Orange Book Blog

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

• Earlier this week, FDA Law Blog provided an update on Teva's suit against the FDA, seeking relisting of Janssen's patent on Risperdal (risperidone) and confirmation of Teva's 180-day exclusivity on a generic version of the drug.
• Last week, FDA Law Blog reported on a recent FDA determination that Watson Labs forfeited its 180-day exclusivity on generic Camptosar (irinotecan HCl) because it failed to obtain tentative approval of its ANDA within 30 months of filing, as required by the MMA.
• Pharmalot and the WSJ Health Blog recently ran posts on a series of articles in the Los Angeles Times examining whether generic drugs are as good as brand-name drugs.
• Eighteen states recently sued Abbott Labs for antitrust violations, alleging that Abbott made trivial changes to the formulation of its TriCor cholesterol drug, thereby delaying generic competition.  Statements were released by the Attorneys General from Florida and Iowa.
• William Kovacic was appointed the new Chairman of the Federal Trade Commission this week, succeeding Deborah Platt Majoris.  The Wall St. Journal reported that Mr. Kovacic has been a strong proponent of FTC action against "reverse payment" settlements.

OBB News Briefs

• The New York Times had another article Thursday on the investigation into the Chinese supply of heparin.  Pharmalot had this related post Friday.
• FTC Commissioner Jon Leibowitz wrote an editorial for the Washington Post Monday on "reverse-payment" settlements (or "pay-for-delay" settlements), and the FTC's recently filed case against Cephalon, in particular.
• Dow Jones reported Monday that Apotex and Pfizer settled their patent litigation over generic Neurontin (gabapentin).  Pfizer's cases against Eon Labs, Purepac and Teva are continuing.
• FDA Law Blog had an interesting post on a long-shot citizen petition filed by Apotex, who is seeking to recover its 180-day exclusivity on generic Plavix (clopidogrel).
• Also last week, FDA Law Blog posted a draft of Rep. Eshoo's biosimilar's bill.  Word on the street is that it has little chance of passing.
• Pharmalot reported last week that growth in sales of generic drugs slowed to just 3.8% last year, largely due to increased competition.

FDA Answers Ramipril Letters, Explains Why Cobalt Has 180-Day Exclusivity

As we reported last November, the Federal Circuit's decision invalidating U.S. Patent No. 5,061,722 on Altace (ramipril) was followed by a flood of letters to FDA concerning 180-day exclusivity for ramipril.  FDA responded last week, shedding some light on how pre-MMA 180-day exclusivity issues are decided.

In FDA's response, posted January 29, FDA explained that Cobalt's 180-day exclusivity period began on December 10, 2007, when the Federal Circuit's mandate issued, and that no other ramipril ANDAs will be eligible for final approval until June 7, 2008, when Cobalt's exclusivity expires.  Although the Federal Circuit's decision came in the litigation involving Lupin, Cobalt was the first to file a ramipril ANDA.

Lupin argued first that Cobalt forfeited its 180-day exclusivity by entering into a settlement of its patent litigation with King Pharmaceuticals.  But FDA rejected this argument, concluding that there is no legal basis for it to find that Cobalt forfeited its exclusivity.  FDA stated, "Because the Act addresses directly the question of forfeiture as a result of a settlement [in 21 USC 355(j)(5)(D)(i)(V)], the agency does not have the discretion to determine that settlements not otherwise meeting the statutory requirements also will result in forfeiture."

In addition, Lupin argued that Cobalt's settlement rendered its paragraph IV certification inaccurate because, by settling its patent litigation, Cobalt had effectively stopped asserting that the '722 patent was invalid.  FDA rejected this argument as well, because "there is no evidence that at any point Cobalt conceded the '733 patent as valid, enforceable, and infringed by the product described in its ANDA."  Here, it appears important that Cobalt's settlement was made "without prejudice to Cobalt's allegations that the claims of the '722 patent are invalid and unenforceable."  FDA stated in its response that its regulations provide only three circumstances under which a patent certification should be amended, and none apply in this case.

Finally, Lupin argued that it "should be permitted to amend its certification so that its approval is not affected by Cobalt's exclusivity" because FDA's regulations provide for changes in certification when circumstances change.  FDA, however, was not persuaded, because its regulations also preclude the withdrawal of a paragraph IV certification until expiration of 180-day exclusivity.  FDA stated: "a subsequent applicant such as Lupin may not make an end run around the continued listing of an invalid patent--and the related 180-day exclusivity--merely by changing its certification.  The fact that Lupin, not Cobalt, was successful in obtaining a judgment that the '722 patent is invalid does not alter this conclusion."

