Orange Book Blog

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.

IIR "Generic Drugs Summit," Washington, D.C., June 18-20

The Institute for International Research will be holding its 9th annual "Generic Drugs Summit," June 18-20 in Washington, D.C.

According to IIR, this is "the leading independent forum addressing business and legal concerns impacting the generics marketplace.  This event attracts 200+ senior-level professionals representing government, regulatory and legal affairs as well as marketing, sales and business development."

The agenda on June 19-20 includes many interesting presentations:

• "Update on Hatch-Waxman Reform," by none other than Rep. Henry A. Waxman
• "Removing Hurdles that Slow Affordable Generics from Coming to Market," by Sen. Debbie A. Stabenow
• "The Future of Biogenerics and Other Measures to Reduce Healthcare Costs," by Rep. Frank Pallone, Jr.
• "Federal Trade Commission Actions Involving Generic Drugs," by Phil Eisenstat, Sr. Attorney, FTC
• "Patent Reform: A Generic Industry Friend or Foe?"
• "The Changing Competitive Landscape of the Generic Drugs Industry"
• "Understanding the 180-Day Forfeiture Provisions of the MMA" (I'll be presenting this topic)
• "Trends in New Pharmaceutical Patent Claim Strategies"

In addition, the Generic Drugs Summit features two pre-conference workshops on June 18: "Strategies for Filing Successful Paragraph IV Certifications" and "Understanding How to Submit Quality ANDAs Based on QbR to Reduce Approval Time."

For more information or to register, please visit the conference website.

Federal Circuit Affirms Decision Holding Lovenox Patent Unenforceable

Aventis Pharma v. Amphastar and Teva, No. 2007-1280 (Fed. Cir. 2008)

          by Robert S. Dailey

Earlier today, the Federal Circuit affirmed a district court decision holding Aventis's patent on Lovenox (enoxaparin) unenforceable.  The district court had found that renowned Aventis scientist, Dr. Andre Uzan, committed inequitable conduct during the prosecution of U.S. Patent  No. 5,389,618, later reissued as RE38,743.  Judge Prost wrote for the Court, joined by Judge Moore.  Judge Rader dissented.

Dr. Uzan was not an inventor on the patent.  Instead, he assisted in drafting one of the examples (Example 6) in the originally filed application.  He also submitted two declarations during the course of the U.S. prosecution.  The prosecution revolved around whether the claimed admixture of low molecular weight heparin (LMWH) was novel and/or nonobvious over a similar LMWH mixture disclosed in European Patent 40,144.

Example 6 compares the plasma half life for a composition embodying the invention with the half life of the LMWH composition disclosed in the '144 patent.  The district court found that Example 6, coupled with Dr. Uzan's discussions of it in his declarations, overstated the case for the patentability of the claimed invention.  The data from the '144 patent were for a 60 mg dose, but Example 6 failed to mention the dose.  The example presented 40-mg and 60-mg data for the claimed LMWH.  The 40-mg dose had a longer half life than the LMWH of the '144 patent, while the 60-mg dose did not.  The district court found that Example 6 presented these data in a manner that highlighted the favorable results for the 40-mg dose, while obscuring the unfavorable results for the 60-mg dose.  The district court found that Dr. Uzan's declarations compounded these potentially misleading aspects of Example 6.  Thus, the district court found that the patent would never have issued apart from Dr. Uzan's exaggerated efforts to use Example 6 to distinguish the claimed LMWH from the prior art's LMWH.

Inequitable conduct requires an accused infringer to demonstrate that (1) the withheld or erroneous information was material to patentability, and (2) that the lack of candor was borne out of intent to deceive.  Upon such a showing, the district court evaluates the equities and determines an appropriate equitable remedy.  In a prior decision, the Federal Circuit had already held that Dr. Uzan's (mis)use of Example 6 was material to patentabilty.  The case was remanded to determine whether he acted with deceptive intent.

In a previous post, we questioned whether the district court, in this instance, applied the correct legal standard for determining deceptive intent.  For example, the district court appeared to employ a burden shift, requiring Dr. Uzan to prove the absence of deceptive intent.

