Can Exelixis’ Cabometyx patent suit overcome MSN’s polymorph defense?

Zachary Silbersher

We previously blogged about Exelixis ($EXEL) shortly before it commenced its Hatch-Waxman suit against MSN Pharmaceuticals in connection with its prospective generic for Cabometyx®.  What has happened in the suit since then?

Exelixis has numerous patents covering Cabometyx® that are listed in the Orange Book.  Yet, when MSN originally filed its Paragraph IV certification, it indicated that it would not seek to distribute its generic formulation of Caboymetyx® before expiration of two of those patents, namely, U.S. Patent Nos. 7,579,473 and 8,497,284.  Those two patents are composition-of-matter patents that expire in 2026 and 2024, respectively.  Thus, at the time, it appeared that Cabometyx was safe from generic competition until at least 2026.

In late 2018, Exelixis commenced suit against MSN, but only for a single patent, namely, U.S. Patent No. 8,877,776.  The ‘776 patent covers the crystalline Form N-2 polymorph of cabozantinib (s)-malate, which is the active ingredient in Cabometyx®.  MSN’s principal defense to the allegation that its prospective generic will infringe this patent is that it has developed a non-infringing polymorph of cabozantinib (s)-malate called “Form S.”  

If MSN’s prospective generic does, in fact, use a polymorph of the active ingredient in Cabometyx®, and not the actual compound claimed in the ‘776 patent, that would appear to offer MSN a strong defense in this case.  Yet, litigating patent infringement in the context of polymorphs can be tricky business.  There is some, but not a tremendous amount of precedent to handicap this litigation.  One notable recent example involved Celgene’s Hatch-Waxman suit over Dr. Reddy’s prospective generic for Revlimid®, which also involved polymorph variations to claimed compositions.  There has also been recent guidance from the Federal Circuit over invalidating patents covering polymorphs.

One of the issues that will likely arise in this case is whether MSN’s polymorph changes at all during the drug’s lifetime.  Even if MSN’s drug, when sold, includes a polymorph that is not infringing, there remains the possibility that that the active ingredient converts—either during manufacturing or storage—into an infringing compound.  A discovery dispute between Exelixis and MSN during the case indicates that Exelixis is pursuing this theory of infringement.  (See Exelixis, Inc. v. MSN Laboratories Private Ltd., 1:19-cv-02017 (D. Del.) (Dkt. 57 Sep. 21, 2020) at 4.)  The Federal Circuit previously suggested that a drug that is not infringing when sold, but converts into a patented polymorph in the patient’s stomach, may be infringing.  See Zenith Laboratories, Inc. v. Bristol-Myers Squibb Co., 19 F.3d 1418 (Fed. Cir. 1994).  

Exelixis originally filed suit only on the ‘776 patent, and did not assert the ‘473 and ‘284 patents against MSN.  In May 2020, however, MSN appears to have amended its ANDA to file a Paragraph IV certification for the ‘473 and ‘284 patents.  That triggered a second lawsuit by Exelixis, which was filed in May 2020.  In that second suit, Exelixis asserted the ‘473 and ‘284 patents.  That new lawsuit has been consolidated with the original suit.  The ‘473 patent is a compound patent for the active ingredient in Cabometyx®, and the ‘248 patent covers using that compound for specific indications.  

Exactly why MSN originally refrained from filing a Paragraph IV letter for the ‘473 and ‘284 patents, but then changed its mind, is not entirely clear from the public docket.  Exelixis’ complaint suggests that MSN’s Paragraph IV notice letter did not contest infringement of these patents.  That would suggest that MSN may have uncovered an invalidity theory for the patents, and thus, no longer wished to wait for their expiration before launching its generic.  That said, MSN’s answer to the complaint contests infringement, and thus, it cannot be said that MSN has given up the right to prove these new patents are not infringed (as well as trying to show they are also, or independently, invalid.)  A better explanation may relate to MSN’s substitution of counsel.  In April 2020, MSN replaced its existing litigation counsel with new counsel, and MSN filed its Paragraph IV certification against the ‘473 and ‘284 patents shortly after that.  

The case is currently mired in fact discovery, and there has not yet been any substantive briefing.  Further, the claim construction briefing, which was originally scheduled to occur in early 2021, has been cancelled.  That briefing would have provided more of a window into each of the party’s respective arguments in this case.  It was cancelled, however, because the parties did not identify any claim terms in dispute.

Currently, the parties are not contemplating trial in this case before May 2022.  The parties are likely to file substantive briefing in the case before that to provide greater opportunities to weigh the strengths and weaknesses of each side’s arguments.