Ltd, [2001] R.P.C. 7, CA.

H22 Henry Can Q. C. and Piers Acland instructed by Bristows appeared on behalf of
the appellants/defendants. John Baldwin Q. C. and Michael Tappin instructed by
Linklaters appeared on behalf of the claimants/respondents.

ALDOUS L.J.:
1 The appellants, Novartis Pharmaceuticals U.K. Ltd and Novartis Pharma AG,
are defendants in a patent action. There is no need to differentiate between them

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and I will refer to them as Novartis. They are also claimants in an action for a
declaration of non-infringement.
The respondents are Professor Sir Roy Calne and American Home Products
Corporation. Professor Sir Roy Calne is the patentee of European Patent (U.K.)
0401747, the patent in issue, and American Home Products Corporation are the
exclusive licensees which work the invention the subject of that patent. Again
there is no need to differentiate between them and I will refer to them as the
patentees.
The parties to the action agreed that the issues of infringement and insufficiency
should be tried first and the remaining attacks upon validity and the issue of
whether both the Novartis companies infringed should be stood over to be heard
at a later date. That course was acceptable to the Court and therefore those issues
came on for trial before Laddie J. In his judgment ([2000] R.P.C. 547) he held the
patent infringed and that the allegation of insufficiency failed. He therefore
refused to make the declaration of non-infringement that was sought.
The patent is based upon the discovery by Professor Sir Roy Calne that a
product, produced by the bacterium streptomyces hygroscopicus, called rapamy-
cin, was useful to suppress transplant rejection. Rapamycin was at the priory date
of the patent, June 6,1989, known to have antifungal and antitumour properties.
Because rapamycin was a known product at the priority date, it could not be
patented: neither could its use as a treatment, because that would offend section
4(2) of the Patents Act 1977. For those reasons the main claims of the patent
followed the form known as "Swiss type" which is used to claim an invention for a
second medical use. Claim 1 therefore claims as inventive:

"1. Use of rapamycin for the preparation of a medicament for inhibiting

organ or tissue transplant rejection in a mammal in need thereof."

The basic issue raised in this appeal revolves around the alleged infringement.
Novartis have produced an immunosuppressant which is referred to as SDZ
RAD. It is a derivative of rapamycin. The judge upheld the patentees contention
that it fell within the ambit of claim 1. Novartis contend that he was wrong and that
the claims of the patent do not cover a derivative such as SDZ RAD. If they do,
then the patent is invalid as "the specification of the patent does not disclose the
invention clearly enough and completely enough for it to be performed by a
person skilled in the art" (section 72(l)(c)). In essence they contend that if the
claims were to be construed as the patentees contend, the specification would be
insufficient as there is no disclosure in the specification of how to make or select
derivatives of rapamycin to prepare a medicament "suitable for inhibiting organ
or tissue transplant rejection in a mammal" as required by claim 1.
The technical background to the invention and the technical information
needed to understand the dispute were set out by the judge with clarity. I
gratefully adopt them in full.

"Technical background
(a) Transplant rejection
2. The patent and this case are concerned with medicaments which are or may
be of use in the treatment of patients who have undergone surgical

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transplants. Save for the case of identical twins, each of us has a genetic
make-up which is different from everyone else. If living tissue, such as a heart
or kidney, is taken from one person and is transplanted into another, the
recipient's immune system is likely to recognise the transplant as foreign. It
will automatically try to attack and exclude or kill the intruder. If this happens
the transplant is said to be rejected. This problem can be reduced to some
extent by selecting a donor whose genetic makeup is very similar to that of the
recipient. For example close relatives may have very similar tissues. If this is
done the transplant will look only a little bit foreign to the recipient's immune
system and the rejection may not be so severe. However, even if this is done,
the immune system in the recipient is still likely to try to reject the graft. For
this reason it is currently necessary to use drugs which weaken the immune
response of the recipient. Such drugs are called immunosuppressants.
3. Although a number of immunosuppressants are known and used they vary
in efficacy and, to a greater or lesser degree, cause undesirable side-effects in
the recipient. It is common to use a cocktail of such immunosuppressants. At
the date of the patent in suit three types of immunosuppressant in particular
were used, frequently together. They are azathioprine, a group of chemicals
known as corticosteroids and cyclosporin. Cyclosporin is the most powerful
of these but it is nephrotoxic, that is to say it is capable of poisoning kidney
tissue. It is not in dispute that scientists have been searching for additional
and preferably better drugs to use as transplant rejection inhibitors.

(b) Biological activity

4. Living organisms contain numerous complicated molecules. A molecule is
made up of a number of different atoms, such as carbon, hydrogen and
oxygen connected together in a particular arrangement. It is convenient and
conventional to draw a molecule's structure by showing a flat plan of the
atoms connected together. For example, benzene, which is made up of a ring
of 6 interconnected carbon atoms (C) each of which is connected to one
hydrogen atom (H) can be depicted as follows:

Illustration 1

5. This is highly stylised and merely indicates which atoms are connected to
which, rather like the map of the London underground system. In fact, just
like the stations in the London underground system, the atoms are usually not
all in one plane. Most large organic molecules take up a complicated
three-dimensional form. This is referred to as the molecule's tertiary
structure or conformation. It is the nature of the atoms in the molecule and
the forces which exist between them which twists the molecules into their

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sometimes complicated three-dimensional shapes. There are numerous

