Generic Treatment Claims: Do They Hold Water?

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."

Consequently, Ariad asserts that claim 14 applies to Xigris because it is used to treat sepsis. Xigris is a recombinant form of human activated protein C, and Lilly discloses that the product functions by inhibiting NFKB. By doing so, it automatically reduces bacterial lipopolysaccharide-induced expression of cytokines in the cells, because that is one of NFKB's effects.

Claim 69 is somewhat more specific, requiring that the inhibition occur by interfering with NFKB binding. It cites "A method for diminishing induced NFKB-mediated intracellular signaling comprising reducing NFKB activity in cells such that NFKB-mediated intracellular signaling is diminished, wherein reducing NFKB activity comprises reducing binding of NFKB to NFKB recognition sites on genes which are transcriptionally regulated by NFKB."

Ariad's lawsuit says that Evista -- a small-molecule drug that modulates the estrogen receptor and is used to treat Osteoporosis -- infringes that claim because Evista acts by inhibiting NFKB binding to its binding site.

Ariad has hired a seasoned New York–based litigation team from Clifford, Chance, Rogers & Wells, a law firm that represents industry notables such as Genentech, Pfizer, and Aventis. The team's biochemists have their work cut out for them. Not only do the '516 claims appear to cover many existing drugs, herbs, and neutraceuticals, but the prosecution promises to be lengthy and complex, and an in-depth understanding of biochemistry is required to follow the intricacies of what was, and was not, disclosed.

The Response

Lilly has not publicly commented on Ariad's challenge. But in answer to the complaint, Lilly filed a combined Motion to Dismiss under F.R.C.P. 12(b)(6) and Motion for Summary Judgment on Invalidity, based on anticipation and failure of enablement. The motions assert that the claims of the '516 patent are invalid as "anticipated" by the allegedly infringing products (Evistra and Xigris), both of which Lilly had described before the earliest possible priority date for the '516 patent. Further, Lilly asserts that the claims are invalid because they are not enabled, meaning that they affect all current NFKB-modulating drugs and any future drugs to be discovered, without "teaching" how to manufacture a single such drug.

Ariad replied to that challenge in a colorful opposition motion. It correctly asserted that Lilly failed to present a detailed claim analysis and thus cannot show "anticipation" of the claims. In its opposition, however, Ariad fails to even mention "inherency," let alone address Lilly's contention that Evistra and Xigris inherently function by inhibiting NFKB.

Ariad does make one strong point that could prove fatal to Lilly's anticipation (not novel) defense. Ariad correctly asserts that Lilly is attempting to patent the new use of Xigris in treating patients who suffer from a disease induced by NFKB. Similarly, Lilly has pending patent claims involving the use of Evista to modulate NFKB. How can Lilly's new uses be patentable if those uses render the Ariad claim invalid as anticipated?

A Complication

The issue has thus devolved to one of whether "inhibition of NFKB" qualifies as a "new use" that is patentable, or whether it is a mechanism of action that inherently occurs whenever the drug is used. It can be difficult to distinguish between a compound's patentable new use and an unpatentable, newly discovered inherent property.

But the Federal Circuit has already answered that question in an earlier Lilly case that held that the mechanism of action of Prozac (fluoxetine) in inhibiting serotonin uptake was a natural biological activity that occurred when the drug was administered to a human for any purpose. In other words, serotonin uptake inhibition was an inherent property of the drug after administration. Thus, the claim was not patentably distinct from an earlier Lilly claim for using Prozac to treat anxiety.

Similarly, the use of Evista and Xigris always results in the inhibition of NFKB, because it is one of the mechanisms of action of those drugs. Under that logic, Ariad's asserted claims are "anticipated," and Lilly should be embarrassed by its efforts to patent similar claims and for using an inconsistent argument in court.

Ariad's answer to Lilly's "lack of enablement" argument, in contrast, seems to miss the point. The Lilly enablement argument is based on the fact that the claims cover the use of every drug that functions to inhibit NFKB, and yet no small molecule drugs that meet those limitations were disclosed in the patent. Ariad's answer focuses on whether the claims are written in functional language and whether they are single element claims or not. Nowhere does Ariad address the substantive question of failing to disclose any drugs in its '516 patent, other than the protein IKB, that act to inhibit NFKB, yet now it asserts the claims against Evista and Xigris.

Lilly has filed a rebuttal and, perhaps wisely, refused to get distracted by Ariad's aspersions about Lilly's NFKB patents. Instead, Lilly is focusing on material fact issues and alleges that Ariad has failed to raise any. The facts remain: if Lilly's products infringe now, they must have also been "anticipated" because they existed and were used in patients before the Ariad patent applications were filed. Knowledge of the mechanism of action of these drugs in inhibiting NFKB is not required for "anticipation" under the established principles of inherency.

Oral hearings for the pending motions have been held and an answer can be expected shortly. Because of its profound importance to biotech and pharma patents, the industry and its legal partners should monitor this lawsuit closely.