# United States **Court of Appeals**  **for the Federal Circuit**

______________________
AMERIGEN PHARMACEUTI CALS 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

______________________

W ILLIAM H ARE , McNeely Hare & War LLP, Princeton, NJ, argued for appellant. Also represented by S HYAM D IXIT , Dixit Law Firm, Tampa, FL.

J EFFREY J. O ELKE , Fenwick & West, New York, NY, argued for appellee. Also represented by R YAN J OHNSON , L AURA M ORAN , J AMES T RAINOR

.

______________________

Before L OURIE , C HEN , and S TOLL , Circuit Judges.

L OURIE , Circuit Judge

.AMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 2

Amerigen Pharmaceuticals Limited (“Amerigen”) a ppeals 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. UC B Pharma GmbH , No. 2016

- 00510 (P .T.A.B. July 19, 2017) (“ Decision ”)

. We conclude that the Board did not err in its conclusion s and affirm.

I. B ACKGROUND

A.
UCB Pharma GmbH (“UCB”) owns the ’650 patent, which covers certain chemical derivatives of 3,3

- d iphenylpropylamines

, including a compound called fesoterodine

. Fesoterodine is an antimuscarinic drug marketed as Toviaz ® to treat urinary incontinence.
The chemical structure of fesoterodine is depicted b elow:

On the upper left hand benzene ring above, w e will refer to the position of the hydroxymethyl group as the 5

- position , and the position of the isobuty ryl ester as the 2

- position

. Fesoterodine is a prodrug. Unlike a typical drug, a prodrug is an inactive molecule as

- deliv ered 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 FesoterodineAMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 4

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.

Th e references fall into three general categories. First, t he 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 Johansso n 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 Musc arinic 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 92/0 845 9.

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 Pharmacodyna mics of Tolterodine , 63 Clinical Pharmacology & Therapeutics 529 (1998).

8 International Application WO 94/11337.AMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 5

pharmaceutical salts. We will summarize each group in
turn.

T he Detrol Label disclose s the structure of tolter odine 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 tolter odine’s therapeutic effect. T he Detrol Label taught that a subset of the population ( known as “poor metabolizers” ) lacks CYP2D6 activity and instead metabolizes tolter odine 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 inf l uence of patients’ varying CYP2D6 activity on tolterodine activity. Like the Detrol Label, Brynne posit s that “the CYP2D6 polymorphism does not appear to be of great importance in the antimuscarinic effect, probably because of the additive action of pare nt drug and active metab olite.” 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 suggest s that this difference mi ght contribute to poor metabolizers exper iencing a slightly worse side effect than extensive metab olizers. But ultimately, Brynne conclude s that the variation in CYP2D6 activity between poor and extensive metabolizers “does not appear to be of great pharm acod ynamic importance.” Id.
Postlind, a nother published research paper, focuse s on tolterodine metabolism

. J.A. 296. Postlind caution sAMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 6

that tolterodine ha s 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 describe s prodrugs and their design pri nciples. The reference define s a prodrug as “a pharmac ologically 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 comple ted, intact prodrug represents unavailable drug.” J.A. 319. Esters are listed as common prodrug substituents. Speci fically, “[a]ctive drug species containing hydroxyl or ca rboxyl 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 state s that esters can be used to improve aqueous solubility of dr ugs containing a hydroxy group and that with esteri fication “it is feasible to obtain derivatives with almost any desirable hydr ophilicity o r lipophilicity. ” J.A. 321. Relatedly, Bundgaard PCT disclose s an ester prodrug of morphine that improve s 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, t he 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 aAMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 7

person of ordinary skill wo uld 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. T his factual determination was premised on several subsidiary findings that Amer igen challenges on appeal

. We summarize these findings here.

T he 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, t estified 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 lipophilic ity of 5

- HMT relative to tolterodine, a known, well

absorbed drug, did not show that 5

- HMT had a bioavail ability 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. Patte rson agreed that a person of ordinary skill would consider the Rule of 5. The Rule of 5 assesses four inherent pro perties 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 Advance d 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

- bondAMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 8

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 dete rmined that a person of ordinary skill would not have been motiva ted 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

so lve a bioavailability problem that did not exist

. Dec ision , 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

com pounds rather than just one

. Id. T he Board also found that Bundgaard defined the prodrug form of a compound as inactive, but the petitioners did not demo nstrate 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 bee n 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 acce ptors; (3) the molecular weight is greater than 500; and (4) the calculated log P is great er than 5.AMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 9

molecular modifications of 5

- HMT consistent with a prodrug design. Id. at 40. For example, Bundgaard explained that di es ters 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 cre dited 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 u niverse 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 claime d 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 ski ll 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. T he 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 claim s 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 raisin g its standing arguments at the merits stage

