January 22, 2016
Case Name: Cumberland Pharms., Inc., v. Mylan Institutional LLC, Civ. No. 12-C-3846, 2015 U.S. Dist. LEXIS 134495 (N.D. Ill. Oct. 2, 2015) (Pallmeyer, J.)
Drug Product and Patent(s)-in-Suit: Acetadote® (acetylcysteine); U.S. Patents Nos. 8,148,356 (“the ’356 patent”) and 8,399,445 (“the ’445 patent”)
Nature of the Case and Issue(s) Presented: Acetadote is an intravenous treatment for suspected acetaminophen overdoses. Acetylcysteine is an unstable molecule and tends to degrade rapidly when in solution and exposed to air. To address this instability issue, all acetylcysteine formulations sold prior to the issuance of the ’356 and ’445 patents were stabilized by the addition of edetate disodium (“EDTA”), a chelating agent. EDTA serves to sequester free metal ions in solution that tend to degrade the acetylcysteine molecule. Although EDTA is an effective chelating agent, it is also known to cause a variety of undesirable side effects, such as allergic reactions, hypokalemia, hypomagnesemia, hypotension and reproductive developmental toxicity in test animals. In response, Cumberland developed an EDTA-free acetylcysteine formulation, which the patents-in-suit cover.
In 2012, Cumberland sued Mylan alleging infringement of the ’356 and ’445 patents. Cumberland withdrew its infringement allegations related to the ’356 patent, and Mylan admitted infringement of claims 1-14 of the ’445 patent, but challenged the validity of the ‘445 patent on the grounds of derivation, anticipation, and obviousness. The parties filed cross-motions for summary judgment of (in)validity concerning the ’445 patent, which the court denied. The court held a bench trial in September of 2014. The court concluded that the ’445 patent was valid and infringed.
Why Cumberland Prevailed: Mylan’s argued that Cumberland’s decision to create an EDTA-free formulation of acetylcysteine was prompted by communications with the FDA; specifically, Cumberland derived the idea for EDTA-free acetylcysteine from employees of the FDA. Mylan relied on a letter from the FDA dated December 10, 2002, wherein FDA made comments in response to Cumberland’s NDA for EDTA-containing Acetadote. The FDA asked Cumberland to provide scientific and regulatory justification for the inclusion of EDTA as a component in the drug product. In addition, the FDA also requested that Cumberland provide a description of the pharmacological properties for EDTA in the product. Leo Pavliv was the senior vice president of operations when the letter was received, as well as the sole inventor of the patents-in-suit. He admitted that prior to receipt of the FDA’s letter, neither he nor any other employee at Cumberland had considered the possibility of removing EDTA from the formulation entirely. He also admitted that the FDA letter prompted him to consider whether including EDTA in Acetadote was even necessary.
But the court disagreed that the December 10 letter proved that FDA employees had conceived of an EDTA-free version of Acetadote. Conception, the court noted, must encompass all limitations of the claimed invention. In this case, the FDA letter did not direct Cumberland to consider removing EDTA and hold every other variable of the formulation constant. Nor did the letter present a concept that could readily be reduced to practice. The letter did not direct Cumberland to remove or minimize EDTA. It simply asked Cumberland to justify the use of EDTA in the product. The court also pointed to subsequent communications between Mr. Pavliv and the FDA that strongly indicated that it was Mr. Pavliv’s suggestion, not the FDA’s, that a protocol should be developed to determine the impact on product stability of decreasing and ultimately completely removing EDTA from the formulation.
The court further noted that at no point did the FDA offer instructions on how, when, or in what order any experiments or tests should be performed, and that Mr. Pavliv was solely responsible for designing and implanting the study protocol. The court also rejected Mylan’s argument that Cumberland was unable to establish a conception date, finding that Mylan had failed to establish that anyone other than Mr. Pavliv ever conceived of a definite and permanent idea of an EDTA-free Acetadote formulation.
The court next addressed Mylan’s anticipation argument. Mylan based its anticipation argument on the Approval Letter sent to Cumberland by the FDA and the approved package insert for the product. The court found that Mylan had not met its burden of establishing invalidity by anticipation. First, the approval letter was posted on the FDA website without the product insert; thus, those documents were not intended to be part of a single communication. The court further rejected Mylan’s incorporation-by-reference argument because the approval letter needed to clearly identify the subject matter and where to find it in the referenced document. The approval letter did not cite the package insert or any other document containing the claim limitations in a manner that made clear that the material was effectively part of the host document. Accordingly, the documents could not be considered a single prior-art reference.
Last, the court addressed Mylan’s obviousness argument, which also relied on the FDA Approval Letter and approved package insert. The court first found that Mylan failed to indicate that there was a motivation to remove EDTA from acetylcysteine formulations. Until Mr. Pavliv conducted his studies, it was generally understood in the relevant scientific community that EDTA or some other chelating agent was necessary to maintain stability. The court determined that evidence related to secondary considerations of non-obvious were essentially irrelevant, due to the fact that Mylan failed to establish a prima facie case of obviousness. Accordingly, the court concluded that the ’445 patent was valid and infringed by Mylan.