CRYSTAL GROWTH & DESIGN 2007 VOL. 7, NO. 7 1213-1215
PerspectiVe Crystals and Patents Francisco Lara-Ochoa* and Georgina Espinosa-Pe´rez Instituto de Quı´mica, UniVersidad Nacional Auto´ noma de Me´ xico, Circuito Exterior, Ciudad UniVersitaria, Coyoaca´ n, Me´ xico D.F., CP 04510, Me´ xico ReceiVed January 12, 2007; ReVised Manuscript ReceiVed April 5, 2007
ABSTRACT: The present analysis attempts to give to the authorities responsible for future patents revision a warning about the possible sources of misunderstandings concerning the concept of cocrystals. At the same time, it seeks to prevent scientists and lawyers responsible for cocrystal patent elaboration and submission from the causes of ambiguities that may provoke refusals or appeals to the authorities’ decisions. .. toute langue est un classement et (que) tout classement est oppressif,” “un idiome se de´ finit moins par ce que’il permet de dire que par ce qu’il oblige a` dire.1 The first meeting on cocrystals, a rediscovered field of crystal engineering, was organized by the Internatonal Quality and Productivity Center (IQPC) recently in Amsterdam. The main particularity of the meeting was the heterogeneous participation of attorneys at law, university academics in organic and inorganic chemistry and in new materials, and personnel from very different departments of the most important international pharmaceutical laboratories. All of them tried to establish a common definition for cocrystals and learn about the opportunities to develop new patents in the field, considering that 30% of the active pharmaceutical ingredients (APIs) marketed in the United States contain carboxylic groups that are capable of eliciting cocrystal formation. A half-day panel discussion was dedicated to defining cocrystals, while a full session and a oneday workshop were dedicated to the interpretation of patent law and applicability criteria for submissions, strategies, and achievements in the intellectual property issues of cocrystals. The Director of “Organic Chemistry and Methods” from the European Patent Office made a broad presentation on how the office is prepared to receive this new type of patent, of which until now only a few have been submitted in the U.S. Among the main issues on how the criteria of patentability will be applied, perhaps the concepts of inventive content (Article 82, European Patent Convention (EPC)) and novelty (Article 84, EPC) will be the most difficult points to surmount for patent approval, in comparison to other concepts, such as sufficient disclosure (Article 83, EPC) or clarity (Article 84, EPC). Article 52(1), EPC establishes that European patents shall be granted for any inventions that are susceptible of industrial * To whom correspondence should be addressed. Telephone: 52-5556224456. E-mail:
[email protected].
application, that are “new”, and that involve an “inventive” step. An invention, within the meaning of Article 52(1) (EPC) must be of both a concrete and a technical character (EPO Guidelines for Examination, Chapter IV, 2.1). The emphasis of the presentation by the EPO representative was that the technical effect of an alleged invention should be clearly proven to be accepted and that, in contrast to new enantiomers or new polymorphs, patentability for new cocrystals will be certainly easier. This is “mainly supported by the unpredictable practical advantages, and more rarely by structure originality or synthesis difficulty.” “New” refers to anything under the sun that is made by man (Diamond v. Chakrabarty, 447 US 303, 309; 206 USPQ 193, 197 (1980)), such as a new composition of matter or any new and useful improvement (35 USC & 101). Thus, a necessary condition to claim a new “composition” of matter is to describe clearly with precision the composition, a great challenge in the case of cocrystals. A definition generally accepted in the discussion panel on cocrystals was “crystalline entities with at least two different components constituting the unit cell and interacting by hydrogen bonds” (for alternative points of view on cocrystal definitions see for instance Desiraju2 and Zaworotko3). Nonetheless, the previous definition was appended with several exceptions, such as they are not “salts, where the strength of the interaction is so strong that the linkage is between two oppositely-charged ions (electrovalent bond; r-1 dependence).” However, this exception, included as an obvious part of the definition, does not strictly apply to those “salts” where the strength of the interaction is not so strong, and the linkage is difficult to differentiate from a hydrogen bonding (for a wide discussion on this topic see Desiraju4). Another exception to be added to the proposed definition was that cocrystallization should be understood to be different from coprecipitation, eutectic formation, solid solution, or dispersion. In light of the above-mentioned definition and incorporated exceptions, as a first approach, we can consider solvated
10.1021/cg070037w CCC: $37.00 © 2007 American Chemical Society Published on Web 05/15/2007
1214 Crystal Growth & Design, Vol. 7, No. 7, 2007
Perspective
Figure 3. sym-Triphenethynylbenzene‚sym-tris(perfluorophenethynyl)benzene complex calculated by the B3LYP method using the Spartan package. The starting coordinates were taken from X-ray experimental data.8
Figure 1. [(C60)(calix[5]arene)]‚toluene as calculated by the PM3 method, using the Spartan package. The coordinates were taken from X-ray experimental data.6
Figure 4. Some types of forces involved in the stabilization of cocrystals. HB is hydrogen bonding, VdW is van der Waals interactions, and π-π is π-π interactions.
