  United States Court of Appeals
      for the Federal Circuit
               ______________________

       ANACOR PHARMACEUTICALS, INC.,
                 Appellant

                          v.

    ANDREI IANCU, UNDER SECRETARY OF
  COMMERCE FOR INTELLECTUAL PROPERTY
   AND DIRECTOR OF THE UNITED STATES
     PATENT AND TRADEMARK OFFICE,
                  Intervenor
            ______________________

                     2017-1947
               ______________________

    Appeal from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in No. IPR2015-
01776.
                 ______________________

               Decided: May 14, 2018
               ______________________

    MICHAEL N. KENNEDY, Covington & Burling LLP,
Washington, DC, argued for appellant. Also represented
by EVAN SMITH KRYGOWSKI, ANDREA GAY REISTER.

    SARAH E. CRAVEN, Office of the Solicitor, United
States Patent and Trademark Office, Alexandria, VA,
argued for intervenor. Also represented by NATHAN K.
KELLEY, THOMAS W. KRAUSE, LORE A. UNT.
2                   ANACOR PHARMACEUTICALS, INC.   v. IANCU



   JAMES CARMICHAEL, Carmichael IP, PLLC, Tysons,
VA, for amicus curiae FlatWing Pharmaceuticals, LLC.
                 ______________________

    Before REYNA, BRYSON, and STOLL, Circuit Judges.
BRYSON, Circuit Judge.
    This is an appeal from a decision of the Patent Trial
and Appeal Board in an inter partes review proceeding.
The Board held all of the claims of a patent owned by
Anacor Pharmaceuticals, Inc., to be unpatentable for
obviousness. Anacor has appealed with respect to only
one of the rejected claims. We affirm.
                             I
                            A
    The patent in suit, U.S. Patent No. 7,582,621 (“the
’621 patent”) is entitled “Boron-containing Small Mole-
cules.” The patent is directed to the use of 1,3-dihydro-5-
fluoro-1-hydroxy-2, 1-benzoxaborole, also known as
tavaborole, to treat fungal infections. In particular, the
patent teaches the use of tavaborole as a topical treat-
ment for fungal infections that develop under fingernails
and toenails. When applied topically, tavaborole can
penetrate the nail plate and treat the underlying fungal
infection.
     The ’621 patent teaches that tavaborole can be used to
treat a fungal infection known as onychomycosis, which is
a disease of the nail that is responsible for approximately
half of all nail disorders in humans. ’621 patent, col. 28,
ll. 18–20. Onychomycosis can be caused by a variety of
yeasts and molds, but it is most frequently caused by
dermatophytes, a group of fungi that includes the genus
Trichophyton and the species Trichophyton rubrum (“T.
rubrum”). Id., col. 28, ll. 23–27. Onychomycosis is also
ANACOR PHARMACEUTICALS, INC.        v. IANCU                     3



sometimes caused by another fungus, a yeast known as
Candida albicans (“C. albicans”). 1
    The single claim of the ’621 patent that is at issue in
this appeal is claim 6, which depends from claims 1 and 4.
The three related claims recite as follows:
    1. A method of treating an infection in an animal,
    said method comprising administering to the an-
    imal a therapeutically effective amount of 1,3-
    dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, or a
    pharmaceutically acceptable salt thereof, suffi-
    cient to treat said infection.
    4. The method of claim 1, wherein said infection
    is onychomycosis.
    6. The method of claim 4, wherein said ony-
    chomycosis is tinea unguium.
Id., col. 67, ll. 34–38; id., col. 68, ll. 20–21; id., col. 68, ll.
25–26. Tinea unguium is the term for onychomycosis that
is caused by a dermatophyte. Id., col. 28, ll. 24–25.
                                B
     In 2015, the Coalition for Affordable Drugs X LLC
filed a petition requesting inter partes review of all 12
claims of the ’621 patent. The Board instituted review
and found that the claims would have been obvious in
light of the combination of Int’l Pat. Appl. No.
PCT/GB95/01206 (“Austin”) and U.S. Pat. Appl. No.
10/077,521 (“Brehove”). Both Austin and Brehove teach
the use of boron heterocycles as antifungal agents that
inhibit C. albicans, among other fungi. Boron heterocy-



