by Chris Holman
A branded drug manufacturer can sometimes extend its exclusive right to market a drug by patenting a method of using the drug and successfully suing a potential generic competitor for infringement based on the premise that an instruction or warning appearing on the generic product’s label will induce doctors and/or patients to infringe the patent. In some cases, a generic company can skirt infringement by means of a “skinny label” that carves out the patented method, a practice that is the subject of a pending petition for certiorari in Teva v. GSK, as discussed by Dennis in a recent post (see an earlier post for a more detailed discussion of Teva and skinny labels).
In Teva, the drug is approved for the treatment of multiple indications, two of which are unpatented, and the generic company attempted to avoid infringement by carving out (unsuccessfully, absent Supreme Court intervention) an indication covered by the patent. In a case in which a patent covers a method of using the drug safely, as opposed to a new indication, the skinny label option is generally not available, and the generic product label will be required to closely track the label of the branded product. A remaining option for a generic company facing such a patent is to challenge it in a Hatch-Waxman proceeding and successfully argue that the patent claims are invalid and/or not infringed. An example of this appears in the Federal Circuit’s recent decision in Genentech v. Sandoz.
The active ingredient at issue in Genentech is pirfenidone, marketed by Genentech under the tradename ESBRIET. Pirfenidone was first studied as an investigational new drug in 1973. In 2004, the United States Food and Drug Administration (“FDA”) granted pirfenidone orphan drug status for treatment of patients with idiopathic pulmonary fibrosis (“IPF”), a chronic, irreversible lung disease. In 2008 it was approved for the treatment of IPF in Japan under the trade name of PIRESPA. Approvals in the European Union and Canada followed in 2011 and 2012, respectively.
When Genentech obtained approval to market pirfenidone (ESBRIET) in the U.S. in 2014, it was granted seven years of orphan drug exclusivity, which expired in 2021. However, Genentech still holds 19 Orange Book-listed patents purportedly covering ESBRIET. The patents were issued between 2009 and 2014, and expire between 2026 and 2033.
Sandoz submitted Abbreviated New Drug Applications (“ANDAs”) seeking approval from the FDA to market a generic version of pirfenidone, to which Genentech responded by bringing a Hatch-Waxman suit, asserting that Sandoz’s generic product would induce the infringement of five of the Orange Book-listed patents. The asserted patents do not claim pirfenidone itself, or the use of pirfenidone to treat IPF. Instead, the patents claim methods for managing certain side effects that can occur when using pirfenidone to treat IPF. The patents fall into two categories: the Liver Function Test (“LFT”) patents and the Drug-Drug Interaction (“DDI”) patents.
The LFT patents are directed to methods for administering pirfenidone to a patient who has exhibited abnormal biomarkers of liver function in response to pirfenidone administration. The asserted claims in these patents recite various options, including: (1) temporarily reducing the dose of pirfenidone and then returning to the full dose, (2) maintaining the full dose of pirfenidone, (3) reducing the dose of pirfenidone, (4) discontinuing pirfenidone for a week and then returning to the full dose, and (5) discontinuing pirfenidone for a week and then returning to a reduced dose.
The DDI patents are directed to methods for avoiding adverse interactions between pirfenidone and fluvoxamine, a drug that can interfere with drug metabolism. The three asserted DDI claims involve methods for administering pirfenidone to a patient taking fluvoxamine by either discontinuing fluvoxamine or modifying the dose of pirfenidone and continuing fluvoxamine.
The district court found the LFT patents invalid for obviousness over a 2005 publication reporting the results of clinicals trials involving the use of pirfenidone in patients with IPF (the “Azuma” reference), combined with the PIRESPA label and “known, standard medical practices.” Prior to reviewing the district court’s analysis, the Federal Circuit noted its:
initial perception that, as the district court noted, varying doses in response to the occurrence of side effects would seem to be a well-established, hence obvious, practice. Thus, claiming it as an invention would appear to be at best a long shot. The district court gave it careful scrutiny, however, as do we.
The Federal Circuit then proceeded to affirm the district court’s obviousness determination, stating that:
The asserted claims in the LFT patents do not represent the invention of a new drug, nor do they recite a novel application of an existing drug. Instead, these claims recite adjusting doses in the presence of side effects, which clinicians routinely do, and which would have been obvious in view of the prior art.
As to the DDI patents, the district court found that although warnings appearing on Sandoz’s proposed label appeared to encourage, recommend, and/or promotes infringement of the patents, there was insufficient evidence of direct infringement. The district court stated that:
Genentech had not shown that any patient would be prescribed both pirfenidone and fluvoxamine such that the methods of the DDI patents would even be relevant. [E]ven if an IPF patient were prescribed fluvoxamine, a physician would likely choose a non-infringing treatment adjustment over any of the claimed methods.
The Federal Circuit affirmed, noting that the evidence of record included testimony from physicians that, in their decades of treating IPF patients, they had never prescribed pirfenidone to an IPF patient taking fluvoxamine; and were they to find themselves in that position, they would choose a noninfringing response—i.e., prescribing nintedanib instead (nintedanib is another drug approved by FDA for the treatment of IPF).
Genentech argued that if an IPF patient needed fluvoxamine, instead of a doctor prescribing nintedanib to treat their IPF, the doctor could prescribe pirfenidone and an alternative to fluvoxamine. However, the court credited Sandoz’s expert testimony to the effect that:
a pulmonologist prescribing pirfenidone would not be able to alter another physician’s prescription of fluvoxamine or take over that aspect of the patient’s treatment. Therefore, the pulmonologist would prescribe nintedanib to be taken in conjunction with the patient’s preexisting prescription of fluvoxamine.
This was a split decision, with Judge Newman dissenting without offering an opinion.