  United States Court of Appeals
      for the Federal Circuit
               ______________________

      SOUTH ALABAMA MEDICAL SCIENCE
               FOUNDATION,
                 Appellant

                         v.

   GNOSIS S.P.A., GNOSIS BIORESEARCH S.A.,
             GNOSIS U.S.A., INC.,
                    Appellees
             ______________________

           2014-1778, 2014-1780, 2014-1781
               ______________________

   Appeals from the United States Patent and Trade-
mark Office, Patent Trial and Appeal Board in No.
IPR2013-00116.
               ______________________

             Decided: December 17, 2015
               ______________________

     THOMAS J. PARKER, Alston & Bird LLP, New York,
NY argued for appellant. Also represented by JITENDRA
MALIK, Durham, NC; KIRK T. BRADLEY, Charlotte, NC;
PETER ROGALSKYJ, Law Office of Peter Rogalskyj, Livo-
nia, NY.

   JOSEPH CWIK, Amin Talati & Upadhye, LLC,
Chicago, IL argued for appellees. Also represented by
JONATHAN JACOB KRIT, Amin Talati, LLC, Chicago, IL.
                ______________________
2            SOUTH ALABAMA MEDICAL SCIENCE   v. GNOSIS S.P.A.



    Before NEWMAN, PLAGER, and HUGHES, Circuit Judges.
    Opinion for the court filed by Circuit Judge HUGHES.
     Dissenting opinion filed by Circuit Judge NEWMAN.
HUGHES, Circuit Judge.
    This is a companion case to Merck & Cie v. Gnosis
S.p.A., No. 14-1777 (Fed. Cir. Dec. 17, 2015) (Gnosis I),
also decided today. As Merck argued in that case, South
Alabama Medical Science Foundation argues here that
the prior art taught away from its claimed use of a re-
duced folate to treat folate deficiency, and that objective
indicia of non-obviousness further demonstrate the validi-
ty of its patents. Although the Patent Trial and Appeal
Board erred in its assessment of the evidence of licensing,
the Board’s other factual findings are supported by sub-
stantial evidence. Because we agree with the Board’s
ultimate conclusion of obviousness in light of those find-
ings, we affirm.
                             I
    South Alabama Medical Science Foundation (SAMSF)
owns U.S. Patent Nos. 5,997,915 (’915 patent), 6,673,381
(’381 patent), and 7,172,778 (’778 patent). At the request
of Gnosis S.p.A., Gnosis Bioresearch S.A., and Gnosis
U.S.A. (collectively, Gnosis) and after granting SAMSF’s
motion to cancel certain claims, the Board instituted
review of claims 37, 94–97, 99–100, and 110–111 of the
’915 patent; claim 32 of the ’381 patent; and claim 15 of
the ’778 patent.
    All three patents relate to administering the “natural”
stereoisomer of 5-methyl-tetrahydrofolic acid (L-5-MTHF)
and other vitamins to treat symptoms associated with
folate deficiency. We explained the background for this
technology in Gnosis I, slip op. at 2–3. In brief, 5-MTHF
is a reduced folate that is a critical component of certain
metabolic cycles. A deficiency of folate causes a variety of
SOUTH ALABAMA MEDICAL SCIENCE    v. GNOSIS S.P.A.         3



