In this review, we discuss the most important recent developments in the biosimilars space, including new biosimilar approvals and launches, litigation under the Biologics Price Competition and Innovation Act (BPCIA), post-grant disputes on biologic drug patents before the United States Patent and Trademark Office (USPTO), and proposed legislation and regulatory activities relating to biosimilars.

I. Biosimilars approvals and launches in 2023

Approvals

In 2023, the Food and Drug Administration (FDA) approved five new biosimilars, bringing the total number of FDA-approved biosimilars in the United States to 45: Avzivi® (bevacizumab-tnjn), Tofidence™ (tocilizumab-bavi), Tyruko® (natalizumab-sztn), Wezlana™ (ustekinumab-auub), and Yuflyma® (adalimumab-aaty). Notably, three of these biosimilars were the first approved biosimilars for Janssen’s Stelara® (ustekinumab), Genentech’s Actemra® (tocilizumab), and Biogen’s Tysabri® (natalizumab), representing a continuation of the next wave of biosimilar approvals that began in 2021.

FDA’s approval of Sandoz’s Tyruko® was the first for a biosimilar product indicated for the treatment of relapsing forms of multiple sclerosis. Sandoz has not yet announced a launch date for Tyruko® in the U.S.

Amgen’s Wezlana™, approved in October 2023 for the treatment of inflammatory disorders like plaque psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis, was the first approval for a biosimilar referencing Johnson & Johnson and Janssen’s top blockbuster Stelara® (ustekinumab). FDA also granted Wezlana™ an interchangeability designation, making it the seventh interchangeable biosimilar¹ approved by FDA. According to a settlement with Johnson & Johnson in a related BPCIA lawsuit, Amgen will launch Wezlana™ no later than January 1, 2025.

Biogen and Bio-Thera’s Tofidence™, approved in September 2023 for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis marks FDA’s first approval for a biosimilar referencing Genentech’s Actemra® (tocilizumab). Biogen stated in a press release shortly after approval of Tofidence™ that it is evaluating the launch timeline for Tofidence™ in the U.S. Prior to its approval, Tofidence™ was subject to BPCIA litigation filed by Genentech against Biogen and Bio-Thera in July 2023. The parties settled the dispute in October 2023, shortly after the biosimilar was approved. The precise terms of the settlement are not public.

Launches

The year 2023 set a record for the most biosimilar launches in a single year, with 13 launches. Nine of those launches were the much-anticipated Humira® (adalimumab) biosimilars. AbbVie’s Humira® was initially commercialized in 2003, and over the course of two decades has accrued an impressive $200 billion in revenue, making Humira® the best-selling drug in the world between 2012 and 2020. Although FDA approved the first Humira® biosimilar in 2016, Amgen’s Amjevita™, 2023 was the first year Humira® biosimilars could enter the U.S. market pursuant to settlement agreements between biosimilar makers and AbbVie.

Other biosimilar launches from 2023 include Eli Lilly’s Rezvoglar™ (insulin glargine-aglr), Celltrion’s Vegzelma® (bevacizumab-adcd), Fresenius’ Kabi’s Stimufend® (pegfilgrastim-fpgk), and Amneal’s Fylnetra® (pegfilgrastim-pbbk).

Figure 1: Biosimilars approvals and launches

Numerous biosimilar Biologics License Applications (BLAs) are currently under review at FDA. According to FDA’s Pre-Approval Safety Review Biosimilars Dashboard, there were 101 development programs enrolled in the agency’s Biosimilar Biological Product Development Program as of Q4 of Fiscal Year 2023. FDA also reported that 19 original BLA submissions were submitted in Fiscal Year 2023. Several relate to blockbuster reference products that did not yet have an approved biosimilar, such as Soliris® (eculizumab) and Eylea® (aflibercept). Table 1 summarizes publicly available information regarding select pending BLAs on biosimilars.

Table 1: Select pending biosimilar BLAs

More biosimilars for reference products that are expected to lose regulatory and/or patent exclusivity in the coming years are in the pipeline. For example, in May 2023, Alvotech announced the initiation of its confirmatory patient study for AVT05, a biosimilar candidate to Simponi® and Simponi Aria® (golimumab). And Celltrion’s proposed Xolair® (omalizumab) biosimilar, CT-P39, is reportedly nearing the end of its 40-week phase three clinical trial assessing efficacy and safety in patients with chronic spontaneous urticaria.

Additionally, biosimilar uptake in the U.S. is continuing to trend upwards. While uptake speed has varied depending on therapeutic area, it has been reported that on average, biosimilars gain 53% market share within the first three years of initial launch.

II. BPCIA litigation

We summarize below overall statistics regarding BPCIA District Court litigation to-date, and then review ongoing BPCIA District Court cases and BPCIA District Court cases that settled or resolved in 2023. The Federal Circuit did not decide any BPCIA appeals in 2023, and there were no BPCIA appeals pending before the Federal Circuit at the end of 2023.

Since the BPCIA’s enactment in 2010, District Courts have handled more than 60 BPCIA cases. Many of these cases involve the same parties and the same biosimilar products. It is common, for example, for a reference product sponsor to file an infringement action, and the accused biosimilar developer to file a separate declaratory judgment action. Genentech and Amgen are the most active plaintiffs (with 18 and 17 cases respectively) and together account for the plaintiff side in more than half of all BPCIA litigation. Amgen is also the most common BPCIA defendant (with nine cases), and Celltrion and Sandoz (each defendant in eight cases) are not far behind. Other parties active in BPCIA litigation include Janssen (plaintiff in six cases and declaratory judgment defendant in two cases), AbbVie (plaintiff in five cases and declaratory judgment defendant in one case), Regeneron (plaintiff in five cases — one filed in 2022 and four filed in 2023), and Samsung Bioepis (defendant in six cases, two of which were filed in 2023).

Figure 2: BPCIA cases filed by year since BPCIA enactment

Prior to 2022, all BPCIA litigation involved biosimilars of the same nine reference products, several of which had been on the market long past the 12 years of marketing exclusivity afforded by the BPCIA: Remicade®, Neulasta®, Neupogen®, Avastin®, Herceptin®, Rituxan®, Humira®, Enbrel®, and Epogen®. The year 2022 saw a new wave of lawsuits related to newer reference products, including Tysabri®, Stelara®, and Eylea®. This trend continued in 2023, with new BPCIA litigations brought by reference product sponsors on biosimilars of the next wave of reference products such as Prolia®/Xgeva®, Actemra®, and Eylea®, all of which were approved by FDA in 2010 and onward. Only one BPCIA lawsuit filed in 2023 involved a biosimilar of one of the nine older reference products, Rituxan®, which was first approved in 1997.

A. Ongoing BPCIA District Court litigation

Seven BPCIA cases were filed in 2023, four of which involve biosimilars of the same reference product, Eylea® (aflibercept). Six of the BPCIA cases filed in 2023 and two filed in 2022 remain ongoing.

