Hitzeman v. Rutter, 99-1604

Citation243 F.3d 1345,58 USPQ2d 1161
Decision Date21 March 2001
Docket NumberNo. 99-1604,99-1604
Parties(Fed. Cir. 2001) RONALD A. HITZEMAN, ARTHUR D. LEVINSON, AND DANIEL G. YANSURA, APPELLANTS, v. WILLIAM J. RUTTER, PABLO D.T. VALENZUELA, BENJAMIN D. HALL AND GUSTAV AMMERER, APPELLEES. RONALD A. HITZEMAN, ARTHUR D. LEVINSON, AND DANIEL G. YANSURA, APPELLANTS, v. WILLIAM J. RUTTER, PABLO D.T. VALENZUELA, BENJAMIN D. HALL AND GUSTAV AMMERER, APPELLEES. & 99-1605
CourtUnited States Courts of Appeals. United States Court of Appeals for the Federal Circuit

Appealed from: Patent & Trademark Office Board of Patent Appeals and Interferences (Interference No. 102,416) (Interference No. 102,989) [Copyrighted Material Omitted] R. Danny Huntington, Burns, Doane, Swecker & Mathis, L.L.P., of Alexandria, Virginia, argued for appellants. With him on the brief were Donna M. Meuth, and Bruce T. Wieder.

Debra A. Shetka, Morrison & Foerster, L.L.P., of Palo Alto, California, argued for appellees in 99-1604. Gladys H. Monroy, Morrison & Foerster, L.L.P., of Palo Alto, California, argued for appellees in 99-1605. With them on the brief were Emily A. Evans, and Catherine M. Polizzi. Of counsel was Karl J. Kramer. Of counsel on the brief were P. Martin Simpson, Jr., and Sandra S. Schultz, The University of California, Office of General Counsel, of Oakland, California.

Before Michel, Linn, and Dyk, Circuit Judges.

Michel, Circuit Judge.

This is a patent interference case. Ronald Hitzeman, Arthur Levinson, and Daniel Yansura (collectively, "the Hitzeman inventors" or "Hitzeman") are the junior parties in the two interferences at issue. William Rutter, Pablo Valenzuela, Benjamin Hall, and Gustav Ammerer (collectively, "the Rutter inventors" or "Rutter") are the senior parties. On July 30, 1990, the United States Patent and Trademark Office ("PTO") declared Interference No. 102,416 ("the '416 interference") between U.S. Application Serial No. 07/209,504 by Rutter, entitled to a filing date of August 4, 1981 ("the '504 Rutter application"), and U.S. Patent No. 4,803,164 to Hitzeman, entitled to a filing date of August 31, 1981 ("the '164 Hitzeman patent"). On October 22, 1992, the PTO declared Interference No. 102,989 ("the '989 interference") between U.S. Patent No. 4,769,238 to Rutter, entitled to a filing date of August 4, 1981 ("the '238 Rutter patent"), and U.S. Application Serial No. 07/248,863 by Hitzeman, entitled to a filing date of August 31, 1981 ("the '863 Hitzeman application"). On June 30, 1999, the Board of Patent Appeals and Interferences ("Board") issued separate Final Decisions in each of the interferences, awarding priority in both interferences to Rutter. On August 27, 1999, Hitzeman filed a timely notice of appeal to this court. We have jurisdiction pursuant to 35 U.S.C. §§ 141 (West Supp. 2000). We heard oral arguments in this case on January 9, 2001. The issues raised on appeal are nearly identical in the two interferences, and so we address both interferences in this opinion, with distinctions noted between the two interferences where appropriate. Because we conclude that the Board properly determined that the particle size and sedimentation rate limitations recited in both counts are material limitations, and because substantial evidence supports the Board's conclusion that Hitzeman had not conceived of the particle size and sedimentation rate limitations prior to Rutter's reduction to practice of the invention, and because the legal standards applied by the Board were correct, we affirm.

I. Factual and Procedural Background
A. Overview of the Technology

The interferences at issue concern claims to technology for producing a hepatitis B vaccine by means of genetically altered yeast. Hepatitis B, which is transmitted by a virus ("HBV"), is a major worldwide health problem that causes, among other things, severe liver damage and death. The hepatitis B virus comprises a DNA molecule surrounded by an envelope composed of proteins including a surface antigen ("HBsAg"), a core antigen ("HBcAg"), and an "e" antigen ("HBeAg").1 Prior to the invention at issue, it was known that the surface antigen could be purified from the blood sera of certain populations of humans, particularly in Australia, who were infected with the hepatitis B virus. The HBsAg isolated from humans is called the "Australia antigen." By the mid-1970s, it was found that the HBsAg particles isolated from humans could be used in a vaccine to stimulate the production of antibodies capable of defending the body against infection by the hepatitis B virus. The 1976 Nobel Prize for Physiology or Medicine was awarded to Baruch Blumberg for his recognition of the utility of HBsAg for conferring protection to humans against hepatitis B viral infections.

