  United States Court of Appeals
      for the Federal Circuit
                ______________________

    IN RE: CONSTANTIN EFTHYMIOPOULOS,
                    Appellant
             ______________________

                      2016-1003
                ______________________

    Appeal from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in No. 08/737,141.
                  ______________________

               Decided: October 18, 2016
                ______________________

   LYNNE A. BORCHERS, Myers Bigel Sibley & Sajovec,
PA, Raleigh, NC, argued for appellant. Also represented
by PETER DANIEL SIDDOWAY, ANTHONY P. DEROSA,
SHAWNA CANNON LEMON.

   FARHEENA YASMEEN RASHEED, Office of the Solicitor,
United States Patent and Trademark Office, Alexandria,
VA, argued for appellee Michelle K. Lee. Also represented
by THOMAS W. KRAUSE, SCOTT WEIDENFELLER, KAKOLI
CAPRIHAN, LORA DRISCOLL.
                 ______________________

Before PROST, Chief Judge, NEWMAN and BRYSON, Circuit
                       Judges.
    Opinion for the court filed by Chief Judge PROST.
   Dissenting opinion filed by Circuit Judge NEWMAN.
2                                    IN RE: EFTHYMIOPOULOS




PROST, Chief Judge.
     This appeal arises from the examination of a number
of claims of U.S. Patent Application No. 08/737,141 (“’141
application”). The examiner rejected all pending claims
as obvious and the United States Patent and Trademark
Office, Patent Trial and Appeal Board (“Board”) affirmed
all of those rejections. Appellant Constantin Efthymi-
opoulos (“Efthymiopoulos”) then requested rehearing,
which the Board denied. For the following reasons, we
affirm the Board’s decision.

                       BACKGROUND
    The ’141 application relates to methods of treating or
preventing influenza by administering the drug
zanamivir 1 by oral inhalation. On appeal, Efthymiopou-
los challenges the rejection of claims 14-30, 32, 34-38, and
43-65. Independent claim 14 is representative:
    14. A method for treating a human suffering from
    an infection by an influenza virus, wherein the
    method comprises administering to the human an
    effective amount of [zanamivir], wherein the
    [zanamivir] is administered by inhalation through
    the mouth alone.
J.A. 1697.
    The examiner rejected the pending claims as obvious
over Australian Patent No. AU-A1-27242/92 (“Von Itz-
stein II”), in view of WIPO Publication WO 91/16320
(“Von Itzstein I”) and a number of other references. Like
the ’141 application, Von Itzstein I discloses that


    1   The ’141 application uses the chemical name of
zanamivir: 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-
glycero-D-galacto-non-2-enopyranosonic acid. For ease of
reference, we refer to the compound as zanamivir
throughout the opinion.
IN RE: EFTHYMIOPOULOS                                     3



zanamivir can be administered to treat and prevent
infections by the influenza virus. Von Itzstein I only
discloses intranasal administration (and not oral inhala-
tion) of zanamivir. Von Itzstein II discloses the admin-
istration of a compound similar to zanamivir by
“inhalation” for the treatment and prevention of influen-
za. The examiner concluded that Von Itzstein II disclosed
all of the limitations of the challenged claims except that
it did not teach zanamivir specifically and did not ex-
pressly teach inhalation only by mouth of its compounds.
The examiner found, however, that Von Itzstein I taught
zanamivir and suggested administering that compound to
the respiratory tract to treat or prevent influenza. The
examiner further determined that zanamivir and the
compound disclosed in Von Itzstein II are “adjacent
homologues” (meaning they are part of a series of com-
pounds that differ in structure only by a single substitu-
ent) and thus concluded that using zanamivir in the
method disclosed in Von Itzstein II would have been
obvious.
    Finally, the examiner noted that, with respect to ad-
ministration, there are only two possible inhalation
methods: through the mouth (oral) or through the nose
(nasal). In view of the other prior art references that
taught the well-known availability of inhalers, that oral
inhalation delivers more drug to the lungs than nasal
inhalation, and the fact that influenza infects the lungs,
the examiner concluded that treating influenza by oral
inhalation of zanamivir would have been obvious.
    The Board agreed with and extensively cited the ex-
aminer and affirmed all of the rejections. The Board
found that Von Itzstein II’s disclosure of “inhalation” for
treating influenza with its compounds “is reasonably
understood to disclose inhalation by either the nose alone,
mouth alone, or both” and thus concluded that Von Itz-
stein II in view of Von Itzstein I’s disclosure of zanamivir
rendered the claims obvious. J.A. 12-13. The Board also
4                                    IN RE: EFTHYMIOPOULOS




