Board of Patent Appeals and Interferences
Patent and Trademark Office (P.T.O.)
*1 EX PARTE DAVID M. KRANZ, SUSUMU TONEGAWA AND HERMAN N. EISEN
Appeal No. 88-2847
June 28, 1990
HEARD: March 20, 1990
Application for Patent filed October 31, 1984, Serial No. 666,880. Process For Making A Targeted Cell Susceptible To Lysis By Cytotoxic T Lymphocytes.
Patrea L. Pabst et al. for Appellants
Primary Examiner--John E. Tarcza
Before Goldstein, Goolkasian and Kimlin
This is an appeal from the examiner's final rejection of claims 1 through 15 and 19 through 31, which are all the claims remaining in the application.
Claim 1 is illustrative of the invention and reads as follows:
1. A process for making a targeted cell susceptible to lysis by a cytotoxic T lymphocyte comprising attaching an antibody specific for determinants of an antigen specific cytotoxic T lymphocyte receptor to a targeted cell not having major histocompatibility complex proteins recognized by the cytotoxic T lymphocyte receptor.
The references relied on by the examiner are:
Smith 4,401,764 Aug. 30, 1983
Kung et al. (Kung) 4,515,893 May 7, 1985
Reinherz et al. (Reinherz) 4,550,036 Oct. 29, 1985
Dennert et al. (Dennert), "Induction And Properties Of Cytotoxic T Cells Specific For Hapten-Coupled Tumor Cells," Journal Of Immunology, Vol. 114, No. 6, June 1975, pages 1705 through 1712.
Lancki et al. (Lancki), Federation Proceedings, Vol. 43, No. 6, abstract #1419, May 1, 1984, page 1659.
Appellants' invention is directed to a process for making a cell (the target) susceptible to lysis (attack and disintegration) by a cytotoxic T lymphocyte (killer cell) when that lymphocyte does not normally recognize the targeted cell and is ordinarily incapable of destroying the target. Appellants' process involves attaching an antibody to the target cell, which antibody is specific for determinants of certain receptors on the cytotoxic T lymphocyte, such that the lymphocyte will now recognize the target, attach thereto and destroy it. Preferably the process provides that the antibody used is in the form of a dual function molecule which includes a portion which specifically binds to the surface of the targeted cell and a second portion which constitutes the anti-receptor antibody to which the T lymphocyte binds.
Appellants' Brief [FN1] notes that the practical application of the claimed method is that one can form hybrid molecules which are conjugates of monoclonal antibodies directed against a patient's cytotoxic T lymphocytes (CTL) receptor with molecules which can bind to the surface of target cells, e.g., cancer cells. The hybrid molecules may be injected into the patient. In the absence of these molecules, the patient's own cytotoxic T lymphocytes would not destroy the cancer cells. However, the hybrid molecules bind to the target cancer cells and activate the patient's own CTLs which attach to the antibody portion of the molecule and destroy the targeted cancer cells.
*2 All of appellants' claims stand rejected under 35 U.S.C. 103 over either Lancki or Ertl in view of Dennert. The examiner notes that both Lancki and Ertl teach that antibodies to a CTL antigen receptor will be recognized by the CTL which will consequently lyse any cell to which the antibody is bound. It is the examiner's position that having this knowledge, one of ordinary skill in the art would have considered it obvious to attach such an antibody to any cell one wished to kill.
We have carefully reviewed the references relied on by the examiner but are in agreement with appellants that the teachings therein would not have made the claimed subject matter obvious to one of ordinary skill in the art. The Lancki reference simply teaches that T lymphocytes will not only lyse target cells bearing the proper alloantigen but will also lyse a hybridoma cell line which does not express the proper alloantigen but which instead expresses a surface Ig reactive with an antigen receptor on the T lymphocyte. There is simply no suggestion in the Lancki reference that this knowledge should be utilized to modify unrecognizable cells by the addition thereto of an antibody reactive with an antigen receptor on the lymphocyte cell. There is clearly no suggestion regarding how this can be done.
The Dennert reference does not add to the teachings of Lancki. Dennert does teach that a cell may be modified by associating a hapten therewith and that the modified cell will in some instances be attacked by CTL cells. Nevertheless, Dennert indicates that there is an inconsistency in the overall capability of the CTL cells to lyse the hapten treated cells. For example, TNP-coupled chicken erythrocytes were readily lysed by CTL cells whereas TNP-coupled tumor cells were not lysed to an extent greater than the uncoupled tumor cell unless special inducement procedures were used. In any event, the Dennert reference contains no suggestion of coupling cells with an antibody to make the cells susceptible to lysing by CTL cells.
The Ertl reference has teachings therein similar to Lancki regarding the ability of T lymphocytes to lyse noninfected target cells which express an anti-idiotypic antibody directed against an antibody (termed G-5) which recognized certain neutralization epitopes for the virus. Ertl teaches that this anti-idiotypic surface Ig can mimic real virus determinants and can be recognized by CTL cells. Ertl has no suggestion that this observed phenomenon be utilized to the extent that antibodies recognized by the CTL cells be attached to a targeted cell so that the CTL cell will recognize and lyse the target itself. As indicated previously, the Dennert reference does not add this necessary teaching.
