Scripps Clinic & Research Foundation v. Genentech, Inc., Nos. 89-1541
| Decision Date | 11 March 1991 |
| Docket Number | 89-1542,89-1543,89-1646 and 89-1647,Nos. 89-1541 |
| Citation | 18 USPQ2d 1001,927 F.2d 1565 |
| Parties | , 18 U.S.P.Q.2d 1896 SCRIPPS CLINIC & RESEARCH FOUNDATION, Revlon, Inc., and Rorer Group Inc., Plaintiffs-Appellants, v. GENENTECH, INC., Defendant/Cross-Appellant, and Miles, Inc., Defendant-Appellee. SCRIPPS CLINIC & RESEARCH FOUNDATION and Revlon, Inc., Plaintiffs-Appellants, v. CHIRON CORPORATION, Defendant-Appellee. |
| Court | U.S. Court of Appeals — Federal Circuit |
William S. Feiler, Morgan & Finnegan, New York City, argued, for plaintiffs-appellants. With him on the brief were Eugene Moroz, Patricia S. Rocha, Bruce A. Pokra and Stephen V. Bomse, Heller, Ehrman White & McAuliffe, San Francisco, Cal., of counsel.
James W. Geriak, Lyon & Lyon, Los Angeles, Cal., argued, for defendant/cross-appellant. With him on the brief were Douglas E. Olson, Bradford J. Duft and Karol M. Pessin. Also on the brief were Thomas J. Morgan and Melvin Blecher, Lyon & Lyon, Washington, D.C. Arnold Sprung, Sprung Horn Kramer & Woods, New York City, argued, for defendant-appellee. With him on the brief were Nathaniel D. Kramer and Alan J. Grant.
William L. Anthony, Townsend & Townsend, Palo Alton, Cal., represented Chiron Corporation. Of counsel was Noemi C. Espinosa, Townsend & Townsend, Palo Alton, Cal.
Before MARKEY * and NEWMAN, Circuit Judges, and BEER, District Judge. **
This litigation concerns a substance called human Factor VIII:C, a complex protein that occurs naturally in normal blood and is essential to the clotting of blood. The patent in suit, United States Reissue Patent No. 32,011 (the "R'011" patent), is entitled "Ultrapurification of Factor VIII Using Monoclonal Antibodies", inventors Theodore S. Zimmerman and Carol A. Fulcher. Assigned to Scripps Clinic and Research Foundation, it was licensed exclusively to Revlon, Inc. Subsequent to the filing of this suit Revlon sold its interest to Rorer Group, Inc.
By appeal and cross-appeal, the parties 1 raise various issues of patent validity and enforceability, infringement and inducement to infringe, and reissue law and practice, all of which were decided on motions for summary judgment. Each side challenges the decision of certain issues adverse to it, and the final judgment based thereon. 2
Factor VIII:C, called the clotting or procoagulant factor, is found in all mammals, although it differs among species. It has been the subject of extensive scientific research, over many years. At the time the claimed invention was made, it was known that human Factor VIII:C is a complex protein produced by the Factor VIII:C gene and secreted into the blood stream. It occurs in normal blood plasma (plasma is the fluid fraction of blood) at a concentration of about 200 nanograms per milliliter. The total protein content of plasma is about 70 milligrams (0.070 gram) per milliliter; since a nanogram is one billionth of a gram, the total protein in plasma is 350,000 times greater than the Factor VIII:C protein in plasma. Most of the problems faced by researchers attempting to isolate Factor VIII:C were due to the amount and nature of the other proteins in the plasma.
It was known that in normal blood Factor VIII:C exists in complex association with another protein, named the "von Willebrand factor" or Factor VIII:RP (RP means "related protein"). The weight ratio of Factor VIII:C to Factor VIII:RP in normal blood is about 1:100.
Before the invention here at issue was made, scientists had succeeded in concentrating the Factor VIII:C in plasma. This concentrate has been used to replace transfusions of whole blood in the treatment of hemophilia. The process was expensive and, because of the large volume of whole blood needed as starting material, the possibility of contamination and disease from impurities in the source blood, the large amount of extraneous plasma proteins in the concentrate, and the large volume of concentrate that still had to be administered to the patient, there has been a continuing search for improvement. The record reflects the difficulties, over decades of research, in isolating and studying Factor VIII:C. Scripps reports that Genentech's scientists had been working in the field and had not isolated human Factor VIII:C in sufficient purity and amount to conduct successful characterization experiments.
