  United States Court of Appeals
      for the Federal Circuit
                ______________________

   AMERIGEN PHARMACEUTICALS LIMITED,
                Appellant

                          v.

               UCB PHARMA GMBH,
                      Appellee
               ______________________

                      2017-2596
                ______________________

    Appeal from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in No. IPR2016-
01665.
                 ______________________

               Decided: January 11, 2019
                ______________________

   WILLIAM HARE, McNeely Hare & War LLP, Princeton,
NJ, argued for appellant. Also represented by SHYAM
DIXIT, Dixit Law Firm, Tampa, FL.

   JEFFREY J. OELKE, Fenwick & West, New York, NY,
argued for appellee. Also represented by RYAN JOHNSON,
LAURA MORAN, JAMES TRAINOR.
                 ______________________

    Before LOURIE, CHEN, and STOLL, Circuit Judges.
LOURIE, Circuit Judge.
2          AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH




    Amerigen Pharmaceuticals Limited (“Amerigen”) ap-
peals from the decision of the United States Patent and
Trademark Office Patent Trial and Appeal Board (the
“Board”) in an inter partes review (“IPR”) holding that
claims 1–5 and 21–24 of U.S. Patent 6,858,650 (the “’650
patent”) are not unpatentable as obvious. Mylan Pharm.
Inc. v. UCB Pharma GmbH, No. 2016-00510 (P.T.A.B.
July 19, 2017) (“Decision”). We conclude that the Board
did not err in its conclusions and affirm.
                     I. BACKGROUND
                            A.
    UCB Pharma GmbH (“UCB”) owns the ’650 patent,
which covers certain chemical derivatives of 3,3-
diphenylpropylamines, including a compound called
fesoterodine. Fesoterodine is an antimuscarinic drug
marketed as Toviaz® to treat urinary incontinence.
    The chemical structure of fesoterodine is depicted be-
low:




                        Fesoterodine

On the upper left hand benzene ring above, we will refer
to the position of the hydroxymethyl group as the 5-
position, and the position of the isobutyryl ester as the 2-
position.
    Fesoterodine is a prodrug. Unlike a typical drug, a
prodrug is an inactive molecule as-delivered and requires
transformation within the body into its active therapeutic
form. A prodrug may be employed when administering
the active molecule itself is infeasible because of poor
4          AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH




                           B.
    Mylan Pharmaceuticals Inc. petitioned for IPR of the
’650 patent, and the Board instituted review of claims 1–5
and 21–24 on two grounds: (1) obviousness over the
Detrol Label, 2 Postlind, 3 Bundgaard, 4 Bundgaard PCT, 5
and Berge 6; and (2) obviousness over Brynne, 7
Bundgaard, Bundgaard PCT, and Johansson. 8 After
institution, Amerigen and two other companies were
joined as parties to the proceeding. Only Amerigen has
appealed.
                            1.
    The references fall into three general categories.
First, the Detrol Label, Postlind, and Brynne discuss
tolterodine and its metabolism and pharmacokinetics.
Second, Bundgaard and Bundgaard PCT focus on prodrug
design principles. Third, Berge and Johansson relate to




focused on the motivation to make the claimed alkyl ester,
which we do as well.
    2   Detrol® Prescribing Information (1998).
    3   Hans Postlind et al., Tolterodine, a New Musca-
rinic Receptor Antagonist, Is Metabolized by Cytochromes
P450 2D6 and 3A in Human Liver Microsomes, 26 Drug
Metabolism & Disposition 289 (1998).
    4   Hans Bundgaard, Design of Prodrugs (1985).
    5   International Application WO 92/08459.
    6   Stephen M. Berge et al., Pharmaceutical Salts, 66
J. Pharm. Sci. 1 (1977).
    7   Niclas Brynne et al., Influence of CYP2D6 Poly-
morphism on the Pharmacokinetics and Pharmacodynam-
ics of Tolterodine, 63 Clinical Pharmacology &
Therapeutics 529 (1998).
    8   International Application WO 94/11337.
AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH              5



