Ranbaxy Australia Pty Ltd v Warner-Lambert Co LLC (No 2)
[2006] FCA 1787
•20 December 2006
FEDERAL COURT OF AUSTRALIA
Ranbaxy Australia Pty Ltd v Warner-Lambert Company LLC (No 2)
[2006] FCA 1787PATENTS - construction of patent - principles of construction - skilled addressee - composition of a team skilled in the relevant field of art - common general knowledge - patent not restricted to racemate
PATENTS - revocation of later patent – selection patent - whether patent obtained by false suggestion or misrepresentation - whether claimed invention is a patentable invention - whether claimed invention is a manner of manufacture within the meaning of Statute of Monopolies - whether claimed invention is useful
Patents Act 1990 (Cth) ss 3, 18(1), 18(1)(a), 18(1)(c), 138(3)(b), 234, Sch 1
Patents Act 1952 (Cth) ss 100(1)(d), 100(1)(e), 100(1)(h)
Patents Act 1903 (Cth)Welch Perrin & Co Pty Ltd v Worrel (1961) 106 CLR 588 applied
Interlego AG v Toltoys Pty Ltd (1973) 130 CLR 461 applied
Décor Corp Pty Ltd v Dart Industries Inc (1988) 13 IPR 385 applied
Fisher & Paykel Healthcare Pty Ltd v Avion Engineering Pty Ltd (1991) 22 IPR 1 cited
Fresenius Medical Care Australia Pty Ltd v Gambro Pty Ltd (2005) 67 IPR 230 cited
Pfizer Overseas Pharmaceuticals v Ely Lilly & Co (2005) 68 IPR 1 applied
Kirin-Amgen Inc v Hoechst Marion Roussel Ltd (2004) 64 IPR 444 applied
PhotoCure ASA v Queen’s University at Kingston (2005) 216 ALR 41 applied
Sachtler GmbH & Co KG v RE Miller Pty Ltd (2005) 221 ALR 373 applied
Clorox Australia Pty Ltd v International Consolidated Business Pty Ltd (2006) 68 IPR 254 applied
Nesbit Evans Group Australia Pty Ltd v Impro Ltd (1997) 39 IPR 56 cited
Root Quality Pty Ltd v Root Control (2000) 49 IPR 225 approved
The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited [1972] RPC 457 cited
NSI Dental Pty Ltd v University of Melbourne (2006) 69 IPR 542 approved
Aktiebolaget Hassle v Alphapharm Pty Ltd (2002) 212 CLR 411 cited
Minnesota Mining & Manufacturing Co v Beiersdorf (Aust) Ltd (1980) 144 CLR 253 approved
W R Grace & Co v Asahi Kasei Kogyo Kabushiki Kaisha (1993) 25 IPR 481 approved
Asahi Kasei Kogyo Kabushiki Kaisha v W R Grace & Co (1991) 22 IPR 491 cited
NutraSweet Australia Pty Ltd v Ajinomoto Co Inc (2005) 67 IPR 381 cited
Ranbaxy (UK) Ltd v Warner-Lambert Company [2006] EWCA 876 considered
Houssein v Under Secretary, Department of Industrial Relations and Technology (NSW) (1982) 148 CLR 88 cited
Wentworth v NSW Bar Association (1992) 176 CLR 239 cited
Bristol-Myers Squibb Company v FH Faulding and Co Limited (2000) 97 FCR 524 explained
FAI Traders Insurance Co Ltd v Savoy Plaza Pty Ltd [1993] 2 VLR 437 cited
Pfizer Inc v Ranbaxy Laboratories Limited 457 F3d 1284 (2006) considered
Ranbaxy UK Limited v Warner-Lambert Company [2005] EWHC 2142 cited
Pfizer Inc v Ranbaxy Laboratories Ltd 405 FSupp2d 495 (D Del 2005) cited
Pfizer Canada Inc v The Minister of Health [2006] FC 1471 cited
Commissioner of Patents v Microcell Ltd (1959) 102 CLR 232 applied
NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd (1995) 183 CLR 655 applied
NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd (1993) 44 FCR 239 applied
ICI Chemicals & Polymers Ltd v The Lubrizol Corporation Inc (2000) 106 FCR 214 cited
Advanced Building Systems Pty Limited v Ramset Fasteners (Aust) Pty Limited (1998) 194 CLR 171 considered
National Research Development Corporation v Commissioner of Patents (1959) 102 CLR 252 applied
Sunbeam Corporation v Morphy-Richards (Aust) Pty Ltd (1961) 180 CLR 98 considered
Merck & Co Inc v Arrow Pharmaceuticals Ltd (2006) 68 IPR 511 considered
Wm Wrigley Jr Company v Cadbury Schweppes Pty Ltd (2005) 66 IPR 298 considered
Prestige Group (Australia) Pty Ltd v Dart Industries Inc (1990) 19 IPR 275 approved
JMVB Enterprises Pty Ltd v Camoflag Pty Ltd (2005) 67 IPR 68 approved
Rehm Pty Ltd v Webster’s Security Systems (International) Pty Ltd (1981) 81 ALR 79 applied
Old Digger Pty Ltd v Azuko Pty Ltd [2000] FCA 676 approved
Alsop’s Patent (1907) 24 RPC 733 approved
Lane-Fox v Kensington & Knightsbridge Electric Lighting Co Ltd [1892] 3 Ch 424 cited
Hatmaker v Joseph Nathan Co Ltd (1919) 36 RPC 231 cited
IG Farbenindustrie AG’s Patents (1930) 47 RPC 289 applied
May & Baker Ltd v Boots Pure Drug Co Ltd (1948) 65 RPC 255 approved
E.I. Du Pont Nemours & Co (Witsiepe’s) Application [1982] FSR 303 cited
Badische Anilin Und & Soda Fabrik v Levinstein (1887) 4 RPC 449 approvedTA Blanco White, Patents for Inventions, 5th edn, Stevens & Sons, London, 1983
Terrell on the Law of Patents, 14th edn, ed D Young et al, Sweet & Maxwell, London, 1994
RANBAXY AUSTRALIA PTY LTD (ACN 110 871 826) v WARNER-LAMBERT COMPANY LLC AND COMMISSIONER OF PATENTS
VID 926 OF 2005YOUNG J
20 DECEMBER 2006
MELBOURNE
IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY
VID 926 OF 2005
BETWEEN:
RANBAXY AUSTRALIA PTY LTD (ACN 110 871 826)
Applicant/Cross-RespondentAND:
WARNER-LAMBERT COMPANY LLC
First Respondent/Cross-ClaimantCOMMISSIONER OF PATENTS
Second Respondent
JUDGE:
YOUNG J
DATE OF ORDER:
20 DECEMBER 2006
WHERE MADE:
MELBOURNE
THE COURT ORDERS THAT:
1.Australian Letters Patent No 628198 be revoked.
2.The cross-respondent, Ranbaxy Australia Pty Ltd, whether by itself, its directors, officers, servants or agents or otherwise, be restrained during the term of Australian Letters Patent No 601981, and any extension of that term, from infringing claims 1 to 4 (inclusive), 8 and 9 of that patent by importing into Australia, or selling or supplying in Australia, any pharmaceutical product containing atorvastatin calcium as its active ingredient.
Note: Settlement and entry of orders is dealt with in Order 36 of the Federal Court Rules.
IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY
VID 926 OF 2005
BETWEEN:
RANBAXY AUSTRALIA PTY LTD (ACN 110 871 826)
Applicant/Cross-RespondentAND:
WARNER-LAMBERT COMPANY LLC
First Respondent/Cross-ClaimantCOMMISSIONER OF PATENTS
Second Respondent
JUDGE:
YOUNG J
DATE:
20 DECEMBER 2006
PLACE:
MELBOURNE
REASONS FOR JUDGMENT
The first respondent, Warner-Lambert Company LCC (‘Warner-Lambert’) is the owner of two Australian patents: patent number 601981 (‘the 981 Patent’) which commenced on 18 May 1987, with a priority date of 30 May 1986; and patent number 628198 (‘the Enantiomer Patent’) which commenced on 23 July 1990, with a priority date of 21 July 1989. The named inventor in each patent is Bruce Roth.
Warner-Lambert is part of the Pfizer group of companies. Both the 981 Patent and the Enantiomer Patent profess to claim patent protection over ‘atorvastatin calcium’, the active ingredient in the prescription drug marketed in Australia by the Pfizer group of companies under the pharmaceutical product name ‘Lipitor’.
Lipitor is prescribed to patients suffering from hypercholesterolemia (high levels of cholesterol in the blood) to lower the level of cholesterol in the blood and thereby reduce the incidence of cardiovascular disease. It does this by inhibiting the activity of HMG-CoA reductase, an enzyme which is instrumental in the natural synthesis of cholesterol in the body.
Cardiovascular disease is a leading cause of death in Australia and, according to statistics published in 2004, accounted for 38 per cent of all deaths in Australia for that year. It is estimated that the incidence of cardiovascular disease today is at a similar level to that in 2004. Lipitor is the most widely prescribed cholesterol inhibiting drug in Australia.
The applicant, Ranbaxy Australia Pty Ltd (‘Ranbaxy’), is the Australian subsidiary of a pharmaceutical company based in India. In 2004, Ranbaxy applied to the Therapeutic Goods Administration (‘TGA’) to register in Australia a pharmaceutical product for the treatment of hypercholesterolemia, the active ingredient of which is atorvastatin calcium (‘the Ranbaxy Product’). TGA registration has not yet been obtained and the Ranbaxy Product is not yet on the market in Australia.
Warner-Lambert seeks a permanent injunction restraining Ranbaxy, during the term of the 981 Patent as extended, from infringing the 981 Patent, and during the term of the Enantiomer Patent as extended, from infringing the Enantiomer Patent.
Ranbaxy has agreed to undertakings by which it will refrain from importing into Australia and selling any pharmaceutical composition containing as its active ingredient the compound known as ‘atorvastatin calcium’ until the final decision of the Court in this matter.
The Commissioner of Patents did not seek to be heard in these proceedings.
the issues
The 981 Patent
There is no challenge to the validity of the 981 Patent. The issue is essentially one of construction.
Ranbaxy contends that structural formula I, which appears in claim 1 of the patent, when properly construed refers only to the racemate form of the compounds of the invention. A racemate is an equal mixture of right (R) and left (S) enantiomers. The parties agree that, as a matter of common general scientific knowledge, an individual enantiomer can have a very different interaction with a biological system than its enantiomeric pair, or the racemate which contains both the R and S enantiomers. A detailed explanation of these terms is given below.
It follows, so Ranbaxy contends, that all claims of the 981 Patent should be restricted to the racemate form of the compounds of the invention. In contrast, the Enantiomer Patent claims only the R enantiomer. Accordingly, Ranbaxy contends that the Ranbaxy Product, which is the R enantiomer of atorvastatin calcium, will not infringe the 981 Patent.
Warner-Lambert, on the other hand, argues for a wider construction of structural formula I. It contends that structural formula I, and therefore the claims of the 981 Patent, refers to all of the following forms of the compounds of the invention:
·the racemate (or racemic mixture);
·the R-trans enantiomer, individually;
·the S-trans enantiomer, individually; and
·unequal mixtures of the R-trans and S-trans enantiomers.
On the basis of this wider construction, Warner-Lambert alleges by its amended defence and cross claim dated 17 May 2006, that Ranbaxy’s intended importation and sale of the Ranbaxy Product will infringe claims 1 to 4, 8 and 9 of the 981 Patent.
The Enantiomer Patent
Ranbaxy challenges the validity of the Enantiomer Patent, and seeks revocation of the patent under s 138(3) of the Patents Act 1990 (Cth) (‘the 1990 Act’) on the following grounds:
·the alleged invention as claimed in each claim of the Enantiomer Patent is not a patentable invention within the meaning of s 18(1) of the 1990 Act because it is not a manner of manufacture within the meaning of s 6 of the Statute of Monopolies 1623;
·the Enantiomer Patent was obtained by false suggestion or misrepresentation and is therefore liable to be revoked pursuant to s 138(3)(d) of the 1990 Act;
·the alleged invention as claimed in each claim of the Enantiomer Patent is not a patentable invention within the meaning of s 18(1)(c) of the 1990 Act because it is not useful.
In its amended statement of claim dated 26 April 2006, and in its particulars of invalidity dated 10 August 2005, Ranbaxy also raised issues of novelty, inventive step and fair basis as grounds of invalidity of the Enantiomer Patent. However, in its opening submissions to this Court, Ranbaxy abandoned those grounds. The narrowed grounds of invalidity are reflected in amended particulars of invalidity dated 9 October 2006.
By its amended defence and cross claim dated 17 May 2006, Warner-Lambert alleges that Ranbaxy’s intended importation and sale of the Ranbaxy Product will infringe claim 6 of the Enantiomer Patent.
