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Enzo Biochem, Inc. v. Applera Corp.

March 26, 2010

ENZO BIOCHEM, INC., ENZO LIFE SCIENCES, INC., AND YALE UNIVERSITY, PLAINTIFFS-APPELLANTS,
v.
APPLERA CORP. AND TROPIX, INC., DEFENDANTS-APPELLEES.



Appeal from the United States District Court for the District of Connecticut in case no. 3:04-CV-929, Judge Janet Bond Arterton.

The opinion of the court was delivered by: Linn, Circuit Judge.

Before MICHEL, Chief Judge, PLAGER, and LINN, Circuit Judges.

Enzo Biochem, Inc., Enzo Life Sciences, Inc., and Yale University (collectively, "Enzo") appeal the grant of summary judgment by the U.S. District Court for the District of Connecticut in favor of Applera Corp. and Tropix, Inc. (collectively, "Applera") that all asserted claims of U.S. Patents No. 5,328,824 ("the '824 patent"), No. 5,449,767 ("the '767 patent"), and No. 5,476,928 ("the '928 patent") are invalid as either indefinite or anticipated, and that U.S. Patent No. 5,082,830 ("the '830 patent") is not infringed. Enzo Biochem, Inc. v. Applera Corp., No. 3:04-CV-929 (D. Conn. Mar. 5, 2009). Because we conclude that the claims of the '824 and '767 patents are not indefinite, and because we find genuine issues of material fact as to anticipation, we reverse the district court's summary judgment of invalidity of those two patents. Although we find that the '928 patent is not indefinite, we affirm the district court's judgment of anticipation as to that patent. Because the district court correctly construed the claims of the '830 patent, under which the patent is not infringed, we affirm the judgment of noninfringement. The case is remanded.

BACKGROUND

Enzo's patents-in-suit are directed to various techniques for labeling and detecting nucleic acids, such as DNA and RNA. To put the analysis in context, we begin with a brief discussion of the basic technology and vocabulary related to this case and undisputed by the parties.

I. Basic Technology and Vocabulary

DNA and RNA are composed of a series of units, called "nucleotides." Each nucleotide is composed of a nitrogenous base, a pentose sugar, and a phosphate group. The phosphate group of one nucleotide forms a covalent bond with the pentose sugar of an adjacent nucleotide, thereby linking the nucleotides along a "sugar-phosphate backbone." Aside from linking the nucleotide units into a polynucleotide strand, the sugar-phosphate backbone provides structural support for the nitrogenous bases. The bases fall into two categories: pyrimidines and purines. Pyrimidines include cytosine ("C"), thymine ("T"), and uracil ("U"). Purines include adenine ("A") and guanine ("G"). DNA contains the bases adenine, thymine, cytosine, and guanine; RNA also includes adenine, cytosine, and guanine, but contains the base uracil in place of thymine. Two strands of DNA or RNA having complementary bases will bind, or "hybridize," to form a double-stranded complex, or "hybrid," which is held together by hydrogen bonds between complementary bases. In DNA, adenine on one strand binds to thymine on the other; in RNA, adenine binds to uracil; and in both DNA and RNA, cytosine binds to guanine. The process of forming a double-stranded hybrid is called "hybridization." The reverse process, resulting in two separate strands, is called "denaturation."

Because hybridization occurs in a predictable manner between complementary strands, it is possible to detect the presence of a nucleic acid of interest in a sample. For example, a chemical entity, called a "label," can be attached to or incorporated into a nucleic acid strand of a known sequence, called a "probe," which will hybridize with a complementary sequence of interest, called a "target." Once the probe is hybridized with the target, a detectable signal is generated either from the label itself (referred to as "direct detection") or from a secondary chemical agent that is bound to the label (referred to as "indirect detection"). If a signal is detected from the sample after all unhybridized probes have been removed, detection of the signal implies the presence of a target in that sample.

