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  • Committee Publishes National Model Patent Jury Instructions

        By Sherri Oslick —

    Judge Michel Assembled by Chief Judge Paul R. Michel (at right) of the United States Court of Appeals for the Federal Circuit, a committee comprising litigators and judges from across the nation has prepared and published model jury instructions for patent infringement cases based on the experience of those both on the bench and in the bar.  The model jury instructions have not been endorsed by the CAFC, nor were they intended to be "official" model jury instructions.  Rather the committee's focus was "to benefit from the collective experience of both judges and attorneys who [were] interested in creating an easier to understand and streamlined set of model jury instructions."

    Committee members include:  Kenneth C. Bass III (Senior Counsel with Sterne, Kessler, Goldstein & Fox, P.L.L.C., Washington, D.C., now deceased), Donald R. Dunner (Partner with Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, Washington, D.C.), Pamela Banner Krupka (Krupka Law Group, P.C., Los Angeles, California), Roderick R. McKelvie (Partner with Covington & Burling LLP, Washington, D.C.), Teresa Stanek Rea (Partner with Crowell & Moring, Washington, D.C.), Judge Patti B. Saris (U.S. District Court Judge, District of Massachusetts), Judge T. John Ward (U.S. District Court Judge, Eastern District of Texas), and Judge Ronald M. Whyte (U. S. District Court Judge, Northern District of California).  The committee is chaired by Edward R. Reines (Litigation Partner with Weil, Gotshal & Manges LLP, Redwood Shores, California).

    Jury Box In preparing the model jury instructions, the committee reviewed and drew from the work of others, including that of the committees for the Northern District of California, The Federal Circuit Bar Association, the AIPLA, and the District of Delaware.  Public comments from federal judges, inventors, attorneys, law firms, corporations, bar groups, and trade associations were also taken into consideration, including comments from the American Bar Association Section of Intellectual Property Law, Federal Circuit Bar Association, and Intellectual Property Owners Association.

    The National Patent Jury Instructions may be downloaded here, in either PDF or Microsoft Word format.  They will be updated in a timely manner to incorporate new developments in the law.

  • The Genetics of Complex Behaviors: It Really Isn’t That Simple

        By Kevin E. Noonan —

    Early last week, the Journal of the American Medical Association published a study ("Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression") by Neil Risch at the University of California, San Francisco and colleagues at the National Institutes of Mental Health, Johns Hopkins University, Yale University School of Medicine, the Rockefeller University, the University of Pittsburgh School of Medicine, and Virginia Commonwealth University that showed no statistically-significant link between depression and the short HTT allele.  The study provided a statistical meta-analysis of data accumulated for 14,250 participants from 14 separate studies from the medical literature and a second meta-analysis of 10,943 participants from 10 of these studies.  These Moffitt, Terrie results were contrary to the results published by Avshalom Caspi and collaborators (including Terrie E. Moffitt (at right), Knut Schmidt Nielsen Professor, Departments of Psychology and Neuroscience, Psychiatry and Behavioral Sciences, and Institute for Genome Sciences and Policy, Duke University) that individuals bearing at least one copy of a specific genetic polymorphism in a serotonin transporter gene were more susceptible to depression as a consequence of environmental (life) stressors (see Caspi et al., 2003, "Influence of Life Stress on Depression:  Moderation by a Polymorphism in the 5-HTT Gene," Science 301: 386-89).

    Dr. Moffitt has graciously provided us with three points in rebuttal to the conclusions of the Risch study, set forth in her own words:

    1.    The JAMA article ignores the wider body of scientific evidence.  In the past 6 years, extensive research in experimental neuroscience using both animals and humans has validated the original report by showing that 5-HTTLPR short allele-carriers are excessively vulnerable to stress.  Experimental studies that expose human participants to stressors in the laboratory show that individuals having the 5-HTTLPR short genotype have greater stress responses on measures of cognitive reactivity (e.g., Beevers et al., 2007, J. Abnorm. Psychol. 116: 208-12; Fox et al., 2009, Proc. Biol. Sci. 276: 1747-51), hormonal  reactivity (e.g., Chen et al., 2009, Psychoneuroendocrinology 34: 681-86; Gotlib et al., 2008, Biol. Psychiatry. 63: 847-51), physiological reactivity (e.g., Lonsdorf et al., 2009, Psychol. Sci. 20: 198-206) and reactivity in the brain's emotion-circuitry (e.g., Hariri et al., 2006, Arch. Gen. Psych. 62: 146-52; Canli et al. 2006, Proc. Natl. Acad. Sci. U.S.A. 103: 16033-38).  This vulnerability of 5-HTTLPR S carriers has also been confirmed in animal research (e.g., Carola et al., 2008, Biol. Psychiatry. 63: 840-46; Barr et al., 2004, Biol. Psych. 55: 733-38; Kalin et al., 2008, Mol. Psychiatry. 13: 1021-27, online at DOI: 10.1038/mp.2008.37; Watson et al., 2009, PLoS One, published online January 14, 2009).  Further validation comes from studies which have shown that 5-HTTLPR Short allele carriers are vulnerable not only to depression, but also to other mental-health problems caused by stress, including PTSD and anxiety (e.g., Gunthert et al., 2007, Psychosom. Med. 69: 762-68; Kilpatrick et al., 2007, Am. J. Psychiatry. 164: 1693-99).

