Farewell time for world’s largest selling chartbuster pharmaceutical brand Lipitor®: What next after November 30, 2011

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About Authors:
Dr. Amit Gangwal,
Smriti College of Pharmaceutical Education,
Indore

Introduction
Lipitor® is the best-selling drug ever, accounting for $106 billion sales over the last decade. Two generic drug manufacturers are ready to compete starting December 1, 2011. Watson Pharmaceuticals is making a generic version authorized by Pfizer under a profit-sharing agreement. Pending federal approval, Ranbaxy Laboratories also plans to sell a generic version. It is noteworthy that when a drug’s patent protection expires, the federal law permits only limited generic competition in the first six months1.

Because Ranbaxy was the "first to file" and challenge a Lipitor patent, it is likely that no other generic manufacturers will be allowed to make a generic version until 180 days after Ranbaxy first starts selling its version in US market. Lipitor (atorvastatin calcium) is a synthetic lipid-lowering agent. Atorvastatin (a member of stain family is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. Lipitor is manufactured by Pfizer and distributed by Parke-Davis (Division of Pfizer Inc, NY). Atorvastatin was first synthesized in 1985 by Bruce Roth while working at Parke-Davis Warner-Lambert Company (now Pfizer). Oral tablets are white, elliptical, and film-coated. Pfizer also packages the drug in combination with other drugs under the brand name Caduet. In some countries, atorvastatin calcium is made in tablet form by generic drug makers under various brand names including Stator (India), Atoris, Atorlip, Lipvas, Sortis, Torvast, Torvacard, Totalip, and Tulip2. One of the most critical medicines in recent medical history, Lipitor remains the world’s best-selling pharmaceutical brand prescribed to treat elevated LDL (bad) cholesterol and triglycerides, and to prevent cardiovascular disease. Lipitor is proven to reduce the risk of heart attack, stroke and other cardiovascular events in patients with certain cardiovascular risk factors or with heart disease.
As the company is on the brink of loosing the hold from this blockbuster brand, Pfizer’s chief executive officer (CEO), Ian Read, said “company will try to introduce a nonprescription form (over the counter, OTC) of its top-seller Lipitor to help cushion tumbling sales of the cholesterol pill (as generic versions are desperate to hit the market); it is expected to come in market in 2013, because of the regulatory process to get it approved”. The nonprescription version of Lipitor, however, will not be available immediately after its patent expiry as a significant amount of time will be needed to persuade the U.S. Food and Drug Administration (USFDA) that patients could take the drug without a physician’s prescription, and this seems difficult. Along with trying to get an OTC Lipitor to market, Pfizer has entered into an agreement with pharmacy benefit management companies including Medco Health Solutions Inc. and Express Scripts Inc. to sell brand-name Lipitor at a lower price3. After loosing the patent rights, this New York-based company is slated to be toppled from its place atop the pharmaceutical world, where it leads all competitors in drug sales. If market reports are something to go by, then it is estimated that in 2012, Paris-based Sanofi will hold the top spot.

Reference ID: PHARMATUTOR-ART-1181

Lawsuit faced by Lipitor  
Lipitor is currently the world’s highest selling medicine and thus the atorvastatin market offers an alluring prize to generics – particularly any generic which can gain access to the market before the rest of its competitors. Lipitor market is extremely important to Pfizer which controls the relevant Supplementary Protection Certificates (SPCs) through Warner-Lambert4. Lipitor is backed by an unprecedented clinical trials data involving more than 80,000 patients and a research investment of more than $800 million to ascertain the safety, efficacy and potential additional benefits of Lipitor. No generic company would make this commitment, and research-based companies would have no incentive to pursue this work sans a stable patent system. Since Lipitor's introduction in the U.S. in 1997, it has become the world's most-prescribed cholesterol-lowering medication. More than 18 million people in the U.S. have been prescribed Lipitor to lower their cholesterol, and the medicine is approved in more than 70 countries.  Recently, the USFDA approved a new indication for Lipitor to reduce the risk of stroke, including in the millions of people who suffer from rapidly spreading diabetes5. Lipitor’s basic patent is U.S. Patent No. 4,681,893, which expired in March 2010 and the patent covering the calcium salt of Lipitor is U.S. Patent No. 5,273,995, which expired in June 20115. Here are few summaries of some patent lawsuits.  

