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”) appeals 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 below: 

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 

Fesoterodine

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 Berge6; 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 Muscarinic 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 Polymorphism on the Pharmacokinetics and Pharmacodynamics 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 tolterodine’s therapeutic effect. The Detrol Label taught that a 

subset of the population (known as “poor metabolizers”) 

lacks CYP2D6 activity and instead metabolizes tolterodine 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 influence 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 metabolite.” 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 experiencing a slightly worse side effect than extensive metabolizers. But ultimately, Brynne concludes that the 

variation in CYP2D6 activity between poor and extensive 

metabolizers “does not appear to be of great pharmacodynamic 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 principles. The reference defines a prodrug as “a pharmacologically 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 completed, intact prodrug represents unavailable drug.” J.A. 319. 

Esters are listed as common prodrug substituents. Specifically, “[a]ctive drug species containing hydroxyl or carboxyl 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 hydrophilicity 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 Amerigen 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 insufficiently 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 lipophilicity of 5-HMT relative to tolterodine, a known, wellabsorbed drug, did not show that 5-HMT had a bioavailability 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. Patterson agreed that a person of ordinary skill would consider 

the Rule of 5. The Rule of 5 assesses four inherent properties 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 determined 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. Decision, 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 demonstrate 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 acceptors; (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 credited 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. Accordingly, UCB contends that Amerigen is foreclosed from 

infringing the ’650 patent, and without a possibility of 

infringement there can be no justiciable dispute. Separately, 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 already 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 decisions 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 appeal 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 procedural right to a litigant, such as the right to appeal an 

administrative decision, certain requirements of standing—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 Evaluations.”

13 Amerigen had initially filed a Paragraph IV certification 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”) holder14 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 expressly 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 eligible for 180–day exclusivity based on a paragraph IV 

certification to that patent or after the 180–day exclusivity period of a first applicant based on that patent has 

expired or has been extinguished.” Id. 

Amerigen has represented that its “ANDA has already 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 Amerigen 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 invalid and was infringed resulted in the conversion of Amerigen’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 license 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 company’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 delisting 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 controversy “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 HatchWaxman 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 infringement 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 accelerating 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 originated 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 exclusivity period. Id. at 1362. 

 

15 The Hatch-Waxman Act, as amended by the Medicare 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, including 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. Consequently, “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. However, unlike Daiichi, Janssen applied the pre-MMA version 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 inability 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 controversy, 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 “person 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 dissatisfied with the final written decision of the [Board] . . . may 

appeal the decision . . . .” Id. § 319. The AIA thus provides 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 warrant 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 arguments. 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 company’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 alleged 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 consider the evidence in support of obviousness. In particular, 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 prodrug; 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 findings. 

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 determinations 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 subject 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 secondary 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 findings. 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 compared to tolterodine suggested that 5-HMT had a bioavailability 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 modified 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 bioavailability problem if a compound meets two of the following 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 substantial 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 underpinning 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 compounds: the prodrug and the active compound. Decision, 
20 AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH

slip op. at 35. Given such complexities, the Board determined 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 lipophilicity 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 modifications 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 pharmacologically 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. 319 (“The prodrug per se is an inactive species, 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 prodrug 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 treatment. Id. Again, Amerigen argues that the Board imposed 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 artisans had not considered “a prodrug of an antimuscarinic 

drug or any sort of overactive bladder drug.” Id. Although not dispositive, the Board did not err in inquiring 

whether there existed at the time of the invention prodrugs 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 modifying 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 macromolecular 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 contrary evidence persuasive: Dr. Patterson argued that 

modifying only the 5-position would pose a risk of transesterification, 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 neither 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 modifications 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 working backwards from that compound, with the benefit of 

hindsight, once one is aware of it does not render it obvious. 

Amerigen also challenges the Board’s findings concerning 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 necessary 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 reasons, we affirm the Board’s decision.
24 AMERIGEN PHARMACEUTICALS v. UCB PHARMA GMBH

AFFIRMED