GlaxoSmithKline's delisting of three Paxil patents will clear the way for approval of generic versions of the antidepressant, and set up a potential dispute over how 180-day exclusivity will be awarded.

FDA must determine who holds generic exclusivity for paroxetine now that GSK has agreed to lift the 30-month stay of approval on Apotex' ANDA.

GSK announced July 1 that it is asking FDA to delist from the "Orange Book" three paroxetine product-by-process patents: Nos. 6,172,233; 6,080,759; and 6,063,927.

The delisting of the '233 patent will remove the final 30-month stay of approval holding up Apotex' ANDA. The stay was scheduled to expire Sept. 19.

Apotex, through its TorPharm subsidiary, is the only ANDA holder with tentative approval for paroxetine. Apotex believes it was first to file Paragraph IV certifications against approximately half a dozen Paxil patents, including the '233 and '927 patents. GSK did not sue Apotex over the '927 patent.

Currently, the Orange Book lists 12 Paxil-related patents.

FDA plans to delist the three patents as requested by GSK. However, the agency must determine what impact delisting would have on ANDA holders' claims to 180-day exclusivity and whether there should be shared exclusivity among generic companies who were first to file against different patents.

FDA conducted a similar analysis in January when Pfizer requested a patent covering the unapproved use of gabapentin ( Neurontin ) in neurodegenerative diseases be delisted. FDA determined that TorPharm was not entitled to 180-day exclusivity regarding the neurodegenerative disease patent.

FDA's conclusion about gabapentin exclusivity was upheld by a D.C. federal court in April (¹ Also see "Purepac Gabapentin 180-Day Exclusivity Award “Reasonable,” Judge Says" - Pink Sheet, 5 May, 2003., p. 8).

As in the gabapentin case, FDA could face a lawsuit over its decision about 180-day exclusivity for paroxetine.

The paroxetine exclusivity question also could provide more fuel for legislators and policymakers seeking to reform the current system of awarding 180-day exclusivity to the first ANDA filer.

During a June 17 Senate Judiciary Committee hearing, Sen. Orrin Hatch (R-Utah) suggested Congress should consider legislation that would restore the practice of awarding exclusivity to the first company to successfully litigate a patent challenge (² [A#00650250013], p. 19).

At the same hearing, FDA Chief Counsel Dan Troy said the agency would be open to changes in the exclusivity rules.

GSK's delisting of the three Paxil patents will not end the litigation surrounding paroxetine. If the Apotex ANDA is approved, the generic firm will have to consider whether to launch and risk damages if it subsequently loses an infringement ruling.

Apotex and GSK are in litigation in Philadelphia federal court related to the '759 patent, as well as a separate patent covering paroxetine hydrochloride anhydrous Form A. In addition, GSK is appealing a Chicago federal judge's ruling that Apotex' ANDA does not infringe GSK's hemihydrate paroxetine patent (³ Also see "Apotex Paxil ANDA: Presence Of Hemihydrate Does Not Infringe GSK’s Patent" - Pink Sheet, 10 March, 2003., p. 19).

In addition, Apotex is suing GSK and FDA, maintaining that five Paxil patents were improperly listed in the first place (see ⁴ Also see "Paxil Delisting: Will Appellate Case On FDA Patent Listing Role Be Moot?" - Pink Sheet, 7 July, 2003.).

Geneva, Ivax, Alphapharm, Andrx and Teva also are in litigation with GSK over paroxetine ANDAs.

Under a recent settlement with GSK, Par and Pentech will be allowed to launch an authorized Paxil generic on the U.S. mainland once another generic enters the market (⁵ Also see "Paxil Authorized Generic: Par Gets Puerto Rico Now, States Later" - Pink Sheet, 21 April, 2003., p. 40).

GSK does not appear to expect generic paroxetine in 2003. In announcing the Paxil patent delisting request, GSK said it maintained its previously stated 2003 forecast for "high single-digit percentage growth in business performance earnings per share," which assumes no generic paroxetine competition in the U.S.

GSK has been working to buffer the effect of any generic entry by converting Paxil users to a controlled-release version, Paxil CR (⁶ Also see "GSK Switch Success: Paxil CR Has 31% Of New Scripts; Augmentin ES, 49%" - Pink Sheet, 17 February, 2003., p. 10). The Paxil franchise had $2.12 bil. in U.S. sales in 2002.

GSK said it requested the patents be delisted to "proactively align with the new criteria" for patent listings, as set forth in FDA's final rule on generic drug issues.

The June 18 final rule requires patent holders to file declaration forms asserting that a "product-by-process" patent claims a novel product (⁷ [A#00650240007], p. 13).

GSK said it believes its listing of the three product-by-process patents at issue conformed with FDA's previous rules on patent listings, and that it is making a good faith effort to adhere to the new requirements, particularly in light of ongoing scrutiny and criticism of the drug industry.

The company is not expected to submit the three patents for relisting after the final generic drug rule takes effect Aug. 18.

Paxil is one of the most prominent remaining examples of a generic drug approval that would presumably have occurred more quickly if the new FDA rules were in place.

The appropriateness of the Paxil patent listings was characterized as "questionable" by the Federal Trade Commission in its July 2002 report on generic drugs. The antidepressant was one of eight brand name drugs cited by FTC for which the manufacturer listed a patent after the first ANDA was filed (⁸ Also see "Paxil Late-Listed Patents Are Questionable For Orange Book Listing – FTC" - Pink Sheet, 5 August, 2002., p. 8).

Efforts at regulatory and legislative reform of the generic drug system have targeted the issues of late-listed patents and multiple 30-month stays.

Under the Gregg/Schumer proposal now working its way through Congress as part of the Medicare drug benefit package, brand name companies would be entitled to a single 30-month stay on generic applications for patents listed in the Orange Book prior to an ANDA filing.

FDA's final generic rule also limits innovators to one 30-month stay but places no time restriction on the stay.

GSK Paxil Patent Delistings Open Door For Generic Paroxetine Approvals

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