August 22, 2013

The Lion is King

Leo Pharma v. Rea and the non-obviousness of pharmaceutical combinations

The Danish drug-maker Leo Pharmaceuticals markets Taclonex® (0.064% betamethasone dipropionate; 0.005% calcipotriene hydrate), as a treatment for psoriasis. Taclonex® is a combination of betamethasone, a potent anti-inflammatory glucocorticosteroid, and calcipotriene, a vitamin D derivative. Both betamethasone and vitamin D have long been used to treat psoriasis, and it is well established that they work better in combination than either single compound used alone. However, betamethasone is most stable at a pH between 4 and 6, while vitamin D derivatives are most stable at a pH above 8. Therefore, it has long been difficult to formulate the two drugs in a single formulation, and co-administration of two drugs required a first application of the steroid, and then a later application of the vitamin D derivative.

Leo was able to overcome this difficulty by using polyoxypropylene 15 stearyl ether (POP-15-SE) as a solvent for the formulation of both the steroid and the vitamin D derivative in a single, topical ointment. Leo filed an application on this combination of glucocorticosteroid, vitamin D, and POP-15-SE on 22 October 2001, which issued as U.S. Patent 6,753,013 (‘013). Because the new ointment required only a single daily administration, it was a success with patients, who found it more convenient than the prior art methods that required two different ointments to be applied at different times of day.

Galderma persuaded the PTO to institute an inter partes re-examination of the ‘013 patent. The PTO concluded that all claims of the ‘013 patent were obvious over U.S. Patent 4,083,974 (Turi) in view of U.S. Patent 4,610,978 (Dikstein) and WO 94/14453 (Serup). The BPAI affirmed this conclusion and Leo appealed to the Federal Circuit.

Turi, which published in 1978, discloses steroid compositions in POP-15-SE, but does not disclose vitamin D in those compositions. Dikstein published in 1986 and discloses formulations of glucocorticosteroids in combination with vitamin D derivatives, suspended in water, almond oil, or propylene glycol. The Dikstein reference does not evidence that the author was even aware of the co-storage problems associated with glucocorticosteroids and vitamin D. Serup published in 1994 and described co-administration of vitamin D with glucocorticosteroids to ameliorate some of the side-effects associated with steroid treatments. All of Serup’s formulations of steroid and vitamin D involved water or almond oil, two solvents which the ‘013 specification shows to be ineffective for stabilizing the steroid/vitamin D combination. The Federal Circuit unanimously reversed the BPAI’s conclusion of obviousness.

Motivation to combine

It is very easy to say that one could make the claimed invention by combining Turi, Dikstein, and Serup, but these are just three references out of billions in the world. In order for the invention to be obvious, there must have been some reason why an ordinary medicinal chemist would have combined the cited references. However, Judge Rader’s opinion notes that none of the cited art even acknowledges that there is a problem formulating a storage-stable composition with both glucocorticosteroid and vitamin D. There can be no motivation to solve a problem when the art has not even realized that a problem exists. The court cited Cardiac Pacemakers v. St. Jude Med., 381 F.3d 1371, 1377 (Fed. Cir. 2004) for the well-established proposition that sometimes the recognition of a problem is itself the invention.

Both Dikstein and Serup report formulations that contain both corticosteroid and vitamin D. Neither Dikstein nor Serup ever suggests that there will be a problem with the long-term stability of these combinations. The data presented in the ‘103 patent show, however, that the formulations of Dikstein and Serup decay in relatively short time spans, and are thus not “storage stable.” In other words, there was no reason in the art why one should ever have known that it was worthwhile to make a “storage stable” combination, but the ‘013 patent’s inventors discovered how to make one. The court held that this was not obvious.

Age of the references

The court was very impressed by the amount of time that had elapsed between the publication of the allegedly invalidating references (1978, 1986, and 1994, respectively) and the filing of the application for the ‘013 patent in 2001. The court repeatedly emphasized (slip op. at pgs. 11, 13, 14, 17, 18, 19, 21, and 22) that if it were really so obvious to formulate all three ingredients in a single combination, using the POP-15-SE solvent, why did 22 years elapse between the publication of the oldest of these references and the filing of the patent. The force of emphasis that the court puts on this point should give patent prosecutors in the chemical arts encouragement to make arguments about objective indicia of non-obviousness when the art cited is much older than the claims at issue. As Judge Rader put it, “[t]he intervening time between the prior art’s teaching of the components and the eventual preparation of a successful composition speaks volumes to the nonobviousness of the ’013 patent.” One hopes that MPEP §2145.VIII will be updated in light of this holding.

The above article was written by Greg DeLassus, an associate in the St. Louis, MO office of Harness Dickey.  Greg can be reached at 314.446.7687 or