Court Opinion

ID: 4415292
Source: CourtListenerOpinion
Date Created: 2019-07-10 16:00:43.778338+00
Date Added: 2024-06-11T14:51:18.402619
License: Public Domain

United States Court of Appeals
      for the Federal Circuit
                ______________________

  STEPHEN QUAKE, HEI-MUN CHRISTINA FAN,
                Appellants

                           v.

YUK-MING DENNIS LO, ROSSA WAI KWUN CHIU,
           KWAN CHEE CHAN,
                  Appellees
           ______________________

           2018-1779, 2018-1780, 2018-1782
               ______________________

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

                 Decided: July 10, 2019
                ______________________

    EDWARD R. REINES, Weil, Gotshal & Manges LLP, Red-
wood 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.
                ______________________
2                                               QUAKE v. LO

    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 proceed-
ings.
    The claims cover a method of determining the presence
of a chromosomal abnormality (called aneuploidy) in fe-
tuses by using massively parallel sequencing (MPS) tech-
nology to sequence deoxyribonucleic acid (DNA) fragments
from a sample of the mother’s blood that contains both ma-
ternal 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-rep-
resented in the sample as compared to a reference chromo-
some. 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 pa-
tent and the ’833 application), however, only expressly de-
scribes 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 de-
scription. 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
QUAKE v. LO                                              3

describe the final claimed comparison step in terms that
would be applicable to random MPS, namely adjusting/nor-
malizing 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 an-
other proceeding, and we find that the Board did not abuse
its discretion in not doing so. Accordingly, we affirm.
                      BACKGROUND
     The primary issue on appeal is whether the patent
specification shared by the ’018 patent and the ’833 appli-
cation sufficiently describes using random MPS to deter-
mine 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 con-
dition where a fetus is born with either an abnormally high
or low number of chromosomes. For example, Down syn-
drome is the presence of an extra chromosome 21. Histor-
ically, testing for fetal aneuploidy required invasive and
risky procedures. One such procedure, amniocentesis, in-
volves sampling amniotic fluid from the womb with a nee-
dle. Alternative non-invasive methods existed, but their
accuracy was suboptimal.
    The two competing inventors in the underlying inter-
ferences on appeal—Stanford Professor Quake and Chi-
nese 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 chromoso-
mal and other abnormalities, but researchers developing
4                                                 QUAKE v. LO

techniques for assaying cff-DNA had to overcome interfer-
ence from maternal DNA in the maternal blood sample.
    Both Quake’s and Lo’s inventions, which are at the cen-
ter 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 chromo-
some would no longer be 1:1.
     Additionally, both inventions incorporate MPS technol-
ogy, 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 tar-
geted 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 (empha-
sis 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
QUAKE v. LO                                                   5

(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 numer-
ous 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 cop-
ies of a target in the DNA molecules;” “[d]etecting the pres-
ence 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 pre-
sent 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, includ-
ing 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”) (empha-
ses added); col. 21 ll. 8–12 (explaining the quantitative
6                                                 QUAKE v. LO

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 digi-
tal PCR” and “the number of target sequences needed for
statistical[ly significant] sequences may be reduced by us-
ing controls sequences”) (emphases added); col. 22 ll. 26
(providing “[e]xamples of diseases where the target se-
quence 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 chro-
mosome 21 and GAPDH for control chromosome 12).
     The specification states that the digital polymerase
chain reaction (PCR) technique is the preferred embodi-
ment 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 am-
plified by target-specific primers located in those wells. If
either target sequence is present in any particular individ-
ual reaction well, it will be amplified by PCR (positive re-
sult); 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 pres-
ence of the target sequences. Id. at col. 7 l. 62–col. 8 l. 9.
     The specification also identifies some alternative detec-
tion methods to digital PCR, one of which is MPS. Id. at
col. 19 ll. 5–12. Only two paragraphs in the thirty-plus col-
umns 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 dis-
cussion below.
QUAKE v. LO                                                   7

     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 se-
quence leads to a ratio of the reference and test chromo-
somes. Id. If the ratio of the two chromosomes is not 1:1
and the deviation is statistically significant, the fetus is de-
termined to have aneuploidy. See, e.g., id. at col. 28 ll. 5–
25 (Table 1). The specification describes running a “Stu-
dent’s T-test” and z-test/chi-squared test to analyze the sta-
tistical 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 Applica-
tion 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 re-
cites:
    1. A method for determining presence or absence of
    fetal aneuploidy in a maternal tissue sample com-
    prising fetal and maternal genomic DNA, wherein
    the method comprises:
        a. obtaining a mixture of fetal and mater-
        nal genomic DNA from said maternal tis-
        sue sample:
        b. conducting massively parallel DNA se-
        quencing of DNA fragments randomly
8                                               QUAKE v. LO

       selected from the mixture of fetal and ma-
       ternal genomic DNA of step a) to determine
       the sequence of said DNA fragments;
       c. identifying chromosomes to which the se-
       quences 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 deter-
       mining 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 deter-
mine fetal aneuploidy.
   Also in 2007, Lo, along with Rossa Wai Kwun Chu and
Kwan Chee Chan (collectively, Lo), filed a patent applica-
tion 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 de-
voted to, and describes in considerable detail, randomly se-
quencing 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 frag-
ments to the random sample, Lo’s application explains that
QUAKE v. LO                                               9

