How long can Pfizer keep out generics for its tafamidis Vyndamax and Vyndaqel drugs?

Zachary Silbersher

Pfizer is currently attempting to fend off generics for Vyndamax and Vyndaqel.  Both drugs indicated for treatment of cardiomyopathy caused by transthyretin amyloidosis.  Both contain the same active ingredient, tafamidis, but one is a salt form.  Vyndamax contains the free acid form of tafamidis, whereas Vyndaqel contains the meglumine salt of tafamidis. Pfizer has patents for both drugs, expiring as early as 2025 and as late as 2035. How long can Pfizer keep out generics?

Pfizer has sued five prospective generics in Delaware, and the cases have been consolidated.  The generics and the patents asserted against them are listed below:

For both the ‘695 and ’696 patents, the patents’ owner has sought to extend the expiration date of each patent by up to five years, i.e., until December 19, 2028.  The extension request is for Patent Term Extension (PTE), which is available for delay due a drug’s regulatory review at the FDA.   

The Patent Office, which makes PTE determinations, has granted two interim extensions of one year each.  Accordingly, these two patents currently expire on December 19, 2025.  The FDA has concluded that the testing period and approval period for both drugs was almost 5,000 days.  PTE is typically calculated by adding half the testing period plus the approval period, but it cannot exceed five years.  Given the FDA’s finding, if PTE is awarded for the ’695 or ‘696 patents, it is likely to add another five years to that particular patent. 

At the same time, the Patent Office has also indicated that the ‘695 and ‘696 patents are not both eligible for PTE—rather, only a single patent can receive PTE.  (This appears to be an about-face by the Patent Office, which historically granted PTEs on more than one patent for the same drug product.)  That said, even if Pfizer receives PTE for only one of the two patents, it is unlikely to have a substantial impact on generic entry.  Pfizer is likely to apply PTE to the ‘695 patent, which is a compound patent.  That patent alone could theoretically exclude generics until it expires.  If Pfizer is awarded the full five years of PTE for this patent, it would therefore not expire until roughly 2029 (i.e., December 19, 2028).

The ’441 patent is scheduled to expire in 2035.  (There is no pending PTE request for this patent.)  This patent therefore holds the greatest potential for excluding generics for Vyndamax for another 10 years.  On the other hand, the patent is not listed in the Orange Book for Vyndaqel.  For the reasons discussed below, this wrinkle may mean that generics will nevertheless eat into Pfizer’s monopoly for both drugs, Vyndamax and Vyndaqel.

The ‘695 patent is directed to the tafamidis compound.  As a compound patent covering the active ingredient in Vyndamax, the ‘695 patent is presumably strong from both an infringement and validity perspective.  In other words, the generics are likely to face difficulty proving the patent is either not infringed or invalid.  Indeed, it appears that only two of the generics are challenging it, Dexcel and Aurobondino, which likely suggests the other two filed Paragraph III certifications against this patent (i.e., agreeing to wait until the patent expires before entering the market.) 

The ’696 patent is directed to “a method of treating transthyretin amyloidosis” with tafamidis.  The label for Vyndamax and Vyndaqel states that, “VYNDAQEL and VYNDAMAX are transthyretin stabilizers indicated for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.”  Accordingly, because the ‘696 patent appears to cover the indication identified in the label for Vyndamax and Vyndaqel, the generics are likely to infringe the ‘696 patent.  Although the validity of method-of-use patents is generally less certain than compound patents, the generics may nonetheless face difficulty invalidating the ‘696 patent given that the patent was filed contemporaneously with the compound ‘695 patent. 

The ‘441 patent is a polymorph patent.  The patent claims a specific polymorphic crystalline form of tafamidis.  To prove infringement requires showing that the particular small-molecule intended to be sold by a prospective generic would not only match the claimed chemical formula (i.e., 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole), but would also satisfy three precise measurements taken by solid-state NMR, powder X-ray diffraction and Raman spectroscopy. 

Polymorph patents historically pose unique infringement challenges that do not typically arise when proving infringement of a regular composition-of-matter patent.  For instance, although the molecule within a generic drug may not read upon a polymorph patent when it is sold, the molecule may change over the lifetime of the drug’s manufacturing or shelf-life, and therefore infringe at a later time.  The Federal Circuit, which the authoritative appellate court for patent cases, 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).  Polymorph patents may also be invalidated where the prior art demonstrates that the claimed polymorph could be synthesized through routine experimentation.  Proving that can be a very fact-intensive exercise.

In a recent case involving the drug Caboymetyx®, the brand distributor, Exelixis, asserted a polymorph patent against MSN.  At trial, MSN claimed to have designed around Exelixis’ polymorph patent.  Exelixis conceded that MSN’s molecule did not satisfy the precise measurement conditions required by its polymorph patent.  Yet, Exelixis alternatively argued that MSN’s molecule would convert into an infringing polymorph during its lifecycle.  To prove this, Exelixis subjected the molecule to “accelerated conditions” that when tested, allegedly proved infringement.  The court, however, rejected Exelixis’s purported “accelerated conditions” as not representative of the drug’s manufacturing or storage conditions.  As a result, Exelixis could not prove infringement of its polymorph patent.  See Exelixis, Inc. v. MSN Laboratories Private Ltd., Case No. 19-2017 (D. Del.) (ECF No. 327) (Jan. 19, 2023).

Given the unique difficulties involving polymorph patents, it is far from guaranteed that Pfizer will be able to use the ‘441 patent to exclude generic competition until 2035.  On the other hand, Pfizer is likely to argue that the year 2029 is a floor to any negotiated entry date for the generics.  For Cipla and Zenera, they appear to have filed Paragraph III certifications against the ‘695 and ‘696 patents, which expire in 2029 if full PTE is granted.  And for the reasons discussed above, for Dexcel, Pfizer is unlikely to agree to anything earlier than 2029 before Dexcel achieves some success beating the ‘695 or ‘696 patents. 

For Aurobondino, however, the dynamics are different. Given that Aurobondino is pursuing a different drug, Vyndaqel, and that drug is not protected by the ‘441 patent, then an entry date by 2029, at the latest, is very likely.  That creates a unique scenario where Aurobondino could be the first generic to enter.  That entry would technically be for Vyndaqel only, rather than also for Vyndamax.  Yet, if doctors prescribe these two drugs interchangeably, or potentially could prescribe them interchangeably, then Aurobondino’s entry could technically eat into Pfizer’s market share for both drugs.  Then, even if Pfizer succeeds in enforcing the ‘441 patent—which will not expire until 2035—Aurobondino’s entry may nonetheless moot Pfizer’s ability to preserve its monopoly over Vyndaqel as well as Vyndamax.