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Celltrion hopes to blaze path for first U.S. biosimilar MAb

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By Mari Serebrov
Washington Editor

Anticipating FDA approval early next year of its infliximab biosimilar, Celltrion Inc. is trying to clear the patent path so it can launch Remsima in the U.S. as soon as the approval comes down.

With Remsima posed to become the first biosimilar monoclonal antibody (MAb) approved for the U.S. market, the Korean company filed suit this week in a federal court in Massachusetts seeking declaratory judgment that Janssen Biotech Inc.’s remaining patents on the reference drug Remicade (infliximab) are invalid and unenforceable.

The two drugmakers are on an “inevitable collision course” and relief is needed sooner rather than later, Celltrion said in its complaint. That sense of urgency underlies the entire complaint, as Celltrion hopes to avoid the delay Sandoz Inc. encountered when it tried to clear the patent path for an Enbrel (etanercept) biosimilar still in development.

Sandoz sought a declaratory judgment last year that its etanercept biosimilar doesn’t infringe two patents owned by Roche AG and exclusively licensed to Amgen Inc. A federal judge in California denied Sandoz’s complaint, saying it was premature. (See BioWorld Today, Nov. 15, 2013.)

Before parties can take a biosimilar patent challenge to court, they must first follow the steps of the information exchange Congress laid out in the Biologics Price Competition and Innovation Act, the judge ruled. They can only start clearing the path after the FDA approves the biosimilar, she told Sandoz, which is appealing the decision.

With its final pre-filing meeting scheduled with the FDA this month, Remsima is closer to approval than the Sandoz biosimilar. If everything’s a go, Celltrion plans to file its biologic license application (BLA) for Remsima shortly after that meeting, giving the biosimilar a PDUFA date in the first quarter of 2015.

If Celltrion has to wait for the FDA’s approval of Remsima before it can litigate declaratory judgment claims, it would be forced into launching the biosimilar without the benefit of discoverable information regarding Janssen’s patents and legal positions or delaying the launch until what could be a lengthy legal process is played out.

“An at-risk launch without the benefit of discovery could create serious risks and exposure for Celltrion and could subject it to substantial damages and significant commercial harm,” according to the complaint. Delaying the launch would hurt Celltrion financially as it is gearing up to manufacture several months’ supply of Remsima ahead of its U.S. launch. A delay also would harm the public interest, because drug costs would remain high if Remicade were the only available treatment on the U.S. market.

Remicade was approved in 1998 to treat Crohn’s disease. Since then, it has been approved for plaque psoriasis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis and ulcerative colitis. The blockbuster biologic is based on the cA2 molecule, which is a murine-human MAb capable of binding to TNF-alpha. While it has faced competition from newer biologics, it has not had to compete with lower-priced follow-ons.

According to Celltrion’s complaint, Janssen’s predecessor Centocor Inc. applied for patents describing Remicade in March 1991, with the first being granted in 1997. “Since then, Janssen has applied for dozens of patents that all claim the same purported invention covering cA2 and its uses, or obvious variations of that purported invention,” Celltrion said. Some of those were granted as recently as 2008.

At least three Remicade patents extend beyond this year, and Janssen has said its MAb has patent protection into 2018. As part of its legal challenge, Celltrion said Janssen purposefully delayed prosecution of one of the patents to improperly extend its term. The patent application was filed 24 years ago. Over the following seven years before the patent was granted, the claims were amended numerous times, and claims that were covered by an earlier patent were added.

Celltrion also accused Janssen, a Johnson & Johnson company, of inequitable conduct before the Patent and Trademark Office in obtaining another Remicade-related patent, because it didn’t disclose prior art.

A BIOSIMILAR PATH

Aside from laying out Celltrion’s case against Janssen’s patents, the complaint provides a behind-the-scenes glimpse at biosimilar development and the brand company’s global efforts to fight competition.

Celltrion began work on Remsima in 2008, investing more than $112 million in out-of-pocket external costs plus significant internal manpower and other corporate resources. In the process, it produced several technological breakthroughs, including a patented system for introducing the “instructions” for its biologic products into the cells that produce the drugs, proprietary cell lines, and manufacturing and purification processes.

Remsima began global trials in 2010. The phase I and III trials enrolled a total of 1,471 subjects in 20 countries and at 115 sites. On the strength of those trials, Remsima was first approved in 2012 in Korea, making it the world’s first follow-on biologic to be approved on a biosimilar regulatory path. It was approved in the EU the following year. Today, Remsima is approved in 47 countries and marketing applications are pending in another 23 countries. (See BioWorld Today, Aug. 9, 2012, and Sept. 11, 2013.)

The company’s current focus is on U.S. approval. Celltrion had a data review meeting with the FDA in July 2013. At that meeting, the FDA received the global trial results favorably, Celltrion said, and recommended that the drugmaker conduct a short follow-up clinical trial. That bridging study was completed last month. Before submitting its BLA, the company will discuss the format and content of the application at its final meeting with the FDA this month.

LEGAL CHALLENGES

While it’s been pursuing Remsima approval all over the world, Celltrion has been fighting Janssen at almost every step of the way. Janssen opposed Celltrion’s trademarks for Remsima in Argentina, Australia, Bolivia, Brazil, Canada, Chile, India, Korea, the Philippines, South Africa and Uruguay, and brought invalidation proceedings in Korea and Paraguay. Most of those cases were decided in Celltrion’s favor, according to the complaint.

Janssen also opposed Remsima’s approval in Mexico on the grounds of data exclusivity, which Mexico doesn’t grant. “Janssen asserted [it] anyway knowing that any challenge, no matter how frivolous, would automatically result in a stay of a pending market application,” Celltrion said. A stay was granted, delaying Remsima’s launch in Mexico.

Janssen had another legal victory in Peru after regulators approved Remsima. The Peruvian court suspended the approval, agreeing with Janssen’s charge that the drug was approved hastily before biosimilar guidelines were established.

When it looked like Celltrion and its partner, Hospira Inc., were going to succeed with a patent challenge in the UK, the Mathilda and Terrence Kennedy Institute of Rheumatology Trust negotiated a licensing agreement with Celltrion. As part of the negotiations, the trust – which holds title to some patents relating to uses of cA2 – discussed giving Celltrion a global license, including licenses to its Canadian and U.S. patents.

However, Janssen, which has a nonexclusive license to the Kennedy patents, demanded that Celltrion not be given a license in Canada and the U.S., Celltrion said in its complaint. Kennedy and Janssen then asserted infringement against Celltrion in Canada. As part of those proceedings, Janssen refused to discuss the possibility of granting Celltrion a U.S. license.