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					WISTA                                                                                                       DECEMBER 2007

   From the Desk of Chairman                                                        IPR Biotechnology :        Part 8 - 48

        Microarray, a novel genetic platform being widely used to bridge the gap between gene sequence and function, is
   an orderly arrangement of known or unknown DNA samples attached to a solid support. It provides a versatile tool
   for utilizing information from the human genome project to benefit human health and help study how large number of
   genes interact and how a cell’s regulatory networks control vast batteries of genes simultaneously. The microarray
   technologies allow for rapid access to molecular pathways, and have found broad use in diagnosis and prognosis of
   disease, better understanding of drug action, and better therapeutic strategies.

       The Special Feature in the present issue of the WISTA: IPR Biotechnology highlights the ways DNA microarray
   sequence capture technology can be utilized, and the many new informatics approaches being developed to analyse
   data generated by microarray studies. It provides a broad review of microarrays and gives briefs on key patents that
   could shape the industry in the days to come.

       The ‘Perspective’ deals with "Special Protocol Assessment (SPA)", a declaration from the US Food and Drug
   Administration (FDA) that an uncompleted Phase III trial’s design, clinical endpoints, and statistical analyses are
   acceptable to support regulatory approval. It is binding upon the FDA unless a substantial scientific issue essential to
   determining safety or efficacy is identified after the testing commences.

       Cytokinetics, Inc, founded in 1998, is a development stage biopharmaceutical company, engaged in discovery,
   development, and commercialisation of small molecule drug therapeutics for the treatment of cardiovascular diseases
   and cancer. “On to Excellence” profiles Cytokinetics and its various areas of operation.

       Other features covered are: Scan Around the Globe; Watch-Out IPR; In Focus; Strategic Alliances; Clinical Trials;
   Business Trend; and Legal Scene.
       We welcome comments and suggestions.

                                                                                                       Dr K V Swaminathan

                                                                                             RESEARCH & ANALYSIS TEAM
    • From the Desk of Chairman [P 2 ]
    • Scan Around the Globe: Antioxidant Fruits (Australia); Eisai's New Marketing         Mr S R Adige        Principal Advisor
      Subsidiary (Belgium); Genome Analysis of Fungi (Finland); Europe's Drug
                                                                                           Dr Shelley Lahiri        Consultant
      Discovery Hub (Germany); Intravenous Anaesthetic (Japan); Fluorescent Protein
      (Russia); Worldwide Rights for Multiferon® (Sweden)[P 3- 4]                          Mr S S Kalra             Director
    • Watch-Out IPR: Adjunct Chemotherapy; European Patent for Testosterone
      Gel; Green Fiber Laser; Nanofluidics Patent; Novel Surgical Adhesives; Nucleic       This     publication     aims    at
      Acid Sequences in Urine; US Patent for VIAject; Viruses for Treatment of Cellular    disseminating information on
      Proliferative Disorders. [P 5 - 6]                                                   pertinent developments in its
    • Perspective: Special Protocol Assessment. [P 7]                                      specific field of coverage. The
    • In Focus: Adult Stem Cell Regulation; Blood Typing Test; Evolution of Unique         information published does not,
      Human Traits; Genetic Code of Elephantiasis Worm; Genetic Lab Test for               therefore, imply endorsement of any
      Warfarin Sensitivity; Immune Response of Flies; New Way to Identify Enzymes;         product/process/ producer or
      Real-Time PCR System. [P 8 -9 ]                                                      technology by WITT.
    • Strategic Alliances: Agreement on Recombinant Human Insulin; Bristol-Myers
      Squibb Acquries Adnexus; Collaboration for Cancer Drug; Global Collaboration
      on Drug Reactions; GNS Collaboration with CombinatoRx; License Agreement             Editor : Dr K V Swaminathan
      to Develop Glufast; Marketing Approval for Elaprase; Wyeth Acquires Haptogen.        Printed and Published by
      [P 10 - 11]                                                                          Dr K V Swaminathan on behalf of
    • On to Excellence: Cytokinetics, Inc. [ P 12]                                         Waterfalls Institute of Technology
    • Special Feature: Microarray Sequence Capture Technology. [P 13 - 15]                 Transfer, J-29 South Extension Part I,
    • Clinical Trials: ARRY-380's Phase I Trial; Phase 2 Trial of Marqibo®. [P 16]         New Delhi - 110 049.
    • Bussiness Trends: Novartis' Singapore Biotech Plant; Xencor Expands Inves-
      tor Base. [P 16]                                                                      Printed at Sagar Printers
    • Fine Tuning: MutS Recognition. [P 17]                                                 1880 Udaichand Marg,
    • Legal Scene : Adenoscan Patent Lawsiuts Settled; Alma Denies Infringement Claims;     Kotla Mubarakpur,
      Diazepam Patent Case; Merck Faces Joint Lawsuit; Mylan Settles Patent Case; Patent    New Delhi - 110 003.
      Infringement Lawsuit; UROXATRAL Patent Challenge. [P18 - 19]

VOL 9 ISSUE 6                                                    1                                 IPR BIOTECHNOLOGY
                                                                                                   IPR BIOTECHNOLOGY
WISTA                                                                                                    DECEMBER 2007

                                                                    Genome Analysis of Fungi
                                                                         Mikko Arvas, a research scientist at the University
                                                                    of Helsinki, has compared in his thesis the genomes of
  Antioxidant Fruits                                                mould and yeast fungi. He has also developed
      Twelve native Australian fruits that are exceptional          computational and laboratory methods for analysing
  sources of antioxidants have been identified, according           the expression of the genome of Trichoderma reesei
  to the journal Innovative Food Science & Emerging                 fungus. Mould fungi are used for producing enzymes and
  Technologies. The fruits: Kakadu plum, Illawarra plum,            other proteins. Enzymes are generally used in industrial
  Burdekin plum, Davidson’s plum, riberry, red and                  food, pulp, textile and energy processes. Characteristics
  yellow finger limes, Tasmanian pepper, brush cherry,              of biomass can be modified with the help of enzymes, eg,
  Cedar Bay cherry, muntries and Molucca raspberry;                 in bleaching of jeans or paper. The Trichoderma reesei
  were compared with blueberries (cultivar Biloxi), a fruit         mould is especially known for its capability to produce
  renowned for its high antioxidant properties. Food
                                                                    proteins efficiently.
  Science Australia’s research team leader said that unique
  food ingredients and flavours with health-promoting                    Arvas compared computationally the genomes of
  properties are key market requirements.                           mould and yeast fungi. The yeasts have half smaller
       While Australian native fruits have been eaten by            genomes than moulds and they produce less proteins.
  indigenous people for thousands of years, this is the first       The dissertation improves understanding of fungal
  scientific study of the fruits as a source of antioxidants.       genomes and the relationships of genomes and external
  This research supports CSIRO (Commonwealth Science                characteristics i.e. phenotypes of fungi. This is important
  and Industrial Research Organisation) efforts to realise          to successfully modify the genomes of fungi in order to
  the potential of Australia’s fledgling native food industry       enhance their protein productivity. Arvas developed
  which is currently estimated to be worth $14 million              computational and laboratory methods to study gene
  annually.                                                         expression and tested how these can be applied for
      (Australia – Medical Science News, Aug 5, 2007)               Trichoderma reesei. In addition, he studied gene
  Eisai's New Marketing Subsidiary                                  expression of fungi in conditions relevant for protein
                                                                    production. He noticed novel expression responses that
      Eisai Co, Ltd. announced that the company has                 can partly explain the good protein productivity of the
  established its pharmaceutical marketing subsidiary,              fungi Trichoderma reesei.
  Eisai SA/NV in Belgium. Eisai SA/NV is owned by Eisai
  Europe Limited and serves Benelux (Belgium,                           (Finland – University of Helsinki, Oct 17, 2007)
  Netherlands and Luxembourg), the sixth largest market
  region in the EU. Eisai SA/NV started marketing activities        Europe’s Drug Discovery Hub
  in all three Benelux countries with focus on the anti-
  epileptic drugs Zonegran(R) and Inovelon(R), as well as               Hamburg is fast becoming a leading hub of Europe’s
  the non-opioid severe chronic pain agent Prialt(R). In            academic drug discovery. European ScreeningPort a
  addition, Eisai SA/NV plans to start its Alzheimer’s              company established with the support of the German
  disease treatment Aricept(R) in Belgium and                       Federal Ministry of Education and Research, the Free
  Luxembourg with its co-promotion partner.                         and Hanseatic City of Hamburg, will operate a state-of-
                                                                    the-art drug discovery service centre.
      Eisai SA/NV is the company’s ninth marketing
  subsidiary in Europe. It brings the total number of                   Hamburg’s new European ScreeningPort will build
  countries where Eisai undertake sales and marketing               upon research results generated in academia. It will
  operations through its own distribution channels to 17,           enable a more systematic and efficient search for promising
  including the United Kingdom, France, Germany, Italy,             new compounds which can subsequently be further
  Spain, Switzerland, Sweden, Ireland, Austria, Denmark,            developed. This novel concept in advancing drug
  Finland, Norway, Portugal, Iceland, Belgium,                      discovery will also be supported with considerable funds
  Netherlands, and Luxembourg.
                                                                    from the German Federal Ministry of Education and
               (Belgium – Eisai Co. Ltd, Sep 28, 2007)              Research.

