Board of Patent Appeals and Interferences
Patent and Trademark Office (P.T.O.)
*1 EX PARTE PATRICK CHUNG-SHU KUNG AND GIDEON GOLDSTEIN
Appeal No. 88-0962
January 30, 1990
Application for Patent filed August 31, 1984, Serial No. 645,895, which is a division of Serial No. 432,456 filed October 4, 1982, now abandoned, which is a division of Serial No. 110,509, filed January 8, 1980, now Patent No. 4,364,936. Hybrid Cell Line for Producing Monoclonal Antibody to a Human Monocyte Antigen, Antibody and Methods.
Leonard P. Prusak for Appellants
Primary Examiner--John E. Tarcza
Before Rollins, W. Smith and Kimlin
This is an appeal from the final rejection of claims 18-24, all the claims remaining in the present application. Claims 18, 19, 21 and 24 are sufficiently illustrative.
18. Mouse monoclonal antibody which reacts with an antigen found on normal human monocytes, but not on normal human B cells.
19. A monoclonal antibody produced by a hybridoma formed by fusion of cells from a mouse myeloma line and spleen cells from a mouse previously immunized with human mononuclear cells which reacts with an antigen found on normal human monocytes and granulocytes, but not on normal human B cells.
21. A mouse monoclonal antibody produced by a hybridoma formed by fusion of cells from a mouse myeloma line and spleen cells from a mouse previously immunized with human mononuclear cells, which antibody reacts with an antigen found on normal human monocytes and granulocytes.
24. A mouse monoclonal antibody that reacts with an antigen found on normal human monocytes and granulocytes and on about 13% of E+ human mononuclear cells, but not with normal human peripheral B cells.
Ugolini et al., (Ugolini) Proc.Natl.Acad.Sci. 77(11), p. 6764-8 (1980)
Brown, et al., (Brown) European Journal of Immunology, 9: p. 272-5 (1979)
Claims 18-24 stand rejected under the first paragraph of 35 USC 112 as being based upon a non-enabling disclosure. Claim 21 is also rejected under 35 USC 102 as being anticipated by Brown.
Appellants' invention is directed to a class of antibodies against an antigen found on normal human peripheral blood monocytes and granulocytes, but not found on normal human peripheral lymphoid cells (T cells, B cells, or null cells), thymocytes, lymphoblastoid cell lines, or tumor cells of T or B cell lineage. In addition, the appellants' monoclonal antibodies react with an antigen that is found on about 13% of E+ human mononuclear cells (T cells). As set out in product-by-process claims 19, 21 and 22, the monoclonal antibodies are produced by a hybridoma formed by fusion of cells from a mouse myeloma line and spleen cells from a mouse previously immunized with human mononuclear cells. According to appellants, the monoclonal antibodies of the present invention stand in contrast to prior art monoclonal antibodies inasmuch as the antibodies of the prior art are not monospecific for a human monocyte antigen. For an overview of the technology of forming hybridomas which produce monoclonal antibodies see In re Wands, --- F.2d ----, 8 USPQ2d 1400 (Fed.Cir.1988), and Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 231 USPQ 81 (Fed.Cir.1986).
*2 Preliminarily, we note that appellants have not seen fit to separately argue with any reasonable specificity the claims on appeal. However, inasmuch as the product-by-process claims and the remaining monoclonal antibody claims present different issues for our consideration, we will treat the two groups of claims separately.
In the examiner's opinion all the appealed claims, including product-by-process claims 19, 21 and 22, "are much broader" than that which is enabled by the present specification, insofar as it would require "undue experimentation" by the skilled artisan to reproduce the claimed antibodies. Contrariwise, it is appellants' position that the Ugolini article evidences that the present specification enables one ordinarily skilled in this art to produce antibodies which fall within the scope of the appealed claims.
There is little doubt that the issue of whether or not undue experimentation is required is one which must be decided on the facts of each particular case. In re Wands, supra; Ex parte Jackson, 217 USPQ 804 (PTO Bd.App.1982). In addition, as will become apparent from our decision, resolvement of the issue is also contingent upon the breadth of separate, individual claims appearing in a given case. In our judgment, based upon the evidence before us, we are satisfied that the particular monoclonal antibodies within the scope of the product-by-process claims could have been manufactured by those ordinarily skilled in this art without undue experimentation. On the other hand, we are equally persuaded that undue experimentation would be required to produce the monoclonal antibodies reasonably commensurate with the scope of appealed claims 18, 20, 23 and 24.