As disclosed in the Rutter '238 patent, it was known by 1980 that the HBsAg antigen is comprised of a cluster of protein molecules, known as the S-protein. The structure of the particles reveals that they are formed when pairs (or "dimers") of the S-protein molecules aggregate with lipids into spherical particles having diameters ranging from about 16 to 25 nm. The patents at issue refer to these particles as "22 nm particles."

Because of the costs and difficulties associated with isolating sufficient quantities of HBsAg from humans, scientists sought to develop alternative means for producing the antigen. The approach at issue on appeal concerns the attempt to obtain HBsAg or its immunologically reactive equivalent by genetically modifying microorganisms to endow them with the capability to produce the S-protein. Prior to the invention at issue, the gene encoding for the S-protein, the HBV "s" gene, had been cloned and its nucleotide sequence determined.

As explained in the prosecution history of the Hitzeman '164 patent, prior attempts to artificially produce HBsAg in microorganisms focused on bacteria such as E. coli. Through a technique that will be described in greater detail below, E. coli were genetically modified to incorporate the HBV "s" gene. While it was found that the genetically modified, or "recombinant," bacteria expressed the S-protein, the bacteria were not able to assemble HBsAg particles, as had been isolated from human sera. Consequently, it was found that the non-particulate S- protein isolated from the recombinant bacteria did not confer immunogenicity (i.e., stimulate the production of antibodies) in humans to hepatitis B infection, as would be required for a vaccine.

Hitzeman's and Rutter's technique for producing HBsAg employs yeast, rather than bacteria. Under this method, a loop of DNA known as a "vector" (or "shuttle vector" or "plasmid") is cleaved with enzymes known as "restriction endonucleases" and mixed with fragments of the HBV "s" gene, such that the HBV "s" gene is incorporated into the vector. Similarly, a "promoter," the importance of which is described below, is spliced into the vector. Through a process known as "transformation," the vector is then introduced into a population of yeast, where it is taken up into the nuclei of some of the organisms. Through the use of techniques to selectively grow the yeast that take up the vectors, colonies of yeast incorporating the vector can be obtained.

After the vector enters the nucleus of the yeast cell, an enzyme called RNA polymerase binds to the promoter region of the vector and initiates transcription of the HBV "s" gene. A messenger RNA is produced, which after exiting the nucleus and binding to a ribosome, is translated into a polypeptide chain that constitutes the S-protein. Through a process that was not fully understood by 1992 (approximately the start of the interference proceedings), the S-proteins aggregate to form particles with a diameter of roughly 22 nm, similar to the Australia antigen. The undisputed record indicates that prior to 1981 (the date of alleged conception), the ability of yeast to process the S- protein into particles was not known, and indeed there was doubt that it would occur.

The HBsAg particles expressed in the yeast strain can be extracted and isolated by centrifugation. The density of the HBsAg particles obtained from yeast is similar to that of the Australia antigen, such that the particles derived from yeast and humans have a similar "sedimentation rate" in a centrifuge. The sedimentation rate is a function of the buoyant density of the particle.

B. The Inventive Processes of Hitzeman and Rutter
1. Hitzeman's Alleged Conception

In the years leading up to 1980, Ronald Hitzeman collaborated with John Carbon to successfully express an "interferon" protein in yeast, using techniques analogous to those discussed above. Hitzeman and Carbon filed a patent application claiming this technique, which eventually issued on September 12, 1989 as U.S. Patent No. 4,865,989, assigned to the University of California.

In 1980, Hitzeman joined Genentech, Inc., where he continued to perform work on interferon in a collaborative effort with researchers at the University of California and the University of Washington. After successfully expressing interferon in yeast in January 1981, Hitzeman sought to apply this same technique to produce HBsAg. The goal of this work was to develop a human vaccine for hepatitis B. On February 3, 1981, Hitzeman disclosed, in a meeting with his supervisor, David Goeddel, his goals concerning the expression in yeast cells of HBsAg using the vector he had employed in his interferon experiments. Hitzeman also suggested producing HBsAg using a modified vector containing a PGK promoter, rather than the ADH promoter he had used to produce interferon. Hitzeman's laboratory notebook contains notes from the meeting. The notes do not indicate whether Hitzeman anticipated obtaining 22 nm particles of HBsAg from yeast.

At the time of the February 3, 1981 meeting, Hitzeman allegedly possessed all the necessary DNA materials to conduct the experiments to produce HBsAg in yeast. These materials included the vector containing the ADH promoter Hitzeman had...

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