Irena Royzman, Ph.D., Partner

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.

This post, Part III, of a three-part series (Part I and Part II) on FDA’s interchangeability draft guidance highlights a number of open issues that stakeholders have identified in their comments to FDA.  These include the naming and labeling for interchangeable products as well as the relationship between multiple interchangeable products for the same reference product.  Biosimilar makers also wanted FDA to make clear that physician-mediated switching is possible for non-interchangeable biosimilar products even if pharmacy-level substitution is not.  A number of patient groups, by contrast, expressed concern that payers were in effect mandating pharmacy-level substitution for non-interchangeable biosimilars by taking innovator products off formularies.

The comment period for FDA’s draft guidance Considerations in Demonstrating Interchangeability With a Reference Product closed on Friday, May 19, 2017.  Innovators, biosimilar makers, patients, healthcare providers and other stakeholders have weighed in on the long-awaited guidance.  Interchangeable biosimilars, unlike other biosimilars, may be substituted for the innovator product without the intervention of the healthcare provider who prescribed the innovator product.  FDA’s guidance for interchangeable biosimilars is thus particularly important to stakeholders.  This post, Part I of a three-part series, provides an overview of the key provisions of the guidance.  Parts II and III will focus on the comments from stakeholders and open issues. 

When a small pharmaceutical company discovers a new medicine, it’s not uncommon for the company – which may not itself have the resources or infrastructure to get that medicine to patients – to seek a distribution partner early in development.  If the partners make a deal – say the distributor pays for the right to sell the drug (if it gets approved) – and the partners publicize the existence of the deal (but not the full details of the medicine), does the deal bar a patent filed more than one year later?  In Helsinn Healthcare S.A v. Teva Pharms. USA, Inc. (May 1, 2017), a unanimous panel of the Federal Circuit ruled that the on-sale bar of the America Invents Act (AIA) precludes such a patent, just as the pre-AIA on-sale bar would.  But, in a decision with the potential to chill deals between small bio/pharma companies and potential commercialization partners, the court left unresolved some important questions about the meaning of the AIA’s on-sale bar.

In Life Technologies Corp. v. Promega, the Supreme Court reversed the Federal Circuit’s interpretation of 35 U.S.C. § 271(f)(1), and held that a single component does not constitute a “substantial portion of the components of a patented invention” under the statute. The Court, however, declined to address how many components are needed to trigger liability.

Despite nearly universal opposition from both biosimilar makers and innovator companies, FDA has issued final guidance adopting its controversial August 2015 proposal for naming biologics.  Under the guidance adopted by FDA, the nonproprietary name of a biologic will consist of the core nonproprietary name of the originator product plus a meaningless but distinguishable suffix of four lowercase letters unique to each product.

The America Invents Act established inter partes review proceedings within the U.S. Patent and Trademark Office for certain challenges to the validity of issued patents.  More than 5,000 IPR petitions have been filed to date, and more often than not the PTO institutes review of the challenged claims. In over 80 percent of IPRs that have reached a final decision, the PTO has invalidated some or all of the instituted claims.  IPR proceedings have impacted patents across technologies, including pharmaceutical and biotech patents.

On the same day that FDA approved the first biosimilar of Humira, the fourth biosimilar to be approved in the U.S., it also denied a citizen petition filed by Abbott Laboratories (now AbbVie) requesting that FDA not accept any filing or approve any application for a biosimilar version of Humira® (adalimubab), AbbVie’s best-selling biologic, or any other product for which a biologics license application (BLA) was submitted to FDA prior to March 23, 2010, the date on which the Biologics Price Competition and Innovation Act (BPCIA) was signed into law.  AbbVie argued that to accept or approve any such biosimilar filing would constitute an unconstitutional taking under the Fifth Amendment.  AbbVie filed its petition in April 2012, long before any biosimilar was approved in the U.S. and before Amgen filed its biosimilar application for Humira with FDA.  All four of the U.S. biosimilars approved to date have relied on BLAs submitted to FDA prior to March 23, 2010.  

It has been four years since the first inter partes review proceedings were filed in the United States.  The first IPR petition, filed on September 16, 2012 (the first day IPRs became available), made it all the way to the Supreme Court, and the number of IPRs has greatly exceeded expectations, making the Patent Trial and Appeal Board one of the most important and busiest forums for patent validity litigation in the US.  IPRs were intended to help high-tech innovators besieged with suits from patent trolls to efficiently and cheaply invalidate dubious patents and focus on innovation.  But the impact of these proceedings goes far beyond electrical and computer fields as they have had a major impact on biotech and pharmaceutical patents as well.  The PTAB proceedings for U.S. Patent No. 6,331,415 (better known as the “Cabilly II patent”) – one of the most litigated biotech patents in the US – offer key insights into IPRs and why they are widely used across technologies. 