molecules which have very specific biological activities. Examples are
antibiotics, enzymes and antibodies. It has become recognised over time that
in many cases the biological activity of these molecules is largely dependent
upon the molecule's shape. It is the ability of a molecule to fit onto another
moleculefor example on the suface of a living cellwhich allows it to
perform or causes its biological function. For example enzymes are large
molecules, only particular parts of which, because of their spatial relationship
to one another, help to promote particular chemical reactions. If the molecule
is modified so as to alter significantly the shape of that part of the molecule
which is responsible for its biological action, it may lose all or most of that
activity. Although all analogies break down at some point, the importance of
the shape of a biologically active molecule can be explained as follows. The
molecule can be likened to a key. The complicated shape of part of it
(equivalent to the wards on the key) enables it to fit into a complementary
location (equivalent to the wards in the lock) on another molecule: for
example, on the surface of a cell. The interaction allows the molecule to
perform its biological function, just as the interfit between the key and lock
allows the former to operate the latter. If the part of the molecule which has
the important shape is modified, it may lose its ability to interact with the
other molecule. In much the same way, modification of the shape of the
'business end' of a key may make it incapable of fitting into or operating
the lock. On the other hand, altering a part of the molecule which has little
effect on the shape of the interfitting parts has little effect on biological
activity. In much the same way, modification of the shape of the shank or
handle of a key is much less likely to stop it opening the lock.
6. Unlike the key and lock analogy, the interfit between a biologically active
molecule and its target is 'soft'. Whereas a key either does or does not operate
a lock, in the case of biologically active molecules, the better the fit the more
active the molecule is.
7. A molecule may have more than one biological activity. Part may render it
poisonous, another part may make it an effective enzyme, a third may give it
hormonal properties and so on. Furthermore a molecule which through
evolution has developed to perform one particular biological function may
happen to have a shape which enables it to perform another, and unintended,
function. For example a molecule taken from one living system may have an
entirely different and unexpected effect on another living system, the shape
of the molecule bestowing on it activity which it either did not need or did not
have in the system from which it is derived. Once again, using the analogy of
keys and locks, it is as if a piece of shaped metal designed, say, as a paper-clip
is found by chance to have the necessary shape to fit and operate a lock.
8. A chemical discipline has grown up, called medicinal chemistry. The
expertise of a medicinal chemist was discussed by Professor Bycroft, himself a
medicinal chemist and Head of the Pharmacy School and of the School of
Pharmaceutical Sciences at the University of Nottingham, who gave evidence
on behalf of the claimants. He said that a medicinal chemist is typically an
organic chemist who has experience of synthesising organic molecules and is
involved in the study of structure-activity relationshps of pharmacologically
active compounds i.e. the use of organic compounds (synthetic or natural) as
drug agents. The medicinal chemist has to have not only a knowledge of the

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molecular chemistry of the compounds with which he is concerned but also a

'feel' for the biological effects, including the possible effects of modifications.
The medicinal chemist, by his experience and training, will accordingly have
and need to have a working knowledge of the various disciplines which
surround the strict organic chemistry concerned. A medicinal chemist will
also develop expertise in looking at the shape of molecules. As the evidence
in this trial showed, he would be expected to know in many cases how the
atoms within a molecule interact with each other spatially. For example, he
will know that some types of atom-to-atom bonds will twist or modify the
shape of the molecule in which they are located. Thus he may know that a
particular atom-to-atom bond in a particular location will make it difficult for
those atoms, and therefore the parts of the molecule immediately adjacent to
them, to twist or rotate in relation to each other as compared to a different
pairing of atoms at the same position in an otherwise identical molecule.

10. In fact the molecule known as rapamycin was not discovered by Professor
Calne. It is produced naturally in a particular strain of bacterium called
Streptomyces hygroscopicus. It is a large molecule the structure of which is
depicted in two dimensions and schematically as follows:

Illustration 2:

11. The numbers 1 to 40, with the exception of 7, all represent carbon atoms
while 7 represents a nitrogen atom. Hydrogen atoms (H) bonded directly to
carbon atoms are now shown but it is readily apparent where they are, since it
is known that carbon has a valency of 4. Thus the carbon at position 12 has
two of its bonds occupied (by single bond connections to the carbon atoms at
11 and 13). It therefore has two free bonds. Each bond is capable of
connecting to a single hydrogen atom so there are two hydrogen atoms at this
location. On the other hand the carbon at 18 has three of its bonds shown as
occupied. Therefore there is a single remaining bond connected to a single
hydrogen atom. If one starts with the carbon atom indicated by 1, it will be
seen that there is a strong of interconnected atoms all the way round to
carbon 34. This is then connected to carbon at 1 by an oxygen (O) atom. This

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therefore is a loop of interconnected atoms. It is referred to as the macrolide

ring. To it is attached a side chain consisting of the part of the molecule
containing carbons 35 to 40. The macrolide ring is therefore:

Illustration 3:

The defendants' product

13. The defendants have also produced an immunosuppressant containing a
macrolide ring. It is referred to as SDZ RAD. It has the following structure:

Illustration 4:

HOCH,-CH,-0

CH.O

14. It is made by a two-step process in which the hydroxyl (OH) unit

connected to the carbon atom at position 40 on the side ring of rapamycin is
O-alkylated with a 2-hydroxyethyl group. Save in this respect, it has a

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chemical composition which is identical to rapamycin. The proper chemical

name for SDZ RAD is 40-O-(2-hydroxyethyl)-rapamycin."

The judge also made these findings of fact:

"37.1 do not think that there was much dispute between the parties and I find
as a fact that on reading the patent a skilled addressee would have understood
the following as a result of the content of the patent and common knowledge
in the art in the late 1980's:
(a) At that time it was very likely that the immunosuppressive effect
discovered by Professor Calne, like the biological activity in other known
large molecules, was dependent on the shape of the rapamycin molecule or
a part of it.
(b) The immune response is a multi-stage process, details of which were not
then (and even now are not) known. It was likely that rapamycin acted in
the second half of the process but where precisely and how was not known
and would be likely to take a long time to find out.
(c) The mechanism by which rapamycin worked was not known. That is to
say, it was not known what part or parts of the molecule gave it its efficacy
nor was the shape or location of the receptor sites in the molecules to which
it attached itself known.
(d) There was a strong probability that other molecules derived from
rapamycin would exhibit similar conformation in those areas which made
rapamycin efficacious and would also exhibit similar immunosuppressant
activity. Put the other way round, it was most unlikely that rapamycin was
the only molecule of similar shape which exhibited such efficacy although it
was not possible to be certain that this was so. As a corollary it was unlikely
that Professor Calne had happened to hit upon the only molecule within
the large number of molecules with similar composition and shape which
happened to work.
(e) Similarly, it was unlikely that Professor Calne had struck upon the most
efficacious molecule.
(f) Whether any particular molecule derived from rapamycin would work
at all was impossible to predict with certainty.
(g) The number of possible derivatives of rapamycin is vast. It is almost
certain that many of them would not exhibit immunosuppresant activity:
just as it would not be possible to predict with certain which derivatives
have immunosuppressant activity, it would not be possible to predict how
many would have such activity.
(h) It was likely, but not known, that the important part or parts of the
shape of the rapamycin molecule was or were to be found on the macrolide
ring.
(i) It was at the time possible to make changes to rapamycin which would
be expected to produce little or no change to the shape of the macrolide
ring and others which would be expected to produce large changes to the
shape of that ring.
(j) Those derivatives of rapamycin which were most likely to work were
those which involved small changes to the side chain rather than changes to
the macrolide ring.
(k) A skilled addressee team would be able to make up a list of possible

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derivatives with whose most likely to exhibit immunosuppressive activity

at the top and those least likely to work at the bottom. Finding derivatives
which work would involve a systematic and progressive iterative process in
which different derivative's were made by modifying different parts of the
rapamycin molecule. That process would not be rapid or guaranteed of
success.
(1) Even if a rapamycin derivative were produced which had immuno-
suppressant activities, it would be impossible to be certain that it did not
exhibit unpredictable defects, such as toxicity, low rates of absorption and
so on which would render it insuitable for clinical use. Discovering whether
such defects exist would involve testing, some of it in vivo, and would take a
long time."

