2015: year of the biosimilar

In March 2010, US President Barack Obama signed the Patient Protection and Affordable Care Act, also known as Obamacare, into law. It was preceded in 2009 by the Biologics Price Competition and Innovation Act (BPCIA), which introduced a shortened pathway for approving biosimilars, medicines that have been developed to be close to existing biologic drugs.

Last July, the US Food and Drug Administration (FDA) approved for review the US’s first biosimilar application—Sandoz’s Zarzio.

Zarzio is a follow-on version of Amgen’s drug Neupogen (filgrastim), which stimulates the growth of white blood cells in the body, and is used to treat patients who have low levels of white blood cells because of cancer, or have recently undergone a bone marrow transplant.

The US is fairly late to the biosimilars game. The European Medicines Agency approved its first biosimilar drug in 2006, and now there are more than 20 biosimilars available in the EU. In fact, Zarxio (as Zarzio is known in Europe) is the first biosimilar in the EU to overtake its reference product in terms of market share.

With many blockbuster biologics either soon to lose patent protection in the US or having already fallen over the patent cliff (Neupogen lost patent protection in the US in 2013), this year we’re likely to see many more applications with the FDA for biosimilar approval. What lessons can those applicants take from Zarzio’s approval process?

Zarzio

As it has already received marketing approval in more than 40 countries, creating a substantial amount of clinical data, Zarzio is ahead of the game in many ways.

“Zarzio is very lucky to have so much data,” says Patrice Jean, a partner at law firm Kenyon & Kenyon in New York.

“If there’s one lesson for biosimilar makers in countries that already have a lot of experimental data, it would be to get their ducks in a row and get their experimental data ready to use at the FDA so that they can get their products approved very quickly.”

However, given the complexity of biological drugs compared to small molecule pharmaceuticals, FDA approvals for biosimilars are likely to be considered on a case-by-case basis.

Courtenay Brinckerhoff, partner at law firm Foley & Lardner in Washington, DC, says that some biosimilars will be simpler than others, and that the amount of guidance biosimilar makers may take from Zarzio’s journey will depend on how much of the approval process is transparent to the public.

The approval pathway for biosimilars will differ enormously from that of generic pharmaceuticals, which have far simpler reference products.

The story so far

Under the 1984 Hatch-Waxman Act, a generic drug maker can quickly determine what patents cover the reference drug that it seeks to make, by using the FDA’s Orange Book.

However, the biologics counterpart to the Orange Book, the Purple Book, does not list patents, so it will take biosimilar applicants longer to exchange information with the biologic maker in accordance with the BPCIA, in a process that has been branded a ‘patent dance’.

The biosimilar maker will provide the reference product maker with a confidential notice of its intent to make a version of its biologic, then the reference product maker will provide a list of patents that it either believes will be infringed by the product, or that it would be willing to license. To date, this process has not been tested.

"Successful litigation may not be likely until the biosimilar maker has either filed its application for approval or, at least, the product is far enough down the development pipeline."

Biosimilar litigation has so far come in the form of declaratory judgment actions—pre-emptive suits filed by biosimilar makers at district courts that allege the originators’ patents are invalid and unenforceable. The originators have so far not been the aggressors in court,
Jean notes, as no biosimilar has yet been approved in the US.

One of these declaratory judgment actions was filed by Sandoz in 2013 against Amgen and Roche at the US District Court for the District of Massachusetts. Sandoz alleged that two patents covering rheumatoid arthritis drug Enbrel (etanercept) are invalid and unenforceable, and would not be infringed by its biosimilar.

The case was dismissed as ‘not ripe’, as Sandoz had not filed an application for the biosimilar’s approval under the BPCIA.

On appeal, the US Court of Appeals for the Federal Circuit in late 2014 threw out the case, affirming the lower court’s findings.

Anthony Sabatelli, a partner at law firm Dilworth IP in Connecticut, says that the appeals court failed to address the questions of whether a biosimilar developer must go through the complex patent infringement adjudication requirements of the BPCIA, or whether other litigation options are available.

Successful litigation may not be likely until the biosimilar maker has either filed its application for approval or, at least, the product is far enough down the development pipeline, he says.

Celltrion’s declaratory judgment case against Johnson & Johnson, however, may shed some light on this.