    2.    The selection of studies for meta-analysis clearly fails to represent the pool of papers in the literature.  4 out of 17 positive replications were included (24%) but 6 out of 9 published negative
    studies (67%), a bias that violates a basic requirement of the meta-analysis method to examine a representative sample of the existing literature.  Further, the article opted not to analyze several well-designed studies of individuals exposed to stress.  For example, studies of children who are victims of abuse (e.g., Cicchetti et al., 2007, Dev. Psychopathol. 19: 1161-80; Kaufman et al., 2004, Proc. Natl. Acad. Sci. U.S.A. 101: 17316-21) and patients suffering hip fractures, strokes and coronary heart disease (Kohen et al., 2008, Arch. Gen. Psychiatry. 65: 1296-302; Lenze et al., 2008, Amer. J. Geriatric Psych. 13: 428-32; Otte et al., 2007, Am. J. Psychiatry. 164: 1379-84) have reported positive findings for this "GxE" hypothesis.  Several other positive replications from studies with very strong research designs were omitted from the meta-analysis as well (Kendler et al., 2005, Arch. Gen. Psych. 62: 529-35; Drachmann-Bukh et al., 2009, J. Affect. Disord. 2009 Mar. 30 (e-publ. ahead of print at doi:10.1016/j.jad.2009.02.023); Lazary et al., 2008, Biol. Psychiatry. 64: 498-504).

    3.    Within the smaller subset of studies in the meta-analysis, there is important heterogeneity.  The article says this heterogeneity was not statistically significant.  However, we have learned that the test fell just short of statistical significance.  One obvious characteristic that varies widely across studies in the meta-analysis is measurement quality.  As one example, meta-analysis gives more mathematical weight to studies with the largest samples.  But in this case the big studies had to collect their data through telephone calls or self-complete postal questionnaires, which are known to be weak methods of measuring life events and depression.  Not surprisingly, these big studies with weak measures tended not to find positive results, tilting the meta-analysis toward a null finding.  In the existing literature of tests of this GxE hypothesis, 13 studies have replicated the finding, using measures collected in face-to-face clinical assessments, and 10 studies failed to replicate the finding, using measures collected via phone or postal questionnaires.  This clear methodological pattern was ignored in the meta-analysis.  This is one example of heterogeneity could have been followed up in a meta-analysis, there may be others.

    Dr. Moffitt concluded her response to Dr. Risch's work by noting that "[w]hat is needed is not less research into gene-environment interaction, as Risch et al. recommend, but more research of better quality, and a more thorough and thoughtful evaluation of it."

    Dr. Moffitt has extensive experience in studying the biological basis of complex behaviors, and in addition to her Duke University appointment is also Professor of Social Behaviour and Development, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London and Associate Director, Dunedin Multidisciplinary Health and Development Research Unit, Dunedin School of Medicine, Dunedin, New Zealand.

    This
    controversy illustrates one of the many pitfalls frequently faced by academic inventors motivated by the dual (and occasionally conflicting) needs of disseminating the results of their studies as rapidly as possible and protecting the intellectual property aspects of their work to maximize the likelihood that it can be commercialized (and not merely expropriated by others based on its disclosure in the academic literature).  As a result, often the research is not as developed as it might be if it were developed by a commercial concern initially.  This situation presents particular challenges to university technology transfer offices and their clients, university faculty and university administrations.  It is an imperfect system, which motivates some to say there is a flaw in the basic premise of promoting university patenting under the Bayh-Dole regime.  However, the alternative (not protecting university-generated inventions) is indeed worse, since then the public stands no chance of seeing the fruits of these labors helping to finance the next generation of technologies.