health issues, including cardiovascular disease, neurologi-
cal disorders, birth defects, and skeletal disorders.
    Claim 37 of the ’915 patent recites “a method of in-
creasing a human subject’s dietary intake of folate com-
prising administering . . . one or more natural isomers of
reduced folate selected from [a group including L-5-
MTHF]” and “an essential nutrient preparation . . . com-
prising a vitamin other than ascorbic acid . . . in an
amount equal to or greater than 25% of the daily re-
quirement for the vitamin.” ’915 patent, col. 23 ll. 16–31.
Claims 94–97, 99–100, and 110–111 ultimately depend
from claim 37, and specifically require that “the one or
more natural isomers of reduced folate is substantially
chirally pure [5-MTHF] or a polyglutamyl derivative
thereof.” ’915 patent, reexamination certificate, col. 4 ll.
34–50, 55–62; col. 6 ll. 26–31.
     Claim 32 of the ’381 patent similarly recites a method
of treating vascular disease using a composition including
one or more substantially chirally pure natural isomers of
reduced folate (e.g. L-5-MTHF) and an essential nutrient
preparation comprising a vitamin other than ascorbic
acid. ’381 patent, col. 18 ll. 33–35.
    Claim 15 of the ’778 patent covers a composition con-
taining substantially chirally pure natural isomers of
reduced folate (e.g. L-5-MTHF), in an amount effective for
the treatment of vascular disease and certain pregnancy-
related conditions, and an essential nutrient preparation
containing a vitamin other than ascorbic acid. ’778 pa-
tent, col. 18 ll. 18–20.
    The Board found that all of the contested claims were
obvious in light of two prior art references: European
Patent App. No. 0 595 005 (Serfontein) and U.S. Patent
No. 5,194,611 (Marazza). Serfontein discloses a pharma-
ceutical preparation for treating elevated levels of homo-
cysteine, which is often associated with folate deficiency.
The preparation includes “folate or a suitable active
4           SOUTH ALABAMA MEDICAL SCIENCE    v. GNOSIS S.P.A.



metabolite of folate,” along with vitamins B6 and B12.
Serfontein, at 4 ll. 37–42. Marazza identifies L-5-MTHF
as a “natural metabolite” of folate in which there is an
“increasing interest” for the treatment of folate deficien-
cies. Marazza, col. 1 ll. 26–29. 1 As in Gnosis I, the Board
found that based on the close similarity of purpose and
disclosure of these references a person of ordinary skill
would have been motivated to combine them to arrive at
the claimed use of L-5-MTHF and a vitamin supplement
to treat symptoms of folate deficiency.
     The Board also considered SAMSF’s evidence of objec-
tive indicia of non-obviousness. The Board found that
SAMSF failed to demonstrate an adequate nexus between
that evidence and the novel features of the contested
claims. Accordingly, the Board concluded that the con-
tested claims of the ’915, ’381, and ’778 patents are inva-
lid for obviousness under 35 U.S.C. § 103.
    SAMSF appeals. We have jurisdiction under 28 U.S.C.
§ 1295(a)(4)(A).
                             II
    Obviousness is a question of law based on underlying
findings of fact, which include the motivation to combine
multiple prior art references and any objective indicia of
non-obviousness. Medichem, S.A. v. Rolabo, S.L., 437
F.3d 1157, 1164 (Fed. Cir. 2006); see also Graham v. John
Deere Co., 383 U.S. 1, 17–18 (1966). We review the
Board’s factual findings for substantial evidence and the
ultimate conclusion of obviousness de novo. In re Mouttet,
686 F.3d 1322, 1330–31 (Fed. Cir. 2012).
    SAMSF makes essentially the same arguments for re-
versing the Board’s obviousness analysis that Merck



    1    For more detail on these references, see Gnosis I,
slip op. at 4–5.
SOUTH ALABAMA MEDICAL SCIENCE    v. GNOSIS S.P.A.          5



made in Gnosis I. SAMSF argues that the Board’s obvi-
ousness analysis was insufficiently thorough, and that the
prior art teaches away from combining Serfontein and
Marazza, because it suggests that L-5-MTHF may in-
crease homocysteine levels, is too unstable for therapeutic
use, and is a poor substrate for polyglutamation. SAMSF
also argues that the Board imposed an overly strict nexus
requirement to find that its evidence of objective indicia of
non-obviousness is not sufficiently tied to the novel fea-
tures of the contested claims.
    For the same reasons discussed in Gnosis I, slip op. 7–
13, the Board’s finding of a motivation to combine Serfon-
tein and Marazza was adequately explained and support-
ed by substantial evidence.       Serfontein calls for a
“suitable active metabolite of folate,” and Marazza dis-
closes that an increasingly popular option for treating
folate deficiency is L-5-MTHF. Although SAMSF points
to isolated disclosures suggesting L-5-MTHF may not be
“suitable,” substantial evidence supports the Board’s
finding that the prior art as a whole teaches otherwise.
We find no error in the Board’s conclusion that the prior
art and expert testimony here provide strong evidence
that the contested claims were obvious.
    The Board also properly determined that SAMSF’s ev-
idence of objective indicia of non-obviousness was insuffi-
cient to overcome the other evidence of obviousness. Like
Merck in Gnosis I, SAMSF argued here that the commer-
cial success of the Metanx®, Cerefolin®, CerefolinNAC®,
Néevo®, and NéevoDHA® products manufactured by
Pamlab demonstrate non-obviousness. But these prod-
ucts contain a specific combination of L-5-MTHF and
several vitamins and other active ingredients that are not
recited in the claims. See Gnosis I, slip op. at 14–15.
Substantial evidence thus supports the Board’s finding
that the commercial success of these products was inade-
quately linked to the claimed methods and composition—
which call for L-5-MTHF or another reduced folate and
6           SOUTH ALABAMA MEDICAL SCIENCE   v. GNOSIS S.P.A.