At the Scripps Clinic & Research Foundation, Dr. Zimmerman and Dr. Fulcher were studying Factor VIII:C from human and porcine blood. These scientists succeeded in isolating and, for the first time, characterizing Factor VIII:C, by a process of chromatographic absorption of the Factor VIII:C complex using monoclonal antibodies specific to Factor VIII:RP, followed by separation of the Factor VIII:C. 3 Monoclonal antibodies are produced by the cloned copies of a single hybridoma cell. A hybridoma is a hybrid cell that is immortal: that is, it does not die as do normal cells, but continues to reproduce clones that in turn produce a specific antibody. As described in the R'011 patent, the hybridoma was made by fusing a mouse spleen cell that produced the desired antibody to Factor VIII:RP, with a mouse cancer cell, which contributed the immortality. The patent describes the method of assay for clones producing antibodies to VIII:RP, their isolation, and preparation of the monoclonal antibodies for use as the immunoadsorbent.
The claimed process whereby the Factor VIII:C/VIII:RP complex is separated from the other materials in blood, followed by separation of the VIII:C from the VIII:RP, is described in the R'011 patent and was summarized by Scripps as follows:
The first step involves the application of a solution containing Factor VIII complex (Factor VIII:C/Factor VIII:RP) to a column packed with agarose beads. Attached to the beads is a monoclonal antibody to Factor VIII:RP. The monoclonal antibody binds and immobilizes the Factor VIII:RP part of the Factor VIII complex while the non-Factor VIII materials simply pass through the column. A calcium salt solution is then applied to break the bond between the Factor VIII:C and the Factor VIII:RP. The Factor VIII:C is eluted from the column while the Factor VIII:RP remains bound to the antibody.
The procedure produces purified but dilute Factor VIII:C:
After this first step the Factor VIII:C is highly purified, but dilute. A second step to concentrate the Factor VIII:C solution may then be performed. This involves absorbing the Factor VIII:C on an aminohexylagarose column. The Factor VIII:C on the aminohexyl column is then eluted with a very small amount of calcium salt solution, resulting in a highly concentrated solution of highly purified Factor VIII:C.
The potency and activity 4 of the fractions obtained by this technique were summarized by Scripps as follows When the Factor VIII:C is eluted from either type of column it is collected serially in a number of small, individual portions called "fractions." When the Factor VIII:C is eluted from the monoclonal antibody column, for example, the initial fractions will have little VIII:C. The VIII:C increases as the Factor VIII:C is released. After the majority of Factor VIII:C has been released, the later fractions will contain decreasing amounts.
Table I in the Zimmerman patent contains an analysis of two individual fractions. Patent Fraction 3 has a potency of 1172 units/ml and a specific activity of 2294 units/mg. Patent Fraction 4 is from another experiment and has a potency of 545 units/ml and a specific activity of 2370 units/mg.
Issues raised in this litigation concern purified Factor VIII:C and the reliability and reproducibility of the process, as these aspects relate to the validity, enforceability, and infringement of the R'011 patent claims.
The claims in suit are product-by-process claims 13, 14, 17, 18, and 34, and product claims 24-29. Claim 13 is representative of the product-by-process claims:
13. Highly purified and concentrated human or porcine VIII:C prepared in accordance with the method of claim 1.
Claim 1 is:
(d) eluting the adsorbed VIII:C, and
(e) recovering highly purified and concentrated VIII:C.
Product claims 24-29 were added by reissue, and are the focus of most of the controversy:
24. A human VIII:C preparation having a potency in the range of 134 to 1172 units per ml, and being substantially free of VIII:RP.
25. A human VIII:C preparation of claim 24, wherein the VIII:C concentration is at least 160,000 fold purified relative to VIII:C in plasma. 5
26. A human VIII:C preparation of claim 24, wherein the ratio of VIII:C to VIII:RP is greater than 100,000 times the ratio in plasma.
27. A human VIII:C preparation of claim 24, wherein said VIII:C is isolated from VIII:C/VIII:RP and 90-100 percent of the VIII:RP has been removed.
28. A human VIII:C preparation having a specific activity greater than 2240 units/mg.
29. A human VIII:C preparation of claim 28 wherein the potency is in the range of 134 to 1172 units/ml.
Summary judgment is a useful procedural tool whereby an unnecessary trial is avoided when there are no material facts in dispute. However, summary proceedings are not intended to substitute for trial when it is indeed necessary to find material facts. Meyers v. Brooks Shoe, Inc., 912 F.2d 1459, 1461, 16 USPQ2d 1055, 1056 (Fed.Cir.1990) (). A factual question is material if a reasonable jury could return a verdict for the non-moving party based at least in part on...
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