United States: Apotex Biosimilar Cleared Of Infringement But Pre-Marketing Notice Still Required

In what may be the first decision on the merits in a patent infringement suit brought under the Biologics Price Competition and Innovation Act (BPCIA), the U.S. District Court for Southern District of Florida has found that the method of making the Apotex biosimilar versions of Amgen's Neupogen® (filgrastim) and Neulasta® (pegfilgrastim) products does not infringe the asserted Amgen patent. Nevertheless, the court enjoined Apotex from entering the market until 180 days after it gives Amgen notice of commercial marketing once its biosimilar products are approved.

The Amgen Patent At Issue

As discussed in this article, after Apotex filed its biosimilar applications, Amgen and Apotex followed the patent dance provisions of the BPCIA, and Amgen's U.S. Patent No. 8,952,138 was selected for litigation.

The '138 patent relates to a method of refolding a protein expressed in a non-mammalian expression system, a process that often is necessary to obtain proteins with the correct three-dimensional structure from a preparation that contains "inclusion bodies" of misfolded proteins. Refolding methods typically involve the use of mixtures of reducing agents, denaturants, and aggregation inhibitors under specific pH and redox potentials. Independent claim 1 of the '138 patent recites:

1. A method of refolding a protein expressed in a non-mammalian expression system and present in a volume at a concentration of 2.0 g/L or greater comprising: (a) contacting the protein with a refold buffer comprising a redox component comprising a final thiol-pair ratio having a range of 0.001 to 100 and a redox buffer strength of 2 mM or greater and one or more of: (i) a denaturant; (ii) an aggregation suppressor; and (iii) a protein stabilizer; to form a refold mixture; (b) incubating the refold mixture; and (c) isolating the protein from the refold mixture.

Apotex's Biosimilar Applications

Apotex filed abbreviated Biologics License Applications (aBLA) Nos. 761026 and 761027 seeking FDA approval of biosimilar versions of Amgen's Neupogen® (filgrastim) and Neulasta® (pegfilgrastim) products. According to the district court decision, Apotex's protein refolding process involves solubilizing 144-216 grams of inclusion bodies in 7.2 L of solubilization buffer to which is added dithiothreitol (DTT), which in turn is added dropwise into 160 L of refolding buffer without redox components. Oxidant, reductant, and oxidant are then added stepwise as illustrated below.

'138 Patent Not Infringed

In a bench trial, the U.S. District Court for the Southern District of Florida found that Apotex's method did not infringe the '138 patent.

  • The court had construed clause (a) of claim 1 as resulting in the formation of a "refold mixture" with a "high protein concentration" of 1.0 g/L or greater. The court determined that Apotex's refold mixture did not have that much protein. In this regard, the court noted that the aBLAs specified a total protein limit of 0.708g/L and, in 91 batches, 0.56 g/L was the highest total protein concentration in the refold buffer.
  • The court had construed clause (a) as reciting a "redox buffer strength" of between 2 mM and 100 mM, noting that the upper limit was required because of solubility issues. Amgen had asserted that this aspect of the claims was infringed under the doctrine of equivalents, but the court disagreed. In particular, the court found that Apotex used a smaller volume of more concentrated redox components, and that Amgen had failed to show that methodology was equivalent to the claimed methodology.

Permanent Injunction Against Apotex

Notwithstanding its finding of no infringement, the court entered a permanent injunction against Apotex under the pre-marketing notice provisions of the BPCIA (42 U.S.C. § 262(1)(8)(A)):

Apotex must provide Amgen with at least 180 days' notice before the date of the first commercial marketing of the biological product approved by the FDA. 42 U.S.C. § 262(1)(8)(A). Apotex and those acting in concert with it are enjoined from any commercial marketing of Apotex's Filgrastim [or Pegfilgrastim] Product, including selling that product or offering it for sale for use in the United States, until Apotex gives Amgen proper notice, at least 180 days before first commercial marketing but not before Apotex's Filgrastim [or Pegfilgrastim] Product is licensed by the FDA, and the 180-day notice period is exhausted.

Inter Partes Review Of The '138 Patent

Apotex filed a petition for Inter Partes Review of the '138 patent that was accorded a filing date on August 25, 2016. Amgen likely will defend the patent, and unless Amgen and Apotex settle their dispute over filgrastim and pegfilgrastim, Apotex likely still will want to invalidate the patent.

Other Neupogen® Biosimilar Litigation

Sandoz's Zarxio® (filgrastim-sndz) product was the first biosimilar product approved by the FDA, and has been on the market since September 2015. Amgen has asserted U.S. Patent No. 6,162, 427 and U.S. Patent No.8,940,878 against Sandoz in litigation pending in the U.S. District Court for the Northern District of California.

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