Labeling of nucleic acids has been accomplished using a variety of chemical entities. For example, with radioactive labels, an isotope of hydrogen (3 H), phosphorous (32 P), or carbon (14 C) is substituted for a non-radioactive atom within the probe, and the isotope is then detected using a radiation detector. But radioactive labels have drawbacks. As explained in the '824, '767, and '928 patents, radioactive labels are "potentially hazardous," "expensive to purchase and use," and "often very unstable." '824 patent col.1 ll.34-45.*fn1

To avoid these drawbacks, the inventors of the patents-in-suit developed a series of nucleotide probes that do not rely on traditional radioactive labels. The '824, '767, and '928 patents are directed to these developments and all claim priority to an application filed on April 17, 1981. The '830 patent issued from an application filed on February 26, 1988 and is directed to improvements over some of the probes claimed in the earlier patents.

II. The '824, '767, and '928 Patents

In general, the claims of the '824, '767, and '928 patents are directed to a "compound" (whose structure is depicted below), or a method of using that compound as a detection probe. In this compound, a nitrogenous base "B" is covalently attached, either directly or through a "linkage group" (represented by the dotted line), to a chemical moiety "A."

The "linkage group" is not recited in the independent claims in structural terms. Rather, the linkage group is recited functionally as "not interfering substantially" with both hybridization and detection ('824 and '767 patents) or simply detection ('928 patent). See '824 patent col.31 ll.31-34 ("said linkage group not interfering substantially with the characteristic ability of said compound to hybridize with said nucleic acid or of A to be detected" (emphases added)); '767 patent col.31 ll.2-7 ("a linkage group that does not substantially interfere with the characteristic ability of the oligo- or polynucleotide to hybridize with a nucleic acid and does not substantially interfere with formation of the signalling moiety or detection of the detectable signal" (emphases added)); '928 patent col.30 ll.29-30 ("said linkage group not interfering substantially with detection of A" (emphasis added)). The specification describes the function of the linkage group as follows:

[I]t is generally preferred that the chemical linkage include an olefinic bond at the α-position relative to B.... [Which] serves to hold the moiety A away from the base when the base is paired with another in the well known double-helix configuration. This permits interaction with polypeptide to occur more readily, thereby facilitating complex formation. Moreover, single bonds with greater rotational freedom may not always hold the moiety sufficiently apart from the helix to permit recognition by and complex formation with polypeptide. '824 patent col.8 ll.54-68.

The chemical moiety A is the label that facilitates detection. In claim 1 of the '824 and '767 patents, moiety A "comprises at least three carbon atoms and represents at least one component of a signalling moiety capable of producing a detectable signal." In claim 1 of the '928 patent, moiety A "represents at least three carbon atoms and an indicator molecule selected from the group consisting of fluorescent dyes, electron-dense reagents, enzymes which can be reacted with a substrate to produce a visually detectable reaction product, and radioisotopes."

The symbols "x," "y," and "z" represent, variously, one of the following: hydrogen, hydroxyl, or one or more components of the sugar-phosphate backbone.

III. The '830 Patent

The later-filed '830 patent contains claims to both a compound and a method of detection using that compound. The claimed compound is a nucleotide labeled with "at least one non-radioactive moiety directly or indirectly attached to each of the 5' and 3' end nucleotides thereof." '830 patent col.13 ll.63-65, col.14 ll.58-61. The 5' and 3' positions are locations on a pentose sugar: the 5' end is the so-called "left" end of the polymer; the 3' end is the so-called "right" end of the polymer. In the method claim, a "target" strand is contacted under hybridization conditions with both (i) a "probe" strand having 5' and 3' labels and (ii) a "preformed detectable molecular complex." Id. col.14 ll.53-64. Detection is accomplished by "detecting any hybridized complexes." Id. col.14 ll.65-66.

