Decisions in the Amgen v. Sandoz case involving Sandoz's biosimilar versions of Amgen's Neupogen® and Neulasta® drugs have provided significant guidance to biosimilar litigants over the years. In the context of this case, the Supreme Court held that the "patent dance" is optional and that a Notice of Commercial marketing may be provided before FDA approval. In a recent opinion involving the same case, the Federal Circuit addressed possible outcomes where, during litigation, a biosimilar manufacturer makes clear its intention to amend its abbreviated biologics license application and its manufacturing process. Among other things, the Federal Circuit provided guidance about whether a non-infringement finding would insulate any subsequent manufacturing and abbreviated biologics license application changes.
Background
Through the Biologics Price Competition and Innovation Act ("BPCIA"), Congress provided manufacturers an abbreviated means for achieving FDA clearance to manufacture, market, and sell "biosimilars" of biologic drugs. The BPCIA permits biosimilar manufacturers to submit an abbreviated biologics license application ("aBLA") to the FDA to demonstrate that the biosimilar drug is highly similar to the reference product in terms of safety, purity, and potency. This abbreviated process is intended to save the biosimilar manufacturer time and money, so that the biosimilar drug can be sold at lower cost. The BPCIA does not, however, excuse biosimilar manufacturers from liability for infringing patents covering a reference product.
The BPCIA and provisions governing infringement in the Patent Act allow a biosimilar manufacturer to determine whether its biosimilar would infringe any relevant patents of the reference product manufacturer by receiving infringement rulings from a federal court. This process provides some business certainty to biosimilar manufacturers by allowing them to mitigate risk by resolving some patent disputes before launch through the "patent dance." If the parties choose to engage in the patent dance, a biosimilar applicant generally shares its confidential aBLA with the reference product sponsor, and may share detailed information about its proposed manufacturing process. The parties then exchange a list of patents that may be asserted, along with contentions regarding those patents, which culminates in litigation in federal court. A potential benefit to biosimilar manufacturers is that they may receive clearance from a court by way of final judgment of non-infringement or invalidity of patents identified during the patent dance before making any sales. One open question is what may happen if an aBLA applicant later amends its aBLA, or changes its manufacturing process during the litigation and this issue was addressed in Amgen v. Sandoz.
Amgen v. Sandoz Federal Circuit Opinion (May 2019)
In the Sandoz case, Amgen asserted, inter alia, that U.S. Patent Nos. 8,940,878 (the "'878 Patent) and 6,162,427 (the "'427 Patent") were infringed by Sandoz's launched Zarxio® product, a biosimilar of Neupogen® (filgrastim), and Sandoz's proposed biosimilar of Neulasta® (pegfilgrastim). After claim construction, Amgen and Sandoz stipulated to non-infringement of the '427 Patent. In December 2017, the Northern District of California granted summary judgment of non-infringement of the '878 Patent because the asserted protein purification method required separate washing and eluting steps, but Sandoz's process for both its biosimilars involved a single, simultaneous washing and eluting step.
The district court also denied Amgen's Rule 56(d) motion to deny or continue the motion for summary judgment until Sandoz submitted its intended new purification method to the FDA. During discovery, Sandoz disclosed that it planned to change certain aspects of its manufacturing process by changing a refold solution used in its separation matrix and consequently amend its aBLAs. The district court denied Amgen's motion because the revised method would substitute one separation matrix for another, which was immaterial to the infringement analysis because the new process would still involve a simultaneous washing and eluting step. While the appeal turned significantly on specific issues of claim construction, this article focuses on the Rule 56(d) arguments.
Rule 56(d) allows a district court to deny or postpone summary judgment if the nonmovant shows that "it cannot present facts essential to justify its opposition." Fed. R. Civ. P. 56(d). During the district court litigation, it was undisputed that Sandoz intended, at some point in the future, to modify its purification process to use a different resin in its separation matrix. Amgen Inc. v. Sandoz Inc., __F.3d__, 2019 WL 2017501, at *5 (Fed. Cir. May 8, 2019). Amgen contended that Sandoz had neither submitted its amended aBLA, nor provided Amgen with the details of the modification such that it could properly respond to the motion for summary judgment of non-infringement. Id. Amgen further contended that the court could not render a final judgment on a technical act of infringement where a biosimilar applicant plans to submit a modification of a relevant process to the FDA but has not done so. Id. Finally, Amgen contended that if infringement were determined before aBLA amendment, then it would be effectively "deprived of the ability to allege infringement in the future," and that Sandoz would be free "to make any changes it wishes to the modified process because it has been declared non-infringing in advance." Id.
Sandoz argued in response that it provided sufficient detail about the modified process and that Amgen's alleged inability to stave off summary judgment was due to its failure to diligently pursue discovery. Id. Sandoz also highlighted that the details sought by Amgen were immaterial to infringement because the claim did not require a specific resin and Sandoz would continue its non-infringing single-step washing and eluting process. Id.
