Polymorphism and patents

Scientists do not deal in certainties, only in likelihoods. In mathematical terms, we deal in probabilities . Unlike most lawyers, we are not in the absolute business of proving something is true and another thing is false . Applied to our technological studies, we believe that this sort of lawyers language would take us into the realm of metaphysics because such categorical statements are not relatable to opinions derived from observations. (Smith 1993) 

Courts of law are not the optimal fora for trying questions of scientific truth... (Zenith Laboratories v. Bristol-Myers Squibb 1994) 

A patent is a social contract, known since the Middle Ages. According to the Oxford English Dictionary definition, it is 

Originally patents granted the right to sell, specifically tobacco, and were expanded to other commodities. Today s patents only give the right to exclude. As noted by Maynard and Peters (1991), 

Polymorphism presents interesting issues to patent systems. Since crystal modifications of a substance represent different crystal structures with potentially different properties, the discovery or preparation of a new crystal modification represents an opportunity to claim an invention that potentially can be recognized in the awarding 

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Cabri, W., Ghetti, P., Pozzi, G, and Alpegiani, M. (2007). Polymorphisms and patent, market, and legal battles cefdinir case studyQrg. Process Res. Dev., 11 64-72. 

Bernstein, J. Polymorphism and Patents from a Chemist s Point of View. In Hilfiker, R. (Ed.), Polymorphism In the Pharmaceutical Industry. Weinheim, Germany Wiley-VCH, 2006, Chapter 14. 

United States polymorph and solvatomorph patents issued during 2005 276... 

UNITED STATES POLYMORPH AND SOLVATOMORPH PATENTS ISSUED DURING 2005... 

The listing of patents published by the United States Patent Office was searched for polymorph and solvatomorph patents using the keywords polymorph(s), polymorphic, solvate(s), hydrate(s), crystal form(s), and crystal modification, and the following patents issued during 2005 were returned using these keywords. 

US patent 6,696,458, Compositions and formulations of 9-nitrocamptothecin polymorphs and methods of use thereof [101]. Amorphous forms of 9-nitrocamptothecin are obtained by grinding or pulverizing different polymorphic forms of 9-nitrocamptothecin, and the polymorphic forms are characterized by having an X-ray powder diffraction pattern with discernable diffraction lines at different scattering angles for Cu Ka radiation. 

US patent 6,723,728, Polymorphic and other crystalline forms cis-FTC [106], The present invention relates to polymorphic and other crystalline forms of (—)-and ( )-cA-(4-amino-5-fluoro-l-(2-(hydroxymethyl)-l,3-oxathiolan-5-yl)-2(lH)-pyrimidinone, or FTC) [106]. Solid phases of (—)-cz>FTC that were designated as amorphous (—)-FTC, and Forms II and III were found to be distinguishable from Form I by X-ray powder diffraction, thermal analysis properties, and their methods of manufacture. A hydrated crystalline form of ( )-cA-FTC and a dehydrated form of the hydrate, were also disclosed, and can similarly be distinguished from other forms of FTC by X-ray powder diffraction, thermal properties, and their methods of manufacture. These FTC forms can be used in the manufacture of other forms of FTC, or as active ingredients in pharmaceutical compositions. Particularly preferred uses of these forms are in the treatment of HIV or hepatitis B. 

US patent 6,753,426, Polymorph and process for preparing same [111], In this patent are disclosed are processes, a new polymorph, and intermediate compounds for preparing various aryl- and heteroaryl-substituted urea compounds. The product compounds are useful in pharmaceutical compositions for treating diseases... 

Polymorphism is critically important in the design of new drug API [9] and affects a number of areas. The main impact is to the bioavailability and release profile of a drug substance into the body. This is due to differences in solubility and dissolution rate, between the polymorphs. The chemical and physical stability of the formulated drug substance is also dependent on the polymorphic form. Patented registration of all discovered forms and their manufacturing conditions is an important element in protecting a pharmaceutical companies intellectual property. 

