COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM THE HIGH COURT OF JUSTICE
CHANCERY DIVISION (PATENTS COURT)
The Hon Mr Justice Pumfrey
HC 04 CO2059 and HC 04 CO3986
Strand, London, WC2A 2LL
B e f o r e :
LORD JUSTICE JACOB
LORD JUSTICE NEUBERGER
| Ranbaxy (UK) Limited
|- and -
Arrow Generics Limited
for Ranbaxy (UK) Ltd
Andrew Waugh QC and Mark Chacksfield (instructed by Forsyth Simpson)
for Arrow Generics Ltd
Simon Thorley QC and Richard Meade (instructed by Bird and Bird)
for Warner-Lambert Company
Crown Copyright ©
Lord Justice Jacob: :
The '633 Patent and the claimed declaration of non-infringement
"A compound of structural formula I
" The tetrahedral arrangement of the covalent chemical bonds that a carbon atom may make with four other atoms means that if there are four different units at the ends of the four different bonds those units may be arranged in two different ways. When one says two different ways, it means that no amount of rotating will permit one arrangement to be superimposed on the other. They will be mirror images of each other, and are called enantiomers. This is shown in this diagram:
Figure 1. Enantiomers
 This is an attempt to show a tetrahedral structure. Conventionally the bonds depicted by single lines are in the plane of the paper: the bonds denoted by a solid wedge (a heavy line may also be used) are out of the paper and the bonds denoted by a dotted wedge (or dotted line) are into the paper. The picture shows two imaginary molecules with an asymmetric carbon atom C. A, B, X and Y denote different atoms or groups positioned at the apexes of the tetrahedron. Because the molecules are handed, they are called chiral, and the asymmetric carbon atom(s) they contain are called chiral centres. A molecule is an enantiomer if it cannot be mapped to its mirror image by rotations and translations alone.
 Enantiomers do not differ in any of their physical properties (melting point, boiling point and so on) but one, differing in their effect on plane polarised light. One enantiomer will rotate the plane of polarisation to the left or anticlockwise, and the other will rotate it to the right. A (+) or d- is conventionally used to denote the enantiomer which rotates the plane of polarisation to the right, and a (-) or l- is conventionally used to denote the enantiomer that rotates the plane of polarisation to the left.
 Alternatively, the absolute configuration of the molecule can be worked out according to certain rules. The result of applying the rules is a decision either that the molecule is right-handed (denoted R) or left-handed (denoted S).
 One enantiomer can only be synthesised in preference to the other if the stereochemistry is already present in the starting materials or if enantiomeric reagents are used. Unless the conditions for the reaction are stereospecific the result of the synthesis will inevitably be a 50/50 mixture of the two enantiomers of the chiral molecule. This is called a racemic mixture or racemate. There is no guarantee that the physical properties of the racemate will be the same as the physical properties of the individual enantiomers that go to make it up: for example the melting point may be higher, lower or the same. The racemate has no effect on plane polarised light, the mixture being precisely 50% (+) and 50% (-).
 Where there are two asymmetric centres in a molecule, there are unsurprisingly four possible isomers. Looking just at the chiral atoms, both may be mirror images of each other, and the molecules form an enantiomeric pair. If one only is a mirror image of the other, then the molecules are called diastereoisomers. Thus each molecule of the four will have one corresponding enantiomer and two corresponding diastereoisomers. To distinguish the diastereoisomers terminology describing the relative position of significant groups may be used. If the significant groups are on the same side of a ring, it is called a cis- structure, and if on the opposite sides of a ring, it is called a trans- structure:
Diastereoisomers do not generally have the same properties, and may be separated in reliance on that fact."