8 The judge also held that "no one in 1989 was able to set down on a piece of paper
with certainty what other derivatives work": even among the experts, predicting
which derivatives were most likely to work would produce different lists of
candidate molecules. Also, testing rapamycin, which included in vitro and in vivo
tests, was a lengthy and, no doubt, costly process. Doing the same for a number of
derivatives would be commensurably longer and most costly.

The Patent
9 The patent is entitled "Use of rapamycin and derivatives and pro-drugs thereof
in the manufacture of a medicament for inhibiting transplant rejection in
mammals". At the outset the specification states that the invention relates to the
use of rapamycin for the preparation of a medicament for inhibiting organ or
tissue transplant rejection in mammals. It goes on to explain what the judge set out
in paragraph 3 of his judgment (see above). It then states, page 3 lines 19 to 21,
that:

"It would be extremely useful to discover a compound having immuno-

suppressive activity which could be employed to increase transplant accept-
ance in a recipient but without causing serious toxic side effects typically
associated with conventional immunosuppressant therapy, such as discussed
above."

10 The patent continues with a review of what was known about rapamycin and
then comes to the object of the inventor which was to discover a compound having
increased immunosuppressant activity with low toxicity. There follows on page 3
lines 43 to 47 this description of what the inventor discovered.
"The present inventor has discovered that rapamycin can be used for the
preparation of a medicament for inhibiting organ or tissue transplant
rejection in a mammal in need thereof.
The present inventor has also discovered a pharmaceutical composition
comprising (a) rapamycin in combination with (b) one or more other
chemotherapeutic agents for inhibiting transplant rejection selected from the
group consisting of azathioprine, corticosteroids, cyclosporin and FK-506."
11 The specification continues with two paragraphs relied on by the patentees to
support their submission that the word "rapamycin", when used in claim 1,
includes derivatives of rapamycin.

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Rapamycin is an antifungal antibiotic which is extractable from a streptomy-

cete, e.g. Streptomyces hygroscopicus. Methods for the preparation of
rapamycin are disclosed in Sehgal et al, U.S. Patent Nos 3,929,992 and
3,993,749. In addition monoacyl and diacyl derivatives of rapamycin and
methods for their preparation are disclosed by Rakhit U.S. Patent No.
4,316,885. Furthermore, Stella etal, U.S. Patent No. 4,650,803 disclose water
soluble pro-drugs of rapamycin i.e. rapamycin derivatives including the
following rapamycin pro-drugs: glycinate pro-drugs, propionate pro-drugs
and the pyrrolidino butyrate pro-drugs.
The present invention includes the use of natural and synthetic rapamycin,
genetically, engineered rapamycin and all derivatives and pro-drugs of
rapamycin, such as described in the aforementioned U.S. patents, U.S. Patent
Nos 3,929,992: 3,993,749: 4,316,885: and 4,650.803."

12 The specification goes on to explain that the inventor had noted the efficacy of
rapamycin in inhibiting transplant rejection e.g. by depressing the immune system
in mammals without the attendant toxic side-effects associated with other
conventional immunosuppressive agents. It also explains how rapamycin can be
used in combination with other drugs. To illustrate the invention the specification
sets out the results of studies that were conducted using rapamycin on rats and
pigs.
13 The specification ends with this conclusion:

"In conclusion, rapamycin is a very effective immunosuppressive agent which

can be employed to inhibit allograft transplantation rejection in mammalian
subjects."

14 There follows 11 claims of which only claim 1, 5 and 11 are relevant.

"1. use of rapamycin for the preparation of a medicament for inhibiting organ
or tissue transplant rejection in a mammal in need thereof."

5. Use of rapamycin according to any one of claims 1 to 4, wherein said

medicament is formulated for administration of rapamycin to said mammal in
an amount of from 1 to 5 mg/kg/day.

11. A pharmaceutical composition for use as a medicament comprising a

combination of (a) rapamycin and (b) one or more chemotherapeutic agents
from the group consisting of azathioprine, corticosteroids, cyclosporin and
FK-506."

Infringementthe appeal
15 The main issues on the appeal depend upon the construction of claim 1. The
primary issue concerns the meaning of the word "rapamycin" in claim 1. In
particular, whether SDZ RAD, being a derivative of rapamycin, falls within the
claim.
16 Mr Baldwin Q.C., counsel for the patentees, submitted that claim 1 should be
read as meaning "rapamycin itself and derivatives thereof which exhibit the same
type of inhibition to organ rejection as rapamycin and which are suitable for the
preparation of a medicament for inhibiting organ or tissue transplant rejection in a

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mammal". The judge, I think, construed claim 1 differently. He construed the

word "rapamycin" as including derivatives with the result that the functional
words in the claim limited it to rapamycin and its derivatives which were suitable
for preparation of a medicament which was suitable for treating organ transplant
rejection. He said in paragraph 46 of his judgment:

"46.... Notwithstanding the wording used in the claims, I have come to the
conclusion that the scope of protection afforded by the patent includes
derivatives of rapamycin. It does not, however, cover all derivatives. The
claims refer to the use of rapamycin in the preparation of 'a medicament for
inhibiting organ or tissue transplant rejection'. All the derivatives covered by
the claims must have similar utility. It follows that the scope of the patent
includes such derivatives of rapamycin as exhibit the same type of inhibition
to organ rejection as rapamycin itself does."

