Illumina Inc v. Molecular Loop Biosciences Inc

1. Case Identification

• Case #: IPR2024-00965
• Patent #: 11,768,200
• Filed: July 2, 2024
• Petitioner(s): Illumina Inc.
• Patent Owner(s): Molecular Loop Biosciences, Inc.
• Challenged Claims: 1-6

2. Patent Overview

• Title: Methods for Validating Nucleic Acid Sequence Identity
• Brief Description: The ’200 patent describes methods for validating nucleic acid sequences in a multiplex sequencing reaction. The method involves tagging nucleic acid analytes from a sample with a unique pair of "different" identifier sequences (barcodes), one at each end, to detect and exclude erroneous sequences generated during the process.

3. Grounds for Unpatentability

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

• Prior Art Relied Upon: Gloor (a 2010 publication titled "Microbiome profiling by Illumina sequencing of combinatorial sequence-tagged PCR products").
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that Gloor, which was not considered during prosecution, discloses every element of the challenged claims. Gloor described a method for sequencing nucleic acids from 272 clinical samples in a multiplex reaction using an Illumina platform. Each sample's analytes were tagged with a unique combinatorial pair of identifier sequences ("sequence tags"), one at each end (5' and 3'). Gloor disclosed that the majority of these identifier sequences were four or more nucleotides long and were different from each other. The method explicitly validated sequences by extracting reads containing "two valid sequence tags" and excluding sequences that were incorrect, such as those "lack[ing] the left or right end sequence tag." This process of identifying correct pairs and excluding incorrect ones allegedly meets all limitations of independent claim 1 and its dependent claims.
  • Key Aspects: Petitioner contended Gloor’s method of using combinatorial unique pairs of tags to ensure accurate sequence assignment and eliminate errors is the same method claimed in the ’200 patent.

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

• Prior Art Relied Upon: Parameswaran (a 2007 publication titled "A pyrosequencing-tailored nucleotide barcode design unveils opportunities for large-scale sample multiplexing").
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner asserted that Parameswaran, though cited during prosecution of a parent patent, was improperly overcome and fully anticipates the claims. Parameswaran taught a dual-indexing method for multiplex sequencing using a Roche 454 platform. It assigned a unique pair of "10-nucleotide barcodes" to opposite ends of nucleic acids from each sample. These forward and reverse barcodes were explicitly designed to be different from each other. Parameswaran validated the resulting sequences by analyzing for the presence of both correct forward and reverse barcode motifs. It further identified and quantified erroneous sequences, such as those with "mismatched" barcode pairs or only a single correct barcode, demonstrating a method for excluding incorrect identifiers from the final analysis.
  • Key Aspects: Petitioner highlighted that during prosecution of the parent ’281 patent, the applicant distinguished Parameswaran by arguing it taught "different" barcodes while amending the claims to require the "same" barcodes. The ’200 patent now claims the very feature—"different" identifiers—that the applicant previously admitted Parameswaran taught.

Ground 3: Claims 1-6 are obvious over Parameswaran and Binladen under 35 U.S.C. §103

• Prior Art Relied Upon: Parameswaran and Binladen (a 2007 publication titled "The Use of Coded Primers Enables High-Throughput Sequencing...").

• Core Argument for this Ground:

  • Prior Art Mapping: Petitioner argued that Parameswaran discloses the core dual-indexing method using unique, different identifiers of sufficient length to validate sequences, as detailed in Ground 2. Binladen, which was also not considered by the Examiner, taught a similar dual-indexing approach to address errors in multiplex sequencing. Binladen disclosed using pairs of identifier tags, including tetranucleotide (4-nucleotide) tags, and confirmed that longer tags resulted in lower rates of sequence misassignment compared to shorter tags.
  • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA) would combine Parameswaran and Binladen to improve multiplex sequencing accuracy. Both references addressed the known problem of technical errors leading to incorrect sequence assignment. Parameswaran itself characterized work like Binladen's as valuable but explained that longer, more distinct barcodes were needed for "a more definitive assignment of samples." A POSA would therefore be motivated to apply Parameswaran's teaching of using longer, unique identifier sequences (e.g., 10-base barcodes) to the dual-indexing framework taught by both references to achieve a predictable improvement in accuracy.
  • Expectation of Success: A POSA would have a reasonable expectation of success because both references provided detailed methods for dual-indexing on the same type of sequencing platform (Roche 454). The combination represented a predictable variation of a known technique—using longer barcodes, a principle taught in Binladen and optimized in Parameswaran—to achieve the known goal of increased accuracy.

• Additional Grounds: Petitioner asserted additional obviousness challenges, including that claims 1-6 are obvious over Parameswaran and Gloor, and that claim 6 is obvious over Parameswaran, Binladen, and Bentley (a 2008 publication on Illumina sequencing). These grounds relied on similar motivations to combine methods to improve accuracy and adapt established barcoding strategies to more efficient sequencing platforms.

4. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under §325(d) is unwarranted. Key prior art references, including Gloor, Binladen, and Bentley, were never considered by the Examiner during prosecution.
• Furthermore, Petitioner contended the Examiner made a material error by overlooking the applicant's prior admission during prosecution of the parent ’281 patent that Parameswaran taught the use of "different" barcodes—the exact feature claimed in the ’200 patent.

5. Relief Requested

• Petitioner requests institution of an inter partes review and cancellation of claims 1-6 of the ’200 patent as unpatentable.