Obviousness is tested by what the combined teachings of the references would have suggested to one of ordinary skill in the art. In re Keller, 642 F.2d 413, 425, 208 USPQ 871, 881 (CCPA1981). Before obviousness may be established, the examiner must show that there is either a suggestion in the art to produce the claimed invention or a compelling motivation based on sound scientific principles. See Carl Schenck A.G. v. The Nortron Corp., 713 F.2d 782, 218 USPQ 698, 702 (Fed.Cir.1983). Logic compels that the suggestion or motivation be accompanied by a general knowledge of the existence of art recognized techniques for carrying out the proposed invention.
*3 In the case before us, the examiner has noted certain phenomena observed by those working in the art. However, the observations are not only devoid of any suggestion to put the phenomena to practical use but also devoid of advice regarding how to accomplish the necessary "attaching" procedure of appellants' claims. A prima facie case of obviousness has not been established. We reverse the rejection under 35 U.S.C. 103.
Pursuant to 37 CFR 1.196(b) we make the following rejection. Claims 1 through 15 and 19 through 31 are rejected under 35 U.S.C. 112, first paragraph, as based upon a disclosure which would not have enabled a person of ordinary skill in the art to carry out the claimed process at the time the instant application was filed. In re Glass, 492 F.2d 1228, 1232, 181 USPQ ?? Illegible Text?? (CCPA1974).
Appellants' invention is directed to a process which involves physiological activity. The disclosure requirements are controlled by the precepts set forth in In re Fisher, 57 CCPA1099, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). As stated therein:
[35 U.S.C. 112] ... requires that the scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art. In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. (Emphasis added)
In the present case, appellants' specification (page 8) and Brief (page 13) clearly indicate that the claimed process has as its practical objective a use in vivo, specifically against cancer cells as the targets. None of the work depicted in the specification is directed to in vivo experimentation. Moreover, the only method of attaching the antibody to the target cells which is exemplified or described as effective in the specification is crosslinking the antibody to the cell surface using glutaraldehyde as the crosslinking agent. This technique is clearly unavailable for use in vivo. Appellants' have proposed a method of attaching the antibody to the target cell in vivo which involves coupling the antibody with a second molecule that will bind to the surface of the targeted cell. It is well known, however, that the human body has many mechanisms therein which are specifically designed to prevent the intrusion of strange molecules and foreign substances into the organism. Among such defense mechanisms are antibodies which combine with and inactivate molecules [FN2] and enzymes which tend to break up and, consequently, inactivate molecules. Assuming, arguendo, one were to prepare and inject the necessary coupling compound, there is no predictability that the coupling compound would ever reach the target cell or upon reaching the target cell be in a form such that it will combine as predicted. Appellants have provided no guidance regarding which conjugates will reach the target effectively.
*4 We note the warning of the Supreme Court in Brenner v. Manson, 383 U.S. 519, 148 USPQ 689, 695 (1966) to the effect that a process patent in a chemical field which has not been developed creates a monopoly of knowledge which should be granted only if clearly commanded by the statute. This is because such patents may engross unknown and perhaps unknowable area and may confer power "to block off whole areas of scientific development, without compensating benefit to the public." See also the discussion in Monsanto Chemical Co. v. Coe, U.S. App. D.C., 145 F.2d 18, 21-24, 62 USPQ 37 (1944).
We have considered the general unpredictability of the field in which appellants' invention is said to be of practical concern (anti-cancer treatment). We have also noted that appellants have not exemplified how to carry out the claimed invention in vivo and, indeed, have not exemplified a specific combination type molecule of the type claimed in claim 6 which would be effective in an in vivo application of the process. We are satisfied that the specification does not teach and would not enable one of ordinary skill in the art to carry out the invention commensurate with the scope of the claimed subject matter.
The examiner's rejection of claims 1 through 15 and 19 through 31 under 35 U.S.C. 103 is reversed. A new ground of rejection has been made under 35 U.S.C. 112, first paragraph, pursuant to 37 CFR 1.196(b).
Effective August 20, 1989, 37 CFR 1.196(b) has been amended to provide that a new ground of rejection pursuant to the rule is not considered final for the purpose of judicial review under 35 U.S.C. 141 or 145.
Any request for reconsideration or modification of this decision by the Board of Patent Appeals and Interferences based upon the same record must be filed within one month from the date of the decision (37 C.F.R. 1.197). Should appellant elect to have further prosecution before the examiner in response to the new rejection under 37 C.F.R. 1.196(b) by way of amendment or showing of facts, or both, not previously of record, a shortened statutory period for making such response is hereby set to expire two months from the date of this decision.
No time period for taking any subsequent action in connection with this appeal may be extended under 37 CFR 1.136(a). See the final rule notice, 54 F.R. 29548 (July 13, 1989), 1105 O.G. 5 (August 1, 1989).
BOARD OF PATENT APPEALS AND INTERFERENCES
John T. Goolkasian
Edward C. Kimlin
FN1. Page 13.
FN2. As evidence thereof we attach hereto a copy of page 90 of the text Biochemistry, Second Edition, by Geoffrey Zubay (1988) which indicates that vertebrates contain major defense systems against invading foreign substances.