While Sequenom’s appeal of the district court’s summary judgment of invalidity of U.S. Patent 6,258,540 under 35 USC § 101 has been pending at the Federal Circuit, the USPTO has been considering the validity of the patent under 35 USC §§ 102 and 103 in an Inter Partes Review proceeding. Now that the decision of the Patent Trial and Appeal Board also is on appeal at the Federal Circuit, will the court wait even longer to decide the patent eligibility issues?

The Patent At Issue

The Sequenom patent at issue is U.S. Patent 6,258,540. Claim 1 recites:

A method for detecting a paternally inherited nucleic acid of fetal origin performed on a maternal serum or plasma sample from a pregnant female, which method comprises amplifying a paternally inherited nucleic acid from the serum or plasma sample and detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample.

The district court held the claims invalid for lack of subject matter eligibility under § 101. The Federal Circuit heard oral arguments in that appeal on November 7, 2014. 

The IPR Proceeding

Ariosa filed two IPR petitions challenging the validity of the ‘540 patent under §§ 102 and 103. The USPTO’s Patent Trial and Appeal Board (PTAB) determined that claims 1, 2, 4, 5, 8, 19, 20, 24, and 25 are invalid as anticipated by Kazakov et al., “Extracellular DNA in the Blood of Pregnant Women,” Cytology (Tsitologia) 37(3): 232–36 (1995), but that Ariosa had not shown by a preponderance of the evidence that claims 3, 12, 13, 15, 18, 21, and 22 are unpatentable.

The PTAB gave the following “broadest reasonable interpretation” to claim 1:

Claim 1 comprises two steps, an amplification step, and a detecting step, wherein a paternally inherited nucleic acid is amplified, and its presence is detected. In the Decision to Institute, we construed the amplification step as including “a step of amplifying nucleic acid from a serum or plasma sample from a pregnant female, such as by PCR. The amplified nucleic acid would necessarily include fetal nucleic acid, and the fetal nucleic acid necessarily includes paternally inherited nucleic acid.” Dec. Institute, 7–8. …. We then interpreted the “detecting” step of claim 1 as not requiring that the nucleic acid specifically is identified as being inherited from the father or even as being from the fetus, only that it be identified as containing some level of nucleic acid.

How can the step of “detecting the presence of a paternally inherited nucleic acid of fetal origin” be met without identifying the nucleic acid as paternally inherited nucleic acid of fetal origin? In Aria Diagnostics, Inc. v. Sequenom, Inc., the Federal Circuit reversed the district court’s claim construction that required the nucleic acid to be “known in advance” to be of paternal origin, but did not indicate that the claims do not require the nucleic acid’s paternal origins to be ascertained at some point. The PTAB’s claim construction seems to re-write the claim language as “detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample.” That may be a “broadest” interpretation, but is it “reasonable”?

The PTAB found that Kazakov anticipated claim 1:

Kazakov discloses the same method of claim 1. That is, as discussed above in the section on claim construction, all that is required by the amplification step of claim 1 is a step of amplifying nucleic acid from a serum or plasma sample from a pregnant female, such as by PCR, as such amplified nucleic acid would necessarily include fetal nucleic acid, and the fetal nucleic acid necessarily includes paternally inherited nucleic acid. Moreover, as also discussed above, the detecting step does not require that the detected nucleic acid specifically be identified as being inherited from the father or even as being from the fetus, only that it be identified as containing some level of nucleic acid, which would include, necessarily, nucleic acid from the fetus that was inherited from the father. Here, Kazakov performs both of those steps: That is, DNA from the serum of
pregnant women is amplified using PCR, and the amplified DNA is detected using gel electrophoresis, as demonstrated by Figures 1 and 2 of Kazakov.

That is, the PTAB found that because Kazakov “amplified the DNA in serum that was obtained from pregnant women in their first and third trimesters of pregnancy,” Kazakov anticipated the method of claim 1 because it’s methods inherently amplified paternally inherited nucleic acids that were present in the samples and inherently detected the presence of those paternally inherited nucleic acids, even though it never identified any nucleic acids as being paternally inherited fetal DNA.

Ariosa appealed the PTAB decision that upheld claims 3, 12, 13, 15, 18, 21, and 22, while  Sequenom cross-appealed the PTAB decision that invalidated claims 1, 2, 4, 5, 8, 19, 20, 24, and 25.

The Eligibility Issue 

If the Federal Circuit affirms the PTAB decision, it may have to re-focus its § 101 analysis on the remaining claims. Several of the remaining claims are set forth below.

(Claims presented in italics were invalidated but are presented for reference in the context of dependent claims that were not invalidated.) 

[2. The method according to claim 1, wherein the foetal nucleic acid is amplified by the polymerase chain reaction.]

3. The method according to claim 2, wherein at least one foetal sequence specific oligonucleotide primer is used in the amplification.

[5. The method according to claim 1, wherein the presence of a foetal nucleic acid sequence from the Y chromosome is detected.] 

6. The method according to claim 5, wherein the Y chromosome sequence is from the DYS14 locus.

7. The method according to claim 5, wherein the Y chromosome sequence is from the SRY gene.

[8. The method according to claim 1, wherein the presence of a foetal nucleic acid from a paternally-inherited non-Y chromosome is detected.]

9. The method according to claim 8, wherein the non-Y sequence is a blood group antigen gene.

10. The method according to claim 8, wherein the non-Y sequence is a gene which confers a disease phenotype in the foetus.

13. The method according to claim 5, which comprises determining the concentration of the foetal nucleic acid sequence in the maternal serum or plasma.

14. The method according to claim 13, wherein the determination of the concentration of foetal nucleic acid sequence in the maternal serum or plasma is by quantitative PCR.

While the dependent claims are more specific than independent claim 1, many seem to raise similar eligibility issues in that they either recite detecting naturally-occurring nucleic acids or using conventional techniques to do so. Thus, a Federal Circuit decision on their eligibility could provide useful guidance for the diagnostic and personalized medicine industries that have been waiting for the Sequenom decision.