What can the Patent Office do to prune Keytruda’s patent thicket?
Zachary Silbersher
Merck’s blockbuster Keytruda® earned over $20 billion in 2022. The drug has now joined the ranks of Humira® as one of the biggest revenue drugs of all time. Like Humira®, Keytruda® is a biologic, and also like Humira®, its bumper profits are slated to face biosimilar competition in a few short years. FDA exclusivity covering many of Keytruda®’s indications will expire between 2024 and 2026. As of late 2022, approximately five potential Keytruda® biosimilarswere in development. And also like Humira®, Merck appears to have a plan to delay entry of lower-cost biosimilars for its blockbuster by another ten years. And like Humira®, that plan has been seeded with a thicket of patents.
Congress has taken notice. In February 2023, United States Senators Elizabeth Warren and Bernard Sanders and Members of Congress Katie Porter and Pramila Jayapal penned a letter to Kathi Vidal, Director of the USPTO, asking her to use the powers of the Patent Office to blunt Merck’s use of patents to stall entry of lower-cost alternatives. The letter highlights statistics showing how dense Keytruda®’s patent thicket has grown. As of 2021, Merck had purportedly already gathered 53 patents covering Keytruda® along with another 129 pending patent applications. Half of those patents were filed after Keytruda® received FDA approval—thereby underscoring that half Merck’s patents for Keytruda® most likely do not represent critical R&D that was needed to develop the drug in the first instance. Indeed, only a quarter of the patents and applications cover the key antibody itself.
Senator Warren’s letter emphasizes that Merck’s patent thicket could extend Keytruda®’s monopoly pricing for another 10 years after its FDA exclusivity expires. The letter also highlights that Merck is developing a new subcutaneous formulation for Keytruda® that could yield another crop of patents that could extend the drug’s protection from lower-cost biosimilars for years beyond 2036.
The letter is itself a call to action. It claims that the USPTO’s response to Merck’s request for more patents is an opportunity to advance the current administration’s goal of “facilitating access to affordable drugs.” To that end, Senator Warren asks Director Vidal to answer specific questions that seek to better understand how the USPTO can stop, thwart, shrink or block Merck from improperly growing a thicket of patents around Keytruda® that all but guarantees consumers will not have access to lower-cost alternatives for the foreseeable future.
Director Vida has either yet to response to Senator Warren’s February letter, or the Director’s response is not yet public. Yet, what are some likely answers to Senator Warren’s questions?
First, Senator Warren asks for the number of patents covering Merck’s Keytruda®, including the number that have been approved or denied. This question is unlikely to yield a helpful or satisfactory answer. The reason is that the USPTO probably does not know the answer.
For one thing, it is not always obvious that a patent covers a particular drug. In some cases, it may be obvious, such as for patents that claim the antibody pembrolizumab, which is sold with Keytruda®. Yet, three-quarters of Keytruda®’s patents are directed to other things, including formulations and manufacturing processes. The patents covering the manufacturing processes may be agnostic to any particular drug. They may relate to specific aspects of a manufacturing process applicable to pembrolizumab as well as other antibodies. Merck may also hold patents on combinations of pembrolizumab and other drugs that do not necessarily cover Keytruda®.
Another thing, the Patent Office may not have a list of patents that may or may not cover a particular drug, such as Keytruda®. The business of counting patents is not straightforward. In fact, Senator Warren’s letter relies heavily upon statistics from a patent report on Keytruda® by The Initiative for Medicines, Access and Knowledge, otherwise known as I-MAK. I-MAK has itself faced its scrutiny over its methodology for how it counts patents protecting a particular drug.
In short, the USPTO may not have any mechanism for identifying and cataloging how many patents cover a particular drug. The FDA may not know either. Importantly, Keytruda® is a biologic drug. Unlike the Orange Book, which requires manufacturers of small-molecule drugs to submit lists of patents well in advance of any filed ANDAs, the Purple Book only requires manufacturers of biologics to list patents once biosimilars have been filed.
