Laboratory Corporation of America Holdings v. Ravgen, Inc.

NOTE: This disposition is nonprecedential.
United States Court of Appeals
for the Federal Circuit
______________________
LABORATORY CORPORATION OF AMERICA
HOLDINGS,
Appellant
v.
RAVGEN, INC.,
Appellee
______________________
2023-1342, 2023-1345
______________________
Appeals from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in Nos. IPR2021-
00902, IPR2021-01054.
______________________
Decided: January 6, 2025
______________________
GREGORY A. CASTANIAS, Jones Day, Washington, DC,
argued for appellant. Also represented by AMELIA A.
DEGORY, BRENDAN D. DUFFY, TRACY A. STITT, JENNIFER L.
SWIZE; GASPER LAROSA, New York, NY; JOHN C. ALEMANNI,
Kilpatrick Townsend & Stockton LLP, Raleigh, NC; TINA
WILLIAMS MCKEON, Atlanta, GA.
BRIAN MATTY, Desmarais LLP, New York, NY, argued
for appellee. Also represented by JOHN M. DESMARAIS,
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LABORATORY CORPORATION OF AMERICA HOLDINGS v.
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KERRI-ANN LIMBEEK; GABRIELLE E. HIGGINS, San
Francisco, CA.
______________________
Before LOURIE, BRYSON, and STARK, Circuit Judges.
LOURIE, Circuit Judge.
Laboratory Corporation of America Holdings
(“Labcorp”) appeals from two final written decisions of the
U.S. Patent Trial and Appeal Board (“the Board”)
collectively holding that claims 55–63, 66–69, 80–96, and
127–133 of U.S. Patent 7,332,277 (“the ’277 patent”) had
not been shown to have been obvious. Lab’y Corp. of Am.
Holdings v. Ravgen, Inc., No. IPR2021-00902, 2022 WL
16579960 (P.T.A.B. Nov. 1, 2022) (holding that claims 81–
96 and 133 had not been shown to be unpatentable) (“00902
Decision”); Lab’y Corp. of Am. Holdings v. Ravgen, Inc., No.
IPR2021-01054, 2022 WL 16641665 (P.T.A.B. Nov. 1, 2022)
(holding that claims 55–63, 66–69, 80, and 127–132 had not
been shown to be unpatentable) (“01054 Decision”).1 The
Board determined that Labcorp had failed to demonstrate
that a person of ordinary skill in the art would have been
motivated to combine the asserted prior art references. For
the following reasons, we affirm.
BACKGROUND
Ravgen, Inc. (“Ravgen”) owns the ’277 patent, which is
directed to non-invasive methods for sampling DNA and
detecting genetic disorders in a fetus. ’277 patent,
Abstract. The ’277 patent relates to, inter alia, analyzing
cell-free fetal DNA (“cffDNA”) found in a blood sample
drawn from a pregnant mother with a cell lysis inhibitor
1 The final written decisions share nearly identical
analyses of the issues relevant to the parties’ dispute on
appeal. Unless otherwise indicated, we cite the 01054
Decision as representative.
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added to the sample. Id. at col. 89, ll. 1–15; see also id. at
col. 26, ll. 15–24, 40–44. The ’277 patent provides a list of
agents that can act as cell lysis inhibitors, including
formaldehyde, formaldehyde derivatives, and formalin
(collectively, “formaldehyde compounds”). Id. at col. 31, l.
57–col. 32, l. 3. Claims 55 and 132 are illustrative for the
issues on appeal.
Claim 55 reads as follows:
55. A method comprising determining the sequence
of a locus of interest on free fetal DNA isolated from
a sample obtained from a pregnant female, wherein
said sample comprises free fetal DNA and an agent
that inhibits lysis of cells, if cells are present,
wherein said agent is selected from the group
consisting of membrane stabilizer, cross-linker, and
cell lysis inhibitor.
Id. at col. 472, l. 66–col. 473, l. 5. Claim 132 depends from
claim 60, which depends from claim 59, which depends
from claim 55. Claim 59 adds “wherein said agent is a cell
lysis inhibitor.” Id. at col. 473, ll. 13–14. Claim 60 adds
“wherein said cell lysis inhibitor is selected from the group
consisting of: glutaraldehyde, derivatives of
glutaraldehyde, formaldehyde, derivatives of
formaldehyde, and formalin.” Id. at col. 473, ll. 15–18. And
finally, claim 132 reads as follows:
132. The method of claim 60, wherein said cell lysis
inhibitor is selected from glutaraldehyde,
formaldehyde, and formalin.
