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Copper-free click chemistry between cyclooctynes and azide is a mild, fast and selective technology for conjugation of oligonucleotides. However, technology for site-specific introduction of the requisite probes by automated protocols is scarce, while the reported cyclooctynes are large and hydrophobic. In this work, it is demonstrated that the introduction of bicyclo[6.1.0]nonyne (BCN) into synthetic oligonucleotides is feasible by standard solid-phase phosphoramidite chemistry. A range of phosphoramidite building blocks is presented for incoporation of BCN or azide, either on-support or in solution. The usefulness of the approach is demonstrated by the straightforward and high-yielding conjugation of the resulting oligonucleotides, including biotinylation, fluorescent labeling, dimerization and attachment to polymer.

The current patent landscape in the US has not undergone major legislative reform since 1952. The US Senate version of the most recently proposed patent reform legislation puts forward a number of rule changes that could impact the pharmaceutical industry. Among the bill's major provisions are moving to a first-to-file system, changes to post-grant review and reexamination procedures, and damages reform. Various industries with a stake in patent reform have responded to the proposed changes. The need for balanced reform makes the stakes particularly high for the pharmaceutical industry which must invest a significant amount of time and money in the research and development process in exchange for already abbreviated patent lifetimes due to the lengthy clinical trial process.