17 Novartis submitted that the claim when properly construed was limited to use of
rapamycin. They went on to submit that if its ambit was widened to include
derivatives, or rapamycin-like derivatives, the patent was invalid because there
was no sufficient disclosure to enable performance. I will come to the submissions
on insufficiency, but first I will construe claim 1.
18 This Court has explained in a number of cases the correct approach to
construction. The most recent is the explanation in paragraphs 18 to 26 of my
judgment in Wheatley v. Drillsafe Limited C.A. July 5, 2000. I shall adopt that
approach.
19 In the present case, both parties put forward distinguished experts in thefieldof
chemistry, transplant medicine and toxicology. Some of them expressed their
views as to how the word "rapamycin" would be understood by them in the
context of claim 1. Not surprisingly there was a difference of opinion. There is no
need to resolve which opinion was right as they are irrelevant. The task of the
Court, once educated as to technical words, is to interpret the claim as a claim, in
the context of the specification, according to the principles laid down in the
Protocol. None of the witnesses were qualified to do that and did not purport to do
so.
20 The judge considered how the word "rapamycin" had been used in the
specification. He held that "all the description in the specification is directed at a
single known chemical". I agree. Throughout the specification the word "rapamy-
cin" is used to donate the molecule rapamycin. In a passage, I have quoted the
specification states that "the present inventor has discovered that rapamycin can
be used for preparation of a medicament . . . " for treating transplant rejection.
That must be read as meaning rapamycin itself. The specification four lines later
states that "the present invention provides the use of rapamycin for the
preparation of a medicament for inhibiting organ or tissue transplant rejection
...". A similar statement is made in the concluding paragraph of the specification.
That amounts to a clear statement that the invention was the use of rapamycin
itself, not a derivative. That is not surprising as no derivative had at that time been
produced and tried and as the judge found "finding other similar molecules (to
rapamycin) with similar activities would have been a long and laborious job". The
only references to derivatives are in the title and in the passage on page 3 line 54 to

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page 4 line 3. That passage draws the distinction between rapamycin and
derivatives, but the specification does not itself identify a single derivative which
had been shown to work.
21 Against that background I turn to consider the question of infringement with
the aid of the questions, called in Wheatley "the Protocol questions".
22 Question 1Does the variant have a material effect upon the way that the
invention worked?
It is important to have in mind that the invention is the discovery of a second
medical use for rapamycin. The variation is the class of compounds called
derivatives of rapamycin. The actual variant in issue is SDZ RAD.
23 Mr Baldwin relied upon the functional parts of the claim. He submitted that as
the claim only covered variants which were suitable for producing a medicament
which had to be suitable for inhibiting rejection, the variants could not have a
material effect upon the way that the invention worked. Further the functional
limitation meant that the second question would be answered in the affirmative as
it would be obvious that the variant would work in the same way.
24 That submission, as Mr Carr Q.C., who appeared for Novartis pointed out,
meant that the first two Protocol questions had to be answered in a patentee's
favour if a claim was limited to variants which would work and obviously work.
The fallacy involved in that approach can be demonstrated by taking SDZ RAD,
the derivative in question, as the variant. The invention is the second medical use
of rapamycin. Thus the first question can be stated asDoes the variant, the
derivative of rapamycin called SDZ RAD, have a material effect upon the way
that the invention worked, namely the way rapamycin worked as a medicament
for inhibiting rejection? so stated, it is clear that the variant is the derivative and
the invention to be considered is the second medical use contained in the
functional requirements of the claim.
25 I think Mr Baldwin realised that there could be difficulty in relying upon the
functional part of the claim to answer the first two questions. It was for that reason
that he submitted that the variants, the derivatives, should be limited to those that
had rapamycin-like activity. If that was the definition, then the first two questions
would be answered in the affirmative. The conclusion is logically right, but it is a
hopeless submission. As the judge held, the specification used the word
"rapamycin" as denoting the molecule rapamycin. Derivatives are referred to in
the passage bridging pages 3 and 4 and in the heading. The word "derivative" is
never qualified: to the contrary the passage at the top of page 4 states in terms
"The present invention includes use of natural and synthetic rapamycin,
genetically engineered rapamycin and all [my emphasis] derivatives and pro-drugs
of rapamycin...". There is no basis in the specification to enable the skilled person
to decide whether a particular derivative had rapamycin-like effect other than the
requirement of the functional part of the claim. Some test or standard would be
needed before such a limitation could be read into the claim, particularly as the
mechanism by which rapamycin worked was not known nor was it described in the
specification (see above in paragraph 36(c) of the judge's judgment). Thus, such a
claim would never have been allowed by the European Patent Office and would be
invalid for insufficiency.
26 It is sufficient, for the purpose of answering the first question, to take SDZ RAD
as the variant. Although the judge did not make any explicit finding as to the
equivalence of SDZ RAD to rapamycin, there was evidence that use of SDZ
RAD would not matrially affect the way the invention worked. I will therefore

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assume that question 1 should be answered in favour of the patentee, namely in

the affirmative.
27 Question 2Would it have been obvious to a skilled person that the variant
would not have a material effect upon the way the invention worked?
I have already rejected the primary submission of the patentees that the answer
should be in the affirmative because the variant was a derivative which had
rapamycin-like effect or was a derivative which complied with the functional
limitation in the claim. The variant is either all derivatives of rapamycin or the
particular derivative SDZ RAD.
28 Upon the findings of fact by the judge, this question has to be answered "No".
As the judge held, there was, at the date of the patent, a strong probability that
other derivatives would work, but it was impossible to predict with certainty
whether any particular one would. It may be that SDZ RAD was a good candidate
to try, but it was not obvious that it would work as an immunosuppressant. To find
out, the product would have to be made and tested. A similar conclusion would be
reached for other derivatives. At most it was likely that one or more derivatives
would work, but which would require research.
29 Mr Baldwin, relying upon a sentence in my judgment in Wheatley, submitted
that this question should be modified so that an affirmative answer would be
obtained if the skilled person would have expected that the variant would not
produce a material effect. That submission fails for two reasons. First, the judge
did not find that the skilled person would have had that expectation. Second, the
modification of the question is inconsistent with the settled law and I believe with
the aim of the Protocol. As I pointed out in Wheatley, it is fair to the patentee to
include within the claim immaterial variants and to exclude material variants: thus
question 1. However, third parties have to be taken into account. Question 2 is
designed for that purpose in that it excludes variants unless third parties should
have realised they were immaterial. For there to be reasonable certainty, those are
the variants which are obviously or clearly immaterial.
30 Mr Baldwin reminded us that the patentees had disclosed that rapamycin was a
good immunosuppressant. He submitted that that disclosure had given to the
world, not only the second medical use of rapamycin, but also the knowledge that
derivatives of rapamycin would work as immunosuppressants. It followed that the
technical contribution of the patent extended beyond the second medical use of
rapamycin and included derivatives which had the same effect. That submission
fails upon the facts found by the judge. The skilled person, who read the
specification, would not be able to predict how many derivatives would have the
appropriate effect nor be able to predict with any certainty whether any would or
which would. The inventor, as stated in the specification, had only discovered and
described the second medical use of rapamycin. It was left to others to find out
which derivatives, if any, worked. Also, concentration on what was the technical
contribution does not reflect the true task of the Court which is construction of the
claim according to the Protocol. As pointed out in Wheatley, it is unfair to a
patentee to construe his claim in a way not intended. To ignore a limitation could
render a patent invalid contrary to the wishes of the patentee. In any case it would
be unfair to third parties to construe a claim in a way that the patentee had
indicated by language that it should not be construed. That of course is the
purpose of the third question, which does not arise in this case as I have answered
question 2 in the negative. However, I will go on to consider question 3 upon the
assumption that question 2 was answered in the affirmative.

