A fundamental U.S. biotech patent expired last week (May 5), accompanied by a flurry of legal activity. The patent holder and its licensee filed a patent-infringement lawsuit the day before the patent's expiration. They also asked the US Patent and Trade Office (USPTO) to extend the life of the patent.
Massachusetts biotech firm Repligen and the Massachusetts Institute of Technology (MIT) filed suit May 4 in US District Court, Boston, in which they allege patent infringement by ImClone Systems Inc., in the development and manufacturing processes of its anti-cancer drug, Erbitux (Cetuximab). Erbitux is a chimeric (human/mouse) monoclonal antibody directed against the epidermal growth factor receptor (EGFR). The US Food and Drug Administration (FDA) on February 12, 2004, approved the drug for use in the treatment of EGFR-expressing, metastatic colorectal cancer.
ImClone has not yet formally responded to the allegations, but David Pitts, ImClone's assistant vice president of corporate communications, said, “Our manufacturing process in no way infringes on the patent in question. It is therefore our belief that the suit is without merit, and we intend to vigorously defend against it.”
The court filing alleges that Erbitux is the product of a cell line that was developed by Repligen's predecessor, Damon Biotech, under an agreement with the National Cancer Institute. This cell line, plaintiffs contend, is covered by US patent #4,663,281, which is owned by MIT and licensed exclusively to Damon's successor, Repligen. The patent by Stephen Gillies and Nobel laureate Susumu Tonegawa, describes a method for boosting the production of a protein in mammalian cells by using a tissue-specific enhancer.
The 1983 discovery of lymphoid-specific enhancers in the introns of immunoglobulin genes by Gillies and Tonegawa, among others, was novel on several levels, said Ranjan Sen, a senior investigator at the National Institutes of Health who studies immunoglobulin gene expression.
Bacterial and yeast cellular genes do not contain such elements, Sen explained; they are controlled primarily through promoter-proximal sequences. The SV40 virus was known to have an enhancer element, but it is not tissue-restricted. Finally, all known RNA polymerase II-dependent regulatory sequences were located upstream of the transcription start site. The immunoglobulin enhancers therefore represented a paradigm shift in the understanding of gene expression, Sen said.
Despite the age of the '281 patent, its claims remain valuable to bench scientists today. Sen noted that gene-therapy strategies, for instance, depend on the ability to control genes in a spatially and temporally restricted manner. And Yossi Shiloach, chief of the biotechnology unit at the National Institute of Diabetes and Digestive and Kidney Diseases, said that anything a researcher can do to squeeze more protein out of a culture is beneficial when growing biologics.
According to Laura Whitehouse, Repligen's vice president of market development, Erbitux is the first drug to come to market that directly relies on the '281 patent. She said that Repligen has no drugs in development based on the patent.
The plaintiffs are not seeking to stop the sale of Erbitux, Whitehouse said. They are asking the court to order ImClone to pay royalties and damages on the drug's sales. But how much money Repligen and MIT could possibly receive depends on how long the infringement occurred while the patent was in force. As it stands, ImClone sold Erbitux for less than three months before the patent expired, generating over $17 million in sales in the US in its first five weeks.
Recently Repligen and MIT asked the USPTO to extend the patent's term. The USPTO can grant extensions to compensate patent holders for time lost due to regulatory delays, such as time spent obtaining FDA approval of a drug. Such extensions can be for as long as five years, though as a practical matter they are generally shorter, said patent attorney Jerry Cohen, a partner in the Boston firm Perkins, Smith, and Cohen.
Key to such a claim is the “due diligence” of the patent holder. In this particular case, however, neither Repligen nor MIT can make that claim directly, as they had no drugs under FDA consideration, said Cohen. Instead, they are asking to be compensated for ImClone's regulatory delays. “Repligen is trying to say, my opponent, my enemy, the pirate who ripped off my patent, was duly diligent and I should get credit for the due diligence of my opponent,” said Cohen. “It is bizarre.”
“It's an aggressive case,” he said. “It's bound to make new law one way or the other on the patent term extension.” Whatever the legal outcome, however, the case will not likely affect ImClone significantly, said Jason Kantor, a biotech analyst with WR Hambrecht & Co. “ImClone can make this go away with a pretty small check relative to their market cap. These guys have hundreds of millions of dollars in cash,” Kantor said.