pharmaceutical salts. We will summarize each group in
turn.
    The Detrol Label discloses the structure of tolterodine
and its metabolism to 5-HMT via the enzyme CYP2D6.
The metabolite 5-HMT is reported to have antimuscarinic
activity similar to tolterodine and contribute to toltero-
dine’s therapeutic effect. The Detrol Label taught that a
subset of the population (known as “poor metabolizers”)
lacks CYP2D6 activity and instead metabolizes toltero-
dine by means of the enzyme CYP34A. Since the CYP34A
pathway metabolizes tolterodine more slowly than
CYP2D6, poor metabolizers have higher concentrations of
tolterodine and negligible concentrations of 5-HMT.
However, because the sum of unbound tolterodine and 5-
HMT concentrations is similar in extensive (i.e., patients
with normal CYP2D6 activity) and poor metabolizers, the
Detrol Label teaches that the net therapeutic activity of
tolterodine would be similar between both groups.
     Brynne is a research paper that describes the influ-
ence of patients’ varying CYP2D6 activity on tolterodine
activity. Like the Detrol Label, Brynne posits that “the
CYP2D6 polymorphism does not appear to be of great
importance in the antimuscarinic effect, probably because
of the additive action of parent drug and active metabo-
lite.” J.A. 301. However, Brynne did observe that
“[t]olterodine is tenfold more lipophilic than 5-HM[T], and
consequently tolterodine penetrates membranes more
rapidly.” J.A. 310. The reference suggests that this
difference might contribute to poor metabolizers experi-
encing a slightly worse side effect than extensive metabo-
lizers.    But ultimately, Brynne concludes that the
variation in CYP2D6 activity between poor and extensive
metabolizers “does not appear to be of great pharmacody-
namic importance.” Id.
    Postlind, another published research paper, focuses
on tolterodine metabolism. J.A. 296. Postlind cautions
6          AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH




that tolterodine has a potential for drug-drug interactions
because other drugs are metabolized by CYP2D6 and that
CYP2D6 poor metabolizers could be particularly affected
by such interactions.
     Bundgaard describes prodrugs and their design prin-
ciples. The reference defines a prodrug as “a pharmaco-
logically inactive derivative of a parent drug molecule
that requires spontaneous or enzymatic transformation
within the body in order to release the active drug, and
that has improved delivery properties over the parent
drug molecule.” J.A. 316. Thus, “[t]he prodrug per se is
an inactive species, and therefore, once its job is complet-
ed, intact prodrug represents unavailable drug.” J.A. 319.
Esters are listed as common prodrug substituents. Specif-
ically, “[a]ctive drug species containing hydroxyl or car-
boxyl groups can often be converted to prodrug esters
from which the active forms are regenerated by esterases
within the body.” J.A. 319; see J.A. 320 (listing ester
prodrugs). Bundgaard further states that esters can be
used to improve aqueous solubility of drugs containing a
hydroxy group and that with esterification “it is feasible
to obtain derivatives with almost any desirable hydro-
philicity or lipophilicity.” J.A. 321. Relatedly, Bundgaard
PCT discloses an ester prodrug of morphine that improves
transdermal delivery and is more lipophilic than the
parent drug.
    Berge and Johannson both disclose pharmaceutical
salts including fumarate salts.
                             2.
    In its obviousness analysis, the Board accepted that a
person of ordinary skill would have chosen 5-HMT as a
lead compound for development in order to reduce the
number of potential metabolic steps and to avoid
CYP2D6-related drug-drug interactions. Decision, slip op.
at 22. However, after considering expert testimony from
both the petitioners and UCB, the Board found that a
AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH               7



person of ordinary skill would not have been motivated to
modify 5-HMT to make a prodrug by replacing the 2-
position hydroxy group with an alkyl ester of six or fewer
carbons. Id. at 34–35, 40–41. This factual determination
was premised on several subsidiary findings that Ameri-
gen challenges on appeal. We summarize these findings
here.
     The Board found that a person of ordinary skill would
not have been motivated to modify 5-HMT to improve its
bioavailability. Decision, slip op. at 32–33. Petitioners’
expert, Dr. Patterson, testified that 5-HMT was insuffi-
ciently lipophilic because of its two hydroxy groups, and
that its lipophilicity would cause bioavailability problems.
In support, Dr. Patterson pointed to Brynne’s statement
that tolterodine is 10-fold more lipophilic than 5-HMT
and could penetrate cell membranes more rapidly. UCB
responded that no prior art reference suggested that 5-
HMT would not be well-absorbed, and that the lipophilici-
ty of 5-HMT relative to tolterodine, a known, well-
absorbed drug, did not show that 5-HMT had a bioavaila-
bility problem.
    Furthermore, UCB’s expert, Dr. Roush, conducted an
analysis of 5-HMT using the “Rule of 5” discussed in a
research article on drug delivery by Lipinski. 9 Dr. Patter-
son agreed that a person of ordinary skill would consider
the Rule of 5. The Rule of 5 assesses four inherent prop-
erties of a compound that may help to predict whether it
will have a bioavailability problem. 10 Dr. Roush consid-