any number of vitamins other than ascorbic acid—as
opposed to the specific formulations in these products.
    Contrary to SAMSF’s argument, the Board’s analysis
does not effectively require SAMSF to produce evidence of
commercial success for every potential embodiment of the
claims. See Rambus Inc. v. Rea, 731 F.3d 1248, 1257
(Fed. Cir. 2013) (holding such a strict requirement is
improper). Rather, the Board applied the appropriate
standard and found that the commercially successful
products were not “reasonably commensurate in scope
with the claims” and that SAMSF had not provided an
“adequate basis to support the conclusion that other
embodiments falling within the claim will behave in the
same manner.” J.A. 39–40, 84–86, 131–32 (citing In re
Huai-Hung Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011)).
We therefore reject SAMSF’s contention that the Board
applied an overly strict nexus requirement.
     The Board’s nexus analysis for the evidence of indus-
try praise was also sound. This evidence consisted of
praise for the Pamlab products, which the Board found
were not reasonably commensurate with the scope of the
claims. Moreover, substantial evidence supports the
Board’s finding that the praise was particularly directed
to the use of L-5-MTHF, an element already known in the
prior art. The industry award touted by SAMSF was for
Metafolin®, the L-5-MTHF ingredient in the Pamlab
products. Likewise, although the industry praised the
positive patient outcomes associated with the Pamlab
products, SAMSF’s experts testified that those outcomes
are attributable to the patient’s increased dietary intake
of folate, referring to the L-5-MTHF ingredient. The
Board’s finding that SAMSF failed to connect the evidence
of industry praise to the novel elements of the claims was
thus supported by substantial evidence.
     SAMSF further argues that its inventors were the
first to recognize that a subset of the population had
SOUTH ALABAMA MEDICAL SCIENCE    v. GNOSIS S.P.A.         7



difficulty processing folic acid, and that L-5-MTHF would
therefore be an effective alternative. But the claims are
not limited to treating this subset of the population. And
administering L-5-MTHF generally was known in the
prior art. Accordingly, substantial evidence supports the
Board’s finding that this evidence was not adequately tied
to the novel features of the claimed invention. 2
    We agree with SAMSF, however, that the Board erred
in assessing SAMSF’s licensing evidence. The Board
discounted SAMSF’s licenses to Merck, and Merck’s
sublicenses to Pamlab, because SAMSF failed to show a
nexus between the claimed inventions and Pamlab’s
products. But the relevant inquiry is whether there is a
nexus between the patent and the licensing activity itself,
such that the factfinder can infer that the licensing “arose
out of recognition and acceptance of the subject matter
claimed” in the patent. In re GPAC Inc., 57 F.3d 1573,
1580 (Fed. Cir. 1995). Although evidence that the licen-
see ultimately manufactured a product that embodies the
claimed invention may be probative of a nexus between
the claimed invention and the licensing activity, the
patentee is not necessarily required to establish an inde-



   2    An inventor’s discovery of a previously unrecog-
nized problem is generally accounted for in the analysis of
the scope of the prior art and a motivation to combine
prior art elements. See Leo Pharm. Prods., Ltd. v. Rea,
726 F.3d 1346, 1353–54 (Fed. Cir. 2014) (finding that
because the prior art does not disclose the problem dis-
covered, there was no motivation to combine prior art
elements to solve that problem). Any error in treating
this point as a secondary consideration, however, was
harmless. Under either heading, this evidence does not
show patentability in this case, because the contested
claims are not limited to solving the allegedly unrecog-
nized problem.
8           SOUTH ALABAMA MEDICAL SCIENCE    v. GNOSIS S.P.A.



