By Paul Cole* --
The June 12, 2015 decision of the Federal Circuit in the above case has been discussed by Kevin Noonan in his posting of 22 June, but it is believed that the factual and legal background could benefit from further discussion.
It is convenient to consider claims 1 and 2 of US Patent No. 6,258,540 together since PCR is the technique exemplified and both claims 1 and 2 were held not to be patent eligible.
The kernel of the opinion of Judge Reyna is contained in the two passages set out below:
It is undisputed that the existence of cffDNA in maternal blood is a natural phenomenon. Sequenom does not contend that Drs. Lo and Wainscoat created or altered any of the genetic information encoded in the cffDNA, and it is undisputed that the location of the nucleic acids existed in nature before Drs. Lo and Wainscoat found them. The method ends with paternally inherited cffDNA, which is also a natural phenomenon. The method therefore begins and ends with a natural phenomenon. Thus, the claims are directed to matter that is naturally occurring.
Like the patentee in Mayo, Sequenom contends that the claimed methods are patent eligible applications of a natural phenomenon, specifically a method for detecting paternally inherited cffDNA. Using methods like PCR to amplify and detect cffDNA was well-understood, routine, and conventional activity in 1997. The method at issue here amounts to a general instruction to doctors to apply routine, conventional techniques when seeking to detect cffDNA. Because the method steps were well-understood, conventional and routine, the method of detecting paternally inherited cffDNA is not new and useful.
It is useful to consider the steps of the claimed method against these statements to determine the extent to which they can legitimately be held to fall within the natural phenomenon exclusion. Detail in addition to the express wording of the claim is believed to indicate what would be implicit to a skilled reader.
The first step requires the use of a maternal serum or plasma sample from a pregnant female. In Example 1, 10μl of centrifuged and heated plasma or serum are placed into a 0.5 ml Eppendorf tube. While the presence of cffDNA in the maternal serum or plasma is a natural phenomenon, the decision to make use of the serum or plasma sample for amplification and detection is arguably a step towards an application of that phenomenon.
The second step involves addition of pair of primers to the blood or serum sample. In Example 1 of the patent in issue these are Y1.7 andY1.8 which are specific for the Y-chromosome which is passed only from father to son and determines the sex of the fetus. Those primers enable amplification of a sequence of the Y-chromosome of length 198 base pairs. The experimental details in Example 1 are less than complete, but comparison with Example 2 shows that ~300 nM of each amplification probe would have been added and 200μM each of dATP, dCTP, dGTP and dUTP to provide the monomeric nucleotides needed for polymerisation, together with polymerization enzyme and incidental materials. The serum or plasma samples were then subjected to 60 cycles of polymerase chain reaction in a PCR machine, 30-40 cycles being generally regarded as sufficient for the reaction to go to completion. As explained at page 3 of the slip opinion, amplifying cffDNA results in a single copy, or a few copies, of a piece of cffDNA being exponentially multiplied across several orders of magnitude, generating thousands to millions of copies of that particular DNA sequence to reach detectable levels. If a sample originally contains one or more parentally-derived Y-chromosomes, then after amplification thousands or millions of copies of the selected 198 bp short sequence are present in it.
The product of the second step could therefore most appropriately be described as a composition of matter which is for that reason inherently within the realm of patent-eligibility, said composition comprising the blood or serum of the sample, the naturally occurring cffDNA, thousands to millions of copies of the the Y-chromosome short sequence and residual primer, nucleotides, enzyme and other starting materials. Even if concentration is focused on the short sequences to the exclusion of other relevant process and composition of matter features, the short sequence copies are a wholly artificial creation, being the result of the synthetic chain reaction and to describe them as a natural product gives rise to an error, on the figures of the slip opinion, of 103-106 which is on any view an exuberant margin. They have new utility compared to the original blood or serum sample insofar as they are present at levels that are detectable in subsequent test procedures whereas the original cffDNA is not.
