`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`————————————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`————————————————
`
`AZURITY PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`HELSINN HEALTHCARE S.A.,
`Patent Owner.
`
`————————————————
`Case IPR2025-00945
`Patent US 8,623,826 B2
`————————————————
`
`PETITION FOR INTER PARTES REVIEW
`
`

`

`TABLE OF CONTENTS
`Introduction ...................................................................................................... 1
`I.
`Standing Certifications .................................................................................... 1
`II.
`III. Challenges and Precise Relief Requested ........................................................ 1
`IV. Trento’826 Patent ............................................................................................ 3
`A.
`Specification .......................................................................................... 4
`B.
`Challenged Claims ................................................................................ 5
`C.
`Prosecution History ............................................................................... 6
`Level of Ordinary Skill .................................................................................... 8
`V.
`VI. Claim Construction .......................................................................................... 9
`VII. Prior Art ......................................................................................................... 10
`A. MASCC ............................................................................................... 10
`B.
`Hoffmann ............................................................................................. 12
`C.
`Bös ....................................................................................................... 13
`D. ALOXI ................................................................................................. 14
`E.
`Herrstedt .............................................................................................. 14
`F.
`Hargreaves ........................................................................................... 15
`G. Herrington ........................................................................................... 16
`VIII. Legal Standards ............................................................................................. 16
`IX. Ground 1: Claims 19, 22-23 and 25—Obvious Over MASCC and
`Hoffmann ....................................................................................................... 17
`A.
`Claim 19 .............................................................................................. 18
`B.
`Claim 22: “further comprising, if said patient is
`undergoing highly emetogenic chemotherapy,
`administering a sub-therapeutic dose of dexamethasone
`on days one, two, three and four, wherein day one is the
`day on which netupitant and palonosetron, or
`pharmaceutically acceptable salts thereof, are
`administered.” ...................................................................................... 20
`Claim 23: “further comprising, if said patient is
`-i-
`
`C.
`
`

`

`
`
`D.
`
`undergoing highly emetogenic chemotherapy, orally
`administering 12 mg of dexamethasone on day one and 8
`mg of dexamethasone on days two, three and four,
`wherein day one is the day on which netupitant and
`palonosetron, or pharmaceutically acceptable salts
`thereof, are administered.” .................................................................. 21
`Claim 25: “wherein said netupitant or pharmaceutically
`acceptable salt thereof and said palonosetron or
`pharmaceutically acceptable salt thereof are
`synergistically effective to antagonize NK1 activity.” ....................... 21
`Obvious to Combine and Reasonably Expect Success ....................... 22
`E.
`X. Ground 2: Claims 19-20, 22-23, and 25—Obvious Over MASCC and
`Bös ................................................................................................................. 23
`A.
`Claim 19 .............................................................................................. 23
`B.
`Claim 20: “comprising orally administering from about
`200 to about 400 mg of netupitant or a pharmaceutically
`acceptable salt thereof, and from about 0.25 to about 0.75
`mg of palonosetron or a pharmaceutically acceptable salt
`thereof.” ............................................................................................... 26
`Claims 22-23: MASCC teaches these limitations ............................... 27
`Claim 25: “wherein said netupitant or pharmaceutically
`acceptable salt thereof and said palonosetron or
`pharmaceutically acceptable salt thereof are
`synergistically effective to antagonize NK1 activity.” ....................... 27
`Obvious to Combine and Reasonably Expect Success ....................... 27
`E.
`XI. Ground 3: Claims 19-23, and 25—Obvious Over MASCC, Bös and
`ALOXI ........................................................................................................... 28
`A.
`Claims 19-20, 22-23, and 25: ALOXI provides additional
`disclosure about palonosetron ............................................................. 28
`Claim 21: “comprising orally administering about 300
`mg of netupitant as the free base and about 0.56 mg of
`palonosetron hydrochloride.” .............................................................. 30
`Obvious to Combine and Reasonably Expect Success ....................... 31
`C.
`XII. Ground 4: Claims 1-3, 8-10, 15-18 and 24—Obvious Over Herrstedt,
`
`C.
`D.
`
`B.
`
`-ii-
`
`

