Patents Invalidated for Measuring cfDNA to Detect Transplanted Organ Rejection | Insights – Holland & Knight | Candle Made Easy

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 — known as cell-free DNA (cfDNA) — can be distinguished from the recipient’s own DNA, since the donor’s DNA will always have certain differences that can be identified. Early detection of transplant organ rejection can guide treatment to improve the process.

background

CareDx is the exclusive licensee of three patents related to this technology. In short, all claimed methods of detecting incipient rejection or measuring the amount of donor cfDNA using techniques that the joint patent specifications have identified as conventional, such as multiplex sequencing or amplification using polymerase chain reaction (PCR) . An example patent claim read as follows:

1. A method for detecting transplant rejection, transplant 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 create a polymorphism profile for the detection of 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 cell-free donor nucleic acids and cell-free subject nucleic acids; and

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

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

Judgment of the District Court

In a joint proceeding in the District of Delaware against accused infringers Natera and Eurofins Viracor, the district court denied the defendants’ motions to dismiss under Section 101, but stayed the proceeding, except for limited disclosure, to determine whether the matter was amenable to resolution under Section 101 summary judgment. The district court took a somewhat unusual approach and conducted an evidentiary hearing, at which the parties’ competing experts testified to determine whether there were actual issues of fact that would preclude a summary judgment being issued. CareDx, Inc. vs. Natera, Inc., 563 F.Supp. 3d 329, 338-39 (D. Del. 2021). After hearing the experts, the regional court declared the nullity in summary proceedings.

In its statement, the district court was very critical of CareDx because it had argued Alice Step 2 that the measurement and quantification techniques cited in the claims were not conventional, although they were described as “routine and conventional” in the joint description of the patents. Because such a statement “appears verbatim in countless patents and patent applications covering various technologies,” according to CareDx, it should not “be construed as some sort of purported voluntary admission that the specification lacks an inventive concept.” ID. at 343. The district court was unimpressed by this argument:

The patent proprietor’s unequivocal and binding admission in the written description that the cited detection methods are conventional ends the matter before me. . . . The idea that a patentee is bound by the words he uses in his patent – whether in the claims or elsewhere in the description – is a fundamental tenet of patent law. The PTO relies on the representations of the patent applicant when deciding whether to grant a patent; and the patentee’s words in the claims and written description are to alert the public to the scope of the claimed invention.

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It doesn’t matter that CareDx’s representation that the cited techniques are conventional “appears in countless patents.” Logically, the frequency with which an account is made has no bearing on its veracity. But in any case, there is a reason why patentees often present to the PTO that the techniques cited in their patents are conventional. Section 112 of the Patents Act requires that the description sufficiently explain the claimed invention to enable a person of ordinary skill in the art to make and use the invention. To avoid or overcome a Patent Office objection that the patent being applied for is not sufficiently detailed to satisfy Section 112, patent applicants will often expressly state that the techniques cited are conventional. Having done so, CareDx can now no longer escape the consequences of its exposure.

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Allowing CareDx to alter the clear public record it created containing the claims and written description of the asserted patents with external evidence would render the defendants’ right to remodel meaningless. It would also reward CareDx for being dishonest – either when it told the PTO that the techniques put forward were conventional or when it insisted in this court that this was not the case.

ID. at 343-47 (citations omitted).

Federal district decision

On appeal, CareDx argued that the district court erred on both Step 1 and Step 2 Alice. Regarding Step 1, CareDx argued in part that “the advance claimed by the patents is not the discovery of a natural correlation between organ rejection and the donor’s cfDNA levels in the recipient’s blood,” but rather “measurements to improve upon the claims.” at 11. He further contended that the district court erred in consolidating step 1 into step 2, based on its finding that the steps listed were conventional be. ID. The U.S. Court of Appeals for the Federal Circuit rejected this argument, ruling that it was appropriate to consider conventionality in Step 1:

CareDx also incorrectly characterizes our precedent as restricting the conventionality investigation to step two. On the contrary, and as the district court acknowledges, we have repeatedly analyzed the conventionality in step one. In fact, we have stated that “the two phases are clearly linked: many of our submissions make it clear not only that the two phases involve an overlapping examination of the content of the claims, but … there may be narrow questions as to when the examination takes place should move from the first stage to the second.” Therefore, our precedent dismisses CareDx’s efforts to draw a clear line between the two steps.

Slip op. at 16 (quotes omitted).

In Step 2, the Federal Circuit found that the district court did not rely on the statements in the specification that the measurement techniques cited in the claims were routine in the art, and found that:

Each of the procedures in the listed steps has already been performed by professionals. Furthermore, the claimed combination of steps adds nothing new. The specification confirms that the claimed combination of steps—collection of a sample, genotyping, sequencing, and quantification—was a straightforward, logical, and conventional method for detecting cfDNA previously used in other contexts, including cancer diagnostics and prenatal testing. Thus, the exercise of the asserted method claims does not lead to an inventive concept that transforms the natural phenomena into a patentable invention.

ID. at 18 (quotes omitted). Accordingly, the court upheld the nullity judgment.

Conclusion

An interesting procedural aspect of this case not addressed by the federal court was the district court’s decision to 1) limit the hearing to the Section 101 matter after denying the defendants’ motions to dismiss, and 2) convene an evidentiary hearing, at which the parties gave expert testimony in connection with the defendants’ motions for summary judgment. Citing a consistent opinion from federal judge Mayer, the district court held that addressing Section 101 issues from the outset was an efficient way to conserve both judicial and partisan resources and “to stem the tide of harassment,” 563 F. Supp . 3d at 338, although, to be clear, the district court did not find the lawsuit in the bar annoying.

The case is CareDx, Inc. vs. Natera, Inc.Nos. 2022-1027 (Federal Circ. July 18, 2022), aff’g, 563 F.Supp. 3d 329 (D. Del. 2021).

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