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Pharmaceutical companies today are faced with increased costs for drug discovery and development and aggressive competition from generic drug companies. As research costs skyrocket, generic drug companies sit poised and ready to compete as soon as a patent expires.
Pharmaceutical companies today are faced with increased costs for drug discovery and development and aggressive competition from generic drug companies. As research costs skyrocket, generic drug companies sit poised and ready to compete as soon as a patent expires. Maximizing patent term for successful products is an effective strategy for fending off generic competition and extending product lifecycle. This article will explore strategies for keeping a product under the patent umbrella.
The costs associated with discovering a compound, turning that discovery into a suitable drug candidate, and getting that candidate to market have risen dramatically. Some estimates indicate that the cost for developing and marketing a single pharmaceutical product has risen from $54 million in the 1970s to greater than $800 million by 2000.1
Figure 1. U.S. Patent Application Process.9Patent protection and the market exclusivity that comes with it help to ensure a return on investment. A patent holder has the right to exclude others from making, using, and selling the patented invention for a defined period (Figure 1). Therefore, patented drugs are temporarily safe from the competition of generics, often resulting in substantial revenues. For example, US sales for Prilosec in 2000 were over $4 billion,2 and worldwide sales of on-patent Lipitor and Prevacid totaled over $9.2 billion and $2.5 billion, respectively, in 2003.3,4
Table 1. Blockbuster Drugs Facing Patent Expiration10, 11, 12Over the next few years, a remarkable number of patented "blockbuster" drugs will lose their protection (Table 1). When Eli Lilly's patents for Prozac (fluoxetine) expired in 2001, the concomitant multi-million dollar losses in revenue demonstrated the devastating impact of patent expiration. Table 2 shows three examples of revenue losses following patent expiration.
Table 2. Revenue Losses Following Patent Expiration and Generic Drug Entry13-16Pharmaceutical companies can employ a number of strategies to maximize patent protection on important compounds, thereby maximizing the commercial lifecycle. During the research and development phase of drug discovery, a company will typically obtain patent protection for the general compound and likely a method of using the compound in the treatment or prevention of a particular disease or condition. Often, additional patents can be obtained to effectively extend patent term and market exclusivity.
Table 3. Strategies for Extending Drug Commercial LifecycleOnce a compound or pharmaceutical composition has been patented, that patent becomes a prior art reference that must be considered when seeking additional patent protection around the compound or pharmaceutical. As a result, the new patent protection generally encompasses narrow improvements or new uses for the pharmaceutical not disclosed or suggested in the original patent. Strategies for maximizing patent term are summarized in Table 3.
One means for extending patent protection for a commercially successful drug is to obtain additional patents covering new formulations of the known compound. Developing and patenting new formulations that promote patient compliance through reduced dosing or ease of use, or that exhibit improved therapeutic outcomes or more-favorable side-effect profiles, is particularly advantageous for defending against generics and protecting market share. Moreover, new formulations, as long as sufficiently similar to the original approved drug, have the additional advantage of a shorter FDA approval route.
Murray Spruill, Ph.D., J.D Examples include sustained-release formulations of existing drugs. When Lilly was faced with the expiration of its patent for the blockbuster anti-depressant drug Prozac, the company developed and obtained patent protection and FDA approval for a once-weekly, sustained-release fluoxetine formulation. Bristol-Myers Squibb also obtained patent protection and FDA approval for its extended-release formulation of the diabetes drug Glucophage (metformin hydrochloride). Marketed under the brand name Glucophage XR, this new formulation permits once-daily dosing for Type II diabetics.
Additional patent protection can also be obtained around new formulations that permit new routes of administration for known drugs. The migraine treatment Imitrex (sumatriptan) accounts for more than $1 billion in annual sales for GSK.5 The patent directed to the original compound is set to expire in 2006, so in an effort to extend patent protection and maintain its market share, GSK has developed and obtained FDA approval and patents directed to Imitrex formulations for intranasal delivery.
Drug manufacturers have also successfully exploited the stereoselectivity of drug action in developing single-enantiomer versions. Most active drug compounds are chiral - meaning the compound can exist in at least two structural forms in which the spatial arrangements are mirror images of each other. These two compounds are enantiomers and are chemically identical except for their molecular orientation in 3-D space. Single-enantiomer versions of drugs often have the advantage of increased efficacy and reduced side effects.
