Jeffrey A. Lindeman, Ph.D., of Nixon Peabody, LLP, speaks on how patent law and practice are changing and adapting in response to this emerging chemistry in the Developing IP Strategies for Crystalline Forms conference this November.

A crystalline form of an API (active pharmaceutical ingredients) often carries its own unique, and beneficial, properties – properties derived from the particular crystalline form itself.  The pharmaceutical industry is aggressively pursuing research on the crystalline forms of its APIs, and both branded and generic pharmaceutical companies are fully engaged in that pursuit. 

This is not merely a research effort but new chemistry whose impetus is causing changes in the patent strategies for APIs.  As seen with the HIV drug Ritonavir, the vagaries of polymorphs can turn otherwise normal drug development or commercialization into a precarious situation.  The choice of one crystalline form over another, for example, can increase bio-availability or provide efficient processing into the final dosage form.  Crystalline synthetic intermediates can transform a synthesis from a process having multiple purification steps to a process with just one or two resulting in significant cost savings. 

When we speak of crystalline forms of an API, this is not meant to imply just polymorphic forms. Crystalline solvates (such as hydrates) and crystalline salts of APIs also can have their own unique activity profile.  Beyond that, co-crystals (a crystal having an API host and a guest bound together in the unit cell) are being prepared to modify the properties of the API.  For example, co-crystal formation may be use to either speed or slow down an API’s rate of dissolution. 

But, as fascinating as this solid state chemistry is, there is another key driver in crystalline form research, and that is patents.

A new crystalline form of an API is often patentable.  For branded pharmaceutical companies, crystalline form patents offer another brick in the IP wall designed to protect the product.  For a generic pharmaceutical company, a crystalline form patent offers the chance to establish its own patent space around an API.  As the chemistry of crystalline forms rapidly develops, so is patent law and practice which are changing and adapting in response to the momentum of this emerging chemistry. 

The Patent Examiners are asking questions.  At a recent continuing education seminar on solid state analytical techniques, the Examiners were asking:

1. Questions of nomenclature.

• The Examiners are still not comfortable and facile with terminology (polymorph, co-crystal, amorphous) used to describe the solid state.
• The Examiners do not readily appreciate the differences/distinctions being made by the terminology.

2.  Questions of technique.

• How do the analytical techniques used in solid state chemistry work?
• What are the limits of a particular technique?
• What does the data tell you? And, what does it not tell you?
• How much data is needed to describe a particular from?

3.  Questions of patentability.

• Why is “this solid state form” important?  How is it patentable?
• What properties of the solid state are important for patentability? 
• Which properties of the solid state form differentiate it from the prior art?
• What information needs to be included in the specification? In the claims?

But that is not all. 

The examination of crystalline form patents – an even their availability as patentable subject matter – differs among various patent offices.

One finds different perspectives in the U.S. Patent and Trademark Office, the European Patent Office, and patent offices of other countries, e.g., India.  For example, while both look at the property of the crystalline form, U.S. Patent Examiners tend to reject claims using the theory of inherent anticipation based on a prior disclosure of the compound (generally not as a crystalline form); while European Patent Examiners apply an inventive step analysis.  More recently, however, U.S. Patent Examiners have begun to make more obviousness rejections applying the recent KSR decision from the U.S. Supreme Court.

The importance of crystalline forms to the pharmaceutical industry and the questions asked by Patent Examiners, both on the solid state chemistry fundamentals and during examination, have placed a premium on drafting strong and effective patents for the crystalline forms of an API.  There is, however, more at stake than just drafting a single application.  Crystalline form patents are not drafted in the same way as traditional pharmaceutical compound patents with their broad generic structure and multiple R groups.  A crystalline form is not generic but very specific – what can be termed “the ultimate species.” 

When an API can form multiple polymorphs, along with crystalline salts or solvates, for example, the question becomes whether or not to package all those crystalline forms in one application.  Cost considerations may dictate the answer.  Yet, it is important to remember that a crystalline free base has a different chemical composition (think empirical formula) than does a crystalline salt.  It is often helpful to divide and file patent applications along these chemical compositional lines.  A co-crystal, representing an entirely new avenue of crystalline from research, may be both a novel, patentable compositions by itself and a patentable crystalline form of that novel composition.

Furthermore, the developing patent law surrounding crystalline forms of APIs is not merely occurring in the patent offices.

There have been significant cases in the courts.  For example, the contours of inherent anticipation are again being explored by U.S. courts in the context of crystalline forms, as in the Paxil case, SmithKline Beecham v. Apotex.  While the legal theories of validity and infringement are undergoing change in these cases, another trend has emerged: the significant reliance on scientific expert testimony to determine just what was in the prior art or what crystalline form is present in the allegedly infringing product.  This reliance on expert testimony needs serious consideration as the understanding and presentation underlying solid state chemistry can be argued to have been outcome determinative in many recently decided cases.

The strong momentum within pharmaceutical research to develop new crystalline forms of APIs has pushed its way out into the world of patents.  Crystalline form patents are not, and cannot be, drafted in the same way as pharmaceutical compound applications.  They require careful consideration and a clear understanding of the crystalline form and its properties to establish patentability and answer Examiners’ questions during prosecution.

While better patents must be drafted to gain more meaningful patent protection for crystalline APIs, the real test, as for any patent, comes in litigation.  Litigation enforcing crystalline form patents is currently testing the boundaries and contours of patent law principles such as inherent anticipation and obviousness/inventive step.  Due to the complex nature of crystalline forms, scientific experts are playing significant roles in bringing a proper scientific understanding of solid state chemistry into court. 

The patentability of crystalline forms, as with the research to develop them, requires an in-depth look to equip patent lawyers to effectively handle all that this new chemistry brings to the pharmaceutical industry and to patent law.

Dr. Jeffrey A. Lindeman will be speaking at Developing IP Strategies for Crystalline Forms taking place November 10-11, 2008 in London.