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Application for Patent filed August 8, 1988, Serial No. 07/227,500, which is a continuation of Serial No. 07/001,689 filed January 9, 1987, which is a continuation of Serial No. 06/325,969 filed November 30, 1981, which is a continuation-in-part of Serial No. 06/234,508 filed February 17, 1981. Production of Antibodies For Human Fibroblast Interferon.
18. Continuous cell lines producing antibodies specific for human fibroblast interferon which comprise fused cell hybrids derived from human fibroblast interferon primed vertebrate antibody producing cells and cancer cells.
19. Continuous cell lines of claim 18 wherein said cancer cells are myeloma cells.
20. Monoclonal antibodies secreted by the cell lines of claim 18.
21. Continuous cell lines of claim 19 comprising fused cell hybrids selected from the group consisting of CE/F 11 (HB 8043), CE/F 12 (HB 8044), CE/F 13 (HB 8045), CE/F 14 (HB 8047, CE/F 16 (HB 8048) and their progency.
51. Monoclonal antibodies secreted by the continuous cell lines of claim 21.
Galfre et al., "Antibodies To Major Histocompatibility Antigens Produced By Hybrid Cell Lines", Nature, Vol. 266, pages 550-552 (April 1977).
Koprowski et al., "Production Of Antibodies Against Influenza Virus By Somatic Cell Hybrids Between Mouse Myeloma And Primed Spleen Cells", Proc. Natl. Acad. Sci, USA, Vol. 74, No. 7, pages 2985-2988 (July 1977).
Stewart, "Purification And Characterization Of Interferons", Interferons And Their Actions, Chapter 4, page 58 (1977).
Koprowski et al. (Koprowski), "Study Of Antibodies Against Human Melanoma Produced By Somatic Cell Hybrids", Proc. Natl. Acad. Sci, USA, Vol. 75, No. 7, pages 3405-3409 (July 1978).
Wiktor et al. (Wiktor), "Monoclonal Antibodies Against Rabies Virus Produced By Somatic Cell Hybridization: Detection OF Antigenic Variants", Proc. Natl. Acad. Sci. USA, Vol. 75, No. 8, pages 3938-3942 (August 1978).
Parham et al. (Parham), "Monoclonal Antibody To A Human Histocompatibility Alloantigen, HLA-A2", Nature, Vol. 276, pages 397-399 (November 1978).
Kennett et al. (Kennett), "Hybrid Myelomas Producing Antibodies Against A Human Neuroblastoma Antigen Present On Fetal Brain", Science, Vol. 203, pages 1120-1121 (March 1979).
*2 Parham et al. (Parham), "Use Of A Monoclonal Antibody (W6/32) In Structural Studies Of HLA-A, B, C Antigens", The Journal Of Immunology", Vol. 123, No. 1, pages 342-349 (July 1979).
Kearney et al. (Kearney), "A New Mouse Myeloma Cell Line That Has Lost Immunoglobulin Expression But Permits The Construction Of Antibody-Secreting Hybrid Cell Lines", The Journal Of Immunology", Vol. 123, No. 4, pages 1548-1550 (October 1979).
Luben et al. (Luben), Chemical Abstracts, Vol. 91, 89308f, page 588 (1979).
Young et al. (Young), Chemical Abstracts, Vol. 92, 39574q, page 591 (1980).
Sevier et al. (Sevier), "Monoclonal Antibodies In Clinical Immunology", Clin.Chem. Vol. 27, No. 11, pages 1797-1806 (July 1981).
Claims 18 through 21 and 51 stand rejected under 35 USC § 103 as unpatentable over Stewart in view of any one of Kearney, Sevier or the admitted state of prior art set forth on page 7 of the present specification. Alternatively, the claims on appeal stand rejected under 35 USC § 103 as unpatentable over Stewart in view of Luben, Young, either Koprowski reference, Kennett, Galfre, Wiktor and either Parham reference. We affirm.
Similar subject matter was before this Board in parent application Serial No. 06/325,969, Appeal No. 624-56, Ex parte Erlich, 3 U.S.P.Q.2d 1011 (BPAI 1986). Rejections under 35 USC § 103 which were based upon some of the references and the same reasoning now relied by the examiner were affirmed.
