  United States Court of Appeals
      for the Federal Circuit
               ______________________

 INSTITUT PASTEUR & UNIVERSITE PIERRE ET
              MARIE CURIE,
                Appellant,

                          v.

            MARGARET A. FOCARINO,
            Commissioner for Patents,
                   Appellee,

                         AND

         PRECISION BIOSCIENCES, INC.,
                    Appellee.
             ______________________

                     2012-1485
               ______________________

    Appeal from the United States Patent and Trademark
Office, Board of Patent Appeals and Interferences in
Reexamination No. 95/000,443.

             ----------------------

 INSTITUT PASTEUR & UNIVERSITE PIERRE ET
              MARIE CURIE,
                Appellant,

                          v.

            MARGARET A. FOCARINO,
2             INSTITUT PASTEUR & UNIVERSITE V. FORCARINO




             Commissioner for Patents,
                    Appellee,

                         AND

          PRECISION BIOSCIENCES, INC.,
                     Appellee.
              ______________________

                     2012-1486
               ______________________

    Appeal from the United States Patent and Trademark
Office, Board of Patent Appeals and Interferences in
Reexamination No. 95/000,490.

             ----------------------

    INSTITUT PASTEUR & UNIVERSITE PIERRE ET
                 MARIE CURIE,
                   Appellant,

                          v.

            MARGARET A. FOCARINO,
            Commissioner for Patents,
                   Appellee,

                         AND

          PRECISION BIOSCIENCES, INC.,
                     Appellee.
              ______________________

                     2012-1487
               ______________________
INSTITUT PASTEUR & UNIVERSITE   v. FOCARINO              3



    Appeal from the United States Patent and Trademark
Office, Board of Patent Appeals and Interferences in
Reexamination No. 95/000,491.
                 ______________________

               Decided: December 30, 2013
                ______________________

   THOMAS H. JENKINS, Finnegan, Henderson, Farabow,
Garrett & Dunner, LLP, of Washington, DC, argued for
appellant. With him on the brief was KENNETH J.
MEYERS, of Washington, DC and AMELIA F. BAUR, of
Boston, Massachusetts.

    MARY L. KELLY, Associate Solicitor, United States Pa-
tent and Trademark Office, of Alexandria, Virginia,
argued for appellee Margaret A. Focarino, Commissioner
for Patents. With her on the brief were NATHAN K.
KELLEY, Acting Solicitor, and KRISTI L. R. SAWERT, Asso-
ciate Solicitor.

   MICHAEL J. TWOMEY, Wilmer Cutler Pickering Hale
and Dorr, LLP, of Boston, Massachusetts, argued for
appellee Precision BioSciences, Inc. Of counsel was
ANDREJ BARBIC.
                 ______________________

   Before NEWMAN, CLEVENGER, and TARANTO, Circuit
                      Judges.
TARANTO, Circuit Judge.
    The Institut Pasteur owns U.S. Patent Nos. 7,309,605,
6,610,545, and 6,833,252, which claim methods and tools
for the site-directed insertion of genes into eukaryotic
chromosomes.      Precision BioSciences requested inter
partes reexamination of each of the patents, and the
Patent and Trademark Office examiner rejected a number
of Pasteur’s claims for obviousness, under 35 U.S.C. § 103.
4               INSTITUT PASTEUR & UNIVERSITE V. FORCARINO




On appeal, the Board of Patent Appeals and Interferences
(now the Patent Trial and Appeal Board) affirmed the
rejections, concluding that the claimed inventions were
obvious extensions of two prior-art references disclosing
similar methods of targeting non-chromosomal DNA in
prokaryotic cells. Pasteur appeals the Board’s conclusions
to this court. For the ’605 patent, we dismiss Pasteur’s
appeal as moot, because Pasteur presented only substan-
tively amended claims to the Board and to this court, and
amended claims cannot be entered now that the patent
has expired. For the ’545 patent, we reverse the Board’s
conclusion as based on factual findings unsupported by
substantial evidence and an erroneous obviousness analy-
sis, including an improper discounting of Pasteur’s objec-
tive indicia of non-obviousness. For the ’252 patent, we
vacate the Board’s decision and remand for consideration
of what motivation, if any, a skilled artisan at the rele-
vant time would have had to pursue the claimed inven-
tion.
                       BACKGROUND
     In the early 1990s, scientists at the Institut Pasteur
made a series of inventions that allowed for the insertion,
deletion, or modification of genes at targeted locations in
the chromosomes of living cells. Specifically, Pasteur
discovered a class of enzymes—group I intron-encoded
(GIIE) endonucleases—that cleave both backbones of the
DNA double helix at the location of a specific nucleotide
sequence, called a recognition site. Pasteur established,
first, that GIIE endonucleases can cleave DNA in the
chromosomes of eukaryotic (nucleus-possessing) cells and,
second, that eukaryotic cells can successfully repair such
cleavages by initiating a process known as homologous
recombination. This process uses a DNA template whose
sequence is, in certain places, highly similar (i.e., homolo-
gous) to that of the cleaved chromosomal DNA. It re-
quires that the DNA template be homologous only at two
portions, which must, respectively, match the regions of
INSTITUT PASTEUR & UNIVERSITE   v. FOCARINO            5