Table 2. Ongoing BPCIA cases from 2023

The year 2023 saw some notable trends in BPCIA litigation. For one, numerous BPCIA complaints have alleged a lack of compliance with the patent dance on the part of the biosimilar manufacturer based on a failure to provide “other” manufacturing information as required by § 262(l)(2)(A). This has been a common theme from BPCIA cases from previous years, and it has continued in 2023. Another interesting development is an uptick in preliminary injunction motions compared to previous years, with reference product sponsors requesting preliminary injunctions in seven cases in 2023. Each of these cases involved biosimilars to the new wave of reference products, namely Regeneron’s Eylea® (aflibercept), Amgen’s Xgeva®/Prolia® (denosumab), Biogen’s Tysabri® (natalizumab), and Janssen’s Stelara® (ustekinumab).

We discuss each ongoing case briefly below.

Biogen v. Sandoz, Polpharma (1:22-cv-01190 D. Del.)

This is a case of several firsts: It is the first BPCIA litigation involving Biogen as the reference product sponsor, the first BPCIA litigation involving Polpharma, and the first BPCIA litigation involving a proposed biosimilar of Tysabri® (natalizumab). Biogen filed a complaint against Sandoz and Polpharma on September 9, 2022, related to the defendants’ proposed natalizumab biosimilar, PB006 (now called Tyruko®), alleging infringement of 28 patents relating to natalizumab and associated manufacturing and testing methods. (Dkt. 10 ¶¶ 2, 4, 112–167.) On December 1, 2022, Biogen filed a first amended complaint, reducing the number of asserted patents from 28 to 17. (Dkt. 56.)

On January 20, 2023, Polpharma moved to dismiss the first amended complaint. (Dkt. 71.) In response, on February 8, 2023, Biogen filed a second amended complaint “with additional allegations directed to Polpharma only.” (Dkt. 122 ¶ 1 n.1.)

On March 3, 2023, Polpharma moved to dismiss the second amended complaint, arguing that: (1) Polpharma is not a proper defendant for a claim brought under 35 U.S.C. § 271(e)(2) because Sandoz, not Polpharma, submitted the BLA; (2) Biogen has not alleged facts to show that Polpharma will make, use, sell, offer to sell, or import the proposed natalizumab biosimilar in the U.S. and thus infringe under 35 U.S.C. § 271(a) or (g) or that Polpharma will market or promote the biosimilar to healthcare professionals in the U.S. and thus infringe under 35 U.S.C. § 271(b); and (3) any infringing acts by Polpharma alleged in the complaint fall within the scope of a statutory safe harbor. (Dkt. 165 at 3–4; see also Dkt. 256.) Biogen opposed Polpharma’s motion, arguing that Polpharma was a “submitter” of the BLA because it was “actively involved” in preparing the BLA and stands to benefit significantly from its approval, that Polpharma is liable for future acts of infringement because it has and will continue to collaborate with Sandoz following approval of the BLA, and that Polpharma’s activities were not protected by the safe harbor. (Dkt. 232 at 7–19.) Polpharma also filed an opposed motion to stay proceedings pending resolution of its motion to dismiss on March 3, 2023. (Dkt. 166 at 1; see also Dkt. 233, 255.) On March 5, 2024, the court denied both of Polpharma’s motions. (Dkt. 303.) The opinion is sealed and not publicly available.

On January 20, 2023, Biogen filed a motion for preliminary injunction pursuant to 42 U.S.C. § 262(l)(8)(B), seeking to enjoin the defendants from “engaging in the commercial importation, marketing, and sale of their natalizumab biosimilar . . . and companion assay . . . until Biogen’s patent infringement claims against Defendants are fully adjudicated.” (Dkt. 100 at 1.) Biogen sought preliminary relief based on four of 17 asserted patents, which are directed to methods of treatment with natalizumab, methods of manufacturing antibody products like natalizumab, and a companion assay used to reduce natalizumab patients’ risk of developing serious side effects. (Dkt. 101 at 1–2.) After oral argument, the court denied Biogen’s motion for preliminary injunction, finding that Biogen failed to prove it would suffer irreparable harm and a likelihood of success on the merits. (Dkt. 270 at 4.) Regarding irreparable harm, the court found that Biogen’s alleged harms of price erosion, lost sales and market share, and reputational harm were “speculative and uncertain,” and that Biogen had failed to show a causal nexus “between the alleged infringement and harm such that the infringing feature drives consumer demand for the accused product.” (Id. at 5, 8.) With respect to likelihood of success on the merits, the court found that Biogen failed to show based on the evidence of record that defendants would infringe any of the four patents at issue. (Id. at 11, 14, 18–20.)

The claim construction process is underway, with a joint technology tutorial and claim construction hearing scheduled for May 17 and 29, 2024, respectively. (Dkt. 280 at 8–9; Dkt. 294 at 1.) A five-day trial is scheduled for May 5, 2025. (Dkt. 280 at 14.)

Amgen v. Sandoz (1:23-cv-02406 D.N.J.)

This case is the first BPCIA litigation involving a proposed biosimilar of Amgen’s Prolia®/Xgeva® (denosumab). On May 1, 2023, Amgen filed a complaint related to Sandoz’s proposed denosumab biosimilar GP2411. Amgen asserted 21 patents, which “cover denosumab . . . and methods of manufacturing denosumab and denosumab products.” (Dkt. 1 ¶ 3.)

According to the complaint, the parties started but did not complete the patent dance. The complaint alleges that Sandoz served its BLA to Amgen on December 13, 2022, “even though it had not been accepted by the FDA (and would not be accepted until February 2023),” and that Sandoz “took the position . . . that its early BLA production . . . triggered the start of the BPCIA information exchange.” (Id. ¶¶ 4, 76.) The complaint also asserted that Sandoz failed to comply with § 262(l)(2)(A) of the BPCIA because it refused provide to Amgen “other” manufacturing information as required by the statute, that Amgen provided Sandoz its list of patents under § 262(l)(3)(A), and that Sandoz provided its “Detailed Statement” pursuant to § 262(l)(3)(B), which allegedly relied on the information that Sandoz was required to but did not provide to Amgen under § 262(l)(2)(A). (Id. ¶ 4; see also id. ¶¶ 77–83.) Amgen therefore contends that it was entitled to file a declaratory judgment action under § 262(l)(9)(C). (Id. ¶ 5.)

On September 8, 2023, Amgen filed a motion for preliminary injunction. Following briefing, the court held a “science hearing” on October 20, 2023, and a four-day preliminary injunction hearing on October 30 through November 1 and November 3, 2023. In relation to Amgen’s preliminary injunction motion, on November 14, 2023, the court ordered, inter alia, Sandoz to “notify the Court in writing of the specific date on which Sandoz first intends to make announcement concerning the launch of any denosumab biosimilar product” 30 days before making any such announcement. (Dkt. 253 at 2.) On November 30, 2023, the court held a fifth day of hearings on the preliminary injunction motion, (Dkt. 270), and following the hearing, the parties filed proposed findings of fact and conclusion of law. (Dkt. 394.) Amgen’s motion remains pending.

The case is currently in fact discovery, and the parties have brought several discovery disputes to the court for resolution. Claim construction discovery and briefing is scheduled for April through September 2024, and the parties are to propose a Markman hearing schedule to the court by September 30, 2024. (Dkt. 151 at 5–6; Dkt. 295 at 2.)

Genentech v. Dr. Reddy’s Laboratories, Fresenius Kabi (1:23-cv-22485 D.N.J.)

