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OUTER HOUSE, COURT OF SESSION
[2006] CSOH 146
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P1606/03
P1031/03
A652/04
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OPINION OF LORD
GLENNIE
in the Petitions of
ARROW GENERICS LIMITED
Petitioners
and
in the case
ORGANON
LABORATORIES LIMITED AND OTHERS
Pursuers
against
NORTON HEALTHCARE
LIMITED
Defenders
ญญญญญญญญญญญญญญญญญ________________
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Petitioners: Currie QC, Higgins;
Maclay, Murray & Spens
Respondents: Davidson QC, Delibegović-Broome; McClure Naismith
Pursuers: Davidson QC, Delibegović-Broome; McClure Naismith
Defenders: C. Campbell QC, Clive;
Morton Fraser
15 September 2006
Introduction
[1] Akzo NV
are the registered proprietors of patent EP 0 389 035 (hereafter "the
035 patent"). Akzo Nobel NV are the
registered proprietors of patent EP 1 121 375 ("the
375 patent"). I shall refer to them
collectively as "Akzo". They are
represented in Scotland
by Organon Laboratories Ltd ("Organon").
Both patents relate to a pharmaceutical product called tibolone. Tibolone has been known since the 1960s;
and, since the 1980s, has been marketed as Livial. It has combined estrogenic, progestagenic
and androgenic characteristics. In
tablet form, it is used for treating menopausal complaints, for modulating the
immune system, and for combating osteoporosis.
[2] The
035 patent is concerned with tibolone of a high degree of crystalline
purity, whereas the 375 patent is concerned with tibolone of a high degree
of chemical purity. In both cases the
tibolone of the relevant purity is to be incorporated into a pharmaceutical
composition.
The proceedings before the Court
[3] In
these consolidated proceedings, there are challenges to both patents.
(a) By petition (P1606/03) lodged in November 2003, Arrow
Generics Ltd ("Arrow") seek revocation of claims 1-3 and 5 of the
035 patent.
(b) There are two challenges to the 375 patent, by Arrow and
by Norton Healthcare Ltd ("Norton"). By
petition (P1031/03) lodged in July 2003, Arrow seek revocation of
claims 1-3, 7 and 9-14 of the 375 patent. Norton's challenge, seeking revocation of the
same claims of the 375 patent, arises by way of counterclaim in separate
proceedings brought against them in 2004 by Akzo and Organon.
[4] The
patents are European patents. They take
effect in the United Kingdom
as if granted by the UK Patents Office.
They may therefore be challenged, as in this case, in the UK
Courts. But they may also be challenged
in the European Patent Office ("EPO").
The interrelationship between proceedings for revocation before the
national court and opposition proceedings before the EPO is explained in ITP SA v Coflexip Stena Offshore Ltd
2005 SC 116. There are in this case
concurrent proceedings before the EPO in respect of the 375 patent. It will be necessary to refer to those
proceedings in the context of dealing with applications made by Akzo to amend
the 375 patent.
The 035 Patent
[5] The
035 patent has a priority date of 18 March
1989. According to the
description in the patent, the invention relates to "a pharmaceutical composition
which contains a pharmaceutically suitable carrier and the compound having the
structure (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one";
and also to "a method for the preparation of this compound for use in the
pharmaceutical composition." The
compound there referred to is tibolone.
[6] The
patent recites that tibolone has been known for some time, for example from two
American Patents, namely 3,340,279 ("the 279 patent") and 4,701,450
("the 450 patent"). But the authors
of the patent claim to have discovered that tibolone, prepared in accordance
with the method described in those patents, "is polymorphous and consists of
two crystalline pure forms." For
pharmaceutical purposes, it would be desirable to use a pure rather than a
polymorphic form of tibolone. As they
explain:
"It may be
expected of polymorphous compounds that their biological activity is comparable
or identical to the biological activities of the crystalline pure forms of
which the polymorphous compound consists.
Nevertheless, if the polymorphous compound is used as a medicament great
drawbacks are associated therewith compared with its crystalline pure
components. The differences in crystal
structure can lead to a difference in physico-chemical parameters such as
stability, rate of dissolution, melting point, analytical data and the like
which frequently are strongly influenced by the crystal forms in the
polymorphous compound. This is all the
more obvious since in practice it is virtually impossible to make each batch of
a polymorphous compound exactly identical in respect of composition. As a consequence of these differences, it is
frequently regarded as undesirable to incorporate polymorphous compounds in
medicaments and it is sometimes demanded that only one of the crystalline pure
components of the polymorphous compound is used."
[7] The
authors go on to state that the aim of the invention covered by the 035 patent
is:
"to obtain a pharmaceutical
composition which contains a crystalline pure form ... which is completely or
virtually free from the other crystalline form."
By this, as they explain, they mean
one which contains less than 10%, and preferable less than 5%, of the
other crystalline form.
[8] The authors of the patent claim to have
found that by using specific crystallisation techniques, two crystalline pure
forms (in the above sense) can be obtained.
These are designated in the patent as "Form I", which is the
monoclinic P21 form, and "Form II", the triclinic P1 form. They say that Form I is chemically much
more stable than the already known polymorphous compound, with consequent
advantages both in terms of the shelf-life of the pharmaceutical product and in
terms of reproducibility. Against this
background, the invention is described as relating to
"a
pharmaceutical composition which contains a pharmaceutically suitable carrier
and the compound having the structure (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one
[i.e. tibolone], characterized in
that the said compound is a crystalline pure or virtually pure form which is
completely or virtually completely free from the other crystalline form."
In light of the extended definition
of "crystalline pure form" mentioned above, the word "virtually" would appear
to add nothing of substance.
[9] The
patent then sets out the following methods of producing Form I and
Form II:
"Form I is
obtained by crystallizing the polymorphous compound from mixtures of water and
acetone or ethanol. A suitable method is
to dissolve the polymorphous compound in acetone or ethanol, after which the
solution is added to water. Conversely,
water can also be added to a solution of the polymorphous compound in acetone
or ethanol. Other suitable solvents are,
for example, ethyl acetate, acetonitrile and acetone/hexane mixtures. Mixtures of methanol and water, from which
only mixtures of the two crystalline forms always crystallize, are unsuitable.
Form II can be
obtained by crystallizing the polymorphous compound from a selection of apolar
solvents. Toluene is very suitable, as
is also hexane to which a little ethyl acetate has been added. Another suitable solvent is
trichloroethylene"
[10] The patent goes on to discuss the crystallisation process, the
ability to differentiate between Forms I and II, and the advantage,
from a pharmaceutical point of view, of the crystalline pure forms,
particularly Form I. Various
examples are given to illustrate the invention.
From amongst these I need mention only two at present: Example 5, which
described a process resulting in Form II tibolone of 100% crystalline purity;
and Example 9, which identifies structural data from examples of the
Form I and Form II.
The claims in the patent
[11] It is convenient at this stage to set out the claims in
patent 035. I shall quote them in
full:
"1. A pharmaceutical
composition which contains a pharmaceutically suitable solid carrier and the
compound having the structure (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one
[i.e. tibolone], characterized in
that the compound is crystalline pure, which purity is greater than 90%.
2. The pharmaceutical
composition of claim 1, characterized in that the crystalline purity is
greater than 95%.
3. The pharmaceutical
composition according to claim 1, characterized in that the crystalline
pure compound has the monoclinic P21 form [i.e.
Form I].
4. The pharmaceutical
composition according to claim 1, characterized in that the crystalline
pure compound had the triclinic P1 form [i.e.
Form II].
5. A method for the
preparation of a crystalline pure compound for use in the pharmaceutical
composition according to claim 3, characterized in that the polymorphous
compound is crystallized from mixtures of water and acetone or ethanol, or from
ethyl acetate, acetonitrile, or acetone-hexane mixtures.
6. A method for the
preparation of a crystalline pure compound for use in a pharmaceutical
composition according to claim 4, characterized in that the polymorphous
compound is crystallized from an apolar solvent."
As can be seen, claims 1 and 2
relate to the crystalline purity of the compound (of whichever Form) in
the pharmaceutical composition, while claims 3 and 4 relate to the crystalline form
of the compound of a given purity.
Claims 5 and 6 are claims to a method of preparation of the compound of
the appropriate purity and form for use in the pharmaceutical
compositions. Arrow's challenge in these
proceedings - to claims 1, 2, 3 and 5 - does not include a challenge to any
claims relating specifically and exclusively to Form II of the compound.
Arrow's
case
[12] Arrow's primary case on Record is that the invention claimed in
claims 1-3 was not patentable because it lacked novelty. During the hearing, it became clear that the
patentability of the method claimed in claim 5 was also attacked on this
ground. Their secondary case on Record
is that the inventions in claims 1-3 and 5 were not patentable because they
were obvious and involved no inventive step.
In support of both lines of attack, Arrow rely upon a paper by J.-P.
Declercq and M. van Meersche published in the Journal of the Royal Netherlands
Chemical Society, 103/5, May 1984 entitled "Conformational analysis of 3-oxo
5(10)-unsaturated steroids.
Single-crystal X-ray structure analysis of
17-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one (Org OD
14)". I shall refer to this paper as
"Declercq" or "the Declercq paper".
Their case on lack of novelty is that tibolone of the requisite
crystalline purity, which is the subject of claims 1-2, is disclosed in the
monoclinic form, Form I, in Declercq in Table 1 (at p.146 of the Journal). Those claims, and also claim 3, were
therefore anticipated. Although the
claims were to a pharmaceutical composition rather than simply to the compound,
tibolone, that added nothing: the pharmaceutical composition was merely the
combination of the compound with a pharmaceutically suitable solid
carrier. The method, in claim 5, was
also disclosed. In support of their case
based on obviousness, Arrow also rely on two other patents, the 279 patent and
a United Kingdom patent, GB1,177,845 ("the 845 patent"), and on the Common
General Knowledge which, they say, is exemplified by a number of
publications. The compound is disclosed
in the 279 patent and, in its monoclinic form and of the relevant purity, in
Declercq. It is a steroid, and the
majority of steroids are polymorphic.
They say that at the priority date of the patent it was standard
practice for those skilled in the art to conduct polymorphic screens on
proposed drug substances, in particular on those likely to be polymorphic. It would have been obvious to the man skilled
in the art at the priority date of the patent: (i) to ascertain whether there
were polymorphs present in the active compound; (ii) where such polymorphs were
present, to identify the most stable polymorphic form of the compound; and
(iii) to obtain and use that that polymorph in its pure crystalline form. The solvents used in the method claimed at
claim 5 are examples of solvents which, at the priority date, would routinely
have been used by the skilled man to conduct a polymorph screen; but in any
event the use of such solvents was disclosed in the 845 patent and in
Declercq. It would have been obvious to
use a solvent screen comprising acetone and water.
Akzo's case
[13] Akzo's answer on Record consisted of bare denials and calls for
further specification. It is convenient
to refer to the arguments advanced on their behalf at the proof in the course of discussing the
particular issues.
Anticipation/ Lack of novelty
[14] Section 1(1) of the Patents Act 1977 provides as follows:
"A patent may be granted
only for an invention in respect of which the following conditions are
satisfied, that is to say -
(a) the invention is new;
(b) it involves an inventive step ..."
I am not here concerned with paras.
(c) and (d). A patentable invention is
one for which these conditions are satisfied.
Section 2(1) of the Act provides that an invention shall be taken to be
new "if it does not form part of the state of the art". In terms of section 2(2), the state of the
art comprises all matter "which has at any time before the priority date of
that invention been made available to the public (whether in the United
Kingdom or elsewhere) by written or oral
description, by use or in any other way."
As I have said, Arrow contend that the inventions disclosed by claims
1-3 and 5 are not new and do not satisfy the test in section 1(1)(a) of the
Act. They say that those claims have
been anticipated by prior publication.