In UCB, Inc. v. Yeda Research and Development Co., the Federal Circuit affirmed the determination by the District Court for the Eastern District of Virginia that UCB, Inc.’s  Cimzia® (certolizumab pegol), a humanized antibody fragment that treats inflammatory conditions such as rheumatoid arthritis and Crohn’s disease, does not infringe a monoclonal antibody patent owned by Yeda Research and Development Co., Ltd..  (Fed. Cir. No. 2015-1957, September 8, 2016).  Based on actions taken during prosecution, the Federal Circuit agreed that Yeda was “estopped from including chimeric and humanized antibodies within the scope of the monoclonal antibodies claimed” in its patent.  

Six years after the biosimilar pathway was enacted into law, FDA has approved three biosimilars for marketing in the US.  Sandoz’s Zarxio, a biosimilar of Amgen’s Neupogen, was the first biosimilar to be approved.  Zarxio, a relatively simple biologic, was approved in March 2015 under the Biologics Price Competition and Innovation Act of 2009 (BPCIA).  This year, FDA approved two complex biologics, Celltrion and Pfizer’s Inflectra, a biosimilar of Janssen’s Remicade, and Sandoz’s Erelzi, a biosimilar of Amgen’s Enbrel.  FDA staff and its arthritis advisory committee also recommended approval of Amgen’s proposed biosimilar of AbbVie’s Humira.  On the other hand, Sandoz revealed in July that its biosimilar application for Amgen’s Neulasta, a long-acting version of Neupogen, had been rejected by FDA and Hospira did the same last year for its biosimilar application for Amgen’s EPO.  Although the approvals (and rejections) provide significant insights as to FDA’s requirements, there are no simple lessons to be drawn.

In July, the Federal Circuit decided Amgen v. Apotex, No. 2016-1308 (Fed, Cir. July 5, 2016), its second decision interpreting the U.S. biosimilar statute, the Biologics Price Competition and Innovation of Act of 2009 (BPCIA).  The Federal Circuit affirmed the district court’s preliminary injunction barring Apotex from selling its proposed biosimilar until 180 days after post-licensure notice of first commercial marketing.  The Federal Circuit held that 180 days’ notice was mandatory regardless of whether the biosimilar maker provided its regulatory application to the innovator as prescribed at the outset of the BPCIA procedures or not.  The decision has impacted other district court litigation, including the Janssen v. Celltrion/Hospira and Amgen v. Hospira cases, since the biosimilar makers in those cases also argued that they did not need to provide 180 days’ notice of commercial marketing after being licensed by FDA.

The Supreme Court today denied Sequenom Inc.’s petition for writ of certiorari, in which Sequenom asked the Court to review a decision of the Federal Circuit invalidating its patent on a breakthrough prenatal diagnostic procedure.  In denying the petition, the Court has declined to revisit the patent eligibility framework it set out in Mayo Collaborative Servs. v. Prometheus Labs. Inc., 132 S. Ct. 1289 (2012) and reaffirmed in Alice Corp. Pty. Ltd. v. CLS Bank International, 134 S. Ct. 2347 (2014).

In Cuozzo Speed Technologies, LLC v. Lee, No. 15-446, the Supreme Court affirmed the Federal Circuit’s holdings that an alleged defect in the PTO’s institution of an inter partes review (IPR) was not subject to judicial review even on appeal of a final decision, and that the PTO can apply the “broadest reasonable interpretation” claim construction standard in IPR proceedings.  Over 30 amicus briefs were filed in this case, with pharma/biotech innovators urging the Court to reverse the Federal Circuit.  

A 70-group coalition of healthcare stakeholders urged the FDA to incorporate meaningful and therefore memorable suffixes into its distinguishable naming system for biological medicines to provide strong patient protections and provider confidence.  The coalition emphasized that “meaningful suffixes are easier for patients, providers and pharmacists to both recognize and remember, thus facilitating accurate association between adverse effects and specific products.”  The coalition explained that meaningful suffixes based on the name of the manufacturer, such as the “sndz” suffix used for the first approved biosimilar, Sandoz’s Zarxio (filgrastim-sndz), instead of the random suffixes proposed in FDA’s most recent draft guidance and used for the first time in FDA’s recent approval of a second biosimilar, Celltrion and Pfizer’s Inflectra (infliximab-dyyb), would promote manufacturer accountability.  Notably, FDA used a random suffix for the nonproprietary name of Inflectra despite widespread criticism by innovators and biosimilar makers alike of FDA’s naming approach.

Amgen’s Enbrel (etanercept), a blockbuster biologic treatment for a number of autoimmune diseases, including rheumatoid arthritis and psoriasis, has been an attractive target for biosimilar makers.  Sandoz, the maker of Zarxio (filgrastim-sndz), the only biosimilar launched in the US to date, is also first in line with an Enbrel biosimilar in the US.  Last October, Sandoz announced that FDA accepted its regulatory application for a proposed Enbrel biosimilar for review.  Sandoz is seeking marketing approval for all of Enbrel’s medical indications.  But Sandoz’s proposed Enbrel biosimilar brought litigation under the US biosimilars statute, the Biologics Price Competition and Innovation Act of 2009 (BPCIA).

