A biosimilar is a biologic drug that is highly similar, but not identical, to an already approved biologic drug, i.e. the reference product. Biologic drugs are made from natural and living sources, such as cells or bacteria, and are generally more complex than small molecule drugs. Like the Hatch-Waxman Act, which created an abbreviated approval pathway for small molecule drugs, the Biologics Price Competition and Innovation Act (BPCIA) created an abbreviated approval pathway for biosimilars. But the BPCIA differs from the Hatch-Waxman Act in several key aspects, including the absence of any automatic stay of FDA approval, that impact the patent litigation strategy under the BPCIA. Recent decisions concerning Regeneron’s blockbuster biologic drug Eylea^® provide some insight on how to litigate patent disputes under the BPCIA. 

In a pair of decisions issued on January 29, 2025,¹ the Federal Circuit affirmed two preliminary injunction orders, each of which halts the launch of a biosimilar to Eylea^®. The two decisions considered personal jurisdiction over foreign biosimilar developers and requirements for injunctive relief. The Federal Circuit just heard three appeals in three related cases (one denying injunctive relief and two granting injunctive relief) and will likely decide those cases soon. 

Although four out of five approved biosimilars to Eylea^® have currently been prohibited from launching, the fifth biosimilar is already on the market following the district court’s denial of a preliminary injunction motion. Thus, the two recent Federal Circuit decisions may not have a huge impact on the landscape of Eylea^® on the market. Regardless, as injunctive relief is frequently sought in biosimilar litigations and often against foreign biosimilar developers, these decisions provide very helpful guidance on how to strategize and litigate biosimilar cases. 

This article briefly reviews relevant background concerning the Eylea^® biosimilar litigations, analyzes the two newly issued Federal Circuit decisions and discusses what can be learned from these two decisions. Follow-up articles will discuss the upcoming Federal Circuit decisions on the three pending appeals and any new development in Eylea^® biosimilar litigations.

Eylea^® and Its Biosimilars

Eylea^® is a biologic drug that was first approved by the FDA in 2011 to treat “Neovascular Age-Related Macular Degeneration[.]”² The active ingredient of Eylea^®, aflibercept, is a recombinant fusion protein. It acts as an inhibitor of vascular endothelial growth factor (VEGF), and known as “VEGF antagonist” or “VEGF trap.” In addition to aflibercept, Eylea^® also has several inactive ingredients, including a buffer, which is claimed in U.S. Patent No. 11.084,865 (the “’865 Patent”), a key patent involved in all BPCIA litigations concerning Eylea^®. 

At least nine pharmaceutical companies have developed—or are developing—aflibercept biosimilars,³ and five have been approved by the FDA as of January 31, 2025.⁴ Among the biosimilar developers, groups developing six biosimilar products have been sued by Regeneron under BPCIA: Mylan Pharmaceuticals and Biocon Biologics (Mylan); Celltrion, Inc. (Celltrion); Samsung Bioepis Co. Ltd. (SB); Formycon AG (Formycon); Amgen Inc. and Amgen USA Inc. (Amgen); and Sandoz Inc. (Sandoz). All but Celltrion’s biosimilar products have been approved by the FDA. The other developers remain unknown as they have not been sued and their products have not been approved. 

The table below provides some basic information regarding the six groups’ abbreviated Biologics License Applications (aBLAs) and corresponding cases involving their biosimilars to Eylea^®.   

The Status of BPCIA Litigation Concerning Eylea^®

Regeneron filed the first action against Mylan, the first filer of a biosimilar to Eylea^®, in the Northern District of West Virginia. Subsequent actions filed under BPCIA concerning Elyea^® were either filed in the same court or later centralized to the same court by the Judicial Panel on Multidistrict Litigation (J.P.M.L.) at the request of Regeneron. The J.P.M.L. found that, in each action, Regeneron asserts a common set of thirteen patents, including the ’865 Patent that is central in every case.

Following a bench trial in the Mylan action, the district court found that the ’865 Patent was infringed and not invalid, and granted Regeneron’s motion for a permanent injunction. Subsequently, the district court, applying the four-factor Winter test,⁸ also granted Regeneron’s motions for preliminary injunction against SB, Formycon and Celltrion, stating that Regeneron was likely to succeed in proving that the ’865 Patent is infringed by the three defendants’ biosimilar products, the three defendants failed to raise a substantial question of invalidity or non-infringement, and Regeneron would suffer irreparable harm if defendants were allowed to launch their biosimilars. 