The Federal Circuit sided with Sandoz. With respect to Sandoz's proposed pegfilgrastim biosimilar, the Federal Circuit first stated that "a proper analysis of a technical act of infringement under § 271(e)(2) requires a determination of whether 'what is likely to be sold' will infringe 'in the conventional sense' of patent infringement." Id. at *6 (internal quotations omitted). The Court acknowledged that the inquiry may be complex because abbreviated new drug application ("ANDA") and aBLA applicants are permitted to amend their process while the application is pending. Id. Thus, while a district court cannot "ignore amendments to an ANDA or aBLA," "it also has a broad mandate to render a just, speedy, and inexpensive decision based on the evidence of record." Id. (internal quotations and citations omitted) (citing Ferring B.V. v. Watson Labs., Inc.-Fla., 764 F.3d 1382, 1391 (Fed. Cir. 2014) (holding that a district court has discretion to consider an amended ANDA after issuing a decision but before final judgment)). The district court was therefore "not obligated to postpone summary judgment until Sandoz submitted its amended pegfilgrastim aBLA." Id.
The Court noted that the proposed pegfilgrastim biosimilar would likely follow the same one-step washing and eluting process, and would therefore not infringe under the affirmed claim construction. Id. The proposed process would only substitute resins, and the asserted claim did not distinguish between types of resins. Id. Accordingly, the Federal Circuit held that the district court did not abuse its discretion in denying Amgen's Rule 56(d) motion.
With respect to Sandoz's Zarxio® biosimilar, the Court stated, "[b]ecause Zarxio® is currently marketed, it is unnecessary to determine 'what is likely to be sold,' as is required for a technical act of infringement." Id. Instead, infringement turned on whether Sandoz's current process for manufacturing infringed the claim according to "conventional principles of patent infringement." Id. "Applying those principles . . . the district court did not err either in construing claim 7 or in granting summary judgment." Id.
The Federal Circuit further clarified that Amgen would not be without a remedy for possible future infringement should Sandoz change its process. "It [Amgen] may in a future action plead infringement of claim 7 by Zarxio® or, if approved, Sandoz's pegfilgrastim biosimilar to the extent permitted by the Patent Act and the principles of res judicata and collateral estoppel." Id. (citing Bayer AG v. Biovail Corp., 279 F.3d 1340, 1349-50 (Fed. Cir. 2002) (declining to apply collateral estoppel from previous Hatch-Waxman case when defendant's marketed product differed from that of the hypothetical inquiry)). Thus it appears that if Sandoz were to change its manufacturing process for Zarxio® or its proposed pegfilgrastim biosimilar in a way that would infringe the claim, Amgen would not be precluded from seeking relief.
Notably, the collateral estoppel issue in Bayer turned on a distinction between litigation based on hypothetical infringement as compared to infringement by manufacture of commercial tablets. See Bayer, 279 F.3d at 1350. The court there noted that "evidence of actual infringement (contrasted with evidence of a 'hypothetical' infringement) may differ in substance and may become available only after manufacture of the composition." Id. Thus, in the earlier Hatch-Waxman case Bayer "did not have a full and fair opportunity to litigate the issue of infringement by the commercial tablets because those tablets were not available until after ANDA approval." Id. Based on the Federal Circuit's opinions in Sandoz and Bayer, it appears that being absolved at one stage (pre-approval) doesn't necessarily absolve at all stages (post-approval, particularly where there are amendments or changes to the biosimilar actually manufactured). In Sandoz, the proposed manufacturing process would not change in any way material to the infringement analysis, so this pre-approval/post-approval distinction did not matter.
Looking Forward
In situations where a biosimilar manufacturer signals that its process and aBLA may change, reference product manufacturers should make early and repeated efforts to pursue discovery into those changes. District courts have discretion to move forward with summary judgment findings of non-infringement with or without that information. But a court may be more likely to wait to rule on summary judgment where a reference product manufacturer has diligently sought such discovery and been denied by the other party. Alternatively, as happened here, district courts may consider the limited new information along with the original process disclosed to find non-infringement on summary judgment. This does not mean a biosimilar manufacturer would then have free-rein to change its process after a final judgment of non-infringement. As explained by the Court in Sandoz, collateral estoppel may not apply where the marketed product materially differs from the product found to not infringe.
It is also worth noting, in Sandoz, the Federal Circuit again analogized several BPCIA issues with Hatch-Waxman litigation. First, the Court analogized the "technical act of infringement" included in § 271(e)(2) of the Patent Act, as requiring a look at "what is likely to be sold" in both instances. For example, in the Hatch-Waxman context, this requires a look at the process disclosed in an ANDA, whereas the same inquiry requires a look at the aBLA in a biosimilar litigation. Sandoz, 2019 WL 2017501, at *6 (noting that this inquiry may be complex because ANDA and biosimilar applicants can amend their applications). Second, the Court acknowledged that both ANDA and biosimilar applicants may amend their applications while they are pending. Id. Third, the Court analogized principles of res judicata between Hatch-Waxman and biosimilar cases as described above. In short, the Federal Circuit seems inclined to draw analogies from the more advanced body of law in the Hatch-Waxman context.
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