The Federal Circuit affirmed two decisions by the District of Delaware to assert personal jurisdiction in ANDA cases over West Virginia-based manufacturer Mylan.  Mylan had argued that it could only be sued in West Virginia in ANDA cases post the Supreme Court's decision in Daimler AG v. Bauman, 134 S.Ct. 746 (2014) because such cases are litigated before actual sales of its generic drug product are made in Delaware (and elsewhere).  The Federal Circuit grounded its rejection of Mylan's approach on Mylan's filing of its ANDAs with the clear intent to market its proposed generic drugs in Delaware upon FDA approval, as well as the injury Mylan would cause in Delaware through such sales.  Under the Federal Circuit's decision, plaintiffs in ANDA and BPCIA cases can obtain jurisdiction over defendants in their forum of choice based on defendants' regulatory filings with the intent to market their proposed products so long as consideration of fairness, such as undue burden on defendants, do not render jurisdiction in the chosen forum unreasonable.

In the latest skirmish between Amgen and Sandoz under the U.S. biosimilars statute, the Biologics Price Competition and Innovation Act of 2009 (BPCIA), Amgen has filed a new declaratory judgment claim alleging violations of the BPCIA.  As described in Amgen’s March 4 complaint, after filing an application for a biosimilar version of Amgen’s cancer drug Neulasta, Sandoz cut short the BPCIA patent dance and demanded that Amgen file an immediate patent infringement suit, claiming that Amgen would otherwise lose its rights to seek lost profits and injunctive relief.  Amgen responded with a suit for a declaration that it had no obligation to go forward with the immediate litigation phase of the BPCIA after Sandoz cut off the pre-suit procedures.

2015 was a landmark year for biosimilars.  It began with the approval of the first US biosimilar, Sandoz’s Zarxio, in March 2015 under the biosimilars pathway.  Zarxio entered the US market in September.  Many expected the floodgates to open after Zarxio’s approval but Zarxio remains the only approved US biosimilar to this day, although that is expected to change this year.  Seven other biosimilar applications were filed in 2014/2015 and are either being reviewed by FDA or have to be refiled.  Most of these applications are to complex biologics.  2016 should provide significant insights into how FDA determines biosimilarity and extrapolation for these complex products.

Earlier this week, the Patent Trial and Appeal Board (PTAB) set the stage for what is expected to be an epic battle over who owns the intellectual property rights to “the biggest biotech discovery of the century.”  On January 11, 2016, the PTAB declared an interference to decide who was first to invent the use of the groundbreaking gene-editing technique known as CRISPR in eukaryotic cells. The CRISPR proceeding may be one of the last great biotech interferences.  The claims at issue are viewed by many as the “holy grail” for correcting and curing human genetic diseases and interferences will ultimately become obsolete under the America Invents Act.

On November 19, 2015, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) gave a positive opinion, recommending marketing authorization of Samsung Bioepis’s Benepali, the first biosimilar of Enbrel (etanercept), in Europe.  Enbrel is a blockbuster treatment for rheumatoid arthritis and a number of other autoimmune conditions associated with elevated levels of tumor necrosis factor alpha (TNF-alpha), a protein that plays an important role in promoting inflammation.  The CHMP recommended approval of Benepali for these conditions.  In the US, FDA recently accepted Sandoz’s regulatory application for its proposed biosimilar of Enbrel for review.  Sandoz is seeking approval for all of Enbrel’s indications.  FDA’s review of Sandoz’s proposed biosimilar will provide important information on the requirements for biosimilarity and extrapolation for complex biologic products.

In its draft guidance, FDA proposed distinguishable nonproprietary names for biosimilars to promote the safety of patients receiving biologic medicines and minimize inadvertent substitution of biologics that have not been determined to be interchangeable.  FDA did not make a proposal for naming interchangeable biological products.  Instead, FDA requested comments on how to name such products in addition to seeking comments on its approach to naming biosimilars.  Stakeholders’ comments are now in.  Innovator companies (including those that also develop biosimilars), healthcare providers and patient advocacy groups favor distinguishable nonproprietary names for biosimilars.  Biosimilar makers, insurers, pharmacies, and the FTC, by contrast, largely fall into a different camp; they argue that distinct names are unnecessary for monitoring biosimilars and will likely bias providers against prescribing them.  Notably, the two camps came together on the naming of interchangeable products.  Since interchangeable products will likely first be approved as biosimilars, both camps advocated keeping the initial biosimilar name rather than changing it after approval as an interchangeable product.  As a result of this unified view, FDA is likely to expand the naming approach it ultimately adopts for biosimilars to interchangeable products.  

After the FDA approved the first U.S. biosimilar, Sandoz’s Zarxio (filgrastim-sndz), earlier this year, many predicted that the floodgates would open for biosimilar products.  That has not been the case.  No other U.S. biosimilar product has been approved.  And, as FDA’s recent rejection of Hospira’s  EPO biosimilar application suggests, Zarxio’s approval may ultimately provide little guidance for more complex products.