After filing a series of five continuation-in-part (“CIP”) applications, which added new matter , a patent finally issued containing claims covering Abbott’s antibody.  Centocor then relied on the added material as evidence of written description to support later asserted claims.

The Federal Circuit poo-poohed the idea saying that PTO guidelines prevent claiming a high affinity, neutralizing, A2 specific antibody with a human variable region if it was not possible at the time of filing using “conventional,” “routine,” “well developed and mature” technology. Centocor Ortho Biotech v. Abbott Labs, U.S. Court of Appeals for the Federal Circuit (10-1144).

Patent holders Centocor Ortho Biotech and New York University sued Abbott Labs 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. Hence, Abbott appealed.

The patent involves antibodies to human tumor necrosis factor a (TNF-a). Overproduction of TNF-a can lead to various autoimmune conditions, including arthritis.

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. While such antibodies 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.

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”). Centocor then used known techniques to modify its mouse antibody to make it 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.

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. The resulting chimeric antibody was less immunogenic than the A2 mouse antibody because it contained significantly less mouse protein.

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-human antibody to a human protein like TNF-α.

Centocor subsequently filed a series of continuation-in-part (CIP) applications. In 1993, the U.S. Patent and Trademark Office rejected certain pending claims in a CIP application because they encompassed antibodies with “less than an entire mouse variable region[].” 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. So, 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 relied 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.

Abbott pursued an alternative path and sought to engineer a fully-human antibody. First, Abbott’s collaborators created an enormous phage display library containing a spectrum of human variable regions. They searched this library for variable regions that bind to human TNF-α. In the process, they developed a technique known as “guided selection” to help identify variable regions from the library that bind in a specific place so the variable regions have neutralizing activity. After identifying human variable regions that bind to human TNF-α, they used various techniques including “chain shuffling” and “affinity maturation” to improve the binding affinity of the variable regions. These human variable regions were combined with known human constant regions to create fully-human antibodies.

By 1995, Abbott had created the therapeutic antibody Humira®. Abbott filed a patent application disclosing this high affinity, neutralizing, fully-human antibody to human TNF-α in 1996. See U.S. Patent No. 6,090,382. The PTO granted the patent in 2000, and Abbott obtained regulatory approval to market Humira® in 2002.

After the grant of Abbott’s patent and after regulatory approval of Humira®, Centocor filed its claims to fully-human antibodies. Because the patent family disclosing Centocor’s own chimeric antibody was still pending in 2002, Centocor filed the claims as part of a thirteenth application in the family, explicitly claiming human variable regions and fully-human antibodies. Asserted claim 2 and the claim from which it depends are illustrative:

  1. An isolated recombinant anti-TNF-α antibody or antigen-binding fragment thereof, said antibody or antigen-binding fragment comprising a human constant region, wherein said antibody or antigen binding fragment (i) competitively inhibits binding of A2 (ATCC Accession No. PTA-7045) to human TNF-α, and (ii) binds to a neutralizing epitope of human TNF-α in vivo with an affinity of at least 1×108 liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis.
  2. The antibody or antigen-binding fragment of claim1, wherein the antibody or antigen binding fragment comprises a human constant region and a human variable region.

Independent claim 1, which is not at issue in this appeal, covers antibodies with a human constant region and a variable region from any source. The scope of claim 1 includes, but is not limited to, chimeric antibodies. Asserted claim 2 is limited to antibodies with human constant regions and human variable regions. Asserted claim 3, which also depends from claim 1, likewise claims antibodies with human variable regions. All of the asserted claims cover human variable regions and fully-human antibodies like Abbott’s Humira®.

The district court jury found that the asserted claims were not invalid for anticipation, lack of enablement, or lack of written description.

The written description requirement of 35 U.S.C. § 112, ¶ 1 provides, in pertinent part, that:

The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.

To satisfy the written description requirement, “the applicant must ‘convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention,’ and demonstrate that by disclosure in the specification of the patent.” Carnegie Mellon Univ. v. Hoffmann-La Roche Inc., 541 F.3d 1115, 1122 (Fed. Cir. 2008) (quoting Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64 (Fed. Cir. 1991)). Assessing such “possession as shown in the disclosure” requires “an objective inquiry into the four corners of the specification.” Ariad, 598 F.3d at 1351. Ultimately, “the specification must describe an invention understandable to [a person of ordinary skill in the art] and show that the inventor actually invented the invention claimed.” Id. A “mere wish or plan” for obtaining the claimed invention is not adequate written description. Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1566 (Fed. Cir. 1997).

The pivotal issue in this case concerns whether the ’775 patent provides adequate written description for the claimed human variable regions. The asserted claims cover fully-human antibodies that possess the same therapeutic properties as Centocor’s chimeric antibody, i.e., high affinity, neutralizing activity, and binding at a specific place on human TNF-α. Accordingly, the 1994 CIP applications must provide written description for an antibody to human TNF-α with (1) a human constant region, (2) a human variable region, (3) high affinity for human TNF-α, (4) neutralizing activity, and (5) the ability to bind to TNF-α in the same place as Centocor’s A2 mouse antibody (“A2 specificity”).

Abbott pointed out that the specification does not disclose any fully-human, high affinity, neutralizing, A2 specific antibody. Moreover, the specification does not disclose a single human variable region. Abbott argued that the only described antibody is the chimeric antibody, which has a mouse variable region. Abbott also argued that Centocor has merely disclosed tools that might be used in an attempt to make the claimed invention—essentially, that Centocor’s disclosure is no more than a mere wish or plan for how one might search for a fully-human antibody that satisfies the claims. Finally, Abbott pointed to testimony from Centocor’s inventor indicating that the disclosure did not include examples about making a human antibody because “it was never [Centocor’s] intention to make a human antibody.” J.A. 18312, 18:19-24.

The court agreed:

Contrary to Centocor’s assertions, very little in the ’775 patent supports that Centocor possessed a high affinity, neutralizing, A2 specific antibody that also contained a human variable region. The overwhelming majority of the ’775 patent describes the A2 mouse anti-body and the single chimeric antibody that Centocor made based on A2’s mouse variable region.

At bottom, the asserted claims constitute a wish list of properties that a fully-human, therapeutic TNF-α antibody should have: high affinity, neutralizing activity, and the ability to bind in the same place as the mouse A2 antibody. The specification at best describes a plan for making fully-human antibodies and then identifying those that satisfy the claim limitations. But a “mere wish or plan” for obtaining the claimed invention is not sufficient. See id. at 1566. At the time the 1994 CIP applications were filed, it was entirely possible that that no fully-human antibody existed that satisfied the claims. Because Centocor had not invented a fully-human, high affinity, neutralizing, A2 specific antibody in 1994, a reasonable jury could not conclude that it possessed one.

While our precedent suggests that written description for certain antibody claims can be satisfied by disclosing a well-characterized antigen, that reasoning applies to disclosure of newly characterized antigens where creation of the claimed antibodies is routine.

Claiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described.

Indeed, we have repeatedly indicated that the written description requirement does not demand either examples or an actual reduction to practice. Ariad, 598 F.3d at 1352. What it does demand is that one of skill in the art can “visualize or recognize” the claimed antibodies based on the specification’s disclosure. Eli Lilly, 119 F.3d at 1568.

  Print This Post Print This Post  

One Comment

  1. […] Humira (Adalimumab) – US: You can’t CIP your way out of the written description requirement: Centocor v Abbott (Patent Baristas) […]