Pennsaid® patent illustrates importance and strength of exception excipient rules.

Some of the most interesting intersections between patent and FDA laws occur at FDA’s exception excipient rules.  Under these rules, an innovator can secure a narrow formulation patent with huge tactical advantage.  On the one hand, FDA will force a generic application filed under section 505(j) of the FD&C Act to use the innovator's patented formulation, thereby ensuring that a generic manufacturer infringes the patent.  On the other, the patent’s validity will be easier to defend owing to its narrow breadth.

These issues came to the fore recently in Horizon Pharma Ir. Ltd. v. Actavis Labs., UT, Inc., 2017 U.S. Dist. LEXIS 77440 (D.N.J. May 12, 2017), a case involving Horizon’s topical Pennsaid® 2% diclofenac topical gel. Pennsaid® was originally introduced in 1986 as a 1.5% topical solution administered 4 times per day, but in 2014 Horizon secured FDA approval for a 2% gel that could be applied only 2 times per day.  The 1.5% solution and 2.0% gel formulations were very similar.  Horizon increased the diclofenac concentration from 1.5% to 2%, retained the DMSO concentration at 45.5%, increased the ethanol concentration from 11.79% to 23-29%, retained the propylene glycol concentration at ~11.2%, and added 2.5% HPC as a thickening agent.  In effect, Horizon increased the percentage of diclofenac, increased the percentage of ethanol, and added a thickening agent so that it had a gel instead of a solution.  Horizon’s patent (U.S. 9,066,913) (“the ‘913 patent”) claimed, in paraphrased terms:

A method for treating pain due to osteoarthritis of a knee of a patient in need thereof, said method comprising administering to the knee twice daily a topical formulation comprising:

  • 2% w/w diclofenac sodium;
  • 45.5% w/w DMSO;
  • 23-29% w/w ethanol;
  • 10-12% w/w propylene glycol;
  • 2.5% w/w HPC; and
  • water q.s. to 100%,
  • wherein the formulation has a viscosity of 500-5000 centipoise.

It is not clear from the decision whether Actavis ever attempted to design around the ‘913 patent.  From the court's decision, it appears that Actavis simply copied Horizon’s formulation to make FDA approval easiest, because it is not always easy to predict how FDA will react to a change in formulation for topical drug products.  FDA’s bioequivalence recommendations for 1% diclofenac topical gels illustrate this difficulty, stating:

If the inactive ingredients are different than those contained in the RLD or in significantly different amounts, then the sponsor is to clearly describe the differences and provide information to show that the differences will not affect the safety, efficacy and/or systemic or local availability of the drug.

FDA’s testosterone gel precedent also well illustrates the difficulty generics can have meeting FDA's excipient requirements for topical products.  In that citizen petition response, FDA confirmed that generic applicants that changed the penetration enhancer from the RLD would be required to conduct additional safety studies, and that FDA would not review the safety studies under section 505(j), thus necessitating a 505(b)(2) application and entirely new paragraph 4 certifications.  See October 4, 2010, FDA/CDER letter to Hogan & Hartson, LLP (Abbott Laboratories) (FDA-2010-P-0196).  Pennsaid® 2% gel has two penetration enhancers, DMSO and ethanol.

The story for Pennsaid® 2% gel so far has ended well.  The trial court rejected Actavis’s invalidity defense and entered judgment in favor of Activis, reasoning:

Defendant's evidence does not show that the prior art showed "clearly delineated steps" that if taken and merely tweaked would achieve the desired result. Rather, as in Judge Sleet's Pfizer case, at best, a POSA would have been led to a wide range of possible penetration enhancers, humectants, thickening agents, and other components, each with strengths and weaknesses. Even then only broad ranges were disclosed and without any guidance on how to choose within a range. All in the context of not knowing how choosing one component and at what concentration would compel a change to another component and, even if it stayed, what concentration would allow it to work harmoniously with the other variables. This is not routine optimization of a known formula proven in the prior art to achieve a particular result. As Dr. Kisak's testimony demonstrated, it was more akin to a crap shoot.

Given the trial court's excellent reasoning and analysis of the evidence, we would be very surprised if the decision is disturbed on appeal.  We will report back if we learn of any 505(b)(2) applications filed against Pennsaid®.