Orange Book Blog

After Court Victory over FDA, Teva Receives Final Approval of Risperidone ANDA and Launches With 180-Day Exclusivity

Teva announced yesterday that the FDA granted final approval to its ANDA for generic Risperdal (risperidone) tablets, that it was awarded 180-day exclusivity as the first paragraph IV filer for risperidone, and that it immediately commenced a commercial launch.  FDA confirmed the final approval in a press release.  Risperdal is a schizophrenia drug marketed by Janssen, a unit of Johnson & Johnson, with annual U.S. sales of $2.8 billion.

FDA's decision to grant 180-day exclusivity to Teva follows an April 11, 2008, order of the U.S. District Court for the District of Columbia, granting Teva's request to require FDA to relist Janssen's U.S. Patent No. 5,158,952 in the Orange Book and enjoin FDA from approving any other risperidone ANDAs until Teva's 180-day exclusivity period expires.

Teva was the first ANDA applicant to file a paragraph IV certification on the '952 patent, but FDA delisted the patent in 2001, in response to a request from Janssen.  FDA argued to the district court that the '952 patent was delisted before Teva filed its ANDA.  Teva argued that the delisting "did not become effective until January 2002, when the official Orange Book reflected the delisting of that patent."

FDA has appealed the district court's decision to the U.S. Court of Appeals for the D.C. Circuit, and oral argument is scheduled for September 12, 2008.  Meanwhile, according to the FDA website, risperidone ANDAs filed by Mylan and Pliva (a subsidiary of Barr Labs) have tentative approval.  Thus, if the D.C. Circuit reverses the district court, Teva's 180-day exclusivity period would be cut short.

RELATED READING:

• Janssen press release, announcing launch of authorized generic
• Motley Fool article
• April 11 FDA Law Blog post
• January 17 OBB post

OBB News Briefs

• Last Thursday, FDA Law Blog reported on the Lupin v. Abbott case scheduled for oral argument at the Federal Circuit on Wednesday.  The case concerns a very unusual situation, where Abbott obtained two patent term extensions under 35 U.S.C. § 156 for a single drug product.
• In what is being reported as a setback for the prospects of a biosimilars industry in the United States, the FDA recently denied Genzyme's request to change the manufacturing site of its drug Myozyme.  For more: Boston Globe, Pharmalot, WSJ Health Blog.
• The L.A. Times published an interesting op-ed last week about safety concerns with biotech drugs.
• The New York Times reported last week on a lobbying fight between the brand-name and generic drug industries over inequitable conduct provisions in patent reform legislation.
• FDA Law Blog recently updated their coverage of two interesting cases: Teva vs. FDA, concerning 180-day exclusivity on Risperdal, in which Apotex filed a motion to intervene; Nu-Pharm v. FDA, Nu-Pharm's ANDA for generic Depakote, in which the D.C. Circuit summarily affirmed the district court's decision in favor of FDA.
• On April 16, a district court denied Perrigo's motion for summary judgment that its generic version of Olux (clobetasol propionate foam), a treatment for scalp psoriasis, does not infringe Connetics' U.S. Patent No. 6,126,920.
• On March 19, a district court denied Ranbaxy's motion for summary judgment that Roche's patent on Valcyte (valganciclovir HCl), U.S. Patent No. 6,083,953, is invalid due to incorrect inventorship.  Numerous other summary judgment motions are still outstanding in the case.

Apotex Sues FDA to Recover 180-Day Exclusivity on Generic Plavix

In November 2001, Apotex became the first company to file an ANDA for a generic version of Plavix (clopidogrel bisulfate) with a paragraph IV certification.  In March 2002, Sanofi-Synthelabo and Bristol-Myers Squibb sued Apotex for infringing the Orange Book-listed patent, U.S. Patent No. 4,847,265, thereby initiating an automatic 30-month stay of FDA approval of Apotex's ANDA.

With the patent litigation still pending, the stay expired in May 2005.  In January 2006, FDA granted final approval to Apotex's ANDA.  The litigation was proceeding toward trial when, on August 8, 2006, Apotex launched its generic clopidogrel bisulfate product at risk, starting its 180-day exclusivity period.  23 days later, the U.S. District Court for the Southern District of New York preliminarily enjoined Apotex from continuing to sell its generic version of Plavix.  Thus, Apotex was enjoined, but its exclusivity continued to run.

The Federal Circuit affirmed the preliminary injunction in December 2006.  After a bench trial, the district court ruled in June 2007 that Apotex failed to prove that the '265 patent is invalid and entered a permanent injunction.  Apotex appealed that decision to the Federal Circuit, which heard oral argument on March 3, 2008.  A decision from the Federal Circuit could come at any time.

