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Quake v. Lo

United States Court of Appeals, Federal Circuit

July 10, 2019


          Appeals from the United States Patent and Trademark Office, Patent Trial and Appeal Board in Nos. 105, 920, 105, 923, 105, 924.

          Edward R. Reines, Weil, Gotshal & Manges LLP, Redwood Shores, CA, argued for appellants. Also represented by Derek C. Walter.

          Charles E. Lipsey, Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, Reston, VA, argued for appellees. Also represented by Steven O'Connor; Jeffrey Daniel Smyth, Palo Alto, CA; Michele C. Bosch, Washington, DC.

          Before Reyna, Chen, and Hughes, Circuit Judges.

          Chen, Circuit Judge.

         This appeal arises from a decision of the U.S. Patent and Trademark Office Patent Trial and Appeal Board (Board) finding the four claims of Dr. Stephen Quake and Dr. Christina Fan's (collectively, Quake) U.S. Patent No. 8, 008, 018 and Claim 25 of their U.S. Patent Application No. 12/393, 833 unpatentable for lack of written description under 35 U.S.C. § 112 as part of three interference proceedings.

         The claims cover a method of determining the presence of a chromosomal abnormality (called aneuploidy) in fetuses by using massively parallel sequencing (MPS) technology to sequence deoxyribonucleic acid (DNA) fragments from a sample of the mother's blood that contains both maternal and fetal DNA, identifying what chromosomes those DNA fragments come from based on their sequences, and determining if the test chromosome is over- or under-represented in the sample as compared to a reference chromosome. The claims recite a random MPS method for the detection step, meaning that all of the DNA in the sample is sequenced, as opposed to sequencing specific, targeted sequences. Quake's specification (shared by the '018 patent and the '833 application), however, only expressly describes detection of target sequences in its thirty-plus column specification.

         The Board issued a first decision in 2015, finding the random MPS claims at issue invalid for lack of written description. That decision was appealed to this court. This court remanded to the Board to correct three errors and redo its § 112 analysis. On remand, the Board found that a citation to a reference and a single sentence in Quake's specification support random sequencing, but that the two, on their own, are insufficient to describe the claimed method of determining fetal aneuploidy through random MPS. The Board also found that the specification did not describe the final claimed comparison step in terms that would be applicable to random MPS, namely adjusting/normalizing for chromosome size before assessing the over- or under-representation of a chromosome. In this fact-specific case, substantial evidence supports the Board's findings on lack of adequate written description. The Board also did not reopen the record to admit expert testimony from another proceeding, and we find that the Board did not abuse its discretion in not doing so. Accordingly, we affirm.


         The primary issue on appeal is whether the patent specification shared by the '018 patent and the '833 application sufficiently describes using random MPS to determine fetal aneuploidy, such that it meets the requirements of § 112.

         A. Technology and Patents

         Humans are normally born with twenty-three pairs of chromosomes. Chromosomal aneuploidy describes the condition where a fetus is born with either an abnormally high or low number of chromosomes. For example, Down syndrome is the presence of an extra chromosome 21. Historically, testing for fetal aneuploidy required invasive and risky procedures. One such procedure, amniocentesis, involves sampling amniotic fluid from the womb with a needle. Alternative non-invasive methods existed, but their accuracy was suboptimal.

         The two competing inventors in the underlying interferences on appeal-Stanford Professor Quake and Chinese University of Hong Kong Professor Dennis Lo-both developed methods for diagnosing aneuploidies using cell-free fetal DNA (cff-DNA) from maternal blood samples. In 1997, Lo and a colleague discovered that cff-DNA circulates in maternal blood in small amounts. This discovery made possible new prenatal screening techniques for chromosomal and other abnormalities, but researchers developing techniques for assaying cff-DNA had to overcome interference from maternal DNA in the maternal blood sample.

         Both Quake's and Lo's inventions, which are at the center of the interferences here, involve successful use of mixed maternal and fetal DNA samples to determine fetal aneuploidy. Assuming the mother does not have aneu-ploidy, aneuploidy in the fetus would affect the mother's blood sample such that the ratio between the amount of any given normal chromosome to the abnormal chromosome would no longer be 1:1.

