Merck Sharp & Dohme Corp. v. Sandoz Inc.

Lead compound analysis established that the asserted claims were not invalid as obvious.

October 14, 2015

Robins Kaplan GENERICally Speaking: A Hatch-Waxman Litigation Bulletin

Case Name: Merck Sharp & Dohme Corp. v. Sandoz Inc., Civ. No. 3:12-cv-03289-PGS-LHG, 2015 U.S. Dist. LEXIS 113710 (D.N.J. Aug. 27, 2015) (Sheridan, J.)

Drug Product and Patent(s)-in-Suit: Emend® (fosaprepitant dimeglumine); U.S. Patent No. 5,691,336 ("the '336 patent") 

Nature of the Case and Issue(s) Presented: The issue here concerns whether a lead-compound analysis was necessary to the Defendant’s prima facie obviousness case.

Merck is the assignee of the '336 patent that claims fosaprepitant dimeglumine, which prevents chemotherapy-induced nausea and vomiting ("CINV"), a side effect of highly emetogenic chemotherapy administered for the treatment of certain forms of cancer. Fosaprepitant dimeglumine is able to obstruct a neurological pathway known as the Substance P-NK-1 receptor system, and is administered in intravenous form to patients.

On January 24, 2012, Sandoz filed an ANDA with the FDA seeking approval to manufacture, use, and sell fosaprepitant dimeglumine intravenous powder prior to the expiration of the ’336 patent. Sandoz’s ANDA submission included a Paragraph IV certification indicating that all claims of the ’336 patent were invalid, unenforceable, and/or not infringed. In response, Merck filed suit against Sandoz alleging infringement of claims 15, 16, 18 and 19. Sandoz filed counterclaims against Merck asserting that each of those claims was invalid due to obviousness. The parties stipulated that Sandoz’s ANDA product infringed the asserted claims. The issue of obviousness was the subject of a 6-day bench trial. The court found the patent not invalid.

Why Merck Prevailed: The first issue concerned whether to perform a lead-compound analysis in order for Sandoz to make a prima facie case of obviousness, and if it were performed, whether the compound known as aprepitant would have been the logical choice for modification to a person of ordinary skill in the art at the time that the compound now known as fosaprepitant dimeglumine was developed. Sandoz relied on several cases suggesting that a lead-compound analysis was not necessary. But the court found those cases distinguishable. In one case, the court noted that there was no lead-compound analysis because a patent examiner had initially rejected a patent application due to obviousness. In another case, there was no need for a lead-compound analysis because that court short circuited the issue when it presumed that a prima facie case of obviousness had already been established. After rejecting the case law relied on by Sandoz, the court determined that a lead-compound analysis was, in fact, warranted.

Merck argued that at the time of invention, a person of skill in the art would have had to choose from a "wall" of prior art that included well-studied, potent and promising compounds from companies such as Pfizer, Sanofi, Glaxo, Rhone-Poulenc Rorer and even Merck itself. Additionally, one of the cited prior-art references disclosed 601 different morpholine chemical compounds that a person of skill in the art could have selected from. In comparison to compound 96 (one of the precursor compounds that lead to the patented compound), the other compounds would have been a more reasoned starting point because they were well-characterized and were accompanied by in vitro and in vivo data showing them to be highly potent, promising compounds, which were described in contemporaneous scientific literature as “leads for further optimization.” Sandoz argued in response that researchers at Merck were able to synthesize fosaprepitant in about three months, which was a relatively short period of time to synthesize a new compound. This rapid synthesis, Sandoz argued, was evidence that the compound was obvious. But the court rejected this argument, finding that the length of time it took to synthesize a new compound was a legally insufficient basis to find that the compound was obvious. Accordingly, the court found that Sandoz had failed to establish a prima facie case of obviousness.

Even though the case could have been disposed of at this point, the court reviewed Merck’s objective indicia of non-obviousness. With respect to unexpected results, the court was persuaded by Merck’s evidence that fosaprepitant dimeglumine exhibited (i) stability prior to administration, (ii) rapid conversion in vivo, despite its excellent stability outside of the body, (iii) exceptional solubility prior to administration, and (iv) safety and efficacy in vivo compound. Of particular importance to the court were the last three factors, which the court found to be especially unexpected. The court also determined that fosaprepitant dimeglumine fulfilled a long-felt, unmet need. Merck’s expert testified that at the time of invention there was a very strong need for a drug that could be used in the treatment of CINV that could be administered intravenously. Merck’s patented compound met that need. Finally, the court found that commercial success was not in dispute. Sandoz admitted in court that it tended to pursue products that it can "make a profit at selling." The court also noted that Sandoz has specifically pursued a generic version of fosaprepitant dimeglumine, despite the fact that it could also sell aprepitant, a different drug.

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