  • Court Report

        By Sherri Oslick —

    Gavel_2About
    Court Report:  Each week we will report briefly on recently filed
    biotech and pharma cases, and a few interesting cases will be selected
    for periodic monitoring.


    Sepracor Inc. et al. v. Synthon Pharmaceuticals, Inc. et al.
    5:09-cv-00264; filed June 17, 2009 in the Eastern District of North Carolina

    Infringement of U.S. Patent No. 5,698,558 ("Methods for Treating Allergic Disorders Using Optically Pure (-)Cetirizine," issued December 16, 1997), licensed to UCB, following a Paragraph IV certification as part of Synthon's filing of an ANDA to manufacture a generic version of UCB's XYZAL® (levocetirizine dihydrochloride, used to treat seasonal and perennial allergic rhinitis).  View the complaint here.

    Pfizer Inc. et al. v. Mylan Inc. et al.
    1:09-cv-00441; filed June 15, 2009 in the District Court of Delaware

    Pfizer Inc. et al. v. Mylan Inc. et al.
    1:09-cv-00079; filed June 15, 2009 in the Northern District of West Virginia

    The complaints in these cases are substantially identical.  Infringement of U.S. Patent Nos. 5,969,156 ("Crystalline [R- (R*,R*)]-2-(4-Dfluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin)," issued October 19, 1999), 6,087,511 ("Process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)- β,δ -dihydroxy-5-(1-methylethyl )-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid) calcium salt (2:1)," issued July 11, 2000), and 6,274,740 (same title, issued August 14, 2001) based on Mylan's filing of an ANDA to manufacture a generic version of Pfizer's Lipitor® (atorvastatin calcium, used to treat high cholesterol and heart disease).  View the Delaware complaint here.

    Public Patent Foundation, Inc. v. McNeil-PPC, Inc.
    1:09-cv-05471; filed June 15, 2009 in the Southern District of New York

    False marking based on McNeil's marking of certain Tylenol® products indicating that these products are covered by certain of U.S. Patent Nos. 4,820,522 ("Oral Sustained Release Acetominophen Formulation and Process," issued April 11, 1989), 4,968,509 (same title, issued November 6, 1990), 5,004,613 (same title, issued April 2, 1991), 5,658,589 ("Subcoated Simulated Capsule-Like Medicament," issued August 19, 1997), 5,436,026 ("Discharge and Transfer System for Apparatus for Gelatin Coating Tablets," issued July 25, 1995), 5,228,916 ("Apparatus for Creating a Gelatin Coating," issued July 20, 1993), and 5,679,406 ("Tablet Dipping Systems for Apparatus for Gelatin Coating Tablets," issued October 21, 1997), some of which are expired.  View the complaint here.

    Ortho-McNeil-Janssen Pharmaceuticals, Inc. v. Sandoz, Inc.
    2:09-cv-02863; filed June 4, 2009 in the District Court of New Jersey

    Infringement of U.S. Patent No. 6,214,815 ("Triphasic Oral Contraceptive," issued April 10, 2001) following a Paragraph IV certification as part of Sandoz's filing of an ANDA to manufacture a generic version of Ortho-McNeil's Ortho Tri-Cyclen Lo® (norgestimate and ethinyl estradiol, used for oral contraception).  View the complaint here.

  • Future Drug Sales Predictions Highlight Importance of Follow-on Biologics Legislation

        By Kevin E. Noonan —

    EvaluatePharma As reported last week by FierceBiotech, EvaluatePharma, a market forecasting firm specializing in the life sciences sector, released its prediction on the future of the pharmaceutical industry.  According to EvaluatePharma, six of the top ten selling drugs by 2014 will be biologics.  Today, half of the top ten best-selling drugs are conventional small molecule drugs, as shown in the table below; in terms of sales, these drugs account for about 61% of the revenues garnered by the top ten best-selling drugs.

    Top 10 Drug Products by Sales in 2008

    Table 1

    EvaluatePharma predicts this situation will change dramatically by 2014:  as shown below, seven out of the top ten best-selling drugs will be biologic drugs.  Moreover, biologics drugs are predicted to account for a 75% of the revenues, an almost 2-fold increase in the relative contributions of biologic drugs to the sector.

