While the biosimilar market in the United States has gotten off to a relatively slow start compared with Europe – where biosimilars have been available since 2006 – it has recently gained momentum and will continue to grow in the coming years as more blockbuster biologics lose regulatory exclusivity and patent protection. This article reviews the biosimilar space since the enactment of the Biologics Price Competition and Innovation Act (BPCIA) 2009 and considers the future of biosimilars and related patent disputes.
BPCIA: where are we now?
The BPCIA is part of the Affordable Care Act and provides an abbreviated approval pathway for biologics that demonstrate biosimilarity to, or interchangeability with, a Food and Drug Administration (FDA-)approved reference product. The BPCIA also created a litigation scheme involving various information exchanges between a biosimilar manufacturer and a reference product sponsor, often referred to as the 'patent dance', that occur prior to filing an infringement litigation.
In the 10 years since the BPCIA's enactment, 17 biosimilars have been approved,(1) seven of which have launched,(2) and at least 10 applications are pending with the FDA.(3) Thirty-two BPCIA-related litigations have been filed so far,(4) with many of the early litigations challenging various parts of the BPCIA patent dance. The courts' decisions in these cases have clarified that:
- the BPCIA's patent dance is not mandatory;(5)
- a 180-day notice of commercial marketing can be given prior to biosimilar FDA approval;(6)
- injunctions to force compliance with the BPCIA procedures are not available under federal or state law;(7) and
- declaratory judgment suits are not available to biosimilar manufacturers.(8)
While the BPCIA procedures are not mandatory, companies have been taking advantage of the initial aspects of the patent dance, which involve the biosimilar manufacturer providing the reference product sponsor with its abbreviated biologic licence application (aBLA) and other manufacturing information, to which the reference product sponsor responds by giving the biosimilar manufacturer a list of patents that it determines the proposed biosimilar infringes.(9) There have been only four cases to date where the biosimilar manufacturer refused to provide its aBLA under the BPCIA, and in one of those cases it was provided under another agreement.(10) However, many complaints alleged that the biosimilar manufacturer failed to provide other manufacturing information in addition to their aBLAs, and at least 16 complaints alleged that the patent dance had not been completed prior to filing the litigation or that one of the parties had stopped the patent dance and later attempted to re-initiate it outside of statutory time periods specified for the exchanges.(11)
Many of the BPCIA cases are still pending. Among those that have been decided, the majority have determined that the proposed biosimilar did not infringe,(12) although Retacrit was found to infringe Amgen's patent in Case 1:15-cv-00839 (D Del) (appeal pending).
Future of BPCIA and biosimilar patent disputes
Although many issues with the BPCIA have been clarified, its future remains largely uncertain. Part of the Affordable Care Act was recently ruled unconstitutional in Texas v Azar,(13) after which there has been concern that a Supreme Court affirmance may completely eliminate the BPCIA's biosimilar regulatory and litigation pathway. Should the Affordable Care Act be found unconstitutional in its entirety, the BPCIA would have to be reintroduced and passed by Congress again. Introducing a new BPCIA would likely elicit debate over whether to make changes that have caused concern and litigation (eg, making the biosimilar pathway mandatory and requiring exchange of other manufacturing information in addition to the aBLA) and whether certain potential ambiguities should be addressed (eg, determining when a reference product sponsor should include patents on indications not currently part of the proposed biosimilar's label, but where studies have been completed).
Inter partes reviews In addition, there is some concern over whether the inter partes review and post-grant review Patent Trial and Appeal Board proceedings will remain available to biosimilar manufacturers seeking approval through the abbreviated biosimilar pathway. The pending Hatch-Waxman Integrity Act 2018 would require biosimilar manufacturers to choose between using the abbreviated regulatory pathway, patent dance and filing or relying on any decisions in inter partes reviews or post-grant reviews.(14) This could essentially eliminate the availability of inter partes review and post-grant review proceedings for biosimilar manufacturers, as without the abbreviated approval pathway, biosimilars would need to submit a full biologics licence application. Although the rate of inter partes review filings decreased in 2018 after an influx in 2017, inter partes reviews have been popular with biosimilar manufacturers – with 104 biosimilar-related inter partes review petitions filed to date challenging a total of 53 patents.(15) Thirty-two (60%) of these patents have also been subject to biosimilar-related litigations.(16) Therefore, this legislation could significantly change patent strategies in the biosimilar space. Biosimilar-related post-grant reviews have not been popular, as only one has been filed to date,(17) but this could change with the next wave of biosimilars, depending on the outcome of the pending legislation.
