PTAB

IPR2021-00401

Pillar Biosciences Inc v. Integrated DNA Technologies Inc

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Key Events
Petition

1. Case Identification

2. Patent Overview

  • Title: Multiplex PCR Methods and Compositions
  • Brief Description: The ’359 patent discloses methods for multiplex polymerase chain reaction (PCR) amplification of target nucleic acids. The method uses target-specific primers designed with a common 5’ noncomplementary sequence, which, after amplification, results in amplicons whose ends are complementary, allowing them to form stable secondary loop structures that prevent their further amplification and reduce amplification bias for shorter amplicons.

3. Grounds for Unpatentability

Ground 1: Claims 1-6 are anticipated by Xie under 35 U.S.C. §102.

  • Prior Art Relied Upon: Xie (Application # 2014/0200146)
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Xie, which discloses a whole genome amplification method (MALBAC), teaches every element of the challenged claims. Xie’s method uses multiple primers, each comprising a 3’ portion that hybridizes to a target sequence and a 5’ common constant sequence that is noncomplementary to the target. This process generates a library of overlapping amplicons. Petitioner contended that after the initial amplification cycles, the resulting amplicons have complementary sequences at their 3’ and 5’ ends derived from the common primer sequence. Xie explicitly disclosed that these ends hybridize to form a stable loop structure, which protects the 3’ ends and prevents the amplicon from being used as a template in subsequent amplification steps, thereby meeting the core limitations of the claims.
    • Key Aspects: The argument relied on interpreting Xie's MALBAC method, which involves linear and exponential amplification steps, as a form of "multiplex PCR" and its primers as "target-specific" within the meaning of the claims.

Ground 2: Claims 1-6 are anticipated by Lao under 35 U.S.C. §102.

  • Prior Art Relied Upon: Lao (Application # 2009/0291475)
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner asserted that Lao discloses a PCR method designed to selectively amplify long DNA segments while reducing the amplification of shorter segments. Lao’s primers were described as having a 3’ target-specific portion (which can be a random or degenerate sequence for whole genome amplification) and a 5’ noncomplementary "tail" region that is the same for all primers. Petitioner argued that Lao explicitly teaches that this design causes shorter amplicons to preferentially self-hybridize into stable loop structures, effectively removing them from the reaction. This directly maps to the claimed method of generating a "third amplicon" (the shortest amplicon) that forms a stable secondary structure to prevent its own amplification. Petitioner further argued that Lao’s use of degenerate primers for whole genome amplification inherently produces the claimed overlapping amplicons.

Ground 3: Claims 1-6 are obvious over Gardner in view of Lao under 35 U.S.C. §103.

  • Prior Art Relied Upon: Gardner (a 2014 journal article on multiplex PCR design) and Lao (’475 application).
  • Core Argument for this Ground:
    • Prior Art Mapping: Gardner discloses a method for designing multiplex PCR primers to amplify various viral genomes. Gardner recognized that using primers for overlapping genomic regions in a single reaction produces "undesired shorter amplicons." To solve this, Gardner taught performing two separate PCR reactions to avoid amplifying overlapping sequences together. Lao was presented as teaching the solution to Gardner’s exact problem: using primers with a common 5’ noncomplementary sequence to cause shorter amplicons to form stable loops, thereby preventing their amplification. The combination of Gardner's multiplex primer sets with Lao's looping technique would result in the claimed method.
    • Motivation to Combine: A POSITA would combine Gardner and Lao to improve Gardner's method. Gardner explicitly identified the problem of short amplicons from overlapping primers, and Lao provided a known solution. Combining them would allow all of Gardner's primers to be used in a single, more efficient, and cost-effective reaction rather than multiple separate reactions.
    • Expectation of Success: A POSITA would have a reasonable expectation of success because the techniques are similar and address a known problem in multiplex PCR. The combination would only require adding the 5' noncomplementary sequence from Lao to the target-specific primers of Gardner, a straightforward modification for a skilled artisan.

4. Key Claim Construction Positions

  • "third amplicon": Petitioner proposed this term should be construed to mean either the shortest or the longest of the possible amplicons, depending on the relative orientation of the primers. This construction was important because the prior art (e.g., Lao) specifically discusses the preferential looping and removal of the shortest amplicons, which Petitioner argued meets the claim limitation.
  • "target-specific primer": Petitioner argued this term is not limited to primers with unique, specific sequences but also includes mixtures of degenerate or random primers used for whole genome amplification, as long as each individual primer hybridizes to a target sequence. This construction was critical for applying references like Xie and Lao, which disclose whole genome amplification, to the claims.

5. Key Technical Contentions

  • Priority Date Challenge: Petitioner argued the ’359 patent is not entitled to its earliest claimed priority date of January 31, 2014. The petition asserted that the corresponding provisional application completely lacks written description support for the claimed invention, including any discussion of multiplex PCR, overlapping amplicons, or the formation of stable secondary structures. Therefore, Petitioner contended the effective priority date is no earlier than November 11, 2014, making both Xie (published July 2014) and Gardner (published August 2014) available as prior art.

6. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1-6 of the ’359 patent as unpatentable.