HC 04 C02167
HC 04 C03986
Royal Courts of Justice
Strand, London, WC2A 2LL
B e f o r e :
| Ranbaxy UK Limited
||Claimant in 2059 and 2167
|Arrow Generics Limited
||Claimant in 3986
|- and -
David Kitchin QC and Michael Tappin (instructed by SJ Berwin) for Ranbaxy
David Kitchin QC and Mark Chacksfield (instructed by Forsyth Simpson) for Arrow
Hearing dates: 18-22, 25 July 2005
Crown Copyright ©
Mr Justice Pumfrey :
'633: legal principles
'Our client is considering whether to manufacture and/or import and/or sell atorvastatin calcium in the UK upon expiry of the data package exclusivity attaching to that pharmaceutical. The purpose of this letter is to ensure that our client's path is sufficiently cleared of patent issues prior to considering a launch and is sent pursuant to section 71 of the Patents Act 1977.
Our client's atorvastatin calcium will comprise the single optically pure enantiomer [R-(R*,R*)]-2-(4-f1uorophenyl)-(,(-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-lH-pyrrole-1-heptanoic acid, calcium salt trihydrate.
Our client requires acknowledgement from you that any acts including; manufacture, keeping, importing for disposal, sale and any other acts of the kind mentioned in Section 60 of the Patents Act 1977 and done in the United Kingdom would not constitute infringement of any of the claims of the '633 patent.'
"A compound of structural formula I
wherein X is -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH(CH3)-; R1 is 1-naphthyl; 2-naphthyl; cyclohexyl; norbornenyl; 2-, 3-, or 4-pyridinyl; phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl; trifluoromethyl; alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms; either of R2 or R3 is -CONR5R6 where R5 and R6 are independently hydrogen; alkyl of from one to six carbon atoms; 2-, 3-, or 4-pyridinyl; phenyl; phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms; and the other of R2 or R3 is hydrogen; alkyl of from one to six carbon atoms; cyclopropyl; cyclobutyl, cyclopentyl, cyclohexyl; phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl; trifluoromethyl; alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms; R4 is alkyl of from one to six carbon atoms; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or trifluoromethyl; or a hydroxy acid or pharmaceutically acceptable salts thereof, derived from the opening of the lactone ring of the compounds of structural formula I and having the formula X
where X, R1, R2, R3 and R4 are as defined above."
Principles of construction
The skilled person
The common general knowledge as to notation
Diastereoisomers do not generally have the same properties, and may be separated in reliance on that fact.
The importance of chirality
'15. For many years it has been recognised that the vast majority of drugs exert their activity by binding to a protein receptor to form a drug-receptor complex. Although there are exceptions, this process is usually readily reversible and does not generally involve the formation of covalent bonds. The drug receptor complex is formed by a combination of hydrogen bonds, p-p stacking between aromatic rings, salt bridge formation between carboxylic acids and amines and hydrophobic binding. The particular parts of a drug that cause it to bind to its receptor are together termed the pharmacophore. Since the protein receptors are composed of a complex array of chiral amino acids it follows that the drug's binding site is in a chiral environment (although the drug itself may or may not be chiral).
16. However, in circumstances where the drug substance does have an asymmetric carbon atom or atoms, the binding efficiency to a given receptor and therefore the biological activity of the enantiomers or diastereoisomers will be different. Within a chiral environment the two enantiomers of a racemate are totally different compounds and very often the majority of the biological activity observed for a racemate resides within a single enantiomer. Sometimes both the enantiomers of a racemate are biologically active but act at different receptors and cause different effects.
17. One of the most unfortunate and best known examples of this was the mild sedative and anti-emetic Thalidomide. The drug has an asymmetric centre but was marketed as the racemate. The R-isomer is a non-mutagenic sedative, whilst the S-isomer is mutagenic and caused widespread deformities amongst those children whose mothers took the drug during pregnancy …. Although this is a specific example, the principle was well understood by the skilled person at the 30 May 1986 priority date of the '633 Patent.'
The common general knowledge in relation to statins
It may be seen that the lactone ring in the top right of the structure is the same as the lactone ring of formula I of the patent. What is different is the substituent at the 6 position on that ring.