Mylan, SB, Formycon and Celltrion all appealed the injunctive orders to the Federal Circuit. The Federal Circuit heard the SB and Formycon oral arguments on December 5, 2024, and issued its opinions on January 29, 2025. The Federal Circuit heard oral arguments for the Mylan and Celltrion appeals on February 7, 2025, and the decisions are likely to be issued in a few weeks if the Federal Circuit will consider the two pending appeals on a similar schedule. 

In the Amgen action, however, the district court denied Regeneron’s motion for preliminary injunction because Amgen’s biosimilar product does not have a buffer as claimed in the ’865 Patent, and therefore, Regeneron cannot show a likelihood of success on infringement. Regeneron appealed that decision to the Federal Circuit and oral argument was heard on January 14, 2025. The oral argument centered around whether the claimed “buffer” has to be separate from the claim “VEGF antagonist,” an issue that only exists in the Amgen case. No decision has been issued. In November 2024, Amgen launched its biosimilar, the first and only biosimilar to Eylea^® on the market as of now. 

The sixth developer, Sandoz, was sued after its biosimilar was approved by the FDA. Regeneron alleges in the complaint that Sandoz failed to comply with its obligations under the BPCIA that require Sandoz to provide information regarding its aBLA within 20 days after FDA acceptance of its aBLA. Regeneron further alleges that Sandoz failed to provide any notice of its biosimilar and Regeneron learned Sandoz’s biosimilar only after FDA approval. As of January 31, 2025, the case is still at the pleading stage and Sandoz has not announced the date for launching its product.⁹

Federal Circuit Affirmed Two Preliminary Injunction Orders Against SB and Formycon

The Federal Circuit’s decisions on the SB and Formycon appeals focused on three specific issues: (1) whether the district court has personal jurisdiction over foreign biosimilar developers SB and Formycon; (2) whether the ’865 Patent is invalid for obviousness-type double patenting and for lack of written description; and (3) whether there is a causal nexus between the accused infringement and the irreparable harm Regeneron would suffer without injunctive relief. Regeneron Pharms., Inc. v. Mylan Pharms. Inc., 2025 U.S. App. LEXIS 1980 (Fed. Cir. Jan. 29, 2025) (“SB Opinion”); Regeneron Pharms., Inc. v. Mylan Pharms. Inc, 2025 U.S. App. LEXIS 1976 (Fed. Cir. Jan. 29, 2025) (“Formycon Opinion”).¹⁰ The Federal Circuit found no errors of the district court’s factual findings and affirmed the district court’s decisions. 

1. Personal Jurisdiction

“A court may exercise specific personal jurisdiction when the defendant ha[s] certain minimum contacts with [the forum] such that the maintenance of the suit does not offend traditional notions of fair play and substantial justice.” SB Opinion, at 11 (internal citations and quotations omitted). In the context of an ANDA infringement suit brought under § 271(e)(2), “the ANDA submission with an intent to distribute the generic product in a given state was sufficient for personal jurisdiction purposes.” Id. at 12 (internal citations and quotations omitted). The parties do not dispute that the same standard applies to aBLA submissions. Id. at 11-12.

Here, SB is a biosimilar developer headquartered in South Korea. Its filing of an aBLA for SB15, a biosimilar to Elyea^®, is a formal act that “reliably confirms a plan to engage in real-world marketing of SB15 within the U.S.” Id. at 13 (internal citations and quotations omitted). SB entered into several agreements with a U.S. company (Biogen MA Inc.) to commercialize several drugs, including SB15, but did not carve out any states of the United States market. Id. The record supports the district court’s finding that SB’s distribution channels are of a nationwide nature. Id. at 14. The agreements and other documents also support the district court’s finding that SB “retains significant … involvement in Biogen’s U.S. commercialization activities” including “active participation in a joint steering committee[.]” Id. Thus, the Federal Circuit concluded that “personal jurisdiction lies against SB in West Virginia[.]” Id. at 15.

