In re Wands, 858 F.2d 731 (1988)
`57 USLW 2264, 8 U.S.P.Q.2d 1400
`
`KeyCite Yellow Flag - Negative Treatment
` Distinguished by Ex Parte Marianne Harboe, Bd.Pat.App. &
`Interf., May 19, 2009
`
`
`
`858 F.2d 731
`United States Court of Appeals,
`Federal Circuit.
`
`In re Jack R. WANDS, Vincent R.
`Zurawski, Jr., and Hubert J.P. Schoemaker.
`
`No. 87–1454.
`|
`Sept. 30, 1988.
`
`Inventors of method to create immunoassay of hepatitis
`B surface antigen using monoclonal antibodies sought
`patent. The Board of Patent Appeals and Interferences
`denied the patent on grounds it was not enabling. On
`appeal, the Court of Appeals, Edward S. Smith, Circuit
`Judge, held that: (1) determination of enablement is
`reviewed as question of law; (2) while deposit of living
`cells can be used to satisfy enabling requirement, it is not
`necessary; (3) undue experimentation was not necessary
`to produce art for method of immunoassay of hepatitis
`B surface antigen using monoclonal antibodies; and (4)
`enablement of patent involving living microorganisms is
`not precluded by necessity of some experiments such as
`routine screening.
`
`Reversed.
`
`Pauline Newman, Circuit Judge, concurred in part and
`dissented in part with opinion.
`
`Attorneys and Law Firms
`
`*732 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.
`
`Opinion
`
`*733 EDWARD S. SMITH, Circuit Judge.
`
`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.
`§ 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.
`
`1
`
`In re Wands, Appeal No. 673–76 (Bd.Pat.App. & Int.
`Dec. 30, 1986).
`
`I. Issue
`
`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. § 112, first paragraph,
`of all remaining claims in appellants' patent application,
`serial No. 188,735.
`
`II. Background
`
`A. The Art.
`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
`
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`In re Wands, 858 F.2d 731 (1988)
`57 USLW 2264, 8 U.S.P.Q.2d 1400
`
`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.
`
`are many
`there
`applications
`commercial
`For
`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
`*734 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
`
`2
`
`For a concise description of monoclonal antibodies
`and their use in immunoassay see Hybritech, Inc. v.
`Monoclonal Antibodies, Inc., 802 F.2d 1367, 1368–71,
`231 USPQ 81, 82–83 (Fed.Cir.1986), cert. denied, 480
`U.S. 947, 107 S.Ct. 1606, 94 L.Ed.2d 792 (1987).
`
`B. The Claimed Invention.
`the
`for
`involves methods
`The claimed
`invention
`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. § 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.
`
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`In re Wands, 858 F.2d 731 (1988)
`57 USLW 2264, 8 U.S.P.Q.2d 1400
`
`for
`The application on appeal claims methods
`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 −1 .
`
`Certain claims were rejected under 35 U.S.C. § 103;
`these rejections have not *735 been appealed. Remaining
`claims 1, 3, 7, 8, 14, 15, 19, and 25–27 were rejected
`under 35 U.S.C. § 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.
`
`III. Analysis
`
`A. Enablement by Deposit of Microorganisms and Cell
`Lines.
`[1]
` The first paragraph of 35 U.S.C. § 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
`
`3
`
`4
`
`5
`
`6
`
`W.L. Gore & Assocs., Inc. v. Garlock, Inc., 721 F.2d
`1540, 1556, 220 USPQ 303, 315 (Fed.Cir.1983), cert.
`denied, 469 U.S. 851, 105 S.Ct. 172, 83 L.Ed.2d 107
`(1984).
`
`Lindemann Maschinenfabrik GMBH v. American
`Hoist & Derrick Co., 730 F.2d 1452, 1463, 221 USPQ
`481, 489 (Fed.Cir.1984).
`
`Coleman v. Dines, 754 F.2d 353, 356, 224 USPQ 857,
`859 (Fed.Cir.1985).
`
`Moleculon Research Corp. v. CBS, Inc., 793 F.2d
`1261, 1268, 229 USPQ 805, 810 (Fed.Cir.1986), cert.
