Deuel, In re, 94-1202

• Decision Date: 28 March 1995
• Docket Number: No. 94-1202,94-1202
• Citation: 34 USPQ2d 1210,51 F.3d 1552
• Parties: , 34 U.S.P.Q.2d 1210 In re Thomas F. DEUEL, Yue-Sheng Li, Ned R. Siegel and Peter G. Milner.
• Court: U.S. Court of Appeals — Federal Circuit

Page 1552

51 F.3d 1552

63 USLW 2624, 34 U.S.P.Q.2d 1210

In re Thomas F. DEUEL, Yue-Sheng Li, Ned R. Siegel and Peter

G. Milner.

No. 94-1202.

United States Court of Appeals,

Federal Circuit.

March 28, 1995.

G. Harley Blosser, Senniger, Powers, Leavitt & Roedel, of St. Louis, MO, argued for appellants. With him on the brief was Donald G. Leavitt.

Donald S. Chisum, Morrison & Foerster, Seattle, WA, argued for amicus curiae, The Biotechnology Industry Ass'n and The Bay Area Bioscience Center. With him on the brief were Debra A. Shetka, Morrison & Forester, Palo Alto, CA and Robert P. Blackburn, Emeryville, CA.

Teddy S. Gron, Acting Associate Sol., Arlington, VA, argued for appellee. With him on the brief was Albin F. Drost, Acting Sol. Nancy J. Linck, Office of the Sol., Arlington, VA, represented appellee.

Before ARCHER, Chief Judge, NIES and LOURIE, Circuit Judges.

LOURIE, Circuit Judge.

Thomas F. Deuel, Yue-Sheng Li, Ned R. Siegel, and Peter G. Milner (collectively "Deuel") appeal from the November 30, 1993 decision of the U.S. Patent and Trademark Office Board of Patent Appeals and Interferences affirming the examiner's final rejection of claims 4-7 of application Serial No. 07/542,232, entitled "Heparin-Binding

Growth Factor," as unpatentable on the ground of obviousness under 35 U.S.C. Sec. 103 (1988). Ex parte Deuel, 33 USPQ2d 1445 (Bd.Pat.App.Int.1993). Because the Board erred in concluding that Deuel's claims 5 and 7 directed to specific cDNA molecules would have been obvious in light of the applied references, and no other basis exists in the record to support the rejection with respect to claims 4 and 6 generically covering all possible DNA molecules coding for the disclosed proteins, we reverse.

BACKGROUND

The claimed invention relates to isolated and purified DNA and cDNA molecules encoding heparin-binding growth factors ("HBGFs"). ¹ HBGFs are proteins that stimulate mitogenic activity (cell division) and thus facilitate the repair or replacement of damaged or diseased tissue. DNA (deoxyribonucleic acid) is a generic term which encompasses an enormous number of complex macromolecules made up of nucleotide units. DNAs consist of four different nucleotides containing the nitrogenous bases adenine, guanine, cytosine, and thymine. A sequential grouping of three such nucleotides (a "codon") codes for one amino acid. A DNA's sequence of codons thus determines the sequence of amino acids assembled during protein synthesis. Since there are 64 possible codons, but only 20 natural amino acids, most amino acids are coded for by more than one codon. This is referred to as the "redundancy" or "degeneracy" of the genetic code.

DNA functions as a blueprint of an organism's genetic information. It is the major component of genes, which are located on chromosomes in the cell nucleus. Only a small part of chromosomal DNA encodes functional proteins.

Messenger ribonucleic acid ("mRNA") is a similar molecule that is made or transcribed from DNA as part of the process of protein synthesis. Complementary DNA ("cDNA") is a complementary copy ("clone") of mRNA, made in the laboratory by reverse transcription of mRNA. Like mRNA, cDNA contains only the protein-encoding regions of DNA. Thus, once a cDNA's nucleotide sequence is known, the amino acid sequence of the protein for which it codes may be predicted using the genetic code relationship between codons and amino acids. The reverse is not true, however, due to the degeneracy of the code. Many other DNAs may code for a particular protein. The functional relationships between DNA, mRNA, cDNA, and a protein may conveniently be expressed as follows:

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Collections ("libraries") of DNA and cDNA molecules derived from various species may be constructed in the laboratory or obtained from commercial sources. Complementary DNA libraries contain a mixture of cDNA clones reverse-transcribed from the mRNAs found in a specific tissue source. Complementary DNA libraries are tissue-specific because proteins and their corresponding mRNAs are only made ("expressed") in specific tissues, depending upon the protein. Genomic DNA ("gDNA") libraries, by contrast, theoretically contain all of a species' chromosomal DNA. The molecules present in cDNA and DNA libraries may be of unknown function and chemical structure, and As disclosed in Deuel's patent application, Deuel isolated and purified HBGF from bovine uterine tissue, found that it exhibited mitogenic activity, and determined the first 25 amino acids of the protein's N-terminal sequence. ² Deuel then isolated a cDNA molecule encoding bovine uterine HBGF by screening a bovine uterine cDNA library with an oligonucleotide probe designed using the experimentally determined N-terminal sequence of the HBGF. Deuel purified and sequenced the cDNA molecule, which was found to consist of a sequence of 1196 nucleotide base pairs. From the cDNA's nucleotide sequence, Deuel then predicted the complete amino acid sequence of bovine uterine HBGF disclosed in Deuel's application.