         Additionally, both inventions incorporate MPS technology, which allows for sequencing of large amounts of DNA samples simultaneously. When a sequence is long enough, it can be uniquely identified as originating from a certain chromosome. Counting how many sequences come from various chromosomes is useful for determining over- or un-der-representation of a chromosome, thereby determining the presence of fetal aneuploidy. MPS can be performed by "random" or "targeted" methods. In the random format, all DNA in a sample is amplified, then sequenced. In the targeted format, only the target sequence(s) are amplified, then sequenced.

         Quake is the named inventor of the '018 patent. The patent's "Brief Summary of the Invention" states that the "present invention is directed to a method of differential detection of target sequences in a mixture of maternal and fetal genetic material." '018 patent, col. 4 ll. 43-45 (emphasis added). The '018 patent specification outlines four steps in the method: (1) obtaining a maternal tissue sample, preferably blood; (2) distributing single DNA molecules from this sample to a number of discrete reaction samples; (3) "[d]etecting the presence of the target in the DNA in a large number of reaction samples"; and (4) performing "[q]uantitative analysis of the detection of the maternal and fetal target sequences." Id. at col. 8 l. 35-col. 9 l. 6 (emphasis added); see also id. at col. 4 l. 39-col. 6 l. 60 ("Brief Summary of Invention").

         The '018 patent specification consistently focuses on detection of targeted sequences, using the term "target" more than sixty times throughout the patent. See, e.g., id. at col. 7 l. 62-col. 8 l. 17 (In Fig. 1A, "[s]hown in the wells are targets representing chromosome 21 and 22," "no target DNA is found" in well 2A, "[a] single run will have numerous random variations, such as wells that have no target sequence," "samples with no target will clearly result in no peak at all," and "wells with two or more targets[] will give peaks significantly higher.") (emphases added); col. 8 l. 35- col. 9 l. 6 ("[T]he number of reaction samples is selected to give a statistically significant result for the number of copies of a target in the DNA molecules;" "[d]etecting the presence of the target in the DNA in a large number of reaction samples;" "[q]uantitative analysis of the detection of the maternal and fetal target sequences," which in "some case cases . . . may include targets to different regions, such as probes to a target on a chromosome suspected of being present in an abnormal copy number (trisonomy) compared to a normal diploid chromosome, which is used as a control.") (emphases added); col. 11 ll. 40-43 (For digital PCR, "[a] reaction sample in general will contain a single template molecule (haplotype), two target molecules (diploid) or three target molecules (trisomy).") (emphases added); col. 14 ll. 27-28 (describing detection through digital PCR via "probes[] which become fluorescent on binding to the target sequence(s)") (emphasis added); col. 12 ll. 28-30, col. 19 ll. 10-12, 51-52 (describing detection by sequencing, including MPS, as "carried out by directly sequencing a region of interest to determine if it is the target sequence of interest," "sequenc[ing] the target sequence in the reaction sample directly," "sequenc[ing] . . . by labeled probes to detect a target specific sequence," and "[l]onger sequences [being able to] uniquely identify more particular targets") (emphases added); col. 21 ll. 8-12 (explaining the quantitative analysis step as follows: "[i]f chromosome A is euploid and represents an internal control, and chromosome B is aneu-ploid and is the target to be measured, then one can amplify representative segments from both chromosomes via digital PCR" and "the number of target sequences needed for statistical[ly significant] sequences may be reduced by using controls sequences") (emphases added); col. 22 ll. 26 (providing "[e]xamples of diseases where the target sequence may exist" in one copy in the maternal DNA, but with two copies in the fetal DNA) (emphasis added); col. 25 ll. 49-col. 28 ll. 43 (describing an exemplary detection method with two target sequences: amyloid for test chromosome 21 and GAPDH for control chromosome 12).

