Orange Book Blog

At the intersection of Patent and FDA Law

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  • ACI “FDA Boot Camp” Conference, Boston, July 17-18

    American Conference Institute’s popular "FDA Boot Camp" comes to Boston on July 17-18.  According to ACI, seats at this year’s New York and last year’s Chicago editions sold out.

    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 top FDA regulatory 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
    • Understanding the Clinical Trial Process for Drugs and Biologics
    • Patent and IP Overview for Drugs and Biologics: Hatch-Waxman, Trade Dress, and More
    • Drugs and Biologics: Labeling
    • Medical Devices: Classification and the Essentials of the Device Premarket Review Process

    The chair for the conference is Michael P. Peskoe of Edwards Angell Palmer & Dodge LLP.  Additional details and registration information are available at the conference website.

    Orange Book Blog is a media partner of this conference.

  • Pharma News Briefs

    • On Monday, the Supreme Court followed the Solicitor General’s advice and denied certiorari in Joblove v. Barr Labs, which concerned the legality of a "reverse payment" settlement of Hatch-Waxman litigation.  Last year, the Court denied certiorari in a similar case, FTC v. Schering.  Dow Jones reports that the FTC has vowed to press forward in its campaign against reverse payment settlements.
    • Synthon and Teva announced this week that the FDA granted final approval to their ANDAs for generic Norvasc (amlodipine besylate).  They join Mylan, which launched in March, and Apotex, which launched in May. 
    • FDA Law Blog reported earlier this week on an interesting new paper examining the regulatory challenges facing drug/device combination products.

  • Federal Circuit Affirms Validity of Takeda’s ACTOS Patent, Rejecting Alphapharm’s Obviousness Arguments

    Takeda v. Alphapharm, No. 2006-1329 (Fed. Cir. 2007)

    In an opinion released today, the Federal Circuit affirmed the validity of Takeda's U.S. Patent No. 4,687,777, which covers pioglitazone HCl (among other compounds).  Pioglitazone HCl is the active ingredient in ACTOS, Takeda's blockbuster drug for the treatment of type 2 diabetes.  The decision is particularly important because the generic challenger, Alphapharm, had argued on appeal that the Supreme Court's recent decision in KSR v. Teleflex, as well as the Federal Circuit's recent decision in Pfizer v. Apotex, mandated reversal.

    Alphapharm argued that pioglitazone HCl would have been prima facie obvious over a prior art compound, named "compound b," that is structurally similar to pioglitazone.  According to the Federal Circuit, in chemical cases "normally a prima facie case of obviousness is based upon structural similarity, i.e., an established structural relationship between a prior art compound and the claimed compound."  Moreover, to prove prima facie obviousness based on structural similarity, "a showing that the prior art would have suggested making the specific molecular modifications necessary to achieve the claimed invention is also required."

    The district court found that there was no motivation in the prior art to select compound b as a lead compound in the first place, and that the prior art taught away from its use as a lead compound.  The Federal Circuit agreed with this finding, stating that it alone was a sufficient basis for concluding that Alphapharm had failed to establish a prima facie case of obviousness.

    The Federal Circuit squarely addressed whether KSR affects its "structural obviousness" jurisprudence:

    [The] test for prima facie obviousness for chemical compounds is consistent with the legal principles enunciated in KSR.  While the KSR Court rejected a rigid application of the teaching, suggestion, or motivation ("TSM") test in an obviousness inquiry, the Court acknowledged the importance of identifying "a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does" in an obviousness determination.

    The Federal Circuit concluded:  "Thus, in cases involving new chemical compounds, it remains necessary to identify some reason that would have led a chemist to modify a known compound in a particular manner to establish prima facie obviousness of a new claimed compound."

    In a separate decision today (made under Rule 36, without opinion), the Federal Circuit affirmed the district court's conclusion that the '777 patent is not unenforceable for inequitable conduct.

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  • Follow-on Biologics Bill Approved by Senate Committee, Moves On to Full Senate

    MarketWatch.com is reporting this afternoon that the Senate Committee on Health, Education, Labor and Pensions has voted in favor of the Biologics Price Competition and Innovation Act of 2007.  It is unclear whether the Committee amended the bill before voting on it.  The bill will now move to the Senate floor.

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  • Senate Committee To Vote Wednesday on Bipartisan Follow-on Biologics Bill

    After several previous bills went nowhere, lawmakers may have finally reached a viable compromise on follow-on biologics legislation.  Last Friday, a bipartisan group of Senators led by Ted Kennedy (D-MA) and Orrin Hatch (R-UT) announced an agreement on a new bill that would establish an abbreviated pathway for FDA approval of biologic drugs.  The Senate Committee on Health, Education, Labor, and Pensions, chaired by Sen. Kennedy, is expected to mark up the bill and vote on an amended version of it in a session tomorrow.

    The draft bill (S.1693) would amend the Public Health Service Act “to establish a pathway for the licensure of biosimilar biological products, to promote innovation in the life sciences, and for other purposes.”  It is entitled the “Biologics Price Competition and Innovation Act of 2007.”