IPR   BIOTECHNOLOGY                                             2
WISTA                                                                                                      DECEMBER 2007

      ScreeningPort provides the missing link in Europe              bodies of small animals. The new imaging agent will allow
 between academic research and the pharmaceutical                    biologists to monitor the progression of diseases like
 industry. The research centre will accelerate translating           cancer noninvasively and over time in live animals.
 promising results generated in basic research on the
                                                                          Fluorescent proteins have been a basic tool for
 causes of diseases into new therapeutics. It will act as a
                                                                     biologists since the early 1990s, allowing them to track
 service provider that enables academic research institutes
                                                                     the molecular activity of cells in lab dishes and of tissues
 to access its state-of-the-art technology, its vast amount
                                                                     just beneath the skin of mice and other animals. But even
 of chemical compounds as well as its sample and data
                                                                     with the best of these red, green, and yellow light-
 processing capabilities. New therapeutic concepts
                                                                     emitting proteins, researchers haven’t been able to see
 developed at universities can, in future, undergo the
                                                                     deep inside the bodies of live, whole animals. The new
 same standardised, more efficient and thus more cost-
                                                                     red protein was developed by Dmitriy Chudakov of the
 effective development processes that have, until now,
                                                                     Shemiakin-Ovchinnikov Institute of Bioorganic
 been available only to industry. ScreeningPort is planned
                                                                     Chemistry, Moscow, which is part of the Russian
 to be at the heart of an international network.
                                                                     Academy of Sciences.
     (Germany – Pharmaceutical News, Sep 4, 2007)                         Biologists can use the glowing proteins in two ways.
 Intravenous Anaesthetic                                             First, they can engineer organisms that produce the red
                                                                     dyes in conjunction with another protein. This allows
     Ono Pharmaceutical Co Ltd, has obtained from                    them to track the movement of cells during the
 CeNeS Pharmaceuticals plc the exclusive rights in Japan             development of the embryo and the movement of tumor
 to develop and commercialize CNS-7056 developed                     cells during cancer progression and treatment. Second,
 by CeNeS as a general anaesthetic and short-acting
                                                                     biologists can join the red proteins to antibodies that bind
 sedative. Under this agreement, Ono will pay to CeNeS
                                                                     to specific target molecules in the body, such as biomarkers
 upfront and milestone payments based on development
                                                                     on the surface of cancer cells. These targeted imaging
 stage as well as royalties on sales of CNS-7056.
                                                                     proteins can be injected intravenously to spotlight
      CNS-7056 is a new short-acting general anaesthetic             specific cells.
 and sedative that acts on GABAA receptors. Pre-
                                                                             (Russia – Technology Review, Aug 28, 2007)
 clinical studies demonstrate that, after intravenous
 administration, the compound rapidly induces deep                   Worldwide Rights for Multiferon(R)
 sedation which is maintained during continuous                          Swedish Orphan International is a Swedish company
 administration. Importantly the sedative effects rapidly            specialized in the development, distribution and marketing
 disappear after cessation of administration. The rapid              of ”orphan drugs” (pharmaceuticals for treatment of
 offset of effect of the compound is due to its metabolism           serious and rare diseases) in Europe. The company has
 by esterase enzymes that are widely distributed                     since April 2007 the distribution rights for Multiferon®
 throughout the body. Therefore, it is anticipated that              in most European countries.
 CNS-7056 can be clinically developed as a sedative
                                                                          Multiferon is a unique product which potentially is
 agent for the induction and maintenance of anaesthesia
                                                                     lifesaving for a significant number of patients. The
 and as a sedative for mechanical ventilation in the Intensive
                                                                     pharmaceutical company Swedish Orphan International
 Care Unit (ICU). CeNeS plans to start a Phase I study
                                                                     AB took over the assets in ViraNative AB, a biotech
 in the USA in the first half of 2008 and Ono plans to start
                                                                     company based in Umeå, Sweden. ViraNative AB filed
 a Phase I study in Japan as early as the second half of
                                                                     for bankruptcy in September and Swedish Orphan
                                                                     International acquired the bankruptcy estate. Through
        (Japan – CeNeS Pharmaceuticals plc, Aug 07,                  the take over Swedish Orphan International acquires the
                                             2007)                   worldwide rights for the drug Multiferon®, approved in
                                                                     Sweden for the treatment of malignant melanoma, and
 Fluorescent Protein                                                 ensures future supply of the drug to patients across the
     Russian researchers have developed a bright-red                 world.
 fluorescent protein that can be seen from deep within the                        (Sweden – BioSpace.com, Oct 26, 2007)

                                                                 3                                 IPR     BIOTECHNOLOGY
WISTA                                                                                                     DECEMBER 2007

                                                                        Bentley’s licensee-Auxilium Pharmaceuticals, Inc.
                  WATCH - OUT IPR                                   successfully launched this testosterone gel in the United
                                                                    States in early 2003 under the brand name Testim®, and
                                                                    the product now commands nearly 20 percent of the US
  Adjunct Chemotherapy                                              market for topical testosterone replacement therapy.
       Helix BioPharma Corp. has announced the issuance             Testim has been approved for marketing in Canada and
  of its second DOS47 patent (US Patent # 7, 264,800)               15 EU countries including Belgium,              Germany,
  from the United States Patent and Trademark Office.               Greece, Ireland, Portugal, Spain, Sweden and the United
  The patent describes a method and composition for                 Kingdom, and has received scientific approval in Italy.
  combining targeted DOS47 therapeutics with weakly                 This European patent significantly strengthens and extends
  basic chemotherapeutic drugs in adjunct treatment                 the intellectual property          franchise protecting
  applications. This patent offers a significant extension          Bentley’s drug delivery technology.
  to Helix’s DOS47 intellectual property position,
  opening up the possibility for expanded commercial                       (Bentley Pharmaceuticals Inc, Aug 29, 2007)
  opportunities. With the grant of this second DOS47                Green Fiber Laser
  patent, Helix now has patent protection covering the
  use of targeted DOS47–based therapeutics alone                        Zecotek Medical Systems Inc. announced that it has
  and in certain combined chemotherapy applications.                completed the development of a break-through Green
  Moving forward, the company intends to pursue                     Fiber Laser that operates in all known wavelengths of the
  the development of DOS47 therapies for both                       green spectral range. The company has filed a patent
  applications, with a view to maximizing its DOS47                 application with the US Patent Office, covering the
  commercialization potential.                                      unique intellectual property related to the Green Fiber
                                                                    Laser. Limited production will begin immediately, with
       L-DOS47 combines Helix’s proprietary DOS47                   ramp up to large scale manufacture expected to begin in
  new drug candidate with a highly specific single domain           January 2008.
  antibody, to form a potential new targeted drug product
                                                                        Applications for the Green Fiber Laser series include
  for the treatment of adenocarcinoma of the lung, the most         replacement of existing lon Gas and DPSS (diode
  common form of cancer in the world today. L-DOS47                 pumped solid state) lasers used in both industrial and
  is thought to function by leveraging a natural process in         scientific applications as well as new technological niches
  the body called the urea cycle, to produce an anti-cancer         based on the advantages of Zecotek’s fiber laser system.
  effect. It is based upon a naturally occurring enzyme             Zecotek has initiated sales discussions with a number of
  called urease that essentially reverses the urea cycle by         potential customers in different industries ranging from
  breaking down urea into metabolites that include                  bio-instrumentation (DNA sequencing, flow cytometry,
  ammonia and hydroxyl ions. By doing so at the site of             scanning laser microscopy); and fundamental research
  cancerous tissues in the body, L-DOS47 is believed to             (spectroscopy, fluorescent analysis). The new laser
  modify the microenvironmental conditions of lung                  series performs exceptionally well in existing operating
  cancer cells in a manner that leads to their death.               wavelengths: 515, 521, 529, 531, 532 nm. But, due to
                                                                    proprietary functionality, Zecotek has extended the
               (Helix BioPharma Corp., Sep 19, 2007)                operating range to include 532-560 nm offering new
  European Patent for Testosterone Gel                              opportunities in advanced applications.
       Bentley Pharmaceuticals, In, a specialty                             (Zecotek Medical Systems Inc, Aug 8, 2007)
  pharmaceuticals company said that the European
  Patent Office has issued a patent, No. 1425019 entitled           Nanofluidics Patent
  “Pharmaceutical Composition,” that provides coverage                  BioNanomatrix has announced the issuance of a
  for the pharmaceutical composition process and method             patent for a key element of the company’s whole genome
  of use of testosterone as a gel as well as other androgens,       analyzer. The patent covers a novel technique for the
  incorporating Bentley’s CPE-215® drug delivery
                                                                    integration of nanofluidic channels with sample delivery
  technology. The new European patent provides
                                                                    systems, enabling single molecules of DNA, RNA or
  proprietary protection to Bentley for 20 years from the
  date of filing.                                                   other proteins to be separated out from standard

