Patents on Measuring cfDNA to Detect Rejection of Invalid Transplanted Organs | Holland & Knight LLP

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

Background

CareDx is the exclusive holder of three patents relating to this technique. In short, all claimed methods of detecting incipient rejection or measuring the amount of donor cfDNA using techniques declared conventional in the common patent specifications, such as multiplex sequencing or amplification by chain reaction by polymerase (PCR). An example of a patent claim reads as follows:

1. A method of 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 donor-specific polymorphisms genotype or a subject-specific polymorphisms genotype. . . establish a polymorphism profile to detect 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 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 acidic subject cells free nucleic acids by multiplexed sequencing, an increase in the amount of donor cell-free nucleic acids over time indicating graft rejection, graft dysfunction, or organ failure. . . .

US Patent No. 8,703,652.

District court decision

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

In his view, the district court sharply criticized CareDx for arguing to Alice Step 2 that the measurement and quantification techniques set out in the claims were unconventional even though the common patent specification called them “routine and conventional”. According to CareDx, because such a statement “appears verbatim in a myriad of patents and patent applications covering different technologies”, it should not be understood “as some sort of assumed voluntary admission that there is no of inventive concept in the specification”. Identifier. at 343. The District Court was unimpressed with this argument:

The patentee’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 specification, is a fundamental principle of patent law. The PTO relies on representations from the patent applicant when deciding whether to grant a patent; and the patentee’s words in the claims and written description inform the public of the scope of the claimed invention.

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It is immaterial that CareDx’s representation that the cited techniques are conventional “appears in a myriad of patents”. Logically, the number of times a representation is made has no bearing on its veracity. But in any event, there is a reason why patent holders frequently tell the PTO that the techniques set forth 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 a PTO objection that the applied patent lacks sufficient detail to satisfy § 112, patent applicants will often expressly state that the cited techniques are conventional. Having done this here, CareDx can no longer avoid the consequences that flow from its representation.

* * *

Allowing CareDx to alter by extrinsic evidence the unambiguous public record it has established with the claims and written description of the claimed patents would render the defendants’ right to design around meaningless. It would also reward CareDx for its dishonesty, either when it told the PTO that the cited techniques were conventional or when it insisted in court that they were not.

ID. at 343-47 (citations omitted).

Federal Circuit Decision

On appeal, CareDx argued that the District Court erred in Steps 1 and 2 of Alice. Regarding Stage 1, CareDx argued in part that “the advance claimed by the patents is not the discovery of a natural correlation between organ rejection and donor cfDNA levels in the recipient’s blood”, but rather “the improvement of the measurement methods set forth in the claims as superior to the inadequate measurement techniques of the prior art.” Slip-op. at 11. Further, he argued, the District Court erred in merging Step 1 into Step 2 based on its determination that the stated steps were conventional. Identifier. The United States Court of Appeals for the Federal Circuit rejected this argument, holding that it was appropriate to consider conventionality at Stage 1:

CareDx also incorrectly characterizes our precedent as limiting the conventionality survey to the second stage. On the contrary, and as the District Court recognized, we also repeatedly analyzed conventionality at the first stage. Indeed, we explained that “the two stages are clearly linked: not only do many of our opinions make it clear that the two stages involve a cross-examination of the content of the claims, but … there may be narrow questions about the when the investigation should move from the first stage to the second.” As such, our precedent rejects CareDx’s efforts to draw a clear line between the two stages.

Slip-op. at 16 (quotations omitted).

Proceeding to Step 2, the Federal Circuit found no error in the District Court’s reliance on statements in the specification that the measurement techniques set forth in the claims were common in the prior art, observing that :

Each of the processes in the cited steps was already carried out by those skilled in the art. Moreover, the claimed combination of steps does not provide anything inventive. The specification confirms that the claimed combination of steps – collection of a sample, genotyping, sequencing and quantification – was a simple, logical and conventional method for detecting cfDNA previously used in other contexts, including cancer diagnosis and prenatal tests. Thus, practice of the claimed method claims does not result in an inventive concept that transforms natural phenomena into a patentable invention.

ID. at 18 (quotations omitted). Consequently, the court upheld the judgment of invalidity.

Conclusion

An interesting procedural aspect of this case that was not addressed by the Federal Circuit was the District Court’s decision to 1) limit discovery to the Section 101 issue after denying defendants’ motions to dismiss, and 2) convene an evidentiary hearing at which the expert parties testified in connection with the defendants’ motions for summary judgment. Citing a concurring opinion from federal circuit judge Mayer, the district court explained that dealing with Section 101 issues from the outset was an effective way to conserve judicial and party resources and “stem the tide of vexatious prosecution”, 563 F. Supp. 3d at 338, although to be clear the district court did not find the prosecution to be vexatious.

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

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