" Kirin Amgen v Hoechst Marion Roussel Limited  UKHL 46,  RPC 9 (page 169) paragraphs  to  summarises the modern approach. Extracting short passages may tend to distort the overall meaning of this passage, but from it, and from the approval that it gives to the judgment of Jacob LJ in Rockwater Ltd v Technip France SA  EWCA Civ 321,  RPC 6 at  (and by inference also to the slightly different statement in Mayne Pharma v Pharmacia  EWCA Civ 137 at ), I conclude that it is now clear that in deciding what the person skilled in the art would have understood the patentee to be using the language of the claim to mean, the court must approach the problem from the standpoint that the language chosen will be usually of critical importance. An over-meticulous analysis is one that is too willing to draw from a detailed analysis of the grammar, the punctuation and the particular words and phrases used inferences as to meaning that the words might support but which the skilled person would not draw, and it is the antithesis of giving to the words chosen in their context the meaning that the skilled person"
"a synthetic organic chemist who has got additional training and, in particular, additional training in the biological aspects of pharmaceutical action."
" Different enantiomers of a chiral molecule react differently with other chiral molecules. This is of particular importance in natural systems since enzymes, which are proteins responsible for all the chemical reactions carried out by the cell, are chiral molecules and are present only as a single enantiomer. I quote Dr Newton's report:
'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.'
 I understood the evidence to be that the skilled person at the priority date would expect that where a drug was a chiral molecule, it was highly likely that only one of the enantiomers and diastereoisomers (if any) would be responsible for its pharmaceutical activity. This did not mean, and does not mean, that chiral drugs had to be administered as single enantiomers but there is undoubtedly a modern tendency to prefer single enantiomers where resolution of the racemate is practicable."
" The other aspect of the common general knowledge which it is necessary to consider is the common general knowledge in respect of statins generally. By 1986, statins were a well-known class of compounds recognised as having a potential application for cholesterol-lowering drugs. The first statins, mevinolin and compactin, were natural products that existed as single enantiomers. Much work had been done on these compounds, and it was recognised that they had a 4(R)-trans- structure:
In compactin, R= H, and in mevinolin R=CH3.
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 document called Stokker ('3-Hydroxy-3-methylglutaryl coenzyme A Reductase Inhibitors' J Med Chem 1985 28, 347-358 also seems to have been accepted to be a document the skilled person would undoubtedly become aware of in doing any statin work, if not common general knowledge in the strict Beloit v Valmet sense, at the priority date. It reports a substantial statin study, and both Prof Clive and Dr Newton said that it disclosed that it was likely that all the activity lay in the 4(R)-trans- isomer.
 It was also known that the active form of the molecule was the open-chain hydroxy acid formed by hydrolysing the lactone ring. This acid can readily form salts, for example the sodium salt."
"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."
"The present invention is related to compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents. More particularly, this invention concerns certain [classes of compound] which are potent inhibitors of the enzyme [name set out] "
Some prior art is then acknowledged. It includes mevinolin and compactin. The final acknowledgement (of EP A 179559) is about a structure similar to that of Formula I but with different substituents in the 3 and 4 positions on the pyrroll (left hand) ring. The patent then says:
"the specification, however, does not mention the 3- or 4-carboxamido-substitution, which makes the compounds surprisingly more active."
This reflected the title of the patent itself: "Trans-6-[2-(3- or 4-Carboxamido-substiuted pyrrol-1-yl)-alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis. The heart of the teaching, submitted Mr Thorley, is that this particular substitution produces a surprising increase in activity. The emphasis is on what has been put onto the pyrrol ring, not the lactose ring (opened out or not). The centre of the teaching is about that, not about stereochemistry at all.
