Board of Patent Appeals and Interferences
Patent and Trademark Office (P.T.O.)
*1 EX PARTE KANAME SUGIMOTO
Appeal No. 677-95
August 15, 1988
HEARD: August 1, 1988
Application for Patent filed January 31, 1983, Serial No. 462,239. Process For Producing Human Immune Response Suppressor.
Sheridan Neimark et al. for appellants
Supervisory Patent Examiner--Thomas G. Wiseman
Examiner--J. Huleatt
Before Pellman, Steiner and Skinner
Pellman
Examiner-in-Chief
This is an appeal from the examiner's decision finally rejecting claims 13 through 34, all of the claims remaining in the application.
The subject matter on appeal involves a method for producing human Soluble Immune Response Suppressor (hIRS). In the process, human cells capable of producing hIRS are fused with a human lymphoblastoid line to produce hybridoma cells capable of producing said suppressor. The hybridoma is implanted in a non-human warm-blooded animal wherein the cells are permitted to multiply. Subsequently, the tumor from the non-human animal is extracted and disaggregated to obtain the multiplied hybridoma cells. Thereafter said cells are cultured in vitro to accumulate hIRS, which is then recovered. To describe the invention in greater detail and illustrate the claims on appeal, a copy of claims 13 and 18 are appended to this decision.
For evidence of obviousness, the references listed below are cited by the examiner:
Sugimoto et al (Sugimoto) 4,377,513 Mar. 22, 1983
Rocklin et al (Rocklin), Cellular Immunology 51, 226-237 (1980)
Goding "Antibody Production By Hybridomas", J of Immunological Methods 39, 285-308 (1980)
All of the claims stand rejected for being unpatentable (35 U.S.C. 103) in view of Sugimoto taken with Rocklin. At page 3 of his answer, the examiner, in setting forth his position, states that it would have been "obvious to select cells such as human T-lymphocytes as taught by Rocklin et al, which produce a human immune response suppressor factor, and to substitute these cells for the erythropoietin producing cells in the process as taught by Sugimoto et al to obtain enhanced production of human Soluble Immune Response Suppressor."
At page 2 of his supplemental answer, the examiner, commenting upon appellant's arguments referring to the asserted high yields of the claimed process, states that:
"It is well known to those skilled in the hybridoma art that production of the product (antibody) is greater when the hybridoma is grown in a mouse rather than in vitro."
To support his statement, the examiner relies upon the cited Goding article. The examiner contends that the difference in production between growth in mice (3-15 mg/ml), compared with that in vitro (10-100 mg/ml) is significant. Accordingly, the examiner holds appellant's reported increased production of the Immune Response Suppressor obvious.
Conversely, appellant, after discussing the reference disclosures and the limitations in the claims, at page 14 of his principal brief, contends that the routineer would not have considered it obvious to employ the patented process, directed to producing increased amounts of the hormone, erythropoietin, to obtain an unrelated protein, such as hIRS, which is a lymphokine, and not a hormone. At page 15 of the principal brief, appellant frames the issue in the present appeal as "whether or not Sugimoto et al makes obvious extremely high titered and high quantity production of every possible human protein."
*2 At page 18 of the principal brief, appellant reiterates his position with the following argument:
"On the present record there is clearly nothing which would suggest to one of ordinary skill in the art that if parental human cells inherehtly [sic, inherently] capable of producing hIRS are substituted for the human cells capable of producing human erythropoietin, prior to the step of fusing with a human lymphoblastoid line to obtain hybridoma cells, in the process of Sugimoto et al, and if the multiplied hybridoma cells are cultured in vitro under conditions appropriate to accumulate hIRS (as opposed to conditions appropriate to accumulate erythropoietin) in the process of Sugimoto et al, one will be able to recover accumulated hIRS in amounts which are vastly superior to the amounts which are capable of being obtained using the parental cells alone or using hybridoma cells alone."
In appellant's reply brief, he responds to the examiner's suggestion that increased amounts of suppressor may be due to the increased number of cells due to the higher cell multiplication predicted by Sugimoto. However, referring to the data in his specification, appellant stresses that both the control and the experiment embracing the present invention were conducted with the same cell density and the same inducer, with the same cell incubation period.