Id. at col. 478, ll. 12–14.
In two inter partes review petitions, Labcorp
challenged claims 55–63, 66–69, 80–96, and 127–133 of the
’277 patent, arguing that the claims would have been
unpatentable as obvious under 35 U.S.C. § 103.
Specifically, Labcorp argued that a person of ordinary skill
in the art would have been motivated to combine the
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maternal blood processing method disclosed in a 2001
Clinical Chemistry article (“Chiu”)2 with the formaldehyde
compounds disclosed in U.S. Patent 5,648,220 (“Bianchi”)
or in International Patent Application Publication WO
03/018757 (“Rao”), thereby rendering the claims obvious.3
Chiu reports a study on the effects of blood-processing
protocols on fetal and total DNA quantification in maternal
plasma. J.A. 17638–44. Bianchi discloses a method of
labeling a cell where the plasma membrane of the cell is
permeabilized so that substantially all the DNA of the cell
remains in the cell. Bianchi at Abstract. Bianchi’s method
involves the use of paraformaldehyde. Bianchi at col. 3, ll.
36–53. And Rao discloses a method of stabilizing rare
cancer cells in a blood sample using paraformaldehyde.
Rao at p. 3, ll. 12–15, p. 24, ll. 2–17.
The Board determined that the challenged claims had
not been shown to be unpatentable. 01054 Decision, at
*22–23. The Board found that a person of ordinary skill in
the art would not have been motivated to combine Chiu and
Bianchi because one “would have expected Bianchi’s
paraformaldehyde to create gaps in the cell membranes,
providing a means for maternal DNA to escape into the
sample.” 01054 Decision, at *14. The Board also found
that a person of ordinary skill in the art would not have
been motivated to combine Chiu with Bianchi or Rao
because “formaldehyde was known to damage nucleic
acids.” Id. At bottom, the Board determined that
“[Ravgen]’s reasoning and evidence on [motivation to
2 Chiu et al., Effects of Blood-Processing Protocols on
Fetal and Total DNA Quantification in Maternal Plasma,
47:9 CLINICAL CHEMISTRY 1607–13 (2001), J.A. 17638–44.
3 IPR2021-01054 included an additional reference in
its proposed Chiu-Bianchi and Chiu-Rao combinations;
however, the additional reference is not relevant to the
issues on appeal.
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combine] . . . outweigh[ed] [Labcorp]’s.” Id. Labcorp timely
appealed, and we have jurisdiction under 28 U.S.C.
§ 1295(a)(4)(A).
DISCUSSION
Labcorp raises both legal and factual challenges on
appeal. It argues that the Board’s motivation to combine
analysis was legally flawed for three reasons. According to
Labcorp, the Board (1) required a heightened and
untenable standard for proving a motivation to combine,
(2) did not adhere to precedents that require reading each
reference as a whole, and (3) in effect engaged in post hoc
claim construction to read additional limitations into the
claims. Labcorp also argues that the Board’s factual
findings were not supported by substantial evidence. We
address those arguments in turn.
I
Obviousness is a question of law based on underlying
findings of fact. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
427 (2007). We review the Board’s legal conclusion on
obviousness de novo and its findings of fact for substantial
evidence. HTC Corp. v. Cellular Commc’ns Equip., LLC,
877 F.3d 1361, 1369 (Fed. Cir. 2017). What a reference
teaches and the presence or absence of a motivation to
combine references are questions of fact. PAR Pharm., Inc.
v. TWI Pharms., Inc., 773 F.3d 1186, 1196–97 (Fed. Cir.
2014).
A
Labcorp’s first argument—that the Board imposed an
improperly heightened standard for obviousness—
mischaracterizes the analysis of the Board in an attempt
to reframe factual issues as legal ones. According to
Labcorp, the Board erroneously required Labcorp’s
proposed combinations to be perfect, rather than merely
desirable, which is all the case law requires. See Labcorp
Br. 30–32. Specifically, Labcorp argues that the Board’s
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analysis of Bianchi (or its “DNA Leakage” rationale) is
legally flawed because it “fixated on the fact that even the
potential for only 1% leakage [in Bianchi] would have been
‘contrary to’ the goals of Chiu.” Id. at 33. According to
Labcorp, the Board’s focus on “a minuscule amount of
maternal DNA” leakage as opposed to the benefits of cell
stabilization disclosed in Bianchi amounts to legal error by
demanding “the most desirable combination,” id. at 32–33
(quoting In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004)),
and ignores that “simultaneous advantages and
disadvantages . . . do[] not necessarily obviate motivation
to combine,” id. at 34 (quoting Medichem, S.A. v. Rolabo,
S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006)).