    Top 10 Drug Products by Sales in 2014

    Table 2

    The reason for this expected change is generic competition for small molecule drugs that will be off-patent by 2014, including current best-sellers Nexium®, Lipitor®, Plavix®, Advair® and Diovan®.  The report also notes that "anti-cancer antibodies appear set to easily become the most valuable therapeutic class of drug."  The report also notes that some traditional Big Pharma companies stand to benefit from their association (partnering) or acquisition of biotechnology companies, with Roche being a clear example as purveyors of three of the top ten predicted best-selling drugs in 2014 (Avastin®, Rituxan® and Herceptin®) representing about one third of the revenues from these drugs.  Notably absent from the list are companies like Pfizer and GlaxoSmithKline that today have drugs in the best-selling top ten.  Accordingly, EvaluatePharma suggests that it may behoove such companies to pursue small and mid-sized biotech companies, particularly now during the economic downtrend that has reduced the valuations of these biotech companies.

    These results are consistent with other reports.  Biologics sales currently are around $75 billion, with 22 biologics drugs breaking the $1 billion "blockbuster" drug barrier in 2007.  These revenues can only be expected to increase, and much of this cost can be expected to be borne by government under Medicare, Medicaid, and other programs, particularly since many biologic drugs are directed to end-of-life diseases like cancer.  Senator Schumer, in a press release issued in conjunction with the introduction of his follow-on biologics bill in the Senate (S. 726) estimated that the bill "would save federal programs like Medicare and Medicaid at least $10 billion dollars by bringing needed competition to the marketplace" (see "Third Follow-on Biologics Bill Introduced in 111th Congress").  This estimate is consistent with a Congressional Budget Office report, stating that implementation of a follow-on biologics regulatory scheme would save health programs such as Medicare and Medicaid about $8.1 billion over the 2010–2019 period, as well as reduce costs for private health insurance plans and lower insurance premiums for employers by almost 0.2% by 2019 (see "BIO Says CBO Estimate of Follow-on Biologics Savings Is Based on 'Troubling Assumption'").

    While these numbers pale in comparison with the monies expended by the Federal government over the past several months, they bring to mind Senator Everett Dirksen's famous (perhaps apocryphal) aphorism that "A billion here, a billion there, and pretty soon you're talking real money."  These numbers provide more than adequate political motivation for follow-on biologics legislation, making it all the more critical that interested observers make sure their Congressional representatives know precisely what is at stake in this debate.

  • News from Abroad: Utility under Canadian Patent Law and the Doctrine of Sound Prediction

        By Ariadni Athanassiadis, Catherine Lemay, and Claire Palmer —

    Canadian Flag In Canada, for subject matter to be patentable, it must be novel, inventive, and have utility.  A patent will fail for lack of utility if it can be shown that "the invention will not work, either in the sense that it will not operate at all or, more broadly, that it will not do what the specification promises that it will do" (Consolboard Inc. v. MacMillan Bloedel (Saskatchewan) Ltd., (1981) 56 CPR (2d) 145 (S.C.C.)).  At the time a patent is applied for, the inventor must be in a position to establish utility, "on the basis of either demonstration or sound prediction" (Apotex Inc. v. Wellcome Foundation Ltd., [2002] 4 S.C.R. 153, 2002 SCC 2007, 2002 SCC 77).

    Apotex #1 As is often the case for both biotechnology and pharmaceutical inventions where working examples demonstrating promised utility are not available at the time of filing, the doctrine of sound prediction, as established by the Supreme Court of Canada in Apotex Inc. v. Wellcome Foundation Ltd., must be relied on to support the utility of the invention.

    To meet the test for "sound prediction," there must be:

    (i)    a factual basis for the prediction;

    (ii)    an articulable and "sound" line of reasoning from which the desired result can be inferred from the factual basis, and

    (iii)    proper disclosure.

    With respect to the first requirement, the factual basis from which utility can be soundly predicted may be provided by way of examples but there is no requirement to do so.  Nor is there any requirement to establish the factual basis with human clinical trial data.  In fact, in Apotex Inc. v. Wellcome Foundation Ltd., the factual basis was provided by way of in vitro examples.

    A recent Canadian Federal Court of Appeal decision in Eli Lilly Canada Inc. v. Apotex Inc., 2009 FCA 97, has examined the sound prediction doctrine and sets a troubling precedent with regard to inclusion of performed clinical trial data in pharmaceutical applications in order to satisfy the third prong of the test relating to disclosure.

    Lilly On March 25, 2009, the Federal Court of Appeal dismissed Eli Lilly Canada's appeal of a lower court decision pursuant to the Patented Medicines (Notice of Compliance) Regulations ("PM(NOC) Regulations") in favor of Apotex for its raloxifene hydrochloride drug (generic  version of EVISTA7).  The PM(NOC) Regulations are Canada's version of a Hatch-Waxman-type regime linking the approval of generic drugs under the Canadian Food and Drugs Act and Regulations with the Canadian Patent Act.

