Thermo Fisher Scientific Inc v. 454 Life Science Corp

1. Case Identification

• Case #: IPR2016-00321
• Patent #: 7,323,305
• Filed: December 30, 2015
• Petitioner(s): Thermo Fisher Scientific Inc., Life Technologies Corp., and Ion Torrent Systems, Inc.
• Patent Owner(s): 454 Life Sciences Corporation
• Challenged Claims: 1, 3-11

2. Patent Overview

• Title: Methods for Amplifying and Sequencing Nucleic Acids
• Brief Description: The ’305 patent describes methods for high-throughput nucleic acid sequencing. The process involves isolating and amplifying single nucleic acid fragments onto beads within individual aqueous microreactors of a water-in-oil emulsion, then delivering these beads to a high-density array for simultaneous sequencing.

3. Grounds for Unpatentability

Ground 1: Obviousness over Rothberg and Holliger - Claims 1, 3-7, and 9-11 are obvious over Rothberg in view of Holliger.

• Prior Art Relied Upon: Rothberg (WO 02/077287) and Holliger (WO 02/22869).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that Rothberg taught a method for preparing and sequencing clonal beads on a high-density array, but used the array wells themselves as microreactors for amplification. Holliger taught the key missing element: a more efficient method of generating clonal beads using "emulsion PCR" where amplification occurs on beads within discrete droplets of a water-in-oil emulsion. Petitioner asserted that Rothberg disclosed all steps of claim 1 except for performing the amplification in an emulsion, which was explicitly taught by Holliger.
  • Motivation to Combine: A POSITA would combine these references to replace Rothberg's array-based amplification with Holliger's simpler and more scalable emulsion PCR method for generating clonal beads. Holliger's method offered significantly higher throughput, capable of producing over 10^9 microreactors/ml compared to Rothberg’s array of up to 16 million wells. This would allow for the creation of a massive number of clonal beads which could then be loaded onto Rothberg's high-density array for the final, parallel sequencing step.
  • Expectation of Success: A POSITA would have a reasonable expectation of success because both references described generating and sequencing clonal beads. The specific techniques, such as using biotin-streptavidin linkages to bind DNA to beads and performing pyrosequencing on those beads, were well-known and established in the art, as confirmed by both references. Holliger explicitly stated its emulsion-generated beads could be "sorted for sequencing."

Ground 2: Obviousness over Holliger and Gunderson - Claims 1, 3-5, 7, and 8 are obvious over Holliger in view of Gunderson.

• Prior Art Relied Upon: Holliger (WO 02/22869) and Gunderson (WO 00/63437).

• Core Argument for this Ground:

  • Prior Art Mapping: Petitioner argued this combination represented a predictable sequence of known steps. Holliger taught the generation of clonal beads on an "unprecedented scale" using emulsion PCR and stated they could be analyzed by sequencing. Gunderson taught methods for analyzing large numbers of clonal beads (10^5 to 10^6) on high-density fiber-optic arrays. A POSITA would start with Holliger’s efficient bead generation method and then use Gunderson's established high-throughput array platform for the analysis and sequencing step.
  • Motivation to Combine: A POSITA would be motivated to combine these references to achieve a more efficient overall method for preparing and analyzing DNA. Holliger provided a superior method for generating vast quantities of clonal beads, but did not detail a high-throughput parallel sequencing format. Gunderson addressed a "significant need for robust, high-throughput methods" and provided the ideal tool—a high-density bead array—to analyze the large number of beads produced by Holliger's method, thereby increasing throughput and reducing costs compared to other analysis formats.
  • Expectation of Success: Success was predictable because the combination involved applying a known analysis method (Gunderson's array sequencing) to a known product (Holliger's clonal beads). Both references taught compatible sequencing methods like pyrosequencing, and the primer-bead linkage systems were proven and disclosed in both the prior art and the ’305 patent itself.

• Additional Grounds: Petitioner asserted an additional obviousness challenge for claims 9-11 based on Holliger, Gunderson, and Kawashima (WO 98/44151). This ground added Kawashima's teachings on using unique sequence tags to track DNA from different biological sources in a pooled sample, a technique Petitioner argued was a logical and known addition to the high-throughput sequencing platform established by Holliger and Gunderson.

4. Key Technical Contentions (Beyond Claim Construction)

• Priority Date Challenge: A central contention was that the ’305 patent was not entitled to its earliest claimed priority date of January 2003. Petitioner argued the relevant provisional application (’471 provisional) failed to disclose the key concept of using an "emulsion" for amplification, instead describing amplification only in the wells of a plate. This lack of written support allegedly limited the patent's effective priority date to April 2003, which rendered Holliger (published March 2002) prior art under 35 U.S.C. §102(b).

5. Relief Requested

• Petitioner requested the institution of an inter partes review and cancellation of claims 1 and 3-11 of Patent 7,323,305 as unpatentable for obviousness.