What is the Dupixent® patent fight among Amgen, Regeneron and Sanofi all about?

Zachary Silbersher

Dupixent® is a recently-released drug forecasted to reach $4B in annual sales.  The drug is a co-venture between Regeneron and Sanofi, which also teamed up to launch Praluent®, one of the two available drugs within the new class of PCSK9-inhibitors.  In the case of Praluent®, Amgen brought Regeneron to court arguing that Praluent® infringed Amgen’s patents and thus the drug should be taken off the market.  Once again, Amgen, Regeneron and Sanofi are back in court.  Amgen has squared off against Regeneron and Sanofi and argued that Dupixent® infringes one of Amgen’s patents.

Dupixent® (dupilumab) is a biologic drug indicated for treating atopic dermatitis.  Dupilumab is a human monoclonal antibody that inhibits overactive signaling of two key proteins, IL-4 and IL-13, which drive inflammation in atopic dermatitis and other potential conditions.  Regeneron and Sanofi have achieved additional favorable clinical trial results for asthma, and intend to seek an additional indication for the drug.  Analysts predict that asthma could propel Dupixten® to $4B in sales.

Meanwhile, Amgen has been trying to slow down Dupixent®’s rise with allegations of patent infringement.  Amgen, on one side, and Regeneron and Sanofi, on the other, have already squared off on multiple fronts over whether part of Dupixent®’s revenues will have to be diverted to Amgen.   Regeneron and Sanofi pre-emptively sued Amgen for a declaratory judgment that Dupixent® does not infringe Amgen’s patent, U.S. Patent No. 8,679,487.   A few days later, on March 23, 2017, Regeneron and Sanofi filed an IPR against the ‘487 Patent.  About a week later, on March 28, 2017, Regeneron and Sanofi received FDA approval to market Dupixent®.  A few days after that, on April 5 2017, Amgen sued Regeneron for infringement of its ‘487 patent.  The first IPR was denied institution, but Regeneron and Sanofi followed up two more IPRs of the ‘487 Patent in late July 2017.  The institution decisions for those IPRs are due by mid-February 2018.  Meanwhile, Regeneron and Sanofi pulled their declaratory judgment action.  Thus, principal litigation is now the one commenced by Amgen in California.

These pitched battles reveal that both sides have a story to tell.  First, Amgen.  Amgen argues that Regneron/Sanofi have ripped off their potential blockbuster protein dupilumab from Amgen’s ‘487 Patent.  Importantly, Amgen argues that Regeneron and Sanofi were previously aware of the ‘487 Patent, and are now infringing it willfully.  What is Amgen’s proof? 

The ‘487 Patent issued in March 2014.  The patent discloses human antibodies that bind to the IL-4 receptor (IL-4R), thereby inhibiting the activity of IL-4 and IL-13.  Interleukin-4 (“IL-4”) and interleukin-13 (“IL-13”) are both signaling molecules in the immune system that purportedly cause certain inflammatory conditions.  The ‘487 Patent discloses six monoclonal antibodies (“mAbs”) that bind to IL-4R, including mAbs 12B5, 6-2, 27A1, 5A1, 63 and 1B7. 

Amgen argues that Regneron’s own patents show that it relied upon Amgen’s mAb 12B5 antibody in the course of developing dupilumab.  (Those Regeneron patents include U.S. Patent 7,605,239 and 8,337,839.)  Examples from those patents disclose assays of binding affinity of certain antibodies to IL-4.  Those examples teach that a control antibody was used with the same heavy chain and light chain variable region sequences as Amgen’s mAb 12B5.  In short, Amgen argues that Regeneron’s own patents show that it relied upon Amgen’s 12B5 antibody as a control protein in the course of developing its own dupilumab protein.  That, according to Amgen, confirms that Regeneron and Sanofi were well-aware of Amgen’s ‘487 Patent, and any infringement is therefore willful.

Amgen’s allegation of willful infringement is very important in this case.  Unlike Amgen’s PCSK9 lawsuit against Regeneron and Sanofi, Amgen is not seeking an injunction against Dupixent®.  The reason is because Amgen does not currently sell a competing product to Dupixent®, even though recent data suggests it may have a competitor in its pipeline.  Instead, Amgen is essentially seeking a royalty for infringement of its ‘487 Patent. 