    1     The evidence before the Board showed that der-
matophytes are responsible for approximately 90 percent
of all cases of onychomycosis, while C. albicans is respon-
sible for approximately five percent of all such cases.
4                   ANACOR PHARMACEUTICALS, INC.   v. IANCU



cles are organic compounds that contain both boron and
carbon in a ring structure. 2
    Austin teaches the use of oxaboroles—boron heterocy-
cles that include a five-member ring containing three
carbon atoms, one oxygen atom, and one boron atom—as
fungicides. Austin discloses tavaborole as one of a small
group of oxaboroles that were tested for antifungal activi-
ty and teaches that tavaborole is a highly effective agent
that inhibits a variety of fungi, including C. albicans.
    Brehove teaches the use of boron heterocycles in a
topical composition to treat onychomycosis. Specifically,
two dioxaborinanes—boron heterocycles that include a
six-member ring containing three carbon atoms, two
oxygen atoms, and one boron atom—were determined
through in vitro testing to have powerful potency against
C. albicans. Brehove also reports the results of five in
vivo tests, each involving a single individual, in which the
individual’s onychomycosis was successfully treated by
the topical application of Brehove’s two dioxaborinanes.
Brehove does not identify whether each individual’s
onychomycosis was caused by C. albicans or some other
microorganism, such as a dermatophyte.
   The petition posited that the combination of Austin
and Brehove would have rendered all the claims of the



    2   The Board also instituted review on a second
ground, the combination of Austin with Int’l Pat. Appl.
No. PCT/US02/23252 (“Freeman”). The Board found that
all the claims of the ’621 patent were unpatentable for
obviousness in light of that combination. Because we
affirm the Board’s conclusion that claim 6 would have
been obvious in light of the combination of Austin and
Brehove, we need not address Anacor’s additional argu-
ments on appeal challenging the Board’s decision on the
second ground.
ANACOR PHARMACEUTICALS, INC.   v. IANCU                  5



’621 patent obvious. According to the petition, a person of
ordinary skill would have had a reason to combine Austin
and Brehove because the compounds in both references
are boron heterocycles that are effective as fungicides
and, in particular, in inhibiting C. albicans. The petition
argued that a skilled artisan would have expected that
those compounds would share other fungicidal activity,
such as treating onychomycosis caused by dermatophytes.
In addressing claim 6, the petition referred to Brehove’s
in vivo tests, which reported the successful use of Bre-
hove’s compounds to treat onychomycosis, a condition that
is most often caused by dermatophytes. In addition, the
petition pointed out that tavaborole has a lower molecular
weight than the Brehove compounds, and would therefore
be expected to be more likely than those compounds to
penetrate the nail barrier at lower concentrations.
    In its patent owner’s response, Anacor argued that
the combination of Austin and Brehove would not disclose
treating onychomycosis caused by a dermatophyte, and
that a person of ordinary skill would not have combined
Austin and Brehove because they concern structurally
different compounds. In addition, Anacor argued that a
person of ordinary skill would not have had an expecta-
tion of success in treating a dermatophyte infection with
tavaborole, because such a person “could not have pre-
dicted activity against dermatophytes based on activity
against a yeast such as C. albicans.”
    In support of that argument, Anacor cited an article
by Dr. Rina Segal (“Segal”). 3 Among other things, Anacor
noted that the Segal article reported that a compound
known as terbinafine was very effective against dermato-



   3    Rina Segal et al., Treatment of Candida nail infec-
tion with terbinafine, 35 J. Am. Acad. Dermatology 958
(1996).
6                    ANACOR PHARMACEUTICALS, INC.   v. IANCU



phytes but had “variable and species-dependent” effec-
tiveness against different species of the Candida genus.
    The petitioner also relied on Segal, introducing that
article during the deposition of the petitioner’s expert, Dr.
Narasimha Murthy. In his deposition, Dr. Murthy ex-
plained that terbinafine was effective against both derma-
tophytes and various Candida species.           Dr. Murthy
testified that the information in the Segal article support-
ed his opinion that a person of ordinary skill would have
understood that “most antifungal drugs are found to be
active against different strains over a broad spectrum of
organisms.” 4
    As part of its patent owner’s response, Anacor also in-
cluded declarations from several experts, including Dr.
Marjella Lane and Dr. Mahmoud A. Ghannoum. Dr. Lane
addressed whether a person of ordinary skill would have
expected tavaborole to be suitable for topical application
to a human nail. In the course of her testimony, Dr. Lane
cited two installments of a study by Dirk Mertin and
Bernhard C. Lippold that was published in 1997 in the
Journal of Pharmacy and Pharmacology. Dr. Lane ar-
gued that those articles supported her view that a person
of ordinary skill would not have expected the combination
of Austin and Brehove to be successful.



