After decades of paying homage to Roche Holding AG's Cabilly patents, makers of recombinant monoclonal antibodies (MAbs) are about to be set free.
The last of the Cabillies will expire next month, releasing a who's who list of the biopharma industry – both innovators and biosimilar sponsors – from licensing deals for the patents that have been foundational to MAb development.
With the end of the licensing agreements, Roche will lose a not-insignificant stream of revenue. By some estimates, the patents were expected to generate up to $1 billion in royalties this year – an amount that will be shared by the Basel, Switzerland-based drug company and the City of Hope, a nonprofit cancer research center and hospital in Duarte, Calif.
The exact duration or terms of the agreements weren't made public, but even single-digit royalties can add up quickly from years of sales of multiple blockbuster biologics such as Abbvie Inc.'s Humira (adalimumab).
The Cabillies broadly cover methods used to make antibodies and antibody fragments by recombinant DNA technology, as well as recombinant cells and DNA that are used in those methods. Roche acquired the patents as part of its $46.8 billion bid to take over Genentech Inc. in 2009. (See BioWorld Today, March 13, 2009.)
The application for the first Cabilly patent, named for inventor Shmuel Cabilly, was filed in the U.S. in 1983, covering the use of recombinant technology to synthesize functional antibodies from bacterial host cells. It was issued six years later. From the time of the filing of the application to its issuance in 1989, researchers were gaining a better understanding of recombinant technology and were improving their ability to develop and apply it.
Cabilly II was filed in 1988, but it wasn't issued until late 2001. A third Cabilly was filed in April 1995. Although it wasn't issued until 2011, it was linked to Cabilly II, sharing its December 2018 expiry. Since claims filed before June 8, 1995, received 17 years of patent protection following issuance, the Cabillies extended the broad, foundational claims that governed a generation of MAb development.
Over the Cabillies' 35-year reign, they have seen several challenges, and Cabilly II was at the heart of a precedent-setting case in which the Supreme Court ruled 8-1 that licensees can dispute the intellectual property they're licensing without breaching their contract. Although Medimmune Inc.'s challenge was allowed to proceed in that case, the U.S. Patent and Trademark Office upheld the patent following a re-examination. (See BioWorld Today, Jan. 10, 2007.)
Two factors gave the Cabillies such a dominant role in MAb development. First, they claimed a platform technology that was the basis for what's become a multibillion-dollar industry. "The claims were the absolute bedrock of how to manufacture that antibody," Stacie Ropka, a partner with Axinn, Veltop & Harkrider LLP, told BioWorld, as they "disclosed and claimed fundamental methods for making recombinant cells expressing both an immunoglobulin light chain and heavy chain to produce immunoglobulin molecules or functional fragments of immunoglobulin molecules having specificity for a known antigen."
Ropka, who was working as a research scientist in immunology when Cabilly I was issued, said, "We understood the impact of the patent immediately."
The claims proved to be so broad and fundamental for MAb development that no one was able to work around them until recent years. That meant the entire first generation of MAbs and some biosimilars had to rely on Cabilly licenses.
Matter of timing
The second factor for the Cabillies' huge success was timing. Although Cabilly II didn't issue until 2001, it was filed before the 1995 cutoff date that determined expiry based on 17 years after issuance. Since then, the term of a utility patent is 20 years from the earliest filing date of the application on which the patent was granted and any prior U.S. applications from which the patent claims priority.
Had today's patent reckoning been in force then, Cabilly II, which claimed priority from the first Cabilly, would have expired April 8, 2003 – if there were no patent extension for review delays. What a difference that would have made in MAb development and the royalties Genentech collected. Since 2003, the FDA has approved 68 new MAbs and nine biosimilar MAbs, according to the agency's Purple Book. Many of those have been subject to Cabilly licensing fees.
While foundational patents for platform technologies are possible in the future, it's unlikely that any will have the reach of the Cabillies due to the changes in patent law. With barriers to submarining claims and the 20-year term based on first filing, a patent so basic to a new technology probably would expire before the technology could develop a profitable market that would generate a deep royalty stream.
Had the Cabillies expired in 2003, only nine MAbs would have been subject to royalties, and some of those, including Rituxan (rituximab) and Herceptin (trastuzumab), were Genentech products. In addition, companies such as Abbvie may have waited until the patents expired before launching their MAbs.
As it was, Humira, which was approved in late 2002, didn't generate much in sales before April 8, 2003. According to Cortellis, Humira had less than $300 million that entire year. But in 2018, the last year of the Cabilly patents, Humira is expected to have nearly $20.5 billion in sales.
Aside from the changes in patent law, claims that are as foundational as the Cabillies are few and far between. While there are important claims such as those covering CRISPR technology, workarounds and other gene editing technologies are available. Thus, CRISPR/Cas9 patents such as those held by the Broad Institute and the University of California, although foundational, are not expected to become the Cabillies of the gene editing space.