Category: Biosimilars

The fight over proposed Enbrel^® (etanercept) biosimilar Erelzi^® continues. Sandoz Inc., Sandoz International GmbH and Sandoz GmbH (“Sandoz”) recently filed a petition for certiorari requesting review of the judgement of the Federal Circuit on whether:

FDA has published new draft guidance for industry titled “Biosimilarity and Interchangeability: Additional Draft Q&As on Biosimilar Development and the BPCI Act.” 

The draft guidance supplements two prior documents concerning biosimilar interchangeability published in December 2018.  This new guidance, in particular, has some useful information for prospective applicants who seek licensure of an “interchangeable” biosimilar product.

Earlier this month, in Immunex Corp. v. Sandoz Inc., the Federal Circuit upheld two patents covering Enbrel’s active protein and a process used to manufacture the drug, effectively blocking Sandoz’s Enbrel® biosimilar Erelzi from the U.S. market until 2029 and providing a major victory for Amgen.[1]  Enbrel is the brand name for the molecule etanercept, which is used to treat rheumatoid arthritis and several other inflammatory conditions.  A blockbuster drug, last year Enbrel generated over $5.2 billion in sales for Amgen, representing 22% of the company’s revenue.

Last month, Judge Manish Shah of the United States District Court of the Northern District of Illinois dismissed an antitrust complaint brought by indirect purchasers of AbbVie’s blockbuster rheumatoid arthritis drug, Humira®.  The suit alleged antitrust violations under a novel “patent thicket” theory, citing § 2 of the Sherman Act, and “pay-for-delay” and “market allocation” theories under § 1 of the Sherman Act.  Mem. Op. and Order (Dkt. 170), In Re: Humira (Adalimumab)Antitrust Litigation, No. 19-cv-1873 (N.D. Ill. June 8, 2020).

Last week, the U.S. Food and Drug Administration (“FDA”) issued a final rule to amend its regulation that defines the term “biological product” in line with the definition set by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), as amended by the Further Consolidated Appropriations Act, 2020, enacted on December 20, 2019 (“FCA Act”). 

Recently, in Amgen Inc. v. Hospira, Inc., the Federal Circuit clarified the limits of the Safe Harbor defense in cases involving patented manufacturing methods.

In a case brought in the District of Delaware, Amgen alleged that Hospira infringed several patent claims over methods of manufacturing erythropoietin (EPO), a biologic drug used to treat anemia. Following a trial, a jury issued a $70 million verdict for Amgen, which was based in part on the jury’s conclusion that fourteen batches of drug substance for Hospira’s EPO biosimilar product were not covered by the Safe Harbor provision of 35 U.S.C. § 271(e)(1). After the district court denied Hospira’s motion for judgment as a matter of law or alternatively for a new trial, Hospira appealed on a number of issues, including the jury instructions and jury findings on its Safe Harbor defense.

In Amgen’s long-running dispute with biosimilar-maker Sandoz over biosimilar versions of Amgen’s filgrastim (Neupogen®) and pegfilgrastim (Neulasta®) biologics, the Federal Circuit earlier this year affirmed summary judgment of no literal infringement and no infringement under the doctrine of equivalents.  Amgen Inc. v. Sandoz Inc., 923 F.3d 1023 (Fed. Cir. May 8, 2019).  In so holding, the panel stated that “the doctrine of equivalents applies only in exceptional cases.”  Amgen petitioned for rehearing en banc, arguing that the Federal Circuit had overstated the law.  According to Amgen’s petition, “[s]uch a rule is contrary to Supreme Court precedent and [Federal Circuit] precedent.”  This week, the Federal Circuit course-corrected, granting Amgen’s petition without explanation for the limited purposes of removing the “exceptional” language from its prior decision. 

Amgen Inc. v. Coherus Biosciences Inc., No. 2018-1993, Slip op. at 6 (Fed. Cir. July 29, 2019) stems from a Biologics Price Competition and Innovation Act action brought by Amgen against Coherus seeking FDA approval to market a biosimilar version of Amgen’s pegfilgrastim product Neulasta.

Earlier this month, the President signed into law the Patient Right to Know Drug Prices Act (Public Law 115-263). The Act mainly focuses on eliminating so-called “gag clauses” that prevent pharmacists from telling patients when paying for a drug out of pocket is cheaper than paying through insurance.  In addition, the Act amends the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (Public Law 108-173) to require branded drug companies and biosimilar applicants to disclose settlement agreements relating to the “manufacture, marketing, or sale” of biosimilar products to the Federal Trade Commission (“FTC”) and U.S. Department of Justice (“DOJ”) for evaluation under the antitrust laws. The new legislation brings biosimilar litigation in line with ANDA litigation, for which the same disclosure requirements were already in place. 

Earlier this month, AbbVie filed suit against Sandoz’s proposed biosimilar to AbbVie’s HUMIRA® (adalimumab).  Invoking the Biosimilar Price Competition and Innovation Act (“BPCIA”), AbbVie asserts two patents protecting Humira, a fraction of the 84 patents AbbVie wished to litigate.  Taking full advantage of the pre-litigation “patent dance,” Sandoz limited the number of patents-in-suit to just two.  As this case illustrates, following the patent dance affords biosimilar makers considerable control and power over the scope of biosimilar lawsuits.

