Centocor Ortho Biotech Inc v. Laboratories
| Decision Date | 23 February 2011 |
| Docket Number | 2010-1144 |
| Parties | CENTOCOR ORTHO BIOTECH, INC. AND NEW YORK UNIVERSITY, Plaintiffs-Appellees, v. ABBOTT LABORATORIES, ABBOTT BIORESEARCH CENTER, INC., AND ABBOTT BIOTECHNOLOGY LTD., Defendants-Appellants. |
| Court | U.S. Court of Appeals — Federal Circuit |
Appeal from the United States District Court for the Eastern District of Texas in case no. 07-CV-0139, Judge T. John Ward.
Dianne B. Elderkin, Akin Gump Strauss Hauer & Feld LLP, of Philadelphia, Pennsylvania, argued for plaintiffs-appellees. With her on the brief were Barbara L. Mullin, Steven D. Maslowski, Angela Verrecchio, and Matthew A. Pearson. Of counsel on the brief were Philip S. Johnson and Eric I. Harris, Johnson & Johnson, of New Brunswick, New Jersey.
WILLIAM F. Lee, Wilmer Cutler Pickering Hale and Dorr LLP, of Boston, Massachusetts argued for defendants-appellants. With him on the brief were WILLAIM G. MCELWAIN, AMY K. WlGMORE, THOMAS G. SAUNDERS, and ARTHUR W. COVIELLO, of Washington, DC.
OAKAR Liivak, Cornell Law School, of Ithaca, New York, for amicus curiae Professor Oskar Liivak.
MARK J. STEWART, Eli Lilly and Company, of Indianapolis, Indiana, for amicus curiae Eli Lilly and Company. With him on the brief were ALEJANDRO MARTINEZ, PAUL R. Cantrell, Amy E. Hamilton, and Robert A. ARMITAGE,
Before BRYSON, CLEVENGER, and PROST, Circuit Judges.
This patent infringement suit involves pharmaceutical antibodies used to treat arthritis. The patent owners, Centocor Ortho Biotech, Inc. and New York University (collectively, "Centocor") sued Abbott Laboratories, Abbott Bioresearch Center, Inc., and Abbott Biotechnology Ltd. (collectively, "Abbott"), alleging that Abbott's Humira® antibody infringes claims 2, 3, 14, and 15 ("the asserted claims") of U.S. Patent No. 7, 070, 775 ("'775 patent"). After a five-day trial, the jury found Abbott liable for willful infringement. The jury rejected Abbott's argument that the asserted claims were invalid, and awarded Centocor over $1.67 billion in damages.
Abbott moved for judgment as a matter of law ("JMOL") on invalidity, noninfringement, damages, and willfulness. The district court granted Abbott's motion for JMOL of no willful infringement but denied Abbott's other JMOL motions. Abbott appeals the district court's denial of its JMOL motions. Because the asserted claims of the '775 patent lack written description under 35 U.S.C. § 112, we need not reach Abbott's other invalidity arguments, its infringement arguments, or the question of damages. We reverse the district court's denial of JMOL on this ground and hold the asserted claims invalid for failure to meet the statutory written description requirement.
The technology in this case involves antibodies to human tumor necrosis factor a ("TNF-a"). Overproduction of TNF-a can lead to various autoimmune conditions, including arthritis. Although TNF-a antibodies have the potential to reduce the harmful activity caused by excess TNF-a, the human body does not typically make antibodies to human TNF-a. As a result, pharmaceutical companies have been keenly interested in engineering antibodies that can "neutralize" human TNF-a for use as a drug.
TNF-a was identified long before Centocor and Abbott began developing therapeutic antibodies. In fact, by 1985, many researchers had produced antibodies to human TNF-a. These antibodies were typically produced in mice and were not suitable for use in human patients for several reasons. First, many of the antibodies did not have sufficient binding affinity for human TNF-a. Because the antibodies must stick to human TNF-a to work, their binding ability is important. A high affinity antibody sticks better than an antibody that binds with low affinity. If an antibody's affinity is too low, it will not be a viable drug. Second, many of the known antibodies did not have the desired neutralizing activity. While suchantibodies do bind to TNF-a, they do not bind to a place on TNF-a that reduces the harmful TNF-a activity. Since such antibodies do not reduce TNF-a activity, they cannot be used to produce the desired therapeutic effect. In other words, the activity of an antibody is related to both how tightly the antibody sticks as well as the specific location on TNF-a where the antibody binds. Third, human patients frequently have immunological reactions when they are treated with antibodies produced in mice or other non-human species. This is because the human immune system recognizes foreign proteins and attacks them. By engineering foreign antibodies to look more human, scientists try to trick the human immune system and prevent this undesirable immune response. Given these therapeutic limitations of the known TNF-a antibodies, pharmaceutical companies sought to develop an antibody with (1) high affinity, (2) neutralizing activity, and (3) reduced immunogenicity.
