Of Evergreening and Efficacy

By Ryan Abbott

An important case was decided yesterday that may have a significant impact on access to medicines for patients in developing countries. India’s high court rejected an appeal by the pharmaceutical company Novartis to grant a patent for its cancer drug Glivec.

The case involved a challenge to Section 3(d) of the Indian Patents Act which was designed to prevent patent holders from extending the duration of their patents by making minor changes to existing formulations—a practice referred to as “evergreening.” Section 3(d) stipulates that “the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance” is not eligible for patent protection.

The drug Glivec was initially invented and patented as a compound in its free base form. Novartis subsequently obtained a patent in the U.S. and Europe on a beta crystal version of the compound, which was found to possess 30% greater bioavailability. In yesterday’s case, one of the central questions before the court was whether the “new” drug form qualified for a new patent under Section 3(d). The court ruled that it did not.

To arrive at this conclusion, one of the more interesting issues the court had to resolve was how to define efficacy. It elected to define efficacy as therapeutic efficacy, but even within that definition the court was presented with multiple visions.

On the one hand, efficacy could be thought of as the capacity of a drug to produce an effect. That is, the property of a drug that causes a stimulus at a receptor site, as distinct from characteristics such as affinity, potency, and bioavailability. A broader conception of efficacy would include considerations such as improved safety or reduced toxicity.

Theoretically, I suspect a more holistic approach is justified.

At the extreme end of the spectrum, a new drug could cure multiple sclerosis yet be so toxic it kills more patients than it helps. If a new form of the drug is discovered that is not better at treating MS but that doesn’t cause any side effects, it would be hard to argue that it isn’t a leap forward in efficacy.

The broader question is where in the development chain someone should be entitled to a patent. Not too long ago, the U.S. Patent and Trademark Office required significant evidence of clinical efficacy for pharmaceutical product patents to comply with the utility requirement. In re Brana (Fed. Cir. 1995) changed that, when the Court of Appeals for the Federal Circuit decided it would deter innovation to require FDA approval or even Phase II testing to find a compound useful within the meaning of the patent law. Amgen Inc. v. Hoechst Marion Roussel, Inc (Fed Cir 2006) went further and held that therapeutic utility is not dependent on a product having an effect in a living being, such as curing disease.

Now researchers try to patent compounds at the earliest available opportunity, a trend which is only going to intensify with last month’s transition from a first-to-invent system to a first-to-file system under the America Invents Act. For good reasons the pharmaceutical industry is involved in a competitive race, but there’s no great philosophical reason that the finish line for patentability should be closer to the moment a new compound is generated. The proposition that a new form of a drug should be more effective to get a patent isn’t that radical.  It would mean researchers would spend less time racing to invent compounds, and more time discovering what compounds do.

On a doctrinal level what’s happening in India isn’t all that revolutionary, which makes it a bit disingenuous for the pharmaceutical industry to claim this is the end of the world. For example, Novartis announced yesterday that, “this ruling is a setback for patients that will hinder medical progress for diseases without effective treatment options.” But what India is doing now is no different than when our Supreme Court sets limits on patentability and intellectual property protection. Why, just last month our court set new limits on IP protections in Kirtsaeng v. John Wiley & Sons where it ruled that the first-sale doctrine applies to lawfully made works manufactured abroad and imported into the U.S.

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