Aventis, however, took a different course in its appeal.  It elected to demonstrate that Dr. Uzan's conduct was indeed reasonable, and that the District Court clearly erred in reaching its finding of deceptive intent.  The Federal Circuit was unpersuaded.  Particularly, the court noted that some of Dr. Uzan's explanations for his conduct did not emerge until mid-way through the litigation.

In a further twist, the majority and the dissent both appear to question the court's prior materiality determination.  After all, Aventis surrendered its original patent, deleted Example 6, and was awarded a reissue patent on the claimed LMWH.

Judge Rader's dissent takes a policy-oriented approach to the question of inequitable conduct.  In ignoring the particulars of the case, he appears to concede that a mechanical application of the Court's recent jurisprudence may support the result that the majority reaches.  Nevertheless, he suggests that equity is not well served when such a disproportionately harsh punishment is visited upon Aventis for conduct that was not even sufficient to affect the validity of the patent.  Judge Rader notes that the Court's 1988 Kingsdown decision sought to make inequitable conduct an extraordinary and rare remedy.  But the promise of Kingsdown has not lasted.

Barring an en banc reversal, the enoxaparin patent is no longer an impediment to the marketing of generic versions of bioequivalent LMWH.  Amphastar, Teva and Momenta/Sandoz are all seeking FDA approval for a generic version of enoxaparin.  LMWH is not a typical small-molecule drug, however; it is a complicated admixture of polysaccharides of varying molecular weights.  Therefore, demonstrating bioequivalence is not a simple matter.  Some have suggested that generic manufacturers may need to conduct limited clinical trials to gain marketing approval.  Momenta recently stated that the FDA has decided not to require it to conduct clinical trials to gain approval for its generic enoxaparin.

For the immediate future, Aventis will continue to market Lovenox without generic competition.  It is unclear when that will change.

RELATED READING:

• Reuters
• Wall St. Journal

GPhA Files Amicus Brief in Appeal of "Baseless Paragraph IV Certification" Case; Warns of Chilling Effect on Future Patent Challenges

Takeda v. Mylan and Alphapharm, Nos. 2007-1269, -1270 (Fed. Cir.)

In February 2006, the U.S. District Court for the Southern District of New York determined that Takeda's patent on pioglitazone, the active ingredient in ACTOS, is neither invalid for obviousness nor unenforceable due to inequitable conduct.  In the court's 124-page opinion, the court remarked, "The length of this Opinion is occasioned by the need to address the many iterations of the defendants' arguments, as they searched for a viable theory to attack the '777 patent."

Later in 2006, the court awarded $16.8 million in attorney fees to Takeda ($5.4 million from Alphapharm; $11.4 million from Mylan), finding this to be an exceptional case under 35 U.S.C. § 285.  In a 51-page opinion, the court explained that "Alphapharm and Mylan each filed baseless Paragraph IV certifications attacking the validity of the '777 Patent," in violation of the "duty of due care" ANDA filers are held to under the Hatch-Waxman Act.  Moreover, according to the court, they "each engaged in other litigation misconduct," including (by Alphapharm), "constantly shifting its theory of obviousness," in bad faith; attempting at trial to insert "entirely frivolous" arguments of inequitable conduct; and ignoring a court order and offering an untimely advice of counsel defense; and (by Mylan), acting "without a reasonable basis and in bad faith in pursuit of its inequitable conduct claim."

Alphapharm and Mylan appealed both decisions to the Federal Circuit.  In June of last year, the Federal Circuit affirmed the decision on the merits of the patent case, which will keep any generic versions of ACTOS off the market until at least 2011, when the '777 patent expires.  The appeal of the attorney fees decision has now proceeded to the briefing stage.  And, signaling that it has a "critical interest" in the case, GPhA has weighed in with its own amicus brief.

GPhA's brief asserts that the district court "placed too much weight on Mylan's and Alphapharm's decision to take the case to trial on grounds other than the particular theories of invalidity that they had stated in their respective pre-suit notice letters."  According to GPhA, "such an evolution of a defendant's litigating position is unexceptional.  Reversal is vital because this aspect of the district court's ruling will undermine the efficacy of the Hatch-Waxman scheme by deterring future ANDA filings by many companies, keeping generic drugs off the market and increasing the cost of drugs to the consumers who depend on them."  GPhA's brief addresses only this aspect of the district court decision.

