FDA's determination that Purepac is eligible for 180-day generic exclusivity on gabapentin capsules (Pfizer's Neurontin ) was reasonable and "an appropriate application of administrative discretion," D.C. federal court Judge Ellen Segal Huvelle ruled April 25.

In the most recent court decision in the complex web of Neurontin patent litigation, the judge upheld FDA's finding that Purepac, not TorPharm, was the first to file a Paragraph IV certification against Pfizer's drug composition patent (No. 6,054,482).

In so ruling, the court validated FDA's procedures for determining when an ANDA amendment with a new Paragraph IV certification is effectively filed.

In addition, the court agreed with FDA that no ANDA applicants were eligible for 180-day exclusivity based on Paragraph IV certifications filed against Pfizer's patent (No. 4,084,479) covering the unapproved use of gabapentin in neurodegenerative diseases.

TorPharm sued FDA shortly after the agency announced in January that it was awarding first-to-file rights to Purepac after Pfizer requested that the '479 patent be delisted from the "Orange Book" (¹ Also see "Purepac Gabapentin Is “First Generic” After Pfizer Delists Neurontin Patent" - Pink Sheet, 3 February, 2003., p. 20).

In March 1998, Purepac submitted an ANDA for gabapentin capsules for treating epilepsy and included a "section viii statement" regarding the '479 patent. Section viii statements can be used by ANDA filers when a method-of-use patent does not claim the use sought in the ANDA. They do not provide exclusivity, but also do not trigger the 30-month stay.

Neurontin, originally developed by Warner-Lambert, now part of Pfizer, is approved for epilepsy and post-herpetic neuralgia.

TorPharm's ANDA, containing both a section viii and a Paragraph IV certification for the '479 patent, was filed in April 1998.

In April 2000, Warner-Lambert submitted the '482 composition patent to FDA for Orange Book listing. FDA received amended applications with Paragraph IV certifications for the newly listed patent from Purepac on May 26, 2000 and TorPharm on June 16, 2000.

After FDA deemed Purepac's section viii filing improper, Purepac sued the agency. In December, Judge Huvelle upheld Purepac's decision to file a section viii statement rather than a Paragraph IV certification against the '479 patent. The court remanded the case to FDA with instructions to accept Purepac's application with the section viii statement.

Separately, Pfizer requested the '479 patent be delisted after a Federal Circuit Court of Appeals panel concluded on Jan. 16 that gabapentin ANDAs seeking an epilepsy indication did not infringe the '479 patent.

In a Jan. 28 decision letter, FDA determined TorPharm was not entitled to 180-day exclusivity regarding the '479 patent. Neither TorPharm nor any other ANDA applicants could maintain a Paragraph IV certification as to the '479 patent because a section viii statement was, instead, appropriate for that patent, FDA said.

FDA also determined that Purepac was entitled to 180-day exclusivity because it was the first to submit a Paragraph IV certification against the '482 patent.

In its lawsuit against the agency, TorPharm argued that it was entitled to exclusivity on the '482 patent. The Apotex subsidiary maintained it was the first ANDA applicant to comply with statutory provisions requiring that notice of a Paragraph IV certification be provided to the NDA holder at the same time the applicant amends an ANDA to include the certification.

Although Purepac filed its amended ANDA with the agency on May 26, 2000, the company did not notify NDA holder Warner-Lambert until June 13, 2000. In contrast, TorPharm sent both its Paragraph IV certification to the agency and its notice to W-L on June 13, 2000, although the certification was not received by FDA until June 16, 2000.

TorPharm argued that Purepac's failure to notify the NDA holder simultaneously with the ANDA amendment filing warranted nullification of Purepac's Paragraph IV certification.

The court disagreed, however, saying there is nothing in the FD&C Act "that actually compels, or even suggests, such a harsh result. The statute is in fact silent on the issue of what follows from an applicant's failure to follow the mandate of simultaneity."

Saying the agency has "considerable flexibility in deciding what the appropriate consequence of such a violation should be," the court agreed with FDA that Purepac's certification did not become effective until the notice was actually sent to W-L on June 13, 2000.