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31 Question 3Would the skilled person have understood from the language of the
claim that the patentee intended that strict compliance with the primary meaning was
an essential requirement of the invention?
In my view the answer must be "yes". As I have explained the specification
throughout uses the word "rapamycin" as denoting the molecule rapamycin.
Derivatives are referred to as such. It would therefore be surprising if a different
nomenclature was used in the claims. Second the specification sets out on page 3
line 43 to 47 what the inventor discovered, namely that rapamycin was a useful
immunosuppressant either by itself or in combination with other drugs. It would
therefore be surprising to find in the claim that the word "rapamycin" was used in
a different sense as meaning compounds extending outside the discovery. The
suggestion that all derivatives were included could not be right as the skilled
person would not believe that they would all work. Third, claim 1 is not a claim
which contains words which are difficult to construe. The word "rapamycin"
prima facie has the same meaning in the claim as it does in the specifiction. If the
patentee had intended to cover derivatives he could easily have done so. Fourth, a
claim to rapamycin and rapamycin derivatives or rapamycin-like derivatives
would not have been allowed by the European Patent Office as it would have
lacked support and would have been speculative. This forms the basis of the
insufficiency dispute to which I turn. To do that I shall assume that claim 1 should
be construed as suggested by the patentees despite the conclusion reached that
Novartis are right on construction.

Insufficiency
32 Section 72(l)(c) of the Patents Act 1977 provides that a patent may be revoked
on the ground that "the specification of the patent does not disclose the invention
clearly enough and completely enough for it to be performed by a person skilled in
the art".
33 Having regard to the findings of fact made by the judge, there is no dispute as to
what is the disclosure in the specification. But there are two differences of
substance between the parties. The first requires a decision as to whether the
disclosure has to be suficient for the full ambit of the claim to be performed and the
second, what particularity of disclosure is necessary.
34 The first was settled in principle by the House of Lords in Biogen Inc. v. Medeva
Pic [1997] R.P.C. 1. The reasons for the conclusion reached were given by Lord
Hoffmann. In the relevant passages of his speech he also indicated, in general
terms, the answer to the second. At page 53 he pointed out that his reasons for
deciding that the Biogen patent was not entitled to the earliest priority date
applied to consideration of whether the claims were sufficient. That reasoning
appears at pages 47 to 49. The parts relevant to section 72 are as follows:

"The concept of an enabling disclosure is central to the law of patents. For

present purposes, it touches the matters in issue at three different points.
First, as we have seen, it forms part of the requirement of "support" in section
5(2)(a). Secondly, it is one of the requirements of a valid application in
section 14. And thirdly, it is essential to one of the grounds for the revocation
of a patent in section 72.1 shall start with section 14. Subsection (3) says:
'The specification of an application shall disclose the invention in a manner
which is clear enough and complete enough for the invention to be
performed by a person skilled in the art.'

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This is plainly a requirement of an 'enabling disclosure'. In addition,

subsection (5)(c) says that the claim or claims shall be 'supported by the
description'. It was by reference to subsection (3) that Lord Oliver of
Aylmerton, who gave the leading speech in Asahi, reasoned at page 536 that a
descripton would not support' the claims for the purpose of subsection (5)(c)
unless it contained suficient material to enable the specification to constitute
the enabling disclosure which subsection (3) required: 'the Act can hardly
have contemplated a complete application for a patent lacking some of the
material necessary to sustain the claims made'. By parity of reasoning, he said
that 'support' must have the same meaning in section 5(2)(a).
The absence of an enabling disclosure is likewise one of the grounds for the
revocation of a patent specified in section 72(1). Paragraph (c) says that one
such round is that
'the specification of the patent does not disclosure the invention clearly
enough and completely enough for it to be performed by a person skilled in
the art.'
This is entirely in accordance with what one would expect. The requirement
of an enabling disclosure in a patent application is a matter of substance and
not form. Its absence should therefore be a ground not only for refusal of the
application but also for revocation of the patent after grant. Similarly, the
same concept is involved in the question of whether the patent is entitled to
priority from an earlier application. This is not to say that the question in each
case is the same. The purposes for which the question is being asked are
different. But the underlying concept is the same.

The need for an enabling disclosure to satisfy the requirements of support

under section 5(2)(a), valid application under section 14 and sufficiency
under section 72(l)(c) has, I think, been plain and undisputed since the
decision in Asahi. What has been less clear is what the concept of an enabling
disclosure means. Part of the difficulty has been caused by a misinterpretation
of what the Technical Board of Appeal of the E.P.O. said in Genentech
I/Polypeptide expression (T 292/85) [1989] O.J. E.P.O. 275. This was a patent
for a plasmid suitable for transforming a bacterial host which included an
expression control sequence or "regulon" which could enable the expression
of foreign DNA as a recoverable polypeptide. The Examining Division was
willing to grant a patent only in respect of the plasmids, bacteria and
polypeptides known at the date of application. The Technical Board of
Appeal allowed the appeal, saying that the Examining Division had taken too
narrow a view of the requirement of enabling disclosure:
'What is also important in the present case is the irrelevancy of the
particular choice of a variant within the functional terms "bacteria",
"regulon" or "plasmid". It is not just that some result within the range of
polypeptides is obtained in each case but it is the same polypeptide which is
expressed, independent of the choice of these means Unless variants of
components are also embraced in the claims, which are, now, or later on,
equally suitable to achieve the same effect in a manner which could not
have been envisaged without the invention, the protection provided by the
patent would be ineffectual... The character of the invention this time is
one of general methodology which is fully applicable with any starting