The Board did not apply an improperly heightened
motivation-to-combine standard in its analysis of Bianchi.
It evaluated the disclosures of Bianchi and found that a
person of ordinary skill in the art “would have been
dissuaded from adding Bianchi’s paraformaldehyde [to the
cffDNA detection method of Chiu] because the [person of
ordinary skill in the art] would have expected Bianchi’s
paraformaldehyde to create gaps in the cell membranes,
providing a means for maternal DNA to escape into the
sample.” 01054 Decision, at *14. In reaching that
conclusion, the Board evaluated the testimony of both
experts and analyzed the teachings of Bianchi and Chiu,
which ultimately led it to disagree with Labcorp’s view.
See, e.g., id. at *15 (“We credit [Ravgen’s expert]’s opinion
that adopting Bianchi’s approach to treating cells with
paraformaldehyde creates a means for cellular DNA to
escape.”); id. (“As [Labcorp’s expert] concedes, ‘DNA
leaking out of cells’ is something ‘Chiu tells us you do not
want [] to happen.’”). The Board recognized that Bianchi
“most preferably” retains “99% or greater” of the DNA in
the cell but found that a person of ordinary skill in the art
“would realize that releasing 1% of cellular DNA in a
sample in Chiu would have a negative effect on Chiu’s fetal
cell-free DNA analyses.” Id. At their core, those are
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factual—not legal—determinations. See Arctic Cat Inc. v.
Bombardier Recreational Prods. Inc., 876 F.3d 1350, 1360
(Fed. Cir. 2017) (“The prior art, skill, and knowledge of an
ordinary artisan may also provide reasons not to combine
which would likewise be a question of fact.”). The Board
therefore did not require an improperly heighted standard
for obviousness by rejecting Labcorp’s positions; rather, it
found that Labcorp failed to “provide persuasive argument
or evidence to explain why creating holes in the cell
membranes . . . would have been seen by the [person of
ordinary skill in the art] as acceptable.” 01054 Decision, at
*15.
Simply put, Labcorp’s “disagreement with the Board’s
interpretations of [Bianchi] does not amount to a
demonstration that the Board somehow failed to use the
proper analysis.” Eli Lilly & Co. v. Teva Pharms. Int’l
GmbH, 8 F.4th 1331, 1347 (Fed. Cir. 2021).
Labcorp makes similar arguments with respect to the
Board’s “DNA damage” rationale and the standard for
obviousness applied by the Board. According to Labcorp,
the Board legally erred because it improperly relied on
generic concerns of DNA damage, failed to consider if a
person of ordinary skill in the art would have pursued the
invention despite those concerns, and did not follow our
precedent on what constitutes teaching away. Labcorp Br.
34–40. Again, we disagree with Labcorp’s attempt to recast
factual issues as legal ones.
The Board did not impermissibly rely on generic
concerns of formaldehyde’s potential to damage DNA, as
Labcorp asserts. See Labcorp Br. 36. Labcorp compares
the Board’s analysis to that in Auris Health, Inc. v.
Intuitive Surgical Operations, Inc., 32 F.4th 1154 (Fed. Cir.
2022), where the Board impermissibly relied on “vague
expert testimony that ‘there was great skepticism for
performing telesurgery.’” Id. at 1159. However, that is not
the case here where the concerns relied on by the Board
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were specific to the claimed invention. Id. (“[S]pecific
evidence of industry skepticism related to a specific
combination of references might contribute to finding a
lack of motivation to combine.”). The claims recite a
method for “determining the sequence of a locus of interest
on free fetal DNA isolated from a sample,” ’277 patent, col.
