Pfizer's Biosimilar Launch: Three Possible Dates For Inflectra

Celltrion Inc.'s marketing partner Pfizer Inc. is moving ahead with plans to launch Inflectra (infliximab-dyyb), a biosimilar to Janssen Biotech Inc.'s Remicade (infliximab), in the US this year. But it could face delays because of its early notification of commercial launch and Janssen's pending infringement claims.

FDA approved Inflectra, the second biosimilar to clear the agency, on April 5. Pfizer said the launch timing would depend on several factors, including market dynamics and intellectual property considerations, but that it was continuing to prepare to launch in 2016 (Also see "Biosimilar Template Revisited: Inflectra Approval Binds And Separates From Remicade" - Pink Sheet, 5 Apr, 2016.).

One theoretical date is June 30, 2016, the day after a patent covering a method of using infliximab to treat Crohn's disease expires. In a March 22 court filing ending litigation over one of Janssen's patents, Pfizer said it would not sell Inflectra in the US before the end of June. The Crohn's method-of-use patent is one of six patents Janssen asserted in its March 2015 infringement suit against Celltrion and Hospira (now Pfizer). Three other patents have also been dismissed from the complaint.

But the two remaining patents may prove sticking points. "Our patents for Remicade remain valid and enforceable until September 2018," Janssen said following the approval of Inflectra. Even if Celltrion and Pfizer aren't worried about those patents -- and a court does not find they are infringed -- the partners still may not be able to launch Inflectra at a time of their choosing because of intricacies of biosimilar launch notification requirements.

Unraveling Launch Notification Timing

Perhaps one of the more surprisingly controversial elements of the biosimilars statute is the requirement that biosimilar sponsors provide reference sponsors 180 days notice before launch. When this issue first went to court, naturally around the approval of the first biosimilar, a deeply conflicted appeals court panel ruled in favor of Amgen Inc. and against Sandoz Inc., concluding that the law requires a biosimilar applicant to wait until after FDA licensure to provide launch notice.

As a result, Sandoz had to wait to launch Zarxio (filgrastim-sndz), a biosimilar to Amgen's Neupogen (filgrastim), until 180 days after FDA approved it. Even though Zarxio is already on the market, Sandoz is now hoping to get the decision overturned by the Supreme Court (Also see "Supreme Court Should Pass On Zarxio, Wait For Another Biosimilar Suit, Amgen Says" - Pink Sheet, 23 Mar, 2016.).

Other biosimilar sponsors doing other variations of the patent dance are hoping that their different circumstances will result in different judicial rulings. Last year, Janssen asked the court to issue an injunction enjoining Celltrion and Hospira from marketing their biosimilar until at least 180 days after FDA approval. Janssen says the Biologics Price Competition and Innovation Act (BPCIA) requires companies to provide 180-day notice of commercial launch after FDA approval to allow a reference product sponsor to assess its patents and decide whether to seek a preliminary injunction. Celltrion provided the notice of Inflectra's launch on Feb. 5, 2015 (Also see "Biosimilar Launch Notification: Celltrion Claims Loophole In Remicade Suit" - Pink Sheet, 1 Sep, 2015.).

Janssen said it received another launch notification from Pfizer and Celltrion following FDA approval of the biosimilar. If a court finds that the 180-day notice must come after approval, Pfizer would not be able to begin selling the tumor necrosis factor inhibitor until October.

But Celltrion contends that the notification requirement is mandatory only where the biosimilar applicant "completely fails" to provide its abbreviated biologics license application (aBLA) and manufacturing information to the reference product sponsor within 20 days of FDA accepting the application. Celltrion says that unlike Sandoz, it timely provided its aBLA, which included detailed manufacturing information, to Janssen. It says Janssen subsequently provided a list of six patents subject to infringement claims and that it, in turn, provided Janssen with a statement agreeing that each of the patents would be the subject of an infringement suit.

Janssen disagrees with this interpretation of the statute and says that even if this reading was applied, the post-approval notification would be mandatory for Celltrion since it refused to provide other information describing its manufacturing processes that was not in the aBLA.

The same question about the applicability of the notice provision is at issue in Amgen's suit against Apotex Inc., in which Amgen challenges Apotex's early notification of its intent to launch a biosimilar to Amgen's Neulasta (pegfilgrastim). The Federal Circuit heard oral arguments in that case on April 4.

Janssen's motion for a preliminary injunction and Celltrion's cross-motion for summary judgment were denied to await the Federal Circuit's upcoming decision in Amgen v. Apotex. Janssen can renew its motion for a preliminary and permanent injunction if the Federal Circuit does not issue a decision soon.

Damages Vs. Royalties

The notification question for Inflectra seems likely to be resolved before the remaining patents expire. Of the patents that remain in litigation, Janssen seems to have more confidence in the earlier expiring one, mentioning the 2018 date in its post-approval announcement but not 2027, when the other patent expires.

