Wands, In re
| Decision Date | 30 September 1988 |
| Docket Number | No. 87-1454,87-1454 |
| Citation | 858 F.2d 731,8 USPQ2d 1400 |
| Parties | , 8 U.S.P.Q.2d 1400 In re Jack R. WANDS, Vincent R. Zurawski, Jr., and Hubert J.P. Schoemaker. |
| Court | U.S. Court of Appeals — Federal Circuit |
Jorge A. Goldstein, of Saidman, Sterne, Kessler & Goldstein, Washington, D.C., argued for appellant. With him on the brief was Henry N. Wixon, Washington, D.C.
John H. Raubitschek, Associate Sol., Com'r of Patents and Trademarks, of Arlington, Va., argued for appellee. With him on the brief were Joseph F. Nakamura, Sol. and Fred E. McKelvey, Deputy Sol., Washington, D.C.
Before SMITH, NEWMAN, and BISSELL, Circuit Judges.
This appeal is from the decision of the Patent and Trademark Office (PTO) Board of Patent Appeals and Interferences (board) affirming the rejection of all remaining claims in appellant's application for a patent, serial No. 188,735, entitled "Immunoassay Utilizing Monoclonal High Affinity IgM Antibodies," which was filed September 19, 1980. 1 The rejection under 35 U.S.C. Sec. 112, first paragraph, is based on the grounds that appellant's written specification would not enable a person skilled in the art to make the monoclonal antibodies that are needed to practice the claimed invention without undue experimentation. We reverse.
The only issue on appeal is whether the board erred, as a matter of law, by sustaining the examiner's rejection for lack of enablement under 35 U.S.C. Sec. 112, first paragraph, of all remaining claims in appellants' patent application, serial No. 188,735.
The claimed invention involves immunoassay methods for the detection of hepatitis B surface antigen by using high-affinity monoclonal antibodies of the IgM isotype. Antibodies are a class of proteins (immunoglobulins) that help defend the body against invaders such as viruses and bacteria. An antibody has the potential to bind tightly to another molecule, which molecule is called an antigen. The body has the ability to make millions of different antibodies that bind to different antigens. However, it is only after exposure to an antigen that a complicated immune response leads to the production of antibodies against that antigen. For example, on the surface of hepatitis B virus particles there is a large protein called hepatitis B surface antigen (HBsAg). As its name implies, it is capable of serving as an antigen. During a hepatitis B infection (or when purified HBsAg is injected experimentally), the body begins to make antibodies that bind tightly and specifically to HBsAg. Such antibodies can be used as regents for sensitive diagnostic tests (e.g., to detect hepatitis B virus in blood and other tissues, a purpose of the claimed invention). A method for detecting or measuring antigens by using antibodies as reagents is called an immunoassay.
Normally, many different antibodies are produced against each antigen. One reason for this diversity is that different antibodies are produced that bind to different regions (determinants) of a large antigen molecule such as HBsAg. In addition, different antibodies may be produced that bind to the same determinant. These usually differ in the tightness with which they bind to the determinant. Affinity is a quantitative measure of the strength of antibody-antigen binding. Usually an antibody with a higher affinity for an antigen will be more useful for immunological diagnostic tests than one with a lower affinity. Another source of heterogeneity is that there are several immunoglobulin classes or isotypes. Immunoglobulin G (IgG) is the most common isotype in serum. Another isotype, immunoglobulin M (IgM), is prominent early in the immune response. IgM molecules are larger than IgG molecules, and have 10 antigen-binding sites instead of the 2 that are present in IgG. Most immunoassay methods use IgG, but the claimed invention uses only IgM antibodies.
For commercial applications there are many disadvantages to using antibodies from serum. Serum contains a complex mixture of antibodies against the antigen of interest within a much larger pool of antibodies directed at other antigens. These are available only in a limited supply that ends when the donor dies. The goal of monoclonal antibody technology is to produce an unlimited supply of a single purified antibody.
The blood cells that make antibodies are lymphocytes. Each lymphocyte makes only one kind of antibody. During an immune response, lymphocytes exposed to their particular antigen divide and mature. Each produces a clone of identical daughter cells, all of which secrete the same antibody. Clones of lymphocytes, all derived from a single lymphocyte, could provide a source of a single homogeneous antibody. However, lymphocytes do not survive for long outside of the body in cell culture.
