Pharmaceutical inventions usually require human clinical testing in order to obtain regulatory approval to market the new product. Often a patent application is filed before the invention undergoes human testing, but sometimes a human clinical trial may be started—or even completed—first. While U.S. patent law provides that a “public use” of the invention within the U.S. can constitute prior art, a clinical trial often does not qualify as prior art, either because it was not “public” (e.g., it was conducted under confidentiality) or it qualifies as an “experimental use.”

Practitioners familiar with European patent law know that the EPO takes a stricter view of prior art than the U.S. in many ways, applying an absolute novelty standard with no grace period. Still, a recent decision by the EPO Technical Board of Appeal (T0007/07) finding that a human clinical trial constituted invalidating prior art is striking.

The Patent At Issue

The patent at issue was EP 1 214 076, granted to Bayer Pharma Aktiengesellschaft and directed to an oral contraceptive (Yasmin®):

A pharmaceutical composition in an oral dosage form comprising, as a first active agent drospirenone in an amount corresponding to a daily dosage, on administration of the composition, of from about 2 mg to 4 mg, and as a second active agent, ethinylestradiol in an amount corresponding to a daily dosage of from about 0.01 mg to 0.05 mg, together with one or more pharmaceutically acceptable carriers or excipients, wherein said drospirenone is in micronized form.

The patent had a priority date of August 31, 1999.

The Clinical Trial

A clinical trial of the claimed product was conducted in the U.S. between December 1996 and July 1998, well before the patent application was filed. The following factors appear to be relevant to the EPO Technical Board decision:

  • The principal investigators, but not the patients, entered into confidentiality agreements.
  • The patients knew the active ingredients in the product, but were not informed that the drospirenone was in micronized form.
  • Not all unused product was returned at the end of the clinical trial.
  • A skilled person could have studied a sample product and determined that it contained drospirenone in micronized form.

EPO Legal Principles

The EPO Technical Board cited the following legal principles:

[I]f a single member of the public, who is not under an obligation to maintain secrecy, has the theoretical possibility to access particular information, this information is considered as being available to the public within the meaning of Article 54(2) EPC.

[T]he chemical composition of a product is state of the art when the product as such is available to the public and can be analysed and reproduced by the skilled person, irrespective of whether or not particular reasons can be identified for analysing the composition …. If it is possible for the skilled person to discover the composition or the internal structure of a product and to reproduce it without undue burden, then both the product and its composition or internal structure become state of the art ….

The EPO Technical Board Decision

The EPO Technical Board found it significant that not all of the unused product was returned at the end of the clinical trial, and determined that this fact indicated that the invention was “publicly available” before the application was filed:

It appears that after having handed out the drugs the respondent effectively lost control over them as the participants in the clinical trials were in no way barred from disposing of the drugs as they wanted.

In view of these circumstances, the board comes to the conclusion that the handing out of the drugs to the participants made them became publicly available.

Having found public availability, the Board had to determine whether “the skilled person was in a position …. to determine the micronized state of drospirenone, which is an item of information that was not communicated to the women participating in the clinical trials.” The Board credited evidence that RAMAN spectroscopy could have been used for this purpose “without undue burden,”  and so concluded that

it was possible for the skilled person to discover the composition or the internal structure of the product Yasmin® used in the clinical trials mentioned above and to reproduce it without undue burden.

Thus, the patent was held invalid for lack of novelty.

The U.S. District Court Decision

The U.S. District Court for the District of New Jersey reached a different conclusion on similar arguments in the context of the corresponding U.S. patent (U.S. 6,787,531). The U.S. court rejected arguments that the clinical trial constituted a public use, giving weight to the confidentiality obligations of the principal investigators, and to the fact that the invention—the use of micronized drospirenone—was not disclosed to the patients. The U.S. court also rejected arguments that the clinical trial was not an experimental use, crediting testimony that the clinical trial results were necessary to determine whether the invention would work in a U.S. patient population. The ultimate outcome was the same in the U.S., however, because the patent was held invalid as obvious.

The Importance of Confidentiality and Control over Clinical Trials

Although these issues are decided on a fact-specific, case-by-case basis, this case underscores the general importance of confidentiality and control over clinical trials. Pharmaceutical companies preparing to launch clinical trials could do well to seek the advice of patent counsel to ensure that appropriate guidelines and safeguards are in place to preserve their patent rights.