   9   Christopher Lipinski et al., Experimental and
Computational Approaches to Estimate Solubility and
Permeability in Drug Discovery and Development Settings,
23 Advanced Drug Delivery Reviews 3 (1997).
    10 Specifically, poor absorption is more likely under
the Rule of 5 if: (1) there are more than 5 hydrogen-bond
8          AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH




ered these properties as they pertained to 5-HMT and
concluded that none of them indicated that 5-HMT had a
bioavailability problem. Dr. Patterson did not rebut this
analysis. The Board thus credited Dr. Roush and deter-
mined that a person of ordinary skill would not have been
motivated to modify 5-HMT because of bioavailability
concerns. Decision, slip op. at 32–33.
    Given its determination that 5-HMT did not have a
bioavailability problem, the Board found that a person of
ordinary skill would not have made a 5-HMT prodrug to
solve a bioavailability problem that did not exist. Deci-
sion, slip op. at 35. Designing a prodrug was a complex
endeavor, the Board found, as toxicity, bioavailability,
and other drug characteristics must be monitored for two
compounds rather than just one. Id. The Board also
found that Bundgaard defined the prodrug form of a
compound as inactive, but the petitioners did not demon-
strate that esters of 5-HMT would be inactive. Id. at 36.
Moreover, the petitioners did not point to any prodrugs
analogous to fesoterodine, for example, prodrugs in the
same chemical class, with the same mechanism of action,
or in the same field of treatment. Id. at 36–37. The
Board thus found that a person of ordinary skill would not
have been motivated to develop a prodrug of 5-HMT.
    Even assuming that a person of ordinary skill would
have been motivated to modify 5-HMT, the Board found
that producing the specific claimed compounds would not
have been a matter of routine optimization. Id. at 40–43.
No prior art reference disclosed the molecule fesoterodine.
Id. at 38, 40. Considering competing expert testimony,
the Board determined that there were many possible


donors; (2) there are more than 10 hydrogen-bond accep-
tors; (3) the molecular weight is greater than 500; and
(4) the calculated log P is greater than 5.
AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH                9



molecular modifications of 5-HMT consistent with a
prodrug design. Id. at 40. For example, Bundgaard
explained that diesters could be used in a prodrug. Id.
The Board credited Dr. Roush’s testimony that a person of
ordinary skill would have considered esterifying the
hydroxy groups at both the 2- and 5-positions. Id. at 42.
And even if a person of ordinary skill only considered
esterifying the 2-position hydroxy group, the Board cred-
ited Dr. Roush’s testimony that there was no scientific
justification to limit the ester to six carbons or fewer. Id.
at 43. Finally, even if the universe of possible esters was
limited to alkyl esters of six carbons or fewer at the 2-
position, that still left 86 possible monoesters. The Board
found that it would not have been routine to test each one.
Id. at 41. Altogether, the Board held that the prior art
did not suggest modifying 5-HMT to make the specific
claimed compounds. Id. at 40.
    Regarding the dependent claims, the Board held that
it would not have been obvious to make the R-enantiomer
or a fumarate salt of the claimed compounds. Id. at 45,
47. As we resolve this appeal with respect to independent
claim 1, we do not further discuss the Board’s findings on
the dependent claims.
     Petitioners also argued, in a footnote in the petition,
that a person of ordinary skill would have been motivated
to modify 5-HMT because at the time of the invention 5-
HMT was covered by a patent. Id. at 23. The Board gave
little weight to this argument. Id. at 24. Based on the
above findings, the Board concluded that the petitioners
did not sustain their burden to prove any of the instituted
claims unpatentable as obvious over the references in
either ground. Id. at 48–50.
    Amerigen appealed. UCB moved to dismiss for lack of
standing, which we denied without prejudice to UCB
raising its standing arguments at the merits stage.
Amerigen Pharm. Ltd. v. UCB Pharma GmbH, No. 17-
10         AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH




2596, ECF No. 23 (Fed. Cir. Mar. 15, 2018). As UCB’s
standing challenge implicates our jurisdiction, we begin
with standing and then turn to the merits.
                     II. DISCUSSION
                       A. Standing
    UCB argues that Amerigen lacks standing to appeal
from the Board’s decision because the Food and Drug
Administration (“FDA”) will not approve Amerigen’s
abbreviated new drug application (“ANDA”) until the
expiration of the ’650 patent, previously upheld in a
separate suit in the District of Delaware, in 2022. Accord-
ingly, UCB contends that Amerigen is foreclosed from
infringing the ’650 patent, and without a possibility of
infringement there can be no justiciable dispute. Sepa-
rately, UCB argues any alleged injury is traceable to
Amerigen’s own conduct, not UCB’s, because Amerigen
acquiesced to the Delaware district court’s infringement
and validity holdings.
    Amerigen responds that its ANDA product has al-
ready secured tentative approval from the FDA, that the
’650 patent delays entry of its competing product, and
that invalidating the claims of the ’650 patent would
advance the launch of its product. By blocking its release
of a competing drug, Amerigen argues that the ’650
patent imposes a concrete injury sufficient for Article III
standing.
    Although we have jurisdiction to review final deci-
sions of the Board under 28 U.S.C. § 1295(a)(4)(A), an
appellant must meet “the irreducible constitutional
minimum of standing,” Lujan v. Defenders of Wildlife, 504
U.S. 555, 560 (1992), even if there is no such requirement
in order to appear before the administrative agency being
AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH               11



