Exploiting the diagnostic value of fetal DNA proves well-conceived
Sequenom, Inc. v Ariosa Diagnostics, Inc.  FCA 1011
(27 June 2019)
Patents –invalidity – discovery of naturally occurring phenomenon – claims for methods of applying that discovery – whether method of manufacture – whether inventive step
The applicant (Sequenom) is the patentee of an invention consisting of a method for “non-invasive prenatal diagnosis” (“NIPD”). The respondents (collectively, Ariosa) are the providers or Australian licensees of a “non-invasive prenatal diagnosis test” marketed as the “Harmony test”. Sequenom alleged that Ariosa infringed a number of the claims of the patent in suit, and Ariosa cross-claimed with the usual suite of grounds for revocation. For the reasons discussed below, Sequenom was successful in respect of its infringement claims for all but one of the patent claims, in respect of which Ariosa was successful in making out a lack of fair basis.
The patent in suit claims a priority date of 4 March 1997. As at that date, various screening techniques had been developed to diagnose the likelihood that an unborn fetus might have, for example, a genetic disorder (such as Down syndrome) or have a particular sex (and so be at risk for certain sex-linked disorders). Many of these techniques are “invasive” in the sense that they require a direct sample of DNA be taken from the fetus. These techniques posed a risk to the mother and the pregnancy. Further, the standard test at the time could only be administered after the first trimester and was only 50 percent accurate. Although work had started on a test that could be administered during the first trimester, it also was less than 100 percent accurate and could yield false positives.
As at the priority date, the potential for NIPD had been recognised, following the discovery that whole fetal cells could be found in maternal blood. The analysis of fetal DNA present in such cells would allow diagnosis of fetal conditions without risk to the fetus or mother. Accordingly, research was focused on detecting and isolating fetal cells among the cellular component of maternal blood, being the white blood cells, red blood cells and platelets. The challenge at the priority date was separating fetal cells from the vastly more numerous maternal cells in a maternal blood sample, and verifying that isolated cells were actually fetal cells.
At the time, the remaining “cell free” component of maternal blood, called “plasma”, or if certain clotting factors had been removed, “serum”, routinely was discarded as a waste product. One of the inventors named in the patent in suit discovered, however, that “cell free” fetal DNA (“cffDNA”) was detectable in maternal plasma/serum samples and at higher levels than had been observed for fetal cells in maternal blood.
The method described in the claim 1 of the patent is said to exploit this previously unknown property of a maternal plasma/serum sample for NIPD by providing for:
A detection method performed on a maternal serum or plasma sample from a pregnant female, which method comprises detecting the presence of a nucleic acid of foetal origin in the sample.
The bulk of the remaining claims are dependent claims that elaborate on claim 1 by specifying additional steps to isolate greater amounts of fetal DNA, the use of particular detection techniques, and adding a focus on the presence of Y chromosomes for the purposes of determining the sex of the fetus. The patent also includes independent claims, notably claim 26 for:
A method of performing a prenatal diagnosis on a maternal blood sample, which method comprises obtaining a non-cellular fraction of the blood sample and performing nucleic acid analysis on the fraction.”
The patent also gave five examples of how the invention could be applied but which did not in any way limit the scope of the invention. These included analyses of fetal DNA to determine sex, detect certain genetic or chromosomal abnormalities, and to identify potential pre-eclampsia in a pregnant woman.
On Ariosa’s revocation cross-claim, the threshold issue was whether the application of a naturally occurring phenomenon (namely the presence of usefully detectable amounts of fetal DNA in maternal plasma/serum samples) amounted to a method of manufacture. Previously, claims to isolated DNA or a naturally occurring gene were considered to be outside the “established boundaries of what is patentable”, such that “other considerations come into play”: D’Arcy v Myriad Genetics Inc (2015) 258 CLR 334 (“Myriad”). In Myriad, the claims in question failed as they sought, in effect, a monopoly over the use of long-accepted methods to isolate a naturally occurring gene; the presence or absence of the gene was a matter of chance, and not an “artificially created state of affairs”. In the present case, however, Justice Beach noted that the relevant claims were method claims, and in particular “a method by which the discovery of the existence of cffDNA can be put to practical use.”. In other words, the invention claimed a monopoly over certain uses of a naturally occurring phenomenon, rather than the information comprised in the phenomenon itself, and was analogous to a claim for a previously unknown method of treatment using a known product. Prima facie the relevant claims therefore fell within the established concept of “method of manufacture” as set out in National Research Development Corporation v Commissioner of Patents (1959) 102 CLR 252 and affirmed in Myriad.
His Honour noted at  that:
A claimed process that results in a new and useful effect, so that the new result is an artificially created state of affairs providing economic utility, may be considered a manner of manufacture in the vast majority of cases.
The presence of cffDNA cannot be detected without human action; that detection therefore results in “an artificially created state of affairs discernible by an observer”. Further, the invention was of obvious economic significance and achieved a significant advantage over the existing state of affairs at the priority date. His Honour concluded that the invention was clearly patentable.
On the question of inventive step and obviousness, Ariosa relied upon a 1995 paper describing an investigation in changes in concentration in extracellular DNA in maternal blood. There were some obstacles to that paper being considered part of the prior art base, however. It was published in an obscure Russian language journal (although an English abstract was later published and indexed in medical literature databases), there was no evidence that the journal was peer-reviewed, and the paper contained internal inconsistencies. Further, a hypothetical skilled addressee would have trouble accessing the paper: finding the English language abstract would require using “peculiar search terms”, and the full paper would then need to be sourced (from “an unspecified library”) and translated. Finally, the purpose of the investigation described in the paper was not to test for the presence of extracellular DNA of a fetus, as opposed to the pregnant mother (and the paper did not suggest that fetal DNA was detectable). The expert evidence of actual cffDNA researchers showed that none of them had encountered the paper at the priority date, and others could not even find the paper when conducting more recent, targeted searches for literature on fetal DNA. His Honour also concluded that a person skilled in the art who did manage to access the paper would not have considered it to be relevant or useful, nor would they have been directly led to follow a course that would have resulted in them trying to detect cffDNA in maternal plasma/serum (bearing in mind that at the priority date, the skilled person would not have had a reasonable expectation of success). Accordingly, Ariosa’s attack on inventive step failed.
Ariosa’s attack on the grounds of inutility, false suggestion and lack of sufficiency similarly were unsuccessful. As to the latter, his Honour concluded at  that “the Patent provides sufficient information to enable a skilled person to produce something within each of the relevant claims without new inventions or additions, or prolonged study of matters presenting additional difficulty.” And although it did appear that certain of the specific applications of the invention in claim 1 might not have been feasible at the priority date in light of the state of technology at the time, the relevant claims were not pressed, and a “person skilled in the art could perform something falling within the scope of each of the relevant claims in any event.”
Only claim 26 fell foul of Ariosa’s attack on internal fair basis. In contrast to claim 1 and its dependent claims, the use of the phrase “prenatal diagnosis” in claim 26 went beyond the detection method invention described in the body of the specification. The other claims otherwise were held to be supported adequately by references in the specification.
With Ariosa’s cross-claim for revocation being almost entirely unsuccessful, Sequenom’s infringement claims were relatively straightforward (at least to those with an intimate understanding of the science involved!).