the pieces of the broken DNA on either side of the break.
When such matching occurs, the whole template se-
quence, including the nucleotides lying between the
matching portions, gets copied to become part of a re-
joined DNA molecule in a chromosome. The cell faithfully
reproduces the DNA template, including the interior
nucleotides, which need not match the broken DNA at all.
In this way, it is possible to design a DNA template that
adds a DNA sequence to the chromosome or makes specif-
ic alterations to its sequence.
    GIIE endonucleases are particularly well suited for
genetic engineering. Their recognition sites, i.e., the
nucleotide sequences at which they cleave DNA, are much
longer than most other endonucleases. Whereas other
classes of endonucleases recognize and bind to DNA
sequences as short as four to eight nucleotides long, the
recognition sites of GIIE endonucleases extend over
eighteen nucleotides. This makes GIIE endonucleases
much more discriminating in where they cleave a DNA
molecule. By sheer probability, a given sequence of eight
nucleotides occurs much more frequently than one of
eighteen nucleotides. So whereas other endonucleases
tend to cleave an organism’s DNA at many different sites,
GIIE endonucleases provide far superior specificity.
    Pasteur first encountered GIIE endonucleases in
yeast mitochondria, which are membrane-enclosed struc-
tures found within most eukaryotic cells. Although most
of an organism’s DNA is contained in chromosomes locat-
ed in the cell nucleus—a different membrane-enclosed
cellular structure—mitochondria have a small amount of
their own DNA. Pasteur identified a specific DNA se-
quence that is repeatedly copied from one location in the
mitochondrial DNA to another location in that DNA, i.e.,
a mobile genetic sequence. The mobile DNA sequence
that Pasteur identified resided in the introns of mito-
chondrial genes, i.e., those nucleotides in a gene that
generally do not code for the protein that the gene ex-
6               INSTITUT PASTEUR & UNIVERSITE V. FORCARINO




presses. After analyzing this mobile intronic sequence,
Pasteur determined that it coded for an endonuclease, an
enzyme that cleaves DNA backbones. Pasteur named the
newly discovered endonuclease “I-SceI,” and the new class
became known as group I intron-encoded endonucleases.
    Pasteur recognized that GIIE endonucleases could be
useful laboratory tools and set out to determine whether
they could cleave DNA other than the yeast mitochondrial
DNA that they naturally cleave. First, Pasteur inserted
an artificial GIIE endonuclease recognition site into a
yeast chromosome and demonstrated that the GIIE
endonuclease cleaved yeast chromosomes after they had
been extracted from yeast cells and purified. See, e.g.,
’545 patent, col. 15, line 63, to col. 16, line 8. Next, Pas-
teur created a plasmid—a small DNA molecule that is
separate from and can replicate independently of chromo-
somal DNA—containing an artificial GIIE endonuclease
recognition site and injected the plasmid into the yeast
nucleus. The GIIE endonuclease successfully cleaved the
plasmid. See, e.g., id., col. 18, lines 35-39. Finally, and of
particular significance, Pasteur found that GIIE endonu-
cleases could cleave chromosomes in living cells and that,
if DNA homologous to the cleavage site was present or
added, the cell could repair the break using homologous
recombination. See, e.g., id., col. 18, lines 42-53.
    Pasteur filed a series of patent applications relating
generally to GIIE endonucleases and methods of using
them to insert DNA at a targeted location in an organ-
ism’s DNA. All of the patents at issue here—the ’605,
’545, and ’252 patents—claim priority to the same patent
application, which was filed on May 5, 1992, and is now
abandoned. All three patents expired on May 6, 2012.
The ’605 and ’252 patents have a common specification,
which differs in only minor ways from the specification of
the ’545 patent. Each specification describes first intro-
ducing a GIIE recognition site into a cell’s chromosomal
DNA. See, e.g., ’545 patent, col. 18, line 43, to col. 19, line
INSTITUT PASTEUR & UNIVERSITE   v. FOCARINO                7



64. By introducing into the cell both (a) a GIIE endonu-
clease and (b) a plasmid that is homologous to the cleav-
age site and contains the DNA sequence to be inserted,
the Pasteur inventors taught, it is possible to achieve the
“site specific insertion of a DNA fragment from a plasmid
into a chromosome.” Id., col. 19, lines 42-44.
    The ’605 patent claims methods for using a GIIE en-
donuclease to cleave DNA at a specific location and (for
some claims) the subsequent insertion of DNA. During
reexamination, Pasteur proposed amendments to claim 1
and the dependent claim now at issue, claim 14. Specifi-
cally, the proposed amendments would limit the claims to
targeting chromosomal DNA in viable cells. Claim 1
reads as follows, with the amendments underlined:
    1. A method for inducing at least one site directed
   double-stranded break in the chromosomal DNA
   of an organism comprising:
   (a) providing an isolated, viable cell of said organ-
   ism containing at least one Group I intron encod-
   ed endonuclease recognition site at a location in
   the chromosomal DNA of the cell,
   (b) providing said Group I intron encoded endonu-
   clease to said cell by genetically modifying the cell
   with a nucleic acid comprising said Group I intron
   encoded endonuclease or by introducing said
   Group I intron encoded endonuclease protein into
   the cell such that the Group I intron encoded en-
   donuclease cleaves said Group I intron encoded
   endonuclease site at the location in the DNA of
   the cell.
’605 patent, col. 69, lines 22-35; see also J.A. 79 (as
amended). Although claim 1 does not claim the insertion
of new DNA sequences into the cleaved DNA, dependent
claim 14, the only claim now at issue, adds that element.
It reads (also with a proposed amendment underlined):
8              INSTITUT PASTEUR & UNIVERSITE V. FORCARINO