[15] The classic statement of the test of anticipation, or lack of
novelty, remains that of the Court of Appeal in General Tyre & Rubber Company v The Firestone Tyre and Rubber Company Ltd [1972] RPC 457 at 485,
albeit that that judgment was given under reference to the previous Act:
"To determine whether a
patentee's claim has been anticipated by an earlier publication it is necessary
to compare the earlier publication with the patentee's claim. The earlier publication must, for this
purpose, be interpreted as at the date of its publication, having regard to the
relevant surrounding circumstances which then existed, and without regard to
subsequent events. The patentee's
invention must similarly be construed as at its own date of publication having
regard to the relevant surrounding circumstances then existing. If the earlier publication, so construed,
discloses the same device as the device which the patentee by his claim, so
construed, asserts that he has invented, the patentee's claim has been
anticipated, but not otherwise. In such
circumstances the patentee is not the true and first inventor of the device and
his claimed invention is not new ..."
Later on
the same page the test is put in this way:
"... the question whether the
patentee's claim is new ... falls to be decided as a question of fact. If the prior inventor's publication contains
a clear description of ... something that would infringe the patentee's claim if
carried out after the grant of the patentee's patent, the patentee's claim will
have been shown to lack the necessary novelty, that it to say, it will have
been anticipated."
The Court went
on to say this:
"The prior inventor,
however, and the patentee may have approached the same device from different
starting points and may for this reason, or it may be for other reasons, have
so described their devices that it cannot be immediately discerned from a
reading of the language which they have respectively used that they have
discovered in truth the same device; but if carrying out the directions
contained in the prior inventor's publication will inevitably result in
something being made or done which, if the patentee's patent were valid, would
constitute an infringement of the patentee's claim, this circumstance
demonstrates that the patentee's claim has in fact been anticipated.
If, on the other hand, the
prior publication contains a direction which is capable of being carried out in
a manner which would infringe the patentee's claim, but would be at least as
likely to be carried out in a way which would not do so, the patentee's claims
will not have been anticipated, although it may fail on the ground of
obviousness. To anticipate the
patentee's claim the prior publication must contain clear and unmistakeable
directions to do what the patentee claims to have invented: ... A signpost, however clear, upon the road to
the patentee's invention will not suffice.
The prior inventor must be clearly shown to have planted his flag at the
precise destination before the patentee."
[16] It is useful also to refer to a short
passage from the speech of Lord Hoffman in Merrell
Dow Pharmaceuticals Inc. v H.N.
Norton & Co. Ltd [1996] RPC 76 at 82-3.
For the purpose of considering infringement, he said
"It does not matter how the
product is made or what form it takes.
The monopoly covers every method of manufacture and every form which
comes within the description in the claim.
So claim 24 includes the making of the acid metabolite in one's liver
just as much as making it by synthetic process; in the body as well as in
isolation. Nor does it matter that the
infringer knows that he is making, using etc. the patented product. Liability is absolute
The corollary of this
principle is that the novelty of the invention must be co-extensive with the
monopoly. If there is any method of
manufacture or form of the product which is part of the state of the art, then
to that extent the invention is not new.
As the Enlarged Board of Appeal of the EPO said in its MOBIL/Friction reducing additive Decision
G02/88 [1990] E.P.O.R. 73, 83:
'It is
generally accepted as a principle underlying the EPC that a patent which claims
a physical entity per se, confers
absolute protection upon such physical entity; that is, wherever it exists and
whatever its context. ... It follows that if it can be shown that such
physical entity (that is, a compound) is already in the state of the art (for
example in the context of a particular activity), then a claim to the physical
entity per se lacks novelty'"
[17] Two points of particular relevance to the
arguments in the present case emerge from these passages. First, any prior existence of the product
is sufficient to defeat a product claim on grounds of anticipation, regardless
of how it was produced and the context in which it is found. Thus, for example, the reason why Declercq
was looking at the sample before him is irrelevant - it is irrelevant even to
ask whether he knew what the compound was or what, if any, medicinal values it
might have. Secondly, any consideration
of the quantity in which the product was previously identified is also
irrelevant unless, of course, some quantitative criterion is present, expressly
or by implication, in the definition of the claim limiting the extent of the
monopoly sought by the patentee.
Claims 1-3
[18] Claims 1-3 (and also claim 4) are claims to a product, in each
case a pharmaceutical composition containing tibolone. In claims 1 and 2, that tibolone is of a
particular crystalline purity; in claims 3 and 4, the tibolone of that purity
is of a particular form. Arrow's anticipation
attack on claims 1-3 is based on pure Form 1 tibolone having been revealed in
Declercq.
[19] I heard evidence in relation to the issue of novelty from Dr
Roger Newton, who was called on behalf of Arrow, and Professor Joel Bernstein,
who was called by Akzo. Both gave
evidence in chief by reference to their Reports lodged in process. It goes without saying that both were
impressive witnesses with impressive credentials, though their respective
backgrounds and experiences differed. In
attempting a brief summary, I am conscious of doing each of them an
injustice. Dr Newton has recently
retired as resident medicinal chemist in the chemistry department of the University
of Cambridge, a position he held
since 1996, and he is visiting professor at the University
of Sussex. He holds a number of posts with various
scientific companies and, possibly most relevant to the present proceedings,
was employed by Glaxo from 1971 to 1996, originally as a senior research
chemist and subsequently as director of various research projects. Professor Bernstein is and has been since
1971 professor of chemistry at Ben-Gurion
University of the Negev,
Beersheva, Israel. He teaches courses in general chemistry,
crystallography and organic state chemistry, including polymorphism and
crystallisation. He has specialised and
built an international reputation in the field of crystallography and has
participated in a large number of conferences on the subject. Indeed, Dr Newton was willing to defer
to Professor Bernstein on matters of pure crystallography.
[20] In relation to the question whether tibolone of the claimed
purity and form was revealed in Declercq, however, there was nothing between
the experts on the points that mattered.
Dr Newton stated that data recorded in Table 1 of the Declercq paper
showed that the compound under discussion there was the monoclinic form of
tibolone (i.e. Form I). Further, being a
single crystal, it was by definition 100% pure.
Professor Bernstein agreed. In
his first Report he said: "The Declercq paper does describe the crystal
structure of the material that later became known as Form 1 in the
Patent". Later in that Report he said:
"The nature of the structure determination is such that the experiment is done
on a single crystal, which by definition of a crystal is comprised of a pure
substance". In his evidence, under
cross-examination he confirmed that claim 3 of the patent was for a
pharmaceutical composition containing tibolone with the crystal structure
disclosed in Declercq, and that the single crystal analysed by Declercq had a
crystalline purity greater than that claimed in claims 1 and 2.
[21] The agreement between the experts that Declercq did in fact
refer to the monoclinic (Form 1) form of tibolone, and that it was of 100%
crystalline purity, enables Arrow to say, simply, that claims 1-3 were
anticipated by Declercq. Akzo dispute
this. They advance a number of arguments
in support of their submission that the invention was, none the less,
patentable. The first, which is directed
only to the validity of claim 3, is that spoken to by Professor Bernstein and
first articulated by him, so far as I am aware, in para. 63 of his Report,
beginning with the sentence already quoted:
"The Declercq
paper does describe the crystal structure of the material that later became
known as Form 1 in the Patent. But at
the time of the Declercq paper the existence of polymorphism of Tibolone had
not been discovered. The structure
determined by Declercq et al., could not be called that of Form I until Form II
was discovered, in the same way that there was no Queen Elizabeth I until Queen
Elizabeth II ascended to the throne."
I cannot accept this argument. It confuses the existence of a particular
thing with the name given to it.
Professor Bernstein is wrong to say that there was no Queen Elizabeth I
before Queen Elizabeth II ascended the throne.
There was a Queen Elizabeth I, at least in England,
albeit she was then simply called Queen Elizabeth. Similarly, Form I tibolone existed at the
time of Declercq's work and was identified by him in Table 1 of his paper, but
it was not then called "Form I". When
considering a challenge to a claim in the patent to Form I tibolone, it does
not matter that no one knew of Form II.
Knowledge of Form II would, of course, be relevant if there were a
challenge to claim 4 of the patent, but there is no such challenge. Only the claim to Form I is challenged, and
that challenge must succeed because Form I, albeit without that name, is
revealed in Declercq.
[22] It may be that Akzo's argument on this point is not best served
by the particular analogy with Queen Elizabeth.
The substance of the argument may be more directly focused in Professor
Bernstein's unchallenged evidence, both in that passage and elsewhere, that at
the time of the Declercq paper it had not been discovered that tibolone was polymorphous. This was a point developed by
Mr Davidson in his submissions. He
submitted that the patent teaches that tibolone is polymorphous, and that the
claims are concerned with methods of producing one or other form of
tibolone. It is unrealistic, therefore,
he argued, to regard any part of the invention relating to the two polymorphic
Forms of tibolone as having been anticipated by a paper which reveals nothing
about polymorphism in tibolone.
[23] I do not agree. I
accept, of course, that the patent teaches that tibolone is polymorphous. But claim 3 is a claim to a particular
product, namely tibolone of a particular crystalline structure. The answer to the question of whether that
product has or has not been anticipated must depend on whether that product is
revealed in the prior art. It cannot be
affected by the state of knowledge about the existence of other crystalline
forms. Such knowledge might be relevant
to a claim to a method of producing Form I tibolone, for example claim 5, in so
far as it is necessary for a method of producing the one Form of tibolone to
exclude production of the other. But I
am not concerned with that question at this stage. In relation to claim 3, I am concerned with a
claim not to a method of production but to a product, namely the monoclinic
form of tibolone. That monoclinic form
of tibolone was revealed in Declercq.
Whether or not Declercq knew that tibolone was polymorphous, his paper
reveals what we now know as Form I. The
claim to Form I per se therefore lacks
novelty.
[24] Akzo's second argument was that the fact that Declercq revealed
a single crystal of Form I, which was by definition 100% pure, was irrelevant
on a proper construction of claims 1-3.
The claims in the patent were to a "pharmaceutical composition"
containing the compound, i.e. tibolone.
That must involve a recognition that a single crystal is not sufficient:
a pharmaceutical compound clearly cannot be made of a single crystal. Declercq only analysed a single crystal from
the sample he was given. There is no
reason to believe that the whole sample was pure Form I; or at least Arrow
cannot show that it was, since no analysis of the whole sample was carried
out. Many of the crystals may have been
what we now know to be Form II. The
Declercq paper, therefore, only reveals the composition of the single crystal
chosen for analysis, which happens to be pure Form I (and it could just as
easily have been pure Form II). This
does not reveal how to obtain Form I in sufficient quantities or with sufficient
repeatability to use in a pharmaceutical compound. It therefore makes no practical sense to
speak of Declercq having anticipated the claim to a composition containing pure
Form I tibolone.
[25] There was some dispute on the evidence as to whether the
sample, from which the single crystal analysed by Declercq was selected, was
likely to have been made up wholly of Form I crystals or from a mixture of
Forms I and II. The Declercq paper is
silent on the point. Dr Newton suggested
that since acetone was the medium used it was likely that the whole sample
comprised Form I. Further, it was
suggested that if there had been any Form II present in the sample, Declercq
would probably have noticed and recorded it.
Such speculation seems to me to go beyond what is justified by the
evidence. Although various scenarios
were suggested as to what might have happened, we in fact know nothing about
how, or even by whom, the single crystal was selected. We do not know whether Declercq would have
been interested in observing different crystalline forms or referring to them
in his paper if he did observe them. I
therefore do not find it established on the evidence that the whole sample was
Form I tibolone. Indeed, since none of
Examples 1-3 in the patent resulted in 100% crystalline purity despite the use
of acetone as the solvent, I consider it unlikely that the sample before
Declercq would be made up entirely of Form I crystals.
[26] Nonetheless, there are, in my opinion, two quite separate
answers to Akzo's argument. The first is
this: that part of the argument which focuses on the omission from Declercq of
any method of obtaining Form I in sufficient quantities has nothing at all to
do with claims 1-4. Those claims are
claims to a product. The methods of obtaining
the product, i.e. tibolone of the requisite form and purity, if new, is
protected by claims 5 and 6 of the patent, which claims may, indeed, reflect
the "teaching" of the patent as explained by Mr Davidson. The "single crystal" argument is not relied
on by Arrow in relation to claims 5 and 6 - it impacts, if at all, only on
claims 1-4. In
this respect Akzo's argument confuses the claims to the method, on the one
hand, with the product claims on the other.
