Massachusetts Institute of Technology v. AB Fortia

• Decision Date: 07 October 1985
• Docket Number: No. 84-1766,84-1766
• Citation: 227 USPQ 428,774 F.2d 1104
• Parties: , 227 U.S.P.Q. 428, 4 Fed. Cir. (T) 8 MASSACHUSETTS INSTITUTE OF TECHNOLOGY, Petitioner, v. AB FORTIA, Pharmacia AB, Pharmacia Fine Chemicals AB, Pharmacia, Inc. and U.S. International Trade Commission, Respondents. Appeal
• Court: U.S. Court of Appeals — Federal Circuit

Page 1104

774 F.2d 1104

7 ITRD 1405, 227 U.S.P.Q. 428, 4 Fed.

Cir. (T) 8

MASSACHUSETTS INSTITUTE OF TECHNOLOGY, Petitioner, v. AB FORTIA, Pharmacia AB, Pharmacia Fine Chemicals AB Pharmacia, Inc. and U.S. International Trade Commission, Respondents.

Appeal No. 84-1766.

United States Court of Appeals Federal Circuit.

Oct. 7, 1985.

David E. Brook, Hamilton, Brook, Smith & Reynolds, of Lexington, Md., and Harvey Kaye, Lalos, Leeds, Keegan, Lett, Marsh, Bentzen & Kaye, Washington, D.C., argued for petitioner. With them on brief were James M. Smith and Leo R. Reynolds, of Hamilton, Brook, Smith & Reynolds, Lexington, Md., and David S. Klontz, of Lalos, Leeds, Keegan, Lett, Marsh, Bentzen & Kaye, Washington, D.C.

Maurice B. Stiefel, Stiefel, Gross, Kurland & Pavane, P.C., New York City, argued for respondent AB. With him on brief were Marc S. Gross, Thomas C. Pontani and James A. Quinton, New York City.

Wayne W. Herrington, Office of Gen. Counsel, U.S. Intern. Trade Com'n, Washington, D.C., argued for respondent Intern. Trade Com'n. With him on brief were Lyn M. Schlitt, Gen. Counsel and Michael P. Mabile, Asst. Gen. Counsel, Washington, D.C.

Before MARKEY, Chief Judge, and FRIEDMAN, and RICH, Circuit Judges.

RICH, Circuit Judge.

This appeal is from the final decision of the United States International Trade Commission (Commission or ITC) in Certain Limited-Charge Cell Culture Microcarriers, Investigation No. 337-TA-129, an investigation under section 337 of the Tariff Act of 1930, as amended, 19 U.S.C. Sec. 1337 (section 337), determining that there was no violation of section 337 by the importation of certain biological cell culture products by respondents AB Fortia, Pharmacia AB, et al. We affirm.

Background

Cell culture technology is concerned with the development of the most efficient and safe or hygienic means of growing different types of cells, which are important for the production of cell growth by-products, including viral agents for vaccines, interferon, and hormones. Mammalian cells in particular are used to synthesize many valuable proteins. In many cases, the best or only source of these proteins is culturing the mammalian cells known to produce them. Interferon, for example, is a glyco-protein product of certain mammalian cells such as fibroblasts (connective tissue) or lymphocytes (white blood cells).

Culturing mammalian cells on a large scale requires strict nutritional and environmental controls. Among these environmental requirements is the need for a solid surface or substrate on which the cells can grow. The majority of mammalian cells are thus said to be "anchorage-dependent." One technique for culturing anchorage-dependent cells on a large scale involves the use of cell culture "microcarriers," which are microscopic beads suitable for cell attachment and growth.

The earliest microcarrier culture system was developed in the Netherlands by Dr. Anton L. van Wezel, conceded to be the "father" of microcarriers, and was reported in the journal Nature in 1967. In this research, Dr. van Wezel employed commercially available anion exchange resin beads, specifically respondent Pharmacia's DEAE-Sephadex A-50 (A-50) beads, which he called "microcarriers." As a result of the positively charged amino (diethylaminoethyl, or DEAE) groups attached to the beads, these A-50 beads have a positive ionic charge on their surfaces. The amount of positive charge is known as the "total charge capacity." Mammalian cells, which are negatively charged, attach and grow on the A-50 beads because of the positive charge groups.

When Dr. van Wezel attempted to increase the concentration of A-50 beads in his cell cultures, he encountered problems that he characterized as the "toxicity phenomenon," and reported these in a 1969 article in the journal Biotechnology and Bioengineering. Although van Wezel experimented with beads having a lower total charge capacity than the A-50 beads in an attempt to overcome the toxicity phenomenon, he reported in a 1973 article that the toxicity problem could best be overcome by coating the beads with a negatively charged polyanion, nitrocellulose.