IPR   BIOTECHNOLOGY                                             4
WISTA                                                                                                        DECEMBER 2007

 laboratory samples for direct imaging and analysis. The              Nucleic Acid Sequences in Urine
 technology makes possible the isolation and
 linearization of intact multi-megabase DNA in a                          Xenomics, Inc. has announced the issuance of its first
 standardized format for molecule-by-molecule gene                    European patent “Methods for detection of nucleic acid
 haplotyping, mapping and sequencing applications.                    sequences in urine”. EP 1634966 A2 covers use of its
                                                                      proprietary transrenal nucleic acid technology in the area
      The issuance of this fundamental broad patent is a              of prenatal diagnostics and genetic testing. Transrenal
 major milestone for BioNanomatrix. Single molecule                   nucleic acids are fragments of DNA and RNA from cells
 analysis of DNA and other proteins is central to the                 dying throughout the body that cross the kidney barrier
 unprecedented capabilities of company's whole genome                 from blood to urine and can be used for genetic analysis.
 analytic platform. This new patent covers company’s                  Early gender detection will be the first application of
 unique ability to integrate nanofluidic channels into
                                                                      transernal DNA (Tr-DNA) technology for prenatal
 company’s sample delivery systems, enabling its
 NANOANALYZER (R) system to rapidly and efficiently                   diagnostics. Using a new proprietary method for isolation
 separate out genomic length DNA from conventional                    of Tr-DNA, Xenomics scientists successfully detected
 laboratory samples and direct it into nanoscale channels             sequences of a single copy Y chromosome-specific SRY
 for live, continuous molecule-by-molecule analysis.                  gene in urine of women pregnant with male fetuses from
                                                                      the 6th week of pregnancy.
      The NANOANALYZER is an integrated system
 that for the first time enables pan-genomic identification                                     (Xenomics, Inc, Aug 6, 2007)
 and analysis on a molecule-by-molecule basis, delivering             US Patent for VIAject
 single molecule sensitivity in a highly parallel format. It is
 designed to provide ultra high-resolution analyses of                     Biodel Inc, has received US patent for VIAject and
                                                                      VIAtab. VIAject (TM) is a rapid-acting injectable
 DNA, RNA and other proteins more rapidly,
                                                                      human insulin intended for meal-time use by patients with
 comprehensively and cost effectively than currently
                                                                      Type 1 or Type 2 diabetes. In Phase I and II clinical trials,
 available approaches, with potential applications in                 VIAject (TM) has been shown to have a more rapid
 diagnostics, personalized medicine and biomedical                    onset of activity than those reported for the existing
 research.                                                            rapid-acting insulin analogs. As a result, VIAject (TM)
                        (BioNanomatrix, Sep 25, 2007)                 may be safer, require a lower doses and promote weight
                                                                      loss when compared to currently marketed meal-time
 Novel Surgical Adhesives                                             insulins.. VIAject (TM) is currently being tested in two
                                                                      pivotal Phase III clinical trials, which are comparing the
      Cohera Medical, Inc., a rapidly growing medical
                                                                      effect of VIAject (TM) to Humulin (R) R, the leading
 device company developing a suite of novel surgical                  recombinant human insulin. VIAtab (TM) is a sublingual
 adhesives, has been awarded a US patent on its                       tablet formulation of insulin, currently in Phase I clinical
 innovative surgical adhesive. The technology, developed              trials. VIAtab (TM) demonstrated encouraging safety
 at the University of Pittsburgh, provides a platform for             and pharmacokinetic profiles in Phase I clinical testing.
 strong, resorbable adhesives for use inside the body.
                                                                                                    (Biodel Inc, Sep 28, 2007)
     Cohera’s first product, TissuGlu™ , is currently in
 pre-clinical testing and is designed to adhere tissues               Viruses for Treatment of Cellular Proliferative
 to prevent fluid accumulation in deep wounds. Cohera                 Disorders
 has also won a Phase 1 SBIR Award for the design and
 development of a bioresorbable bone adhesive for                          Oncolytics Biotech Inc. has been granted US patent
 orthopedic use. This award, for $130, 000, is the                    entitled “Viruses for the Treatment of Cellular Proliferative
 company’s second SBIR award this year. In addition to                Disorders.” The claims cover the use of modified herpes
 the patent and funding secured by the SBIR Award,                    simplex viruses (HSV) to treat cellular proliferative
 Cohera Medical also has secured the talents of a key                 disorders which include neoplasias (cancers). This patent
 regulatory affairs professional with deep roots in the               expancds company’s intellectual property portfolio in
 medical device sector.                                               viruses other than reovirus.

                    (Cohera Medical Inc, Aug 2, 2007)                                 (Oncolytics Biotech Inc, Aug 7, 2007)

                                                                  5                                 IPR     BIOTECHNOLOGY
WISTA                                                                                                    DECEMBER 2007

                                                                  B. Modernization Act Provisions for Meetings and
                    PERSPECTIVE                                   Agreements on Clinical Trials
                                                                      Section 119(a) of the Modernization Act amends
  SPECIAL PROTOCOL ASSESSMENT                                     section 505(b) of the Act (21 U.S.C. 355(b). New
  Introduction                                                    section 505(b)(4)(B) of the Act directs FDA to meet
                                                                  with sponsors, provided certain conditions are met, for
      A Special Protocol Assessment (SPA) is a                    the purpose of reaching agreement on the design and
  declaration from the Food and Drug Administration               size of clinical trials intended to form the primary basis of
  (FDA) that an uncompleted Phase III trial’s design,             an efficacy claim in a marketing application submitted
  clinical endpoints, and statistical analyses are                under section 505(b) of the Act or section 351 of the
  acceptable for FDA approval.                                    Public Health Service Act (42 U.S.C. 262).
       It is intended to provide guidance to industry on          C. Focus of The Guidance
  procedures adopted by the Center for Drug Evaluation
                                                                      Sections 505(b)(4)(B) and (C) of the Act and the
  and Research (CDER) and the Center for Biologics
                                                                  PDUFA goals describe the Agency’s plan for evaluating
  Evaluation and Research (CBER) for evaluating issues
                                                                  certain protocols and working towards, and achieving,
  related to the adequacy (e.g., design, conduct, analysis)
                                                                  agreement with sponsors and applicants on the design
  of certain proposed studies associated with the
                                                                  and size of studies and clinical trials that can be used for
  development of products in human drug applications
                                                                  approval of a drug or biological product.
  as defined in section 735(1) of the Federal Food,
  Drug, and Cosmetic Act (the Act) (21 U.S.C. 379g(1))            Procedures for Requesting Special Protocol
  (PDUFA products). This guidance implements section              Assessment
  119(a) of the Food and Drug Administration                          The procedures for regulating special protocol
  Modernization Act (the Modernization Act) by                    assessment are described below.
  describing procedures sponsors should use to
  request special protocol assessment and the Agency              A. Timing of Request
  should use to act on such requests. For the purposes                CDER and CBER generally recommend that a
  of this guidance document, the term sponsor includes            sponsor submit a protocol intended for special protocol
  any sponsor or applicant interested in special                  assessment to the Agency at least 90 days prior to the
  protocol assessment.                                            anticipated start of the study. The protocol should be
                                                                  complete, and enough time should be allowed to discuss
  A. PDUFA Goals for Special Protocol Assessment
                                                                  and resolve any issues before the study begins. Special
      In conjunction with the reauthorization of the              protocol assessment will not be provided after a study
  Prescription Drug User Fee Act of 1992 (PDUFA) in               has begun. The Protocols are:(1) Carcinogenicity
  November 1997, FDA agreed to specific performance               Protocols, (2) Stability Protocols, (3) Clinical Protocols.
  goals (PDUFA goals) for special protocol assessment             B. Format of Request
  and agreement.
                                                                       A sponsor should submit each protocol for
       The PDUFA goals for special protocol assessment            assessment. The submission cover letter should
  and agreement provide that, upon request, FDA will              clearly identify the submission as a REQUEST FOR
  evaluate within 45 days certain protocols and issues            SPECIAL PROTOCOL ASSESSMENT in bold block
  relating to the protocols to assess whether they are            letters at the top and should clearly state the type of
  adequate to meet scientific and regulatory                      protocol being submitted (i.e., carcinogenicity, stability,
  requirements identified by the sponsor. Three types             or clinical).
  of protocols related to PDUFA products are eligible
  for this special protocol assessment under the PDUFA            C. Where to Send a Request
  goals: (1) animal carcinogenicity protocols, (2) final              The request should be submitted to the appropriate
  product stability protocols, and (3) clinical protocols         review division in CDER or applications division in
  for phase 3 trials.                                             CBER.

IPR   BIOTECHNOLOGY                                           6
WISTA                                                                                                   DECEMBER 2007

                                                                    Blood Typing Tests
                       IN FOCUS
                                                                        The US Food and Drug Administration has
                                                                    licensed 15 new blood typing tests that were
 Adult Stem Cell Regulation                                         previously unavailable in the United States. These tests,
     Forsyth Institute scientists have discovered an                known as blood grouping reagents, are used to
 important mechanism for controlling the behavior of                determine the blood type of blood donors, an essential
 adult stem cells. Research with the flatworm, planaria,            step in ensuring safe blood transfusion for patients. If
 found a novel role for the proteins involved in cell-to-cell       mismatched blood is administered to a patient, it may
 communication. This work has the potential to help                 cause a serious and potentially fatal reaction. To
 scientists understand the nature of the messages that              prevent such problems, people must receive compatible
 control stem cell regulation, such as the message that             blood based on the results of blood typing tests.
 maintains and tells a stem cell to specialize and to become            The newly approved ALBAclone Blood Grouping
 part of an organ, eg liver or skin.                                Reagents include the common ABO and Rh tests,
     In recent years, planarians have been recognized as            plus tests for rare blood types. The reagents are
                                                                    monoclonal antibodies, highly specific antibodies that
 a great model system to molecularly dissect conserved
                                                                    ensure product uniformity and availability. The
 stem cell regulatory mechanisms in vivo. Planarians
                                                                    reagents are manufactured by Alba Bioscience, Inc.
 have powerful regeneration capability that makes                   of Durham, NC.
 them ideal for studying this process. The Forsyth team
 uses planarians and other animal models to study                                 (Pharmaceutical News, Sep 17, 2007)
 development and regeneration.                                      Evolution of Unique Human Traits
      The Forsyth team previously found that                             Researchers from the University of Colorado Health
 communication through gap-junctions (microscopic                   Sciences Center, along with colleagues from Stanford
 tunnels directly linking neighboring cells) controls the           University, report the results of a large-scale, genome-
 left-right asymmetric positioning of the internal organs           wide study to investigate gene copy number differences
 during embryonic development. In this study, they turned           among ten primate species, including humans. The study
 to the role of gap junctional signals as regulators of adult       provides an overview of genes and gene families that
 stem cells in repair of injury.                                    have undergone major copy number expansions and
     Dr Oviedo and Dr Levin of Forsyth team focused on              contractions in different primate lineages spanning
 direct cell-cell transfer of small molecules and ions as           approximately 60 million years of evolutionary time. In
 crucial signals that determine behavior of adult stem              the report the scientists speculate how unique, lineage-
 cells in vivo. They showed that when one of many                   specific gene copy number expansions and contractions
 specific gap junction channel types was abolished, the             in humans may underlie traits such as endurance running,
 adult stem cell pool disappeared along with the                    higher cognitive function, and susceptibility genetic
 regenerative capabilities, suggesting that gap junction-           disease.
 permeable signals are necessary to maintain stem cell
 state and tissue regeneration. This research demonstrates              Primates first appeared on earth approximately
 a novel role for gap-junction proteins and suggests gap            90 million years ago, and today, about 300 different
 junction-mediated signaling as a new and tractable                 species of primates exist. One of the main genomic
 control point for adult, somatic cell regulation.                  driving forces in primate evolution is gene duplication.
                                                                    This study is the most comprehensive assessment of
      Most recent work in the stem cell field has focused           gene copy number variation across human and non-
 on the secreted protein factors that control embryonic             human primate species so far.
 stem cell differentiation. However, no specific gap junction
 protein had been functionally linked to adult/somatic                             (Medical Science News, Aug 1, 2007)
 stem cell behavior in vivo or to organ regeneration. This          Genetic Code of Elephantiasis Worm
 work demonstrates that gap junction channels providing
 direct cell-to-cell communication are a critical component             More than 150 million people worldwide are infected
                                                                    with filarial parasites long, thread-like worms that can
 for development and normal physiology.
                                                                    live for years inside the human body and cause severe,
                       (Forsyth Institute, Aug 3, 2007)             debilitating diseases, such as elephantiasis. Mosquitoes