Amgen has sued Apotex in connection with Apotex’s efforts to market biosimilar versions of Amgen’s cancer drugs Neupogen (filgrastim) and Neulasta (pegfilgrastim). In a complaint filed on August 7 in the Southern District of Florida, Amgen alleges infringement of U.S. Patent No. 9,856,287. This is the third time that Amgen has filed a BPCIA lawsuit against Apotex in connection with its filgrastim and pegfilgrastim biosimilars.

On July 18, FDA released its long-awaited Biosimilars Action Plan (“BAP”).  In prepared remarks to the Brookings Institution the same day, FDA Commissioner Scott Gottlieb described the BAP as “enabling a path to competition for biologics from biosimilars” in order to “reduc[e] costs and to facilitat[e] more innovation.”  While the BAP is straightforward, the Commissioner’s remarks included unexpected jabs at innovator drug makers for what FDA believes is anticompetitive conduct.  The speech was likely driven by the Trump Administration’s American Patients First plan, which sets as a top FDA priority the reduction of prescription drug prices, including by reducing “gaming” of regulatory requirements, but what the speech achieves given the role of FDA remains unclear.

Generics and biosimilar makers have increasingly used inter partes reviews, proceedings made possible by the America Invents Act, to challenge patents protecting innovator small-molecule drugs and biologic medicines.  Senator Orrin Hatch, co-author of the Hatch-Waxman Act, has introduced an amendment that would require these manufacturers either to take advantage of the abbreviated regulatory approval pathways provided by the Hatch-Waxman Act and BPCIA and challenge innovator patents in district court or to challenge innovator patents in IPRs before the PTAB, but not both.  Senator Hatch explains that while he strongly supports IPRs and the America Invents Act and that IPRs are of particular importance to the tech community to fight “patent trolls,” they are also “producing unintended consequences in the Hatch-Waxman context” and “threaten[] to upend the careful Hatch-Waxman balance by enabling two separate paths to attack a brand patent.”  If enacted, generics and biosimilar makers that choose to take advantage of the abbreviated regulatory process will challenge innovator patents in court rather than in IPRs before the PTAB.

Yesterday, Pfizer announced that FDA had approved Retacrit® (epoetin alfa-epbx), a biosimilar of Amgen’s Epogen® and Johnson & Johnson’s Procrit® (epoetin alfa).  Epoetin alfa (EPO) is a blockbuster treatment for anemia.  Retacrit is the first EPO biosimilar approved in the United States. EPO biosimilars have been marketed in the EU for over a decade.   Hospira (now a Pfizer company) initially filed an application for approval of its EPO biosimilar in 2014.  FDA rejected that application in a complete response later and Hospira later resubmitted it after addressing FDA's concerns.  While Retacrit received a favorable FDA advisory committee recommendation in May 2017, it was rejected again in a second complete response letter due to concerns with the proposed manufacturing site for the biosimilar.  Nearly a year later, FDA approved Retacrit.  Pfizer plans to launch Retacrit this year.

Biosimilar developers have been aggressive in filing petitions for inter partes reviews (IPRs) of biologics patents before the Patent Trial and Appeal Board (PTAB), many of them preceding the filing of a marketing application.  Such early IPRs are attractive to biosimilar makers, because they provide a chance to challenge innovator patents years before the biosimilar maker files a marketing application with FDA.  Since a petitioner need not have Article III case-or-controversy standing to bring an IPR, the remoteness and uncertainty of future infringement in such circumstances does not preclude these early IPRs.  Under settled precedent, however, a biosimilar maker must have Article III standing to seek a Federal Circuit appeal if the PTAB issues a final decision upholding the challenged patent.  A decision expected from the Federal Circuit this quarter in Momenta Pharmaceuticals, Inc. v. Bristol-Myers Squibb Co., No. 17-1694 (Fed. Cir. argued Dec. 5, 2017) will address how and when a biosimilar maker can establish that standing.

The Federal Circuit’s recent decision in Amgen v Sandoz provides a measure of clarity for innovator companies and biosimilar makers eyeing patent litigation. While the Supreme Court of the US held in June that initiating the pre-litigation information exchanges set out in the Biologics Price Competition and Innovation Act (BPCIA) – colloquially referred to as the “patent dance” – cannot be enforced under federal law, the Federal Circuit’s decision goes a step further. It holds that initiation of the exchanges cannot be enforced under state law, either. As a result, innovators seeking to compel disclosures from biosimilar makers have no recourse other than to sue for infringement. For a number of reasons, however, the decision might not prove as impactful in the long run as it may seem.

To continue reading Irena Royzman and Michael Fresco's article from Intellectual Property Magazine, please click here.

Marketing approval for US biosimilars has taken off in 2017.  FDA has approved five biosimilar products this year, increasing the number of approved biosimilars from four to nine.  In addition to new biosimilars of AbbVie’s Humira and Janssen’s Remicade, FDA has approved the first two biosimilars for the treatment of cancer.  All five of the products approved this year are biosimilars of complex blockbuster therapeutic antibodies.