First-wave biosimilars As new waves of biosimilars come to market, biosimilar patent strategies continue to evolve. In the first wave of biosimilars, which consisted of biosimilars for cytokines, growth factors and hormones, such as filgrastim and epoetin alfa, there were very few inter partes reviews and a number of patent litigations. The majority of litigations were on manufacturing patents, all of which were filed after the reference products lost regulatory exclusivity.(18)
Second-wave biosimilars The second wave of biosimilars – which generally involved monoclonal antibodies with patents expiring before 2020 (eg, adalimumab, infliximab and trastuzumab) – saw a very different landscape, with many patents challenged in both inter partes reviews and litigations that were all filed after the reference products lost regulatory exclusivity.(19) In addition to manufacturing patents, many method of treatment patents were challenged, particularly in inter partes reviews. These challenges were dominated by a small number of large drug companies, including Amgen, Apotex, Celltrion, Coherus, Mylan and Sandoz.
Third-wave biosimilars The third wave of biosimilars – which generally involves more complex monoclonal antibodies, such as eculizumab, nivolumab and ranibizumab, with patents and regulatory exclusivities expiring after 2020 – is in its infancy, with most potential biosimilars in preclinical and early phase clinical trials. These biosimilars are many years from approval. Thus the strategies employed could look different to what has previously been seen. For example, litigations may start taking place earlier, prior to the expiration of regulatory exclusivity, allowing biosimilars to launch as soon as regulatory exclusivity ends. Settlements may become more frequent to increase certainty as to when biosimilars can enter the market or to minimise costs from litigating large patent portfolios. Whether biosimilar manufacturers will continue using patent office proceedings to challenge patents remains to be seen, particularly as many manufacturers involved in the third wave are different to those previously seen, with companies such as Alteogen and Formycon working on Eylea biosimilars, Dyadic, Formycon, Pfenex and Xbrane working on Lucentis biosimilars and Mabpharma working on an Opdivo biosimilar.
Since the third wave of biologics has generally increased complexity and the potential availability of biosimilars is still many years away, innovators have more time to get patents on these reference products. This could create complex litigations on even larger and more robust patent portfolios. Composition of matter patents may be harder to invalidate due to the complexity of these biologics. Thus method of treatment and manufacturing patents are likely to continue to be targeted by biosimilar manufacturers, particularly in inter partes reviews, if they remain available.
The size and complexity of the third-wave biologic patent portfolios may affect at-risk launches in the future. So far, almost all biosimilar launches have been at-risk, but the pending litigations involved few patents at the time of launch, making potential liability easier to assess. In the future, cases with more patents and more complex technology could make the outcome of an at-risk launch less predictable. Biosimilar manufacturers may begin filing their aBLAs earlier and attempting to resolve any litigation prior to loss of regulatory exclusivity to avoid making the decision on whether to launch at-risk.
Biosimilar-biosimilar litigation Although only one has been seen so far, biosimilar-biosimilar litigations are likely to pick up in the future as more manufacturers compete to enter the market with biosimilars of the same reference products. The first case, Coherus Biosciences, Inc v Amgen Inc,(20) relating to Amgen's Amjevita, alleges infringement of Coherus's formulation patents. With companies such as Alteogen announcing that it obtained patents on its composition and formulation of ALT-L9, which it is investigating as a biosimilar to Eylea, it is likely that third-wave biosimilars will also face biosimilar-biosimilar lawsuits.
Biosimilar settlements are becoming more frequent, with numerous companies settling ongoing disputes and even settling with biosimilar manufacturers prior to submission of aBLAs or initiation of inter partes reviews, and it is likely there will be further settlements in the future. Although there have yet to be any branded biosimilars or authorised biologics, it is possible that these will be included in future settlement agreements. It will be interesting to see how the recently passed Patient Right to Know Drug Prices Act,(21) which requires Federal Trade Commission review of settlements between biologic and biosimilar developers to prevent 'pay-for-delay' type settlements, will affect future biosimilar settlement agreements.
While some clarity has been provided on BPCIA procedures, many questions remain for the future of the BPCIA regulatory and litigation pathway, including whether it will need to be passed again by Congress, possibly in an altered form. Whether the future of patent disputes will be focused on inter partes reviewsor litigation remains to be seen, but one thing is for sure: biosimilar-related patent disputes will be increasing as the US biosimilar market continues to grow.
This article was first published by the International Law Office, a premium online legal update service for major companies and law firms worldwide. Register for a free subscription.
(13) 4:18-cv-00167 (ND Tex), Docket Entry 211, available at https://oag.ca.gov/system/files/attachments/press-docs/211-texas-order-granting-plaintiffs-partial-summary-judgment.pdf?rel=0
(15) https://biologicshq.com/stats_entry/biosimilar-related-ipr-petitions/ (includes 13 inter partes reviews related to insulin).