                                                                7                               IPR     BIOTECHNOLOGY
WISTA                                                                                                          DECEMBER 2007

  spread the larvae of these parasitic nematodes from                   interests of self-preservation, it is just as important to
  human to human, placing at risk more than a billion                   turn the immune system off to avoid damage to oneself
  people who live in places in Africa, Asia and Latin                   by “friendly fire.” The fruit fly Drosophila has served as
  America where filarial parasites thrive.                              a good model for the induction of an innate immune
      A team of researchers funded by the National Institute            response, pointing to conserved pathways and
  of Allergy and Infectious Diseases (NIAID), one of the                mechanisms. Recent work shows that the fly’s immune
  National Institutes of Health (NIH), has solved the                   response is more subtly regulated and produces a
  complete genome of Brugia malayi, one of the worms                    wider range of responses than was thought possible
  that causes the often debilitating disease elephantiasis.             even just a few years ago.
  The B. malayi gerome reveals dozens of potential new
  targets for drugs on vaccines for treating the disease.                                (Medical Science News, Sep 4, 2007)
                  (Medical Science News, Sep 23, 2007)                  New Way to Identify Enzymes
  Genetic Lab Test for Warfarin Sensitivity                                    Two Massachusetts General Hospital (MGH)
                                                                        researchers have found a way of creating novel enzymes
       The US Food and Drug Administration cleared for
                                                                        that, for the first time, does not require prior understanding
  marketing a new genetic test that will help physicians
                                                                        of exactly how the enzymes work. Scientists used a
  assess whether a patient is especially sensitive to the
                                                                        technique called mRNA display that allows the
  blood-thinning drug warfarin (Coumadin), which is used
                                                                        identification and amplification of proteins that fit
  to prevent potentially fatal clots in blood vessels. Research
                                                                        particular criteria. In order to create an enzyme that
  has shown that some of the unexpected response to
                                                                        would stimulate or catalyze the joining of two segments
  warfarin depends on variants of two genes, CYP2C9
                                                                        of RNA in a way that does not occur naturally, they
  and VKORC1. The Nanosphere Verigene Warfarin
                                                                        began by generating a library of 4 trillion small proteins
  Metabolism Nucleic Acid Test detects some variants of
                                                                        with slight variations in their sequences. Each protein was
  both genes.
                                                                        then brought together with the RNA segments to be
     Warfarin can be a difficult drug to use because the                joined, called substrates. If a particular protein induced
  optimal dose varies depending on many risk factors,                   the RNA substrates to join, that signified the protein was
  including a patient's diet, age, and the use of other                 an active enzyme. They could select larger RNA strands
  medications. Rapidly achieving the correct dose is
                                                                        and generate more of the enzymes.
  important. Patients who receive doses that are higher
  than needed to correctly thin the blood are at risk of life-             (Massachusetts General Hospital, Sep 15, 2007)
  threatening bleeding. Those who receive doses that are
                                                                        Real-Time PCR System
  too low may remain at risk of life-threatening blood clots.
  Warfarin is the second most common drug, after insulin,                   The new 96-well StepOnePlus™ Real-Time PCR
  implicated in emergency room visits for adverse drug                  System from Applied Biosystems provides both new
  events.                                                               and experienced researchers with a highly-functional,
       In August, FDA approved updated labeling for                     easy to use and cost-effective way to conduct real-time
  Coumadin, the brand name version of warfarin,                         PCR experiments. The StepOnePlus System, equipped
  explaining that people with variations of the genes                   with fluorophore detection chemistries, including
  CYP2C9 and VKORC1 may respond differently to the                      FAM™/SYBR® Green I, VIC®/JOE™, ROX™,
  drug. FDA cleared the test based on results of a study                and TAMRA™ dyes, performs both standard and fast
  conducted by the manufacturer of hundreds of DNA                      thermal cycling for any real-time PCR application, such
  samples as well as on a broad range of published                      as gene expression analysis, SNP genotyping, gene
  literature. In a three site study, the test was accurate in all       detection and viral load analysis.
  cases where the test yielded a result.
                                                                            All users benefit from the space-saving small
                              (www.fd.gov, Sep 18, 2007)
                                                                        footprint of the system. The StepOnePlus System
  Immune Response of Flies                                              expands the family of real-time PCR systems offered by
     The immune response is actively turned on to target                Applied Biosystems for laboratories of all sizes.
  and destroy foreign infectious elements, but in the                                     ( Applied Biosystems, Sep 16, 2007)

IPR   BIOTECHNOLOGY                                                 8
WISTA                                                                                                    DECEMBER 2007

                                                                   approximately $75 million, in three increments of
           STRATEGIC ALLIANCES                                     approximately $25 million each, in the event certain
                                                                   development and regulatory milestones are achieved.
                                                                   The closing of the transaction is subject to customary
 Agreement on Recombinant Human Insulin                            regulatory approvals. Adnectins are a proprietary class
     Millipore Corporation announced an expansion of               of targeted biologics developed by Adnexus.
 its agreement with Novo Nordisk to provide the                    PROfusion(TM) is Adnexus’ proprietary protein design
 biopharmaceutical market with recombinant human                   engine, with which trillions of protein variations can be
 insulin, a key cell culture supplement used to manufacture        engineered at one time. Angiocept is an Adnectin designed
 biologic drugs. Under the terms of the agreement,                 to be an anti-angiogenic drug and is currently in Phase I
 Millipore will have exclusive worldwide rights to                 development.
 market and sell Novo Nordisk’s recombinant human                     (Bristol-Myers Squibb & Adnexus Therapeutics,
 insulin, branded by Millipore as Incelligent (TM) SG and                                             Sep 25, 2007)
 Incelligent (TM) AF, for cell culture media applications.
                                                                   Collaboration for Cancer Drug
 The two insulin products are manufactured in separate
 and independent facilities thereby offering greater                    Kosan Biosciences Incorporated announced that
 supply chain security to customers. Cell culture                  Roche and Kosan are concluding their epothilone
 supplements are products that help engineered cells to            development and commercialization collaboration. The
 efficiently produce the proteins that are the basis of            collaborative research, development and
 biologic drugs. The use of animal-free supplements                commercialization agreement entered into in September
 reduces risk and eases regulatory concerns for                    2002 will terminate after a transition period, following
 biopharmaceutical manufacturers. The current long-                which Kosan will re-acquire worldwide rights to its
 term supply agreement between Milliopre and Novo                  epothilone program and have full control of clinical
 Nordisk was extended for several years and ensures that           development of KOS-1584 and its other epothilone
 biopharmaceutical manufacturers will have a guaranteed,           product candidates going forward. Roche believes that
 secure supply of insulin to use in the production of              KOS-1584 is worthy to proceed into Phase 2 clinical
 biologic drugs and the development of new cell lines.             trials, and that the Roche-Kosan collaboration has been
                                                                   highly productive. Kosan has been an excellent
               (Millipore Corporation, Aug 17, 2007)               development partner.
 Bristol-Myers Squibb Acquires Adnexus
                                                                               (KOSAN Biosciences, Inc, Aug 29, 2007)
      Bristol-Myers Squibb and Adnexus Therapeutics
 have signed a definitive agreement under which Bristol-           Global Collaboration on Drug Reactions
 Myers Squibb will acquire privately held Adnexus                        The London School of Hygiene and Tropical
 Therapeutics, developer of a new therapeutic class of             Medicine is to be a key player in the first global research
 biologics called Adnectins. The acquisition of Adnexus            collaboration aimed at identifying the genetic markers
 will help advance Bristol-Myers Squibb’s biologics                related to Adverse Drug Reactions (ADRs). The Serious
 strategy across multiple therapeutic areas and includes a         Adverse Event Consortium (SAEC) is a non-profit
 Phase I oncology biologic, Angiocept. Adnexus                     global partnership between leading pharmaceutical
 Therapeutics will become a subsidiary of Bristol-Myers            companies, drug regulatory authorities and academic
 Squibb and remain based in Waltham, Massachusetts.                institutions aimed at identifying genetic markers that
     Under the terms of the agreement, Bristol-Myers               may help to predict which patients are at risk from
 Squibb will acquire all of Adnexus’ issued and outstanding        adverse or serious drug reactions (ADRs). It will provide
 shares of capital stock and stock equivalents in an all-          a global knowledge base about these genetic variations
 cash transaction for a gross purchase price of $430               and will be a major step forward in the drive to develop
 million, with the net purchase price being $415 million           and deliver safer medicines. ADRs are important causes
 after deducting Adnexus’ net cash balance at closing. In          of illness, limit the usefulness of many otherwise effective
 addition, there is an earn-out structure which could result       drugs, and are under strong genetic influence. Identifying
 in Bristol-Myers Squibb paying an additional amount of            the genetic variants that may influence a patient’s

