Orange Book Blog

At the intersection of Patent and FDA Law

Recent Posts

  • Barr Labs Prevails in Yasmin Case; Bayer’s Patent Held Invalid for Obviousness

    Bayer Schering Pharma AG v. Barr Labs., No. 05-2308 (D.N.J. 2008)

    On Monday, the U.S. District Court for the District of New Jersey invalidated
    Bayer's U.S. Patent No. 6,787,531
    on grounds of obviousness, relying heavily on KSR.  The '531 patent,
    claiming pharmaceutical formulations of micronized drospirenone and
    ethinylestradiol, protects Bayer's Yasmin birth control pill. 
    Barr Labs had challenged the '531 patent in a paragraph IV certification with
    its ANDA filing.

    The court's opinion
    follows a bench trial held over a two-week period late last year.  The main
    issues in the case were whether it would have been obvious "to (1) micronize
    drospirenone so as to increase its bioavailability, and (2) not protect the
    drospirenone from the gastric environment with an enteric coating." 
    Drospirenone is a relatively difficult molecule to formulate due to its poor
    water solubility and sensitivity to acid.

    While Bayer argued that the prior art taught away from micronizing
    acid-sensitive drugs like drospirenone, the court concluded: "Undoubtably, there
    would be some concern about dissolution of a poorly water soluble acid sensitive
    drug, but the person of ordinary skill in the art could conclude that
    micronization is a viable option."  Similarly, while Bayer asserted that the
    prior art taught that acid sensitive drugs must be enteric coated, the court
    credited Barr's argument, finding that "inter- and intra-subject variability is
    a major disadvantage" of enteric coating, and concluding therefore that one
    "could not rule out formulating a micronized drospirenone without enteric
    coating."  Furthermore, the court concluded that a prior art reference teaching
    that drospirenone isomerzies when exposed to hydrochloric acid in vitro
    (Nickisch) should be discounted because its results were not corroborated by in
    vivo studies.

    In addition to concluding that the invention claimed in the '531 patent would
    have been obvious, the court concluded that the invention was obvious to
    try:

    As noted, in KSR the Supreme Court ruled that a patent claim may be obvious
    if the combination of elements was "obvious to try."  In this case, the
    testimony was limited to discussion about whether or not to employ to common
    formulation techniques — micronization and enteric coating.  As in KSR "there
    are a finite number of identified predictable solutions."  In this case, based
    on the prior art as a whole, micronizing and immediately releasing drospirenone
    was obvious to try.

    The '531 patent, which would expire in 2020, is one of three Orange Book-listed patents for Yasmin.  The others are U.S. Patent No. 5,569,652, claiming methods of use and expiring in 2013; and U.S. Patent No. 6,933,395, claiming compositions and expiring in 2017.  Although Barr is the first ANDA filer for a generic version of Yasmin, if Barr filed paragraph III certifications with respect to the '652 and '395 patents, then it must wait at least until those patents expire before it launches its generic product.

    The U.S. market for Yasmin is approximately $500 million annually.  Bayer is expected to appeal Monday's decision to the U.S. Court of Appeals for the Federal Circuit.

    RELATED READING:

  • 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.

  • OBB News Briefs

    • The Biotechnology Industry Organization CEO, Jim Greenwood, spoke with reporters and bloggers Thursday morning about follow-on biologics and patent reform.  Mr. Greenwood sounded optimistic that a forthcoming bill sponsored by Reps. Eshoo and Barton will represent a reasonable compromise between earlier proposals that stalled in Congress last year.  Patent Docs has two posts summarizing the call.  The AP was there too.
    • The Federal Trade Commission announced Wednesday that it has sued Cephalon "for a course of anticompetitive conduct that is preventing competition to its branded drug Provigil."  According to the FTC’s complaint, Cephalon paid four generic drug companies a total of more than $200 million to abandon their paragraph IV patent challenges.  Cephalon responded with a press release.  For more information, see: Antitrust Review; Pharmalot; and WSJ Health Blog.
    • Reuters reported Wednesday that AstraZeneca has no plans to settle its Hatch-Waxman cases concerning Nexium and Seroquel.
    • After the FDA announced Monday that Baxter’s heparin has been linked to severe allergic reactions, reports surfaced in the Wall St. Journal, New York Times and Capital Times implicating the Chinese plant that manufactures the drug’s active ingredient.  Thursday, Pharmalot posted an interview with a Rutgers business professor, who thinks the pharmaceutical industry should stop doing business with China entirely.