Formycon is a biopharmaceutical company based in Germany. It developed FYB203, a biosimilar to Elyea^®, pursuant to a development and licensing agreement with Klinge Biopharma, another German company. Formycon Opinion, at 6. Similar to SB, the record also shows Formycon’s plan to market FYB203 in West Virginia and other states. Id. at 7. Formycon filed an aBLA seeking approval of FYB203 but never claims that it would not market in West Virginia. Id. at 7-8. The agreements show Formycon has continuing rights and responsibilities regarding FYB203, including meetings regarding commercialization of FYB203. 6-7. Accordingly, the Federal Circuit also affirmed the district court’s finding of personal jurisdiction over Formycon. 

2. Validity of the ’865 Patent

Regeneron asserted dozens of patents against each biosimilar developer, but to streamline the dispute, it only relied on the ’865 patent in seeking preliminary-injunction against SB and Formycon. The ’865 patent is directed to VEGF antagonist formulations with particular stability limitations. The relevant claims at issue recite a “vial” comprising a formulation that comprises “a [VEGF] antagonist” wherein “said VEGF antagonist . . . is glycosylated” (the glycosylation requirement) and “wherein at least 98% of the VEGF antagonist is present in native conformation following storage at 5°C for two months as measured by size exclusion chromatography” (the stability requirement). The ’865 patent, Cl. 1.

On appeal, SB and Formycon challenged the validity of the ’865 Patent on two grounds: obvious-type double-patenting (ODP) and written description.

a. Obvious-Type Double-Patenting (ODP)

The ODP is a judicially created doctrine that prohibits claiming in a later patent an obvious variation of an invention claimed in an earlier patent. To determine ODP, the court first compares the differences between claims of the later and earlier patents, and then determines whether the differences render the claims of the later one patentably distinct. 

On appeal, the parties agreed that the ODP analysis are limited to three limitations in claim 1 of the ’865 Patent that are directed to (1) the stability requirement, (2) the glycosylation requirement and (3) a vial.

With respect to the stability requirement, the reference patent merely requires “stable for at least four months” while the ’865 Patent requires “at least 98% of the VEGF antagonist is present in native conformation … for two months” measured by a specific method. The district court found that the stability requirement of the reference patent is broader than the stability requirement in the ’865 Patent, and “the 98% native conformation for two months . . . was not inherent in [the reference patent] and a [POSA] would not have been motivated to arrive at this requirement with a reasonable expectation of success.” SB Opinion, at 19.

On appeal, SB argued that the 98% native conformation is an obvious variant because it is an additional property of what is claimed in the reference patent. Id. at 19. The Federal Circuit disagreed because SB failed to support that an additional property is sufficient to defeat patentable distinctness. Id. at 20. In addition, this is a genus-species issue and SB did not challenge the district court’s findings that the genus of “stable” VEGF-trap formulations is not so small. Id. at 20-21. The Federal Circuit also rejected Formycon’s argument that the limitation of the ’865 Patent is inherent in the stability limitation of the reference patent because this is a claim construction issue but Formycon failed to present analysis to support its position or challenge the district court’s claim construction. Formycon Opinion, at 12-13.

Although the finding that one limitation is distinct would be sufficient to reject the ODP assertion, the Federal Circuit also agreed with the district court on the glycosylation requirement. The district court found a POSA would lack motivation to use a glycosylated protein because it “would increase the size of aflibercept, thus reducing retinal penetration, and would increase systemic exposure and inflammation risk.” SB Opinion, at 22. SB did not challenge the lack of motivation finding and instead argued that glycosylation is an additional property, which was found unpersuasive. Id. Formycon contended that a POSA would understand that aflibercept can exist in either glycosylated state or not and thus would envision both options. Formycon Opinion, at 13. The Federal Circuit disagreed because the genus at issue is not so limited: the ’865 Patent discloses five potential glycosylation sites, meaning there are at least thirty potential glycosylated forms. Id. at 13-14. Formycon also challenged the district court’s finding of no motivation to use glycosylated form but failed to provide sufficient evidence to disturb that finding. Id. at 14. The Federal Circuit concluded that the glycosylation requirement is a second basis for rejecting the ODP argument. 

b. Written Description

To show adequate written description, the specification must show that the inventor had possession of the invention.

