Centocor v. Abbott Labs: A Tale of Specificity
Earlier this week the Court of Appeals for the Federal Circuit reversed the Eastern District of Texas’ decision in Centocor Ortho Biotech v. Abbott Laboratories. The district court case resulted in a jury verdict of patent infringement and Centocor was awarded $1.67 billion in damages. The patents at issue claimed cloned human antibodies against Tumor Necrosis Factor Alpha (TNFα). TNFα is an immune signaling molecule that can cause autoimmune disorders (such as arthritis) when overproduced. An antibody is an immune system protein that recognizes a particular part of a protein and binds to that protein. Normally, antibodies act as signals that activate an arm of the immune system to attack a foreign invader, such as a bacterium. However, the simple act of binding to a protein can inactivate that protein if the antibody’s binding physically interferes with the protein’s mechanism of action. The patented product at issue here was a pair of cloned antibodies that inactivated TNFα via specific binding.
When these patents were issued, the scientific community at large had developed mouse antibodies to human TNFα. However, these antibodies were not therapeutically useful because the human immune system would recognize that the mouse antibodies were foreign and attack them. Both Centocor and Abbott Labs set out to develop an antibody that would bind with high specificity to human TNFα, but would not trigger a separate immune response. This kind of research is challenging because of the innate nature of antibodies. An antibody is generally conceived of as a Y-shape, with two types of regions. The base of the Y-shape is termed a constant region and is generally consistent within a given species. The branching arms of the Y-shape are termed the “variable” region and are created via complicated genetic mechanisms that have the potential to produce millions of different variations. It is the variable region that determines what an antibody will bind to (i.e. its specificity). You cannot simply read the sequence of a mouse antibody’s variable region and determine a corresponding human antibody sequence. Rather, the human variable region specific to a particular target must be discovered by repeating the entire process used to develop the mouse antibody using human cells. Abbott Laboratories pursued this approach and in 1996 filed a patent application for an antibody that they market as Humira®.
Centocor took an entirely different approach, by generating chimeric antibodies. Chimeric antibodies are antibodies that are generated by combining DNA sequences from two different species. In 1991, Centocor patented its mouse antibody and a chimeric antibody composed of the mouse variable region spliced to a human constant region. By removing the mouse constant region, Centocor significantly reduced the degree to which this chimeric antibody triggered the unwanted immune response. However, some immune response remained and Centocor set out to eliminate it. Over the following years, Centocor filed a number of applications for “continuation-in-part” (CIP) in which it sought claims for chimeric antibodies that replaced portions of the variable region with human sequences. These regions still retained the critical specificity from the mouse antibody, but by increasing the percentage of the antibody composed of human sequences they sought to reduce the undesirable immune response. For a “continuation-in-part” to be granted, its claim must fall within the written description accompanying the original patent application. The patent examiner ruled that Centocor’s original description included only chimeric antibodies including “fully mouse variable regions” and denied the applications. However, the patent examiner approved Centocor’s claim to a fully human antibody based upon CIP language filed in 1994.
For a patent to be valid, it must include a written description that would enable a person having normal skill in the art to make and/or use the invention. Thus, the question before the court was whether Centocor’s descriptions as written in 1994 would have enabled an immunologist to create a fully human antibody. The court correctly recognized that the key to the claimed material is the sequence of the human variable regions specific to TNFα. While Centocor’s patent application disclosed a mouse antibody and a chimeric antibody, it did not disclose a fully human antibody. As the court points out, Centocor’s writings do not “disclose any relationship between the human TNFα protein, the known mouse variable region that satisfies the critical claim limitations, and potential human variable regions that will satisfy the claim limitations.” The Court proceeded to invalidate Centocor’s claims to fully human anti-TNFα antibodies based upon their failure to fulfill the written description requirement.
The Federal Circuit’s ruling in this case was correct, and in keeping with the goal of the Patent Act. In order to receive a monopoly on a discovery, an inventor must place sufficient information in the public domain to make that discovery accessible to the general public. Simply informing the public of a discovery that you would like to make is insufficient to allow the public to make use of the invention, and insufficient basis to grant a monopoly. However, the ruling of the patent examiner in denying Centocor’s CIP applications for modified chimeric antibodies is harder to support. Had Centocor challenged that ruling, they could have argued that their application clearly taught towards the creation of an antibody containing portions of a mouse gene governing the antibody’s specificity; with the remainder of the antibody composed of human sequences. While granting the CIP applications would not preclude Abbott Laboratories from patenting a fully human antibody and marketing Humira®, it would have allowed Centocor to retain its priority of invention against any competitors developing similar chimeric antibodies.