    14. The method of claim 1, wherein said method
    further comprises providing to said cell
    a plasmid comprising a DNA sequence homolo-
    gous to the sequence of the chromosome, which al-
    lows homologous recombination, and
    a modified sequence,
    wherein said Group I intron encoded endonucle-
    ase cleaves the Group I intron encoded endonucle-
    ase recognition site,
    whereby said cleavage promotes the insertion of
    said modified sequence into said chromosomal
    DNA of said cell at a specific site by homologous
    recombination.
’605 patent, col. 70, lines 26-39; see also J.A. 4029 (as
amended).
     The ’545 patent similarly claims methods for the site-
specific insertion of DNA sequences into the chromosomes
of living cells. As amended during reexamination, Claim
7 reads:
    7. A method for in vivo site directed genetic re-
    combination in an organism comprising:
    (a) providing a transgenic eukaryotic cell having
    at least one Group I intron encoded endonuclease
    recognition site inserted at a unique location in a
    chromosome;
    (b) providing an expression vector that expresses
    said endonuclease in said transgenic cell;
    (c) providing a plasmid comprising a gene of inter-
    est and a DNA sequence homologous to the se-
    quence of the chromosome, allowing homologous
    recombination;
INSTITUT PASTEUR & UNIVERSITE   v. FOCARINO                 9



   (d) transfecting said transgenic cell with said
   plasmid of step (c);
   (e) expressing said endonuclease from said ex-
   pression vector in said cell; and
   (f) cleaving said at least one Group I intron encod-
   ed endonuclease recognition site with said endo-
   nuclease, whereby said cleavage promotes the
   insertion of said gene of interest into said chromo-
   some of said organism at a specific site by homol-
   ogous recombination.
’545 patent, col. 51, lines 14-33; see also J.A. 121 (as
amended). Dependent claims 10 and 12, the only claims
at issue in this appeal, limit the method to yeast and
mammalian cells, respectively. ’545 patent, col. 51, lines
40-41; id., col. 52, lines 3-4.
    The ’252 patent claims a mammalian chromosome
that contains a GIIE endonuclease recognition site. Its
claims, unlike the claims of the ’605 and ’545 patents at
issue here, do not require the targeted insertion of DNA
through homologous recombination. Claim 1 reads:
   1. A recombinant mammalian chromosome com-
   prising an exogenous Group I intron encoded en-
   donuclease site,
   wherein the endonuclease site is within an inte-
   grated nucleic acid sequence from a vector,
   wherein the site is selected from the group con-
   sisting of an I-SceIV site, an I-CsmI site, I-PanI
   site, I-SceII site, an I-CeuI site, an I-PpoI site, an
   I-SceIII site, an I-CreI site, an I-TevI site, an I-
   TevII site, an I-TevIII site, and an I-SceI site.
’252 patent, col. 67, lines 57-65. Pasteur did not amend
claim 1 during reexamination.
10             INSTITUT PASTEUR & UNIVERSITE V. FORCARINO




    In 2009, Precision BioSciences filed inter partes reex-
amination requests for the ’605, ’545, and ’252 patents
and for related U.S. Patent No. 7,214,536. See 35 U.S.C.
§ 311 et seq. (2006). The PTO granted all four requests,
and during the ensuing reexaminations, the Examiner
rejected most claims as anticipated or obvious.
    In each reexamination, Pasteur timely appealed the
rejections to the Patent Trial and Appeal Board. On
decisions dated the same day and before the same panel,
the Board relied on the same prior-art references to
conclude that the matter claimed in the claims now at
issue would have been obvious to one skilled in the art as
of May 1992. See Precision BioSciences, Inc. v. Institut
Pasteur, No. 11-012285, 2012 WL 1050572 (B.P.A.I. Mar.
14, 2012) (’605 Board Decision); Precision BioSciences, No.
11-010715, 2012 WL 1050569 (B.P.A.I. Mar. 14, 2012)
(’545 Board Decision); Precision BioSciences, No. 11-
011261, 2012 WL 1050570 (B.P.A.I. Mar. 14, 2012) (’252
Board Decision); Precision BioSciences, No. 11-010572,
2012 WL 1050568 (B.P.A.I. Mar. 14, 2012) (’536 Board
Decision).
     The Board founded its analysis on two articles from
scientific journals—the Quirk and Bell-Pedersen refer-
ences—that disclosed using a GIIE endonuclease to
transfer DNA from a plasmid to non-chromosomal DNA in
bacterial (i.e., prokaryotic) cells. See J.A. 12535 (Quirk
reference); id. at 8508 (Bell-Pedersen reference). Relying
on certain statements in the prior art, the Board found
that there was “reason to substitute the [non-
chromosomal prokaryotic] DNA described in Quirk and
Bell-Pedersen with chromosomal DNA of a eukaryotic
cell.” ’545 Board Decision, at *6; see ’605 Board Decision,
at *18; ’252 Board Decision, at *5.
    In its decisions on the ’605 and ’545 patents, the
Board then considered if “one of ordinary skill in the art
[had] a reasonable expectation that the teachings of Quirk
INSTITUT PASTEUR & UNIVERSITE   v. FOCARINO                11