Alphapharm's and Mylan's opening briefs are available below.  Takeda's opposition brief is due May 23rd; reply briefs will be due in June; and oral argument is expected to be scheduled for late fall.

More:

• Alphapharm's opening brief
• Mylan's opening brief
• 2006 article about baseless paragraph IV certifications, authored by lead counsel for Takeda

ACI "FDA Boot Camp" Conference, San Francisco, May 29-30

American Conference Institute's very popular "FDA Boot Camp" returns to San Francisco later this month, May 29-30.

The conference is designed to give patent lawyers, product liability lawyers, and life sciences investment and securities experts a strong working knowledge of core FDA regulatory competencies.  The conference features FDA regulatory and patent law experts from pharmaceutical companies and outside law firms.

Presentations on the agenda include:

• The Basics: Understanding and Working with the FDA -- Jurisdiction, Functions, Organization, and Operations
• The Nature of the Approval Process
• Patent and IP Overview: Hatch-Waxman, Trademark Protection, and More
• From Theory to Practice: FDAAA, Future FDA and Legislative Priorities, Other Enforcement Initiatives, and Beyond
• Non-Patent Exclusivity
• Bioequivalence: What Lawyers Need to Know
• Follow-On (Comparable or Biosimilar) Biologics

For more information or to register, please visit the conference website.

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.

ACI "In-House Counsel Forum on Pharmaceutical Antitrust," National Harbor, Maryland, May 20-21

American Conference Institute is holding its fourth annual "Pharmaceutical Antitrust" conference on May 20-21, in National Harbor, Maryland.

According to ACI, at the conference, "leading in-house pharmaceutical counsel, government regulators, and expert attorneys will provide practical advice on how to successfully tackle the most complex antitrust issues facing brand-name and generic pharmaceutical companies."

Several of the presentations look particularly interesting:

• A Keynote Address by Stephen Calkins, Former General Counsel of the Federal Trade Commission
• "Assessing What the Authorized Generic Study and Report on Intellectual Property Collectively Mean for the Pharmaceutical Industry"
• "The Law of Hatch-Waxman Patent Infringement Settlements and Where it is Going"
• "Congressional Action on Pharmaceutical Patent Settlements: Pending Legislation and Strategies to Employ"
• "Life Cycle Management Strategies for Protecting Your Product and Reducing Antitrust Exposure"
• "DOJ Perspective on Recent Developments in Antitrust and IP Law"
• A Keynote Address by Jon Leibowitz, Commissioner, Federal Trade Commission

The conference also features a Master Class on May 2: "Navigating the Pharmaceutical Merger Process."

For more information or to register, please visit the conference website.

Barr and Caraco Win Summary Judgment that Ortho-McNeil's Formulation Patent on Ultracet is Invalid

Ortho-McNeil Pharm. v. Kali Labs., No. 06-CV-3533 (DMC)

          by Robert S. Dailey

In a decision released April 17th, the U.S. District Court for the District of New Jersey granted summary judgment that certain claims of U.S. Patent No. RE39,221 are invalid as obvious. The '221 patent claims combinations of acetaminophen and tramadol, marketed by Ortho-McNeil (OMI) as Ultracet.  Barr and Caraco are challenging the patent.

OMI had previously asserted U.S. Patent No. 5,336,691 (the predecessor patent to RE39,221) against Barr and Kali. In early 2007, the district court granted summary judgment that the asserted claims of the '691 patent were invalid as anticipated and obvious.

While the litigation over the '691 patent was pending, OMI surrendered the '691 patent and requested a reissue from the USPTO. When the '691 patent reissued in 2006 as the '221 patent, OMI filed suit against Kali, Barr, Par and Caraco.  By that time, several of the defendants were already selling generic versions of Ultracet.

As part of the reissue, OMI obtained new claims that were less likely to be found invalid or not infringed. Therefore, it was unclear whether the generic companies would be able to knock out the claims of the '221 reissue patent.  In July 2007, Par and Kali decided not to take that risk, and settled their litigation with OMI, agreeing to cease selling their generic products by November of last year.  Barr and Caraco remained in the litigation.

The asserted claims of the '221 patent are directed to a formulation "consisting essentially of" a tramadol-to-acetaminophen ratio that ranges from about 1:5 to about 1:19. Ultracet has a ratio of 1:8.67.

