Patents have always been an important tool for pharmaceutical and biotechnology companies to protect their biopharmaceutical products from competition. The composition patents for many basic biopharmaceutical products have expired or will expire soon, and as the market for biopharmaceuticals continues to expand, companies are seeking innovative patent strategies to protect their products and market share.
These strategies include obtaining patents on methods for producing or purifying the biomolecule or on pure or novel forms of the molecule. A recent case, Novo Nordisk Pharmaceuticals v. Bio-Technology General, illustrates some of the pitfalls in obtaining patents on supposedly novel forms of known molecules. In particular, it illustrates the problems of inherency in the prior art and enablement of later inventions by priority documents.
The Novo Nordisk Case
The Federal Circuit Court of Appeals decided the case between Novo Nordisk (www.novonordisk-us.com) and Bio-Technology General in October 2005. The facts of the case are typical of a patent strategy, seeking to obtain patent protection on a novel form of a known protein, in this case, human growth hormone (hGH).
In the background section of the case the court noted that hGH is a known protein that is secreted from the pituitary gland and, until the mid-1980s, hGH for therapeutic purposes was obtained from the pituitary glands of human cadavers. Since hGH from cadaver pituitary glands carries a high risk of contamination and infection for patients, attempts were made to produce a biosynthetic hGH that would be free from contaminants and have the same in vivo activity as the pituitary-derived hGH.
Novo Nordisk obtained U.S. Patent 5,633,352 (the 352 patent) claiming a biosynthetic ripe hGH produced by recombinant DNA techniques free of contaminants from pituitary-derived hGH. This biosynthetic hGH was produced by transfecting a bacterium with the gene sequence for a fusion protein, comprising the gene sequences for a bacterial protein and human hGH. The pure hGH was produced by enzymatic cleavage of the expressed fusion protein using a proteolytic enzyme, DAP I.
The case at hand arose when Novo Nordisk sued Bio-Technology General (BTG) for infringing this patent. BTG counterclaimed that the 352 patent was invalid as being anticipated, or lacking novelty in light of the prior art, and was unenforceable due to inequitable conduct by the patentee during prosecution. The District Court agreed with BTG and found the 352 patent to be both invalid and unenforceable, and the Federal Circuit Court affirmed the District Courts findings.
Inherent in the Prior Art
The finding of invalidity was based on a prior art reference, disclosing production of recombinant hGH in monkey cells. Novo Nordisk argued that the prior art reference failed to disclose that the hGH protein produced was composed of a 191-amino acid sequence identical to that of pituitary-derived hGH that has the full biological activity of pituitary-derived hGH.
The court ruled that although the reference did not specifically disclose these characteristics, they were inherent in the hGH produced, according to the prior art. The court pointed out that the reference disclosed the results of tests, including gel electrophoresis and receptor binding studies, showing that the recombinant hGH produced in the prior art was identical in all respects to pituitary hGH, i.e., possessed a 191-amino acid sequence identical to that of pituitary-derived hGH, and was free of contaminants. The court thus determined that the prior art reference inherently disclosed each limitation of the broadest claim of the 352 patent and held the claim to be invalid.
The finding of inequitable conduct was based on statements made by Novo Nordisk inventors and attorneys during prosecution of certain applications in the priority chain of the 352 patent.
According to the facts stated in the case, the 352 patent claimed priority through a chain of continuation applications to a PCT application filed in 1983, which in turn claimed priority to a Danish application that was filed in 1982. The 1982 and 1983 applications did not disclose the use of the DAP I enzyme to produce hGH. Rather, they disclosed the use of only the LAP enzyme in a prophetic example. The Novo Nordisk inventors accidentally discovered the effectiveness of DAP I when they used LAP contaminated with DAP I, and the use of DAP I itself was first disclosed in an application filed in 1986.
During prosecution, Novo Nordisk distinguished a 1983 prior art reference on the basis that the LAP enzyme itself was ineffective to produce ripe hGH. The inventors of the 352 patent also submitted declaration evidence, stating that LAP enzyme alone would not produce hGH. However, these arguments were unsuccessful in overcoming the prior art. Hence Novo Nordisk amended its priority claim to claim priority back to the 1983-PCT application and the 1982-Danish application it was based upon, in order to remove the reference as prior art.
Novo Nordisk argued that the claims were enabled by the 1983 and 1982 applications, because these applications disclosed the general concept of producing recombinant hGH by adding an amino-terminal extension and isolation of mature hGH. The company also argued that the experiment in these applications using LAP was successful because it had successfully produced ripe hGH when it used LAP contaminated with DAP I. Novo Nordisk failed to disclose to the examiner that it was the activity of DAP I and not LAP that was effective.
The District Court based its finding of inequitable conduct on the failure of the patent holder to disclose to the PTO that the experiment in the 1983 and 1982 applications that relied upon the production of ripe hGH using LAP alone had never been successfully performed.
The problem of inherency is a troubling issue for applicants trying to obtain patent protection on pure forms or different polymorphic forms of known compounds. The law states that a claimed composition is novel if the prior art fails to disclose each and every limitation in a claim. Conversely, it is a well-established legal principle that the discovery of a previously unknown property of a known composition does not render the composition novel, if it can be shown that the property was inherent in the prior art material.
Therefore, a patentee can obtain a claim on a composition by proving to the patent office that the prior art does not disclose a composition having the claimed characteristics. However, as illustrated by the Novo Nordisk case, a patent containing such claims are vulnerable to a validity challenge if it can be shown that these characteristics are inherent in the composition. Inherency can be shown by reproducing the prior art process and showing that the prior art process inherently produces material covered by the claims.
The inequitable conduct portion of the case illustrates the tension between the requirements for obtaining a patent and those for enforcing it. Strategies for overcoming prior art rejections to obtain allowance include distinguishing the invention from the prior art or removing the reference as prior art by claiming priority to an earlier-filed application that is enabling for the invention being claimed in the later application. How much information to disclose is often a judgment call for patent applicants. In the Novo Nordisk case, the strategy achieved the objective of getting the patent issued, but ultimately resulted in it being unenforceable.