reviewed, Consumer Watchdog v. Wis. Alumni Research
Found., 753 F.3d 1258, 1261 (Fed. Cir. 2014). 11 Standing
requires an appellant to have “(1) suffered an injury in
fact, (2) that is fairly traceable to the challenged conduct
of the defendant, and (3) that is likely to be redressed by a
favorable judicial decision.” Spokeo, Inc. v. Robins, 136 S.
Ct. 1540, 1547 (2016). As the party seeking judicial
review, the appellant bears the burden of proving that it
has standing. Phigenix, Inc. v. Immunogen, Inc., 845 F.3d
1168, 1171 (Fed. Cir. 2017). We accept as true Amerigen’s
material representations of fact for purposes of assessing
its standing. See Warth v. Seldin, 422 U.S. 490, 501
(1975); James v. J2 Cloud Servs., LLC, 887 F.3d 1368,
1372 (Fed. Cir. 2018); see also Am. Inst. of Certified Pub.
Accountants v. IRS, 804 F.3d 1193, 1197 (D.C. Cir. 2015).
    We agree with Amerigen that it has standing to ap-
peal from the Board’s decision because the launch of its
tentatively approved drug is blocked by the ’650 patent,
and invalidation of the patent would advance its drug’s
launch. The ’650 patent is listed in the FDA’s “Orange
Book” 12 entry for Toviaz®. Amerigen has a Paragraph III
certification for the ’650 patent, 13 which means that the



    11  However, “where Congress has accorded a proce-
dural right to a litigant, such as the right to appeal an
administrative decision, certain requirements of stand-
ing—namely immediacy and redressability, as well as
prudential aspects that are not part of Article III—may be
relaxed.” Consumer Watchdog, 753 F.3d at 1261 (citing
Massachusetts v. EPA, 549 U.S. 497, 517–18 (2007)).
    12  This publication is formally entitled “Approved
Drug Products with Therapeutic Equivalence Evalua-
tions.”
    13  Amerigen had initially filed a Paragraph IV certi-
fication against the ’650 patent.         See 21 U.S.C.
12          AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH




FDA will only approve Amerigen’s ANDA after the ’650
patent has expired. 21 U.S.C. § 355(j)(5)(B)(ii). However,
if the ’650 patent is held unpatentable through reversal of
the Board’s decision, then the New Drug Application
(“NDA”) holder 14 must “promptly notify” the FDA that the
patent “no longer meet[s] the statutory requirements for
listing.” 21 C.F.R. § 314.53(f)(2)(i). And § 314.53 express-
ly states that a patent does not meet the requirements for
listing “if there has been a judicial finding of invalidity for
a listed patent, from which no appeal has been or can be
taken.” Id. After a notification from the NDA holder that
a patent may no longer be listed, the FDA “will remove a
patent . . . from the list if there is no first applicant eligi-
ble for 180–day exclusivity based on a paragraph IV
certification to that patent or after the 180–day exclusivi-
ty period of a first applicant based on that patent has
expired or has been extinguished.” Id.
     Amerigen has represented that its “ANDA has al-
ready received tentative approval and would be able to
obtain final approval for launch in 2019 if the ’650 patent
is invalidated.” Reply Br. 13. The ’650 patent expires on
July 3, 2022. UCB’s other earlier-expiring patents listed



§ 355(j)(2)(A)(vii)(IV). Pfizer and UCB then sued Ameri-
gen for patent infringement under 35 U.S.C. § 271(e)(2),
Amerigen stipulated to infringement, and the district
court held the ’650 patent not invalid. Pfizer v. Sandoz,
No. 12-1110-GMS, 2016 WL 1611377, at *6, *10 (D. Del.
Apr. 20, 2016). Amerigen waived its right to appeal. The
district court’s holding that the ’650 patent was not inva-
lid and was infringed resulted in the conversion of Ameri-
gen’s Paragraph IV certification to a Paragraph III. See
21 C.F.R. § 314.94(a)(12)(viii)(A).
    14   The NDA holder is Pfizer Inc., which holds a li-
cense to UCB’s ’650 patent.
AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH              13