[27] The second answer is that it would have been open to Akzo to
attempt to limit claims 1-4 by reference to some quantitative criteria. But, for whatever reason, they have not done
so. It was not suggested that, even
adopting a purposive construction, those claims should be read as incorporating
some such criteria capable of being expressed with sufficient precision. Even if it had been so argued, I would have
felt unable to construe the relevant claims as being restricted to pure Form I
tibolone in some quantity greater than a single crystal. On that basis, the prior disclosure in
Declercq of a single crystal of what we now know to be Form I tibolone and
which, being a single crystal, is by definition 100% pure, is sufficient to
invalidate claims 1-3.
[28] The fact that claims 1-4 were claims to a pharmaceutical
composition, rather than simply to tibolone of certain forms and purity gave
rise to another argument on behalf of Akzo.
Mr. Davidson argued that whatever the Declercq paper showed in terms of
the form or purity of the crystal, it said nothing about a pharmaceutical
composition. There was no Record, he
submitted, for an attack on novelty in respect of the pharmaceutical
composition (though he made it clear that he was not submitting that the point
was not open to Arrow). More substantively,
he submitted that any challenge to claims 1-3 on grounds of lack of novelty
would have to demonstrate not just that the form and purity of the crystal were
anticipated but also that the incorporation of the tibolone of the requisite
form and purity into the pharmaceutical composition similarly lacked
novelty. They had not sought to do
this. The incorporation of the tibolone
into a pharmaceutical composition was not anticipated in Declercq. A challenge to the whole of claims 1-3,
properly construed, would, he submitted, involve Arrow in "mosaicing", i.e.
building a case on anticipation by putting together a mosaic of different
sources of prior disclosure: see Terrell on the Law of Patents, 16th
ed. at para. 7-26, Von Heyden v Neustadt (1880) 50 LJCh 126,
128. In this case it would mean putting
together the prior disclosure of crystalline pure Form I tibolone (i.e.
Declercq) with the prior art of making a pharmaceutical composition.
[29] I do not accept this argument.
Tibolone has been in use in pharmaceutical compositions for many
years. This is made clear in the patent
itself, as well as, for example, in Declercq.
It cannot be, and was not, suggested that there is anything novel about
the making of a pharmaceutical composition incorporating tibolone. As the descriptive part of the patent
explains, the discovery claimed by Akzo is not that tibolone can be used in a
pharmaceutical composition but that tibolone is polymorphous; and the claimed
invention relates, not to any particular method of combining tibolone with a
suitable carrier to make the pharmaceutical composition, but to particular
forms and purity of tibolone to be so combined.
It is not suggested in the patent that the incorporation of such a compound
into a pharmaceutical composition involves any inventive step. Nor was it suggested in evidence that this
could or would have been understood to have been part of the invention. The claims in the patent have to be construed
in their context, that context including the description in the patent and the
state of surrounding knowledge: see s.125 of the Patent Act 1977, Article 69 of
the European Patents Convention and the Protocol on the Interpretation of
Article 69, Lubrizol Corp. v Esso Petroleum Co. Ltd [1998] RPC 727,
737-8 and 742, Mayne Pharma Pty. Ltd v Pharmacia Italia Spa [2005] EWCA Civ 137 (unreported 17 February 2005).
Further, the claims must be construed from the standpoint of the
notional addressee of the patent, i.e. the skilled man reasonably well versed
in the relevant art. In a highly
developed industry such as this, the "skilled man" can, and will often be a
"composite entity" or a "team" working within the particular field: see e.g. General Tyre & Rubber company v The Firestone Tyre and Rubber Company Ltd
[1972] RPC 457, 482, 485. In the context
of the 035 patent, there was little or no difference between the parties on the
identity of the skilled man. Adopting
Professor Bernstein's description, with which Dr Newton broadly agreed, the
skilled person here is "a process research chemist working with an analytical
chemist in the pharmaceutical industry", having a batchelor's degree in
chemistry and about 2-3 years experience (perhaps more) in the industry, and
having some familiarity and experience in dealing with solids and the
analytical techniques used to characterise and distinguish the two forms of
tibolone under discussion. I consider
that the addressee of the patent would not understand the incorporation of the
compound into the pharmaceutical composition to be part of the invention
claimed by the patent. Nor is this a
realistic interpretation of the claims read in context, even if construed by
the Court without looking through the eyes of the notional addressee. I should add that this argument by Akzo was
wholly at odds with the stance which they themselves adopted in relation to the
375 patent, where they accepted that the claim to a pharmaceutical composition
incorporating tibolone of a particular chemical purity stood or fell with the
claims to tibolone of that purity, the incorporation of the tibolone into the
pharmaceutical compound not in itself being an inventive step (see paras. 96
and 107 below).
Claim 5
[30] Claim 5 is a claim to a method for the preparation of the Form
I crystalline pure compound for use in the pharmaceutical composition, the
characteristic feature of the method ("characterized in that") being that the
polymorphous tibolone is crystallised from "mixtures of water and acetone or
ethanol" or from other solvents. In
other words, in order to produce Form I tibolone, a polar solvent is used, one
such solvent being a mixture of water and acetone. An apolar solvent, according to the patent
and claim 6, results in Form II.
[35] Arrow's attack on claim 5 on grounds of anticipation or lack of
novelty therefore succeeds.
Obviousness/ lack of inventive step
[36] Section 3 of the Patent Act 1977 states: "An invention shall be
taken to involve an inventive step if it is not obvious to a person skilled in
the art, having regard to any matter which forms part of the state of the art
by virtue only of section 2(2) above ...".
The argument that the invention claimed in the patent did not involve
any inventive step is sometimes described as one of "obviousness".
[37] I was referred to certain authorities on the test to be applied. I should mention two in particular. The first is Windsurfing International Inc. v
Tabur Marine (G.B.) Ltd [1985] RPC 59, a decision of the Court of Appeal
decided under the 1949 Act but which, it was agreed, was directly applicable to
disputes arising under the 1977 Act. At
p.73, Oliver LJ, giving the Judgment of the Court, set out four steps which
required to be taken in answering what he called the "jury question" whether
the alleged inventive step was obvious to a normally skilled addressee in the art:
"The first is to identify
the inventive concept embodied in the patent in suit. Thereafter, the court has to assume the
mantle of the normally skilled but unimaginative addressee in the art at the
priority date and to impute to him what was, at that date, common general
knowledge in the art in question. The
third step is to identify what, if any, differences exist between the matter
cited as being "known or used" and the alleged invention. Finally the court has to ask itself whether,
viewed without any knowledge of the alleged invention, those differences
constitute steps which would have been obvious to the skilled man or whether
they require any degree of invention."
The second authority is the
decision of the Court of Appeal in Beloit
Technologies Inc. v Valmet Paper
Machinery Inc. [1997] RPC 489. In
identifying the test for obviousness, Aldous LJ at pp.493-4 emphasised the
objective nature of the test and warned against looking back with
hindsight. He added:
"It has never been easy to
differentiate between common general knowledge and that which is known by
some. It has become particularly
difficult with the modern ability to circulate and retrieve information. Employees of some companies, with the use of
libraries and patent departments, will become aware of information soon after
it is published in a whole variety of documents; whereas others, without such
advantages, may never do so until that information is accepted generally and
put into practice. The notional skilled
addressee is the ordinary man who may not have the advantages that some
employees of large companies may have.
The information in a patent specification is addressed to such a man and
must contain sufficient details for him to understand and apply the
invention. It will only lack an
inventive step if it is obvious to such a man."
The cases
often, correctly, refer to the hypothetical skilled man as
"unimaginative". But that is not to say
that he is to be regarded as "uninterested" in accomplishing the result. One must assume, I think, that he is at least
sufficiently interested to address his mind to the subject and to consider the
practical application of the information which he is taken to have: see Windsurfer at p.73, and see also Pharmacia Corp v Merck & Co. [2002] RPC 41 at para.124. Aldous LJ in Beloit added
the reminder that the fact that something is well known to a witness does not
establish that it forms part of the common general knowledge. Nor is it necessarily part of the common
general knowledge just because it is recorded in a document, however widely
read, unless it has become generally known and accepted at least to the extent
of being regarded as a good basis for further action.
[38] As I have indicated, the parties were
agreed that the person skilled in the art for the purpose of the 035 patent is
a process research chemist working with an analytical chemist in the
pharmaceutical industry.
[39] The common general knowledge in play here
related to knowledge of polymorphism, that is to say the phenomenon of a
substance crystallising in more than one crystal structure. The most commonly cited definition of
polymorphism is that given by McCrone: "A polymorph is a solid crystalline
phase of a given compound resulting from the possibility of at least two crystalline
arrangements of the molecules of that compound in the solid state"
(W.C.McCrone, Physics and Chemistry of the Organic Solid State, vol.2, 1965 at
p.725). Different crystal forms of a
compound may exhibit different properties
[40] Dr Newton gave evidence to the effect that
polymorphism was well known. Having
referred in his first Report (at paras. 5.1.8 and 5.1.9) to polymorphism being
a very common phenomenon, and having referred in support of that proposition to
numerous textbooks, he said this:
"7.6 A skilled man wishing to develop Tibolone
as a pharmaceutical product would need to identify a robust and repeatable
process for making a well defined stable form of the drug.
7.7 The synthetic route to the compound is
described in the 279 [patent]. ... The
skilled man would be well aware of the fact that most steroids exhibit
polymorphism (see references to common general knowledge at paragraph
5.1.9). Since he would have known that
different steroidal polymorphs may have different melting points, densities,
spectroscopic properties, bio availabilities and stabilities ... he would want to
define a single polymorph having suitable physical and bioavailability
profiles.
7.8 The skilled man would have been aware of
the prior art and of the 1984 [Declercq] Paper. The latter would have been a very important
document since it teaches how to make a pure polymorph and defines it
analytically. Thus, by following the
teaching of the 279 to make the compound and then recrystallising it from
acetone as taught by the 1984 [Declercq]
Paper the skilled man would have a method of preparing pure form I polymorph.
7.9 For these reasons I think that claims 1
and 2 of the Patent are obvious since the 1984 [Declercq] Paper already described form I Tibolone. Claim 3 is likewise obvious since the 1984 [Declercq] Paper precisely describes the
crystal structure referred to in the Patent as monoclinic P21
form. Claim 5 is also obvious
because the 1984 [Declercq] Paper
describes recrystallisation from acetone rather than anhydrous acetone and one
would expect the former solvent to contain some water. In support of this the Patent examples 1, 2
and 3 do not mention adding water to the acetone. ... So
although the Patent on page 2 line 53 talks about recrystallisation from
mixtures of water and acetone none of the examples include specifically adding
additional water to the acetone. However
on page 3 line 6 the Patent says: "Thus,
in general good results are obtained from anhydrous acetone only when the
crystallisation is carried out at a relatively low temperature". Since the Patent talks specifically about
anhydrous acetone and indicates that it is less satisfactory than mixtures of
acetone and water it is logical to conclude that the acetone used in the
examples to illustrate the invention, which the authors refer to as acetone, is
the standard solvent found on any bench top.
This will contain some water.
Since water is a very polar solvent its presence in the acetone will
increase the polarity of that solvent and favour the formation of form I."
He then
gives his conclusion in relation to obviousness:
"7.10 In my opinion it would have been obvious at
the priority date of the Patent to obtain and use the polymorph claimed at
claims 1-3 in its pure crystalline form.
Furthermore, the solvents claimed at claim 5 are examples of solvents
routinely used to conduct a polymorph screen."
[41] Professor Bernstein took a different
view. As I understood his evidence, the
difference between him and Dr Newton lay in his assessment of the level of
common awareness of polymorphism and the uncertainties in that aspect of the
science. He considered that even today
there was a general lack of awareness of polymorphism amongst chemists. Although chemistry textbooks tended to
mention the best known form of polymorphism or allotropism - that of graphite
and diamond, both polymorphic forms of carbon - "physical chemistry texts
discuss polymorphism in the context of thermodynamics and the phase rule, but
rarely as a more general phenomenon encountered, say, in the field of
pharmaceuticals". In his first Report he
expressed the opinion that "in their proper context the citations and
quotations [relied on by Dr Newton] do not support his conclusion" that
polymorphism in steroids is very well known.