Teva Vs. Pfizer
In June 2011 Teva decided to launch its generic atorvastatin in the United Kingdom.  As soon as it heard about the launch, Warner-Lambert solicited immediate relief from the court. In quick succession three judgments were issued. The first application in the proceedings between Warner-Lambert and Teva was heard ex parte on 20 June 2011. Teva had communicated to Warner-Lambert in June 2010 that it intended to launch generic atorvastatin on expiry of Warner-Lambert’s atorvastatin SPC, which at that time was due to expire in November 2011 (it has subsequently been extended by 6 months pursuant to the Pediatric Regulation). Despite Teva’s stated intentions, on 20 June 2011 Warner-Lambert discovered that Teva had sought to bring its medicine to the United Kingdom market during the term of the SPC and had in fact sold approximately one million packets of atorvastatin through two distributors. As such, Warner-Lambert requested a temporary restraining order (TRO) pending full hearing of its interim injunction application. The Court found that Warner-Lambert would suffer permanent harm if forced to wait two and a half to three weeks to obtain interim relief against Teva on the basis that it would be difficult, if not impossible, for Warner-Lambert to raise its price to the level that it was at prior to Teva entering the market. The prohibition of the sale of generic atorvastatin did not extend to that which had already been stocked by retailers prior to the grant of the TRO on the grounds that the harm to the patentee occurs when the product is sold to wholesalers and not when it is dispensed by pharmacies. As such, the retail pharmacists were free to sell the stock that they had already acquired to the end customer. The full hearing of the inter-partes interim relief application scheduled for 11 July 2011 did not materialize as the parties were able to reach agreement without assistance from the court.  A further hearing took place on 22 July 2011 at which Teva made an application for a speedy trial in November 2011 in the hope that it could achieve a lucrative duopoly in the event that the patent / SPC in suit were held invalid.  Warner-Lambert argued that such expedition was inappropriate and would prevent it from, among other things, undertaking a full disclosure exercise.  Having assessed all the circumstances, including Teva’s offer to waive disclosure, the Judge ordered that the trial should take place in the second half of November and thus a decision could be expected either just before, or just after Christmas. These judgments give an important indication of the court’s analysis of an application for a TRO in a pharmaceutical patent case4.

Apotex Vs. Pfizer
After thorough examination, in January 2009, the U.S. Patent and Trademark Office (USPTO) said that it would reissue a patent that expires in June 2011 after the Pfizer altered what an appeals court had called inconsistent language that made the patent invalid. This has prevented Apotex Inc. and Teva Pharmaceutical Industries Ltd. from selling a copy before November 2011. Had they been allowed to launch copy of Lipitor in market, as per Pfizer, it would have been infringement of the patent. The lawsuits triggered an automatic 30-month period in which the FDA can’t act on the respective applications unless a court rules in the case before then. In Apotex’s case, that period will end after the patent’s expiration6.