                                                               9                                 IPR     BIOTECHNOLOGY
WISTA                                                                                               DECEMBER 2007

  susceptibility to ADRs will greatly improve company’s        Marketing Approval for Elaprase
  understanding of the risk and molecular basis of
  adverse drug reactions.                                           Genzyme Corp has announced that it has received
                                                               approval to market Elaprase (idursulfase) in Japan for
                (Pharmaceutical News, Sep 28, 2007)            the treatment of Hunter syndrome. Elaprase is an enzyme
  GNS Collaboration with CombinatoRx                           replacement therapy developed by Shire Human Genetic
                                                               Therapies Inc., and Genzyme is commercializing the
      Gene Network Sciences, Inc. (GNS) has entered            product in Japan and other Asia Pacific countries under
  into an agreement with CombinatoRx, Inc (CRXX) to            an agreement with Shire. Genzyme intends to launch
  contribute to ongoing mechanism of action research for       Elaprase this quarter, following reimbursement approval.
  synergistic combinations in development.                     Hunter syndrome, also know as Mucopolysaccharidosis
       Under the agreement, the parties will use protein       II (MPS II), is a rare, life-threatening genetic condition
  expression and transcriptional profiling data generated      mainly affecting males that results from the absence or
  by CRXX and the GNS proprietary REFSTM (reverse              insufficient levels of the lysosomal enzyme iduronate-2-
  engineering and forward simulation) software platform        sulfatase. Without this enzyme, cellular waste products
  to characterize unanticipated mechanisms underlying          accumulate in tissues and organs which then begin to
  the synergistic interactions between the components of       malfunction, leading to severe clinical complications and
  multi-target therapeutic candidates. Combination effects     early mortality.
  are often caused by non-obvious interactions between
  biological targets and signaling pathways that can be            Under its agreement with Shire, Genzyme will record
  uncovered using the REFSTM technology. This is the           product sales in the region and allocate approximately
  second agreement that GNS has announced in the               one-third of net sales to Shire. Genzyme will make a
  critical area of understanding drug combinations and         $3 million milestone payment to Shire in recognition of
  synergies in 2007. Earlier this year, GNS entered into an    Japanese marketing approval, and it will make a
  agreement with Well Cornell Medical College to               $4 million milestone payment upon reimbursement
  characterize the synergies between two commonly used         approval.
  classes of cancer drugs, farnesyl transferase inhibitors
  and taxanes.                                                                         (Genzyme Crop, Oct 7, 2007)

           (Gene Network Sciences Inc, Aug 3, 2007)            Wyeth Acquires Haptogen
  License Agreement to Develop Glufast
                                                                   Wyeth Pharmaceuticals, a division of Wyeth,
       Kissei Pharmaceutical Co Ltd, and Eisai Co Ltd,         announced the signing of a definitive agreement under
  announced the conclusion of a license agreement for          which it has acquired Haptogen Ltd, a Scottish company
  Glufast(R), a rapid-acting insulin secretagogue. In          based in Aberdeen that is focused on the discovery
  this agreement, Eisai gained the exclusive development       of biopharmaceutical therapies. This acquisition
  and commercialization rights of Glufast(R) in China          significantly increases Wyeth’s already robust
  from Kissei. Kissei is now conducting Phase III              biotechnology drug discovery capabilities.
  clinical trial for Glufast(R) in China. Eisai will market
  Glufast in China after Kissei has been granted importing         Haptogen has developed a number of technologies
  approval by the Chinese authorities. In June 2007,           that allow for the discovery and optimization of
  Kissei and Eisai had entered into a license agreement        protein therapeutics with significantly improved profiles
  for Glufast in 10 ASEAN countries.                           over the current generation of protein therapies. Such
       This strategic alliance between Kissei and Eisai in     benefits include the potential for more convenient
  China following ASEAN countries is expected to               routes of administration as well as cell and organ
  contribute to the improvement of health and healthcare       penetration, opening the opportunity to address
  for people worldwide.                                        diseases that are not treatable with the first generation
                                                               of protein therapeutics.
      (Kissei Pharmaceutical Co Ltd & Eisai Co Ltd,
                                     Aug 11, 2007)                           (Wyeth Pharmaceuticals, Oct 8, 2007)

IPR   BIOTECHNOLOGY                                       10
WISTA                                                                                                 DECEMBER 2007

                                                                candidates that have arisen from this program, ispinesib
              ON TO EXCELLENCE                                  and SB-743921, each a novel inhibitor of kinesin
                                                                spindle protein (KSP), a mitotic kinesin. Ispinesib has
 CYTOKINETICS, INC                                              been the subject of a broad clinical trials program
                                                                comprised of nine Phase II clinical trials as well as eight
 Introduction                                                   Phase I or Ib clinical trials. Cytokinetics plans to conduct
      Cytokinetics, Incorporated, was founded in 1998           additional clinical trials with ispinesib and is conducting
 by cell biology pioneers working to create a unique and        a Phase I/II trial of SB-743921 in non-Hodgkin’s
                                                                lymphoma. Under a strategic alliance established in
 powerful approach to drug discovery. It is headquartered
                                                                2001, Cytokinetics and GlaxoSmithKline (GSK) are
 in South San Francisco, California. The biopharmaceutical
                                                                conducting research and development activities
 company is dedicated to the discovery, development             focused on the potential treatment of cancer. GSK has
 and commercialization of novel classes of small-molecule       obtained an option for the joint development and
 therapeutics and focused to the field of cytoskeletal          commercialization of ispinesib and SB-743921,
 pharmacology. Its development efforts are directed to          exercisable during a defined period.
 advancing multiple drug candidates through clinical trials
 to demonstrate proof-of-concept in humans, specifically           Cytokinetics’ focus on the cytoskeleton enables it
 in the areas of heart failure and cancer. Its cancer           to develop novel and potentially safer and more
 program in focused to miotic kinesins, proteins essential      effective classes of drugs directed at treatments for
 to cell division.                                              cancer and cardiovascular disease.
     The cytoskeleton is a complex, dynamic framework
 that impacts all aspects of cell division, cell motility,         Cytokinetics and GSK are conducting collaborative
 intracellular transport, muscle ontractility and               research activities directed to the mitotic kinesin
 regulation of cellular organization. Cytoskeletal proteins     centromere-associated protein E (CENP-E). GSK-
 have been implicated in the etiology or pathogenesis of        923295, a CENP-E inhibitor, is being developed
 a wide variety of diseases, including cancer,                  under the strategic alliance by GSK. GSK began a
 cardiovascular disease, inflammatory disease and               Phase I clinical trial with GSK-923295 in 2007. All
 fungal, bacterial and viral infections.                        of these drug candidates have arisen from Cytokinetics’
                                                                research efforts and are directed towards the
      Cytokinetics’ cardiovascular disease program is           cytoskeleton.
 focused to cardiac myosin, a motor protein essential to
                                                                Drugs in Pipeline
 cardiac muscle contraction. Cytokinetics’ lead
 compound from this program, CK-1827452, a novel                    The company focuses on advancing multiple drug
 small molecule cardiac myosin activator, recently              candidates through clinical trials to demonstrate proof-
 entered Phase II clinical trials for the treatment of heart    of-concept in humans in two markets: cardiovascular
 failure in 2007. Under a strategic alliance established in     disease and cancer. As at Dec 31, 2006, company's
 2006, Cytokinetics and Amgen Inc. plan to conduct              drug development pipeline consists of CK-1827452,
 research with activators of cardiac myosin in order to         a drug candidate for the treatment of heart failure,
 identify potential treatments for patients with heart          which is being developed in an intravenous and oral
 failure. Amgen has obtained an option for the joint            formulation; as well as ispinesib and SB-743921 and
 development and commercialization of CK-1827452                its potential drug candidate GSK-923295 for the
 exercisable during a defined period, the ending of which       treatment of cancer. The drug candidates and potential
 is dependent on Cytokinetics’ conduct of further clinical      drug candidates are all novel small molecules that
 trials of CK-1827452.                                          arose from its internal research programs and are
                                                                directed toward the biology of the cytoskeleton.
 Cancer Program
                                                                   Cytokinetics continually updates the industry
     Cytokinetics’ cancer program is focused on mitotic         about their progress by presenting at the relevant
 kinesins, a family of motor proteins essential to cell         industry financial, partnering and scientific clinical
 division. Cytokinetics is developing two novel drug            conferences.