`denied, 479 U.S. 1030, 107 S.Ct. 875, 93 L.Ed.2d 829
`(1987); Raytheon Co. v. Roper Corp., 724 F.2d 951,
`960 n. 6, 220 USPQ 592, 599 n. 6 (Fed.Cir.1983), cert.
`denied, 469 U.S. 835, 105 S.Ct. 127, 83 L.Ed.2d 69
`(1984).
`
`[2]
` 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 after the patent
`issues. 7 Administrative guidelines and judicial decisions
`have clarified the conditions under which a deposit of
`organisms can satisfy the requirements of section 112. 8
`A deposit has been held necessary for enablement where
`the starting materials (i.e., the living cells used to practice
`the invention, or cells from which the required cells can be
`produced) are not readily available to the public. 9 Even
`when starting materials are available, a deposit has been
`necessary where it would require undue experimentation
`
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`In re Wands, 858 F.2d 731 (1988)
`57 USLW 2264, 8 U.S.P.Q.2d 1400
`
`to make the cells of the invention from the starting
`materials. 10
`
`7
`
`8
`
`9
`
`10
`
`In re Argoudelis, 434 F.2d 1390, 1392–93, 168 USPQ
`99, 101–02 (CCPA 1970).
`
`In re Lundak, 773 F.2d 1216, 227 USPQ 90
`(Fed.Cir.1985); Feldman v. Aunstrup, 517 F.2d 1351,
`186 USPQ 108 (CCPA 1975), cert. denied, 424 U.S.
`912, 96 S.Ct. 1109, 47 L.Ed.2d 316 (1976); Manual
`of Patent Examining Procedure (MPEP) 608.01(p)
`(C) (5th ed. 1983, rev. 1987). See generally Hampar,
`Patenting of Recombinant DNA Technology: The
`Deposit Requirement, 67 J.Pat. Trademark Off. Soc'y
`569 (1985).
`
`In re Jackson, 217 USPQ 804, 807–08 (Bd.App.1982)
`(strains of a newly discovered species of bacteria
`isolated from nature); Feldman, 517 F.2d 1351, 186
`USPQ 108 (uncommon fungus isolated from nature);
`In re Argoudelis, 434 F.2d at 1392, 168 USPQ at 102
`(novel strain of antibiotic-producing microorganism
`isolated from nature); In re Kropp, 143 USPQ 148,
`152 (Bd.App.1959) (newly discovered microorganism
`isolated from soil).
`
`In re Forman, 230 USPQ 546, 547 (Bd.Pat.App.
`& Int.1986) (genetically engineered bacteria where
`the specification provided insufficient information
`about the amount of time and effort required); In re
`Lundak, 773 F.2d 1216, 227 USPQ 90 (unique cell line
`produced from another cell line by mutagenesis).
`
`In addition to satisfying the enablement requirement,
`deposit of organisms also can be used to establish the filing
`date of the application as the prima facie date of invention,
`*736 11 and to satisfy the requirement under 35 U.S.C.
`§ 114 that the PTO be guaranteed access to the invention
`during pendency of the application. 12 Although a deposit
`may serve these purposes, we recognized, in In re
`Lundak, 13 that these purposes, nevertheless, may be met
`in ways other than by making a deposit.
`
`11
`
`12
`
`13
`
`In re Lundak, 773 F.2d at 1222, 227 USPQ at 95–96;
`In re Feldman, 517 F.2d at 1355, 186 USPQ at 113; In
`re Argoudelis, 434 F.2d at 1394–96, 168 USPQ at 103–
`04 (Baldwin, J. concurring).
`
`In re Lundak, 773 F.2d at 1222, 227 USPQ at 95–96;
`In re Feldman, 517 F.2d at 1354, 186 USPQ at 112.
`
`In re Lundak, 773 F.2d at 1222, 227 USPQ at 95–96.
`
`A deposit also may satisfy the best mode requirement
`of section 112, first paragraph, and it is for this reason
`that the 1F8 hybridoma was deposited in connection with
`the '145 patent and the current application. Wands does
`not challenge the statements by the examiner to the effect
`that, although the deposited 1F8 line enables the public
`to perform immunoassays with antibodies produced by
`that single hybridoma, the deposit does not enable the
`generic claims that are on appeal. The examiner rejected
`the claims on the grounds that the written disclosure was
`not enabling and that the deposit was inadequate. Since we
`hold that the written disclosure fully enables the claimed
`invention, we need not reach the question of the adequacy
`of deposits.