However, in cross-examination (very late in the afternoon of Day 9) he
accepted that he had carried out no investigation as to whether people working
in the pharmaceutical industry, and in particular process research chemists,
would have been familiar with the texts to which Dr Newton referred. On resuming his evidence the next morning, he
asked to be allowed to elaborate upon those answers. I allowed him to do so, despite opposition
from Mr Currie, because giving evidence is tiring and a witness can often
"flag" towards the end of the day.
However, as Professor Bernstein began to elaborate, it emerged that he
wished not simply to expand on his previous answers but to give further
evidence by reference to enquiries he had made of colleagues overnight. This seemed to me to be going a step further,
and I stopped him on the basis that if this line was to be developed it should
be for counsel to take it up or not as they considered appropriate. In the event, Mr Davidson did not seek
to bring out the evidence of these further enquiries. It did not seem to me, however, that
Mr Currie's criticism of Professor Bernstein for having made these
enquiries overnight was warranted. An
expert witness will often, in the course of prolonged examination or
cross-examination, wish to check references or consider other aspects of his
expert evidence overnight, and may need assistance, away from home, in finding
materials. Sometimes this may involve
outlining the problem to, or discussing it with, a colleague. I see nothing wrong with this at all. It is quite different from discussing the
matter with clients or solicitors.
Indeed, it is usually of assistance to the court. In the instant case Professor Bernstein's
enquiries went slightly further. He
felt, in light of the cross-examination directed to him, that he ought to have
made those enquiries earlier, and he sought to make good that omission. I do not consider that he should be
criticised for that.
[42] Despite Professor Bernstein's undoubted
eminence in his field, I prefer the evidence of Dr Newton to the effect that by
the late 1980s polymorphism as a phenomenon would have been well-known to a
process research chemist working in the pharmaceutical industry; and they would
have known that it was widespread in pharmaceuticals, particularly
steroids. The prevalence of polymorphism
was vouched by Professor Bernstein's citation of McCrone's view, as early as
1965, that "every compound has different polymorphic forms and ... in general, the
number of forms known for a given compound is proportional to the time and
money spent in research on that compound."
Whilst emphasising that considerable caution should be exercised in
asserting that polymorphism is the rule rather than the exception, Professor
Bernstein went on to say (at para. 31 of his Report) that it "appears to be
true that instances of polymorphism are not uncommon in those industries where
the preparation and characterisation of solid materials are integral aspects of
the developing and manufacturing of products (i.e. those on which a great deal
of time and money are spent)", thus endorsing McCrone. The extent to which the skilled man (as
previously defined) would be expected to have this knowledge is, of course, a
separate question. However, Dr Newton's
references included student text books, which would (as I understood his
evidence, which I accept) have been read by process research chemists and
analytical chemists during their student days, and I have no difficulty in
accepting that knowledge of polymorphism was part of the common general
knowledge of the skilled addressee of the patent.
[43] But there is a difference between, on the
one hand, knowing of polymorphism as a phenomenon, or even knowing that it is
likely to be found in steroids; and, on the other hand, being able to use or
apply that knowledge. The point
Professor Bernstein was making, for example in para.12 of his Report, was that
polymorphism in any particular compound was usually discovered by serendipity
rather than by systematic research. The
important conclusion from this was that set out at para.56 of that Report,
that: "... even the skilled person could
not know in advance that any steroid might be polymorphic. He certainly would not know in advance how to
obtain it, or what its properties might be."
Despite the existence of polymorphic screening - which was less common
in the 1980s than it is today - I did not understand Dr Newton to disagree
strongly with this opinion; and, in any event, I accept it as correct. Ultimately there did not seem to be as much
between Dr Newton and Professor Bernstein as at first appeared. The relevant issue is not so much whether
there was an awareness of polymorphism amongst the relevant people at the
relevant time, but whether that knowledge pointed the way to a discovery of
polymorphism in any particular case.
[44] The obviousness attack on the claims in
the patent has to be considered against this background. Let it be assumed that the skilled but
unimaginative addressee of the patent knows of tibolone, and knows that there
is a likelihood that tibolone, being a steroid, is polymorphous. Without the benefit of hindsight, I do not
see why he would want to look for a pure polymorphic form of tibolone. After all, tibolone had been known from the
1960s, and there was no evidence of any concerted effort to find out if it was
polymorphous. Nor do I see how he would
go about finding a new polymorphic form.
He might know of the Declercq paper, which would tell him about what is
now called Form I, and about the use of acetone, but not about tibolone being
polymorphic. If he carried out a
crystallisation using acetone, he would probably have produced what we now know
as Form I tibolone. But that would
support Arrow's argument on anticipation rather than obviousness (see para.34
above). It seems to me that the
"obviousness" line of attack, as distinct from that based on anticipation,
assumes that the skilled but unimaginative addressee of the patent would be
looking to develop a pure polymorphic form of tibolone and would have had the
knowledge of how to achieve it. Without
the benefit of knowing (with hindsight) that such a form had been found, I do
not consider that he would have had either the motivation or the means.
[45] Applying the four stage approach identified
in the Windsurfing case, the question
of obviousness can be considered in this way: (i) the inventive concept in the
patent is the identification of a crystalline pure form of tibolone and a
method of producing it; (ii) the skilled addressee would have known of tibolone
and would have knowledge that steroids are likely, though not certain, to be
polymorphous; (iii) the difference is the discovery of polymorphism in tibolone
and the identification of the method of producing one of the two different polymorphic
forms. Stage (iv) requires one to ask
whether the steps required to achieve this would have been obvious to the
skilled man. To that question the
answer, in my opinion, is a clear: No.
[46] Accordingly, I would have rejected the
attack on Claims 1-3 and 5 of the 035 patent if that attack had been based
solely on obviousness. As it is, I shall
uphold the attack based on anticipation or lack of novelty, so my rejection of
this additional line of attack is immaterial.
The 375 Patent
"[0007] The customary amount of Tibolone in
the known dosage unit is 2.5mg in tablets or capsules of 100 mg i.e. 2.5%. For the sake of providing therapies better
tailored to the individual woman's needs.
It is desired to provide dosage units having a lower amount.
[0008] However, adaptation of a known
formulation by simply including a lower amount of Tibolone further decreases the
stability of the dosage unit substantially.
E.g., if a 2.5mg Tibolone dosage unit has a shelf-life of, e.g., 2-3
years at room temperature, the same unit upon lowering the amount of Tibolone
to e.g. 0.3 mg can only be kept at 4บC for a period of 6-12 months. Such a lower stability is unacceptable in
daily practice. It is a further object
of the invention to provide dosage forms having a lower content of Tibolone
(which are more prone to stability problems than regular dosage forms) and that
can be suitably kept for a prolonged period of time."
The authors explain that one of the
possible ways of keeping the amount of OM38 below a desired level after a
prolonged storage time is to limit the amount initially present in the bulk
preparation. Thus they say in para.
[0009]:
"there is a need to
synthesize high purity Tibolone batches with a low contamination content of
OM38. It is an object of the present
invention to provide for such high purity batches of Tibolone."
They explain in the next paragraph
that during the last step of the synthesis of tibolone, a solution of
(7α17α)-3.3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one
in a mixture of pyridine and ethanol is mixed with a solution of oxalic acid in
water and the mixture is stirred for 3 hours at approximately 30บC. The solution is then poured out in a mixture
of pyridine and water and the resulting suspension is filtered. The crystals are washed with a mixture of
water and pyridine and subsequently, the crystals are dried under vacuum at
40บC to give (7α17α)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one. The authors refer to a 1986 paper by van
Vliet et al, "An alternative synthesis of
17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one (Org
OD 14)" ("van Vliet" or "the van Vliet paper").
As tibolone has a lower stability than the corresponding OM38, a small
percentage of OM38 forms in the compound via acid catalysed isomerisation. Furthermore, this isomerisation takes place
at higher temperature and upon long term storage of the crystals.
[50] The authors then proceed to identify the discovery underlying
the invention claimed in the patent.
"[0012] Unexpectedly, it now has been found
that the rate of formation of OM38 during drying and storage in a specific
batch can be decreased if crystals of Tibolone are washed with water and are
allowed to age for at least 24 hours in the presence of water. Thus, the Tibolone is left for at least
24 hours under wet conditions.
Preferentially the crystals are left under these conditions for a period
of at least 3 days. There is no
limit to a maximum period but a period of 3-6 days is best suited. The aging temperature preferentially is room
temperature.
[0013] Thus according to the procedure of
the present invention highly pure Tibolone with a low OM38 impurity is obtained
by including a delay of several days before drying. The procedure reliably results in batches of
Tibolone having a low OM38 content. A
further advantage is that these batches have an excellent stability. Furthermore, these batches do not form additional
amounts of the latter compound upon heating or long term storage."
[51] It is convenient at this stage to set out in full certain other
paragraphs of the descriptive part of the patent before identifying the claims
made by the patentees.
"[0014] The crystal formation procedure of
the present invention can perfectly well be combined with the last step of the
Tibolone synthesis wherein
(7α17α)-3-3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-
en-20-yn-3-one in a mixture of pyridine and ethanol is mixed with a solution of
oxalic acid in water. In general, this
reaction proceeds under mild acidic conditions in the presence of an organic
solvent and water within a pH range of 5-3, preferentially 3.5-4.5. The acid preferentially is a weak organic
acid having a pKa value in the range 1-5 such as citric acid, malonic acid,
oxalic acid, dichloracetic acid and acetic acid, optionally buffered with a
base such as pyridine. As organic
solvent e.g. ethanol, methanol, acetone, 2-propanol or tetrahydrofuran can be
used. The solution is then poured out in
water, which is made slightly alkaline by addition e.g. of a low amount of
pyridine. After filtering the suspension
the crystals are washed with a mixture of water made slightly alkaline by e.g.
pyridine. Before drying the crystals are
left wet for at least 24 hours.
[0015] Inclusion of the crystal aging
step according to the invention results in bulk Tibolone batches with a low
Org OM38 content. Routinely,
batches are obtained with an Org OM38 content of less than 0.5%. Often even batches with less than 0.25% or
even 0.1% of Org OM38 are obtained.
Thus high purity compositions with Tibolone having less than 0.5% of
Org OM38, preferably 0.25%, more preferably 0.10% of Org OM38 form
part of the present invention. The
amount of Org OM38 is calculated as the percentage (w/w) of the total
amount of the bulk substance including some minor impurities. The amount of Tibolone usually is more than
98%.
[0016] The batches of these high purity Tibolone
compositions with their low initial Org OM38 content are perfectly well suited
to be used as a source for the preparations of pharmaceutical
formulations. This guarantees a
formulation with a low initial Org OM38 content and improves therefore its
storage properties. Pharmaceutical
preparations prepared with high purity Tibolone usually result in preparations
with less than 1% of Org OM38, often even less than 0.7% of Org OM38 and these
preparations are less prone to increase in Org OM38 content during storage.
[0017] As indicated before the amount of
Org OM38 in a dosage form also depends upon the concentration of the
active substance, the amount of impurity being higher as the amount of Tibolone
in the dosage unit decreases. Therefore,
using high purity Tibolone as the active substance, dosage units can now be
prepared with a lower amount of Tibolone and still having an acceptable shelf
life. Thus, the invention also relates
to pharmaceutical dosage units, which can be prepared by admixture of a
pharmaceutically suitable solid carrier and the high purity composition of the
present invention.
[0018] A typical known formulation for
Tibolone is a 100 mg dosage unit having 2.5 mg of Tibolone contained therein, a
relatively small amount (e.g. approximately 1% by weight) of pharmaceutically
acceptable auxiliaries, and a carrier making up the body of the tablet. The carrier typically is composed of 10% by
weight of starch, e.g. potato starch, and 90% by weight of lactose.
[0019] Due to the excellent stability
properties of dosage units with a lower amount of active substance than the
present commercially available tablets of 2.5mg active substance, the present
invention now makes it also possible to provide for stable dosage units
comprising Tibolone in an amount of less than 2.50mg, preferably 1.25mg or
less, more preferably 0.625mg or less.
At a shelf life of 1.5 years, preferably 2 years these dosage units
still comprise less than 5% of OM38 (relative to the amount of Tibolone).