in the Orange Book, which are not at issue in this appeal,
expire on May 11, 2019. Consequently, there would be a
roughly three-year period beginning in May 2019 during
which Amerigen’s sales would be blocked by the ’650
patent. The record is unclear whether a different compa-
ny’s generic product is eligible for the 180–day exclusivity
period. However, even assuming that another generic
product is entitled to 180-day exclusivity, a conclusion
from this court that the instituted claims of the ’650
patent are unpatentable and the FDA’s consequent delist-
ing of the patent would enable Amerigen to launch its
competing product substantially earlier than it otherwise
could upon the patent’s expiration. We thus conclude that
Amerigen has a concrete, economic interest in the sales of
its tentatively approved drug obstructed by the listing of
the ’650 patent, and has thereby demonstrated a contro-
versy “of sufficient immediacy and reality” for Article III
standing. MedImmune, Inc. v. Genentech, Inc., 549 U.S.
118, 127 (2007); see E.I. DuPont de Nemours & Co. v.
Synvina C.V., 904 F.3d 996, 1004 (Fed. Cir. 2018).
    UCB’s arguments that Amerigen lacks standing are
largely premised on the theory that under the Hatch-
Waxman Act, 21 U.S.C. §§ 355, 360 (2012), a “Paragraph
IV certification is the fundamental, jurisdictional basis
enabling parties to litigate Orange Book-listed patents in
the Article III courts,” and without that basis there can be
no injury in fact. Appellee’s Br. 27. But this case does not
arise under the Hatch-Waxman Act, and the causes of
action available under that Act do not necessarily control
the standing inquiry in an appeal from an IPR decision.
They do not control here because Amerigen does not rely
on a risk of infringement liability as a basis for injury in
fact; rather, it contends that the mere listing of the ’650
patent in the Orange Book inflicts a concrete commercial
injury redressable by this court.
    We have previously recognized that listing a patent in
the Orange Book may create a cognizable injury inde-
14         AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH




pendent of the prospect of infringement liability. In
Apotex, Inc. v. Daiichi Sankyo, Inc., one generic company,
Apotex, sought to cause the forfeiture of a third-party
generic company’s 180-day exclusivity period by securing
a declaratory judgment of noninfringement of Daiichi’s
patent that had been disclaimed. 781 F.3d 1356, 1359–61
(Fed. Cir. 2015). 15 Apotex could not show harm via in-
fringement because the disclaimed patent could not be
infringed. But Apotex could show harm from the fact that
the patent was still listed in the Orange Book, because
the listing delayed the start of the third party’s 180-day
exclusivity period, which in turn delayed the date on
which Apotex could market its drug. Apotex argued that
a declaratory judgment of noninfringement, in accelerat-
ing the end of the third party’s exclusivity period, “would
allow it to enter the market earlier than it could without
the judgment.” Id. at 1360. We agreed that Apotex
demonstrated a controversy “of sufficient immediacy and
reality” for Article III standing. Id. at 1361–62 (quoting
MedImmune, 549 U.S. at 127). That controversy origi-
nated from the “listing of [a] patent, with its current
consequence of preventing FDA approval” of Apotex’s
proposed drug during the other generic company’s exclu-
sivity period. Id. at 1362.



     15  The Hatch-Waxman Act, as amended by the Med-
icare Modernization Act (“MMA”), Pub. L. No. 108-173,
117 Stat. 2066 (2003), provides for forfeiture of a first
filer’s 180-day exclusivity under certain conditions, in-
cluding via a declaratory judgment of non-infringement in
favor of a different generic company.           21 U.S.C.
§ 355(j)(5)(D)(i)(I)(bb). Such a judgment triggers a 75-day
period for the first filer to market its drug—and start its
180 days of exclusivity—or otherwise lose its period of
exclusivity. Id.
AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH               15



    This case presents the same essential scenario, where
the listing of a drug company’s patent delays the launch
of a competing generic product. If Amerigen succeeds in
invalidating the ’650 patent here and having the patent
delisted, then it, like Apotex, could launch its proposed
drug substantially earlier than it otherwise could. Conse-
quently, “by any common-sense measure,” Amerigen has a
“substantial, concrete stake[] in whether” it succeeds in
proving the invalidity of the ’650 patent. Id. at 1363.
     UCB contends that this case is controlled by Janssen
Pharmaceutica, N.V. v. Apotex, Inc., 540 F.3d 1353 (Fed.
Cir. 2008), not Daiichi. Similar to Daiichi, Janssen
involved one generic company, coincidentally also Apotex,
seeking a declaratory judgment of noninfringement of
Janssen’s listed patent in order to trigger another generic
company’s 180-day exclusivity period, thereby advancing
the launch of Apotex’s drug. 540 F.3d at 1358–60. How-
ever, unlike Daiichi, Janssen applied the pre-MMA ver-
sion of the Hatch-Waxman Act that did not provide an
express path for one generic firm to trigger the forfeiture
of the first filer’s 180-day exclusivity period. Daiichi, 781
F.3d at 1367–68. Janssen thus concluded that the inabil-
ity of the later filing generic company “to promptly launch
its generic [product] because of [the first filer’s] 180–day
exclusivity period is not a cognizable Article III controver-
sy, but a result envisioned by the Hatch-Waxman Act.”
540 F.3d at 1361.
    The America Invents Act (“AIA”) and its provisions
governing IPRs do not support an analogous statutory
implication. Congress granted parties broad access to
challenge patents through the IPR procedure. Any “per-
son who is not the owner of a patent may file with the
[Patent] Office a petition to institute an [IPR] of the
patent.” 35 U.S.C. § 311. Likewise, any “party dissatis-
fied with the final written decision of the [Board] . . . may
appeal the decision . . . .” Id. § 319. The AIA thus pro-
vides no basis for us to premise standing in an appeal
16         AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH




from an IPR decision on the availability of particular
causes of action under the Hatch-Waxman Act. Rather,
an appellant must demonstrate an injury consistent with
the generally applicable requirements of Article III, i.e., a
controversy “of sufficient immediacy and reality” to war-
rant the requested judicial relief. MedImmune, 549 U.S.
at 127; DuPont, 904 F.3d at 1004. Because Amerigen has
demonstrated such a controversy traceable to UCB’s ’650
patent and redressable by this court, it has standing to
appeal from the Board’s decision even though it may be
incapable (as a Paragraph III filer) of maintaining a
parallel Hatch-Waxman suit.
    We are not persuaded by UCB’s remaining argu-
ments. UCB contends that any delisting-based relief
would be too speculative to support standing. However,
as Amerigen has already been granted tentative approval
for its proposed drug, the only uncertainty is whether
Amerigen would have to wait for another generic compa-
ny’s potential 180-day exclusivity period to expire. As we
have explained, Amerigen’s launch would be substantially
advanced even if another generic company has 180 days of
exclusivity.
    UCB additionally disputes whether Amerigen’s al-
leged injury is traceable to UCB. The injury plainly is
caused by UCB’s listing of the ’650 patent; absent that
entry barrier, approval of Amerigen’s proposed drug
would be advanced. See Daiichi, 781 F.3d at 1363.
    For the foregoing reasons, we conclude that Amerigen
has standing to appeal from the Board’s decision. We
therefore proceed to the merits.
                      B. Obviousness
     Amerigen argues that the Board did not properly con-
sider the evidence in support of obviousness. In particu-
lar, Amerigen alleges that: (1) the Board misunderstood
Amerigen’s arguments concerning lipophilicity, and it
AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH              17



should have recognized that a person of ordinary skill
would have increased the lipophilicity of 5-HMT for its
own sake; (2) the Board placed an excessive burden on
Amerigen to show a motivation to make a 5-HMT pro-
drug; and (3) the Board failed to recognize that arriving at
the specific claimed compounds would have been routine
optimization. Amerigen additionally contends that the
Board ignored its argument concerning the effect of the
patent covering 5-HMT.
    UCB responds that Amerigen points to no legal error
and that substantial evidence supports the Board’s find-
ings.
     Our review of a Board decision is limited. In re Baxter
Int’l, Inc. 678 F.3d 1357, 1361 (Fed. Cir. 2012). While we
review the Board’s legal determinations de novo, In re
Elsner, 381 F.3d 1125, 1127 (Fed. Cir. 2004), we review
the Board’s factual findings underlying those determina-
tions for substantial evidence, In re Gartside, 203 F.3d
1305, 1316 (Fed. Cir. 2000). A finding is supported by
substantial evidence if a reasonable mind might accept
the evidence as adequate to support the finding. Consol.
Edison Co. v. NLRB, 305 U.S. 197, 229 (1938).
   Under 35 U.S.C. § 103 (2006), 16
        [a] patent may not be obtained . . . if the
        differences between the subject matter
        sought to be patented and the prior art are
        such that the subject matter as a whole
        would have been obvious at the time the
        invention was made to a person having


   16    Because the application of the ’650 patent was
filed before March 16, 2013, the pre-Leahy-Smith America
Invents Act version of § 103 applies. See Pub L. No. 112-
29, 125 Stat. 284 (2011).
18         AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH




        ordinary skill in the art to which said sub-
        ject matter pertains.
Obviousness is a question of law based on underlying
facts, including the scope and content of the prior art,
differences between the prior art and the claims at issue,
the level of ordinary skill, and relevant evidence of sec-
ondary considerations. Graham v. John Deere Co., 383
U.S. 1, 17–18 (1966). Whether a person of ordinary skill
would have been motivated to modify the teachings of a
reference is a question of fact. WBIP, LLC v. Kohler Co.,
829 F.3d 1317, 1327 (Fed. Cir. 2016). In an IPR, the
petitioner has the burden of proving unpatentability by a
preponderance of the evidence. 35 U.S.C. § 316(e).
    We agree with UCB that the Board did not legally err
and that substantial evidence supports the Board’s find-
ings. We address Amerigen’s arguments in turn.
    Amerigen argues that a person of ordinary skill would
have been motivated to modify 5-HMT to increase its
lipophilicity. Based on the analysis of UCB’s expert, Dr.
Roush, the Board disagreed. Decision, slip op. at 31–33.
Petitioners argued that 5-HMT’s lower lipophilicity com-
pared to tolterodine suggested that 5-HMT had a bioa-
vailability problem. Id. at 28 (“Petitioner argues that ‘a
person of ordinary skill in the art would have appreciated
that 5-HMT was [too hydrophilic] and needed to be modi-
fied in a way to improve bioavailability . . . .’” (alteration
in original)). Dr. Roush, however, testified that since 5-
HMT did not violate any of the Lipinski rules, a person of
ordinary skill would not have thought 5-HMT had a
bioavailability problem. Id. at 29–30. Specifically, Dr.
Roush testified that Lipinski predicts a potential bioa-
vailability problem if a compound meets two of the follow-
ing four factors: (1) more than 5 hydrogen bond donors;
(2) a molecular weight over 500; (3) a logP over 5; and (4)
more than 10 hydrogen bond acceptors. According to Dr.
Roush, 5-HMT had: (1) 2 hydrogen bond donors; (2) a
AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH             19



