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Harmony Brings Discord:  Federal Circuit Affirms Finding that Ariosa Diagnostics’ Harmony® Pre-Natal Test Infringes Illumina and Verinata Health Patents

(Co-authored by Kevin Mosier)

Overview

Cell-free fetal DNA technology was again the centerpiece of a dispute between plaintiffs Illumina and Verinata Health (referred together as Illumina), and defendants Ariosa Diagnostics and Roche Molecular Systems (referred together as Ariosa) in Verinata Health, Inc., et al v. Ariosa Diagnostics, Inc., et al., No. 18-2198 (Fed. Cir. Apr. 24, 2020). At issue in the case was Ariosa’s pre-natal diagnostic test marketed as Harmony®. While Section 101 eligibility was not at issue, the Federal Circuit provided important commentary related to enablement and availability of injunctive relief, affirming a jury determination of validity in view of an enablement challenge, largely based on the referenced prior art and other evidence not strictly tied to the disclosures in the patent itself. Specifically, the jury below found that Harmony® infringed U.S. Patent Nos. 7,955,794 (‘794 patent) and 8,318,430 (‘430 patent), held by Illumina and Verinata Health, respectively. The district court denied Ariosa’s motion for judgment as a matter of law (JMOL) on the validity of the ‘430 and ‘794 patents and its motion for JMOL on infringement of the ‘794 patent. The district court also denied Illumina’s post-trial motions for a permanent injunction and supplemental damages. The parties filed cross-appeals on the denials of these motions, and the Federal Circuit affirmed the district court’s denials. The court also declined to issue an injunction, citing the parties’ respective sales models as evidence that irreparable harm was lacking.

Technology and Patents at Issue

Ariosa commercialized the Harmony® test in March 2012. The Harmony® test, which consists of materials supplied by Illumina, is a non-invasive prenatal DNA-sequencing test that analyzes fetal cell-free DNA (cfDNA) from a blood sample of an expecting mother for the presence of genetic indicators of a range of chromosomal conditions, including trisomies (e.g., Down syndrome), sex chromosome aneuploidies, and microdeletions. Specifically, the test screens for 6800 different gene sequences in a sample of isolated fetal cfDNA. A mixture of single-stranded oligonucleotides complementary to the 6800 gene sequences are added to a sample of denatured cfDNA and if the sample contains one of the target sequences, the oligonucleotides will hybridize. If the sample does not, the oligonucleotides remain unbound in the solution.  After two hours, magnetic beads coated with streptavidin for binding the cfDNA are added to the mixture. The magnetic beads are immobilized, along with the sample DNA and bound oligonucleotides, and the remainder of the mixture, including unbound oligonucleotides, is discarded. A single DNA strand is created and then amplified and purified.  The solution of purified amplicons is digested into fragments and the solution, including readout cassettes, is applied to an array.  Where a readout cassette corresponds to one of the 6800 target sequences, it will bind to the array. Fluorescently labeled oligonucleotides complementary to the unbound portions of the readout cassettes are added and given time to bind. Heat is applied to the array to separate out readout cassettes from fluorescently tagged chips. A machine reads the array, differentiating between fluorescent tags and their positions. This permits the test to calculate the probability that one of the 6800 sequences was present in the cfDNA sample, and therefore, providing a prediction for the presence of one or more chromosomal conditions (e.g., Down syndrome).

Illumina subsequently brought suit against Ariosa, alleging that the Harmony® test infringes its ‘794 and ‘430 patents. The ‘430 patent, entitled “Methods of Fetal Abnormality Detection,” describes methods for non-invasive prenatal test screening of fetal chromosomal abnormalities. The ‘794 patent, entitled “Multiplex Nucleic Acid Reactions,” describes a DNA optimization technique where target DNA sequences within a sample hybridize to probes introduced into the sample with complementary sequences. 

