Orange Book Blog

In re Gabapentin Patent Litigation, No. 2006-1572 (Fed. Cir. 2007)

Last Friday, the Court of Appeals for the Federal Circuit reversed a 2005 district court ruling granting summary judgment of noninfringement to several companies who sought to market generic versions of Pfizer’s epilepsy drug Neurontin (gabapentin).  The district court had ruled on summary judgment that generic versions of Neurontin made by Teva, IVAX, and Eon did not infringe Pfizer’s U.S. Patent No. 6,054,482, which covers a process for the preparation of, and compositions containing, gabapentin.

Claim 7 of the ‘482 patent is directed to a composition consisting essentially of gabapentin, containing "less than 20 ppm of an anion of a mineral acid . . . ."  The main issue on appeal was whether the defendants had shown, beyond dispute, that their generic gabapentin formulations do not meet the 20 ppm limitation.  According to the district court, Pfizer "failed to adduce sufficient evidence to establish that the accused products meet the limitation."  But on appeal, the Federal Circuit reviewed Pfizer’s evidence and concluded that it was sufficient to raise a genuine issue of material fact, requiring resolution at trial.

It’s amazing how long some Hatch-Waxman cases drag on.  This litigation has been active since at least 2000, when Warner-Lambert (now part of Pfizer) filed suit against the first of many ANDA applicants who filed paragraph IV certifications with respect to the ‘482 patent.  Between 2001 and 2003, the defendants filed various summary judgment motions, including for summary judgment of noninfringement and invalidity.  While those motions were pending, Warner-Lambert unsuccessfully sought a preliminary injunction to enjoin the defendants from launching their products at-risk.

Teva began selling its generic Neurontin in 2004, and others followed suit in 2005.  In the first half of 2004, before Teva launched, Pfizer’s U.S. sales of Neurontin were $1.2 billion; in the first half of 2005, after Teva launched, Pfizer’s sales were down to $91 million.  The ‘482 patent won’t expire until 2017.  The case now goes back down to the district court, for a trial to determine whether Teva and the other generics will have to pay damages to compensate Pfizer for billions of dollars in lost sales.

RELATED READING:

• Bloomberg.com article
• Press releases: Pfizer; Teva

Roche Palo Alto LLC v. Apotex, Inc., No. C05-02116-MJJ (N.D. Cal. 2007)

Apotex suffered a loss last week in its effort to relitigate the validity of U.S. Patent No. 5,110,493, which covers Roche's ketorolac tromethamine (KT) ophthalmic solution (i.e., Acular®).  The U.S. District Court for the Northern District of California granted Roche's motion for summary judgment.

Apotex had previously filed an ANDA for a 0.5% solution of KT solution.  Roche sued.  After a couple of trips to the Federal Circuit, including a petition by Apotex for rehearing in light of KSR, the patent was found to be valid, enforceable, and infringed.  Apotex’s last hope was a petition for certiorari.  But wait a moment . . .

Apotex later developed a 0.4% KT solution, and submitted a second ANDA for that formulation.  Roche again sued.  Last week, the district court ruled in Roche's favor, holding that claim preclusion and issue preclusion barred nearly all of Apotex's arguments and that Apotex had failed to establish an equitable defense based on the reverse doctrine of equivalents.

The reverse doctrine of equivalents is an equitable defense that permits an accused infringer to escape liability when his device performs a similar function to the patented invention in such a substantially different manner that it would be inequitable to hold him liable.  According to the Federal Circuit's 1991 Scripps Clinic case, application of the doctrine "requires that facts specific to the accused device be determined and weighed against the equitable scope of the claims, which in turn is determined in light of the specification, the prosecution history, and the prior art."

Apotex argued that the 0.4% KT solution is substantially different from the 0.5% KT solution because the former does not depend on micelle formation to stabilize the active ingredient.  Nevertheless, the legal standard nowhere asks the court to compare the infringing device to the patentee's device.  Rather, the infringing device is compared against the objective teachings of the patent document and its file wrapper.  The intrinsic record of the Roche patent never discusses micelle formation.  Moreover, the specification even discloses an example showing a 0.4 % KT solution.  This proved fatal to Apotex's argument.  There is one slight wrinkle, though:  in the earlier trial, the district court had cited micelle formation as a fact supporting the patent's utility.  But Scripps Clinic permits the court to look only at the intrinsic record.  A court opinion from prior litigation is not part of that intrinsic record.