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 ¶¶ 69–70. Lo filed U.S.
Provisional Application No. 60/951,438 describing this
method on July 23, 2007, and subsequently filed U.S. Pa-
tent Application Nos. 13/070,275, 12/178,181, 13/070,240,
12/614,350, 13/070,251, and 13/417,119 on the same inven-
tion.
                    B. Procedural History
    Both Quake and Lo requested interferences to deter-
mine who first invented the random MPS method and
when the method was invented. In early 2013, the Board
declared three interferences between Quake’s patent and
application and Lo’s applications. 1 In each proceeding, Lo
attacked the claims of Quake’s ’018 patent or ’833 applica-
tion as unpatentable for lack of written description. Alt-
hough the ’018 patent specification is over thirty columns,
MPS is discussed in just two paragraphs at columns 19 to
20. In Quake’s view, these two paragraphs not only teach
MPS as a sequencing tool, but also describe a second detec-
tion methodology—i.e., random sequencing—distinct from
targeted sequencing. The Board, however, disagreed with
Quake and granted Lo’s written description motions in all
three interferences and, in 2015, found Quake’s claims un-
patentable for lack of written description.
     Quake appealed the Board’s decisions to the U.S. Dis-
trict Court for the Northern District of California under 35

   1    Interference No. 105,920 involved Lo Application
No. 13/070,275 and the ’018 patent. Interference No.
105,923 involved Lo Application Nos. 12/178,181,
13/070,240, 12/614,350, and 13/070,251 and Quake’s ’833
application. Interference No. 105,924 involved Lo Applica-
tion No. 13/417,119 and Quake’s ’833 application.
10                                               QUAKE v. LO

U.S.C. § 146. Some expert discovery took place before the
case was removed to this court once the law mandated that
the district court lacked jurisdiction to review the Board’s
interference decisions. See Biogen MA, Inc. v. Japanese
Found. for Cancer Research, 785 F.3d 648 (Fed. Cir. 2015)
(holding that this court has exclusive appellate jurisdiction
over Board decisions), cert. denied, 136 S. Ct. 1450 (2016).
    In 2017, this court vacated the Board’s 2015 decisions
and remanded with instructions for the Board: (1) to con-
sider whether the patent’s written description at columns
19 to 20 discloses random MPS, as opposed to the Board’s
2015 finding that the description in those columns “does
not preclude targeted MPS”; (2) to explain the meaning of
various phrases in that portion of the patent specification,
including “using attachment of randomly fragmented ge-
nomic DNA,” “solid phase amplification,” “~1,000 copies of
template,” “templates,” and “[t]hese templates are se-
quenced using four-color DNA sequencing-by-synthesis
technology”; and (3) to examine whether a skilled artisan
would have known, as of the priority date, that the specifi-
cation’s reference to Illumina products meant random MPS
sequencing based on record evidence describing Illumina
products or any other random MPS products existing as of
the filing date. Bd. of Trs. of Leland Stanford Junior Univ.
v. Chinese Univ. of Hong Kong, 860 F.3d 1367, 1377–79
(Fed. Cir. 2017).
    On remand, the Board held a conference call with the
parties and issued an order declining to reopen the record,
in relevant part denying Quake’s request for admission of
testimony by Lo’s expert from the terminated district court
proceedings. J.A. 7576–620; Interference No. 105,920, Or-
der–New Briefing and Evidence 37 C.F.R. § 41.104(a) (De-
cember 12, 2017). The Board issued its remand decisions
on December 20, 2017. J.A. 6, 31, 53. The Board’s analysis
was substantively identical in each interference, so for pur-
poses of this appeal, we refer primarily to the Board’s
QUAKE v. LO                                                  11

findings as to the ’018 patent and treat them as representa-
tive of the Board’s findings as to the ’833 application.
     In its decisions, the Board first followed this court’s in-
structions. It focused on whether the ’018 patent describes
random MPS, rather than on whether its written descrip-
tion does not preclude targeted MPS. The Board explained
the various phrases in the two MPS-related paragraphs at
columns 19 to 20 in the specification as describing MPS
generally, without reference to targeted versus random
MPS. The Board also credited an admission from Lo that
“Illumina sequencing platforms [referenced in column 19 of
the ’018 patent specification] can perform either random or
targeted DNA sequencing, depending on whether predeter-
mined target DNA fragments are specifically identified or
targeted prior to sequencing,” but found no record evidence
of the Illumina products’ capabilities as of the date of in-
vention. J.A. 11.
    The Board then looked elsewhere in the two MPS par-
agraphs of the ’018 patent specification for evidence of writ-
ten description of the ’018 claims:
    [Passage A:] A methodology useful in the present
    invention platform is based on massively parallel
    sequencing of millions of fragments using attach-
    ment of randomly fragmented genomic DNA to a
    planar, optically transparent surface and solid
    phase amplification to create a high density se-
    quencing flow cell with millions of clusters, each
    containing ~1,000 copies of template per sq. cm.
    These templates are sequenced using four-color
    DNA sequencing-by-synthesis technology.        See,
    products offered by Illumina, Inc., San Diego Calif.
    Also, see US 2003/0022207 to Balasubramanian,
    et al., published Jan. 30, 2003, entitled “Arrayed
    polynucleotides and their use in genome analysis.”
    [Passage B:] Sequencing may be combined with
    amplification-based methods in a microfluidic chip
12                                                 QUAKE v. LO

