Introduction

The Amgen, Inc. and Amgen Manufacturing, Limited (“Amgen”) litigation against Hospira, Inc. (“Hospira”), filed in September 2015, was one of the earliest cases filed under the Biologics Price Competition and Innovation Act (“BPCIA”).  The case involves Hospira’s proposed biosimilar to Amgen’s Epogen®/Procrit® (epoetin alfa).  The procedural posture is somewhat complicated, as there are district court proceedings and an interlocutory appeal to the Federal Circuit underway simultaneously.  Furthermore, several issues raised in the dispute will be directly affected by the outcome of the decision in the consolidated Sandoz v. Amgen and Amgen v. Sandoz cases that are currently under consideration by the Supreme Court.

Epoetin alfa is a human erythropoietin that stimulates the production of red blood cells (erythropoiesis).  Epoetin alfa is produced in cell cultures using recombinant DNA technology.  The product is manufactured by Amgen and sold in the United States by Amgen as Epogen® and by Janssen, a subsidiary of Johnson & Johnson, as Procrit®.  Epoetin alfa is approved in the United States for treating anemia due to chronic kidney disease, anemia due to the use of zidovudine in HIV-infected patients, and the effects of concomitant myelosuppressive chemotherapy treatment. Epoetin alfa is also indicated to reduce the need for blood transfusions in certain patients undergoing certain types of elective surgery.

Epogen® first received FDA approval in 1989. Amgen prevailed in legal battles in the early 1990’s regarding patent ownership, and epoetin alfa has gone on to become a  blockbuster biologic, with yearly revenues consistently reaching over $1 billion annually since the mid-1990s, peaking at $2.6 billion in 2004, with around $1.3 billion in 2016.

Hospira, Inc. (“Hospira”) submitted an abbreviated biologics license application (“BLA”) seeking to market a proposed biosimilar (referred to by FDA as “Epoetin Hospira”) to Amgen’s Epogen® (epoetin alfa) in December 2014. Hospira publicly announced the submission of the application (BLA 125545) in January 2015, and the application was acquired by Pfizer when it purchased Hospira in 2015.  The original BSUFA date (target goal for FDA action) on the application was November 2015, but the FDA initially rejected the application.  Pfizer and Hospira resubmitted the application in December 2016. As we previously reported here, the FDA’s Oncologic Drugs Advisory Committee (ODAC) reviewed the application at a public meeting on May 25, 2017, and recommended approval across all indications.  Pfizer has publicly stated that, once approved, the product will be commercialized pursuant to an agreement between Pfizer and Vifor Pharma, Inc.

Hospira’s Retacrit® was approved in the EU in 2007, and according to Pfizer, its product is the first biosimilar erythropoiesis-stimulating agent (“ESA”) recommended for approval by an FDA Advisory Committee.  The FDA will take the ODAC’s recommendation into consideration before taking final action on the application, and although a specific date has not been announced, based on the date of the ODAC recommendation, a final decision on “Epoetin Hospira” could come as early as this summer.

The “Patent Dance” Between the Parties

In the Complaint, Amgen noted that this case was one of the first BPCIA infringement cases generally, and that it was also one of the first actions seeking to specifically enforce the application disclosure provision of section (l)(2)(A) and commercial notice provision of section (8)(A) of the BPCIA.  While this is a substantive patent infringement case, the disclosure and notice provisions of the BPCIA have taken center stage in the litigation thus far.  As previously discussed here, here, and here, at the time of this writing, the Supreme Court is considering the issues of: (1) whether a biosimilar applicant is required to provide the reference product sponsor with a copy of its biologics license application and related manufacturing information or whether the “patent dance” is optional; and (2) whether a biosimilar product must be “licensed” (meaning FDA-approved) before a biosimilar applicant can provide an effective 180-day  notice of commercial marketing (“NCM”) to the reference product sponsor (“RPS”), or whether such notice can be provided any time after the FDA has accepted the application for review.  The outcome of the Supreme Court’s decision will impact the issues surrounding these same questions in the Amgen v. Hospira litigation.

Hospira filed its application in December 2014, and the application was accepted for review by FDA in February 2015. This acceptance kicked off the complex series of deadlines for the exchange of information related to patent infringement, validity, and enforceability, affectionately known as the “patent dance.” One of Congress’s stated goals of the BPCIA’s “patent dance” is to potentially streamline and narrow patent litigation for biosimilar products.  According to the Compliant, Hospira notified Amgen when the FDA had accepted its BLA.  Although Hospira provided a copy of its BLA to Amgen on February 23, 2015, Amgen alleges that Hospira did not satisfy the disclosure requirements of section (l)(2)(A) of the BPCIA because Hospira did not provide any manufacturing information in addition to its BLA.