The MIT Patents

Research at Massachusetts Institute of Technology (MIT) in the microcarrier field was initiated as a result of a National Science Foundation grant in 1974. In September, 1975, David Levine of the MIT research team delivered an oral presentation in Birmingham, Alabama, printed copies of which were distributed to a number of scientists (the "Birmingham paper"), which indicated that optimal cell adhesion and growth could be obtained by reducing the total charge capacity of microcarriers such as the A-50 beads.

In December, 1975, the MIT group observed that significantly improved cell growth was occurring on synthesized microcarriers that had total charge capacities ¹ considerably lower than the A-50 beads. Further experiments by the MIT group indicated that the appropriate charge capacity range was 0.1 to 4.5 microcarrier charge milliequivalents (meq) per gram. Microcarriers having charge capacities within this limited range were termed "limited-charge cell culture microcarriers."

The MIT group filed a patent application covering the development of limited-charge cell culture microcarriers on November 11, 1976, and on October 19, 1977, filed a continuation in-part (C-I-P) application that included experimental results obtained subsequent to the filing of the parent application. The claims in the C-I-P application pertained to the use of limited-charge (0.1 to 4.5 meq/gram, measured on the MIT basis) cell culture microcarriers to grow anchorage-dependent cells and to produce cell-growth by-products. The C-I-P application issued as U.S. Patent No. 4,189,534 ('534 patent) on February 19, 1980. The parent application was restricted to claims directed to the microcarriers per se, and a divisional application with those claims issued as U.S. Patent No. 4,293,654 ('654 patent) on October 6, 1981.

To commercially develop its microcarrier technology, MIT licensed Flow General, Inc., under the '534 and '654 patents. Flow General and its subsidiary Flow Laboratories (collectively, "Flow") are located in McLean, Virginia, and manufacture and sell products for cell culturing, including media and sera required for cell growth. The microcarriers involved in the process at issue here were actually manufactured in Scotland. Flow Laboratories, Ltd., Flow's subsidiary in Scotland, purchased the commercially available uncharged Sephadex G-50 beads from Pharmacia, to which the positively charged DEAE groups were attached. The microcarriers were bottled in Scotland, then shipped to the United States for final quality control testing.

MIT later agreed to a modification of its original agreement with Flow, effective January 1, 1981, that appointed Flow as the exclusive licensing agent for MIT in regard to limited-charge cell culture microcarrier technology, in return for which Flow guaranteed minimum annual royalties to MIT of $400,000.

The Section 337 Investigation

The ITC investigation under review here was initiated on July 19, 1982, based on a complaint filed under section 337 by MIT and Flow. Pharmacia AB (formerly known as AB Fortia), Pharmacia Fine Chemicals AB, all of Upsala, Sweden, and Pharmacia, Inc., of Piscataway, New Jersey (collectively, "Pharmacia"), were named as respondents.

Pharmacia imports three microcarrier products into the United States. Their "Cytodex" microcarriers admittedly have a total charge capacity of 0.1 to 1.5 meq/gram, measured on the conventional basis. MIT's complaint alleged that Pharmacia's microcarriers infringed MIT's '534 and '654 patents and that their importation from Sweden constituted unauthorized manufacture abroad. As a result of MIT's complaint, the Commission initiated this investigation, made its final determination on November 18, 1983, and issued a written opinion on November 22, 1983.

The Commission Decision

The Commission determined there was no violation of section 337 because the '534 and '654 patents were invalid and because, to the extent there was "an industry ... in the United States" within the meaning of section 337, the importation and sale of Pharmacia's Cytodex microcarriers did not substantially injure that industry.

Based upon an examination of the scope and content of the prior art and the patent claims, the Commission concluded that the inventions claimed in the '534 and '654 patents would have been obvious. The Commission noted that the prior art A-50 ion exchange beads were "well-known to be useful as cell culture microcarriers," and that the only difference between the A-50 beads and the claimed microcarriers "is the lower charge capacity of the latter." The "toxicity phenomenon" noted by van Wezel with respect to high concentrations of A-50 beads was known to have been overcome by pretreatment with serum or a polyanion, such as nitrocellulose. The Birmingham paper expressly stated that to reduce the total charge capacity of the A-50 beads would have the same effect as the pretreatment. Finally, the Commission noted that the prior art clearly showed how to achieve this reduced charge capacity, and also indicated that anion exchange beads with such a reduced charge capacity were already commercially available. On this basis, the Commission concluded that the claimed inventions would have been obvious.

The Commission also found that there were two separate industries under the two MIT patents because microcarriers (covered by the '654 patent) and cell growth by-products (covered by the '534 patent) were distinct commercial products. Specifically, the Commission found that operations under the '654 patent were not "an industry ... in the United States" because all of Flow's microcarriers were manufactured in Scotland and the nature and significance of Flow's activities in the United States with respect to them did not justify treatment as "an industry in the...