Additionally, in his supplemental reply brief, appellant discusses the Goding publication item upon which the examiner relies in his supplemental answer. Appellant dismisses said Goding item with the observation that it is not clear whether the author obtains increased production per cell, rather than increased production due to the total number of cells present. Additionally, appellant remarks that the present invention does not recover hIRS from the serum or the ascites of the mouse on which the tumor is grown. Rather, we are told, after the tumor is cultivated in the mouse, the tumor cells are grown in vitro. Finally, appellant contends that Goding refers only to the production of antibodies, while the invention at issue herein concerns the production of the lymphokine hIRS. Appellant again emphasizes that, because of the difference between antibodies and lymphokines, a person skilled in the art would not automatically expect a process for producing one, likewise to produce the other in the same manner.
After giving full consideration to the opposing arguments and supporting evidence of appellant and of the examiner, we are unpersuaded of any reversible error in the examiner's rejection, which will be sustained.
At page 7.5 of his principal brief, appellant acknowledges:
"... for the purpose of this brief that the process steps of Sugimoto et al are substantially identical to those of the present invention except for the fact that the parental human cells which are fused to the human lymphoblastoid line in the present invention are different, and the conditions under which the multiplied hybridoma cells are cultured, are different, as conditions appropriate to accumulate hIRS are not necessarily the same as those appropriate to obtain erythropoietin and, finally, the accumulated product being recovered is different."
*3 Thus, Sugimoto employs human cells known to be inherently capable of producing erythropoietin, while appellant in the present application employs human cells known to be inherently capable of producing hIRS. Since there can be no denying that human cells capable of producing soluble immune response suppressor would have been known and available, we are satisfied that the employment of such cells in the Sugimoto process would have been an obvious expedient.
Furthermore, it must be noted that the same precise human lymphoblastoid line recited in appellant's claims 18 and 29 are specifically employed in the Sugimoto process in the several examples. Consequently, not only would it have been expected that said cell lines would propagate under the conditions of the Sugimoto process, but it would have been reasonably expected that the process, employing said cell lines, would be characterized by stabler and higher cell multiplication, as disclosed at column 1, lines 52 to 54 of Sugimoto. Moreover, it will be observed that only through the use of a human lymphoblastoid line, as taught by Sugimoto, is the increase in hIRS production per cell increased. In this connection, attention is invited to page 6 of the specification, wherein appellant discloses that the use of a human lymphoblastoid line, instead of various known human cell lines, "results in an extreme increase in cell multiplication rate and/or hIRS production per cell, i.e., about 2-10-fold higher than that attained with the use of the above described normal or tumor cells."
Although appellant does not concede that the conditions under which the multiplied hybridoma cells are cultured are the same in the Sugimoto patent as in the present application, we are aware of no significant difference in the process conditions. Thus, at page 9 of the specification, appellant discloses that:
"Any method by which the multiplied human cells are induced to produce hIRS can be employed in the present invention. For example, the multiplied human cells, obtained by harvesting from ascite suspension, or extracting and disaggregating the massive tumor(s), formed, e.g., subcutaneously, are suspended in a nutrient medium, prewarmed to a temperature in the range of about 20<<degrees>>-40<<degrees>> C, to give a cell density of about 104-10 @8 cells per ml, and incubated therein to obtain hIRS. In this case, the human cells may be exposed to an IRS inducer to enhance further the IRS production."
The foregoing may be compared with the similar paragraph appearing at column 3, lines 29 to 43, of Sugimoto.
Among the IRS inducers disclosed at page 10 of appellant's specification, concanavalin A is named, it also being identified by Rocklin as a known activator for producing human Immune Suppressor Factor. Consequently, we are convinced that it would have been prima facie obvious to employ concanavalin A in the Sugimoto process to stimulate the cells to produce human Immune Response Suppressor, as taught by Rocklin. Note that at page 236, last paragraph, Rocklin states:
*4 "The HSF-producing cells are T lymphocytes with histamine type 2 receptors and Fc receptors for IgG. Furthermore, this subpopulation can be activated by Con A and specific antigen to express suppressor function. A unifying hypothesis would suggest that the same cell(s) possesses the above-mentioned receptors and can be activated to perform its suppressor function by an immunologically specific trigger such as antigen or by nonspecific stimuli such as histamine, Con A, or antigen-antibody complexes."