Either claim preclusion or issue preclusion barred the rest of Apotex's arguments.  In light of KSR, the district court did devote a bit more page-space to thinking through the appropriate means of handling Apotex's obviousness argument.  If KSR resulted in a "major change[] in the law," issue preclusion may not apply to the court's prior determination that the patent is nonobvious.  The court seemed to suggest, however, that KSR created no such "major" change, but only undercut the Federal Circuit's occasional overly-rigorous application of the TSM test.  In the end, though, the court punted on this issue.  In this instance, claim preclusion dealt the knockout blow.

Claim preclusion, after all, bars relitigation even when there has been a major change in the law.  But the later case must involve the same claim.  Apotex argued that its 0.4% solution presents the court with a different claim.  Indeed, it is not the same product that Apotex proffered in the prior litigation.  But in patent actions, "changes unrelated to the limitations in the claim of the patent would not present a new cause of action for purposes of claim preclusion."  Although Apotex had varied the concentrations of four ingredients in producing its new formulation, those concentrations still fell squarely within the ranges specified in the Roche patent.  Under this standard, it seems that a defendant could only succeed by raising strong arguments of non-infringement.  Apotex was unable to do that in this case.

The facts of the case do cast some doubt on whether claims encompassing the 0.4% KT solution are indeed valid.  If Apotex had known in 2003 what it knew in 2005, they may have stood a better chance of proving invalidity of claims that encompassed concentrations that failed to produce stabilizing micelles.  Based on what we now know, those broader claims may indeed have been invalid for lack of utility and/or enablement.  But for Apotex, that train had already left the station.

Novartis Pharms. v. Teva Pharms. USA, No. 05-1887 (D.N.J. 2007)

Novartis and Teva have been in litigation over Teva’s ANDA for generic Famvir (famciclovir), Novartis’s antiviral treatment for herpes, since 2005.  Teva was prepared to launch its generic famciclovir product on August 24, 2007–the day the 30-month stay expired.  To prevent such an at-risk launch, Novartis filed a motion for a preliminary injunction, claiming that Teva infringes U.S. Patent No. 5,246,937.

Last Wednesday, following a one-and-a-half hour oral argument, the district court denied Novartis’s motion.  On Thursday, the court released its opinion, in which it concluded that Novartis was unlikely to succeed on the merits of its case and that Novartis would not suffer irreparable harm from denial of the injunction.  Specifically, the court ruled that Novartis failed to show that Teva’s obviousness and inequitable conduct defenses lack substantial merit.  The court further ruled that any economic harm to Novartis is not irreparable since Teva is able to pay whatever damages may arise and that Novartis’s research activities would not be disrupted by a temporary reduction in Famvir sales revenue.

On Thursday afternoon, Novartis filed an Emergency Motion for an Injunction Pending Appeal with the Federal Circuit.  Friday morning, Teva announced that it had "commenced shipment of Famciclovir Tablets" and that it is the 180-day exclusivity holder.  Friday afternoon, the Federal Circuit ordered that Teva "is temporarily enjoined from selling its generic famciclovir product, pending the court’s receipt of Teva’s response and the court’s consideration of the papers submitted."  Teva filed its opposition brief this past Tuesday, and Novartis filed its reply brief on Wednesday.  The Federal Circuit is still considering the parties’ submissions.

The primary issue on appeal is whether the claims of the ‘937 patent are invalid as obvious.  The district court ruled that it would have been obvious to select penciclovir as a lead compound from which to design famciclovir because it was "one of only five known acyclic nucleosides to have strong activity and low toxicity."  On this basis, the court distinguished the case from Takeda Chemical.  Quoting KSR, the district court stated that "selecting penciclovir was a matter of ‘ordinary skill and common sense.’"  Further, the court ruled that it would have been obvious to modify penciclovir into an effective orally-absorbed prodrug (famciclovir).  Both of these questions are hotly contested on appeal.  The inequitable conduct and irreparable harm issues are secondary.

