Orange Book Blog

At the intersection of Patent and FDA Law

Recent Posts

  • Federal Circuit Refuses to Rehear Caraco v. Forest

    We previously reported that on April 1, in a 2-1 decision in Caraco v. Forest, the Federal Circuit held that an ANDA applicant may in some circumstances bring a declaratory judgment action for noninfringement even if the patentee has granted the applicant a covenant not to sue.  Today, the Federal Circuit denied Forest's petition for rehearing or rehearing en banc, without opinion.

    The Caraco v. Forest decision expanded declaratory judgment jurisdiction for ANDA applicants that have not been sued on an Orange Book-listed patent.  Indeed, several ANDA applicants have filed DJ complaints since the decision.

    It would not be surprising if Forest now appealed to the Supreme Court.  However, given that the Court recently decided a declaratory judgment case, MedImmune v. Genentech, and that the Federal Circuit appeared to follow that decision in Caraco v. Forest, Supreme Court review seems unlikely.

  • Mylan Prevails Over AstraZeneca in Appeal of Prilosec Case

    In re Omeprazole Patent Litigation, Nos. 2007-1476, -1477, -1478 (Fed. Cir. 2008)

    Yesterday, the Court of Appeals for the Federal Circuit affirmed a June 2007 district court decision finding that Mylan's generic version of Prilosec (omeprazole) does not infringe two AstraZeneca patents, U.S. Patent Nos. 4,786,505 and 4,853,230.

    Omeprazole is difficult to formulate because it is acid-labile.  Astra scientists developed a formulation that protects omeprazole from degradation in the acidic environment of the stomach.  Astra's formulation, which is claimed in the '505 and '230 patents, includes a core containing omeprazole and an alkaline reacting compound ("ARC"), a water soluble subcoat, and an outer enteric coating.

    Mylan's ANDA product consists of an inert sugar/starch sphere; an active coating of omeprazole, talc and HPMC; two subcoatings; and an enteric coating.  Astra argued that the talc in Mylan's formulation contains carbonates, which serve as an ARC.  However, after a forty-two day bench trial, the district court determined that Astra failed to prove the presence of carbonates in Mylan's product.  The district court also determined that talc cannot satisfy the ARC limitation of the claims because the specification of the patents indicates that talc is not an ARC but rather an ordinary excipient, and because of statements Astra made during prosecution of the European counterpart of the '505 patent.

    In the decision released yesterday, the Federal Circuit concluded that the district court's factual findings with respect to the presence or absence of carbonates in Mylan's formulation were not clearly erroneous.  Astra argued on appeal that the district court applied the wrong legal standard by requiring "conclusive evidence" that carbonates were present in the talc, but the Federal Circuit disagreed, finding that the district court correctly applied the preponderance of the evidence standard.  Having determined that the district court did not clearly err in finding that Astra failed to prove the presence of "non-negligible amounts of carbonates" in Mylan's formulation, the Federal Circuit declined to address Astra's remaining arguments.

    The omeprazole patent litigation began in 2000, when Astra sued several companies who filed ANDAs for generic Prilosec.  The lawsuits were consolidated as a multidistrict litigation and tried in two waves.  Mylan, which launched its generic Prilosec in August 2003, was part of the second wave.  Other companies in the second wave included Lek Pharmaceutical, Apotex, and Impax Labs.  In the same June 2007 decision in which it ruled in favor of Mylan, the district court also found that Lek's products do not infringe Astra's patents, and that Apotex's and Impax's products do infringe.  Those determinations were appealed separately.

    RELATED READING:

  • OBB News Briefs

    • The Federal Trade Commission announced the release of its FY 2007 Summary of Pharmaceutical Company Settlement Agreements.  For commentary, see FDA Law Blog, Pharmalot.
    • Wyeth sued Sandoz over a generic version of Protonix I.V.  The WSJ Health Blog recapped all the Protonix ANDA litigation.
    • India's drugmakers recently threatened to stop production of 33 bulk drugs, Pharmalot reports.
    • The Washington Legal Foundation announced that it filed an amicus brief urging the Federal Circuit to rehear the Caraco v. Forest Labs case.

