Mayne, In re, 95-1522

• Decision Date: 17 January 1997
• Docket Number: No. 95-1522,95-1522
• Parties: In re Nancy G. MAYNE, Rama Belagaje, Paul J. Burnett and Hansen M. Hsiung.
• Court: U.S. Court of Appeals — Federal Circuit

Page 1339

104 F.3d 1339

41 U.S.P.Q.2d 1451

In re Nancy G. MAYNE, Rama Belagaje, Paul J. Burnett and

Hansen M. Hsiung.

No. 95-1522.

United States Court of Appeals, Federal Circuit.

Jan. 17, 1997.

Paul J. Gaylo, Eli Lilly and Company, Indianapolis, IN, argued, for appellants. With him on the brief, were John E. Parrish and Edward P. Gray. Of counsel was Paul R. Cantrell.

Scott A. Chambers, Associate Solicitor, U.S. Patent and Trademark Office, Arlington, VA, argued, for the Commissioner. With him on the brief, were Nancy J. Linck Solicitor, Albin F. Drost, Deputy Solicitor, and Richard Torczon, Associate Solicitor.

Before ARCHER, Chief Judge, MICHEL and RADER, Circuit Judges.

RADER, Circuit Judge.

The Patent and Trademark Office Board of Patent Appeals and Interferences (Board) affirmed the rejection of claims 30 and 31 of patent application 07/686,016 as obvious under 35 U.S.C. § 103 (1994). The Board also rejected applicants' attempt to rebut the prima facie case of obviousness with evidence of unexpected properties. Because the applicants merely substituted one element known in the art for a known equivalent, this court affirms.

Background

The patent application at issue in this case relates to the field of protein engineering. Initially, biotechnology was used to create large quantities of a known, pharmaceutically significant protein in its pure form. However, advances in genetic engineering now allow protein engineers to dissect and reassemble segments of known proteins to create new and useful proteins.

Proteins are large polymeric molecules made up of individual amino acids linked by peptide bonds to form a peptide chain. One end of a peptide chain ends in an amino group (NH2) and the other ends in a carboxyl group (COOH). Although there are only twenty common amino acids, each distinguishable by its side chain, they produce innumerable potential polypeptide sequences. In turn, these polypeptide sequences relate to a virtually infinite number of possible protein structures.

Each amino acid in the protein sequence plays a role in defining the structure of the protein. Depending on its composition and resulting polarity or nonpolarity, the side chain is either hydrophobic or hydrophilic. Each amino acid interacts with adjacent amino acids dependent upon their polarity. This interaction, along with the rotational flexibility of the polypeptide chain, is a key component in the definition of the conformation and three-dimensional structure of the protein.

Once a protein is developed, it often has a specific application in biotechnology. For example, the development of recombinant bovine somatotrophin made possible the administration of this protein to dairy cows in order to increase milk production. One possible side effect of the introduction of engineered proteins into living organisms is the stimulation of an immune response. A triggered immune response can have numerous effects, ranging from blocking the efficacy of the protein to adverse health consequences to the organism.

Applicants claim two compounds made with recombinant DNA technology. These compounds are proteins each comprising the amino acid Met, an enterokinase cleavage site, and either human or bovine growth hormone (HGH or BGH). Met necessarily results from translation of RNA into proteins. The enterokinase cleavage site is an amino acid sequence (peptide chain) in the form Asp-Asp-Asp-Asp-Lys ((Asp) sub4 -Lys). Enterokinase recognizes the sequence (Asp) sub4 -Lys as the point at which to cleave the initial peptide chain (between Lys and either the HGH or the BGH) to produce a mature protein. The HGH and BGH are well known proteins in the prior art.

Thus, the claims on appeal require Met-Phe-Pro-Leu-(Asp) sub4 -Lys-HGH and Met-Phe-Pro-Leu-(Asp) sub4 -Lys-BGH. Hybrid proteins in the form of the claimed compounds are known as fusion proteins because different parts of the protein are coded by the DNA of different genes. Moreover, in this case, two of the amino acids in the cleavage site between the Met and (Asp) sub4 -namely, Phe and Leu--are hydrophobic.

The Board relied on three primary prior art references in determining obviousness. First, Rutter, U.S. Patent No. 4,749,326 (Rutter), teaches recombinant DNA technology to fuse an enzyme cleavage site to a desired protein, in this case the HGH or BGH. The second reference, Light, et al., Analytical Biochemistry 106: 199-206 (1980) (Light), teaches the uses of enterokinase to identify the cleavage site. Light also teaches two naturally occurring forms of the enterokinase recognition sequences, which begin with Phe-Pro-Ile and Leu-Pro-Leu. Finally, Goeddel, et al., Nature 281: 544-48 (1979) (Goeddel), discloses the nucleotide and amino acid sequences of HGH and BGH. Applicants claim that their compounds viewed as a whole are not prima facie obvious because the cited references provide insufficient motivation to combine.