     having reaction chambers for both PCR and micro-
     scopic template-based sequencing. Only about 30
     bp of random sequence information are needed to
     identify a sequence as belonging to a specific human
     chromosome. Longer sequences can uniquely iden-
     tify more particular targets. An algorithm for de-
     signing unique sequences is described in Yamada
     et al. illustrative of software methods that can be
     used to identify a sequence in comparison to the
     known genome sequence. See, also Zhu et al., de-
     scribing a single-molecule-based technology for
     studying mRNA.
J.A. 9–10, 14 (quoting ’018 patent, col. 19 l. 59–col. 20 l. 20
and referring to the first paragraph as Passage A and the
second paragraph as Passage B) (emphases added).
     The Board found that the citation to Balasubramanian
in Passage A “provides some[] disclosure of massively par-
allel sequencing of DNA fragments selected randomly”
based on the testimony of Lo’s expert, Dr. Gabriel. J.A. 13
(citing J.A. 2828 (Gabriel Depo. at 60:18–22)). The Board
then found that Passage B “expressly describe[s] random
sequencing” because it uses the phrase “random sequence
information” in the sentence “about 30 bp of random se-
quence information are needed to identify a sequence as
belonging to a specific human chromosome.” ’018 patent,
col. 20 ll. 7–9.
    But the Board subsequently found that Balasubrama-
nian and the “30 bp of random sequence information are
needed to identify a sequence” sentence are not sufficient
to meet the requirements of § 112. The Board character-
ized passages A and B as providing “some express descrip-
tion of individual elements recited in Quake’s claims,” but
found these disclosures “[in]sufficient to have demon-
strated [to a skilled artisan] that the inventors were in pos-
session of a method of determining fetal aneuploidy with
QUAKE v. LO                                                 13

random massively parallel sequencing as claimed by
Quake.” J.A. 15 (emphasis added).
    Specifically, the Board found that although the “the ex-
press language describes some of the elements of the
claimed method, . . . it is not sufficient to provide a written
description under 35 U.S.C. § 112” because the ’018 patent
(1) “does not tie these elements together into a complete
method” and (2) “does not explain how to use the data from
random massively parallel sequencing of a mixture of ge-
nomic DNA to determine fetal aneuploidy.” Id. First, the
Board contrasted the scant information in the ’018 patent
regarding random MPS to the thirty columns of detailed,
step-by-step description of targeted detection and targeted
MPS, tying the steps together into a complete method. J.A.
15–17. Second, the Board explained that nothing in the
’018 patent suggests to a skilled artisan to adjust for chro-
mosome size when doing the comparison claimed in step
D—a statistical normalization step necessary when using
random MPS data to determine the presence or absence of
aneuploidy, as disclosed in Lo’s applications and explained
above. J.A. 17–22. Quake argued that a skilled artisan
would have known how to do so, but the Board found that
“Quake did not direct [it] to a portion of the ’018 patent that
describes the need to do so,” and therefore, a skilled artisan
“would not have considered that the inventors of the ’018
patent contemplated a method requiring” normalizing for
chromosome size. J.A. 21 (emphasis added).
    As in its 2015 decision, the Board again granted Lo’s
written description motions and found Quake’s claims un-
patentable.
    Quake appeals both the Board’s written description
findings and its decision not to admit testimony from the
14                                                QUAKE v. LO

district court proceedings. We have jurisdiction pursuant
to 28 U.S.C. § 1295(a)(4)(A). 2
                        DISCUSSION
                              I.
     Compliance with the written description requirement
of § 112 is a question of fact, judged from the perspective of
a skilled artisan as of the patent’s filing date. Ariad
Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed.
Cir. 2010) (en banc). Accordingly, in an appeal from the
Board, this court examines whether the Board’s decision is
supported by substantial evidence. Harari v. Lee, 656 F.3d
1331, 1341 (Fed. Cir. 2011). “A finding is supported by sub-
stantial evidence if a reasonable mind might accept the ev-
idence to support the finding.” Redline Detection, LLC v.
Star Envirotech, Inc., 811 F.3d 435, 449 (Fed. Cir. 2015)
(citation omitted).
     “The essence of the written description requirement is
that a patent applicant, as part of the bargain with the pub-
lic, must describe his or her invention so that the public
will know what it is and that he or she has truly made the
claimed invention.” AbbVie Deutschland GmbH & Co. v.
Janssen Biotech, Inc., 759 F.3d 1285, 1298 (Fed. Cir. 2014).
The written description requirement is satisfied if the in-
ventor “convey[s] with reasonable clarity to those skilled in
the art that, as of the filing date sought, he or she was in
possession of the invention,’ and demonstrate[s] that by
disclosure in the specification of the patent.” Centocor