Background Chemistry
Fundamental principles of stereochemistry lie at the heart of the technical terms that appear in the patents which are the subject of these proceedings. These principles require some explanation. The terminology, and the visual conventions that I have used in representing structural formulae, are the same as those appearing in the 981 Patent and the Enantiomer Patent. My summary of the relevant principles is based on the Agreed Technical Primer prepared by the parties and the evidence given by the expert witnesses in this case.
Stereochemistry is the study of the three-dimensional structure of molecules, the smallest unit of a compound. Isomers are compounds that have the same chemical formula (that is, the same number and type of atoms) but differ in the connection or arrangement of atoms in the molecule. Isomers that differ in the way they are connected are known as ‘structural isomers’. This can be illustrated figuratively by an example that depicts structural isomers for C4H10, where ‘C’ denotes the element carbon, and ‘H’ the element hydrogen.
Figure 1
Stereoisomers are another type of isomer. They are compounds with the same chemical formula but they differ in the precise arrangement of the atoms in space. The three-dimensional structure of molecules can be represented by structural formula in which a series of symbols are used to represent the orientation of the atoms in space: — (dash) refers to bonds in the plane of the page; (wedge) refers to bonds coming out of the plane of the page; and or ---- (broken lines/hashed lines) refer to bonds that go behind the plane of the page.
When a carbon atom bonds with four non-identical atoms or groups of atoms it forms a tetrahedral shape and can be arranged three-dimensionally in two different ways. These three-dimensional arrangements are non-superimposable mirror images of each other, in the same way that a left hand and a right hand are non-superimposable mirror images. Any physical object that exists in left and right-handed forms, that is, whose mirror image is not identical with itself, is said to be ‘chiral’ (which derives from the Greek word for ‘hand’).
Chirality and enantiomers
Taking the example of a carbon atom bonded with four non-identical atoms or groups of atoms to form a tetrahedral shape, the carbon atom is said to be the chiral centre of the molecule. The mirror images of the chiral centre are not superimposable. Stereoisomers which are non-superimposable mirror images are called enantiomers. This is shown in Figure 2 below:
Figure 2
In Figure 2, (a) and (b) are enantiomers as they are non-superimposable mirror images. In each enantiomer, the carbon atom is the chiral centre.
Pairs of enantiomers have many of the same chemical and physical properties, such as identical melting points and the same solubilities and colours. However, they can be differentiated from one another based on the effect they have on the rotation of polarised light. When polarised light is passed through a solution containing only one enantiomer of a compound, the plane of polarised light is rotated either in a clockwise direction (right, denoted with a ‘(+)’ or ‘d-’) or in an anti-clockwise direction (left, denoted with a ‘(-)’ or
‘l-’). Because of their ability to rotate the plane of polarised light, enantiomers are said to be ‘optically active’. They are sometimes referred to as ‘optical isomers’.
To distinguish between different enantiomers of the same compound, chemists assign absolute stereochemistry at the chiral centre according to a naming system, known as the Cahn-Ingold-Prelog priority rules. For the purpose of these reasons for judgment, it is sufficient to say that these priority rules require the atoms attached to the carbon centre to be ranked according to their atomic number: the higher the atomic number, the larger the atom in three-dimensional space, and therefore the higher the priority. It is this ranking which will ultimately determine whether the chiral centre has an ‘R’ configuration (from the Latin word ‘rectus’), which has a clockwise arrangement of atoms from highest to lowest priority, or an ‘S’ configuration (from the Latin word ‘sinister’) which signifies an anti-clockwise arrangement of atoms.
Figure 3
In Figure 3, absolute stereochemistry has been assigned according to the Cahn-Ingold-Prelog priority rules, where atom ‘1’ has the highest priority (highest atomic number) and atom ‘4’ the lowest priority (and therefore the lowest atomic number).
An enantiomer with absolute stereochemistry or configuration of ‘R’ will not necessarily rotate polarised light in a clockwise direction. Likewise, an enantiomer with absolute stereochemistry of ‘S’ will not necessarily rotate polarised light in an anti-clockwise direction. The designation of (+) or (-) must be determined through testing the enantiomer. There is no correlation between the absolute stereochemistry or configuration of an enantiomer and the (+) or (-) designations.
Another way in which enantiomers can be distinguished from one another is the manner in which they interact with other chiral molecules. As noted above at [10], an individual enantiomer may have a different interaction with other chiral molecules when compared to a racemate or racemic mixture which contains both the R and S enantiomers. The importance of chirality in biological systems is discussed below.
Racemates or racemic mixtures
A chemical reaction normally produces a mixture of equal amounts of enantiomers. This equal mixture of R and S enantiomers is called a ‘racemate’ or ‘racemic mixture’. These expressions are now regarded as synonyms. The physical properties of a racemic mixture can vary significantly from the individual enantiomers that make it up. A racemic mixture may be denoted by ‘(±)’, ‘dl’ or ‘(rac)’. The naming conventions for racemates and their diagrammatical representations are discussed in more detail below.
A chemist may obtain a product containing only the R or S enantiomer by one of two methods. First, the chemist may undertake a method known as ‘chiral synthesis’. In chiral synthesis, chiral starting materials or reagents (that is, starting materials or reagents that are R or S) are used in the reaction to produce a product with a predominance for one hand of the enantiomeric pair. Secondly, the chemist may undertake a synthesis without using chiral reagents to produce a racemate or racemic mixture (this type of synthesis is known as ‘achiral synthesis’), and then separate the racemate into its two optically active enantiomers by ‘resolving’ each of the enantiomers.
A racemate can be resolved into its individual enantiomers by a laboratory technique known generally as ‘column chromatography’. For present purposes, it is sufficient to describe column chromatography as a technique whereby a vertical glass or metal column is filled with some form of solid support, and the racemate solution to be separated is placed on top of this support. The rest of the column is filled with a solvent which, under the influence of gravity, moves the racemate solution through the column. The solid support causes the individual enantiomers to pass through the column at different speeds, or can retain one enantiomer on the column while allowing the other enantiomer to pass through the column. In this way, the individual enantiomers can be isolated and separated from one another. By then testing each eluted solution for the rotation of polarised light, the enantiomers can be identified as either the (+) or (-) enantiomer.
Column chromatography encompasses a number of laboratory techniques including ‘flash column chromatography’ and ‘high pressure liquid chromatography’, also known by its abbreviation ‘HPLC’. For the purposes of this decision, it is not necessary for me to give any further description of these techniques beyond identifying them.
The products obtained from chiral synthesis, or from the resolution of racemate solutions, may not be enantiomerically pure, ie they may contain contamination of the other enantiomer. The level of impurity will vary depending on the synthesis method employed and/or the technical laboratory skills of the chemist.
Molecules which have more than one chiral centre
Where a molecule has two chiral centres there are four possible isomers. Relative stereochemistry describes the position of substituents of a compound relative to each other. Where both the major substituents lie on the same side of the plane of reference this is called a ‘cis’ arrangement. Where the major substituents appear on the opposite sides of the ring, this is called a ‘trans’ arrangement. This is best set out in diagrammatic form:
Figure 4
In Figure 4(a), groups ‘Z’ and ‘X’ are on the same side of the ring; whereas in Figure 4(b) they are on opposite sides of the ring. A carbon ring containing two chiral centres, as in Figure 4, gives rise to four possible isomers. If the isomers are not mirror images of one another, then the isomers are called ‘diastereomers’. The isomers depicted in (a) and (b) are diastereomers, that is, they are not mirror images of each other.
Where both chiral centres are mirror images of one another, the isomers form an enantiomeric pair:
Figure 5
In Figure 5, (a) and (b) have the same relative stereochemistry (that is, both enantiomers are in the trans form), but different absolute stereochemistry. Likewise, (c) and (d) have the same relative stereochemistry (that is, both enantiomers are in the cis form), but different absolute stereochemistry.
The importance of chirality
Many molecules in biological systems are chiral. Enzymes are an example of a chiral molecule occurring in a biological system. While enantiomers share many identical physical and chemical properties with their enantiomeric pair, they may interact with other chiral molecules, such as enzymes, in very different ways.
Enzymes, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), are capable of ‘selecting’ one enantiomer for biological interaction or, at the least, can display a preference for activity with one enantiomer of an enantiomeric pair over the other. During re-examination, one of the expert witnesses explained the particular relevance of enzyme chirality:
‘An enzyme is a particular sort of protein and it has an active site that has a function and we are dealing in this case with an enzyme target. So the enzyme site is very specifically designed… it has a very specific shape that will generally only accurately recognise what it’s designed to react with.’
As a consequence of this ‘selective’ activity or preference for activity, one enantiomer of an enantiomer pair may have most or all of the biological activity when interacting with enzymes, while the other has little activity or in some cases no biological activity. In other cases, the other (less active or inactive) enantiomer may have a very different type of biological activity altogether. This point is commonly illustrated by giving the example of thalidomide, as one expert witness did:
‘Thalidomide is an example of a drug where the two enantiomeric forms of the compound have different and unpredictable activities. Thalidomide is a sedative drug that was produced and sold in the 1950’s and 1960’s as a racemic mixture (ie an equal mixture of two enantiomers). A side effect, not detected in the course of testing and clinical trials, was that the drug acted as a teratogen and caused birth defects when it was taken by pregnant women. After the drug was withdrawn from market, it was discovered that only one of the two enantiomers had teratogenic activity. The other was an effective and (unless some interconversion occurred, which in practice did occur) a theoretically safe sedative.’
Nomenclature
There are a number of ways to describe the R-trans and S-trans enantiomers in stereochemistry nomenclature. Taking the R enantiomer as an example, witnesses and documents variously referred to ‘RR’, ‘R-trans’ and simply ‘R’. On occasions, the evidence contains terms such as ‘4R,6R’. The numerals refer to the position of the groups on the ring. In these reasons for judgment, I have used the words ‘RR’ wherever the context permits, but in some places the use of other expressions is unavoidable, such as where the evidence under discussion uses the terminology of ‘R-trans’ or simply ‘R’.
Structural formulae
Chemists sometimes use shorthand to draw the structure of molecules. In shorthand, hydrogen atoms are not shown at all, and the structure is reduced to the linkage of carbon atoms. The carbon atoms are represented by points at which each of the line segments meet or terminate. The line segments represent the bonds between carbon atoms. This shorthand is illustrated in Figure 6.
Figure 6
This figure shows three ways of drawing the structure for the same molecule. Structure (a) shows a complete representation of the molecular structure. Structure (b) shows a ‘condensed’ version of the molecular structure showing the ‘groups’ at each carbon. The bonds with the hydrogen atoms are not shown but are implicit from their grouping with the respective carbon. Structure (c) shows the simplest shorthand version of the structure.
Atorvastatin
Atorvastatin is a member of a class of drugs known by the generic term ‘statin’. Other members of the ‘statin’ class include simvastatin, pravastatin, lovastatin and fluvastatin. The drawing in Figure 7 below depicts the lactone form of atorvastatin.
Figure 7
The lactone is the six-membered ring at the right-hand side of Figure 7 where one of the six members is oxygen.
The lactone is shown in more detail in Figure 8. The members identified in the ring from ‘2’ to ‘6’ are all carbon atoms. Position 1 is an oxygen atom. The groups attached to the pyrrole ring (the five-membered ring where four of the members are carbon and one of the members is nitrogen ‘N’) are simplified to ‘R1’, ‘R2’, ‘R3’, and ‘R4’ for ease of reference.
Figure 8
The active ingredient in Lipitor, atorvastatin calcium, is the calcium salt of the atorvastatin hydroxy acid. Atorvastatin hydroxy acid is formed by opening the lactone ring. This is achieved by hydrolysis, ie by adding water. The opened structure is shown in Figure 9.
Figure 9
The 981 Patent Specification
The 981 Patent is entitled ‘TRANS-[2–(3–OR 4–CARBOXAMIDO–SUBSTITUTED PYRROL–1–YL)ALKYL]–4–HYDROXYPYRAN–2–ONE INHIBITORS OF CHOLESTEROL SYNTHESIS’. It discloses a class of compounds that have the ability to inhibit HMG-CoA reductase, which is the rate-controlling enzyme involved in biosynthesis of cholesterol.
In the summary of the invention in the specification, the class of compounds is described as certain trans–6–[2–(3–or 4–carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran–2–ones and the corresponding ring-opened hydroxy acids derived therefrom which are potent inhibitors of the enzyme HMG-CoA reductase, pharmaceutical compositions containing such compounds, and a method of inhibiting the biosynthesis of cholesterol by employing such pharmaceutical compositions.
The structural formula for the class of compounds is set out diagrammatically at pg 3 and other places in the specification, including claim 1:
Structural formula I is a partial structure in which annotations X, R1, R2, R3 and R4 are used to denote positions on the compound where a range of substitutions may occur. The annotations R1, R2 etc have no relationship to the system of assigning absolute stereochemistry at a chiral centre.
The molecule depicted in structural formula I consists of two structural parts: a heterocyclic moiety in the form of a five-membered pyrrole ring at the left-hand side of the diagram which includes a number of possible substituents (R1, R2, R3 and R4); and a six-membered lactone ring on the right-hand side of the diagram. The two moieties are joined by a ‘linkage’ group (shown as X).
