IP Law Daily Method claims for DNA labeling patent were invalid as obvious
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Monday, May 9, 2016

Method claims for DNA labeling patent were invalid as obvious

By Mark Engstrom, J.D.

The Patent Trial and Appeal Board correctly found that multiple claims of an Illumina Cambridge patent on a method of labeling nucleotides in a strand of DNA were invalid as obvious over a combination of prior art references, the U.S. Court of Appeals for the Federal Circuit has ruled (Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd., May 9, 2016, O’Malley, K.). Because the plaintiff, Intelligent Bio-Systems (IBS), failed to establish the obviousness of the challenged claims, the decision of the Board was affirmed.

Defendant Illumina Cambridge owned U.S. Patent No. 7,566,537, titled “Labelled Nucleotides.” The patent disclosed a method of labeling nucleotide bases in a strand of DNA. The only independent claim under review (claim 1) described a method of labeling a nucleic acid molecule by incorporating a nucleotide or nucleoside molecule, wherein the nucleotide or nucleoside molecule had: (1) a base that was linked to a detectable label through a cleavable linker and (2) a ribose or deoxyribose sugar moiety that included a protecting group that was “attached via the 2’ or 3’ oxygen atom” and could be “modified or removed to expose a 3’ OH group and the protecting group comprises an azido group.”

Plaintiff IBS requested an inter partes review (IPR) of seven claims of the patent at issue. The Board instituted an IPR and found that IBS failed to prove obviousness by a preponderance of the evidence. IBS appealed.

IBS argued that the patent was invalid as obvious over a combination of prior art references—either Zavgorodny and Tsien or Zavgorodny and Ju. Both Ju and Tsien disclosed a method of sequencing unknown DNA bases using the “sequencing by synthesis” (SBS) method, including the labeling of nucleotides for detection and the use of a protecting group at the 3’-OH position of the nucleotide.

Neither Ju nor Tsien disclosed a protecting group that included an azido group, but the Board found that: (1) Zavgorodny taught that an azidomethyl moiety was a suitable protecting group for the 3’-OH position of nucleosides—the position that required protecting in Ju’s or Tsien’s process—and (2) the azidomethyl group was cleavable from the nucleoside under “specific and mild conditions.” The azidomethyl group had a special interest because it could be removed with triphenylphosphine in aqueous pyridine at 20 degrees Celsius.

Significantly, Tsien taught that one of the criteria for the successful use of 3’- blocking groups was the availability of mild conditions for rapid and quantitative “deblocking” (the removal of the protecting group). For the deblocking to be quantitative, it had to occur at 100 percent (or near-100 percent) efficiency. Similarly, Ju described the “fundamental requirement” that “the tag and the [protecting] group capping the 3’-OH needed to be removed with a high yield to allow the incorporation and detection of the next nucleotide.”

In its final written decision, the Board construed independent claim 1 to encompass the use of “any protecting group attached via the 2’ or 3’ oxygen atom of a [sugar] moiety, in which the protecting group c[ould] be modified or removed to expose a 3’ OH group.” In addition, the Board noted that its construction of claim 1 did not require the removal of the protecting group to allow subsequent nucleotide incorporation.

Based on the teachings of Tsien and Zavgorodny, IBS argued that, to improve the efficiency, reliability, and robustness of the SBS method that was taught in Tsien, an ordinary artisan would have been motivated to use other protecting groups that met the criteria of Tsien, “such as the azidomethyl group taught by Zavgorodny.”

Illumina argued that an ordinary artisan would not expect the azidomethyl group of Zavgorodny to meet the specific criteria of Tsien or Ju. Tsien, for example, required “quantitative and rapid removal” of the protecting group, which Illumina understood to mean 100 percent removal. Although prior art (Loubinoux) showed that an ordinary artisan would have expected Zavgorodny’s azidomethyl group to be removed at a much lower efficiency than required by Tsien’s methods, the Board credited Illumina’s argument that, given Loubinoux, IBS failed to show that an ordinary artisan would have considered it obvious to use Zavgorodny’s azidomethyl group as the 3’-hydroxyl protecting group in Tsien’s processes.