However, the enforceability of the patent expiring in September 2018, patent No. 6,284,471, is uncertain, after the Patent and Trademark Office found the patent, which covers the infliximab antibody, to be invalid in a reexamination proceeding. The decision is on appeal before the PTO's Patent Trial and Appeal Board. Janssen has asked the court to stay litigation on the '471 patent pending resolution of the reexamination proceeding.

Celltrion opposes the stay, saying the court should hold Janssen to its decision to sue. It says the BPCIA gave Janssen the choice of asserting patent infringement now and seeking all available remedies, including lost-profits damages, or asserting patent infringement later and seeking only a reasonable royalty. Alternatively, Celltrion states that Janssen could dismiss the suit on the '471 patent without prejudice, which would allow it to reassert the patent later and seek a reasonable royalty if the patent emerges from reexamination.

Janssen responded that it has properly asserted its claims and is entitled to seek lost-profits damages. It states that whether the measure of damages is lost profits or a reasonable royalty will be due in large part to the facts in the case.

"Defendants do not assert, and could not credibly assert, that they will launch at risk if defendants are limited to reasonable royalty damages, but will not launch at risk if defendants may recover lost profits," Janssen asserts.

Cell Media Patent Could Impact Foreign Supplier

On a separate track, Janssen may seek a preliminary injunction based on its claim that Inflectra infringes patent No. 7,598,083, which covers a particular cell media culture and expires in February 2027.

Last year, Janssen filed a motion to modify the court's protective order so it could bring a new infringement action against Celltrion and its cell media supplier on the '083 patent. In court filings Janssen says Celltrion and its third-party supplier have been using the same 61 ingredients specified in Janssen's patent to make the cell media in the US that is used to grow the infliximab biosimilar.

Celltrion argues that Janssen is seeking to use highly confidential information produced under the BPCIA to support a new lawsuit in which it will allege "widespread" infringement and try to seek damages for the sales of its biosimilar outside of the US.

"This proposed lawsuit is not just a stretch – as far as we can tell, it is unprecedented," Celltrion says in a brief opposing modification of the protective order. "Janssen apparently hopes to disrupt the relationship between Celltrion and its supplier. This is Janssen's last chance to delay competition."

Celltrion states that at a minimum, the court should wait to take action on Janssen's motion until the claim for infringement of the '083 patent is decided in the current case.

In a redacted March 1 brief, Janssen states that at the time its suit against Celltrion was filed in March 2015 it had only limited information to support a claim of infringement and that Celltrion had said there was no infringing activity in the US and that the cell media did not meet the limitations of the '083 patent.

"Celltrion aggressively misled Janssen about both the fact and the location of infringement," and Janssen did not have information sufficient to assert its new claims until, at the earliest, June 8, 2015, after the protective order had been agreed upon, the filing states.

Broad Label Is Good Sign For Future Biosimilars

Morningstar analysts said in a note that they expect Janssen's patents and upcoming litigation will delay Pfizer's launch until early 2018. They pointed out that the Remicade biosimilar launched in Europe in 2015 is ramping up quickly, gaining over 15% volume share, suggesting strong potential for the US launch.

They said that FDA's wide support for Inflectra, approving it using data extrapolation in all key Remicade indications, reinforces Morningstar's conviction that global sales for the top 10 industry biologics facing biosimilar competition will decline from just over $60bn in 2015 to $35bn in 2020.

Inflectra got all but one of Remicade's seven indications. FDA did not approve the pediatric ulcerative colitis claim, which is protected by orphan drug exclusivity. However, the agency included language on the labeling suggesting the biosimilar is safe and effective for this pediatric use (Also see "Inflectra Label Not Exactly Silent On Remicade's Orphan-Protected Claim" - Pink Sheet, 5 Apr, 2016.).

While the broad label is a good sign, Inflectra's path to approval wasn't nearly as smooth as the one taken by Zarxio, the first biosimilar approved by FDA last year. Inflectra also had a 2015 user fee date, but its initial advisory committee review scheduled for March 2015 was cancelled after an FDA information request.

FDA's approval letter refers to a resubmission by Celltrion in October responding to a June 8, 2015, FDA "action letter." It is unclear what the action letter addresses; the agency usually refers to complete response letters as action letters. Celltrion referred a question about the letter to Pfizer, which did not respond to that question.

The clinical development program for Inflectra included nine completed studies, only one of which was conducted specifically to support US licensure. And all but the latter trial used the European-approved version of Remicade as a comparator (Also see "Celltrion's Biosimilar Clinical Evidence Heavily Weighted By Ex-US Data" - Pink Sheet, 15 Feb, 2016.).