We first consider the rejection of the product-by-process claims. Claims 19, 21 and 22 define a specific class of monoclonal antibodies which are produced "by a hybridoma formed by fusion of cells from a mouse myeloma line and spleen cells from a mouse previously immunized with human mononuclear cells." Claims 19 and 22 recite that the monoclonal antibody reacts with an antigen found on normal human monocytes and granulocytes but not on normal human B cells, whereas claim 21 does not require that the reactive antigen is not found on normal human B cells. Ugolini, in producing three monoclonal antibodies which react with human peripheral blood monocytes and not with B cells, followed essentially the same steps disclosed by appellants' specification. This is not disputed by the examiner. The examiner's concern is that although Ugolini "was able to produce monoclonal antibodies within the claims," the Ugolini antibodies have "a striking difference" with respect to reactivity with human peripheral blood T lymphocytes. While appellants' deposited antibody (OKM1) exhibits a reactivity with 13% of human peripheral blood T lymphocytes, Ugolini's 63D3 antibody reacts with less than 1/1000 cells of the T cell population.
*3 Notwithstanding that Ugolini produced an antibody having a property different than appellants' OKM1, we concur with appellants that Ugolini demonstrates that the skilled artisan would have been enabled by the present specification to produce antibodies within the scope of the product-by-process claims on appeal. That is, Ugolini shows that by following essentially the same procedure taught by appellants' specification, which incorporates well-known, basic Kohler-Milstein methodology, one of ordinary skill in this art possessed the expertise to produce a monoclonal antibody which reacts with an antigen found on normal human monocytes and granulocytes, but not on normal human B cells. In our view, while these claims encompass specific antibodies formed by Ugolini which are not exactly the same as appellants' OKM1 on deposit, the reported difference in reactivity with T cells is not indicative of sufficient unpredictability to warrant a finding of undue experimentation. On the contrary, Ugolini evidences that by immunizing with human mononuclear cells within the framework of the Kohler-Milstein method, the skilled artisan is able to produce a class of monoclonal antibodies within the scope of the product-by-process claims on appeal. Here, as in Wands, supra, appellants' evidence effectively rebuts the examiner's challenge to the enablement of their disclosure.
The enablement of the present specification regarding the production of antibodies within the broad scope of claims 18, 20, 23 and 24 is another matter. Unlike the antibodies defined by the product-by-process claims, the antibodies within the scope of these claims are not restricted to the specific class of monoclonal antibodies formed by appellants' disclosed process that requires immunization with human mononuclear cells. Indeed, claims 18, 20, 23 and 24 are sufficiently broad to encompass any antibody which reacts with any antigen found on normal human monocytes and/or granulocytes, but not on B cells, regardless of the particular immunogen and formative process employed. Unlike in In re Wands, supra, where the applicant claimed a specific IgM class of antibodies reactive with a specific antigen (hepatitis B surface antigen), the broad claims at issue are not limited to a particular class of antibodies formed by the specific immunization step of the enabling process disclosed. Further, unlike Wands, the monoclonal antibodies of these claims are reactive with antigens found on a multitude of sources, i.e., monocytes, granulocytes and/or about 13% of E+ human mononuclear cells. Appellants acknowledge the considerable breadth of the claims at page 7 of their brief:
"All monoclonal antibodies having the claimed reactivities will lie within the scope of Applicants' claims. Applicants readily admit that there are undoubtedly many different monoclonal antibodies which will have the claimed reactivities and which meet all the limitations of Applicants' claims but will be different to some degree, i.e., chemically, from those monoclonal antibodies made by Applicants and set out in Applicants' enabling example. Further, any subsequent succession of investigators, following Applicants' teachings, could make monoclonal antibodies falling within the scope of Applicants' claims but which would be different in some degree than those made by Applicants."
*4 Consequently, since appellants are seeking protection for all monoclonal antibodies having, at most, four common properties (reactivity with monocytes, granulocytes, 13% of E+ cells, and non-reactivity with B cells), regardless of any other number of differences in chemical and immunoreactive properties, it follows that appellants' specification must be commensurately enabling. Hence, the issue becomes whether it would take undue experimentation for one ordinarily skilled in this art to produce the monoclonal antibodies falling within the scope of claims 18, 20, 23 and 24 beyond those obtained through the disclosed immunization step. In accordance with current patent jurisprudence, factors to be considered in determining whether a disclosure would require undue experimentation include, inter alia, the breadth of the claims, the nature of the invention, the amount of direction or guidance presented, the presence or absence of working examples, and the predictability or unpredictability of the art. In re Wands, supra; Ex parte Forman, 230 USPQ 546, 547 (PTO Bd.App. and Intf.1986). The only guidance or direction given by the present specification takes the form of a single exemplary process corresponding to the method of product-by-process claims 19, 21 and 22.