As in the previous appeal, the claimed subject matter is directed to hybridomas which produce monoclonal antibodies specific for human fibroblast interferon, a known protein useful as an antiviral agent, and the monoclonal antibodies produced by the hybridomas. In the previous appeal, we agreed with the examiner that at the time of the present invention one of ordinary skill in the art would have found the claimed hybridomas and monoclonal antibodies obvious from a consideration of prior art. Specifically, we agreed with the examiner that one of ordinary skill in the art, aware of the antigenicity and therapeutic value of human fibroblast interferon, would have found it obvious to use the classical method of Kohler and Milstein to form monoclonal antibodies specific to this valuable protein.
Appellants argued then and continue to argue now that at the time of the present invention, the production of monoclonal antibodies to a given antigen was empirical in nature and one would not have embarked upon the experimentation needed in order to produce monoclonal antibodies specific for human fibroblast interferon with any expectation of success.
We have carefully considered the respective positions of the appellants and the examiner as set forth in the Briefs and Examiner's Answers. As a result of this review, we conclude that the subject matter on appeal would have been obvious to one of ordinary skill in the art from a consideration of the references relied upon by the examiner.
*3 The evidence of record establishes that by 1980 [FN2] numerous researchers were able to form hybridomas which produce monoclonal antibodies specific to a wide variety of antigens. The basis of this large body of research work was the discovery by Kohler and Milstein in 1975 of a procedure for producing hybridomas which secrete monoclonal antibodies. Sevier is one publication which documents the success researchers had in extending the discovery of Kohler and Milstein during 1975-1980 to obtain a wide variety of monoclonal antibodies using hybridoma technology. As recognized by the examiner, the Sevier publication itself is not prior art against the present claims. However, the reference does cite a large number of references bearing publication dates of 1979 and 1980 which are stated to report successful obtention of monoclonal antibodies using the hybridoma technology discovered by Kohler and Milstein. To the extent that Sevier establishes the level of ordinary skill in this art at and around the time of the present invention, i.e., 1980-81, it is properly relied upon by the examiner in rejecting the present claims under 35 USC § 103. Thomas and Betts Corp., v. Litton Systems, Inc., 720 F.2d 1572, 1581, 220 USPQ 1, 7 (Fed.Cir.1983) ( "[references] though not technically prior art, were, in effect, properly used as indicators of the level of the ordinary skill in the art to which the invention pertained"); In re Farrenkopf, 713 F.2d 714, 219 USPQ 1 (CCPA 1983).
Alternatively, the secondary references relied upon in the second rejection by the examiner are representative of the articles cited in Sevier which were published in 1979. These references are clearly prior art to the present claims and document the success researchers had after 1975 up to the point of the present invention in adapting and extending the fundamental technique of Kohler and Milstein to other antigens in order to produce monoclonal antibodies specific to these antigens.
Therefore, one of ordinary skill in the art at the time of the present invention, recognizing the antigenicity of the human fibroblast interferon and its potential therapeutic value, would have had ample motivation to make monoclonal antibodies to this protein using the classical Kohler and Milstein hybridoma technology. Such a person would have entered this venture with a reasonable expectation of success given the large number of successes other researchers had at that point in time in adapting hybridoma technology to other antigens. In re O'Farrell, 853 F.2d 894, 7 U.S.P.Q.2d 1673 (Fed.Cir.1988).
Appellants argue that in 1980, one of ordinary skill in the art would not have used the hybridoma technology to make monoclonal antibodies to human fibroblast interferon with a reasonable expectation of success. We disagree.
As set forth above, the examiner has introduced a number of references into this record which establish the success researchers have had since 1975 in adapting the Kohler and Milstein hybridoma technology to a wide variety of other antigens. This fact has been recognized by the Court of Appeals for the Federal Circuit. In re Wands, 858 F.2d 731, 736, 8 U.S.P.Q.2d 1400, 1404 (Fed.Cir.1988) [methods for obtaining and screening monoclonal antibodies were well known in 1980] citing Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1384, 231 USPQ 81, 94 (Fed.Cir.1986). As in Wands, there is no evidence that the requisite starting materials, i.e., human fibroblast interferon and myeloma cells, were not available to the public at the time of the present invention.
