Document ID: s3://data.kl3m.ai/documents/govinfo/USCOURTS/USCOURTS-ca13-23-01345/USCOURTS-ca13-23-01345-0/pdf.json

Parties Involved:
Laboratory Corporation of America Holdings
Appellant
Ravgen, Inc.
Appellee

Document Text:

NOTE: This disposition is nonprecedential.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,

Case: 23-1345 Document: 10 Page: 1 Filed: 01/06/2025
LABORATORY CORPORATION OF AMERICA HOLDINGS v.

RAVGEN, INC.

2

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. 

Case: 23-1345 Document: 10 Page: 2 Filed: 01/06/2025
LABORATORY CORPORATION OF AMERICA HOLDINGS v.

RAVGEN, INC.

3

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 

Case: 23-1345 Document: 10 Page: 3 Filed: 01/06/2025
LABORATORY CORPORATION OF AMERICA HOLDINGS v.

RAVGEN, INC.

4

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. 

Case: 23-1345 Document: 10 Page: 4 Filed: 01/06/2025
LABORATORY CORPORATION OF AMERICA HOLDINGS v.

RAVGEN, INC.

5

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

Case: 23-1345 Document: 10 Page: 5 Filed: 01/06/2025
LABORATORY CORPORATION OF AMERICA HOLDINGS v.

RAVGEN, INC.

6

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 

Case: 23-1345 Document: 10 Page: 6 Filed: 01/06/2025
LABORATORY CORPORATION OF AMERICA HOLDINGS v.

RAVGEN, INC.

7

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 

Case: 23-1345 Document: 10 Page: 7 Filed: 01/06/2025
LABORATORY CORPORATION OF AMERICA HOLDINGS v.

RAVGEN, INC.

8

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 

Case: 23-1345 Document: 10 Page: 8 Filed: 01/06/2025
LABORATORY CORPORATION OF AMERICA HOLDINGS v.

RAVGEN, INC.

9

[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 

Case: 23-1345 Document: 10 Page: 9 Filed: 01/06/2025
LABORATORY CORPORATION OF AMERICA HOLDINGS v.

RAVGEN, INC.

10

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] 

Case: 23-1345 Document: 10 Page: 10 Filed: 01/06/2025
LABORATORY CORPORATION OF AMERICA HOLDINGS v.

RAVGEN, INC.

11

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.

Case: 23-1345 Document: 10 Page: 11 Filed: 01/06/2025
LABORATORY CORPORATION OF AMERICA HOLDINGS v.

RAVGEN, INC.

12

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

Case: 23-1345 Document: 10 Page: 12 Filed: 01/06/2025