PTAB

IPR2013-00154

Taiwan Semiconductor Mfg Co Ltd v. ZipTronix Inc

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1. Case Identification

2. Patent Overview

  • Title: Method for Introducing a Double-Stranded Break into Chromosomal DNA
  • Brief Description: The ’605 patent relates to a method for inducing a site-directed double-stranded break in the chromosomal DNA of a viable cell. The method is accomplished by providing a Group I intron encoded endonuclease (GIIE endonuclease) to a cell containing a corresponding recognition site in its chromosomal DNA.

3. Grounds for Unpatentability

Ground 1: Claims 1, 10, 11, 14, and 15 are anticipated by Bell-Pedersen

  • Prior Art Relied Upon: Bell-Pedersen (Deborah Bell-Pedersen et al., 18 Nucleic Acid Research 3763 (1990)).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Bell-Pedersen inherently disclosed every limitation of the claimed method. The reference described experiments where a phage containing a GIIE endonuclease recognition site was integrated into the chromosomal DNA of a viable E. coli host cell. The GIIE endonuclease itself was expressed from a plasmid under the control of a temperature-inducible promoter. Petitioner, supported by expert testimony from Dr. Bell-Pedersen and Dr. Derbyshire, contended that cleavage of the recognition site necessarily occurred while the phage was integrated into the host chromosome. The argument centered on the known "leaky" nature of the promoter, which would have produced a low but effective level of endonuclease at the permissive temperature (30°C) when the phage was resident in the chromosome, thereby causing the claimed chromosomal cleavage before the main induction event.
    • Key Aspects: The central thrust of this anticipation argument was not based on express disclosure but on inherency, supported by expert testimony interpreting the inevitable outcome of the experimental conditions described in the prior art.

Ground 2: Claim 18 is obvious over Bell-Pedersen in view of Frey

  • Prior Art Relied Upon: Bell-Pedersen (1990 journal article) and Frey (B. Frey et al., 343 Fresenius' J. Analytical Chemistry 122-123 (1992)).

  • Core Argument for this Ground:

    • Prior Art Mapping: Petitioner asserted that Bell-Pedersen taught the claimed method of using a GIIE endonuclease to cleave chromosomal DNA in a prokaryotic organism. The only difference in claim 18 was the requirement that the cell be eukaryotic. Petitioner argued that Frey explicitly taught the cleavage of purified, intact eukaryotic chromosomes (from yeast) using a GIIE endonuclease (I-SceI). Therefore, a person of ordinary skill in the art (POSA) would have found it obvious to apply the in vivo method of Bell-Pedersen to a eukaryotic cell, as Frey demonstrated that eukaryotic chromosomes were suitable substrates for GIIE endonucleases.
    • Motivation to Combine: A POSA would combine these references to achieve the well-known goal of facilitating site-directed gene insertion in a eukaryotic chromosome. Petitioner also cited another reference, Eddy (1992), which expressly suggested using a GIIE endonuclease system like that in Bell-Pedersen for genome engineering "in a variety of organisms," providing a clear motivation to extend the bacterial method to other cell types, including eukaryotes.
    • Expectation of Success: Petitioner argued a POSA would have had a reasonable expectation of success. Frey showed a GIIE endonuclease could cut a eukaryotic chromosome. Further, a separate reference, Dujon (1990), was cited as providing direct evidence that a GIIE endonuclease could be expressed in a viable yeast cell and successfully introduce a double-stranded break in the chromosomal DNA in vivo. This combination of teachings confirmed the feasibility of performing the claimed method in a viable eukaryotic cell.

  • Additional Grounds: Petitioner supported additional obviousness challenges, including grounds based on Schiestl (a reference teaching gene targeting with conventional restriction enzymes) in combination with Frey. The argument was that it would have been an obvious design choice to substitute the BamHI restriction enzyme used by Schiestl with a known GIIE endonuclease like I-SceI from Frey to achieve more specific chromosomal cleavage.

4. Key Claim Construction Positions

  • "Viable cell": This term, added during reexamination, was central to the dispute. Petitioner's position relied on the interpretation that a cell could remain "viable" (i.e., alive and not dying) even after the GIIE endonuclease induced a double-stranded break in its chromosome. This construction was critical because the Patent Owner argued that such cleavage would be toxic and kill the cell, meaning it would no longer be viable. Petitioner's experts testified that E. coli possesses natural repair mechanisms capable of repairing such breaks, allowing the cell to remain viable as required by the claim.

5. Key Technical Contentions (Beyond Claim Construction)

  • Timing of DNA Cleavage: The core technical dispute for the anticipation ground was the timing of endonuclease activity in the Bell-Pedersen experiments. Petitioner's experts strongly contended that cleavage of the target DNA site occurred while the phage DNA was integrated into the host cell's chromosome. This was contrasted with the Patent Owner's position that cleavage only occurred after the phage was excised from the chromosome.
  • "Leaky" Promoter Effect: A cornerstone of Petitioner's technical argument was that the temperature-inducible pL promoter described in Bell-Pedersen was widely known in the art to be "leaky." Petitioner argued this leakiness would result in a baseline level of GIIE endonuclease expression even at permissive temperatures, which was sufficient to cause the claimed chromosomal cleavage before any temperature shift was applied to induce high-level expression and phage excision.

6. Relief Requested

  • Petitioner requested that the Examiner's final rejection of claims 1-18 be affirmed and that the claims be cancelled as unpatentable under 35 U.S.C. §102 and §103.