If Amgen can show willful infringement, that will enhance and potentially triple the royalty rate.  Predicting a royalty rate for infringement of the ‘487 Patent at this stage is very difficult.  But Amgen’s patent technically covers the protein itself, rather than a formulation, indication or dosage for that protein.  Thus, if infringement actually exists, then during the hypothetical negotiation both Regeneron and Sanofi would have presumably needed a license to the ‘487 Patent, with little chance of designing around it.  Thus, the royalty rate will likely be high, and any rate enhanced by willfulness will be even higher.  Under these circumstances, it is not unlikely that if Amgen prevails in this suit, it could be entitled to a rate above 20%.  On a potentially four billion dollar drug, that’s not immaterial.

Amgen may have more in mind than just a royalty.  Its PCSK9 case against Regeneron and Sanofi remains pending.  Amgen’s chances of securing an injunction against Praluent® is currently unlikely.  Yet, Amgen filed its Dupixent® case before the Federal Circuit’s October decision that reversed the PCSK9 jury verdict and vacated the injunction.  In short, Amgen’s Dupixent® case may, itself, simply be a play for increased leverage in any settlement discussions between the parties.  For instance, Amgen may have sought to drop an injunction against Regeneron’s Praluent® in exchange for a tax on Dupixent®.  It is therefore not wholly impossible that a global settlement among Amgen, Regeneron and Sanofi is reached, touching both Praluent® and Dupixent®.

So, what is the story that Regeneron and Sanofi are telling?  The ‘487 Patent is part of a family of patents that claim priority back to May 2001.  (The actual priority date for the ‘487 Patent may end up being a material dispute between the parties in this case, but will be discussed in a future post.)  As mentioned above, the specification for the ‘487 Patent technically discloses six unique antibodies that bind to IL-4R.  The parent patents to the ‘487 Patents claimed some of these exact antibodies.  Yet, the ‘487 Patent is different.  It did not claim one of the six unique antibodies that Amgen purportedly discovered and disclosed in the patent family leading up to the ‘487 Patent.  Rather, it recites much broader, functional claims that cover a genus of antibodies that bind to IL-4R, and cover scores of antibodies other than the six Amgen actually disclosed in its patents. 

Regeneron and Sanofi argue that Amgen pursued broad, functional claims in the ‘487 Patent only after Regeneron and Sanofi published their discoveries in this field.  Specifically, in July 2008, a patent application filed by Regeneron published.  That application described an antibody that binds to IL-4R and competes with Amgen’s mAb 12B5.  Shortly after that publication, in November 2008, Amgen filed another patent application (the ‘702 Application) within the ‘487 Patent family.  (At this point, the ‘487 Patent itself had not yet been applied for.)  That patent application diverged from its earlier applications.  Rather than claiming one of the precise antibodies disclosed in the patents, it more broadly and functionally claimed an antibody that binds to IL-4R and competes with Amgen’s mAb 125.  Amgen eventually abandoned the ‘702 Application, but followed it up with a similar application that eventually issued as the ‘487 Patent.  The ‘487 Patent claims a broad genus of antibodies that bind to IL-4R and competes with antibodies such as Amgen’s mAb 125. 

In short, Regeneron and Sanofi argue that Amgen sought patent protection for a very broad, functional patent that would cover their protein only after Amgen realized that Regeneron and Sanofi had discovered their own antibody in the same field.  Because the claims for the ‘487 Patent are so braod, Regeneron and Sanofi argue that they can be invalidated by some of Amgen’s own earlier patents.

Very interestingly, Amgen’s patent prosecution tactics potentially implicate the same legal issue that resulted in a huge setback in its PCSK9 case against Regeneron.  As we discussed here and here, the Federal Circuit’s recent decision in that case has made it much harder for broad, functionally-claimed antibody patents to survive invalidity challenges.  Amgen’s failure at the Federal Circuit in its PCSK9 case may thus end up dooming its case against Regeneron and Sanofi over Dupixent®.  Indeed, Amgen has petitioned for en banc review of that decision, so the stakes for that en banc review may include much more than just PCSK9 drugs.