Meanwhile, other generic drug companies were pursuing their own ANDAs for generic Plavix.  Dr. Reddy's, Teva and Cobalt each filed ANDAs with paragraph IV certifications and were sued by Sanofi and BMS.  Teva and Cobalt are permanently enjoined, pending the outcome of Apotex's appeal.  Dr. Reddy's, however, is not enjoined.  Instead, according to Apotex, Dr. Reddy's agreed with Sanofi and BMS that it would provide ten days' notice before launching its generic product.  Presumably, such notice would allow Sanofi and BMS sufficient time to prepare and file a motion for a preliminary injunction against Dr. Reddy's.  On January 14, 2008, FDA granted final approval to Dr. Reddy's ANDA, thereby clearing Dr. Reddy's for a commercial launch.

On February 13, 2008, Apotex filed a Petition for Stay of Action with FDA, seeking "only to stay the effective date of Dr. Reddy's formal approval in a manner that would protect Apotex's remaining 156 days of generic exclusivity but would permit unrestricted generic competition at the end of that exclusivity period."  See FDA Law Blog.  Apotex asked FDA to respond no later than March 15, 2008.  FDA has not yet responded, and therefore, last Wednesday, Apotex filed suit against FDA in the U.S. District Court for the District of Columbia, requesting declaratory and injunctive relief.

In its complaint, Apotex seeks "to set aside FDA's refusal to stay the effectiveness of" Dr. Reddy's final approval.  According to Apotex, "[a]bsent a stay, Dr. Reddy's will be permitted to distribute generic clopidogrel bisulfate tablets during the remainder of the 180 days during which Apotex is entitled to be the sole generic manufacturer of that drug under the [Hatch-Waxman Act]."

Apotex alleges that FDA's action violates the Food, Drugs and Cosmetics Act and must be set aside by the court as "arbitrary, capricious, an abuse of discretion and otherwise not in accordance with law," in violation of the Administrative Procedure Act.  Specifically, Apotex asserts that the language of the Hatch-Waxman Act

demonstrates a clear congressional intent to provide the first ANDA applicant to file a paragraph IV certification for a listed patent with the economic benefit of 180 days of generic marketing exclusivity to encourage prompt challenges to questionable or inapplicable patents.  The "not earlier than" language provides a safety valve to ensure that the 180-day period will not be unfairly curtailed by, for example, an improvidently granted injunction issued during the period of marketing exclusivity against a first filer who commences commercial marketing prior to a determination that a listed patent is invalid or not infringed.

Apotex further asserts that unless the district court grants the relief sought, "Dr. Reddy's would be able to commence marketing almost immediately in the event of a CAFC decision of invalidity, while Apotex would remain bound by injunction until the mandate issues."  If the Federal Circuit invalidates the '265 patent (which is a pretty big "if," given that it previously affirmed the preliminary injunction), Sanofi/BMS would certainly file a request for rehearing or rehearing en banc, which would likely delay the issuance of a mandate for several weeks.  Thus, according to Apotex, "[n]ot only would Apotex be denied its remaining 156 days of exclusivity, but Dr. Reddy's would have a significant head start over Apotex in the marketplace, a marketplace that would be made available only by Apotex's challenge to the '265 patent."

OBB News Briefs

• Last Monday, the Federal Circuit affirmed a district court decision in McNeil-PPC v. Perrigo, concerning a generic version of Pepcid Complete.  The decision was affirmed without an opinion, under Rule 36.
• Tuesday, AstraZeneca and Ranbaxy announced a settlement of their patent litigation over generic Nexium (esomeprazole), with Astra granting Ranbaxy exclusive rights to sell a generic version of Nexium in 2014, six months before the first patent expires.  Teva and Dr. Reddy's plan to continue challenging Astra's patents.  Astra press release; Ranbaxy press release; AP; Bloomberg; Pharmalot; WSJ Health Blog.
• In a very surprising decision, a D.C. district court recently ruled in favor of Teva in a case in which Teva alleged that the FDA wrongfully delisted a patent on Risperdal (risperidone) from the Orange Book, depriving Teva of 180-day exclusivity.  FDA Law Blog has a full report.
• Earlier this month, Depomed announced a settlement of patent litigation against Teva over generic Glumetza (metformin HCl).  Depomed press release; AP story.
• Pharmalot recently had two interesting posts about biosimilars: the first suggested, based on a report about the Food and Drug Law Institute's annual meeting, that biosimilars legislation may actually be passed this year; the second reported on lobbying for a biosimilars bill.
• FDA Law Blog recently updated their coverage of the generic Depakote (divalproex sodium) litigation between Nu-Pharm (a former subsidiary of Apotex) and FDA, in which Nu-Pharm is seeking an injunction requiring FDA to grant final approval to its divalproex ANDA.
• Pharmalot posted a summary of a recent article in the Seattle Post-Intelligencer about a citizen petition that has stymied Nastech Pharmaceutical's bid to market a generic version of Miacalcin (calcitonin), a treatment for postmenopausal osteoporosis.
• Takeda announced earlier this month that on March 31, the Supreme Court denied Alphapharm's cert petition from the Federal Circuit's decision last year in the Actos (pioglitazone) litigation.

