The Hindu Business Line : What's the racemate in `Formula 1' of the pharma race?

ALMOST every court verdict creates winners and losers in equal measure. For instance, the December 16 verdict of the US District Court of Delaware has www.pfizer.com announcing as the latest news headline, `Pfizer Prevails in Challenges to Lipitor Patents in the US'. And Arizona Daily Star reported that, `Lipitor patent win causes solid jump in Pfizer's stock.' And `Ranbaxy Laboratories continues to top the list of Sensex losers,' as http://sify.com noted about the market around noon on Tuesday.

"The US decision marks Pfizer's second major victory over Ranbaxy, which is using legal challenges in an attempt to overturn Pfizer's atorvastatin patents in the US and many other markets," notes Pfizer's site. The earlier `victory' that Pfizer scored over Ranbaxy was on October 12, when the UK's High Court of Justice `upheld the exclusivity of the basic patent covering atorvastatin' thus prohibiting Ranbaxy from introducing a generic version of atorvastatin in the UK until the patent expires in November 2011.

But the UK decision was unusual; it didn't create a clear winner of Pfizer. "The British court ruled that the calcium salt patent, which expires in the United Kingdom in 2010, was invalid," informs Pfizer, adding that it would go on appeal. "UK High court rules in favour of Ranbaxy over one key atorvastatin patent, but says its product infringes another. Ranbaxy to Appeal," reads an October 12 press release on www.ranbaxyusa.com. "Ranbaxy has been successful in invalidating the 281 patent while it was held to infringe another of Pfizer's patent (633). Ranbaxy has appealed on the 633 patent and remains confident of its position," clarifies the company spokesperson, as at the time of writing this.

"Ranbaxy wins on atorvastatin process patent in Norway — will appeal court ruling on intermediate compound patent," informed the company in its November 10 communiqué. A week earlier to that, it informed about the permission granted both to Pfizer and Ranbaxy to appeal the October 12 UK judgment. "The outcome of both appeals is expected by the end of 2006," opines Ranbaxy.

Patents 633 and 281

While the US decision runs to 66 pages, the UK one is about a third long, running to about 10,000 words. And both merit a careful reading. First, the UK verdict in Ranbaxy UK Ltd and Arrow Generics Ltd vs Warner-Lambert Co, by Mr Justice Pumfrey of the High Court of Justice, Chancery Division, Patents Court.

"Technically the case was brought against Warner Lambert, the original holder of the patents. Warner Lambert was acquired by Pfizer in 2000," clarifies www.ranbaxyusa.com. In dispute were UK patents 633 and 281 (that is, 0247633 and 0409281), granted by the European Patent Office, and "concerned with atorvastatin, a cholesterol synthesis inhibitor of great commercial importance". The calcium salt is sold under the name Lipitor, informs the judgment.

To know about Lipitor, check the `press kit' on www.pfizer.com where `company history' has this against 2005: "Lipitor, the most prescribed medicine in the world, reaches 87 million patient years of experience." Lipitor, you'd learn from www.lipitor.com, "is proven to reduce your risk of having a heart attack by 36 per cent". Along with diet and exercise, it can lower `bad' low-density lipoprotein or LDL cholesterol "by 39 per cent to 60 per cent (average effect depending on dose)" and increase `good' high-density lipoprotein or HDL cholesterol levels "by 5 per cent to 9 per cent", it adds. "The drug had sales of about $12 billion in 2004, according to IMS Health," says www.smartmoney.com.

Stereochemistry, enantiomer, chirality and racemate

Dispute can be traced to the letter that Ranbaxy sent to Pfizer to inform about intention to manufacture or sell atorvastatin calcium, which was to comprise "the single optically pure enantiomer [R-(R*,R*)]-2-(4-f1uorophenyl)-(, (-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-lH-pyrrole-1-heptanoic acid, calcium salt trihydrate."