472, ll. 66–67 (emphasis added), and the industry’s
concerns were specific to “formaldehyde’s potential effects
on DNA, and cell-free fetal DNA in particular,” 01054
Decision, at *16; see, e.g., id. at *19 (“Rao discloses that
formaldehyde released from formaldehyde donors was
known to ‘irreversibly cross link[] nucleic acids.’”). As such,
it is clear from the Board’s analysis that it did not rely on
general “industry skepticism,” but rather relied on
concerns specific to the combination of references. See
Auris Health, 32 F.4th at 1159.
Similarly, the Board did not fail to consider whether a
person of ordinary skill would have pursued the invention
despite any concerns of formaldehyde’s potential to damage
DNA. Rather, it acknowledged the high level of skill in the
art, see 01054 Decision, at *5, considered Labcorp’s
arguments relating to that high level of skill, and rejected
them, see, e.g., id. at *18 (“[I]nasmuch as [Labcorp] is
suggesting a [person of ordinary skill in the art] might
simply ‘tailor’ the processing conditions for using
formaldehyde effectively, [Labcorp]’s argument fails.”).
And as with the Board’s DNA Leakage rationale, Labcorp’s
“disagreement with the Board’s interpretations . . . does
not amount to a demonstration that the Board somehow
failed to use the proper analysis.” Eli Lilly, 8 F.4th at 1347.
Finally, with respect to Labcorp’s arguments associated
with the Board’s analysis of Bianchi, the Board did not
ignore our precedent on teaching away. See Labcorp Br.
38–40. The Board did not rely on a teaching away, but
found that, on the balance of the evidence, “the literature
would have dissuaded a [person of ordinary skill in the art]
from using formaldehyde or paraformaldehyde in the
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[Chiu] modified method.” 01054 Decision, at *17. Even if
evidence does not “rise to the level of teaching away,” it is
still proper for the Board to consider evidence that
“suggests reasons that a skilled artisan would be
discouraged from pursuing such a combination.” Arctic Cat
Inc., 876 F.3d at 1363. For the foregoing reasons, we find
Labcorp’s arguments that the Board legally erred in its
analysis of the DNA Leakage rationale unpersuasive.
B
Next, Labcorp argues that the Board legally erred by
failing to consider Bianchi and Rao for everything they
teach. With respect to Bianchi, Labcorp argues that the
Board ignored the teaching of Bianchi that “99% or
greater” of the DNA should remain in the cells. Labcorp
Br. 42–43. With respect to Rao, Labcorp argues that the
Board ignored Rao’s teaching that paraformaldehyde is
“frequently used for fixing and stabilizing tumor cells in
blood” despite its shortcomings and that handling those
concerns would be “readily apparent to one skilled in cell
biology.” Id. at 43–44 (citing Rao, p. 3, ll. 16–18, p. 7, ll. 30–
33). Again, we disagree.
Contrary to Labcorp’s arguments, the Board did not
ignore the identified teachings. The Board
“acknowledge[d] that Bianchi prefers that greater amounts
of DNA stay in the cells,” 01054 Decision, at *15, and cited
the exact passage that Labcorp now asserts was ignored,
see id. (quoting Bianchi’s “most preferably 99% or greater”
teaching). Similarly, the Board explicitly cited Rao’s
teaching that paraformaldehyde is “frequently used for
fixing and stabilizing tumor cells in blood.” Id. at *9. And,
although less explicit, the Board’s consideration of Rao’s
teaching that using paraformaldehyde in a concentration
effective to stabilize cells without causing damage “would
be readily apparent to one skilled in cell biology,” was clear,
see Reply Br. 17 (quoting Rao, p. 3, ll. 16–18) (emphasis in
Reply Br. omitted), because the Board considered and
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rejected Labcorp’s related argument that a person of
ordinary skill could “simply ‘tailor’ the processing
conditions for using formaldehyde effectively,” 01054
Decision, at *18. However, even if the Board’s
consideration of these teachings were not so clear, “we have
said numerous times, failure to explicitly discuss every
fleeting reference or minor argument does not alone
establish that the Board did not consider it.” Yeda Rsch. v.
Mylan Pharms. Inc., 906 F.3d 1031, 1046 (Fed. Cir. 2018).
C
In one final attempt to gain de novo review, Labcorp
argues that the Board engaged in improper post hoc claim
construction. According to Labcorp, the Board read into
the claims additional limitations prohibiting DNA damage
and requiring a certain degree of cell stabilization.