This month's decision largely draws from the 2007 summary judgment that invalidated the claims of the '691 patent as obvious and anticipated. Both opinions rely on U.S. Patent No. 3,652,589, which discloses various embodiments of a four-agent tablet that includes acetaminophen and tramadol as two of the active ingredients. In particular, the '589 patent discloses formulations where the acetaminophen-to-tramadol ratio falls within the ratio range claimed in the '221 patent.

Nevertheless, the '589 patent uses "consisting of" language in its description of the pharmaceutical formulations. In an anticipation context, this "consisting of" language would prevent the '589 patent's four-agent formulations from reading on the two-agent formulations claimed in the '221 patent. But what effect should this linguistic choice have in the context of obviousness?

OMI argued that the "consisting of" language in the '221 patent would not have instructed a person of ordinary skill in the art to combine only acetaminophen and tramadol into a two-agent tablet.  The court, however, was not persuaded, concluding that "[h]ere, a person of ordinary skill in the art would not be misled by the 'consisting of' language."

Essentially, OMI appears to have argued that the "consisting of" language is an instance of "teaching away" from the two-agent formulations claimed in the '221 patent.  But is it? Does one of skill in the relevant art have knowledge of patent lingo, such as the distinction between "comprising" and "consisting of"? If not, then the district court may be correct. This does pose an interesting question, though. "Teaching away," after all, is evaluated from the perspective of one of skill in the relevant art, and not from the perspective of a patent lawyer having ordinary skill in the relevant art.

The court also cited another piece of prior art that disclosed a three-agent formulation that included acetaminophen and tramadol in ratios similar to those claimed in the '221 patent. No "teaching away" appeared in this second reference. Thus, the Federal Circuit could affirm the judgment without having to consider whether "consisting of," as recited in the '589 prior art patent, can constitute teaching away.

WBR "PharmaBiotech IP Summit," Philadelphia, May 28-30

Worldwide Business Research will be holding a conference entitled "PharmaBiotech IP Summit," May 28-30 at the Ritz-Carlton in Philadelphia.

According to WBR, "the event balances the challenges of IP protection, enforcement and management, providing both strategic and actionable insights through case studies and interactive session formats."

The conference will bring together over 35 speakers from the pharmaceutical and biotechnology industries, who will focus on protecting critical patents while driving sustainable growth through IP-driven business strategies.  They will address how patent reform legislation will impact IP practitioners in these industries.  In addition, they will tackle key issues such as strategic patent portfolio management, IP lifecycle extension and IP commercialization.

The conference begins with a "Patent Enforcement and Protection Master Class," on May 28.  The main conference, May 29-30, includes the following panel presentations:

• "Aligning IP Strategy and the Business -- Becoming a Resource Not a Roadblock," with Scott Brown, VP, General Counsel, Head of NIBR Patents, Novartis; Guy Donatiello, VP IP, Endo Pharmaceuticals; and Karen F. Clark, Assoc. General Counsel, Global Health, Well Being and Beauty Care, Procter & Gamble Co.
• "Patent Reform, Resolutions and Additional Rulings -- Interpretations, Impacts and Strategies for the Challenge Ahead," with Robert Hrubiec, VP IP and Chief Patent Counsel, Cephalon; Gary Creason, VP IP, Aveo Pharmaceuticals; and John T. Li, Patents, Head, Biology and Biologics, Novartis
• "Biosimilars and Follow-on Biologics -- Preparing for the Road Ahead," with James Kelley, Assoc. General Counsel, Eli Lilly & Co.; John M. Engel, Managing Partner, Engel & Novitt, LLP; and Bradford J. Badke, Partner, Ropes & Gray LLP
• "Ensuring Protection and Enforcement Post-KSR," with James Gould, Legal Director, Global Patent Litigation, Schering-Plough; Kathleen Fonda, Legal Advisor, Office of Patent Legal Administration, USPTO; and Cindy Clay, Sr. Counsel, IP, Global Personal Health Care and Pharmaceuticals, Procter & Gamble Co.

Orange Book Blog readers can receive a 15% discount on registration with Booking Code WUS_XZ206EN.

For more information or to register, please visit the conference website.

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."