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material, and is, as it was already stated, also independent from the known,
trivial, or inventive character of the end-products.' [paras 3.1.3,3.1.5,3.3.2]
In other words, the applicants had invented a general principle for enabling
plasmids to control the expression of polypeptides in bacteria and there was
no reason to believe that it would not work equally well with any plasmid,
bacterium or polypeptide. The patent was therefore granted in general terms.
In Molnlycke AB v. Procter & Gamble Ltd [1992] F.S.R. 549, however,
Morritt J. interpreted this decision to mean that it was a general rule of
European patent law that an invention was sufficiently disclosed if the skilled
man could make a single embodiment. This interpretation was followed by
Aldous J. in Chiron Corporation v. Organon Teknika Ltd [1994] F.S.R. 202,
although I think I detect in his judgment some surprise that the E.P.O. should
have adopted such a mechanistic and impoverished approach to the concept
of enabling disclosure. As we shall see, he applied the same rule in the present
case.
In fact the Board in Genentech I/Polypeptide expression was doing no more
than apply a principle of patent law which has long been established in the
United Kingdom, namely, that the specification must enable the invention to
be performed to the full extent of the monopoly claimed. If the invention
discloses a principle capable of general application, the claims may be in
correspondingly general terms. The patentee need not show that he has
proved its application in every individual instance. On the other hand, if the
claims include a number of discrete methods or products, the patentee must
enable the invention to be performed in respect of each of them.
Thus if the patentee has hit upon a new product which has a beneficial effect
but cannot demonstrate that there is a common principle by which that effect
will be shared by other products of the same class, he will be entitled to a
patent for that product but not for the class, even though some may
subsequently turn out to have the same beneficial effect: see May & Baker
Ltd v. Boots Pure Drug Co. Ltd (1950) 67 R.P.C. 23,50. On the other hand, if
he has disclosed a beneficial property which is common to the class, he will be
entitled to a patent for all products of that class (assuming them to be new)
even though he has not himself made more than one or two of them.

I think that in concentrating upon the question of whether Professor

Murray's invention could, so to speak, deliver the goods across the full width
of the patent or priority document, the courts and the E.P.O. allowed their
attention to be diverted from what seems to me in this particular case the
critical issue. It is not whether the claimed invention could deliver the goods,
but whether the claims cover other ways in which they might be delivered:
ways which owe nothing to the teaching of the patent or any principle which it
disclosed.
It will be remembered that in Genentech I/Polypeptide expression the
Technical Board spoke of the need for the patent to give protection against
other ways of achieving the same effect 'in a manner which could not have
been envisaged without the invention'. This shows that there is more than one
way in which the breadth of a claim may exceed the technical contribution to
the art embodied in the invention. The patent may claim results which it does
not enable, such as making a wide class of products when it enables only one
of those products and discloses no principle which would enable others to be

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made, or it may claim every way of achieving a result when it enables only one
way and it is possible to envisage other ways of achieving that result which
make no use of the invention."

35 Mr Baldwin submitted that the inventor had disclosed in the specification a

beneficial property of a class of products, namely that rapamycin and derivatives
with rapamycin-effect had immunosuppressant qualities. I disagree.
36 As the judge held, Professor Calne hit upon a new use for rapamycin. The
specification contains an enabling disclosure of that product. Whether any
particular molecule derived from rapamycin would work at all was impossible to
predict with certainty nor how many would have immunosuppressant activity.
Even if a rapamycin derivative were produced which had immunosuppressant
activity, it would be impossible to be certain that it did not exhibit unpredictable
defects. Discovering those defects would need in vivo tests which would take a
long time. As the judge described the claim, it covered all the molecules which
would work, but left it uncertain as to which ones do and how many of them there
are. Such a claim does not reflect a class with a unifying characteristic. It is a claim
to a number of compounds with the number and identity being left to the skilled
person to find out.
37 Professor Calne had not discovered nor had he disclosed in his patent a class or a
beneficial property of a class of compounds. Rapamycin had before the priority
date been reported as inhibiting two experimental immunopathies (see page 3 line
25 of the specification). But the reports did not, according to the specification,
teach its use for transplant rejection in mammals nor did they disclose the
discovered beneficial effect on toxicity. The invention as described was the
discovery that rapamycin had those advantages. Some derivatives would be
expected to have similar advantages, but the skilled person would not be able to
predict which ones would have that actuality and, even if the right one was
selected, it would take prolonged tests to find out whether it had the appropriate
qualities. It follows that, as Lord Hoffmann pointed out in Biogen, the patent, to
be sufficient, must provide an enabling disclosure across the breadth of the claim.
38 General guidance was given by this Court in Mentor Corporation v. Hollister
Inc. [1993] R.P.C. 7 on what was required to establish an enabling disclosure, or to
put it another way, what standard of disclosure was needed for a patent to be
sufficient as required by section 72(l)(c). At page 13 Lloyd L.J. said:

"But if a working definition is required then one cannot do better than that
proposed by Buckley L.J. in giving the judgment of the Court of Appeal in
Valensi v. British Radio Corporation [1973] R.P.C. 337. After referring to a
number of earlier authorities, including Edison & Swan v. Holland, he said:
'We think that the effect of these cases as a whole is to show that the
hypothetical addressee is not a person of exceptional skill and knowledge,
that he is not to be expected to exercise any invention nor any prolonged
research, inquiry or experiment. He must, however, be prepared to display
a reasonable degree of skill and common knowledge of the art in making
trials and to correct obvious errors in the specification if a means of
correcting them can readily be found.'
Then a little later:
'Further, we are of the opinion that it is not only inventive steps that cannot
be required of the addressee. While the addressee must be taken as a

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person with a will to make the instructions work, he is not to be called upon
to make a prolonged study of matters which present some initial difficulty:
and, in particular, if there are actual errors in the specificationif the
apparatus really will not work without departing from what is described
then, unless both the existence of the error and the way to correct it can
quickly be discovered by an addressee of the degree of skill and knowledge
which we envisage, the description is insufficient.'
In that case there was a mistake in the specification. But Buckley L.J.'s
language is equally apt to cover an omission. Aldous J. held that the Valensi
test is as apposite under the 1977 Act as it was under the 1949 Act. I agree."