Labcorp Br. 46, 49–51. Relatedly, Labcorp argues that the
Board improperly evaluated whether a person of ordinary
skill in the art would have incorporated a feature of
Bianchi and Rao, i.e., formaldehyde, into the requirements
of Chiu rather than the requirements of the claims. Reply
Br. 7–8, 21 (citing Axonics, Inc. v. Medtronic, Inc., 73 F.4th
950 (Fed. Cir. 2023)). We disagree.
During the IPR proceedings, neither party identified
terms in need of construction, and the Board found it
unnecessary to expressly construe any terms. 01054
Decision, at *6. Nor do we see any implicit claim
construction by the Board, post hoc or at any time. Instead
of requiring a certain degree of cell stabilization, as
Labcorp unpersuasively charges, the Board properly relied
on the claims’ recitation of a method for “determining the
sequence of a locus of interest on free fetal DNA isolated
from a sample.” ’277 patent, col. 472, ll. 66–67. Consistent
with this claim requirement, the Board focused its
motivation to combine inquiry on issues specific to cffDNA.
See, e.g., 01054 Decision, at *16 (“A key question presented
in this case is whether a [person of ordinary skill in the art]
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would have been concerned with formaldehyde’s potential
effects on DNA, and cell-free fetal DNA in particular.”).
In fact, the parties’ arguments focused on those exact
issues, Bianchi’s disclosure of cell permeabilization, and
the potential for formaldehyde compounds to damage DNA.
See id. at *10–12 (summarizing the parties’ motivation to
combine arguments). The Board’s analysis, which
considered the contours of those arguments and found no
motivation to combine, does not amount to reading
unclaimed requirements into the claims. See, e.g., id. at
*15 (finding Ravgen’s expert’s testimony persuasive that a
person of ordinary skill in the art “would realize that
releasing 1% of cellular DNA in a sample in Chiu would
have a negative effect on Chiu’s fetal cell-free DNA
analyses.”); id. at *17 (“[W]e have a dearth of evidence
suggesting formaldehyde’s use in a sample where cell-free
DNA is the analyte, and no sufficient, persuasive evidence
or technical reasoning to explain why a [person of ordinary
skill in the art] would not have been concerned with
potential damage to the cffDNA.”).
Similarly, the Board did not err by focusing its
obviousness inquiry on the context or the requirements of
the prior art rather than the claims. But see Axonics, 73
F.4th at 958 (finding that the Board erred by limiting its
obviousness analysis to the context of a specific facial nerve
addressed by the prior art when the claims were not limited
to that specific facial nerve). Here, as discussed above, the
Board focused its obviousness analysis on the context of
cffDNA, which is the context of the claims and also the
context of Chiu. See ’277 patent, col. 472, ll. 66–67
(“determining the sequence of a locus of interest on free
fetal DNA”); see Chiu at 1608, J.A. 17639 (“[I]t is the
objective of this study to investigate the effects of different
blood-processing protocols on the quantitative analysis of
total and fetal DNA in maternal plasma[.]”). As such, we
fail to see how the Board’s analysis here is analogous to the
error identified in Axonics. See 73 F.4th at 958.
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For those reasons, we find no legal error in the Board’s
motivation to combine analysis.
II
Finally, Labcorp argues that the Board’s findings were
not supported by substantial evidence because the Board
(1) failed to account for the evidence that both justified and
detracted from its decision, (2) “grossly misinterpreted
Bianchi,” and (3) “relied on pure conjecture.” Labcorp Br.
53–58. We disagree on all three counts.
As is apparent from the discussion of the legal issues
above, the Board thoroughly considered the references and
expert testimony provided by both parties. Labcorp has
failed to identify any factual finding by the Board that was
not reasonably supported by substantial evidence. At
bottom, the Board weighed the evidence both for and
against a motivation to combine the references and found
that Ravgen’s “reasoning and evidence on those issues,
separately and cumulatively, outweigh[ed] [Labcorp’s]
comparatively weak showing on whether a [person of
ordinary skill in the art] would have combined the art in
the manner proposed.” 01054 Decision, at *14. “This court
does not reweigh evidence on appeal.” In re NTP, Inc., 654
F.3d 1279, 1292 (Fed. Cir. 2011).
CONCLUSION
We have considered Labcorp’s remaining arguments
and find them unpersuasive. For the forgoing reasons, we
affirm the Board’s decisions in IPR2021-00902 and
IPR2021-01054.
AFFIRMED
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