Board of Patent Appeals and Interferences
Patent and Trademark Office (P.T.O.)
*1 EX PARTE DIRK M. ANDERSON, DAVID J. COSMAN AND VIRGINIA L. PRICE
Appeal No. 92-3157
September 14, 1993
Application for Patent filed January 20, 1987, Serial No. 07/004,466. Human Interleukin-3 Proteins.
Primary Examiner--Joan Ellis
Before Goldstein, Winters and Goolkasian
This is an appeal from the examiner's final rejection of claims 6, 8 through 10, 12 through 14 and 16 through 18, which are all the claims remaining in the application.
Claim 18 is illustrative of the invention and reads as follows:
18. An isolated DNA sequence encoding a mature human IL-3 protein having a proline residue at position 8 of the mature polypeptide, said protein possessing bone marrow proliferation-inducing activity in a human bone marrow proliferation assay.
The references relied on by the examiner are:
Clark et al. (Clark) 4,877,729 Oct. 31, 1989
Kurjan et al. (Kurjan) 4,546,082 Oct. 8, 1985
Yang et al. (Yang), Cell, "Human IL-3 (Multi-CSF): Identification by Expression Cloning of a Novel Hematopoietic Growth Factor Related to Murine IL-3," Vol. 47, October 10, 1986, pages 3-10.
Maniatis et al. (Maniatis), Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, CSH, NY, 1982, pages 404-433.
Appellants' invention is directed to a DNA coding for a mature, human IL-3 polypeptide, and to a method of using the DNA to produce the polypeptide. Human IL-3 polypeptide is a glycoprotein said to be a "colony stimulating factor" (CSF), i.e., a naturally occurring human protein thought to regulate the growth and differentiation of numerous subclasses of early hematopoietic and lymphoid progenitor cells. The IL-3 protein contains a sequence of over 150 amino acids of various types connected by peptide bonds.
Appellants are not the first to isolate a DNA coding for human IL-3. Yu-Chung Yang et al. appear to have been first in this endeavor. Descriptions of the Yang work are contained in the Yang and Clark references noted above. Importantly, the claimed DNAs differ from that specifically described in the prior art because the IL-3 proteins coded for by the claimed DNAs contain the amino acid proline at position 8 [FN1] of their sequence as opposed to serine as described in the Yang and Clark references.
Claim 18 stands rejected under 35 U.S.C. § 103 over the combined teachings of Yang and Clark. The remaining claims stand rejected under 35 U.S.C. § 103 over Yang and Clark, and further in view of Kurjan and Maniatis.
It is the examiner's position that the claimed Pro 8 proteins, and consequently the DNAs coding for the proteins, are minor biological variants ("alleles") of the Ser 8 proteins and DNAs described in the Yang and Clark references. The examiner has concluded that because the references teach the nucleotide sequence of the human IL-3 Ser 8 allele of the gene, it would have been obvious to produce and/or discover the human IL-3 Pro 8 allele, especially in view of Clark's explicit suggestions that (a) the human protein IL-3 specifically described therein was one of "a family of primate IL-3-like growth factors," and (b) other IL-3 factors existed which would be homologous to the IL-3 factors specifically set forth therein. Clark included as members of the "family" of homologous DNA sequences those unspecified sequences "caused by point mutations [FN2] or by induced modifications to enhance the activity or production of the polypeptides" (column 2, lines 50 through 54). The examiner is of the opinion that one skilled in the art, knowing the DNA sequence set forth in the Clark and Yang references, would have considered it obvious to modify any one of the amino acids set forth therein and, consequently, any one of the codons of the DNA set forth therein to have obtained a DNA and protein having essentially the same characteristics as the materials set forth in the references.
*2 Obviousness is a question of patent law, not chemistry. In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA1963). Nevertheless, the factual basis for the legal conclusion is often a matter of highly sophisticated chemistry. In the case before us, the examiner has set forth sufficient scientific basis from which one could properly conclude that the primate IL-3-like hematopoietic growth factors are part of a family of proteins which are similar in their amino acid sequence but are minor variants or point mutations of each other. This is because, as a matter of textbook chemistry, a single variation in the amino acid structure of a protein does not normally change the activity and function of the protein unless the single variation is in a critical region of the protein. [FN3] Accordingly, the examiner was technologically correct when she stated that the substitution of any one of the amino acids in the protein chain and the similar substitution of the DNA coding for the amino acid would not normally have been expected to have a significant effect on the activity of the protein.
Appellants urge that the examiner's legal conclusion of obviousness is in error because there is no explicit suggestion in the prior art to make the specific change in the DNAs claimed herein. We are unpersuaded by this argument which does not reflect the law. On this point we note the concurring opinion of Chief Judge Nies in In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed.Cir.1992) which indicates that obviousness may be found without "something specific in a prior art reference [which] would lead an inventor to combine the teachings therein with another piece of prior art." (Emphasis added.)