Regarding the nature and predictability of the hybridoma art, we note that Ugolini reported unpredictability in producing monoclonal antibodies not reactive with normal B cells, even when following the methodology disclosed by appellants. For instance, noting Table II at page 6766, Ugolini discloses that monoclonal antibody 63D3 exhibits greater binding with B lymphocytes than with granulocytes. Ugolini found that these "intermediate values are difficult to interpret." Hence, it is evident that appellants' singular exemplary process provides guidance for forming only a very limited species of antibodies, and not without certain unpredictability. Inasmuch as Ugolini produced antibodies having properties different than appellants' upon following essentially the same procedure, we are not inclined to conclude that all antibodies embraced by the broad claims on appeal, regardless of their likely variance in functional properties, are enabled by the presently disclosed invention.
Moreover, the breadth of claims 18, 20, 23 and 24 renders them tantamount to single means claims, which are generally viewed without favor by our review court. As stated by the Court in In re Hyatt, 708 F.2d 712, 218 USPQ 195, 197 (Fed.Cir.1983);
"The long-recognized problem with a single means claim is that it covers every conceivable means for achieving the stated result, while the specification discloses at most only those means known to the inventor."
Manifestly, the claims at issue cover every conceivable monoclonal antibody which achieves the stated result of recited reactivity, whereas appellants' specification teaches only one very particular method or means for accomplishing the claimed objective. Hence, we find that the enabling disclosure of the present specification is not commensurate in scope with the breadth of claims 18, 20, 23 and 24.
*5 We now consider the examiner's rejection of appealed claim 21 under § 102 over Brown. Although the examiner's stated purpose for maintaining this rejection "is to bolster the 35 USC 112 rejection," the propriety of the rejection must nevertheless be decided in accordance with the principle that to constitute anticipation within the meaning of § 102, all material elements of a claim must be present in one prior art source. In re Marshall, 577 F.2d 301, 198 USPQ 344 (CCPA 1978); In re Kalm, 378 F.2d 959, 154 USPQ 10 (CCPA 1967). However, as pointed out by appellants, whereas claim 21 defines an antibody which "reacts with an antigen found on normal human monocytes and granulocytes," Brown describes the disclosed antibody as being reactive with lymphocytes, without ever mentioning reactivity with monocytes and granulocytes. While the examiner states that Brown's monoclonal antibody binds to all HLA containing cells, including monocytes and granulocytes, it is the examiner's burden to provide evidentiary support for his factual finding. In re Warner, 379 F.2d 1011, 154 USPQ 173 (CCPA 1967). The examiner's mere invitation to consult a basic immunology text hardly suffices. Furthermore, not without significance is that claim 21 is presented in product-by-process format. As such, even though the examiner bears a lesser burden of proof in making out a prima facie case of anticipation or obviousness, it remains upon the examiner to show that the Brown antibody reasonably appears to be either identical with or only slightly different than the claimed antibody which is produced by the recited process. In re Fessmann, 489 F.2d 742, 180 USPQ 324 (CCPA 1974); In re Brown, 459 F.2d 531, 173 USPQ 685 (CCPA 1972). The examiner is not afforded the option of ignoring the process claim language which defines how the monoclonal antibody is produced. Claim 21 requires that the monoclonal antibody be one that is "produced by a hybridoma formed by fusion of cells from a mouse myeloma line and spleen cells from a mouse previously immunized with human mononuclear cells." Accordingly, it is incumbent upon the examiner to advance evidence that the Brown antibody appears to be identical to or only slightly different than the claimed monoclonal antibody that is produced by the recited process. However, rather than offering such an argument, the examiner acknowledges that Brown's "antibody is not even remotely related to any monoclonal antibody in the specification or suggested by it." Thus, we do not find that the examiner has met his burden of establishing that the monoclonal antibody of Brown either anticipates or would have rendered obvious the antibody claimed. Hence, we cannot sustain the examiner's rejection under § 102.
Rule 37 CFR 1.136(a) does not apply to the times for taking any subsequent action in connection with this appeal.
BOARD OF PATENT APPEALS AND INTERFERENCES
Alton D. Rollins
William F. Smith
Edward C. Kimlin