'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.' (p.48-12)
" In the '633 patent, it is absolutely clear from context throughout that formula (I) is being used to denote a racemate. In my judgment, every time the skilled person sees formula I or formula X he will see it with eyes that tell him that in that racemate, there is a single enantiomer that is the effective compound, and that he can resolve the racemate using conventional techniques to extract that enantiomer. When one comes to claim 1, which echoes the purpose of the invention with its conventional reference to pharmaceutically acceptable salts, he will, in my judgment, continue to see the formulae in this light."
i) The only method of production of the compounds described in the patent produces the racemate;
ii) The perception of the skilled man will be that the S,S-enantiomers will have no effect;
iii) So he will think the patentee cannot have intended to claim the S,S-enantiomers especially so since the patent opens with the promise that the invention is related to "potent" compounds.
iv) This is reinforced by the fact that if the patent indeed covered the S,S-enantiomers it would be invalid on the grounds of insufficiency ("invention not disclosed clearly enough and completely enough for it to be performed", s.72(1)(c) of the Patents Act 1977). Mr Waugh particularly relied on American Home Products v Novartis  RPC 159 and Pharmacia v Merck  EWCA Civ 1610;  RPC 775.
v) Since it is common ground that the skilled man would have known how to resolve the racemate, the patentee could readily have claimed the R,R- enantiomer explicitly. That he failed to do so would be taken by the skilled reader as a deliberate decision not to claim it.
vi) There would be good reason for limiting the monopoly claimed to the racemate. In particular the patentee had done no work with the enantiomer and had no data on it. Moreover at the date of the patent many chiral pharmaceuticals were in racemic form. So a monopoly over the racemate only would be of value.
"I take this opportunity of re-stating that if detailed and semantic analysis of words in a commercial contract is going to lead to a conclusion that flouts business commonsense, it must be made to yield to business commonsense"
Lord Hoffmann made it clear in Kirin at  that this applies equally to the construction of patent claims. It applies here.
[Talking about Stokker's discussion of the prior art compounds]  " both Prof Clive and Dr Newton said that disclosed that it was likely that all the activity lay in the 4(R)-trans- isomer"
"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" 
"the near certainty that only one enantiomer composing the racemate will matter" 
The validity of Patent EP (UK) 0409 281
" If I may summarise the effect of these two well-known statements, the matter relied upon as prior art must disclose subject-matter which, if performed, would necessarily result in an infringement of the patent It follows that, whether or not it would be apparent to anyone at the time, whenever subject-matter described in the prior disclosure is capable of being performed and is such that, if performed, it must result in the patent being infringed, the disclosure condition is satisfied. The flag has been planted, even though the author or maker of the prior art was not aware that he was doing so."
Although the rule is found in those old cases, it remains the rule under the European Patent Convention and the UK-see s.2(1) of the 1977 Act. You cannot monopolise that which forms part of the state of the art.
 But the prior disclosure must be construed as it would have been understood by the skilled person at the date of the disclosure and not in the light of the subsequent patent. As the Technical Board of Appeal said in T/396/89 UNION CARBIDE/high tear strength polymers  EPOR 312 at para 4.4:
'It may be easy, given a knowledge of a later invention, to select from the general teachings of a prior art document certain conditions, and apply them to an example in that document, so as to produce an end result having all the features of the later claim. However, success in so doing does not prove that the result was inevitable. All that it demonstrates is that, given knowledge of the later invention, the earlier teaching is capable of being adapted to give the same result. Such an adaptation cannot be used to attack the novelty of a later patent.'"
"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."
"The preferred isomer in this invention is the 4R,6R-isomer of the compounds of Formulas I, Ia and XII above"
" It follows that the material claimed in claim 1 is an expressly specified salt (calcium) of the preferred isomer of one of the three materials explicitly specified. If one is in any doubt, it is easy to compare the final structural formula on page 12 of '281 against formula XII on page 40 of '598. They are identical, save that in '281 the calcium salt, and in '598 the acid, are shown. In fact, the synthetic route described in '598 actually produces a racemate. But this time, the precise enantiomer (4R,6R) is specified. This notation means the same thing as the [R-(R*,R*] used in respect of the acid in claim 1 of '281. The evidence (which I have already discussed) was that resolution to obtain the enantiomers was common general knowledge. It is no answer to an allegation of anticipation that the specification gives clear and unmistakable directions to use the common general knowledge to produce a specific material."
That seems to me to be both elegant and clearly right.
Lord Justice Neuberger :
Lord Justice Chadwick: