At the conclusion of a report on a patent litigation involving the drug Viagra, the Economist quoted one of the attorneys involved as saying, "Forget horse racing, patent litigation is the true sport of kings." Indeed, patent cases involving drugs provide a meeting ground for issues involving science and the law, and the courtroom can serve as a true intellectual battleground. This non-technical lecture will cover a number of issues related specifically to litigations involving another major blockbuster drug, including excerpts from the courtroom proceedings.

The active pharmaceutical ingredient (API) in a solid drug product (pill or capsule) can exhibit a number of different crystal forms known as polymorphs and solvates (in a manner similar to carbon existing as diamond and graphite). In principle, each of these crystal forms can exhibit different physical, chemical and biological properties, meaning that its effectiveness as a drug can change with the crystal form. Thus each form can be a valuable source of intellectual property, either to protect a particular molecular entity, or to provide a means for circumventing the intellectual property of another party. In addition, regulatory agencies are increasingly demanding evidence for the understanding of the polymorphic behavior of a substance and control over the crystal form to be used in pharmaceutical applications.

Over nearly the last twenty years there has been a major increase in the awareness of the intellectual property implications and manifestations of the existence of multiple crystal forms, due in part, at least, to a number of high profile litigations involving some leading pharmaceutical products. The prosecution of these litigations involves the recruitment of expert witnesses, who are called by the opposing sides to inform the court of the scientific principles involved in the legal conflict as well as to provide evidence in support of the party that has retained them. The scientific issues often deal with fundamental questions on the definition of chemical and physical terms, the precision, accuracy and interpretation of various analytical methods employed in the identification and characterization of different crystal forms, and the similarities and differences in the modus operandi of scientists and lawyers. These discussions frequently involve legitimate differences in scientific opinion with the courts left to decide either on which side is "right", or perhaps which side is most convincing.

Examples of these issues will be given in the course of the lecture.

In its ultimate manifestation the aim crystal of engineering ¹, the subject of this symposium, is to prepare a designed or predicted crystal structure which is desirable because it is expected to exhibit specific properties. In spite of some noteworthy recent computational successes in the effort to predict crystal structures from the molecular formula ², it is still not possible to design the crystal structure(s) of any particular substance given simply its structural formula. Moreover, we have no way of prescribing a priori either how to prepare as yet undiscovered crystal forms or the properties that those new forms might exhibit. The unexpected appearance of a new crystal form, say of an API after the launch of a new drug, can be a regulatory and public relations disaster, while the serendipitous discovery of an improved crystal form in the early days of drug product development can be the key to a market success.

The recent piqued interest in co-crystals ³ has led to some impressive successes in preparing crystals of two or more components, but there still remains the considerable engineering challenge of designing and preparing crystal structures of systems with more than one molecular entity. That challenge can be partially met by utilizing particular hydrogen bonding patterns in the generation of specific structural features in co-crystals.

Some successes and some ?failures? in dealing with crystal engineering, polymorphs and co-crystals will be described, with all providing useful information for utilization and modification of the design strategy, the understanding and control of polymorphism in particular and crystal chemistry in general.

[1] G.R. Desiraju, Crystal Engineering-The Design of Organic Solids , Elsevier, Amsterdam, 1989;
[2] G.M. Day et al., Acta Crystallogr. Sect. B 2009;
[3] Ö. Almarsson and M.J. Zaworotko, Chem. Commun. , 2004, 1989.

Supported by U.S.-Israel Binational Science Foundation Grant 2004118.

For the drug manufacturer, the preparation of additional crystal forms either by systematic screening, by chance, or by serendipity can provide the opportunity for the modification and improvement of the solid state properties of the API, or it may result in a serious deleterious effect on the properties of the API. For competing drug companies, the preparation of a new crystal form may provide a path for early entry into the market by circumventing the patent covering the crystal form of the marketed API.

The questions of patentability and infringement are very much legal ones, but the legal outcome often depends upon the opinions of experts retained by the two sides. Legitimate chemical and crystallographic questions arise. Legitimate differences of opinion (even among friends and colleagues) are exposed. Is the chemistry involving the preparation of the different forms really different? Are new forms really different from previously patented forms or from each other? What techniques should be used to characterize the different forms? What characterizing information should or must be put into the patent claims? How does one detect an allegedly infringing crystal form (especially in a formulations with many other excipients)? How much of the allegedly infringing material must be present in order for that to constitute infringement of the patent? How much is really dtectable? Does that quantity make a difference in terms of the properties or efficacy of the final drug product? All of these questions are open to differences of opinion among the scientific advisors/co nsultants and the expert witnesses in patent prosecutions and patent infringement litigations.

A number of "true life" examples of these scientific and legal dilemmas will be presented.