    4     Dr. Stephen Kahl, another of the petitioner’s ex-
perts, testified to the same effect. He stated, “I think a
[person of ordinary skill] would presume that if a com-
pound showed significant antifungal activity against any
of a variety of fungi, would have reasonable reason to look
at those against a specific fungus and expect some suc-
cess. . . . [F]ungi are rather simple organisms. And it’s
not unusual that a compound that . . . has antifungal
activity in one fungus, might be expected or at least
evaluated in another fungus.”
ANACOR PHARMACEUTICALS, INC.   v. IANCU                  7



    During the depositions of Anacor’s experts, the peti-
tioner introduced the third installment of the study by
Mertin and Lippold, which was published in 1997 as part
of the same series of articles (“Mertin”). 5 The petitioner
used the third Mertin article to challenge Dr. Lane’s
testimony regarding the relationship between a com-
pound’s molecular weight and its ability to penetrate the
nail plate. When questioned about the study, Dr. Lane
explained that she was aware of the article, but that she
disagreed with its findings about the inverse relationship
between permeability and molecular weight.
    The petitioner also used the third Mertin article dur-
ing Dr. Ghannoum’s deposition. Dr. Ghannoum relied on
a paper by Kazuhiro Nimura (“Nimura”), which teaches
that some antifungals, such as ketoconazole, are effective
against C. albicans but ineffective against dermatophytes
such as T. rubrum. 6 Based on Nimura, Dr. Ghannoum
testified that a person of ordinary skill would not have
predicted activity against dermatophytes based on activi-
ty against other microorganisms such as C. albicans. In
challenging Dr. Ghannoum’s testimony on that issue, the
petitioner directed his attention to a statement from the
third Mertin article that “[d]ermatophytes are usually
more sensitive to antimycotics than yeast.” 7



   5     Dirk Mertin & Bernhard C. Lippold, In-vitro Per-
meability of the Human Nail and of a Keratin Membrane
from Bovine Hooves: Prediction of the Penetration Rate of
Antimycotics Through the Nail Plate and Their Efficacy,
49 J. Pharmacy & Pharmacology 866 (1997).
    6    Kazuhiro Nimura et al., Comparison of In Vitro
Antifungal Activities of Topical Antimycotics Launched in
1990s in Japan, 18 Int’l J. Antimicrobial Agents 173
(2001).
    7    The various Candida species are fungi that are
classified as yeasts.
8                   ANACOR PHARMACEUTICALS, INC.   v. IANCU



    In its reply brief to the Board, the petitioner respond-
ed to Anacor’s argument that a person of ordinary skill
would not have predicted a compound’s activity against
dermatophytes based on its activity against C. albicans.
In the course of that discussion, the petitioner discussed
Mertin’s conclusion that antimycotics are often more
effective against dermatophytes than against yeasts. The
petitioner’s expert, Dr. Murthy, also noted in his reply
declaration that Segal and Nimura teach that a number
of antifungal drugs are equally or more effective against
dermatophytes than against C. albicans.
                             C
    In its final written decision, the Board observed that
Austin teaches that tavaborole is a known fungicide with
particular potency against C. albicans. The Board also
found that molecular weight was the most important
factor in predicting whether a molecule would penetrate
the nail plate. The Board then pointed out that, of the 16
tested compounds listed in Tables 8 and 9 of Austin,
tavaborole was the most effective against various fungi,
including C. albicans, of any of the seven compounds in
Table 9 and that it had a lower molecular weight than
any of the nine compounds in Table 8. Based on the
evidence before it, the Board found that a person of ordi-
nary skill in the art would have considered tavaborole as
a promising candidate for treating onychomycosis.
    The Board found that Brehove taught the treatment
of onychomycosis with boron heterocycles and, in particu-
lar, that Brehove’s compounds were effective against C.
albicans, which Brehove characterized as a common cause
of onychomycosis. In light of Brehove’s test results, the
Board concluded that a person of ordinary skill in the art
would have used Austin’s tavaborole in Brehove’s topical
treatment of onychomycosis with a reasonable expectation
of success. The Board acknowledged that “there are
obviously structural differences between the dioxa-
ANACOR PHARMACEUTICALS, INC.   v. IANCU                    9