. Amerigen Pharm. Ltd. v. UCB Pharma GmbH

, No. 17

-AMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 10

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. D ISCUSSION

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 pate nt , 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. Sep aratel y, 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 a lready secured tentative app roval 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 w e have jurisdiction to review final dec isions of the Board under 28 U.S.C. § 1295(a)(4)(A), an appellant must meet “the irreducible constitutional minimum of standing,” Lujan v. Def enders of Wildlife , 504 U.S. 555, 560 (1992), even if there is no such requirement in order to appear before the administrative agency beingAMERIGEN PHARMACEUTI CALS 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 f act 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 a ppeal 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 liste d 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 proc edural right to a litigant, such as the right to appeal an administrative decision, certain requirements of stan ding

— 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 p ublication is formally entitled “ Approved Drug Products with Therapeutic Equivalence Evalu ations .”

13 Amerigen had initially filed a Paragraph IV cert ification against the ’650 patent. See 21 U.S.C.AMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 12

FDA will only approve Amerigen’s ANDA after the ’650

p atent 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 expres sly 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 fr om 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 elig ible for 180

– day exclusivity based on a paragraph IV certification to that patent or after the 180

– day exclusiv ity period of a first applicant based on that patent has expired or has been extinguished.” Id.
Amerigen has represented that its “ANDA has a lready 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 Amer igen 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 in v alid and was infringed resulted in the conversion of Amer igen’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 l icense to UCB’s ’650 patent.AMERIGEN PHARMACEUTI CALS 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 comp any’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 delis ting of the patent would enable Amerigen to launch its competing product substantially ear lier 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 demon strated a contr ove rsy “ of sufficient immediacy and reality” for Article III standing. MedI mmune, Inc. v. Genentech, Inc. , 549 U.S. 118, 127 (2007); s ee 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
t he Article III co urts, ” 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 inju ry redressable by this court.
We have previously recognized that listing a patent in the Orange Book may create a cognizable injury ind e-AMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 14

pendent of the prospect of infringement liability. In Apotex, Inc. v. Daiichi Sankyo, Inc. , one generic company , Apot ex, 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 no t show harm via i nfringement 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 exclu sivity period, which in turn delayed the date on which Apotex could market its drug

. Apotex argued that

a declaratory judgment of noninfringement , in accelera ting 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

. I d. at 1361

– 62 (quoting MedI mmune , 549 U.S. at 127). That controversy orig inated 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 excl usivity period. I d. at 1362

.

15 The Hatch

- Waxman Act, as amended by the Me dicare Modernization Act (“MMA”), Pub. L. No. 108

- 173, 117 Stat. 2066 (2003), provide s for forfeiture of a first filer’s 180

- day exclusivity under certain conditions, i ncluding 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 trigger s a 75

- day period for the first filer to market its drug

— and start its 180 days of exclusivity

— or other wise lo se its period of exclusivity. Id.AMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 15

This case presents the same essent ial 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 . Cons equently , “by any common

- sense measure, ” Amerigen has a

“ substa ntial, concrete stake[] in whether” it succeeds in proving the invalidity of the ’650 patent. Id. at 1363.

UCB con tends 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 noninfr ingement 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. Ho wever, unlike Daiichi

, Janssen applied the pre

- MMA ve rsion 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 inabi lity 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 controve rsy, 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 chal lenge patents through the IPR procedure . Any “pe rson who is not the owner of a patent may file with the [P atent] Off ice a petition to institute an [IPR] of the patent.” 35 U.S.C. § 311. Likewise, any “party dissati sfied with the final written decision of the [Board] .

. . may appeal the decision .

. . .” Id. § 319. The AIA thus pr ovides no basis for us to premise st anding in an appealAMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 16

from an IPR decision on the availability of particular causes of action under the Hatch

- Waxman Act. Rather,

a n appellant must demonstrate an injury consistent with the generally applicable requirements of Article III, i.e. , a controver sy “of sufficient immediacy and reality” to wa rrant the requested judicial relief. MedI mmune , 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 arg uments. 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 comp any’ s potential 180

- day exclusivity period to expire. A s 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 a lleged injury is traceable to UCB. T he 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 sta nding to appeal from the Board’s decision. We therefore proceed to the merits.

B. Obviousness
Amerigen argues that the Board did not properly co nsider the evidence in support of obviousness. In partic ular, Amerigen alleges that: (1) the Board misunde rstood Amerigen’s arguments concerning lipophilicity, and itAMERIGEN PHARMACEUTI CALS 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 pr odrug; 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 fin dings.