[0020] It is another aspect of the
present invention to provide dosage units comprising Tibolone in amounts of
less than 2.50mg, preferably 1.25mg or less, more preferably 0.625mg or less
and comprising at a shelf life of 6 months less than 3%, preferably 2% of OM38. The shelf life preferably is extended up to 1
year, preferably 1.5 year, more preferably 2 years.
[0021] As used herein shelf life means
storage during a specified period under temperature conditions varying from
2.25บC. Dosage units can be packed e.g.
in push-through packs (PTP, blister) and are preferably stored in dark (e.g.
enclosed in carton). Alternatively they
might also be stored in bottles e.g. high-density polyethylene bottles.
[0022] The pharmaceutical dosage units of
the present invention will generally take the form of tablets or capsules, but
other solid or dry pharmaceutical preparations are included.
[0023] Methods for making such dosage
units are well known. For example in the
standard English language text, Gennaro et al, Remington's Pharmaceutical
Sciences (18th ed. Mack Publishing Company, 1990, see especially
Part 8: Pharmaceutical Preparations and Their Manufacture), methods of making
tablets, capsules and pills and their respective components are described.
[0024] Tablets and capsules are prepared
of granulates using dry or wet granulation techniques as disclosed in The
Theory and Practice of Industrial Pharmacy (Third Edition) L Lachman, H
A Liebeman and J L Kanig (1986) p1-99 and 293-345.
[0025] The aim of granulation is to
improve the flowability and compressibility of the powder mixture. Wet granulation forms the granules by binding
the powders (a mixture of a diluent and disintegrant) together with an
adhesive. The wet granulation technique
employs a solution, suspension or slurry containing a binder, which is usually
added to the powder mixture; however the binder may be incorporated dry to the
powder mix and the liquid may be added by itself. The wet granulation process is performed in
mixers/kneaders or fluid bed systems.
[0026] Usually an amount of water is
incorporated in the basic granulae ranging from 5.5 - 7%. Preferably the amount of water incorporated
is at least 6%.
[0027] After granulation the mass is
dried to the desired water content using fluid bed dryers, tray dryers, vacuum
dryers or other suitable dryers.
[0028] To attain a good distribution of
the active (Tibolone) over the total mass, the active is premixed with a part
of the granulate, sieved using an oscillating sieve, a high speed sieve or
other suitable sieving equipment. Next
this mixture is mixed with the remaining part of the granulate and a
lubricant. This mixture is compressed to
tablets, or filled into capsules."
"1. A high purity compound
(7α17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one [i.e. tibolone] characterised in that
said compound comprises
(7α17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one [i.e. OM38] in an amount less than 0.5%.
2. The compound according to claim 1
characterised in that the amount of [OM38]
is 0.25% or less.
3. The compound according to claim 1
characterised in that the amount of [OM38]
is 0.1% or less.
4. A process for preparing the high purity
compound of claims 1-3 characterised in that crystals of [tibolone] are allowed to age in the presence of water for at least
24 hours.
5. The process according to claim 4
wherein the aging lasts 3-6 days.
6. The process according to claims 4 or 5
characterised in that the crystals are formed in the last step of the Tibolone
synthesis comprising the steps of
a. reacting
(7α17α)-3-3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one
in an organic solvent with a weak acidic aqueous solution.
b. pouring out the solution in water which
is made slightly alkaline.
c. washing the crystals with water which
is made slightly alkaline.
7. A pharmaceutical dosage unit obtainable
by admixture of a pharmaceutically suitable solid carrier and the compound
according to any one of the claims 1-3.
8. A pharmaceutical dosage unit obtainable
by admixture of a pharmaceutically suitable solid carrier and the compound
obtainable by the process of claims 4-6.
9. A dosage unit comprising a
pharmaceutically suitable solid carrier and [tibolone]
in an amount of less than 2.50mg and comprising less than 5% of [OM38] at shelf life of at least
1.5 years.
10. The dosage unit according to claim 9
characterised in that [tibolone] is
present in an amount of 1.25mg or less.
11. The dosage unit according to claim 9
characterised in that [tibolone] is
present in a amount of 0.625mg or less.
12. The dosage unit according to claims 9-11
wherein the shelf life is 1.5 years, more preferably 2 years.
13. The dosage unit according to claim 9-11
wherein at a shelf life period of 6 months the amount of [OM38] is 3% or less, more preferably 2%
or less.
14. The dosage unit according to claim 9-11
wherein at a shelf life period of 11/2 years, more preferably 2 years, the
amount of [OM38] is 3% or less, more
preferably 2% or less."
[53] The claims can, for convenience, be grouped together under four
headings. The first group, comprising
claims 1-3, is concerned only with the chemical purity of tibolone in terms of
its contamination by OM38. Those claims
are claims to tibolone in which the OM38 is present in only very small amounts
(<0.5%, 0.25% or less and 0.1% or less).
The claims in the second group, claims 4-6, are claims to a process (the
"crystal ageing step" or more commonly referred to in evidence and submissions
as the "ageing process") for preparing tibolone of the purity identified in
claims 1-3. Though there was some
argument about the precise ambit of claim 8, the third group, comprising claims
7-8, may be described in general terms as being concerned with claims to a
pharmaceutical dosage unit combining a pharmaceutically solid carrier and
tibolone of the requisite purity. The
claims in the fourth group, claims 9-14, are claims to a pharmaceutical dosage
unit combining a carrier and various quantities of tibolone and having a shelf
life defined by reference to the amount of OM38 present after certain specified
periods.
Amendment by Arrow and Norton
[54] The claims challenged by Arrow and Norton on Record are those
numbered 1-3, 7 and 9-14. In their closing
submissions Mr Currie QC for Arrow and Mr Campbell QC for Norton both
sought leave to amend to include a challenge to claim 8 as well. This was opposed by Mr Davidson QC for
Akzo. Having considered the application
carefully, I am satisfied that it would be in the interests of justice to allow
the amendment to be made, for reasons which will become apparent when I deal
with that claim. I shall accordingly
consider also the validity of claim 8.
In the event, therefore, only the second group of claims, i.e. claims
4-6, which were concerned with the ageing process itself, was not challenged in
these proceedings.
Proposed amendment by Akzo
[55] Mr Davidson moved the court in October 2005 to allow the
claims in the patent to be amended. The
amendments followed the terms of Akzo's Second Auxiliary Request in opposition
proceedings before the EPO.
Mr Davidson described the amendments as being by way of
re-writing. He said that they were
sought for the purposes of further defining the invention. They involved the deletion of claims 1-14 of
the patent and their replacement with 13 new claims. I do not propose to set out the whole terms
of the proposed amendment but the flavour of it can be gathered from the following. Claim 1 of the proposed amended claims
read as follows:
"A high purity
compound [tibolone] comprising [OM38] in an amount less than 0.5%
obtainable by a process wherein crystals of tibolone are allowed to age in the
presence of water for at least 24 hours."
Claims 2 and 3 were to a
similar effect with different quantities of OM38. Claims 4-6 were again similar except for
variations to the period of ageing and the temperature at which the ageing was
carried out. Claims 7-9 were
identical to Claims 4-6 of the unamended patent whilst Claims 10-13
were in broadly similar terms to Claims 7-11 of the unamended patent. The key difference was the introduction of
the ageing process into the definition of the product in the product claims,
i.e. claims 1-3 of the original patent and 1-6 of the proposed amended
patent. Akzo's motion to amend was in a
somewhat unusual form, in that it sought the amendment on a contingent basis,
namely only if as a result of the proof before answer the court held that any
of the claims of the unamended patent were subject to revocation.
[56] The motion came before me in November 2005 and was continued
twice. It was opposed by Arrow and by
Norton on essentially three grounds:
first, that it was incompetent;
second, that it was irrelevant, the proposed amendment being to
introduce "product by process" claims (cf. Kirin-Amgen
Inc. v Hoechst Marion Roussel Ltd
[2005] RPC 169 per Lord Hoffman at paras. 91-101); and third, that it was too late, the new
claim raising issues which could not properly be investigated and dealt with
before the proof due to commence in January 2006.
[57] The question of competency was argued at some length. In view of its general importance, it is
right that I should set out briefly my reasons for holding the motion to be
competent. Section 75 of the
Patents Act 1977 permits the court to allow the patentee to amend the
specification of a patent in such manner and subject to such terms as to
advertising and as to expenses or otherwise as the court thinks fit. Rule of Court 55.5 governs the procedure
in Scotland. There are requirements for notice and
advertisement. The advertisement allows
persons who are not parties to the proceedings to become aware of the proposed
amendment and to give notice of their intention to oppose it. Within 35 days after the appearance of
the advertisement, the applicant for the amendment must apply to the court by a
motion intimated to the Comptroller-General of Patents, Designs and Trade Marks
("the Comptroller"), the other parties to the action and to any person who has
intimated his intention to oppose the amendment. At the hearing of the motion, where there is
opposition to it, the court ordains the applicant to lodge a minute setting out
the grounds of his application within such period as the court thinks fit and
allows other parties to lodge answers to the minute. Within 7 days after the expiry of the
time for lodging answers, the applicant is required to apply by motion for an
order for further procedure. On the
hearing of that motion the court may grant the application or determine whether
the motion shall be heard at the same time as the hearing of the cause
depending before it relating to the patent in question, or may lay down other
procedure as it thinks fit. It was
submitted on behalf of Arrow and Norton that the Rules of Court to which I have
referred did not permit a contingent application such as the one intimated by
Akzo. I see no reason why that should be
so. The effect of Akzo's motion, which I
allowed to be amended at the bar so that it could be clarified, was that they
would wish to move the amendment only if they were unsuccessful in upholding
the claims put in issue by Arrow and Norton.
Such a position seems to me to be consistent with the terms of Rule 55.5(8)(b)
entitling the court to order that the motion be heard at the same time as the
hearing of the cause depending before the court. At that stage the issues relating to the
validity of the unamended claims will be canvassed before the court; and it
seems to me that it would be unrealistic, and contrary to common sense, to
require the applicant to make an election before he knows what the court's
answer to the challenges will be.
Provided that all the material necessary for a consideration of both the
existing claims and the proposed amended claims is before the court - and that
is important - it causes no difficulty to any party to allow the applicant to
defer making a final decision on whether to proceed with his motion.
[58] Nonetheless, I refused the motion to amend since it seemed to
me to raise issues which were not covered by the existing dispute between the
parties and which neither Arrow nor Norton could reasonably be expected to
address in the relatively short time leading up to the proof. These issues related, in effect, to the
ageing process and the product produced as a result of it. As I have already indicated, the ageing
process itself was not in dispute before me.
Although evidence was given about it and submissions were made, no party
had prepared for the proof on the basis that there was to be a full examination
of the ageing process and the tibolone produced by that process. Nor had the expert evidence been focused on
what, if any, differences there were in the product of the ageing process as
compared with that which had not been through that process. In consequence, it would have been virtually
impossible, so it seemed to me, for Arrow or Norton to deal properly with the
amended claims 1-6. Equally, although I
would not have refused the amendment simply on the basis that it was arguably
irrelevant having regard to the test for "product by process" claims set out in
Kirin-Amgen, it seemed to me that the
question whether that test was satisfied in relation to the proposed new claims
1-6 was something that required evidence - and it would have been unfair to
Arrow and Norton to require them to deal with this matter at relatively short
notice before the proof. In coming to
this conclusion, I took into account the submissions made on behalf of Akzo to
the effect that Arrow and Norton, through the opposition proceedings before the
EPO and certain other matters, were or ought to have been aware of the desire
on their part to make these amendments.
However, this did not seem to me to address the relevant issue. I was told by counsel for Arrow and Norton
that their respective experts had not addressed these issues in the detail that
would be required if the amendments were allowed. That did not surprise me. Why should Arrow or Norton incur expenditure
and divert their energies - in advance of the proof due to commence in January
- preparing to deal with issues which had not been raised in proof.
[59] Accordingly, I refused the motion to amend. I indicated that it would, of course, be open
to Akzo to make a new application to amend at the end of the proof. They duly did so. I shall deal with this renewed application at
the end of this Opinion.
Expert evidence
[60] I heard expert evidence in relation to the subject matter of
the 375 patent from Dr Newton (for Arrow), Dr Widdowson (for Norton) and
Professor Pattenden (for Akzo). I have
already identified Dr Newton's field of expertise. Dr Widdowson and Professor Pattenden were
also similarly qualified.