OBB News Briefs

• Fosamax, Merck's blockbuster osteoporosis drug, went generic on Wednesday.  The In Vivo Blog posted an interesting report on the unusual steps Merck took to promote Fosamax in the last month, before its patents expired.
• The WSJ Health Blog posted an interesting story this week on contributions from the pharmaceutical industry to the presidential candidates.  Apparently drug company employees are not fans of John McCain.
• FDA Law Blog reported Tuesday that the Bush Administration announced, as part of its FY2009 budget proposal, that it will seek new statutory authority to allow FDA to approve follow-on biologics in abbreviated applications.  In response to the budget announcement, Insmed, Inc., a developer of follow-on biologics and biopharmaceuticals, announced that it is launching a "national awareness" campaign on follow-on biologics.
• FDA Law Blog reported last week that the district court in D.C. dismissed Nu-Pharm's lawsuit against the FDA, in which Nu-Pharm sought to force FDA to grant final approval to its ANDA for a generic version of Abbott Labs' Depakote.  Nu-Pharm, a former subsidiary of Apotex, has appealed the decision to the D.C. Court of Appeals.
• On Feb. 1, FDA posted a new comprehensive list of FDA Guidance Documents, which could come in handy for FDA-regulated companies.
• Wyeth recently launched of an authorized generic version of Protonix, as Pharmalot and the WSJ Health Blog reported.  The WSJ Health Blog also reported on speculation about why Teva declined to ship any additional generic Protonix.

Pharma News Briefs

• Last week, the U.S. District Court for the District of Columbia denied Mylan's emergency motion for a temporary restraining order that would have forced FDA to relist Pfizer's Norvasc patent in the Orange Book.  Until June 22, when FDA delisted Pfizer's patent, Mylan and Apotex had the only approved ANDAs for generic Norvasc.
• Bloomberg reported Thursday that Pfizer and Sandoz have settled their litigation over Sandoz's ANDA for generic Zithromax.  The district court entered an order dismissing the case on June 25.
• Also Thursday, The Wall St. Journal Health Blog reported that the government of Brazil and Abbott Labs stepped back from the brink and agreed on a price for Kaletra, Abbott's AIDS drug.
• The National Law Journal had this article Friday on alleged abuse of the citizen petition process by pharmaceutical companies.
• FDA released a new final guidance document entitled "ANDAs: Pharmaceutical Solid Polymorphism -- Chemistry, Manufacturing, and Controls Information."  The guidance provides recommendations on assessing sameness when a drug substance exists in polymorphic forms.

Mylan Obtains Injunction Preventing FDA from Approving Any Other Generic Norvasc Until April 13

Mylan Laboratories announced this morning that the U.S. District Court for the District of Columbia has enjoined the FDA from approving any other ANDAs for generic Norvasc (amlodipine besylate) until at least April 13, 2007.  Mylan launched its generic Norvasc last week and, with the exception of Pfizer's authorized generic, currently has the only generic on the market.

Mylan was the first generic drug maker to file an ANDA for generic Norvasc, and is therefore entitled to a 180-day generic exclusivity period.  However, FDA's policy for pre-Medicare Modernization Act ("MMA") ANDAs (like Mylan's) is that the 180-day exclusivity period cannot extend beyond patent expiration.  Pfizer's patent on Norvasc expired on Sunday, and therefore without the injunction Mylan's 180-day exclusivity period might have been cut short.  (The MMA introduced numerous 180-day exclusivity "forfeiture provisions," one of which is that 180-day exclusivity ends upon patent expiration.  Since Mylan's ANDA was filed before December 8, 2003, however, the MMA does not apply.)

Mylan filed its Complaint against the FDA and Emergency Application for a Temporary Restraining Order and/or Preliminary Injunction yesterday, and the district court ruled on it the same day.  According to the district court's Order, the "FDA will now solicit the views of other interested parties on this matter by April 4, 2007 and will render an agency decision on April 11, 2007."  The FDA is to notify the court of its decision no later than April 11 and is enjoined from taking final agency action "until April 13, 2007 at 5:00 pm to enable the court to rule formally on the plaintiff's application for a TRO."

