Enzo Biochem v. Calgene

• Court: U.S. Court of Appeals — Federal Circuit
• Writing for the Court: Before LOURIE, Circuit Judge, SMITH, Senior Circuit Judge, and SCHALL; LOURIE
• Citation: Enzo Biochem v. Calgene, 188 F.3d 1362, 52 USPQ2d 1129 (Fed. Cir. 1999)
• Decision Date: 24 September 1999
• Parties: (Fed. Cir. 1999) ENZO BIOCHEM, INC., Plaintiff-Appellant, v. CALGENE, INC., Defendant-Cross Appellant. 98-1438, -1479 DECIDED:

Page 1362

188 F.3d 1362 (Fed. Cir. 1999)

ENZO BIOCHEM, INC., Plaintiff-Appellant, v. CALGENE, INC., Defendant-Cross Appellant.

98-1438, -1479

United States Court of Appeals for the Federal Circuit

DECIDED: September 24, 1999

Appealed from: United States District Court for the District of Delaware Chief Judge Joseph J. Farnan, Jr.

[Copyrighted Material Omitted]

[Copyrighted Material Omitted]

Richard L. DeLucia, Kenyon & Kenyon, of New York, New York, argued for plaintiff-appellant. With him on the brief were Charles A. Weiss and John R. Hutchins, Kenyon & Kenyon, of Washington, DC.

William F. Lee, Hale and Dorr, LLP, of Boston, Massachusetts, argued for defendant-cross appellant. With him on the brief were James L. Quarles, III, and William G. McElwain, Hale and Dorr, LLP, of Washington, DC.

Before LOURIE, Circuit Judge, SMITH, Senior Circuit Judge, and SCHALL, Circuit Judge.

LOURIE, Circuit Judge.

Enzo Biochem, Inc. ("Enzo") appeals from the decision of the United States District Court for the District of Delaware that certain claims of its U.S. Patents 5,190,931 and 5,208,149 are invalid and not infringed by Calgene, Inc.'s FLAVR SAVR tomato. See Enzo Biochem, Inc. v. Calgene, Inc., 14 F. Supp. 2d 536 (D. Del. 1998); Enzo Biochem, Inc. v. Calgene, Inc., Civ. Action Nos. 93-110-JJF, 94-57-JJF (D. Del. June 4, 1998) (final judgment order). Enzo further appeals from two district court orders denying its post-trial evidentiary motions. See Enzo Biochem, Inc. v. Calgene, Inc., Civ. Action Nos. 93-110-JJF, 94-57-JJF (D. Del. June 23 and 30, 1998) (orders). Calgene cross-appeals from the district court's dismissal of its declaratory judgment counterclaim asserting that the claims of Enzo's U.S. Patent 5,272,065 are invalid as nonenabled, obvious, and anticipated. See Enzo, 14 F. Supp. 2d at 549 n.8. Calgene also cross-appeals from the district court's decision that this case is not exceptional.

Because the district court did not err in concluding that the claims at issue in the '931 and '149 patents are invalid as nonenabled, we affirm, and thus do not reach the issue of infringement as to those claims. We also conclude that the district court correctly held that Calgene failed to prove by clear and convincing evidence that Enzo's '065 patent is invalid, and that the court did not abuse its discretion in its evidentiary rulings. However, because the district court erred in not deciding the issue of inequitable conduct before it ruled on whether this case was exceptional, we vacate and remand on this issue.

BACKGROUND

A. Antisense Technology

Genetic antisense technology provides a powerful methodology for controlling gene expression in a particular organism.¹ Gene expression is the process by which information encoded in an organism's DNA is interpreted and processed to give rise to the various proteins which characterize that organism, thereby creating that organism's particular traits. The steps common to both eukaryotic and prokaryotic² gene expression are outlined in Figure 1.

Figure 1: Common steps in eukaryotic and prokaryotic gene expression
                5' 3' 
                X ---- X 
                X ---- X 5'
                A ---- T  A 
                G ---- C transcription G translation
                C ---- G ----------------> C ---------------------> Protein generated
                T ---- A U (RNA to ribosomes)
                G ---- C G
                C ---- G C
                Y ---- Y 3'
                Y ---- Y mRNA
                3' 5' 
                coding antisense 
                strand strand 
                

As indicated in Figure 1, a gene (indicated in bold)³ is a double-stranded DNA molecule which contains the information necessary to generate all or part of a particular protein. The two DNA strands are oriented in an antiparallel fashion (designated 3' and 5'), and the bases which comprise each strand hydrogen-bond to those of the opposing strand (indicated by "----") based on their complementarity. One DNA strand codes for the protein of interest, and is thus referred to as the "coding" or "sense" strand. The opposing, complementary strand is referred to as the "template" or "antisense" strand.