The lactone ring has two major substituents, a hydroxy group (the OH group shown at the top of the ring); and the linkage group (X attached to the pyrrole ring). These two major substituents are in a trans relationship, that is to say, the hydroxy group is above the plane of the lactone ring (denoted by ) and the linkage group is below the plane of the lactone ring (denoted by ).
The specification concludes with ten claims that define the invention. Claim 1 is a claim for a compound of structural formula I ‘or a hydroxy acid or pharmaceutically acceptable salts thereof, derived from the opening of the lactone ring of the compounds of structural formula I ...’. Claims 2 to 7 are dependent product claims. Claim 8 is for a pharmaceutical composition containing as its active ingredient a compound of claim 1. Claim 9 is for a method of inhibiting cholesterol biosynthesis by administering a pharmaceutical composition of claim 8. Claim 10 is for a method of preparation of a compound having structural formula I.
The claims alleged to be infringed are claims 1, 2, 3, 4, 8 and 9. As the claims are limited by reference to structural formula I, the dispute on infringement of the 981 Patent turns on the construction of claim 1.
The specification commences with a discussion of the background of the invention:
‘The present invention is related to compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents. More particularly, this invention concerns certain trans-6-[2-(3- or 4-carbox-amidosubstituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and the corresponding ring-opened acids derived therefrom which are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase), pharmaceutical compositions containing such compounds, and a method of inhibiting the biosynthesis of cholesterol employing such pharmaceutical compositions.’
The specification then adds that high levels of blood cholesterol and blood lipids are conditions involved in the onset of arteriosclerosis and that it is well known that inhibitors of HMG-CoA reductase are effective in lowering the level of blood plasma cholesterol, especially low density lipoprotein cholesterol, so as to afford protection from cardiovascular disease.
The specification describes certain known inhibitors of the biosynthesis of cholesterol, including mevalonic acid and the corresponding ring-closed lactone form, mevalonolactone, and a natural product, now called compactin, which was disclosed in several United States patents. The specification describes compactin as having a complex structure which includes a mevalonolactone moiety.
The specification then refers to several other United States patents and a patent application. The United States patents to Oka and Mitsue are said to disclose derivatives of mevalonolactone having antilipidemic activity and are useful in the treatment of hyperlipidemia. United States Patent 4,375,475 to Willard et al (‘the Willard Patent’) is said to disclose certain substituted 4-hydroxytetrahydropyran-2-ones which, in the 4(R)-trans-stereoisomeric form, are inhibitors of cholesterol biosynthesis.
Published PCT application WO 84/02131 (which subsequently resulted in the grant of a patent to Kathawala) is said to disclose certain derivatives of mevalonolactone having utility as hypolipoproteinemic and antiatherosclerotic agents.
Under the heading ‘Summary of the Invention’, the specification states:
‘In accordance with the present invention, there are provided certain trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and the corresponding ring-opened hydroxy-acids derived therefrom which are potent inhibitors of cholesterol biosynthesis by virtue of their ability to inhibit the enzyme 3-hydroxy- 3-methylglutaryl coenzyme A reductase (HMG-CoA reductase).
In particular, in its broadest aspect the present invention provides compounds of structural formula I…’.
Structural formula I is then set out. The specification adds that the hydroxy acids, and pharmaceutically acceptable salts thereof, derived from the opening of the lactone ring of the compounds of structural formula I are also contemplated as falling within the scope of the invention.
The specification then turns to three other aspects of the invention. First, at pg 4, the specification describes a method of preparing the compounds of structural formula I. Secondly, the specification says that the invention provides pharmaceutical compositions useful as hypolipidemic or hypocholesterolemic agents comprising a hypolipidemic or hypocholesterolemic effective amount of a compound in accordance with the invention, in combination with a pharmaceutically acceptable carrier. The third aspect is that the invention provides a method of inhibiting cholesterol biosynthesis in a patient in need of such treatment by administering an effective amount of the pharmaceutical composition.
The next section of the specification contains a detailed description of the invention. It commences as follows:
‘The compounds of the present invention comprise a class of trans-6-[2-(3- or 4-carboxamidosubstituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones in which the pyran-2-one moiety is attached, through an alkyl chain, to the substituted pyrrole nucleus at the nitrogen, or 1-position, of the pyrrole. The alkyl group may be methylene, ethylene, propylene, or methylethylene. The preferred alkyl chain linking the substituted pyrrole nucleus and the 4-hydroxypyran-2-one ring is ethylene.
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.
In the compounds of the present invention, position 2 of the substituted pyrrole nucleus is substituted with 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. Preferred substituent groups at the 2-position of the pyrrole nucleus are phenyl and substituted phenyl.
In the compounds of this invention, position 5 of the pyrrole nucleus is substituted with alkyl of from one to six carbon atoms; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or trifluoromethyl. Preferred substituents are alkyl or trifluoromethyl with isopropyl being particularly preferred.’
The specification then describes the preferred reaction sequence which is used to prepare compounds of the invention. Between pg 7 and pg 12, reaction sequence 1 and reaction sequence 2 are described diagrammatically and in the text.
At pg 12, the specification describes the formation of salts from ring-opened hydroxy acids of the compounds:
‘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, aluminium, 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 nontoxic base addition salts of compounds of the present invention form a class whose limits are readily understood by those skilled in the art.’
The specification states that the base addition salts may differ from the free acid forms of the compounds of the invention in such physical characteristics as solubility and melting point, but are otherwise considered equivalent to the free acid form for the purposes of the invention.
The specification then turns to discuss the effectiveness of the compounds of the invention as inhibitors of the biosynthesis of cholesterol through inhibition of the HMG-CoA reductase enzyme. It is said that the ability of compounds of the invention to inhibit the biosynthesis of cholesterol is measured by two methods: a designated Cholesterol Synthesis Inhibition screen and a designated CoA Reductase Inhibition screen. The activity of several representative examples of compounds in accordance with the invention is set out in Table 1 and compared with the prior art compound, compactin. Table 1 provides:
I interpolate that the lower the IC50 value in this table, the more effective the compound. According to the table, therefore, compound 3 was the most effective, followed by compactin, and then compound I and lastly compound 2.
Pages 14 to 17 of the specification discuss various excipients in pharmaceutical preparations containing compounds of the invention as well as means for making such preparations and recommended dosage levels.
Commencing at pg 17, the specification sets out four examples which are said to ‘illustrate particular methods for preparing compounds in accordance with this invention’. The specification states that the examples ‘are illustrative and are not to be read as limiting the scope of the invention as it is defined by the appended claims’.
The specification concludes with the ten claims defining the invention which I have already summarised. It is helpful to set out claim 5 as it is relied upon as an aid to the construction of claim 1. It provides:
‘A compound as defined by Claim 1 having the name trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.’
Principles of Construction
The parties were not in dispute as to the principles that apply to the construction of the 981 Patent. I was referred to numerous authorities in which these principles have been clearly articulated, including Welch Perrin & Co Pty Ltd v Worrel (1961) 106 CLR 588 (‘Welch Perrin’) at 610; Interlego AG v Toltoys Pty Ltd (1973) 130 CLR 461 (‘Interlego’) at 478 (see also Stephen J at first instance at 466); Décor Corp Pty Ltd v Dart Industries Inc (1988) 13 IPR 385 at 400; Fisher & Paykel Healthcare Pty Ltd v Avion Engineering Pty Ltd (1991) 22 IPR 1 at 18-19; Fresenius Medical Care Australia Pty Ltd v Gambro Pty Ltd (2005) 67 IPR 230 at 236 [39], 238 [52] and 245-246 [91]-[94]; Pfizer Overseas Pharmaceuticals v Ely Lilly & Co (2005) 68 IPR 1 (‘Pfizer’) at 52-54 [247]-[250]; Kirin-Amgen Inc v Hoechst Marion Roussel Ltd (2004) 64 IPR 444 (‘Kirin-Amgen’) at 452-457 [27]-[35]; PhotoCure ASA v Queen’s University at Kingston (2005) 216 ALR 41 (‘PhotoCure’) at 85 [172] and 85-86 [168]-[174]; Sachtler GmbH & Co KG v RE Miller Pty Ltd (2005) 221 ALR 373 (‘Sachtler’) at 380-382 [39]-[42]; Clorox Australia Pty Ltd v International Consolidated Business Pty Ltd (2006) 68 IPR 254 (‘Clorox’) at 260-262 [13]-[22].
I do not propose to summarise all of the guiding principles that emerge from these authorities. That task has already been undertaken, most helpfully, by Bennett J in Sachtler at 380-382 [39]-[42] and Stone J in Clorox at 260-262 [13]-[22]. I gratefully adopt their Honours’ summaries of the relevant principles.
For present purposes, however, it is helpful to refer specifically to several principles that have particular resonance with the circumstances of this case:
(1)The underlying consideration in the construction of the patent is that it is a public instrument, conferring a public monopoly, that is meant to define the monopoly in such a way that it is not capable of being misunderstood: see eg Pfizer at 52 [247]. The patentee must define the invention with sufficient precision to permit the monopoly to be determined and to allow the general public to identify from the words of the claims the conduct that is prohibited: see eg Clorox at 261 [18].
(2)The claims define the invention which is the subject of the patent. They must be construed according to their terms by applying the ordinary rules of construction that apply to any written instrument: see eg Décor at 400; Clorox at 260 [15].
(3)The claims must be construed in the context of the specification as a whole. The rest of the specification may explain the background to the claims, assist in ascertaining the meaning of technical terms, or aid in resolving ambiguities in the construction of the claims: Clorox at 260 [16]; Sachtler at 381 [42].
(4)Although the claims are to be construed in the context of the specification as a whole, ‘the settled rule is that it is not permissible to vary or qualify the plain or unambiguous meaning of the claim by reference to the body of the specification’: see Interlego per Barwick CJ and Mason J at 478. Further, ‘it is not legitimate to narrow or expand the boundaries of monopoly as fixed by the words of a claim by adding to those words glosses drawn from other parts of the specification. Similarly, if a claim be clear it is not to be made obscure simply because obscurities can be found in particular sentences in other parts of the document’: WelchPerrin at 610 per Dixon CJ, Kitto and Windeyer JJ; see also Clorox at 261 [17].
(5)A patent specification must be given a purposive rather than a purely literal construction. This involves construing the claims in a practical, commonsense manner, avoiding too technical or narrow a construction of the claims, and preferring a construction under which the invention will work to one where it may not work: Pfizer at 53-54, citing Nesbit Evans Group Australia Pty Ltd v Impro Ltd (1997) 39 IPR 56. It also means construing the claims in light of what a reasonable person to whom the patent was addressed would have understood the language of the claim to mean: Kirin-Amgen at 453-454 [30], [32] and [34] per Lord Hoffman.
(6)The hypothetical addressee of the patent specification is the non-inventive person skilled in the art before the priority date. The words used in the specification and the claim are to be given the meaning that the skilled addressee would attach to them, both in the light of his or her own general knowledge and what is disclosed in the body of the specification: Clorox at 261-262 [20]; Décor at 391; PhotoCure at 85 [170].
(7)The proper construction of the specification is a matter of law for the Court to determine. However, evidence can be given by experts on the meaning which those skilled in the art would give to technical or scientific terms and phrases and on unusual or special meanings given by such persons to words that might otherwise bear their ordinary meaning: see Clorox at 262 [21]; see also Root Quality Pty Ltd v Root Control (2000) 49 IPR 225 (‘Root Quality’) at 237 [49].
The Skilled Addressee
As patent specifications and claims must be construed in light of the common general knowledge of a person skilled in the art before the priority date, it is necessary to ask: who is the skilled addressee? Various descriptions have been given to the skilled addressee, including the ‘notional skilled addressee’, the ‘uninventive skilled worker in the particular field’, the ‘non-inventive worker in the field’, the ‘person skilled in the art’, the ‘non-inventive hypothetical skilled addressee’, and ‘those likely to have a particular interest in the subject matter of the invention’: Root Quality at 241 [70]-[71] per Finkelstein J. The person skilled in the art is a ‘relative expression which does not identify any specific person’ and may consist of a team of persons with combined skills: Root Quality at 242 [71]; see also The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited [1972] RPC 457 (‘General Tire’) at 485.
In NSI Dental Pty Ltd v University of Melbourne (2006) 69 IPR 542 (‘NSI Dental’) Tamberlin J said at 570 [151]:
‘At the outset, it is necessary to describe the attributes of the skilled addressee and the relevant patent area. The skilled addressee is a legal construct and is assumed to be a person, or team, who is “not ‘particularly imaginative or inventive’”: Pfizer Overseas Pharmaceuticals v Eli Lilly and Co [2005] FCAFC 224 at [288] per French and Lindgren JJ. This does not mean that the addressee is a technician or person with only practical and non-academic qualifications. In fields such as chemistry, the addressee can be a person or group with high level qualifications and a capacity for original research: Aktiebolaget Hassle v Alphapharm Pty Ltd (2002) 212 CLR 411 at [30].’