The disclosure of the specification
'The compounds of structural formula I above possess two asymmetric carbon centers, one at the 4-hydroxy position of the pyran-2-one ring, and the other at the 6-position of the pyran-2-one ring where the alkylpyrrole group is attached. This asymmetry gives rise to four possible isomers, two of which are the R-cis- and S-cis-isomers and the other two of which are the R-trans- and S-trans-isomers. This invention contemplates only the trans- form of the compounds of formula I above.'
i) The skilled person knew that compactin and mevinolin were potent anti-cholesterolaemics, and were single (R, R) enantiomers;
ii) He knew from Stokker that it was likely that all active compounds of this description would be single trans- enantiomers, the (R,R) enantiomers, the (S,S) enantiomers being likely to have no activity;
iii) He knew from his common general knowledge that a racemic mixture can be resolved into its component enantiomers. Professor Clive under cross-examination described this as a standard procedure, but not mindless. He put it like this (transcript pages 329-330):18 Q. … You have given evidence, and I am not going to go19 through it again, as to the teaching of the 633 patent, the20 specific examples of the 633 patent, which you say teach you21 to make a racemate.22 A. They do indeed.23 Q. The skilled man would not need to be told how to resolve that24 racemate if he wished to.25 A. The skilled man would know how to go about the business of2 resolving racemates.3 Q. You accept, as I understand it, that the skilled man reading4 the 633 patent would know that one enantiomer was likely to be5 more active than the other.6 A. That is correct.7 Q. Can I suggest to you that that would be a reason for any8 skilled addressee wanting to resolve the racemate that was9 produced by carrying out the teaching of 633.10 A. The way I put it on the other side of the Atlantic is that if11 somebody were given the 633 and told to do something helpful12 with it, they would immediately decide to do a resolution.13 Q. They do not need to be told to do it or how to do it.14 A. They would be motivated to do it and would have a high15 expectation of success. They might need to consult the16 literature on particular methods, but they would know the17 general drift of things.
The '281 patent
'7.5 In the case of a prior document, the lack of novelty may be apparent from what is explicitly stated in the document itself. Alternatively, it may be implicit in the sense that, in carrying out the teaching of the prior document, the skilled person would inevitably arrive at a result falling within the terms of the claim. An objection of lack of novelty of this kind should be raised by the examiner only where there can be no reasonable doubt as to the practical effect of the prior teaching…' (Guidelines for Examination Part C chapter IV)
Compound XII (see the reaction scheme on page 40 of the application) is the ring-opened hydroxy acid form of compound Ia. Then, at page 44, lines 33-5 '598 says that the preferred isomer of this invention is the 4R, 6R-isomer of the compounds of formulas I, Ia and XII. So far as compound Ia is concerned, this is atorvastatin in its lactone form, and so far as compound XII is concerned it is the carboxylic acid, which can either be made following the explicit reaction scheme, stopping before the lactone or, as the patent says, may be produced from the lactone compound of Formula Ia by conventional hydrolysis of the lactone compound of Formula Ia (page 43 line 11)
'In the ring-opened dihydroxy acid form, compounds of the present invention react to form salts with pharmaceutically acceptable metal and amine cations formed from organic and inorganic bases. The term "pharmaceutically acceptable metal salt" contemplates salts formed with the sodium, potassium, calcium, magnesium, aluminum, iron and zinc ions.'
(e) and if desired, converting the resulting
compound of Formula Ia to a hydroxy acid
corresponding to the opened lactone ring of
structural Formula Ia by conventional hydrolysis
and further, if desired, converting the hydroxy
acid to a corresponding pharmaceutically
acceptable salt by conventional means, and if so
desired, converting the hydroxy acid to
a compound of Formula Ia by heating in an inert solvent.
'4.1 Claim 1 of the present application is directed to the hemicalcium salt of a particular R-enantiomer of a 4-carboxamido substituted (,(-dihydroxy-1H-pyrrole-1-heptanoic acid showing hypocholesterolemic activity. ['633A], which is the state of the art acknowledged in the application as filed on page 1, line 10, refers to similar compounds having the identical hypocholesterolemic activity (column 7, line 33), notably the sodium salt of the racemate of the claimed enantiomer.
The Board considers, in agreement with the Appellant and the Examining Division, that this disclosure of ['633A] represents the closest state of the art and, hence, takes it as the starting point when assessing inventive step.
