On August 7, 2018, Amgen and Amgen Manufacturing Limited (collectively, “Amgen”) sued Apotex Inc. and Apotex Corp. (collectively, “Apotex”) in a third lawsuit[1] over Apotex’s pending Biologics License Applications (“BLAs”) to make biosimilar versions of Amgen’s pegfilgrastim and filgrastim products, Neulasta® and Neupogen®.[2] Notably, although the current patent-in-suit, U.S. Patent No. 9,856,287 (“the ’287 patent”), claims priority to a patent asserted by Amgen in its two earlier actions against Apotex, the ’287 patent did not issue until after the parties had already completed “patent dance” exchanges[3] pursuant to the Biologics Price Competition and Innovation Act (“BPCIA”) in connection with the two earlier actions. Amgen’s current action illustrates how owners of biologic drugs can use later-issued patents to extend biosimilar litigation after an initial BPCIA action has concluded.

Overview of the BPCIA Patent Dance

Enacted in 2010, the BPCIA establishes a statutory framework for the submission and approval of biosimilar applications. The BPCIA sets forth a series of pre-suit information-exchange steps, commonly referred to as the BPCIA “patent dance.” As part of this patent dance, following acceptance of a biosimilar applicant’s BLA by the U.S. Food and Drug Administration (“FDA”), the BPCIA provides for the exchange of: (1) the biosimilar applicant’s BLA and “such other information that describes the process or processes used to manufacture the biological product that is the subject of such application” to the biologic owner, i.e., the reference product sponsor; (2) a list of patents that the reference product sponsor believes may be infringed by the biosimilar product; (3) a detailed statement describing the biosimilar applicant’s factual and legal bases for why any of the identified patents would not be infringed or are invalid; and (4) a detailed statement describing the reference product sponsor’s factual and legal bases for why the identified patents are valid and would be infringed.[4] Following these exchanges, the BPCIA provides for negotiations between the parties regarding the number and identity of patents to be litigated in an initial action, which the reference product sponsor “shall bring” within 30 days.[5] Among other things, the BPCIA further provides that the reference product sponsor may identify any newly issued or licensed patent that it reasonably believes could be asserted against the biosimilar applicant on a supplemental list within 30 days of the new patent’s issuance or licensing.[6]

The Amgen v. Apotex Litigations

In 2015, Amgen filed two patent infringement actions against Apotex in the Southern District of Florida that were subsequently consolidated.[7] As mentioned above, these lawsuits followed the parties’ completion of the full patent dance described in § 262(l)(3) during which Amgen identified U.S. Patent No. 8,952,138 (“the ’138 patent”)[8] as a patent having claims[9] that would be infringed by Apotex’s pegfilgrastim and filgrastim BLAs.[10] Amgen specifically asserted that Apotex’s BLAs infringed the ’138 patent and that the commercial manufacture, use, offer for sale, sale, or importation of Apotex’s proposed biosimilar products in the United States would infringe certain claims of the ’138 patent.[11] In response, Apotex sought in part declaratory judgments of non-infringement and invalidity, alleging that the processes specified in its BLAs fell outside the scope of the asserted claims and that the asserted claims were invalid as non-enabled.[12]

Amgen’s theory of literal infringement centered on the claim term “refold mixture,” which was construed to require “a high [filgrastim] concentration . . . at or above about 1 g/L protein.”[13] This theory was predominantly based on information contained in Apotex’s BLA.[14] As evidence of infringement, Amgen focused on Apotex’s BLA specifications, which required the concentration of inclusion bodies (and not specifically pure protein) used in the downstream manufacturing process[15] to be between 0.9 to 1.4 grams per liter of Apotex’s refolding buffer.[16] After a bench trial, the district court found Apotex’s BLAs did not (and its proposed biosimilar products would not) infringe the asserted claims of the ’138 patent in part based on evidence that Apotex’s downstream batches contained a maximum of 0.708 g/L filgrastim, well below the claimed amount recited in the asserted claims of the ’138 patent.[17] Apotex’s batch records, which were submitted to the FDA in connection with its BLAs, confirmed that its manufacturing process uses a protein concentration below that required by the asserted claims.[18] This decision was later affirmed by the Federal Circuit, which issued its final mandate on December 20, 2017.[19]

Amgen’s current litigation, also in the Southern District of Florida, similarly involves a patent directed to methods of refolding recombinant proteins expressed in non-mammalian cells.[20] The ’287 patent claims priority to the ’138 patent through a series of continuation and divisional applications. As discussed above, Amgen was unable to show infringement of the “refold mixture” claim element. This claim element, however, is present in only two of the four independent claims of the now-asserted ’287 patent.

Notably, the ’287 patent issued on January 2, 2018, two weeks after the Federal Circuit’s mandate issued in the initial consolidated action. As a result, the ’287 patent was not (nor could it have been) part of the parties’ earlier BPCIA patent dance exchanges. Amgen had, however, supplemented its lists of patents that it believed could reasonably be asserted to include the ’287 patent within 30 days of that patent’s issuance pursuant to § 262(l)(7).[21]

Considerations for Biosimilar Manufacturers

The series of lawsuits between Amgen and Apotex illustrates the issues that biosimilar applicants may face when biologics makers have acquired comprehensive patent portfolios through diligent prosecution efforts. Apotex successfully defended against two separate (albeit consolidated) litigations against Amgen only to face an additional challenge more than seven months after the issuance of the Federal Circuit’s mandate based on a newly-issued patent identified by Amgen under § 262(l)(7). Amgen’s prosecution and litigation strategies have now provided it with an opportunity to enjoin the launch of Apotex’s pegfilgrastim and filgrastim biosimilar products until the expiration date of the ’287 patent, and to litigate claims related to the subject matter of its original actions in a new case. Because two independent claims of the ’287 patent lack the “refold mixture” limitation, litigation of the ’287 patent may give Amgen a chance to prove infringement free of the limitation that proved problematic during the litigation of the ’138 patent. Moreover, Amgen’s opportunity to attack Apotex’s pegfilgrastim and filgrastim biosimilar products may not end with the ’287 patent litigation. Indeed, there are three additional pending patent applications that claim priority to the ’138 patent.[22]

Biosimilar makers should expect to see the owners of biologic drugs investing more frequently in comprehensive patent portfolios that can include issued patents and related pending applications. Biosimilar makers should take care to (i) closely monitor pending applications that relate to the subject matter of any patents currently in litigation, and (ii) fully analyze the specifications of such applications to anticipate the potential scope of future claims. Such considerations are particularly important in view of the likelihood that information included in the BLA can be made public during the course of litigation, informing the patent prosecution strategies of others in the field.