PTAB

IPR2014-00337

Sequenom Inc v. Sequenom Inc

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Noninvasive Diagnosis of Fetal Aneuploidy by Sequencing
  • Brief Description: The ’415 patent describes methods for noninvasively detecting fetal aneuploidy (an abnormal number of chromosomes) from a maternal blood sample. The method involves conducting random "shotgun" sequencing on the mixed sample of maternal and fetal DNA, mapping the resulting sequence tags to a reference genome, and enumerating the tags per chromosome to identify abnormal distributions indicative of a fetal chromosomal abnormality.

3. Grounds for Unpatentability

Ground 1: Obviousness over Lo I and Shimkets - Claims 1-6 and 8-12 are obvious over Lo I in view of Shimkets.

  • Prior Art Relied Upon: Lo I (U.S. Provisional Application # 60/951,438) and Shimkets (Application # 2005/0221341).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Lo I taught a method for detecting fetal aneuploidy (e.g., trisomy 21) by performing random sequencing of DNA fragments from a pregnant woman's plasma, which contains a mixed sample of fetal and maternal DNA. Lo I further disclosed normalizing the resulting sequence data to account for chromosome size. Shimkets taught a sequence-based karyotyping method to determine chromosomal abnormalities using massively parallel sequencing (MPS), mapping fragments to a genomic scaffold, and using statistical methods, including analyzing sequence distribution within defined "windows," to identify abnormalities. Petitioner contended that Lo I taught the foundational method on a mixed sample, while Shimkets provided the well-known statistical and mapping techniques required to analyze the data.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSITA) would combine these references because both described using random sequencing methods to detect chromosomal abnormalities. Petitioner asserted it would have been obvious to apply the more detailed statistical analysis and normalization methods taught in Shimkets to the mixed maternal/fetal sample sequencing method of Lo I to improve the accuracy and reliability of the aneuploidy detection.
    • Expectation of Success: A POSITA would have had a reasonable expectation of success because the combination involved applying known data analysis techniques (Shimkets) to a known method of generating sequencing data from a relevant sample type (Lo I) to achieve the predictable result of detecting chromosomal abnormalities.

Ground 2: Obviousness over Lo I, Shimkets, and Wang - Claims 13 and 16 are obvious over Lo I and Shimkets in further view of Wang.

  • Prior Art Relied Upon: Lo I (U.S. Provisional Application # 60/951,438), Shimkets (Application # 2005/0221341), and Wang (a 2002 publication titled "Digital karyotyping").
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground built upon the combination of Lo I and Shimkets to address the limitations of claim 13, which specifically recited mapping sequence tags within a "sliding window." While Shimkets introduced the concept of "windows," Petitioner argued that Wang explicitly taught a digital karyotyping method that used "sliding windows" to analyze tag densities along each chromosome for quantitative analysis of DNA copy number at high resolution. Wang disclosed that this method could identify whole chromosome changes.
    • Motivation to Combine: A POSITA looking to implement the method of Lo I and Shimkets would have been motivated to incorporate the sliding window analysis from Wang. Wang's method was a well-known technique for improving quantitative sequence analysis and yielding predictable results in detecting chromosomal gains and losses, making it a logical and obvious tool to apply.
    • Expectation of Success: Success was expected because applying Wang’s established sliding window analysis to the methods of Lo I and Shimkets was merely the use of a known technique to improve a similar method, which Wang itself demonstrated was successful in identifying abnormal copy numbers.

Ground 3: Obviousness over Lo I, Shimkets, and Green - Claims 1-6 and 8-12 are obvious over Lo I in view of Shimkets and Green.

  • Prior Art Relied Upon: Lo I (U.S. Provisional Application # 60/951,438), Shimkets (Application # 2005/0221341), and Green (a 2006 publication on sequencing Neanderthal DNA).

  • Core Argument for this Ground:

    • Prior Art Mapping: Petitioner presented this as an alternative combination for the base claims, arguing that Green provided further teachings on analyzing mixed DNA samples. Green described high-throughput sequencing of mixed Neanderthal and modern human DNA, mapping sequences to a human reference genome, and using a sliding window to determine "hit density." Green explicitly stated that local deviations in hit density could represent copy-number differences between the Neanderthal and reference genomes. This reinforced the teachings of Lo I and Shimkets regarding sequencing mixed samples and performing statistical analysis to find chromosomal abnormalities.
    • Motivation to Combine: A POSITA would have been motivated to consider Green because it described sequencing and genome analysis techniques (MPS, mapping, sliding windows) that were highly similar to those discussed in Lo I and Shimkets. The sequence redundancy made possible by the MPS method described in Green would have provided a further reason to combine the teachings.
    • Expectation of Success: A POSITA would have expected success because Green demonstrated that these analytical techniques were effective for identifying copy-number variations in a mixed DNA sample, providing strong evidence that the approach would work for the fetal/maternal mixed sample.

  • Additional Grounds: Petitioner asserted numerous additional obviousness challenges, primarily by adding further references to the Lo I and Shimkets combination to teach specific claim limitations. These included adding Tarasov, Hillier, or Smith for allowing one mismatch during sequence mapping; Dohm for correcting for GC content bias; and Quake for using a t-statistic in the data analysis.

4. Key Claim Construction Positions

  • "Chromosome Portion": Petitioner argued this term should be construed as "either an entire chromosome or a significant fragment of a chromosome," directly adopting the definition from the ’415 patent’s specification.
  • "Window" and "Sliding Window": Petitioner noted that the ’415 patent treats "window" and "bin" as equivalent. Based on the specification, Petitioner argued that a "window" is a predefined subsection of a chromosome. For "sliding window," Petitioner contended it should be broadly construed to mean a contiguous, overlapping, or non-overlapping predefined subsection of a chromosome used for analysis. These constructions were central to mapping the statistical analysis steps taught by Shimkets and Wang to the claims.

5. Arguments Regarding Discretionary Denial

  • Petitioner argued that the grounds in this petition were not redundant or cumulative to those in a previously filed IPR (IPR2013-00390) against the same patent. The prior IPR was instituted based on a reference known as "Lo II." Petitioner contended this petition was distinct because it relied on "Lo I," a provisional application with a filing date one year earlier than Lo II. Furthermore, Petitioner argued that the obviousness combinations in this petition included new references not relied upon in the earlier petition, such as Green and Tarasov.

6. Relief Requested

  • Petitioner requested that the Board institute an inter partes review and cancel claims 1-17 of the ’415 patent as unpatentable under 35 U.S.C. §103.