Orange Book Blog

FDA Delay in Reviewing Ditropan XL Citizen Petition Helps Alza, Hurts Mylan and Impax

Mylan and Impax were the first generic drug companies to file substantially complete ANDAs for generic versions of Ditropan XL (oxybutynin chloride, extended release), an incontinence treatment with annual sales of about $400 million.  Mylan was the first to file for the 5 mg and 10 mg dosage strengths and Impax was the first to file for the 15 mg strength.

As we previously reported, on September 6th the Court of Appeals for the Federal Circuit affirmed the invalidity of Alza's patent on Ditropan XL.  Ordinarily, one would have expected the FDA to grant final approval of Mylan and Impax's ANDAs shortly thereafter (both companies had already received tentative approval), but in this case FDA review of a citizen petition caused final approval to be delayed for over two months.

On August 29, 2005, shortly before the district court invalidated Alza's patent on Ditropan XL, Ortho-McNeil filed a citizen petition asking the FDA to demand additional data from any companies filing ANDAs for generic Ditropan XL.  Both Ortho-McNeil and Alza are subsidiaries of Johnson & Johnson.  Ortho-McNeil's citizen petition asked FDA (1) to require that standard bioequivalence criteria be applied separately to oxybutynin and its active metabolite, desethyloxybutynin, to ensure that approved generic versions of Ditropan XL are both bioequivalent and clinically equivalent to the innovator product; (2) to apply bioequivalence criteria to the R- and S-enantiomers of oxybutynin and desethyloxybutynin; and (3) to require that all bioequivalence studies be conducted under both fasting and fed conditions.

On November 9th of this year, FDA responded to the citizen petition, granting it in part but denying most of its requests.  On the same day, FDA granted final approval to Mylan and Impax for generic versions of Ditropan XL and the two companies launched their generic products immediately.  Thus, FDA's delay in ruling on Ortho-McNeil's citizen petition appears to have resulted in an extra two months of market exclusivity for Alza.

Even worse for Mylan (and Impax too, presumably) is that FDA's delay in ruling on the citizen petition appears to have cost it two months of its 180-day exclusivity.  While FDA's approval letter to Mylan asks Mylan to submit correspondence indicating when its exclusivity began to run, it seems pretty clear that Mylan's exclusivity began with the September 6th appeals court decision.  Mylan filed its ANDA before enactment of the Medicare Modernization Act (MMA), and therefore the "court decision" trigger applies to Mylan's ANDA.

It seems particularly important for FDA to expedite its review of citizen petitions in situations such as this, where a portion of the 180-day marketing exclusivity period may be lost through no fault of the ANDA filer.

RELATED READING:

• November 10, 2006 Impax press release
• November 10, 2006 Mylan press release

Federal Circuit Affirms Finding That Mayne Pharma Infinges Abraxis Bioscience's Patent on Diprivan

Last week the U.S. Court of Appeals for the Federal Circuit affirmed a district court's finding that Mayne Pharma's ANDA for generic Diprivan (propofol) infringes Abraxis Bioscience's U.S. Patent No. 5,714,520 (and two other related patents).  The '520 patent covers improved formulations of Diprivan, an injectable drug used to induce and maintain general anesthesia and sedation in patients.  Specifically, the patent claims a propofol formulation containing edetate, an antimicrobial preservative.  Mayne filed its ANDA for a propofol formulation containing a different preservative, the calcium trisodium salt of pentetate (also referred to as DTPA), and obtained a patent on the formulation.

In an opinion written by Judge Lourie for a unanimous panel, the Federal Circuit affirmed the district court's finding of infringement under the doctrine of equivalents (DOE).  The most interesting aspect of the opinion addressed Mayne's argument that the district court improperly defined the "way" prong of the familiar function-way-result test of DOE infringement.  The district court found that the "way" edetate works is by metal ion chelation.  Mayne asserted that the proper definition of "way" was narrower: one that incorporates the specific metal ions that are chelated, the strength of the bonds that are formed during chelation, and stability constants.

According to the Federal Circuit:

"What constitutes equivalency must be determined against the context of the patent, the prior art, and the particular circumstances of the case."  [citing Graver Tank] . . . Here, the district court properly assessed the "way" edetate works by referring to the patent and the evidence presented at trial.  The record evidence supports the conclusion that the "way" in which both edetate and calcium trisodium DTPA perform as an antimicrobial agent is by metal ion chelation.