pendent nexus between those products and the claimed
invention for the licensing activity to be relevant. The
Board erred in requiring SAMSF to make this showing
here.
    Nonetheless, the Board’s error was harmless. The
Board found persuasive the evidence that a person of
ordinary skill would have been motivated to combine
Serfontein and Marazza to arrive at the contested claims.
And it applied the correct legal standards to the remain-
der of SAMSF’s evidence of secondary considerations,
finding that it was not adequately tied to the merits of the
claimed inventions. These findings were supported by
substantial evidence. Even if the Board had correctly
considered SAMSF’s evidence of licensing, that evidence
is not enough to overcome the strong evidence of obvious-
ness found in the prior art and the expert testimony,
relied upon by the Board to reach its conclusion of obvi-
ousness. We therefore agree with the Board that the
contested claims are invalid for obviousness.
                            III
    Because substantial evidence supports the Board’s
factual findings, except on the evidence of licensing, and
because we agree with the ultimate conclusion of obvious-
ness, we affirm the Board’s finding that claims 37, 94–97,
99–100, and 110–111 of the ’915 patent; claim 32 of the
’381 patent; and claim 15 of the ’778 patent are invalid
under 35 U.S.C. § 103.
                       AFFIRMED
  United States Court of Appeals
      for the Federal Circuit
                ______________________

      SOUTH ALABAMA MEDICAL SCIENCE
               FOUNDATION,
                 Appellant

                           v.

   GNOSIS S.P.A., GNOSIS BIORESEARCH S.A.,
             GNOSIS U.S.A., INC.,
                    Appellees
             ______________________

            2014-1778, 2014-1780, 2014-1781
                ______________________

   Appeals from the United States Patent and Trade-
mark Office, Patent Trial and Appeal Board in No.
IPR2013-00116.
               ______________________
NEWMAN, Circuit Judge, dissenting.
    This appeal is a companion to Merck & Cie v. Gnosis
S.p.A., No. 14-1777 (Gnosis I), decided concurrently, and
consolidates the appeals of three related Inter Partes
Review decisions of the Patent Trial and Appeal Board
(PTAB). The claims of the three appeals are directed to
compositions containing L-5-methyltetrahydrofolic acid
(L-5-MTFA) and various uses thereof. In each IPR pro-
ceeding the PTAB held the claims invalid as obvious
based on the combination of the Serfontein reference
(European Patent No. 0595005 (“EP ’005”)) and the
Marazza reference (United States Patent No. 5,194,611
(the “’611 Patent”)). One IPR decision, IPR2013-00119,
2           SOUTH ALABAMA MEDICAL SCIENCE   v. GNOSIS S.P.A.



included in the combination a third reference, Ueland and
Redsum, Plasma homocysteine, a risk factor for vascular
disease: Plasma levels in health, disease, and drug thera-
py, J. Lab. Clin. Med., Vol. 114, pp. 473–501 (1989).
    For the reasons I discussed in Gnosis I, these refer-
ences do not fill the gap between the folate compounds
described by Marazza and the uses described by Serfon-
tein, such that a person of ordinary skill in this field
would have been motivated to combine these references to
treat elevated homocysteine with a reasonable expecta-
tion of success. Ueland provides a description of folate
and homocysteine biochemistry, and shows the biochemi-
cal relationship between homocysteine and L-5-MTHF.
Ueland adds to the scientific investigations that have
been conducted, but Ueland does not suggest that L-5-
MTHF would successfully treat the specified diseases and
overcome the known uncertainties of stability, metabo-
lism, and bioavailability. Ueland does not suggest that
there would be a likelihood of success in using L-5-MTHF
compositions for the specific purposes discovered and
developed by the South Alabama scientists. The scientific
acclaim and licensing and copying that followed their
work add to the evidence of unobviousness. The PTAB
erred in evaluating and weighing this evidence.
    For the reasons discussed in my dissenting opinion in
Gnosis I, obviousness was not established by a prepon-
derance of the evidence. From my colleagues’ contrary
ruling, I respectfully dissent.
