Bristol-Myers Squibb appears to have at least two more chances to block a generic version of BuSpar from coming to market following a March 13 preliminary injunction imposed by Judge Ricardo Urbina in Washington, D.C. federal court.

The court ordered FDA to grant "immediate approval" to Mylan's generic buspirone ANDA and instructed Bristol to de-list its Nov. 21 buspirone metabolite patent from the "Orange Book." Bristol's motion for a stay of the order was denied by the D.C. federal court March 15.

Bristol, however, immediately filed for a stay of the court order in both the Washington, D.C. and federal appeals courts. The federal court imposed a stay March 16 while it considered the case briefs.

A third potential option would be a long-shot appeal to the Supreme Court.

In denying Bristol's motion, Urbina modified his ruling to clarify the process by which FDA would approve the generic applications. If the motion for a stay is denied on appeal, Mylan would be required to post a $25 mil. bond, requiring Bristol to immediately delist the patent. Once FDA receives Bristol's request, it would approve all the generic doses.

One complication from a commercial standpoint is the number of generic companies that have 180-day exclusivity on different doses. Mylan is understood to have first-to-file rights on a 15 mg buspirone dose; Watson on 5 mg and 10 mg; and Par Pharmaceuticals has exclusivity on a 7.5 mg dose (which is not a strength marketed by Bristol).

FDA said it is studying the ruling and evaluating the effect on the entire buspirone market.

The court order directing approval of the Mylan generic has obvious immediate significance to the parties in the suit, but the order for Bristol to delist the patent could have broader significance by clearing the way for approval of all the "first generic" versions of buspirone - and potentially by setting a precedent in other cases involving "late-listed" patents.

There are several pending cases where brand name sponsors added patents to the "Orange Book" while generic applications were pending, triggering a stay-of-approval under Waxman/Hatch procedures. The stay lasts for 30 months or until a court ruling.

The BuSpar decision could signal that the delay in generic launches could be significantly less than the 30-month maximum. AstraZeneca's Prilosec is the latest example of a product with new patents shortly before a potential generic launch (¹ Also see "AstraZeneca Awaits "Orange Book" Listing For Three Prilosec Patents" - Pink Sheet, 19 March, 2001.).

Mylan filed suit against FDA and Bristol Nov. 30, arguing that Bristol's patent covering the anxiolytic action of a BuSpar metabolite (6-hydroxy-buspirone) did not claim a method of using the drug (² Also see "Bristol BuSpar Metabolite Data Requested By FDA Before Final Patent Listing" - Pink Sheet, 4 December, 2000.).

The patent (No. 5,150,365) was issued Nov. 21, 12 hours before generic competition was expected (³ Also see "Bristol BuSpar Metabolite Patent Issued One Day Before Watson Generic" - Pink Sheet, 27 November, 2000.).

The '365 patent was "provisionally listed" while FDA asked Bristol for clarification between its assertion to the agency that the patent claims the active ingredient and a press release stating that it covers a method of use of a buspirone metabolite.

In his ruling, Urbina found that Mylan was likely to succeed on the merits of its case at trial. The court agreed with Mylan's argument that Bristol's patent was improperly listed because it did not "claim" BuSpar or its method of use.

Urbina agreed with Mylan's assertion that the filing violated Hoechst-Roussel v. Lehman (1997), in which a federal circuit court concluded that a metabolite patent for the Alzheimer's drug Cognex did not "claim" tacrine hydrochloride itself.

While Bristol argued that Hoechst pertained to a different section of Waxman/Hatch and should therefore be disregarded, Urbina determined that the circuit court's interpretation of the statute is applicable to the BuSpar case.

Bristol further maintained that unlike the Hoechst patent, the BuSpar patent is not limited to the use of a metabolite, but encompasses a method of use of BuSpar.

Urbina disagreed: "The flaw in Bristol's argument is that it does not address the fact that the '365 patent expressly disclaims coverage of the administration of buspirone in the manner currently approved."

The patent, he added, specifically states that the "systemic administration" of the buspirone metabolite "improves upon and differs from the known standard method of oral administration of buspirone."

