Expert Declarations in Inter Partes Review Proceedings Must Do More Than Create Noise: PTAB Silences Challenge to Patented Method for Cleaning “Noisy” Genetic Data

Marie A. McKiernan

Feb 5, 2021 7 min read

Overview

On December 11, 2020, the PTAB issued a Final Written Decision in Illumina, Inc. v. Natera, Inc., IPR2019-01201, upholding the validity of Natera Inc.’s patent for determining genetic data from fragmentary DNA. Illumina, Inc. (“Illumina”) filed its petition, challenging claims 1-27 of Natera Inc.’s (“Natera” or “Patent Owner”) U.S. Patent No. 8,682,592 B2 (“’592”). The PTAB instituted inter partes review of all the challenged claims on obviousness grounds. While Illumina carried its burden at the institution stage, it failed to prove the unpatentability of the challenged claims by a preponderance of the evidence as required by 35 U.S.C. § 316(e). The PTAB determined that the challenged claims were not unpatentable, and also denied Illumina’s Motion to Exclude Evidence. Central to the PTAB’s decision were the expert declarations submitted by the parties, and the noted failure by Illumina to include all of its expert’s declarations in its petition.

The Patent

The ’592 patent claims a “System and Method for Cleaning Noisy Genetic Data from Target Individuals Using Genetic Data from Genetically Related Individuals.” The patented invention provides for “more effective identification of genetic irregularities” by using “known genetic data of genetically related individuals” to make “imperfectly measured genetic data” “more precise.” ’592 patent at 1:23-29. The PTAB found sole independent claim 1 of the ’592 patent illustrative. Claim 1 recites:

An ex vivo method for determining a number of copies of a chromosome or chromosome segment of interest in the genome of an individual, the method comprising:

using a single nucleotide polymorphism (SNP) genotyping array or high throughput DNA sequencing to measure genetic material and produce genetic data for some or all possible alleles at a plurality of at least 100 loci on the chromosome or chromosome segment of interest in the individual, wherein the genetic data is noisy due to a small amount of genetic material from the individual; and wherein the small amount of genetic material from the individual is from fifty or fewer of the individual’s cells, 0.3 ng or less of the individual’s DNA, extracellular DNA from the individual found in maternal blood, or combinations thereof;

creating a set of one or more hypotheses specifying the number of copies of the chromosome or chromosome segment of interest in the genome of the individual;

determining, on a computer, the probability of each of the hypotheses given the produced genetic data; and

using the probabilities associated with each hypothesis to determine the most likely number of copies of the chromosome or chromosome segment of interest in the genome of the individual.

Id. at 62:39-62.

Claim 5 of the ’529 patent, which depends from claim 1, recites “wherein the small amount of genetic material is from extracellular DNA from the individual found in maternal blood.”

Claims 1 and 5 were the primary claims disputed by the parties and addressed by the PTAB.

A Battle of the Experts

Illumina sought to exclude the declaration of Natera’s expert in its entirety, arguing that the expert did not have the proper qualifications for the opinions therein. The PTAB rejected this argument, gently chiding Illumina for attempting to revisit or revamp arguments made in its brief and for improperly raising arguments regarding sufficiency on a motion concerning admissibility. The PTAB denied the motion to exclude. In light of the PTAB’s analysis, discussed below, this was detrimental for Ilumina, as Natera’s expert declaration carried the day and was repeatedly credited by the PTAB as providing persuasive reasoning as to why Illumina’s cited art failed to disclose the limitations of the ’529 patent.

Patent Owner Persuasion

For claim 1, Natera successfully rebutted Illumina’s argument that US 2004/0137470 A1 (“Dhallan”), published July 14, 2004, could be used with an SNP genotyping array and DNA from a single fetal cell. The PTAB found, relying in large part on Natera’s expert’s declaration, that Illumina failed to present sufficient evidence to “address the interplay between the amount of DNA in a single cell [as detailed in Dhallan] and the amount of DNA or amplified DNA needed to carry out the claimed method using a SNP genotyping array and Dhallan’s aneuploidy analysis.” Natera’s expert was able to persuasively highlight the missing link—while DNA from single cells may have been routinely used for genetic screening, this did not include SNP genotyping arrays since such low amounts of DNA were not reliably used in SNP arrays at the relevant time. Illumina’s cited references and expert’s declaration failed to bridge this gap.

