Editor's note: The following is a guest post from attorneys Michael Cottler, Joshua Whitehill and Alison Siedor.
The 2010 Biologics Price Competition and Innovation Act (BPCIA), enacted as part of the Affordable Care Act, set up an abbreviated biosimilar regulatory pathway and a unique litigation framework for resolving related patent disputes. While regulatory and litigation activity for biosimilars began as a trickle — with the first patent case filed in 2014 and first Food and Drug Administration approval in 2015 — it has steadily increased each year. Today there are nine FDA-approved biosimilars, including three on the market, and more active BPCIA litigations. This year saw numerous new complaints about the law, five new FDA approvals, another biosimilar launch, the first U.S. Supreme Court decision concerning on the topic, the first jury trial and damages award in a biosimilar case, and other significant activity.
The new year is likely to bring more activity, with three cases scheduled for trial, several others in discovery or appeal, and new complaints likely.
Neupogen and Neulasta
Amgen's Neupogen (filgrastim) and Neulasta (pegfilgrastim) won FDA-approval in 1991 and 2002, respectively. By 2016, Amgen was reporting nearly $4.5 billion in U.S. sales of Neupogen and Neulasta.
Several abbreviated Biologics License Applications (aBLAs) for both products have been filed, leading to lawsuits. In March 2015, Sandoz's filgrastim biosimilar Zarxio received FDA approval and reported U.S. sales exceeding $100 million in the first year. Amgen reported a 33% year-over-year decline in U.S. sales of Neupogen for 2016.
No other aBLAs have been approved. Sandoz received a Complete Response Letter last year for its pegfilgrastim product and does not expect to resubmit its application until 2019. Although accepted by FDA for review in 2014, Apotex's filgrastim and pegfilgrastim aBLA are not yet approved. And both Mylan and Coherus received CRLs for their pegfilgrastim aBLAs in the past six months.
Amgen has filed six BPCIA patent litigations regarding the biosimilars.
In 2014 and 2016, Amgen sued Sandoz in the Northern District of California based on Sandoz's aBLAs. In those cases, which are coordinated for discovery and trial, Amgen is asserting one manufacturing process patent. Sandoz has moved for summary judgment of non-infringement and to limit any damages exposure. A summary judgment hearing is set for Dec. 18, 2017, and a jury trial for March 26, 2018.
A dispute regarding interpretation of the BPCIA arose early on in the filgrastim litigation and was heard by the Supreme Court in early 2017. The Court held in June that no injunction is available under federal law to force compliance with the patent dance and that an aBLA applicant can provide notice of commercial marketing (NCM) before FDA approval. It also remanded the appeal for further consideration of Amgen's state law claims relating to Sandoz's alleged patent dance violation. A Federal Circuit decision issued today, affirming the dismissal of Amgen's state law claims concerning the patent dance as being preempted by federal law (i.e., the BPCIA).
Second, in August and October 2015, Amgen sued Apotex in the Southern District of Florida based on its respective biosimilar applications. Late in 2017, the Federal Circuit affirmed the district court's post-trial judgment that Apotex did not infringe the asserted protein refolding process patent.
In 2017, Amgen sued Coherus in the District of Delaware and Mylan in the Western District of Pennsylvania for infringing one or more protein purification process patents based on their respective pegfilgrastim aBLAs. To the extent the Coherus and Mylan cases proceed beyond the pleadings phase, both are expected to be in their discovery phases in 2018.
Approved in 1998, Janssen's infliximab product, Remicade, is a monoclonal antibody inhibitor of human tumor necrosis factor-α to treat various inflammatory conditions. In 2016, the drug generated U.S. sales of $4.6 billion.
FDA has approved three infliximab biosimilars: Celltrion and Pfizer's Inflectra in 2016, as well as Pfizer's Ixifi and Samsung Bioepis' Renflexis in 2017. Inflectra launched late last year with a 15% discount to Remicade's list price, and Renflexis this past summer with a 35% discount. Janssen has suggested, however, that biosimilar competition has not significantly impacted U.S. sales. (Pfizer alleges in an antitrust suit that Janssen has taken anticompetitive steps to protect its Remicade market from biosimilar competition.)
In March 2015, Janssen sued Celltrion and Hospira in the District of Massachusetts based on the defendants' infliximab aBLA. The case was ultimately narrowed to an antibody patent and a cell culture media patent. In August 2016, the district court granted summary judgment of invalidity as to the antibody patent. The Patent Office found the same patent to be invalid during a reexamination proceeding. Janssen appealed those rulings to the Federal Circuit, which heard oral argument in October. A decision is expected by early 2018.
Meanwhile, the parties continued to litigate the cell culture media patent and have requested a jury trial in 2018. Numerous motions are pending, including motions to exclude expert testimony and Hospira's summary judgment motion for noninfringement. Oral argument is scheduled to start on January 30, 2018.
In October 2017, the district court denied defendants' motion to dismiss for lack of standing, but the defendants now seek to file an interlocutory appeal and to stay the case pending appeal.
Amgen has marketed Epogen (Epoetin alfa) since its FDA-approval in 1989, treats anemia and for reducing allogenic red blood cell transfusions. Amgen reported U.S. 2016 sales of Epogen of $1.3 billion.