With its proposed version of Johnson & Johnson’s Remicade (infliximab), which it will market as Remsima, Celltrion may have the next biosimilar product in line. Remicade treats disorders including Crohn’s disease, rheumatoid arthritis and psoriasis.

Celltrion filed its application for FDA approval of the drug last August, after filing for a declaratory judgment against Johnson & Johnson at the US District Court for the District of Massachusetts in March 2014.

Jean says it will be interesting to watch out for the outcome of this case, as Johnson & Johnson has argued that Celltrion’s case isn’t ripe, even though it had filed an FDA application—something Sandoz had not done in the Enbrel case.

“One of Johnson & Johnson’s arguments was that the Celltrion case still isn’t ripe because there’s still no FDA approval and their approval may be years away,” she says.

“Celltrion is arguing that even if approval is years away, the case is still ripe and Johnson & Johnson can’t keep them out of court, and that if it does, it could add another ten to 12 months to legal proceedings, time in which the Remicade biosimilar could be on the market. Celltrion says that it should be able to litigate this now and get this taken care of,” Jean explains.

The somewhat fuzzy definition (there doesn’t appear to be an agreed one worldwide) of biosimilars might also provide some options for the drugs’ makers, an issue which Jean says will play out away from the district courts.

“Biosimilars makers may push for legislation in Congress, or start filing citizens’ petitions with the FDA, asking for more clarification on what a biosimilar is,” she explains.

Introducing the Purple Book

That biological products are, compared with small molecule pharmaceuticals, so difficult to make and so complex in structure, is what makes settling on a regulatory pathway for biosimilars (compared with generic drugs) so challenging.

However, the FDA has lent a hand in the establishment of the Purple Book, a list of licensed biological products and proprietary names. At the moment it’s a work in progress, missing data on the patent expiry dates of reference products. But when the first biosimilars begin to be approved, it will feature information on those products’ interchangeability with the reference product.

It’s the differences between the Orange Book and the Purple Book that will make the approval processes for generic drugs and biosimilars so different, Jean says.

The Purple Book will be useful for those considering making biosimilar products, but they will have to do their own research and gather their own intelligence to identify the patent landscape, Brinckerhoff says.

The impact of Myriad

Biosimilars are making their US debut in a turbulent time for naturally-derived products. Since the Supreme Court’s decisions in Myriad and Mayo, which narrowed the scope of patentability for products made from natural materials, it’s been unclear which biologic products may or may not be patent-protected.

Jean says that because of the matter concerned in biosimilars, including proteins, vaccines and antibodies, a lot more challenges to reference biologic products under section 101 are likely. This, she says, is very different from what has occurred with small molecules.

She predicts that biosimilar companies may start filing inter partes reviews at the US Patent and Trademark Office’s Patent Trial and Appeal Board, where many companies have successfully revoked patents under section 102 and 103, which also state conditions for patentability.

The new BPCIA framework will make way for new patent litigation strategies, Brinckerhoff says.

“It will be interesting if all patents are litigated at once, whether parties try to drag out the litigation, or if they try to resolve the big issues first and then save lesser important patents for a second round,” she says.

It’s a “bidding process”, Brinckerhoff continues. “As the patent owner lists its patents and the biosimilar company can decide how many to be litigated, there can be strategies involved where patents are concerned in the first instance, how many patents the biosimilar decides to litigate are in the second, and then which patents the patent owner decides to enforce.

“It’s a very odd poker game,” she adds.

If a company loses at the patent game, there are other options available.

“We might see a surge in trademark actions,” says Jean. She believes that brand companies will bring actions at US district courts or at the International Trade Commission to keep biosimilars off the market due to a likelihood of consumer confusion based on the brand’s trademark or trade dress.

“Many people get tied to the name of a certain drug and there may be a real push for the generics to gain access to those names. If a brand company somehow has its patent invalidated, the only thing it’s going to have to lay its hat on is its trademark or trade dress.”

Among all the uncertainty biosimilars bring, one thing is for sure: it will be a compelling year in terms of district court litigation for those drug makers, which will be furiously revising their legal strategies to secure FDA approval. Even more compelling will be what may follow: a steady decrease in the cost of healthcare for all.