Centocor v. Abbott Labs: Must You Only Preach What You Practice?

The Federal Circuit's decision on Feb. 23, 2011 in Centocor Ortho Biotech., Inc. v. Abbott Labs., __ F.3d __, 2011 WL 635291 (C.A. Fed. (Tex.) 2011), vacated a $1.67 billion verdict based on invalidity for insufficient written description. The case provides an example of when technology can be so complicated or unpredictable that the specification does not adequately explain how to practice the claimed invention.

Specifically, Centocor held that the written description of U.S. Patent No. 7,070,775 (“the '775 patent”) describing a mouse antibody and chimeric antibody having a mouse variable region was inadequate to show possession of an invention relating to human antibodies that could neutralize human TNF-a for use as a drug. The court also found that generating human antibodies with the properties claimed would not have been within the skill of one of ordinary skill in the art at the time of the original invention. Rather, the court held that the claimed antibody was merely a “wish list” of desired properties.

Centocor highlights the current disparity between the viewpoint of some Federal Circuit judges and the USPTO's ' 112 guidelines, which suggest an “antibody exception.” This “exception” allows an applicant to claim an antibody capable of binding to a protein when the specification characterizes the protein but lacks any actual or prophetic examples of actual antibodies binding to the protein. Such an exception allows inventors to claim outside the boundaries of the invention they actually reduced to practice, which is permitted in other areas. Previously, cases such as Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004) have reinforced the guidelines. In Noelle, the Federal Circuit stated, “as long as an applicant has disclosed a 'fully characterized antigen,' either by its structure, formula, chemical name, or physical properties, or by depositing the protein in a public depository, the applicant can then claim an antibody by its binding affinity to that described antigen.” Id. at 1349.

Background

The technology at issue in Centocor is human TNF-a antibodies, useful for treating various autoimmune conditions, including arthritis. Researchers had previously produced TNF-a antibodies in mice, and had not facilitated a suitable use in human patients. Given the 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.

Centocor attempted to create a fully-human TNF-a antibody by identifying a mouse antibody to human TNF-a that had both high affinity and neutralizing activity (“the A2 mouse antibody”). Antibodies effectively consist of two regions: a constant region and a variable region. The variable region determines the antibody. Centocor used the mouse antibody's variable region, then substituted a human constant region to make it suitable for humans. The result was a chimeric antibody.

Centocor filed a patent application disclosing both the A2 mouse antibody and chimeric antibody in 1991. This application included 18 examples detailing methods for making a mouse antibody and a corresponding chimeric antibody based on the mouse antibody. Centocor subsequently filed a series of continuation-in-part (“CIP”) applications. Centocor never presented claims to human variable regions in the CIP applications.

While Centocor focused its efforts on making a chimeric antibody, Abbott decided to construct a fully-human antibody from scratch. By 1995, Abbott had created the therapeutic antibody Humira'. It filed a patent application disclosing this high affinity, neutralizing, fully-human antibody to human TNF-a in 1996, which issued as U.S. Patent No. 6,090,382.

After the grant of Abbott's patent and after regulatory approval of Humira', Centocor, for the first time, filed claims to fully-human antibodies, as part of a 13th application in the family. This application explicitly claimed human variable regions and fully-human antibodies. All of the asserted claims covered human variable regions and fully-human antibodies like Abbott's Humira'.

Centocor's application, which contained a priority claim to its earlier applications, issued as the '775 patent in 2006. Shortly thereafter, Centocor sued Abbott, alleging that Abbott's Humira' antibody infringed the asserted claims of the '775 patent. At trial, Abbott argued that the asserted claims were invalid for lack of written description. The jury rejected Abbott's arguments, finding infringement of the asserted claims. After a five-day trial, the jury found Abbott liable for willful infringement, and awarded Centocor more than $1.67 billion in damages. Abbott appealed, and the Federal Circuit reversed, based on the written description requirement of 35 U.S.C. ' 112.

The Federal Circuit's Analysis

According to the Federal Circuit, “[t]he pivotal issue in this case concerns whether the '775 patent provides adequate written description for the claimed human variable regions.” To satisfy the written description requirement, an applicant must describe the claimed invention in sufficient detail such that one skilled in the art can reasonably conclude that the inventor had “possession” of the claimed invention. The Manual of Patent Examining Procedure also highlights that the essential goal of the written description requirement is to clearly convey the information that an applicant has invented the claimed subject matter. ' 2163.

The Federal Circuit observed that the asserted claims covered fully-human antibodies that possessed the same therapeutic properties as Centocor's chimeric antibody. Therefore, to be entitled to claim a fully-human antibody, the CIP applications filed in 1994 must have provided written description for an antibody to human TNF-a with:

(1) a human constant region, (2) a human variable region, (3) high affinity for human TNF-a, (4) neutralizing activity, and (5) the ability to bind to TNF-a in the same place as Centocor's A2 mouse antibody.