There are currently no FDA-approved biosimilars of epoetin alfa. Although Hospira filed an aBLA in January 2015, it has since then received two CRLs.
Amgen sued Hospira in September 2015 for infringement of two manufacturing process patents. Amgen contended that Hospira's manufacture of 21 batches of drug substance before patent expiration was infringing. Hospira countered that the patents were invalid and not infringed, and that any infringing activity was protected by the safe harbor of 35 U.S.C. § 271(e)(1), which generally protects uses reasonably related to FDA approval. After a September trial, a jury concluded that one of the two patents-in-suit was infringed and not invalid, and that 14 of the accused batches were not protected by the safe-harbor. The jury awarded Amgen $70 million as a reasonable royalty. Both parties have filed post-trial motions, challenging various aspects of the jury verdict. The court is likely to decide the motions in the first half of 2018.
Amgen subsidiary Immunex's Enbrel (etanercept) is a fusion protein that inhibits human TNF to treat certain inflammatory conditions. It was approved in 1998, and Amgen reported 2016 U.S. sales of $5.7 billion. FDA has approved one etanercept biosimilar, Sandoz's Erelzi, but it is not yet on the U.S. market.
In February 2016, Immunex sued Sandoz in the District of New Jersey for infringement of five patents directed to etanercept, nucleic acids and host cells to make etanercept, or methods of treating psoriasis and psoriatic arthritis, based on Sandoz's etanercept aBLA. A trial is scheduled for April 17, 2018.
AbbVie's Humira (adalimumab) is a mAb inhibitor of human TNF for the treatment of numerous inflammatory conditions. Approved in 2002, Humira reportedly generated U.S. sales of $10.4 billion in 2016.
FDA has approved two adalimumab biosimilars: Amgen's Amjevita in September 2016, and Boehringer Ingelheim's Cyltezo in August 2017, but neither is marketed. In September 2017, AbbVie and Amgen announced that they had settled their patent litigation regarding Amjevita, and Amgen indicated that it expected to launch its biosimilar in the U.S. in 2023.
In August 2017, AbbVie sued Boehringer Ingelheim in the District of Delaware based on Boehringer Ingelheim's adalimumab aBLA. The district court entered a schedule that should have the case trial-ready in June 2020. AbbVie is asserting eight patents covering compositions, formulations, manufacturing processes, and methods of treatment. According to the pleadings, AbbVie identified 66 other patents during the patent dance, but Boehringer Ingelheim only agreed to litigate a smaller number as part of a first wave of litigation.
Genentech's Avastin (bevacizumab) is a humanized anti-VEGF mAb for various cancers. Approved in 2004, Avastin generated U.S. sales of $3 billion in 2016.
In September 2017, FDA approved the first bevacizumab biosimilar, Amgen and Allergan's Mvasi, but the product has not launched.
There are three co-pending patent litigations between Genentech and Amgen. On October 6, 2017, after engaging in the patent dance with Genentech and providing its NCM, Amgen filed a complaint in the Central District of California seeking a declaratory judgment that it does not infringe 27 patents that Genentech listed during the patent dance or that the patents are invalid or unenforceable. Shortly thereafter, Genentech filed suit in the District of Delaware asserting infringement by Amgen of 24 of those patents.
Later, Genentech filed a second complaint in Delaware, adding another patent. Genentech has moved to dismiss Amgen's complaint for lack of jurisdiction, and Amgen has moved to transfer the Delaware actions to California. Rulings on these motions, expected in early 2018, may provide guidance on whether Amgen's preemptive filing of a declaratory action is a viable strategy.
Approved in 1998, Genentech's breast cancer drug Herceptin (trastuzumab) brought in U.S. sales of $2.5 billion in 2016.
Earlier this month, FDA approved the first trastuzumab biosimilar, Mylan and Biogen's Ogilivi. During inter partes review proceedings, Mylan and Genentech reached a settlement that provided Mylan with a global license that will allow Mylan to commercialize its biosimilar, though the parties did not publicly disclose the potential timing of a U.S. launch.
Last month, Genentech sued Pfizer for infringement of 40 patents based on its trastuzumab aBLA. The case is still in the pleadings stage and will likely be in the discovery phase in 2018.
Anticipated New Litigations
According to company announcements, the FDA had accepted many additional aBLAs in the second half of 2017 that could potentially lead to new BPCIA litigations in 2018. Those include Celltrion and Teva's rituximab (Rituxan) and trastuzumab aBLAs, Amgen and Allergan's trastuzumab aBLA, Sandoz's rituximab aBLA, and Adello Biologics' filgrastim aBLA. Companies have also reported that they are on track to file aBLAs in late 2017 or in 2018. For example, Sandoz and Momenta each indicated this year that they aim to submit adalimumab aBLAs by the end of 2017. Any of these submissions have the potential to spur further BPCIA litigation activity in 2018.
Michael Cottler is a partner, Joshua Whitehill is a senior associate, and Alison Siedor is a law clerk, all in the New York office of Goodwin Procter LLP. They are contributing editors to the firm's biosimilars blog, BigMoleculeWatch.com.
Editor's note: This article has been updated to reflect the issuance of a Federal Circuit decision on Dec. 14 2017