borinanes of Brehove and the benzoxaboroles of Austin,”
and it recognized that “small structural differences can
cause different biological actions and activities.” Coal. for
Affordable Drugs X LLC v. Anacor Pharm., Inc., No.
IPR2015-01776, at 21 (P.T.A.B. Feb. 23, 2017) (“Final
Written Decision”). Nonetheless, the Board was persuad-
ed by the petitioner’s experts that “the combination of the
structural similarities and the similar fungicidal activity
against C. albicans would have led a person of ordinary
skill in the art to combine Brehove’s method of treating
onychomycosis using Austin’s tavaborole.” Id. The Board
explained that “a person of ordinary skill in the art would
have been less concerned about the possibility of differ-
ences in biological function given Brehove and Austin’s
disclosure confirming that [Brehove’s compounds] and
tavaborole have similar fungicidal activity against C.
albicans.” Id. at 21–22.
     Addressing claim 6, the Board noted that “neither
Austin nor Brehove expressly teaches whether the dis-
closed compounds exhibit any activity against dermato-
phytes.” Id. at 29. Accordingly, the Board identified the
question posed by claim 6 as whether “a person of ordi-
nary skill in the art would have expected that tavaborole,
which shares functional activity with the compounds of
Brehove” against C. albicans would also share functional
activity against other fungi responsible for onychomyco-
sis, i.e., dermatophytes. Id. at 29.
    On that issue, the Board concluded that “the weight of
the evidence favors Petitioner’s argument.” Id. at 30. In
support of that conclusion, the Board cited evidence that
included Segal, Nimura, and Mertin. The Board noted
that Segal shows that terbinafine, an antifungal, is highly
potent against dermatophytes and also active (albeit less
so) against C. albicans; that although Nimura discloses
that ketoconazole has potent antifungal activity against
C. albicans but poor activity against dermatophytes,
another antifungal, amorolfine, exhibits potent antifungal
10                  ANACOR PHARMACEUTICALS, INC.   v. IANCU



activity against all fungal species tested, including both
C. albicans and T. rubrum; and that Mertin teaches that
dermatophytes are usually more sensitive to antimycotics
than yeasts are.
    In light of all the evidence of record, the Board con-
cluded that a person of ordinary skill “would have had a
reasonable expectation that a compound with activity
against C. albicans would also have activity against
dermatophytes, particularly given the teaching that
dermatophytes are usually more sensitive to antimycotics
than yeast.” Id. at 31. The Board therefore held that “the
combination of Austin and Brehove teaches each limita-
tion of” the claims and that the claims of the ’621 patent,
including claim 6, were invalid for obviousness. Id.; see
also id. at 37.
                             II
                             A
    On appeal, Anacor first argues that the Board violat-
ed due process and the procedural requirements of the
Administrative Procedure Act (“APA”) by failing to pro-
vide Anacor with adequate notice of, and an opportunity
to respond to, the grounds of rejection ultimately adopted
by the Board.
     Under the APA, a patent owner involved in an inter
partes review is entitled to notice of and a fair opportuni-
ty to address the grounds of rejection. 5 U.S.C. §§ 554(b)–
(c), 557(c); Dell Inc. v. Acceleron, LLC, 818 F.3d 1293,
1301 (Fed. Cir. 2016). Therefore, an agency “may not
change theories in midstream without giving respondents
reasonable notice of the change and the opportunity to
present argument under the new theory.” Genzyme
Therapeutic Prod. Ltd. P’ship v. Biomarin Pharm. Inc.,
825 F.3d 1360, 1366 (Fed. Cir. 2016) (quoting Belden Inc.
v. Berk-Tek LLC, 805 F.3d 1064, 1080 (Fed. Cir. 2015)).
ANACOR PHARMACEUTICALS, INC.   v. IANCU                  11



    Anacor argues that the Board’s decision violated the
APA and due process in two related ways. First, Anacor
contends that the petitioner abandoned one prior art
reference in its reply (Brehove) and shifted to a new
theory of invalidity (relying on Austin in light of Segal
and Mertin), and that the Board adopted that new theory
without giving Anacor proper notice or an opportunity to
respond to it. Second, Anacor argues that, in bolstering
this new theory of obviousness, the petitioner impermissi-
bly relied on new evidence, not included in the petition, to
satisfy its burden of showing a prima facie case of obvi-
ousness.
    We reject Anacor’s argument that the Board violated
the APA or due process by adopting a new theory of
obviousness not presented in the petition. Unlike in In re
NuVasive, Inc., 841 F.3d 966 (Fed. Cir. 2016), on which
Anacor relies, the Board’s final written decision was
based on the same combination of references—Austin and
Brehove—and the same series of inferences that the
petition proposed.
    To demonstrate effectiveness against dermatophytes,
the petition cited Brehove’s in vivo tests to demonstrate
that boron heterocycles can be effective against ony-
chomycosis, which is most often caused by dermatophytes.
The petition suggested that Brehove’s compounds would
likely show effectiveness against dermatophytes and that,
therefore, Austin’s tavaborole would do so also, since the
compounds in both references were effective against C.
albicans.
    The Board’s final written decision was based on the
same combination of references, and it concluded that the
weight of the evidence supported the inferences drawn by
the petition. The Board stated that “[f]or the reasons
stated in the Petition and by Dr. Murthy, we are persuad-
ed that the combination of Austin and Brehove teaches or
suggests each limitation of dependent claims 2–10.” Final
12                  ANACOR PHARMACEUTICALS, INC.   v. IANCU