On November 13, 2023, Genentech, Hoffman-La Roche, and Biogen filed a complaint asserting 15 patents “relating to the manufacture and use of Rituxan®” against Dr. Reddy’s Laboratories (“DRL”) and Fresenius Kabi. (Dkt. 1 ¶ 5.) This case involves DRL_RI, the defendants’ proposed biosimilar of Genentech’s Rituxan® (rituximab). It is the sixth BPCIA case that Genentech has brought against developers of a rituximab biosimilar.

According to the complaint, the parties engaged in some, but not all, steps of the patent dance. The plaintiffs alleged that DRL SA, the filer of the BLA for DRL_RI, provided its BLA to plaintiffs but failed to provide “other” manufacturing information as required under § 262(l)(2)(A), thus allegedly “hamper[ing]” the plaintiffs’ “ability to evaluate Defendants’ infringement of their patent estate.” (Id. ¶¶ 69, 76.) The plaintiffs also alleged that they provided Defendants an operative list of patents pursuant to § 262(l)(3)(A) based on the “deficient materials” received to date and requested multiple times that DRL SA provide to plaintiffs the “required manufacturing information” under § 262(l)(2)(A). (Id. ¶¶ 70–71.) Additionally, the complaint alleged that DRL SA provided a Notice of Commercial Marketing on November 16, 2023, which “started a “180-day clock before the first possible date on which DRL SA or its partners could market and/or sell . . . DRL_RI.” (Id. ¶ 72.) In view of DRL SA’s Notice of Commercial Marketing and DRL SA’s alleged failure to comply with § 262(l)(2)(A), the plaintiffs “exercise[d] the right to bring suit pursuant to . . . § 262(l)(8) and . . . § 262(l)(9).” (Id. ¶¶ 72–74.)

The defendants’ response to the complaint is due on April 5, 2024.

Eylea® (aflibercept) cases

Eylea® (first FDA-approved in 2011) is the youngest biologic to be subject to BPCIA litigation. It is also the first biologic to be challenged prior to the expiration of its 12-year regulatory exclusivity under § 262(k)(7)(A) of the BPCIA, which has raised issues of first impression. In August 2022, Regeneron filed the first BPCIA litigation involving a proposed biosimilar of Eylea® (aflibercept), which was also Regeneron’s first BPCIA litigation and the first BPCIA litigation filed in the Northern District of West Virginia. The court held a trial on this first case on June 12–23, 2023, and found one asserted patent infringed and not invalid. In November and December 2023, Regeneron filed four more BPCIA cases also in the Northern District of West Virginia against three other aflibercept biosimilar developers. And in January 2024, Regeneron filed a sixth BPCIA case against an aflibercept biosimilar developer in the Central District of California. Regeneron has moved with the Judicial Panel for Multi-District Litigation to consolidate and transfer the pending cases in the Northern District of West Virginia for coordinated pretrial proceedings. All six cases remain ongoing, and we discuss each case briefly below.

Regeneron v. Mylan, Biocon (1:22-cv-00061 N.D.W. Va.)

This case relates to Biocon’s proposed Eylea® (aflibercept) biosimilar Yesafili™ (previously known as M710), which was transferred to Biocon from Mylan in 2023. On August 2, 2022, Regeneron filed a complaint against Mylan asserting infringement of 24 patents. (Dkt. 1, ¶ 6.) Shortly thereafter, Regeneron requested an expedited trial no later than June 2023 so that it may avail itself of the statutory injunctive relief provided by 35 U.S.C. § 271(e)(4)(D). (Dkt. 7.) The court granted Regeneron’s request to proceed at trial in June 2023 on six patents from three patent families, with the proceedings on the remaining patents deferred until after the initial trial. (Dkt. 87.)

Before the June 2023 trial, the court entered several rulings, including a claim construction order (Dkt. 427), an order granting Mylan’s motion for leave to amend its answer, defenses, and counterclaims to add a declaratory judgment counterclaim of no lost profits or injunctive relief with respect to patents that Regeneron had not selected to proceed in this first stage of litigation (Dkt. 434), and an order denying the parties’ motions for summary judgment (Dkt. 525).

From June 12 through 23, 2023, the court held a nine-day bench trial on three patents: U.S. Patent Nos. 10,888,601, 11,084,865, and 11,253,572. The ’865 patent was directed to compositions containing aflibercept and the ’601 and ’572 patents were directed to methods of treatment using aflibercept. After post-trial briefing and closing arguments, on December 27, 2023, the court issued an order finding the asserted claims of Regeneron’s U.S. Patent No. 11,084,865 infringed and not invalid and the asserted claims of U.S. Patent Nos. 10,888,601 and 11,253,572 infringed and invalid as obvious following the bench trial. (Dkt. 692.)

On December 11, 2023, the defendants filed a motion to enforce the protective order and for sanctions, arguing that Regeneron “improperly disclosed information designated as ‘CONFIDENTIAL’ or ‘OUTSIDE COUNSEL’S EYES ONLY’ at least six times to in-house and outside counsel, domestic and foreign, not cleared under the Stipulated Protective Order in the months following trial.” (Dkt. 658 at 1.) Regeneron’s opposition and the defendants’ reply were filed under seal. (Dkt. 661; Dkt. 668.) The court has not yet ruled on the defendants’ motion.

The parties in the Mylan case are scheduled to appear at a permanent injunction hearing on the ’865 patent on May 2, 2024. (Dkt. 714.) As discussed below, this is the same date as the preliminary injunction hearing for the related aflibercept BPCIA cases in West Virginia.

Regeneron v. Celltrion (1:23-cv-00089 N.D. W. Va.); Regeneron v. Samsung Bioepis (1:23-cv-00094 and -00106 N.D. W. Va.); Regeneron v. Formycon (1:23-cv-00097 N.D. W. Va.)

These cases relate to Celltrion, Samsung Bioepis, and Formycon’s proposed Eylea® (aflibercept) biosimilars, CT-P42, SB15, and FYB203, respectively.

On November 8, 2023, Regeneron filed a complaint against Celltrion asserting infringement of 38 patents. (-0089, Dkt. 1 ¶ 5.) Regarding the patent dance, the complaint alleges that on September 13, 2023, Celltrion served a copy of its biosimilar BLA for CT-P42 under § 262(l)(2)(A), and on November 7, 2023, Regeneron served its list of patents under § 262(l)(3)(A). (Id. ¶¶ 23, 27.) The complaint also alleges that Celltrion served its notice of commercial marketing, “indicating its intent to begin marketing and selling CT-P42 immediately upon receiving approval from the FDA.” (Id. ¶ 25.) Following these exchanges, Regeneron filed suit, seeking a judgment of infringement and declaratory judgment of infringement pursuant to § 262(l)(9)(A). (Id. ¶ 28.)

Regeneron filed a complaint against Samsung Bioepis alleging infringement of 37 patents on November 21, 2023. (-94 Dkt. 1 ¶ 6.) Eight days later, on November 29, 2023, Regeneron filed a complaint against Formycon alleging infringement of 39 patents. (-97 Dkt. 1 ¶ 6.) Both complaints, which were heavily redacted, suggest that the parties engaged in some steps of the patent dance but did not complete the entire process. (-94 Dkt. 1 ¶¶ 18–34; -97 Dkt. 1 ¶¶ 17–25.) Regeneron brought both actions seeking a judgment of infringement and declaratory judgment of infringement pursuant to § 262(l)(9)(A). (-94 Dkt. 1 ¶ 34; -97 Dkt. 1 ¶ 25.)

