Patents on Measuring cfDNA to Detect Rejection of Transplanted Organs Held Invalid

When a person who has received an organ transplant experiences rejection, DNA from the transplanted organ is released into the bloodstream as the organ's cells are attacked by the person's immune system. The circulating DNA from the transplanted organ — referred to as cell-free DNA (cfDNA) — can be distinguished from the recipient's own DNA because the donor's DNA will always have certain differences that can be identified. Detecting early rejection of a transplanted organ can guide treatment to ameliorate the process.

Background

CareDx is the exclusive licensee of three patents directed to this technique. In brief, all claimed methods of detecting incipient rejection or measuring the amount of donor cfDNA using techniques that were stated in the common patent specifications to be conventional, such as multiplex sequencing or amplification using polymerase chain reaction (PCR). An exemplary claim of one patent read as follows:

1. A method for detecting transplant rejection, graft dysfunction, or organ failure, the method comprising:

(a) providing a sample comprising cell-free nucleic acids from a subject who has received a transplant from a donor;

(b) obtaining a genotype of donor-specific polymorphisms or a genotype of subject-specific polymorphisms . . . to establish a polymorphism profile for detecting donor cell-free nucleic acids . . .;

(c) multiplex sequencing of the cell-free nucleic acids in the sample followed by analysis of the sequencing results using the polymorphism profile to detect donor cell-free nucleic acids and subject cell-free nucleic acids; and

(d) diagnosing, predicting, or monitoring a transplant status or outcome of the subject who has received the transplant by determining a quantity of the donor cell-free nucleic acids based on the detection of the donor cell-free nucleic acids and subject cell-free nucleic acids by the multiplexed sequencing, wherein an increase in the quantity of the donor cell-free nucleic acids over time is indicative of transplant rejection, graft dysfunction or organ failure . . . .

U.S. Patent No. 8,703,652.

District Court Ruling

In consolidated proceedings in the District of Delaware against accused infringers Natera and Eurofins Viracor, the district court denied the defendants' motions to dismiss based on Section 101, but stayed proceedings except for limited discovery to determine if the Section 101 issue was amenable to resolution on summary judgment. Taking a somewhat unusual approach, the district court held an evidentiary hearing at which the parties' competing experts testified in order to determine if there were indeed genuine issues of material fact that would preclude the grant of summary judgment. CareDx, Inc. v. Natera, Inc., 563 F. Supp. 3d 329, 338-39 (D. Del. 2021). After hearing the experts testify, the district court granted summary judgment of invalidity.

In its opinion, the district court was highly critical of CareDx for arguing at Alice Step 2 that the measurement and quantification techniques recited in the claims were not conventional even though the patents' common specification characterized them as "routine and conventional." According to CareDx, because such a statement "appears verbatim in myriad patents and patent applications covering different technologies," it should not be understood "to be some sort of supposed voluntary confession that there is no inventive concept in the specification." Id. at 343. The district court was unimpressed with this argument:

The patentee's unequivocal and binding admission in the written description that the recited detection methods are conventional ends the matter before me. . . . The idea that a patentee is bound by the words it uses in its patent—whether in the claims or elsewhere in the specification—is a fundamental tenet of the patent law. The PTO relies on the patent applicant's representations when it decides whether to issue a patent; and the patentee's words in the claims and written description put the public on notice of the scope of the claimed invention.

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It is of no moment that CareDx's representation that the recited techniques are conventional "appears in myriad patents." As a logical matter, the number of times a representation is made has no bearing on its truthfulness. But in any event, there is a reason why patentees frequently represent to the PTO that techniques recited in their patents are conventional. Section 112 of the Patent Act requires that the specification provide sufficient explanation of the claimed invention to enable an artisan of ordinary skill to make and use the invention. To avoid or overcome an objection by the PTO that the requested patent lacks adequate detail to satisfy § 112, patent applicants will often expressly represent that recited techniques are conventional. Having done that here, CareDx cannot now avoid the consequences that flow from its representation.

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Allowing CareDx to alter by extrinsic evidence the unambiguous public record it established with the claims and written description of the asserted patents would make Defendants' right to design around meaningless. It would also reward CareDx for being dishonest—either when it told the PTO that the recited techniques were conventional or when it insisted before this Court that they were not.

Id. at 343-47 (citations omitted).

Federal Circuit Ruling

On appeal, CareDx argued that the district court erred at both Steps 1 and 2 of Alice. As to Step 1, CareDx argued in part that "the patents' claimed advance is not the discovery of a natural correlation between organ rejection and the donor's cfDNA levels in the recipient's blood," but rather "improvement measurement methods spelled out in the claims as superior to the inadequate prior art measurement techniques." Slip op. at 11. Further, it contended, the district court erred by collapsing Step 1 into Step 2 based on its determination that the recited steps were conventional. Id. The U.S. Court of Appeals for the Federal Circuit rejected this argument, holding that it was appropriate to consider conventionality at Step 1:

CareDx also incorrectly characterizes our precedent as limiting the conventionality inquiry to step two. On the contrary, and as the district court recognized, we have repeatedly analyzed conventionality at step one as well. Indeed, we have explained that "the two stages are plainly related: not only do many of our opinions make clear that the two stages involve overlapping scrutiny of the content of the claims, but . . . there can be close questions about when the inquiry should proceed from the first stage to the second." As such, our precedent rejects CareDx's effort to draw a bright line between the two steps.

Slip op. at 16 (citations omitted).

Turning to Step 2, the Federal Circuit found no error in the district court's reliance on the specification's statements that the measurement techniques recited in the claims were routine in the prior art, observing that:

Each of the methods in the recited steps was already being performed by those in the art. Furthermore, the claimed combination of steps adds nothing inventive. The specification confirms that the claimed combination of steps—collecting a sample, genotyping, sequencing, and quantifying—was a straightforward, logical, and conventional method for detecting cfDNA previously used in other contexts, including cancer diagnostics and prenatal testing. Thus, the practice of the asserted method claims does not result in an inventive concept that transforms the natural phenomena into a patentable invention.

Id. at 18 (citations omitted). Accordingly, the court affirmed the judgment of invalidity.

Conclusion

An interesting procedural aspect of this case not addressed by the Federal Circuit was the district court's decision to 1) limit discovery to the Section 101 issue after it denied the defendants' motions to dismiss, and 2) convene an evidentiary hearing at which the parties' experts testified in connection with the defendants' motions for summary judgment. Citing a concurring opinion of Federal Circuit Judge Mayer, the district court explained that addressing Section 101 issues at the outset was an efficient way to conserve both judicial and party resources and "stem the tide of vexatious suits," 563 F. Supp. 3d at 338, although to be clear the district court did not find the suit at bar to be vexatious.

The case is CareDx, Inc. v. Natera, Inc., No. 2022-1027 (Fed. Cir. July 18, 2022), aff'g, 563 F. Supp. 3d 329 (D. Del. 2021).