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se, is usually filed very early in the develop- Chemical Compounds and Biologics ment process. Since the ultimate patent term (species IP exclusivity) is 20 years from the original filing date of the application, entity Developing Issues Relevant species-IP exclusivity is often substantially limited at the time (if and when) the entity to Market Exclusivity receives regulatory approval. BY PATRICK H. HIGGINS OF Biologics REGULATORY APPROVAL ECKERT SEAMANS Biopharmaceuticals, on the other hand, Human testing does not begin with any CHERIN & MELLOTT, LLC tend to be relatively large and complex gly- therapeutic entity before the filing and FDA cosylated proteins of secondary and tertiary approval of an Investigational New Drug conformation which are, in many ways, dif- application (IND).6 The IND application ficult to define structurally at the molecular contains preclinical data in pharmacology 2, 3 level. Nevertheless, biologics are gener- and toxicology, manufacturing information, ally defined in terms of function and exact as well as clinical protocols and investiga- starting materials (identity, features, and tor information. At that point, the entity sequences of nucleic acid constructs), the falls under the Federal Food, Drug, and This article originally appeared as a two- cell-line employed for synthesis, and exact Cosmetic Act (FDCA (21 USC §§301, 4 part series in Intellectual Property Today production conditions. In other words, in 321)) and becomes a new drug subject to (July & August 2011 issues) contrast to small molecule compounds, not requirements of the drug regulatory system. only are exact forms of a biologic difficult to define structurally, exact means of pro- Clinical Trials duction in fact frequently define what the Phase I clinical trials are conducted PHARMA / BIOPHARMA INDUSTRY biopharmaceutical is, per se. in a small group (20-100) of healthy individuals to determine dosage range, he drug-discovery industry is funda- duration of activity, and safety profile (nor- mentally based upon the development, R&D mally take from six months to one year). An R&D investment of about $1 bil- T regulatory approval, and prospect in Pharmacokinetic studies also examine how lion and 14 years is generally required to fact for a period of market exclusivity for a drug is absorbed, distributed, metabo- bring a new therapeutic entity to market.5 therapeutic entities, i.e., chemical com- lized, and excreted. Small molecule compounds are tradition- pounds and biologics. Since a total of Phase II clinical trials are placebo- ally developed by means of screening large controlled to establish efficacy and optimal about 14 years is generally required to compound collections or rational design at dosage. Phase II also takes between six bring a new therapeutic entity to market, the molecular level to identify or otherwise months and one year and usually involve the period of exclusivity afforded in terms generate a “lead” which exhibits pharmaco- 100 to 500 volunteer patients diagnosed IP and/or Regulatory is paramount in the logical/biological activity. Medicinal chem- with the prospective indication. business equation. Each of these classes ists then adjust and substitute atoms and Phase III randomized placebo-con- moieties on the lead structure to optimize of therapeutics, however, presents distinct trolled trials are then conducted to gener- activity and bioavailability while minimizing advantages as well as challenges to the ate statistically significant efficacy and toxicity. Similar to the rational design route industry. This article briefly reviews the side-effect data. These studies normally of small molecule compounds, biologics process and developing issues relevant to take one to four years involving 1,000 to tend to be directed to modulating specific market exclusivity characteristic of each 5,000 closely-monitored volunteer patients. biological mechanisms of human disease class of therapeutics. by having affinity to a specific biological NDA Small Molecule Compounds target. Biologics are generally constructed The NDA (New Drug Application (FDCA The Pharmaceutical Industry has histor- from portions of native entities including 505 (21 USC §355)) or BLA (Biological signal transduction molecules, receptors and ically been based upon highly characterized License Application (Public Health Service ligands, or are monoclonal antibodies which Act (PHS) §351 (42 USC §262)) is filed small synthetic organic molecules that are bind a specific site. Nevertheless, similar — seeking approval from the FDA upon easily reproduced. Indeed the Holy Grail to small molecule compounds, biologics in completion of clinical trials — if the small of the industry, until relatively recently, development frequently require many types