    2101356_19981116_representativedrawing_page1_scale25_rotate0 The patent at issue, Canadian Patent No. 2,101,356 ('356 patent) is directed to the use of a group of compounds (including raloxifene) in the treatment or prevention of osteoporosis and for inhibiting bone loss in a human.  The patent specification disclosed four examples of in vivo rat studies and a fifth example of an anticipated study on a group of post-menopausal women where certain results were expected.  In its Notice of Allegation, Apotex alleged that the rat studies disclosed in the '356 patent did not provide a factual basis for a sound prediction; specifically, that it could not be soundly predicted that the results obtained from in vivo testing in rats would demonstrate utility in humans.  According to Apotex, the inventors had not demonstrated that raloxifene HCl could be used as a treatment for the prevention of osteoporosis and/or bone loss in humans and that, while the disclosure mentioned that a clinical trial in healthy post-menopausal women was underway to confirm this, the results of the study were not reported in the '356 patent.

    The first instance trial judge agreed with Apotex and held that the '356 patent lacked proper disclosure as required by the sound prediction test articulated in Apotex Inc. v. Wellcome Foundation Ltd.  Of relevance was an abstract published by Eli Lilly before the Canadian filing date of the '356 Patent, but after its U.S. priority date which described a study (referred to as the Hong Kong study) conducted on a group of post-menopausal women demonstrating that raloxifene showed promising skeletal anti-resorptive properties.  The Court ruled that, although there was a good basis for a prediction as of the priority date of the application based on the in vivo rat studies described in the application, and a sound line of reasoning as of the Canadian filing date based on the Hong Kong study, the third prong of the test had not been met as the Hong Kong study itself was not disclosed in the '356 patent.  Eli Lilly argued that the Hong Kong study abstract was available to the public at the Canadian filing date and that, as such, sufficient disclosure to satisfy the third prong of the test had been made.  However, this was rejected by the trial judge who, as mentioned above, ruled that the disclosure must be in the patent, not elsewhere.

    On appeal, Eli Lilly argued, inter alia, that the trial judge had committed a legal and factual error as recent case law on the issue of sound prediction had established that there was no requirement that the underlying data supporting a sound prediction be disclosed in the patent.  The Federal Court of Appeal disagreed with Eli Lilly and confirmed that a heightened obligation to disclose the underlying facts and the line of reasoning for inventions that comprise the prediction was required in sound prediction cases.  According to the Court, "when a patent is based on a sound prediction, the disclosure must include the prediction.  As the prediction was made sound by the Hong Kong study, this study had to be disclosed."

    It is unclear from the decision why both the trial level and appeal Courts found (and Eli Lilly's counsel accepted) that the particular Honk Kong study was necessary to provide a sound line of reasoning, i.e., that in vivo data in rats alone was not sufficient to provide both the factual basis and the sound line of reasoning.  Eli Lilly appears to have simply argued its case on the basis that the doctrine of sound prediction did not require that the study be actually disclosed in the application.  Perhaps it should have gone still further and argued that the judge had erred in finding that it was the testing in humans that made the prediction sound.  In the vast majority of cases, when a patent application is filed, no such human clinical trial data is available; therefore, it is typical for applicants to support their sound predictions with in vitro or animal in vivo data only.

    Therefore, this case should not be taken as establishing a requirement to provide human clinical trial studies in support of a sound prediction.  As mentioned above, in the Apotex Inc. v. Wellcome Foundation Ltd. case itself, the factual basis had been established by in vitro data only.  However, if an applicant does have human clinical trial studies available prior to filing its Canadian patent application (as was the case for Eli Lilly in the case at hand), then it would be advisable for the applicant to include the results of the studies in the patent application.

    For more information regarding the Doctrine of Sound Prediction please contact Ariadni Athanassiadis (aathanassiadis@mbm.com), Catherine Lemay (clemay@mbm.com) or Claire Palmer (cpalmer@mbm.com).