OBB News Briefs

• Earlier this week, FDA released its highly anticipated response concerning granisetron 180-day exclusivity.  This marks the first time that FDA has interpreted the "failure to market" forfeiture provisions of the 2003 MMA.  FDA Law Blog posted a nice summary of FDA's response.
• FDA Law Blog also posted on a very interesting case recently filed by Nu-Pharm against FDA, in which Nu-Pharm seeks to force FDA to grant it final approval to market generic Depakote (divalproex sodium).
• The Wall St. Journal had an interesting article yesterday on health plans that pay doctors $100 each time they switch a patient to a generic drug.  The WSJ Health Blog posted this summary of the article.
• A district court in New York recently held that three Purdue Pharma patents on Oxycontin are not unenforceable for inequitable conduct.
• Cypress Pharmaceutical announced today that it has settled patent litigation with GSK concerning its generic version of Zantac (ranitidine) syrup.

Teva Seeks Relisting of J&J's Risperdal Patent and Asserts Right to 180-Day Exclusivity

A reader recently e-mailed me about an interesting citizen petition that Teva filed last August.  In the petition, Teva requests that FDA:  (1) relist U.S. Patent No. 5,158,952 in the Orange Book for Risperdal (risperidone) tablets; (2) confirm Teva's right to 180-day exclusivity for risperidone tablets; and (3) refrain from approving any other ANDAs for risperidone tablets until Teva's exclusivity expires.  Risperdal is Johnson & Johnson's blockbuster treatment for schizophrenia and other neurological disorders.

Teva filed its ANDA for risperidone tablets on August 28, 2001, with a paragraph III certification to U.S. Patent No. 4,804,663 and a paragraph IV certification to the '952 patent.  At the time, both patents were listed in the Orange Book for Risperdal.  On October 12, 2001, FDA notified Teva that it had delisted the '952 patent from the Orange Book and informed Teva that it would not accept Teva's ANDA for filing unless Teva amended its paragraph IV certification to reflect the fact that the '952 patent had been delisted.  Teva complied by amending its ANDA.

Five years later, in Ranbaxy v. Leavitt, the D.C. Circuit ruled that FDA had improperly delisted two patents on Zocor because the effect of delisting would be to deny the first ANDA filer of 180-day exclusivity on simvastatin tablets.  According to Teva's citizen petition, following that decision "Teva began reviewing its portfolio of pending ANDAs to determine whether FDA's unlawful delisting practices had deprived Teva of its entitlement to 180-day exclusivity for any other generic product."

In its risperidone petition, Teva contends that because the '952 patent was listed in the Orange Book when it filed its ANDA for risperidone tablets, it had no choice but to certify as to the '952 patent.  "Teva thus did precisely what it was obligated to do under the plain text of the governing statute and Agency regulations, and it therefore earned its exclusivity as the first applicant to file a paragraph IV certification to a patent listed as claiming the reference listed drug."  Teva argues that the Ranbaxy decision compels FDA to relist the '952 patent and restore Teva's right to 180-day exclusivity.  Teva further argues that "the fact that FDA never accepted Teva's paragraph IV ANDA for filing has no bearing on the fact that FDA must relist the '952 patent."

The '663 patent (whose validity was affirmed in a Federal Circuit decision last year) expired on December 29, 2007.  Pediatric exclusivity on Risperdal extends to June 29, 2008.  Thus, FDA must decide the issues presented in Teva's citizen petition before then.  FDA will post its decision in the docket established for Teva's petition.

OBB News Briefs

• Teva announced last week that it was granted 180-day exclusivity for its generic Kytril injection product (granisetron HCl, 1 mg/mL in 1 mL vials).  Thus, it appears the FDA decided the 180-day exclusivity issue raised in Teva's citizen petition--namely, whether Teva's failure to market its generic product within 30 months of ANDA submission caused forfeiture of its exclusivity.  FDA is expected to release a formal response to Teva's petition in the near future.
• King Pharma and CorePharma settled their patent litigation over generic Skelaxin (metaxalone).  According to this AP story, however, analysts disagreed over the impact of the settlement.
• Taro Pharma and Breckenridge Pharma announced settlements with Novartis of their patent cases concerning generic Trileptal (oxcarbazepine).  According to their press releases, Taro and Breckenridge are sharing 180-day exclusivity for the product.
• Bloomberg published an interesting article earlier this week about the faltering biotechnology industry in China.
• Both Pharmalot and the WSJ Health Blog had posts this week about a Bloomberg story that reported the FDA approved only 19 new drugs last year, the fewest since 1983.
• Pharmalot also posted this week on a new report from Cutting Edge Information entitled "Combating Generics 2008," which found that 66 percent of brand name drug companies do not begin strategizing against generics until at least two years after product launch.