39 It is also right to bear in mind what I said in that case, cited by Lloyd L.J. at page
11. He said:

"It is dangerous to generalise. Aldous J. made the point well in his judgment
in the present case (at page 19B to D):
'Even where patents relate to articles, the inventions disclosed in different
specifications can be different in mind. For example, the invention
disclosed may relate to an article which will perform a particular function
or an article which is cheaper to make than similar articles. In the latter
case, it is the very essence of the invention disclosed in the specification that
the article can be made more cheaply and therefore to perform the
invention, the person skilled in the art must be able to make the article
cheaply as described in the specification. In the former case, the person
skilled in the art must be able to produce the article which will perform the
function, as that is the invention disclosed.'
Then a little later he said:
'In each case, it is a question of fact, depending on the nature of the
invention, as to whether the steps needed to perform the invention are
ordinary steps of trial and error which a skilled man would realise would be
necessary and normal to produce a practical result.'

40 There is a difference between on the one hand a specification which requires the
skilled person to use his skill and application to perform the invention and, on the
other, a specification which requires the skilled person to go to the expense and
labour of trying to ascertain whether some product has the required properties.
When carrying out the former the skilled person is trying to perform the invention,
whereas the latter requires him to go further and to carry out research to ascertain
how the invention is to be performed. If the latter is required the specification
would appear to be insufficient.
41 The patentees wish to construe claim 1 to include derivatives of rapamycin
which exhibit inhibition to organ rejection like rapamycin itself. Thus upon the
patentees' construction, the specification must teach how to perform the invention
with such derivatives of rapamycin. Upon the judge's findings of fact, the
specification does not contain that teaching and therefore the patent would be
insufficient, if that were the correct construction of claim 1.
42 The judge held that the number of possible derivatives was vast and whether
any particular molecule derived from rapamycin would work at all was impossible
to predict with certainty. Many derivatives would not exhibit immunosuppressant
activity. Those which involved small changes to the side chain would be the most

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likely to work. Thus the skilled person could make up a list of possibles, with those
believed to be the most likely at the top of the list. Even so, finding appropriate
derivatives, if they existed, would involve a systematic and iterative process.
Further, when a derivative which had appropriate activity had been identified, it
would be impossible to be certain that it did not exhibit unpredictable defects. To
discover whether it did would require further tests which would take a long time.
43 The very uncertainty and unpredictability found by the judge meant that the
skilled person was being required to carry out research. The duty upon the
patentee is to provide a description which enables the skilled person to perform
the invention, in this case across the breadth of the claim; not to supply a starting
point for a research programme. If the claim includes derivatives of rapamycin, an
enabling description of such derivatives is needed so that the products of the claim
can be ascertained.
44 The judge concluded in paragraph 65 of his judgment that the "amount of work
involved in finding useful derivatives of rapamycin does not impose an undue
burden on those working in the field and this argument of insufficiency fails".
However the specification has to be sufficient to enable the invention to be
performed. There is a difference between research to find out which derivatives
work and the application of the teaching in the specification with appropriate skill
and tenacity. In this case the specification tells the skilled man where to start but,
upon the construction of claim 1 sought by the patentees, it leaves him to ascertain
by research what will work. Once it is appreciated that a claim which encompasses
derivatives has to be sufficient across its breadth, the extent of the research task
becomes apparent. The number of derivatives is vast and the task of ascertaining
which will satisfy the functional part of the claim will also be vast and
correspondingly burdensome.
45 The judge appears to have been influenced by his view as to the needs of a
patentee, such as Professor Sir Roy Calne, who has discovered a second medical
use of one molecule, to obtain a monopoly covering more than the particular
molecule in a case where the skilled person would realise that some derivatives
were likely to work. This can be illustrated from these paragraphs in his judgment:

"44.1 do not believe that any reasonable and objective person skilled in the
art would read this patent as indicating that the inventive contribution was
limited to rapamycin alone or that Profesor Calne intended to restrict his
monopoly simply to the use of that single chemical To do that would have
rendered the patent virtually valueless. It would have left out of its scope, for
example, those closely similar molecules which could be derived by standard
chemistry from rapamycin and which probably would have included many
which those in the art would have expected to have equivalent or even better
immunosuppressant properties. It would have disclosed to the art the novel
seam of interrelated molecules but have claimed only one of them. In practice
it was inevitable that the discovery of the activity of rapamycin would lead
workers in the art to look for similar molecules derived from rapamycin
which would have a better profile of properties. That is inherent in the
evidence of Professor Acheson, another of the defendants' expert witnesses.
He said:
'I have been informed by Novartis that the aim of the SDZ RAD program
within Novartis was to develop new and improved rapamycin derivatives.
Such a project was clearly justifiable. There is no reason why a natural

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 [NO. 5] COURT OF APPEAL ALDOUS L.J.

product, such as rapamycin, should be the best drug for treating a particular
medical condition. There are known examples of synthetic derivatives,
developed from a natural product, which show improved or advantageous
functions and properties over the natural product itself. The production
and screening of potentially useful derivatives is a hugh task but vital.
Because there is no sure way of predicting which derivatives of complex
biological molecules, if any, will possess new and improved properties, it is,
however, a high risk venture."

64.... Furthermore, even if Professor Calne had been lucky and sufficiently
funded enough to have a large team of technicians working with him so that
he had been able to put into his patent application not only the good news
about rapamycin but also the same good news about one or two derivatives,
Mr Carr's argument would have applied with exactly the same force to all the
other derivatives which had not been tried by the Professor and his team. In
addition Mr Carr's argument would apply with equal force whether the scope
of the patent is as I have held it to be here, namely applying to rapamycin and
working derivatives, or had been limited to an arbitrary list of identified
derivatives. In each case the same process of synthesis and testing would be
needed. It would follow that the only safe course in thisfieldwould be to limit
one's patents to those molecules you have tried and tested. Again, that would
make patents in relation to pharmaceuticals more or less valueless. As a
practical matter it is likely that full testing even of one molecule such as
rapamycin itself is not possible before a patent is applied for."