`
`B. Undue Experimentation.
`[4]
`[5]
`[3]
`involving
`inventions
`
`
` Although
`microorganisms or other living cells often can be enabled
`by a deposit, 14 a deposit is not always necessary to satisfy
`the enablement requirement. 15 No deposit is necessary
`if the biological organisms can be obtained from readily
`available sources or derived from readily available starting
`materials through routine screening that does not require
`undue experimentation. 16 Whether the specification in
`an application involving living cells (here, hybridomas) is
`enabled without a deposit must be decided on the facts of
`the particular case. 17
`
`14
`
`15
`
`16
`
`17
`
`In re Argoudelis, 434 F.2d at 1393, 168 USPQ at 102.
`
`Tabuchi v. Nubel, 559 F.2d 1183, 194 USPQ 521
`(CCPA 1977).
`
`Id. at 1186–87, 194 USPQ at 525; Merck & Co. v.
`Chase Chem. Co., 273 F.Supp. 68, 77, 155 USPQ
`139, 146 (D.N.J.1967); Guaranty Trust Co. v. Union
`Solvents Corp., 54 F.2d 400, 403–06, 12 USPQ 47, 50–
`53 (D.Del.1931), aff'd, 61 F.2d 1041, 15 USPQ 237 (3d
`Cir.1932), cert. denied, 288 U.S. 614, 53 S.Ct. 405, 77
`L.Ed. 987 (1933); MPEP 608.01(p)(C) (“No problem
`exists when the microorganisms used are known and
`readily available to the public.”).
`
`In re Jackson, 217 USPQ at 807; see In re Metcalfe,
`410 F.2d 1378, 1382, 161 USPQ 789, 792 (CCPA
`1969).
`
`[6]
` Appellants contend that their written specification
`fully enables the practice of their claimed invention
`because the monoclonal antibodies needed to perform
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`In re Wands, 858 F.2d 731 (1988)
`57 USLW 2264, 8 U.S.P.Q.2d 1400
`
`the immunoassays can be made from readily available
`starting materials using methods that are well known
`in the monoclonal antibody art. Wands states that
`application of these methods to make high-affinity IgM
`anti-HBsAg antibodies requires only routine screening,
`and that does not amount to undue experimentation.
`There is no challenge to their contention that the starting
`materials (i.e., mice, HBsAg antigen, and myeloma cells)
`are available to the public. The PTO concedes that the
`methods used to prepare hybridomas and to screen them
`for high-affinity IgM antibodies against HBsAg were
`either well known in the monoclonal antibody art or
`adequately disclosed in the '145 patent and in the current
`application. This is consistent with this court's recognition
`with respect to another patent application that methods
`for obtaining and screening monoclonal antibodies were
`well known in 1980. 18 The sole issue is whether, in this
`particular case, it would require undue experimentation to
`produce high-affinity IgM monoclonal antibodies.
`
`18
`
`Hybritech, 802 F.2d at 1384, 231 USPQ at 94.
`
`[7]
` Enablement is not precluded by the necessity for
`some experimentation such as *737 routine screening. 19
`However, experimentation needed
`to practice
`the
`invention must not be undue experimentation. 20 “The
`key word is ‘undue,’ not ‘experimentation.’ ” 21
`
`19
`
`20
`
`21
`
`Id.; Atlas Powder Co. v. E.I. DuPont De Nemours
`& Co., 750 F.2d 1569, 1576, 224 USPQ 409, 413
`(Fed.Cir.1984); In re Angstadt, 537 F.2d at 502–504,
`190 USPQ at 218; In re Geerdes, 491 F.2d 1260,
`1265, 180 USPQ 789, 793 (CCPA 1974); Mineral
`Separation, Ltd. v. Hyde, 242 U.S. 261, 270–71, 37
`S.Ct. 82, 86, 61 L.Ed. 286 (1916).
`
`Hybritech, 802 F.2d at 1384, 231 USPQ at 94; W.L.
