Case: 17-2596
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`Document: 54
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`Page: 1
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`Filed: 01/11/2019
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`@Hm'teh étates Qtuurt of gppeals
`
`for the jfeheral QEittuit
`
`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.
`
`

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`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 US. '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
`
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`bioavailability (i.e., the fraction of a drug dose that is
`absorbed into the bloodstream) or other drug delivery
`problems.
`
`Fesoterodine is a prodrug of the active compound 5-
`hydroxymethyl
`tolterodine (“5-HMT”).
`5-HMT is a
`metabolite
`of
`the
`compound tolterodine,
`an older
`antimusarinic drug sold under the trade name Detrol® to
`treat overactive bladder.
`In the body,
`tolterodine is
`converted to 5-HMT by cytochrome P450 2D6 (“CYP2D6”).
`The metabolite
`5-HMT,
`like
`tolterodine,
`has
`antimuscaranic activity and thus contributes to the
`therapeutic effect of tolterodine. Such metabolites are
`known as active metabolites. The chemical structures of
`
`tolterodine and 5-HMT are shown below:
`
`0 \NK
`
`O I
`
`'3 00 N
`a
`CYP2D6
`
`O
`
`y
`
`Tolterodine
`
`5-HMT
`
`As depicted, CYP2D6 converts the methyl group at
`the 5-position of tolterodine to a hydroxymethyl group in
`5-HMT. Fesoterodine, on the other hand, differs from 5-
`HMT at the 2-position:
`5-HMT has a hydroxy group,
`while fesoterodine has an isobutyryl ester. The issue
`before us is whether it would have been obvious to modify
`the 2;position hydroxy group of 5-HMT to an alkyl ester of
`six carbons or less as in fesoterodine.1
`
`1 Claim 1, the broadest of the challenged claims,
`encompasses a genus of esters including “C1—Cs-alkyl, Cs—
`C1o-cycloalkyl, [and] substituted or unsubstituted phenyl.”
`’650 patent col. 23 11. 30—31. The parties and the Board
`
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`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“;
`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.
`
`into three general categories.
`The references fall
`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.
`3
`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).
`3
`International Application W0 94/ 11337 .
`
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`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
`
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`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
`
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`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
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`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.
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`molecular modifications of 5-HMT consistent with a
`
`For example, Bundgaard
`Id. at 40.
`prodrug design.
`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
`
`Id. at 45,
`or a fumarate salt of the claimed compounds.
`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-
`
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`AMERIGEN PHARMACEUTICALS V. UCB PHARMA GMBH
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`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.
`
`H. 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 U. Defenders of Wildlife, 504
`US. 555, 560 (1992), even if there is no such requirement
`in order to appear before the administrative agency being
`
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`1 1
`
`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 U. Seldin, 422 US. 490, 501
`(1975); James U. J2 Cloud Serus., LLC, 887 F.3d 1368,
`1372 (Fed. Cir. 2018); see also Am. Inst. of Certified Pub.
`Accountants 0. IRS, 804 F.3d 1193, 1197 (DC. 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 0. EPA, 549 US. 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.
`
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`FDA will only approve Amerigen’s ANDA after the ’650
`patent has expired. 21 U.S.C. § 355G)(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 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
`
`§ 3550')(2)(A)(vii)(lV). 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.
`
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`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 US.
`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-
`
`

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`AMERIGEN PHARMACEUTICALS V. UCB PHARMA GMBH
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`In
`liability.
`pendent of the prospect of infringement
`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
`
`Id. at 1360. We agreed that Apotex
`the judgment.”
`demonstrated a controversy “of sufficient immediacy and
`reality” for Article III standing.
`Id. at 1361—62 (quoting
`MedImmune, 549 US. 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.
`§ 3550)(5)(D)(i)(1)(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.
`
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`Case: 17-2596
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`Document: 54
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`Page: 15
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`AMERIGEN PHARMACEUTICALS V. UCB PHARMA GMBH
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`15
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`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 stakel] 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, NV. 0. 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
`J anssen’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
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`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 US.
`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 ISO-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
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`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 US. 197, 229 (1938).
`
`Under 35 U.S.C. § 103 (2006),16
`
`. .if the
`[a] patent may not be obtained .
`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).
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`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
`US. 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
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`(3) a logP of 3.7; and (4) 3
`molec