     2  This court has exclusive jurisdiction over an appeal
from a decision of the Board in an interference declared af-
ter September 15, 2012 pursuant to the version of 28 U.S.C.
§ 1295(a)(4)(A) as it existed on September 15, 2012. Bio-
gen, 785 F.3d at 654; Technical Corrections—Leahy-Smith
America Invents Act, Pub. L. 112-274, 126 Stat. 2456
§ 1(k)(3).
QUAKE v. LO                                               15

Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1348
(Fed. Cir. 2011) (quoting Carnegie Mellon Univ. v. Hoff-
mann–La Roche Inc., 541 F.3d 1115, 1122 (Fed. Cir. 2008)).
     “[T]he purpose of the written description requirement
is to prevent an applicant from later asserting that he in-
vented that which he did not,” and the requirement is par-
ticularly important when, as here, claims are added later
during prosecution in response to development by others.
Agilent Techs., Inc. v. Affymetrix, Inc., 567 F.3d 1366, 1383
(Fed. Cir. 2009). Here, the first time Quake tried to cover
random MPS with this specification was after the publica-
tion of Lo’s patent application directed to random MPS:
Quake then canceled all his pending claims and replaced
them with claims covering random MPS, creating a mis-
match between the claims and the originally filed specifi-
cation.
     An invention is usually expressly described in the spec-
ification; there is no reasonable argument for that being
the case here. Though the Board found some express dis-
closure of two elements of the claimed invention in Pas-
sages A and B, the term “random MPS” is never mentioned
in the ’018 patent, the process of amplifying all the DNA in
a sample before sequencing is never described, and Quake
admits that there is no embodiment describing the statis-
tical analysis needed to determine fetal aneuploidy from
data generated by random MPS. Oral Arg. at 9:39–53. The
method as a whole is not expressly described.
     However, “ipsis verbis disclosure is not necessary to
satisfy the written description requirement of section 112.”
Fujikawa v. Wattanasin, 93 F.3d 1559, 1570 (Fed. Cir.
1996). “[T]he disclosure need only reasonably convey to
persons skilled in the art that the inventor had possession
of the subject matter in question.” Id. This court has anal-
ogized such a disclosure as “mark[ing] trails by making
blaze marks on . . . trees” to “find[] one’s way through the
woods” of a specification such that a skilled artisan would
16                                             QUAKE v. LO

be able to follow that trail and understand what the inven-
tors had invented. In re Ruschig, 379 F.2d 990, 994–95
(CCPA 1967). The Board made such an inquiry here.
    We address the Board’s findings as to the Balasubra-
manian citation in Passage A and the single sentence in
Passage B, and then its treatment of the chromosome size
adjustment necessary for claimed step D.
   We find that there is substantial evidence for the
Board’s finding that Balasubramanian supports random
MPS and clarify that the record indicates that Balasubra-
manian also supports targeted MPS.
    Balasubramanian is directed to a method of MPS that
involves immobilizing polynucleotides (e.g., DNA) to an ar-
ray and sequencing the polynucleotides to detect differ-
ences between sequences. U.S. Patent Publication No.
2003/0022207 A1 at Abstract. In particular, the publica-
tion focuses on finding single polynucleotide polymor-
phisms (SNPs). See, e.g., id. at ¶¶ [0006], [0034], [0069],
[0070]. SNPs tend to occur at unique locations, so identi-
fying them in DNA samples can indicate which chromo-
some the polynucleotide belongs to. Significantly, the
amplification step that differentiates targeted and random
MPS 3 is a preparatory step in the Illumina methods that
comes before any of the steps disclosed in Balasubrama-
nian. J.A. 5763. Consequently, as Lo’s expert Dr. Gabriel
explains, the teachings of Balasubramanian could be used
in either random or targeted MPS, depending on the na-
ture of the preceding amplification step. Id.

     3  As explained above and in our previous opinion, the
main difference between random and targeted MPS is that
in targeted MPS, the target sequence(s) are specifically
amplified before sequencing, whereas in random MPS, all
DNA in the sample is amplified. Stanford, 860 F.3d at
1370.
QUAKE v. LO                                                 17

    So, while we agree with Quake and the Board that Dr.
Gabriel admitted that Balasubramanian “supports ran-
domly massively parallel sequencing,” J.A. 2828, record ev-
idence     cited  by    the    Board      establishes      that
Balasubramanian supports targeted sequencing as well.
Dr. Gabriel stated that “Balasubramanian discloses both
targeted and random sequencing approaches.” J.A. 5763
(emphasis added). The Board previously credited this tes-
timony when discussing Illumina products based on the
Balasubramanian technology. 4 Stanford, 860 F.3d at
1372–73 (noting that the Board relied on “Dr. Ga-
briel’s statement that the Illumina platform referenced in
the specification could be used for both random and tar-
geted sequencing”). The Board also cited to this fact in the
decisions now on appeal. J.A. 11, 36, 58 (citing a “Material
Fact” in Lo’s motions that “Illumina sequencing platforms
can perform either random or targeted DNA sequencing,
depending on whether predetermined target DNA frag-
ments are specifically identified or targeted prior to se-
quencing” (emphasis added)). 5 Further, as Lo points out,
the Balasubramanian reference is cited in the ’018 patent
specification for “sequenc[ing] using four-color DNA se-
quencing-by-synthesis technology,” a statement applicable
to sequencing generally, rather than random versus tar-
geted sequencing. ’018 patent, col. 19 l. 65–col. 20 l. 3; Oral
Arg. at 22:04–22.