The Board decided that the IPR petition did not identify any specific evidence that would explain why an ordinary artisan would have expected Zavgorodny’s azidomethyl protecting group to meet the quantitative deblocking requirement of Tsien. Moreover, because Loubinoux disclosed that the removal of an azidomethyl protecting group from a phenolic hydroxyl resulted in de-protected phenols as pure products at a yield between 60 and 80 percent, IBS’s petition did not provide a specific or credible explanation as to why an ordinary artisan would have expected Zavgorodny’s azidomethyl protecting group to meet Tsien’s quantitative deblocking requirement under conditions that were suitable for use in Tsien’s sequencing methods.

On appeal, IBS challenged the Board’s conclusion that IBS did not show that the challenged claims were obvious.

Motivation to combine, reasonable expectation of success. The Board found that Zavgorodny would not be “obvious to use” with Tsien or Ju because its azidomethyl group would not be removed quantitatively at or near 100 percent. IBS argued that, because the claims did not require quantitative cleavage, the Board should not have imposed that requirement through the reasonable expectation of success analysis.” To the extent that the Board’s decision was based on the “reasonable expectation of success” requirement, the court agreed.

Under the Board’s uncontested construction, independent claim 1 did not require the removal of the protecting group to allow subsequent nucleotide incorporation. Therefore, it did not matter that Zavgorodny’s protecting group would not be removed quantitatively in Tsien or Ju’s sequencing method—removal was simply not required by the claim of the asserted patent. The Board seemed to believe that the “reasonable expectation of success” inquiry looked to whether one would reasonably expect the prior art references to operate as intended once combined, but that was not the correct inquiry. According to the court, one must have a motivation to combine accompanied by a reasonable expectation of achieving whatever was claimed in the patent at issue. The Board’s reliance on the absence of a reasonable expectation of success was therefore improper.

Nevertheless, the Board made sufficient factual findings to support its judgment that the claims at issue were not invalid. IBS had to show that a skilled artisan would have: (1) been motivated to combine the teachings of the prior art references to achieve the claimed invention and (2) had a reasonable expectation of success in doing so. Despite the loose language that was used by the Board, its factual findings supported its invalidity findings.

In the court’s view, the Board was justified in finding that the IPR petition failed to provide a specific or credible explanation as to why an ordinary artisan would have expected Zavgorodny’s azidomethyl protecting group to meet Tsien’s quantitative deblocking requirement under conditions that were suitable for use in Tsien’s sequencing methods.

Although that shortcoming was irrelevant to a finding that there was no reasonable expectation of success in meeting the claims of the ’537 patent, which did not require quantitative deblocking, it was central to a finding of no motivation to combine because IBS’s sole argument for finding that a skilled artisan would be motivated to combine Zavgorodny’s azidomethyl group with Tsien’s SBS method was that it would meet Tsien’s quantitative deblocking requirement. Moreover, substantial evidence supported a finding that a person of ordinary skill would not have had a reason to combine Tsien or Ju with Zavgorodny to achieve the claimed invention.

The Board acknowledged two background references that were presented by Illumina: (1) Loubinoux, which taught that azidomethyl methyl groups were removed from phenols with modest efficiency (60 to 80 percent yield) and (2) Greene & Wuts, which taught that the removal of an azidomethyl methyl group from the 3’-hydroxyl position of a DNA moiety was likely to proceed with an even lower efficiency. Those references supported the conclusion that the claimed efficiency that allegedly motivated the combination would not be achieved, and that a person of ordinary skill in the field would not have been motivated to use the azidomethyl group of Zavgorodny as a protecting group that could be modified or removed to expose a 3’-hydroxyl group of a nucleic acid molecule, as the claim required, because the azidomethyl group would have been expected to perform inefficiently in that role.

Because the factual finding by the Board was supported by substantial evidence, the Board did not err in finding that the asserted grounds of invalidity were not established.

The case is No. 2015-1693.

Attorneys: Robert R. Baron, Jr., Marc S. Segal, and Scott David Marty (Ballard Spahr LLP) for Intelligent Bio-Systems, Inc. William R. Zimmerman, Jonathan Edward Bachand, Brenton R. Babcock, Joseph S. Cianfrani, Sheila N. Swaroop, Nathanael Luman, and Kerry S. Taylor (Knobbe, Martens, Olson & Bear, LLP) for Illumina Cambridge, Ltd.

Companies: Intelligent Bio-Systems, Inc.; Illumina Cambridge, Ltd.

MainStory: TopStory Patent FedCirNews

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