  • Informa Life Sciences “Global Generics Strategy Summit” Conference, Barcelona, March 4-5

    Informa Life Sciences will hold its 7th annual "Global Generics Strategy Summit" conference in Barcelona, Spain, March 4-5, 2008.  The conference "represents the largest gathering of Generics leaders from across the globe and will explore new and emerging strategies and regulations that must be followed to remain competitive in this cut-throat industry."

    The conference features keynote presentations from executives of Ratiopharm Group, Ranbaxy, Barr Labs, and Biogenerics.  In addition, several talks are offered on each of the following subjects: legal and regulatory issues; biosimilars; pricing and reimbursement; and business development.

    Moreover, four pre- and post-conference workshops will be offered: on March 3rd, "Merger and Acquisition Within the Generics Marketplace" and "Evaluation of Existing and Development of New Strategic Business Models to Stay Ahead in the Generics Sector"; and on March 6th, "Criteria for Selecting Member States to Include in a Decentralised Procedure Application" and "Implementing Fast-Track Development and Launch Strategies and Being the First Generic to Market."

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

  • OBB News Briefs

    • Fosamax, Merck’s blockbuster osteoporosis drug, went generic on Wednesday.  The In Vivo Blog posted an interesting report on the unusual steps Merck took to promote Fosamax in the last month, before its patents expired.
    • The WSJ Health Blog posted an interesting story this week on contributions from the pharmaceutical industry to the presidential candidates.  Apparently drug company employees are not fans of John McCain.
    • FDA Law Blog reported Tuesday that the Bush Administration announced, as part of its FY2009 budget proposal, that it will seek new statutory authority to allow FDA to approve follow-on biologics in abbreviated applications.  In response to the budget announcement, Insmed, Inc., a developer of follow-on biologics and biopharmaceuticals, announced that it is launching a "national awareness" campaign on follow-on biologics.
    • FDA Law Blog reported last week that the district court in D.C. dismissed Nu-Pharm’s lawsuit against the FDA, in which Nu-Pharm sought to force FDA to grant final approval to its ANDA for a generic version of Abbott Labs’ Depakote.  Nu-Pharm, a former subsidiary of Apotex, has appealed the decision to the D.C. Court of Appeals.
    • On Feb. 1, FDA posted a new comprehensive list of FDA Guidance Documents, which could come in handy for FDA-regulated companies.
    • Wyeth recently launched of an authorized generic version of Protonix, as Pharmalot and the WSJ Health Blog reported.  The WSJ Health Blog also reported on speculation about why Teva declined to ship any additional generic Protonix.

  • Federal Trade Commission Files Amicus Brief in Ciprofloxacin “Reverse Payment” Case

    The Federal Trade Commission announced last week that it recently filed an amicus brief in In re Ciprofloxacin Hydrochloride Antitrust Litigation, currently pending in the Federal Circuit.  In the case, direct purchaser plaintiffs of Cipro (ciprofloxacin) alleged that settlements of patent litigation between Bayer and several generic drug companies violated federal and state antitrust laws.  The case is an appeal of a 2005 decision granting motions for summary judgment filed by Bayer and the generic defendants.

    According to the FTC’s brief, the case involves agreements between Bayer and generic manufacturers Barr Labs and The Rugby Group (which has since been acquired by Watson Pharmaceuticals).  The FTC states that under the agreements (executed in January 1997), Bayer paid the generic companies $398 million to agree not to manufacture any form of Cipro and for Barr’s agreement to convert its paragraph IV certification (challenging the validity of the U.S. Patent No. 4,670,444) to a paragraph III certification (permitting Barr to market its generic drug only upon expiration of the ‘444 patent, in December 2003).  The FTC states that the case "illustrates the kind of abuse of the Hatch-Waxman law that prompted congressional intervention in 2003," when it required such agreements to be submitted to the FTC for review.

    In short, FTC’s brief makes three arguments:

    • The district court erred in holding that patent settlement agreements containing exclusion payments are immune from antitrust scrutiny;
    • Paying a potential competitor not to compete is a well established antitrust violation; and
    • The district court misconstrued the policies and incentives of the Hatch-Waxman Act and misconceived the practical implications of its ruling.

    The FTC has continued to pursue court review of reverse payment cases since the Supreme Court denied certiorari in the Tamoxifen and FTC v. Schering cases.  The Senate has also taken interest, but a bill

    that would have banned reverse payment settlements stalled last year.

  • 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."

