Will Pharmacyclics’ Imbruvica patent lawsuit knock BeiGene’s Brukinsa off the market?
Zachary Silbersher
AbbVie’s Pharmacyclics recently sued BeiGene for patent infringement. Both companies distribute Bruton’s tyrosine kinase (BTK) inhibitors for treatment of, among other indications, chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Pharmacyclics sells Imbruvica® and BeiGene sells Brukinsa®. Will Pharmacyclics prevail, and if so, what will it gain?
Pharmacyclics’ suit alleges only a single patent, U.S. Patent No. 11,627,803. The patent is a method-of-use patent that is generally directed to treating CLL and SLL by administering an “effective amount” of a BTK-inhibitor. In particular, the patent requires that “lymphocytosis is not considered progression of the CLL or SLL.”
Does BeiGene infringe the ‘803 patent?
At the outset, on the face of its complaint, Pharmacyclics appears to have alleged a passable claim for infringement. The active ingredient in BeiGene’s Brukinsa® is zanubrutinib, and Brukinsa®’s label indicates that zanubrutinib is a BTK-inhibitor (Sec. 12.1). The label also states the drug is indicated for CLL or SLL.
Pharmacyclics’ patent also requires that “lymphocytosis is not considered progression of the CLL or SLL.” The patent discloses that its inventors had the alleged “unexpected discovery” that BTK inhibitors induce lymphocytosis. The purportedly novel aspect of the invention is that observed lymphocytosis during treatment with ibrutinib should not be viewed as an indication of disease progression.
During prosecution of the patent, Pharmacyclics explained the purported invention in greater detail. It alleged that, before its discovery, “the conventional wisdom for diagnosing and treating CLL and SLL was that a rise in lymphocyte counts, known as lymphocytosis, was a sign of disease progression.” Therefore, according to Pharmacyclics, doctors previously believed that it was therapeutically preferable to “stop dosing of ibrutinib upon observing continued or increased levels of lymphocytes based on the guidelines for treating lymphoma.” Yet, the patent discloses the results of a Phase IB/II trial purportedly showing that patients treated with ibrutinib experienced an initial rise in lymphocyte counts, but then returned to pretreatment levels while other indicia of therapeutic efficacy were observed. (See U.S. Patent Application No. 16/926,208, Amendment, Aug, 23, 2022 at 9).
Accordingly, to prove infringement, Pharmacyclics must show that BeiGene instructs doctors that lymphocytosis should not be viewed as a sign of disease progression for CLL or SLL during treatment with Brukinsa®. In its complaint, Pharmacyclics cites to a statement within Brukinsa®’s label (at 4): “Asymptomatic lymphocytosis should not be regarded as an adverse reaction, and these patients should continue taking BRUKINSA.”
On its face, this establishes a likely basis for infringement. There are a few ways that BeiGene may to try to show non-infringement. For instance, the patent does not cover ibrutinib itself, but rather a broader scope of potential BTK-inhibitors. If BeiGene can show that zanubrutinib falls outside of the scope of molecules covered by the patent, that will be a full defense to the lawsuit. BeiGene may also try to argue that doctors would understand that the scope of lymphocytosis, as recited in the patent, is more limited than the “asymptomatic lymphocytosis” recited in BeiGene’s patents. Yet, overall, Pharmacyclics appears to be on generally good footing that Brukinsa® infringes Pharmacyclics’ patent.
(As an aside, the reason why the wording of Brukinsa®’s label is so important to the question of whether BeiGene infringes Pharmacyclics’ patent is because the patent is a method-of-use patent. In particular, it is directed to a method of administering a drug to treat a disease. BeiGene is a drug company, and it technically does not treat patients. Rather, doctors treat patients. Accordingly, BeiGene does not directly infringe the patent. Instead, Pharmacyclics must rely upon a theory of indirect infringement. To show BeiGene indirectly infringes the patent, Pharmacyclics must show that BeiGene essentially instructs doctors to perform the method recited in the patent. It is generally understood that a drug’s label embodies a drug company’s instructions to doctors.)
Is Pharmacyclics’ patent invalid?
Yet, even if BeiGene infringes the ‘803 patent, that does not mean Pharmacyclics is likely to prevail in this lawsuit. Rather, BeiGene’s principal defense is likely to be showing that the patent is invalid. During prosecution of the patent, the Examiner stated that the reason the patent was granted was because the prior art allegedly did not teach that lymphocytosis should not be considered a sign of disease progression. BeiGene, however, is likely to uncover prior art that may teach just that.
For instance, a scientific article published in 2012 from Blood, which is journal published by The American Society of Hematology, states, “[c]linical responses to SYK, BTK, and PI3K inhibitors in CLL are characterized by a . . . transient lymphocytosis [that] typically takes several months to resolve. In the face of improvement in other clinical parameters and a decrease of tumor burden in lymphoid organs, the rising ALC does not indicate disease progression, and there is currently no evidence that it is associated with morbidity. Thus, patients can and should be maintained on the drug.”