Written Decision, at 28; see also id. at 31 (concluding that
“a person of ordinary skill in the art would have had a
reason to combine Austin and Brehove with a reasonable
expectation of success”). In particular, the Board conclud-
ed that “a person of ordinary skill in the art would have
had a reasonable expectation that a compound with
activity against C. albicans would also have activity
against dermatophytes,” id. at 30–31, which was the same
argument raised in the petition.
    We also reject Anacor’s argument that the Board im-
properly relied on new evidence to which Anacor did not
have an opportunity to respond. Anacor argues that the
Board improperly cited two references—Mertin and
Segal—that were not cited in the petition. There is,
however, no blanket prohibition against the introduction
of new evidence during an inter partes review proceeding.
In fact, “the introduction of new evidence in the course of
the trial is to be expected in inter partes review trial
proceedings and, as long as the opposing party is given
notice of the evidence and an opportunity to respond to it,
the introduction of such evidence is perfectly permissible
under the APA.” Genzyme, 825 F.3d at 1366; see also
Novartis AG v. Torrent Pharm. Ltd., 853 F.3d 1316, 1325–
26 (Fed. Cir. 2017) (finding no APA violation because
patent owner was not “surprised” where a reference was
discussed in patent owner’s response, in depositions, and
at the hearing, because “it is quite clear that [the patent-
ee] had more than sufficient notice and opportunity to be
heard on [the reference’s] potential relevance”).
    In addition, the petitioner in an inter partes review
proceeding may introduce new evidence after the petition
stage if the evidence is a legitimate reply to evidence
introduced by the patent owner, or if it is used “to docu-
ment the knowledge that skilled artisans would bring to
bear in reading the prior art identified as producing
obviousness.” Genzyme, 825 F.3d at 1369 (quoting Ariosa
ANACOR PHARMACEUTICALS, INC.   v. IANCU                   13



Diagnostics v. Verinata Health, Inc., 805 F.3d 1359, 1365
(Fed. Cir. 2015)). 8
     It was not improper for the Board to cite Segal and
Mertin (along with Nimura) as evidence of the knowledge
that a skilled artisan would bring to bear in reading
Austin and Brehove, even though those references were
not cited in the petition. Anacor argues that Segal, Mer-
tin, and Nimura “surfaced for the first time in Petitioner’s
Reply,” but that is not so. Anacor discussed both Nimura
and Segal in its patent owner’s response and related
submissions; indeed, Anacor spent three pages of its
patent owner’s response addressing Segal. For that
reason, it was not improper for the Board to rely on those
references to show what a person of skill in the art would
believe about whether a compound effective against a
yeast such as C. albicans would be likely to be effective
against a dermatophyte.
   As for Mertin, the first two installments in Mertin
and Lippold’s three-part series of articles were first intro-
duced and addressed by Anacor in the declaration of Dr.


    8   Intelligent Bio-Systems, Inc. v. Illumina Cam-
bridge Ltd., 821 F.3d 1359 (Fed. Cir. 2016), cited by
Anacor, is not to the contrary. In that case, the court
upheld the Board’s refusal to consider the petitioner’s
reply brief on the ground that the reply brief presented a
new argument for the first time. The Board found that
the reply violated a Board regulation, 37 C.F.R.
§ 42.23(b), which provides that a reply “may only respond
to arguments raised in the corresponding opposition or
patent owner response.” Id. at 1369–70. In this case, the
reply appropriately responded to arguments made in the
patent owner’s response and evidence elicited in the
course of the proceeding through the depositions of the
parties’ experts, and the Board accordingly did not refuse
to consider the petitioner’s reply.
14                  ANACOR PHARMACEUTICALS, INC.   v. IANCU