Inter partes review proceedings for biosimilar products are soaring. Biosimilar makers are taking advantage of IPR proceedings to challenge patents protecting some of the world's most important biologic medicines due to the advantages that these proceedings offer: no standing requirement, no presumption of validity, a lower burden of proof and potentially broader claim construction. More than half of the IPR petitions challenging these patents were filed in fiscal 2017. But the results are mixed, with the Patent Trial and Appeal Board denying a high percentage of the petitions. Many of these patents are ultimately litigated in district court under the U.S. biosimilar statute, the Biologics Price Competition and Innovation Act of 2009 (BPCIA). 

In Sandoz v. Amgen, the Supreme Court interpreted the U.S. biosimilars statute, the Biologics Price Competition and Innovation Act (BPCIA), for the first time. The Court held unanimously that provisions of the BPCIA requiring disclosure allowing innovator companies to assess whether their patents are infringed cannot be enforced under federal law. The ruling also allows biosimilar makers to provide notice of commercial marketing long before FDA approval of the biosimilar. The Court’s decision introduces uncertainty into provisions of the BPCIA that many viewed as necessary and enforceable. But, due to the value of certainty for both biosimilar makers and innovators alike in resolving patent disputes for blockbuster biologics, the impact of the Supreme Court’s decision may ultimately be modest.

To read the article by Irena Royzman and Nathan Monroe-Yavneh in Nature Biotechnology, please click here.

Amgen filed patent infringement claims against Mylan over Mylan’s proposed Neulasta biosimilar.  The suit is the latest in a number of litigations over the blockbuster drug.

FDA announced Thursday that it has approved Mvasi (bevacizumab-awwb), Amgen and Allergan’s biosimilar of Genentech’s Avastin (bevacizumab), a monoclonal antibody used in the treatment of a number of different cancers. Mvasi is the seventh biosimilar approved in the United States under the BPCIA and the first biosimilar approved by FDA for cancer treatment. Mvasi was approved for all six indications of Avastin that are not protected by orphan drug exclusivities, with Avastin’s other indications protected by exclusivities expiring in 2021 and 2023.

Many biosimilar makers have tried and failed to obtain approval for biosimilar versions of Amgen’s Neulasta (pegfilgrastim), a long-acting version of Amgen’s Neupogen (filgrastim).  Coherus BioSciences, Inc. is the latest biosimilar maker to encounter such hurdles.  FDA denied Coherus’s biosimilar application in June, pushing any approval of the proposed biosimilar back by at least a year.  Coherus was forced to lay off a third of its workforce after FDA’s rejection of the application.  On Tuesday, it asked a federal court to stay the BPCIA litigation recently brought against it by Amgen.  Coherus seeks to stay discovery until resolution of its pending motion to dismiss to allow it to conserve resources while preparing to resubmit its biosimilar application.

Pfizer’s proposed biosimilar of Amgen’s Epogen® and Johnson & Johnson’s Procrit® (epoetin alfa) is poised to be the first erythropoietin (EPO) biosimilar in the U.S.  FDA staff recommended approval of Pfizer’s product as a biosimilar for the four indications of Epogen/Procrit.  On May 25, 2017, FDA’s advisory committee agreed with that assessment, but FDA did not approve Pfizer’s product following the meeting.  Instead, in a first for biosimilar products, FDA issued a complete response letter in June rejecting Pfizer’s EPO biosimilar application for a second time.  Pfizer revealed that FDA did not approve the application after the advisory committee meeting due to FDA’s concerns with a manufacturing site for the EPO biosimilar.  Pfizer’s product may not be approved, much less launched, this year due to outstanding manufacturing issues.

On June 12, 2017, the Supreme Court decided Amgen v. Sandoz, the landmark case about the meaning of the Biologics Price Competition and Innovation Act (BPCIA). First, the Supreme Court held that no federal injunction is available to force biosimilar applicants to participate in the BPCIA’s patent dispute resolution procedures (a/k/a the patent dance); but it remanded to the Federal Circuit to address whether such an injunction is available under state law.  Second, the Court held that under the BPCIA, a biosimilar applicant may provide 180-day notice of commercial marketing before the biosimilar product is licensed, meaning that as a practical matter, the 180-day notice period need not affect the timing of the biosimilar product’s launch.   

This post, Part II, of a three-part series (Part I) on FDA’s interchangeability draft guidance, highlights the key issues that were raised in the stakeholder comments provided to FDA.  FDA received 52 comments in total from a variety of stakeholders, including patients, physicians, insurers, innovators and biosimilar makers.  The stakeholders were divided in their views in a number of areas.  Patient and physician groups and innovators urged FDA to adopt more stringent requirements for interchangeability assessments.  Biosimilar makers and insurers, by contrast, generally pressed for a loosening of the guidance provided by FDA as well as clarification that interchangeable biosimilar products were not more similar to the innovator product than the non-interchangeable ones.  The comments also raised a number of issues not addressed by the guidance, which will be discussed in the third post in this series.