`Gore, 721 F.2d at 1557, 220 USPQ at 316; In re
`Colianni, 561 F.2d 220, 224, 195 USPQ 150, 153
`(CCPA 1977) (Miller, J., concurring).
`
`In re Angstadt, 537 F.2d at 504, 190 USPQ at 219.
`
`The determination of what constitutes undue
`experimentation in a given case requires the application
`of a standard of reasonableness, having due regard for
`the nature of the invention and the state of the art.
`Ansul Co. v. Uniroyal, Inc. [448 F.2d 872, 878–79; 169
`USPQ 759, 762–63 (2d Cir.1971), cert. denied, 404 U.S.
`1018, 92 S.Ct. 680, 30 L.Ed.2d 666 (1972) ]. The test is
`
`not merely quantitative, since a considerable amount of
`experimentation is permissible, if it is merely routine,
`or if the specification in question provides a reasonable
`amount of guidance with respect to the direction in
`which the experimentation should proceed * * *. 22
`In re Jackson, 217 USPQ at 807.
`
`22
`
`[8]
` The term “undue experimentation” does not
`appear in the statute, but it is well established that
`enablement requires that the specification teach those in
`the art to make and use the invention without undue
`experimentation. 23 Whether undue experimentation is
`needed is not a single, simple factual determination,
`but rather is a conclusion reached by weighing many
`factual considerations. The board concluded that undue
`experimentation would be needed to practice the invention
`on the basis of experimental data presented by Wands.
`These data are not in dispute. However, Wands and the
`board disagree strongly on the conclusion that should be
`drawn from that data.
`
`23
`
`See Hybritech, 802 F.2d at 1384, 231 USPQ at 94;
`Atlas Powder, 750 F.2d at 1576, 224 USPQ at 413.
`
`[9]
` Factors to be considered in determining whether
`a disclosure would require undue experimentation have
`been summarized by the board in In re Forman. 24 They
`include (1) the quantity of experimentation necessary, (2)
`the amount of direction or guidance presented, (3) the
`presence or absence of working examples, (4) the nature
`of the invention, (5) the state of the prior art, (6) the
`relative skill of those in the art, (7) the predictability or
`unpredictability of the art, and (8) the breadth of the
`claims. 25
`
`24
`
`25
`
`In re Forman, 230 USPQ at 547.
`
`Id.; see In re Colianni, 561 F.2d at 224, 195 USPQ
`at 153 (Miller, J., concurring); In re Rainer, 347 F.2d
`574, 577, 146 USPQ 218, 221 (CCPA 1965).
`
`In order to understand whether the rejection was proper,
`it is necessary to discuss further the methods for making
`specific monoclonal antibodies. The first step for making
`monoclonal antibodies is to immunize an animal. The
`'145 patent provides a detailed description of procedures
`for immunizing a specific strain of mice against HBsAg.
`Next the spleen, an organ rich in lymphocytes, is removed
`and the lymphocytes are separated from the other spleen
`cells. The lymphocytes are mixed with myeloma cells,
`
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`In re Wands, 858 F.2d 731 (1988)
`57 USLW 2264, 8 U.S.P.Q.2d 1400
`
`and the mixture is treated to cause a few of the cells
`to fuse with each other. Hybridoma cells that secrete
`the desired antibodies then must be isolated from the
`enormous number of other cells in the mixture. This is
`done through a series of screening procedures.
`
`The first step is to separate the hybridoma cells from
`unfused lymphocytes and myeloma cells. The cells are
`cultured in a medium in which all the lymphocytes and
`myeloma cells die, and only the hybridoma cells survive.
`The next step is to isolate and clone hybridomas that
`make antibodies *738 that bind to the antigen of interest.
`Single hybridoma cells are placed in separate chambers
`and are allowed to grow and divide. After there are
`enough cells in the clone to produce sufficient quantities of
`antibody to analyze, the antibody is assayed to determine
`whether it binds to the antigen. Generally, antibodies from
`many clones do not bind the antigen, and these clones
`are discarded. However, by screening enough clones (often
`hundreds at a time), hybridomas may be found that secrete
`antibodies against the antigen of interest.