4.2 In view of this state of the art, the problem underlying the present application as submitted by the Appellant consists in providing a hypocholesterolemic compound having improved handling properties, in particular improved hygroscopicity and solubility.
4.3 As a solution to this problem the present application proposes the hemicalcium salt of the particular R-enantiomer as defined in claim 1.
4.4 To support his submission that the alleged improvement is achieved by the claimed invention, the Appellant referred to his experimental report filed on 20 June 2000. That test report comprises experimental data about the hygroscopicity and the solubility of the hemicalcium salt of the R-enantiomer according to the claimed invention, on the one hand, and of the sodium salt of the racemate of that enantiomer according to example 2 of ['633A], on the other….The Board is satisfied that the problem underlying the patent in suit as defined in point 4.2 above is successfully solved by the claimed subject-matter.
4.5 Finally, it remains to be decided whether or not the proposed solution to the problem underlying the patent in suit involves an inventive step.
['633A], i.e. the closest prior art document (see point 4.1 above) is directed inter alia to pharmaceutically acceptable salts of the racemates of 4-carboxamido substituted (,(-dihydroxy-1H-pyrrole-1-heptanoic acids having hypocholesterolemic activity. However, that document does not address the problem underlying the present application of improving the handling properties, in particular hygroscopicity and solubility, of hypocholesterolemic compounds. Thus, ['633A] neither gives any hint on how to solve that problem nor any incentive to modify those salts of the racemates into the hemicalcium salt of the particular R-enantiomer as defined in claim 1 in order to improve the handling properties thereof. Thus,['633A] does not point to the claimed solution proposed for solving the problem underlying the present application.'
'The ring-opened hydroxy acids of structural formula II above are intermediates in the synthesis of the lactone compounds of formula I and may be used in their free acid form or in the form of a pharmaceutically acceptable metal or amine salt in the pharmaceutical method of the present invention. These acids react to form pharmaceutically acceptable metal and amine salts. The term "pharmaceutically acceptable metal salt" contemplates salts formed with the sodium, potassium, calcium, magnesium, aluminum, iron and zinc ions. The term "pharmaceutically acceptable amine salt" contemplates salts with ammonia and organic nitrogenous bases strong enough to form salts with carboxylic acids. Bases useful for the formation of pharmaceutically acceptable non-toxic base addition salts of the present invention form a class whose limits are readily understood by those skilled in the art.'
'The present position was compendiously stated by Lord Diplock:
"The patents at any rate to the extent that they claim the products parahydroxy-penicillin and Amoxycillin respectively, are selection patents.
"The inventive step in a selection patent lies in the discovery that one or more members of a previously known class of products possess some special advantage for a particular purpose, which could not be predicted before the discovery was made (In re I. G. Farbenindustrie A.G.'s Patents (1930) 47 R.P.C. 283 per Maugham J at pp. 322/3). The quid pro quo for the monopoly granted to the inventor is the public disclosure by him in his specification of the special advantages that the selected members of the class possess." (Beecham Group Ltd. v Bristol Laboratories International S.A.  R.P.C. 521 AT 579.)"
My own opinion contains observations to a similar effect—l.c. p. 568.
That case was concerned not with any question as to validity, but with one arising under a contract, but it has been applied to a validity issue by the New Zealand Court of Appeal in a judgment dated 22nd December 1981. The general principle is now securely part of the law and needs no fresh discussion in the present case. I confine myself to such aspects as are necessary for our decision.
In the first place, in order to leave open a field for selection by a subsequent inventor, it does not matter whether the original field is described by formula or by enumeration. A skilled chemist could, in most cases, quite easily transform the one into the other and the rights of the subsequent inventor cannot depend upon the notation used. In the present case, the I.C.I. specification uses both a formula, and, to some extent, an enumeration: it does not matter to which one directs attention.
Secondly, the size of the initial group or class is not in itself decisive as to the question of prior publication of an invention related to a selected member or members. A selection patent might be claimed for one or several out of a class of 10 million (cf. I.G. Farbenindustrie A.G.'s Patents v.s. p. 321) or for one out of two (cf. the selection of one of two epimers of a synthetic penicillin combination). The size of the class may be relevant to a question of obviousness, and that question in turn may depend, in part, upon whether the later invention relates to the same field as that occupied by the prior invention, or to a different field. If an ordinary uninventive man would not be likely to look for the advantages he desires to produce in the area occupied by the prior invention a decision to do so may well amount to the beginning of an inventive step…'[my emphasis].