Axiomatically, the identity of the person who is skilled in the art will vary with the nature of the invention and the field with which it is concerned. The level of skill which can properly be attributed to the skilled addressee will be an important determinant of his or her common general knowledge. The qualifications of the skilled addressee, the setting in which and the resources with which he or she operates, and the practices and techniques that he or she regards as commonplace and known will also be important considerations: see Aktiebolaget Hassle v Alphapharm Pty Ltd (2002) 212 CLR 411 (‘Alphapharm’) at 465 [153] per Kirby J.
In Minnesota Mining & Manufacturing Co v Beiersdorf (Aust) Ltd (1980) 144 CLR 253 (‘Minnesota’) at 292, Aickin J described ‘common general knowledge’ as:
‘… that which is known or used by those in the relevant trade. It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge.’
Aickin J went on to add that those working or studying in some fields of endeavour may make themselves familiar with all patent specifications as they become available for inspection, in one or in many countries, so that their contents become common general knowledge in that particular trade or field of manufacture in the country in question. But that is not so in all fields or in all countries. There must be evidence that the content of a patent specification has become part of the common general knowledge of those working in the relevant field before it can be regarded as part of the background knowledge and experience of the skilled addressee: at 294-295. The High Court confirmed this analysis in Alphapharm at 426-427 [31], 430-431 [44]-[45] and 434 [55].
There is, accordingly, an important distinction between common general knowledge and public knowledge. In General Tire at 482, the Court of Appeal illustrated the distinction by saying that each and every patent specification of the last 50 years would form part of relevant public knowledge if it is resting anywhere in the shelves of the patent office, whereas common general knowledge is a different concept derived from a commonsense approach to the practical question of what would in fact be known to an appropriately skilled addressee – the sort of person good at his or her job that could be found in real life. The Court then observed at 482 that:
‘… individual patent specifications and their contents do not normally form part of the relevant common general knowledge, though there may be specifications which are so well known amongst those versed in the art that upon evidence of that state of affairs they form part of such knowledge, and also there may occasionally be particular industries (such as that of colour photography) in which the evidence may show that all specifications form part of the relevant knowledge.’
The Full Federal Court referred to this distinction, with approval, in W R Grace & Co v Asahi Kasei Kogyo Kabushiki Kaisha (1993) 25 IPR 481 at 492; see also Heerey J at first instance: Asahi Kasei Kogyo Kabushiki Kaisha v W R Grace & Co (1991) 22 IPR 491 at 523.
In PhotoCure at 52 [31], Merkel J said:
‘The common general knowledge will encompass not only information that is retained in the memory of the skilled person, but also information that the person knows of, and to which he or she might refer as a matter of course, or habitually consult: see ICI Chemicals & Polymers Ltd v Lubrizol Corp Inc (1999) 45 IPR 577 at [112] and Aktiebolaget Hässle v Alphapharm Pty Ltd (2000) 51 IPR 375; [2000] FCA 1303 at [73]. However, common general knowledge does not include information merely because it would have been able to be found if a routine literature search was conducted: see Alphapharm (HCA) at [31], [44]-[45] and [55]. Nor does it follow from the fact that a publication “may have been held in a library readily accessible to a particular formulator” that such a publication formed part of the common general knowledge: see Aktiebolaget Hässle v Alphapharm Pty Ltd (1999) 44 IPR 593; [1999] FCA 628 at [105] … per Lehane J.’
In Root Quality at 241-242 [71], Finkelstein J observed that, generally speaking, the skilled addressee is the person who works in the art or science with which the invention is connected. He or she is a person, or team, likely to have a practical interest in the subject matter of the invention: at 241-242 [71].
In an international field such as drug discovery and development, the Court may have regard to evidence given by experts from outside Australia in assessing the state of common general knowledge of a skilled addressee or a skilled team working in Australia at the priority date: Pfizer at 63 [293]-[295]. Evidence from such witnesses may support the inference of a global pool of common general knowledge on issues relevant to the invention which would have been known to the skilled addressee in Australia: at 63 [294]; see also NutraSweet Australia Pty Ltd v Ajinomoto Co Inc (2005) 67 IPR 381 at 387-388 [29]-[32] per Finkelstein J.
Both Warner-Lambert and Ranbaxy called evidence from expert witnesses as to the identity of the skilled addressee in the relevant field, and as to the matters that would fall within the common general knowledge of the skilled addressee immediately before the priority dates of the 981 Patent (30 May 1986) and the Enantiomer Patent (21 July 1989). Neither party, nor any witness, suggested that the nature of the relevant field, or the identity of the skilled addressee, differed between May 1986 and July 1989.
The expert witnesses
Professor Christopher Easton gave evidence on behalf of Warner-Lambert. He is a professor at the Research School of Chemistry, Institute of Advanced Studies, Australian National University. He was awarded the Degree of Doctor of Philosophy by the University of Adelaide in 1981. His PhD involved research in the area of organic chemistry. In 1982, he was a Research Fellow in the Research School of Chemistry at the Australian National University, working on projects relating to organic and biological chemistry including reactions involving the biosynthesis of penicillin. From 1983 to 1986, he was a Lecturer and Senior Lecturer in the Department of Chemistry at the University of Canterbury, New Zealand. From 1986 to 1988 he was a Lecturer in the Department of Organic Chemistry at the University of Adelaide and on 1 January 1992 he was appointed a Reader in the Department of Organic Chemistry. Since 1995, he has held the positions of a Senior Fellow, Professor and Distinguished Professor at the Research School of Chemistry. From 1988, he has also been involved in numerous research projects in the field of medicinal chemistry and drug research.
The inventor named in both patents, Dr Bruce Roth, gave evidence on behalf of Warner-Lambert. He currently holds the position of Vice President of Chemistry, Pfizer Global Research and Development. At all relevant times, he was in charge of the drug discovery team at Warner-Lambert that developed Lipitor. One difference between his evidence, and that given by other expert witnesses, was that he said he would not expect medicinal chemists in the field to be aware of particular information relating to HMG-CoA reductase inhibitors, including statins, without conducting a search and careful review of the relevant literature in that area. This is a matter to which I will need to return.
Professor Peter Scammells gave evidence on behalf of Warner-Lambert. He is a Professor of Medicinal Chemistry in the Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University. He was not qualified as a medicinal chemist at either of the relevant priority dates of 30 May 1986 or 21 July 1989. In May 1986, he was an undergraduate science student and in July 1989 he was studying for his doctorate which was awarded in 1991. Between 1994 and 2001, he was a Lecturer and Senior Lecturer in the School of Biological and Chemical Sciences, Deakin University, Melbourne. He was appointed Professor of Medicinal Chemistry at Monash University in 2001.
Professor Scammells did not have relevant qualifications and experience at the priority dates of the patents, which has a bearing on the weight that should be attributed to his evidence. However, I accept that Professor Scammells has, by virtue of his professional experience, a detailed understanding of medicinal chemistry, that is to say synthetic organic chemistry and the interaction of chemical compounds with biological systems. He has worked on projects related to the synthesis and testing of chemical compounds in order to maximise (in terms of activity and selectivity) the interaction of drugs with biological molecules. He is, I accept, in a position to give evidence as to what was generally known by workers of ordinary skill in the field of synthetic organic chemistry concerned with drug identification and development as at the relevant priority dates.
The remaining expert witness called by Warner-Lambert was Professor William Charman, a Professor of Pharmaceutics at the Victorian College of Pharmacy, Monash University. Professor Charman is not a medicinal chemist. He graduated with a degree of Bachelor of Pharmacy in 1981 and studied for his Masters of Science Degree from the University of Kansas in the USA between 1983 and 1985. He was awarded a PhD with Honours from the University of Kansas in May 1986 in the area of pharmaceutical chemistry. Between 1986 and 1989, he was employed at the Department of Pharmaceutical Sciences at Sterling-Winthrop Research Institute in New York State. He returned to Australia in 1989 to take up the position of Senior Lecturer at the Department of Pharmaceutics at the Victorian College of Pharmacy and was appointed Professor of Pharmaceutics in 1995. His practical experience has been in the process side of drug development work, rather than in the design and synthesis of compounds with high biological activity.
Ranbaxy called evidence from three experts: Dr Terence Scallen, Dr Keith Watson and Dr Ian Cunningham.
Dr Scallen obtained his PhD in biochemistry and organic chemistry in 1965, and devoted much of his career to cholesterol biosynthesis inhibition. He obtained a patent for an HMG-CoA reductase inhibitor in 1979 and was then appointed as a consultant to Sandoz Pharmaceutical to oversee all of the HMG-CoA reductase assays for Sandoz’s statin project which eventually led to the development of fluvastatin. He worked as a consultant to Sandoz for a period of 14 years, including the whole of the 1980s. During this period he also held professorial positions at the University of New Mexico School of Medicine. In his evidence, Dr Scallen tended to identify the relevant field of art with which the patents were concerned somewhat more precisely than Warner-Lambert’s witnesses, namely synthetic organic chemistry as applicable to the discovery and development of drugs directed towards the regulation of the cholesterol biosynthesis pathway, including HMG-CoA reductase inhibitors.
Dr Watson is currently a Special Fellow at the Walter and Eliza Hall Institute in Victoria. He obtained his PhD in 1973 and after post-doctoral research in London he was employed by the CSIRO from 1975 to 1977 and at ICI Australia between 1977 and 1991. His work at these organisations largely involved the application of synthetic organic chemistry to the preparation of small molecules with biological activity. He described his primary interest as the relationship between chemical structure and biological activity and the creation of new molecules with potentially beneficial properties, particularly as drugs or chemicals for industrial or agricultural application. While working at ICI, he assisted in the development of two new selective herbicides and a new method of synthesis of a heart disease drug known as ‘Diltiazem’. He returned to work with the CSIRO’s Division of Chemicals and Polymers between 1991 and 1994 and in 1994 he was employed as Head, Biota Chemistry Laboratory, in the Chemistry Department of Monash University. He remained in that position until 2001.
Dr Cunningham currently works as an independent consultant to the pharmaceutical and fine chemical industries. He obtained his PhD in 1973 and after post-doctoral studies he was employed by ICI Pharmaceuticals (which later became AstraZeneca) from 1975 to 1990. Between 1975 and 1983 he worked as a team leader in medicinal chemistry and between 1983 and 1985 he worked as a team leader in process development. From 1985 to 1990 he led eight teams of chemists seeking to discover new antibacterials and was the antibacterials project manager. At the relevant priority dates, he had industry experience both as a medicinal chemist and as a process chemist. In 1990, he joined ICI Agrochemicals and in 1991 was appointed Head of Chemistry in that business. In 1994, he took up employment with GlaxoSmithKline (‘Glaxo’) and eventually became Senior Vice-President of Chemical Development at Glaxo.
The composition of the skilled team
The evidence from the experts concerning the identity of the skilled addressee of the 981 Patent and the Enantiomer Patent was broadly to the same effect. All of the experts considered that the patents were addressed to a team involved in drug discovery and development. The team would include medicinal chemists responsible for designing and making compounds with high biological activity, assisted by biologists, clinical researchers and technicians. The medicinal chemists would have the skill to undertake work designed to determine the relationship between the structure and biological activity of compounds, ie the structure activity relationship. The team would include highly qualified team leaders assisted by a number of research associates (including PhD students and post-doctoral researchers). It would also include biologists and/or biochemists who would be consulted in connection with creating and developing biological assays in which to test compounds.
The size and composition of the team would vary depending on the project being undertaken and the focus of its work would be directly related to the particular drug discovery process being pursued. Where relevant, the team would also include other chemists or pharmaceutical scientists with expertise in relation to relevant disease mechanisms and therapeutic opportunities. Physical chemists and pharmacologists may be required to test the physiochemical and pharmacokinetic properties of the most promising new molecules, and it is likely that formulation and process chemists would be retained during the development phase of the project. Toxicologists may also have been required to carry out in vivo testing of any compounds which show sufficient promise to be considered for further development. It is possible that, as Dr Watson suggested, a computer molecular modeller, with qualifications in science and information technology, may have been engaged to suggest new molecular structures which could inhibit the target biological system but the weight of evidence was that this would not have been common in the 1980s.
Accordingly, I find that the skilled addressee of the patents was a skilled team constituted in the manner described above.
The relevant field of art
It is unrealistic to identify the relevant field of art as broadly as the whole field of synthetic organic chemistry as applicable to the discovery and development of new pharmaceutical drugs, as Professor Easton, Professor Scammells and Professor Charman tended to suggest in their evidence. The 981 Patent, and the subsequent Enantiomer Patent, disclose classes of compounds that have the ability to inhibit HMG-CoA reductase. In my opinion, the relevant field is that of synthetic organic chemistry as applicable to the discovery and development of drugs directed towards the regulation of the cholesterol biosynthetic pathway, including HMG-CoA reductase inhibitors, as suggested by Dr Scallen and Dr Cunningham in their evidence. Accordingly, I prefer, and accept, the evidence of Dr Scallen and Dr Cunningham as to the identification of the relevant field of art to which the patents are directed.