  • Conference & CLE Calendar

    CalendarJune 21-23, 2009 – IP Business Congress (Intellectual Asset Management magazine) – Chicago, IL

    June 22-27, 2009 – Innovation Week 2009 (U.S. Patent and Trademark Office) – Arlington, VA

    June 29-30 – Product and Pipeline Enhancement for Generics (Marcus Evans) – Washington, DC

    July 6, 2009 – Prior Art & Obviousness 2009: The PTO & CAFC Perspective on Patent Law Sections 102 & 103 (Practising Law Institute) – New York, NY

    July 8, 2009 – Markman Hearings and Claim Construction in Patent Litigation (Practising Law Institute) – New York, NY

    July 14-15, 2009 – Pharma/Biotech Collaborative Agreements (American Conference Institute) – San Francisco, CA

    July 15, 2009 – Cost-Effective Patent Strategies (Law Seminars International) – Seattle, WA

    July 15, 2009 – Corporate Intellectual Property Conference (Law Bulletin Publishing Company) – Chicago, IL

    July 18-21, 2009 – National Association of Patent Practitioners (NAPP) 2009 Annual Meeting – San Diego, CA

    July 20, 2009 – Buying, Selling and Licensing Patents: Strategies for Turning Your Patent Portfolios into Revenue Streams (Law Seminars International) – Washington, DC

    July 21-22, 2009 – FDA Boot Camp*** (American Conference Institute) – Chicago, IL

    July 23-24, 2009 – Advanced Patent Prosecution Workshop 2009: Claim Drafting & Amendment Writing (Practising Law Institute) – New York, NY

    July 30 – August 4, 2009 – 2009 Annual Meeting (American Bar Association) – Chicago, IL

    August 17-18, 2009 – Advanced Patent Prosecution Workshop 2009: Claim Drafting & Amendment Writing (Practising Law Institute) – San Francisco, CA

    September 1, 2009 – Prior Art & Obviousness 2009: The PTO & CAFC Perspective on Patent Law Sections 102 & 103 (Practising Law Institute) – San Francisco, CA

    ***Patent Docs is a media partner of this conference or CLE

  • Corporate Intellectual Property Conference

    Chicago #5 The Law Bulletin Publishing Company will be holding its 4th Annual Corporate Intellectual Property Conference on July 15, 2009 in Chicago, IL.  The conference will address the following topics:

    • Protecting and leveraging IP assets in a down economy;
    • Update on major case law affecting IP;
    • Licensing IP assets:  Strategies for success;
    • Damages: Valuation and presentation; and
    • Copyright and trademark issues.

    Law Bulletin Seminars Additional information regarding the conference can be found here (although a program for the conference is not yet available).  The registration fee for the conference is $99.  Those registering before July 1, 2009 will receive a $20 discount off the registration fee.  Those interested in registering for the conference can do so here.

  • Generic Pharmaceuticals Conference

    Washington Mall Marcus Evans has announced its 2nd Annual Product and Pipeline Enhancement for Generics conference on "Formulating a Concrete Plan for Sustainability in the Rapidly Changing Global Generic Pharmaceutical Market."  The conference, to be held on June 29-30, 2009 in Washington, DC, will offer presentations on the following topics:

    • Ensuring the sustainability of the generics industry;
    • Devising a risk-balanced patent strategy to mitigate potential lawsuits;
    • Recent developments in the law impacting Hatch-Waxman litigation;
    • Integrating your patent and regulatory strategies;
    • Comprehending the factors involved in a profitable IP strategy;
    • Best practices for navigating the global biogenerics terrain;
    • Important considerations when breaking into the biogenerics market;
    • Encouraging a tighter focus on innovative projects through strong project execution;
    • Focusing on core competencies to overcome shrinking innovator pipelines;
    • The impact of the globalization of the pharmaceutical industry;
    • Achieving global success in the generics industry through strategic partnering;
    • Securing your supply chain through strong API relationships;
    • Understanding the global healthcare climate to ensure an accurate pricing strategy;
    • Insight on changing standards in generics regulation;
    • Developing a specialty product strategy to ensure a prosperous portfolio; and
    • Avoiding the commoditization of your generic products.

    Marcus evans A brochure for this conference can be requested here.  The registration fee for the conference is $2,500.  Those interested in registering for the conference can do so here.

  • AEI Believes Advantages of Longer Data Exclusivity Period Outweigh Disadvantages

        By Donald Zuhn —

    American Enterprise Institute In a follow-on biologics report that has received widespread media attention, the Federal Trade Commission concluded last week that a 12-14 year data exclusivity period was not needed to promote innovation by pioneer biologics companies (see "No One Seems Happy with Follow-on Biologics According to the FTC").  The FTC's conclusion was significant in that it directly conflicts with the conclusion reached in a number of prior economic studies, including that of Duke University economist Henry Grabowski in a paper published in May 2008 in Nature Reviews Drug Discovery (see "Follow-on biologics: data exclusivity and the balance between innovation and competition").  In his paper, Prof. Grabowski determined that it takes between 12.9 and 16.2 years for an innovator to generate profits for a given biologic.  Other studies, however, have leaned more towards the FTC's conclusion.  For example, last November, a Teva-funded white paper determined that a 7-year data exclusivity period would be sufficient (see "Former House Ways and Means Economist Claims 7-Year Data Exclusivity Period Is Sufficient").