considered Efthymiopoulos’s evidence of secondary con-
siderations—namely of unexpected results—but found it
to be unpersuasive.
    Efthymiopoulos sought rehearing, but the Board de-
nied its request. Efthymiopoulos then timely appealed
the Board’s decision to us. We have jurisdiction under 28
U.S.C. § 1295(a)(4)(A) (2012).

                       DISCUSSION
    We review the Board’s legal determinations de novo
and its underlying factual determinations for substantial
evidence. Rambus Inc. v. Rea, 731 F.3d 1248, 1251 (Fed.
Cir. 2013). Obviousness is a legal question based on
underlying fact findings. In re DBC, 545 F.3d 1373, 1377
(Fed. Cir. 2008).
    Efthymiopoulos argues that the Board erred in reject-
ing the pending claims as obvious. Efthymiopoulos con-
tends that none of the prior art references, alone or in
combination, teach administration of zanamivir by inha-
lation through the mouth. Moreover, Efthymiopoulos
says that a person of ordinary skill would not have ex-
pected that the administration of zanamivir through
inhalation by mouth only would be effective. That is
because oral inhalation delivers more drugs to the lower
respiratory tract, and, at the time of the invention, it was
thought that delivery of anti-influenza drugs to the upper
respiratory tract was required to be effective. Finally,
Efthymiopoulos faults the Board for failing to consider its
evidence of unexpected results.
    We conclude that the Board did not err in its obvious-
ness determination. There is no dispute that Von Itz-
stein I discloses the use of zanamivir to treat and prevent
influenza. There is also no dispute that Von Itzstein II
discloses several pages of different administration meth-
ods for an adjacent homologue of zanamivir to achieve the
same result—treating or preventing influenza. In partic-
IN RE: EFTHYMIOPOULOS                                     5



ular, Von Itzstein II expressly discloses administration
through “oral,” “nasal,” or other forms “suitable for ad-
ministration by inhalation,” among other methodologies.
The Board’s finding then, that a skilled artisan would be
motivated to use zanamivir in the methods disclosed by
Von Itzstein II, is supported by substantial evidence.
     The Board also agreed with the examiner’s conclusion
that Von Itzstein II’s disclosure of administration through
“inhalation” includes oral inhalation. That finding is
supported by substantial evidence. As the Board noted,
“[I]nhalation can only be carried out via the nose or the
mouth. Since Von Itzstein II does not limit its disclosure
to nasal inhalation, it is reasonably understood to disclose
inhalation by either the nose alone, the mouth alone, or
both.” J.A. 12-13.
    The Board’s conclusion is further supported by the
fact that both Von Itzstein references teach that the
compounds may be administered in many forms, includ-
ing as a dry powder through an inhaler. And, as the
Board noted, the state of the art at the time of invention
established that dry-powder compositions were often used
specifically for oral inhalation.
    Efthymiopoulos’s argument that a skilled artisan
would not reasonably expect zanamivir to be effective if
administered through oral inhalation is also unpersua-
sive. As the examiner noted, it was known in the art at
the time that, although the influenza virus primarily
attacks the upper respiratory tract, certain strains of the
virus also attack the lower respiratory tract and that
young children in particular were more susceptible to
lower respiratory tract infections from the virus. And as
the examiner observed, oral inhalation delivers more
drugs to the lungs as compared to nasal inhalation. Thus,
substantial evidence supports the determination that a
skilled artisan would have a reasonable expectation of
success in combining the Von Itzstein references.
6                                    IN RE: EFTHYMIOPOULOS




