Source: https://www.patentdocs.org/followon_biologics/
Timestamp: 2019-04-18 11:07:22+00:00

Document:
Earlier this week, Judge Richard G. Andrews, U.S. District Court Judge for the District of Delaware decided a veritable plethora of post-trial motions (by both parties) in Amgen Inc. v. Hospira, Inc. (he denied them all). These included Hospira's Rule 50(a) Motion for Judgment as a Matter of Law on the Issues of Safe Harbor, Noninfringement, Invalidity, and Damages and related briefing, Hospira's Motion for Judgment as a Matter of Law Under Rule 50(b) and, in the Alternative, For Remittitur or New Trial Under Rule 59 and related briefing, Hospira's Motion to Seal Confidential Exhibits Admitted at Trial and related briefing, Amgen's Renewed Motion for Judgment as a Matter of Law of Infringement of the '349 Patent or, in the Alternative, for a New Trial and related briefing, and Amgen's Motion for Prejudgment and Post-judgment Interest and related briefing. Of note is the basis for the Court's denial of Hospira's safe harbor motion under the provisions of the Biologics Price Competition and Innovation Act (BPCIA).
24. A method of preparing erythropoietin molecules having a predetermined number of sialic acids per molecule said number selected from the group consisting of 1-14, comprising applying material containing erythropoietin to an ion exchange column and selectively eluting said molecules from the column.
27. A method for obtaining an erythropoietin composition having a predetermined in vivo specific activity comprising preparing a mixture of two or more erythropoietin isoforms of claim 1.
1. An isolated biologically active erythropoietin isoform having a single isoelectric point and having a specific number of sialic acids per molecule, said number selected from the group consisting of 1-14, and said isoform being the product of the expression of an exogenous DNA sequence in a non-human eucaryotic host cell.
1. Vertebrate cells which can be propagated in vitro and which are capable upon growth in culture of producing erythropoietin in the medium of their growth in excess of 100 U of erythropoietin per 106 cells in 48 hours as determined by radioimmunoassay, said cells comprising non-human DNA sequences which control transcription of DNA encoding human erythropoietin.
2. Vertebrate cells according to claim 1 capable of producing in excess of 500 U erythropoietin per 106 cells in 48 hours.
3. Vertebrate cells according to claim 1 capable of producing in excess of 1000 U erythropoietin per 106 cells in 48 hours.
4. Vertebrate cells which can be propagated in vitro which comprise transcription control DNA sequences, other than human erythropoietin transcription control sequences, for production of human erythropoietin, and which upon growth in culture are capable of producing in the medium of their growth in excess of 100 U of erythropoietin per 106 cells in 48 hours as determined by radioimmunoassay.
5. Vertebrate cells according to claim 4 capable of producing in excess of 500 U erythropoietin per 106 cells in 48 hours.
6. Vertebrate cells according to claim 4 capable of producing in excess of 1000 U erythropoietin per 106 cells in 48 hours.
7. A process for producing erythropoietin comprising the step of culturing, under suitable nutrient conditions, vertebrate cells according to claim 1, 2, 3, 4, 5 or 6.
The Court also assessed damages in the amount of $70 million, inclusive of pre- and post-judgment interest.
Hospira contended that the jury instructions were "legally erroneous and prejudicial," inter alia, because "ulterior motives and intent are irrelevant to [entitlement to] the Safe Harbor." Specifically, Hospira argued that the instructions did not clarify the use of the terms "use" and "make" as relevant to whether an activity was entitled to the safe harbor provisions of the statute. ("We would urge the broader standard for uses, but focus on the instruction should be on the uses and not the motives or purposes in making [a] batch. The statutory exemption is premised on the use aspect.") According to Hospira, the jury was asked to determine whether "manufacture" of the accused infringing article (biosimilar erythropoietin, bEPO) fell under the safe harbor when the only burden Hospira rightfully was obliged to meet was whether "use" of the allegedly infringing bEPO was "reasonably related to obtaining FDA approval." The Court disagreed, stating that "Hospira's potentially infringing 'use' of Amgen' s patented invention is Hospira's manufacture of the EPO drug substance referred to in its BLA (i.e., Hospira's performance of the steps of Amgen's method claims), not Hospira's subsequent use of the EPO drug substance (i.e., Hospira's subsequent use of the product obtained by practicing Amgen's method claims)." Thus, the safe harbor is available to Hospira only if manufacture of its bEPO was "reasonably related to obtaining FDA approval." Hospira's subsequent use of the bEPO is "probative in determining whether Hospira's manufacture of its EPO drug substance was reasonably related to obtaining FDA approval, [but] it is the manufacture itself (not Hospira's subsequent uses of EPO drug substance) that is the potentially infringing act which must be evaluated for safe harbor protection."
[A]dopting Hospira's interpretation of the safe harbor defense would expand the defense beyond recognition and create a loophole that would make it virtually impossible to prove infringement in cases involving products regulated by the FDA. Since Hospira's interpretation requires ignoring intent in deciding whether the safe harbor applies, a party could manufacture 200 drug substance batches and earmark them for future use as commercial inventory without infringing, so long as the party used each of those batches for at least one test to generate data of the type used by the FDA in determining whether to approve the drug. In that scenario, each batch would be tested to generate data that could conceivably be used to respond to inquiries from the FDA, making each batch reasonably related to obtaining FDA approval. Essentially, Hospira's interpretation allows a single "token" submission of information derived from a potential infringing act to exempt that act from infringement, without regard to the realities surrounding the potentially infringing act. It seems to me that Hospira's interpretation reads the words "solely" and "reasonably" out of the statute, and that a party's stated intent may be considered as part of whether the manufacture or use of a patented drug was "solely for uses reasonably related to" obtaining FDA approval. I think that the jury instructions properly recited the role of intent in the safe harbor analysis.