and Bell-Pedersen could be successfully applied to [chro-
mosomal DNA in] yeast cells.” 1 ’545 Board Decision, at
*7; see ’605 Board Decision, at *17-18. In finding a rea-
sonable expectation of success, the Board relied on two
references—Frey and Dujon. ’545 Board Decision, at *8
(“Frey and Dujon[] achieved cleavage of eukaryotic chro-
mosomes using a GIIE[ endonuclease], giving rise to a
reasonable expectation of success that the claimed inven-
tion could be practiced successfully.”). The Board charac-
terized both references as disclosing cleavage of
chromosomal DNA in yeast cells. See id. (“In sum, each of
Frey and Dujon[] showed that a GIIE endonuclease
cleaved yeast chromosomal DNA when expressed in yeast
cells.”); id. at *7 (“Frey and Dujon . . . both . . . describe
results using GIIE endonucleases in yeast.”). (For the
Board’s similar findings in its ’605 ruling, see ’605 Board
Decision, at *17-18.) For the ’545 and ’252 patents, the
Board considered Pasteur’s evidence that the claimed
inventions were praised, copied, and licensed by the
industry, but concluded that the evidence did not out-
weigh “the strong case of obviousness.” ’545 Board Deci-
sion, at *10; see also ’252 Board Decision, at *6-7.
    Pasteur timely sought this court’s review of the
Board’s decisions. The PTO then moved to dismiss Pas-
teur’s appeal with respect to the ’536 patent, the ’605
patent, and all claims of the ’545 patent except dependent
claims 10 and 12. The PTO argued that, because all of
the patents had expired since the Board issued its deci-
sions, and because the Board could not enter amendments



    1  The Board’s analysis of the ’252 patent did not in-
clude a similar consideration, because “[c]laim 1 is di-
rected to a mammalian chromosome with a [GIIE
endonuclease] cleavage site” only. ’252 Board Decision, at
*6. Thus, the Board found that “the claims do not require
endonuclease activity.” Id.
12              INSTITUT PASTEUR & UNIVERSITE V. FORCARINO




to claims in expired patents, the challenges to the rejec-
tion of all claims that Pasteur had proposed to amend
during reexamination were moot. Pasteur did not oppose
the PTO’s motion with respect to the ’536 patent and to
certain claims of the ’545 patent, but did oppose dismiss-
ing its appeal of claim 14 of the ’605 patent. This court
dismissed Pasteur’s appeal with respect to the ’536 pa-
tent, as all parties agreed, but not with respect to the ’605
patent, explaining that the parties should address the
mootness of the ’605 patent claims in their briefing.
Order, Institut Pasteur, No. 12-1484 (Fed. Cir. Nov. 27,
2012).
    This court     has    jurisdiction   under   28   U.S.C.
§ 1295(a)(4)(A).
                         DISCUSSION
    Pasteur challenges the Board’s determinations of ob-
viousness as to claim 14 of the ’605 patent, claims 10 and
12 of the ’545 patent, and all claims of the ’252 patent.
We find Pasteur’s appeal moot as to the ’605 patent, and
we address the merits of the ’545 and ’252 patents.
                              A
    The ’605 patent has expired since the Board’s deci-
sion. Pasteur does not dispute that the PTO cannot issue
amended claims for an expired patent if the amendments
change the claim’s scope. 37 C.F.R. § 1.530(j), (k). We
conclude, contrary to Pasteur’s contention, that the
amendments it proposed during reexamination of the ’605
patent did substantively narrow claim 1 and dependent
claim 14. It follows that there is no live controversy over
the Board’s rejection of amended claim 14: even if the
Board erred, the claim cannot issue.
    Pasteur proposed amendments both to independent
claim 1 and to dependent claim 14 that limited the tar-
geted “DNA of an organism” to chromosomal DNA only.
While agreeing that the amendments changed the scope
INSTITUT PASTEUR & UNIVERSITE   v. FOCARINO              13



of claim 1, which is not at issue, Pasteur argues that they
did not change the scope of claim 14, because the una-
mended claim 14 itself was implicitly limited to chromo-
somal DNA. Specifically, Pasteur argues that the original
claim’s requirement that the targeted DNA undergo
homologous recombination with a newly introduced
plasmid whose sequence is “homologous to the sequence of
[a] chromosome,” ’605 patent, col. 70, lines 28-29, limited
the claim to targeting chromosomal DNA.
    Pasteur’s reasoning is flawed. That homologous re-
combination occurs between the targeted DNA and an
introduced plasmid that is homologous to a chromosome
does not require that the targeted DNA actually be chro-
mosomal DNA. It requires only that the targeted DNA be
homologous to chromosomal DNA. Non-chromosomal
DNA, such as mitochondrial DNA or DNA in an addition-
al plasmid, can be homologous to chromosomal DNA.
Thus, the original claim covered situations where non-
chromosomal DNA is the targeted DNA. The amendment
substantively narrowed the claim in requiring chromoso-
mal DNA as the target.
    Because amending the claim to target only “chromo-
somal” DNA substantively altered (narrowed) its scope,
the PTO may not issue the amended claim now that the
patent has expired, as stated in applicable provisions of a
PTO regulation, 37 C.F.R. § 1.530(j), (k). That rule fol-
lows from the relevant statutory provisions. Looking
backward, if the claim were to issue on reexamination,
Pasteur could not enforce it for the period before issuance
of the reexamination certificate. That is because, for inter
partes reexaminations under the pre-2013 version of 35
U.S.C. § 316(b) applicable here, as for reissues under 35
U.S.C. § 252, when a claim is substantively amended, the
analysis of intervening rights after issuance, considering
pertinent references and prosecution history, treats the
amendment as raising an irrebuttable presumption that
the original claim was materially flawed, so there can be
14              INSTITUT PASTEUR & UNIVERSITE V. FORCARINO