    4   The ’833 application notes that “the assignee of the
Balasubramanian PG Publication, Solexa, was acquired by
Illumina,” and that Balasubramanian’s teachings form a
partial basis of Illumina’s commercial sequencing system
described in the Quake’s specification. J.A. 4330 n.2.
    5   There is no evidence in the record that skilled arti-
sans disputed that MPS could be used in either random or
targeted sequencing approaches at the time of filing of
Quake’s patent application.
18                                               QUAKE v. LO

    In sum, we agree with the Board that the citation to
Balasubramanian in Passage A “provides some . . . disclo-
sure of massively parallel sequencing of DNA fragments
selected randomly,” J.A. 13, but note, in line with the
Board’s other findings, that skilled artisans would have un-
derstood the specification to support targeted MPS as well,
see J.A. 11–12 (Board rejecting Quake’s argument that
“passage A does not describe targeted sequencing and
therefore must describe random sequencing”). Our previ-
ous decision did not reject a finding that Quake’s specifica-
tion supports targeted sequencing; rather we explained
that Quake’s description “might be able to disclose both
random and targeted sequencing” and therefore directed
the Board on remand to “examine whether a [skilled arti-
san] would have understood that the ’018 patent’s specifi-
cation disclosed random MPS sequencing, as opposed to
whether the specification did not preclude targeted MPS
sequencing.” Stanford, 860 F.3d at 1378, 1379. That a
skilled artisan would understand Balasubramanian to sup-
port targeted sequencing as well makes the Quake specifi-
cation’s citation to Balasubramanian consistent with the
rest of its discussion of detecting target sequences.
     As for the disclosure of Passage B, the Board does not
cite to any record evidence that a skilled artisan would un-
derstand the sentence—“about 30 bp of random sequence
information are needed to identify a sequence as belonging
to a specific human chromosome”—as referring to random
MPS. First, the Board found elsewhere that simply using
the word “random” is not enough to indicate random MPS.
See J.A. 11 (finding that the phrase “randomly fragmented
genomic DNA” from Passage A is “not necessarily the
same” as the phrase referring to random MPS in the
claims). Second, the 30 bp statement precedes the sen-
tence, “Longer sequences can uniquely identify more par-
ticular targets,” indicating that the 30 bp language covers
identifying the chromosomes of origin for DNA fragments
generated through targeted MPS. ’018 patent, col. 20 ll. 9–
QUAKE v. LO                                                 19

10 (emphasis added); J.A. 4755, ¶ 80 (Lo’s expert stating
the 30 bp “statement refers to the minimum size of a
unique target sequence in the genome for use in amplifica-
tion, particularly given the statements in the following sen-
tence[]”). But the passage could also cover identifying the
chromosomes of origin for DNA fragments generated
through random MPS. We agree with the Board that the
30 bp sentence is more generally “about the number of base
pairs needed to identify the chromosomal origin of a se-
quence.” J.A. 16. There is no indication in the record that
the length of a sequence needed to identify the chromosome
of origin is any different for DNA fragments sequenced via
random and targeted MPS.
     However, given the specification’s repeated discussion
of targeted sequencing, a bare citation to Balasubramanian
and use of the phrase “about 30 bp of random sequence in-
formation are needed to identify a sequence” in the context
of this patent would be a highly elliptical, cryptic way to
communicate possession of a second method of sequencing
to determine fetal aneuploidy. An alternative explanation
consistent with the entire patent specification is that
Quake invented using targeted MPS for determining fetal
aneuploidy and wrote the ’018 patent specification to de-
scribe targeted MPS, among other ways of performing tar-
geted detection such as digital PCR. Balasubramanian
was cited in Passage A to support a sentence describing de-
tection via sequencing with four-color DNA sequencing-by-
synthesis technology. That method of detection would re-
sult in a ratio of two targeted sequences that would be an-
alyzed, as described in the specification, for statistically
significant deviations from a 1:1 ratio to determine fetal
aneuploidy. ’018 patent, col. 21 ll. 1–45, col. 28 ll. 5–34.
    In light of the limited disclosure value of the single Bal-
asubramanian citation and the “about 30 bp of random se-
quence information are needed to identify a sequence”
sentence, substantial evidence supports the Board’s find-
ing that those two items together are not adequate to
20                                                 QUAKE v. LO