Hybridoma technology provides a way to obtain large numbers of cells that all produce the same antibody. This method takes advantage of the properties of myeloma cells derived from a tumor of the immune system. The cancerous myeloma cells can divide indefinitely in vitro. They also have the potential ability to secrete antibodies. By appropriate experimental manipulations, a myeloma cell can be made to fuse with a lymphocyte to produce a single hybrid cell (hence, a hybridoma) that contains the genetic material of both cells. The hybridoma secretes the same antibody that was made by its parent lymphocyte, but acquires the capability of the myeloma cell to divide and grow indefinitely in cell culture. Antibodies produced by a clone of hybridoma cells (i.e., by hybridoma cells that are all progeny of a single cell) are called monoclonal antibodies. 2
The claimed invention involves methods for the immunoassay of HBsAg by using high-affinity monoclonal IgM antibodies. Jack R. Wands and Vincent R. Zurawski, Jr., two of the three coinventors of the present application, disclosed methods for producing monoclonal antibodies against HBsAg in United States patent No. 4,271,145 (the '145 patent), entitled "Process for Producing Antibodies to Hepatitis Virus and Cell Lines Therefor," which patent issued on June 2, 1981. The '145 patent is incorporated by reference into the application on appeal. The specification of the '145 patent teaches a procedure for immunizing mice against HBsAg, and the use of lymphocytes from these mice to produce hybridomas that secrete monoclonal antibodies specific for HBsAg. The '145 patent discloses that this procedure yields both IgG and IgM antibodies with high-affinity binding to HBsAg. For the stated purpose of complying with the best mode requirement of 35 U.S.C. Sec. 112, first paragraph, a hybridoma cell line that secretes IgM antibodies against HBsAg (the 1F8 cell line) was deposited at the American Type Culture Collection, a recognized cell depository, and became available to the public when the '145 patent issued.
The application on appeal claims methods for immunoassay of HBsAg using monoclonal antibodies such as those described in the '145 patent. Most immunoassay methods have used monoclonal antibodies of the IgG isotype. IgM antibodies were disfavored in the prior art because of their sensitivity to reducing agents and their tendency to self-aggregate and precipitate. Appellants found that their monoclonal IgM antibodies could be used for immunoassay of HbsAg with unexpectedly high sensitivity and specificity. Claims 1, 3, 7, 8, 14, and 15 are drawn to methods for the immunoassay of HBsAg using high-affinity IgM monoclonal antibodies. Claims 19 and 25-27 are for chemically modified (e.g., radioactively labeled) monoclonal IgM antibodies used in the assays. The broadest method claim reads:
1. An immunoassay method utilizing an antibody to assay for a substance comprising hepatitis B-surface antigen (HBsAg) determinants which comprises the steps of:
contacting a test sample containing said substance comprising HBsAg determinants with said antibody; and
determining the presence of said substance in said sample;
wherein said antibody is a monoclonal high affinity IgM antibody having a binding affinity constant for said HBsAg determinants of at least 10 9 M 81 .9
Certain claims were rejected under 35 U.S.C. Sec. 103; these rejections have not been appealed. Remaining claims 1, 3, 7, 8, 14, 15, 19, and 25-27 were rejected under 35 U.S.C. Sec. 112, first paragraph, on the grounds that the disclosure would not enable a person skilled in the art to make and use the invention without undue experimentation. The rejection is directed solely to whether the specification enables one skilled in the art to make the monoclonal antibodies that are needed to practice the invention. The position of the PTO is that data presented by Wands show that the production of high-affinity IgM anti-HBsAg antibodies is unpredictable and unreliable, so that it would require undue experimentation for one skilled in the art to make the antibodies.
The first paragraph of 35 U.S.C. Sec. 112 requires that the specification of a patent must enable a person skilled in the art to make and use the claimed invention. "Patents * * * are written to enable those skilled in the art to practice the invention." 3 A patent need not disclose what is well known in the art. 4 Although we review underlying facts found by the board under a "clearly erroneous" standard, 5 we review enablement as a question of law. 6
Where an invention depends on the use of living materials such as microorganisms or cultured cells, it may be impossible to enable the public to make the invention (i.e., to obtain these living materials) solely by means of a written disclosure. One means that has been developed for complying with the enablement requirement is to deposit the living materials in cell depositories which will distribute samples to the public who wish to practice the invention...
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