Introduction and Background

The Apotex filgrastim/pegfilgrastim biosimilar litigation was the first biosimilar litigation where the parties participated in the patent dance.  As a result, important issues regarding the interpretation of the Biologics Price Competition and Innovation Act (the “BPCIA”) were raised, including whether a biosimilar applicant (“(k) applicant”) must give 180-days’ notice to the reference product sponsor (“RPS”) before its first commercial marketing in accordance with 42 U.S.C. § 262(l)(8)(A).  The district court (Southern District of Florida) and the Federal Circuit both concluded that such notice was mandatory even when the (k) applicant participates in the patent dance.

Filgrastim and pegfilgrastim have been some of the most-targeted biologics for biosimilars to date.  Sandoz’s Zarxio® (filgrastim) was the first biosimilar approved by FDA, and several applications for pegfilgrastim biosimilars are currently under review by FDA, including at least applications filed by Sandoz, Coherus, and Mylan, in addition to Apotex.

Neupogen® (filgrastim) is indicated to:  (1) decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever; (2) reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia; (3) reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ e.g.‚ febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation; (4) mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; and (5) reduce the incidence and duration of sequelae of severe neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia. Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

Apotex seeks to market and sell its filgrastim product under the name GrastofilTM.  Its BLA was accepted by FDA on February 13, 2015.  Apotex seeks to market and sell its pegfilgrastim product under the name LapelgaTM, and that BLA was accepted by FDA in December 2014.  Neither application has yet been approved.

Litigation:  Round 1 (BPCIA Interpretation)

District Court

On August 6, 2015, Amgen filed its Complaint for patent infringement regarding Apotex’s pegfilgrastim BLA in the Southern District of Florida alleging infringement of two patents, U.S. Patent Nos. 8,952,138 (“the ’138 Patent”) and 5,824,784 (“the ’784 Patent”), and the case was assigned to Judge Cohn (Civil Action No. 15-cv-61631).  According to the Complaint, the inclusion of the ’138 and ’784 Patents is the result of the parties’ participation in the patent dance.  In its October 5, 2015 Answer, Apotex sought not only a declaration of non-infringement and invalidity of the ’138 Patent, but it also asserted that Amgen violated the Sherman Act.  Apotex asserted that Amgen engaged in sham litigation because Apotex told Amgen during the patent dance that it would not begin commercial marketing prior to the expiration date of the ’784 Patent (which expired October 20, 2015) as well as the ’933 Patent (which was not included in the action and was also expired).  Apotex also alleged that it provided irrefutable proof that it would not infringe the ’138 Patent during the patent dance.  Similarly, Apotex included a patent misuse counterclaim—alleging that the litigation was filed to delay Apotex’s market entry—stating that Amgen failed to carry out a good faith investigation based on Apotex’s BLA documents.  Most important to BPCIA interpretation issues, Apotex also sought a declaration that an RPS’s remedy against a (k) applicant that participates in the patent dance but elects not to provide notice of commercial marketing under section (8)(A) is a declaratory judgment suit pursuant to section (9)(B), and not an injunction.

On October 2, 2015, Amgen filed a separate Complaint for patent infringement regarding Apotex’s filgrastim BLA in the same court (Civil Action No. 15-cv-62081).  Apotex again alleged infringement of the ’138 Patent and also asserted infringement of U.S. Patent No. 6,162,427 (“the ’427 Patent”).   The two cases were consolidated in November 2015.