    The bill outlines three requirements to gain approval of a follow-on biologic: “(1) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (2) animal studies; and (3) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency . . . and designed to avoid needlessly duplicative or unethical clinical testing.”  The bill grants FDA discretion to waive one or more of these requirements if it determines such requirement “is unnecessary in an application submitted under this subsection.”

    The bill provides for substitutability of a biosimilar for a brand product at the pharmacy: “An application submitted under this subsection may include information demonstrating that the biological product is interchangeable with the reference product.”

    The bill further provides for market exclusivity for innovator products: 12 years from the date of approval for innovator products and one year (after first commercial marketing) to 18 or 42 months for “first interchangeable biological products.”

    The bill would also establish a complex process for providing notice of a biosimilar application, exchanging patent information, and resolving patent issues through agreement or litigation.  For instance, within 20 days after the FDA accepts a biosimilar application, the applicant “shall provide to the reference product sponsor a copy of the application . . . and such other information that describes the process or processes used to manufacture the biological product.”  Within 60 days of receiving that information, the reference product sponsor shall provide to the biosimilar applicant “a list of patents for which the reference product sponsor believes a claim of patent infringement could reasonably be asserted.”  Then, within 60 days after receiving that list, the biosimilar applicant shall provide “a detailed statement that describes, on a claim by claim basis,” the factual and legal basis of its opinion of invalidity, unenforceability, or noninfringement.  Within 60 days of receiving that statement, the reference product sponsor shall provide the factual and legal basis of its opinion that its patents will be infringed and a response to the invalidity or unenforceability statement.  Provisions relating to negotiations and litigation are even more complicated.

    Democrats have made passage of a follow-on biologics bill a priority for this Congress.  Sen. Kennedy tried, but failed, to attach an earlier bill to the FDA Revitalization Act.  The major pharmaceutical trade associations–BIO, PhRMA and GPhA–have not yet weighed in publicly on the new bill, but are expected to do so soon.

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  • Informa Life Sciences “Legal Strategies for Developing Generic Medicines” Conference, July 9-11, Amsterdam, The Netherlands

    Informa Life Sciences will hold its 2nd annual "Legal Strategies for Developing Generic Medicines" conference July 9-11 in Amsterdam, The Netherlands.  ILS announces that the conference offers "the unrivalled opportunity to hear how the latest updates in the European Pharmaceutical Legislation and issues in patent litigation will affect your generics business."

    According to the conference brochure, at this conference you will:

    • Discuss the implications of the most recent updates in European Pharmaceutical Legislation and regulatory procedures, including an overview of some of the new EU Member States;
    • Learn from case-study presentations of recent law court proceedings in pharmaceutical patent litigation;
    • Receive advice from experts in the generics industry on strategies to overcome evergreening and thoughts on authorised generics and reverse payments in Europe and the US;
    • Meet delegates in patent and IP departments from generics companies from all across Europe and the CEE.

    The event features a pre-conference workshop on Monday, July 9: "Selecting a Reference Member State for your Generics Application."  And, there will be an Evening Briefing on Tuesday, July 10: "Introduction to EU Pharmaceutical Law."

    For additional information and to register, please visit the conference website.

    Informa Life Sciences also invites all those interested to participate in their Confidential Generics Industry Poll.  The results will be released at the conference next month.

    Orange Book Blog is a media partner of this conference.

  • Pharma News Briefs

    • Pharmalot had this post Friday about a new bipartisan follow-on biologics bill in the Senate.
    • MarketWatch reported Friday that European regulators have moved a step closer to approving Sandoz’s follow-on version of J&J’s blockbuster Eprex, sold in the U.S. as Procrit.
    • On Thursday, a House committee marked up the PDUFA reauthorization legislation (Pharmalot).  PhRMA reacted positively in this press release.
    • FDA Law Blog had this post Tuesday reporting that the Senate-passed version of FDARA would open the door to 5-year New Chemical Entity exclusivity for enantiomers of previously-approved racemic drug compounds.

  • Bristol-Myers Squibb and Sanofi-Aventis Prevail Over Apotex in Plavix Case

    Sanofi-Synthelabo et al. v. Apotex, No. 02-2255 (S.D.N.Y. 2007)

    Following a month-long trial held earlier this year, in an opinion released today a federal district court upheld the validity of Sanofi's U.S. Patent No. 4,847,265.  The '265 patent covers clopidogrel bisulfate, the active ingredient in Plavix.  The court permanently enjoined Canadian generic drug maker Apotex from infringing the '265 patent and stated that damages will be set in future proceedings.

    At trial, Apotex argued that a prior Aventis patent had inherently anticipated clopidogrel bisulfate ("CBS").  The earlier patent disclosed a broad genus of thienopyridines which included CBS in addition to millions of other compounds.  Apotex argued that the court should see this as a type of Petering anticipation, where the patentee’s stated preferences can limit a broad disclosure to an effective disclosure of a very small subgenus of compounds.  The court rejected this argument, though.  The Petering rule appears to require precise, unambiguous statements that single out the narrow subgenus from the broad disclosure.  In this instance, the court found that the alleged statements lacked precision and could reasonably have pointed to other subclasses as well.  Thus, the prior disclosure of the broad genus failed to inherently disclose CBS.

