United States: Fetal Diagnostics Patent Claims Fall In Inter Partes Review

Post grant inter partes review proceedings have lowered the hurdle to invalidate U.S. patents. The "broadest reasonable construction" of the claims and the lower burden to prove invalidity (by a preponderance of the evidence) of inter partes review proceedings have resulted in many successful challenges. Indeed, the Patent Trial and Appeal Board (PTAB) of the USPTO recently invalidated all challenged claims of a patent claiming methods to diagnose fetal abnormalities. In Ariosa Diagnostics v. The Board of Trustees of the Leland Stanford Junior University (IPR2013-00308) ("Decision") the PTAB invalidated 13 claims of U.S. Patent No. 8,296,076 entitled "Noninvasive Diagnosis of Fetal Aneuoploidy by Sequencing" ("the '076 Patent") assigned to the Board of Trustees of the Leland Stanford Junior University ("Stanford").

The '076 Patent

A chromosomal aneuploidy is a condition where the number of chromosomes in a cell is incorrect, because of either an extra chromosome or a missing chromosome. The discovery of cell-free nucleic acid in the bloodstream of pregnant women has led to the development of non-invasive prenatal tests for a variety of traits. However, the measurement of fetal chromosomal aneuploidy using prenatal diagnostics had remained a challenge because fetal DNA is often less than 10% of the total DNA in maternal cell-free plasma.

The '076 Patent teaches a method to overcome the challenges faced by prior prenatal diagnostics. As noted in the Decision, "[i]n a preferred method of the '076 patent, DNA is obtained from maternal serum, wherein the DNA is mixture of maternal and fetal DNA. The DNA is sequenced partially to provide a large number of short reads, which act as sequence tags with a significant number of the short reads being sufficiently unique such that they can be mapped to specific chromosomes or chromosomal locations of the human genome. By counting the number of sequence tags mapped to each chromosome, the over- and under-representation of any chromosome portion in the mixed DNA contributed by an aneuploidy fetus can be detected.... [t]he method does not rely on a priori sequence information to distinguish fetal DNA from maternal DNA." Decision on page 3, internal citations omitted.

The '076 Patent was filed in the USPTO on April 20, 2012 and claims priority to September 20, 2008. Fifteen claims issued on October 23, 2012. Claim 1 was the only independent claim. Certain key claim elements are bolded.

1. A method of testing for an abnormal distribution of a chromosome in a sample comprising a mixture of maternal and fetal DNA, comprising the steps of:

(a) obtaining maternal and fetal DNA from said sample;

(b) sequencing predefined subsequences of the maternal and fetal DNA to obtain a plurality of sequence tags aligning to the predefined subsequences, wherein said sequence tags are of sufficient length to be assigned to a specific predefined subsequence, wherein the predefined subsequences are from a plurality of different chromosomes, and wherein said plurality of different chromosomes comprise at least one first chromosome suspected of having an abnormal distribution in said sample and at least one second chromosome presumed to be normally distributed in said sample;

(c) assigning the plurality of sequence tags to their corresponding predetermined subsequences;

(d) determining a number of sequence tags aligning to the predetermined subsequences of said first chromosome and a number of sequence tags to the predetermined subsequences of the second chromosome; and

(e) comparing the numbers from step (d) to determine the presence or absence of an abnormal distribution of said first chromosome.

Ariosa's Grounds for Invalidity

Ariosa challenged 13 of the 15 total issued claims of the '076 Patent. Claims 1-5, 7-9, 12 and 13 were alleged to be anticipated under 35 U.S.C. § 102(e) by U.S. Patent Publication No. 2009/0029377, entitled "Diagnosing Fetal Chromosomal Aneuploidy Using Massively Parallel Genomic Sequencing" filed in the name of inventors Lo et al. ("Lo et al."). Claims 10 and 11 were challenged as being obvious in view of Lo et al. and U.S. Patent Publication No. 2006/0177832. Claims 1-5 and 7-13 were challenged under 35 U.S.C. § 103 for being obvious in view of the combined teachings of U.S. Patent Publication Nos. 2007/0202525 and 2008/0138809. Claim 6 was alleged to be obvious in view of a combination of the above noted patent publications along with Li et al. "Mapping Short DNA Sequencing Reads and Calling Variants Using Mapping Quality Scores. 18 Genome Research 1851-1858 (2008).

Claim Construction of Key Terms

The claims in an inter partes review are interpreted according to their broadest reasonable construction in light of the specification of the patent in which they appear. Decision on page 7. The PTAB broadly construed the claim terms "sequencing predefined subsequences" and "predetermined sequences" which in turn supported a finding of anticipation and obviousness over the cited art.