During the transcription step of gene expression, an enzyme, RNA polymerase, locates and binds to a promoter site (a sequence of nucleotides indicated schematically by "Xs"), which triggers the RNA polymerase to begin transcription. The RNA polymerase unwinds the DNA duplex and transcribes the template strand, thereby making a complementary RNA strand. The RNA strand generated by this process, known as messenger RNA ("mRNA"), is nearly identical in sequence and structure to the DNA coding strand, except that the sugar ribose is used in place of deoxyribose, and the RNA strand contains the base uracil instead of thymine. A termination sequence (indicated schematically by "Ys") signals the enzyme to cease transcription. Following transcription, the mRNA enters the ribosomes, the organelles that control protein synthesis. Within the ribosomes, the information encoded in the mRNA is interpreted, and based on the mRNA sequence, amino acids are arranged to make the protein for which that mRNA encodes; this step is referred to as translation.

As indicated in Figure 2, antisense technology aims to control the expression of a particular gene by blocking the translation of the mRNA produced by the transcription of that gene.⁴ Translation is blocked by incorporation of a specially designed DNA construct into the cell of interest; this construct contains part or all of the nucleotide sequence of the gene to be blocked, except that the sequence is "inverted"

Figure 2. Translation blocked by insertion of a DNA construct containing an inverted gene sequence which generates micRNA.

5' 3' 
                X ---- X 
                X ---- X 5' 5' 3'
                G ---- C G A ---- U
                C ---- G  C micRNA complexes G ---- C translation
                A ---- T transcription A with native mRNA C ---- G blocked
                G ---- C ----------------> G ----------------> U ---- A ---X---> no protein
                C ---- G C G ---- C generated
                T ---- A U C ---- G
                Y ---- Y 3' 3' 5'
                Y ---- Y micRNA mRNA micRNA
                3' 5' mRNA/micRNA complex
                construct containing
                inverted gene of Fig. 1
                

relative to its natural conformation.⁵ The construct in Figure 2 contains the entire gene sequence represented in Figure 1, but in an inverted orientation. The antisense DNA constructs typically resemble their native counterparts in that the inverted gene sequence is preceded by a promoter sequence (indicated schematically by "Xs") and followed by a termination sequence (indicated schematically by "Ys"). The inverted gene sequence is transcribed by an RNA polymerase as if it were the gene sequence in its proper orientation, thereby generating an RNA strand which is complementary to, and thereby able to bind to, the mRNA transcript of the native gene. This RNA strand is known as messenger interfering complementary RNA ("micRNA"), because when it binds the native mRNA, that mRNA cannot be translated. Consequently, the protein for which that gene codes can no longer be produced, and gene expression is thereby blocked.

B. The Patents and the Accused Product

The '931, '149, and '065 patents are all assigned to the Research Foundation of the State University of New York and are exclusively licensed to Enzo, which has the right to bring suit to enforce the patents. See Enzo, 14 F. Supp. 2d at 542. The patents possess essentially identical written descriptions and claim various fundamental aspects of genetic antisense technology. They teach the application of antisense technology in regulating three genes in the prokaryote E. coli, viz., the lpp (lipoprotein), ompC (outer membrane protein C), and ompA (outer membrane protein A) genes. Despite this limited disclosure, Inventor Masayori Inouye broadly asserted that:

The practices of this invention are generally applicable with respect to any organism containing genetic material which is capable of being expressed. Suitable organisms include the prokaryotic and eukaryotic organisms, such as bacteria, yeast, and other cellular organisms. The practices of this invention are also applicable to viruses, particularly where the viruses are incorporated into the organism.

'931 patent, col. 19, ll. 21-28. The claims of the three patents were likewise drafted to encompass application of antisense methodology in a broad range of organisms. The claims at issue in the '931 patent are directed to antisense constructs, methods of regulating gene expression in a cell using antisense constructs, and cells containing antisense constructs. Representative cell, method, and construct claims read as follows:

1. A prokaryotic or eukaryotic cell containing a non-native DNA construct, which construct produces an RNA which regulates the function of a gene, said DNA construct containing the following operably linked DNA segments:

a. a transcriptional promoter segment;

b. a transcription termination segment; and therebetween

c. a DNA segment;

whereby transcription of the DNA segment produces a ribonucleotide sequence which does not naturally occur in the cell, is complementary to a ribonucleotide sequence transcribed from said gene, and said non-naturally occurring ribonucleotide sequence regulates the function of said gene.

3. A method of regulating the function of a gene in a prokaryotic or eukaryotic cell which comprises introducing into said cell the DNA construct of claim 1.

5. A non-native DNA construct which, when present in a prokaryotic or eukaryotic cell containing a gene, produces an RNA which regulates the function of said gene, said DNA construct containing the following operably linked DNA segments:

a. a transcriptional promoter segment;

b. a transcription termination segment; and

c. a DNA segment comprising a segment of said gene, said gene segment located between said promoter segment and said termination segment and being inverted with respect to said promoter segment and said termination segment, whereby the RNA produced by transcription of the inverted gene segment regulates the function of said gene.

'931 patent, col. 21, ll. 37-51, 66-68; col. 22, ll. 8-21 (emphasis added). The...