Thursday, March 6, 2008

The Federal Circuit Considers Equivalence of Nucleic Acids and Peptide Nucleic Acids (PNAs)

Nucleic acids, such as DNA and RNA, are polymers of purine and pyrimidine bases linked together by a sugar-phosphate backbone. Peptide nucleic acids (PNAs), on the other hand, are synthetic polymers of purine and pyrimidine bases linked together by peptide bonds, the same bonds present in polypeptides, i.e. proteins. Like nucleic acids, PNAs are capable of hybridizing to a complementary nucleic acid strand, and thus can be used as functional analogs for nucleic acids in a host of research and diagnostic applications that employ nucleic acids as hybridization probes, as well as in antisense therapies.

However, there are important functional differences between nucleic acids and PNAs. Because the backbone of a PNA contains no charged phosphate groups, the binding between PNA/DNA strands is stronger than between DNA/DNA strands (due to a lack of electrostatic repulsion). PNAs also show greater specificity in binding to complementary DNAs, with a PNA/DNA base mismatch being more destabilizing than a similar mismatch in a DNA/DNA duplex. This binding strength and specificity also applies to PNA/RNA duplexes. PNAs are not easily recognized by either nucleases or proteases, making them resistant to enzyme degradation. PNAs are also stable over a wide pH range.

In Regents of the University of California v. Dakocytomation (Doc. No. 2006-1334), decided by the Federal Circuit on February 28, 2008, defendant Dako argues that its diagnostic test kits do not infringe the University of California's patent because the claims recite "blocking nucleic acids” (which the parties stipulate to be limited to RNA and DNA), and the accused kits employ PNAs. The kits are used to identify the presence of excess HER2 genes in cancerous cells, in order to decide if treatment with Herceptin is appropriate.

Although the stipulation precludes a finding of literal infringement, UC argues that the use of PNAs infringes under the doctrine of equivalents. The district court ruled on motion for summary judgment that UC was precluded under Festo from establishing infringement under the doctrine of equivalents by prosecution history estoppel, since the "blocking nucleic acid" limitation was added by narrowing amendment to overcome prior art. However, on appeal the Federal Circuit reversed, finding that the motivation for UC’s narrowing amendment "centered on the method of blocking-not on the particular type of nucleic acid that can be used for blocking.” The case was remanded to the trial court to determine the question of infringement under the doctrine of equivalents.

In dissent, Judge Prost argued that the majority had misapplied Festo, finding that prosecution history estoppel should apply to the nucleic acid itself, not just the blocking method.

Applying the traditional function-way-result test, Dako might be able to successfully argue non-equivalence. Dako submitted expert testimony to the trial court that “PNA probes accomplish blocking in a substantially different way from DNA probes and are not ‘interchangeable’ with DNA. For example, PNA probes can bind to DNA that is not been denatured. PNA is also less susceptible to changes in hybridization conditions, such as temperature.” UC presumably submitted testimony that would minimize the significance of these functional distinctions. It should be interesting to see how the trial court, and perhaps eventually the Federal Circuit, decides on the issue of equivalents.


Claes said...

Stumbled on your blog today. Great stuff. Please keep it up. I'm specifically collecting anything you write regarding hybridization claims / % identity claims.

The PNA vs DNA discussion brings up all the different variants of nucleotide backbones that have been published (mainly in the antisense field). These include the phosphorothioates and the methylphosphonates, but also oximes and aminohydroxys and lots of other weird backbone have been published. There has got to be prior art and prior claims on this one. The phosphorothioate backbone has been around since early 70ies and I think most early antisense RNA were phosphorothioates.
I assume the UC patent lawyers were competent enough to foresee all the possible oligonucleotide derivates that already at that time were well established in the field. And that more derivates were certain to appear over time.

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