Last month, in Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., the Federal Circuit affirmed a decision by the U.S. District Court for the District of Delaware finding the asserted claims of U.S. Patent Nos. 6,992,180 and 8,097,405 invalid for lack of enablement. Enzo had asserted the '180 patent in three separate suits against (1) Roche Molecular Systems, Inc.; Roche Diagnostics Corp.; Roche Diagnostics Operations, Inc.; and Roche Nimblegen, Inc. ("Roche"); (2) Becton, Dickinson and Co.; Becton Dickinson Diagnostics Inc.; and GeneOhm Sciences, Inc. ("BD"); and (3) Abbott Laboratories and Abbott Molecular, Inc. ("Abbott"). In a fourth suit, Enzo asserted the '405 patent against Abbott.
The '180 patent relates to non-radioactive labeling of polynucleotides where the label is attached at the phosphate position of a nucleotide. Representative claim 1 of the '180 patent recites:
1. An oligo- or polynucleotide which is complementary to a nucleic acid of interest or a portion thereof, said oligo- or polynucleotide comprising at least one modified nucleotide or modified nucleotide analog having the formula
Sig-PM-SM-BASE
wherein PM is a phosphate moiety, SM is a furanosyl moiety and BASE is a base moiety comprising a pyrimidine, a pyrimidine analog, a purine, a purine analog, a deazapurine or a deazapurine analog wherein said analog can be attached to or coupled to or incorporated into DNA or RNA wherein said analog does not substantially interfere with double helix formation or nucleic acid hybridization, said PM being attached to SM, said BASE being attached to SM, and said Sig being covalently attached to PM directly or through a non-nucleotidyl chemical linkage, and wherein said Sig comprises a non-polypeptide, non-nucleotidyl, non-radioactive label moiety which can be directly or indirectly detected when attached to PM or when said modified nucleotide is incorporated into said oligo- or polynucleotide or when said oligo- or polynucleotide is hybridized to said complementary nucleic acid of interest or a portion thereof, and wherein Sig comprises biotin, iminobiotin, an electron dense component, a magnetic component, a metal-containing component, a fluorescent component, a chemiluminescent component, a chromogenic component, a hapten or a combination of any of the foregoing.
(emphasis in opinion).
The '405 patent is directed to in situ hybridization using a probe non-radioactively labeled at any non-Ward position to identify chromosomes, and liquid phase hybridization using a non-radioactively labeled probe to hybridize and detect a target sequence in a liquid medium.
The opinion notes that the asserted patents are based on work done by Dr. David Ward and others at Yale University, who developed a non-radioactive probe by attaching a label to a polynucleotide via a chemical linker at a base position of a nucleotide. Dr. Ward had demonstrated that attaching labels at certain positions of the nucleotide ("Ward positions") would not disrupt the polynucleotide's ability to hybridize and be detected upon hybridization. Enzo licensed the patent portfolio encompassing Dr. Ward's discovery and filed an application directed to non-radioactive labeling at additional positions on a nucleotide.
In characterizing the claims of the '180 patent, the opinion indicates that:
The claims are not directed to any specific polynucleotide, nor do they focus on the chemistry or linker used to attach a label, the number of labels to attach to a polynucleotide, or where within the polynucleotide to attach those labels. Instead, the claims encompass all polynucleotides with labels attached to a phosphate, as long as the polynucleotide remains hybridizable and detectable upon hybridization.
With respect to the '405 patent, the opinion indicates that "[t]hese claims cover using probes labeled non-radioactively at any position on the nucleotide, including the three Ward positions."
In the suits against Roche and BD, the District Court granted summary judgment in favor of the Defendants, finding the asserted claims of the '180 patent invalid for lack of enablement. With respect to the '405 patent, the District Court granted summary judgment in favor of Abbott, finding the asserted claims of that patent invalid for lack of enablement. Enzo appealed those judgments, and the Federal Circuit consolidated the appeals.
The panel begins its analysis by noting that "the issue in this appeal is not simply whether the specification enables labeling; the question is whether it enables creation of a labeled probe that is both hybridizable and detectable upon hybridization." And in affirming the District Court's determinations that the asserted claims of the '180 and '405 patents are invalid for lack of enablement, the Federal Circuit concludes that "even if we assume that the specification teaches one of skill in the art how to create the broad range of labeled polynucleotides covered by the claims, . . . the specification still fails to teach one of skill in the art which combinations will produce a polynucleotide that is hybridizable and detectable upon hybridization, as required by the claim language."
Citing the Court's decision in Wyeth v. Abbott Laboratories, 720 F.3d 1380 (Fed. Cir. 2013), the opinion notes that "[t]he facts in this appeal largely mirror those in Wyeth," explaining that "[a]s in Wyeth, the asserted claims here require not just a particular structure, but a particular functionality (i.e., the labeled polynucleotides must be hybridizable and detectable upon hybridization)." And the Court concludes that in the instant case "the specification fails to teach one of skill in the art whether the many embodiments of the broad claims would exhibit that required functionality."
Finding that "[t]he scope of the claims is quite broad," the Court determined that claim 1 of the '180 patent "places almost no limitations on the structure of the claimed polynucleotide, other than the fact that the label is attached to the phosphate portion of the nucleotide," and "does not restrict the chemistry used to attach the label, the chemical linker used, the number of labels within a probe, or the location of the labels on the probe (i.e., whether they are terminal or internal)." And according to the opinion, "[t]he specification's guidance as to how such variables would or would not impact the functionality of the claimed probes is sparse." The panel concludes that:
Given the unpredictability of the art at the time and the serious doubts held by those of skill in the art regarding whether labels could be attached to non-Ward positions without disrupting hybridization, merely stating that a labeled polynucleotide will work as a probe is not sufficient to enable one of skill in the art to know that it would indeed function as a probe—i.e., be hybridizable and detectable upon hybridization.
The opinion also notes that Enzo's expert had explained that one of skill in the art "would need to actually make the compound and test it in a hybridization experiment" in order to be comfortable that an oligonucleotide or polynucleotide encompassed by the asserted claims would work as a probe.
With respect to the '405 patent, the opinion indicates that the asserted claims of that patent are broader than the asserted claims of the ʼ180 patent, explaining that "rather than covering only phosphate-labeled polynucleotides, they also cover labeling at other locations on a nucleotide." The opinion concludes that "[b]ecause the specification does not enable the narrower scope of polynucleotides claimed in the '180 patent, it also cannot enable the broader scope of polynucleotides claimed in the ʼ405 patent." The Federal Circuit therefore affirmed the District Court's grant of summary judgment that the asserted claims of the '180 and '405 patents are invalid for lack of enablement.
Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc. (Fed. Cir. 2019)
Panel: Chief Judge Prost and Circuit Judges Reyna and Wallach
Opinion by Chief Judge Prost
