We recently came across a nicely sequenced series of patents owned by Nalpropion Pharmaceuticals, Inc. ("Nalpropion"), covering its hugely successful weight management drug Contrave®. Contrave is a combination of two old drugs – bupropion and naltrexone – in sustained release form. Remarkably, each of these drugs had been reported to cause weight loss before Nalpropion filed its first patent application. One prior art patent (“the O’Malley Patent”) had even disclosed this combination of drugs for minimizing weight gain during smoking cessation therapy.
Nalpropion filed its first patent application on April 29, 2003, based on some mouse data showing that the combination reduced food intake in a mouse model, and some other in vitro data. Nalpropion did not disclose its formulation for the drug, but it did disclose that bupropion and naltrexone could be co-formulated in a sustained release dosage form. In the patent that eventually granted, U.S. Patent 7,462,626 ("the '626 patent"), Nalpropion claimed:
A method of treating overweight or obesity, comprising administering a weight loss effective amount of a first and second compound to an individual who has been diagnosed as suffering from overweight or obesity in order to treat said over-weight or obesity, wherein said first compound is bupropion, or a pharmaceutically acceptable salt thereof, and said second compound is naltrexone, or a pharmaceutically acceptable salt thereof, and wherein the weight loss activity of said first and second compounds is enhanced compared to the administration of the same amount of either compound alone.
A dependent claim covered the combination of naltrexone and bupropion in a sustained release format.
Three years later, on June 5, 2006, Nalpropion filed another patent application, based on the dissolution profile of a sustained release formulation it had developed. The patent that eventually granted, U.S. Patent 8,916,195 ("the '195 patent"), claimed:
A method of treating overweight or obesity having reduced adverse effects comprising orally administering daily about 32 mg of naltrexone and about 360 mg of bupropion, or pharmaceutically acceptable salts thereof, to a person in need thereof, wherein the bupropion or pharmaceutically acceptable salt thereof is administered as a sustained release formulation, wherein the naltrexone or pharmaceutically acceptable salt thereof is administered as a sustained release formulation, and wherein said sustained release formulation of naltrexone has an in vitro naltrexone dissolution profile in a dissolution test of USP Apparatus 2 Paddle Method at 100 rpm in a dissolution medium of water at 37° C. of:
a) between 39% and 70% of naltrexone released in one hour;
b) between 62% and 90% of naltrexone released in two hours; and
c) at least 99% in 8 hours;
wherein about 16 mg of said sustained release formulation of naltrexone or a pharmaceutically acceptable salt thereof is administered twice daily, and about 180 mg of said sustained release formulation of bupropion or a pharmaceutically acceptable salt thereof is administered twice daily.
FDA approved Contrave on September 10, 2014, and a mere six months later, on March 12, 2015, Nalpropion received its first paragraph 4 challenge from Actavis Pharmaceuticals (“Actavis”). If you are impressed by the speed of this generic challenge you are not alone.
However, speed does not always guarantee success in this business. Nalpropion was very successful at the trial court in its lawsuit against Actavis, and the trial court sustained the validity of both of its patents. The appeal, in contrast, produced mixed results. The Federal Circuit held that the claims to the combination in the ‘646 patent were invalid based on obviousness, based on the O’Malley patent, but that the ‘195 patent was valid. Nalpropion Pharm., Inc. v. Actavis Labs. FL, Inc., 934 F.3d 1344 (Fed. Cir. 2019).
What caught our attention was Actavis’ sole challenge to the ‘195 patent. Actavis did not challenge the ‘195 patent based on obviousness or inherent anticipation, but only on the basis of written description. Nalpropion had made an almost fatal error when drafting the application, and had only described a USP Type 1 dissolution apparatus.
On reviewing the prosecution history for the ‘195 patent, we learned why Actavis had not challenged the patent based on obviousness. Nalpropion had studied a combination of naltrexone and bupropion during phase II of its development program, in which the naltrexone was immediate release and the bupropion was sustained release, and this combination had produced an undesirable amount of adverse events such as nausea, headache, and dizziness. However, when it administered both ingredients in a sustained release format during its phase III program, it reduced these adverse events by 46%.
The examiner allowed the ‘105 patent to issue, even though Nalpropion had previously disclosed and claimed the formulation of both ingredients in a sustained release format in the ‘646 patent, because Nalpropion’s claims in the ‘105 patent recited the dissolution profile of the product that produced these unexpected results. Kudos to Nalpropion and its patent counsel!