Common General Knowledge
It was common ground between Warner-Lambert and Ranbaxy that the basic principles of stereochemistry described at [17] to [38] above formed part of the common general knowledge that should be attributed to the skilled addressee before the priority dates of the 981 Patent and the Enantiomer Patent. Further, I accept Dr Watson’s evidence that there were no material differences in the fundamental principles of stereochemistry between 30 May 1986 and 21 July 1989.
The drug discovery process
It was also common ground that the skilled addressee would be aware of the way in which drug discovery and development was customarily undertaken. Professor Easton described the broad nature of the drug discovery process in his affidavit sworn 28 August 2006 at paras 3.4 to 3.12:
‘Drug discovery typically involves three major aspects - identification of a disease state, identification of a therapeutic target (such as a protein, enzyme or receptor), and identification of compounds which have biological activity relevant to the therapeutic target. Drug discovery is not necessarily carried out in these progressive stages. The first stage of drug discovery may, for example, involve identifying a compound having a certain biological activity - before identification of a therapeutic target or disease state. This was how taxol, a cancer treatment, was discovered.
Typically however, pharmaceutical companies, advised by medical researchers or clinicians, identify a disease state for which a treatment is required and, in some cases, also a therapeutic target for that treatment.
I am, and others in the Field are, then responsible for identifying compounds to be screened for biological activity relevant to that therapeutic target. Those working in the Field have expertise in both the design and synthesis of compounds with biological activity. Usually, I have a number of research associates (including PhD students and post-doctoral researchers) assisting me in the design and synthesis of such compounds.
Sometimes very little is known about the therapeutic target and the initial screening process involves a range of diverse compounds. Sometimes more is known, and the range of compounds selected for screening at the outset will be more specific. For example, if it is known that a particular compound has the desired inhibitory activity at a target enzyme, the range of compounds initially synthesised and then screened will more likely be those having a chemical structure similar to that of the known inhibitor.
The compounds to be screened are then tested in in vitro biological assays in order to identify those compounds having the highest activity relevant to the target. An ‘in vitro’ assay is carried out using isolated cells or enzymes rather than a living animal. In some cases, where the assay is complex, the compounds are sent to collaborators (usually biologists), who are responsible for performing the assay. In cases where the assay is less complex, I and others in the Field perform the in vitro assays and/or supervise the performance of those assays in our own laboratories.
I am, and others in the Field are, then responsible for the interpretation of the structure activity relationship based on the results of in vitro assays. The most active compounds are selected for further investigation. In that investigation, new compounds having small modifications over those that show promising activity are synthesised and screened in in vitro assays in an attempt to obtain improved activity at the target. Through successive rounds of synthesising and screening of new compounds, the parts of the compound's molecular structure that are important to its activity at the target can be identified. This work is referred to as determining ‘the structure activity relationship (SAR)’ of the compound at or in relation to a particular target. This is commonly described as ‘SAR’ work.
The people with the skills and expertise required to carry out the matters described in paragraphs 3.4 to 3.9 are, working in combination, an example of the ‘team’ involved in the initial stage of drug discovery.
The usual experience in drug discovery is that many hundreds or thousands of compounds will be synthesised and screened in the course of a drug discovery program before even a single compound is identified and selected for pre-clinical and clinical (human) trials on the ground that it has sufficient activity in an in vitro assay.
The determination of what to synthesise, the carrying out of the synthesis of the compounds to be tested and discovery of activity by screening of those compounds leading to the identification of a compound or compounds for pre-clinical and clinical trials (or failure to do so), is only the first step in the drug discovery process. The development and selection of a final drug for therapeutic use depends on many other factors, such as its selectivity for the target, absorption, distribution, bioavailability, stability, metabolism, excretion and toxicity (including side effects) in a human. Such development work also involves determining whether and if so how a compound can be manufactured on a commercial scale and whether it can be suitably formulated.’
Similar evidence was given by Dr Roth and Professor Scammells.
In his affidavit evidence, Dr Roth expanded on the way in which medicinal chemists pursue a structure activity relationship (‘SAR’). He said that the work of medicinal chemists in designing and making compounds with high biological activity involves the determination of the relationship between the structure and the biological activity of compounds. This determination is pursued by making incremental changes to the structure of a compound and then studying any resulting change in biological activity. SARs are used to plan modifications to a compound in order to improve its biological activity at the therapeutic target. Medicinal chemists consult with biologists and clinical researchers in relation to the biology of the therapeutic target for the drug, and biologists create and develop assays in which the activity of the compounds can be tested.
It may be helpful to give a brief outline of the way in which Warner-Lambert pursued its drug discovery research in relation to HMG-CoA reductase inhibitors, not because those matters were generally known in the relevant field, but because it illustrates the drug discovery process. In his affidavit evidence, Dr Roth said that he initially examined the different parts of compactin and considered other kinds of molecular structures that might mimic those parts in a biological system, such that the modified compound would still demonstrate biological activity. Based on the relative stereochemistry of compactin, he concluded that he wanted a lactone ring with trans relative stereochemistry to mimic that of compactin. After the publication of the Willard Patent in March 1983 by the researchers at Merck Sharpe & Dohme (‘Merck’), he compared the structures of compactin and the preferred compound in the Willard Patent. From this comparison, he developed the hypothesis that it was important for the biological activity of the compound to have the lactone ring in the right relationship in space to a large lipophilic group, using a template that would serve to hold the lactone and the lipophilic group in that spatial relationship. Thereafter he pursued compounds that used a pyrrole ring as the template, and introduced symmetrical substituents on the pyrrole ring at the three and four positions. He found that placing a carboxamido group at either the three or four position on the pyrrole ring resulted in very good biological activity. This work led to his synthesis in June 1985 of the compound that later became known as racemic atorvastatin lactone.
Other aspects of common general knowledge
In many other respects, the expert witnesses agreed about the matters that would fall within the scope of the common general knowledge of the skilled addressee. The main issue in contention concerned the extent to which specific information concerning HMG-CoA reductase inhibitors, including knowledge derived from several important patent specifications and published articles, should be attributed to the skilled team as part of its common general knowledge.
Ranbaxy submitted that for a skilled team working in drug discovery in, or for, pharmaceutical companies, it was imperative to keep up to date with what competitors were doing. Therefore, skilled teams of this kind were continually updated in-house with patent documents and journal articles relating to their competitors’ work. Members of the team would also carry out their own programs of reading, such as reading and reviewing leading journals and patent documents. It also submitted that patent documents were regarded as an important source of information, since much of the work undertaken by competitors went unpublished in scientific journals for many years for reasons of commercial secrecy. It said that major pharmaceutical companies, such as ICI, circulated patent information and other documents relating to competitors’ drug discovery projects to its drug discovery teams.
Ranbaxy submitted that the evidence was that skilled teams working in the field of HMG-CoA reductase inhibitors prior to May 1986 kept up to date, so far as possible, concerning drug discovery work being undertaken by competitors at other pharmaceutical companies.
Once the relevant field of art is identified as synthetic organic chemistry as applicable to the discovery and development of drugs directed to the regulation of the cholesterol biosynthetic pathway, including HMG-CoA reductase inhibitors, and the skilled addressee is identified as a drug discovery team working in, or having an interest in, that field, I see no reason to doubt that the skilled team would have been aware of several landmark papers and patent specifications that were published in the field of HMG-CoA reductase inhibitors before 30 May 1986. Those publications were referred to in some detail in the evidence and it is appropriate to summarise the significant matters that they disclosed:
(1)The Alberts Paper
In July 1980, Alberts et al, who were members of the drug discovery team at Merck working on HMG-CoA reductase inhibitors, published an article in the proceedings of the National Academy of Science, USA, entitled ‘Mevinolin: A highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent’. The paper reported that mevinolin in the hydroxy acid form, mevinolinic acid, is a potent competitive inhibitor of HMG-CoA reductase. In the paper, the authors determined the absolute configuration of mevinolin and mevinolinic acid and reported that each contained a trans-substituted lactone ring with a 4R configuration.
(2)Stokker I
The article by Stokker et al, entitled ‘3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors. 1. Structural Modification of 5-Substituted 3,5-Dihydroxypentanoic Acids and Their Lactone Derivatives’, was published in the Journal of Medicinal Chemistry in 1985. Stokker was a member of the Merck team that included Alberts and Willard. The article reported on various compounds which had been prepared and tested in vitro for inhibition of HMG-CoA reductase. The compounds tested were compactin-like mimics and afforded a series of moderately effective HMG-CoA reductase inhibitors typified by the ring-opened form of the lactone. Separation of the lactone into the racemic cis and trans lactones showed that activity resided principally in the racemic trans lactone. Further, resolution of the trans lactone afforded enantiomers which, when evaluated, showed that the activity displayed by the racemate resulted solely from the (+) or d- isomer.
(3)Stokker II
A second paper by Stokker, Alberts, Willard et al, entitled ‘3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors. 3. 7-(3,5-Disubstituted [1,1¢-biphenyl]-2-yl)-3,5-dihydroxy-6-heptenoic Acids and Their Lactone Derivatives’, was published in the Journal of Medicinal Chemistry in February 1986. The paper reported on the HMG-CoA reductase inhibitory activity of various compounds. It confirmed the conclusion of the first Stokker paper that all of the activity in the compounds resided in one enantiomer. The paper reported on the activity of the racemates and the individual enantiomers of the various compounds, as follows:
‘The contribution of the lactone moiety stereochemistry to intrinsic inhibitory activity was shown earlier to be very important in that all of the activity resides in one of the enantiomers of the trans isomer. This observation was extended and confirmed in this study by resolving lactones 100 and 110 to afford enantiomers 100(+) and 110(+), each of which had about 2.8 times the intrinsic inhibitory potency of compactin.
Two independent chiral syntheses of 110(+) have recently been published and the in vivo activity will be described elsewhere.
Conclusion
Analysis of the intrinsic inhibitory potencies of the compounds evaluated in this study suggests that inhibitory binding to HMG-CoA reductase is augmented by (a) a 3- and 5-chloro or –methyl group on the central phenyl ring and (b) a 3¢-methyl and 4¢-halo group on the external phenyl ring, while binding is decreased by (c) increasing the distance between the two phenyl rings, (d) saturation of the ethenyl bridge between the biphenyl an lactone moieties, and (e) introduction of a methyl at the 4-position of the lactone ring. The absolute stereochemistry of the lactone ring must be the same as in compactin and mevinolin; in the present case, 4R,6S.’
In relation to the absolute configuration of the more potent (+) or d- enantiomer of the trans lactone 100(±), the paper reported that this enantiomer was found to have 4R, 6S chirality in the lactone portion, corresponding to the analogous centres in compactin or mevinolin. The authors also reported that any activity which was apparently referable to the opposite enantiomer was probably due to trace elements of the active enantiomer.
(4)The Willard Patent
The Willard Patent was sealed on 1 March 1983. This patent is referred to in the 981 Patent at pg 3 under the heading ‘Background of the Invention’, where it is described as a patent that discloses certain compounds which, in the 4(R)-trans-stereoisomeric form, are inhibitors of cholesterol biosynthesis. The invention arose from the work done by the research team at Merck responsible for the publication of the Stokker I and Stokker II papers. The Willard Patent claims compounds of a specified structural formula, all of which are enantiomers having a 4(R) configuration of the trans racemate. The patent only describes activity in respect of the R enantiomer and only claims the R enantiomer. It contains no description of the S enantiomer and there is no claim to the S enantiomer or to the racemate itself. At column 3, the patent specification states:
‘The designation 4R with respect to these compounds indicates that the absolute configuration in space at the 4-carbon of the pyranone ring is believed to be the Rectus (R) series. All the compounds synthesized in the (R) series have been found to be dextrorotatory [(+) or d-, ie they rotate the plane of polarised light to the right].’
The specification does not set out the grounds for this belief.
(5)The Kathawala Patent application
The 981 Patent also refers to patent application WO 84/02131 which was published on 7 June 1984. This is the application for United States Patent 4,739,073 that was granted to Kathawala as inventor on 19 April 1988. The patent application describes research done at Sandoz as part of its drug discovery program. It relates to a class of compounds which are analogues of mevalonolactone and derivatives thereof and which are useful as hypolipoproteinemic and antiatherosclerotic agents. The application states that ‘as is self evident to those in the art’ each compound of formula I (which defines claim 1) has at least two centres of asymmetry and these lead to four stereoisomeric forms (enantiomers) of each compound (2 racemates or pairs of diastereoisomers). The application specifically states that all four stereoisomers are within the scope of the invention. According to Professor Easton’s evidence, which I accept, the application expresses a preference for the equivalent of the R-trans enantiomer of the compounds in the 981 Patent. One of the synthetic compounds described in the patent application was subsequently commercialised as fluvastatin.
Ranbaxy relied upon this literature as providing a very strong line of data going back to 1980 indicating that the R enantiomer was the active enantiomer and that a skilled person reading the 981 Patent would have expected that the S enantiomer did not have any activity.