Presumably, such interested parties include Apotex, Dr. Reddy's, Gedeon Richter USA, Kali Labs, Matrix, Roxane, Teva, and Watson, each of which has been granted tentative approval to market generic Norvasc and is awaiting only resolution of the exclusivity issues.

The other party with a huge stake in this case is Pfizer--the innovator who developed Norvasc and whose patent the Federal Circuit declared invalid last Thursday.  Pfizer has 6 months of pediatric exclusivity on Norvasc and indicated last week that it will "pursue all available legal remedies" to protect that exclusivity.

This case is far from over.  We'll post additional briefs and submissions as they become available.

RELATED READING:

• Reuters
• TheStreet.com

UPDATES:

• FDA Law Blog reports that Mylan filed a citizen petition with the FDA on Monday to enforce its 180-day exclusivity period.

Ondansetron Update: Apotex Loses Emergency Appeal, Dr. Reddy's Launches Generic Zofran

We previously reported on Apotex's lawsuit against the FDA concerning generic Zofran (ondansetron HCl) tablets.  Apotex sought an injunction directing FDA to approve Apotex's ANDA for generic Zofran tablets when GlaxoSmithKline's pediatric exclusivity on Zofran expired on December 24, 2006.  Although Dr. Reddy's was the first to file an ANDA for generic Zofran tablets, Apotex argued that a May 2005 district court dismissal of GSK's lawsuit against Apotex triggered Dr. Reddy's 180-day exclusivity period, which then ran to completion in December 2005.

On December 7, 2006, Judge Rosemary M. Collyer of the U.S. District Court for the District of Columbia denied Apotex's motion for a preliminary injunction against the FDA, prompting Apotex to file an emergency motion to stay the district court's order pending appeal.  On December 22, the D.C. Circuit Court of Appeals denied Apotex's motion.  That cleared the way for FDA to grant final approval for ondansetron HCl tablets to Dr. Reddy's, which it did on December 27.  The same day, Dr. Reddy's announced that it would "commence the shipment of this product shortly."

Zofran, which is indicated for the prevention of nausea and vomiting associated with chemotherapy, is available in several different dosage forms and strengths.  Besides granting final approval to Dr. Reddy's, FDA announced in November that it granted final approval to Teva and SICOR for generic Zofran Injection and Zofran Injection Premixed.  Additionally, FDA announced in December that it granted final approval to Kali Laboratories' ANDA for generic Zofran ODT (ondansetron orally disintegrating tablets) and to Roxane Laboratories' ANDA for generic Zofran Oral Solution.  The various forms of Zofran accounted for well over $1 billion in sales last year for GSK.

Meanwhile, it appears that Apotex's lawsuit against the FDA is moving forward.  On January 18, the FDA and Dr. Reddy's answered Apotex's complaint.  Today, the court set a March date for the initial scheduling conference.  With Dr. Reddy's already on the market as the sole generic supplier of ondansetron HCl tablets, it is unclear what Apotex has to gain by pursuing the case.

Apotex Sues FDA Over Decision on Generic Zofran, Challenging FDA's Interpretation of "Court Decision" Trigger Again

Apotex filed a complaint and motion for preliminary injunction against the FDA in the U.S. District Court for the District of Columbia last week, alleging that the FDA unlawfully refused to acknowledge that the dismissal of its patent infringement suit against GlaxoSmithKline over generic Zofran was a "court decision" triggering the first ANDA filer's 180 day period of exclusivity.  The dismissal order was entered May 25, 2005, and therefore Apotex claims that the 180 day exclusivity period expired in November, 2005.  Apotex would like to launch its generic Zofran next month, when the last of GSK's patents expire.  Unless the FDA changes its position, however, Apotex will have to wait until at least 180 days later.

Apotex had previously challenged the FDA's interpretation of a "court decision" sufficient to trigger a 180 day exclusivity period, in a declaratory judgment action involving generic Pravachol.  In that case, FDA decided that the dismissal of a patent suit was not such a court decision; instead, a court must issue a holding on the merits of the suit.  FDA explained in a November 3rd letter to counsel for Apotex that its "holding-on-the-merits" standard "is equally applicable to affirmative patent suits," such as the Zofran case.  Apotex filed its lawsuit against the FDA shortly after receiving the letter.

The impact of this case will be relatively limited because the Medicare Modernization Act of 2003 got rid of the "court decision" trigger entirely.  For ANDAs filed after December 8, 2003, if no other ANDAs containing a paragraph IV certification for the listed drug were filed prior to December 8, 2003, a court decision no longer triggers the 180-day exclusivity period.  Instead, the exclusivity period does not begin until the first commercial marketing of the generic drug.

NOTE:  Thanks to Kurt Karst for bringing this case to my attention.