Professor Pattenden has recently stood down as the Sir Jesse
Boot professor of organic chemistry at the University
of Nottingham and is now professor
of organic chemistry there. He was
elected in 1991 to the Fellowship of the Royal Society. Dr Widdowson is currently reader (albeit
now on a part-time basis) in Organic Chemistry in the department of chemistry,
Imperial College London, and before that was a lecturer in the department of
chemistry at Imperial College. In 1997 he was awarded the Bader prize of the
Royal Society of Chemistry for "Eminence in Organic Chemistry". They all gave their evidence in a clear and
helpful manner. I formed the view that
they were all aware of their obligations as expert witnesses and were trying to
assist the court to the best of their ability.
Unsurprisingly, there were large areas on which they agreed. Where there were differences between them on
which I am required to make a decision I do so not on the basis of any general
preference for one expert over the other but because of my perception of the
strengths and weaknesses of the particular arguments.
[61] In addition I heard evidence in relation to two series of tests
or experiments. One was carried out by
Resolution Chemicals Ltd ("Resolution") on 7 February and 18 August 2003 ("the Resolution
experiments"). Resolution had attempted
to replicate Example 5 of the 035 patent, though on a larger scale. The result of the experiments was tibolone of
a chemical purity which met the claims in Claims 1-3 of the 375 patent. The other tests were carried out by
Synnovation Ltd, according to a protocol set out in a document entitled "Notice
of Experiments". These test were carried
out at the instance of Norton and were, in effect, an attempt to re-run the
exercise carried out by van Vliet to see whether the tibolone resulting
therefrom was of the chemical purity to which Claims 1-3 of the patent
referred.
OM38
[62] I did not understand there to be any significant difference
between the expert witnesses on the basic science which forms the background to
the patent in issue. I take the following
brief summary from Dr Newton's report as amplified by the evidence. Compounds such as tibolone, which contain a
double bond and a carbonyl group in a 6-membered ring, have a tendency to
undergo a rearrangement so that the double bond moves into conjugation with the
carbonyl group and, in the case of tibolone, forms OM38. The process is called isomerisation (and OM38
is sometimes referred to as "iso-tibolone").
The isomerisation process can be catalysed by acid. The strength of the acid affects the speed of
the reaction. The stronger the acid, the
faster the conversion. The removal of
acid slows the process. Impurities such
as OM38 will have a different biological activity from that of tibolone, which
may have an effect on the shelf-life of the product. As the patent notes in
para.[0006], a maximum of 5% OM38 is permitted in pharmaceutical compositions
comprising tibolone at the end of their shelf life. It is important, therefore, to control the
level of OM38 in tibolone insofar as that level affects the shelf life of the
product. That is the problem which the
375 patent addresses.
[63] The patent claims to have achieved this by the ageing
process. There was considerable
discussion during the evidence about whether and, if so, how the ageing process
worked. Although, as I have noted, the
ageing process as disclosed in Claims 4-6 of the patent was not challenged, it
is necessary to consider this issue in some detail since it informs an
understanding of the patent and the issues (of anticipation and obviousness)
relevant to the other Claims.
The ageing process
[64] The first mention of the ageing process in the patent appears
at paras.[0012]-[0015] of the specification.
I have already quoted those paragraphs (see paras.50-51 above). A number of examples are given in the patent
to illustrate the effect of the ageing process and to invite conclusions from a
comparison of "aged" and "un-aged" tibolone, using that terminology to mean,
respectively, tibolone prepared by the ageing process and that prepared without
using the ageing process. Thus, Example
1 did not include the ageing process, whereas Examples 2 and 3 did. Those Examples are as follows, substituting [tibolone] and [OM38] for the chemical expressions used in the Examples:
"Example 1
[0030] A
solution of
(7α,17α)-3,3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one
(15kg) in a mixture of pyridine (630ml) and ethanol (315 litres) was mixed with
a solution of oxalic acid (750gr) in water (90 litres) and the mixture was
stirred for 2 hours at approximately 30บC.
The solution was poured out in a mixture of pyridine (1350ml) and water
(300 litres) and the resulting suspension was filtered. The crystals were washed with a mixture of
water and pyridine and dried under vacuum at 40บC to give [tibolone] containing 0.6% of the corresponding [OM38] as indicated by HPLC analysis; a
stress test at 45บC (duration 1 month) indicated a 0.4% increase of the latter
compound.
Example 2
[0031] A
solution of
(7α,17α)-3,3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one
(15kg) in a mixture of pyridine (630ml) and ethanol (315 litres) was mixed
with a solution of oxalic acid (375gr) in water (90 litres) and the mixture was
stirred for 3 hours at approximately 30บC.
The solution was poured out in a mixture of pyridine (1350ml) and water
(300 litres) and the resulting suspension is filtered. The crystals are washed with a mixture of
water and pyridine and allowed to age for 3-6 days at room temperature. Subsequently, the crystals were dried under
vacuum at 40บC to give [tibolone] containing
≤ 0.1% of the corresponding [OM38]
as indicated by HPLC analysis; a stress test at 45บC (duration 1 week)
indicated a < 0.1% increase of the latter compound.
Example 3
[0032] The
preparation as described in example 2 was repeated. [Tibolone]
was obtained which contained 0.2% of the corresponding [OM38] as indicated by HPLC analysis; a stress test at 45บC
(duration 1 week) indicated a 0.1% increase of the latte compound."
[65] Example 4 set out a method of producing
tablets. There was nothing either novel
or inventive about that method. The text
was silent on the question whether the tablets were made from aged or un-aged
tibolone, and I do not think there was any consensus on which it was. For my part I consider it more likely that it
was un-aged. The stability of the
tablets thus made was determined and the results set out in Table 1.
Table
1:
|
Content
of decomposition product (Org OM38) in percentage of the declared amount of
Tibolone per tablet, in tablets containing a various amount of Tibolone,
after storage at 25บC and 60% relative humidity
|
|
Storage
time (months)
|
Concentration
of Tibolone per tablet
|
|
0.46
|
0.96
|
1.92
|
2.5
|
|
|
Amount
of Org OM38 formed during storage (in percentage of the declared amount of
Tibolone)
|
|
0
|
1.2
|
0.8
|
0.5
|
0.4
|
|
6
|
6.5
|
3.5
|
1.8
|
1.6
|
|
12
|
9.5
|
5.1
|
2.7
|
2.2
|
|
18
|
12.2
|
6.1
|
3.3
|
2.7
|
The
figures against a storage time of 0 (zero) months indicated the amount of OM38
in the tibolone after tabletting, rather than when the tibolone was made. As can be seen, the concentration of tibolone
in the tablets tested in Table 1 varied.
[66] Examples 5 and 6 set out to measure the
OM38 content of tablets containing 1.25 mg tibolone over different lengths of
storage time. I set out those examples
below, since much discussion focussed on them.
"Example 5
[0036] Tablets
of 1.25mg of Tibolone have been prepared as described in example 4. The tablets were stored at 25บC and 60%
relative humidity and the decomposition product (Org OM38) was measured.
|
|
|
Storage time (months)
|
Batch
no
|
|
049514001
|
049515001
|
049516001
|
|
|
Amount
of Org OM38 formed during storage (in percentage of the declared amount of
Tibolone)
|
|
0
|
0.7
|
1.0
|
1.3
|
|
6
|
2.3
|
2.6
|
2.9
|
|
12
|
3.5
|
3.7
|
3.8
|
|
18
|
4.3
|
4.2
|
4.3
|
|
24
|
5.1
|
4.9
|
4.9
|
[0037] It can be concluded that the shelf
life of tablets containing 1.25mg of Tibolone per tablet of 65mg is
borderline."
There was some debate as to whether
the tibolone used in Example 5 was aged or un-aged. Although the text is silent on this point, it
seems to me that the context shows it to have been un-aged, since the clear
intention behind setting out the results in this form was to compare the
shelf-life of un-aged tibolone (Example 5) and aged tibolone (Example 6).
[67] The tibolone in Example 6 was prepared as in Example 2, and
was, therefore, aged tibolone.
"Example 6
[0038] Tibolone
as prepared as in example 2 was used as the active compound to prepare tablets
as described in example 4. The amount of
Org OM38 formed in several batches during storage was determined.
Table
3
|
The stability of six
tablet batches (1.25mg of Tibolone per 65mg) was assessed (storage at 25บC
and 60% relative humidity). The amount
of water incorporated in the basic granulate was varied from 6.0% to 6.5%
|
|
|
Storage
time (months)
|
Batch
No.
|
|
TD96.1128
|
TD96.1132
|
TD96.1133
|
162454001
|
162455001
|
162456001
|
|
|
Amount
of Org OM38 formed during storage (in percentage of the declared amount of
Tibolone)
|
|
0
|
0.7
|
0.5
|
0.5
|
0.9
|
0.8
|
0.9
|
|
6
|
1.3
|
1.1
|
1.1
|
1.8
|
1.7
|
1.8
|
|
12
|
1.8
|
1.5
|
1.6
|
|
|
|
|
18
|
2.0
|
1.5
|
1.7
|
|
|
|
|
Water
content of the basic granulate
|
6.5
|
6.5
|
6.5
|
6.3
|
6.1.
|
6.1
|
|
|
|
|
|
|
|
|
[68] The data in these Examples was the only material placed before
the court relevant to the issue of whether or not the ageing process was
effective to produce pure and stable tibolone.
In saying this, I put to one side the evidence of Dr Vrijhof, who was
called by Akzo and gave evidence that the ageing process had been observed to
work in practice. Objection was made to
his evidence, principally on the basis that there was no Record for it. In light of the fact that other witnesses had
spoken to the question of whether the ageing process worked, I would not have
rejected it simply on that ground.
However, Dr Vrijhof began to explain how, in his opinion, the process
worked. His evidence came after all the
experts had given their evidence, and was not foreshadowed by any Report or
statement either lodged in process or intimated to the other parties. I was concerned that evidence from him at
that stage as to the way in which the ageing process might work presented a
risk of re-opening the expert evidence.
I would, on that ground, have excluded that part of his evidence, but in
the event Mr Davidson accepted the validity of that concern and confirmed
that he placed no reliance on it. The
same concerns seem to me to apply to any detailed observation confirming the efficacy of the process - the
experts might have had something to say about that had they been given the
opportunity - and I propose to exclude such evidence also. What remains of Dr Vrijhof's evidence amounts
to little more than anecdotal evidence of his belief that the process works,
and whilst I repel the objection to its admissibility I do not think it proper
to place any reliance on it.
[69] Professor Pattenden, in his evidence, enthusiastically
supported Akzo's case that the ageing process worked. He considered that this conclusion was
supported by the data. He compared
Example 1 (un-aged) with Examples 2 and 3 (both aged). In Example 1, without the ageing step, the
level of OM38 was 0.6% after drying, whereas in Examples 2 and 3, with the
ageing step, it was only 0.1% and 0.2%.
So also, in the stress tests, the aged tibolone in Examples 2 and 3
performed much better than the un-aged tibolone in Example 1. Under stress tests,
the OM38 in the un-aged tibolone of Example 1 increased from 0.6% to 1.0%, an
increase of 0.4%. In the aged tibolone
of Example 2, the increase in OM38 was from ฃ0.1% to <0.2%, an increase of ฃ0.1%; whereas in Example 3 (also aged) it increased by 0.1%
(from 0.2% to 0.3%). Professor Pattenden
relied both upon the final reading for OM38 after the stress tests and also
upon the rate of continuing isomerisation during those tests. He attributed all aspects of the
better performance of Examples 2 and 3 to the introduction of the ageing
step. The differences in the initial
levels of OM38 in the Examples, and in the levels of OM38 after the tibolone
had undergone stress tests, he said, "are very significant and must reflect the
importance of the ageing process." He
also compared the results in the Tables in Example 5 (un-aged) with Example 6
(aged). The tablets of aged tibolone
(Example 6) gave better results in terms of OM38 content over the 24 month
period that those containing the un-aged tibolone. This too could be attributed to the ageing
process.
