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: Nucleoside Analogues for Sequencing
• Brief Description: The ’358 patent is directed to a specific cytosine deoxyribonucleotide analogue used in DNA sequencing. The analogue features a small, chemically cleavable capping group at the 3'-OH position to reversibly terminate DNA synthesis and a detectable fluorescent tag attached to the cytosine base via a chemically cleavable linker.

3. Grounds for Unpatentability

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

• Prior Art Relied Upon: Tsien (International Publication No. WO 91/06678).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that Tsien discloses all elements of the claimed nucleotide analogue. Tsien teaches DNA sequencing using nucleotides with a 3'-OH blocking group and a fluorescent tag. Specifically, Tsien discloses a 3'-O-allyl group that meets all functional requirements of the claimed capping group "R," including being small, chemically cleavable, stable during polymerization, and not containing a ketone, methoxy, or ester group. Tsien also discloses attaching a fluorescent tag to the 5-position of a cytosine base via a cleavable linker, which Petitioner asserted meets the limitations for the "Tag" and linker "Y." Petitioner contended that the structure in Claim 1 is merely a pictorial representation of a nucleotide previously found unpatentable by the Board and the Federal Circuit based on the teachings of Tsien.
  • Motivation to Combine (within a single reference): Petitioner asserted that a Person of Ordinary Skill in the Art (POSA) would be motivated to combine Tsien’s disclosures to arrive at the claimed invention. Tsien expressly taught the advantages of using a 3'-O-allyl capping group for its stability and selective cleavage. Simultaneously, Tsien taught the benefits of labeling a cytosine base at the 5-position, citing its flexibility for linker chemistry and consistency with known advantages like minimizing interference. The motivation to combine these features, both described as desirable within the same reference, would have been apparent.
  • Expectation of Success: A POSA would have had a reasonable expectation of success. Petitioner noted that prior Board decisions, affirmed by the Federal Circuit, had already determined that a POSA could successfully synthesize similar 3'-capped, base-labeled nucleotides based on Tsien’s teachings. The synthetic steps, such as adding an allyl group and attaching a labeled linker, were well-established procedures in the art.

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

• Prior Art Relied Upon: Dower (Patent 5,547,839), Prober (a 1987 Science journal article), and Metzker (a 1994 Nucleic Acids Research journal article).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that the combination of references teaches every element of Claim 1. Dower provided the foundational system, disclosing DNA sequencing with nucleotide analogues having a small, removable 3'-OH blocking group and a fluorescent label removably attached to the base. To improve upon Dower's labeling, a POSA would look to Prober, which Dower repeatedly cites, for its teaching of attaching labels via a linker to the 5-position of pyrimidines like cytosine. To select an optimal 3'-capping group for Dower's system, a POSA would have been led to Metzker, which taught that 3'-O-allyl ether groups (unlike esters) are successfully incorporated by DNA polymerase, appropriately sized ("small"), stable, and can be chemically cleaved with high yield. This 3'-O-allyl group also meets the negative limitations of the claim.
  • Motivation to Combine: A POSITA would combine these references to create an optimized reversible-terminator sequencing system. Dower’s repeated citation of Prober for labeling methods would have motivated a POSA to incorporate Prober's advantageous 5-position labeling strategy. The known benefits of 5-position labeling, such as reduced interference with polymerase and increased DNA duplex stability, provided additional motivation. A POSA would have been motivated to replace Dower’s generally described capping group with Metzker’s specific 3'-O-allyl group to achieve better performance, as Metzker demonstrated this group was stable and an effective substrate for polymerase.
  • Expectation of Success: There was a strong expectation of success in combining these elements. The synthetic chemistry required to prepare the resulting nucleotide analogue was routine and well within the skill of a POSA. The ’358 patent itself acknowledged that similar nucleotides could be made using "well-established" procedures taught by references like Prober.

4. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under 35 U.S.C. §325(d) would be improper due to the Patent Owner’s conduct during prosecution. Petitioner alleged that Columbia re-litigated the patentability of a "small" capping group before the Examiner, an issue that had already been decided against it in a prior inter partes review (IPR).
• Furthermore, Petitioner asserted that this petition presented significant new evidence and arguments not before the Examiner. Specifically, Columbia never addressed the patentability of the claim over Tsien's disclosure of a 3'-O-allyl capping group during prosecution. This petition, supported by new expert testimony, rectified that oversight and presented the prior art in a new light.

5. Relief Requested

• Petitioner requests institution of IPR and cancellation of claim 1 of the ’358 patent as unpatentable.