The court found Bristol's case unconvincing for another reason: during its discussions with the Patent & Trademark Office, "Bristol surrendered the subject matter it now says is covered by the claim of the '365 patent, namely, the administration of a prodrug."

Bristol abandoned a patent on a claim covering the administration of buspirone as a prodrug (as opposed to the metabolite) after it was rejected by the PTO. The company then filed a different application claiming methods of using the 6-hydroxy-buspirone metabolite.

The actions invalidate Bristol's argument, Urbina maintained. "When a patent applicant surrenders subject matter during the prosecution of the patent, it cannot then assert a claim that encompasses the surrendered subject matter," the ruling states.

Urbina also outlined the differences between the Mylan case and the lawsuit brought against Bristol by Watson and its subsidiary Danbury Pharmacal in Greenbelt, Md. court. Judge Frederic Smalkin denied the companies' request for injunctive relief Jan. 18.

While Danbury sued only FDA and did not seek relief against Bristol, Mylan took the opposite tactic and placed the burden of the case on the brand name manufacturer, not the agency.

Therefore, since Mylan argued that Bristol improperly submitted the '365 patent (not that FDA improperly listed it), it avoided the problem Danbury faced: that the agency's "ministerial" role in patent listing caused the court to determine FDA's actions to be reasonable.

During oral arguments, Mylan explained that if it were to sue Bristol and not FDA, the company would still need relief against the agency if Bristol were ordered to delist the BuSpar patent and FDA declined to do so.

Courts have traditionally agreed that FDA's role is not to examine the merit of a patent, but to list a patent if a company attests that it applies to the approved drug. That consensus was confirmed in the Danbury ruling, which suggested that patent listing disputes should be between manufacturers and not involve FDA.

Urbina found that the potential harm to either FDA or Bristol "does not weigh heavily against preliminary injunctive relief." Since Bristol did not demonstrate that it was entitled to the additional exclusivity period, he noted, it cannot show harm.

Likewise, FDA did not show that it would be harmed by an injunction. "If the court allows Mylan's generic buspirone to assume its rightful place on the market, and not on the loading dock where it currently sits, this order would not frustrate the FDA's mission to protect the public by ensuring that drugs are safe and effective," Urbina observed.

The court, however, also determined that Mylan would not suffer "irreparable harm" if the injunction were not granted. Mylan "has not shown that its economic losses would be either 'irretrievable' or 'would significantly damage its business above and beyond a simple diminution in profits,'" the ruling states.

The court found that a broader public interest weighed in Mylan's favor. "By creating new - and probably impermissible - ways to extend its monopoly, Bristol not only limits the public's access to low-cost drugs, but impedes the very innovation that Hatch/Waxman is designed to protect," the ruling declares.

If the court order is upheld on appeal, Bristol will still likely see a return on its patent defense strategy. With $677 mil. in U.S. sales in 2000, the delay adds up to $13 mil. each week. Bristol has already rung up about $221 mil. since Nov. 22.

The timing of the Buspar ruling cast an ironic sidelight on Bristol's March 14 announcement that it would not enforce its intellectual property rights for its HIV drugs in Africa (⁴ Also see "Bristol HIV Price Cut Includes Pledge Not To Enforce Patent Rights In Africa" - Pink Sheet, 19 March, 2001.).

In the U.S., Bristol has been among the most aggressive companies in defending its mature brands against generic competition. For the oncologic agent Taxol, a consent order between Bristol and Taxol patent owner American Biosciences delayed Ivax' generic paclitaxel launch by two-and-a-half weeks. During the delay, Taxol sales were about $50 mil.

Bristol's largest product, the antidiabetic Glucophage (metformin), is off-patent and could see generic entries this year. The company is trying to move patients to new formulations of the drug.

The Federal Trade Commission has disclosed an investigation of Bristol's actions with Taxol, and the agency has been petitioned by a consumer group organized by the Gray Panthers to look into BuSpar.

Watson is also seeking punitive damages from Bristol in an anti-trust suit filed in D.C. federal court March 14, alleging Bristol illegally blocked generic buspirone. Watson will ask for damages totaling three times the "unlawful profits" secured by BMS since Nov. 22.

Mylan Buspirone Launch Awaits Bristol Appeal Of BuSpar Patent Order

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