Furthermore in equating the selected and amplified short sequences with a natural product, the Court is implicitly disregarding long-established precedents such as Parke-Davis & Co. v. H. K. Mulford Co (adrenalin), Kuehmsted v. Farbenfabriken of Elberfeld Co. (aspirin) and Merck & Co. v. Olin Mathieson Chemical Corp (Vitamin B12) which show that an isolated or purified natural product having new utility is patent-eligible. By the same logic, the amplified short sequences are a new and different product having new utility in that they have been brought to detectable levels and cannot be equated simply with the corresponding region of the Y-chromosome as a natural product.
The third step involves detecting the presence of the paternally inherited nucleic acid, and although specified at a high degree of generality is not unduly broad having regard to the range of tests that can be performed. In Example 1, the mere presence of a Y-positive signal distinguishes a male fetus from a female fetus. In Example 2, quantitative PCR is used as a screening marker for aneupoloid pregnancies e.g. Downs syndrome, Example 3 describes tests for RhD, Example 4 describes tests for pre-eclampsia and Example 5 provides data showing the very high concentration of fetal DNA in serum or plasma compared to the cellular fraction of maternal blood.
Prometheus requires the claim to be considered not merely as an isolated aggregation of features but as an ordered combination. If that is done, the new result emerges of a test of high sensitivity for a range of medical conditions that can be applied early in pregnancy and avoiding the risks to the fetus inherent in amniocentesis and that starts from a new and hitherto overlooked starting material and that, in the words of Judge Reyna "revolutionised medical care." The question in Prometheus was whether the described processes added enough, and it is submitted that the benefits achieved should not have been dismissed as adding nothing of significance.
The proposition that because the method steps were well-understood, conventional and routine, the method of detecting paternally inherited cffDNA is not new and useful verges on the incomprehensible. Essentially the same claim was examined by the EPO Appeal Board T 0146/07 ISIS/Prenatal diagnosis. The closest prior art was a paper from one of the inventors, Dr Lo. That paper describes a method for the detection of foetal RhD sequences in peripheral blood of sensitized RhD-negative pregnant women. In the earlier method described, antecubital venous blood was collected from pregnant women and DNA was extracted from the buffy coat fraction, i.e., peripheral blood mononuclear cells (PBMC) isolated from maternal peripheral blood. Foetal RhD sequences were detected by PCR using specific primers. The method therefore differed from that now claimed in that the presence of nucleic acid of foetal origin was detected in buffy coat cells rather than in maternal serum or plasma. As explained in the patent in issue, it was surprisingly found that foetal DNA is enriched in maternal plasma or serum compared to the amount present in the cellular fraction. The Opposition Division found that a skilled person starting from the cited document and confronted with the problem of providing a more sensitive method for detecting foetal blood cells would not have derived the solution claimed. In affirming this finding, the Appeal Board held that even of the technical problem were reformulated to the lesser task of finding an alternative source of foetal nucleic acid a skilled person starting from Dr Lo's paper would not have been motivated to consider serum or plasma samples. Lack of industrial applicability was not a ground of opposition, but nevertheless it is disturbing that subject matter held inventive by the EPO should be summarily dismissed as ineligible in the U.S. under §101.
The steps quoted from the Prometheus opinion recur in Alice and to that extent may reflect a settled view within the Supreme Court. However, it is submitted that it is inappropriate to select specific passages from these opinions without taking into account the caution with which they were originally expressed, and the warning at the end of the Prometheus opinion that a new protective rule that seems to suit the needs of one field might produce unforeseen results in another. It is difficult to avoid the conclusion that in Ariosa the Court is extending the second part of the two-part Prometheus test beyond the original intention of the Supreme Court and has fallen into the trap of making its findings of fact to fit the earlier opinions on which it wished to rely, rather than straightforwardly finding the objective facts and then applying the appropriate jurisprudence to them.
* Mr. Cole is a European Patent Attorney and Partner with Lucas & Co. in Warlingham, Surrey, UK and Professor of IP Law at Bournemouth University.