SB argued that three limitations are not adequately supported by the specification. First, SB argued that the specification does not disclose the glycosylated form with the claimed stability. SB Opinion, at 24. But the specification provides embodiments, including a glycosylated form of aflibercept, with their stability data within the claimed range. Id. at 24-25. Thus, the Federal Circuit concluded that “as a whole” a POSA would understand that the specification discloses this limitation. Id. at 25.

SB next argued that the upper bound of the limitation “at least 98% of the VEGF antagonist is present in native conformation following storage . . . for two months”  is not supported because the highest native conformation after two-month disclosed in the specification is 99.3% whereas the upper bound of this limitation is 100%. Id. at 26. The Federal Circuit disagreed. The court held that “[t]he specification does not need to describe every conceivable and possible future embodiment of [the] invention.” Id. (internal citations and quotation marks omitted). For open-ended claims, adequate written description was found “where the upper bound would be limited by what a person skilled in the art would understand to be workable and where the patent’s specification adequately supported that range.” Id. (internal citations and quotation marks omitted). Here, the Federal Circuit stated that the district court properly relied on expert testimony that “most proteins are not purified to [100%]” to conclude that upper limit would be limited by what would be workable to a POSA. Id. at 27. SB failed to point to any evidence that aflibercept works differently from most proteins in this regard or to show that native conformation above 99.2% would be possible and be a significantly different invention. Id. 

Lastly, SB argued that the lower bound of the “at least 98%. . . ” limitation is not supported because the lowest disclosed amount in native conformation is 98.5% for any formulation and 99.1% and 99.2% for the formulation used for Elyea^®. The Federal Circuit concluded that “the ’865 Patent contains multiple disclosures of native conformations throughout the range of 98% to 100%.” Id. at 28-29. Thus, the specification supports that the inventors had possession of the entirety of the claimed range. Id. at 29.

3. Causal-Nexus

Injunctive relief requires a patentee to show that there is some causal nexus between the infringement and the irreparable harm it would suffer. 

SB challenged the district court’s finding of a causal nexus on two grounds. First, it argued that “SB/Biogen can sell ‘lots of SB15 that are only 96% stable at two months and that therefore do not infringe the ’865 patent,’ causing the same harms to Regeneron.” SB Opinion, at 29. But the Federal Circuit found that “[t]here is no evidence that SB possesses or plans to sell or offer to sell a non-infringing biosimilar under its approved aBLA.” Id. at 29. Rather, the SB’s data show only an infringing biosimilar. Id. Further, the expert testified that it is difficult to alter the formulation to achieve a non-infringing formulation. Id. 

Second, “SB argues that Regeneron must establish a causal nexus between the irreparable harms and the unique limitations of the ’865 patent[.]” SB Opinion, at 30 (emphasis in original). The Federal Circuit rejected that argument because, as the district court correctly found that, “[t]he causal-nexus inquiry may have little work to do in an injunction analysis when the infringing product contains no feature relevant to consumers’ purchasing decisions other than what the patent claims, as is the case with SB15 and the ’865 patent.” SB Opinion, at 31 (internal citations and quotation marks omitted). Here, the biosimilar at issue essentially embodies the claimed invention. The district court also found that “the combination of limitations in the ’865 patent’s claims drives demand.” Id. Thus, the cause-nexus requirement is met. Id.

What’s Next: Pending Cases and Appeals

The two recent Federal Circuit decisions are not the end of Eylea^® litigations. As explained above, three appeals that could determine the fate of biosimilars developed by Mylan, Celltrion and Amgen are pending.  And despite the pending appeal, parties in the Amgen action are conducting discovery the district court.¹¹

The Sandoz action, which is at the pleading stage in the district court, presents some novel issues in BPCIA litigation: what are the consequences if a biosimilar sponsor does not follow the disclosure requirements under BPCIA.   

In addition to the litigation in federal court, SB, Formycon and Celltrion all filed petitions for inter partes review (IPR) challenging the validity of the ’865 Patent before the PTAB between November 2024 and January 2025. If the PTAB institutes one or more petitions, it would be interesting to see how the district court decisions impact the PTAB proceedings and whether the two tribunals would reach some inconsistent decisions. 