Our review of a Board decision is limited. In re Baxter Int’l, Inc. 678 F.3d 1357, 1361 (Fed. Cir. 2012). While w e 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 determin ations for substantial evidence, In re Gartside , 203 F.3d 1305, 1316 (Fe d. 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 (193 8).
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. N o. 112

- 29, 125 Stat. 284 (20 11)

.AMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 18

ordinary skill in the art to whi ch said su bject ma tter 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 o f se condary 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 fin dings. We address Amerigen’s arguments in turn.
Amerige n 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 co mpared to tolterodine suggested that 5

- HMT had a bio availability problem. Id. at 28 (“Petitioner argues that ‘a person of ordinary skill in the art would have appreciated that 5

- HMT was [too hy drophilic] and needed to be mod ified 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 bio availability problem if a compound meets two of the follo wing four factors: (1) more than 5 hydrogen bond donors; (2) a mo lecular weigh t over 500; (3) a l ogP over 5; and (4) more than 10 hydrogen bond acceptors. According to Dr. Roush, 5

- HMT had: (1) 2 hydrogen bond donors; (2) aAMERIGEN PHARMACEUTI CALS 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 i n 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. Patte rson’s testimony that 5

- HMT’s two hydroxy groups suggested a bioavailability problem. Id. at 31. The Bo ard found that Dr. Roush better addressed the bioavailability issue and that the lipophilicity of 5

- HMT relative to tolterodine did not demonstrate a b ioavailability 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 substa ntial 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 bioavailab ility.” 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 unde rpinning the Board’s analysis. The Board found that a person of ordinary skill wo uld have considered prodrug development to involve tradeoffs, including having to monitor “the toxicity, bioavailability, receptor affinity, pharmacokinetics, and pharmacodynamics of” two co mpounds : the prodrug and the active compound. Decision

,AMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 20

slip op. at 35. Given such complexities , the Board dete rmined 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 increa sing 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 B oard, points us to no evidenc e in the record in support of it

, and does not explain why a skilled artisan would modify a drug to increase its lip ophilicity independent of bioavailability

. We thus do not consider Amerigen’s argument persuasive.
Even assuming that a person of ordin ary 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 modific ations leading to the claimed compound s . Amerigen argues that the Board er red in its finding s . 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 pharmacolo gically 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 properti es over the parent drug mol ecule.” ); J.A. 319 (“T he prodrug per se is an inactive sp ecies, 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 “insu r-AMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 21

mountable burden” on petitioners, Appellant’s Br. 38, but we disagree. The Board sensibly found that a ski lled artisan would “seek some degree of certainty that a pr odrug of a particular molecule would be inactive before embarking on the process of a ttempting 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 act ion, or in the same field of trea tment. Id. Again, Amerigen argues that the Board i mposed 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 art isans had not consider ed “a prodrug of an antimuscarinic drug or any sort of overactive bladder drug. ” Id. Al though not dispositive, the Board did not err in inquiring whether there existed at the time of the invention pr odrugs 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 artisa n woul d 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

.AMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 22

Amerigen argues that Bundgaard disclosed esters a s prototypical prodrug moieties and that modifying the 2

- position alone would have been the most obvious choice. While the Boar d 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 ma cromolecular prodrugs. Moreover, the Board also found that a person of ordinary skill would have considered modif ications 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 co ntrary evidence persuasive: Dr. Patterson argued that modifying only the 5

- position would pose a risk of tran sesterification, 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. W e 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 ne ither 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 d id not give sufficient weight to i ts theory

— presented in aAMERIGEN PHARMACEUTI CALS 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

. Howe ver, 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 motiva tion would not be sufficient to prove that the claimed compounds would have been obvious. I t was Amerigen’s burden to show that the “prior art would have suggested making the specific molecular modific ations necessary to achieve the claimed invention.” Takeda Chem. Indus., Ltd. v. Alapharm Pty., Ltd. , 492 F.3d 1350, 1356 (Fed. Cir. 2007) (empha sis 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 a s 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

. A ny compound may look obvious once someone has made it and found it to be useful, but wor king backwards from that compound , with the benefit of hindsight, once one is aware of it does not render it o bv ious. Amerigen also challenges the Board’s findings co ncerning 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 nece ssary to the Board’s judgment, and we do not rely on them for ours

. C ONCLUSION We have considered Amerigen’s remaining arguments but do not find them persuasive . For the foregoing re asons, we affirm the Board’s decision.AMERIGEN PHARMACEUTI CALS v. UCB PHARMA GMBH 24

AFFIRMED