    Calfee, Jack In a report issued by the American Enterprise Institute for Public Policy Research (AEI), the nonpartisan public policy group has indicated that longer data exclusivity periods would provide the more prudent approach (see "When Patents Are Not Enough:  Data Exclusivity for Follow-On Biologics").  The report, authored by John Calfee (at left), begins by noting that "[w]ithout a patent  system and the temporary protection from competition by imitators it provides, developers of new drugs would have little prospect of collecting the profits necessary to motivate innovative research."  However, echoing the title of his report, Mr. Calfee states that "the patents undergirding biologics are often more complex and subject to changing legal standards," and are "therefore more susceptible to legal challenge than patents for small-molecule drugs."  As a result, he argues that for biologics, a market dynamic is created "in which generic manufacturers can observe research on a promising biologic and, if the drug finally meets success and obtains FDA approval, quickly launch patent challenges, which, if successful, would open the door to competition from nonpioneer products."  Thus, he predicts that early patent challenges and early follow-on entry would have obvious adverse consequences for R&D investment.

    Mr. Calfee's report states that "[g]iven the stakes — a substantial amount of future R&D hangs in the balance — Congress should exercise an abundance of caution in designing follow-on biologic legislation so as not to endanger valuable future research."  Not surprisingly, the report considers the problem of setting an appropriate data exclusivity period to be the primary issue requiring Congress' attention.  In analyzing the problem, the report notes that the European biosimiliar regulatory pathway provides for ten years of data exclusivity, with an additional year for new indications approved within eight years of initial approval.  The report also notes that for patented small molecule therapeutics, "the research-intensive pathway to FDA approval tends to leave perhaps ten to twelve years of postapproval patent life."  The report also cites Prof. Grabowski's 12.9 to 16.2 year payback estimates, stating that "[s]uch results might serve as a guide to a suitable period of data exclusivity."  While acknowledging that Prof. Grabowski's calculations involve "numerous assumptions about the cost of capital, profit margins, and prices after the first follow-on enters the market," and therefore could "easily" be off by 30 to 40%, Mr. Calfee ultimately concludes that "the social losses from providing for fairly long exclusivity periods (twelve to fourteen years) would be small compared to what are likely to be substantial social gains from exclusivity."  While the AEI report does not advocate for a particular data exclusivity period, the above statement suggests that the AEI would find favor with the 14-year period specified in the follow-on biologics bill (H.R. 154) introduced by Rep. Anna Eshoo (D-CA).

  • The Uncertain Future of Genetic Diagnosis of Human Behavior

        By Kevin E. Noonan —

    Sickle cell anemia was the first known human disease associated with a genetic polymorphism (an A→T single nucleotide polymorphism, or SNP), resulting in the substitution of a valine residue (encoded by a GTG codon) for a glutamic acid residue (encoded by a GAG codon) in the beta chain of human hemoglobin.  The work, by Linus Pauling and colleagues at Cal Tech was published in the November 25, 1949 issue of the journal Science, about three and a half years before Watson and Crick deciphered the structure of DNA.  Today, sixty years of molecular biology, including the Human Genome Project, has produced the promise of identifying genetic markers for many human diseases, to be used for molecular diagnosis and particularized treatment going under the generic term of "personalized medicine."

    Covermed2003 Although monogenic traits have proven amenable to currently-available diagnostic methods (for diseases including cystic fibrosis, Tay-Sachs disease, Huntington's disease, and Duchenne muscular dystrophy), complex traits, particularly psychiatric and other behavioral disorders have proven more resistant to these methodologies.  Thus, it was a particularly exciting development six years ago when Dr. Avshalom Caspi and his colleagues reported in a landmark study in the journal Science that individuals bearing at least one copy of a specific genetic polymorphism were more susceptible to depression as a consequence of environmental (life) stressors (see Caspi et al., 2003, "Influence of Life Stress on Depression:  Moderation by a Polymorphism in the 5-HTT Gene," Science 301: 386-89).  The polymorphism occurs in the promoter region of the serotonin transporter gene (5-HTT), and the alleles are distinguished by the presence of 14 (the "short" allele) or 16 (the "long" allele) copies of a 20-23 basepair repeat motif.  Individuals with the homozygous long/long ("l/l") genotype were shown to express 1.4-1.7 fold greater amounts of the transporter gene mRNA, to have 2-fold higher levels of labeled serotonin uptake and to bind 30-40% more serotonin than the cells of individuals with the heterozygous short/long ("s/l") or homozygous short/short ("s/s") genotypes.