46 For my part I do not agree that a patent limited to the second use of rapamycin is
virtually valueless. The patent protects the second medical use and the long and
expensive work that has been carried out to obtain regulatory approval. Thus a
person who wishes to market a derivative has to make the derivative and then
carry out the long and expensive work needed to get it on the market. Without the
patent, other manufacturers could use the work of the patentees. In any case, I do
not believe that the patent system should be used to enable a person to
monopolise more than that which he has described in sufficient detail to amount to
an enabling disclosure. If it was, it would in this case stifle research to find a
derivative of rapamycin which was a substantially better immunosuppressant than
rapamycin itself. This statement by Lord Hoffmann in respect of the work done by
Professor Murray, the inventor of the Biogen patent is, I believe, apt:

"It is said that what Professor Murray showed by his invention was that it
could be done. HBV antigens could be produced by expressing Dane particle
DNA in a host cell. Those who followed, even by different routes, could have
greater confidence by reason of is success. I do not think that this is enough to
justify a monopoly of the whole field. I suppose it could be said that Samuel
Morse had shown that electric telegraphy could be done. The Wright
Brothers showed that heavier-than-air flight was possible, but that did not
entitle them to a monopoly of heavier-than-air flying machines. It is
inevitable in a young science, like electricity in the early nineteenth century
orflyingat the turn of the last century or recombinant DNA technology in the
1970s, that dramatically new things will be done for the first time. The
technical contribution made in such cases deserved to be recognised. But care

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 AMERICAN HOME PRODUCTS CORP. V. NOVARTIS PHARMACEUTICALS [2001] R.P.C.

is needed not to stifle further research and healthy competition by allowing

the first person who has found a way of achieving an obviously desirable goal
to monopolise every other way of doing so. (See Merges and Nelson, On the
Complex Economics of Patent Scope (1990) 90 Columbia Law Review 839.)"

47 I conclude that if claim 1 were to be construed in the way suggested by the

patentees, it would be invalid.

Respondents Notice
48 The patentees contended in this Court that infringement had been established
even if claim 1 was restricted to the use of rapamycin itself. The judge did not have
to deal with those contentions and did not do so.
49 First the patentees submitted that Novartis had infringed because they had
done an act falling within section 60(l)(c) of the 1977 Act. That provides that a
person infringes if:
"Where the invention is a process, he disposes of, offers to dispose of, uses
or imports any product obtained directly by means of that process, or keeps
any such product whether for disposal or otherwise."

50 The patentees submitted that claim 1 was a process claim. Novartis had
manufactured SDZ using rapamycin as the starting material. The first step was to
alkylate the C40 hydroxyl. The second step was to hydrolyse off the silyl group to
give SDZ RAD. Thus, Novartis had imported a product (SDZ RAD) obtained by
means of the process of claim 1, in that they had used rapamycin for the
preparation of a medicament (SDZ RAD) which was suitable for inhibiting
transplant rejection.
51 The simplicity of the patentees' submission hides the difficulties. As Mr Carr
pointed out, the submission involves reading the word "medicament" as covering
any medicament which will inhibit transplant rejection. If so, the only connection
that the medicament would have with rapamycin would be that it was the starting
material or a starting material used in what might be a complex manufacturing
process. Such a construction would result in the claim being hopelessly invalid on
the ground of insufficiency because there is no enabling disclosure of any
medicament other than rapamycin.
52 The claim has to be construed in context. It is a Swiss-type claim to an invention
for the second medical use of rapamycin. As the specification makes clear, the
medicament that provides the inhibition is rapamycin. There is no disclosure of
any other medicament. It would be unfair to the patentee to construe the word
"medicment" as meaning any product whether or not it contained rapamycin as
that would render the patent invalid. SDZ RAD is not a medicament within the
meaning of that word in claim 1. As I have pointed out the claim is not a claim to a
class or principle and therefore it has to be sufficient across its width. It follows that
the claim, to be construed as suggested, would be invalid unless there was an
enabling disclosure of medicments which might not have any rapamycin present
and their method of manufacture. There are none. I did not understand that Mr
Baldwin wished the claim to be construed in a way that would make it invalid. It
follows that the word "medicament" must be construed as referring to the product
rapamycin which is the product described in the specification as having been
discovered by the inventor to have the beneficial immunosuppressant properties.

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 [NO. 5] COURT OF APPEAL A L D O U S , S E D L E Y AND
SIMON BROWN LJJ.
53 The second submission was that Novartis had imported a product made by the
process of claim 1 which had the essential characteristics of rapamycin. In effect
the relevant identity of rapamycin was present in SDZ RAD. That submission
cannot be accepted for the same reasons. It is in essence a reformulation of
previous submissions made by the patentees.
54 SDZ RAD is a derivative of rapamycin. Chemically it retains a substantial part
of the molecule rapamycin. For it to come within the ambit of claim 1, the word
"rapamycin" must be construed as covering derivatives of rapamycin which retain
the essential characteristics of rapamycin. For the reasons I have given, that is not
a possible construction. If it was, the patent would have been invalid for
insufficiency.
55 The third submission relies upon the fact that up to 0.8 per cent of SDZ RAD is
rapamycin. It is there as an impurity due to the fact that it is the starting material
for the manufacturing process of SDZ RAD. I am prepared to accept that the
therapeutic effect of the rapamycin will be in proportion to its amount. Even so,
the claim is not infringed. To construe claim 1 as covering a medicament which
only contains 0.8 per cent rapamycin would be contrary to all rules of construction.
The technical contribution of the inventor was the discovery of the second medical
use of rapamycin. He did not discover that medicaments which only contained 0.8
per cent rapamycin had any therapeutic effect and there is no enabling disclosure
of how to make such a medicament. As Lord Hoffmann pointed out in Biogen, the
concept of an enabling disclosure is central to the law of patents. It is only
necessary to contemplate answering the Protocol questions in respect to a variant
where the medicament included only 0.8 per cent rapamycin to see that the claim
must be construed as meaning that the medicament has to be essentially
rapamycin.
56 The patentees also relied upon claim 11. This claim must also be construed in
context. For the reasons already given this claim is not infringed.
57 Finally I draw attention to the decision of the District Court of the Hague Case
No. 99/1435 March 2000 which dealt with the corresponding Dutch patent. I note
that that Court came to the same conclusion as I have. However, I have not relied
upon the reasons given as we were told it was to be appealed and was decided upon
different evidence.

Conclusion
58 For the reasons given, I have come to the conclusion that SDZ RAD does not
infringe any claim of the patent. If so, the patent is sufficient. I would therefore
allow the appeal and make an order to that effect.

SEDLEY L.J.:
59 I agree.

SIMON BROWN L.J.:

60 I also agree.

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