IlLuMina Inc v. Trustees Of Columbia University In City Of New York

1. Case Identification

• Case #: IPR2018-00322
• Patent #: 9,708,358
• Filed: December 18, 2017
• Petitioner(s): Illumina, Inc.
• Patent Owner(s): The Trustees of Columbia University in the City of New York
• Challenged Claims: 1

2. Patent Overview

• Title: Cytosine Deoxyribonucleotide Analogues
• Brief Description: The ’358 patent is directed to a specific cytosine deoxyribonucleotide analogue for use in DNA sequencing. The analogue features a "small," chemically cleavable chemical group (R) capping the 3'-OH position of the deoxyribose and a detectable fluorescent tag attached to the cytosine base via a chemically cleavable linker (Y).

3. Grounds for Unpatentability

Ground 1: Obviousness over Tsien - Claim 1 is obvious over Tsien.

• Prior Art Relied Upon: Tsien (WO 91/06678).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that Claim 1 is merely a pictorial representation of a nucleotide analogue that was previously found unpatentable in prose format in a related case (IPR2012-00007). Petitioner asserted that Tsien teaches all limitations of Claim 1. Specifically, Tsien disclosed DNA sequencing using nucleotide analogues with a 3'-OH blocking group and a fluorescent label. Petitioner contended that Tsien’s disclosure of a 3'-O-allyl group meets all functional and structural requirements for the "R" group in Claim 1, including that it is small, chemically cleavable, stable during polymerase reaction, and does not contain a ketone, methoxy, or ester group. Furthermore, Petitioner argued Tsien taught attaching a fluorescent tag to the 5-position of a cytosine base via a cleavable linker, meeting the "Y" and "Tag" limitations.
  • Motivation to Combine: Petitioner asserted the motivation to combine these features was found entirely within the Tsien reference itself. Tsien allegedly taught that the 3'-O-allyl group was advantageous because it minimized premature deblocking. Tsien also taught the advantages of labeling pyrimidines at the 5-position, noting the flexibility in linker length and functionality, and cited Prober for methods of enzymatic incorporation of such analogues.
  • Expectation of Success: Petitioner argued a person of ordinary skill in the art (POSA) would have had a reasonable expectation of success. This was based on the fact that the Board and Federal Circuit had previously affirmed that synthesizing such nucleotides involved well-established chemical procedures. The ’358 patent itself allegedly provided no new or nonobvious chemistry, and Columbia’s own expert in a prior IPR confirmed the individual synthetic steps were within the level of ordinary skill.

Ground 2: Obviousness over Dower, Prober, and Metzker - Claim 1 is obvious over Dower in view of Prober and Metzker.

• Prior Art Relied Upon: Dower (Patent 5,547,839), Prober (a 1987 article in Science), and Metzker (a 1994 article in Nucleic Acids Research).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued this combination teaches all elements of Claim 1. Dower provided the foundational teaching of a DNA sequencing method using nucleotide analogues with a removable fluorescent label and a "small," removable 3'-OH blocking group. Prober, which is cited repeatedly by Dower, provided the specific teaching of attaching a label via a linker to the 5-position of pyrimidines (including cytosine), a known advantageous position. Metzker provided the key missing piece by disclosing that a 3'-O-allyl group (an ether) is an effective, removable capping group that is successfully incorporated by polymerases, in contrast to ester caps that were not. This combination allegedly supplies the specific 5-substituted cytosine and the 3'-O-allyl capping group not explicitly combined in Dower.
  • Motivation to Combine: Petitioner asserted a POSA would combine these references to optimize Dower’s sequencing method. Dower’s express and repeated citations to Prober would have motivated a POSA to use Prober's established and beneficial 5-position labeling for the base. A POSA would have also been motivated to use Metzker’s 3'-O-allyl ether group to implement Dower’s "small" capping group, as Metzker demonstrated it was a proven, polymerase-compatible group that was superior to other options like esters.
  • Expectation of Success: Petitioner asserted a reasonable expectation of success, as the combination involved applying known solutions to known problems. The synthesis of 5-substituted cytosine analogues was well-established, as shown by Prober and acknowledged in the ’358 patent. The use and chemical cleavage of a 3'-O-allyl group were also well-known. A POSA would have expected that combining these established components would result in a functional nucleotide analogue.

4. Key Technical Contentions (Beyond Claim Construction)

• "Lead Compound" Analysis is Inapplicable: Petitioner argued that a "lead compound" structural analysis for obviousness is not appropriate for Claim 1. The claim defines the key R, Y, and Tag groups using broad functional language and negative limitations, rather than by a specific arrangement of atoms. Petitioner contended that Columbia, having chosen to define its invention functionally, cannot now demand that the prior art provide a more specific structural disclosure than the claim itself requires.
• Alternative "Lead Compound" Argument: Even if a lead compound analysis were required, Petitioner argued that Tsien’s 3'-O-allyl dCTP is a natural lead compound. Tsien allegedly disclosed it as an advantageous 3'-blocking group. A POSA would have been motivated to modify this lead compound by adding a fluorescent label at the 5-position via a cleavable linker, as this modification was also taught as desirable within Tsien.

5. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under §325(d) would be improper. It asserted that the ’358 patent only issued because the Patent Owner, Columbia, engaged in improper prosecution tactics by re-litigating the patentability of a "small" 3'-O-capping group before an examiner, an issue that had already been fully and finally decided against Columbia by the Board in a prior IPR.
• Petitioner further contended that this petition presented the prior art in a "new light" by providing the expert testimony of Dr. Romesberg, which was not before the examiner. This testimony specifically explained why Tsien's disclosure of a 3'-O-allyl group rendered the claim obvious, an argument Petitioner claims Columbia avoided and the examiner overlooked during prosecution.

6. Relief Requested

• Petitioner requests institution of an inter partes review and cancellation of Claim 1 of Patent 9,708,358 as unpatentable.