Merck is on the verge to lose patent protection for its multi-million dollar drug compound Simvastatin, paving way for euphoric generic players to enter U.S. Simvastatin market which worth around U.S. $ 4.4 billion worldwide in 2005. Even though there are no Para IV litigations for Simvastatin tablet, the story so far is quite interesting and central for future of U.S. generic industry, more particularly for First Para IV filer and subsequent Para IV filers. On June 23, 2006 generic players will start commercializing their generic versions of Simvastatin tablets but the debate surrounding the Generic launch and entry still continue to prevail --- Whether all generic players would get FDA final node to market their generic versions or only Teva and Ranbaxy would reap the benefit of 180-days exclusivity for their generic Simvastatin tablets? Food and Drug Administration (FDA), which earlier denied Ranbaxy and Ivax’s citizen petitions for not to approve subsequently filed ANDAs before expiry of their 180-day exclusivity for respective strengths and to reinstate the delisted patents to Orange Book, has already made an appeal with U.S. Court of Appeals against the decision of U.S. District Court which remanded and send the case back to FDA for decision. Now interestingly, rather been a conventional generic tussle between Innovator and Generics, this case is turning out to be decisive regulatory tussle between FDA and first Para IV filers’ concerning 180-day exclusivity issue. Let us go back and revisit this unusual case history from its inception to figure out the issues involved and their impact on future generic industry, particularly when the Authorized Generics are turning out to be next big hurdle for 180-day exclusivity holder. Merck’s Goldmine Merck hit the goldmine when Merck scientists synthetically derived Simvastatin from a fermentation product of Aspergillus terreus while developing and researching lovastatin. In 1980, Hoffmann et al filed a US patent application for Simvastatin, its pharmaceutical composition and use thereof to treat hypercholesterolemia against which U.S. Patent No. 4,444,784 was issued on April 24, 1984. Merck filed the new drug application (NDA) for simvastatin for anti- hypercholesterolemia indication, which was approved by FDA on December 23, 1991 in 5mg, 10mg, 20mg, and 40mg strengths. Subsequently FDA listed Simvastatin tablet along with the ‘784 patent with the Approved Drug Products with Therapeutic Equivalence (Orange Book) under 21 U.S.C. § 355 (b) (1). Listing Additional Patents & PTE On May 20, 1993 USPTO under 35 USC § 156 extended the term of the ‘784 patent for a period of 1704 days, adjusting the patent expiry of the ‘784 from April 24, 2001 to December 23, 2005. FDA later approved 80mg strength of Simvastatin tablet in 1998. In 2000, Merck further listed two additional patents stating to be metabolites of Simvastatin, namely --- 1. U.S. reissued Patent No. RE36,481 (the ‘481 patent) 2. U.S. reissued Patent No. RE36,520 (the ‘520 patent) Later, Merck also obtained Pediatric Exclusivity from Simvastatin tablets extending the patent terms of the ‘784, ‘481, and ‘520 patents with additional 6 months. Ivax Para IV Attack Like other blockbuster drugs, Simvastatin also became Para IV target in the same year when Merck listed additional patents for Simvastatin tablets. On December 14, 2000 Ivax submitted ANDA with FDA seeking marketing approval for its generic version of Simvastatin tablet in 5mg, 10mg, 20mg, and 40mg strengths. Ivax filed Para III certification with respect to the ‘784 patent but filed Para IV certification in respect to additional patents contending that the ‘481 and ‘520 patents were invalid or unenforceable, or that their drugs would not infringe the patents. Ivax notified Merck of Para IV certification, detailing the factual and legal basis for its belief that its generic drug would not infringe the patents, or that the patents are invalid or unenforceable. Ranbaxy Joins the Para IV Race In November 2001, Ranbaxy became the second generic player to file Para IV certification with FDA seeking marketing approval for its generic version of Simvastatin tablet in 5mg, 10mg, 20mg, 40mg, and 80mg strengths. Ranbaxy was, however, first to file Para IV certification in case of 80mg strength as Ivax’s Para IV certification was intended for 5mg, 10mg, 20mg, and 40mg strengths. Like Ivax, Ranbaxy also filed Para III certification with respect to the ‘784 patent and Para IV with respect to additional patents contending that the ‘481 and ‘520 patents were invalid or unenforceable, or that their drugs would not infringe the patents. Ranbaxy also notified Merck of Para IV certification, detailing the factual and legal basis for its belief that its generic drug would not infringe the patents, or that the patents are invalid or unenforceable. Conquering 45 day Barrier Merck did not sued Ivax and Ranbaxy within 45 days as required under 21 U.S.C. 355 (j) (5) (B) (iii) to trigger an automatic 30-month stay of FDA approval of the ANDAs. As a result of this, both Ivax and Ranbaxy get entitled to 180-day exclusivity for their respective strengths and expected to launch their generic Simvastatin tablet after