The hypothetical nicely illustrates the practical considerations behind the scope of the safe harbor, and how these considerations influence how courts evaluate the safe harbor's proper scope.
The high cost of biologic drugs was one of the (if not the) most compelling motivations for Congress to adopt a biosimilar pathway as part of the Affordable Care Act in 2010 (aka "Obamacare"). Passage of the Biologic Price Control and Innovation Act (BPCIA, codified at 42 U.S.C. § 262(k)) created for the first time a pathway for FDA approval of biosimilar drugs in the U.S. But from the beginning there have been grumblings, particularly regarding the term of the data exclusivity period (see "Congress Jumps on Bandwagon to Reduce Biologic Drug Exclusivity Term"; "President's Latest Budget Proposal Seeks Decrease of Data Exclusivity Period and Elimination of Pay-for-Delay Agreements"; "Senators Send Letter on Biosimilars to FDA"; "Senators Back 12-Year Data Exclusivity Period for Biosimilars and President Obama (Once Again) Does Not"; and "President's Latest Budget Proposal Seeks Decrease of Data Exclusivity Period and Elimination of Pay-for-Delay Agreements"). As biosimilar applicants have utilized the FDA's implementation of the abbreviated biologics license application (aBLA) pathway, and parties and the courts have begun to work out the litigation provisions of the Act (42 U.S.C. § 262(l)), the question of settlement of such litigation has arisen. As mentioned in a recent roundup of the biosimilar landscape (see "Status of U.S. Biosimilar Approvals and Pending Applications"), there have been several biosimilar patent litigations that have settled or been avoided by licenses between branded biologic drug makers (termed "reference product sponsors" under the law) and biosimilars applicants. For example, Genentech entered a global licensing agreement on March 31, 2017 with Mylan/Biocon over their Herceptin® biosimilar, Ogivri (trastuzumab-dkst) (although this biosimilar is not yet on the market), and Amgen/Samsung-Bioepsis's Amjetiva® (adalimumab-atto) is scheduled to enter the market in competition with AbbVie's Humira® in January 2023 as the result of a settlement agreement between the parties (see "HUMIRA® Biosimilar Update -- Settlement in AbbVie v. Amgen Case Announced and AbbVie v. Boehringer Ingelheim Litigation Begins").
Settlement agreements between conventional branded and generic drug makers were the source of a long dispute between pharmaceutical companies and the Federal Trade Commission, culminating in the Supreme Court's decision in FTC v. Actavis in 2013. Before that decision, Congress implemented a protocol requiring any such "reverse payment" settlement agreements (called "pay-for-delay" by the FTC and those opposed to the practice) to be vetted by the Commission, wherein ones deserving of suspicion as being anticompetitive would come to the FTC's attention (and presumably corrective action).
No such regime has been put in place for biosimilar drugs, and two Senators, Charles Grassley (R-IA) and Claire Klobucher (D-MN), think the FTC should commence review of the Humira® settlement. Part of their angst on the issue is a disparity of biosimilar entry dates between the U.S. (2023) and Europe (October 2018). Part is their innate inclinations: Senators Grassley and Klobucher have carried the branded company abuse torch for a while (see "The CREATES Act of 2016: Senate Listens to Generics Industry"). And of course perhaps the biggest factor is the high cost of Humira®, which is and has been the top-selling biologic drug for several years, and the price of which cannot but help to be reduced when biosimilar competitors enter the marketplace. It must be noted in passing, however, that the size of such a reduction is unlikely to be as great as has been the case for conventional generic small molecule drugs. In a fashion predicted by an FTC White Paper prepared before enactment of the BPCIA (see "No One Seems Happy with Follow-on Biologics According to the FTC"), the few biosimilar providers on the market have priced their drugs at only 15% less than the reference product sponsor (Sandoz's Zarxio® (filgrastim-sndz) (in competition with Amgen's Neupogen®); Pfizer's Inflectra® (infliximab-dyyb) (in competition with J&J/Janssen's Remicade®), although Merck-Samsung-Bioepsis's Renflexis® (infliximab-abda) (another Remicade® competitor) launched at risk (i.e., while patent litigation was on-going) at a 35% discount). While this is a significant savings in aggregate (say, for example, insurers and the Federal government), it is not the windfall for consumers that some (including perhaps these Senators) seem to think it will be.
As yet the Commission has not responded publicly.
Last month, in Celltrion, Inc. v. Genentech, Inc., District Judge Jeffrey S. White of the U.S. District Court for the Northern District of California granted two motions to dismiss filed by Defendants Genentech, Inc.; Hoffman La-Roche, Inc.; and City of Hope ("Genentech"), which sought to dismiss the first amended complaint filed by Plaintiffs Celltrion, Inc.; Celltrion Healthcare, Co. Ltd.; Teva Pharmaceuticals International GMGH; and Teva Pharmaceuticals USA, Inc. ("Celltrion"). Celltrion had initiated the dispute between the parties by filing complaints for declaratory judgment with respect to patents related to Genentech's Herceptin and Rituxan biologic drugs.