                                                           11                                 IPR     BIOTECHNOLOGY
WISTA                                                                                                     DECEMBER 2007

                                                                    Genetic Platform
                 SPECIAL FEATURE
                                                                         The recent sequencing of the human genome is a
                                                                    critical milestone that has provided a framework for the
  MICROARRAY               SEQUENCE             CAPTURE             identification of thousands of novel potential drug targets
  TECHNOLOGY                                                        and the common genetic factors that affect drug
  Introduction                                                      metabolism and toxicity. Microarrays represent a novel
       The confluence of biotechnology, computer                    genetic platform which is being widely exploited to bridge
  sciences and the completion of genome sequencing                  the gap between gene sequence and function. Microarray
  efforts for several organisms have led to revolutionary           technology has found broad use in the areas of disease
  changes in biomedical research. Genomics and                      diagnosis, pharmacogenomics and toxicogenomics, and
  informatics are playing increasingly important roles as           many opportunities continue to be created in the
  discovery tools in the basic biological sciences and as           marketplace.
  diagnostic and rational therapeutic aids in the clinical              Microarrays provide a method of quantifying the
  arena. The Human Genome Project is expected to                    expression and order of genes in a particular genome-
  lead to the identification of up to 50,000 human genes.           acting as a surrogate measure of cell physiology.
  One of the key technical platforms that has been                  According to scientists of Baylor College of Medicine
  developed to achieve this is microarray analysis. This            (BCM), microarray data are good phenotypes to
  highlights the ways in which DNA microarray
                                                                    determine the order of genes and are a good surrogate
  technology can be utilised in a wide range of
  approaches.                                                       measure of cell status. Microarrays are fairly new
                                                                    technology that can help scientists understand how
       In recent years, the synthesis or fabrication of             genes interact as well as how they are regulated by
  high-density arrays of specified DNA sequences
                                                                    networks within the cell. They are created by the
  comprising all known genes of an organism on a single
                                                                    placement of tiny droplets of functional DNA on glass
  galss slide or ‘chip’ have gained popularity. Labeled
  RNA or DNA targets such as messenger RNAs                         slides. Then researchers attach fluorescent labels to
  (mRNAs) obtained from cells, tissues or organisms                 nucleic acids (DNA or RNA) from the cells under
  under different conditions, can be analyzed by                    study. These labeled nucleic acids are allowed to bind
  hybridization on DNA. This technology allows                      to the DNA on the slides. Researchers then use a
  several types of questions to be asked on a                       microscope to measure how much of a specific nuleic
  qualitatively different scale than has been previously            acid is present.
  possible and will have a dramatic impact on the pace
                                                                         Genotype is the genetic fingerprint of a particular
  of discovery in the field of molecular medicine and
  drug discovery.                                                   cell. Phenotype is the outward manifestation of the
                                                                    genotype. For example, a person may have genes for
       Thedrugdiscoveryprocessseekstodevelopabiological             eye color. That is that individual's genotype. Blue
  or chemical entity that, when administered to a patient, will
                                                                    eyes is the phenotype. The microarray data Shaulsky
  improve the disease symptomatology or actually treat the
  underlyingpathophysiologicalbasisoftheparticulardisease           and his collaborators used, show that they can deter-
  state. A target is the biological entity, usually a gene, mRNA    mine the order in which genes act in a cascade that
  or protein, with which a pharmaceutical is designed to            results in a particular phenotype. Shaulsky et al
  interact. The completion of the human genome sequence             (BCM) performed their work in Dictyostelium
  has defined the genomic relationships between                     (Dictyostelium discoideum), a form of soil amoeba
  drug targets.                                                     used in the laboratory because many of its 10,000
       Gene expression profiling has been a mainstay                genes are homologues or equivalents of genes found in
  molecular biological approach for many years. The                 humans. Using microarray data alone, they
  availability of complete genome sequence information              determined the orders in which genes function in a
  along with improved technology has created a situation            particular pathway in that organism. The protein
  where these techniques can be applied in a much broader           kinase A (PKA) signaling pathway occurs when the
  manner, thereby facilitating profiling of large sections of       organism encounters starvation. The pathway enables
  the transcriptome.                                                the single cells to combine into a multi-cell organism.

IPR   BIOTECHNOLOGY                                            12
WISTA                                                                                               DECEMBER 2007

       Molecular Biology research evolves through the            According to the director of BCM this new technology
 development of technologies used for carrying them out.         will replace polymerase chain reaction (PCR) for many
 It is not possible to research on a large number of genes       purposes. The authors showed that the technique could
 using traditional methods. DNA microarray is one such           be used to discover variation in the human BRCA1 that
 technology which enables the researchers to investigate         have been implicated in a number of hereditary cancers,
 and address issues which were once thought to be non-           such as breast, ovarian and prostate cancer. The
 traceable. One can analyze the expression of many               researchers captured target sequences from Burkitt's
 genes in a single reaction quickly and in an efficient          Lymphoma cell line NA07671 DNA using high-density
 manner. DNA microarray technology has empowered                 oligonucleotide microarrays custom-made by Nimblegen.
 the scientific community to understand the fundamental
                                                                     After taking the DNA to hybridise it on the chip,
 aspects underlining the growth and development of life as
                                                                 everything that doesn't stick is washed away. This can
 well as to explore the genetic causes of anomalies
                                                                 enrich the portion of the genome to be studied by
 occurring in the functioning of the human body.
                                                                 factors of three hundred or more. After the non-
      In the microarray technology, single stranded DNA/         hybridised materials were removed from the array,
 RNA molecules are anchored by one end to the plate/             the captured sequences were sequenced using Roche/
 substrate. These molecules will seek to hybridize with          454 Life Sciences' Genome Sequencer FLX. The
 complementary strands floating in solution. The target          researchers found that the data generated were highly
 molecules are fluorescently labeled, so that the spots on       specific and that the downstream DNA sequencing
 the chip/array where hybridization occurs can be identi-        steps were 'consistently superior' to average perfor-
 fied. The strength of the detected signal somewhat              mance using non-captured DNA sources. The au-
 reflects the amount of stuff which binds to it, and thus the    thors attribute these improvements to the capture-
 amount of the target in solution. Such quantitative             enrichment process removing impurities that can cause
 expression data is not very reliable, however. More             problems during the first emulsion PCR step of the
 accurate data comes from comparing the relative amounts         454 sequencing process.
 of expressed DNA/RNA in two related samples, each of
                                                                     The second report entitled 'Microarray-based
 which is colored with a different fluorophore.
                                                                 genomic selection for high-through put resequencing'
 Sequence Capture Technology                                     used the MGS technique to capture and resequence
     Two new techniques (sequence capture) have                  two X chromosome-linked genomic regions. The
                                                                 researchers showed that large human genomic regions
 been developed that could signal the end of PCR
                                                                 on the order of hundreds of kilobases can be enriched
 (polymerase chain reaction) amplification for sequenc-
                                                                 and resequenced. They believe that when combined
 ing application and dramatically increase the                   with next-generation sequencing technologies such as
 efficiency of sample preparation. The methods pave              the 454 FLX and Illumina's Genome Analyser large-
 the way for cost-effective sequencing of individual             scale resequencing in single-investigator laboratories
 human genomes enabling large numbers of genomic to              would be possible at levels comparable to
 regions to be extracted from a sample before                    conventional genome sequencing centres.
 sequencing, enabling researchers to sequence only
                                                                      Another approach to multiplex amplification is
 the genomic regions of interest. The new techniques
                                                                 entitled 'Multiple amplification of large sets of human
 use microarray gene chips to capture and enrich
                                                                 exons' that uses programmable microarrays to release
 specific genes more efficiently than ever before. The
                                                                 the oligonucleotides used to capture and amplify the
 technique was launched by Human Genome Sequenc-
                                                                 DNA fragments. The programmable microarray
 ing Center (HGSC) scientists at BCM on 14th Octo-
                                                                 synthesises a library of probes that consist of a
 ber 2007. The study title was 'Direct Selection of
                                                                 universal 30 nucleotide motif flanked by 20 nucleotide
 Human Genomic Loci by Microarray Hybridization.'
                                                                 'targeting arm' segments that are designed to hybridise
     The first method uses a 'microarray-based genomic           immediately up and downstream of a specific genomic
 selection' method that removes the need for whole-              target. While the system worked with very high
 genome amplification using PCR techniques that can              specificity, the capture and amplification of target
 bias sequence results and lead to mutations being missed.       sequences was not uniform. They postulate that one

                                                            13                              IPR    BIOTECHNOLOGY
WISTA                                                                                                 DECEMBER 2007

