When did Mylan agree to launch its Herceptin biosimilar?

Zachary Silbersher

Roche and Genentech recently cleared up much uncertainty around biosimilars for Rituxan®.  Sandoz announced on November 2 that it will no longer pursue a biosimilar for rituxmab following the FDA’s request for additional information.  Meanwhile, on November 1, Genentech settled its biosimilar patent litigation against Celltrion and Teva over their proposed biosimilar for Rituxan®.  The terms of the settlement, and the launch date for Celltrion’s biosimilar, do not appear to be public.  Yet, that wraps up the two biosimilar patent cases that were currently pending for Rituxan®.

For Herceptin®, however, the patent cases against Celltrion, Pfizer ($PFE), Amgen ($AMGN) and Samsung have been put onto the same discovery track.  An upcoming Markman hearing in April 2019 is likely to be a significant milestone in the case.  None of those biosimilars have yet to receive FDA approval. 

By contrast, Mylan’s ($MYL) biosimilar for Herceptin® has FDA approval since December 2017.  Several months earlier, in March 2017, Mylan reached a global settlement with Roche and Genentech regarding their patents covering the drug. 

The terms of the settlement have not been made public, which raises the question – when did Mylan agree to launch?  One reason this question is important is because Mylan’s agreed-upon entry date is likely a floor, and Genentech probably cannot agree to give any other biosimilar an earlier date.

There has been speculation that Mylan will launch in 2019, but that year has not been confirmed by the company.  We suspect this year is based upon expiration of Herceptin®’s patent in 2019.  That patent is the ‘213 patent (U.S. Patent No. 6,407,213), which covers the Herceptin® antibody itself. 

The ‘213 patent is a key patent, and biosimilars will be hard-pressed to design around this patent given that it covers the antibody itself.  As shown below, however, Genentech has several other patents covering Herceptin® that can just as easily block biosimilar entry, which expire much later than 2019.  Thus, the ‘213 patent cannot by itself explain when Mylan agreed to enter. 

We were also previously skeptical of a 2019 launch given the likely timeline for any related patent litigation under the BPCIA.  If Mylan filed its aBLA for Herceptin® in 2017, then any corresponding patent litigation would not likely have started until late 2017 or early 2018.   

Indeed, that is approximately the same time period when the pending cases against the other Herceptin® biosimilars were commenced.  Those cases are each fairly large.  Genentech is asserting upwards of 20 patents in each case.  The cases are currently scheduled to go to trial in December 2019.  It will take another three to nine months after trial for the district court to issue its decision, sometime in 2020.  Then, there would be another year for an appeal before any launch can be deemed not to be at-risk. 

Thus, had the parties not reached a global license, then Mylan’s patent litigation with Genentech over Herceptin® would not theoretically have resolved until approximately 2021.  In that case, why would Genentech agree to permit Mylan an earlier launch in 2019?  AbbVie’s settlements with Humira® biosimilars in 2023 is near the end of the expected length of the BPCIA litigations.

On the other hand, many of the patents asserted by Genentech have already expired or will expire in 2019.  It may therefore not matter whether any pending patent litigation regarding those patents has yet to resolve. 

To get some deeper color on this issue, we examined the pending patents currently asserted against one of the Herceptin® biosimilars, namely Celltrion/Teva.  Genentech asserted many of the same patents against the biosimilars for Herceptin®, but there is not perfect overlap among the cases.  Nevertheless, a snapshot of patents asserted against one of the biosimilars is likely provide insight.

Genentech’s complaint against Celltrion initially asserted 40 patents against Celltrion.  Many of these patents were likely to be dismissed from the case since Celltrion did not disclose its manufacturing information prior to suit.  Sure enough, in mid-October, Genentech agreed to dismiss approximately 22 patents from the case.  This was not necessarily a surprise, and should not be construed as a sign of weakness of Genentech’s case.  The dismissed patents cover areas where, after discovery, Genentech likely determined those patents not infringed.  An example includes a family of patents related to combination therapy with Perjeta. 

Below is a list of patents still pending in Genentech’s case against Celltrion:

This chart requires some annotation.  First, the ‘213 patent—the patent covering the Herceptin® antibody—would have provided Genentech strong leverage against agreeing to an entry date before June 2019, when it expires.  Since this patent covers the active protein itself, it is likely a hard patent for a biosimilar to design around. 

Protein patents are also typically more difficult to invalidate, as compared to dosage, formulation or indication patents.  That has not stopped biosimilars from trying.  The ‘213 patent has faced eight individual IPRs.  Two of those IPRs are ripe for a Final Written Decision any day now.   