Takeaways

1. Claimed Ranges Do Not Require Written Description Support of the Exact Boundaries or Every Possible Embodiment

Claims directed to a range, such as “at least 98%” in the ’865 Patent, are frequently litigated for Section 112 issues in pharmaceutical cases. Regeneron Pharmaceuticals, Inc. v. Samsung Bioepis Co., Ltd. Case No. 1-23-cv-00094 (N.D. W.Va.), dkt. 250, Redacted Order Granting Motion for Preliminary Injunction (SB Dist. Ct. Opinion), at 112. SB challenged the upper and lower bounds of the “at least 98%” limitation for lack of written description because the specification only discloses 98.5% to 99.3% for various formulations. The district court found that the disclosures were sufficient to support the claimed range of 98%-100% based on expert testimony. The Federal Circuit agreed because the specification does not need to disclose “every conceivable and possible future embodiment” of the invention. Further, for an open-ended claim, the upper bound could inherently be limited “by what a person skilled in the art would understand to be workable.” SB Opinion, at 26. Thus, if the specification adequately supports that range, as the district court found for the ’865 Patent, then the written description requirement is met.

2. Irreparable Harm Is Not Difficult to Establish in the Context of Biosimilar Litigation

Although SB and Formycon did not challenge the findings of irreparable harm on appeal, the district court conducted a thorough analysis and found Regeneron would suffer many forms of irreparable harm, which include loss of sales and market share, price erosion, disruption of patentee-payor relationships, reputational harm, and marketing and training costs. SB Dist. Ct. Opinion, at 117-157. In the context of biosimilar litigation, many forms of irreparable harm found in the Regeneron cases could also apply to other biologic drugs. 

3. A Causal Nexus Is Straightforward for Patents That Cover a Drug

Another aspect of irreparable harm analysis is the causal-nexus requirement. As affirmed by the Federal Circuit, when a patent in dispute covers the entire product rather than a feature of the product, the causal-nexus requirement is satisfied as the product contains no features relevant to consumer purchasing decisions other than what the patent claims. This usually applies to patents that claim the drug product, such as the ’865 Patent. However, the same may not apply to method of use patents because the claimed method may not be relevant to consumer purchasing decisions. 

4. Obtaining an Injunctive Relief Is Not Uncommon in Biosimilar Litigation 

Unlike the Hatch-Waxman Act, the BPCIA does not provide for a statutory stay of FDA approval while the parties resolve patent disputes. Thus, a branded biologic drug sponsor has to seek injunctive relief to delay the launch of a biosimilar if the biosimilar would receive FDA approval before patent disputes are resolved. 

An injunction is an extraordinary remedy. The biosimilar litigation concerning Eylea^® provides a roadmap for seeking injunctive relief. In addition to the likelihood of success on the merit and the irreparable harm factors discussed in this article, the district court also found that the balance of equities and public interests factors for preliminary injunctions favored Regeneron. SB Dist. Ct. Opinion, at 164-177. Since the district court found many forms of irreparable harm to Regeneron while SB could be compensated by monetary relief for its loss of sales, the balance factor tips in Regeneron’s favor. The court based its analysis on the public interest factor on the public interest in protecting patent rights, which almost always weighs in favor of the patentee. Thus, if a brand-sponsor can satisfy the first factor, i.e. the likelihood of success on the merit on a drug product patent, then it has a good chance to satisfy the other three factors to obtain an injunction.

It is worth noting that a preliminary injunction is a temporary relief designed to preserve the status until the court can make a final decision on the merits. Thus, a defendant may further develop the case after being temporarily enjoined to market its product. However, once a preliminary injunction is granted, a plaintiff is in a very powerful position to negotiate an agreement to make the injunction final. Thus, unless the defendant chooses to fight on through trial, the lawsuit could end quickly. 

5. Foreign Companies Are Unlikely to Be Immune from BPCIA Litigation 

Both SB and Formycon are foreign companies that have no presence in the United States. Both used distributors to market their products in the U.S. However, the West Virginia court has specific personal jurisdiction over both because they have “minimum contacts” with that state. The minimum contacts finding is supported by their filing of aBLAs with an intent to distribute their biosimilars to the U.S. without carving out West Virginia, and their involvements in the marketing and distribution. 