Applicants argue in the alternative that even if a prima facie case of obviousness is made, two unexpected results establish the nonobviousness of the compounds. First, they argue it is unexpected that the proteins would induce such a low immune response when administered by injection to rats. Second, they argue it is unexpected that the proteins would be biologically active even before cleavage of the initial peptide chain.

Applicants rely on four references to rebut obviousness. First, U.S. Patent No. 4,703,004 (the '004 patent), discloses immune responses to certain peptides. Second, J.T. Barrett, Textbook of Immunology 12-83 (3d ed. 1978) (Barrett) describes expected immunogenic responses to similar compounds. Third, Juskevich, et al., Science 249: 875-84 (1990) (Juskevich), discusses biological activity of bovine growth hormone. Finally, Bick, et al., Animal Biotechnology 1: 61-71 (1990) (Bick), describes the immune response of dairy cattle to introduced proteins. Applicants urge that each of these references establish that the claimed compounds exhibit unexpected properties.

After evaluation of the evidence, the Board was not convinced: "Since the [applicants] have merely substituted one functional equivalent for another, we concur with the examiner that a fusion protein comprising the enterokinase cleavage site, Phe-Pro-Leu-(Asp) sub4 -Lys, would have been prima facie obvious to one skilled in the art at the time the present application was filed." Moreover, the Board stated that the applicants "failed to establish that those skilled in the art would have considered" the results unexpected.

Discussion

Section 103(a) precludes the grant of a patent "if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person of ordinary skill in the art." 35 U.S.C. § 103(a). Although reviewing the ultimate question of obviousness as a question of law, this court reviews the foundational facts for that conclusion for clear error. Dennison Mfg. Co. v. Panduit Corp., 475 U.S. 809, 810-11, 106 S.Ct. 1578, 1579, 89 L.Ed.2d 817 ("While the ultimate question of patent validity is one of law ... the § 103 condition [that is, nonobviousness] ... lends itself to several basic factual inquiries." (quoting Graham v. John Deere Co., 383 U.S. 1, 17, 86 S.Ct. 684, 694, 15 L.Ed.2d 545, 148 USPQ 459, 466-67 (1966))); In re Deuel, 51 F.3d 1552, 1557, 34 USPQ2d 1210, 1214 (Fed.Cir.1995) (citing In re Vaeck, 947 F.2d 488, 493, 20 USPQ2d 1438, 1442 (Fed.Cir.1991)); In re Beattie, 974 F.2d 1309, 1311, 24 USPQ2d 1040, 1041 (Fed.Cir.1992).

The legal determination under section 103 is whether the claimed invention as a whole would have been obvious to a person of ordinary skill in the art at the time the invention was made. In re O'Farrell, 853 F.2d 894, 902, 7 USPQ2d 1673, 1680 (Fed.Cir.1988). The foundational facts for the prima facie case of obviousness are: (1) the scope and content of the prior art; (2) the difference between the prior art and the claimed invention; and (3) the level of ordinary skill in the art. Graham v. John Deere Co., 383 U.S. at 17-18, 86 S.Ct. at 693-94; Miles Labs., Inc. v. Shandon Inc., 997 F.2d 870, 877, 27 USPQ2d 1123, 1128 (Fed.Cir.1993). Moreover, objective indicia such as commercial success and long felt need are relevant to the determination of obviousness. Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 1538, 218 USPQ 871, 878-79 (Fed.Cir.1983). Thus, each obviousness determination rests on its own facts. In re Durden, 763 F.2d 1406, 1410, 226 USPQ 359, 361 (Fed.Cir.1985).

Prima Facie Obviousness

The Patent and Trademark Office (PTO) has the burden of showing a prima facie case of obviousness. In re Bell, 991 F.2d 781, 783, 26 USPQ2d 1529, 1530 (Fed.Cir.1993)- ; see In re Fine, 837 F.2d 1071, 1074, 5 USPQ2d 1596, 1598 (Fed.Cir.1988). Standards for the patenting of chemical entities have evolved. At one time, the PTO focused only on the "structural obviousness" of the chemical entity. Under this standard, the structural formula of the claimed compound was compared for similarity with the structural formulae of known compounds. This regime did not allow evidence of unexpected results to trump the conclusion of obviousness based on structure. Over thirty years ago, courts recognized that unexpected properties can show that a claimed compound that appeared to be obvious on structural grounds was not obvious when looked at as a whole. See, e.g., In re Papesch, 50 C.C.P.A. 1084, 315 F.2d 381, 391, 137 USPQ 43, 51 (1963). In In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed.Cir.1990) (en banc), this court noted the effect of unexpected results in the obviousness determination for chemical entities, but rejected as a requirement for establishing prima facie obviousness that there be an expectation or suggestion in the prior art that the claimed compound will have similar utility as the one newly discovered by...