Orange Book Blog

Non-Patent Exclusivity and 180-Day Exclusivity Forfeiture Slides Posted

Last week, I gave a talk about non-patent exclusivity at ACI's FDA Boot Camp conference in Boston.  The talk covered new chemical entity (5-year) exclusivity; new clinical trial (3-year) exclusivity; orphan drug exclusivity; pediatric exclusivity; and generic drug (180-day) exclusivity.  You can download a copy of my slides here.

In June, I gave a talk about forfeiture of 180-day exclusivity at IIR's Generic Drugs Summit conference in Washington.  The talk included a discussion of the "failure to market" forfeiture provisions, particularly the FDA's Acarbose and Granisetron decisions.  You can download a copy of those slides here.

In a "Surprising" Victory, Barr and Mylan Invalidate Boehringer Ingelheim's Patent on Mirapex

Boehringer Ingelheim v. Barr and Mylan, No. 05-700-JJF (D. Del. 2008)

Last week, following a bench trial held in March, the U.S. District Court for the District of Delaware held that Boehringer Ingelheim's patent on Mirapex (pramipexole dihydrochloride) is invalid for obviousness-type double patenting.  Mirapex, indicated for the treatment of Parkinson's disease and Restless Leg Syndrome, has annual U.S. sales of approximately $380 million.

Barr Labs filed its ANDA for a generic version of Mirapex in 2005 with paragraph IV certifications to Boehringer's U.S. Patent Nos. 4,843,086 and 4,886,812.  Mylan filed its ANDA, with paragraph IV certifications to the same patents, shortly thereafter.  Barr's approval letter confirms that Barr was the first to file, and therefore is entitled to 180-day exclusivity.

Boehringer responded by filing suit against Barr and Mylan, and the cases were consolidated for trial.  The '086 patent expired while the litigation was pending, leaving only the '812 patent in suit.

The district court's opinion explains that the "basic premise of double patenting is that the same invention cannot be patented twice."  Here, the '086 patent claimed methods of treating certain diseases by administering tetrahydrobenzthiazoles, while the '812 patent claims the tetrahydrobenzthiazole compounds themselves, including the active ingredient in Mirapex, pramipexole dihydrochloride.  The court concluded that "although there are differences between the '812 patent and the '086 patent, . . . those differences are insufficient to support the patentability of the '812 patent in light of the '086 patent."

Of course, obviousness-type double patenting can be avoided by a terminal disclaimer.  Interestingly, Boehringer filed a terminal disclaimer of the '812 patent on the second day of trial of the case, on March 12, 2008.  Boehringer terminally disclaimed:

only the terminal part of the statutory term of the '812 patent which would extend beyond the 1,564 days after the full statutory term of the '086 patent as that term is defined in 35 U.S.C. § 154, so that by virtue of this disclaimer, the '812 patent will expire on October 8, 2010.

Boehringer received a 1,564-day extension under 35 USC § 156 due to FDA regulatory review of Boehringer's New Drug Application for Mirapex.  As a result of this patent term extension, the original expiration date of the '812 patent, December 12, 2006, was extended to March 25, 2011.  Thus, by its terminal disclaimer, Boehringer disclaimed five and a half months of patent term--the period of time between the expiration date of the '086 patent and the original expiration date of the '112 patent.

Boehringer argued that the terminal disclaimer obviated Barr and Mylan's double-patenting argument.  However, the court noted that "a dual problem is presented in that the terminal disclaimer was not only filed at or near the conclusion of trial in this action, but it was also filed after the expiration of the earlier '086 patent."  Citing two cases, the court observed that "the Federal Circuit has at least suggested in dicta that for a terminal disclaimer to be effective, the earlier filed patent must not have expired at the time of the filing of the disclaimer."  Boehringer tried to distinguish these cases "because neither case involved a terminal disclaimer in the context of a Section 156 patent term extension," but the court was not persuaded.  The district court held that Boehringer's terminal disclaimer was ineffective to moot the double patenting issue because it was filed after the '086 patent had expired.

According to an investor note from Bernstein Research, the decision was surprising because the district court was not expected to "make a controversial opinion on what is likely to be a precedent-setting ruling by the appellate court on patent extensions and terminal disclaimers."  In addition, the note indicates that Bernstein expects Barr to "maximize the value of the challenge through settlement."  According to Bernstein, "the most likely settlement is that Barr would have a date-certain launch of generic Mirapex in 2010 with an agreement protecting it from both an authorized generic and a potential Boehringer win on appeal."

The "failure to market" forfeiture provisions, however, will likely complicate any settlement discussions.  Under the MMA, the 180-day exclusivity period may be forfeited if the first applicant does not launch its generic drug product within 75 days after "a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed."  If Boehringer and Barr settle the case, for example, with an agreement that Boehringer will not appeal, Barr's 180-day exclusivity would be forfeited later this summer.  For at least this reason, Boehringer is expect to appeal the district court decision.

RELATED READING:

• Barr press release
• Bloomberg article
• Motley Fool article

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

King Pharmaceuticals Files Citizen Petition Relating to New Patent on Altace (Ramipril)

King Pharmaceuticals markets Altace (ramipril), which is indicated for the treatment of high blood pressure.  Until last year, when the Federal Circuit invalidated King's compound patent on ramipril, King earned about $700 million annually from U.S. sales of Altace.

Although Lupin was the ANDA filer who prevailed against King in the patent litigation, Cobalt Labs, as the first ANDA filer, won the 180-day exclusivity rights.  In a letter dated January 29, 2008, to attorneys for Lupin, FDA explained that Cobalt's exclusivity was triggered on December 10, 2007, and will expire on June 7, 2008.

Recently, on May 16, 2008, King submitted a citizen petition requesting that FDA require ANDA applicants for generic ramipril to submit a paragraph III or IV certification to U.S. Patent No. 7,368,469, which issued May 6, 2008, prior to final approval.  The '469 patent claims methods "for reducing the risk of a cardiovascular event" by administering an ACE inhibitor such as ramipril.

According to the FDA website, at least seven ANDA filers have tentative approval for ramipril and thus appear to have planned on obtaining final approval on June 7, when Cobalt's 180-day exclusivity expires.  Those plans may now be in doubt, as it may take FDA some time to decide how to rule on King's petition.

RELATED READING:

• Sept. 11, 2007 OBB post on Fed. Cir. decision
• Oct. 8, 2007 OBB post on FDA request for comments re: 180-day exclusivity
• Nov. 6, 2007 OBB post on comments submitted to FDA
• Feb. 4, 2008 OBB post on FDA decision re: 180-day exclusivity

OBB News Briefs

• As reported by FDA Law Blog, FDA determined on May 7 that Cobalt forfeited its 180-day exclusivity on acarbose and Cobalt sued FDA on May 8 for injunctive relief.  Last Friday, for some reason, Cobalt voluntarily dismissed its suit against FDA.
• Also last Friday, FDA appealed the D.C. district court's decision requiring relisting of Janssen's patent on Risperdal (risperidone).
• Ivax recently filed a declaratory judgment complaint against AstraZeneca, reportedly seeking to trigger Ranbaxy's 180-day exclusivity on esomeprazole.  AstraZeneca and Ranbaxy settled their esomeprazole litigation last month.
• The district court in Washington, D.C. recently transfered the FTC v. Cephalon "reverse payment" antitrust case to the Eastern District of Pennsylvania, Reuters reported, possibly throwing a wrench into the FTC's plans to get a "reverse payment" case before the Supreme Court.
• Pharmalot had an interesting post last week on the coming wave of generic drugs from Chinese generic drug companies.

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."