Written Description and Antibody Claims; Centocor Ortho Biotech, Inc. v. Abbot Laboratories

In the recent Centocor v. Abbot case, the Federal Circuit reversed the district court’s denial of judgment as a matter of law (JMOL) on invalidity, noninfringement and damages, and held the claims at issue invalid for failure to meet the written description requirement under 35 U.S.C. § 112, first paragraph.

This case involves antibodies to the known protein human Tumor Necrosis Factor α (TNF-α). Because TNF-α can contribute to various autoimmune conditions, including arthritis, pharmaceutical companies have been interested in developing antibodies that can bind to and neutralize TNF-α for use as a drug.

Centocor’s strategy for developing a therapeutically useful antibody to human TNF-α involved identifying a mouse antibody that bound to human TNF-α with high affinity and neutralized the activity of the TNF-α. To reduce the undesirable immune response in humans, less critical portions of the antibody were exchanged with human sequences, creating a chimeric antibody having a mouse variable region and a human constant region. In contrast, Abbot engineered a fully human antibody by screening a phage display library for a human variable region that binds to human TNF-α with high affinity and useful neutralizing activity, and combined this variable region with known human constant regions.

After the grant of Abbot’s patent and regulatory approval of the fully human anti-TNF-α antibody (Humira®), Centocor obtained a patent (U.S. Patent No. 7,070,775) directed to fully human antibodies as one of a series of continuations of Centocor’s original patent application directed to chimeric antibodies. Asserted claim 2 of the ‘775 patent, and claim 1 from which it depends, recite:

1. An isolated recombinant anti-TNF-α anti-body 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.

The pivotal issue concerned whether the ’775 patent provides adequate written description support for the claimed human variable region. In determining the inadequacy of Centocor’s written description, the Federal Circuit noted that the ‘775 specification only includes a mouse variable region and does not disclose a single human variable region. The court further stated that Centocor’s mouse variable region was “very different” from the sequence of a human variable region like the one in Abbot’s fully human antibody, and that the specification does not “disclose any relationship between the human TNF-α protein, the known mouse variable region that satisfies the critical claim limitations, and potential human variable regions that will satisfy the claim limitations.” Therefore, the mouse variable region did not serve as a “stepping stone” to identifying a human variable region within the scope of the claims. Centocor’s claims reciting human variable regions were categorized as constituting merely a “plan” or a “wish list” of properties that a fully-human, therapeutic TNF-α antibody should have.

In reaching a decision, the court distinguished this case from Noelle v. Lederman, 35 F.3d 1343 (Fed. Cir. 2004), and the U.S. Patent and Trademark Office written description guidelines.

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. Here, both the human TNF-α protein and antibodies to that protein were known in the literature. The claimed “invention” is a class of antibodies containing a human variable region that have particularly desirable therapeutic properties: high affinity, neutralizing activity, and A2 specificity. 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 . . . Centocor simply failed to support its contention that generating fully-human antibodies with the claimed properties would be straightforward for a person of ordinary skill in the art given the state of human antibody technology in 1994. Unlike the antibody example cited in the PTO guidelines, therefore, simple possession of the known TNF-α protein did not place Centocor in possession of the claimed antibodies.

Thus, although disclosure of a known protein does not necessarily provide written description support for claims to any antibodies to that protein, the court affirmed the U.S. Patent and Trademark Office’s established practice of allowing broad claims to antibodies specific for novel, well characterized proteins.

Prepared by Lisa E. Stahl, Ph.D.