Lane. The third installment was introduced by the peti-
tioner during the deposition of Anacor’s experts and was
then referred to in the petitioner’s reply. But the third
installment did not come as a surprise to Anacor. As
noted, Dr. Lane admitted she was familiar with the
article, which related to the first two installments she had
cited in her declaration. Moreover, the third Mertin
article was offered in direct response to testimony by Dr.
Lane at her deposition: it was brought up in the deposi-
tion as part of the petitioner’s challenge to Dr. Lane’s
testimony regarding the relationship between molecular
weight and nail permeability. 9
    Following Dr. Lane’s deposition, the Mertin article
was brought up again during the deposition of Anacor’s
expert, Dr. Ghannoum. In that proceeding, the petition-
er’s counsel questioned Dr. Ghannoum about the conclu-
sions reached in the Mertin article as part of the petition-
petitioner’s challenge to Dr. Ghannoum’s assertion, based
in part on Nimura, that compounds that showed activity
against C. albicans often were not particularly effective
against dermatophytes. In particular, the petitioner’s
counsel cross-examined Dr. Ghannoum regarding his
opinion on that point by referring to the statement in
Mertin that “[d]ermatophytes are usually more sensitive
towards antimycotics than yeasts.”
    Finally, Anacor discussed Mertin extensively at the
hearing before the Board, including discussing Mertin’s
findings with respect to permeability, and arguing that
Mertin “highlights the unpredictability of going from
predicting the activity of one species and going to another


     9  In addition, the third Mertin article was cited and
discussed at some length in another reference relied on by
Dr. Lane and cited in her declaration. See Sudaxshina
Murdan, Drug Delivery to the Nail Following Topical
Application, 236 Int’l J. of Pharmaceutics 1, 9–11 (2002).
ANACOR PHARMACEUTICALS, INC.    v. IANCU               15



species.” In response to the petitioner’s argument that
Mertin says that dermatophytes are more sensitive to
antimycotics than yeasts, Anacor argued at the hearing
that “nowhere in the Mertin article does it talk about
Candida albicans. So they are extrapolating much beyond
the teachings of Mertin[.]”
    Based on this record, we conclude that Anacor was not
denied its procedural rights with respect to the theory of
obviousness adopted by the Board or any evidence relied
on by the Board. The Board did not materially deviate
from the theory of obviousness set forth in the petition,
and Anacor had ample notice of and an opportunity to
respond to the Segal and Mertin references, which in any
event were properly offered in reply to arguments made
by Anacor and for the purpose of showing the state of the
art at the time of the patent application.
                            B
    Anacor next argues that the Board improperly shifted
the burden of proof by requiring the patent owner to
disprove obviousness. Relying on In re Magnum Oil Tools
International, Ltd., 829 F.3d 1364 (Fed. Cir. 2016), Ana-
cor contends that the record provides no basis to conclude
that tavaborole’s activity against dermatophytes would be
expected and that, in adopting the petitioner’s position
without supporting evidence, the Board necessarily shift-
ed the burden of proof to Anacor.
    Unlike in In re Magnum, nothing in the Board’s final
written decision suggests that the Board improperly
shifted the burden to the patent owner to disprove obvi-
ousness. To the contrary, the Board expressly and re-
peatedly stated that it was the petitioner’s burden to
“show[] by a preponderance of the evidence that claims 1–
12 of the ’521 patent are unpatentable.” Final Written
Decision, at 3; see also id. at 9, 10, 18, 22, 23, 37, 42.
16                  ANACOR PHARMACEUTICALS, INC.   v. IANCU



    Notwithstanding those statements, Anacor argues
that the Board effectively shifted the burden of proof to
the patent owner because the Board’s conclusions rested
not on the petitioner’s presentation of evidence in support
of an argument, but rather on whether Anacor had suffi-
ciently disproved that argument. In particular, Anacor
contends that the Board failed to require proof from the
petitioner as to the mechanism of action that would lead
to the conclusion that tavaborole would kill both C. albi-
cans and dermatophytes, and that the Board did not
explain why the evidence that dermatophytes are usually
more sensitive than yeasts to antimycotics applies to
tavaborole.
     In substance, Anacor’s argument is not that the Board
shifted the burden of proof to Anacor, but that the Board
improperly relaxed the burden on the petitioner to prove
its case. That argument, however, does not suggest that
the Board shifted the burden of proof to Anacor, but
instead is directed to the question whether there was
substantial evidence to support the Board’s finding of
obviousness.
    As to that issue, the Board found that a person of skill
in the art would have been motivated to combine Austin
and Brehove and would have had a reasonable expecta-
tion of success in doing so. Austin disclosed the use of
oxaboroles, a subset of boron heterocycles, as fungicides
that were effective against five different species of fungi,
including C. albicans. It stated that compounds contain-
ing an oxaborole ring, such as tavaborole, are particularly
effective against fungi. Tavaborole, in particular, was
identified as being especially potent against the various
species of fungi that Austin tested. Austin also disclosed
that tavaborole was a low molecular weight compound,
which would enable the compound to penetrate the nail
plate covering the locus of the infection.
ANACOR PHARMACEUTICALS, INC.    v. IANCU                   17