Ranbaxy Vs. Pfizer
U.S. patent protection was slated to be expired in June 2011, but Pfizer made an agreement with Ranbaxy Laboratories (India based pharmaceutical generic giant) to delay the generic launch in the U.S. until November 30, 2011. Pfizer announced that it has entered into an agreement with generics manufacturer Ranbaxy Laboratories and certain of its affiliates to end substantially all their patent litigation worldwide involving Lipitor. Under the terms of the agreement, Ranbaxy will have a license to sell generic versions of Lipitor and Caduet in the United States from November 30, 2011. Caduet (combination of atorvastatin calcium and amlopedin besylate) is a medicine that combines the active ingredients of Lipitor and Norvasc and treats both high blood pressure and high cholesterol. In addition, the agreement provides a license for Ranbaxy to sell generic versions of Lipitor on varying dates in seven additional countries: Canada, Belgium, Netherlands, Germany, Sweden, Italy and Australia. Pfizer and Ranbaxy have also resolved their disputes regarding Lipitor in Malaysia, Brunei, Peru and Vietnam. "Without patents and rigorous defense of intellectual property rights, innovators would face significant challenges that could inhibit the discovery of new medicines. The settlement provides Ranbaxy with licenses to all the patents it needs to make the generic product and enables Ranbaxy to manufacture and launch a generic version of Lipitor prior to the expiration of the crystalline and amorphous patents. The Lipitor patents involved in this agreement are the basic compound patent, which expired in the United States in 2010; the enantiomer patent, which expires in the United States in 2011; as well as various process and crystalline form patents, which expire in 2016 and 2017; and the combination patent for Caduet, which expires in 2018. The agreement pertains solely to Ranbaxy and its affiliates and does not cover legal challenges to the Lipitor patents involving other generic manufacturers. The patent infringement litigation between Pfizer and Ranbaxy relating to Lipitor will continue in five other European countries -- Finland, Spain, Portugal, Denmark and Romania. Court cases involving the enantiomer patents are pending in Spain and Portugal, while an infringement action on the commercial process patent is pending in Finland. Patent cases involving the enantiomer patent are pending in Denmark and Romania7. In addition, the agreement provides a license for Ranbaxy to sell generic versions of Lipitor on varying dates in seven additional countries and resolves disputes regarding Lipitor in four other countries3. After defeating Ranbaxy’s patent challenge to Lipitor in the US on December 16, 2005, Hank Mckinnell-chairman and CEO, Pfizer- told “we will continue to defend against any and all patent challenges that seek to undermine our mission of finding new therapeutic innovations for the patients we serve”8.

Merck Vs. Pfizer
In August Pfizer filed a law suit against Merck to prevent latter from marketing a pill combining a generic version of Lipitor with Zetia (ezetimibe). Merck's Zetia blocks absorption of cholesterol within the digestive tract, as opposed to statins like Lipitor that work within the liver. The Merck drug cannot be approved by the FDA for at least 30 months, according to federal laws that govern generic drugs9.

In conclusion, such is the popularity of this brand that MS word spelling check software automatically corrects the spelling of this word besides indicating it in capital L. Google (search giant) throws about 24,700,000 results if one types Lipitor in Google’s rectangular box and clicks on web page search option, as on November 20, 2011).Pfizer might be in trouble with the Lipitor going off patent, but has a host of drugs that could make up for the lost revenue. AstraZeneca will suffer (indirectly) more than expected due to the deterioration of Lipitor-rival Crestor. The revenue lost by other companies will probably not be as significant, as Lipitor and Crestor dominate the world of cholesterol statins for now. Low price copies of atorvastatin could be a huge catalyst for price reductions across the board in the statin medication market. This farewell of Lipitor is a great event for patients and perhaps for generic companies but a sad event for big pharma10. It is now over for Lipitor but will any other drug molecule will witness such a success, while being helpful for patients?

References
1. Duff Wilson, Plan-would-delay-sales-of-generic-for-Lipitor, New York Times (nytimes.com/2011/11/12).
2. wikipedia.org/wiki/Atorvastatin.
3. Drew Armstrong, Pfizer may bring over the counter Lipitor to market CEO says,  (bloomberg.com/news/2011-11-01).
4. Brian Cordery and Steven Willis., Recent decision in Warner-Lambert v Teva (atorvastatin), (bristows.com/19/09/2011)
5. Pfizer Prevails in Challenges to Lipitor Patents in the United States. (thefreelibrary.com/PFIZER+INC+-+Court+Decision)
6. icmrindia.org/casestudies/catalogue/economics/ranbaxy.
7. Susan Decker, Pfizer Wins New Lipitor Patent Expiring in June 2011, (bloomberg.com/apps/news/ January 6, 2009)
8. marketwatch.com/story/big-pharma-tackles-asia-as-major-patent-cliffs-loom-2011-10-26.
9. medicalnewstoday.com/releases/23 Jun 2008.
10. seekingalpha.com/article/298700-agony-from-lipitor-s-expiration-won-t-be-exclusive-to-pfizer

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