Figure 2. 4,4′-Bipyridine‚1,4-diiodobenzene complex calculated by the B3LYP method, using the Spartan package. The coordinates correspond to X-ray experimental data.7
polymorphs, where each one has a specific crystalline array and where a solvate participates as a structural part of the unitary cell. Then, this type of compound, denominated also as pseudopolymorphs, is constituted by at least two components that interact with solutes by hydrogen bonds, conforming then to the above definition of cocrystals. A second case is solid pharmaceutical formulations, where it is known that, in many cases, the crystalline mixture of inert excipients establishes hydrogen bond interactions with the APIs, which favors its solubility and other properties.5 Another type of compounds is that in which two or more components are stabilized in a crystalline array by van der Waals interactions (r-6 dependence) (Figure 1), by halogen bonding (Figure 2), by π-π stacking interactions (Figure 3), etc. In consequence, the conditions of patentability discussed by the EPO authorities, mainly based on the technical effects or the unpredictable practical advantages of an alleged invention,
and considering the vagueness of the above-mentioned definition for cocrystals, could unchain a complexity of verdicts to the expected avalanche of patent submissions. Primarily, this could be based on the notion that a huge number of salt adducts and heterogeneous crystalline arrays of compounds stabilized by forces other than hydrogen bonds, or simply pharmaceutical compositions, will be patented as cocrystals. This would result in an onset of trials due to infringements of API patents if other criteriassuch as a precise description of the composition proven by physical data or reproducible parameters that are reliable and representative and that permit the discrimination of cocrystals from other types of crystalline arrayssare not applied as a central criteria (as of August 31, 2006, the list of decisions by the EPO Technical Board of Appeal concerning cocrystals was zero). Nonetheless, these criteria will be very difficult to apply given the vagueness of the definition, such as was proven in the mentioned meeting. Consequently, perhaps a good description for cocrystals may be the definition used during the meeting but modified here based on our arguments (illustrated in Figure 4). Acknowledgment. F.L.-O. gratefully acknowledges Laboratorios Silanes for sponsoring and supporting the travel expenses and registration fee to the conference, and Edith LaraMoreno for her invaluable help in the manuscript elaboration. References (1) Roland Barthes, cited by Lehn, J.-M. Supramolecular Chemistry; VCH: Weinhem, Germany, 1995; p. 9.
Perspective (2) (a) Desiraju, G. R. Cryst. Eng. Comm. 2003, 5, 466. (b) Dunitz, J. D. Cryst. Eng. Comm. 2003, 5, 506. (3) Zaworotko, M. J. Cryst. Growth Des. 2007, 7, 4, and references therein. (4) Desiraju, G. R. Acc. Chem. Res. 2003, 35, 565. (5) (a) Huang, W. X.; Desai, A.; Tang, Q.; Yang, R.; Vivilecchia, R. V.; Joshi, Y. Int. J. Pharm. 2006, 311, 33. (b) Alexander, K. S.; Riga, A. T.; Chatterjee, K. J. Pharm. Sci. 2003, 92, 747. (c) Govindarajan, R.; Zinchuk, A.; Hancock, B.; Shalaev, E.; Suryanarayanan, R. Pharm. Res. 2006, 23, 2454. (d) Nassab, P. R.; Rajko,
Crystal Growth & Design, Vol. 7, No. 7, 2007 1215 R.; Szabo-Revesz, P. J. Pharm. Biomed. Anal. 2006, 41, 1191. (e) Sarisuta, N.; Lawanprasert, P.; Puttipipatkhachorn, S.; Srikummoon, K. Drug DeV. Ind. Pharm. 2006, 32, 463. (6) Atwood, J. L.; Barbour, L. J.; Heaven, M. W.; Raston, C. L. Angew. Chem. Int. Ed. 2003, 42, 3254. (7) Walsh, R. B.; Padgett, C. W.; Metrangolo, P.; Resnati, G.; Hanks, W.; Pennington, W. T. Cryst. Growth Des. 2001, 1, 165. (8) Ponzini, F.; Zhaga, R.; Hardcastle, K.; Siegel, J. S. Angew. Chem., Int. Ed. 2000, 39, 2323.
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