IV. Proceedings Below

On June 7, 2004, Enzo sued Applera for infringement of six patents, four of which are here on appeal.*fn2 The asserted claims of the four patents on appeal are: claims 1, 18, 19, 21, 26, 28, 32, and 33 of the '824 patent; claims 1, 2, 8, 11, 13, 42, 46-51, 67, 68, and 70 of the '767 patent; claims 1 and 2 of the '928 patent; and claims 1, 12, and 18 of the '830 patent.

The district court issued a claim construction ruling on October 12, 2006. Enzo Biochem, Inc. v. Applera Corp., No. 04-929, 2006 WL 2927500 (D. Conn. Oct. 12, 2006) ("Claim Construction"). With regard to the linkage group in each of the '824, '767, and '928 patents, the district court construed the "not interfering substantially" language to mean that "the linkage group neither substantially interferes with the ability of the compound to hybridize with the nucleic acid nor substantially interferes with the ability of A to be detected." Id. at *6. With regard to the moiety A, the district court found the differing claim language of the '824, '767, and '928 patents to be relevant to whether A constitutes the whole or merely a portion of the entity that produces a detectable signal. More specifically, with regard to the '824 and '767 patents, the district court held that "A may be a part of or the entire signalling moiety," and therefore adopted Enzo's proposed construction that "A comprises at least three carbon atoms and is one or more parts of a signalling moiety, which includes, in some instances, the whole signalling moiety." Id. at *4. By contrast, the district court held that the plain language of the '928 patent "precludes a construction where A is the entire [indicator] molecule," and therefore adopted Applera's proposed construction that "A must have at least three carbon atoms and an indicator molecule selected from the group consisting of (i) fluorescent dyes, (ii) electron-dense reagents, (iii) enzymes which can be reacted with a substrate to produce a visually detectable reaction product, or (iv) radioisotopes." Id. at *5. Finally, as to the "non-radioactive moiety" of the '830 patent, because the claims call for the use of a "detectable molecular complex," the district court construed "non-radioactive moiety" to mean "a moiety that is utilized in indirect detection, i.e., a moiety that can be detected with a preformed detectable molecular complex." Id. at *11.

Enzo conceded that under the district court's construction it could not prove infringement of the '830 patent. Based on this concession, the district court granted summary judgment of noninfringement of the '830 patent on August 7, 2007. Applera then moved for summary judgment of invalidity of all asserted claims of the '824, '767, and '928 patents based on: (1) lack of written description under 35 U.S.C. § 112, ¶ 1; (2) lack of enablement under 35 U.S.C. § 112, ¶ 1; (3) indefiniteness under 35 U.S.C. § 112, ¶ 2; and (4) anticipation under 35 U.S.C. § 102.

On September 6, 2007, the district court denied Applera's summary judgment motion as to lack of written description and enablement, but granted the motion as to indefiniteness and anticipation. Enzo Biochem, Inc. v. Applera Corp., No. 3:04-CV-929, 2007 WL 2669025 (D. Conn. Sept. 6, 2007) ("Summary Judgment"). With regard to indefiniteness, the district court held that the "not interfering substantially" language in the asserted claims of all three patents is indefinite because "[t]he specifications neither set forth how one would gauge substantial interference, nor delimit the threshold at which interference with the procedure prevents [the claimed] method from being implemented." Id. at *12. Alternatively, the district court found these same claims to be anticipated by at least one of three prior art references.*fn3 In concluding that there was no genuine issue of material fact that the prior art taught a linkage group that did "not substantially interfere" with hybridization and detection, the district court observed that "[a]lthough this Court has determined that the 'substantially interfere' language in the ['824, '767, and '928 p]atents is the basis for their invalidity, interpretation of the phrase for purposes of anticipation does not affect the invalidity ruling." Id. at *13. Thus, on summary judgment, all asserted claims of the '824, '767, and '928 patents were held invalid as either indefinite or anticipated.

The district court entered final judgment with respect to all six patents on March 5, 2009. Enzo appeals the final judgment with respect to the '824, '767, '928, and '830 patents. We ...


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