Combination Drug Product Patent Validity. Pioneer pharmaceutical companies may have been reluctant to make the significant research and development investments required to bring combination drug products to market based on the perception that patents covering the combination would be vulnerable to attack. This perception of vulnerability stemmed from a 2007 opinion of the Supreme Court, holding that “a combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 401 (2007). But the principle articulated in KSR does not end the validity inquiry.
In two recent cases, the Federal Circuit has upheld the validity of claims to combinations of known agents, in view of evidence that the combination provides unexpected, significant advantages over the prior art. In addition, the District of Delaware recently sustained the validity of combination drug patents in a case where the patentee was represented by the Firm. Together, these opinions may encourage companies to invest in combination drug products, leading to improved therapies for patients.
In April 2014, the Federal Circuit upheld the validity of a patent claiming the combination of an ACE inhibitor (trandolapril) and calcium channel blocker (verapamil hydrochloride) for the treatment of hypertension, in Sanofi-Aventis Deutschland GmBH v. Glenmark Pharmaceuticals Incorporated, USA, No. 12-1489, __ F.3d __, 2014 WL 1552167 (Fed. Cir. Apr. 21, 2014). The court held that substantial evidence supported the jury verdict that the alleged infringer had not proved the patent-in-suit obvious even though combinations of ACE inhibitors and calcium channel blockers were disclosed in the prior art as possible treatments for hypertension. Id. at *4-5. While the court noted that the structural dissimilarity between trandolapril and prior art ACE inhibitors supported the jury’s verdict, id. at 6, the court placed particular emphasis on the surprising evidence that the claimed combination product was superior to the prior art, noting that the combination demonstrated a better side effect profile and longer-lasting efficacy than prior art combinations of the same class of compounds at more frequent dosing intervals. See id. at *4-5.
The unexpectedly superior properties of the claimed combination distinguished Sanofi’s patent from others. See id. at *5 (distinguishing Richardson-Vicks Inc. v. Upjohn Co., 122 F.3d 1476 (Fed. Cir. 1997), holding a patent claim to a combination drug product obvious in the absence of unexpected results, from Pozen Inc. v. Par Pharmaceutical, Inc., 696 F.3d 1151 (Fed. Cir. 2012), holding a patent claim to a combination drug product nonobvious when the combination produced greater efficacy than each active ingredient on its own).
The rationale in Sanofi tracks another recent opinion of the court in Allergan Incorporated v. Sandoz Incorporated, 726 F.3d 1286, 1294 (Fed. Cir. 2013). There, the Federal Circuit sustained the validity of a claim to a method of treating glaucoma or ocular hypertension with a combination of brimonidine and timolol, relying primarily on evidence that the claimed combination was surprisingly no less effective, and had a better side effect profile, at the claimed reduced dosage amounts (twice daily administration instead of three times per day). Id. at 1293-94.
The Federal Circuit rejected the appellant’s arguments that certain disclosures in the prior art, i.e., brimonidine and timolol as single agent treatments for glaucoma in the same concentrations claimed in the patent, id. at 1290; and concurrent administration of brimonidine and timolol dosed twice per day, warranted finding the patent to be obvious. Id. at 1294. The court noted that the prior art lacked any evidence that either active ingredient in the combination produced greater efficacy or better side effects, when combined with an active from the same class of compounds as the second ingredient to the combination. See id. (“[W]e see no reason why the success of unrelated drugs would make it obvious to one of ordinary skill that a fixed combination of brimonidine and timolol could be dosed twice per day without loss of efficacy.”).
In April 2014, the Firm was also able to obtain a significant victory for innovator pharmaceutical company, Avanir Pharmaceuticals, Inc., when the company asserted its patents that covered the use of its Nuedexta® product, a combination of previously known single agents dextromethorphan (DM) and quinidine (Q) that had previously been used in combination, albeit at higher doses, by relying upon unexpected results. After a six-day bench trial before Judge Leonard P. Stark in the District of Delaware, the Court ruled in Avanir’s favor, crediting the evidence the Firm presented that skilled artisans would not have expected the use of the claimed amounts of DM and Q to be effective in treating PBA where “the dose of Q administered was reduced approximately 80-93%” from the prior-art dose, and the treatment unexpectedly remained efficacious and exhibited a better side effect profile.
The two Federal Circuit cases and the recent decision obtained by the Firm provide insight into how pioneer pharmaceutical companies can develop more solid patent protection for combination drug products before litigation ensues. The cases also provide a significant roadmap to litigation when the product covered by such patents come under attack.