convey using random MPS to determine fetal aneuploidy
as claimed. In terms of Ruschig’s analogy of the written
description requirement being akin to creating a trail
through the woods, the two are (at most) faint “blaze
marks” for determining fetal aneuploidy by random MPS,
while the rest of the specification marks a clear trail to tar-
geted MPS. Ruschig, 379 F.2d at 994–95.
     As for claim step D, as the Board recognized, if the ’018
patent had contained some description of adjusting for
chromosome size when comparing the data resulting from
the MPS step, then a skilled artisan may have had an in-
direct, but clear indication that the inventor contemplated
a method of using random MPS to determine fetal aneu-
ploidy. But the ’018 patent only describes statistical anal-
yses, such as a “Student’s T-test” and z-test/chi-squared
test, in the context of assessing divergence from a 1:1 ratio
between a targeted sequence and a sequence from a refer-
ence chromosome. ’018 patent, col. 5 l. 64–col. 6 l. 3, col. 28
ll. 5–34. There is no discussion of adjusting for chromo-
some size before performing those statistical analyses. We
agree with the Board that “[i]n the absence of a description
of such analysis, [the] teachings in the specification about
[the Balasubramanian] equipment useful for random mas-
sively parallel sequencing and techniques for determining
sequences are not sufficient to demonstrate possession of
the claimed method.” J.A. 21 (emphasis added).
    On appeal, Quake incorrectly characterizes the Board’s
decision as finding that all but the normalization for chro-
mosome size in claim step D are disclosed in the ’018 patent
and then focuses solely on why the Board’s step D finding
should be reversed. Lo counters, and we agree, that the
Board’s findings did not go so far. The Board found no ex-
press description or sufficient blazemarks of the claimed
method as a whole and also relied on the chromosome size
adjustment issue as a key missing disclosure that could
have cured Quake’s written description problem. Under
QUAKE v. LO                                                21

this understanding of the Board’s decision, we reject each
of Quake’s six specific arguments.
     First, Quake argues that conducting statistical analy-
sis on random MPS data was known and predictable, and
not a “mere wish or plan” as in Centocor Ortho Biotech, 636
F.3d 1341, 1351 and Regents of the University of California
v. Eli Lilly & Co., 119 F.3d 1559, 1566 (Fed. Cir. 1997). The
Board cites to these two decisions when concluding that
“the inventors had only ‘a mere wish or plan’ to use this
new technology in their invention.” J.A. 22. We under-
stand this statement as characterizing the two-paragraph,
very-brief suggestion of using MPS (as an alternative to
digital PCR) in the ’018 patent as a “mere wish or plan” to
use MPS in its method of detecting targeted sequences,
such that the details could be filled in by a skilled artisan.
But that view as to the use of MPS technology for targeted
sequencing is consistent with the Board’s core finding that
the patent fails to reasonably convey using MPS to detect
the chromosomal origin of “DNA fragments randomly se-
lected from the mixture of fetal and maternal genomic
DNA” to determine the presence or absence of fetal aneu-
ploidy, as claimed. ’018 patent, col. 33 ll. 48–67.
    Second, Quake argues that the normalization (chromo-
some size adjustment) details necessarily required for us-
ing random MPS data to perform the comparison step
claimed in step D are unclaimed limitations and thus did
not need to be described to satisfy § 112. The language of
claim step D requires using the data from random MPS (re-
cited in claim steps B and 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 chro-
mosome in said mixture of maternal and fetal genomic
DNA, wherein said at least one first chromosome is pre-
sumed to be euploid in the fetus, wherein said at least one
second chromosome is suspected to be aneuploid in the fe-
tus, thereby determining the presence or absence of said fe-
tal aneuploidy.” ’018 patent, col. 33 ll. 59–67 (emphases
22                                                QUAKE v. LO

added). Quake argues that the claim language only re-
quires a comparison of two chromosome amounts to deter-
mine aneuploidy and cites three passages from the
specification as disclosing how to conduct such a compari-
son:
     Quantitative analysis of the detection of the mater-
     nal and fetal target sequences. In some cases this
     may include targets to different regions, such as
     probes to a target on a chromosome suspected of be-
     ing present in an abnormal copy number (trison-
     omy) compared to a normal diploid chromosome,
     which is used as a control.
Id. at col. 9 ll. 1–6 (emphases added).
     A control sequence is used to distinguish an abnor-
     mal increase in the target sequence, e.g., a trison-
     omy. Thus there is a differential detection of target
     sequences, one of which is chosen to represent a
     normal genotype present in both mother and off-
     spring, and one of which is chosen for detection of
     an abnormal genotype in the offspring, where the
     target sequence in the offspring will be different
     from that of the mother, e.g. in trisomy.
Id. at col. 7 ll. 54–61 (emphases added).
     The presence or absence of different target se-
     quences in the discrete samples is detected; and the
     results are analyzed whereby the number of results
     from the discrete samples will provide data suffi-
     cient to obtain results distinguishing different tar-
     get sequences. In one aspect, the method involves
     an analysis of a trisomy. In this method, one of the
     different target sequences (e.g. chromosome 21) is
     diploid in maternal genetic material and aneuploid
     in fetal genetic material and another of the differ-
     ent target sequences (e.g. chromosome 12) is dip-
     loid in both maternal and fetal genetic material.
QUAKE v. LO                                                23