There is a convincing body of evidence that the five publications described above had been absorbed into the common general knowledge of the skilled addressee of the 981 Patent by 30 May 1986. Before May 1986, Professor Easton regularly scanned 20 to 30 journals in the field of medicinal and organic chemistry to keep abreast of developments that were relevant to his work. He also read literally hundreds of patents in the context of his work. As a result, he was generally aware before 30 May 1986 that cholesterol biosynthesis and cholesterol absorption, including HMG-CoA reductase inhibitors, were major areas of interest to pharmaceutical companies and researchers generally. He also said that it was generally known that a number of major pharmaceutical companies, including Merck and Sandoz, were working in this area.
Professor Easton’s evidence was that he expected that he may have scanned the Stokker I article before May 1986. He said that the important conclusion for those in the field from Stokker I was that it showed that the biological activity of compactin may be retained when the hexahydronapthalene moiety is replaced by some simpler synthetic structures and that the ring-opened lactone was important for HMG-CoA reductase inhibitory activity.
Professor Easton did not suggest that he actually read or scanned the Alberts article or the Stokker II article before 30 May 1986. He observed in evidence that the Alberts article described the discovery of a natural HMG-CoA reductase inhibitor, lovastatin, in which the absolute stereochemistry of the lactone was reported to be R-trans and the active form was reported to be the hydroxy acid (open lactone) structure. Professor Easton said that this literature confirmed that the more active enantiomer of other HMG-CoA reductase inhibitors was the RR enantiomer. Consequently, he said it would have been expected by the skilled addressee of the 981 Patent that the RR enantiomer was likely to be the more active enantiomer in the compounds of the 981 Patent. However, he said this could not be known with certainty without isolating the individual enantiomers of the particular HMG-CoA reductase inhibitor and testing them.
Generally speaking, Professor Scammells and Professor Charman did not read or access patent specifications to the same extent or in the same routine way as those experts who worked in pharmaceutical companies in the field of drug research and development, such as Dr Scallen, Dr Cunningham and Dr Roth.
Professor Scammells gave evidence that he reviewed the contents of eight prominent scientific journals on a regular basis, reading those articles which were of particular interest to him, so as to keep abreast of developments in his field. As for patents, Professor Scammells said his experience was that patents and patent applications were not regularly scanned by people in the field before May 1986. Personally, he said he did not regularly read patents, but would have placed an order for a patent and read it if it were identified through a literature search to be of interest to him. Professor Scammells did not suggest that he would have read or reviewed any of the five publications in the ordinary course before May 1986 or 21 July 1989. However, he said that the following information about HMG-CoA reductase inhibitors was generally known in the field as at 21 July 1989:
(a)HMG-CoA reductase is one of the enzymes in the pathway to cholesterol biosynthesis. As it is the rate limiting enzyme (that is, the enzyme responsible for controlling the rate of the reaction responsible for cholesterol biosynthesis), a compound that could inhibit that enzyme would be useful in preventing cholesterol biosynthesis (and therefore in treating hypercholesterolemia).
(b)Statins are a class of drugs being investigated as they had been found to be potent inhibitors of HMG-CoA reductase.
(c)Statins exist both as natural products and analogues of the natural products (ie synthetic and semi-synthetic products). Compactin and mevinolin are natural statins. They were discovered in the late 1970s and in the early 1980s respectively.
Professor Scammells did not separately address the question whether these matters were generally known in the field as at 30 May 1986. It is apparent, however, that these facts do not depend on disclosures that occurred for the first time between 30 May 1986 and 27 July 1989.
Professor Charman scanned numerous scientific journals on a regular basis for articles that related to his work. Like Professor Scammells, he did not routinely read or access patents. He regarded patents as part of the broader scientific literature which a person in the field might have found by a literature search carried out in pursuit of a particular line of research to which the patents were relevant.
Dr Watson did not specifically address the publications by Alberts, Stokker I or Stokker II, the Willard Patent or the Kathawala Patent application. However, he regularly read well known publications such as the Journal of Medicinal Chemistry, as well as patent specifications, to keep up to date in his field. He also said that he, and others working as synthetic organic chemists in Australia, routinely travelled to national and occasionally to international conferences to obtain further knowledge and experience in synthetic organic chemistry and its applications.
In his evidence, Dr Roth did not describe the extent to which he and other medicinal chemists at Warner-Lambert kept up to date with the work of competitors in the field of HMG-CoA reductase inhibitors. But it is clear from the whole of the evidence that Dr Roth and his team regularly reviewed published articles and patent documents to keep up to date with developments in the field. For instance, Dr Roth was aware of the structure of the statins being developed by competitive firms and tested them for comparative purposes alongside the Warner-Lambert compounds. In his affidavit evidence, Dr Roth said that the work being done by the teams at Merck (including that described in the Willard Patent) and Sandoz was of particular interest to him and to others working on HMG-CoA reductase inhibitors. He said that these companies were publishing widely on the development of improved HMG-CoA reductase inhibitors and that this work was cited by many others working in the area.
In his affidavit evidence, Dr Roth said that on or before 30 May 1986 he expected that most medicinal chemists would have adopted the practice of regularly reviewing leading journals in the field, such as the Journal of Medicinal Chemistry, the Journal of the American Chemical Society, the Journal of Organic Chemistry, Tetrahedron Letters and Bioorganic and Medicinal Chemistry, so as to keep abreast of developments in medicinal chemistry. He said that he would not expect other medicinal chemists in general to be aware of specific developments in the field of HMG-CoA reductase inhibitors without conducting a search and careful review of the relevant literature in that field. The specific developments to which Dr Roth referred included the following:
(a)The identification of compactin as a potent inhibitor of HMG-CoA reductase in the late 1970s and the determination of its relative stereochemistry.
(b)The publication of the absolute stereochemistry of compactin, which has the R-trans configuration in the lactone, by Sato et al in 1984.
(c)The publication in around 1980 by Merck of the structure of a second natural HMG-CoA reductase inhibitor, mevinolin, which subsequently came to be called ‘lovastatin’. The absolute stereochemistry of lovastatin, which has the R-trans configuration in the lactone, was published in 1980.
(d)The Willard Patent, published in March 1983, was the first publication to indicate that the complex structure of the natural HMG-CoA reductase inhibitors could be replaced with a simple structure without loss of biological activity.
(e)In the early 1980s, drug discovery teams at Merck and Sandoz were publishing widely on the development of improved HMG-CoA reductase inhibitors and that work was cited by many others working in the field. At that time other statins under development included pravastatin, simvastatin (produced by Merck), and fluvastatin which had been discovered by Sandoz and which was in a fairly advanced state of development.
Nonetheless, Dr Roth accepted that medicinal chemists generally may have been aware, at a high level, of some of these developments.
More generally, Dr Scallen explained that in order to conduct the in vitro screen correctly, it is necessary to get the compounds to be tested into a uniform solution as that is the only way to deliver an accurate amount of test compound. If the test compound does not dissolve, the concentration of stock solution and all subsequent serial dilutions is unknown, which presents serious difficulties for accurate testing. Dr Scallen said that in his work at Sandoz he used a solvent control and at any sign of cloudiness the experiment was stopped and steps were taken to ensure that the compound was dissolved.
Dr Watson considered that the results in CSI 118 were very suspect and that it would be inaccurate to use the data from CSI 118 in isolation. In paras 5.25 and 5.26 of his affidavit, Dr Watson said:
‘When I compare assay results across a row I observe more than a twenty-five fold difference in CSI 118 between the racemic sodium salt and racemic calcium salt. I would not expect there to be significant differences in activity in an in vitro test between salts. The results in CSI 122 in columns E and F are more typical. In this experiment the differences in activity [0.00313 and 0.00359] are not significant.
My review of the CSI data suggests to me that there may, for example, be a solubility problem in the testing of the calcium salt in CSI 118 that led to the extremely low value of [0.257]. I also note that in CSI 118 the racemic calcium salt has only 6% of the activity of the internal control, compactin. This further indicates a problem with CSI 118 …’.
In cross-examination, Dr Watson also said that the results for the racemic calcium and the racemic sodium salt in CSI 118 should not be so different, given that in the assay they both equilibrate and form the acid. He said that in a CSI asssy there should not be much difference between salts as the assay aims to get everything into solution creating a brew of the compounds. Consequently, it does not really matter much what salt form one starts with and there should not be much difference in activity levels between different salts.
Dr Cunningham said that CSI 118 was seriously flawed. In para 2.41 of his affidavit sworn 15 September 2006, he said:
‘The problem with CSI 118, however, and not mentioned by Dr Roth, is that the racemic sodium salt exhibits a remarkably better IC50 value than any other compound tested in CSI 118, and far better than the value shown for the racemic calcium salt. Further, the R-trans calcium salt had a worse result than the racemic sodium salt. I refer to the extracts from the “Central Binder” at Exhibit BDR-11. If CSI 118 correctly represented the IC50 value for the compounds tested, then Warner-Lambert should have developed the racemic sodium salt as it was far more active than the R trans calcium salt (Lipitor) and it might reasonably be expected to be more soluble in vivo (as sodium salts are generally more soluble than calcium salts). The racemic sodium salt had a reported value of 0.0097mM and the racemic calcium salt had a reported value of 0.26mM. As the IC50 values for these two compounds should have been very similar, it is clear that there was something badly wrong with this test. The reported value for the R-trans calcium salt was 0.025mM which can be seen shows far less potency than the racemic sodium salt. It is clear to me that CSI 118 was seriously flawed.’
Dr Roth was isolated in his defence of CSI 118. While he noted the large differences in CSI 118 between the results for the racemic sodium salt and the racemic calcium salt, he said it is inappropriate to compare between salts. He refused to admit any problem with CSI 118. This was despite the evidence given by the other witnesses, and despite his agreement that the calcium salt in CSI 118 is much less active than the compactin control, whereas in the other tests that is not the case.
Warner-Lambert also submitted that the Court should feel comfortable in accepting the results of CSI 118, notwithstanding the criticisms of it by Ranbaxy’s witnesses, because Ranbaxy had not relied on its own testing or called evidence based on any tests it commissioned. I do not agree with this submission. No adverse inference is to be drawn because Ranbaxy chose to rely on Warner-Lambert’s own data. It was fully entitled to make this choice.
I prefer, and accept, the evidence given by Dr Scallen, Dr Watson, Dr Cunningham and Professor Easton concerning solubility problems and the deficiencies in CSI 118. I do not accept Dr Roth’s evidence. In my opinion, the evidence establishes that the results in CSI 118 were not scientifically sound, and that those results do not support a claim of surprising difference in activity between the RR enantiomer and the racemate, let alone a ten-fold difference in activity.
Other CSI test results: CSI 111, 112 and 124
On the evidence, I accept Warner-Lambert’s submission that no account should be taken of CSI 111 which was repeated in CSI 112. Dr Watson’s evidence was that it was probably appropriate to delete CSI 111 from any analysis on the basis that there was a dilution error. Dr Scallen agreed that this experiment, like others, should have been repeated, but he preferred to err on the side of caution by including the result in his analysis rather than being selective. However, I consider that the better course is to exclude the result in making an assessment of what constitutes a fair assessment of all relevant CSI data.
I have already noted that the correct value for CSI 119, after correcting the transcription error, is 0.0324mM.
Warner-Lambert contended that no account should be taken of CSI 124 which reported a value of 0.001mM for the racemic sodium salt. It submitted that it was an ‘outlier’ that differed greatly from the result for the racemic sodium salt in CSI 118 and that it should be disregarded.
In my opinion, the weight of expert evidence is against the exclusion of CSI 124. Dr Scallen rejected the suggestion that it should be excluded, pointing out that the result is not so different from that in CSI 118. Dr Watson agreed that the figure in CSI 124 could be regarded as an outlier but he would not rule it out any more than some of the other CSI test results.
In vivo AICS assays
Warner-Lambert’s laboratory records of testing revealed that Warner-Lambert had three different types of assay tests available to assess the activity of new compounds with respect to the inhibition of cholesterol biosynthesis. Aside from the CSI assays, which have already been discussed, the other tests were in vivo Acute Inhibition of Cholesterol Synthesis assay (commonly known as an ‘AICS’ assay) and in vitro COR assays. The latter are discussed at [350]-[354] below.
It was not in dispute that Warner-Lambert conducted in vivo AICS assays to test potential HMG-CoA reductase inhibitors. The AICS assays were carried out according to a protocol whereby four groups of rats (five animals per group to account for biological variability between animals) were given a test compound in different concentrations, and the fifth group remained as a control and did not receive the test substance. After 50 minutes blood samples were taken and the level of [14C] cholesterol was measured. In this manner, four different test amount concentrations were assessed against a control.