    Finally, Efthymiopoulos contends that the Board dis-
regarded its evidence of unexpected results, namely the
testimony of Dr. Hayden. We disagree. The record shows
that the Board thoroughly considered and discussed
Dr. Hayden’s declaration in its decision and found that
Dr. Hayden’s testimony insufficient to overcome the
prima facie case of obviousness. For example, the Board
found that a study by Dr. Hayden did not show unexpect-
edly superior results between oral and intranasal inhala-
tion. That finding is supported by substantial evidence.
As the Board observed, Dr. Hayden himself conceded that
the conclusion of the study he conducted was that “adding
intranasal administration of zanamivir did not obviously
improve” the results of using oral administration alone for
the treatment of influenza. J.A. 1706. Thus, after consid-
ering Dr. Hayden’s testimony and the manner in which it
was conducted, the Board properly concluded that the
claimed method would not necessarily yield an unexpect-
edly superior result.
    Dr. Hayden also cited the Kaiser study which involved
preventing influenza and showed that the rate of influen-
za was “substantially although not statistically signifi-
cantly reduced” in patients treated with orally inhaled
zanamivir compared to those treated with intranasal
zanamivir. J.A. 1458. But, as the Board found, the
Kaiser study is also unpersuasive because it did not
disclose superior results, its findings were admittedly not
statistically significant, and it dealt only with prevention
of influenza, while the claims are directed to the treat-
ment of influenza.
     The Board therefore properly considered Efthymi-
opoulos’s evidence of unexpected results and simply found
it lacking. That finding is supported by substantial
evidence. We thus conclude that the Board correctly
affirmed the examiner’s rejection of all pending claims as
obvious.
IN RE: EFTHYMIOPOULOS                                   7



                        CONCLUSION
    For the foregoing reasons, we affirm the Board’s deci-
sion.
                        AFFIRMED
  United States Court of Appeals
      for the Federal Circuit
                 ______________________

    IN RE: CONSTANTIN EFTHYMIOPOULOS,
                    Appellant
             ______________________

                       2016-1003
                 ______________________

    Appeal from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in No. 08/737,141.
                  ______________________

NEWMAN, Circuit Judge, dissenting.
    This litigation concerns the influenza drug zanamivir,
marketed under the trademark Relenza®. The PTAB and
now this court rule that it was obvious to administer this
drug by oral inhalation, although there is no reference, no
prior art, no suggestion, proposing that this mode of
application might succeed, or that it should be tried.
There was evidence of skepticism even as oral inhalation
was evaluated. There was no contrary evidence. The
evidence on which the Board and now this court rely is
the evidence in the patent application itself, describing
oral inhalation, its benefits, and its effectiveness. Upon
learning this information from this inventor’s disclosure,
the Board found that it was obvious, and my colleagues
agree that it is obvious to them.
    Zanamivir was a known drug for treatment of influ-
enza, administered by nasal inhalation, for the influenza
virus was believed to infect the upper respiratory tract.
The PTAB recognized that “the Examiner acknowledges
that Von Itzstein II does not specifically teach inhalation
2                                    IN RE: EFTHYMIOPOULOS




of the compound through the mouth.” PTAB Op. 7. Nor
does any other reference teach or suggest treatment of
influenza by oral inhalation of this compound or any
related compound. My colleagues nonetheless deem this
treatment of influenza obvious on the ground that inhala-
tion occurs only through the nose or the mouth. Thus the
court rules that the discovery of effective treatment by
oral inhalation is obvious to the court, although not
obvious to experts, and not suggested in the prior art.
    The applicant provided the expert opinion of Dr. Hay-
den, who discussed a large international study in which
he participated, and concluded that the “effectiveness of
orally inhaled zanamivir as compared with nasal admin-
istration . . . could be considered an unexpected result”:
    In part because uncertainties existed regarding
    the transmission and pathogenesis of influenza as
    of the effective filing date of the present applica-
    tion, it was unclear whether oral inhalation of
    zanamivir with the dry powder inhaler device uti-
    lized in the studies would be clinically effective
    alone for prevention or treatment of naturally oc-
    curring uncomplicated influenza. In view of this
    uncertainty, the clinical effectiveness of orally in-
    haled zanamivir as compared to nasal administra-
    tion for prevention of naturally occurring
    uncomplicated influenza above could be consid-
    ered an unexpected result. Similarly, the effec-
    tiveness of orally inhaled zanamivir without
    intranasal zanamivir for treatment of naturally
    occurring uncomplicated influenza alone could be
    considered an unexpected result.
Decl. of Frederick G. Hayden, M.D. at 7 (filed in U.S.
Patent Application No. 08/737,141 Mar. 12, 2013). Both
the Board and the court discount Dr. Hayden’s opinion
because these experiments were not conducted for patent
purposes but for scientific purposes, and were not direct
IN RE: EFTHYMIOPOULOS                                     3



