United States: Invalidity Of Broad Claims For Lack Of Enablement In The Absence Of Sufficient Disclosure Of The Structure/Function Correlation And Unpredictability In The Art

Last Updated: July 19 2019
Article by Marina I. Miller

Enzo Life Sciences, Inc. ("Enzo") appealed the decision of the U.S. District Court for the District of Delaware granting summary judgment against Enzo and holding that the asserted claims were invalid for lack of enablement. The Federal Circuit affirmed.

In 1981, Dr. David Ward and others at Yale University successfully developed a nonradioactive probe by attaching a label to a polynucleotide via a chemical linker at a base position of a nucleotide. Dr. Ward demonstrated that attaching labels at certain positions of the nucleotide ("the Ward positions") would not disrupt the polynucleotide's ability to hybridize and be detected upon hybridization.   In December 1981, Enzo licensed the exclusive rights to the patent portfolio covering Dr. Ward's discovery. In June 1982, Enzo filed a patent application covering non-radioactive labeling at additional positions on a nucleotide. The two patents in the appeal generally relate to the use of non-radioactively labeled polynucleotides in nucleic acid hybridization and detection applications. The patents share the same specification in relevant parts.

U.S. Patent No. 6,992,180 ("the '180 patent") relates to non-radioactive labeling of polynucleotides where the label is attached at the phosphate position of a nucleotide. 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. The claims of U.S. Patent No. 8,097,405 ("the '405 patent") are in situ hybridization claims and liquid phase hybridization claims. In January 2012, Enzo filed suit against Roche Molecular Systems, Inc., Roche Diagnostics Corp., Roche Diagnostics Operations, Inc., and Roche Nimblegen, Inc. ("Roche") alleging infringement of the '180 patent. In March 2012, Enzo filed separate suits against Becton, Dickinson and Co., Becton Dickinson Diagnostics Inc., and GeneOhm Sciences, Inc. ("BD"); and Abbott Laboratories and Abbott Molecular, Inc. ("Abbott") alleging infringement of the '180 patent.

The Court of Appeals for the Federal Circuit ("the Court") identified the issue in the appeal as being "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."

Roche and BD argued that the specification failed to sufficiently disclose internal phosphate labeling. The Court noted 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."

In regard to the functionality required by the claims, the Court relied upon its decision in Wyeth and Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380 (Fed. Cir. 2013), controlling this case. In Wyeth, the Court noted the breadth of the claims, the limited guidance provided in the specification, the large number of possible candidates falling within the claimed genus (tens of thousands), and the fact that it would be necessary to first synthesize and then screen each of those candidates to determine whether it had the required functionality." In Wyeth, "one of the patentee's scientists had confirmed the unpredictability in the art by testifying that one would need to test each compound to understand whether it would have the desired functionality." The Court pointed out that facts in Enzo largely mirrored those in Wyeth, as the asserted claims here required not just a particular structure, but a particular functionality (i.e., the labeled polynucleotides must be hybridizable and detectable upon hybridization), while the specification failed to teach whether the embodiments of the broad claims would exhibit that required functionality.  

The Court explained that claim 1 of the '180 patent encompassed all phosphate-labeled polynucleotides that were hybridizable and detectable. The claim placed almost no limitations on the structure of the claimed polynucleotide, other than the fact that the label was attached to the phosphate portion of the nucleotide. "It 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). As to the type of non-radioactive label used, the claim provides broad categories, such as any 'electron dense component' or 'magnetic component.'   The specification's guidance as to how such variables would or would not impact the functionality of the claimed probes is sparse. At the time of the invention, the art was highly unpredictable."  The Court concluded that "[g]iven 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."

Enzo relied on Example V as an example of an internal phosphate-labeled polynucleotide that was hybridizable and detectable. However, during prosecution Enzo admitted that Example V was a "paper" example. Furthermore, Enzo's expert testified that he was not aware of Enzo having ever tested a phosphate-labeled probe for hybridizability and detectability. The Court noted that even viewing Example V as a "working" example, Example V was insufficient to enable the breadth of the claims here, especially in light of the unpredictability in the art. "The deficiencies in the description as to enablement cannot be cured in this case by looking to the knowledge of those skilled in the art at the time of the invention. Although 'a specification need not disclose what is well known in the art,' that rule is 'not a substitute for a basic enabling disclosure.' Genentech, Inc. v. Novo Nordisk A/S, 108 F.3d 1361, 1366 (Fed. Cir. 1997). As we have said before, a patentee 'cannot simply rely on the knowledge of a person of ordinary skill to serve as a substitute for the missing information in the specification.' ALZA Corp. v. Andrx Pharm., LLC, 603 F.3d 935, 941 (Fed. Cir. 2010). And, more importantly, all parties acknowledge that serious doubts existed in the art as to whether the use of non-radioactive probes at non-Ward positions would be useful as probes."  The Court acknowledged that according to Enzo's expert, the number of possible polynucleotides that would fit within the limitations of claim 1 would be at least "tens of thousands." The Court concluded that even if Example V described one working embodiment with the claimed functionality, undue experimentation would still be required with regard to the many other embodiments of the claims based on the number of possible embodiments and the unpredictability in the art.

The claims of the '405 patent are broader than the claims of the '180 patent and cover not only phosphate-labeled polynucleotides, but also labeling at other locations on a nucleotide, and also require the claimed polynucleotides to be hybridizable and detectable upon hybridization. The Court concluded that because the specification does not enable the narrower scope of polynucleotides claimed in the '180 patent, it also could not enable the broader scope of polynucleotides claimed in the '405 patent. Even though the claims of the '405 patent pertained to certain processes, the claims were still not enabled for the same reasons as in the '180 patent.  

Enzo Life Sciences, Inc. is another example of broad functional claims and a limited disclosure of structural elements that provide the claimed function where the art is unpredictable. It is important to describe common structural elements of a broad group and how to identify molecules/species of the group that have the claimed activity/desired function. More than one example is likely needed in the specification to provide an enabling description for broad functional claims with limited structural elements.

Enzo Life Sciences, Inc. v.  Roche Molecular Systems, Inc., No.17-2498 (Fed. Cir. July 5 2019)

http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/17-2498.Opinion.7-5-2019.pdf

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