molecule compound or biologic, respec- has been an efficacious small molecule of adjustments in production at the molecu- tively, is demonstrated to be both safe compound that exhibits high bioavailabil- lar level to maximize efficacy while minimiz- and effective.7 Typically 100,000 pages ity, low toxicity, a long biological half-life, ing side-effects. or longer, the NDA or BLA sets forth all is inexpensive to manufacture, and is free Patent Applications relevant to the of the studies, data and conclusions, i.e., of third party IP rights. Chemical species prospective therapeutic entity, production, preclinical testing, all clinical trials, dos- tend to be easily described in exact terms of formulations and methods of use, including ing information, manufacturing details and dosage and administration, are normally proposed labeling. definite structure and physical properties.1 filed throughout the development and regu- PHS emphasizes the importance of man- Importantly, once a compound structure is latory process. However, the original and ufacturing control for all biological entities known, regardless of the process, the spe- most important composition of matter disclo- and provides for a system of controls over cies can be reproduced. sure of the prospective therapeutic entity, per all aspects of the manufacturing process. 24 INTELLECTUAL PROPERTY TODAY JULY-AUGUST, 2011 PHS §351 defines “biological product” and ket the generic version (e.g., during appeal Section 351(k) of the PHS Act (42 USC how to obtain FDA approval to market a to the Federal Circuit).13 During the period §262(k)), added by the BPCI Act, describes biologic by issuance of a Biologics License. of exclusivity no other ANDAs can be filed. the general requirements for an Abbreviated Importantly, PHS was amended March Accordingly, significant incentive is pres- Biological Product Application (ABPA) 23, 2010 (BPCI Act), discussed infra, to ent for prospective generic manufacturers (§351(k) application) for a “biosimilar” and change the statutory authority under which to challenge pharmaceutical IP exclusivity. for a proposed “interchangeable” biosimilar. biologics are regulated by amending the a. New Chemical Entity exclusivity A biosimilar may be approved under new sec- definition of “biological product”. Section (NCE), provided by the Hatch Waxman tion 351(k) of the PHS Act if clinically dem- 351(i) of PHS is now amended to include a Act, grants a five (5) year period of regula- onstrated to be “highly similar” to a reference protein except any chemically synthesized tory exclusivity which comes into existence biopharmaceutical in terms of safety, purity polypeptide.8 upon approval of a new small molecule and potency. To meet the higher standard FDA NDA/BLA review requires about 14 compound.14 NCE exclusivity effects a 5 of “interchangeability,” a candidate biologic months. Fast Track, Accelerated Approval, year bar to ANDA submission and runs con- must be demonstrated to be expected to pro- and Priority Review FDA programs are current with any patent protection.15 duce the same clinical result as the reference available to reduce review time approxi- b. Supplemental NDA (sNDA) product in any given patient. mately in half. Nevertheless, a total of about exclusivity, also resulting from the Hatch BPCIA provides a maximum one-year twelve (12) years is generally required to Waxman Act, is a three (3) year bar to period of market-exclusivity incentive for obtain FDA approval, if at all, of a new ANDA approval awarded upon approval of a the first ABPA “interchangeable” biosimi- therapeutic entity. supplemental application for a new indica- lar (similar to the 180-day market-exclusiv- tion or formulation.16 New clinical investi- ity incentive provided to the generic drug 20 MARKET EXCLUSIVITY gation must be human studies conducted by industry under the Hatch Waxman Act). The discovery industry is fundamentally the applicant toward safety or effectiveness. i) 12 Years New Biologic Exclusivity based upon prospects in fact for a period of Supplemental NDA Exclusivity runs con- (NBE) market exclusivity, i.e., IP (patent) and/or current with any patent protection. Similar in concept to NCE under the regulatory exclusivity. 2. Orphan Drug Exclusivity Hatch Waxman Act, under BPCIA the (ODE).17 Orphan Drug Act (PL 97-414) biopharmaceutical industry is now afforded Regulatory Exclusivity 12-years NBE (data exclusivity) upon amended FDCA January 4, 1983 to create Regulatory exclusivity is effected by approval of a new biologic therapeutic an incentive for the drug discovery industry statutory barrier to FDA acceptance of a entity.21 Specifically, PHS Act §351(k) to address treatment of rare diseases and competing application or approval of a com- (7) now provides
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