Dr Roth gave evidence that in vivo assays were not used in SAR work by medicinal chemists because the results were affected by factors that might be inherent in the particular animal under testing, such as the rate of the drug’s dissolution in the stomach, absorption of the drug across the intestinal wall, the time taken for the drug to reach the target, and metabolism of the drug in the animal. For these reasons, he said that in vivo assays cannot be used validly as a direct measure of the intrinsic activity of the compound. This evidence does not sit very comfortably with other passages in Dr Roth’s evidence or with Warner-Lambert’s internal records concerning the use which it made of in vivo assays as indicators of the intrinsic activity of the compound.
In his affidavit, Dr Roth made the following observations at paras 8.13 and 8.15 regarding Warner-Lambert’s use of in vivo and in vitro assays:
‘The intrinsic activity of a compound measured in an in vitro assay and its in vivo efficacy and toxicity are both important considerations when selecting lead compounds for development. Senior management are particularly interested in the results of in vivo assays, and that information is often presented to them, because it indicates whether a compound may be suitable for development as a drug in terms of its bioavailability at the target and toxicity in an animal.
…
There was a lot of excitement within Warner-Lambert when the AICS assay was developed because this assay was a rapid way of determining if a test compound was bioavailable and resulted in inhibition of cholesterol biosynthesis in a live animal (a rat).’
In his oral evidence, Dr Roth said:
‘I am not suggesting they [in vivo assays] are useless at all. They have value. In fact, if you are going to take a compound forward, you would want to get a sense that it has some in vivo activity. However, the in vivo data tells you many things. It tells you something about whether the drug is absorbed, it tells you something about metabolism. Only one of the things that is measured is the intrinsic activity. You do need to have intrinsic activity in order to see an effect in vivo. So you want that, clearly. One of the things that we did was to test compounds in this AICS model. We had other in vivo models as well. Again, the importance of that is that it tells you that in a whole animal your drug is being absorbed, it is getting to the target and having an effect. Obviously, what is important is what happens in humans, but it gives you an indication that you get oral absorption, and, clearly, oral absorption is something that is important.’
On the other hand, Dr Scallen commented on the usefulness and importance of in vivo AICS assays in assessing the activity of potential HMG-CoA reductase inhibitors in the following way:
‘I think because of the short-term nature of the AICS single dose one hour only for the drug to act, followed by labelling of cholesterol from C14 acetate, that is such a short-term intervention that, indeed, by doing a dose response curve with different amounts of the compound you can get at least an estimate of intrinsic activity under circumstances of the live animal. I think that’s very, very valuable. You don’t have to have drug metabolism going on to an appreciable degree during those 60 minutes, and it is an extraordinarily valuable determination.’
The results of Warner-Lambert’s AICS assays on racemic and chiral forms of the calcium salts of atorvastatin are reported in numerous internal reports of Warner-Lambert. One such report is dated 31 May 1989 and entitled ‘Research Report No: RR-740-02620, Acute Inhibition of Cholesterol Synthesis in the Rat by the Calcium Salts (Racemic and Chiral) of CI-971’. The document reports on the repeated head-to-head AICS testing in rats of the control (lovastatin, another HMG-CoA reductase inhibitor), the racemic calcium salt of atorvastatin (PD 124,488-38A) and the R-trans enantiomeric calcium salt of atorvastatin (PD 134,298-38A). The report states as follows:
‘RESULTS
In two separate experiments… the chiral [R,R] calcium salt of CI-971 (PD 134298-38A) was approximately twofold more active at inhibiting cholesterol synthesis acutely in vivo compared to the racemic mixture (PD 124488-38A). This is to be expected if 50% of the racemic salt is the inactive [S,S] isomer…CONCLUSION
The chiral calcium salt of CI-971 (PD 134298-38A) is twofold more active than the racemic calcium salt (PD 124,488-38A) and equal in activity to lovastatin for acutely inhibiting cholesterol synthesis in vivo in rats.’The report was signed by Dr Sliskovic, a chemist who worked under Dr Roth’s direction and in close liaison with him in carrying out the CSI testing of atorvastatin.
Another memorandum prepared by Warner-Lambert dated 1 June 1989 also reported a twofold increase in activity of the active enantiomer over the racemate:
‘Animal Efficacy Conclusions
Unlike the racemic lactone (CI-971), PD 134298-38A [R-calcium salt] inhibited cholesterol synthesis in vivo in rats when gavaged as an aqueous suspension… The ED50 for inhibition was 0.89 mg/kg, which is identical to that for lovastatin. As expected, PD 134298-38A was twofold more potent than PD 124488-38A, the racemic calcium salt, which contains 50% inactive isomer.’
The 1 June 1989 report was signed by Dr Roth together with a Dr Roger Newton.
Later internal memoranda of Warner-Lambert dated 28 September 1989 and 5 December 1989 make the same comparison with the racemic mixture – ie twofold more potent as expected.
In Dr Scallen’s opinion, the in vivo assay is the most important form of testing of the two (in vivo and in vitro), and he considered it to be ‘the ultimate test’. In his affidavit at para 112, he attached particular importance to the results of the AICS tests that were reported in Warner-Lambert’s report of 31 May 1989 as:
‘…this is the only data from Warner-Lambert, whether in vivo or in vitro, which involved two repeated paired, or head to head, experiments, in which the repeated experiment confirmed the first paired experiment. They are head to head in the sense that the racemate of atorvastatin calcium is going head to head (or is paired) against the R-trans enantiomer of atorvastatin calcium. Therefore this particular data has great scientific strength.’
In cross-examination, he said that these two experiments provided results which are in excellent agreement, and none of the in vitro data provided numbers which were anywhere near as close. Further, it is the only example of two head-to-head experiments where one confirms the other: the data is therefore reliable and reproducible.
Dr Watson also considered that these two head-to-head AICS tests were important data that should be taken into account before drawing conclusions as to the activity levels of potential new compounds. More generally, Dr Cunningham also considered it necessary to ‘have had regard to the totality of the data that was available in order to carry out a proper comparison’. He disagreed with Dr Roth’s evidence that in vivo assays are not used in SAR work by a medicinal chemist.
These internal reports were put to Dr Roth during cross-examination. Dr Roth sought to distance himself from the conclusions contained in the 1 June 1989 report that he signed:
‘Do I take it that although you signed that memorandum, you didn't agree with it?--- Sir, I wrote the chemistry part, Roger [Dr Newton] wrote the biology part. Basically what Roger - he has an interpretation of the in vivo data. However, without knowing the detailed pharmacokinetics of the compound, you really can’t draw this conclusion that it’s twofold more potent, but – so I would disagree with the conclusion. But frankly, it's not a significant conclusion to senior management. All they care about is: is the compound active? How does it compare with compactin?
You were prepared nevertheless to sign a statement to the effect that a twofold increase was to be expected?--- I didn't sign in agreement to that statement necessarily. My name is on the front.
But it has not only got your name, it has got - you actually signed it?--- I signed it. Again, it doesn't necessarily mean that I agreed with Roger's interpretation of the biology data.
Would you agree that it reflects the general view of the correct interpretation of the biology data?--- It reflects Roger's interpretation.
Did you raise any objection to the statement we have just been looking at, Dr Roth?--- To Dr Newton?
I mean, here is your name on the document. It states a conclusion with which you say you disagree. Did you make your disagreement clear?--- I don't recall what discussions Roger and I had about the data, if any. His responsibility was the biology section, mine was the chemistry section. Frankly, whether it was twofold more active in the in vivo experiment and whether Roger expected that or not is really his opinion. I would not - again, unless you know the detailed pharmacokinetics, you don't know what you’re testing in an in vivo experiment. You don’t know whether absorption is the same, whether you are testing active metabolites, and so it’s really difficult to draw that conclusion unless you understand the pharmacokinetics of your compound, which we did not at that time. So Roger's conclusion there is inaccurate. Did we dispute it? Was it worth disputing about? I don't [know] that it was worth arguing about one way or another at the time.
In any event, so far as you remember, you didn't dispute it at the time?--- I don't recall what conversations Roger and I had about the data.’
At the time of signing the report, Dr Roth did not voice any disagreement with Dr Newton’s findings, or attempt to have the statement of twofold increase in activity corrected. Nor did he do so at any time thereafter. In my opinion, Dr Roth consciously sought to downplay the importance and usefulness of the AICS assay data to this Court. There was no proper justification for doing so. I do not accept that he had any genuine issue or disagreement with these reports or the results contained therein.
The reports were directed to Warner-Lambert’s senior management and treated the AICS data as important data of great scientific strength that afforded direct evidence of the activity levels of the RR enantiomer of atorvastatin.
The AICS assays contradict the claim of ten-fold increased activity. Instead, they confirm the normal expectation of a person skilled in the art of a twofold increase in activity of the active RR enantiomer over the racemate.
The AICS assay results reported in the internal reports pre-date the application for the Enantiomer Patent, which was lodged on 23 July 1990. Dr Roth’s knowledge of these AICS assay results is confirmed by his signature on the 1 June 1989 memo. I reject Dr Roth’s evidence about the usefulness of the AICS assays generally, and his attempt to distance himself from the AICS assay results as reported in the internal memos.
I have no doubt that Dr Roth was aware of the AICS assay results at the time he was asked by senior management to find data that would support ‘surprising’ activity for the active enantiomer. I find that Dr Roth chose not to include the AICS assay results in the patent specification of the Enantiomer Patent. Those results were ‘as expected’ and did not meet senior management’s request or suit his objective of selecting data that supported ‘surprising’ activity.
In vitro COR assay
In his affidavit evidence, Dr Roth explained that while the CSI screen measured the ability of a test compound to inhibit overall cholesterol biosynthesis (without indicating which specific step in the cholesterol biosynthetic pathway was being inhibited), the COR assay measured the ability of a test compound to inhibit HMG-CoA reductase specifically. He said that the COR test became available at the end of 1982 but after approximately six months was found to produce some ‘false positive’ results, that is it wrongly recorded some compounds as having biological activity. The CSI screen was introduced in the middle of 1983 and it produced more reliable results and became the primary assay for testing the cholesterol inhibition activity of compounds. Dr Roth stated that in early 1984 a modified COR assay was introduced. However, as noted at [245] above, Dr Roth said that his team continued to use the CSI screen as the primary assay. He used the COR ‘as a secondary assay to confirm that the compound was inhibiting the target HMG-CoA reductase enzyme’. This approach of using COR assay results as a secondary confirmation of activity is consistent with Table 1 of 981 Patent specification.
Contemporaneous internal reports of Warner-Lambert reveal that Warner-Lambert presented comparative CSI, COR and AICS assay results for HMG-CoA reductase inhibitors, eg the ‘Atherosclerosis Drug Discovery Team Report’ dated 12 December 1989 at pg 28.
On the COR assay results, Dr Scallen had this to say in his affidavit at para 129:
‘After having examined all Warner-Lambert’s COR data on atorvastatin, I have formed the opinion that there was tremendous variability between the various experiments conducted. This variability was of such a kind that it is impossible for me to draw any scientifically valid conclusions when looking at the COR data as a whole. However, the COR data is entirely consistent with my expectation that the R-trans enantiomer of atorvastatin would be approximately twice as active in inhibition of HMG-CoA reductase activity than the racemate of atorvastatin. It certainly does not support a ten fold difference in HMG-CoA reductase inhibitory activity between the R-trans enantiomer and the racemate.’
This evidence was not challenged in cross-examination. Nor did Dr Roth assert that the COR assay results confirmed a ten-fold activity increase.
Warner-Lambert’s approach to the Enantiomer Patent application differs from its 981 Patent application, and its own comparative internal reporting, in that COR assay data is not included. On the evidence, I find that there was no valid reason for excluding the AICS and COR assays from the field of relevant data when reporting on the activity of the RR enantiomer in the Enantiomer Patent specification. Further, I find that the results from the COR assays do not support the claim of ten-fold increased activity. Rather, the results are consistent with the normal expectation of a person skilled in the art of a twofold increase in activity of the active RR enantiomer over the racemate.
The claim of ten-fold activity
On any view of the expert evidence, Warner-Lambert’s alleged finding that the RR enantiomer had ten-fold greater activity than the racemate would amount to a very significant finding. It is remarkable, therefore, that this finding is not referred to in any of Warner-Lambert’s internal documents, or in any of the literature published by Dr Roth and his team concerning their discovery of atorvastatin.
The claimed finding of ten-fold increased activity is not referred to by Dr Roth in either his 1991 or 2002 papers concerning the development of atorvastatin. The Warner-Lambert internal reports dating from 1989 concerning the results of AICS tests state that the R-trans enantiomer demonstrated activity that was two times greater than the racemic mixture, as expected. If Warner-Lambert truly had CSI data that established that the RR enantiomer was ten times more active than the racemate, as claimed in the Enantiomer Patent specification, one would expect to find some commentary or explanation as to the different outcomes of the earlier CSI testing and the later AICS testing. There is no such commentary.
The clear inference is that the claim of surprising and unexpected inhibition of the synthesis of cholesterol by the RR enantiomer, in the order of ten times greater activity than the racemate, is an artificial and unsupported claim that was generated by Dr Roth’s search for data that could be used selectively to support the Enantiomer Patent application. I so find.