"sequencing predefined subsequences"

This claim term was construed by the PTAB broadly, therefore including any sequencing method, e.g. shotgun sequencing and hybridization. Stanford argued against this construction, alleging that the methods are limited to targeted sequencing, i.e., only predetermined sequences are actually sequenced. The PTAB disagreed, noting that the term "targeted sequencing" was not recited in the '076 Patent and that the specification disclosed various methods to perform the method steps, including shotgun sequencing. The PTAB also stated that the '076 Patent specification did not limit its teachings to sequencing only the predefined sequences, but rather "discloses sequencing the predefined sequences along with other sequences, and then using various techniques to locate the predefined sequences in the material that has been sequenced." Decision on page 11.

"predetermined subsequences"

The term "predetermined subsequences" was previously construed as "reference sequence information" in the PTAB's decision to grant inter partes review. Decision on page 13. Stanford disagreed, alleging that the term describes "subsequences of said first chromosome" and "subsequences of the second chromosome" and are therefore representative of information that represents less than all of the chromosome. Decision on page 13.

The PTAB found that because step (d) of claim 1 recites "determining a number of sequence tags aligning to the predetermined subsequence of said first chromosome and a number of sequence tags to the predetermined subsequence of the second chromosome", adoption of Stanford's interpretation would read the limitation out of the claim. Thus, the term was construed to be less than the entire chromosome sequence, but two or more predetermined subsequences may include the entire length of the chromosome sequence.

"polymorphism-independent"

Stanford also requested that the claims of the '076 Patent be construed "as being directed to polymorphism-independent methods of detecting fetal aneuploidy." Decision on page 14. While the patent's specification made repeated reference to the fact that the invention is polymorphism-independent, the PTAB noted that Stanford did not point to any claim language that was consistent with this interpretation. Thus, under the "broadest reasonable construction" standard, the claims were interpreted to encompass methods of testing for both polymorphism-dependent and independent abnormal distributions of a chromosome. Decision on page 15.

Anticipation by Lo et al.

The PTAB interpreted Lo et al. as teaching a method of testing for an abnormal distribution of a fetal chromosome, using genetic material obtained from maternal blood, and those fragments of fetal DNA being sequenced using sequence tags and aligning the tagged sequences to each chromosome. After comparison of the fetal DNA to a reference chromosome, chromosomal gains or losses can be identified. Decision on page 20.

Ariosa contended that with the construction of the claims to include shotgun sequencing, claims 1-5, 7-9, 12 and 13 were anticipated by Lo et al. The PTAB agreed, finding all elements of the construed claims as disclosed in Lo et al. and disagreed with Stanford's argument that the reference did not describe methods using predefined subsequences. Decision on page 23.

Obviousness by Combination of Cited Art

Having determined that most of the claims were anticipated by Lo et al., the PTAB turned to the contentions of obviousness over a combination of references. Interestingly, Stanford presented no evidence or argument to counter Ariosa's allegations that claims 10 and 11 were obvious in view of the combined teachings of Lo et al. and U.S. Patent Publication No. U.S. 2006/0177832. Thus, under a preponderance of the evidence standard, the claims were held as obvious and invalid over the combined teachings of the references.

Claims 1-5 and 7-13 were alleged to be obvious over the combined teachings of U.S. Patent Publication Nos. 2007/0202525 and 2008/0138809. Here, the PTAB agreed with Stanford's defense, i.e., that one of skill in the art would not have combined the references to arrive at the inventions of claim 1-5 and 7-13.

Finally, claim 6 was challenged as allegedly obvious over two alleged combinations of the prior art. The first challenge was over a combination of Lo et al. and Li et al. (Genome Research) and the second over a combination of U.S. Patent Publication Nos: 2007/020525 and 2008/0138809; and Li et al. As no defense was offered by Stanford against the combination of Lo et al. and Li et al., the claim was found invalid as obvious over the combined teachings. For the second challenge, the PTAB found that the combined teachings did not render the claim obvious because it would not be obvious to one of skill in the art to combine the alleged teachings of the cited art.

The Importance of Precise Claiming

The new USPTO inter partes review proceedings provides patent challengers with a cost-effective forum for challenging the validity of any U.S. patent for lack of novelty (35 U.S.C. § 102) or being obvious (35 U.S.C. § 103) in view of printed publications or patent documents. The "preponderance of the evidence" standard is applied in inter partes review, which is a lower burden than the higher "clear and convincing evidence" standard applied in civil actions such as patent infringement cases. Also, and as shown in this decision, the PTAB's construction of patent claims is likely to be broader than in district court, and therefore, the construed claims are more likely to read on prior art. Thus patentees are advised to claim all embodiments of an invention and to clearly articulate an invention's distinctive features in the claims.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

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