The examiner has relied on the teachings of Clark regarding the preparation of and/or existence of other members of the IL-3 DNA family which are minor variants or point mutations of the DNA described by Clark. The examiner has indicated that structural obviousness provides the motivation to make appellants' variation. We agree with the examiner. See In re Dillon, 919 F.2d 688, 692, 16 USPQ2d 1897, 1901 (Fed.Cir.1990), wherein the Federal Circuit stated:
This court, in reconsidering this case in banc, reaffirms that structural similarity between claimed and prior art subject matter, proved by combining references or otherwise, where the prior art gives reason or motivation to make the claimed compositions, creates a prima facie case of obviousness, and that the burden (and opportunity) then falls on an applicant to rebut that prima facie case.
A protein is composed of a long chain of amino acids arranged in a highly complex, twisted, intertwined, three-dimensional array. The protein is coded for by a considerably longer chain of nucleotides. When one steps back and views the twisted structure of the protein as a whole, and considers the overall similarity of the protein of the prior art versus that coded for by the DNA claimed herein, and also considers the similarity of the DNA of the prior art versus that claimed herein, the minor change in the chemical configuration or design of the molecule discovered or made by appellants is so negligible that a prima facie case of obviousness exists. In legal parlance, on the record herein appellants' structural modification is de minimis.
*3 Appellants urge that the particular substitution claimed herein, i.e., a codon for proline versus a codon for serine would have been unobvious because proline is a cyclic amino acid having a unique structural characteristic. Appellants support this argument by citation of the Lehninger reference. We are unpersuaded by this argument for the reasons set forth by the examiner on page 19 of the Answer. The Lehninger reference, submitted by appellants in support of the argument, is somewhat incomplete. As noted by the examiner, the normal IL-3 protein polypeptide consists of a varied distribution of all 20 amino acids and is not properly compared to the polyproline type homopolymer discussed by Lehninger. As noted by Lehninger, when proline residues occur in a normal polypeptide chain, the interruption in the helix of the protein causes no more than a minor kink or bend in the chain (page 131, lines 5-7). [FN4] Lehninger does not state or otherwise indicate that a proline substitution in a protein would have been expected to inactivate or adversely affect the molecule. As indicated previously, it is well known in the art that usually the substitution of one amino acid for another in a nonessential region of the protein will have no effect on the biological activity of the protein. There is no evidence of record that position 8 of the mature protein is essential for biological activity.
Any prima facie case of obviousness established by an examiner is subject to rebuttal, however the burden of rebuttal falls on the patent applicant. What constitutes rebuttal has been broadly set forth in In re Dillon, supra, 919 F.2d at 692-93, 16 USPQ2d at 1901 as follows:
[R]ebuttal or argument can consist of a comparison of test data showing that the claimed compositions possess unexpectedly improved properties or properties that the prior art does not have (citations omitted), that the prior art is so deficient that there is no motivation to make what might otherwise appear to be obvious changes (citations omitted), or any other argument or presentation of evidence that is pertinent. There is no question that all evidence of the properties of the claimed compositions and the prior art must be considered in determining the ultimate question of patentability, but it is also clear that the discovery that a claimed composition possesses a property not disclosed for the prior art subject matter, does not by itself defeat a prima facie case. (Emphasis added.)
In rebuttal, appellants urge that the particular allele they have discovered is the dominant allele [FN5] and the fact of dominance would not have been known to one of ordinary skill in the art at the time the invention was made. In support of this proposition, appellants have submitted the declarations of Drs. David J. Cosman and Abbe Sue Rubin. Both declarations indicate that the gene encoding the Pro 8 hIL-3 allele is the high-frequency allele whereas the gene discovered by Clark and Yang was a low frequency allele occurring in a minor percentage of the population. On this point the Rubin declaration, paragraph 7, concludes "the data reported by Dr. Cosman with a sample size of 13 individuals is sufficiently large enough to draw a conclusion that the Pro 8 allele of IL-3 predominates in the population." In other words, it is appellants' argument that they have discovered and isolated a predominate allele of IL-3 whereas Yang and Clark worked with a lesser variant thereof.
*4 In the case before us, appellants are claiming a DNA and the use of that DNA. What is of concern in the consideration of rebuttal evidence are the properties of the DNA itself and/or the product it produces, i.e., the protein it codes for. Appellants have not provided evidence that the protein coded for by the claimed DNA is any different from that of the prior art in its chemical properties. The only rebuttal evidence supplied by appellants is that the claimed DNA predominates in the human population at large.
The examiner has treated appellants' arguments regarding predominance as largely irrelevant because there is no evidence that the protein coded for by the predominate allele differs in properties from that coded for by the subdominant allele. Though germane, the examiner's position is not necessarily decisive on this issue because the claims are directed to a novel DNA and not the protein produced thereby. The ability of DNA to predominate in the genes of a species may be a "property" of a chemical compound (DNA) that sets it apart from that gene which does not predominate. For example, if the ultimate goal of a patent applicant's work is gene replacement therapy, the ability of a gene to ensure its reproduction and replication in a large proportion of the population may well be a significant property that may afford patentability to otherwise unpatentable subject matter.
