INSIGHT: The Ongoing Debate About Disclosing Manufacturing Process Information in the Patent Dance

The Biologics Price Competition and Innovation Act (BPCIA) established an abbreviated regulatory pathway for biosimilar drug products and a unique litigation framework for resolving associated patent disputes. Since its enactment in 2010, the BPCIA has confounded drug companies, patent litigators, and judges alike, leading to considerable disagreement and uncertainty in the biopharmaceutical industry. Indeed, the Federal Circuit analogized the BPCIA to “a riddle wrapped in a mystery inside an enigma,” quoting Winston Churchill in a 1939 speech describing Russia. While the Supreme Court has provided clarity about some BPCIA provisions, questions of interpretation and compliance persist, particularly regarding the multistep, pre-litigation information exchanges and negotiations between biosimilar applicants (BSAs) and reference product sponsors (RPSs) — the “patent dance.”

Subsection (l)(2)(A) kicks off the patent dance and provides that within 20 days of receiving notice from the Food and Drug Administration that an abbreviated Biologics License Application (aBLA) has been accepted for review, the BSA “shall provide to the [RPS] a copy of the [aBLA], and such other information that describes the process or processes used to manufacture the biological product” (emphasis added). No one disputes that Subsection (l)(2)(A) requires production of the aBLA. But the question remains whether a BSA must produce “other” manufacturing process information, beyond the aBLA, if the aBLA already contains manufacturing process information.

The BPCIA Pathway

Since the first aBLA submissions in 2014, the rate of BPCIA litigation has steadily increased, with patent dance-related disputes arising often. As to the dance itself, BSAs have pursued different strategies, ranging from full to no participation, depending on their ultimate goals.

Participating in every step of the patent dance may provide a BSA with the greatest degree of control over the scope and timing of litigation, including the potential to avoid litigating some patents, to litigate patents in multiple phases, and to negotiate which patents get litigated first. But even when BSAs allege compliance with the dance, RPSs often disagree and contend that BSAs are not entitled to the benefits of full participation.

Alternatively, forgoing the patent dance or skipping steps can expedite initiation and resolution of litigation and, potentially, product launch. At least one court has found, however, that this approach may preclude BSAs from enjoying some benefits of full participation, such as foreclosing the RPS from asserting patents not identified during the dance.

In the first BPCIA litigation, Amgen v. Sandoz, the courts considered, among other things, whether the patent dance is mandatory. There, Sandoz refused to dance, and Amgen, in its infringement suit, asserted federal and state law claims seeking to compel Sandoz’s participation or penalize it for nonparticipation. What we know now — from a split Federal Circuit panel that did its “best to unravel the riddle, solve the mystery, and comprehend the enigma” of the BPCIA, a unanimous Supreme Court that partially reversed and vacated, and a unified Federal Circuit panel on remand — is that the dance is mandatory but a BSA cannot be compelled by injunction under federal or state law to engage in the patent dance and, when the BSA does not dance, the RPS’s sole remedy is to file an action for declaratory judgment (DJ) of patent infringement. Questions remain, however, regarding which actions constitute compliance with the patent dance.

Can Producing the aBLA, Alone, Comply With Subsection (l)(2)(A)?

Biologic drug products are derived from natural, biological sources such as animals or microorganisms. A biosimilar is a biologic that is highly similar to a reference product, notwithstanding minor differences in clinically inactive components, and has no clinically meaningful differences from the reference product in terms of the safety, purity, and potency. Biologics made by different processes — while potentially “biosimilar” — are never completely identical. Different manufacturing processes may alter a biologic in ways that could affect its safety, purity, or potency. Consequently, aBLAs generally contain detailed manufacturing process information.

To protect against competition, RPSs often procure patents covering, among other things, processes for manufacturing their reference products and later contend that they need BSAs’ manufacturing information to assess which process patents to assert. Nevertheless, some BSAs, though willing to dance, have produced only their aBLAs pursuant to Subsection (l)(2)(A), with no “other information.” RPSs argue that such BSAs violated Subsection (l)(2)(A), which, RPSs contend, always requires production of the aBLA “and other information.” BSAs counter that producing only the aBLA suffices, particularly if it contains extensive manufacturing process information.

Despite the issue being raised, no court has definitively ruled on how to interpret the “and such other information” clause of Subsection (l)(2)(A). In a case regarding Amgen’s bevacizumab biosimilar, Genentech sought a DJ that Amgen violated Subsection (l)(2)(A) by refusing to provide manufacturing documentation beyond its aBLA and that, consequently, Genentech was not required to provide a list of potentially infringed patents pursuant to Subsection (l)(3)(A). Amgen moved to dismiss, relying on the Federal Circuit’s split panel decision in Amgen v. Sandoz. During oral argument, the district court suggested that it disagreed with Amgen’s interpretation of Subsection (l)(2)(A) that the aBLA alone may suffice, stating: “[Y]ou don’t get to constrain the flow of information to just the application. The statute does not permit that….” The court’s tentative interpretation, however, did not affect the decision. The court concluded that, regardless of how one interprets Subsection (l)(2)(A), under Amgen v. Sandoz the court lacked subject matter jurisdiction over Genentech’s complaint because disclosure under Subsection (l)(2)(A) cannot be compelled.