molecular weight of 341.5; (3) a logP of 3.7; and (4) 3
hydrogen bond acceptors. As 5-HMT satisfied none of the
Lipinski factors, Dr. Roush found that “there would have
been no reason to suspect that 5-HMT would possess poor
oral absorption.” J.A. 1295. Petitioners’ expert, Dr.
Patterson, agreed that a person of ordinary skill would
have considered Lipinski in assessing bioavailability and
did not rebut Dr. Roush’s analysis. Decision, slip op. at
30.
     The Board weighed the unrebutted testimony of Dr.
Roush against petitioners’ argument based on the relative
lipophilicity of 5-HMT to tolterodine and Dr. Patterson’s
testimony that 5-HMT’s two hydroxy groups suggested a
bioavailability problem. Id. at 31. The Board found that
Dr. Roush better addressed the bioavailability issue and
that the lipophilicity of 5-HMT relative to tolterodine did
not demonstrate a bioavailability problem. Id. at 31–32.
We agree with UCB that a reasonable fact finder could
have weighed Dr. Roush’s testimony over Dr. Patterson’s.
Based on the record before us, we conclude that substan-
tial evidence supports the Board’s finding that a person of
ordinary skill would not have been motivated to modify 5-
HMT to increase its lipophilicity.
    On appeal, Amerigen does not point to a specific error
in the Board’s findings, but generally argues that “there
need not be a specific problem with bioavailability of 5-
HMT for one of ordinary skill in the art to be motivated to
modify 5-HMT to further improve its bioavailability.”
Appellant’s Br. 33. While that may be true in some cases,
Amerigen’s conclusory argument is not sufficient to
overcome the substantial evidence to the contrary under-
pinning the Board’s analysis. The Board found that a
person of ordinary skill would have considered prodrug
development to involve tradeoffs, including having to
monitor “the toxicity, bioavailability, receptor affinity,
pharmacokinetics, and pharmacodynamics of” two com-
pounds: the prodrug and the active compound. Decision,
20         AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH




slip op. at 35. Given such complexities, the Board deter-
mined that a person of ordinary skill would not have
turned to a prodrug approach “to solve an undefined
problem.” Id. We see no reversible error in the Board’s
findings.
    Amerigen then argues that increasing lipophilicity “in
and of itself” (i.e., independent of bioavailability concerns)
would have motivated a person of ordinary skill to modify
5-HMT. Appellant’s Br. 32. However, Amerigen did not
present this theory to the Board, points us to no evidence
in the record in support of it, and does not explain why a
skilled artisan would modify a drug to increase its lipo-
philicity independent of bioavailability. We thus do not
consider Amerigen’s argument persuasive.
    Even assuming that a person of ordinary skill would
have had some motivation to modify 5-HMT, the Board
additionally found that the petitioners did not prove that
a skilled artisan would have made the specific modifica-
tions leading to the claimed compounds. Amerigen argues
that the Board erred in its findings. We disagree.
     The Board held that the petitioners did not sustain
their burden of proof for primarily three reasons. First,
the Board considered Bundgaard’s teaching that the
prodrug form of a drug is inactive. Decision, slip op. at
35–36; see J.A. 316 (defining a prodrug as “a pharmacolog-
ically inactive derivative of a parent drug molecule that
requires spontaneous or enzymatic transformation within
the body in order to release the active drug, and that has
improved delivery properties over the parent drug mole-
cule.”); J.A. 319 (“The prodrug per se is an inactive spe-
cies, and therefore, once its job is completed, intact
prodrug represents unavailable drug.”).         Petitioners
presented no evidence that an ester of 5-HMT would be
inactive, and the Board thus found that this deficiency
supported nonobviousness.       Decision, slip op. at 36.
Amerigen argues that the Board imposed an “insur-
AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH              21