On December 27, 2023, Regeneron filed a second complaint against Samsung Bioepis, asserting infringement of 51 patents — 36 of the 37 patents that had been asserted in the -94 case, and 15 additional patents, including five design patents claiming designs of a syringe cap and packaging. (-106 Dkt. 1 ¶¶ 6, 499, 509, 519, 529, 539.) The complaint is heavily redacted, and it is not clear which steps of the patent dance the parties completed. (See id. ¶¶ 18–34.) Regeneron brought this action pursuant to § 262(l)(6). (MDL No. 3103 Dkt. 1 at 3.)

On January 9, 2024, the court issued an order setting a briefing schedule on the defendants’ motions to dismiss and for preliminary injunction proceedings. (-89 Dkt. 61; -94 Dkt. 69; -97 Dkt. 45; -106 Dkt. 40.) Regeneron had filed an “emergency motion” requesting a schedule for preliminary injunction proceedings. (Id. at 2.) The defendants asked the court to decide jurisdictional issues raised in their motions to dismiss first, before preliminary injunction proceedings, whereas Regeneron requested that “the preliminary injunction proceedings run parallel to the resolution of the jurisdictional issue.” (Id.) The court found that it was “appropriate here to allow preliminary injunction proceedings to take place at the same time as the briefing and resolution of the motions to dismiss” because of the “180-day clock” on preliminary injunction proceedings under § 262(l)(8)(A) of the BPCIA. (See id. at 2–3.) Pursuant to the court’s order, within two business days of entry of the order, Regeneron needed to identify “no more than eight patents that may be included in the motion for preliminary injunction.” (Id. at 3.) Discovery relating to and briefing on Regeneron’s motion for preliminary injunction are scheduled for January through April 2024, and a preliminary injunction hearing is scheduled for May 2, 2024. (Id. at 3–4.) Regulatory exclusivity on Eylea® (aflibercept) will expire on May 18, 2024. (Id. at 4.)

Regeneron v. Amgen (2:24-cv-00264 C.D. Cal.)

This case involves Amgen’s proposed biosimilar of Regeneron’s Eylea® (aflibercept), ABP 938. This is the sixth BPCIA case that Regeneron has brought against a developer of an aflibercept biosimilar, following the five ongoing cases discussed above. On January 10, 2024, Regeneron filed a complaint against Amgen asserting 32 patents. (Dkt. 1 ¶ 6.) The parties engaged in the patent dance and agreed on the patents to litigate in the first wave of litigation. (Id. ¶¶ 21–28.)

On January 11, 2024, Regeneron moved to transfer the action to the Northern District of West Virginia pursuant to 28 U.S.C. § 1407 for coordinated pretrial proceedings with the five cases filed by Regeneron that are already pending in the Northern District of West Virginia. (In re Aflibercept Patent Litigation, MDL No. 3103 Dkt. 1 at 1.) Regeneron noted in its motion that 13 of the asserted patents overlap across all six cases and four of those patents had already been construed by the court in Regeneron v. Mylan and Biocon (1:22-cv-00061 N.D. W. Va.). (MDL No. 3103 Dkt. 1 at 2, 4.)

B. BPCIA litigation settled or resolved in 2023

Three BPCIA cases settled or otherwise resolved in 2023.

Table 3: BPCIA cases settled or resolved in 2023

We discuss each of these resolved cases briefly below.

Genentech v. Tanvex (3:22-cv-00809 S.D. Cal.)

This case, filed in June 2022, involved Tanvex’s proposed biosimilar of Genentech’s Herceptin® (trastuzumab), TX-05. It is the fifth BPCIA litigation brought by Genentech against a trastuzumab biosimilar developer. In its complaint, Genentech asserted three patents directed to aspects of cell culture and antibody purification — U.S. Patent Nos. 8,574,869 (“the ’869 patent”), 10,662,237 (“the ’237 patent”), and 10,808,037 (“the ’037 patent”). (Dkt. 1 ¶¶ 63–66.) The ’237 and ’869 patents were asserted in previous BPCIA litigation, but the ’037 patent had not been previously asserted. Tanvex counterclaimed for declaratory judgment of non-infringement and invalidity of each of the three asserted patents. (Dkt. 17.) In January 2023, the parties reached an agreement to settle the case, and in February 2023, the court, at the request of the parties, dismissed all claims and counterclaims without prejudice. (Dkt. 59; Dkt. 60.)

Janssen v. Amgen (1:22-cv-01549 D. Del.)

This case involves Amgen’s ustekinumab biosimilar, Wezlana™ (previously known as ABP 654). It was also the first BPCIA litigation involving a biosimilar of Janssen’s Stelara® (ustekinumab). Janssen initially asserted two patents directed to ustekinumab and methods of treating ulcerative colitis with ustekinumab. (Dkt. 1 ¶ 5.)

After Janssen filed suit, Amgen provided Janssen with information about its manufacturing process, and on February 21, 2023, Janssen amended its complaint to assert four additional patents directed to “methods of using cell culturing processes to target and control features of biosimilar antibodies to assure equivalence to a reference product.” (Dkt. 20 (sealed); Dkt. 46 ¶ 5 (redacted).)

On March 6, 2023⁴, Janssen filed a motion for a preliminary injunction seeking to enjoin Amgen from “manufacturing in commercial quantities, using in commercial quantities, offering to sell, selling within the United States, or importing for commercial purposes into the United States its ABP 654 biosimilar product.” (Dkt. 35 at 1; see also Dkt. 48 at 9.) Janssen sought preliminary relief based on two of the six asserted patents covering methods of controlling certain types of post-translational modifications, arguing that Amgen’s launch of its biosimilar would cause irreparable harm to Janssen. (Dkt. 48 at 1–2, 5.)

The parties settled and the case was dismissed pursuant to a stipulation of dismissal on May 23, 2023. (Dkt. 97.) Amgen has stated that the settlement terms are confidential but will allow it to sell Wezlana™ “no later than January 1st, 2025.”

Genentech v. Biogen MA, Bio-Thera (1:23-cv-11573 D. Mass.)

This was the first BPCIA litigation involving a biosimilar of Genentech’s Actemra® (tocilizumab) and the first BPCIA litigation involving Biogen as a biosimilar developer. On July 13, 2023, Genentech, Hoffman-La Roche, and Chugai Pharmaceutical filed a complaint against Biogen MA and Bio-Thera related to the defendants’ tocilizumab biosimilar, TofidenceTM (then known as BIIB800). Genentech and Biogen MA engaged in the patent dance and negotiated pursuant to § 262(l)(4)(A) regarding which patents on Genentech’s list should be litigated in a § 271(e) infringement action. The parties failed to agree upon a list of patents and thereafter exchanged lists pursuant to § 262(l)(5). (Id. ¶ 32.) The complaint asserted 20 patents identified on one or both of the parties’ lists generally covering aspects of making and using tocilizumab. (Dkt. 1 ¶¶ 32–33.)

On October 23, 2023, before the defendants responded to the complaint, the parties filed a joint stipulation voluntarily dismissing all claims with prejudice because the parties had entered into a settlement agreement. (Dkt. 17 at 1.) The precise terms of the settlement were not made public.