Importantly, in March 2017, only two IPRs against the ‘213 patent had been filed.  They were filed by Mylan.  They were denied institution on March 10, 2017, which is only three days before Mylan announced its global settlement with Genentech. 

Mylan clearly attempted to gain leverage over Genentech by trying instituting IPRs against Herceptin®’s protein patent.  Yet, when that tactic failed, Mylan appears to have quickly agreed to a settlement.  It is therefore highly unlikely that Genentech agreed to an entry date before expiration of the ‘213 patent, namely, June 2019.  Rather, Mylan’s entry is most likely after June 2019. 

Next, two of the combination chemo (‘441 and ‘549) patents expire in May 2020, but they were recently invalidated in IPRs (IPR2017-01121 and IPR2017-00737, respectively.)  Thus, unless Genentech can reverse those decisions on appeal—which is statistically unlikely—that will likely remove these patents, and their juicy 2020 expiration date, from obstacles to biosimilar competition.  The third combination chemo patent (‘908) has already expired. 

Together, these IPR losses were a minor setback for Genentech because it would have likely been difficult for the biosimilars to show these patents are not infringed.  That is likely the reason they were the target for multiple IPRs (roughly four each.)

That said, Mylan would not have had certainty in March 2017 that the two combination chemo patents expiring in May 2020 would have been invalidated.  While some of the IPRs were filed by March 2017, none were instituted by that time.  Thus, when Mylan and Genentech reached their settlement, in addition to the ‘213 patent, Genentech technically had at least two patents on the table expiring May 2020.  And these were patents Mylan would have likely had difficulty designing around.  That likely pushed the agreed entry date farther into the future from June 2019.

The method of administration patents (‘196 and ‘379) recently each survived three separate IPRs each.  While the biosimilars are sure to appeal those rulings, this was a big win for Genentech.  These patents are generally dosage patents that the biosimilars are likely going to have to copy off Herceptin®’s label.  Thus, by shoring up their validity, and having little recourse to showing non-infringement, this is one way that Genentech has likely prohibited any biosimilars before these method of administration patents expire in August 2019.

Again, Mylan would not have known in March 2017 whether or not the method of administration patents would have survived invalidity challenges.  But because they expire in August 2019, Genentech could not theoretically have leveraged them in negotiations with Mylan for a later entry date.

Many of the manufacturing patents have much farther out expiration dates.  These patents are generally directed to cell culture, purification or antibody manufacturing.  Because they do not expire for many years, they are likely to form the focus of the patent cases against the biosimilars.  That is because, unlike the combination chemo or method of administration patents, the biosimilars likely have much more ground to argue they do not infringe manufacturing patents. 

Biosimilars are essentially constrained to copy patents covering an innovator’s dosage, strength or route of administration.  But manufacturing an antibody is very different, and it is likely that biosimilars—such as Mylan—had previously studied these patents and attempted to design around them in the course of developing their biosimilar.  This is why the Markman hearing in April 2019 will be so important—to flesh out these arguments.  This also partially explains why only three of the four foregoing manufacturing patents faced any IPR challenges.  The ‘799 patent faced on IPR challenge, which was successful, thereby invalidating that patent. 

Thus, while the manufacturing patents expire much later, these patents likely provided Genentech less leverage in negotiations with Mylan.  Mylan was likely more confident in its non-infringement of these patents than Genentech.  Indeed, during the negotiation, Mylan knew its manufacturing process, whereas Genentech did not.  That said, Mylan could not discount them completely.

In conclusion, after Mylan lost its IPRs against the Herceptin® antibody ‘213 patent, it is unlikely that Genentech agreed to give Mylan an entry date before that patent’s expiration in June 2019.  Meanwhile, Genentech had additional strong combination chemo patents on the table expiring in May 2020.  While they have now been invalidated, neither Mylan nor Genentech would have had certainty at the time that that would happen.  Meanwhile, Genentech had several other manufacturing and diagnostic patents expiring in 2020 and as late as 2027, although these likely provided Genentech less leverage.

 On the one hand, it is hard to believe that Genentech wrote off the strength of all of its other patents, and simply agreed to let Mylan enter in June 2019 (expiration of the ‘213 patent.)  On the other hand, the first settler always gets a discount. 

That said, given this overall field, an agreement between Mylan and Genentech for late 2019 appears to be the earliest likely date for entry, and a 2020 entry date appears to be more realistic.  And an agreement for a 2021 entry date does not seem impossible. 

(A brief note on the ‘219 patent, which is terminally disclaimed over U.S. Patent No. 6,339,142.  The face of the ‘142 patent indicates that it expires in May 2018.  Yet, Genentech’s 2008 10-k indicated that the patent will expire in 2019, and therefore, we have gone with that date.)