Both of the cases involve the Biologics Price Competition and Innovation Act of 2009 ("BPCIA"), which provides a regulatory approval pathway for biosimilar drugs. Under the BPCIA, a biologic licensed by the U.S. Food and Drug Administration is known as a reference product, and the entity that manufactures the reference product is known as the reference product sponsor ("RPS"). An entity that wishes to manufacture a biosimilar drug -- the biosimilar applicant (BA) -- may apply to the FDA for approval, and upon a showing that there are no "clinically meaningful differences" between the biosimilar drug and the biologic drug, can procure FDA approval for the biosimilar drug.
The two cases between Celltrion and Genentech relating to Herceptin and Rituxan involved §§ 262(l)(5)(A) and 262(l)(5)(B)(i), which specify the steps in the patent dance that take place after the biosimilar applicant and reference product sponsor engage in "good faith negotiations" to reach an agreement identifying the patents that will be the subject of patent infringement litigation (pursuant to § 262(l)(4)(A)). If the biosimilar applicant and reference product sponsor cannot agree on a list of patents to be litigated, the parties must simultaneously exchange lists of patents that each believes should be immediately litigated ("5(B) Lists"), and before that exchange takes place, the biosimilar applicant must identify the number of patents that it will identify on its own 5(B) List ("5(A) Number"). Pursuant to § 262(l)(9)(B), if a biosimilar applicant fails to serve its 5(A) Number or 5(B) List (or comply with several other steps), the applicant may not bring an action for declaratory judgment.
With respect to Herceptin, Celltrion had applied for FDA approval to market a biosimilar of that biologic drug called "Herzuma," and received notice that its application had been accepted by the FDA for review. When it came time for the parties to conduct good faith negotiations, Genentech proposed that the parties agree to litigate a discrete number (fewer than all) of the patents under discussion, and Celltrion responded by indicating that it wished to litigate a larger number of patents than Genentech's opening offer. Without providing its 5(A) Number or 5(B) List, Celltrion served a notice of commercial marketing on Genentech and then filed a declaratory judgment action against Genentech regarding the Herceptin patents it wished to litigate.
With respect to Rituxan, Celltrion had applied for FDA approval to market a biosimilar of that biologic drug called "Truxima," and received notice that its application had been accepted by the FDA for review. During good faith negotiations, Celltrion indicated that it wished to litigate all forty of the patents Genentech had placed on its § 262(l)(3)(A) List. As with Herceptin, Celltrion served a notice of commercial marketing on Genentech without providing its 5(A) Number or 5(B) List, and then filed a declaratory judgment action against Genentech regarding the Rituxan patents Celltrion wished to litigate.
Genentech responded to the declaratory judgment actions by filing motions to dismiss both suits for lack of subject matter jurisdiction, or alternatively, failure to state a claim. With respect to subject matter jurisdiction, the District Court noted that "Genentech has cited no 'clear statement' by Congress suggesting that Congress intended the BPCIA's requirements to be jurisdictional prerequisites," and therefore treated Genentech's motions as seeking dismissal for failure to state a claim under Federal Rule of Civil Procedure 12(b)(6).
In arguing against those motions, Celltrion contended that it may streamline its obligations under the BPCIA and satisfy several steps of the patent dance at once. In particular, Celltrion argued that it was absolved of the responsibility to comply with § 262(l)(5) because it told Genentech it "wished" to litigate all of the patents on Genentech's § 262(l)(3)(A) Disclosure, and that this statement both fulfilled its obligations to engage in "good faith negotiations" under § 262(l)(4) and made the exchange of the 5(A) Number and 5(B) Lists "redundant." The District Court, however, countered that "[t]his argument . . . improperly conflates Sections (l)(4) and (l)(5)," pointing out that "[t]he parties' obligations under Section (l)(5) only arise if the parties are unable to agree, after fifteen days of good faith negotiations, on a final and complete list of patents to litigate in Phase I." The Court concluded that "[g]iven the plain language of this provision, and the relationship between Sections (l)(4) and (l)(5) more generally[,] . . . no single statement or gesture can satisfy the requirements of both sections simultaneously."
With respect to the Rituxan complaint, Celltrion argued that that it was not obligated to offer its 5(A) Number or exchange 5(B) Lists because it filed its lawsuit nine days before the expiration of the fifteen-day period provided under § 262(l)(4) for good faith negotiation. The Court found this argument to be unpersuasive, noting that "[b]y this argument, Celltrion suggests that the filing of this declaratory judgment action was permissible because it skipped required statutory steps, where the non-occurrence of those statutory steps explicitly bars Celltrion from filing this action—an unpersuasive legal Catch-22." The Court stated that "Celltrion was obligated to complete all required procedures before filing this lawsuit, and it did not."
Celltrion's final argument was that the notices of commercial marketing it served for Herzuma and Truxima enabled it to file the declaratory judgment actions regardless of its compliance with other portions of the BPCIA. In particular, Celltrion contended that because a notice of commercial marketing lifts the ban on declaratory judgment actions described in § 262(l)(9)(A), a notice of commercial marketing should also lift §§ 262(l)(9)(B) and (C)'s prohibitions. The District Court, however, pointed out that the Central District of California had recently considered and rejected a similar argument in Amgen v. Genentech, Inc., 17-cv-7349-GHW, 2018 WL 910198 (C.D. Cal. Jan. 11, 2018). The Court reiterated that "a notice of commercial marketing only opens the door for an applicant to file a declaratory judgment action if the applicant complies with the rest of the statute."