The issue arose again in a related case. After the parties danced further, and Amgen gave its “notice of commercial marketing” (NCM) pursuant to Subsection (l)(8)(A), Amgen filed its own DJ action seeking a declaration of noninfringement, invalidity, and/or unenforceability of patents on Genentech’s (l)(3)(A) list. Genentech moved to dismiss, arguing, among other things, that Amgen withheld manufacturing information, constituting noncompliance with Subsection (l)(2)(A), and that Subsection (l)(9)(C) therefore barred Amgen from bringing its DJ action. Subsection (l)(9)(C) states that if a BSA “fails to provide the application and information required under Paragraph (2)(A), the [RPS], but not the [BSA], may bring” a DJ action of “infringement, validity, or enforceability of any patent that claims the biological product or a use of the biological product” (emphasis added). The court, however, dismissed Amgen’s action for reasons unrelated to, and therefore without interpreting, Subsection (l)(2)(A). Instead, the court dismissed Amgen’s action because, among other things, it concluded that Amgen had not completed the patent negotiation step of the dance and was therefore barred from bringing a DJ action under Subsection (l)(9)(B).

BPCIA jurisprudence leaves many unanswered questions regarding compliance with Subsection (l)(2)(A). For example, if Subsection (l)(2)(A) requires production of manufacturing process information beyond the aBLA, how much “other information” must be produced to fully comply with the statute? Amgen suggests in its DJ action that the answer would be “arbitrary” because requiring production of “such other information” would “render applicants’ attempts at compliance … practically impossible,” as the RPS could always identify something allegedly missing from the production. Another question is whether “such other information” would need to be produced even if all relevant manufacturing information beyond the aBLA was duplicative or cumulative? If so, it would seem to extol form over substance. Alternatively, if producing the aBLA, by itself, satisfies Subsection (l)(2)(A), then why does Subsection (l)(2)(A) state that the BSA shall provide a copy of the application “and such other information”?

Will courts ever resolve the issue? What would it take for a court to finally interpret Subsection (l)(2)(A) and eliminate the uncertainty? An RPS would need to allege a potential remedy or right (or unavailability thereof) based on a BSA’s failure to fully comply with Subsection (l)(2)(A), and a court would need to interpret Subsection (l)(2)(A) to determine whether the remedy or right exists and applies. Here are some potential scenarios pertaining to whether the courts will ever provide clarifying guidance about Subsection (l)(2)(A).

1. Seeking to compel compliance with Subsection (l)(2)(A): remedy unavailable.

In the past, RPSs have attempted to compel BSAs to comply with Subsection (l)(2)(A) and participate in the patent dance. While those attempts set the stage for courts to interpret Subsection (l)(2)(A), they were resolved without doing so. For example, in Genentech’s DJ action against Amgen, the court, without interpreting Subsection (l)(2)(A), found that an RPS cannot compel compliance with that subsection. Moreover, the Amgen v. Sandoz courts definitively ruled that an RPS cannot force participation in the dance under federal or state law, effectively making this remedy unavailable.

2. RPS filing DJ action for patent infringement based on alleged violation of subsection (l)(2)(A): unlikely to play out.

Subsection (l)(9)(C) states that a BSA’s failure to comply with Subsection (l)(2)(A) entitles the RPS to immediately seek a DJ of infringement of any patent that claims the biological product or its use. This type of DJ complaint differs from the DJ complaint Genentech filed after Amgen refused to produce manufacturing information beyond its aBLA in that Genentech sought to compel Amgen’s compliance with the patent dance rather than seeking a declaration of patent infringement. If a BSA produces only its aBLA and an RPS files such a DJ action pursuant to Subsection (l)(9)(C), the BSA might move to dismiss for lack of subject matter jurisdiction, arguing that it complied with Subsection (l)(2)(A), violation of which is a prerequisite for filing a DJ action pursuant to Subsection (l)(9)(C). Resolving that motion might require a court to decide whether producing the aBLA alone satisfied Subsection (l)(2)(A). If the court ruled that producing the aBLA was sufficient, there would be no violation of subsection (l)(2)(A), which could negate the RPS’s right to bring a DJ action under Subsection (l)(9)(C) and, accordingly, require dismissal of the DJ complaint. If the court ruled that production of additional manufacturing information was required and that producing only the aBLA violated Subsection (l)(2)(A), the DJ action would continue.