"Where notice is provided after the certification is received, the agency's policy constructively moves the certification's 'submission' date to the day on which the applicant mailed the notice," the court said. This approach "acknowledges that notice and certification must occur together, and therefore refuses to give legal recognition to one act until the other has been effectuated as a result."

Huvelle upheld FDA's finding that the operative date for a Paragraph IV certification is the date the document is actually received by FDA, not the date it is mailed by the ANDA filer, as TorPharm had argued.

TorPharm "points to nothing in the statute that precludes the FDA's date-of-receipt rule, or that mandates an alternative mailbox rule," the judge said. "It is well within the FDA's administrative discretion to adopt this sort of reasonable 'housekeeping' rule to make it easier for the agency to determine the order in which amended Paragraph IV certifications are filed."

At a Food & Drug Law Institute Conference in April, Venable, Baetjer, Howard & Civiletti attorney David Adams suggested FDA should allow applicants who file ANDAs on the same day to share exclusivity (² Also see "ANDA Same-Day Filers Should Share Exclusivity, Industry Lawyer Says" - Pink Sheet, 7 April, 2003., p. 27).

Turning to the question of whether FDA correctly decided that no ANDAs were eligible for exclusivity as to the '479 patent, Huvelle noted FDA has long maintained that Paragraph IV certifications and section viii statements are mutually exclusive.

The judge said that once TorPharm's Paragraph IV certification was deemed improper in light of Purepac's section viii statement, FDA had two choices: require TorPharm to file its own section viii statement, or remove the '479 patent from the Orange Book. The agency took the latter action.

"For exclusivity purposes, however, there is no functional difference between these options for either way TorPharm's claim to exclusivity based on the '479 patent is extinguished," the judge observed.

"Because the court finds that the FDA acted reasonably in not departing from its well-settled rule that a section viii statement and Paragraph IV certification cannot be filed as to the same patent, the agency's corresponding conclusion that no applicant was entitled to exclusivity on the '479 patent must be upheld as well."

The judge expressed some concern, however, that FDA's conclusion on inapplicability of Paragraph IV certifications to the '479 patent could be interpreted as being based, in part, on the Federal Circuit's Jan. 16 ruling in the Neurontin patent infringement case (Warner-Lambert v. Apotex).

"If a judicial determination of non-infringement in patent litigation triggered by the use of a Paragraph IV certification comes to serve as the basis for a subsequent FDA determination that the patent in question should no longer be listed - and therefore that a Paragraph IV certification, and its corresponding promise of exclusivity, is no longer appropriate - the incentive structure created by the Hatch-Waxman Amendments would be turned on its head."

"The fruits of a Paragraph IV lawsuit should not supply the fodder for a later determination that Paragraph IV should not have been used in the first place," she said.

The Warner-Lambert v. Apotex decision has been criticized by a separate Federal Circuit panel (³ Also see "Orange Book Listings For Unapproved Uses May Be OK, Appeals Court Says" - Pink Sheet, 7 April, 2003., p. 25)

TorPharm has appealed Huvelle's ruling to the D.C. Circuit Court of Appeals. Gabapentin patent litigation between Pfizer and generic companies is ongoing in New Jersey federal court, although neither Purepac nor TorPharm are currently subject to any 30-month stays.

No gabapentin ANDAs have received full approval to date. Pfizer has previously indicated it might try to use a patent on gabapentin for neuropathic pain as a defensive strategy (⁴ Also see "Neurontin Bulk Supply May Limit Generic Uptake, Pfizer Says" - Pink Sheet, 27 January, 2003., p. 18). Only the '482 drug composition patent and a drug substance patent (No. 4,894,476) are listed in the Orange Book.

Ivax said it believes it holds first-to-file status for 100 mg, 300 mg and 400 mg gabapentin tablets - dosage forms which are not currently marketed by Pfizer. Pfizer markets Neurontin in 600 mg and 800 mg tablets, as well as 100 mg, 300 mg and 400 mg capsules and an oral solution.

Ivax said that it plans to market the tablets to HMOs and other institutional purchasers under the brand Gabaron and at a discount to Neurontin.

Purepac Gabapentin 180-Day Exclusivity Award “Reasonable,” Judge Says

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