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• Polymorph is the ability of a solid material to exist in more than one form or crystal structure. When a drug substance exists in polymorphic forms, it is said to exhibit polymorphism.
• Polymorphism can potentially be found in any crystalline material including polymers, minerals, and metals.
• Polymorph is a natural property: polymorphs are not ‘created’ or ‘invented’; they are discovered normally as part of routine experimentation related to drug formulation.
• The pharmaceutical sector is a major user of the Patent system. While only a small number of new chemical entities are approved annually, thousands of patents are applied for to protect variants of existing products, processes of manufacture or, where admitted, second indications of known pharmaceutical products.
• With rapid improvements in technology and drug development, keeping up to date with the latest pharmaceutical research and best practice approaches is an essential part of improving drug efficacy, safety and quality.
• Crystalline polymorphs• Single enantiomers• Second therapeutic use• Crystalline polymorphs• Complex molecules can crystallize in many ways:• Diamond, coal and carbon nanotubes are
different crystal structure of the same compounds.
• New polymorphs can have enhanced:• Stability and Shelf life• Improved production process and handling• Biovailability • Examples include: Ranitidine (Zantac®),
• Polymorphism is playing an increasingly important role in establishing and protecting IPR in the pharma industry. Many drugs receive regulatory approval for only a single crystal form or polymorph.
• Independent patent applications on polymorphs have become increasingly frequent and controversial, as patents thereon can be used to obstruct or delay the entry of generic competition.
• The preparation, prosecution and protection of patent involving polymorph are quite challenging.
• Some compounds present in polymorphic forms, i.e., they crystallize in diverse forms. Such forms can be deemed within the prior art and therefore not patentable. However, process patent may be allowed for the new polymorph, if the polymorph is prepared by a novel process involving inventive step.
• Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density.
• These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of the drug product.
• The significance of different polymorphs is almost entirely in their relative rate of dissolution.
• Clarity• A claim in the form of… crystalline form II of compound X
does therefore not comply with the requirement of clarity.• Polymorphs are defined in a claim by parameter values
which relate to the physical data used for defining their crystal structure.
• A polymorph is defined in a claim by its physiochemical parameters
• Ex: Single crystal X-ray diffraction, X-ray powder diffraction, IR spectroscopy
• Ex:• A crystalline tolterodine tartrate form I, characterized by
an x-ray powder diffraction spectrum having peaks expressed as 2.theta. at about 11.9, 13.6, 14.2, 15.9, 16.9, 18.4, 18.8, 20.4, 22.0, 23.9, 25.4, 26.3 and 29.8 degrees.
• The pharmaceutical company GlaxoSmithKline defended its patent for the polymorph type II of the active ingredient in Zantac against competitors while that of the polymorph type I had already
• Roche and Wockhardt• Roche got its first first pharma product
patent for Hepatitis Drug Pegasys in India in 2006. Its struggle over its patents started in 2007, when India’s first post grant opposition was filed by Wockhardt and a Mumbai based NGO for “IN198952” on Pegasys attacking its validity claiming it to be non-inventive and not satisfying Section 3d. Roche could taste success with its patent by defending it successfully by clearing the “enhanced efficacy” test in the Section 3d of the Indian Patent Act.
• Kolkata Patent Office issued an Indian Patent No. 225209 to Eli Lilly & Co. for crystalline non-solvated anhydrous Arzoxifene. Lilly had been fairly successful in prosecuting and convincing Indian Patent Office (IPO) for polymorph and salt patent applications.
To ensure availability of quality medicine at affordable price, patent system should be used judiciously. Indian Patent Act 1970 that was amended in 2005 has ensured that pharmaceutical companies do not misuse the patent system. Provision of effective safeguards and its appropriate implementation would ensure balance between incentive for innovation and access to affordable medicines.