Pharma News Briefs

• Apotex and an anonymous ANDA filer recently submitted new comments to FDA on ramipril 180-day exclusivity issues.  Earlier this month, we summarized previous comments on the ramipril docket.
• Roxane Labs recently submitted new comments to FDA on acarbose 180-day exclusivity, and Impax indicated that it intends to do the same.  Their submissions are available on FDA's acarbose docket.
• The FTC announced Thursday that it has settled its antitrust complaint against Barr Labs concerning Warner Chilcott's Ovcon birth control pill.  According to FTC's press release, the settlement provides that "Barr must refrain from entering into anticompetitive supply agreements with branded companies similar to Barr's agreement with Warner Chilcott regarding Ovcon."
• Via SpicyIP and Pharmalot, Sun Pharma has filed a paragraph IV challenge of Novartis's polymorph patent on Gleevec (imatinib mesylate), which expires in 2019.  The compound patent on imatinib expires in 2015.
• FDA Law Blog had an interesting post last week about a lawsuit by two pharmacy associations against the Center for Medicaid Services, charging that the new "AMP rule," which CMS uses to calculate how much it reimburses states for generic drugs, is unlawful.  Some believe that the new Medicaid reimbursement rules make it cost-prohibitive for brand name drug companies to sell authorized generics in many cases.
• Pharmalot reported recently that legislation that would have banned "reverse payment" settlements of Hatch-Waxman litigation has stalled in the Senate.  For background, see this OBB post from last February.

Dismissal of Invalidity Counterclaims Thwarts Apotex's Attempt to Trigger 180-Day Exclusivity on Cosopt

Merck v. Apotex, No. 06-5789 (D.N.J. 2007)

Merck has sold Cosopt (dorzolamide hydrochloride/timolol maleate), an opthalmic drug indicated for the treatment of ocular hypertension and open-angle glaucoma, since 1998.  In October 2005, Hi-Tech Pharmacal filed the first ANDA for a generic version of Cosopt with paragraph IV certifications to the Orange Book-listed patents: U.S. Patent Nos. 4,797,413; 6,248,735; and 6,316,443.

In January 2006, Merck sued Hi-Tech, asserting infringement of the '413 patent but not the '735 or '443 patents.  On April 18, 2006, Merck filed a statutory disclaimer of the '735 and '443 patents with the USPTO, effectively dedicating its rights under the patents to the public.  Shortly thereafter, on April 25, Merck wrote to the FDA and requested that the agency delist those two patents from the Orange Book.  The FDA, however, did not delist the patents--indeed the patents remain listed today.

In October 2006, Apotex sent Merck a letter notifying it that Apotex had filed an ANDA for a generic version of Cosopt with paragraph IV certifications to all three Orange Book-listed patents.  In response, Merck sued Apotex in December 2006, again asserting infringement of the '413 patent but not the '735 or '443 patents.  Apotex agreed to be bound by the court decision on the '413 patent in the Hi-Tech case, but pursued declaratory judgment counterclaims of invalidity of the disclaimed patents.  On March 29, 2007, the Federal Circuit affirmed the patent term of the '413 patent, leaving only Apotex's counterclaims on the disclaimed '735 and '443 patents in the case.  The '413 patent will expire in April 2008, with pediatric exclusivity extending to October 2008.

Shortly after the Federal Circuit decision on the '413 patent, Merck moved under Fed. R. Civ. P. 12(b)(1) to dismiss Apotex's counterclaims of invalidity of the '735 and '443 patents for lack of subject matter jurisdiction.  In an opinion released earlier this month, the district court granted Merck's motion to dismiss, concluding: "because Merck has formally disclaimed the '735 and '443 patents, and can no longer enforce any claims as to these patents, there is no justiciable case or controversy to support jurisdiction in an action for a declaratory judgment here."  Apotex has appealed the decision to the Federal Circuit.

BRIEFS:

• Merck brief in support of motion to dismiss
• Apotex brief in opposition to motion
• Merck reply brief

ADDENDUM:
In a separate case, relating to Precose (acarbose), Cobalt Pharmaceuticals recently filed a complaint seeking a declaratory judgment of invalidity or noninfringement with respect to another statutorily-disclaimed patent, U.S. Patent No. 4,904,769.  In that case, Cobalt is the first ANDA filer, and the '769 patent is the only Orange Book-listed patent for Precose.  For more information, see this FDA Law Blog post.