expiry of the ‘784 patent. Till here everything seems to be clear and evident that with the expiry of the ‘784 patent Ivax and Ranbaxy would enjoy 180-day marketing exclusivity and would be the sole generic players in U.S. Simvastatin market. Big celebrations for Big Generic Predators! FDA 2003 Rulemaking On June 18, 2003 FDA published its revised rules clarifying the types of patents that must and must not be submitted to FDA for listing in the Orange Book which got effective from August 18, 2003. Under the revised rules, NDA holders are not allowed to submit patent information for listing in the Orange Book for drug packaging, drug metabolites, and intermediates of a drug. In addition to this, revised rules also added requirements for submission of 1) polymorph patents (only if the NDA holder must have the test data demonstrating that a drug product containing the polymorph will perform the same as the drug product described in the NDA) and 2) product-by-process (only if product is novel). However, these developments had no role to play in Ranbaxy and Ivax’s 180-day party. Merck Unexpected Maneuver Following the FDA revision, on October 10, 2003 Merck submitted a letter to the FDA requesting that the ‘481 and ‘520 patents be delisted from Orange Book. The following month, the FDA received a letter from Kenyon & Kenyon (intellectual property law firm) challenging the listing of additional patents under revised FDA regulation published on June 18, 2003. The FDA forwarded this letter to Merck, which renewed its request that the patents be withdrawn. In June 2004, Merck sent a third request to the FDA to delist the patents. In September 2004, Ivax and Ranbaxy learned that the FDA had delisted the ‘481 and ‘520 patents from the Orange Book. FDA Nullify 180-day Exclusivity Discovering that FDA has delisted the ‘481 and ‘520 patents, both Ivax (on January 05, 2005) and Ranbaxy (on February 01, 2005) submitted citizen petitions with FDA requesting that the FDA confirm that it would not approve subsequent ANDAs until after the 180-day period and the FDA relist the patents in the Orange Book. On October 24, 2005 FDA denied both petitions, deciding that it would not relist the disputed patents, that no applicant will be eligible for 180-day exclusivity for delisted patents, and that it will approve all subsequent ANDAs for simvastatin tablets. Following the FDA denial, Ivax and Ranbaxy separately sued the FDA, challenging the FDA’s refusal to relist the ‘481 and ‘520 patents and refusal to grant any ANDA applicant eligibility for 180-day exclusivity for generic Simvastatin tablets. All three parties moved for summary judgment. Ranbaxy and Ivax moved for summary judgment seeking to vacate the FDA decision and the FDA filed a cross for summary judgment seeking to maintain its decision. Thumbs Up for Ranbaxy & Ivax! On April 30, 2006 Judge Richard W. Roberts of U.S. District Court for the District of Columbia, in his memorandum opinion, ruled in the favor of Ranbaxy & Ivax by granting them summary judgment and contending that the FDA has acted contrary to the clear intent of Congress in its decision to deny Ranbaxy and Ivax’s citizen petitions. The issue was sent back to the FDA by the District Court for a decision giving Ranbaxy and Ivax much expected relief. FDA Not Ready to Give Up On May 24, 2006 FDA appealed against the decision of District Court and filed a motion with U.S. Court of Appeals seeking expedited review concerning Ivax and Ranbaxy’s 180-day exclusivity issue and also proposed a schedule whereby the appeal will be fully briefed over the summer, with arguments to be heard at the Court’s earliest convenience thereafter. Teva (which earlier acquired Ivax) has agreed to an expedited schedule as proposed by FDA. The Generic 23/6: The Day Belongs To? As of now, FDA has already re-listed both the delisted patents to the Orange Book which implies that Teva and Ranbaxy will receive final marketing approval for their generic Simvastatin tablets on June 23, 2006 and will market their respective strengths with 180-day exclusivity period. Considering that appeal will be briefed over the summer and Teva and Ranbaxy will commence their marketing in June 2006, there can be either of two situations--- 1. If U.S. Court of Appeals rules in favor of Generics, then Teva and Ranbaxy will enjoy marketing exclusivity till the end of December; or 2. If U.S. Court of Appeals rules against Generics, then FDA will grant final marketing approvals to the rest of generic players and end Teva and Ranbaxy’s marketing exclusivity before 180-days. Whatever the outcome of appeal would be, four things are very much evident on June 23, 2006 --- 1. Simvastatin will lose its patent protection 2. Generics would enter the U.S. Simvastatin market 3. Dr. Reddy’s Laboratories will be there as Authorized Generics 4. Merck will continue to market its branded Zocor What is important is that, in case, if U.S. Court of Appeals rules in the favor of FDA, delisting may become one more viable strategy for Innovators to negate the 180-day exclusivity. However, if U.S. Court of Appeals rules in favor of Generics, Well!!! That will keep there hope intact with this High Risk, High Returns strategy.