*4 Appellants argue on page 8 of the Supplemental Appeal Brief [FN3] that it was known at the time of the invention that using the Kohler and Milstein hybridoma technology to produce monoclonal antibodies against water soluble antigens presented certain experimental barriers. In support of this argument, appellants rely upon Stahli [FN4]. As argued by appellants, Stahli does state that many laboratories initially had very poor success in obtaining monoclonal antibodies using the hybridoma technology with soluble antigens such as proteins. In support of this statement Stahli cites his previous publication bearing a date of 1980. What appellants do not recognize is that Stahli, after acknowledging this problem, goes on to state that success in using soluble antigens such as proteins in the hybridoma technology was "crucially dependent upon the procedure of the final immunization(s) immediately preceding fusion." (Attachment E, p. 27). Stahli goes on to state that that laboratory is "using an optimized method for the final immunizations", citing the same previous 1980 publication which disclosed this problem. Therefore, when read in its entirety, Stahli discloses that to whatever extent water soluble antigens presented difficulties when used in the Kohler and Milstein process in 1980, such difficulties were solved in 1980, a time prior to or just at the time of this invention.
Appellants argue in the paragraph bridging pages 10-11 of the Supplemental Appeal Brief that the next advances in hybridoma practice after its discovery in 1975 were not made until 1983, citing De St. Groth [FN5]. De St. Groth does contain a section entitled "Practice, 1983" in which various advances in hybridoma technology are discussed. However, it is clear from reading this portion of the reference that these improvements were not discovered in 1983, but at some previous point in time. Since appellants have not provided a complete copy of this publication, the publication date of the references cited in De St. Groth as disclosing the discussed improvements can not be determined.
However, one of the disclosed improvements is the obtention of a so-called barren or silent myeloma. These cell lines do not produce antibodies so that upon fusion with an antibody producing spleen cell, the resulting hybridoma would not produce myeloma based antibodies. As seen from Kearney, such barren or silent myelomas were known to be useful in forming hybridomas as early as 1979, well prior to the present invention.
Another improvement disclosed in De St. Groth is the use of polyethylene glycol as the fusing agent for forming the hybridomas. Galfre, which was published on April 7, 1977, discloses fusion procedures resulting in hybridomas producing monoclonal antibodies in which polyethylene glycol was used as the fusion agent. In fact, Galfre discloses that forming hybridomas by fusing the harvested spleen cells with myeloma cells using polyethylene glycol is "becoming a method of choice." This is further evidence that hybridoma technology was well established at the time of the present invention.
*5 Thus, it appears that De St. Groth was summarizing in 1983 the improvements made in hybridoma technology since the Kohler and Milstein discovery in 1975. As established by Kearney and Galfre, at least some of these improvements were discovered prior to the present invention.
Appellants renew the arguments made in the first appeal that our affirmance of the examiner's rejections under 35 USC § 103 is in conflict with Ex parte Old, 229 USPQ 196 (BPAI 1985). The claims in Old were directed to hybridomas and monoclonal antibodies produced by these hybridomas which recognize human renal cell antigenic systems. That subject matter is readily distinguishable from the present subject matter. We also note that the references relied upon by the examiner in this appeal were not applied in the rejections of record in Old. Therefore, it is not seen that the decision in the first appeal or this decision is in conflict with the decision in Old. Any statements in Old concerning the predictability or unpredictability of hybridoma technology must be taken in the context of the facts and evidence in Old.
Appellants argue that the court recognized the empirical nature of this art in Hybritech. However, appellants do not point out where the court made such a determination in that case. The subject matter before the court in Hybritech was not to hybridomas and monoclonal antibodies per se. Rather, the claims in issue were directed to immunometric assays using monoclonal antibodies having a specified affinity. If Hybritech is to be considered controlling as urged by appellants, we must reach the conclusion that the subject matter on appeal herein would have been obvious to one of ordinary skill in the art in view of the statement by the court in Hybritech that production of monoclonal antibodies was "admittedly old after Kohler and Milstein showed how to produce them." Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d at 1384, 231 USPQ at 94 (Fed.Cir.1986).
In regard to appellants' arguments concerning the antigenicity of human fibroblast interferon, we note, as did the examiner, that Stewart does disclose that this protein binds with polyclonal serum. Keeping in mind appellants' admission at page 7, lines 18-20 of the specification that almost any compound can stimulate the production of monospecific antibodies including interferons, we conclude that one of ordinary skill in the art would have recognized at the time of the present invention that human fibroblast was an antigenic protein. In this regard, we note that appellants have neither denied nor presented any evidence on this record that would indicate that at the time of the present invention, those of ordinary skill in this art did not recognize human fibroblast interferon as being antigenic.