While the Federal Circuit reversed the district court's claim construction as to the term "edetate" and its finding of literal infringement, its affirmance of the lower court decision under the doctrine of equivalents was sufficient to doom Mayne Pharma's case.  It appears that Mayne must now wait until expiration of the patents in suit before it can market its generic propofol product.

RELATED READING:

• Patently-O

D.C. Circuit Agrees That FDA Improperly Delisted Merck's Zocor Patents From Orange Book, Unlawfully Denying Teva and Ranbaxy of Simvastatin Exclusivity

The Court of Appeals for the D.C. Circuit today affirmed a district court decision finding that the FDA wrongly delisted two Merck patents on Zocor (simvastatin), which in turn unlawfully denied Teva and Ranbaxy from 180 days of marketing exclusivity on generic simvastatin.  FDA appealed the district court decision but did not request a stay.  FDA then granted final approval of Teva and Ranbaxy's ANDAs in June, after which the two companies launched their generic simvastatin products.

In today's D.C. Circuit opinion, written by Judge Ginsburg for a unanimous panel, the court upheld the district court's finding that FDA's interpretation of the statue was contrary to the clear intent of Congress.  FDA's policy was to allow delisting when a generic drug maker had filed an ANDA containing a paragraph IV certification and the NDA holder had not filed a lawsuit to contest the certification, as occured in the Zocor case.

The appeals court framed the question at issue as "whether the FDA may delist a patent upon the request of the NDA holder after a generic manufaturer has filed an ANDA containing a paragraph IV certification so that the effect of delisting is to deprive the applicant of a period of marketing exclusivity."  In striking down FDA's policy, the court reasoned:

Not only does the statute not require litigation to preserve a generic applicant's eligibility for exclusivity . . . such a requirement is inconsistent with the structure of the statute because, if the patent is delisted before a pending ANDA is approved, then the generic manufacturer may not initiate a period of marketing exclusivity.

By thus reducing the certainty of receiving a period of marketing exclusivity, the FDA's delisting policy diminishes the incentive for a manufacturer of generic drugs to challenge a patent listed in the Orange Book in the hope of bringing to market a generic competitor for an approved drug without waiting for the patent to expire.  The FDA may not, however, change the incentive structure adopted by the Congress.

This case appears to require FDA to set a new policy, whereby it should refuse to delist a patent if a generic manufacturer has filed an ANDA containing a paragraph IV certification with respect to the patent.

RELATED READING:

• November 14, 2006 Reuters article
• May 17, 2006 post, including link to district court decision

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.

Federal Circuit Invalidates Abbott's Sevoflurane Patent in Case Against Baxter

The Federal Circuit today reversed a district court decision that upheld the validity of Abbott's U.S. Patent No. 5,990,176, finding instead that Abbott's patent is inherently anticipated by U.S. Patent No. 5,684,211.  The '176 patent covers compositions of and processes for making sevoflurane, an inhalation anesthetic that Abbott sells under the brand names Ultane and Sevorane.  In 2001 Baxter filed an ANDA to market generic sevoflurane.

The '176 patent claims compositions comprising sevoflurane and a Lewis acid inhibitor (such as water) in an amount effective to prevent degradation of sevoflurane.  The '211 patent discloses a water-saturated sevoflurane composition, though the inventors did not recognize at the time that the water in the composition prevented degradation of sevoflurane.  At trial, the U.S. District Court for the Northern District of Illinois relied on Bristol-Myers Squibb v. Ben Venue in concluding that the '211 patent did not inherently anticipate the '176 patent because the purpose of the '211 patent was not to produce sevoflurane in its final usable form, in distinction to the purpose of the patent-in-suit.

The Federal Circuit's decision, written by Judge Garjarsa for a unanimous panel, noted initially that BMS v. Ben Venue applies only to process claims, and therefore is inapplicable to the composition claims of the '176 patent.  With regard to the process claims of the '176 patent, the Federal Circuit disagreed that the processes described in the '176 and '211 patents are directed to the same purpose.  The court stated:  "All that is contributed by the method claims of the '176 patent is the recognition of a new property of the prior art process."

Judge Gajarsa's opinion reaffirms the general principle that "a reference may anticipate even when the relevant properties of the thing disclosed were not appreciated at the time."  In support of this principle, the Federal Circuit cited its own 1985 opinion in Titanium Metals and an 1892 Supreme Court decision, Ansonia Brass & Copper Co.

Federal Circuit Hears Oral Argument in Plavix Case

The Federal Circuit heard oral argument this past Tuesday in the Plavix case (Appeal No. 06-1613), in which Apotex is appealing a preliminary injunction enjoining Apotex's sales of generic Plavix.  An .mp3 audio file of the oral argument may be downloaded from the Federal Circuit's website (link).