"Because Celltrion did not complete its obligations under Section (l)(5)," the District Court determined that "Celltrion may not file actions for declaratory judgment with respect to the patents at issue," and therefore granted both of Genentech's motions to dismiss, while affording Celltrion leave to amend its complaints.
Amgen Inc. v. Sandoz Inc. (Fed. Cir. 2017) -- One Last Dance . . .
Last June, in Sandoz Inc. v. Amgen Inc., the Supreme Court handed down its interpretation of the Biologics Price Competition and Innovation Act ("BPCIA") for the approval of biosimilar drugs. As we reported at the time, the Court held that the 180-day notice-of-commercial-marketing provision of the statute may be provided either before or after receiving FDA approval. In addition, with respect to the so-called "Patent Dance," the Supreme Court held that a reference product sponsor ("RPS") cannot seek enforcement of the aBLA disclosure provision in 42 U.S.C. § 262(l)(2)(A) by injunction under federal law. This ruling all but made the Patent Dance optional for biosimilar applicants. Nevertheless, the Court left open a tiny ray of hope for patent owners by reversing and remanding the question whether the disclosure provision of the BPCIA was enforceable under state law. In a decision that came out earlier today, the Federal Circuit extinguished any hope. First, the Federal Circuit reasoned that it has discretion to address the preemption issue, and that it should exercise that discretion, notwithstanding the fact that the issue had not yet been addressed on the merits. Second, it held that the BPCIA's comprehensive framework demonstrates the intent of Congress that federal law would exclusively occupy the field of biosimilar patent litigation. And finally, the Federal Circuit held that any remedy provided for under state law would conflict with the careful balance struck by Congress in establishing the BPCIA. As a result, the Court affirmed the District Court's initial dismissal of Amgen's state law claims.
We provide this background possibly for the last time -- this case stemmed from the aBLA filing by Sandoz pursuant to the BPCIA to market a biosimilar version of Amgen's NEUPOGEN® (filgrastrim) biologic drug product. In the interim, the FDA approved the biosimilar known as ZarxioTM in March of 2015, and Sandoz (a Novartis company) has been selling the drug in the U.S. since September 3, 2015. However, despite availing itself of the BPCIA-abbreviated pathway for FDA approval, Sandoz refused to participate in the patent resolution component (the disclosure and information exchange provisions, also known affectionately as the "patent dance"), alleging that it was not a mandatory component. Amgen responded by filing suit in the Northern District of California, requesting in part a preliminary injunction to prevent Sandoz from entering the market. United States District Judge Seeborg of the Northern District of California denied Amgen's motion, the Federal Circuit (in a seriously fractured decision) essentially affirmed, and the case was taken up by the Supreme Court. In ruling as indicated above, the Supreme Court noted that the previous Federal Circuit decision that interpreted California's unfair competition law to not provide a remedy was based on an incorrect interpretation of federal law. With regard to whether Sandoz's failure to disclose its application and manufacturing information was "unlawful" under California's unfair competition law, the Supreme Court declined to resolve that dispute because it was not a question of federal law. The Federal Circuit, therefore, erred in attempting to answer the state-law question by referring to the BPCIA alone (according to the Supreme Court). Therefore, the Federal Circuit was charged with determining "whether California law would treat noncompliance with §262(l)(2)(A) as 'unlawful.'"
If the answer is yes, then the court should proceed to determine whether the BPCIA pre-empts any additional remedy available under state law for an applicant's failure to comply with §262(l)(2)(A) (and whether Sandoz has forfeited any pre-emption defense, see 794 F. 3d, at 1360, n. 5). The court is also of course free to address the pre-emption question first by assuming that a remedy under state law exists.
Sandoz Inc. v. Amgen Inc. (2017).
The Court first addressed the question whether Sandoz had waived the preemption defense. Sandoz has raised preemption as a defense in its answer, although it had not yet been addressed by the District Court or the Federal Circuit. As "'a general rule . . . a federal appellate court does not consider an issue not passed upon below.'" Amgen Inc. v. Sandoz Inc. (citing Singleton v. Wulff, 428 U.S. 106, 120 (1976)). Nevertheless, the Federal Circuit had previously articulated reasons to exercise discretion to address issues anyway. Relevant to this case is when the issue presents significant questions of general impact or of great public concern, specifically here "whether state law claims may play a role in enforcing compliance with § 262(l)(2)(A)." Moreover, because Sandoz had preserved its ability to assert preemption by including it as a defense in its answer, it could have raised it on remand, thereby lessening (or eliminating) any prejudice to Amgen. Finally, the preemption issue had been fully briefed. Of course, it didn't hurt the analysis that the Supreme Court had also directed the Federal Circuit to consider the issue on remand.
The Supremacy Clause of the Constitution (U.S. Const. art. VI, cl. 2), provides that federal law "shall be the supreme Law of the Land; and the Judges in every State shall be bound thereby . . . ." Preemption can either be by express preemption, field preemption, or conflict preemption." The BPCIA did not expressly preempt state law, so the Federal Circuit addressed the other two forms.