This scenario, however, is unlikely to arise. An RPS may perceive little value in immediately filing a DJ action under Subsection (l)(9)(C) if only the aBLA is produced. As noted above, if the court found that the BSA complied with Subsection (l)(2)(A) and therefore dismissed the DJ action, the parties may have to continue dancing anyway. Moreover, motion practice takes time and may consume most, if not all, of the 60 days the RPS has to provide its list of potentially infringed patents pursuant to Subsection (l)(3)(A). Thus, even if an RPS filed such a DJ action, it might feel compelled to serve its (l)(3)(A) list anyway, before the DJ action is resolved, to avoid the risk of forfeiting its patent rights against the BSA under the BPCIA’s list-it-or-lose-it provision, 35 U.S.C. § 271(e)(6)(C). Even if the RPS defeated the motion to dismiss in the district court within the allotted 60 days, the ruling could be subject to an appeal that would likely extend beyond the 60-day window. Again, to avoid the possibility of forfeiture, the RPS would likely provide its (l)(3)(A) list within the 60 days.

3. Seeking discovery based on alleged violation of subsection (l)(2)(A): likely unavailable.

If the BSA produces only the aBLA and the RPS still proceeds to dance by providing its (l)(3)(A) list, the RPS cannot use the BSA’s arguable noncompliance with Subsection (l)(2)(A) as a basis for seeking discovery relating solely to unlisted, unasserted patents. That scenario played out in Amgen v. Hospira. There, Hospira produced only its aBLA, and Amgen omitted certain cell-culture medium patents from its (l)(3)(A) list because, according to Amgen, it could not assess the reasonableness of asserting infringement of the omitted patents without first reviewing requested, but unproduced “other information” regarding Hospira’s cell-culture medium. During the ensuing litigation, Amgen sought discovery on the processes claimed in the unlisted, unasserted cell-culture patents. The district court denied the discovery because it lacked relevance to the patents-in-suit.

Amgen appealed, but the Federal Circuit dismissed, finding that it lacked jurisdiction over the “run-of-the-mill” discovery ruling. In its decision, the Federal Circuit rejected Amgen’s argument that it had been unable to include, in good faith, the cell-culture medium patents on its (l)(3)(A) list. The court indicated that if, based on the information the BSA provided, the RPS believes a patent could reasonably be asserted, the RPS should include the patent on its (l)(3)(A) list, and explained that the BPCIA “provides no sanction for holding or asserting a mistaken belief in good faith.” If the RPS does not list a patent, however, it cannot seek discovery during litigation directed solely to determining whether the unlisted patent could be asserted. Thus, under Hospira, there may be no procedural mechanism by which an RPS who has danced can take discovery on (or amend its complaint to assert) patents omitted from its (l)(3)(A) list, even if the BSA limited its production to the aBLA and that limitation violated Subsection (l)(2)(A). Accordingly, such discovery disputes are unlikely to lead a court to resolve the Subsection (l)(2)(A) debate.

4. BSA’s ability to file DJ action after serving NCM: unclear.

BSAs have filed actions for DJ of noninfringement, invalidity, and/or unenforceability against RPSs immediately after allegedly completing the patent dance and providing NCM. District courts, including in Genentech v. Amgen, have thus far granted motions to dismiss these DJ suits upon finding, among other things, that the BSAs had not fully completed the patent negotiation steps of the dance and therefore could not file DJ actions. The Federal Circuit, however, has not yet addressed this issue. Given the current state of jurisprudence, would that consequence equally apply if a BSA fails to produce manufacturing documentation beyond its aBLA but otherwise fully complies with and completes the patent dance and then provides NCM?

In that scenario, for a court to address what Subsection (l)(2)(A) requires, at least the following events would likely need to occur first:

• The BSA files a DJ action;
• The RPS moves to dismiss in view of Subsection (l)(9)(C);
• The court considers, as a threshold issue, the circumstances under which a BSA may legally bring a DJ action; and
• The court determines that, in view of the facts of the case, the only act that could negate the BSA’s right to bring such an action would be a violation of Subsection (l)(2)(A).

Only then would the court determine whether nonproduction of “other” information violates Subsection (l)(2)(A). Although this scenario is possible, it has not arisen and possibly never will.

Conclusion

Although disagreements about the requirements of Subsection (l)(2)(A) have plagued BPCIA litigation, we might never see the perfect storm of circumstances needed for a court to resolve the issue. Without such resolution, BSAs and RPSs will likely play it safe, choosing litigation strategies that preserve their rights rather than going all-in on a statutory interpretation that, if wrong, could result in forfeiting important rights.