    The compounds of Brehove, also boron heterocycles,
were shown through in vitro testing to be effective against
C. albicans. The results of Brehove’s in vivo testing
showed that Brehove’s compounds were effective against
onychomycosis in each of the patients suffering from that
condition. In light of the fact that approximately 90
percent of all onychomycosis cases are attributable to
dermatophytes, and in the absence of any evidence that
patients with dermatophyte-based onychomycosis were
excluded from the in vivo testing, it is highly likely that at
least some of the five cases discussed by Brehove involved
dermatophyte infections.
     Beyond that, the evidence in the record before the
Board showed that persons of skill in the art would have
known that antifungal agents that are effective against
one species of fungus are typically effective against oth-
ers, as reported by the petitioner’s experts, Dr. Kahl and
Dr. Murthy. In addition, one of skill in the art would
have appreciated that many antifungal agents are more
effective against dermatophytes than against yeasts, as
reported by Dr. Murthy and as indicated by data in the
Segal, Mertin, and Nimura references. 10 In light of the
full record before the Board, we conclude that substantial
evidence supports the Board’s findings that a person of
ordinary skill in the art would have been motivated to
combine the pertinent teachings of Austin and Brehove



    10  As for Anacor’s argument that the Board failed to
require proof of the mechanism of action that caused the
boron heterocycles to be toxic to fungi, no such proof is
required, as it has long been settled that “an inventor
need not comprehend the scientific principles on which
the practical effectiveness of his invention rests.” From-
son v. Advance Offset Plate, Inc., 720 F.2d 1565, 1570
(Fed. Cir. 1983) (citing Diamond Rubber Co. v. Consol.
Rubber Tire Co., 220 U.S. 428, 435–36 (1911)).
18                  ANACOR PHARMACEUTICALS, INC.   v. IANCU



and would have had a reasonable expectation of success in
doing so.
                             C
     In its third argument, Anacor challenges what it re-
fers to as the Board’s “conclusion that the compounds of
Austin are ‘structurally similar’ to the compounds of
Brehove.” Anacor contends that the compounds are
structurally dissimilar, and that a person of ordinary skill
in the art would have expected that even small structural
differences between tavaborole and the Brehove com-
pounds would result in significant differences in their
chemical and biological properties.
    Anacor’s argument is premised on the misapprehen-
sion that the Board viewed structural similarity as a
binary factor—either present or absent—and that the
Board found it was present in this case. That is not an
accurate characterization of the Board’s assessment of the
issue of structural similarity.
    In its final written decision, the Board viewed the ex-
istence of some structural similarity between the com-
pounds in Austin and Brehove as evidence that the
references might be good candidates to be combined. That
is, the Board recognized that the structural similarity
between the boron heterocycles of Austin and Brehove
provides a useful starting point, but it attributed more
significance to the functional similarities of the two
groups of compounds. As the Board observed, Austin
teaches that oxaboroles, a subset of boron heterocycles,
are effective fungicides, and Brehove teaches that certain
dioxaborinanes, a different subset of boron heterocycles,
are likewise effective fungicides. Moreover, notwithstand-
ing the structural differences between the two subsets of
compounds, the Board focused on the fact that both were
shown to be effective against C. albicans, a fungus that
was known to cause onychomycosis.
ANACOR PHARMACEUTICALS, INC.   v. IANCU                  19