comparisons with the Board’s view of the closest prior art.
Dr. Hayden explained that:
   Although this study was not designed to compare
   directly the effects of zanamivir administration by
   oral inhalation alone to the effects of zanamivir
   administration by intranasal administration
   alone, it nonetheless found that the oral inhala-
   tion route alone provided unexpectedly significant
   activity without requiring intranasal administra-
   tion for effective treatment of influenza virus ill-
   ness . . . .
Id. at 3. Dr. Hayden explained that it was unexpected
that this study “demonstrated the therapeutic value of
drug delivery by the oral inhalation route to the posterior
oropharynx (throat) and lower respiratory tract to treat
naturally occurring influenza virus infection.” Id. at 4.
     Dr. Hayden also discussed a study that showed that
the rate of influenza infection during 5 days of prophylax-
is treatment was 6% for nasal inhalation alone – the same
as for the placebo group – but was 2-3% for the group that
received zanamivir “both by oral inhalation and intrana-
sally.” Id. at 4, citing Kaiser et al. Short-Term Treatment
with Zanamivir to Prevent Influenza: Results of a Placebo-
Controlled Study, 30 CLINICAL INFECTIOUS DISEASES 587–
89 (2000). Dr. Hayden concluded that “[t]he results of
this study supported a difference in protection between
intranasal zanamivir and orally inhaled zanamivir” and
“suggest the importance of delivering zanamivir to the
posterior oropharynx and/or lower respiratory tract for
the prevention of naturally acquired influenza virus
illness.” Id. at 4–5. As quoted supra, Dr. Hayden stated
that this result was unpredictable and unexpected. Id. at
7.
    As stated in In re Dihrendra Ranchhoddas Merchant,
575 F.2d 865, 868 (CCPA 1978), “The Board’s basic error
resides in its determination that Pring was the closest
4                                    IN RE: EFTHYMIOPOULOS




prior art and that absent comparative tests vis-à-vis
Pring, there was no rebuttal of what the Board considered
a prima facie case.” The Board erred in refusing to con-
sider Dr. Hayden’s results and in criticizing his tests as
not in accordance with the Board’s design of patent-
oriented directly comparable experiments. The Board
disregarded that Von Itzstein I only evaluated admin-
istration by nasal administration of a solution. See Inter-
national Patent Application No. WO91/16320 at 54 (Oct.
31, 1991) (“Von Itzstein I”) (describing intranasal admin-
istration of aqueous solution). The fact that scientific
studies did not compare oral inhalation to liquid nasal
administration does not mean the comparative evidence
can be disregarded entirely. Dr. Hayden explained his
conclusions; the Board should have considered them.
    The Board did not hold that the result here was ex-
pected. However, the Board held that the claimed subject
matter was obvious, on a rationale akin to “obvious to
try.” However, in the unpredictable arts such as medici-
nal treatment, for a method to be obvious to try, there
must be some suggestion in the prior art that the method
would have a reasonable likelihood of success.
    There is no suggestion in the prior art to pursue oral
inhalation, for the teachings of Von Itzstein II must be
taken in context. It is noteworthy that there is extensive
discussion in Von Itzstein II directed to all of the known
forms of oral administration of this product—plus paren-
teral, topical, rectal, vaginal, and intranasal administra-
tion—but Von Itzstein II lacks any mention of oral
inhalation. The Von Itzstein II reference, which is the
primary reference relied on by the Board, states:
        Pharmaceutical formulations include those
    suitable for oral, rectal, nasal, topical, (including
    buccal and sub-lingual), vaginal or parenteral (in-
    cluding intramuscular, sub-cutaneous and intra-
    venous) administration or in a form suitable for
IN RE: EFTHYMIOPOULOS                                      5