To prevent misunderstanding, it should be expressly emphasised that when examining so-called selection inventions as to novelty the Board adheres to the principle that the sub-range singled out of a larger range is new not by virtue of a newly discovered effect occurring within it, but must be new per se (cf. T12/81 BAYER/Diatereoisomers OJ EPO 8/1982 296 303). An effect of this kind is not therefore a prerequisite for novelty; in view of the technical disparity [sc. between the new class and the old] however, it permits the inference that what is involved is not an arbitrarily chosen specimen from the prior art, that is, not a mere embodiment of the prior description, but another invention (purposive selection)'
9.8 Problem-and-solution approach
In practice, in order to assess inventive step in an objective and predictable
manner, the examiner should normally apply the so-called "problem-and-
In the problem-and-solution approach, there are three main stages:
(i) determining the "closest prior art",
(ii) establishing the "objective technical problem" to be solved, and
(iii) considering whether or not the claimed invention, starting from the
closest prior art and the objective technical problem, would have
been obvious to the skilled person.
9.8.1 Determination of the closest prior art
The closest prior art is that combination of features, disclosed in one single
reference, which constitutes the most promising starting point for an obvious
development leading to the invention. In selecting the closest prior art, the
first consideration is that it should be directed to a similar purpose or effect
as the invention or at least belong to the same or a closely related technical
field as the claimed invention. In practice, the closest prior art is generally
that which corresponds to a similar use and requires the minimum of
structural and functional modifications to arrive at the claimed invention
(T 606/89, not published in OJ).
The closest prior art must be assessed from the skilled person's point of
view on the day before the filing or priority date valid for the claimed
In identifying the closest prior art, account should be taken of what the
applicant himself acknowledges in his description and claims to be known.
Any such acknowledgement of known art should be regarded by the
examiner as being correct, unless the applicant states he has made a
mistake (see VI, 8.5).
9.8.2 Formulation of the objective technical problem
In the second stage, one establishes in an objective way the technical
problem to be solved. To do this one studies the application (or the patent),
the closest prior art and the difference (also called "the distinguishing
feature(s)" of the invention) in terms of features (either structural or
functional) between the invention and the closest prior art and then
formulates the technical problem.
Features which cannot be seen to make any contribution, either independ-
ently or in combination with other features, to the solution of a technical
problem are not relevant for assessing inventive step (see T 37/82,
OJ 2/1984, 71 and T 294/89, not published in OJ). Such a situation can
occur for instance if a feature only contributes to the solution of a non-
technical problem, for instance a problem in a field excluded from patent-
ability (see T 931/95, OJ 10/2001, 441).
In the context of the problem-and-solution approach, the technical problem
means the aim and task of modifying or adapting the closest prior art to
provide the technical effects that the invention provides over the closest
prior art. The technical problem thus defined is often referred to as the
"objective technical problem".
The objective technical problem derived in this way may not be what the
applicant presented as "the problem" in his application. The latter may
require reformulation, since the objective technical problem is based on
objectively established facts, in particular appearing in the prior art revealed
in the course of the proceedings, which may be different from the prior art
of which the applicant was actually aware at the time the application was
filed. In particular, the prior art cited in the search report may put the
invention in an entirely different perspective from that apparent from reading
the application only.
The extent to which such reformulation of the technical problem is possible
has to be assessed on the merits of each particular case. As a matter of
principle any effect provided by the invention may be used as a basis for the
reformulation of the technical problem, as long as said effect is derivable
from the application as filed (see T 386/89, not published in OJ). It is also
possible to rely on new effects submitted subsequently during the proceedings
by the applicant, provided that the skilled person would recognise these
effects as implied by or related to the technical problem initially suggested
(see IV, 9.11 and T 184/82, OJ 6/1984, 261).
It is noted that the objective technical problem must be so formulated as not
to contain pointers to the solution, since including part of a solution offered
by an invention in the statement of the problem must, when the state of the
art is assessed in terms of that problem, necessarily result in an ex post
facto view being taken of inventive activity (T 229/85, OJ 6/1987, 237).
The expression "technical problem" should be interpreted broadly; it does
not necessarily imply that the solution is a technical improvement over the
prior art. Thus the problem could be simply to seek an alternative to a
known device or process providing the same or similar effects or which is