  of the resons for this could be the hybridisation of the          'Identification of a large number of biological
  genomic DNA is inefficient due to the low                         (micro) organisms groups at different levels by
  concentration of targeting oligos on the arrays.                  their detection on a same array. The invention is
  Patent Scenario                                                   related to an identification and/or quantification
                                                                    method of a large number of biological organisms
    Till date there are 82 US patents on “sequence                  groups at different levels (family, genus, species)
  capture” technology. Some of the patents are mentioned            or part of those (possibly present in a biological
  below.                                                            sample) by a detection of their nucleotide se-
  • On November 6, 2007, Karaolis obtained the US                   quence.
    patent (No. 7,291,465), entitled ‘Method for direct         •   On January 23, 2007, Haynes, et al won the US
    detection of fungal pathogens’. The invention relates           patent (No. 7,166,436) on ‘Differential labeling for
    to the detection of pathogenic fungi in building mate-          quantitative analysis of complex protein mixtures’.
    rials.                                                          The invention relates to a method of simultaneously
  •   Rabbani, et al won the US patent (No. 7,264,930)              identifying and determining the levels of expression
      on September 4, 2007, entitled ‘Processes for non-            of cysteine-containing proteins in normal and
      linearly amplifying nucleic acids’. This invention            perturbed cells, a method for proteomic analysis, a
      provides novel processes for amplifying nucleic acid          process for preparing fusion proteins, and
      sequences of interest, including linear and non-linear        compounds and reagentsrelated thereto.
      amplification.                                            •   On February 22, 2005 US patent (No. 6,858,412)
  •   Linnen, et al got the US patent (No. 7,255,996)               was awarded to Willis, et al. The title of the invention
      on August 14, 2007, entitled ‘Compositions,                   was, 'Direct multiplex characterization of genomic
      methods and kits for detecting the nucleic acids of           DNA'. The invention is directed to novel methods of
      HIV-1 and HIV-2’. In the invention particularly               multiplexing nucleic acid reactions, including
                                                                    amplification, detection and genotyping. The
      described are oligonucleotides that are useful as
                                                                    invention relies on the use of precircle probes that are
      hybridization probes and amplification primers,
                                                                    circularized in the presence of the corresponding
      including cross-reacting hybridization probes and             target nucleic acids, cleaved, and then amplified.
      cross-reacting amplification primers, for
      detecting very low levels of viral nucleic acids.         •   US patent (No. 20050003366) on 'Method for
                                                                    reusing standard blots and microarrays utilizing
  •   On July 17, 2007 US patent (No. 7,244,570) was                DNA dendrimer technology'. The invention is
      awarded to Lane, et al. The patent was entitled               related to a mehtod for reuse of standard blots
      ‘Methods and composition for modulating                       and microarrays via removal of the capture reagent
      “marginally indiscriminate” hybridizations'. The              from the array, allowing multiple rounds of
      invention relates to methods and compositions for             experiments using the same blot or
      promoting the hybridization of a nucleic acid probe           microarray,without the need to remove the target
      with a target nucleic acid sequence which is not              molecules or the probe molecules attached to the
      perfectly matched to the probe.                               support.
  •   On May 1, 2007 Meyers, et al won the US patent            Conclusion
      (No. 7,211,392) on ‘2150, human protein kinase                The new process is simpler, more accurate and
      family member and uses therefor’. The invention           efficient than the multiplex PCR that was previously
      provides isolated nuclear acid molecules,                 used to sequence protions of the genome. In one
      designated 2150 nucleic acid molecules, which             experiment, more than 6,400 exons (the part of the
      encode novel protein kinase family members.               genetic code that carries the instructions for making
      Diagnostic and therapeutic methods utilizing              proteins), were analyzed. Using the old technology
      compositions of the invention are provided.               this would have taken at least six months. According
  •   Remacle, et al have got the US patent (No.                to director of HGSC, scientists will be able to use this
      7,202,026) on April 10, 2007 entitled                     technique to sequence all the exons in the genome.

IPR   BIOTECHNOLOGY                                        14
WISTA                                                                                             DECEMBER 2007

                CLINICAL TRIALS                                            BUSINESS TRENDS

 ARRY-380’s Phase 1 Trial                                    Novartis' Singapore Biotech Plant

      Array BioPharma Inc. is a biopharmaceutical                Swiss pharmaceuticals group Novartis AG
 company focused on the discovery, development and           will build a $700 million cell culture plant in
 commercialization of targeted small molecule drugs          Singapore to support its growing biopharmaceutical
 to treat life threatening and debilitating diseases.        business. Construction of the cell culture plant will
                                                             begin early next year and be completed by the end
    The company filed an Investigational New Drug            of 2012, Novartis said. The plant will employ
 (IND) application for ARRY-380 with the US Food             around 300 people.
 & Drug Administration and now plans to proceed
 with Phase 1 clinical trial in cancer patients. ARRY-           The Swiss firm made the announcement at the
 380, a selective, orally-active ErbB-2 inhibitor, has       opening of a $180 million tablet manufacturing
 shown good efficacy in preclinical models of                facility in the city-state, which is trying to boost its
 human breast cancer, resulting in significant anti-         biomedical industry.
 tumor activity.
                                                                Singapore Trade and Industry Minister said the
     Array plans to commence the Phase 1 clinical trial      Novartis cell culture plant will be the city-state’s fifth
 this fall in the United States and Canada. The open-        commercial-scale plant for biological-based products
 label, multiple dose study is designed to evaluate          such as vaccines and cells for gene therapy.
 safety, tolerability and pharmacokinetics of ARRY-
 380 following daily oral administration to patients              Singapore produced S$23.0 billion (US $15.84
 with advanced cancer.                                       billion) worth of biomedical products last year, up 30
                                                             percent from 2005, according to the Industry Minister.
                (Array BioPharma Inc, Aug 3, 2007)
                                                                                           (Reuters, Oct 29, 2007)
 Phase 2 Trial of Marqibo®
                                                             Xencor Expands Investor Base
     Marqibo, a novel, targeted, optisomal formulation
 of vincristine, has shown promising anti-cancer                 Xencor, a company developing protein and
 activity in patients with acute lymphoblastic leukemia      antibody therapeutics, announced that it has raised an
 (ALL), non-Hodgkin’s lymphoma, and melanoma in              additional $15 million in an extension of its Series E
 several trials. Hana Biosciences, a biopharmaceutical       financing, bringing the total raised in this round to $60
 company, focused on advancing cancer care,                  million. The first closing of $45 million occurred in
 announced the initiation of a multi-center, multi-          October 2006.
 national Phase 2 clinical trial of Marqibo® (vincristine
 sulfate injection, OptisomeTM) in adult patients with           New investors, Oxford Bioscience Partners and
 relapsed ALL, also known as the rALLy study.                Merlin Nexus, and existing investor Novo Nordisk
                                                             participated in the extension. Other investors that
    The company also plans to initiate a Phase 3             participated in the Series E included MedImmune
 randomized, multi-center trial comparing Marqibo to         Ventures, HealthCare Ventures and Zen Investments.
 vincristine in the induction, consolidation, and            This financing will be used to advance clinical and pre-
 maintenance phases of treatment in elderly patients with    clinical development of Xencor’s XmAb™ antibody
 newly diagnosed ALL.                                        drug candidates.

                              (BioSpace, Aug 3, 2007)                                      (Xencor, Oct 25, 2007)

                                                        15                                IPR    BIOTECHNOLOGY
WISTA                                                                                                    DECEMBER 2007

                                                                       In vitro, MutS recognizes mispaired bases and
                     FINE TUNING                                    unpaired bases, small DNA insertion/deletion loops of
                                                                    one to three (Whitehouse et al., 1997), four (Parker &
   This section attempts to fine-tune some basic                    Marinus, 1992) or five nucleotides (Stanislawska-
   concepts on a subject of interest about which one                Sachadyn et al., 2005). MutS also binds damaged
   might have already heard of. The current issue                   DNA, like DNA adduct.
   features "MutS Recognition".
                                                                       In eukaryotes, multiple MutS homologues have
                                                                    been identified: MSH1, MSH2, MSH3, MSH4, MSH5,
  MutS Recognition
                                                                    MSH6. Unlike the prokaryotic MutS, the yeast and
       The ability of many species to repair mismatches in          mammalian homologues have specialized roles.
  double-stranded DNA has been well documented. The
  first critical step in this process is the recognition of the     MutS Based Methods
  mismatched DNA. The proteins that mediate the                          In vivo, MutS recognizes premutational changes in
  mismatch repair pathway are conserved across several              genomic DNA. In vitro, mutation detection employing
  species from Escherichia coli to humans. As compared              MutS usually includes four step: PCR amplification of the
  to most of the known repair proteins that recognize only          DNA region containing a mutation, preparation of DNA
  a limited repertoire of DNA aberrations, MutS is more             heteroduplexes, formation of MutS-DNA complexes,
  versatile since it can identify and bind to seven out of eight    and detection of MutS-DNA complexes. The DNA
  mismatches as well as loops that occur within the DNA.            heteroduplex is prepared by mixing equimolar amount
  Mutations                                                         of an examined and a reference PCR product (without
                                                                    mutation), heating to denature DNA, followed by cooling
       Single nucleotide polymorphisms (SNPs) account               to renature it. The heating and cooling could be repeated
  for thousands of genetic diseases and neoplasms, which            several times to mix the examined and reference DNA
  are reported to afflict almost 40% of the human population.       properly. As the result, the DNA strands from the
  SNP detection and genotyping may be helpful in the
                                                                    reference DNA hybridize with the DNA strands from the
  diagnosis, therapy and prophylaxis of thousands of
  single gene disorders, numerous multifactorial diseases           examined DNA, thus forming DNA heteroduplexes. If
  and neoplasms. It also could be invaluable in the                 the examined DNA contains a mutation, the DNA
  prediction and elimination of drug side effects (Roses,           heteroduplex is mismatched. If heterozygotic alleles are
  2001). Although individual genetic disorders are rare,            examined (i.e.one allele contains a mutation, the other
  collectively they comprise over 15500 recognized                  does not), the addition of the reference DNA is not
  diseases. DNA sequencing is a gold standard to detect             necessary (Stanislawska-Sachadyn et.al., 2005).
  mutations, but the approach is relatively expensive and
                                                                         Formation of a MutS-DNA complex may be
  laborious. If a huge number of samples should be
                                                                    detected in many ways: direct microscopic observation
  examined, applying a cheap and rapid screening method
                                                                    of complexes using atomic force microscopy, AFM,
  could be useful to select the mutant samples for the
                                                                    the DNA mobility shift in electrophoresis, DNA
  sequencing analysis. Numerous solutions have been
                                                                    protection by MutS against nuclease digestion, the
  proposed to introduce a cheap, rapid and reliable method
                                                                    detection of MutS-DNA interactions on a solid phase,
  for mutation analysis, and it seem there is still a demand
                                                                    including filter assays with radioactive or biotin labeled
  for improvement. MutS, mismatch binding protein, a
                                                                    DNA, and on chip detection. The detection of MutS
  natural guard of replication fidelity, appears to be an
                                                                    was enabled by using fluorescent MutS or one fused
  excellent tool for the detection of point mutations.
                                                                    with reporter domains like a biotinylated tag or GFP.
       In vivo, MutS and other mismatch binding proteins,
  are the key elements of DNA repair systems, which
  trigger the sequence of events resulting in the correction             MutS seems to be a promising tool for SNP
  of the mismatched site. In the bacterial DNA repair               analysis. MutS fusion with enzymatic domains, like â-
  systems, the MutS binding to the DNA mismatch is the              galactosidase, is an especially interesting solution, as
  first signal. Then, the MutL protein joins MutS-DNA               it could increase the sensitivity of detection, hopefully
  complex and activates the MutH protein.                           enabling direct mutation detection in genomic DNA.

