Generic Treatment Claims: Do They Hold Water? - Pharmaceutical Executive

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Generic Treatment Claims: Do They Hold Water?
A patent issued for the NFKB protein has forced Lilly to defend its right to market Evista and Xigris.


Pharmaceutical Executive


As scientists' knowledge of biochemical pathways increases, so does the number of patents issued for generic treatment claims. Such claims represent methods of treating disease by modulating a particular protein in the body. They typically don't name a specific drug, and they are not linked to the use of a particular class of drugs. They are called "generic" because they cover any compound that affects the particular protein.

That lack of specificity leaves them open to two possible patent invalidity attacks. First, the claims may not be adequately enabled, because the patent does not "teach" the reader/manufacturer how to practice the invention. Second, the claims may be "anticipated" -- a legal term for "not novel" -- because drugs that function to modulate the particular protein are already in use. Thus, the invention is not new and cannot be patented.

Until now, no court has addressed those issues. This article explores an important pending case that will decide the validity of generic treatment claims.

Wide Application On June 25, 2002, the US Patent Office issued a patent representing generic treatment claims that target the nuclear factor kappa B (NFKB) protein. US Patent number 6,410,516 ('516 ) was issued to three co-owners: the president and fellows of Harvard College, the Massachusetts Institute of Technology, and the Whitehead Institute for Biomedical Research. Inventors on the patent include Tom Maniatis, who wrote what is affectionately called "the bible" of biotechnology, a three volume treatise that teaches all of the fundamental techniques of the genetic engineering revolution. Other notables include David Baltimore, PhD, who shared the 1975 Nobel Prize for the discovery of the enzyme reverse transcriptase, and Phillip A. Sharp, PhD, co-winner of the 1993 Nobel Prize for the discovery of split genes.

Baltimore and a team of inventors discovered the NFKB protein in 1986 and showed that it acts to increase the expression of several other genes important in inflammation and immune responses. But the inventors didn't purify the protein, they only demonstrated its existence using a technique that indicates the presence of a protein by a change in the mobility of the DNA to which it binds. They attempted to clone and claim the gene encoding NFKB, but the sequence they obtained was not from NFKB. Instead, another group cloned the full NFKB gene in 1991.

On the same day that the US Patent Office issued the '516 patent, Ariad Pharmaceuticals, which has an exclusive license for it, sued Eli Lilly in a Boston federal court for infringement -- based on sales of its blockbuster drug Evista (raloxifene), with $665 million in 2002 sales and the recently approved Xigris (drotrecogin), with $22 million in sales to date for 2003.

The first of 203 claims in the '516 patent is typical and reads: "A method for inhibiting expression in a eukaryotic cell of a gene whose transcription is regulated by NFKB, the method comprising reducing NFKB activity in the cell such that expression of said gene is inhibited."

Thus, the claim applies to any drug that inhibits NFKB. The patent itself fails to describe a drug that inhibits NFKB, although it does describe a single protein inhibitor of NFKB called "inhibitor of kappa B" or IKB. The claim, at least, has serious invalidity issues under both the written description and enablement requirements of the patent statute.

Moreover, long before the patent was filed, products existed that are now known to act by inhibiting NFKB. A well known example is ibuprofen, which has been around since 1969. Although it was not known until 1998 that ibuprofen inhibited NFKB, knowledge of that fact is not required under existing patent law principles of inherency. It is enough that the drug inhibited NFKB.

Other well known drugs that also inhibit NFKB include aspirin, the immunosuppressive drug gliotoxin, and the rheumatoid arthritis treatment sulfasalazine. NFKB inhibitors that people have used for thousands of years include garlic, red wine, capsaicin (the "hot" ingredient in peppers), and caffeic acid (from honeybee propolis, the material used to seal the honeycomb). Even vitamin E inhibits NFKB.

The Lawsuit Ariad asserts that Lilly infringes claim 14 by the sale of Xigris and claim 69 by the sale of Evista. Those claims include some additional language about the mechanism of action. Claim 14 reads:

"A method for reducing bacterial lipopolysaccharide-induced expression of cytokines in mammalian cells, which method comprises reducing NFKB activity in the cells so as to reduce bacterial lipopolysaccharide-induced expression of said cytokines in the cells."


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