Novo Nordisk v. Bio-Technology General

• Decision Date: 05 October 2005
• Docket Number: No. 04-1581.,04-1581.
• Citation: 424 F.3d 1347
• Parties: NOVO NORDISK PHARMACEUTICALS, INC. and Novo Nordisk A/S, Plaintiffs-Appellants, v. BIO-TECHNOLOGY GENERAL CORP. and Teva Pharmaceuticals USA, Inc., Defendants-Appellees.
• Court: U.S. Court of Appeals — Federal Circuit

424 F.3d 1347

NOVO NORDISK PHARMACEUTICALS, INC. and Novo Nordisk A/S, Plaintiffs-Appellants, v. BIO-TECHNOLOGY GENERAL CORP. and Teva Pharmaceuticals USA, Inc., Defendants-Appellees.

No. 04-1581.

United States Court of Appeals, Federal Circuit.

October 5, 2005.

COPYRIGHT MATERIAL OMITTED

Steven E. Lipman, Darby & Darby, P.C., of New York, New York, argued for plaintiffs-appellants. Of counsel were James Edward Hanft, Paul M. Zagar, Jay P. Lessler, Kevin L. Reiner, Robert Schaffer and Joseph R. Robinson.

John W. Bateman, Kenyon & Kenyon, of Washington, DC, argued for defendants-appellees. On the brief was Richard L. DeLucia, of New York, New York. Of counsel were Steven J. Lee, and Thomas J. Meloro, of New York, New York, and Kenneth R. Corsello, of Washington, DC.

Before SCHALL, Circuit Judge, ARCHER, Senior Circuit Judge, and BRYSON, Circuit Judge.

SCHALL, Circuit Judge.

Novo Nordisk Pharmaceuticals, Inc. and Novo Nordisk A/S (collectively, "Novo") appeal from the final judgment of the United States District Court for the District of Delaware in their suit for patent infringement against Bio-Technology General Corp. and Teva Pharmaceuticals USA, Inc. The district court held the two claims of Novo Nordisk A/S's U.S. Patent No. 5,633,352 ("the '352 patent") invalid by reason of anticipation under 35 U.S.C. § 102(a). The court also held the patent unenforceable due to inequitable conduct. Novo Nordisk Pharms., Inc. v. Bio-Technology Gen. Corp., No. 1:02-CV-00332-SLR, 2004 WL 1739720 (D.Del. Aug. 3, 2004) ("Opinion"). We affirm the judgment of invalidity with respect to claim 1 of the '352 patent, as well as the judgment that the patent is unenforceable. We vacate the judgment of invalidity with respect to claim 2 of the patent.

BACKGROUND

I.

Novo Nordisk Pharmaceuticals, Inc. and Novo Nordisk A/S are research-based pharmaceutical manufacturers. Novo Nordisk A/S is the assignee of the '352 patent, which is entitled "Biosynthetic Human Growth Hormone." The '352 patent is directed to a process for producing "ripe" human growth hormone ("hGH") protein in E.Coli bacteria through the use of recombinant DNA techniques. Novo Nordisk Pharmaceuticals, Inc. is the U.S. healthcare affiliate of Novo Nordisk A/S.

The hGH protein has a specific sequence of 191 amino acids and is secreted by the anterior pituitary gland. The protein, which plays a central role in cell growth and metabolism, is therapeutically useful to treat, among other conditions, growth hormone deficiencies and infertility. It also is useful in wound care. Until the mid-1980's, hGH for therapeutic purposes could be obtained only from the pituitary gland of a human cadaver (known as "pituitary-derived hGH"). However, the use of pituitary-derived hGH carried a high risk of contamination and infection for the patient.

Prior to the '352 patent, numerous attempts were made to produce biosynthetic hGH that would function in vivo in the same manner as pituitary-derived hGH. One such attempt, set forth in U.S. Patent No. 4,342,832, resulted in hGH protein with 192 amino acids, instead of the 191 amino acids found in pituitary-derived hGH. '352 patent col. 1, ll. 20-25. The additional amino acid residue, methionine, resulted in a hGH protein variant that does not function in the same way in vivo as pituitary-derived hGH. Accordingly, there was a need for a method to produce "pure" hGH, or hGH containing the 191 amino acid sequence identical to that of pituitary-derived hGH.

II.

As noted, the '352 patent discloses the production of ripe hGH protein via recombinant DNA techniques. Recombinant DNA techniques make it possible to transfer DNA segments (genes) that code for a human protein to bacteria, such as E. coli, for the purpose of protein synthesis.

Bacteria such as E. coli normally will not recognize a human gene sequence and, thus, will not synthesize the corresponding human protein. However, transferring the gene sequence for a "fusion protein"¹ into E. coli, in effect, "tricks" the bacteria into synthesizing the human protein. The gene sequence for the fusion protein contains, in a side-by-side relationship: (1) the gene sequence for a bacterial protein and (2) the gene sequence for a human protein, such as hGH. The E. coli recognizes the portion of the gene sequence that encodes the bacterial protein and, as a result, synthesizes the entire fusion protein. The fusion protein is made up of: (1) the amino acid sequence for the bacterial protein and (2) the amino acid sequence for the human protein. In order to isolate the desired human protein, the bacterial amino acid sequence, or "pro-sequence," must be removed from the fusion protein. This process can be accomplished through the use of a proteolytic enzyme.² The proteolytic enzyme cleaves the bond between the pro-sequence and the amino acid sequence for the human protein.