    The Board did not regard the structural similarity be-
tween the compounds of Austin and Brehove to be suffi-
cient proof, by itself, that tavaborole would be likely to
have the same functionality as the compounds in Brehove.
The Board correctly acknowledged that there “are obvi-
ously structural differences between the dioxaborinanes of
Brehove and the benzoxaboroles of Austin,” but it con-
cluded that “the combination of the structural similarities
and the similar fungicidal activity against C. albicans
would have led a person of ordinary skill in the art to
combine Brehove’s method of treating onychomycosis
using Austin’s tavaborole instead of [Brehove’s com-
pounds].” Final Written Decision, at 21.
    It is true that in the case of patents on new chemical
compounds, the obviousness inquiry “frequently turns on
the structural similarities and differences between the
compounds claimed and those in the prior art.” Daiichi
Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346, 1352
(Fed. Cir. 2010). In such cases, where the properties of
the new chemical compound are not known, structural
similarity is often sufficient to create an expectation that
the “new compound will have similar properties to the
old.” Altana Pharma AG v. Teva Pharm. USA, Inc., 566
F.3d 999, 1007 (Fed. Cir. 2009) (quoting Eisai Co. v. Dr.
Reddy’s Labs., Ltd., 533 F.3d 1353, 1357 (Fed. Cir. 2008)).
    This case, however, does not involve a patent on a
new chemical compound. Where the patent is directed to
a new treatment using a known compound, it is reasona-
ble to assume that similar compounds that share certain
common properties are apt to share other related proper-
ties as well. See In re Merck & Co., 800 F.2d 1091, 1096
(Fed. Cir. 1986) (the fact that two similar compounds are
both psychotropic drugs and one possesses antidepressive
properties suggests that the other may possess antide-
pressive properties as well); see also In re Mehta, 347 F.2d
859, 864 (CCPA 1965) (“The similarity of properties of a
reference compound as compared with a claimed com-
20                   ANACOR PHARMACEUTICALS, INC.    v. IANCU



pound gives rise to an even stronger inference of obvious-
ness than that of structural similarity alone[.]”); In re
Rosselet, 347 F.2d 847, 850 (CCPA 1965) (referring to a
“prima facie showing of obviousness by reason of the
admitted ‘gross structural similarities’ of the art com-
pounds, coupled with the fact those compounds are shown
to have utility in the same area of pharmacological activi-
ty”).
    To be clear, we recognize that structural similarity is
an important factor in assessing the motivation to com-
bine and reasonable expectation of success. It has been
long recognized that chemical compounds with similar
structures often have similar properties and that similari-
ty in properties can be inferred from structural similari-
ty. In re Hass, 141 F.2d 122, 125 (CCPA 1944). Our cases
have held that the greater the structural similarity be-
tween the compounds, the greater the motivation to
combine and reasonable expectation of success. Eli Lilly
& Co. v. Zenith Goldline Pharm., Inc., 471 F.3d 1369,
1377 (Fed. Cir. 2006) (noting that, for a new chemical
compound, finding obviousness requires “structural
similarity” and a “reason or motivation to make the
claimed compositions” (quoting In re Dillon, 919 F.2d 688,
692 (Fed. Cir. 1990) (en banc))); In re Deuel, 51 F.3d 1552,
1558 (Fed. Cir. 1995) (“Structural relationships may
provide the requisite motivation or suggestion to modify
known compounds to obtain new compounds.”). The
opposite is true, too: the less the structural similarity, the
less the motivation to combine and the reasonable expec-
tation of success. In re Jones, 958 F.2d 347, 350 (Fed. Cir.
1992) (reversing the prima facie obviousness finding
because of the “lack of close similarity of structure”).
    At the same time, our cases recognize that the chemi-
cal arts are unpredictable and that similar structures do
not always result in similar properties. See Eisai Co., 533
F.3d at 1359. The obviousness inquiry often depends on
whether there is evidence demonstrating a nexus between
ANACOR PHARMACEUTICALS, INC.   v. IANCU                 21



structural similarities (or dissimilarities) and functional
similarities (or dissimilarities). In this case, although
there is only limited structural similarity between the
compounds disclosed in Austin and Brehove, we conclude
that, in light of the combination of the structural and
functional similarities between the compounds, substan-
tial evidence supports the Board’s findings.
    The Board understood that the petitioner’s theory was
“not based on structural similarities alone,” but was
“based on the combination of structural similarity and
functional similarity.” Final Written Decision, at 28. And
the Board agreed with the petitioner that “a person of
ordinary skill in the art would have expected that tavabo-
role, which shares functional activity with the compounds
of Brehove, would have shared other activities as well,
such as the inhibition of additional fungi responsible for
onychomycosis.” Id. at 29. The Board thus did not disre-
gard the structural differences between the compounds of
Austin and Brehove or attribute undue significance to
their structural similarities.
    For the foregoing reasons, we reject Anacor’s chal-
lenges to the Board’s reasoning and uphold the Board’s
conclusion that claim 6 of the ’621 patent is invalid for
obviousness.
                      AFFIRMED