Claims 21 and 51 are directed to the specific hybridomas and monoclonal antibodies which were actually produced by appellants. Appellants request separate consideration of these claims on the basis that the obtention of a specific hybridoma would not have been predictable prior to doing the actual work. Appellants argue in the paragraph bridging pages 13-14 of the Supplemental Appeal Brief that, while all of the hybridomas produce monoclonal antibodies specific to a protein with a molecular weight comparable to that of human fibroblast interferon, four of the monoclonal antibodies produced show a greater affinity for human fibroblast human interferon. Appellants conclude that these data establish a degree of unpredictable variance between the monoclonal antibodies. We disagree.
*6 We note that certain of the references relied upon by the examiner clearly establish that it is expected that more than one monoclonal antibody producing hybridoma may be obtained via a fusion according to Kohler and Milstein and that the different monoclonal antibodies produced from these separate hybridomas can vary in terms of their affinity for the starting antigen. See, e.g., Galfre, Kennett and Koprowski. These references were published in 1978 and 1979, well before the earliest date of invention asserted by appellants, June, 1980.
The data relied upon by appellants in arguing the patentability of claims 21 and 51 merely establish that the monoclonal antibodies produced by the recited hybridomas differ in their affinity for the target antigen, human fibroblast interferon. Since the prior art establishes that one of ordinary skill in the art would have expected to obtain a series of hybridomas producing monoclonal antibodies differing in their affinity for the target antigen, appellants' burden is to establish that the actual differences observed in the argued properties represent an unexpected improvement. In re Merck & Co. Inc., 800 F.2d 1091, 231 USPQ 375 (Fed.Cir.1986). Appellants have not met this burden on this record.
Appellants also argue that the Patent and Trademark Office has continued to issue patents directed to hybridomas and monoclonal antibodies. As pointed out in the previous appeal, such arguments are without merit in that each case must be determined on its own merits, In re Gyurik, 596 F.2d 1012, 201 USPQ 552 (CCPA 1979); In re Attwood, 267 F.2d 954, 122 USPQ 378 (CCPA 1959); In re Freedlander, 136 F.2d 759, 760, 58 USPQ 402, 403 (CCPA 1943).
Appellants argue that certain of the hybridomas of claim 21 produce monoclonal antibodies that react with a protein having a molecular weight in excess of 25,000 which is asserted to be a higher molecular weight than that of human fibroblast interferon. The present specification states on page 18 that this high molecular weight proten could be a subspecies of human fibroblast interferon.
We first point out that claim 21 is not limited to any of the hybridomas which also react with this second molecular weight protein. Therefore, the claims are not commensurate in scope with this argument. Further, appellants have not established on this record that the human fibroblast interferon preparation used as the immunogen in the present invention did not include the higher molecular weight protein. If in fact it did, appellants have not explained on this record why one of ordinary skill in the art would have found it unexpected that a hybridoma was obtained to produce monoclonal antibodies specific to this protein.
*7 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).
FN1. Appellants' request that this appeal be heard en banc (Paper No. 32, June 24, 1991) was denied (Paper No. 33, July 15, 1991).
FN2. The effective filing date of the claims on appeal under 35 USC § 120 is February 17, 1981. Subsequent to our first decision, appellants filed a declaration under 37 CFR § 1.131 in which they asserted completion of the invention by June 12, 1980. The examiner found the declaration to be sufficient in an Advisory Action mailed July 14, 1988 (Paper No. 12) in parent application Serial No. 07/001,689.
FN3. The Appeal Brief filed by appellants on May 7, 1990 (Paper No. 21) was determined by the examiner not to be in accordance with 37 CFR § 1.192(c)(5). Therefore, the Supplemental Appeal Brief filed August 24, 1990 (Paper No. 24) is the main brief on appeal.
FN4. Stahli et al., Methods of Enzymology, Vol. 92, pages 26-36 (1983). (Attachment E to Supplemental Appeal Brief).
FN5. De St. Groth, "Monoclonal Antibody Production: Principles and Practice", pages 1, 3, 5, 7, 9 (Attachment H) publication date not supplied.

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