Patentability and Infringement Analysis of New Crystalline Form Inventions

Conflict between branded and generic drug manufacturers has been a common source of controversy in the pharmaceutical industry. Brand-name drug manufacturers devote tremendous human resources and capital to developing new substances such as compounds that have medical uses, performing animal testing, human clinical trials and other such tests, and subsequently passing stringent government standards in various countries. Only after such procedures can these drugs be released onto the market. It is often the case, however, that the patent of the originally-developed substance expires soon after or even before the drug is finally released. Branded drug manufacturers can thus be precluded from enjoying the protection of the patent, and forced to compete with generic drug companies selling the same drugs.

Branded Manufacturers vs Generic Manufacturers

For a brand-name drug manufacturer, the purpose of investing the extensive capital required to develop a new drug is so that it may enjoy exclusive market rights of sufficient duration. Otherwise, there would be no incentive for continued investment, and patients would in turn not benefit from access to new drugs. However, the other side of the argument is that if generic drug companies can widely distribute beneficial drugs with good efficacy to patients at a lower price, it would help raise the quality of medical care, and in turn benefit society as a whole. These conflicts fuel ongoing debate within the industry over the extent and balance of protection afforded to brand-name and generic drug manufacturers.

Patent-related issues are particularly pertinent to this conflict, giving rise to numerous litigation cases internationally. After a branded drug manufacturer obtains a patent for an original compound having medical efficacy, it may subsequently develop related technologies, such as new manufacturing methods, new uses, new dosage forms, new crystalline forms, etc, for which patents may be separately filed. Faced by potential business constraints from such patents, generic drug manufacturers hold an opposing view on the patentability of such new technologies.

In the case of new crystalline forms, generic drug manufacturers are of the opinion that the basic formula of the compound is already known, and persons with ordinary skill and knowledge in the art can easily obtain the new crystalline form through general and routine operations. Hence, there is nothing novel to the development of a new crystalline form; instead, it should be categorized as a “discovery” of a natural substance, not as an “invention” that can be protected under patent law.

Decisions of the Taiwan Intellectual
Property Court

In March 2011, two decisions were rendered by the Taiwan Intellectual Property Court (“TIPC”) regarding the issues of whether the development of a new crystalline form should be recognized as an “invention”, whether it is a patentable objective, and whether the legal requirements for patentability such as “novelty” can be met. The dispute was between Sanofi-aventis and a domestic Taiwanese generic drug manufacturer.

Sanofi-aventis held a patent related to a new crystalline form of Clopidogrel Hydrogen Sulfate (Patent No. 190825). It brought a civil suit against a domestic generic drug manufacturer in the Taiwan Taipei District Court, alleging that the generic drug manufactured and distributed by the latter involved use of the patented crystalline form. The defendant, in addition to challenging the validity of said patent in the civil proceeding, also asked a third party to file a cancellation action with the Taiwan Intellectual Property Office (“TIPO”) in an attempt to invalidate the patent. The Taiwan Taipei District Court and the TIPO both held the patent valid, and the court also found the defendant’s product infringing.

The defendant appealed to the TIPC for the civil case in September 2009, and the cancellation petitioner then initiated an administrative suit for the cancellation action in August 2010. In March 2011, decisions were reached. In the Civil Judgment No. 2009-Min Juan Shan-57 and the Administrative Judgment No. 2010-Hsin Juan Su-148, the TIPC confirmed the validity of the patent and also held that the generic product had infringed the patent.

Patent Validity of Crystalline Forms

With respect to the validity issue, the TIPC took the following views:

• An invention related to a naturally existing substance, unless it is merely a scientific finding, did not necessarily exclude itself from the protection by patent law. For a substance which is firstly separated or extracted from nature, as long as its structure, form or other physical and chemical properties are distinguishable from other known substances, and can be clearly identified and specified, it can be defined as an “invention” under patent law.

• Furthermore, new crystalline forms of known compounds should be patentable, as their special lattice and the number of lattices both require scientific confirmation, and cannot be loosely predicted. For a given compound, the questions of how many crystalline forms can be made and by what kind of process, as well as what properties they each have, all require intensive effort to answer. Therefore, prior disclosure of a known compound should not be the sole reason for its optical isomers, hydrates, and crystals to be devoid of novelty.

• Moreover, a naturally-existing substance usually is present as a mixture. Even if the natural mixture containing the said substance was previously used, the substance does not per se lose its novelty. Therefore, although the defendant claimed that it is possible that before the filing date of the patent, the new crystalline form could be predicted or observed by previous manufacturing results of the known substance (for example, the phenomenon of “seed contamination of new crystalline form” may occur during the manufacture of the known crystalline form), it does not necessarily mean that the new crystalline form lacks novelty.

Patent Infringement Found

In the area of infringement, the court expressed the following opinions in the civil judgment:

• The patent concerned uses the characteristic peaks expressed as interplanar distance (“d values”) in the “X-Ray Powder Diffractogram” (“XRPD”) to identify the claimed new crystalline form. The TIPC held that, similar to the identification of a person by fingerprint, the d values can serve as the fingerprint of a special crystalline form.

• With respect to claim construction, the court interpreted the scope of the d values listed in the patent claims by referring to the precision range provided in the 2006 United States Pharmacopoeia. After comparing the interpreted scope of the d values and the XRPD data of the accused generic drug, the court confirmed the fact of infringement.

• Furthermore, the TIPC held that, in addition to comparing the d values defined in the claims with those of the accused drug, it is also acceptable to use the diffraction pattern of the XRPD for direct comparison.

The judgments in this case were decided in favor of the brand-name drug manufacturer. The TIPC’s opinion is of significant reference value to patent litigation in Taiwan’s pharmaceutical industry.