no liability for acts of infringement before the amended
claim issues. See Bloom Eng’g Co., v. N. Am. Mfg. Co.,
129 F.3d 1247, 1249 (Fed. Cir. 1997); Tennant Co. v. Hako
Minuteman, Inc., 878 F.2d 1413, 1417 (Fed. Cir. 1989)
(“Claims amended during reexamination are entitled to
the date of the original patent if they are without sub-
stantive change or are legally ‘identical’ to the claims in
the original patent.”). Looking forward, the PTO may not
grant Pasteur a patent right extending beyond the statu-
torily authorized term, which has already ended. See 35
U.S.C. §§ 154 (term), 271(a) (limiting infringement to acts
that occur “during the term of the patent”).
                             B
    Pasteur appeals the Board’s conclusion that claims 10
and 12 of the ’545 patent are invalid for obviousness. 2 As
the Board correctly identified, the key issue in making
that determination is whether the relevant skilled arti-
san–after reading Quirk’s and Bell-Pedersen’s disclosure
that a GIIE endonuclease can promote targeted gene
transfer into non-chromosomal DNA in prokaryotic cells–
would have expected that a GIIE endonuclease would
successfully promote targeted gene transfer into the
chromosomal DNA of eukaryotic cells, and thus had good
reason to pursue that possibility. The Supreme Court
summarized the analysis that is relevant here:




     2   During reexamination, Pasteur proposed an
amendment to narrow the method of independent claim 7
to eukaryotes. J.A. 121. Pasteur proposed no amend-
ments specifically for dependent claims 10 and 12. Be-
cause those claims were already limited to eukaryotes
(i.e., yeast and mammals, respectively), ’545 patent, col.
51, lines 40-41; id., col. 52, lines 3-4, their scope was not
altered by Pasteur’s proposed amendment to claim 7.
INSTITUT PASTEUR & UNIVERSITE   v. FOCARINO               15



   When there is a design need or market pressure to
   solve a problem and there are a finite number of
   identified, predictable solutions, a person of ordi-
   nary skill has good reason to pursue the known
   options within his or her technical grasp. If this
   leads to the anticipated success, it is likely the
   product not of innovation but of ordinary skill and
   common sense.
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
The Supreme Court’s reference to “predictable solutions”
and “anticipated success” accords with this court’s
longstanding focus on whether a person of ordinary skill
in the art would, at the relevant time, have had a “rea-
sonable expectation of success” in pursuing the possibility
that turns out to succeed and is claimed. E.g., Bayer
Healthcare Pharms., Inc. v. Watson Pharms., Inc., 713
F.3d 1369, 1375 (Fed. Cir. 2013); In re Vaeck, 947 F.2d
488, 493 (Fed. Cir. 1991).
     The obviousness assessment depends on what the pri-
or art teaches and on what non-prior-art evidence of
“secondary considerations” (or objective indicia) may
indicate about whether the invention would have been
obvious at the relevant time. KSR, 550 U.S. at 406-07.
Here, in ascertaining the scope and content of the prior
art, the Board made factual determinations that were not
supported by substantial evidence. The Board also failed
to give proper consideration to at least two categories of
evidence–(1) teachings in the prior art that targeting a
cell’s chromosomal DNA could be toxic to the cell and
(2) industry praise and licensing of Pasteur’s invention–
that are important to the obviousness evaluation.
    Those errors were prejudicial. Under a proper read-
ing of the prior art, and with the appropriate considera-
tion given to clear teachings that the claimed method
could have been toxic to cells and to Pasteur’s objective
indicia of non-obviousness, we conclude that one of ordi-
16             INSTITUT PASTEUR & UNIVERSITE V. FORCARINO




nary skill in the art would not have reasonably predicted
the successful adaptation of Quirk and Bell-Pedersen to
target chromosomal DNA in eukaryotic cells. See KSR,
550 U.S. at 421. We therefore reverse the Board’s deter-
mination that claims 10 and 12 of the ’545 patent would
have been obvious.
                             1
    Applying the deferential “substantial evidence”
standard of review, see, e.g., Smith & Nephew, Inc. v. Rea,
721 F.3d 1371, 1380 (Fed. Cir. 2013), we conclude that the
Board erred in finding that two references in the prior art,
Frey and Dujon, “showed that a GIIE endonuclease
cleaved yeast chromosomal DNA when expressed in yeast
cells.” ’545 Board Decision, at * 7. In fact, neither refer-
ence discloses a GIIE endonuclease cleaving yeast chro-
mosomes while those chromosomes are in yeast cells.
    Frey discloses cleaving yeast chromosomes that had
already been extracted from yeast cells and purified, not
chromosomes still “in yeast cells.” The reference, a 1992
article from the Journal of Analytical Chemistry, express-
ly states that “[p]urified, intact chromosomes from the
resulting strain [of yeast] were digested [i.e., cleaved]
with” a GIIE endonuclease. J.A. 9345. Thus, contrary to
the Board’s finding that the reference “describe[s] results
using GIIE endonucleases in yeast,” ’545 Board Decision,
at *7, the reference discloses only that a GIIE endonucle-
ase could cleave yeast chromosomes extracted from yeast
cells.
    Nor does Dujon disclose cleaving yeast chromosomes
in yeast cells; the reference is silent about what type of
DNA is cleaved. Dujon is a two-page abstract that lists
some of the ’545 patent co-inventors as authors. See J.A.
11785-86. It teaches that a GIIE endonuclease “can be
expressed in the yeast nucleus from artificial constructs
and the protein is able to cleave efficiently both its natu-
ral site within mitochondria and an artificially placed site
INSTITUT PASTEUR & UNIVERSITE     v. FOCARINO              17