Infringement

On appeal, Ariosa argued that its Harmony® test failed to infringe the ‘794 patent because (1) it does not literally infringe steps (a) and (b) of claim 1; and (2) it does not infringe steps (f) and (g) of claim 1 literally or under the doctrine of equivalents. The Federal Circuit disagreed, finding that the Harmony® test literally infringed steps (a) and (b) and infringed steps (f) and (g) under the doctrine of equivalents.   

Claim 1, in relevant part, states:

A multiplex for determining whether a sample contains at least 100 different target sequences, comprising:

     a) providing a sample which may contain at least 100 different

single-stranded target sequences attached to a first solid support;

     b) contacting said target sequences with a probe set comprising

more than 100 different single-stranded probes . . .

     e) contacting said modified probes with:
      i) at least a first primer that hybridizes to said universal priming site;
     ii) NTPs; and

    iii) an extension enzyme;

wherein said different modified probes are amplified and forming different amplicons;

     f) immobilizing said different amplicons to a second solid support, and
     g) detecting said different amplicons immobilized to said second solid support, thereby determining whether the sample contains at least 100 different target sequences.

As to steps (a) and (b), Ariosa argued that its test does not perform the “providing” step before the “contacting” step, as recited.  In other words, Ariosa argued its Harmony® test did not infringe because it did not perform that recited steps in the claimed order. Ariosa further argued that Illumina’s expert failed to offer evidence that (1) “at least 100 different single-stranded target sequences” remain unbound after the two-hour hybridization period utilized in the Harmony test; and (2) that unbound single-stranded target sequences would bind to the relevant probes once the streptavidin beads were added to the mixture but before the remainder of the solution was washed away. 

The Federal Circuit disagreed. The court found that Illumina’s expert presented substantial evidence demonstrating that the Harmony® test met steps (a) and (b) of claim 1. Namely, the expert testified that the Harmony®’s annealing reaction would be less than 99% complete after the two-hour incubation period. He also testified that the strong covalent bond between streptavidin and the biotin-coated cfDNA fragments permitted quick attachment to target sequences. Thus, the Federal Circuit found that the Harmony® test literally infringed steps (a) and (b) of claim 1.

As to steps (f) and (g), Ariosa argued that IIlumina failed to show literal infringement or infringement under the doctrine of equivalents. Ariosa argued that after amplification, Harmony’s readout cassette is not the complete “amplicon” required by the claims, but is rather only a portion of each of the amplified DNA segments. However, even if the court considered the readout cassettes sufficient to meet the “amplicon” limitation, Ariosa argued that the amplicons are not detected while attached to a second support because they are washed away from the array before the detection step. Ariosa contended these steps prevented a literal infringement read or a read under the doctrine of equivalents. 

The Federal Circuit rejected Ariosa’s arguments. The court credited the testimony of Illumina’s expert who testified that the readout cassettes and amplicons of the Harmony test served substantially the same function in substantially the same way to achieve the same result—namely immobilization onto a solid support to hybridize the DNA molecule for the detection of target DNA sequences in the sample as claimed in steps (f) and (g) of claim 1 of the ‘794 patent. The court concluded that a reasonable factfinder could find this evidence demonstrated infringement under the doctrine of equivalents. Given this conclusion, the court did not address Ariosa’s literal infringement analysis of steps (f) and (g).  

Thus, the Federal Circuit determined that the Harmony® test literally infringed steps (a) and (b) and infringed steps (f) and (g) under the doctrine of equivalents.   

Invalidity

At district court, Ariosa had argued that the ‘794 was invalid as being anticipated by a prior art reference, U.S. Patent Application No. 2003/0228599 A1, entitled “Genomic Profiling:  A Rapid Method for Testing a Complex Biological Sample for the Presence of Many Types of Organisms” and invented by Don Straus (“Straus”). The district court disagreed, denying Ariosa’s motion for JMOL of invalidity. Ariosa appealed, however, the Federal Circuit agreed with the district court that the ‘794 patent was not invalid over Straus.