    Apotex further argued that the '265 patent was invalid as obvious.  The obviousness issue here has some striking similarities to the issue that the Federal Circuit considered in the recent Pfizer v. Apotex case, concerning amlodipine besylate, the active ingredient in Norvasc.  In Pfizer, the CAFC had invalidated a patent because the besylate salt would have been obvious to one of skill in the art based on (1) the instability of the maleate salt, (2) the knowledge of skilled practitioners, and (3) the teachings of the prior art.

    In this case, the prior art revealed the hydrochloride salt of the racemate of CBS.  Apotex argued that this disclosure should render the bisulfate salt of the enantiomer (CBS) obvious.  The court rejected this argument for several reasons.  First, the court held that Apotex failed to show that a person of ordinary skill in the art would have reasonably expected that one enantiomer of the racemate would possess all of the racemate’s therapeutic activity and none of its toxicity.  Second, distinguishing this case from Pfizer, the court found that Apotex could point to nothing that would disclose the highly favorable properties of the bisulfate salt.  (In fact, one reference appeared to teach away from using sulfuric acid salts.)

    The case should present the CAFC with some interesting questions on appeal.  The case will provide a welcome opportunity for the court to refine its post-KSR obviousness jurisprudence and give district courts additional guidance on the breadth of its recent Pfizer holding.

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  • Pharma News Briefs

    • Barr Labs announced Monday that it has amended its paragraph IV certification with respect to Lilly’s Zyprexa Zydis patent to a paragraph III certification, and that Lilly has dropped its related patent suit against Barr.  See also this AP article.
    • FDA Law Blog had this post Tuesday about yet another new study on authorized generics.
    • Patently-O reported today that the district court overseeing Abbott’s Biaxin XL litigation against Sandoz has denied Sandoz’s motion to stay a preliminary injunction pending appeal.  For background, see this April OBB post.
    • The Patent Prospector recently posted Hal Wegner’s new paper on post-KSR chemical obviousness.

  • Teva Defeats Novartis Motion for Preliminary Injunction in Lotrel Litigation

    Novartis v. Teva, No. 04-4473 (D.N.J. 2007)

    Yesterday, a federal judge denied a preliminary injunction motion filed by Novartis to protect Lotrel from generic competition.  With the decision, Teva likely resumed shipping its generic version of Lotrel before nightfall.  After all, Teva had already made an initial launch on May 18 – a launch that fell victim to a temporary restraining order that issued shortly thereafter.

    Novartis sued Teva on U.S. Patent No. 6,162,802.  The patent includes method of treatment claims and formulation claims directed to a combination of amlodipine and benazepril (marketed as Lotrel).

    Novartis lost essentially on the first prong of the four-part preliminary injunction test: likelihood of success on the merits.  The main issue dealt with whether Teva’s amlodipine-benazepril formulation infringes the claims of the ‘802 patent.  Particularly, the parties disagreed over whether the patent requires a physical barrier between the two active ingredients.  (Teva’s product separates the incompatible ingredients by excipient rather than by a barrier.)

    The patent specification and the prosecution history seem to require that the two ingredients be “physically separated” from each other.  Nevertheless, the patent’s broadest claim omits this limitation (while most dependent claims contain it).  Novartis argued that claim differentiation prevents the court from reading the limitation into the broadest claim.  On the other hand, Teva argued that disavowals in the specification and prosecution history require reading the limitation into all claims.  The court held off on deciding the dispute, but agreed that Teva’s argument has substantial merit.

    But Novartis asserted that this makes no substantial difference.  Teva, according to Novartis, “physically separate[s]” the two ingredients by means of its excipient, and therefore still infringes the patent.  Teva argued that the ‘802 patent’s use of the modifier “physical” implies that the separation must occur through use of a physical barrier.  Since Teva uses no physical barrier in its formulation, it does not infringe.  The court rejected both parties’ renderings of this claim term.  Novartis probably construes it too broadly, especially since none of the patent’s embodiments disclose a formulation where the active ingredients were interspersed in a sea of excipient.  Yet Teva’s proposed construction is probably too narrow, failing to include embodiments in which the ingredients were in physical contact with each other.  Hence, neither party proffered a credible construction of the claims.

    This result necessitated a denial of the PI.  Teva raised a substantial issue regarding whether the “physical barrier” imitation should be read into all of the claims.  And Novartis failed to provide a persuasive claim construction that captures Teva’s formulation.

    In the end, the denial of the PI appears to be a reasonable result.  The court basically recognized that PIs are best granted in situations where the court can make a straightforward assessment of claim scope.  When this is not possible, patentees had better come to court with reasonable interpretations of the claim language (and not just proffer constructions that are most favorable to their interests).  Anyway, it looks like we’re headed for one fun Markman showdown.

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