  • C5 “Pharma Patent Lifecycles” Conference, London, June 26-27

    C5 will be holding a “Pharma Patent Lifecycles” conference June 26-27 in London.  According to C5, “since 2001, thousands of life sciences patent professionals have made C5’s Pharma Patent Lifecycles conferences their source of information for the most up-to-date legal developments surrounding patent lifecycle management.”

    The agenda includes numerous presentations that may be of interest to readers:

    • “Critical Update on European Case Law and Legislative Developments”
    • “The Impact of Regulatory Data Protection on Lifecycle Management”
    • “Recent Trends and Developments in Supplementary Protection Certificates and Paediatric Extensions”
    • “Successful Evergreening Strategies to Compete with Generics and Obtain PC’s”
    • “Effective Use of Second Medical Use (Swiss-Type) Claims to Extend Patent Lifecycles”
    • “Brand Name and Generic Litigation as a Defence or Delay Tactic?  UK and US Comparative”
    • “How to Optimise Your Product’s Lifecycle Through Successful Global Patent Lifecycle Management”
    • “Industry Case Study and Break Out Session: Insight into Pfizer’s European Lipitor Litigation”

    In addition, a pre-conference master class is offered on June 25: “Patent Settlements Master Class: A Step-by-Step Guide to Meeting EU Anti-Competition Law Guidelines.”

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

  • 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:

  • Patent Litigation Under a Future Biosimilars Act

        Biopharmaceuticals, such as Epogen® (epoetin) and Erbitux® (cetuximab), are becoming increasingly important for the treatment of disease.  U.S. sales of such drugs were about $40 billion in 2006 and are expected to rise to over $90 billion in 2009.  Accordingly, political pressure is building to allow the sale of “biosimilar” drugs.  Inspired by the success of the Hatch-Waxman Act, which has led to the wide use of generic “small molecule” drugs, four different biosimilars bills have been introduced in Congress in the past fifteen months.  Three of the proposed bills would establish a complex scheme for patent litigation between brand-name and generic biopharmaceutical companies, especially as compared to the Hatch-Waxman Act.

    Hatch-Waxman Act

        The Hatch-Waxman Act, passed by Congress in 1984, amended the Food, Drugs and Cosmetic Act to establish an abbreviated pathway for FDA approval of small molecule drugs.  Under the Act, a company seeking to market a generic small molecule drug must demonstrate only that the generic is “bioequivalent” to the corresponding brand-name drug; it need not conduct large scale clinical trials demonstrating safety and efficacy.  The Hatch-Waxman Act, however, did not amend the Public Health Service Act, under which biopharmaceuticals are approved, and therefore it did not create an abbreviated pathway for the approval of biopharmaceuticals.
        The Hatch-Waxman Act established a relatively straightforward scheme for patent litigation.  In a New Drug Application, a brand-name drug company is required to inform the FDA of any patents claiming the drug or methods of using the drug “with respect to which a claim of patent infringement could reasonably be asserted.”  The patent information is listed in the FDA’s “Orange Book,” which the FDA updates regularly and publishes on the Internet.  When a generic drug company submits an Abbreviated New Drug Application (“ANDA”), it is required to file one of four different patent certifications with respect to any patents listed in the Orange Book for the brand-name drug.  Upon filing a Paragraph IV certification (indicating that a listed patent is invalid, unenforceable, or not infringed), the generic drug company is required to provide notice to the patent owner.  If the patent owner brings suit within 45 days of receiving notice, then the FDA may not grant final approval of the ANDA for 30 months.  This last feature – the automatic 30-month stay – is conspicuously absent from all of the proposed biosimilars bills.

    Access to Life-Saving Medicine Act

        Rep. Henry Waxman introduced the first of the four biosimilars bills, the Access to Life-Saving Medicine Act (H.R. 1038), on February 14, 2007.  The Waxman bill is regarded as the one most favorable to the generic drug industry.  It establishes a complicated system for the private exchange of patent information between brand-name and generic biopharmaceutical companies, and contains unusual provisions regarding patent litigation.

    (more…)

  • 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)

    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:

  • 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.

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