In re Berg

• Decision Date: 20 February 2003
• Docket Number: No. 02-1120.,No. 02-1160.,02-1120.,02-1160.
• Citation: 320 F.3d 1310
• Parties: In re Richard A. BERG, Paul D. Toman, and Donald G. Wallace.
• Court: U.S. Court of Appeals — Federal Circuit

320 F.3d 1310

In re Richard A. BERG, Paul D. Toman, and Donald G. Wallace.

No. 02-1120.

No. 02-1160.

United States Court of Appeals, Federal Circuit.

DECIDED: February 20, 2003.

Richard Aron Osman, Science & Technology Law Group, of Hillsborough, CA, argued for appellant.

Kristin L. Yohannan, Associate Solicitor, United States Patent and Trademark Office, of Arlington, VA, argued for appellee. With her on the brief were John M. Whealan, Solicitor; and Linda Moncys Isacson, Associate Solicitor.

Before BRYSON, Circuit Judge, PLAGER, Senior Circuit Judge, and PROST, Circuit Judge.

BRYSON, Circuit Judge.

Appellants Richard A. Berg, Paul D. Toman, and Donald G. Wallace seek review of two decisions of the United States Patent and Trademark Office Board of Patent Appeals and Interferences, one sustaining a rejection of the appellants' application as obvious under 35 U.S.C. § 103(a) and the other upholding the rejection of a related divisional application for the same reason. We affirm.

I

In 1994, the appellants filed a patent application, Serial No. 08/278,774 ("the '774 application"), claiming "Mutated Recombinant Collagens." Independent claim 1 is representative of the claimed subject matter:

1. A recombinant procollagen polypeptide chain comprising a natural collagen polypeptide chain, a first natural procollagen C-terminal propeptide and a first non-natural site-specific proteolytic agent recognition site, wherein said first non-natural site-specific proteolytic agent recognition site is located between said collagen chain and said first propeptide.

The appellants subsequently filed a divisional application, Serial No. 08/630,654 ("the '654 application"), claiming nucleic acids that encode the proteins claimed in the '774 application. Independent claim 21 is illustrative of the subject matter of the divisional application:

21. A nucleic acid encoding a recombinant procollagen polypeptide chain comprising a natural collagen polypeptide chain, a first natural procollagen C-terminal propeptide and a first non-natural site-specific proteolytic agent recognition site, wherein said first non-natural site-specific proteolytic agent recognition site is located between said collagen polypeptide chain and said first propeptide, and said propeptide is located at the C-terminus of said procollagen polypeptide chain.

The patent examiner who reviewed the two applications rejected certain claims in each application for obviousness. For the '774 application, the examiner concluded that independent claim 1 and dependent claims 2-3, 6-9, 14-16, and 18 were unpatentable over four prior art references — Chu, Prockop, and Olsen in view of Carter. For the '654 application, the examiner rejected independent claim 21 and dependent claims 22-30 as unpatentable over three prior art references — Ryan in view of Carter and Prockop II, a different reference by Prockop. The appellants appealed the rejections to the Board.

The Board agreed with the examiner that Chu, Prockop, and Olsen in view of Carter established an unrebutted prima facie case of obviousness for all but two of the appealed claims of the '774 application, and that Ryan in view of Carter and Prockop II established an unrebutted prima facie case of obviousness for all of the appealed claims of the '654 application. Accordingly, the Board affirmed the examiner's rejection of the claims that are at issue in this appeal. The Board subsequently denied the appellants' requests for reconsideration, and this appeal followed.

II

Collagen is a natural protein found in humans and, in somewhat different form, in other animals. It has been used in a wide range of applications, including as a substrate for cell cultureware and in human reconstructive therapy. As the major macromolecule in most human connective tissue, collagen has many potential therapeutic applications. Because of difficulties encountered in obtaining and using nonhuman collagen or human collagen from cadavers and placentas, it has been considered desirable to produce human collagen as a recombinant protein expressed in E. coli bacteria.

When collagen is synthesized, it is typically expressed as a precursor, procollagen, which consists of collagen with additional peptide extensions at either end of the molecular chain, i.e., at the amino and carboxyl ends (also known as the N-terminus and the C-terminus). The peptide extensions are then removed by specific proteolytic enzymes, known as proteases, to produce collagen.

The claimed invention is a polypeptide chain in which a natural procollagen C-terminal propeptide is fused to a collagen peptide via a non-natural site-specific proteolytic agent recognition site, i.e., a site at which a particular protease can cleave the peptide chain into two pieces. The natural procollagen C-terminal propeptide is useful in folding the peptide into its proper shape, but after the folding process is complete, the C-terminal propeptide can be cleaved off by an appropriate enzyme and purified out of the composition, leaving only the mature collagen.

III

Obviousness is a question of law supported by underlying facts. In re Gartside, 203 F.3d 1305, 1316, 53 USPQ2d 1769, 1776 (Fed.Cir.2000). What the prior art teaches and whether it teaches away from the claimed invention are questions of fact. In re Bell, 991 F.2d 781, 784, 26 USPQ2d 1529, 1531 (Fed.Cir.1993). On appeal, the Board's factual findings are reviewed for substantial evidence. Gartside, 203 F.3d at 1316, 53 USPQ2d at 1776. Because the appellants' arguments focus on the teachings of the prior art, our obviousness inquiry focuses on whether the Board's factual conclusions as to those teachings are supported by substantial evidence.

Because the appellants treat the two related applications together, we do the same. With respect to the '774 application, the appellants did not argue dependent claims 2-3, 8-9, 14-16, or 18 separately to the Board, nor do they in this appeal. The rejected claims therefore stand or fall with representative independent claim 1. With respect to the '654 application, the appellants did not argue dependent claims 22-30 of that application separately to the Board or to us, so the rejected claims stand or fall with representative independent claim 21. See In re Dance, 160 F.3d 1339, 1340 n. 2, 48 USPQ2d 1635, 1636 n. 2 (Fed.Cir.1998).

In the prosecution of the '774 application, the examiner found that Chu and Prockop teach human procollagen and its N and C-terminal propeptides, and that Olsen teaches the C-terminal propeptide of type 1 procollagen. In addition, the examiner relied on Carter as teaching that genes can be engineered so as to produce fusion proteins, and that those fusion proteins can be specifically cleaved using various chemical and enzymatic means. In the prosecution of the '654 application, the examiner found that Ryan teaches a nucleic acid sequence encoding a recombinant procollagen chain comprising a natural collagen polypeptide chain. In addition, the examiner concluded that Prockop II contains the following disclosures: (1) a vector comprising a recombinant human procollagen gene; (2) a promoter not naturally linked to the recombinant gene, and (3) the C-propeptide and N-propeptide of procollagen. The examiner further explained that the C-terminal propeptide is necessary for proper chain assembly of collagen molecules, a teaching found in the Prockop reference. The Board affirmed the examiner's interpretation of each of the prior art references, and the appellants do not challenge those interpretations.

Based on the prior art references of record, the examiner concluded that it would have been obvious to a person of ordinary skill in the art to create a recombinant DNA system for the production of procollagen in which the recombinant procollagen chain consisted of a natural collagen polypeptide and a first natural propeptide, with a first non-natural site-specific proteolytic agent recognition site located between them. It is that conclusion to which the appellants object.

The appellants do not dispute that procollagens (including their natural N and C-terminal propeptides) and the genes that encode them are well known in the art. Instead, they challenge the conclusion of the examiner and the Board that Carter provided the motivation for the inventions claimed in the two...