   administration by inhalation or insufflation. The
   formulations may, where appropriate, be conven-
   iently presented in discrete dosage units and may
   be prepared by any of the methods well known in
   the art of pharmacy. All methods include the step
   of bringing into association the active compound
   with liquid carriers finely divided solid carriers or
   both and then, if necessary, shaping the product
   into the desired formulation.
        Pharmaceutical formulations suitable for oral
   administration may conveniently be presented as
   discrete units such as capsules, cachets or tablets
   each containing a predetermined amount of the
   active ingredient; as a powder or granules; as a so-
   lution, a suspension or as an emulsion. The active
   ingredient may also be presented as a bolus, elec-
   tuary or paste. Tablets and capsules for oral ad-
   ministration may contain conventional excipients
   such as binding agents, fillers, lubricants, disinte-
   grants, or wetting agents. The tablets may be
   coated according to methods well known in the
   art. Oral liquid preparations may be in the form
   of, for example, aqueous or oily suspensions, solu-
   tions, emulsions, syrups or elixers, or may be pre-
   sented as a dry product for constitution with
   water or other suitable vehicle before use. Such
   liquid preparations may contain conventional ad-
   ditives such as suspending agents, emulsifying
   agents, non-aqueous vehicles (which may include
   edible oils), or preservatives. 1



   1    This is the text on which the panel majority ap-
pears to rely for the statement that “Von Itzstein II
expressly discloses administration through ‘oral,’ ‘nasal,’
or other forms ‘suitable for administration by inhalation.’”
Maj. Op. at 5.
6                                      IN RE: EFTHYMIOPOULOS




Australian Patent No. AU-A-27242/92 at 8–9 (April 4,
1993). The description of suitable formulations continues
for almost three more pages, but does not mention or
suggest oral inhalation. No disclosure of administration
of zanamivir by oral inhalation can be found here or
anywhere else in the prior art. One wonders how it can
nonetheless be obvious, particularly in view of the specific
teaching in Von Itzstein I that nasal administration is the
mode for administering zanamivir. To make a prima facie
case, the prior art must provide, and the Board must
identify, a reason or motivation to depart from the prior
art; no reference or combination of references has been so
identified—even in hindsight.
     It cannot be “obvious to try” the only form of oral ad-
ministration that is absent from the Von Itzstein recita-
tions. In KSR v. Teleflex the Court explained that
“obvious to try” may arise “where 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
ordinary skill has good reason to pursue the known op-
tions within his or her technical grasp.” 550 U.S. 398, 416
(2007). The Board’s conclusion relies on a general finding
that “inhalation can only be carried out via the nose or
the mouth.” PTAB Op. 11. But this is a flawed rationale,
for Von Itzstein II teaches a totality of “oral, rectal, nasal,
topical (including buccal and sub-lingual), vaginal or
parenteral (including intramuscular, sub-cutaneous and
intravenous) administration or in a form suitable for
administration by inhalation or insufflation.” Von Itz-
stein II at 8. The omission of oral inhalation from this
compilation of all the “known options” for this drug makes
conspicuously clear that oral inhalation was not an “iden-
tified predictable solution.” The Board’s ruling that oral
inhalation was nonetheless obvious is not supported by
substantial evidence. See In re Huai-Hung Kao, 639 F.3d
1057, 1067 (Fed. Cir. 2011) (“The Board’s own conjecture
IN RE: EFTHYMIOPOULOS                                     7



does not supply the requisite substantial evidence to
support the rejections . . . .”).
    It was undisputed that, at the time of this invention,
it was believed that the influenza virus infected primarily
the upper respiratory tract, that is, the nasal passages. It
was undisputed that there was not a reasonable expecta-
tion that administration to the lower respiratory tract by
oral inhalation would be effective. The Von Itzstein
references do not show or suggest oral inhalation, either
for zanamivir or for any related compounds. The Board’s
statement that inhalation is “reasonably understood” to
include oral inhalation, PTAB Op. 12, is without authori-
ty. There was no record showing or supporting such an
understanding. There was no suggestion or hint in any
reference that treatment by oral inhalation would have a
reasonable expectation of success.
    This mode of therapy is taught only by this inventor.
There was not substantial evidence to support the Board’s
ruling of obviousness. From the court’s flawed analysis
and unsupported conclusion, I respectfully dissent.