It is clear that kinetic effects must be utilized in the design of a process to make the commercially available Form A, because it is never the most thermodynamically stable form. Information from the literature and patents in reference [14] indicates that Form A can be successfully isolated from Acetonitrile, Acetone, Methyl isobutyl ketone, Toluene, the C2 to C4 alkenols, Ethanol, Methanol and Propan-2-ol. In these solvents it is likely that solvation is favourable to the nucleation rate of Form A or detrimental to crystal growth of the other forms, or both. For a new development compound there should be similar solvent interaction data available from polymorph screening experiments. 

The past nearly six decades have seen a chronological progression in molecular sieve materials from the aluminosilicate zeolites to microporous silica polymorphs, microporous aluminophosphate-based polymorphs, metallosilicate and metaHo-phosphate compositions, octahedral-tetrahedral frameworks, mesoporous molecular sieves and most recently hybrid metal organic frameworks (MOFs). A brief discussion of the historical progression is reviewed here. For a more detailed description prior to 2001 the reader is referred to [1]. The robustness of the field is evident from the fact that publications and patents are steadily increasing each year. 

Brand-name companies also have listed patents that claim a drug substance differing from the approved drug substance in some way. These patents generally fall into three subcategories metabolites, polymorphs, and intermediates. Each subcategory raises its own specific issues, as elaborated below. 

Besides regulatory importance, salts, polymorphs, and hydrates/solvates have clear novelty and patentability considering their different chemical compositions or distinguishable solid state ( fon Raumer et al., 2006). Those new forms can affect not only their processibilities, such as crystallization,Lltration, and compression, but also their biological properties, such as solubility and bioavailability. Besides, the manufacturing processes for those forms are often innovative, and thus patentable. 

The topic of polymorphism is of tremendous and increasing academic and industrial importance in modern crystal chemistry and crystal engineering. The industrial interest stems from the pharmaceutical industry and has stimulated wide-ranging academic study. Legally, a molecule (termed an active pharmaceutical Ingredient, API) with particular biological activity in vivo can be patented as a new invention. Moreover, particular crystal forms of that molecule (polymorphs) can be separately patented as distinct inventions. If particular polymorphs are patented after the original API patent then upon the... 

Cover Figure Raman spectra of two polymorphs of Cimetidine are shown on the cover Cimetidine is a pharmaceutical product that has six polymorphic forms and each form has a distinctive Raman spectrum as shown in Figure 4 25 of Chapter 4 (with permission of Ref 47). The particular polymorphic or crystalline form of a compound can be very important since the bio- availability and patent positions often depend upon the form Raman spectra can be used to easily identify the polymorphic form. 

As polymorphism has become an increasingly important factor in the commercial aspects of many solid materials, the number of patents relating to the discovery and use of particular polymorphic forms has increased. This is particularly important for pharmaceuticals, pigments and dyes, and explosive materials, which are discussed in Chapters 7-9. Some examples of the role of polymorphism in patent litigation are described in detail in Chapter 10. The patent literature is readily searchable using terms such as crystal form , polymorph etc., and since polymorphic behaviour often forms the basis of a patent (as opposed to many journal publications, where it may be peripheral to the main point of the paper) instances of polymorphism are relatively straightforward to locate. 

The key issues in the study of drug polymorphism are the identification of different polymorphs (from a regulatory and patent viewpoint as much as from a formulation one), the determination of polymorph stability, and the assessment of processing conditions on polymorph generation. Whereas DSC is widely used as a means of routine screening for polymorphs, it is by no means universally effective as a means of identification. For example, several studies have indicated that DSC shows very similar traces for the various polymorphs of cimetidine (e.g., 15) hence, the generation of apparently identical peaks is not a guarantee of the absence of different crystal modifications. In other cases, however, the differentiation between polymorphs may be more obvious. 

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