    This study was performed on a cohort of 847 non-Maori children in Dunedin, New Zealand, who were followed from ages 3 to 26 (specifically, at ages 3, 5, 7, 9, 11, 13, 15, 18, 21 and 26).  Stressors examined in the study included problems in employment, finances, housing, health, and relationships, as well as childhood maltreatment.  In the study, males experienced more stressors than females; overall, 30% of study participants experienced no stressful life events, 25% experienced one, 20% experienced two, 11% experienced three, and 15% experienced four or more life stressful events.  These results themselves did not have any statistically-significant relationship to the 5-HTT allele genotypes.  17% of study participants were classified as having experienced depression, a level comparable to the results seen in the general population in the U.S.  When these results were compared with the genotypes of the study participants, a statistically-significant correlation (P = 0.02) was found between depression and the presence of the "s" allele, i.e., individuals bearing at least one "s" allele ("s/l" and "s/s" individuals) were more likely to be depressed as a consequence of equivalent numbers of life stressful events.  The authors were careful to emphasize that this correlation did not show a conclusive association between the "s" allele and a predisposition to depression, however.

    This study was widely hailed as providing new insight into predicting depression, at least in young adulthood.  The study garnered accolades such as "absolutely spectacular" work, and Steven Pinker opined that the study provided "successful documentation of the elusive phenomena known as 'gene-environment interactions,' [which] are like the weather, according to Mark Twain:  Everyone talks about them, nobody does anything about them — until now."  The study results also seemed consistent with what was known about neurobiology, in that the serotonin transporter is the target for antidepressants like Prozac®, and was also consistent with other research results that showed more intense brain reactions to fearful stimuli in individuals bearing the "s" allele.

    Jcv061709 However, the correlation between stress-induced depression and the short promoter of the human HTT gene has not held up.  As widely reported on Tuesday, Neil Risch at the University of California, San Francisco and colleagues at the National Institutes of Mental Health, Johns Hopkins University, Yale University School of Medicine, the Rockefeller University, the University of Pittsburgh School of Medicine, and Virginia Commonwealth University showed no statistically-significant link between depression and the short HTT allele.  The study, published yesterday in the Journal of the American Medical Association (see "Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression") was a meta-analysis of data accumulated for 14,250 participants of 14 separate studies from the medical literature and a second meta-analysis of 10,943 participants from 10 of these studies.  These statistical analyses by Risch and his colleagues failed to show any increased susceptibility to depression as a result of environmental stressors as reported by the Caspi study for individuals bearing the short promoter variant of the HTT gene in either homozygous (s/s) or heterozygous (s/l) genotypes.  Although these studies are not without their own acknowledged shortcomings, they cast doubt on the validity of the correlations reported six years ago from a much smaller sample size (albeit the earlier study presented more in-depth assessments on the existence, frequency, and significance of the environmental stressors).

    These results could not have come at a worse time for Dr. Caspi and his collaborators.  These scientists filed a patent application on their predictive method, published as U.S. Publication No. 2005/0037405.  On May 19th, the U.S. Patent and Trademark Office mailed a Notice of Allowance to the inventors, for claims including the following:

    1.    A method for assessing predisposition to depression in a human sub
    ject who has experiences a stressful life event, the method comprising the steps of
        determining whether the subject carries one or more copies of a short promoter allele of a 5-HTT gene; and
        concluding that the subject is predisposed to depression if the subject carries the short promoter allele.

    At a minimum, the Risch study may have raised a Rule 56 obligation on the inventors, their counsel, and anyone else involved in prosecuting the application that could forestall allowance of this claim.  The results also may raise validity issues of operability and enablement.

    There has been justifiable skepticism by some about the capacity for genetic analyses to predict complex behaviors (see, for example, Hamer, 2002, "Rethinking Behavior Genetics," Science 298: 71-72).  These most recent results illustrate once again how difficult it will be to translate the promise of personalized medicine into clinically-validated diagnostic tests, particularly for complex or multigenic traits and diseases.  Of course, these problems make patent protection even more important to support investment in the uncertain promise of personalized medicine.