The court studied the patent claim of 633, and observed, "This claim is couched in highly technical language. It uses the device of the chemical structural formula to convey its meaning." The judge explained that the structural formula does two things. "It shows, in a highly schematic way, how the chemical bonds are located between different atoms of the molecule (or larger components, such as the benzene ring, which may be depicted in many ways." The patent is intended for those who will synthesise an active ingredient and formulate it for use in therapy as a hypolipidaemic or hypocholesterolaemic agent, noted the judge. "The patent is, therefore, directed towards medicinal chemists with skills in organic synthesis."

The case is concerned with stereochemistry, said Justice Pumfrey. This branch of chemistry deals with spatial arrangements of atoms in molecules and the effects of these arrangements on the chemical and physical properties of substances, defines www.answers.com.

What is enantiomer? For answer, read this snatch from the judgment: "The tetrahedral arrangement of the covalent chemical bonds that a carbon atom may make with four other atoms means that if there are four different units at the ends of the four different bonds those units may be arranged in two different ways. When one says two different ways, it means that no amount of rotating will permit one arrangement to be superimposed on the other. They will be mirror images of each other, and are called enantiomers."

The adjective to mean the structural characteristic of a molecule that makes it impossible to superimpose it on its mirror image is `chiral', according to Answers.com.) Know also that enantiomers do not differ in any of their physical properties (melting point, boiling point and so on) but one, differing in their effect on plane polarised light. "One enantiomer will rotate the plane of polarisation to the left or anticlockwise, and the other will rotate it to the right."

Racemate is another word you'd encounter in the judgment. "One enantiomer can only be synthesised in preference to the other if the stereochemistry is already present in the starting materials or if enantiomeric reagents are used. Unless the conditions for the reaction are stereospecific the result of the synthesis will inevitably be a 50/50 mixture of the two enantiomers of the chiral molecule. This is called a racemic mixture or racemate." Racemate is "an equimolar mixture of a pair of enantiomers," defines www.chemicool.com. "It does not exhibit optical activity."

Then come diastereoisomers. "Where there are two asymmetric centres in a molecule, there are unsurprisingly four possible isomers. Looking just at the chiral atoms, both may be mirror images of each other, and the molecules form an enantiomeric pair. If one only is a mirror image of the other, then the molecules are called diastereoisomers."

It may be more complex to read that "the drug receptor complex is formed by a combination of hydrogen bonds, p-p stacking between aromatic rings, salt bridge formation between carboxylic acids and amines and hydrophobic binding." The particular parts of a drug that cause it to bind to its receptor are together termed the pharmacophore, informs the judgment. Get familiar with statins too, "a well-known class of compounds recognised as having a potential application for cholesterol-lowering drugs". The first statins, mevinolin and compactin, were natural products that existed as single enantiomers, informs Justice Pumfrey.

Formula I in the pharma race

In the pharma race that forms the case, Formula I of the patent claim 633 was about `the compound of the invention'. It tells the skilled person to make the compound of the invention by a method which will only produce a racemate, observed the judge. "When it compares compounds of the invention with the prior art compactin, what it compares are, in fact, racemates. In the claim it uses a formula which may also be used to denote the enantiomers of interest in accordance with an acknowledged convention that permits it to be used to denote racemates."

For Ranbaxy, Professor Clive (`an out-and-out synthetic organic chemist of wide experience') submitted that if one is going to use the name, or structure, of a single enantiomer in a document to denote a racemate, then you couldn't use the same name or structure to denote the enantiomer as well. It was Dr Newton (`a medicinal chemist of considerable eminence') who was Pfizer's expert to present a counter-view. In the 633 patent, it is absolutely clear from context throughout that formula I is being used to denote a racemate, stated Justice Pumfrey. "In my judgment, every time the skilled person sees formula I or formula X he will see it with eyes that tell him that in that racemate, there is a single enantiomer that is the effective compound, and that he can resolve the racemate using conventional techniques to extract that enantiomer."

The claim in 633 covers the racemate and the individual enantiomers, he ruled, therefore, refusing Ranbaxy the declaration of non-infringement in respect of 633. While Ranbaxy awaits the result of appeal against this verdict, of greater interest is the 281 ruling that Pfizer is appealing against, because the judge found the patent to be `invalid for anticipation and obviousness'.

(To be continued)

ZeroBase@TheHindu.co.in

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