Although this article essentially teaches the invention of the ‘803 patent, the article’s publication date (2012) is after the priority date for Pharmacyclics’ patent (2010). Based on a series of provisional applications, the earliest effective priority date for the ‘803 patent is likely June 4, 2010.
Yet, the quote from above cites to another article, also from the journal Blood, which was published online on June 3, 2009. This article was published more than one year (June 3, 2009) before the priority date for Pharmacyclics’ patent (June 4, 2010), and therefore, it is likely to be prior art against that patent.
In addition, this article teaches that administration of R406 for CLL observed an “early, transient increase in peripheral lymphocyte counts . . . before induction of remission in a significant proportion of CLL patients with relapsed disease.” The article also includes data that “provide[s] an explanation for this remarkable clinical activity.” R406 is not a BTK-inhibitor, but it is a small-molecule SYK-inhibitor. But the 2012 Blood article discusses the transient lymphocytosis within the context of SYK, BTK and P13 inhibitors in CLL.
Together, these articles suggest that, before the priority date of Pharmacyclics’ patent, scientists may have already understood that patients taking inhibitors for treating CLL may experience a transient lymphocytosis that should not be considered an indication of disease progression. Indeed, the 2009 article provides an explanation for the phenomenon of transient lymphocytosis, which may provide a basis for why that phenomenon was not “unexpected” for BTK-inhibitors, and not just SYK-inhibitors. And if that is the case, the primary inventive feature of the ‘803 patent asserted by Pharmacyclics against BeiGene may be obvious, and therefore, invalid. And if it’s invalid, then Pharmacyclics will lose the lawsuit.
What relief is Pharmacyclics seeking?
If BeiGene can successfully invalidate the patent, then Pharmacyclics will not be entitled to any relief—either money damages or an injunction—even if BeiGene is otherwise found to infringe the patent. Yet, if Pharmacyclics does prevail in the lawsuit, it is likely to seek both monetary damages and an injunction.
With respect to monetary damages, Pharmacyclics is likely to seek both a royalty rate and lost profits. Lost profits are likely to be larger prize in this fight. Lost profits are only typically available where the plaintiff (patentholder) is also selling a product covered by the patent. Here, Brukinsa® is not a generic to Imbruvica®, but it is a competing product. Thus, Pharmacyclics will likely argue that all sales of Brukinsa® prescribed for CLL or SLL were otherwise sales that Pharmacyclics would have earned but for BeiGene’s infringement.
Even in the absence of lost profits, Pharmacyclics can still likely recover a reasonable royalty on past and future sales of Brukinsa®. That royalty would likely only be applied against prescriptions for CLL or SLL, rather than the drug’s other indications. Yet, it is not clear at this time how sizeable the royalty rate would be. In the most extreme case, if the patent covered the zanubrutinib molecule itself, that would likely command the highest royalty. Here, however, the patent essentially covers a consideration for doctors during treatment. That is not likely to command the highest royalty.
The biggest threat to BeiGene is that Pharmacyclics obtains an injunction that requires BeiGene to remove Brukinsa® from the market. Yet, that scenario is unlikely, even if everything breaks in favor of Pharmacyclics, and it prevails in the case. The ‘803 patent is directed to treating only CLL and SLL. However, Brukinsa® is indicated for other indications, including Mantle cell lymphoma and Waldenström’s macroglobulinemia, among others. A court would therefore likely, at most, order BeiGene to remove the indications for CLL and SLL. That may or may not be a good thing for BeiGene depending on whether CLL and SLL comprise a large or small proportion of prescriptions for Brukinsa® relative to its other indications.
What do patients have to gain from this lawsuit?
Yet, even if there is little risk that Brukinsa® will be removed from the market, the result for patients could still be a dire one. The prior art cited above shows that the purported invention of Pharmacyclics’ patent, even if not invalid by clear-and-convincing evidence, was not likely a groundbreaking, revolutionary invention. Rather, that prior art taught that scientists most likely already understood that certain mechanisms-of-action indicated that transient lymphocytosis was likely to be expected for inhibitor treatment for CLL.
Patients deserve as diverse a menu of available treatments as possible given that some patients may either be immune or allergic to one drug over the other. As a result, forcing BeiGene to remove certain indications for a drug based on a patent that is hardly revolutionary means that some patients may be left with less-than-preferable care despite the actual availability of better care. Even for people who believe that patents should reward R&D, many would not likely sanction the use of patents to deprive patients from life-saving care that actually exists.
In fact, the same may be true if Pharmacyclics’ claim for lost profit damages are too high. In other words, if Pharmacylics demands too high a price for infringement of this patent, then that may compromise BeiGene’s business case for Brukinsa®. If it jeopardizes it too much, that may limit the availability of the drug for patients. Pharmacyclics gets to make a lot more money, but patients lose out. And all for what? For a patent that the prior art suggests may have been fairly obvious in the first instance?
Fierce Pharma previously reported that, after Pharmacyclics enforced patents covering Imbruvica® against prospective generics, United States Senator John Cornyn remarked: “I support drug companies recovering a profit based on their research and development of innovative drugs . . . But at some point that patent has to end, that exclusivity has to end, to be able to get it at a much cheaper cost.” The same holds true for competing non-generic options.