One of the success stories for exploiting chirality is Prilosec (omeprazole). The basic patent for this blockbuster acid-reflux drug expired in 2002. In an effort to retain its share of the lucrative gastrointestinal drug market, AstraZeneca began searching for a "better" omeprazole years before the patent was set to expire. The result was the synthesis of the single (S)-enantiomer of omeprazole, esomeprazole, which exhibits superior clinical efficacy and better bioavailability than the original drug. Esomeprazole is marketed as Nexium for the treatment of acid-reflux disease and accounted for nearly $3 billion in sales in 2003.6
In addition to patent protection for the original compound and method of use, patents directed to new uses and treatment indications can be obtained. Developing new methods of use for identified compounds can be a successful strategy for maximizing research dollars and for increasing the commercial life.
Several pharmaceutical companies have successfully obtained patent protection for new methods of use. For example, Merck originally developed, patented, and marketed finasteride as a treatment for benign prostate enlargement under the brand name Proscar. Additional patent protection and FDA approval were sought when a new use for finasteride - treating male pattern baldness - was identified. Finasteride for the treatment of hair loss is marketed under the brand name Propecia. Similarly, the compound atomoxetine was patented in the early 1980s by Lilly and initially investigated as a treatment for depression. Further research and development of atomoxetine led to the identification of a new use for this compound in the treatment of attention deficit hyperactivity disorder. Lilly has obtained patent protection and FDA approval for this new use, marketing it as Strattera. More than two million prescriptions for Strattera were written in its first nine months on the market.7
Ideally, more than one of these approaches should be employed to extend patent protection. For example, in addition to developing a once-weekly formulation, Lilly sought to minimize its losses from the expiration of the Prozac patent by obtaining a patent and FDA approval for a new medical use of fluoxetine in the treatment of premenstrual dysphoric disorder (PMDD). Lilly markets fluoxetine for PMDD as Sarafem and has secured patent protection until 2007 for this new indication.
Bupropion, the GSK drug that was reformulated into a sustained-release formulation, was also shown to aid in smoking cessation. GSK has secured additional patent protection for this new indication and for pharmaceutical formulations for this new use, which GSK markets under the brand name Zyban. Therefore, by developing and patenting both new formulations and new uses for known drugs, Lilly and GSK have enhanced their opportunities for maximizing patent protection for these drugs.
Lilly has FDA approval and an active patent for olanzapine (Zyprexa) to treat schizophrenia. As noted above, the patent for the FDA-approved drug fluoxetine (Prozac) for treating depression has expired. To extend the life cycle of Zyprexa and to recoup losses due to the market entry of generic fluoxetine, Lilly has developed and patented a combination product called Symbyax for the treatment of bipolar disorder, comprising olanzapine and fluoxetine. Zyprexa accounted for more than $1 billion in sales in 2003, and the combination product Symbyax is expected to add $100 million in sales to the Zyprexa product line.8
Developing treatments for HIV infection has been a research focus of GSK for two decades. GSK owns patents directed to pharmaceutical formulations of AZT, lamivudane, and abacavir sulfate, which it markets as individual products under the brand names Retrovir, Epivir, and Ziagen, respectively. All patents directed to pharmaceutical formulations comprising AZT alone will expire in early 2005. To extend its AZT line of products beyond the basic patent terms, GSK obtained additional patents directed to AZT in combination with its other HIV drugs. GSK markets the combination of AZT and lamivudane under the brand name Combivir for the treatment of HIV infection. A second combination of AZT, lamivudane, and abacavir sulfate is sold as Trizivir. Combivir and Trizivir together generated more than $1 billion in sales in 2003.6
In summary, it is critical to devise strategies for maximizing patent protection and product lifecycle early in the development process. In order to maximize patent term, companies should consider seeking patent protection for new formulations, new methods of use, and potential combination products even before launching the original product. Such strategies must be developed before patent expiration and prior to the imminent market entry of generic competitors.
Murray Spruill, Ph.D., J.D., is chair of the biotechnology patent group of Alston and Bird, LLP, 3201 Beechleaf Court, Suite 600, Raleigh, NC, 27604, 919.862.2202, fax 919.862.2260, Wspruill@alston.com
Michelle L. Cunningham, Ph.D., J. D. ,is an associate in the biotechnology patent group of Alston and Bird, LLP, 919.862.2254, Mcunningham@alston.com
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