Field preemption occurs when Congress intended the Federal Government to exclusively occupy a particular field. There is, however, a presumption against preemption in a field in which states have historically legislated. The Federal Circuit easily found no presumption against preemption for biosimilar patent litigation. The Court then noted that patents are 'inherently federal in character' and that the FDA has exclusive authority to license biosimilars. Moreover, the Court noted that the BPCIA is "comprehensive" and "'provide[s] a full set of standards governing' the exchange of information in biosimilar patent litigation, 'including the punishment for noncompliance.'" Amgen Inc. v. Sandoz Inc. (citing Arizona v. United States, 567 U.S. 387, 401 (2012)). Such a comprehensive and calibrated scheme makes the inference that Congress left no room for the States reasonable. Finally, the Court noted that the relief Amgen was seeking from California law was not provided for by the BPCIA. For example, Amgen was seeking an injunction that the Supreme Court made clear was unavailable under Federal law. "This conflict in available remedies between federal and state law 'underscore[s] the reason for field preemption.'" Id.
If state law conflicts with federal law, it can also be preempted. This "occurs 'where it is impossible for a private party to comply with both state and federal requirements, or where state law stands as an obstacle to the accomplishment and execution of the full purposes and objectives of Congress." Amgen Inc. v. Sandoz Inc. (citing Rice v. Santa Fe Elevator Corp., 331 U.S. 218, 230 (1947)). The Federal Circuit found that Amgen's state law claims "clash" with the BPCIA, and that the differences in available and sought-after remedies supports the conclusion that the state law claims are preempted. The Court reasoned that Congress acted intentionally when it did not provide for injunctive relief, and that if Amgen were able to seek such a remedy under state law, it "'would interfere with the careful balance struck by Congress.'" Amgen Inc. v. Sandoz Inc. (citing Arizona, 567 U.S. at 405-06). As the Court ultimately concluded on the issue: "the preemption analysis here demonstrates that Amgen's state law claims conflict with the BPCIA and intrude upon a field, biosimilar patent litigation, that Congress reserved for the federal government."
So will this be the last "Amgen v. Sandoz" case in this family? The Federal Circuit affirmed the dismissal of Amgen's unfair competition and conversion claims because they were preempted on both field and conflict grounds. Correspondingly, the case was not remanded back to the District Court. Therefore, unless a petition for either panel rehearing or rehearing en banc is granted, or the Supreme Court grants another petition for cert., it is very possible that we have just seen the last dance of Amgen v. Sandoz.
Earlier today, both parties to the AbbVie v. Amgen litigation announced a settlement that resolves all intellectual property-related litigation over Amgen's FDA-approved adalimumab biosimilar AMGEVITA™/AMJEVITA™ (see AbbVie press release & Amgen press release). While the financial terms of the agreement were not disclosed, it was reported that AbbVie will grant non-exclusive patent licenses worldwide, on a country-by-country basis, for the use and sale of Amgen's biosimilar product. AMGEVITA is expected to launch in most countries of the European Union on October 16, 2018, and AMJEVITA (adalimumab-atto) in the U.S. on January 31, 2023. AbbVie reported that all related pending litigation will be dismissed, and that "Amgen has acknowledged the validity of AbbVie's intellectual property related to HUMIRA." The prices of both companies' stock were up at the end of the day, although on a percentage basis, AbbVie's was up higher. This could be due to the certainty in the delay of competition that AbbVie will face from Amgen in the United States. However, HUMIRA could face competition from Boehringer Ingelheim's biosimilar Cyltezo (adalimumab-adbm), which was approved by the FDA in late August (see "FDA Approves First Cancer-Treatment Biosimilar -- Amgen's Mvasi").
As we reported at the time, AbbVie filed suit against Amgen in the United States District Court for the District of Delaware on August 4, 2016, pursuant to the BPCIA and 35 U.S.C. 271(e)(2)(C). In its Counterclaims and Answer, Amgen reported that it had certified to AbbVie that it would not begin commercial marketing of its biosimilar before at least one of the patents identified by AbbVie had expired on December 31, 2016. Obviously, Amgen did not launch-at-risk after that date. Moreover, Amgen had stated that it intended to fully comply with the 180-day Notice of Commercial Marketing provision of the BPCIA (at least as it understood it before the Supreme Court's Sandoz v. Amgen case), which would have prevented them from launching until at least March, 2017. However, the present litigation only encompassed 10 of the 61 patents identified by AbbVie and Amgen during the so-called patent dance. Because AbbVie would have certainly filed the second-phase litigation if Amgen had provided commercial-marketing notice, it is reasonable to assume that such notice was not yet given.
The AbbVie v. Boehringer Ingelheim litigation, on the other hand, is just getting started. On August 2, 2016, almost a year after the Amgen case, AbbVie sued Boehringer pursuant to the BPCIA and 35 U.S.C. 271(e)(2)(C) because Boehringer submitted its application to the FDA to market its HUMIRA® biosimilar. Boehringer answered the Complaint on September 11, 2017. AbbVie alleged that there are more than 100 patents concerning the HUMIRA product, and that it identified 74 of which that were (or would be) infringed. Nevertheless, because Boehringer, as the Biosimilar application, had the ability to cap the number of patents in the suit, the initial phase litigation only concerns eight patents. Boehringer had selected the number of patents each side could identify for litigation as five, but the litigation only concerns eight patents because two appeared on both lists. The second wave can only occur after Boehringer provides its 180-day commercial-marketing notice.