The '352 patent discloses a process whereby a proteolytic enzyme, preferably the enzyme dipeptidyl aminopeptidase I (DAP I), cleaves a pre-hGH fusion protein in order to produce "ripe" hGH protein. '352 patent col. 1, l. 56 — col. 2, l. 2. First, the gene sequence for the hGH protein is combined with the gene sequence for a bacterial protein. Id. col. 4, ll. 53-67. This DNA sequence is then introduced into E. coli. Id. col. 5, ll. 1-10. This results in a pre-hGH fusion protein being produced by the E. coli bacteria. The resulting pre-hGH fusion protein is made up of: (1) the 191-amino-acid sequence for the hGH protein; and (2) a variable amino acid sequence with an even number of amino acids that is formulated to take advantage of the cleavage specificity of DAP I. When DAP I is then added, it works to cleave, or cut, the fusion protein at the junction of the two amino acid sequences described above. Id. col. 5, ll. 24-25. This results in "ripe" hGH protein, or hGH protein containing the correct 191 amino acid sequence.

III.

The '352 patent traces priority back through a series of continuation applications to Application Ser. No. 640,081, filed on December 9, 1983, as PCT Application PCT/DK83/001118 ("the 1983 PCT application"). The 1983 PCT application, in turn, traces priority back to a 1982 Danish patent application filed on December 10, 1982. The 1983 PCT application was directed to "A Process for Preparing Ripe Proteins from Fusion Proteins, Synthesized in Pro or Eukaryotic Cells." Unlike the '352 patent, which discloses the use of the proteolytic enzyme DAP I, the 1983 PCT application discloses leucine aminopeptidase (LAP) as the preferred cleavage enzyme to produce ripe hGH protein from a pre-hGH fusion protein.

On November 12, 1992, Novo filed U.S. Application No. 07/959,856 ("the '856 application"), directed to "A Process for Preparing a Desired Protein." The '856 application discloses a process for producing hGH protein from a fusion protein using the DAP I enzyme. The '856 application was the first in a series of applications that claimed a priority date of December 10, 1982, based on the 1983 PCT application. The final application in the chain was U.S. Application Ser. No. 402,286 ("the '286 application"), filed on March 10, 1995. The '352 patent issued from the '286 application on May 27, 1997.

The '352 patent has two claims:

1. Biosynthetic ripe human growth hormone free of contaminants from pituitary derived human growth hormone.

2. Biosynthetic ripe human growth hormone produced by expressing an amino terminal extended human growth hormone fusion protein in a microorganism capable of such expression, enzymatically cleaving the amino terminal extension and recovering the biosynthetically produced ripe human growth hormone.

IV.

On July 7, 2000, the Board of Patent Appeals and Interferences ("Board") of the United States Patent and Trademark Office ("PTO") declared an interference involving Novo's '352 patent and Bio-Technology General Corp.'s³ U.S. Application Ser. No. 09/023,248 ("the '248 application"). Blumberg v. Dalbøge, Interference No. 104,422 (Bd.Pat.App.Int. March 12, 2002) ("Board Decision"). The '248 application is directed to a biosynthetic hGH protein produced via recombinant DNA techniques. In declaring the interference, the Board accorded the '352 patent the benefit of priority of the August 8, 1984 filing date of U.S. Patent Application Ser. No. 06/640,081 ("the '081 application").⁴

In due course, Novo filed a preliminary motion in the interference seeking the benefit, for purposes of priority, of the filing date of the 1983 PCT application. Board Opinion, slip op. at 9. Bio-Technology General Corp., in turn, moved to deny Novo the benefit of the filing date of the 1983 PCT application, as well as the benefit of the filing date of the '081 application. It argued that DAP I was not disclosed in the 1983 PCT application, and that the LAP enzyme that was disclosed in the application was not effective to produce ripe hGH protein. Board Decision, slip op. at 11.

On March 12, 2002, the Board issued its final decision, awarding priority to Novo. The Board noted that during prosecution of its applications resulting in the '352 patent, Novo had made contradictory statements regarding whether the 1983 PCT application enabled the production of ripe hGH protein. However, the Board concluded: "[W]e do not find the evidence relied upon by [Bio-Technology General Corp.] . . . to establish that pure LAP would not work to produce ripe hGH in the methods described in the '081 and [1983] PCT applications to be convincing." Board Decision, slip op. at 33.

On April 1, 2002, pursuant to 35 U.S.C. § 146, Bio-Technology General Corp. appealed the final decision of the Board to the United States District Court for the District of Delaware. The district court eventually reversed the Board's decision awarding Novo priority with respect to the invention claimed in the '352 patent. Bio-Technology Gen. Corp. v. Novo Nordisk A/S, No. 02-235-SLR, slip op. at 59, 2004 WL 1739722 (D.Del. Aug. 3, 2004) ("Priority...