Merck is on the verge of losing patent protection for its multi-million dollar drug compound Simvastatin, paving the way for euphoric generic players to enter the U.S. Simvastatin market, which was worth around U.S. $4.4 Billion worldwide in 2005. Even though there is no current Para IV litigation for the Simvastatin tablet, the story so far is quite interesting, and central for the future of the U.S. generic industry, and more particularly for the 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 continues to prevail. That is, if all generic players get the FDA final nod to market their generic versions, or if only Teva and Ranbaxy would reap the benefit of 180-day exclusivity for their generic Simvastatin tablets.

The Food and Drug Administration (the “FDA”), which earlier denied Ranbaxy and Ivax’s citizen petitions for not approving subsequently-filed ANDAs (before expiry of their 180-day exclusivity for respective strengths, and for reinstating the delisted patents to the Orange Book) has already made an appeal with the U.S. Court of Appeals against the decision of the U.S. District Court, which remanded and sent the case back to the FDA for a decision. Now interestingly, rather than being a conventional generic tussle between Innovator and Generics, this case is turning out to be decisive regulatory tussle between the FDA and the First Para IV filers, concerning a 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 the 180-day exclusivity holder.

Merck’s Goldmine

Merck hit a gold mine when the Merck scientists synthetically derived Simvastatin from a fermentation product of Aspergillus Terreus, while developing and researching lovastatin. In 1980, Hoffmann et al. filed a U.S. 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 (the “NDA”) for simvastatin and for anti- hypercholesterolemia indication, being approved by the FDA on December 23, 1991, in 5 mg, 10 mg, 20 mg, and 40 mg strengths. Subsequently, the FDA listed the Simvastatin tablet along with the ‘784 Patent, with the Approved Drug Products, and with the Therapeutic Equivalence (Orange Book) under 21 U.S.C. § 355 (b) (1).

Listing Additional Patents & PTE

On May 20, 1993 the USPTO, under 35 USC § 156, extended the term of the ‘784 Patent for a period of 1,704 days, adjusting the patent expiry of the ‘784 Patent from April 24, 2001 to December 23, 2005. The FDA later approved the 80 mg strength of the Simvastatin tablet in 1998. In 2000, Merck further listed two additional patents, stating them 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 a Para IV target in the same year when Merck listed additional patents for Simvastatin tablets. On December 14, 2000 Ivax submitted ANDA, with the FDA seeking marketing approval for its generic version of the Simvastatin tablet, in 5 mg, 10 mg, 20 mg, and 40 mg strengths. Ivax filed a Para III certification, with respect to the ‘784 Patent, but filed a Para IV certification 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. Ivax notified Merck of the Para IV certification, detailing the factual and legal basis for its belief, and 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 the FDA, seeking marketing approval for its generic version of the Simvastatin tablet in 5 mg, 10 mg, 20 mg, 40 mg, and 80 mg strengths. Ranbaxy was, however, first to file Para IV certification in the case of the 80 mg strength, as Ivax’s Para IV certification was intended for 5 mg, 10 mg, 20 mg, and 40 mg strengths. Like Ivax, Ranbaxy also filed a Para III certification with respect to the ‘784 Patent, and a Para IV certification with respect to additional patents, contending that the ‘481 and ‘520 Patents were invalid, unenforceable, or that their drugs would not infringe the patents. Ranbaxy also notified Merck of the 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 sue 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 the FDA approval of the ANDAs. As a result of this, both Ivax and Ranbaxy were entitled to a 180-day exclusivity for their respective strengths, and expected to launch their generic Simvastatin tablet after expiry of the ‘784 Patent. Until this, everything seems to be clear and evident that, with the expiry of the ‘784 Patent, Ivax and Ranbaxy would enjoy a 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, the 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, effective as of 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, the 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) a product-by-process (only if the product is novel).

However, these developments had no role to play in the 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 (an intellectual property law firm) challenging the listing of additional patents under revised an 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 the FDA had delisted the ‘481 and ‘520 Patents, both Ivax (on January 05, 2005) and Ranbaxy (on February 1, 2005) submitted citizens’ petitions with the FDA, requesting that the FDA confirm 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, the FDA denied both petitions, deciding that it would not relist the disputed patents, that no applicant would be eligible for a 180-day exclusivity for delisted patents, and that it would 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 their refusal to grant any ANDA Applicant eligibility for the 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. 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, the 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 relisted both the delisted patents to the Orange Book, which implies that Teva and Ranbaxy will receive the 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 the U.S. Court of Appeals rules in favor of Generics, then Teva and Ranbaxy will enjoy marketing exclusivity, until the end of December; or

2. If U.S. Court of Appeals rules against Generics, then the FDA will grant their final marketing approvals to the rest of generic players, and end Teva and Ranbaxy’s marketing exclusivity before the 180 days.

Whatever the outcome of the 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; or
4. Merck will continue to market its branded Zocor.

But what remains critical is, should the U.S. Court of Appeals rule in the favor of the FDA, delisting may become one more viable strategy for innovators to negate the 180-day exclusivity. However, if the U.S. Court of Appeals rules in favor of Generics … Well!!! That will keep their hope intact with this High Risk, High Returns strategy.

Today’s post comes from Varun Chhonkar, Senior Officer – Patents with J.B. Chemicals & Pharmaceuticals Ltd., Mumbai, India (varun.chhonkar[at] © Varun Chhonkar.

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