Addressing the issue of whether a topical gel with an increased concentration of active ingredient would have been obvious over a prior art liquid product, the US District Court for the District of New Jersey concluded that the claimed formulation was not predictable and exhibited unexpected results. Horizon Pharma Ireland Ltd. v. Actavis Labs., UT, Inc., Case No. 14-7992 (D.N.J., May 12, 2017) (Hillman, J).

Actavis filed an abbreviated new drug application (ANDA) seeking to market a generic version of Horizon's PENNSAID® 2%, which is a topical diclofenac sodium formulation indicated for treating the pain associated with osteoarthritis of the knees. Horizon asserted a method of treatment claim that required twice daily administration of a 2 percent diclofenac sodium formulation having a particular viscosity and further containing particular amounts of dimethyl sulfoxide (DMSO), ethanol, propylene glycol, hydroxypropylcellulose (HPC) and water. Actavis stipulated to infringement and argued that the asserted claim was obvious over the prior art PENNSAID® 1.5% formulation. 

Aside from the difference in the concentration of the active ingredient, the branded product and prior art product differ substantially in terms of vehicle and application frequency. PENNSAID® 2.0% is a gel; the prior art PENNSAID® 1.5% formulation was an “unthickened liquid solution” with a “viscosity similar to water.” PENNSAID® 2.0% is administered twice daily, while the prior art PENNSAID® 1.5% product was approved for a dosing regimen of “40 drops four times a day.” However, the claimed formulation differed from the prior art product by only a single ingredient—HPC was used instead of glycerin—and other than the 0.5 percent increase in diclofenac sodium, only ethanol changed in concentration. Actavis argued that these modifications were merely routine optimization, but the court disagreed. 

The court accepted Actavis' argument that, in general, a person having ordinary skill in the art (POSA) would have been motivated to improve the prior art of the 1.5 percent product by “increasing the amount of drug absorbed per application in order to reduce the application frequency” and by “making the formulation thicker to prevent run-off and improve absorption.” But the court cautioned that “[r]ecognition of a need does not render obvious the achievement that meets that need.” The court also acknowledged that the prior art suggested that “HPC was an attractive thickener” and “would have informed a POSA of…the suitable ranges for diclofenac sodium, ethanol, and HPC.” However, “[e]ven if the range of values for a particular variable was set out in the prior art and even if the combination of variables was itself predicted, the result will still not be obvious if the variables interacted in an unpredictable or unexpected way.” 

Ultimately, the court concluded that the claimed formulation “was not a result of routine optimization” because “general principles and ranges of permissible concentrations would not have predicted the exact formulation and dosing frequency that resulted in PENNSAID® 2%.” In reaching this decision, the court emphasized the “daunting hurdles overcome through experimentation” by plaintiff in order to obtain the claimed product. The court was also persuaded by the unpredictability resulting from the need to modify several variables at one time; “[a]lthough individually adjusting one ingredient at a time may provide a predictable result, the combination of adjustments needed to change PENNSAID® 1.5% into PENNSAID® 2% was not predictable from the prior art.” The court concluded that plaintiff's evidence established that the claimed formulation, and “the manner and method of getting there would not have been obvious to the relevant POSA and reflects a protectable step forward.”