III. Biosimilar post-grant challenges at the PTAB

Biologic and biosimilar activity at the Patent Trial and Appeal Board (PTAB) in 2023 was up compared to 2022, with 22 inter partes review (IPR) petitions and two post-grant review (PGR) petitions filed, compared to only 15 IPR petitions and two PGR petitions filed in 2022. In fact, 2023’s filings mark the most filings on biologics and biosimilars since 2017’s record high of 87 IPR petitions filed. Additionally, several of the active post-grant proceedings from 2023 concern patents asserted in the District Court BPCIA litigations discussed above.

Figure 3: Biologic IPR petitions filed by year

The bullets below review exemplary filings and developments.

Eylea® (aflibercept) / Zaltrap® (ziv-aflibercept)

Regeneron’s aflibercept patents saw quite a bit of activity before the PTAB in 2023. After Mylan successfully invalidated U.S. Patent Nos. 9,669,069 and 9,254,338 (IPR2021-00880, -00881) in November 2022 (joined by Apotex and Celltrion and presently on appeal), six other aflibercept patents — U.S. Patent Nos. 10,857,205, 10,406,226, 10,130,681, 10,888,601, 11,253,572, and 10,464,992 — have been challenged in multiple IPRs.

In October 2022, Mylan filed IPR2023-00099 challenging the ’205 patent and in February 2023, Celltrion filed IPR2023-00621 challenging the ’226 patent. The ’205 patent is directed to dosing regimens for treating angiogenic eye disorders and the ’226 patent relates to methods of manufacturing VEGF antagonists. The PTAB denied institution of both IPRs after Regeneron statutorily disclaimed all claims of both the ’205 and ’226 patents.

In January 2023, the PTAB instituted IPR2022-01225 and -01226, filed by Mylan, challenging the ’681 and ’601 patents, respectively. The challenged claims generally concern dosing regimens for treating angiogenic eye disorders using aflibercept or a VEGF antagonist. Celltrion joined both IPRs and Samsung Bioepis joined IPR2022-01226. On January 9, 2024, the PTAB issued final written decisions in both IPRs finding the challenged claims of the ’681 and ’601 patents unpatentable. Relatedly, in July and October 2023, the PTAB instituted two separate additional petitions (IPR2023-00442, -00739) filed by Samsung Bioepis challenging these same two patents. IPR2023-00739, which relates to the ’601 patent, was subsequently joined by Biocon.

Celltrion also filed in January 2023 a petition (IPR2023-00462) challenging the ’992 patent, which concerns aflibercept formulations. The proceeding was subsequently joined by Samsung Bioepis. After institution, Regeneron filed a statutory disclaimer disclaiming all claims of the ’992 patent and moved to terminate the proceeding in view of the disclaimer. In February 2024, the PTAB issued a decision entering adverse judgment against Regeneron with respect to the disclaimed claims.

In April 2023, Samsung Bioepis filed IPR2023-00884 challenging the ’572 patent, which is generally directed to dosing regimens for treating angiogenic eye disorders using aflibercept. The PTAB granted institution of IPR in November 2023, and Celltrion and Biocon subsequently joined the proceeding.

Final written decisions on the pending IPRs are expected to issue in 2024.

Keytruda® (pembrolizumab)

In November 2023, Merck filed an IPR challenging U.S. Patent No. 11,591,393, held by The Johns Hopkins University, directed to methods of treating microsatellite instability high or DNA mismatch repair deficient colorectal cancer with pembrolizumab, (IPR2024-00240). Merck previously filed a declaratory judgment action in November 2022 in the District of Maryland, asserting claims of non-infringement as well as breach of contract (1:22-cv-03059 D. Md., Dkt. 1). Claim construction briefing in the District Court case is under way. An institution decision in the IPR proceeding is expected by June 2024.

Soliris® (eculizumab)

In May and June 2023, Samsung Bioepis filed five IPRs challenging five patents held by Alexion relating to compositions, formulations, and methods of treatment using eculizumab (U.S. Patent Nos. 9,732,149, 9,718,880, 9,725,504, 10,590,189 and 10,703,809, challenged in IPR2023-00933, -00998, -00999, -01069, -01070). In December 2023, the PTAB instituted all five challenges. Final written decisions are expected by December 2024. The challenged patents in these IPRs are also the focus of a related BPCIA litigation, Alexion Pharmaceuticals., Inc. v. Samsung Bioepis Co., No. 24-cv-00005 (D. Del.), filed in January 2024. Notably, Amgen had previously filed IPRs in February 2019 challenging three of these patents (U.S. Patent Nos. 9,732,149, 9,718,880, and 9,725,504, challenged in IPR2019-00739, -00740, -00741). The parties settled these IPRs after institution.

Stelara® (ustekinumab)

In June 2023, Samsung Bioepis filed an IPR challenging Janssen’s U.S. Patent No. 10,961,307 (the “’307 patent”) relating to a method of treatment using ustekinumab (IPR2023-01103). A few months later the parties reached a settlement and terminated the IPR. Under the settlement agreement, Samsung Bioepis will be permitted to begin marketing its proposed biosimilar of Stelara®, SB17, in the U.S. on February 22, 2025. In November 2023, Biocon filed a follow on IPR challenging the ’307 patent, relying on the same prior art grounds and arguments as Samsung Bioepis’s petition (IPR2023-01444). An institution decision is expected by May 2024.

Several post-grant proceedings also reached resolution this year. For example:

Emgality® (galcanezumab-gnlm) / Ajovy® (fremanezumab-vfrm)

In September 2022, the PTAB instituted two IPRs filed by Eli Lilly against Teva concerning U.S. Patent Nos. 11,028,160 and 11,028,161, directed to methods of treating or preventing refractory migraine with anti-CGRP monoclonal antibody, which Teva had asserted against Eli Lilly in pending (stayed) District Court litigation over Eli Lilly’s Emgality® product (1:21-cv-10954 D. Mass.). (IPR2022-00738, -00739.) In October 2022, the PTAB instituted a third IPR challenge by Eli Lilly against a Teva patent not currently asserted in the District Court litigation, U.S. Patent No. 10,392,434 (the “’434 patent”). (IPR2022-00796.) The ’434 patent is directed to methods of treating migraine with CGRP monoclonal antibody. In September and October 2023, the PTAB issued final written decisions finding all three patents invalid as obvious. Teva has not filed a notice of appeal to the Federal Circuit.

These challenges followed a previous round of PTAB petitions brought by Eli Lilly against Teva in 2018 challenging nine other patents related to Ajovy® and Emgality® in connection with a separate litigation (1:18-cv-12029 D. Mass.). The PTAB found six of the Ajovy® patents obvious and the remaining three not invalid. These findings were upheld by the Federal Circuit on appeal. Eli Lilly & Co. v. Teva Pharms. Int’l GmbH, 8 F.4th 1331 (Fed. Cir. 2021); Teva Pharms. Int’l GmbH v. Eli Lilly & Co., 8 F.4th 1349 (Fed. Cir. 2021); Teva Pharms. Int’l GmbH v. Eli Lilly & Co., 856 F. App’x 312 (Fed. Cir. 2021). In November 2022, a jury found that Eli Lilly willfully infringed the remaining three patents and awarded damages to Teva of $176.5 million. (1:18-cv-12029 D. Mass., Dkt. 593.) In September 2023, following post-trial briefing, the court overturned the jury’s verdict, finding all three patents invalid for lack of written description. Both parties have cross-appealed to the Federal Circuit.