The data shows the expected twofold level of activity
On any fair assessment, the whole of the data that was available to Warner-Lambert at the date of its application for the Enantiomer Patent and at all times up to the date when the Enantiomer Patent was granted, did not support a claim that the RR enantiomer was about ten times more active than the racemate. On the contrary, I consider that the data available to Warner-Lambert, taken as a whole, established on the balance of probabilities, that the RR enantiomer had an activity level that is approximately two times greater than the racemate.
Both Dr Scallen and Dr Watson said that the totality of the CSI data, the COR data and the AICS data, taken as a whole, is consistent with the expectation that the R-trans enantiomeric forms of atorvastatin would be approximately twice as active as the racemic forms of atorvastatin. I accept this evidence.
Dr Scallen and Dr Watson also separately considered what conclusions, if any, could be founded upon the CSI data when it was taken as a whole, bearing in mind its variability and the other difficulties they identified with it. Both witnesses reached the conclusion that the CSI data was consistent with the normal expectation of a level of activity twofold greater than the racemate.
Dr Scallen noted that the CSI tests showed slightly more than a seven-fold variation for compactin, which might be due to the use of a new batch of rat liver homogenate for each CSI experiment. To reduce the variability between the tests on account of this factor, Dr Scallen normalised the test results. This means that compactin was arbitrarily assigned a value of 100 in each of the CSI experiments, and the potency of the test compound relative to compactin was calculated. I accept Dr Scallen’s evidence that normalisation is routinely used by scientists as a technique to minimise variability between tests. There was evidence that it was in fact used in this way by Dr Scallen and Dr Roth. When normalised, the CSI tests results were restated as follows:
*transcription error corrected
Dr Scallen concluded that the restated data is consistent with the potency of the RR enantiomer being no more than the expected twofold potency of the racemate.
Relying on this table of normalised data, Ranbaxy submitted that the appropriate comparison was to take all of the values for the racemate in columns A, B and C (ie lactone + sodium + calcium) and compare them with all of the values for the R enantiomer in columns D, E and F (ie lactone + sodium + calcium). Using the figures in the restated table, this comparison produces a figure of 183 per cent, that is to say the R enantiomer is in the order of 1.83 times the potency of the racemate.
Dr Watson also said that the normalised results were consistent with the conclusion that the potency of the R enantiomer is no more than the expected 200 per cent of the potency of the racemate.
In final address, Warner-Lambert also presented various comparisons based on normalised data from the CSI tests which suggested that the RR enantiomer was between four and eight times more potent than the racemate. None of these comparisons included all of the CSI data. Moreover, each comparison excluded the results of CSI 107 which, of itself, renders the comparisons invalid and inappropriate.
I am satisfied that the CSI data, taken as a whole, is consistent with the view that the potency of the RR enantiomer is in the order of two times the potency of the racemate, in accordance with normal expectations. When account is taken of the other evidence discussed above, including the COR assays and the AICS assays, I am satisfied on the balance of probabilities that the potency of the RR enantiomer is in the order of two times the potency of the racemate, in accordance with normal expectations.
Conclusion
Having regard to all of the foregoing matters, I have reached the following conclusions:
(a)The statements in the specification for the Enantiomer Patent that represented that Warner-Lambert had found that the R-trans enantiomer achieved surprising and unexpected inhibition of the biosynthesis of cholesterol in the order of a ten-fold increase above the activity levels of the racemate were false and misleading.
(b)The representation in the specification for the Enantiomer Patent that the results in the CSI Table reflected all of the CSI data available to Warner-Lambert for the relevant compounds, and that the data as a whole provided reasonable grounds for the findings set forth in the CSI Table, were false and misleading.
(c)The representation by Warner-Lambert to the Patent Office in its patent attorney’s letter of 26 June 1992 that the R-trans isomer was ten times more active than its racemic mixture was false and misleading.
Utility
The final ground of invalidity relied upon by Ranbaxy is that the alleged invention, as claimed in each claim of the Enantiomer Patent, is not a patentable invention within s 18(1)(c) of the 1990 Act because it is not useful. There is no material difference between this provision and s 100(1)(h) of the 1952 Act, and neither party suggested that there was.
These provisions are directed to the question whether the invention enables the addressee to attain the result promised by the patentee in the patent specification: see Rehm Pty Ltd v Webster’s Security Systems (International) Pty Ltd (1981) 81 ALR 79 (‘Rehm’) at 96; NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd (1993) 44 FCR 239 at 267 per Lockhart J; Old Digger Pty Ltd v Azuko Pty Ltd [2000] FCA 676 (‘Old Digger’) at [216]; Wrigley at [134]-[141]. Want of utility in this sense is different from want of utility in the broader commercial sense that the invention is useless for any purpose whatsoever: see Alsop’s Patent (1907) 24 RPC 733 at 752; and Lane-Fox v Kensington & Knightsbridge Electric Lighting Co Ltd [1892] 3 Ch 424 at 431.
In Rehm, Gummow J explained the governing principles at 96, as follows:
‘The basic principle has been formulated as follows in Fawcett v Homan (1896) 13 RPC 398 at 405 per Lindley LJ: “If an invention does what it is intended by the patentee to do, and the end attained is itself useful, the invention is a useful invention.”
What the invention is intended to do is a matter to be gathered from the title and the whole of the specification: Blanco White, Patents For Inventions, § 4–403. A distinction may be drawn between a case where a patentee claims a result and bases his claim on the production of that result and the case where a patentee merely points to certain advantages that will accrue from the use of his invention: Fox H G, Canadian Patent Law and Practice, 4th ed, pp 152–4.’
See also TA Blanco White, Patents for Inventions, 5th edn, Stevens & Sons, London, 1983 (‘Blanco White’) at [4-402] and [4-403]; and Terrell on the Law of Patents, 14th edn, ed D Young et al, Sweet & Maxwell, London, 1994 at [5.121]-[5.128].
As the latter part of the passage from Rehm suggests, the grounds of utility and false suggestion or misrepresentation can overlap. False suggestion or misrepresentation is a wider concept; it extends to representations that are extraneous to the specification and representations that do not attract the inutility ground. Blanco White states at [4-405]:
‘It is not easy to distinguish between the sort of failure to fulfil a promise of results made in the specification that will amount to lack of utility and the sort that merely amounts to a false representation and accordingly will invalidate only if the patent has been “obtained” upon it. The distinction has been phrased as one between a promise of results and a mere wrong statement of the purposes for which that which is attained can be used; also as one between a promise of results and a “mere puff”, or between a false representation of the attributes of the product claimed and an accurate representation as to its attributes coupled with an expression of an “over-sanguine and erroneous view of its character.”’
See also Hatmaker v Joseph Nathan Co Ltd (1919) 36 RPC 231 at 239 and Old Digger at [216].
In this case, the overlap between the two grounds of invalidity is substantial. I have already held that, on its proper construction, the Enantiomer Patent specification represents that Warner-Lambert had found that the R-trans enantiomer achieved surprising and unexpected inhibition of the biosynthesis of cholesterol in the order of a ten-fold increase above the activity levels of the racemate, and that this representation was false and misleading: at [253] and [367]. Ranbaxy contends that, on the proper construction of the Enantiomer Patent specification, this representation constituted a promise by Warner-Lambert, as patentee, that the compounds of the invention had achieved, and were capable of achieving, surprising and unexpected inhibition of the biosynthesis of cholesterol in the order of a ten-fold increase above the activity levels of the corresponding racemate. In these circumstances, Ranbaxy submitted that inutility was made out by the same matters as it advanced in support of its case of false suggestion or misrepresentation.
Warner-Lambert did not dispute that the specification promised that the compounds of the invention would achieve surprising and unexpected inhibition of cholesterol biosynthesis. Its case on utility depended essentially upon the same construction issue that I considered in dealing with the arguments concerning false suggestion or misrepresentation. In its closing written submissions, Warner-Lambert submitted that the invention claimed by the Enantiomer Patent is based on identifying from amongst a large number of compounds a single enantiomer with surprising and unexpected inhibition of cholesterol biosynthesis, and that the promise in the specification is that of unexpected activity, which Lipitor fulfils. In his final address, senior counsel for Warner-Lambert acknowledged that what is being promised in the specification is ‘activity which is substantially better than twofold’.
Warner-Lambert’s submission depends on a construction of the specification which I reject. As I have said, the person skilled in the art reading the specification would link the CSI Table at pg 8 of the specification with the claims that the R-trans enantiomer provides surprising and unexpected inhibition of cholesterol biosynthesis: at [252] above. On the proper construction of the specification, Warner-Lambert promised that the compounds of the invention were capable of achieving a particular result, namely surprising and unexpected inhibition of cholesterol biosynthesis in the order of ten times that of the corresponding racemate.
This construction of the specification is consistent with the character of the Enantiomer Patent. It is, in effect, a selection patent: ie the compounds of the Enantiomer Patent have been selected from the broad class of compounds disclosed by the 981 Patent on the ground that those compounds have unexpected properties. The criteria for the grant of a selection patent were considered in IG Farbenindustrie AG’s Patents (1930) 47 RPC 289 (‘IG Farbenindustrie’) at 322-323 and are quite stringent: the selection must be based on some substantial advantage gained or some substantial disadvantage avoided; the whole of the selected members must possess the advantage in question; and the selection must be in respect of a quality of a special character which may fairly be said to be peculiar to the selected group. The authorities also require that the advantages gained, or disadvantages avoided, by the selection must be expressly identified in the body of the specification. Blanco White states at [4-511]:
‘Where the patent is a “selection patent,” there is an additional requirement for sufficiency that the special advantage obtained from the selection must be stated in the specification. More generally, the advantage resulting from the invention must be stated whenever failure to do so leaves the invention inadequately defined.’
In IG Farbenindustrie at 323, Maugham J said:
‘“I must add a word on the subject of the drafting of the specification of such a patent. It should be obvious, after what I have said as to the essence of the inventive step, that it is necessary for the patentee to define in clear terms the nature of the characteristic which he alleges to be possessed by the selection for which he claims a monopoly. He has in truth disclosed no invention whatever if he merely says that the selected group possesses advantages. Apart altogether from the questions of what is called sufficiency, he must disclose an invention; he fails to do this in the case of a selection for special characteristics, if he does not adequately define them”.’
In the Enantiomer Patent specification, Warner-Lambert has defined the claims of unexpected and surprising inhibition of cholesterol biosynthesis by means of the CSI Table at pg 8 of the specification.
The decision in May & Baker Ltd v Boots Pure Drug Co Ltd (1948) 65 RPC 255 provides a useful illustration of the application of these principles in circumstances which are not unlike this case: see also E.I. Du Pont Nemours & Co (Witsiepe’s) Application [1982] FSR 303.
As to whether the results promised by the Enantiomer Patent specification are capable of being achieved, I have reviewed the relevant evidence in the previous section of this judgment. Based on this evidence, I find that the compounds of the Enantiomer Patent have not achieved, and are not capable of achieving, the promised results, that is to say a surprising and unexpected inhibition of cholesterol biosynthesis in the order of ten times that of the corresponding racemate. The evidence before me also establishes that the potency of the RR enantiomer is in the order of two times the potency of the racemate, in accordance with normal expectations. Accordingly, I have concluded that the invention claimed by the Enantiomer Patent is not useful within the meaning of s 18(1)(c) of the 1990 Act and s 100(1)(h) of the 1952 Act.
Warner-Lambert submitted that Lipitor’s commercial success demonstrates that the compounds claimed by the Enantiomer Patent (including claim 6) are undoubtedly useful. It also submitted that Ranbaxy’s intention to market its own version of atorvastatin calcium in Australia supports the view that the compound has surprising activity and consequently utility. These submissions are misdirected. Utility in patent law is directed to the results promised by the specification, and not to the broader question of commercial or financial success: see Terrell on the Law of Patents at [5.128]; Badische Anilin Und & Soda Fabrik v Levinstein (1887) 4 RPC 449 at 462.
Orders
Ranbaxy has succeeded in its challenge to the validity of the Enantiomer Patent. Accordingly, it is entitled to an order revoking the Enantiomer Patent.
Warner-Lambert has succeeded in its cross claim that Ranbaxy’s intended importation and sale of its product will infringe the 981 Patent. It is entitled to a permanent injunction restraining Ranbaxy during the term of the 981 Patent, and any extension of that term, from infringing the 981 Patent.
I will hear submissions on the question of costs.
I certify that the preceding three hundred and eighty-one (381) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Young. Associate:
Dated: 20 December 2006
Counsel for the Applicant/Cross-Respondent: Dr J Emmerson QC, B Caine SC and L Duncan Solicitor for the Applicant/Cross-Respondent: Norman Waterhouse Counsel for the First Respondent/Cross-Claimant: R Macaw QC and A Ryan Solicitor for the First Respondent/Cross-Claimant: Allens Arthur Robinson Counsel for the Second Respondent: The Second Respondent did not appear Date of Hearing: 9, 10, 11, 12, 13, 16, 17, 18, 19, 20 and 23 October 2006 Date of Judgment: 20 December 2006
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