  • OBB News Briefs

    • Earlier this week, FDA released its highly anticipated response concerning granisetron 180-day exclusivity.  This marks the first time that FDA has interpreted the "failure to market" forfeiture provisions of the 2003 MMA.  FDA Law Blog posted a nice summary of FDA’s response.
    • FDA Law Blog also posted on a very interesting case recently filed by Nu-Pharm against FDA, in which Nu-Pharm seeks to force FDA to grant it final approval to market generic Depakote (divalproex sodium).
    • The Wall St. Journal had an interesting article yesterday on health plans that pay doctors $100 each time they switch a patient to a generic drug.  The WSJ Health Blog posted this summary of the article.
    • A district court in New York recently held that three Purdue Pharma patents on Oxycontin are not unenforceable for inequitable conduct.
    • Cypress Pharmaceutical announced today that it has settled patent litigation with GSK concerning its generic version of Zantac (ranitidine) syrup.

  • IQPC “Pharmaceutical Patent Litigation Strategies 2008” Conference, London, March 31 – April 1

    IQPC will be holding its 3rd annual "Pharmaceutical Patent Litigation Strategies" conference in London, March 31 to April 1.

    The conference is split into two days–one focusing on European law, the other focusing on U.S. law–and includes an optional third day, with workshops. 
    The European Focus Day will emphasize proposals for supranational patent litigation; EPLA; and the community patent and how to push it forward.  The U.S. Focus Day will analyze the trends and developments in the pharmaceutical and biotech law sector; the Patent Reform Act 2007; parallel US and European patent litigation strategies; and key rulings.

    Margot Fröhlinger, Director, European Commission, will be speaking during the European Focus Day on "How to Achieve Consistency Across European Courts in the Future."  Dr. Fröhlinger leads an exceptional speaker panel that will discuss successful litigation practices and a changing regulatory framework in order to provide superior practical intelligence.

    IQPC’s 3rd annual "Pharmaceutical Patent Litigation Strategies" conference is sharply focused on improving in-house patent litigation for pharmaceutical companies.  The event will feature the latest updates from both in-house experts and outside counsel.  Key issues to be covered include the link between regulations and actual litigation practices; international litigation processes; patent life extension; and new industry developments.

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

  • Teva Seeks Relisting of J&J’s Risperdal Patent and Asserts Right to 180-Day Exclusivity

    A reader recently e-mailed me about an interesting citizen petition that Teva filed last August.  In the petition, Teva requests that FDA:  (1) relist U.S. Patent No. 5,158,952 in the Orange Book for Risperdal (risperidone) tablets; (2) confirm Teva’s right to 180-day exclusivity for risperidone tablets; and (3) refrain from approving any other ANDAs for risperidone tablets until Teva’s exclusivity expires.  Risperdal is Johnson & Johnson’s blockbuster treatment for schizophrenia and other neurological disorders.

    Teva filed its ANDA for risperidone tablets on August 28, 2001, with a paragraph III certification to U.S. Patent No. 4,804,663 and a paragraph IV certification to the ‘952 patent.  At the time, both patents were listed in the Orange Book for Risperdal.  On October 12, 2001, FDA notified Teva that it had delisted the ‘952 patent from the Orange Book and informed Teva that it would not accept Teva’s ANDA for filing unless Teva amended its paragraph IV certification to reflect the fact that the ‘952 patent had been delisted.  Teva complied by amending its ANDA.

    Five years later, in Ranbaxy v. Leavitt, the D.C. Circuit ruled that FDA had improperly delisted two patents on Zocor because the effect of delisting would be to deny the first ANDA filer of 180-day exclusivity on simvastatin tablets.  According to Teva’s citizen petition, following that decision "Teva began reviewing its portfolio of pending ANDAs to determine whether FDA’s unlawful delisting practices had deprived Teva of its entitlement to 180-day exclusivity for any other generic product."

    In its risperidone petition, Teva contends that because the ‘952 patent was listed in the Orange Book when it filed its ANDA for risperidone tablets, it had no choice but to certify as to the ‘952 patent.  "Teva thus did precisely what it was obligated to do under the plain text of the governing statute and Agency regulations, and it therefore earned its exclusivity as the first applicant to file a paragraph IV certification to a patent listed as claiming the reference listed drug."  Teva argues that the Ranbaxy decision compels FDA to relist the ‘952 patent and restore Teva’s right to 180-day exclusivity.  Teva further argues that "the fact that FDA never accepted Teva’s paragraph IV ANDA for filing has no bearing on the fact that FDA must relist the ‘952 patent."

    The ‘663 patent (whose validity was affirmed in a Federal Circuit decision last year) expired on December 29, 2007.  Pediatric exclusivity on Risperdal extends to June 29, 2008.  Thus, FDA must decide the issues presented in Teva’s citizen petition before then.  FDA will post its decision in the docket established for Teva’s petition.