Actemra® (tocilizumab)

In August 2022, the PTAB instituted two IPRs filed by Celltrion challenging patents held by Chugai Seiyaku Kabushiki Kaisha generally directed to methods for treating interleukin-6 (IL-6) related diseases, U.S. Patent Nos. 8,580,264 and 10,874,677 (IPR2022-00578, -00579). In August 2023, the PTAB found both patents invalid as anticipated and obvious. Chugai has filed notices of appeal in both proceedings. Chugai had previously settled seven challenges against six patents (including the two challenged by Celltrion) following institution.

Yervoy® (ipilimumab) / Keytruda® (pembrolizumab) / Opdivo® (nivolumab)

In November 2022, Replimune filed an IPR challenging Amgen’s U.S. Patent No. 10,034,938, directed to methods of treating late-stage melanoma with an anti-PD-1 antibody or anti-CTLA-4 antibody. (IPR2023-00106.) The PTAB instituted review in May 2023. The parties subsequently settled and terminated the IPR in September 2023.

Tysabri® (natalizumab)

In July 2022, Sandoz filed a PGR petition challenging Biogen’s U.S. Patent No. 11,292,845 (the “’845 patent”), directed to a method of treating a patient with an inflammatory or autoimmune disease by monitoring for symptoms of progressive multifocal leukoencephalopathy. (PGR2022-00054.) Sandoz’s petition alleged the ’845 patent was invalid for lack of written description, invalid as obvious, and directed to patent ineligible subject matter. In February 2023, the PTAB denied institution, finding that the ’845 patent was entitled to an earlier priority date precluding PGR review. Biogen has asserted the ’845 patent against Sandoz in the BPCIA litigation discussed above (1:22-cv-01190 D. Del.).

IV. Antitrust and competition

A. Keytruda®: Letter alleging “patent thickets”

In February 2023, Senators Elizabeth Warren (D-MA) and Bernie Sanders (D-VT), along with Representatives Katie Porter (D-CA) and Pramila Jayapal (D-WA), wrote a letter to USPTO Director Kathi Vidal calling on the agency to scrutinize Merck’s requests for new patents directed to its blockbuster biologic, Keytruda® (pembrolizumab). The letter states that Merck’s aggressive use of the patent system to protect its monopoly on Keytruda®, including the filing of 129 pending patent applications as of 2021 and acquisition of 53 issued patents, appears to be “an example of the anti-competitive business practices, including double-patenting, patent thicketing, product hopping, and evergreening.” It also cautions that, “should the USPTO approve new patent applications for the drug, biosimilar competitors could be shut out of the market until 2036, giving Merck a total period of nearly 35 years of patent protection for Keytruda – monopoly protection that extends well beyond the intent of the [Hatch-Waxman Act] and the [BPCIA].” In light of these concerns, the lawmakers urged the USPTO to give “close scrutiny” to Merck’s requests for new patents for Keytruda® and “reject those that do not clearly meet the agency’s standards of novelty, utility, and non-obviousness.”

B. Stelara®: Allegations of fraud on the USPTO and acquisition of blocking patents

In December 2023, a group of health insurers and administrators filed a class action antitrust complaint against Johnson & Johnson (“J&J”) and Janssen alleging that J&J is delaying biosimilar competition through a “scheme to unlawfully prolong patent protection for Stelara” beyond the September 2023 expiration of J&J’s key composition patent directed to ustekinumab. Carefirst of Maryland, Inc. v. Johnson & Johnson, 2:23-cv-00629-JKW-LRL (E.D. Va.). According to the complaint, J&J’s scheme involved two prongs. First, it alleges that J&J defrauded the USPTO into incorrectly issuing a method-of-use patent covering the treatment of ulcerative colitis using ustekinumab by making false representations to the patent examiner regarding certain clinical trials concerning ustekinumab and concealing prior art. Second, the complaint states that over a decade after the launch of Stelara®, J&J purchased Momenta, a biosimilar research company, in order to obtain and use Momenta’s patents on manufacturing methods “intended to facilitate biosimilar approvals” in order to “block and delay entry of biosimilar products and restrain U.S. biosimilar competition.” According to the complaint, J&J leveraged these patents in order to obtain settlement agreements from a number of Stelara® biosimilar developers—including Amgen, Alvotech/Teva, Celltrion, Fresenius Kabi/Formycon, and Samsung Bioepis—which would delay biosimilar entry until 2025.

On March 5, 2024, J&J filed a motion to dismiss for failure to state a claim on the ground that the complaint fails to allege unlawful exclusionary conduct. According to J&J, all of the asserted exclusionary conduct — J&J’s acquisition of four manufacturing patents through its purchase of Momenta, J&J’s alleged fraudulent acquisition from the USPTO of a patent covering methods of using ustekinumab for ulcerative colitis, J&J’s enforcement of certain patents directed to ustekinumab, and J&J’s settlements with manufacturers of ustekinumab biosimilars — relates to lawfully acquired patents and thus any resulting marketplace exclusion from the enforcement of such patents is not exclusionary conduct under the antitrust laws. (Dkt. 46 at 2–3, 10.) Briefing on J&J’s motion to dismiss remains ongoing.

C. Remicade® and Praluent®: Allegations of exclusionary contracts

A class action antitrust lawsuit brought in 2017 by consumers and third-party payors against Johnson & Johnson and Janssen concerning Remicade®, In re Remicade Antitrust Litigation, No. 2:17-cv-04326-KSM (E.D. Pa.), has come to a close. The case involved allegations that J&J violated federal and state antitrust laws by “imposing a web of exclusionary contracts on both health insurers and healthcare providers” that “suppressed” price competition for Remicade®. The parties had reached a settlement in 2022 for $25 million and received preliminary approval from the court. In March 2023, the Court issued its final order approving the parties’ proposed settlement agreement and further awarding class counsel $7 million in attorneys’ fees and nearly $2.3 million in expenses.

Another biologics case involving allegations of anticompetitive exclusionary contexts was Regeneron Pharms., Inc. v. Amgen Inc., No. 1:22-cv-00697-RGA-JLH (D. Del.). Regeneron filed the lawsuit in May 2022 asserting federal antitrust violations and related state law claims based on Amgen’s alleged anticompetitive campaign to drive Regeneron’s Praluent® out of the PSCK9 inhibitor market. The core allegation was that Amgen was giving pharmacy benefit managers (PBMs) rebates on its blockbuster drugs Otezla® (apremilast) and Enbrel® (etanercept), which, due to the size of the rebates, and the fact that Otezla® has monopoly power and Enbrel® has market power, leave the PBMs with “no viable choice” but to accept Amgen’s offer and exclude Praluent® from their formularies. Amgen moved to dismiss and to stay pending further proceedings by the Supreme Court in the parties’ related patent dispute in August 2022, (Dkt. 17, 27), and in March 2023, Magistrate Judge Hall issued her ruling recommending that the motion to dismiss be denied and ordering that the motion to stay be denied without prejudice. On the motion to dismiss, the judge found that Amgen’s arguments for dismissing the Regeneron’s federal antitrust and state law claims implicated factual matters not suitable for resolution at the motion to dismiss stage. (Dkt. 49 at 10–16.) In denying the motion to stay, the judge noted that while it was possible that a Supreme Court ruling for Amgen would moot or simplify the case, there was “more than a reasonable likelihood” that a ruling for Amgen would actually complicate the case and the potential for simplification is outweighed by the potentially significant prejudice to Regeneron that would result from delaying the ultimate resolution of the case. (Id. at 18.) In March 2023, Judge Andrews adopted the Magistrate Judge’s Report and Recommendation and denied Amgen’s motion to dismiss. (Dkt. 62.)