Abbott argued that the only antibody described in the application was the chimeric antibody, which had a mouse variable region. Abbott also argued that the specification did not disclose a human variable region, and therefore Centocor merely disclosed tools that could be used in an attempt to make or search for a fully-human antibody as claimed. In response, Centocor pointed to specific disclosures in the 1994 CIP applications identified by inventor Dr. John Ghrayeb as evidence that the asserted claims were adequately described and enabled, but presented no expert testimony on written description at trial.

The Federal Circuit agreed with Abbott. It concluded that very little in the '775 patent showed that Centocor “possessed” the A2 specific antibody containing a human variable region. It reasoned that the overwhelming majority of the '775 patent described the A2 mouse antibody and the single chimeric antibody that Centocor made based on A2's mouse variable region. It also found that the application only provided amino acid sequence information for a single mouse variable region, meaning the variable region that the mouse A2 antibody and the chimeric antibody had in common. The Federal Circuit stated:

[T]he mouse variable region sequence does not serve as a stepping stone to identifying a human variable region within the scope of the claims ' [and] while the specification notes that fully-human antibodies can potentially be produced by human B lymphocytes, it does not disclose any B lymphocytes that actually produce a high affinity, neutralizing, A2 specific TNF-a antibody.

Centocor, __ F.3d __, 2011 WL 635291 at *6.

According to the Federal Circuit, the “fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.” The court went on to state:

[W]hile the patent broadly claims a class of antibodies that contain human variable regions, the specification does not describe a single antibody that satisfies the claim limitations. ' It does not disclose any relevant identifying characteristics for such fully-human antibodies or even a single human variable region. ' There is nothing in the specification that conveys to one of skill in the art that Centocor possessed fully-human antibodies or human variable regions that fall within the boundaries of the asserted claims.

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. ' 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.

Id. at *7.

According to the Federal Circuit, Centocor could not prove that it could have made the human antibody if it had tried: “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.” That is, simple possession of the known TNF-a protein did not place Centocor in possession of the claimed antibodies.

The Federal Circuit acknowledged that the written description requirement does not always demand either examples or an actual reduction to practice. What it does demand, however, is that one skilled in the art is able to visualize or recognize the claimed antibodies based on the disclosure in the specification. While some cases, such as Noelle v. Lederman, provide more specific guidelines on how to satisfy the written description requirement, Centocor confirms that the ultimate test for compliance is easier to state than it is to predict.

Irah Donner and Matthew Siegal are partners and Clayton McCraw is an associate in the Intellectual Property department of Stroock & Stroock & Lavan LLP. Siegal is a member of this newsletter's Board of Editors. The views expressed are their own. This article and the facts associated herein are based on the reported Federal Circuit decision.

The Federal Circuit's decision on Feb. 23, 2011 in Centocor Ortho Biotech., Inc. v. Abbott Labs. , __ F.3d __, 2011 WL 635291 (C.A. Fed. (Tex.) 2011), vacated a $1.67 billion verdict based on invalidity for insufficient written description. The case provides an example of when technology can be so complicated or unpredictable that the specification does not adequately explain how to practice the claimed invention.

Specifically, Centocor held that the written description of U.S. Patent No. 7,070,775 (“the '775 patent”) describing a mouse antibody and chimeric antibody having a mouse variable region was inadequate to show possession of an invention relating to human antibodies that could neutralize human TNF-a for use as a drug. The court also found that generating human antibodies with the properties claimed would not have been within the skill of one of ordinary skill in the art at the time of the original invention. Rather, the court held that the claimed antibody was merely a “wish list” of desired properties.

Centocor highlights the current disparity between the viewpoint of some Federal Circuit judges and the USPTO's ' 112 guidelines, which suggest an “antibody exception.” This “exception” allows an applicant to claim an antibody capable of binding to a protein when the specification characterizes the protein but lacks any actual or prophetic examples of actual antibodies binding to the protein. Such an exception allows inventors to claim outside the boundaries of the invention they actually reduced to practice, which is permitted in other areas. Previously, cases such as Noelle v. Lederman , 355 F.3d 1343 (Fed. Cir. 2004) have reinforced the guidelines. In Noelle, the Federal Circuit stated, “as long as an applicant has disclosed a 'fully characterized antigen,' either by its structure, formula, chemical name, or physical properties, or by depositing the protein in a public depository, the applicant can then claim an antibody by its binding affinity to that described antigen.” Id. at 1349.

Background

The technology at issue in Centocor is human TNF-a antibodies, useful for treating various autoimmune conditions, including arthritis. Researchers had previously produced TNF-a antibodies in mice, and had not facilitated a suitable use in human patients. Given the 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.

Centocor attempted to create a fully-human TNF-a antibody by identifying a mouse antibody to human TNF-a that had both high affinity and neutralizing activity (“the A2 mouse antibody”). Antibodies effectively consist of two regions: a constant region and a variable region. The variable region determines the antibody. Centocor used the mouse antibody's variable region, then substituted a human constant region to make it suitable for humans. The result was a chimeric antibody.

Centocor filed a patent application disclosing both the A2 mouse antibody and chimeric antibody in 1991. This application included 18 examples detailing methods for making a mouse antibody and a corresponding chimeric antibody based on the mouse antibody. Centocor subsequently filed a series of continuation-in-part (“CIP”) applications. Centocor never presented claims to human variable regions in the CIP applications.