Id. at col. 5 ll. 21–31 (emphases added). These passages
specifically recite comparison of “target sequences,” which
cannot be random MPS. And we disagree with Quake’s un-
derstanding that the Board required disclosure of the nor-
malization step to show written description of the claimed
method. Rather, the Board found that to establish posses-
sion of random MPS for determining fetal aneuploidy, such
a disclosure would have helped communicate possession of
the claimed subject matter, given that the specification
lacks an express disclosure of the random sequencing-
based invention. J.A. 17. This is because the normaliza-
tion step is relevant for data generated from random se-
quencing and not targeted sequencing. J.A. 17–18.
    Third, Quake argues that because the claim language
does not require normalizing for chromosome size, the al-
leged lack of disclosure is more of an enablement issue than
a written description issue. But the Board cited the lack of
disclosure not because normalization is required by the
claim language of step D, but because disclosure of normal-
ization would have conveyed to a skilled artisan reading
the specification that the inventor contemplated a compar-
ison step for a random sequencing method, in addition to
the specification’s very clear disclosure of a comparison
step for a targeted sequencing method. This missing de-
scription could have provided a supporting blazemark, but
without it, there is no description of “using the data of step
c)” obtained by random MPS to compare chromosomal
amounts and “determin[e] the presence or absence of . . .
fetal aneuploidy.” ’018 patent, col. 33 ll. 59–67 (claim 1,
step D).
    Fourth, Quake argues that the need to normalize ran-
dom MPS results was known to a skilled artisan in 2007
and therefore not necessary to describe in the specification.
Appellants’ Op. Br. 38, 43–44 (characterizing it as an im-
plementation detail that did not need to be described); Ap-
pellants’ Reply Br. 8, 10 (same); Oral Arg. at 7:01–03
(same). Quake argues that MPS (generally) was known in
24                                               QUAKE v. LO

the art, that a skilled artisan would recognize that the 1:1
ratio analysis detailed in the specification would not work
for random sequencing without modification due to differ-
ences in chromosome sizes, and that a skilled artisan would
resort to their knowledge of normalization to fill in the de-
tails. Appellants’ Op. Br. 44. The Board agreed that a
skilled artisan would have known how to normalize the
random sequence data to account for chromosome size if
the artisan understood that there was a need to do so—i.e.,
if the artisan understood that using random MPS to deter-
mine fetal aneuploidy was being described by the rest of
the written description. J.A. 21. As explained above, the
Board reasonably found that the Balasubramanian citation
and the “about 30 bp of random sequence information are
needed to identify a sequence” sentence are not adequate
to do so.
    Fifth, Quake argues that the statistical steps described
in the ’018 patent are sufficient to describe step D. The
disclosure explains, in the context of a simplified digital
PCR example, that one expects to find an increased num-
ber of amplified DNA fragments corresponding to an ab-
normal chromosome compared to a normal chromosome.
’018 patent, col. 21 ll. 4–21. Quake argues that a skilled
artisan would have understood this passage to describe the
concept of using molecular counting and basic statistical
analysis to assess over- or under-representation of the test
chromosome in the DNA, indicating aneuploidy. However,
there is no explicit discussion of normalizing the molecular
counting data, i.e., adjusting the statistical analysis for
chromosome size. J.A. 20–21. And the issue of whether a
skilled artisan would have thought to do so turns on the
strength of the blazemarks disclosing random MPS in Pas-
sages A and B, which we explain above are insufficient for
a skilled artisan to recognize.
     Finally, Quake argues that the Board erroneously
shifted the burden of proof from Lo to Quake by “not iden-
tifying any evidence submitted by Lo, or otherwise present
QUAKE v. LO                                               25

in the record, that a person of ordinary skill in the art
would have been unable to recognize promptly the need for
this basic [chromosome size adjustment/normalization]
step to be performed.” Appellants’ Op. Br. 46. The Board
noted in its 2015 decisions that “[t]o prevail, Lo must pro-
vide sufficient evidence to persuade us that the Quake ’018
patent is so lacking of written description that one of skill
in the art at the time would not have recognized the inven-
tion Quake claims.” J.A. 1007, 1034, 1063. On remand,
the Board determined that step D of Quake’s claims was
not supported by the ’018 patent specification based on Lo’s
arguments and expert testimony explaining that random
MPS requires normalization for chromosome size and ex-
plaining why the ’018 patent does not describe such analy-
sis. J.A. 17–22. We do not find that the Board erroneously
shifted the burden of proof here.
                             II.
    Quake also argues that the Board erred by refusing to
admit expert testimony from the terminated district court
proceedings into the record. According to Quake, Dr. Ga-
briel (Lo’s expert) made key admissions on the issue of
whether there was adequate description of claim step D. 6
    This court already characterized the district proceed-
ing as a “nullity” and declined to consider evidence from it
in the previous appeal. Stanford, 860 F.3d at 1374–75. We
did however leave it “up to the Board to decide whether it
wishes to reopen the record” on remand if it believed that

    6   Lo argues that we should reject this argument be-
cause Quake did not present it to the Board. Appellee’s Br.
54. But Quake raised the issue both in a conference call
with the Board after this court’s remand and in its rehear-
ing request. Interference No. 105,920, Order–New Briefing
and Evidence 37 C.F.R. § 41.104(a) (December 12, 2017);
J.A. 7741–42. We do not find waiver of this issue.
26                                               QUAKE v. LO