         The specification states that the digital polymerase chain reaction (PCR) technique is the preferred embodiment for amplifying and detecting target sequences. See id. at col. 12 ll. 18-20. In digital PCR, a mixed maternal and fetal DNA sample is distributed amongst thousands of reaction wells. Known target DNA sequences-usually one sequence from a reference chromosome and one sequence from the chromosome being tested for aneuploidy-are amplified by target-specific primers located in those wells. If either target sequence is present in any particular individual reaction well, it will be amplified by PCR (positive result); if no target sequence is present in the reaction well, no sequence will be amplified (negative result). Id. at col. 8 ll. 52-56. The reaction wells are then tested for the presence of the target sequences. Id. at col. 7 l. 62-col. 8 l. 9.

         The specification also identifies some alternative detection methods to digital PCR, one of which is MPS. Id. at col. 19 ll. 5-12. Only two paragraphs in the thirty-plus columns in the specification relate to MPS. Id. at col 19 l. 48- col. 20 l. 20. This appeal focuses on the content of those two paragraphs; the relevant text is reproduced in the discussion below.

         Either technique, digital PCR or MPS, can be used to count the number of chromosomes containing the targeted sequence versus the number of chromosomes containing the reference chromosome sequence in the sample. The '018 patent specification describes using this molecular counting data to run statistical analysis. Id. at col. 21 ll. 1-45. The number of positive results from each target sequence leads to a ratio of the reference and test chromosomes. Id. If the ratio of the two chromosomes is not 1:1 and the deviation is statistically significant, the fetus is determined to have aneuploidy. See, e.g., id. at col. 28 ll. 5- 25 (Table 1). The specification describes running a "Student's T-test" and z-test/chi-squared test to analyze the statistical significance of a deviation from the expected 1:1 ratio. Id. at col. 5 l. 64-col. 6 l. 3, col. 28 ll. 5-34.

         Quake claimed his method of determining fetal aneu-ploidy by detecting target sequences in an application filed on February 2, 2007, and filed a continuation as Application No. 12/393, 803 in February 2009. The original claims of Quake's '803 application explicitly recited methods that required the detection of "target sequences." In 2011, Quake split the '803 application into multiple applications. In the application which later issued as the '018 patent, Quake canceled all pending claims and added new claims covering the use of random MPS to determine fetal aneu-ploidy. J.A. 4134-42. Representative issued claim 1 recites:

1. A method for determining presence or absence of fetal aneuploidy in a maternal tissue sample comprising fetal and maternal genomic DNA, wherein the method comprises:
a. obtaining a mixture of fetal and maternal genomic DNA from said maternal tissue sample:
b. conducting massively parallel DNA sequencing of DNA fragments randomly selected from the mixture of fetal and maternal genomic DNA of step a) to determine the sequence of said DNA fragments;
c. identifying chromosomes to which the sequences obtained in step b) belong;
d. using the data of step c) to compare an amount of at least one first chromosome in said mixture of maternal and fetal genomic DNA to an amount of at least one second chromosome in said mixture of maternal and fetal genomic DNA, wherein said at least one first chromosome is presumed to be euploid in the fetus, wherein said at least one second chromosome is suspected to be aneuploid in the fetus, thereby determining the presence or absence of said fetal aneuploidy.

'018 patent, col. 33 ll. 48-67. Claim 25 of Application No. 12/393, 833, another application that continued from the '803 application, also recites using random MPS to determine fetal aneuploidy.

         Also in 2007, Lo, along with Rossa Wai Kwun Chu and Kwan Chee Chan (collectively, Lo), filed a patent application that undisputedly describes and claims a method of using "random" MPS to determine fetal aneuploidy. The application was published in 2009. Lo's application is devoted to, and describes in considerable detail, randomly sequencing the entire sample via MPS after fragmentation and division. See J.A. 4159-60; see also, e.g., J.A. 4154-59 ¶¶ 14, 21, 48, 55, 58, 67, 70-71 (repeatedly stating that "a fraction of the [whole] genome" in the sample is sequenced). The sequencing data is mapped, based on known sequences of the human genome, to determine which chromosome each sequenced fragment is from. However, since some chromosomes are longer and would contribute more fragments to the random sample, Lo's application explains that a skilled artisan would need to adjust for chromosome size, i.e., normalize the data by the length of each chromosome, before being able to accurately determine the presence of fetal aneuploidy. See J.A. 4158 ...

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