the proteins which they encode may be unknown. However, one may attempt to retrieve molecules of interest from cDNA or gDNA libraries by screening such libraries with a gene probe, which is a synthetic radiolabelled nucleic acid sequence designed to bond ("hybridize") with a target complementary base sequence. Such "gene cloning" techniques thus exploit the fact that the bases in DNA always hybridize in complementary pairs: adenine bonds with thymine and guanine bonds with cytosine. A gene probe for potentially isolating DNA or cDNA encoding a protein may be designed once the protein's amino acid sequence, or a portion thereof, is known.

Deuel also isolated a cDNA molecule encoding human placental HBGF by screening a human placental cDNA library using the isolated bovine uterine cDNA clone as a probe. Deuel purified and sequenced the human placental cDNA clone, which was found to consist of a sequence of 961 nucleotide base pairs. From the nucleotide sequence of the cDNA molecule encoding human placental HBGF, Deuel predicted the complete amino acid sequence of human placental HBGF disclosed in Deuel's application. The predicted human placental and bovine uterine HBGFs each have 168 amino acids and calculated molecular weights of 18.9 kD. Of the 168 amino acids present in the two HBGFs discovered by Deuel, 163 are identical. Deuel's application does not describe the chemical structure of, or state how to isolate and purify, any DNA or cDNA molecule except the disclosed human placental and bovine uterine cDNAs, which are the subject of claims 5 and 7.

Claims 4-7 on appeal are all independent claims and read, in relevant part, as follows:

4. A purified and isolated DNA sequence consisting of a sequence encoding human heparin binding growth factor of 168 amino acids having the following amino acid sequence: Met Gln Ala ... [remainder of 168 amino acid sequence].

5. The purified and isolated cDNA of human heparin-binding growth factor having the following nucleotide sequence: GTCAAAGGCA ... [remainder of 961 nucleotide sequence].

6. A purified and isolated DNA sequence consisting of a sequence encoding bovine heparin binding growth factor of 168 amino acids having the following amino acid sequence: Met Gln Thr ... [remainder of 168 amino acid sequence].

7. The purified and isolated cDNA of bovine heparin-binding growth factor having the following nucleotide sequence: GAGTGGAGAG ... [remainder of 1196 nucleotide sequence].

Claims 4 and 6 generically encompass all isolated/purified DNA sequences (natural and synthetic) encoding human and bovine HBGFs, despite the fact that Deuel's application does not describe the chemical structure of, or tell how to obtain, any DNA or cDNA except the two disclosed cDNA molecules. Because of the redundancy of the genetic code, claims 4 and 6 each encompass an enormous number of DNA molecules, including the isolated/purified chromosomal DNAs encoding the human and bovine proteins. Claims 5 and 7, on the other hand, are directed to the specifically disclosed cDNA molecules encoding human and bovine HBGFs, respectively.

During prosecution, the examiner rejected claims 4-7 under 35 U.S.C. Sec. 103 as unpatentable over the combined teachings of Bohlen ³ Maniatis describes a method of isolating DNAs or cDNAs by screening a DNA or cDNA library with a gene probe. The reference outlines a general technique for cloning a gene; it does not describe how to isolate a particular DNA or cDNA molecule. Maniatis does not discuss certain steps necessary to isolate a target cDNA, e.g., selecting a tissue-specific cDNA library containing a target cDNA and designing an oligonucleotide probe that will hybridize with the target cDNA.

                and Maniatis. 4  The Bohlen reference discloses a group of protein growth factors designated as heparin-binding brain mitogens ("HBBMs") useful in treating burns and promoting the formation, maintenance, and repair of tissue, particularly neural tissue.  Bohlen isolated three such HBBMs from human and bovine brain tissue.  These proteins have respective molecular weights of 15 kD, 16 kD, and 18 kD.  Bohlen determined the first 19 amino acids of the proteins' N-terminal sequences, which were found to be identical for human and bovine HBBMs. 5  Bohlen teaches that HBBMs are brain-specific, and suggests that the proteins may be homologous between species.  The reference provides no teachings concerning DNA or cDNA coding for HBBMs
                

The examiner asserted that, given Bohlen's disclosure of a heparin-binding protein and its N-terminal sequence and Maniatis's gene cloning method, it would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to clone a gene for HBGF. ⁶ According to the examiner, Bohlen's published N-terminal sequence would have motivated a person of ordinary skill in the art to clone such a...