Boehringer also identified AbbVie's '041 patent asserted in the Amgen case, and listed the '666 patent, which Amgen had similarly listed. For those interested, the entire list of 74 patents can be found on pages 15-19 of the complaint. Boehringer asserted, though, that at least four of these patents were improperly listed, as they had either expired or had been determined by the PTAB to be unpatentable. This case is at the very early stages, and there have been no reports of its settlement. As always, we will continue to monitor this case and provide updates as warranted.
In the third installment of the "Amgen v." trilogy of BPCIA Federal Circuit cases, the Court in Amgen Inc. v. Hospira, Inc. answered a question that had been lingering since the very first case -- can a reference product sponsor use discovery to obtain information from a biosimilar applicant if it does not receive a copy of the aBLA or other information about the manufacturing process as required by the BPCIA? In Amgen v. Sandoz, the first case in this series, the Federal Circuit found that an aBLA applicant was not required to disclose its application and related information, but noted that such information could be accessed through discovery after an infringement suit is filed. In the second installment, Amgen v. Apotex, the plot centered on the Notice-of-Commercial-Marketing provision, and did not focus significantly on the provisions of 42 U.S.C. § 262(l)(2)(A). In this most recent case, the Court appears to have closed the discovery loophole it created, at least with respect to cases in which the requested information is not relevant to the asserted patents. More importantly, reference product sponsors suffered another blow when the Court suggested that if a patent was not included in its paragraph (l)(3)(A) list, even if there was no reason to suspect that it might be relevant to the present case, the BLA holder could be precluded under 35 U.S.C. § 271(e)(6)(C) from ever asserting that patent (depending on what "under this section" turns out to mean). Of course, this could lead to the unintended (or maybe intended) consequence of overly long patent lists containing every conceivable patent that could be related to the manufacture of biologics in situations when inadequate information has been provided.
This case stems from Hospira's subsection (k) biosimilar application seeking approval to market a version of Amgen's EPOGEN® drug product. BLA 125545 was submitted in December 2014, and shortly thereafter Hospira provided its application to Amgen. Nevertheless, it did not otherwise provide any additional manufacturing information. On March 31, 2015, Amgen alerted Hospira that it had failed to comply with paragraph (l)(2)(A) of the BPCIA. Hospira responded that the application contained sufficient information about both the product and the process of its manufacture. Notwithstanding, the parties conducted the patent dance. However, Amgen did not include any cell-culture patents on its paragraph (l)(3)(A) patent list because it alleged it could not "assess the reasonableness of asserting claims for infringement" without the requested information.
Amgen ultimately filed suit on two patents in the U.S. District Court for the District of Delaware, U.S. Patent Nos. 5,756,349 and 5,856,298. Relying on the Amgen v. Sandoz statement referenced above, Amgen sought discovery of the withheld information, including the composition of Hospira's cell-culture medium. After Hospira refused to produce the information, the Court denied a motion to compel discovery filed by Amgen because the information sought had "essentially no relevance to the patents that are asserted." Amgen sought interlocutory appeal and in the alternative mandamus under the All Writs Act.
With regard to whether the Federal Circuit had jurisdiction, the Court looked to the collateral order doctrine to see if the appeal could be heard regardless of the fact that the judgement was not yet final. The test, established by the Supreme Court, is that "the order must conclusively determine the disputed question, resolve an important issue completely separate from the merits of the action, and be effectively unreviewable on appeal from a final judgment." Coopers & Lybrand v. Livesay, 437 U.S. 463, 468 (1978). After acknowledging that the first two conditions were met, the Court concluded that the lower Court's order was not "effectively unreviewable." In general, discovery rulings fall outside the collateral order doctrine because they are reviewable upon final judgement. Moreover, this was not a case analogous to an order to unseal confidential information or deny a claim of immunity. In essence, this was found to be a "run-of-the-mill discovery dispute," and therefore the Court determined it lacked jurisdiction.
With regard to the request for mandamus, the Court noted that such a writ is a "drastic remedy reserved for the most 'extraordinary causes,'" citing Cheney v. U.S. Dist. Court for D.C., 542 U.S. 367, 380 (2004). Amgen's right to the issuance of a writ, according to Supreme Court precedent, centered on whether there was a "clear and indisputable" right to that relief. The Court identified five potential avenues based on the BPCIA, but immediately shot down two or three of them. The first -- an injunction under federal law compelling the disclosures -- was foreclosed in the Supreme Court's Sandoz v. Amgen decision. The second -- an injunction under state law compelling the disclosures -- was left open by the Supreme Court, but Amgen had not sought a state law remedy in the Hospira case. Third -- suing the biosimilar applicant under the BPCIA and 35 U.S.C. § 271(e)(2) for failure to comply with the information disclosure provision -- was also foreclosed by the Supreme Court. The Court had explained in Sandoz that it was the act of submitting the aBLA to the FDA that gave rise to the artificial infringement, not the failure to comply with the provisions of the BPCIA.
The final two potential avenues arise from the ability of the reference product sponsor to bring an infringement suit: either pursuant to the list of patents created under paragraph (l)(3)(A) (avenue 4), or patents that "could" be identified in the case the aBLA is not disclosed (avenue 5). The Court did not address avenue 5. Rather, it noted that Amgen provided a patent list, and sued Hospira on two of the patents on that list. However, neither of those patents related to cell-culture media. The Federal Circuit back-peddled from its previous statement in Amgen v. Sandoz (that discovery would always be available) by claiming it had never intended to alter the Federal Rules of Civil Procedure.
