Progenity Inc v. Natera Inc

1. Case Identification

• Case #: IPR2021-00280
• Patent #: 9,228,234
• Filed: December 18, 2020
• Petitioner(s): Progenity, Inc.
• Patent Owner(s): Natera, Inc.
• Challenged Claims: 1-30

2. Patent Overview

• Title: Method for Determining Chromosome Copy Number
• Brief Description: The ’234 is directed to methods for determining the copy number of a chromosome or chromosome segment in a fetus. The method involves analyzing a mixed sample of maternal and fetal DNA obtained from the mother, using genetic data from single nucleotide polymorphisms (SNPs) to create ploidy state hypotheses, and calculating probabilities on a computer to determine the fetal chromosome copy number.

3. Grounds for Unpatentability

Ground 1: Claims 1-16 and 18-30 are obvious over Dhallan in view of Stoughton.

• Prior Art Relied Upon: Dhallan (Application # 2004/0137470) and Stoughton (WO 2007/147074).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that Dhallan taught the core method of independent claim 1. Dhallan disclosed obtaining a mixed sample of fetal and maternal DNA and measuring allele ratios at heterozygous SNP loci on a chromosome expected to be disomic (e.g., chromosome 13) to calculate the fetal DNA fraction. Dhallan then compared these ratios to those measured on a chromosome of interest (e.g., chromosome 21) to detect chromosomal abnormalities like trisomy. Petitioner contended Stoughton augmented Dhallan by teaching the use of more robust, computer-based informatics. Stoughton disclosed using computer-executable logic to apply data models (hypotheses) for different ploidy states (e.g., normal, maternal trisomy, paternal trisomy) to SNP data from a mixed sample, calculate likelihood ratios for each model, and select the best-fit model to determine the existence of an aneuploidy. The combination of Dhallan’s method with Stoughton’s computer-implemented modeling allegedly taught all steps of claim 1.
  • Motivation to Combine: A POSITA would combine Dhallan and Stoughton because they address the identical problem of non-invasive prenatal aneuploidy detection and their teachings are highly complementary. Petitioner asserted that a POSITA, starting with the fundamental allele-ratio method taught by Dhallan, would have been motivated to apply the advanced, computer-based data analysis and modeling techniques of Stoughton. This combination represented a predictable path to automate the process, improve its accuracy and efficiency, and handle the large datasets generated from analyzing numerous SNPs.
  • Expectation of Success: Petitioner argued a POSITA would have a high expectation of success. Dhallan itself provided successful working examples identifying Trisomy 21 using mixed DNA samples. Furthermore, Petitioner cited a subsequent peer-reviewed article (Dhallan *Lancet*) that reported the successful implementation of Dhallan’s methods on clinical samples from 60 pregnant women, demonstrating the method's real-world viability and providing a strong evidentiary basis for success.

Ground 2: Claim 17 is obvious over Dhallan and Stoughton in view of Lo 2003.

• Prior Art Relied Upon: Dhallan (Application # 2004/0137470), Stoughton (WO 2007/147074), and Lo 2003 (WO 03/020974).
• Core Argument for this Ground:
  • Prior Art Mapping: Dependent claim 17 adds the limitation of "measuring the difference in methylation between one or more maternal and fetal alleles" to the method of claim 1. Petitioner asserted that Lo 2003 explicitly taught that fetal genetic abnormalities could be diagnosed by differentiating fetal DNA from maternal DNA based on known differences in their DNA methylation patterns. Lo 2003 disclosed this as a viable method for detecting fetal DNA in a maternal sample.
  • Motivation to Combine: A POSITA seeking to improve the base aneuploidy detection method of Dhallan and Stoughton would have been motivated to incorporate the teachings of Lo 2003. Since accurately distinguishing fetal DNA from the maternal background is critical to the method, using known epigenetic markers like methylation differences was a well-understood and predictable technique for achieving this goal. Petitioner argued that incorporating this known technique for its known purpose to improve the overall method would have been an obvious design choice.
  • Expectation of Success: Given that methylation-based differentiation of fetal and maternal DNA was a known and established principle at the time, a POSITA would have reasonably expected to successfully integrate this technique into the SNP-based analysis of Dhallan and Stoughton.

4. Key Claim Construction Positions

• "ratio of fetal to maternal DNA": Petitioner argued that this term, which is central to the claims but not explicitly defined in the ’234 patent, should be construed according to its ordinary meaning to a POSITA at the time. Based on intrinsic evidence and contemporaneous prior art (e.g., the Dhallan Lancet publication), Petitioner contended this term encompassed either the ratio of a unique fetal allele amount to the combined maternal and fetal allele amount, or more broadly, the percentage (or fraction) of fetal DNA in the mixed sample. This construction was critical to show that prior art teaching the calculation of a "percentage of fetal DNA" met this claim limitation.

5. Arguments Regarding Discretionary Denial

• Petitioner argued against discretionary denial under 35 U.S.C. §325(d), asserting that the primary references (Dhallan and Stoughton) were materially different from the art applied by the examiner during prosecution. Petitioner contended that while the references were cited in an Information Disclosure Statement, they were never substantively analyzed or used as the basis for a rejection, and their teachings were not cumulative to the art that was considered.
• Regarding co-pending litigation, Petitioner argued that the Fintiv factors weighed in favor of institution. Petitioner stated that the parallel district court cases were in a very early stage, with no trial date set and minimal investment beyond initial pleadings. To avoid duplicative efforts and address efficiency concerns, Petitioner committed to filing a stipulation that it would not pursue in district court the same invalidity grounds on which the IPR is instituted.

6. Relief Requested

• Petitioner requests institution of an inter partes review and cancellation of claims 1-30 of Patent 9,228,234 as unpatentable under 35 U.S.C. §103.