The “minimum contact” requirement—met by filing an aBLA (or ANDA) with the intent to distribute the product in a given state—is not difficult to satisfy. Filing an aBLA with an intent to distribute the product to every state in the U.S. is expected from most if not all foreign pharmaceutical companies. Even if a company carved out one or a few states from marketing, it would still be subject to personal jurisdiction of other states where it intends to market its product. A foreign company may have less involvement in marketing than SB and Formycon did for their biosimilars to Elyea^®. But the lack of marketing may not defeat the “minimum contact” finding unless the company gives up all its rights in the distribution/marketing. Thus, it is unlikely a foreign company would be shielded from BPCIA litigation. 

_{¹Regeneron Pharms., Inc. v. Mylan Pharms. Inc., __ F.4d __, 2025 U.S. App. LEXIS 1980 (Fed. Cir. Jan. 29, 2025); Regeneron Pharms., Inc. v. Formycon AG, __ F.4d __, 2025 U.S. App. LEXIS 1976 (Fed. Cir. Jan. 29, 2025).  Judges Moore, Reyna and Taranto were on the panel for both cases.}

_{²Initial label for Eylea^®, approved on November 18, 2011, available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125387lbl.pdf.}

_{³Regeneron Pharmaceuticals, Inc. v. Celltrion, Inc. Case No. 1-23-cv-00089 (N.D. W.Va.), dkt. 201, Redacted Order Granting Motion for Preliminary Injunction, at 4.}

_{⁴See Purple Book for Eylea^®, available at https://purplebooksearch.fda.gov/results?query=aflibercept&title=Eylea.}

_{⁵According to FDA, “[a] biosimilar is a biologic that is highly similar to another biologic that is already FDA-approved (known as the original biologic). It is both normal and expected for both biosimilars and original biologics to have minor differences between batches of the same medication. . . . An interchangeable biosimilar is a biosimilar that meets additional requirements outlined by the law . . . . An interchangeable biosimilar product may be substituted for the original product without consulting the prescriber, much like how generic drugs are routinely substituted for brand name drugs.” https://www.fda.gov/consumers/consumer-updates/biosimilar-and-interchangeable-biologics-more-treatment-choices. Although two interchangeables (from Mylan and SB) have been approved by the FDA, both are blocked by injunction orders. Thus, the impact of interchangeables on the market remains unclear.}

_{⁶The lawsuit was originally filed in the Central District of California, but was transferred to the Northern District of West Virginia for all pretrial proceedings by the J.P.M.L.}

_{⁷The lawsuit was originally filed in the District of New Jersey, but was transferred to the Northern District of West Virginia for all pretrial proceedings by the J.P.M.L.}

_{⁸See e.g. Regeneron Pharmaceuticals, Inc. v. Samsung Bioepis Co., Ltd. Case No. 1-23-cv-00094 (N.D. W.Va.), dkt. 250, Redacted Order Granting Motion for Preliminary Injunction, at 28 (“Issuance of a preliminary injunction depends on four factors: whether (1) the plaintiff likely will succeed on the merits at trial; (2) the plaintiff will be irreparably injured if an injunction is not granted; (3) the balance of hardships favors the plaintiff; and (4) the public interest will be furthered by an injunction. See Winter v. NRDC, 555 U.S. 7, 20 (2008).”)}

_{⁹According to Sandoz on an online post dated December 8, 2024, “[l]aunch timing [of its biosimilar] will be dependent on several factors, including the progress and outcome of pending or potential future related litigations or any potential settlements.” Available at https://www.sandoz.com/sandoz-receives-fda-approval-enzeevutm-aflibercept-abzv-further-strengthening-us-biosimilar/.}

_{¹⁰SB and Formycon made substantially overlapping arguments on most issues and the Formycon Opinion relied on the SB Opinion for arguments made by Formycon but already addressed in the SB Opinion. This section does not specifically address Formycon’s arguments unless they were different from SB’s arguments.} 

_{¹¹The parties exchanged discovery requests and responses after the Notice of Appeal was file. See e.g. Regeneron Pharmaceuticals, Inc. v. Amgen, Inc. Case No. 1-24-cv-00039 (N.D. W. Va) dkts 264, 270.}