Introduction

March 6 2015 marked a turning point for the emerging US biosimilars market. The Food and Drug Administration (FDA) approved Sandoz's application to market Zarxio, the first biosimilar drug in the United States. Zarxio (approved as 'filgrastim-sndz') is a biosimilar of Amgen's Neupogen, which had sales of $1.4 billion in 2013. Zarxio is currently on the market in Europe (as 'Zarzio'), and has now been approved in the United States as a 0.5 millilitre (ml) and 0.8 ml injectable for all five of the indications on the Neupogen label, including the treatment of patients with various cancers and various forms of neutropenia (white blood cell disorders).

Biologics Price Competition and Innovation Act

Zarxio was approved under the Biologics Price Competition and Innovation Act 2009, which was enacted on March 23 2010 as part of legislative reforms related to the Patient Protection and Affordable Care Act. Among other things, the Biologics Price Competition and Innovation Act provides data protection and market exclusivity periods for biologic drugs, an expedited FDA approval pathway for biosimilar versions of biologics and a patent dispute resolution procedure for such biosimilars.

Biologics and biosimilars

Biologics are generally made using living cells and are often prepared by genetic engineering. Biologics include viruses, vaccines, blood components or derivatives, antibodies and non-chemically synthesised proteins, and are used to prevent, treat or cure a human disease or condition.(1)

A biosimilar is highly similar to an FDA-approved biologic, allowing for "minor differences in clinically inactive components", but with "no clinically meaningful differences… in terms of safety, purity, and potency".(2)

To obtain marketing approval, a biosimilar applicant must submit in vitro, animal and clinical data to the FDA and must show – among other things – that the biosimilar:

  • "utilize[s] the same mechanism or mechanisms of action" as the biologic;
  • has the same route of administration, dosage form and strength; and

is manufactured, processed and handled in facilities that meet "standards designed to assure that the [biosimilar] continues to be safe, pure, and potent".(3)

Exclusivity and the 'patent dance'

In some respects, the Biologics Price Competition and Innovation Act provides a framework for biosimilars that is similar to that provided for generic small-molecule drugs under the Drug Price Competition and Patent Term Restoration Act 1984 (the Hatch-Waxman Act). However, there are significant differences. For example, while an innovator biologic drug (like an innovator small-molecule drug) is afforded various exclusivity periods – generally, four years of data exclusivity, followed by eight years of market exclusivity(4) – the Biologics Price Competition and Innovation Act does not provide a market exclusivity period for the first biosimilar filer. Further, there is no stay of FDA approval if the innovator biologic licence holder files a patent infringement action, and there is no provision in the act preventing FDA approval if the biosimilar applicant indicates that it will wait for relevant innovator patents to expire before it enters the market.

For biologics, there is also no equivalent of the Orange Book (an FDA publication listing the patents owned by the innovator that purport to cover the innovator's approved small molecule drugs). Instead, the Biologics Price Competition and Innovation Act sets out an elaborate scheme under which the biosimilar applicant must submit certain information regarding its application (under conditions of confidentiality) to the innovator biologic licence holder, which in turn triggers a succession of periods during which the parties exchange lists of patents that they allege will be infringed by the biosimilar and/or are invalid or unenforceable, together with any offers to license those patents.(5) This process has been referred to as a 'patent dance'. It requires both parties to exchange detailed statements describing "on a claim by claim basis, the factual and legal basis" of their patent infringement, validity and unenforceability contentions.(6) This is followed by a short period during which the parties must negotiate in good faith in an attempt to agree on a list of patents to litigate.(7)

Separately, the biosimilar applicant must also give the innovator biologic licence holder at least 180 days' advance notice of the date on which it intends to start first commercially marketing the biosimilar. On receipt, the licence holder may then seek a preliminary injunction.(8) The Biologics Price Competition and Innovation Act also contains provisions limiting declaratory judgment actions.(9)

Whether or not – and the extent to which – parties must respect the procedure set out in the Biologics Price Competition and Innovation Act before filing proceedings in district court is the subject of various litigations. These include Sandoz Inc v Amgen Inc,(10) Amgen Inc v Sandoz Inc(11) andJanssen Biotech, Inc v Celltrion Healthcare Co, Ltd,(12) all of which are ongoing.

In the meantime, while Sandoz now has the FDA's approval to market Zarxio, it has agreed not to launch in the United States until the earlier of April 10 2015, or a favourable ruling on Amgen's motion for a preliminary injunction in Amgen Inc v Sandoz Inc.(13)

Pending biosimilar applications

In February 2015 the FDA accepted Hospira's application to market a biosimilar of Janssen's biologic Remicade (infliximab). This application is the subject of Janssen Biotech, Inc v Celltrion Healthcare Co, Ltd.(14) In addition, Apotex has filed applications to market biosimilars of Amgen's Neupogen and Neulasta (pegfilgrastim).

Sandoz's Zarxio application was approved within seven months. Given that timing, it is likely that Hospira's and Apotex's biosimilar applications may be approved in the near future.

Comment

Now that Zarxio has opened the door to other biosimilar approvals, it may be prudent for IP owners in the biologics industry to begin identifying relevant patents and conducting due diligence to prepare not only for patent litigation, but also potentially for inter partes review proceedings before the US Patent and Trademark Office. More than 70 inter partes review petitions have been filed on biopharmaceutical and biotechnology patents to date, and it is likely that biosimilar applicants will explore inter partes review as a way to limit the number or scope of patents that may have to be litigated in district court.

For further information on this topic please contact Robert S Schwartz or Corinne E Atton at Fitzpatrick, Cella, Harper & Scinto by telephone (+1 212 218 2100) or email (rschwartz@fchs.com orcatton@fchs.com). The Fitzpatrick, Cella, Harper & Scinto website can be accessed at www.fitzpatrickcella.com.

Endnotes

(1) 42 USC § 262(i)(1).

(2) 42 USC § 262(i)(2).

(3) 42 USC § 262(k)(2).

(4) 42 USC § 262(k)(7).

(5) 42 USC § 262(l)(2)-(3).

(6) 42 USC § 262(l)(3).

(7) 42 USC § 262(l)(4).

(8) 42 USC § 262(l)(8).

(9) 42 USC § 262(l)(9).

(10) Civ No 3:13-cv-02904 (ND Cal).

(11) Civ No 3:14-cv-04741 (ND Cal).

(12) Civ No 1:15-cv-10698 (D Ma).

(13) Civ No 3:14-cv-04741 (ND Cal), Id at DI 64.

(14) Civ No 1:15-cv-10698 (D Ma).

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