within the nucleus.” J.A. 11786. Nowhere else does the
reference clarify what is meant by cleaving “an artificially
placed site within the nucleus.” As the PTO bears the
burden of demonstrating a prima facie case of obvious-
ness, see, e.g., In re Rijckaert, 9 F.3d 1531, 1532 (Fed. Cir.
1993), Dujon’s language is insufficient to establish that
the GIIE endonuclease targeted chromosomal DNA.
     The Board relied on its misreading of both references,
and nothing more, to conclude that “one of ordinary skill
in the art [had] a reasonable expectation that the teach-
ings of Quirk and Bell-Pedersen could be successfully
applied to yeast cells.” ’545 Board Decision, at *7; see also
id. at *8 (“Frey and Dujon[] achieved cleavage of eukary-
otic chromosomes using a GIIE[ endonuclease], giving rise
to a reasonable expectation of success that the claimed
invention could be practiced successfully.”). Because no
other references identified by the Board show a GIIE
endonuclease cleaving chromosomal DNA in a eukaryotic
cell, its errors were highly material to whether the ’545
patent claims would have been obvious.
                              2
    The Board compounded its erroneous findings by ig-
noring teachings that targeting a GIIE endonuclease to
chromosomal DNA in a living cell could be highly toxic to
the cell. The sole prior-art reference identified by the
Board that discloses such a method warns of such dan-
gers: a 1990 article in Nucleic Acids Research specifically
teaches that introducing a GIIE endonuclease could be
“highly toxic” to the cell, which might not be able to repair
double-stranded breaks in the chromosome using homolo-
gous recombination. J.A. 10314. Such a teaching counts
significantly against finding a motivation to take the
claimed steps with a reasonable expectation of success.
See, e.g., In re Rosuvastatin Calcium Patent Litig., 703
F.3d 511, 517 (Fed. Cir. 2012); Takeda Chem. Indus., Ltd.
18              INSTITUT PASTEUR & UNIVERSITE V. FORCARINO




v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1361-62 (Fed.
Cir. 2007).
     The Board’s disregard of the toxicity teaching was not
harmless. The Board stated that “[t]he claims [of the ’545
patent] do not expressly require that the cells remain
viable,” ’545 Board Decision, at *8, but it did not deny
that continuing viability was implicit in the claims at
issue, and the Director here does not say otherwise. In
any event, the Board identified no reason at all that a
skilled artisan would have pursued a method toxic to
cells. It relied, rather, on the interest stated by the prior-
art reference Old: “[i]t would be a great advance if such
alterations could be engineered into copies of a chosen
gene in situ within the chromosomes of a living animal
cell.” J.A. 10075 (second emphasis added). Toxicity
would bear heavily on whether a skilled artisan would
have a reasonable expectation of success in achieving that
objective. The Board thus erred by disregarding evidence
of toxicity of the method at issue.
    In short, the prior art confirmed the great potential
payoff of a method that produced a particular result. The
desire for that payoff could motivate pursuit of the meth-
od, but “knowledge of the goal does not render its
achievement obvious,” Abbott Labs. v. Sandoz, Inc., 544
F.3d 1341, 1352 (Fed. Cir. 2008), and obviousness gener-
ally requires that a skilled artisan have reasonably ex-
pected success in achieving that goal. Importantly,
without a sound explanation for doing otherwise, which is
not present here, the expectation-of-success analysis must
match the highly desired goal, not switch to a different
goal that may be a less challenging but also less worth-
while pursuit. See KSR, 550 U.S. at 421 (asking if there
is “a design need or market pressure to solve” a problem
and if that same problem is one having “identified, pre-
dictable solutions”).
INSTITUT PASTEUR & UNIVERSITE    v. FOCARINO             19



     Under a proper reading of the Frey and Dujon refer-
ences, none of the prior art disclosed using a GIIE endo-
nuclease to target gene transfer into chromosomal DNA
without the potential for severe, toxic effects on the cell.
In Frey, the process of extracting and purifying the chro-
mosomes invariably kills the yeast cell; thus, in Frey,
toxicity was not at issue. Dujon, like Quirk and Bell-
Pedersen, did not disclose cleaving chromosomal DNA.
There simply was no teaching that using a GIIE endonu-
clease to cleave eukaryotic chromosomes would success-
fully initiate the cell’s reparative homologous-
recombination machinery. To the contrary, the prior art
teaches only that such cleavages could be highly toxic to
the cell. The Board erred in concluding that one of ordi-
nary skill in the art had a reasonable expectation that the
teachings of Quirk and Bell-Pedersen could be successful-
ly applied to chromosomal DNA in yeast and mammalian
cells. See ’545 Board Decision, at *7.
                             3
    Confirming the non-obviousness of the claims at issue,
Pasteur presented compelling evidence that the industry
has licensed, praised, and copied its inventions. The
Board did not properly weigh this evidence, because it
applied too stringent a standard and misread the Dujon
reference.
    Objective indicia of non-obviousness “can be the most
probative evidence of non-obviousness in the record, and
enables the court to avert the trap of hindsight.” Crocs,
Inc. v. Int’l Trade Comm’n, 598 F.3d 1294, 1310 (Fed. Cir.
2010). Objective indicia of non-obviousness “may often
establish that an invention appearing to have been obvi-
ous in light of the prior art was not.” Stratoflex, Inc. v.
Aeroquip Corp., 713 F.2d 1530, 1538 (Fed. Cir. 1983). To
be afforded substantial weight, the objective indicia of
non-obviousness must be tied to the novel elements of the
claim at issue. See, e.g., In re Kao, 639 F.3d 1057, 1068
20             INSTITUT PASTEUR & UNIVERSITE V. FORCARINO




