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Will Amgen's latest Neulasta® patent loss against Sandoz read-through to other biosimilars?

Zachary Silbersher

Sandoz recently prevailed in court against Amgen by showing it does not infringe a patent covering two of Amgen’s drugs, Neulasta® and Neupogen®.  No biosimilar has yet to receive FDA approval for Neulasata® within the U.S.  Sandoz recently announced successful Phase 1 data indicating it may be getting closer.  Further, other biosimilars for Neulasta® are in the works.  Given that Neulasta® accounts for a third of Amgen’s sales, will Amgen’s recent loss in its case against Sandoz read-through to other biosimilars?

Neupogen® and Neulasta®

The active protein in Neupogen® is filgrastim, which stimulates white blood cell production and is useful for treating cancer patients undergoing chemotherapy.  The active protein in Neulasta® is pegfilgrastim, which is a modified “long acting” version of filgrastim that remains in the circulatory system for a substantially longer period of time.  Because pegfilgrastim is “long acting” versus filgrastim means that Neulasta®’s sales are substantially larger than Neupogen®’s sales. Approximately a third of Amgen’s sales come from Neulasta® and Neupogen®, and approximately a quarter of Amgen’s sales are from Neulasta®.  Neulasta® alone generated close to $4B in U.S. sales in 2016. 

Pending biosimilars

Sandoz has pursued biosimilars of both Neupogen® and Neulasta®, which led to two separate litigations.  The Neupogen® case was commenced in October 2014, and the Neulasta® case was commenced in May 2016.  Sandoz launched its biosimilar version of Neupogen®, which is called Zarxio®, in March 2015.  Sandoz’s biosimilar has already been eating into Amgen’s profits for Neupogen®. 

Yet, Sandoz has yet to successfully receive FDA approval for its Neulasta® biosimilar. In the summer of 2016, the FDA issued a complete response letter rejecting Sandoz’s biosimilar.  In December 2017, however, Sandoz announced Phase I data indicating that it is making progress towards curing that rejection.

Mylan and Biocon have also partnered on a biosimilar for Neulasta®, and have filed an aBLA with the FDA.  But in October 2017, the FDA issued a complete response letter related to “facility requalification activities post recent plant modifications.”  Given that the rejection did not relate to biosimilarity or safety, Biocon has indicated that it expects its biosimilar to be approved shortly.

Apotex has also filed an aBLA for a Neulasta® biosimilar.  Apotex’s biosimilar application was accepted by the FDA for review in December 2014, but the application has yet to be approved.  Meanwhile, Apotex has prevailed at the Federal Circuit in its BPCIA case against Amgen, which means that it can presumably begin selling as soon as it receives approval. 

Each company’s struggle with obtaining FDA approval for a Neulasta® biosimilar is likely unique.  Yet, part of the issue may relate to the fact that Neulasta®’s protein, pegfilgrastim, is twice the molecular weight as Neupogen®’s filgrastim.  That has likely made it harder to study and characterize, and more difficult to show the requisite biosimilarity and safety.

What was the Court’s recent ruling in the Sandoz case?

In December 2017, the District Court in San Francisco granted Sandoz’s motion for summary judgment of non-infringement of U.S. Patent No. 8,940,878 (“the ‘878 patent”).  The ‘878 patent is the only patent currently remaining at issue in either Sandoz’s Neupogen® or Neulasta® case.

Manufacturing proteins such as filgrastim involves multiple steps.  Put simply, human DNA is introduced into a host cell, which then produces the human protein.  For the protein to be therapeutically useful, it must have a three-dimensional shape.  During production, however, the protein can develop without the proper shape.  To remedy this problem, the host cell and mal-formed proteins are put into solution (solubilization) and mixed with various chemicals.  These chemicals help the protein take the proper shape (known as “refolding.”)  Once the protein has refolded, the process must be reversed.  Specifically, the protein must be separated from the chemicals used for solubilization and refolding.  This is where the ‘878 patent comes into play.

The ‘878 patent is directed to a process that separates the “refolded” proteins from the chemicals used for solubilization and refolding.  The process is called “capture” purification.  The solution is run through a separation matrix, otherwise known as “washing.”  In the “washing” step, the separation matrix “captures” the protein while the unwanted chemicals flow through.  After that, the purified protein is “eluted” (i.e., released) from the separation matrix.

The ‘878 patent requires multiple steps.  Three are important to this analysis.  First, the refold solution is applied to the separation matrix.  Second, the separation matrix is washed.  Third, the purified protein is eluted from separation matrix.  Sandoz argued that it does not infringe the ‘878 patent because it does not perform these three steps.

The Court agreed.  The Court interpreted the ‘878 patent to require that the “washing” step and the “eluting” step must be different steps, the eluting step must occur sequentially after the washing step, and each step must use different solutions.  By contrast, under Sandoz’s process, there is only one step and one solution.  In effect, Sandoz “washes” and “elutes” at the same time using one solution.  (The precise solutions and chemicals used by Sandoz are not disclosed in the Court’s opinion because that is confidential information.)  Given that, the Court found that Sandoz cannot infringe the ‘878 patent, and granted Sandoz summary judgment of non-infringement.  The case is likely to be appealed by Amgen shortly.

Does the recent ruling read-through to other Neulasta® biosimilars?

The short answer is very possibly.  In Sandoz’s case, only one patent was eventually at issue (the ‘878 patent), and the Court found that Sandoz did not infringe it.  The patent is itself a manufacturing patent; it is directed to the process of forming the pegfilgrastim protein.  It only covers one portion of what is otherwise probably a very long process.  But if Sandoz’s infringed that one step in the process, that alone could have warranted an injunction that would keep Sandoz’s Neulasta® biosimilar off the market until expiration of the ‘878 patent, which is around 2009.

What does this mean?  It means that Sandoz effectively designed around one of Amgen’s key patents for protecting Neulasta® against biosimilars.  It thus offers a potential roadmap for other biosimilars, such as Mylan and Biocon, or other biosimilar applicants who have yet to file, for designing around the ‘878 patent.  To that extent, the Court’s recent decision in the Sandoz case does have read-through to other potential biosimilars.

That said, Amgen has other patents protecting Neulasta® and Neupogen®.  Indeed, the case against Apotex boiled down to a different patent, U.S. Patent No. 8,952,138.  That patent was also a manufacturing patent, and like Sandoz, Apotex avoided liability not by invalidating the  patent, but by designing around it.  (Separately, Apotex has an IPR on file for the ‘138 patent, which will likely be decided by the middle of February 2018.)  Nevertheless, the fact that Amgen has other patents in its arsenal, and is not exclusively reliant on the ‘878 patent, speaks to strength of its Neulasta® patent portfolio.

Taking a step back, this illustrates a larger issue with BPCIA litigation.  Unlike Hatch-Waxman litigation, biologics drugs are frequently covered by manufacturing patents.  These types of patents can be very powerful because, unlike patents covering the protein itself, their expiration dates are often farther in the future.  Further, to the extent characterization of a protein, versus a small molecule compound, depends on how it is made, that suggests it will be more difficult for biosimilars to design around them.  As an example, AbbVie’s Humira® is protected by upwards of 24 manufacturing patents with far out expiration dates. 

And yet, Amgen appears to be striking out on enforcing its manufacturing patents against Neulasta® biosimilars.  Rather, it is perhaps proving that innovators cannot assume that biosimilars will inevitably fall into copying the innovator’s manufacturing process.  Nonetheless, in the case of Neulasta®, the fact that gaining FDA approval for biosimilars has been so difficult has been Amgen’s saving grace, for now.