V. Biosimilar regulatory updates

A. FDA goals for biologics and biosimilars

FDA kicked off 2023 with Commissioner Robert M. Califf, M.D., delivering opening remarks at an FDA-USPTO Public Workshop. The Commissioner noted that since President Biden’s 2021 Executive Order on Promoting Competition, FDA and USPTO have been working together with an objective to “ensure the patent system is not used in ways that unjustifiably delay . . . biosimilar competition beyond that reasonably contemplated by the law.” And while FDA does not play a direct role in drug pricing, the Commissioner explained that FDA can “support increased competition in the health care market” by “encouraging development of . . . biosimilar products.” The Commissioner highlighted that FDA has a few programs for advancing the R&D, approval, and marketing of high-quality biosimilars, including the regulatory science program pilot under the Biosimilar User Fee Act (BsUFA). In concluding remarks, the Commissioner recognized the need for the USPTO and FDA to strike an “appropriate balance” that “encourages meaningful innovation in drug development while not unduly delaying competition that provides relief from the high cost of medicines.”

In February 2023, FDA published a research roadmap as part of the BsUFA III regulatory research pilot program. The roadmap provides stakeholders with a look at how the program will help FDA enhance regulatory decision-making surrounding biosimilar development. In particular, it highlights the BsUFA III regulatory research pilot program’s two aims: 1) advancing the development of interchangeable products; and 2) improving the efficiency of biosimilar product development. FDA identified two scientific areas as essential for achieving both aims: namely, by increasing the accuracy and capability of analytical, chemistry, and manufacturing controls, and by developing alternatives to and/or reducing the size of studies involving humans.

On October 16 and 26, 2023, FDA hosted a two-part meeting that included an overview of the regulatory science pilot program described above and discussion of the program’s current status as it related to the BsUFA III commitments.

B. FDA biosimilar guidance

Manufacturing. FDA issued “Guidance for Industry” titled “Continuous Manufacturing of Drug Substances and Drug Products” in March 2023. FDA’s stated objective is to describe scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing, which applies to continuous manufacturing of drug substances (the “active pharmaceutical ingredient” or API) and drug products (the API, usually with additives for human applications like a tablet or injectable) for both chemical entities and therapeutic proteins. While FDA styles its guidance as merely recommendations for industry (“nonbinding recommendations”), FDA is expected to apply the guidance in evaluating manufacturing processes in upcoming BLAs and other regulatory filings.

Biosimilar labeling. In September 2023, FDA released draft guidance intended to help section 351(k) applicants develop draft labeling for their proposed biosimilar and interchangeable biosimilar products. This 2023 draft guidance highlights changes from the last 2018 FDA guidance, including changes regarding labeling for interchangeable biosimilar products, product identification when the reference product labeling describes a clinical study conducted with a non-U.S.-approved biological product, pediatric use statements, and incorporating immunogenicity data and information from the reference product labeling in the biosimilar or interchangeable biosimilar product labeling.

Following release of the updated September draft labeling guidance, FDA explained in October 2023 that its recommendations reflected in its draft labeling guidance result from FDA’s last eight years of experience in approving more than 40 biosimilar products. Departing from its previous recommendation that product labels identify a biosimilar’s interchangeability status, FDA now recommends that labeling for biosimilars need not identify biosimilars as interchangeable but instead include a single “biosimilarity statement.” According to FDA, statements identifying products as interchangeable are “not necessary for informing the safe and effective use of the product to prescribing health care professionals.” Further, this single statement allays concerns with drug applications that include both biosimilar and interchangeable biosimilar products at the same time. FDA reiterated that prescribers can prescribe both biosimilar and interchangeable biosimilar products in place of the reference product with equal confidence that both are as safe and effective as their reference products. In the guidance’s conclusion, FDA notes that its updated labeling guidance will not impact pharmacy-level substitutions of interchangeable biosimilar products, and that not including an interchangeability statement in the product’s labeling does not change the status of the product or mean that the product is not interchangeable. Rather, FDA stated that it is more appropriate to include interchangeability status in its Purple Book, which FDA suggests may be easier to use as a pharmaceutical reference, rather than in product labeling, which FDA views as prescriber-focused.

“Biosimilar” versus “interchangeable” status.Near the end of 2023, FDA Center for Drug Evaluation and Research published a research paper evaluating results from its biologic and biosimilar drug data analysis titled “Safety outcomes when switching between biosimilars and reference biologics: A systematic review and meta-analysis.” The paper evaluated concerns about switching a patient to a biosimilar whose condition is stable while on the reference biologic. Researchers analyzed data from 5,252 patients who were switched to or from a biosimilar and its reference biologic. The results found “no difference in the safety profiles or immunogenicity rates in patients who were switched and those who remained on a reference biologic or biosimilar.” The authors also concluded that their findings “support reducing the regulatory burden of switching studies as the default approach for addressing the switching standard for the interchangeable designation.” This may help support recently proposed legislation, discussed below, aimed at reducing the burden on obtaining interchangeability status by removing the requirement for switching studies.

VI. Policy and legislation affecting biosimilars

Inflation Reduction Act. In August 2022, President Biden signed the Inflation Reduction Act (“IRA”) into law. Its provisions include a framework permitting the Department of Health and Human Services (“HHS”) to negotiate drug prices with manufacturers for certain drugs provided under Medicare called the Medicare Drug Price Negotiation Program. The IRA dictates that only “single source” drugs — i.e., drugs with no generic or biosimilar equivalent — are eligible for negotiation.⁵ The IRA also distinguishes between negotiation eligibility for small molecules and biologics. Before they are eligible for negotiation, small molecules must have been approved by FDA for seven years, and biologics must have been approved for 11 years. HHS is required to negotiate the “maximum fair price” (“MFP”) for each selected drug subject to mandatory discounts depending on how long the drug has been on the market, which may amount to between 25% and 60% of the past average price paid by wholesalers for drugs distributed to non-federal purchasers. The IRA proposes a phased structure in which HHS may select an increasing number of drugs for which the MFP will go into effect in certain years (“Initial Price Applicability Year,” or “IPAY”), and expands applicability from Medicare Part D drugs to Medicare Part B drugs over time. Table 4 below shows this phased structure:

Table 4: IRA phased implementation structure

The year 2023 marked significant developments for implementation and challenges to the IRA. With respect to implementation, the Center for Medicare & Medicaid Services (“CMS”), a division of HHS, released initial guidance on the Medicare Drug Price Negotiation Program in March 2023. Following substantial stakeholder comment, CMS issued updated guidance in June 2023. The updated guidance clarifies certain requirements for CMS’ evaluation of the Biosimilar Delay determination. The Biosimilar Delay provision allows biosimilar manufacturers to request a two-year delay in negotiation for drugs otherwise negotiation-eligible under the program’s requirements. For CMS to approve the delay request, the biosimilar manufacturer must demonstrate a high likelihood of “bona fide” marketing of the biosimilar product within two years after the publication of the selected drug list. There is no corresponding delay available for small molecule drugs.