Following receipt of Hospira’s BLA, Amgen provided Hospira with a 3A list of patents which it believes could be asserted against Hospira. According to the pleadings submitted to the Court, Hospira’s 3A list identified only two patents.  The parties exchanged detailed statements, but Amgen has alleged that Hospira’s statement was deficient.  In the next step of the information exchange, section 4(a) of the BPCIA says that the RPS and the applicant “shall engage in good faith negotiations to agree on which, if any, patents” identified on their respective 3A and 3B lists “shall be the subject of an action for patent infringement.” According to Hospira’s Answer filed in the litigation, “Hospira advised Amgen that it accepted the patents” identified on Amgen’s 3A list and that litigation could proceed without further negotiations. Amgen’s Complaint, however, accuses Hospira of violating section (l)(4) of the BPCIA and contends that such acceptance did not amount to good-faith negotiations.

Hospira provided a notice of commercial marketing to Amgen on April 8, 2014.  Amgen objected to the notice as ineffective because it was provided before Hospira received approval (“licensure”) of its proposed product from the FDA.  The pleadings indicate that Hospira responded that it would rely on the April 8, 2015 notice and would not provide any further notice because in its view, further notice is not required.

The Litigation Begins

The Disclosure of Manufacturing Information Under (l)(2)(A)

On September 18, 2015, Amgen filed a Complaint against Hospira alleging infringement of U.S. Patent No. 5,856,298 (“the ’298 patent”), which Amgen identified in its initial list during the Patent Dance, and U.S. Patent No. 5,756,349 (“the ’349 patent”). In addition to counts based on infringement of these patents, Amgen’s complaint also included counts asserting that Hospira had violated the BPCIA by: 1) not providing manufacturing information along with its BLA in its initial notice to Amgen (Section (l)(2)); and 2) refusing to give NCM following the application’s approval.

In October 2015, Hospira moved to dismiss the count charging a violation of section (l)(2) regarding the disclosure requirements of the BPCIA, arguing that there is no private right of action for the enforcement of provisions of the BPCIA. Instead, Hospira argued that when an applicant elects not to disclose its application and manufacturing information pursuant to section (l)(2)(A) of the BPCIA, a reference product sponsor has a statutory remedy in the form of an immediately available declaratory judgment action, as expressly provided in section 9 of the BPCIA.

Following the Federal Circuit’s denial of a request for en banc review of the split majority panel’s decision in Amgen v. Sandoz which held that the BPCIA did not grant the right to compel compliance with the disclosure requirement of section (2)(A) and that the statute provided the only remedy in the form of a declaratory judgment action pursuant to section 9, Amgen filed an Amended Complaint dropping the section (2)(A) disclosure issue as a separate count. However, as the litigation progressed, Amgen has maintained its position that it requires manufacturing information, particularly to determine whether it may reasonably assert method patents directed to the cell culture in which Hospira’s product would be manufactured. In April 2015, the Court entered a scheduling order and the case was set for trial beginning in September 2017.

During discovery, Amgen sought manufacturing information and FDA correspondence from Hospira.  Hospira objected and sought to limit discovery to issues related to the two patents identified and asserted by Amgen.  In April 2015, the parties submitted letter briefings to the court, and Amgen sought to compel the production of manufacturing information and FDA correspondence.  The district court (Judge Andrews) denied the motion to compel, finding that the information sought was not relevant to the two patents which were asserted in the litigation.

Amgen appealed the decision to the Federal Circuit, and Hospira filed a motion to dismiss Amgen’s appeal for lack of jurisdiction, arguing that the Court’s ruling on the discovery dispute is not a final appealable order subject to the Appeals Court’s jurisdiction.  Hospira further argued that the order does not fall within the scope of the collateral order doctrine.  The Court requested briefing on the issue of jurisdiction as well as the denial of the motion to compel.  Briefing in the appeal was completed in November 2016, and the Federal Circuit heard oral argument on April 3, 2017. In that argument, the panel noted that the Sandoz opinion was still binding on the panel pending Supreme Court review.  The Court asked counsel for both sides what was stopping Amgen from filing new infringement suits on its cell culture patents. Amgen’s position is that it does not have enough information to reasonably file suits under the standards of Rule 11.

Notice of Commercial Marketing

Amgen’s complaint contained a count for declaratory judgment that Hospira’s refusal to provide a post-approval NCM violated the BPCIA, and Amgen sought an injunction prohibiting Hospira from marketing the product until 180 days after a post-approval NCM was provided to Amgen.

