Hybritech Inc. v. Monoclonal Antibodies, Inc.

• Decision Date: 28 August 1985
• Docket Number: No. C-84-0930 SC.,C-84-0930 SC.
• Parties: HYBRITECH INCORPORATED, a California corporation, Plaintiff, v. MONOCLONAL ANTIBODIES, INC., a California corporation, Defendant.
• Court: U.S. District Court — Northern District of California

623 F. Supp. 1344

227 USPQ 215

HYBRITECH INCORPORATED, a California corporation, Plaintiff, v. MONOCLONAL ANTIBODIES, INC., a California corporation, Defendant.

No. C-84-0930 SC.

United States District Court, N.D. California.

August 28, 1985.

Lyon & Lyon, Los Angeles, Cal., for plaintiff.

Flehr, Hobach, Test, Albritton & Herbert, Cartwright, Sucherman & Slobodin, San Francisco, Cal., for defendant.

FINDINGS OF FACT AND CONCLUSIONS OF LAW

CONTI, District Judge.

This case came on regularly for trial on the 5th day of August, 1985, without a jury, and the trial consumed fifteen days. Plaintiff was represented by Lyon & Lyon of Los Angeles, California, and defendant was represented by Cartwright, Sucherman, & Slobodin, and Flehr, Hohbach, Test, Albritton & Herbert, of San Francisco, California.

The following exposition and later contents herein are all to be considered the court's Findings of Fact and Conclusions of Law.

The Parties

This is a suit by plaintiff Hybritech, Inc. for alleged infringement by defendant Monoclonal Antibodies, Inc. of U.S. Patent No. 4,376,110, entitled "Immunometric Assays Using Monoclonal Antibodies," issued March 8, 1983, to Gary S. David and Howard E. Greene, on application filed August 4, 1980 (hereinafter referred to as the "'110" patent). The plaintiff, Hybritech, commenced its operations in 1979, and the defendant, Monoclonal Antibodies, Inc. (hereinafter sometimes referred to as MAB) also commenced its operations in 1979; both companies are involved in the development, production and sale of diagnostic kits. While the plaintiff markets a broad range of these kits, defendant's kits are limited for pregnancy and ovulation.

The Patent in Suit

The patent in suit is directed to an alleged invention by Dr. Gary David, an immunochemist, and Ted Greene, a science graduate who has worked in management, relating to the development of diagnostic products.

The patent in suit concerns the use of monoclonal antibodies in sandwich assays. Monoclonal antibodies are genetically engineered cells called "hybridomas". These hybridoma cells are produced by fusing mouse spleen cells and malignant mouse cells (called Myelomas). The said patent, cells and assays will be more fully discussed hereinafter.

The invention is a process for determining the presence of, or the amount of, antigen in a fluid sample, such as a patient's blood or urine. An antigen is a substance, usually a protein or carbohydrate, that when introduced into the body stimulates the production of an antibody. One example of an antigen is a foreign substance in the body which causes disease, such as a virus. Another is a substance which evidences a condition of the body. For example, the antigen IgE (immunoglobulin E) is an indication of an allergy condition; the antigen CEA (Carcinoembryonic Antigen) is an indication of colon cancer; and the antigen hCG (human Chorionic Gonadotropin) is an indication of pregnancy. Generally, an antibody may be defined as a substance produced by the body's immune system in response to the presence of a foreign antigen.

The invention of the patent, sometimes called a "sandwich" or "two-site" assay, is a method of analyzing fluids for antigens, employing certain antibodies called "monoclonal antibodies", and taking advantage of their unique properties to obtain an extremely fast, sensitive and accurate analysis. The key issue in this case is whether the defendant has overcome the presumption of non-obviousness.

The subject matter of this patent deals principally with the medical field of immunology, i.e., the workings of the body's immune system.

One of the miraculous processes of the body is its immune system. Each cell in the body has a distinct shape on its surface that distinguishes it from foreign cells. The body's army, its immune system, controls unfamiliar shapes using special troops made in the bone marrow. Certain blood or plasma cells known as lymphocytes learn to recognize the foreign molecular structure of the foreign cell or substance known as the antigen and produce antibodies which lock on to the antigen. The antigen or harmful foreign substance which "raises" the antibody is then rendered harmless in various ways. The antibody/antigen reaction is still not well understood by scientists but it may be thought of as a lock and key fitting arrangement. An antibody at its reactive site is a shape which fits and locks onto a corresponding site on the antigen known as an epitope.