As stated previously, the burden of overcoming a prima facie case of obviousness is on the patent applicant. In this case, appellants have not advised the Patent and Trademark Office of the significance of this genetic difference in DNA. If predominance is an insignificant variation it cannot be said to overcome a prima facie case of obviousness. In order for a showing of "unexpected results" to be probative evidence of nonobviousness, it falls upon the applicant to at least establish that any asserted differences in properties are of some practical advantage. See In re D'Ancicco, 439 F.2d 1244, 169 USPQ 303 (CCPA1971). Appellants have not explained the practical advantages of the differences in DNA structure and, accordingly, have not overcome the prima facie case established by the examiner.
Appellants urge that the DNAs claimed herein are not "artificial variants" derived from a native sequence, but are alleles--"a natural variation of the same gene" (Brief, page 7). We are unpersuaded by this argument. The claims herein are directed to chemical compounds (DNAs) which may be made via any route, natural or synthetic, and must be treated as such from a patentability viewpoint. It is the patentability of the compound, the DNA, that is at issue, not the method by which the DNA is made. Moreover, though the specific gene isolated by appellants and described in the specification is a naturally occurring, "native" gene, the claims herein do not define and limit the DNA to that specific gene. Claim 18 is generic and includes any DNA sequence which codes for an active human IL-3-like protein having a proline residue at position 8. Such sequences may be artificial and may include DNA variations which code for additional variations in the amino acid sequence so long as the final mature protein is substantially homologous to IL-3 and possesses bone marrow proliferation-inducing activity. [FN6] Indeed, considering the degenerate nature of the genetic code, the claimed DNA need not have a codon sequence at all like that of the natural sequence.
*5 Appellants urge that the claims directed to the process of using the DNA by incorporating the DNA into yeast are separately patentable. On this point appellants note that the Cosman declaration, paragraphs 9 through 11, indicate that there was a degree of unpredictability regarding the efficacy of the protein expressed by yeast because the pattern of glycosylation in yeast is different from that provided by mammalian cells. We are unpersuaded by the declaration because, as noted by the examiner, the Clark reference clearly teaches that the IL-3-like protein can be obtained by incorporating the DNA into yeast cells and cultivating the cells.
We note in passing that Claim 18 is generic and covers any and all analogs of DNAs coding for human IL-3 having a proline at position 8 and having bone marrow proliferation activity. A claim of similar scope was considered invalid by the Federal Circuit in Amgen Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 1201, 18 USPQ2d 1016, 1027 (Fed.Cir.1991). We note also that the specification does not describe how to use the claim compounds "in vivo" and does not exemplify or otherwise describe successful utilization of the proteins prepared from the claimed DNAs. We question whether one skilled in the art would accept appellants' "in vitro" test as predictive of "in vivo" results and whether one skilled in the art would know how to use the Pro 8 protein made. See Ex parte Maas, 9 USPQ2d 1746 (BPAI1987). We note the Watson text, supra, page 976 states (copy enclosed):
The ability of a polypeptide to stimulate growth of a particular cell type in vitro does not prove that it serves the same function in vivo.
Should the claims of this application be prosecuted further in a continuing application we urge the examiner to consider the enablement and utility aspects of patentability.
The examiner's rejections of appellants' claims under 35 U.S.C. § 103 are affirmed.
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
Examiner in Chief
Sherman D. Winters
Examiner in Chief
John T. Goolkasian
Examiner in Chief
FN1. Hereinafter the shorthand designations pro 8 and ser 8 are used to designate the respective amino acids at position 8 of the proteinaceous polypeptide sequence.
FN2. A point mutation is usually the result of a change in a single base pair along the DNA of the gene. In the instant case, the T nucleotide of the TCC codon coding for the amino acid "serine" at position 8 of the polypeptide, is substituted by a C nucleotide resulting in a CCC codon which codes for the different amino acid "proline."
FN3. We take official notice of this fact and base our official notice on the text Watson et al., Molecular Biology of the Gene, Fourth Edition, 1987, The Benjamin/Cummings Publishing Company. Page 224 states, "... many of the amino acids in proteins are not essential, and when they are replaced by somewhat similar amino acids, the proteins often retain full activity." Pages 226-228, begin with the boldfaced statement:
Single Amino Acid Substitutions Usually Do Not Alter Enzyme Activity.
FN4. Page 131 of Lehninger was supplied by the examiner.
FN5. A dominant allele occurs much more frequently in the population.
FN6. See the very broad definition of the phrases "human interleukin-3" and "hIL-3" set forth on page 3 of appellants' specification.