[70] Whilst Doctor Newton did not consider that the ageing process
worked, Doctor Widdowson, in his first Report, took up what appeared to be a
more qualified position. He said, at
para.14: "The 375 process offers no
explanation as to the nature of the ageing process but certain facts are
indicative of the probable role". In his
oral evidence, he qualified this by saying: "if it works at all". It was put to him in cross-examination that
he had shifted his position. I did not
think so. Taking his evidence as a whole,
it seemed to me that he had at no stage accepted that the ageing process
worked. He was simply speculating as to
how it might work, if it did.
[71] It is worth considering this point further at this stage. Doctor Widdowson's suggestion as to how the ageing
process might work was as follows: (a) the synthetic process which produces
tibolone is catalysed by a mild acid; (b) the isomerisation process to OM38 is
also acid catalysed but this is slow under the mildly acidic conditions used in
the synthesis; (c) Tibolone and OM38 are insoluble in water and are
precipitated initially by adding aqueous base to the reaction mixture - this
should also prevent the conversion to OM38 but the rapid precipitation of the
product brought about by the added water may occlude small amounts of the acid
catalyst in the crystals, thereby preventing the neutralisation of that
material by the base dissolved in the water which cannot penetrate the crystals
on the short time-scale of the work-up, even though the bulk of the acid, in
solution, is neutralised; (d) this occluded acid would explain the continued
slow conversion of tibolone to OM38 in the solid state and hence the shortened
shelf-life; (e) the ageing process, consisting of prolonged contact of the
product crystals with water containing a small amount of a base, therefore can
be interpreted as a leaching process for the slow removal of residual acid from
the crystals; (f) the extended shelf life of the product would then be a
consequence of the low to zero acid content of the crystals resulting from the
ageing process. Professor Pattenden
agreed with this explanation of the process.
He described it as like marinading meat or fish. His opinion was that the water leached out
the residual acid and, perhaps simultaneously, protected the keto group in the
tibolone until the bulk of the acid was removed. Dr Newton, for his part, was prepared to
agree that if the process worked then this leaching process was a possible
explanation of how it did. But this
involves further interpretation by the reader of the patent. The patent does not fully explain how the
acid catalyst is removed. One
possibility is that, after completion of the ageing process, the solvents are
simply evaporated off the wet crystals, leaving the acid on the outside of the
crystals where it will continue to have some, albeit reduced, effect. Another is that the wet crystal cake is
filtered to remove the bulk of the solvents and then dried by evaporation of
the residual solvents. A third
possibility, perhaps the most likely, is that the wet crystal cake is washed
with water to remove the acid solution and then filtered and dried by
evaporation. Whichever the explanation,
removal of the acid appears to be an essential part of the process.
[72] Over the course of the evidence there was considerable
discussion about whether, if it worked, the ageing process did so simply by
reducing the acid content in the tibolone crystals and slowing down the
formation of OM38; or whether it added something extra, and indefinable, which
helped achieve stability and the longer shelf life. In his report, Dr Widdowson concluded
his examination of the ageing process by stating his opinion that the extended
shelf life of the product would be a consequence of the low acid content of the
crystals resulting from the ageing process.
Professor Pattenden in his report appeared to agree with this. He confirmed his agreement in his
examination-in-chief. I sought
clarification and asked Professor Pattenden to confirm that he was saying that
the extended shelf life arises from the low acid content. He confirmed that the ageing process for its
own reasons leads to a product which has a very low amount of OM38. He continued:
"As a consequence of that low amount you are starting off with a very
good position. So, it should have an
extended shelf life." I then asked
him: "So, you could reach the lower mark
by some other route and still have this same extended shelf life?" His reply was: "That is my conclusion." In cross-examination, Mr Currie asked
Professor Pattenden if it was his position "that stability is always
described as a function of or in terms of chemical purity". Professor Pattenden responded: "They go hand in hand, yes." Although it is fair to say that
Professor Pattenden subsequently spoke in terms of the ageing process
achieving something more than mere purity of the tibolone, I did not accept
that it was shown that the extended shelf life was achieved other than by
achieving an initial purity in the tibolone.
Insofar as it is necessary for me to make any finding, I am satisfied on
the evidence before me that if the ageing process works - and I am not asked to
decide this - it does so only by reducing the acid content and thereby reducing
the rate of formation of OM38. This is
of some importance in the discussion that follows.
[73] Professor Pattenden's interpretation of
the Examples to which I have referred was the subject of criticism from both Dr
Newton and Doctor Widdowson. Doctor
Newton focused his attention on Examples 1-3.
He suggested that the results were not directly comparable because the
tibolone had not been treated in the same way.
In each of those Examples oxalic acid was used, which he described as
"fairly strong" (although he accepted Professor Pattenden's point that this
description was appropriate only in the context of organic acids). Twice as much acid was used in Example 1
(un-aged tibolone) than was used in Examples 2 and 3 (aged tibolone), and the
timings were different. He questioned
whether the different amounts of OM38 resulting from the process in Example 1
could really be ascribed to the ageing process.
In his opinion there was a direct correlation between the amount of acid
and the level of impurity. He qualified
this in is oral evidence, accepting Professor Pattenden's correction that it
was the acidity of the medium that was important rather than the absolute
amount of acid; and he accepted that there was no information in the Examples
as to the acidity of the media used.
However, he remained of the view that it was the reduction in the
concentration of the acid, rather than some unexplained feature of the ageing
process, which led to the purer product.
He noted in passing that Example 3, which was apparently a repeat of
Example 2, produced 0.2% OM38, which did not meet the levels in claim 3. This cast doubt upon the contention that the
process was capable of reliably producing material according to claim 3. The three Examples taken together suggested
that the process was not particularly robust or repeatable. Nor was Doctor Newton persuaded by Professor
Pattenden's interpretation of the results of the stress tests. The small increase in the OM38 content of
Examples 2 and 3 (aged tibolone) had been measured over only one week, whilst
the larger increase in that of Example 1 (un-aged tibolone) was measured over a
4-week period. If the process was
linear, that difference in time would account for the increase in the amount of
OM38. Professor Pattenden said that he
would have expected a faster rate of conversion to OM38 at the outset, tailing
off over time, but he did not produce any justification for this. The data in the Tables in the patent did not
help on the likely pattern of deterioration over the first 4 weeks, the
relevant period for consideration of Examples 1-3, though from Tables 5 and 6
it appears that over a period of months the rate does slow down.
[74] Doctor Widdowson made similar points in a
somewhat different way. He submitted
that the attempt to draw any conclusions from a comparison of the Examples in
the patent was flawed from the start.
There was no basic data enabling any such comparison to be made. Part of the problem was the difference in the
different batches of tibolone, in terms of their OM38 content, shown in the
patent. The different examples did not
bear meaningful comparison unless one knew the initial OM38 content. To carry out a proper experiment to see if
the ageing process worked, one should start with the same batch of tibolone and
split it three ways so as to remove the uncertainty as to possible differences
in the starting points of the material.
Thereafter, one part of the sample would undergo the ageing process;
another would be re-crystallised (this was important, if it was being said that
the ageing process gave an advantage in terms of purity and stability over
other methods of purification); and the third would be dried un-aged. The drying process would then be the same for
all three parts of the sample. The
initial OM38 content in the three examples could then be compared. Such an experiment would have to be repeated
on a number of occasions to provide robustness to the results. Without doing this, it was uncertain and
potentially misleading to rely upon a comparison of the three examples.
[75] A detailed examination of Examples 1 to 3
illustrates this point. In Example 1 the
crystals were dried under vacuum at 40ฐC. In Examples 2 and
3 they were subjected to the ageing process and then dried under vacuum at the
same temperature. The level of OM38
measured in Example 1 after drying was 0.6%.
But there is no information as to the level of OM38 before drying. It was common ground between the experts that
whatever the ageing process might do, if it did anything, it did not convert
OM38 back into tibolone. All one can
say, therefore, about the OM38 content before drying is that it could not have
been any higher at that stage, i.e. it must have been 0.6% or less. In Example 2, after ageing and drying,
tibolone was produced with ฃ0.1%
OM38. This means that before the sample
was subjected to the ageing process, the OM38 level in Example 2 was no higher
than 0.1%. Similarly, the OM38 level in
Example 3 before the ageing step was no higher than 0.2%. In his Supplementary Report, Professor Pattenden
assumed that the OM38 level in Example 1 at a similar stage, i.e. before
drying, would have been similar to the level in Examples 2 and 3, i.e. about
0.1-0.2%; and from this draws the conclusion that the OM38 content of the
un-aged tibolone in Example 1 increased markedly during the period up to the
end of the drying process, whereas that of the tibolone in Examples 2 and 3,
which underwent the ageing process, did not.
This would be an important observation if justified from the
material. But given the knowledge that
different batches of tibolone show markedly different OM38 content, that
observation could not be justified on the available information. It was, to my mind, pure speculation. While it is possible that Professor Pattenden
is correct that that the level of OM38 in Example 1 before drying only about
0.1-0.2%, it is equally likely, as Doctor Widdowson suggested, that it was 0.5%
or higher - in which case the increase in OM38 at the crucial period would be
similar for each sample.
[76] The criticisms to which I have referred in
para. [74] above bore also upon the comparison sought to be made between
Examples 5 and 6. But in this case the
objection about the lack of any comparison with tibolone which had been
purified by conventional methods was particularly relevant. The comparison was designed to show that the
ageing process produced tibolone having a greater stability over a 24-month
period. Yet the un-aged tibolone tested
in Example 5 had not been the subject of any conventional method of
purification such as re-crystallisation.
To compare the stability of aged tibolone only with that of un-aged and
unpurified tibolone is to run the risk of comparing apples with pears. If Akzo had wanted to show that the ageing
process produced tibolone not just of high purity but with some additional (as
yet unidentified) characteristic that made it more stable, the way to do that
would have been to test over the 24 month period aged tibolone against un-aged
tibolone that had been purified by a conventional method such as
re-crystallisation. Doctor Widdowson's
evidence, to which I have referred, that on any meaningful test one should
start with the same batch of tibolone and then treat it in the relevant different
ways, envisaged that one part of the batch would be re-crystallised. This evidence is in point here. No such comparison was done.
[77] Professor Pattenden was pressed in
cross-examination by Mr Campbell about the flawed methodology in attempting any
meaningful comparison between the un-aged and aged tibolone from the data in
the Examples set out in the patent. At
times he appeared to accept the criticisms, at least to the extent of
recognising that he would not have been happy with a paper submitted along
those lines had he been acting as the referee of a learned journal. Yet he did not appear to accept that these
matters in any way undermined his reliance upon a comparison of the
Examples. I have to say that I found
this aspect of his evidence unsatisfactory.
For whatever reason, and it may be that it simply stemmed from his
enthusiastic support for the ageing process, Professor Pattenden did not appear
to be as rigorous in his analysis of the results as one might have
expected. The criticisms of the exercise
of comparing the three examples which Dr Widdowson advanced were, to my
mind, obviously well founded; and, indeed, would have been apparent to any
reasonably informed and objective person seeking to see the limits of that
exercise. In the results, therefore, I
was unpersuaded by Professor Pattenden's evidence that a comparison of Examples
1-3 showed anything of value about the efficacy of the ageing process.
[78] I accept the validity of the criticisms
spoken to by Doctor Newton and Doctor Widdowson. I consider that Examples 1-3 are an
insufficient basis for the inference that the ageing process produced tibolone
of greater purity as compared either with "raw" un-aged tibolone or with
un-aged tibolone which had been purified by well-known methods. So also, I do not accept that the comparison
of the results set out in Tables 2 and 3 (Examples 5 and 6), whether
taken by themselves or together with a comparison of the results in
Examples 1, 2 and 3, was a sufficient basis for any inference that the
ageing process resulted in the production of tibolone which, in some other
(undefined) way had a greater stability or an increased shelf life (compared
with tibolone purified by conventional methods).
[79] A final point should be noted in connection with the results of
the tests shown in the Examples. Certain
of the results set out in Table 2 (Example 5) showed that some of the
claims in the patent were achieved with un-aged tibolone, even without
purification by a conventional means such as re-crystallisation. Thus, claim 9 of the patent is for a
dosage unit with tablets of less than 2.50mg of tibolone comprising less than
5% OM38 at a shelf life of 18 months.