Following release of the updated guidance, in September 2023, HHS released a list of 10 drugs covered under Medicare Part D for the first cycle of price negotiations effective in IPAY 2026. The list includes seven small molecule drugs and three biologic products, shown in Table 5 below:

Table 5: Drugs selected for negotiation for IPAY 2026

All manufacturers of the 10 selected drugs agreed to negotiate the MFP. If the manufacturers had not agreed and continued to sell the selected drugs under Medicare, the manufacturers would have been subject to a civil monetary penalty or excise tax that could range from 65% to 95% of a drug’s sale price. HHS initiated negotiations on February 1, 2024, by issuing its initial offer to manufacturers. Negotiations must conclude by August 1, 2024.

The IRA is currently subject to challenges filed in various District Courts by seven manufacturers and two industry groups. The litigations mount a number of attacks against the IRA, including constitutional challenges and violations of the Administrative Procedure Act. Briefing on motions for summary judgment are completed in the earliest filed cases, and numerous amici have submitted briefs in support of both manufacturer plaintiffs and CMS defendants. Fresenius Kabi, manufacturer of biosimilars including Idacio® (adalimumab-aacf) and Stimufend® (pegfilgrastim-fpgk), is among the amici in support of the manufacturer plaintiffs. Among the criticisms raised by Fresenius Kabi is that “a branded manufacturer is incentivized under the CMS Guidelines to enter into an agreement to provide the appropriate licenses to allow a single generic to come to market, and then only on limited terms, to avoid the negotiations list.” Bristol Myers Squibb Company v. Becerra, 3:23-cv-03335-ZNQ-JBD, Dkt. No. 37-1 at 8 (D.N.J. Aug. 2023).

New proposed legislation. A number of new pieces of proposed legislation affecting biosimilars were introduced in 2023 directed to various issues perceived to impede patient access to low-cost biosimilars, including barriers to interchangeability, lack of patent transparency for licensed biologic products, and anticompetitive practices.

In March 2023, Representative Richard Hudson (R-NC) introduced the Increasing Access to Biosimilars Act of 2023 (H.R. 1352). If passed, the bill would require the HHS Secretary to establish a voluntary, three-year demonstration project to evaluate the benefits of providing a shared savings payment for future biosimilars within Medicare. In December 2023, the bill passed through a House Energy and Commerce committee legislative markup with bipartisan support.

Also in March 2023, Representatives Mariannette Miller-Meeks (R-IA), Greg Murphy (R-NC), Nanette Barragan (D-CA), and Annie Kuster (D-NH) introduced the Biologics Competition Act of 2023 (H.R. 1790), a proposed legislation to direct the HHS Secretary to study and report to Congress on the process by which interchangeable biological products are approved. The bill also requires the Secretary to update the Purple Book to implement changes deemed necessary to harmonize the approach for communicating the substitutability of interchangeable biological products with the approach for communicating therapeutic equivalence ratings assigned to drugs approved under Section 505 of the Federal Food, Drug, and Cosmetic Act.

In July 2023, Senators Mike Lee (R-UT), Ben Ray Lujan (D-NM), Mike Braun (R-IN), and J.D. Vance (R-OH) reintroduced the Biosimilar Red Tape Elimination Act (S. 2305), which aims to eliminate barriers to interchangeability, thereby increasing access to lower cost biosimilars. The original version of the bill, introduced to Congress in November 2022 prohibited FDA from requiring biosimilar drugs to undergo switching studies before it grants an interchangeable designation with the reference product. The new version deems all biosimilars as interchangeable with their reference product upon approval and requires FDA to conduct private briefing with Congressional committee heads if it wants to require a switching study.

Additionally, a number of bills targeting practices by industry participants believed to result in high drug prices were introduced in 2023. For example, the Preserve Access to Affordable Generics and Biosimilars Act of 2023 (S. 142) would ban “reverse payment” settlement agreements between patent owners and new generic or biosimilar entrants by making such agreements presumptively anticompetitive. The Affordable Prescriptions for Patients Act of 2023 (S.150) seeks to prohibit the practice of “product hopping,” defined as impeding competition by making a “hard” or “soft” product switch within a certain time period after being notified that a generic or biosimilar has referenced its product in an Abbreviated New Drug Application or BLA, by classifying it as an unfair method of competition under the Federal Trade Commission (FTC) Act. The Interagency Patent Coordination and Improvement Act (S.79) would establish an interagency task force between the USPTO and FDA for the purposes of sharing information and providing technical assistance on patents for drugs and biological products. The Prescription Pricing for the People Act of 2023 (S.113) would require the FTC to study the role of pharmaceutical supply chain intermediaries like PBMs and provide recommendations for Congress to improve transparency and competition, prevent and deter anticompetitive behavior, and best ensure that consumers benefit from cost savings or efficiencies that may result from mergers or consolidations. The Stop STALLING Act (S.148) would make it an unfair method of competition to submit a “sham” petition to FDA in an attempt to interfere with a competitor’s application for market approval of a drug or biologic product. It also authorizes the FTC to sue any person who submits such a petition to FDA and provides that a party found liable in such a suit shall be subject to civil penalties, such as a fine up to $50,000 for each day FDA spent reviewing the baseless petition.

VII. Conclusion

2023 was a strong year for the biosimilars industry in the U.S. It revealed a continuing upward trend in biosimilars approvals and achieved a record high in annual biosimilar launches. Additionally, the beginning of 2024 has already seen the approval by FDA of Sandoz’s Jubbonti® and Wyost®,the first Prolia® and Xgeva® (denosumab) biosimilars, as well as two newly filed BPCIA lawsuits involving proposed biosimilars of Soliris® (eculizumab) and Eylea® (aflibercept), continuing the trend of increased activity at FDA and in the courts on biosimilars of more recently approved reference products. With several reference products anticipated to lose exclusivity in the near future, the new wave of biosimilar products is expected to continue growing, and the development landscape is poised for potentially even more biosimilar BLA submissions in 2024 and beyond.

Appendix A: Biosimilars approved as of 2023

1. In 2023, FDA also granted interchangeability designations to Pfizer’s AbriladaTM (adalimumab-afzb) and Samsung Bioepis and Biogen’s ByoovizTM (ranibizumab-nuna).

2. Patents asserted in the original complaints.

3. Patents asserted in the original complaints.

4. Janssen first filed a motion for preliminary injunction on March 1, 2023, along with a stipulation to extend the page limitation for its opening brief in support of its motion to 30 pages. (Dkt. 23; Dkt. 24.) After the court denied the stipulation and motion for failure to comply with the page limits,” Janssen was permitted to “re-file the motion with a brief that complies with the Court’s rules.” (Dkt. 34.) Janssen re-filed the motion on March 6, 2023. (Dkt. 35.)

5. Certain other criteria also apply — for example, orphan drugs are not eligible for negotiation.

6. Mylan filed its New Drug Application (NDA) for Semglee^® on April 27, 2017, and on March 23, 2020, Mylan’s NDA was deemed to be a BLA.

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