The body has millions of different kinds of lymphocytes each capable of producing an antibody of a very particular structure for the purpose of seeking out a single epitope on an antigen. Once the body is invaded by an antigen a lymphocyte which produces an antibody specific for that antigen will reproduce or clone itself in vast numbers so that a large supply of antibodies to conquer the invader may be produced. These antibodies will be specific for a particular epitope on the antigen. These antibodies being of identical molecular structure, all being made of the same clones, may be termed monoclonal antibodies. However, in the body of an animal, even though monoclonal antibodies are produced by the animal, they are always found together with other antibodies. Therefore, when the blood or serum of an animal is taken for its antibodies, the mixture found is known as "polyclonal antibodies" because it is derived from different (poly)-clones.

Introduction of an antigen into the body is termed "immunization" because it stimulates production of polyclonal antibodies which can cause immunity to the infection caused by that antigen. Most antigens are also complex and have a large number of distinct epitopes. One characteristic of an antibody is its specificity or ability to bind to a particular epitope. Another characteristic is sensitivity, defined as the smallest amount of antigen that can be detected by the antibody. Sensitivity is related to a theoretical characteristic known as affinity, which is a measure of the binding strength of an antibody for its antigen. While affinity calculations can be made for simple or small molecules, it is very difficult to do for large, complex molecules involving extremely complex reactions and can only be estimated. Also, the affinity estimations vary to a significant extent, depending upon the conditions of experiments used for the estimations.

Although the polyclonal antibodies were and are effective tools for use in immunoassay, they had certain disadvantages. If the animal died, the source of antibodies was gone and no one knew how antibodies from a different animal would compare. Also, the immune system of the animal could suddenly change the type of antibody being produced. Thus, supply of antibodies was limited and uncertain.

Since it was known that the body produced "monoclonal antibodies" within the body or "in vivo", scientists knew that if they could produce these monoclonal antibodies outside of the body or "in vitro", these problems and others would be solved. However, the plasma cells making the antibodies would not live outside of the animal and the concept of large scale production of monoclonal antibodies was only a dream until Kohler and Milstein produced their classic paper in 1975 based on a discovery they had made on how to produce monoclonal antibodies. For this work, Kohler and Milstein in 1984 received a Nobel prize.

Georges Kohler and Cesar Milstein took a tumor consisting of cancer cells which grew in vitro and fused them with normal antibody producing cells. The fusion resulted in what is called a hybridoma cell. These hybridoma cells could survive, and be cultured in vitro. Through the use of other techniques, the individual hybridoma cells could be segregated and the segregated individual cells could be cloned. These clones produce antibody molecules of identical structure or monoclonal antibodies. Suddenly, it became possible to produce tailor-made, highly specific monoclonal antibodies in vast quantities. The obvious uses for diagnostic purposes of these monoclonal antibodies became evident to those in the scientific and commercial world.

Two well-known diagnostic assay procedures using polyclonal antibodies in the prior art included "competitive assays" and "sandwich assays". In a competitive assay for an antigen in a sample, a known quantity of the same antigen is labelled. In a competitive assay for an antigen, the limited amount of antibody is bound to a solid surface. The sample containing an unknown amount of antigen is contacted with the antibody together with a known amount of labelled antigen. The labelled antigen will "compete" with any unlabelled antigen to react with the bound antibody. If there is no antigen in the test sample, all of the antigen attached to the antibody will be labelled. The greater the amount of antigen in the test sample, the less the amount of labelled antigen there will be detected. Since only a limited amount of antibody is required, this competitive test was popular with polyclonal antibodies because of the difficulty of obtaining large amount of antibodies.

In one form of the sandwich assay for the antigen, a large amount of antibody is bound to the solid surface and it is exposed to the test sample containing the unknown amount of antigen. If antigen with epitopes recognized by the antibody is present, it should bind to the antibody on the solid surface. At that point, labelled antibody, also in excess amount, is added to the solution. The labelled antibody will now bind to an epitope on another part of the antigen, thus the formation of a sandwich. See Figure 1. If all of the reagents, i.e., reacting materials, antibodies and antigen, are added at the same time, it would be termed a simultaneous sandwich assay. All of this was known to the prior art.

People working in immunology aware of the Kohler and Milstein discovery, knew that monoclonal antibodies could be used in place of...