Importantly, the Court addressed a question that Practitioners have been wondering ever since the original Amgen v. Sandoz decision: whether a reference product sponsor could assert a patent in the BPCIA context if it did not receive sufficient information from the biosimilar applicant about that patent. For example, would Amgen have faced Rule 11 sanctions for asserting the cell-culture patent, considering it did not know if Hospira was indeed practicing the invention claimed therein? The solution, according the Federal Circuit, is for a patent owner to include every patent that it could conceivably assert on its (l)(3)(A) list. After all, the statute does not provide for sanctions if a patent is unreasonably listed. In fact, it is the response from the biosimilar applicant in its "detailed statement" that could give rise to the reasonable basis for asserting the patent in litigation. Moreover, Rule 11 only requires that a filing be "to the best of the person's knowledge, information, and belief, formed after an inquiry reasonable under the circumstances." That belief could be based on an inquiry limited to the withholding of information. As such, the Court concluded, "the reasonableness requirement of paragraph (l)(3)(A) does not preclude a sponsor from listing as patent for which an applicant has not provided information under paragraph (l)(2)(A)." Ultimately, therefore, the Court concluded that the denial of discovery did not undermine the BPCIA and that denial of the motion to compel was proper.
Of course, this creates a chicken-and-the-egg situation. If the biosimilar applicant does not disclose its relevant information, the reference product sponsor will not know what patents cover the non-disclosed material. But if the sponsor will be unable to assert such a non-listed patent, it will be motivated to include every conceivable patent when it does create its list. This has the potential of escalating the amount of paperwork needed to be exchanged during the patent dance. Maybe the specter of responding to countless irrelevant patents will ultimately sway some biosimilar applicants to disclosure the information in the first place. Or maybe the question will be resolved in the next installment of the "Amgen v." series of BPCIA cases.
Before we leave this case, there is an update on the FDA approval process for the aBLA underlying this case. We had reported in June that the FDA's Oncologic Drug Advisory Committee recommended approval of Hospira's aBLA (see "Biosimilars Update -- Pfizer's Proposed Epogen®/Procrit® Biosimilar Recommended for Approval"). However, on June 22, 2017, Pfizer announced that it had received another Complete Response Letter (CRL) from the FDA. And even though this CRL did not relate specifically to the manufacture of epoetin alfa, it will likely result in a delay of drug approval. This is the second CRL that Pfizer received for this drug product application, thereby causing this application to be the longest between submission and approval (if it is, in fact, ultimately approved). We will continue to monitor the situation and provide updates as warranted.
Earlier today, the Supreme Court handed down its opinion in Sandoz Inc. v. Amgen Inc., marking the first time the Court has interpreted the Biologics Price Competition and Innovation Act ("BPCIA") for the approval of biosimilar drugs. The Court described the statute as "a carefully calibrated scheme for preparing to adjudicate, and then adjudicating, claims of infringement" related to biosimilar applications. This process begins with the disclosure by the biosimilar applicant of the aBLA and related information in order to "enable the sponsor to evaluate the biosimilar for possible infringement of patents it holds on the reference product . . . ." Nevertheless, the Court held that the reference product sponsor ("RPS") cannot seek enforcement of the disclosure provision in 42 U.S.C. § 262(l)(2)(A) by injunction under federal law. This was essentially the result reached by Federal Circuit. However, the Supreme Court reversed and remanded the question whether the disclosure provision was enforceable under state law, or whether the BPCIA pre-empted any state law claim. With regard to the 180-day notice-of-commercial-marketing provision of the statute, the Court reversed the Federal Circuit and held that the notice may be provided "either before or after receiving FDA approval."
As background, for those who have not being paying close attention for the past three years, in 2014, Sandoz became the first company to file a BLA pursuant to the BPCIA's abbreviated pathway found at 42 U.S.C. § 262(k). This application was for approval to market a biosimilar version of Amgen's NEUPOGEN® (filgrastrim) biologic drug product. NEUPOGEN® is a 175 amino acid recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF), and is often prescribed for cancer patients on chemotherapy at times when they are at most risk of infection because their white blood cell count is low. However, despite availing itself of this pathway for FDA approval, Sandoz refused to participate in the patent resolution component (the disclosure and information exchange provisions, also known affectionately as the "patent dance"), alleging that it was not a mandatory component. Amgen responded by filing suit on October 24, 2014, requesting in part a preliminary injunction to prevent Sandoz from entering the market before the issues can be resolved by the Court. United States District Judge Seeborg of the Northern District of California denied Amgen's motion, ruling that the disclosure and notice provisions of the BPCIA were not mandatory. And, in a seriously fractured decision, the Federal Circuit agreed (see "Federal Circuit Decides Amgen v. Sandoz (in an opinion that will make neither party happy)").
Is an Applicant required by 42 U.S.C. § 262(l)(2)(A) to provide the Sponsor with a copy of its biologics license application and related manufacturing information, which the statute says the Applicant "shall provide," and, where an Applicant fails to provide that required information, is the Sponsor's sole recourse to commence a declaratory-judgment action under 42 U.S.C. § 262(l)(9)(C) and/or a patent-infringement action under 35 U.S.C. § 271(e)(2)(C)(ii)?
