Appeals from the United States Patent and Trademark Office,
Patent Trial and Appeal Board in Nos. 105, 920, 105, 923,
R. Reines, Weil, Gotshal & Manges LLP, Redwood Shores,
CA, argued for appellants. Also represented by Derek C.
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.
Reyna, Chen, and Hughes, Circuit Judges.
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
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
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.
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 §
Technology and Patents
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.
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
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.
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.
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").
'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).
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.
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.
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.
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
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.
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.