mountable burden” on petitioners, Appellant’s Br. 38, but
we disagree. The Board sensibly found that a skilled
artisan would “seek some degree of certainty that a pro-
drug of a particular molecule would be inactive before
embarking on the process of attempting to create the
prodrug,” and the petitioners failed to provide any such
certainty. Decision, slip op. at 36.
     This deficiency is compounded by the Board’s second
finding that the petitioners did not point to any prodrugs
analogous to 5-HMT. Specifically, the Board found no
evidence of prodrugs in the same chemical class, with the
same mechanism of action, or in the same field of treat-
ment. Id. Again, Amerigen argues that the Board im-
posed too high a burden on petitioners, effectively a
“[r]equirement for a [p]rior [t]eaching of a 5-HMT [a]nalog
[p]rodrug.” Appellant’s Br. 39. But the Board did not
require such evidence, Decision, slip op. at 37 (“Petitioner
does not have to demonstrate explicitly that there were
prodrug examples analogous to 5-HMT . . . .”); it just
found that the absence of such evidence supported UCB’s
argument that at the time of the invention skilled arti-
sans had not considered “a prodrug of an antimuscarinic
drug or any sort of overactive bladder drug.” Id. Alt-
hough not dispositive, the Board did not err in inquiring
whether there existed at the time of the invention pro-
drugs similar to the claimed compounds.
    Third, the Board found that it would not have been
routine to make the claimed molecular modifications to 5-
HMT to produce the claimed compounds. Citing Dr.
Roush, the Board found: (1) that a skilled artisan would
have considered diester substitutions as well as other
prodrug moieties taught in Bundgaard, id. at 40; (2) that
a person of ordinary skill would have considered modify-
ing the 5-position in addition to the 2-position, id. at 41–
42; and (3) that Bundgaard did not specifically teach the
isobutyryl ester of fesoterodine, id. at 40.
22         AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH




    Amerigen argues that Bundgaard disclosed esters as
prototypical prodrug moieties and that modifying the 2-
position alone would have been the most obvious choice.
While the Board considered Bundgaard’s disclosure of
ester prodrugs, id. at 39, the Board also observed, citing
Dr. Roush, that Bundgaard taught many other prodrug
substitutions that a person of ordinary skill would have
considered, id. at 40. Dr. Roush testified that these
additional substitutions included ethers, carbamates,
carbonates, phosphate esters, Mannich bases, and mac-
romolecular prodrugs. Moreover, the Board also found
that a person of ordinary skill would have considered
modifications at the 5-position because the prior art did
not indicate a preference for either the 2- or 5-position,
and the inventors themselves considered modifying the 5-
position. Id. at 42. The Board did not consider the con-
trary evidence persuasive: Dr. Patterson argued that
modifying only the 5-position would pose a risk of trans-
esterification, but did not sufficiently explain that risk,
and petitioners primarily relied on a separate theory
altogether regarding possible metabolic complications at
the 5-position that was devoid of evidentiary support, id.
at 42. Amerigen has demonstrated no discernible error in
the Board’s technical analysis, and asks this court to
reweigh these matters on appeal. We conclude that
substantial evidence supports the Board’s determination
that the prior art did not suggest making the claimed
monoester substitutions solely at the 2-position.
    Altogether, the Board found that the petitioners nei-
ther established a general motivation to make a 5-HMT
prodrug nor proved that the specific claimed modifications
would have been obvious. We conclude that Amerigen’s
factual challenges to the Board’s decision are without
merit and that substantial evidence supports the Board’s
findings.
    Amerigen additionally contends that the Board did
not give sufficient weight to its theory—presented in a
AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH             23



single-sentence footnote to its argument about salt forms
of fesoterodine—that a skilled artisan would have been
motivated to modify 5-HMT because 5-HMT was patented
at the time of invention. However, even accepting, for the
sake of discussion, that a patent on 5-HMT would provide
a commercial motivation for a skilled artisan to modify 5-
HMT, such a motivation would not be sufficient to prove
that the claimed compounds would have been obvious. It
was Amerigen’s burden to show that the “prior art would
have suggested making the specific molecular modifica-
tions necessary to achieve the claimed invention.” Takeda
Chem. Indus., Ltd. v. Alapharm Pty., Ltd., 492 F.3d 1350,
1356 (Fed. Cir. 2007) (emphasis added) (quoting In re
Deuel, 51 F.3d 1552, 1558 (Fed. Cir. 1995)). A general
motivation to modify 5-HMT based on a prior patent
would not suffice, and as we have already explained,
Amerigen did not otherwise meet its burden to prove that
the specific claimed modifications to 5-HMT would have
been obvious. Any compound may look obvious once
someone has made it and found it to be useful, but work-
ing backwards from that compound, with the benefit of
hindsight, once one is aware of it does not render it obvi-
ous.
    Amerigen also challenges the Board’s findings con-
cerning whether it would have been routine to optimize
the possible monoesters at the 2-position and whether the
particular salts and enantiomer claimed in the dependent
claims would have been obvious. The Board held in
UCB’s favor for each issue. Decision, slip op. at 42–47.
However, we conclude that these findings were not neces-
sary to the Board’s judgment, and we do not rely on them
for ours.
                       CONCLUSION
    We have considered Amerigen’s remaining arguments
but do not find them persuasive. For the foregoing rea-
sons, we affirm the Board’s decision.
24   AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH




               AFFIRMED