Consequently, it would not have been unexpected to find that the same cell produces more than one biologically active material, such as the suppressor factor and IgG antibodies.
On the basis of the foregoing, we find that the cited references would have established a strong prima facie case of obviousness as to appellant's claimed process. Therefore, we now turn to appellant's evidence of nonobviousness, i.e., the examples in the specification, in accord with the decision by the court in In re Johnson, 747 F.2d 1456, 223 USPQ 1260 (Fed.Cir.1984). In this connection, the tabulated results for appellant's invention and "control" (from the examples in the present specification), as well as those for the Sugimoto process (from the examples in the patent), are listed in the Table below.
Present Application Sugimoto
---------------------------------------------- -------------------------------
Example Invention units/.1ml Control Invention Control
units/.1ml units/1ml units/ml.
1 2400 90 170 6
2 12800 400 100 5
3 8500 240 340 9
4 9400 350 60 3
5 3600 30 420 12
6 4200 -- 130 --
7 3200 -- -- --
It will be observed that the ratio of the units produced by appellant's invention to that of the control, with the exception of appellant's example 5, ranges from about 27 to 35 to 1, while the corresponding ratio of Sugimoto ranges from about 20 to 38 to 1. Insofar as appellant has argued the "unexpected" magnitude of the increase in production of the desired biological component, such increase would seem to be suggested by the values reported by Sugimoto.
*5 Furthermore, turning to the Goding reference, we note the author's revelation that the growth of hybridomas in mice, vis-a-vis in vitro, will allow the production of much larger amounts of antibody. As pointed out by the examiner, these levels increase from 10 to 100 micrograms/ml to 3 to 15 milligrams/per ml. Therefore, it appears that Goding confirms the teaching of Sugimoto insofar as the former predicts significant increases in the yield of product through the initial growth of hybridomas in mice. We are confident that a person of ordinary skill in the subject art would have employed the Sugimoto process, activating the cells with concanavalin A, as taught by Rocklin, to obtain greater yields of the Immune Suppressor Factor, as suggested by Goding.
We are not apprised of any further evidence to support appellant's arguments that a person trained in this field would not have expected increased yields of said Suppressor Factor. Thus, considering all of the evidence of record, we hold that the evidence of obviousness provided by the examiner is not adequately counterbalanced by appellant's evidence of nonobviousness. Accordingly, because appellant has not overcome the inference of obviousness established by the prior art, the examiner's rejection of the present claims must necessarily be sustained.
For the reasons expressed in the answer and those discussed above, the examiner's decision rejecting claims 13 through 34 is affirmed.
37 CFR 1.136(a) does not apply to the times for taking any subsequent action in connection with this appeal.
AFFIRMED
BOARD OF PATENT APPEALS AND INTERFERENCES
Irving R. Pellman
Examiner-in-Chief
Arthur J. Steiner
Examiner-in-Chief
William A. Skinner
Examiner-in-Chief
13. A process for producing human Soluble Immune Response Suppressor (hIRS), comprising:
fusing parental human cells inherently capable of producing hIRS with a human lymphoblastoid line to obtain hybridoma cells capable of producing hIRS;
implanting the hybridoma cells in an immunodeficient or immuno-suppressed non-human warm-blooded animal;
feeding the animal to allow said hybridoma cells to utilize the nutrient body fluid of the animal for their multiplication;
extracting and disaggregating the resultant tumor, formed in the animal, to obtain the multiplied hybridoma cells;
culturing the multiplied cells on an in vitro nutrient medium under conditions appropriate to accumulate hIRS; and
recovering the accumulated hIRS from the culture.
18. A process as set forth in claim 13, wherein said human lymphoblastoid line is a member selected from the group consisting of BALL-1, NALL-1, TALL-1, JBL and Namalwa.
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