(Fed. Cir. 2011). Objective indicia “need only be reasona-
bly commensurate with the scope of the claims.” Rambus
Inc. v. Rea, 731 F.3d 1248, 1257 (Fed. Cir. 2013).
    For the first category—evidence that competitors or
customers had licensed the ’545 patent—Pasteur present-
ed the declaration of Dr. Choulika, one of the named
inventors of the patent and the chief executive officer of
Cellectis S.A., the exclusive licensee. According to Dr.
Choulika, the license permitted Cellectis to enter sub-
license agreements, and since 2002, “Cellectis has entered
into more than a dozen agreements to allow third parties
access to the invention described and claimed in the ’545
patent.” J.A. 13490. Dr. Choulika stated that “[a]ll of the
agreements . . . grant access to a method for in vivo site
directed genetic recombination in an organism as claimed
in the ’545 patent.” J.A. 13491. He listed eight press
releases detailing sub-license agreements that granted
access to Cellectis’s technology for using a GIIE endonu-
clease and homologous recombination to target and modi-
fy a gene of interest in live cells. J.A. 13489, 13491-92.
Among the sub-licensees were BASF Plant Science, Bayer
CropScience, Biogen Idec, Monsanto, and Pioneer Hi-Bred
International. Id.
    The Board too finely parsed Pasteur’s licensing activi-
ties. It rejected the evidence because “Dr. Choulika did
not establish that the third parties specifically licensed
the patent family to gain access to the subject matter
claimed in the ’545 patent, rather than other technology
described in the patent but not claimed or claimed in
related patents.” ’545 Board Decision, at 10. But that
theoretical possibility does not undermine the strong
probative value of the licensing of the ’545 patent. The
central success described in the patent is the one prior art
hoped for and is captured in the claims at issue: a method
that uses GIIE endonucleases and homologous recombina-
tion to achieve the targeted modification of chromosomal
DNA in living cells, specifically in yeast and, indeed, in
INSTITUT PASTEUR & UNIVERSITE   v. FOCARINO              21



mammals. See ’545 patent, col. 51, lines 14-33. Pasteur’s
licensing activities provide “probative and cogent evi-
dence” of non-obviousness of the claims at issue.
Stratoflex, 713 F.2d at 1538.
    The Board also erred in dismissing Pasteur’s second
category of objective indicia—industry praise—based on
its misreading of the Dujon reference, as detailed above.
The Board acknowledged that Pasteur established a
connection between “the praise by the industry and the
homologous recombination step which is claimed,” but it
found that step “was possessed by the prior art” and, thus,
“not a proper basis to rebut the prima facie case of obvi-
ousness.” ’545 Board Decision, at *11. That finding,
however, simply repeats the Board’s misreading of Dujon.
See supra B.2. Under a correct reading of the reference, a
method that uses GIIE endonucleases and homologous
recombination to achieve the targeted modification of
chromosomal DNA was not “possessed by the prior art.”
Thus, industry praise, like others’ licensing of Pasteur’s
invention, provides probative and cogent evidence that
one of ordinary skill in the art would not have reasonably
expected that a GIIE endonuclease could successfully
modify chromosomal DNA in eukaryotic cells.
    A final point is worth noting, though it does not affect
the conclusion. The Board stopped its analysis of Pas-
teur’s evidence of copying prematurely. Copying requires
duplication of features of the patentee’s work based on
access to that work, lest all infringement be mistakenly
treated as copying. See Iron Grip Barbell Co., v. USA
Sports, Inc., 392 F.3d 1317, 1325 (Fed. Cir. 2004). Pas-
teur publicized its method for gene transfer into the
chromosomal DNA of eukaryotic cells in an article, co-
authored by Dr. Choulika, published in Molecular and
Cellular Biology in the spring of 1995. See J.A. 8965.
During reexamination, Pasteur presented excerpts of
more than twenty scientific articles, all published after
the Choulika article, to demonstrate that other scientists
22              INSTITUT PASTEUR & UNIVERSITE V. FORCARINO




adopted the same method for targeted gene transfer. See
J.A. 14001-12. The Board discounted that evidence,
stating (without further analysis) that Pasteur “did not
show that the cited publications referenced Choulika’s
method or that of [the] ’545 patent [whose great grand-
parent, U.S. Patent No. 5,474,896, issued in late 1995],
rather than following another publication.” See ’545
Board Decision, at *11.
    We have no reason to doubt the Board’s statement
that Pasteur did not supply the cited publications and
trace the references cited in those publications, either
directly or indirectly, to the 1995 Choulika article or the
’545 patent’s specification. But the Board did not analyze
whether Pasteur’s showing of the similarities of its meth-
od to the content of the cited publications, e.g., their use of
the same specific GIIE endonuclease, indicated that the
publications’ authors had access to, and borrowed from,
the Pasteur sources. We need not pursue the point fur-
ther, however, ourselves or through a remand. A finding
that Pasteur had persuasive evidence of copying would
only support the non-obviousness conclusion we reach
independently of such evidence.
                              C
     Our disposition of Pasteur’s challenge to the Board’s
rejection of the final patent at issue, the ’252 patent,
follows from our discussion of the ’545 patent. In revers-
ing the Board’s rejection of claims 10 and 12 of the ’545
patent, we conclude, considering all the evidence, that
achieving the ultimate goal of targeted gene transfer into
the chromosomal DNA of eukaryotic cells was not so
likely to succeed as to render the claims obvious. We now
vacate the Board’s conclusion as to the ’252 patent claims,
which concern just the first step in that process. We
remand for consideration of whether one of ordinary skill
would have been motivated simply to create a recombi-
nant chromosome with a GIIE endonuclease recognition
INSTITUT PASTEUR & UNIVERSITE   v. FOCARINO              23