IPR   BIOTECHNOLOGY                                            16
WISTA                                                                                               DECEMBER 2007

                                                                   Alma Lasers continues to stand behind all of its
                  LEGAL SCENE                                  products and their warranties. Customers and
                                                               prospective customers can be assured that this dispute
                                                               will not impact their use of any Alma product.
 Adenoscan Patent Lawsuits Settled                                                  (Alma Lasers Ltd, Oct 15, 2007)
     Astellas Pharma Inc, King Pharmaceuticals, Inc.           Diazepam Patent Case
 and Teva Pharmaceutical Industries Ltd, announced that
 US subsidiaries of Astellas, along with Item Development         Barr Pharmaceuticals, Inc announced that its Barr
 AB and King have executed settlement agreements with          Laboratories, Inc subsidiary and Par Pharmaceutical
 one of Teva’s subsidiaries on lawsuits filed in the United    Companies, Inc have entered into a settlement agreement
                                                               regarding their joint patent challenge with Valeant
 States against Teva’s subsidiaries regarding their
                                                               Pharmaceuticals North America related to Valeant’s
 submission of an abbreviated new drug application
                                                               DIASTAT(R) diazepam rectal gel products.
 (ANDA) for a generic version of Adenoscan (adenosine
 injection), a pharmacologic stress agent.                          Under the terms of the settlement, Barr will have the
     Two lawsuits were filed by Astellas US LLC and            right to launch generic versions of DIASTAT(R) and
 Astellas Pharma US, Inc. in the US District Court in          DIASTAT (R) AcuDial(TM) on or after September 1,
 Delaware on May 26, 2005, one with co-plaintiff Item          2010, or earlier in certain circumstances. Barr will
 and the other with co-plaintiff King. Under the terms of      record sales of the products and split the profits with
                                                               Par. The settlement agreement reflects the terms
 the settlement agreement, Teva will be able to launch
                                                               previously agreed to in principle at a settlement
 their generic version of Adenoscan pursuant to a license
                                                               conference in June, 2007. The patent challenge was
 in September 2012, or earlier under certain conditions.       initiated by Kali Laboratories, Inc. (since acquired by
 Subject to the court’s approval, the cases will be            Par) and PLIVA Inc. (since acquired by Barr). Under
 dismissed and the patents remain in place including US        the terms of an earlier agreement between PLIVA and
 Patent No. 5, 731, 296, which expires in March 2015           Kali, Kali developed DIASTAT and PLIVA assumed
 and US Patent No. 5, 070, 877, which expires in May           responsibility for the litigation and its associated costs.
                                                                   DIASTAT(R) and DIASTAT(R) AcuDial(TM) had
     Adenoscan(R) (adenosine injection), licensed and          combined sales of approximately $75 million for the
 sold by Astellas in the US, is a pharmacologic stress         twelve months ended August 2007, based on IMS sales
 agent indicated as an adjunct to thallium-201                 data. The product is indicated for the management of
 myocardial perfusion scintigraphy in patients unable          selected, refractory, patients with epilepsy, on stable
 to exercise adequately. Astellas is the exclusive licensee    regimens of anti-epileptic medications (AEDs), who
 of the US use patents with regard to adenosine                require intermittent use of diazepam to control bouts of
 injection owned by King and Item and has marketed             increased seizure activity.
 Adenoscan in the US since 1995.                                        (Barr Pharmaceuticals, Inc., Oct 15, 2007)
                  (Astellas Pharma Inc, Oct 23, 2007)          Merck Faces Joint Lawsuit
 Alma Denies Infringement Claims                                   The drug company Merck is facing joint action from
                                                               New York State and New York City over the millions
     Alma Lasers Ltd has filed a response denying all          which were spent on health programs related to the drug
 Lumenis’ patent infringement claims. Alma Lasers will         Vioxx. Vioxx was withdrawn from the market in 2004
 vigorously defend its position. Previously, Lumenis           because of the dangerous side effects of the pain
 tried to enforce two of the same patents it is now            medication among long-term users. The state and city
 asserting against Alma in a lawsuit against another           governments want to be reimbursed for the millions of
 company and failed. With respect to those two patents,        dollars they spent on prescriptions for the arthritis drug
 a federal district judge denied Lumenis’ Motion for           which they say would never have been written if doctors
 Preliminary Injunction, and questioned the validity of        had been properly informed of the risks.
 a Lumenis asserted claim in a published opinion.                  The lawsuit claims Merck deliberately withheld
 Lumenis ultimately settled that case before trial.            information regarding the side effects of Vioxx which

                                                          17                                IPR     BIOTECHNOLOGY
WISTA                                                                                                  DECEMBER 2007

  include a vastly increased risk of heart attacks and           than November 1, 2008, if the FDA does not grant UCB
  strokes. They maintain the company therefore defrauded         pediatric exclusivity.
  the state’s medical program, which paid for the
                                                                                              (Mylan Inc., 7 Oct, 2007)
  government-sponsored prescriptions. State Attorney
  General says even as the evidence was piling up showing        Patent Infringement Lawsuit
  just how dangerous the drug was, Merck put profits                 CryoCath Technologies Inc., the global leader in
  above all else.                                                cardiac arrhythmia products to treat cardiovascular
      Andrew Cuomo, State Attorney General, says the             disease, announced it has filed against CryoCor, Inc. a
  drug company’s irresponsible and duplicitous conduct           patent infringement lawsuit in the United States District
  endangered the health of New Yorkers and wasted tax            Court for the District of Delaware.
  dollars; between 1999 and 2004 Medicaid and EPIC                    CryoCor makes and sells cryosurgical consoles,
  spent more than $100 million on Vioxx prescriptions in         catheters and related hardware and software, including
  New York State. The lawsuit which has been filed in the        its Cardiac Cryoablation System. The complaint charges
  New York State Supreme Court, seeks damages,                   CryoCor Inc. with infringement of several of CryoCath’s
  penalties and restitution for “tens of millions of taxpayer    United States patents related to console systems.
  dollars wrongfully spent on Vioxx prescriptions.”              CryoCath seeks injunctive relief from CryoCor.
                                                                         (CryoCath Technologies Inc., Oct 17, 2007)
      Merck is also facing thousands of lawsuits by former
  users of Vioxx who claim they were harmed by the drug
  and the company has also been sued by insurance                UROXATRAL Patent Challenge
  companies and HMOs seeking to be reimbursed for                    Barr Pharmaceuticals, Inc. has confirmed that its
  their costs for the drug. Merck claims it has acted            subsidiary Barr Laboratories, Inc, has initiated a challenge
  responsibly, from researching the drug prior to approval,      of the patents listed by Sanofi-Aventis US LLC in
  to monitoring the drug while it was on the market, to          connection with its UROXATRAL (alfuzosin
  voluntarily withdrawing the drug when it did.                  hydrochloride extended-release tablets), 10 mg.

                 (Pharmaceutical News, Sep 20, 2007)                  Barr’s Abbreviated New Drug Application (ANDA)
                                                                 containing a paragraph IV certification for a generic
  Mylan Settles Patent Case                                      UROXATRAL product was received as acceptable for
                                                                 filing by the US Food & Drug Administration (FDA) on
       Mylan Inc announced that it and its subsidiary Mylan      June 12, 2007, the first date the FDA could accept an
  Pharmaceuticals Inc have entered into an agreement to          ANDA with a paragraph IV certification for this
  settle pending litigation with UCB Society Anonyme and         product. Following receipt of the notice from the FDA
  UCB Pharma Inc (collectively, UCB) relating to                 that Barr’s ANDA has been accepted for filling, Barr
  Levetiracetam tablets, 250mg, 500mg and 750mg, the             notified the New Drug Application (NDA) and patent
  generic version of UCB’s Keppra. Litigation between            holder.
  Mylan and UCB has been pending in the US District                   On September 21, 2007, Sanofi-Aventis filed suit in
  Court for the Northern District of Georgia since March         the US District Court for the District of Delaware
  2004. The lawsuit involved US Patent No. 4,934,639,            (Wilmington) to prevent Barr from proceeding with the
  which expires on July 14, 2008.                                commercialization of its product. This action formally
                                                                 initiates the patent challenge process under the Hatch-
       Pursuant to the settlement, Mylan has the right to        Waxman Act. Barr understands other companies have
  market the 250mg, 500mg and 750mg strengths of                 filed an ANDA for alfuzosin hydrochloride extended-
  Levetiracetam tablets in the United States on November         release tables, and have been sued. UROXATRAL
  1, 2008, provided that UCB obtains pediatric exclusivity       (alfuzosin hydrochloride extended-release tablets) is
  for Keppra and Mylan’s abbreviated new drug application        indicated for the treatment of the signs and symptoms of
  (ANDA) obtains final approval from the Food and Drug           benign prostatic hyperplasia. The product had annual
  Administration (FDA). If granted, pediatric exclusivity        sales of approximately $140 million in the US based on
  relating to the ‘639 patent would extend to January 14,        IMS sales data ending July 2007.
  2009. Mylan’s entry into the market could come sooner                   (Barr Pharmaceuticals, Inc., Sep 26, 2007)

IPR   BIOTECHNOLOGY                                         18