In October 2015, Hospira moved to dismiss the count regarding the NCM. Hospira argued that under its reading of the BPCIA, the 180-day NCM is only necessary for applicants who were not participating in the patent dance, and that Hospira had participated by providing its BLA to Amgen following its acceptance for review by the FDA.

In August 2016, the district court denied Hospira’s motion to dismiss the count regarding the NCM.  The Court recognized that the Federal Circuit’s Sandoz v. Amgen decision held that NCM is only effective after the FDA has “licensed” (approved) a product, and that the Federal Circuit’s Apotex v. Amgen case also concluded that the 180-day delay between NCM and entering the market was a mandatory requirement enforceable by injunction. As such, the district court held that it was presented with the same question that had been answered by the Federal Circuit, and under current law, Hospira’s motion should be denied.

Under current Federal Circuit precedent, a notice of commercial marketing is a “stand alone” requirement, meaning that it must be provided regardless of whether the parties complete the patent dance, and such notice can only be provided once the biosimilar has been approved by the FDA.  See Amgen, Inc. v. Sandoz, Inc., 794 F.3d 1347 (Fed. Cir. 2015). However, as discussed above, that specific issue is currently under review by the Supreme Court.  The Supreme Court heard oral arguments on April 26, 2017, and a decision is expected in late June.

The Status of the Substantive Patent Infringement Case

The ’298 patent, entitled “Erythropoietin Isoforms,” issued on January 5, 1999, from an application filed on November 3, 1994, and claims priority through a series of applications to October 13, 1989. The ’298 patent is assigned on its face to Amgen Inc. The ’349 patent, entitled “Production of Erythropoietin,” issued on May 26, 1998, from an application filed on June 6, 1995, and claims priority through a series of applications to December 13, 1983. The ’349 patent is assigned on its face to Amgen Inc.

Both of these patents are currently expired. As such, even if Amgen were to prevail on its claims of infringement, the two patents in suit would not prevent Hospira from launching its product upon approval (and effective NCM), but could subject Hospira to potential damages.  Amgen has taken the position that if additional patents are identified based on discovery, or if new patents issue that might be infringed, claims based on those patents could be asserted, which could prevent Hospira from entering the market.  On the other hand, Hospira has taken the position that Amgen is precluded by the BPCIA from asserting any existing patents that were not identified on Amgen’s original 3A patent list.

Infringement and invalidity contentions regarding the two patents were exchanged in April and May 2016. A Markman hearing was held in September 2016, and the district court issued an opinion construing the disputed claim terms and of the ’298 patent in November 2016.  In August 2016, Amgen filed a sealed motion for leave to file an amended complaint adding three additional defendants. As discussed in an October 2016 order granting the motion in part, the court noted that adding defendants so close to trial (scheduled for September 2017) would be prejudicial to the defendant and denied the motion as to that point.  However, the court noted that the proposed amended complaint also added two new theories of infringement based largely on the existing facts of the case, and the court allowed these theories to be added with respect to Hospira. One of these two new theories appears to be that Hospira directed and controlled an unidentified Hospira agent to infringe the patent. An additional count of infringement of the ’349 patent under 35 U.S.C. § 271(b) was added as well. This count alleged induced infringement as a result of Hospira directing two (redacted) companies to infringe claims of the ’349 patent.

Expert discovery closed on May 5, 2017, and dispositive motions were due by May 12, 2017.  Amgen did not file any dispositive motions. Hospira filed a motion for summary judgment that:

1. all of Hospira’s accused erythropoietin drug substance batches are protected by the safe harbor provisions of 35 U.S.C. § 271(e)(1) and thus do not infringe U.S. Patent Nos. 5,756,349 and 5,856,298; and
2. that Hospira does not infringe the asserted claims of U.S. Patent No. 5,856,298 either literally or under the doctrine of equivalents.

Briefing on Hospira’s summary judgment motion should be completed in early June, along with any briefing on Daubert motions. On May 26, 2017, Amgen filed a motion for a preliminary injunction seeking “to enjoin [Hospira] from launching a biosimilar version of Amgen’s EPOGEN® (epoetin alfa) product until Hospira has complied with the [notice of commercial marketing] requirement of 42 U.S.C. § 262(l)(8)(A).” Hospira has not yet responded to the motion for preliminary injunction.

A pretrial conference is currently scheduled for September 8, 2017, and a five-day jury trial will begin on September 18, 2017.  As noted above, a final decision on FDA approval of “Epoetin Hospira” could come as early as this summer.  We will continue to keep you apprised of further developments.