Shortly thereafter, Amgen moved for a preliminary injunction (October 16, 2015), and a hearing was held on December 7, 2015.  The only dispute was the likelihood of success on the merits regarding whether a (k) applicant must give 180-days’ notice before commercial marketing.  The district court granted the preliminary injunction on December 9, 2015.  It relied heavily on the Federal Circuit’s decision in Amgen v. Sandoz, which explains that “the word ‘shall’ in the context of § 262(l)(8)(A) does mean ‘mandatory.’”  Amgen, Inc. v. Apotex Inc., No. 15-cv-61631, 2015 U.S. Dist. LEXIS 183036, at *11 (S.D. Fla. Dec. 9, 2015) (citation omitted).  The district court recognized, however, that because Sandoz did not participate in the patent dance, the Federal Circuit had not directly addressed whether the (8)(A) notice of commercial marketing is also required for a (k) applicant that participates in the patent dance.  Id.  The district court concluded that there is no basis to treat the two applicants differently stating:  “Nothing in the statute or the Sandoz decision leads to or supports such a result; neither the statute nor the Sandoz decision condition the 180 day notice provision of section 262(l)(8)(A) upon a subsection (k) applicant’s compliance with § 262(l)(2).”  Id. at *12.  The district court also countered Apotex’s argument that such a result would give the RPS an extra 180 days of exclusivity by relying on the Federal Circuit’s statement in Amgen v. Sandoz, and that this would not be the “usual case” as applications begin to be filed during the 12-year exclusivity period.[1]  Id. at *13.  In addition, the district court found no basis for a section (l)(9) declaratory judgment action to be the exclusive remedy for failure to comply with the notice of commercial marketing provision.  The district court enjoined Apotex from any commercial marketing until it provided Amgen with notice after FDA licensure and at least 180 days before its first commercial marketing.

Apotex appealed the preliminary injunction on December 10, 2015.

The Federal Circuit Appeal

On July 5, 2016, the Federal Circuit affirmed the district court’s holding that the commercial-marketing provision is mandatory and enforceable by injunction even for (k) applicants that participate in the patent dance.  Amgen Inc. v. Apotex Inc., 827 F.3d 1052 (Fed. Cir. 2016). The Federal Circuit panel was Taranto (opinion author), Wallach, and Bryson, and Apotex’s appeal of the preliminary injunction is Appeal No. 16-1308.

Relying on its Amgen v. Sandoz decision, the Federal Circuit explained that “the notice starting the 180-day clock must follow, not precede, the licensure.”  Id. at 1056.  It reiterated its statements from Amgen v. Sandoz, that the (8)(A) notice requirement is “a standalone notice provision.”  Id. at 1059.  However, given the difference between the two cases, i.e., that Sandoz had not participated in the patent dance whereas Apotex had participated, the Federal Circuit further explained that the notice provision “contains no words that make the applicability of its notice rule turn on whether the applicant took the earlier step of giving the (2)(A) notice that begins the § 262(l) information-exchange process.”  Id. at 1061.  It further concluded that, unlike with (2)(A)’s use of “shall” to initiate the patent dance, there was no statutory basis to give the use of “shall” in the notice provision any meaning other than its usual mandatory meaning.  Id.

The Federal Circuit also made two observations to rebut Apotex’s argument that (8)(A) was not intended to extend the 12-year exclusivity period by an additional 180 days.  First, it relied on its reasoning from Amgen v. Sandoz that delay beyond 12 years will occur less as time goes by and that (k) applicants can seek approval before the 12-year exclusivity period has expired.  Id. at 1061-62.  Second, and perhaps as further explanation for its first point, it stated that “we have been pointed to no reason that the FDA may not issue a license before the 11.5-year mark and deem the license to take effect on the 12-year date—a possibility suggested by § 262(k)(7)(A)’s language about when the FDA approval may ‘be made effective.’”  Id. at 1062.  It explained that (8)(A) would allow “the 180-day notice of commercial marketing to be sent as soon as the license issues, even if it is not yet effective, because it is at the time of the license that ‘the product, its therapeutic uses, and its manufacturing processes are fixed.’”  Id. (citation omitted).

The Federal Circuit also rejected Apotex’s final argument that a declaratory judgment action pursuant to (9)(B) is the exclusive remedy for violating (8)(A).  It found no such exclusivity in the statute, specifically noting that other remedies were not excluded.  Id. at 1064.  It also relied on the monetary and injunctive relief provided by 35 U.S.C. § 271(e)(4) as support for its position that a declaratory judgment action is not intended as the exclusive remedy for (8)(A) violations.  Id.  The Federal Circuit further relied on what it viewed as the likelihood that an RPS would not know “that the applicant will fail to provide the actual 180-day commercial-marketing notice required by (8)(A) until the applicant begins commercial marketing or, at least, declares that it may begin such marketing at any moment.”  Id. at 1065.  It stated that such late notice would result in precisely the rushed decision-making that (8)(A) was designed to prevent.  Id.