`
`Wands used a commercially available radioimmunoassay
`kit to screen clones for cells that produce antibodies
`directed against HBsAg. In this assay the amount of
`radioactivity bound gives some indication of the strength
`of the antibody-antigen binding, but does not yield a
`numerical affinity constant, which must be measured
`using the more laborious Scatchard analysis. In order
`to determine which anti-HBsAg antibodies satisfy all
`of the limitations of appellants' claims, the antibodies
`require further screening to select those which have an
`IgM isotype and have a binding affinity constant of at
`least 10 9 M −1 . 26 The PTO does not question that the
`screening techniques used by Wands were well known in
`the monoclonal antibody art.
`
`26
`
`The examiner, the board, and Wands all point
`out that, technically, the strength of antibody-
`HBsAg binding is measured as avidity, which takes
`into account multiple determinants on the HBsAg
`molecule, rather than affinity. Nevertheless, despite
`this correction, all parties then continued to use
`the term “affinity.” We will use the terminology of
`the parties. Following the usage of the parties, we
`will also use the term “high-affinity” as essentially
`synonymous with “having a binding affinity constant
`of at least 10 9 M −1 .
`
`During prosecution Wands submitted a declaration under
`37 C.F.R. § 1.132 providing information about all of
`the hybridomas that appellants had produced before
`filing the patent application. The first four fusions were
`unsuccessful and produced no hybridomas. The next six
`fusion experiments all produced hybridomas that made
`antibodies specific for HBsAg. Antibodies that bound at
`least 10,000 cpm in the commercial radioimmunoassay
`were classified as “high binders.” Using this criterion,
`143 high-binding hybridomas were obtained. In the
`declaration, Wands stated that 27
`
`27
`
`A table in the declaration presented the binding
`data for antibodies from every cell line. Values
`ranged from 13,867 to 125,204 cpm, and a substantial
`proportion of the antibodies showed binding greater
`than 50,000 cpm. In confirmation of Dr. Wand's
`statement, two antibodies with binding less than
`25,000 cpm were found to have affinity constants
`greater than 10 9 M –1 .
`
`It is generally accepted in the art that, among those
`antibodies which are binders with 50,000 cpm or higher,
`there is a very high likelihood that high affinity (Ka
`[greater than] 10 9 M −1 – 1 ) antibodies will be found.
`However, high affinity antibodies can also be found
`among high binders of between 10,000 and 50,000, as is
`clearly demonstrated in the Table.
`The PTO has not challenged this statement.
`The declaration stated that a few of the high-binding
`monoclonal antibodies from two fusions were chosen for
`further screening. The remainder of the antibodies and the
`hybridomas that produced them were saved by freezing.
`Only nine antibodies were subjected to further analysis.
`Four (three from one fusion and one from another fusion)
`fell within the claims, that is, were IgM antibodies and
`had a binding affinity constant of at least 10 9 M −1 – 1 .
`Of the remaining five antibodies, three were found to be
`IgG, while the other two were IgM for which the affinity
`constants were not measured (although both showed
`binding well above 50,000 cpm).
`
`Apparently none of the frozen cell lines received any
`further analysis. The declaration explains that after useful
`high-affinity IgM monoclonal antibodies to HBsAg had
`been found, it was considered unnecessary to return to the
`stored antibodies to screen for more IgMs. Wands says
`that the existence of the stored hybridomas was disclosed
`
` © 2017 Thomson Reuters. No claim to original U.S. Government Works.
`
`6
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`

`In re Wands, 858 F.2d 731 (1988)
`57 USLW 2264, 8 U.S.P.Q.2d 1400
`
`to the PTO to comply with the requirement under 37
`C.F.R. § 1.56 that applicants fully disclose all of their
`relevant *739 data, and not just favorable results. 28
`How these stored hybridomas are viewed is central to the
`positions of the parties.
`
`28
`
`See Rohm & Haas Co. v. Crystal Chem. Co., 722 F.2d
`1556, 220 USPQ 289 (Fed.Cir.1983).
`
`The position of the board emphasizes the fact that since
`the stored cell lines were not completely tested, there is
`no proof that any of them are IgM antibodies with a
`binding affinity constant of at least 10 9 M −1 – 1 . Thus,
`only 4 out of 143 hybridomas, or 2.8 percent, were proved
`to fall within the claims. Furthermore, antibodies that
`were proved to be high-affinity IgM came from only 2
`of 10 fusion experiments. These statistics are viewed by
`the board as evidence that appellants' methods were not
`predictable or reproducible. The board concludes that
`Wands' low rate of demonstrated success shows that a
`person skilled in the art would have to engage in undue
`experimentation in order to make antibodies that fall
`within the claims.