On August 31st, Judge Sidney H. Stein of the U.S. District Court for the Southern District of New York granted a preliminary injunction to Sanofi-Synthelabo and Bristol-Myers Squibb in their patent infringement case against Apotex.  In a 58-page opinion, Judge Stein found that Apotex was unlikely to prevail at trial in proving invalidity or unenforceability of Sanofi's U.S. Patent No. 4,847,265.  In addition, Judge Stein found Apotex's defenses of laches and unclean hands unconvincing.

Judges Bryson, Clevenger, and Lourie heard the oral argument and will decide the appeal.  Though many issues were briefed, the arguments from the parties and questions from the panel focused on anticipation and irreparable harm.  Apotex argued that the disclosure of a genus of racemic compounds in Sanofi's own prior art U.S. Patent No. 4,529,596 anticipates claim 3 of '265 patent, which is directed to a single enantiomeric compound encompassed in the genus disclosed in the '596 patent.  With respect to irreparable harm, Apotex argued that by agreeing to limit damages to 50% of Apotex's sales of generic Plavix, Sanofi and BMS essentially admitted their damages could be calculated and therefore there is an adequate remedy at law, precluding an injunction.

In my view, the Federal Circuit panel hearing the oral argument seemed convinced that Judge Stein correctly decided the "likelihood of success on the merits" prong (in other words, that Apotex would be unable to prove invalidity at trial), and seemed a bit more skeptical that Sanofi and BMS would suffer irreparable harm if the preliminary injunction was vacated.  Even on irreparable harm, however, the panel asked tougher questions of counsel for Apotex, and seemed to favor plaintiffs' position.  More than once, the panel reminded counsel that Apotex faced "an uphill battle" because of the high standard of review:  abuse of discretion.

The Federal Circuit could release an opinion on Apotex's appeal at any time.  A trial in the district court is scheduled to begin on January 22, 2007.

RELATED READING:

• September 21, 2006 Orange Book Blog post

Paddock Labs Wins Summary Judgment of Noninfringement in Univasc Suit Against Schwarz Pharma and Warner-Lambert

Judge Ann D. Montgomery of the U.S. District Court for the District of Minnesota recently granted Paddock Labs' motion for summary judgment of noninfringement of Warner-Lambert's U.S. Patent No. 4,743,450, which covers pharmaceutical formulations of moexipril hydrochloride, the active ingredient in Univasc.

Warner-Lambert granted Schwarz Pharma an exclusive license under the '450 patent to manufacture and sell drug products containing moexipril hydrochloride, an Angiotensin Converting Enzyme (ACE) inhibitor indicated for the treatment of hypertension and congestive heart failure.  Schwarz Pharma and Warner-Lambert sued Paddock Labs based on Paddock's ANDA to market a generic version of Univasc.  Schwarz Pharma's U.S. sales of Univasc amounted to $80 million last year.

In her opinion granting Paddock's motion for summary judgment, Judge Montgomery rejected Paddock's assertion of argument-based prosecution history estoppel, but agreed with Paddock's assertion of amendment-based prosecution history estoppel.  During prosecution, in order to overcome an obviousness rejection, Warner-Lambert amended claim 1 of the '450 patent from reciting an ACE inhibitor composition comprising "a metal containing stabilizer" to an ACE inhibitor composition comprising "an alkalai or alkaline earth metal salt."  Judge Montgomery found this was a narrowing amendment made for reasons of patentability, raising a presumption of surrender of all equivalents of "metal containing stabilizers" that are not "an alkalai or alkaline earth metal salt"--including magnesium oxide, the alleged equivalent Paddock uses in its generic Univasc formulation.

The court further found that the plaintiffs failed to rebut the presumption by proving either that magnesium oxide was an unforeseeable equivalent or that the claim amendment was merely tangentially related to magnesium oxide.  Accordingly, the court granted Paddock's motion for summary judgment of noninfringement.

In a last-ditch effort to avoid the finality of Judge Montgomery's opinion and order, last week Schwarz Pharma filed a motion to alter or amend judgment pursuant to FRCP 59(e).  In its motion, Schwarz argues that it was legally and factually erroneous for the court to conclude that magnesium oxide was a foreseeable equivalent.

UPDATE:  On Oct. 26, concurrent with its motion under FRCP 59(e), Schwarz Pharma filed a citizen petition asking the FDA not to grant final approval to Paddock Labs' ANDA until the district court rules on its motion.