The Supreme Court Declines Review

Apotex petitioned for a writ of certiorari of the Federal Circuit’s decision in Case No. 16-1308, which was filed on September 9, 2016.  Two questions were presented:

  1. Whether the Federal Circuit erred in holding that biosimilar applicants that make all disclosures necessary under the BPCIA for the resolution of patent disputes (viz. 42 U.S.C. § 262(l)(2)(A)) must also provide the RPS with a notice of commercial marketing under 42 U.S.C. § 262(l)(8)(A).
  2. Whether the Federal Circuit improperly extended the statutory 12-year exclusivity period to 12 1/2 years by holding that a biosimilar applicant cannot give effective notice of commercial marketing under 42 U.S.C. § 262(l)(8)(A) for its biosimilar product until it receives an FDA license and therefore may not commercially market its biosimilar product for 180 days after receiving its license.

The Biosimilars Council and Mylan Pharmaceuticals filed amici curiae briefs in support of Apotex’s petition on October 14, 2016.  Amgen filed its opposition brief on November 8, 2016.

The Supreme Court denied Apotex’s petition on December 12, 2016.[2]

Litigation:  Round 2 (Infringement and Invalidity)

District Court

On December 11, 2015, two days after the district court granted Amgen’s preliminary injunction, the parties began claim construction briefing in the consolidated action.  The claim construction hearing was held on February 5, 2016, and the district court issued its claim construction order on April 7, 2016.

The parties also filed two separate joint stipulations of dismissal on May 31, 2016.  The first sought dismissal (without prejudice) of Apotex’s Sherman Act counterclaim.  The second sought dismissal (without prejudice) of all claims and counterclaims related to the ’427 and ’784 patents.  The district court granted both on June 14, 2016.

A bench trial was held July 11-15 and 18, 2016.  On July 14, 2016, and at the conclusion of Apotex’s presentation of evidence, the district court entered partial findings that the ’138 Patent was not anticipated, did not lack adequate written description, was not indefinite, and was not obvious.[3]

On September 6, 2016, the district court issued its decision finding that Apotex did not infringe the ’138 Patent.  The district court found that Amgen had not established that Apotex’s process had:  “(1) a ‘high protein concentration’ at or above about 1 g/L; and (2) a redox component having a redox buffer strength of 2 to 100 mM.” Dkt. No. 267 at 10.  The district court noted that with respect to the first point, Amgen had only alleged literal infringement and not infringement under the doctrine of equivalents, and that Apotex’s refold mixture was well below “at or above about 1 g/L.”  Id. at 10-11.  For the second point, even though Amgen alleged infringement under the doctrine of equivalents and even assuming that “the combination of Apotex’s Cysteine and Cystine Solutions in a hypothetical volume” satisfied the hypothetical redox component, the district court found that the redox buffer strength would be from 214 to 340 mM with a volume two to three times greater than the hypothetical redox component.  Id. at 17-18.  In other words, “Apotex’s process uses a smaller volume of more concentrated redox component than is claimed in the ’138 Patent to achieve its desired redox conditions.”  Id. at 18.  Given its non-infringement finding, the district court declined to rule on invalidity for lack of enablement and dismissed that counterclaim without prejudice.  Id. at 28.  The district court also declined to award attorneys’ fees.  Id. at 29.

Amgen appealed the non-infringement decision on October 3, 2016.

Appeal of Non-Infringement Decision to the Federal Circuit

Amgen appealed the district court’s non-infringement decision in Appeal No. 17-1010.  Briefing was complete on February 2, 2017, but oral argument has not been scheduled for upcoming court dates through June 2017.

Therefore, at this time, the only remaining issue in the Apotex action is the decision on appeal of infringement.  Because the ’138 Patent was asserted in both Apotex actions, the decision will impact the future of its filgrastim and pegfilgrastim products.  It remains to be seen what impact the Supreme Court’s decision in Sandoz v. Amgen will have on the Apotex case because Apotex participated in the patent dance.  However, the Supreme Court’s decision will likely impact at least the notice of commercial marketing issue in Apotex.


[1] This statement by the Federal Circuit has been subject to substantial scrutiny and was addressed in briefing and at oral argument before the Supreme Court in Sandoz Inc. v. Amgen Inc. (Nos. 15-1039, 15-1195).

[2] As indicated above, however, the Supreme Court granted certiorari in Sandoz Inc. v. Amgen Inc., which also addressed the notice of commercial marketing issue.

[3] Apotex filed a petition for Inter Partes Review of the ’138 Patent on August 5, 2016.  The IPR was instituted on February 17, 2017.