By Gregory Curfman
Three new developments — two based on litigation and one based on a federal statute — may have significant effects on pharmaceutical manufacturers’ use of patents to fend off competition and maintain high prices for therapeutic monoclonal antibodies.
Highly specific monoclonal antibodies have played an increasingly important role as precision therapies for a growing number of diseases, including malignant, cardiovascular, and inflammatory conditions. As therapies derived from research and development, therapeutic monoclonal antibodies may be — and usually are — patented, providing manufacturers with protection from competition and the prospect of high revenues.
Amgen, Inc., v. Sanofi, Inc.
One such therapeutic monoclonal antibody is evolocumab (Repatha®, manufactured by Amgen), a PCSK9 inhibitor.
Evolocumab may result in marked reductions of LDL cholesterol and reduce the risk of cardiovascular disease. This novel class of therapeutics has captured significant attention across the health care community.
In a recent opinion from the U.S. Court of Appeals for the Federal Circuit (Amgen, Inc., v. Sanofi, Inc.), the Court invalidated two of Amgen’s key patents on evolocumab, thus diminishing Amgen’s patent protection and potentially opening the door to competition from biosimilars.
For a patent to be issued, the applicant must successfully address five criteria: patent eligibility, utility, novelty, non-obviousness, and adequate description.
The Amgen patents on evolocumab were invalidated on the basis of the last criterion, the written description requirement (35 U.S.C. § 112), which states that the invention must be described in sufficient detail so that a person skilled in the art will be able to make and use the invention. The Court applied the Wands factors, which set out criteria for when “undue experimentation” would be required for one skilled in the art to successfully apply the invention and concluded that the Amgen patent claims contained overly broad functional language that did not meet the Wands standards. In making this judgment, the Court strengthened the written description requirement as applied to therapeutic monoclonal antibodies, requiring more information on production to be provided and potentially allowing for more competition.
While the Federal Circuit’s opinion may be appealed, for now manufacturers of therapeutic monoclonal antibodies will need to take greater care in written descriptions of their products and expect the possibility of a more active biosimilar market, unless biologic manufacturers desist from applying for patents altogether, which seems an unlikely outcome.
Challenging Humira’s High Cost in Litigation
As many patients, physicians, and policymakers well know, the therapeutic monoclonal antibody adalimumab (Humira®) is among the best-selling drugs in the United States and around the world. The manufacturer, AbbVie, has increased the price of Humira every year since it was first approved by the U.S. Food and Drug Administration (FDA) in 2002. In 2019 the retail price of Humira reached $84,484, and the price is expected to increase by another 7.5% in the coming months. Both because of its high price, and because it has multiple clinical indications (such as psoriasis, Crohn’s Disease, and rheumatoid arthritis, among others), Humira has brought many billions of dollars in revenue to AbbVie. Now, however, the high price of Humira is under challenge on the basis of antitrust litigation against the manufacturer.
The core patent on Humira (patent ‘382) expired in 2016, but biosimilars have not yet entered the U.S. market and brought down the price of Humira. This is due in large part to the extensive patent thicket, consisting of over 130 patents, that AbbVie has assembled around Humira. Many of these are late-entry patents that were issued since 2014 (just as the expiration date of the compound patent was approaching), and their claims address formulations and methods of use. Still, the dense patent thicket surrounding Humira has successfully protected it from biosimilar entry. AbbVie’s patent-infringement litigation against the biosimilar companies ultimately forced all of them to reach settlements with AbbVie that keep them out of the U.S. market until 2023, while concurrently permitting them to enter the lucrative European market.
The antitrust litigation, which was filed by a group of third-party payers for Humira, was based on two central arguments: AbbVie’s extensive patent thicket for Humira is anticompetitive and violates the Sherman Act, and the patent infringement settlements between AbbVie and the biosimilar companies constitute anticompetitive “pay-for-delay” agreements as defined by the Supreme Court in FDA v. Actavis. Judge Manish Shah of the U.S. District Court for the Northern District of Illinois dismissed the case, concluding that petitioning for patents, even numerous patents, and asserting their claims were immune from antitrust violations on the basis of the Noerr Pennington doctrine, and that the patent infringement settlements did not meet the definition of pay-for-delay. On February 25, 2021, the case was heard on appeal by the Seventh Circuit Court of Appeals. The plaintiffs argued that the Noerr Pennngton doctrine did not apply due to the sham exception, and that Judge Shah erred in his determination that the settlements between AbbVie and the biosimilar companies were not pay-for-delay arrangements on the basis of FTC v. Actavis.
The outcome of the antitrust litigation will have significant ramifications for patent law irrespective of which side prevails. The Court’s answers to the two key questions — whether the patent thicket and the patent infringement settlements are anticompetitive — are eagerly awaited.
Application of 28 U.S.C. § 1498
A third potential challenge to high-priced, patent-protected pharmaceuticals that may be unaffordable by many Americans, including therapeutic monoclonal antibodies, was proposed in a recent article by Morten and Duan in the Yale Journal of Law and Technology. This challenge is based not on litigation, but on a statute, 28 U.S.C. § 1498, which grants authority to the U.S. government to use patented technologies without a license, subject to “reasonable and entire compensation for such use and manufacture.” Following a filing of patent infringement litigation by the patentee against the government, the requisite compensation is determined by the U.S. Court of Federal Claims. Morten and Duan use, as an example, potential government use of patents on remdesivir to manufacture and provide more of this costly antiviral drug to patients with COVID-19 in the midst of the pandemic.
If such a government action to utilize patents at will seems extreme, consider that in 2018, Congressman Ro Khanna and 17 other members of Congress wrote a letter to Secretary of Health and Human Services Alex Azar urging him to use the government’s authority under 28 U.S.C. § 1498 to address the high price of certain prescription drugs, such as new drugs for the treatment of hepatitis C. Whether the government would ever use its § 1498 authority to manufacture expensive, patent-protected therapeutic monoclonal antibodies is uncertain, but theoretically possible. Although § 1498 has sometimes been referred to as the nuclear option, on the basis of the argument that wholesale government use of patents may significantly stifle innovation, Morten and Duan still make the case that it could be broadly applicable to pharmaceutical patents and may be a viable approach to lowering drug costs to patients.
Conclusion
Patent protection of costly biologic agents, especially therapeutic monoclonal antibodies, is under new scrutiny. Depending on the outcome of patent litigation involving evolocumab and adalimumab, and the potential, albeit uncertain, application of 28 U.S.C. § 1498 to expensive patented drugs and biologics, what has generally been a reliable business strategy in the pharmaceutical world may ultimately lose some of its impact.
Gregory Curfman, M.D. is the Senior Advisor and Physician Scholar in Residence for the Solomon Center for Health Law and Policy at Yale Law School. He is also the Deputy Editor of JAMA.