`
`Wands views the data quite differently. Only nine
`hybridomas were actually analyzed beyond the initial
`screening for HBsAg binding. Of these, four produced
`antibodies that fell within the claims, a respectable 44
`percent rate of success. (Furthermore, since the two
`additional IgM antibodies for which the affinity constants
`were never measured showed binding in excess of 50,000
`cpm, it is likely that these also fall within the claims.)
`Wands argues that the remaining 134 unanalyzed, stored
`cell lines should not be written off as failures. Instead, if
`anything, they represent partial success. Each of the stored
`hybridomas had been shown to produce a high-binding
`antibody specific for HBsAg. Many of these antibodies
`showed binding above 50,000 cpm and are thus highly
`likely to have a binding affinity constant of at least 10 9
`M −1 – 1 . Extrapolating from the nine hybridomas that
`were screened for isotype (and from what is well known
`in the monoclonal antibody art about isotype frequency),
`it is reasonable to assume that the stored cells include
`some that produce IgM. Thus, if the 134 incompletely
`analyzed cell lines are considered at all, they provide some
`support (albeit without rigorous proof) to the view that
`hybridomas falling within the claims are not so rare that
`undue experimentation would be needed to make them.
`
`The first four fusion attempts were failures, while high-
`binding antibodies were produced in the next six fusions.
`Appellants contend that the initial failures occurred
`because they had not yet learned to fuse cells successfully.
`Once they became skilled in the art, they invariably
`obtained numerous hybridomas that made high-binding
`antibodies against HBsAg and, in each fusion where they
`determined isotype and binding affinity they obtained
`hybridomas that fell within the claims.
`
`Wands also submitted a second declaration under 37
`C.F.R. § 1.132 stating that after the patent application was
`submitted they performed an eleventh fusion experiment
`and obtained another hybridoma that made a high-
`affinity IgM anti-HBsAg antibody. No information was
`provided about the number of clones screened in that
`experiment. The board determined that, because there was
`no indication as to the number of hybridomas screened,
`this declaration had very little value. While we agree that
`it would have been preferable if Wands had included
`this information, the declaration does show that when
`appellants repeated their procedures they again obtained
`a hybridoma that produced an antibody that fit all of the
`limitations of their claims.
`
`We conclude that the board's interpretation of the data
`is erroneous. It is strained and unduly harsh to classify
`the stored cell lines (each of which was proved to
`make high-binding antibodies against HBsAg) as failures
`demonstrating that Wands' methods are unpredictable
`or unreliable. 29 At worst, they prove nothing at all
`about the probability of success, and merely show *740
`that appellants were prudent in not discarding cells
`that might someday prove useful. At best, they show
`that high-binding antibodies, the starting materials for
`IgM screening and Scatchard analysis, can be produced
`in large numbers. The PTO's position leads to the
`absurd conclusion that the more hybridomas an applicant
`makes and saves without testing, the less predictable
`the applicant's results become. Furthermore, Wands'
`explanation that the first four attempts at cell fusion failed
`only because they had not yet learned to perform fusions
`properly is reasonable in view of the fact that the next
`six fusions were all successful. The record indicates that
`cell fusion is a technique that is well known to those of
`ordinary skill in the monoclonal antibody art, and there
`has been no claim that the fusion step should be more
`difficult or unreliable where the antigen is HBsAg than it
`would be for other antigens.
`
` © 2017 Thomson Reuters. No claim to original U.S. Government Works.
`
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`In re Wands, 858 F.2d 731 (1988)
`57 USLW 2264, 8 U.S.P.Q.2d 1400
`
`29
`
`Even if we were to accept the PTO's 2.8% success rate,
`we would not be required to reach a conclusion of
`undue experimentation. Such a determination must
`be made in view of the circumstances of each case
`and cannot be made solely by reference to a particular
`numerical cutoff.
`
`When Wands' data is interpreted in a reasonable
`manner, analysis considering the factors enumerated
`in In re