However, the Court essentially sidestepped the question of whether "shall" means "shall" and instead held that an RPS cannot seek enforcement of this section by injunction under federal law. The Supreme Court essentially agreed with the Federal Circuit that the BPCIA provides the exclusive federal remedy for failure to disclose the required information by authorizing an RPS to bring an immediate declaratory-judgement action.
if the purpose of such submission is to obtain approval under such Act to engage in the commercial manufacture, use, or sale of a drug, veterinary biological product, or biological product claimed in a patent or the use of which is claimed in a patent before the expiration of such patent.
35 U.S.C. § 271 (e)(2)(c). As the Court put it: "The flaw in the Federal Circuit's reasoning is that Sandoz's failure to disclose its application and manufacturing information was not an act of artificial infringement, and thus was not remediable under § 271(e)(4)." Instead, the artificial infringement is the act of submitting the application. The language in the statute regarding noncompliance with § 262(l)(2)(A) is not an element of infringement, but rather "merely assists in identifying which patents will be the subject of the artificial infringement suit." As a result, the exclusive remedies outlined in § 271(e)(4) for this artificial infringement do not apply. Instead, the Supreme Court remanded this issue back to the Federal Circuit to determine whether an injunction is available under state law to enforce § 262(l)(2)(A), or whether state law enforcement is preempted by BPCIA. If the Federal Circuit does determine that state-law remedies are pre-empted, biosimilar applicants will be able to continue withholding information required by the BPCIA without threat of enforcement of that provision.
The subsection (k) applicant shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection (k) [emphasis in opinion].
Sandoz had provided this notice prior to obtaining FDA approval, and the District Court agreed with Sandoz that this notice was effective. Sandoz's biosimilar, under the brand name Zarxio®, obtained FDA approval on March 5, 2015 and under the District Court's interpretation of the statute Sandoz was free to enter the market (an outcome prevented by an injunction granted by the Federal Circuit pending its decision on appeal). The Federal Circuit had agreed with Amgen that notice could only effectively be given after the biosimilar product has been approved by the FDA. According to the Federal Circuit, while in other portions of the statute the biosimilar product is referred to as "the biological product that is the subject of the application," in subsection (l)(8)(A) the statute reads "the biological product licensed under subsection (k)." The change in language indicated to the Federal Circuit that "[i]f Congress intended paragraph (l)(8)(A) to permit effective notice before the product is licensed, it would have used the 'subject of' language." The appellate court appreciated that Congress made this distinction at least in part because it is only after licensure that "the product, its therapeutic uses, and its manufacturing processes are fixed," something that even the biosimilar applicant does not know with certainty when it applies for FDA approval. In addition, "[g]iving notice after FDA licensure, once the scope of the approved license is known and the marketing of the proposed biosimilar product is imminent, allows the RPS to effectively determine whether, and on which patents, to seek a preliminary injunction from the court." This permits "a fully crystallized controversy" between the parties to have arisen when suit is filed, and "provides a defined statutory window during which the court and the parties can fairly assess the parties' rights prior to the launch of the biosimilar product." Interpreting the statute as advanced by Sandoz would, on the contrary, result in a situation where "the RPS would be left to guess the scope of the approved license and when commercial marketing would actually begin."
Whether notice of commercial marketing given before FDA approval can be effective and whether, in any event, treating Section 262(l)(8)(A) as a stand-alone requirement and creating an injunctive remedy that delays all biosimilars by 180 days after approval is improper.
The Supreme Court reversed. The Court's analysis regarding the 180-day notice provisions of the statute was straightforward. The Court held that the Federal Circuit had misinterpreted the statutory language by imposing a requirement for FDA approval before proper notice could be given. According to the opinion, the reference in the statute to a licensed biosimilar product was to the term "commercial marketing" not "notice," and thus just imposed the requirement that a product be licensed before it is marketed. With this interpretation the notice was not tied to a product having been licensed before notice was given, as the Federal Circuit had held, but to the unremarkable reality that the product had to be licensed before it was sold. The Supreme Court found only one timing requirement in the statute, that notice must be provided 180 days prior to marketing the biosimilar product. The opinion recognized the Federal Circuit opinion to contain a second timing requirement, that FDA had approved the biosimilar. This second requirement was not in the statute according to the Court and hence requiring approval was a misinterpretation of the statutory language by the Federal Circuit. This conclusion was supported for the Court by the structure of subsection §262(l)(8)(B) ("After receiving notice under subparagraph (A) and before such date of the first commercial marketing of such biological product, the reference product sponsor may seek a preliminary injunction" (emphasis added)). According to the opinion, Congress would have used this structure in its language for §262(l)(8)(A) if it intended the provision to have the interpretation applied by the Federal Circuit.
Outside this question of statutory interpretation, the Court identified the policy arguments raised by the parties and the government, and refused to be persuaded by the plausible contentions set forth therein. Rather, the Court recommended that Congress is the appropriate body for making these policy distinctions and advised the parties to go there to effect a change in the law.
Justice Breyer filed a brief concurring opinion, directed to his concerns (voiced during oral argument) that Congress had delegated to FDA responsibility for interpreting the statute, based in part on its greater expertise. The Justice thus invited the agency to "depart from, or to modify, today's interpretation" under the appropriate circumstance, citing National Cable & Telecommunications Assn. v. Brand X Internet Services, 545 U. S. 967, 982–984 (2005), to support his interpretation of the agency's authority in this regard.

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