site—without having the reasonable expectation (as the
claims of the ’545 patent but not those of the ’252 patent
require) that the GIIE endonuclease could successfully
cleave the recognition site and that homologous recombi-
nation could successfully repair the break.
    All agree that the claims of the ’252 patent require
less than claims 10 and 12 of the ’545 patent. The claims
of the ’252 patent cover “[a] recombinant mammalian
chromosome comprising an exogenous Group I intron
encoded endonuclease site,” ’252 patent, col. 67, lines 57-
58, whereas the ’545 patent claims at issue also require
that a GIIE endonuclease cleave an equivalent chromo-
some “whereby said cleavage promotes the insertion of
said gene of interest into said chromosome of said organ-
ism at a specific site by homologous recombination,” ’545
patent, col. 51, lines 31-33. Effectively, the claims of the
’252 patent serve as the first step to practicing the method
recited by claim 12 of the ’545 patent (or, for that matter,
claim 10, which covers yeast—because neither party
argues that the distinction matters for present purposes).
    The Board identified only a single reason that one of
ordinary skill in the art would have attempted to make a
recombinant chromosome containing a GIIE endonuclease
recognition site: to apply the homologous recombination
method disclosed by Quirk and Bell-Pedersen to chromo-
somal DNA in mammalian cells. See ’252 Board Decision,
at *5 (finding that the prior art “provided express reason
to use [Quirk and] Bell-Pedersen’s homologous recombi-
nation method in mammal cells”). That is the same
motivation, however, that the Board identified as giving a
skilled artisan good reason to pursue the methods of the
’545 patent. See ’545 Board Decision, at *6. We have held
the evidence insufficient to support that determination.
    Because it mistakenly thought that there was suffi-
cient motivation for the ’545 patent, the Board has never
considered whether other motivations would have made
24             INSTITUT PASTEUR & UNIVERSITE V. FORCARINO




the subject matter claimed in the ’252 patent obvious.
Specifically, the Board has not made a finding about
whether a skilled artisan would have introduced a GIIE
endonuclease recognition site into a mammalian chromo-
some even without reasonably expecting its successful use
for the site-directed insertion of DNA.
    At oral argument, the parties briefly discussed what
uses such recombinant chromosomes would have other
than as a first step for successful targeted gene transfer.
Pasteur admitted that, currently, there are other uses for
the chromosomes, including as laboratory tools or as aids
in gene mapping. Oral Argument at 16:33-17:14 (Pas-
teur’s counsel acknowledging that the recombinant chro-
mosomes “could have some utility in the laboratory”
without “necessarily hav[ing] to proceed” to targeted DNA
insertion). But obviousness is determined at the time the
invention was made, see 35 U.S.C. § 103, so current uses
for the recombinant chromosomes, without more, would
not establish a sufficient motivation at the time of inven-
tion. The issue of motivation at the relevant time has not
been fully explored. The Board should address it on
remand in the first instance. See, e.g., In re Chapman,
595 F.3d 1330 (Fed. Cir. 2010) (remanding after correct-
ing error in obviousness analysis).
    Finally, although the Board may have to reconsider
objective-indicia evidence for the ’252 patent when it
addresses the motivation question, we note that one
argument that Pasteur makes about such evidence is not
sound. Pasteur presented evidence similar to that used to
support the patentability of the ’545 patent—others in the
industry licensed, praised, and copied Pasteur’s method of
targeted gene transfer that cleaves chromosomal DNA at
a specific location and uses homologous recombination to
repair the break. In seeking to rely on that evidence for
the ’252 patent, Pasteur acknowledges that “double-
stranded breaks and homologous recombination are not
mentioned in the [’252 patent] claims,” but it argues that
INSTITUT PASTEUR & UNIVERSITE   v. FOCARINO            25



“neither would be possible without a GIIE endonuclease
site inserted into the chromosome.” Br. of Appellants at
65. That the ’252 patent claims serve as a necessary first
step for a method that others in the industry licensed,
praised, and copied, however, does not demonstrate that
they licensed, praised, and copied the method because of
that first step. Pasteur’s argument does not meet its
burden to show that the praise and adoption were due to
that first step. Cf. Rambus, 731 F.3d at 1256 (objective
indicia of non-obviousness support patentability if “due
to” the claimed features).
                      CONCLUSION
    For the foregoing reasons, we dismiss Pasteur’s ap-
peal with respect to the ’605 patent, reverse the Board’s
rejection of claims 10 and 12 of the ’545 patent, and
vacate the Board’s conclusion for the ’252 patent and
remand for further consideration.
   No costs.
    DISMISSED IN PART, REVERSED IN PART,
      VACATED IN PART, AND REMANDED