“new evidence may have been developed in the district pro-
ceedings,” and specifically “express[ed] no opinion on
whether it should do so.” Id. at 1375.
     On remand, the Board considered and then decided not
to reopen the record. We review that Board decision re-
garding management of its permissive rules governing
trial proceedings for abuse of discretion. Redline Detection,
LLC v. Star Envirotech, Inc., 811 F.3d 435, 442 (Fed. Cir.
2015). Quake argues that this case is like Ultratec, where
we found such abuse when (1) the proffered testimony was
inconsistent with the same witness’s testimony already in
the record (both for substantive and credibility purposes);
(2) there was no reviewable transcript of a conference call
during which the Board discussed the issue with the par-
ties; and (3) the Board provided no written, reviewable rea-
soning for why it did not allow the evidence into the record.
Ultratec, Inc. v. CaptionCall, LLC, 872 F.3d 1267, 1272–
1275 (Fed. Cir. 2017). None of these issues are present
here.
    First, the testimony that Quake argues should have
been considered is not inconsistent to the extent it would
bear on the substance of Dr. Gabriel’s reasoning or her
credibility. One excerpt reads:
     Q. So the written description issue you have with
     Step D of Claim 1 relates to the fact that the data
     comes from Step C, not anything else in Step D,
     right?
     A. Step B and C.
     Q. Step B and C, okay. But nothing else in Step D.
     It’s not the comparison in Step D that’s the prob-
     lem, right? Because that’s described throughout
     the patent specification.
     A. Yes.
QUAKE v. LO                                               27

J.A. 12835. This testimony is consistent with what Dr. Ga-
briel and Lo have been arguing all along and what the
Board found: the written description issue with step D re-
sults from the recitation of random MPS data in preceding
steps B and C. “[N]othing else . . . in Step D [is] the prob-
lem” in that step D is adequately described for analyzing
data resulting from methods such as digital PCR or tar-
geted MPS and would be adequately described for analyz-
ing data from random MPS, if obtaining data via random
MPS (Steps B and C) was expressly described in the speci-
fication.
    Quake also points to Dr. Gabriel’s testimony that the
inventive part of the ’018 patent is using a mixed maternal
and fetal DNA sample to determine aneuploidy, while ad-
mitting that the “digital analysis techniques discussed in
the ’018 patent” were known. J.A. 12838–39. Quake ar-
gues that this would explain “why a skilled artisan would
understand the invention is possessed by Quake even if un-
claimed details of embodiments of the invention were not
expressly spelled out for known sequencing methods.” Ap-
pellants’ Op. Br. 53. As an initial matter, as Lo points out,
this excerpted testimony refers expressly to using “digital
analysis techniques” and “digital analytic methods” to con-
duct aneuploidy detection, which is digital PCR, not ran-
dom MPS. Appellees’ Br. 58–59. Further, this testimony
is not inconsistent; it is inapposite. An admission that
MPS was generally known does not address whether the
’018 specification describes using random MPS to deter-
mine fetal aneuploidy. Finally, whether the step D meth-
ods were inventive or not is irrelevant to the issue here;
they are still part of the claim and need to be adequately
described to satisfy § 112.
    Second, there is a transcript of the conference call be-
tween the Board and parties here, J.A. 7576–620, and the
Board provided written reasoning for its decision. The
Board issued an Order explaining in detail why it would
not reopen the record, pointing out that (1) “[n]either party
28                                                QUAKE v. LO

argued . . . that it lacked an opportunity to present evidence
during the interference”; (2) Quake did not provide a “suf-
ficient reason to give either party a second chance to pre-
sent evidence on the same issues that were originally
before the Board”; (3) “Quake did not provide a persuasive
reason why the arguments and evidence it made in opposi-
tion to Lo’s original motions were not complete during the
interference”; and (4) “Quake did not explain how allowing
additional evidence at this point in the proceeding will lead
to a more ‘just, speedy, and inexpensive’ resolution of the
proceeding.” J.A. 7574. Quake did not seek rehearing of
the Board’s decision in the Order. J.A. 7741.
     Third, the Board again wrote out its reasoning for why
it did not admit the testimony in denying Quake’s requests
for rehearing of the final written decisions now on appeal.
J.A.7740–42. In those requests, Quake asked the Board to
reopen the record to add a specific part of Dr. Gabriel’s dis-
trict court testimony regarding Lo’s statistical analysis dis-
closure and argued that it would be a denial of due process
not to do so. The Board denied that request because it
found the testimony irrelevant to Quake’s written descrip-
tion. J.A. 7741–42. The Board also found that “[b]ecause
Quake has failed to show why it did not have a full and fair
opportunity to present evidence and argument with its
original briefs, including from the cross-examination of Dr.
Gabriel conducted during the interference, it is not clear
what due process was denied.” Id.
    In sum, we find that the Board was within its discre-
tion to not reopen the record for the admission of the testi-
mony at issue.
                        CONCLUSION
    Because the shared specification of Quake’s ’018 patent
and ’833 application does not disclose a method of using
random MPS to determine fetal aneuploidy, substantial ev-
idence supports the Board’s grant of Lo’s motions finding
the four claims of the ’018 patent and claim 25 of the ’833
QUAKE v. LO                                              29

application unpatentable for lack of written description un-
der § 112. We also find that the Board did not abuse its
discretion in not admitting Dr. Gabriel’s testimony from
the district court proceedings. Accordingly, the Board’s
three interference decisions are
                       AFFIRMED