Ariosa contended that Straus discloses a single universal primer, as required by claim 1 of the ‘794 patent. Illumina’s expert testified otherwise. The Federal Circuit found that the jury had substantial evidence on which to base its invalidity ruling and refused to delve into the credibility assessment of experts that Ariosa’s arguments invited. 

Ariosa had also argued at district court that the ‘794 patent was invalid as lacking enablement; however, its JMOL motion of invalidity based on enablement was denied by the district court. On appeal, the Federal Circuit agreed with the lower court. 

Specifically, Ariosa argued that the ‘430 patent failed to disclose the requisite algorithm for determining the presence or absence of a fetal aneuploidy, as claimed in step (f) of claim 1.  Claim 1 of the ‘430 patent recites in relevant part:

A method for determining the presence or absence of a fetal aneuploidy in a fetus for each of a plurality of different pregnant women, said maternal blood samples comprising fetal and maternal cell-free genomic DNA, said method comprising: . . .

(f) for each of the plurality of maternal blood samples, determining the presence or absence of a fetal aneuploidy comprising using a number of enumerated sequence reads corresponding to the first chromosome and a number of enumerated sequence reads corresponding to the reference chromosome of (e). 

Illumina’s various rebuttals included the argument that its own expert testified that the Roche scientists used the “exact statistical methods the ‘430 [p]atent discloses” to determine aneuploidy for the targeted approach successfully. Illumina and its experts also argued that “the alleged missing enablement teachings” were taught in the prior art and that the “skilled artisan is presumed to be aware of all pertinent prior art.” The Federal Circuit found that a reasonable mind might accept this testimony and found the ‘430 patent to be enabled, in agreement with the lower court. Thus, the Federal Circuit affirmed the district court’s denial of Ariosa’s JMOL of invalidity based on lack of enablement. 

Remedies

Illumina argued on appeal that the district court failed to recognize the irreparable harm Ariosa’s infringement posed to Illumina given the direct competition between Roche and Illumina.  Illumina urged that the district court had misunderstood the Federal Circuit’s holding in ActiveVideo Networks, Inc. v. Verizon Communications, Inc., 694 F.3d 1312 (Fed. Cir. 2012). The  Federal Circuit confirmed that in ActiveVideo it held that lack of direct competition is a substantial basis for finding no irreparable harm. The court explained that the district court found that there was no direct competition since Ariosa and Roche compete with Illumina’s licensees, not Illumina. The Federal Circuit found no fault in the district court’s finding that Illumina would not suffer irreparable injury. The court similarly found no abuse of discretion in the district court’s determination that monetary damages, calculated as lost licensing fees, were adequate to remedy the harm caused by Ariosa’s infringement. 

On appeal, Illumina also took issue with the interest rate selected by the district court, the 52-week Treasury Bill rate. However, Illumina failed to articulate a reason why the higher prime rate was appropriate, and the Federal Circuit found that the district court did not abuse its discretion in selecting the interest rate. 

Takeaways

  • The Federal Circuit’s analysis highlights the importance of expert testimony and more specifically, ensuring that the relevant testimony makes it into the trial record with an eye toward issues that may arise on appeal. In multiple instances, Illumina’s expert’s testimony provided multiple, and ultimately sufficient avenues for the court to find substantial evidence to support both the jury’s and district court’s conclusions below. 
  • Practitioners frequently grapple with the interplay between enablement and prior art during prosecution, where the issue is often whether a reference is sufficiently enabled to be considered anticipatory. This case serves as a reminder that prior art can be a patent owner’s friend by filling in allegedly missing disclosures, at least where the prior art is incorporated by reference in the patent. 

This case also highlights that certain business models can affect the scope of remedies available to a successful plaintiff. Where one party utilizes a licensing model and the other utilizes a direct sales model, courts may find that the sales-based entity competes with licensees but not with the licensor. In that instance, money damages will typically be adequate to compensate the plaintiff’s loss of licensing revenue. Consequently, it is important for litigants to consider the parties’ business models when deciding which remedies to pursue.