Petitioner Pitfalls

While Illumina submitted an expert declaration in support of its challenge, the PTAB’s final written decision highlights that Illumina’s expert’s declaration suffered from some of the common pitfalls of such declarations.

The PTAB’s decision noted multiple times that Illumina’s expert included arguments not sufficiently discussed in Illumina’s petition. For example, claim 1 recites that the “small amount of genetic material from the individual is from fifty or fewer of the individual’s cells.” While the claim itself allows for the use of DNA from more than one cell, Illumina limited its arguments in the petition to use of DNA from a single cell. Illumina argued that Dhallan taught this limitation by disclosing different sources of genetic material, including a single cell of an embryo. In an effort to rebut Natera’s expert declaration that DNA from a single cell would be insufficient for use with an SNP genotyping array, Illumina’s expert also argued that a prior art reference cited by Natera’s expert taught using five human cells for amplification and subsequent genotyping techniques. The PTAB expressly criticized that the petition “exclusively focused on a reasonable expectation of success in carrying out claim 1 using DNA from a single cell,” not five cells as taught in the reference. This ran afoul of 37 C.F.R. § 42.6(a)(3), which prohibits incorporation by reference in inter partes review proceedings, and as such represented “an impermissible shift in theory from that presented in the Petition.” The PTAB, consequently, did not consider these arguments.

The PTAB also noted that Illumina’s expert’s declaration failed to provide the details necessary to tie prior art teachings to the specific claim limitations of the ’529 patent. For example, claim 1 recites that the genetic data is noisy because the “small amount of genetic material from the individual is from fifty or fewer of the individual’s cells.” Illumina’s expert argued that a multiple displacement amplification process in a reference generated a certain amount of DNA (35 µg). However, the declaration failed to set forth the rationale for whether this amount of DNA was sufficient to practice claim 1 of the ’529 patent using the method set forth in Dhallan as required.

By way of another example, Illumina relied on its expert’s declaration, among other evidence, to argue that Dhallan “motivates use of fetal DNA found in maternal blood in the disclosed method [of claim 5].” The Board rejected this argument. When assessing Illumina’s expert declaration, the Board noted that while the declaration discussed using SNP genotyping arrays, the it failed to “specifically address isolating extracellular fetal DNA from maternal blood,” including failing to cite any reference addressing the isolation purification of extracellular fetal DNA from maternal blood. Since Illumina’s petition articulated complete isolation of the fetal DNA from the maternal DNA as a prerequisite to using the extracellular fetal DNA in Dhallan’s methodology, the failure to address isolation was fatal to Illumina’s argument.

Takeaways

The PTAB’s analysis highlights the importance of the expert declaration, and how the outcome may turn on its contents aligning with the parties’ submissions. The decision provides the following takeaways:

The Interplay between the parties’ submissions and supporting declarations: The PTAB’s decision highlights that when crafting a petition, you must take caution to include all arguments you would want to support through an expert declaration. Failure to do so could result in an impermissible expansion of the scope of argument in the petition, which will not be considered by the Board. The same care and consideration should be afforded to Patent Owner’s preliminary responses, which may also include supporting evidence.
Spell it Out: The petitioner carries the burden. As a result, its expert’s declaration must connect all dots and provide all rationale to the Board for the opinions tied to the references cited. Failure to heed this advice could result in the Board finding an expert’s declaration conclusory or lacking in support for the opinions presented. This is especially important where a competing expert’s declaration can serve to highlight the insufficiency of petitioner’s reasoning for filling in the blanks.