While Centocor focused its efforts on making a chimeric antibody, Abbott decided to construct a fully-human antibody from scratch. By 1995, Abbott had created the therapeutic antibody Humira'. It filed a patent application disclosing this high affinity, neutralizing, fully-human antibody to human TNF-a in 1996, which issued as U.S. Patent No. 6,090,382.

After the grant of Abbott's patent and after regulatory approval of Humira', Centocor, for the first time, filed claims to fully-human antibodies, as part of a 13th application in the family. This application explicitly claimed human variable regions and fully-human antibodies. All of the asserted claims covered human variable regions and fully-human antibodies like Abbott's Humira'.

Centocor's application, which contained a priority claim to its earlier applications, issued as the '775 patent in 2006. Shortly thereafter, Centocor sued Abbott, alleging that Abbott's Humira' antibody infringed the asserted claims of the '775 patent. At trial, Abbott argued that the asserted claims were invalid for lack of written description. The jury rejected Abbott's arguments, finding infringement of the asserted claims. After a five-day trial, the jury found Abbott liable for willful infringement, and awarded Centocor more than $1.67 billion in damages. Abbott appealed, and the Federal Circuit reversed, based on the written description requirement of 35 U.S.C. ' 112.

The Federal Circuit's Analysis

According to the Federal Circuit, “[t]he pivotal issue in this case concerns whether the '775 patent provides adequate written description for the claimed human variable regions.” To satisfy the written description requirement, an applicant must describe the claimed invention in sufficient detail such that one skilled in the art can reasonably conclude that the inventor had “possession” of the claimed invention. The Manual of Patent Examining Procedure also highlights that the essential goal of the written description requirement is to clearly convey the information that an applicant has invented the claimed subject matter. ' 2163.

The Federal Circuit observed that the asserted claims covered fully-human antibodies that possessed the same therapeutic properties as Centocor's chimeric antibody. Therefore, to be entitled to claim a fully-human antibody, the CIP applications filed in 1994 must have provided written description for an antibody to human TNF-a with:

(1) a human constant region, (2) a human variable region, (3) high affinity for human TNF-a, (4) neutralizing activity, and (5) the ability to bind to TNF-a in the same place as Centocor's A2 mouse antibody.

Abbott argued that the only antibody described in the application was the chimeric antibody, which had a mouse variable region. Abbott also argued that the specification did not disclose a human variable region, and therefore Centocor merely disclosed tools that could be used in an attempt to make or search for a fully-human antibody as claimed. In response, Centocor pointed to specific disclosures in the 1994 CIP applications identified by inventor Dr. John Ghrayeb as evidence that the asserted claims were adequately described and enabled, but presented no expert testimony on written description at trial.

The Federal Circuit agreed with Abbott. It concluded that very little in the '775 patent showed that Centocor “possessed” the A2 specific antibody containing a human variable region. It reasoned that the overwhelming majority of the '775 patent described the A2 mouse antibody and the single chimeric antibody that Centocor made based on A2's mouse variable region. It also found that the application only provided amino acid sequence information for a single mouse variable region, meaning the variable region that the mouse A2 antibody and the chimeric antibody had in common. The Federal Circuit stated:

[T]he mouse variable region sequence does not serve as a stepping stone to identifying a human variable region within the scope of the claims ' [and] while the specification notes that fully-human antibodies can potentially be produced by human B lymphocytes, it does not disclose any B lymphocytes that actually produce a high affinity, neutralizing, A2 specific TNF-a antibody.

Centocor, __ F.3d __, 2011 WL 635291 at *6.

According to the Federal Circuit, the “fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.” The court went on to state:

[W]hile the patent broadly claims a class of antibodies that contain human variable regions, the specification does not describe a single antibody that satisfies the claim limitations. ' It does not disclose any relevant identifying characteristics for such fully-human antibodies or even a single human variable region. ' There is nothing in the specification that conveys to one of skill in the art that Centocor possessed fully-human antibodies or human variable regions that fall within the boundaries of the asserted claims.

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. ' 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.

Id. at *7.

According to the Federal Circuit, Centocor could not prove that it could have made the human antibody if it had tried: “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.” That is, simple possession of the known TNF-a protein did not place Centocor in possession of the claimed antibodies.

The Federal Circuit acknowledged that the written description requirement does not always demand either examples or an actual reduction to practice. What it does demand, however, is that one skilled in the art is able to visualize or recognize the claimed antibodies based on the disclosure in the specification. While some cases, such as Noelle v. Lederman, provide more specific guidelines on how to satisfy the written description requirement, Centocor confirms that the ultimate test for compliance is easier to state than it is to predict.

Irah Donner and Matthew Siegal are partners and Clayton McCraw is an associate in the Intellectual Property department of Stroock & Stroock & Lavan LLP. Siegal is a member of this newsletter's Board of Editors. The views expressed are their own. This article and the facts associated herein are based on the reported Federal Circuit decision.