In developing their therapeutic TNF-a antibodies, Centocor and Abbott pursued very different strategies. Centocor's path began by identifying a mouse antibody to human TNF-a that had both high affinity and neutralizing activity ("the A2 mouse antibody"). While this antibody had two of the key properties, the mouse antibody was of limited therapeutic use because it would produce an undesirable immune response in humans. To tackle this immunogenicity problem, Centocor decided to use known techniques to modify its mouse antibody to make it look more human. By keeping the parts of the mouse antibody that are responsible for the affinity and the neutralizing activity and changing the less critical portions of the antibody to make these portions more human, scientists sought to preserve the activity of the antibody while reducing its immunogenicity.
For purposes of discussion in this appeal, antibodies basically consist of two regions: a "constant region" and a "variable region." As Centocor's inventor explained to the jury, "the variable regions are really what determines what the antibody is." J.A. 18300, 159:10-12. The variable region is the portion responsible for sticking to TNF-a. The variable region is also the portion of the antibody that determines where on TNF-a the antibody will bind. Making changes in the variable region can thus have a dramatic effect on the affinity and activity of the antibody. Even a small change in the variable region can result in an antibody that does not bind to TNF-a or fails to have neutralizing activity. Centocor avoided the potential pitfalls associated with modifying the variable region by focusing on the constant region. By exchanging the A2 mouse antibody's mouse constant region with a known human constant region, Centocor produced a "chimeric" antibody with a mouse variable region and a human constant region. See, e.g., Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1250-52 (Fed. Cir. 2004) (). The resulting chimeric antibody was less immunogenic than the A2 mouse antibody because it contained significantly less mouse protein. At the same time, Centocor's chimeric antibody possessed similar binding and activity to the A2 mouse antibody because they both had the same variable region. Because the chimeric antibody contained a mouse variable region, it was not considered to be "fully human." A chimeric antibody still contains foreign protein, so it is more likely to elicit an immune response than a fully-human antibody.
Centocor filed a patent application disclosing both its A2 mouse antibody and the chimeric antibody in 1991. The application discussed the immunogenicity problem and the difficulties associated with making a fully-humanantibody to a human protein like TNF-a. The application presented chimeric antibodies as the solution to these problems. The 1991 application included eighteen examples detailing methods for making a mouse antibody with high affinity and neutralizing activity and making a corresponding chimeric antibody based on the mouse antibody. The application included claims to Centocor's A2 mouse antibody and chimeric antibodies.
Centocor subsequently filed a series of continuation-in-part ("CIP") applications. In 1993, the U.S. Patent and Trademark Office ("PTO") rejected certain pending claims in a CIP application because they encompassed antibodies with "less than an entire mouse variable region[]." J.A. 38601. The PTO asserted that the specification only enabled antibodies with fully-mouse variable regions. Instead of responding to the rejections, Centocor filed a new CIP application and abandoned the pending application. In due course, the PTO issued the same rejection. Again, instead of responding, Centocor abandoned its application and filed three substantially identical CIP applications in 1994. These 1994 CIP applications added new matter that Centocor now relies on as evidence of written description to support the asserted claims. Although Centocor made these few additions, it did not present claims to human variable regions when it filed the 1994 CIP applications.
While Centocor focused its efforts on making a chi-meric antibody, Abbott pursued an alternative path and sought to engineer a fully-human antibody. As discussed above, there is a progression from making a mouse antibody to obtaining the corresponding chimeric antibody. This is because the two antibodies contain the same variable region. In contrast, no corresponding progression exists with respect to making a fully-human antibody.
J.A. 18462 (). One of skill in the art cannot look at a mouse variable region and know how to turn it into a human variable region with the same affinity and activity as the mouse antibody.1
Abbott decided to work with collaborators to construct a fully-human antibody from scratch. First, Abbott's collaborators created an enormous phage display library containing a spectrum of human...
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