Famvir is a relatively minor product for Novartis, with about $200 million in annual U.S. sales.  Nevertheless, the case is important to the parties, especially since Teva’s 180-day exclusivity is running while it is enjoined from marketing its product.  A decision from the Federal Circuit on Novartis’s motion is expected next week.

RELATED READING:

• Motley Fool article
• Reuters article

Aventis Pharma and King Pharms. v. Lupin, No. 2006-1530 (Fed. Cir. 2007)

The Court of Appeals for the Federal Circuit today reversed a district court trial verdict that held the asserted claims of Aventis's patent on Altace not invalid, finding instead that the claimed invention would have been obvious.  The patent in suit was U.S. Patent No. 5,061,722, which covers ramipril, the active ingredient in Altace.  Aventis owns the '722 patent and King Pharmaceuticals markets Altace under an exclusive license.

Ramipril is a stereoisomer belonging to a family of compounds that includes 25 stereoisomers.  Additionally, ramipril is one of a family of drugs known as Angiotensin-Converting Enzyme inhibitors, or "ACE inhibitors," which are useful for treating high blood pressure.  The prior art asserted by Lupin included structurally similar ACE inhibitors, including enalapril, as well as publications describing how to separate stereoisomers from each other.

The Supreme Court's recent decision in KSR v. Teleflex appears to have been a key to the Federal Circuit's decision today:

The district court held that Lupin failed to meet its burden of proof by clear and convincing evidence that a person of ordinary skill in the art would have been motivated to purify 5(S) ramipril into a composition substantially free of other isomers.  The district court saw this as a close case based principally on the absence of a clear and convincing showing of motivation.  Since the date of that decision, however, the Supreme Court decided KSR Int'l Co. v. Teleflex Inc. . . . .  Requiring an explicit teaching to purify the 5(S) stereoisomer from a mixture in which it is the active ingredient is precisely the sort of rigid application of the TSM test that was criticized in KSR.

Another interesting aspect of today's decision is that just six days ago, in Forest Labs v. Ivax Pharms., the Federal Circuit upheld the validity of another patent on a stereoisomer pharmaceutical compound: Lexapro (escitalopram).  The Federal Circuit held today that ramipril is prima facie obvious (based, in part, on its structural similarity to prior art compounds) and that Aventis and King "failed to show unexpected results that would tend to rebut a prima facie case of obviousness."  In contrast, according to today's opinion, in the Lexapro case "prima facie obviousness of a claim to a particular stereoisomer over a racemic mixture was rebutted where the particular stereoisomer showed unexpected benefits and evidence indicated that the isomers would have been difficult for a person of ordinary skill in the art to separate."

Given the amount of revenue at stake (about $700 million in annual U.S. sales), I would expect Aventis and King to file a petition for rehearing or rehearing en banc with the Federal Circuit.

RELATED READING:

• AP story
• Reuters article
• TheStreet.com article
• Patently-O

Altana Pharma AG and Wyeth v. Teva Pharms. USA, No. 04-2355 (D.N.J. 2007)

Last Thursday, a federal district court denied Wyeth’s motion for a preliminary injunction that would have prevented generic drug manufacturer Teva from launching its generic version of Protonix.  The opinion denying Wyeth's motion was filed under seal; only the order is publicly available currently.

Wyeth amassed $2.5 billion in sales of the heartburn medication for the sales year ending on June 30, 2007.  Last month, the FDA gave Teva the go-ahead to launch 20 mg and 40 mg versions of generic Protonix.  But since the district court has not yet held a trial on the merits of the case, Teva must decide whether to launch at risk or to wait for a favorable verdict.  At this point, Teva has not begun shipment of generic Protonix. 

Wyeth’s stock price has already taken a hit from the ruling.  After the court decision was announced on Thursday, Wyeth’s stock fell by $1.82/share in late-day trading.

UPDATE:  In a research note Monday, pharma analyst Joe Tooley of A.G. Edwards said he expects Sun Pharma to receive final FDA approval today.  Additionally, he stated that if both Teva and Sun decide to launch at-risk, the branded market for Protonix could contract as much as $500 million in the remaining months of this year.

RELATED READING:

• Bloomberg story
• Reuters article
• Teva press release
• WSJ Health Blog post