Table 2 shows that all three batches of unaged tibolone in tablet
form (the tablets containing only 1.25mg of tibolone) were well within this
figure after 18 months. These same
results also meant that un-aged tibolone fell within claim 10. Two of the batches of un-aged tibolone tested
in Table 2 achieved claim 12, having a shelf life (i.e. the period
before the regulatory limit of 5% OM38 was reached) of two years. The three batches of unaged tibolone also met
the requirements of claim 13 (3% or less OM38 at a shelf life of
6 months). It should be added that
if Table 1 was for un-aged tibolone, then two of the batches tested met
claim 9 and also claims 12 and 13, and one satisfied claim 14. (If, on the other hand, that Table set out
results for aged tibolone, then some of the results from the samples in the two
left-hand columns did not satisfy certain of the claims in the patent.)
Evidence relating to the arguments on
anticipation
[80] A number of different issues were raised
by Arrow and Norton in developing their case that Claims 1-3 of the 375 patent
had been anticipated by the prior art.
The first, and in some ways the most straightforward, was something upon
which all the experts were agreed. This
was that there were well known techniques for purifying compounds such as
tibolone. Of these, the discussion
tended to concentrate on re-crystallisation.
It was accepted that if one re-crystallised tibolone one could achieve
purity levels consistent with those identified in Claims 1-3 of the
patent. This might involve two or more
re-crystallisations, but there was no dispute that the purity levels in those
claims could be achieved by this method.
Further, it was agreed that the crystallisation technique could work to
achieve the removal of acid from the tibolone.
It followed that tibolone with a low OM38 content and low levels of
acidity such as could be achieved by use of the ageing process could also be
achieved by re-crystallisation. Tibolone
of the purity claimed in Claims 1-3, for example, could be produced by the
re-crystallisation method. Further,
insofar as shelf life was a product of initial purity and a low level of
acidity, this too could be achieved easily by the re-crystallisation
process. Akzo argued that such
techniques were inefficient and produced a low yield. However, Professor Pattenden agreed with the
other experts that re-crystallisation could be carried out at production scale,
and he presumed that crystallisation was the process used, at any rate
originally, to produce livial. As I
understood his evidence, however, he drew a distinction between this and the
bulk production of pure tibolone achievable, as he would have it, by the ageing
process.
[81] Dr Newton discussed the question of
whether Claims 1-3 were anticipated by the prior art by reference to one of the
Examples in the 035 patent. There is no
doubt that this patent was part of the prior art. Although the 035 patent was concerned with
crystalline purity, the single crystals of 100% crystalline purity would also
be chemically pure. In terms of larger
scale production, Dr Newton referred to Example 5 of the 035 patent. In that Example, 5.0g of tibolone had been
dissolved in 50ml of ethyl acetate, to which a trace of pyridine had been
added, at 40ฐC. 300ml of hexane at about 35ฐC were added whilst stirring vigorously, after which
the mixture was cooled to 0ฐC
and stirred for a further 30 minutes.
The crystals were filtered and washed off with hexane at 0ฐC. This
produced a yield of 4.25g of form II (i.e. the triclinic form of tibolone) with
a polymorphic purity according to the DRIFT method of 100%. In his evidence, Dr Newton referred to experiments
carried out by Resolution Chemicals Ltd. ("Resolution") on 7 February
and 18
August 2003 ("the Resolution
experiments"). Those experiments had
followed Example 5 of the 035 patent, though on a larger scale. There had been minor differences in
temperature, he said, and the product was dried in vacuo, but in Dr Newton's opinion these differences did not
materially affect the experiment or invalidate the result. In each case the result of the experiment was
tibolone of a chemical purity which met the claims in Claims 1-3 of the 375
patent.
[82] Doctor Widdowson referred in his evidence
to the van Vliet paper, which described a synthesis of tibolone, i.e. a method
of producing tibolone from a precursor.
So far as concerned the 375 patent, only the final stage of the van
Vliet procedure, whereby tibolone is generated with only low levels of
iso-tibolone (OM38), was relevant. He
summarised this passage in his Report in the following way:
"(a) a
precursor ... is hydrolysed in aqueous ethanolic solution under mild acid
conditions to generate tibolone;
(b) the
tibolone and the by-products are precipitated from solution, and the acid
catalyst concurrently neutralised, by the addition of 5% aqueous sodium
hydrogen carbonade, a mild base;
(c) the
precipitated product is filtered, washed with water and dried;
(d) the
method of drying is unstated in the paper but normal practice is to remove the
residual solvent by placing the crystals in a vacuum oven and applying slight
warming if necessary;
(e) this
produces the crude product which was further purified by van Vliet by
crystallisation from di-isoropyl ether containing a little pyridine ...;
(f) the
resulting crystals had a melting point in accord with prior reports and were
shown to contain <1% iso-tibolone as judged by quantitative thin layer
chromatography ..., a technique still in use in 1998 but considered less accurate
than the analytical High Pressure Liquid Chromatography (HPLC) ..."
Doctor
Widdowson said that the reader of the van Vliet paper in 1986, as in 1998,
would have understood from that passage that, by carrying out that protocol,
tibolone could be produced with low levels of OM38.
[83] In order to test this, the protocol
described by van Vliet was re-run at the instance of Norton by Synnovation Ltd. Doctor Widdowson approved in advance the
protocol that Synnovation proposed to use.
This protocol was set out in a document called the "Notice of
Experiments". It proposed the use of
HPLC to determine the chemical purity of the product, and crystallisation of
the crude product for the final purification.
Doctor Widdowson said that this represented the steps that a skilled
person would have taken at the priority date of the 375 patent. Having reviewed the experiments carried out,
Doctor Widdowson concluded that direct crystallisation of the crude product
obtained by the van Vliet process was effective to produce tibolone with less
than 0.1% OM38. Further
re-crystallisation would reduce the OM38 content still further.
[84] According to Dr Newton, Claims 7 and 9-14
were all concerned with combinations of the compound and pharmaceutically
acceptable solid carriers, and they did not add anything. A skilled man would be well aware of the use
of tibolone in tablet form. Doctor
Widdowson put it even more robustly. He
said that although claims to pharmaceutical compositions fell outside his areas
of expertise, it seemed to him that once tibolone of sufficient purity had been
obtained in accordance with claims 1-3, "it would appear perfectly obvious to
use the material in a pharmaceutical formulation as claimed".
Arrow's submissions
[85] Arrow's case on Record attacked the validity of the claims not
only on grounds of lack of novelty (anticipation) and lack of inventive step
(obviousness), as in the case of the 035 patent, but also on the basis of
insufficiency. In developing his
argument under these heads, Mr Currie reminded me that tibolone had been
known since the 279 and 450 patents, and the process of producing tibolone was
acid catalysed. Its tendency to
isomerise into OM38 was also acid catalysed.
[86] In support of his case on anticipation, he advanced two
propositions: (1) that conventional methods for purification of organic
compounds are within the common general knowledge of the skilled man; and accordingly,
(2), that a document disclosing such a compound and its manufacture makes the
compound available to the public in all grades of purity - or at least all
grades of purity achievable by those conventional methods. The qualification to that second proposition
is mine, but I think is implicit in the two propositions taken together. As authority for this he cited two decisions
of the Technical Board of Appeal of
the EPO, Decisions T990/96 and T728/98.
The speech of Lord Hoffman in Merrell
Dow recognised that such decisions are of great persuasive authority. He submitted that, since tibolone had been
disclosed by the 279 and 450 patents.
Akzo were not entitled thereafter to patent tibolone of a particular
purity. Put another way, any claims to particular
levels of chemical purity have been anticipated by those earlier patents. Further, he submitted that the Resolution
experiments, involving a re-working of Example 5 of the 035 patent, produced
tibolone of the purity levels claimed in the 375 patent. On this basis also the claims to tibolone of
a particular chemical purity were anticipated.
[87] Turning to his case on obviousness, Mr Currie relied on Dr
Newton's evidence that claims 1-3, 7 and 9-14 would have been obvious to the
skilled man. The skilled man, he
submitted, was either a medicinal chemist or a process research chemist working
in the pharmaceutical industry. The
difference between the experts on this was really just a matter of emphasis. It would be the goal of any medicinal chemist
to avoid impurities occurring or to reduce them as much as possible. In the case of tibolone, a straightforward
recrystallisation would produce tibolone with less that 0.1% OM38, as would
other standard purification techniques such as HPLC. Separately, the correlation between the
amount of concentration of acid and the level of impurity in tibolone would
have been obvious to the skilled man. He
would seek to avoid or reduce the formation of OM38 by lowering the concentration
of acid used. He would also wash the
product to remove as much as possible of the acid, since residual acid would
encourage the continued formation of OM38 and reduce shelf life. Mr Currie pointed out that Professor
Pattenden had agreed that shelf life was a product of initial purity levels:
shelf life and stability go hand in hand.
It followed, he submitted, that claims 1-3 are anticipated, or
alternatively are obvious, and should be revoked. Claim 7 simply put the tibolone of the
requisite purity into a pharmaceutical compound. There was nothing inventive in this. Therefore claim 7 (and claim 8) stood or fell
with claims 1-3. Since shelf life was
simply a function of initial purity, claims 9-14 also stood or fell with claims
1-3.
[88] Mr Currie developed his case on insufficiency by
submitting, in accordance with Arrow's case on Record, that the specification
of the patent did not disclose the invention in claims 1-3 and 7-14 clearly
enough and completely enough for it to be performed by a person skilled in the
art across the whole width of the claims.
These claims were claims to a product, namely tibolone of varying
degrees of purity and stability for use in pharmaceutical compounds. According to the evidence, these products
could be made by a wide range of processes.
Yet the technical contribution revealed in the patent was only the
ageing process. It followed that the
claims to the product extended well beyond the technical contribution to the
art revealed by the patent. He referred
to Biogen Inc. v. Medeva plc [1997] RPC 1, 47, Merrell Dow (supra) at
p.82 and Pharmacia Corp. v. Merck (supra)
at p.798. If, however, the product claims were taken as
limited to tibolone produced by the ageing process, the patent was
insufficiently detailed to enable a skilled man to achieve the claimed
result. He referred to Edison and Swan Electric Light Co. v.
Holland (1889) 6RPC 243. None of the experts thought that the ageing
process was described in sufficient detail.
Norton's submissions
[89] For Norton, Mr Campbell developed his case by reference to
detailed written submissions. He adopted
much of what Mr. Currie had said. He
focussed first on the ageing process. This,
he said, was the only invention disclosed in the 375 patent. Whilst Norton did not concede that the ageing
process worked, or produced the benefits claimed in the patent, the efficacy of
that process was not challenged in these proceedings. There was no challenge in these proceedings
to claims 4-6 of the patent. However,
the claims in the patent went far beyond that ageing process. None of these claims could be justified, in
that none of them related to anything invented by Akzo in this patent. As it stands, the patent prevents competition
from others who seek to make or market tibolone and who might wish to use their
own methods of making tibolone of a particular purity. In the context of an old product, it was hard
to envisage how this could ever be justified by the invention of a new step in
the process of making an old product.
Mr Campbell also founded upon EPO jurisprudence to the effect that
once a product is revealed it is revealed in all degrees of purity, since
purification techniques (such as recrystallisation) are common practice and a
well-established part of basic practical chemistry. Simply to come up with a new step in making
or purifying tibolone could not justify a patent over the product itself. The most that Akzo could hope for was a
patent over the new process. There is no
sound basis for any of the product claims.
Akzo's patent over tibolone had now expired, but the effect of the
product claims, if not revoked, would be to resuscitate and prolong the life of
the old patent.
[90] If, contrary to the above, the tibolone produced by the ageing
process is claimed to have some special feature, then that special feature has
not been disclosed in the patent, neither in terms of what it is or how it
works or how it is obtained. No one can
know in the future whether or not they are infringing the patent. On this basis, all of the product claims would
be invalid for insufficiency of disclosure.
However, he submitted, there was no evidence that tibolone produced by
the ageing process had any special feature.
Professor Pattenden agreed with Dr Widdowson that if the ageing process
achieved anything, and Professor Pattenden thought that it did, it did so by
removing acid from the tibolone, and therefore had the same effect as
crystallisation. It did not create a
different product.