Senator Warren also asks how many Keytruda® patents are pending, and when the USPTO is expected to decide whether to grant those patents or not. Again, there is unlikely a satisfactory answer to this question. If you ask the Patent Office when a particular patent is expected to be granted, it will likely provide general statistics on how long it takes patents within a particular field of technology to be granted—(it’s usually about two to five years.)
Yet, after that, the answer will probably be, “We don’t when the patent will be granted, or if it will ever be granted.” Patent examination is an iterative process. Nearly all patent applications are initially rejected by the Patent Office. After that, applicants can respond, and the Office can respond to those responses, and the process can continue to go back-and-forth for several years. Whether or not a patent is granted typically comes down to the applicant more than the Patent Office—i.e., if the applicant can persuade the Office that its invention is purportedly novel, or if the applicant elects to narrow the scope of its invention to get around the existing prior art.
Senator Warren next asks what can the Patent Office actually do to “address companies that are engaging in abuses of the patent system in ways that hurt patients and providers?” Once again, great question, but probably no satisfactory answer.
Humira®’s one-hundred-plus patent-thicket successfully staved off biosimilar competition from 2016, when its antibody patent expired, until 2023, when AbbVie negotiated agreements for biosimilar entry. A subsequent suit against AbbVie argued that the Humira® patent-thicket was an antitrust violation. Yet, the suit was dismissed on the ground that accumulating an impenetrable wall of patents around a drug, even if many of those patents repeatedly cover the same purportedly inventive features, is not necessarily an antitrust violation.
What can the Patent Office do to stop companies from developing patent thickets like those built around Humira® and Keytruda®? Until Congress legislates or courts hold that a critical or threshold mass of patents constitutes an antitrust or some other type of violation, it is not clear that the Patent Office is empowered to prune or cutback a thicket of patents for a particular drug. Patents are examined individually, not as a group. There are numerous grounds on which a patent can be denied. Yet, almost all of those grounds relate to the novelty or technical adequacy of the individual patent.
One of the few patentability rules that take an applicants’ other patents into account is double-patenting. Yet, even there, patent applications subject to double-patenting rejections are rarely not allowed. Rather, terminal disclaimers are filed wherein the applicant agrees to limit the patent’s term. A patent with a shorter term can still have an outsized impact on pharmaceutical patent litigation, and brand pharma companies can still leverage the cost and time of litigation to compel generics to agree to later entry dates. Humira® is a case-in-point.
Finally, Senator Warren’s first question in her letter—which is really the most important question—is “what actions the USPTO will take to ensure that Merck’s attempts to seek dozens of patents does not unnecessarily delay” lower-cost competition? That is a hard question because, as evident from Humira®’s successful biosimilar strategy, it is not clear that the Patent Office has many tools to address the problem of patent thickets.
In July 2022, in response to a letter from Robert M. Califf, M.D., Commissioner of the Food and Drug Administration, Direct Vidal outlined a number of initiatives that the USPTO was exploring to address this problem. Many of these initiatives are worthy of their own discussion. They are no doubt important initiatives that could help blunt a brand pharmaceutical company’s attempt to gather lots of patents.
For instance, one of the initiatives identified by Director Vidal is to explore inconsistent statements made to the USPTO and the FDA. A brand pharmaceutical company often faces misaligned incentives with respect to what it tells the Patent Office versus the FDA. For instance, a brand may want to tell the FDA that the efficacy and safety of its drug has a wealth of support in the literature, which should support the agency’s decision to approve the drug. Yet, by contrast, the brand may want to tell the Patent Office that its drug has no support in the literature, and in fact the literature teaches away from the drug, which supports the agency’s decision to grant a patent.
Yet, at the end of the day, many of the initiatives identified by Director Vidal’s July 2022 letter are blunt instruments, rather than acute tools. They may indirectly curb patent thickets, or they may just mean brand companies have to be a little more savvy about their patent prosecution strategies.
In sum, Senator Warren’s letter to the Patent Office asks a lot of good questions about Keytruda®’s patent thicket. There just may not be a lot of good answers.