`

`
`
`C.
`
`E.
`
`F.
`
`D.
`
`Hoffmann, and Hargreaves ............................................................................ 31
`A.
`Claim 1 ................................................................................................ 32
`B.
`Claim 2: “further comprising: d) administering to said
`patient, on days two, three and four, a second dose of
`dexamethasone which is ineffective against vomiting
`when administered alone against vomiting, but effective
`against vomiting when administered in combination with
`steps (a) and (b), wherein said second dose comprises
`from 40 to 60% of a minimum effective dose when
`administered alone against vomiting.” ................................................ 43
`Claim 3: “wherein said netupitant occupies at least 80%
`of NK receptors in the striatum seventy-two hours after
`said administration.” ............................................................................ 44
`Claim 8: “wherein said therapeutically minimum
`effective dose of dexamethasone when administered
`alone comprises from about 16 mg to about 20 mg of
`dexamethasone.” .................................................................................. 46
`Claim 9: “wherein only one dose of said palonosetron or
`a pharmaceutically acceptable salt thereof is administered
`during said five days.” ......................................................................... 46
`Claim 10: “wherein said therapeutically effective amount
`of palonosetron or pharmaceutically acceptable salt
`thereof is from about 0.25 to about 0.75 mg based on the
`weight of the free base.” ...................................................................... 47
`Claim 15: “wherein said nausea and vomiting is
`chemotherapy induced nausea and vomiting (‘CINV’),
`radiation therapy induced nausea and vomiting (‘RINV’),
`or post-operative nausea and vomiting (‘PONV’).” ........................... 48
`Claim 16: “wherein said nausea and vomiting is induced
`by moderately or highly emetogenic chemotherapy.” ........................ 48
`Claim 17: “comprising administering moderately or
`highly emetogenic chemotherapy within from about one
`hour to about two hours of said administration of said
`netupitant or pharmaceutically acceptable salt thereof.” .................... 48
`Claim 18: “comprising treating nausea and vomiting in
`
`G.
`
`H.
`
`I.
`
`J.
`
`-iii-
`
`

`

`
`
`K.
`
`response to highly emetogenic chemotherapy during the
`acute phase, or in response to highly emetogenic
`chemotherapy during the delayed phase, or in response to
`moderately emetogenic chemotherapy during the acute
`phase, or in response to moderately emetogenic
`chemotherapy during the delayed phase.” .......................................... 49
`Claim 24: “wherein said netupitant or pharmaceutically
`acceptable salt thereof and said palonosetron or
`pharmaceutically acceptable salt thereof are
`synergistically effective to antagonize NK1 activity.” ....................... 49
`Obvious to Combine and Reasonably Expect Success ....................... 50
`L.
`XIII. Ground 5: Claims 1-3, 6-10, 15-18, and 24—Obvious Over Herrstedt,
`Bös, and Hargreaves ...................................................................................... 51
`A.
`Claims 1-3, 8-10, 15-18, and 24 .......................................................... 51
`B.
`Claims 6 (200-400 mg netupitant) and 7 (300 mg free
`base) ..................................................................................................... 52
`XIV. Ground 6: Claims 4-5—Obvious Over Herrstedt, Bös, Hargreaves,
`and Herrington ............................................................................................... 53
`XV. Ground 7: Claims 10-14—Obvious Over Herrstedt, Bös, Hargreaves,
`and ALOXI .................................................................................................... 55
`A.
`Claim 10: “wherein said therapeutically effective amount
`of palonosetron or pharmaceutically acceptable salt
`thereof is from about 0.25 to about 0.75 mg based on the
`weight of the free base.” ...................................................................... 55
`Claim 11: “wherein said palonosetron is administered as
`palonosetron hydrochloride, and said therapeutically
`effective amount of said palonosetron hydrochloride is
`about 0.56 mg of palonosetron hydrochloride,
`corresponding to about 0.5 mg of palonosetron as a free
`base.” ................................................................................................... 55
`Claim 12: “wherein said palonosetron is administered
`orally.” ................................................................................................. 56
`Claim 13: “comprising orally administering: a) about 300
`mg of netupitant as a free base on day one; b) about 0.56
`mg of palonosetron hydrochloride, corresponding to
`-iv-
`
`B.
`
`C.
`
`D.
`
`

`

`
`
`E.
`
`about 0.5 mg of palonosetron as a free base, on day one;
`and c) about 12 mg of dexamethasone on day one” ........................... 57
`Claim 14: “comprising orally administering: a) about 300
`mg of netupitant as a free base on day one; b) about 0.56
`mg of palonosetron hydrochloride, corresponding to
`about 0.5 mg of palonosetron as a free base, on day one;
`c) about 12 mg of dexamethasone on day one; and d)
`about 8 mg of dexamethasone on days two, three and
`four.” .................................................................................................... 58
`XVI. No Secondary Considerations ....................................................................... 58
`A. Aprepitant Shows Efficacy for Nausea ............................................... 59
`B.
`Data misrepresented during examination ............................................ 63
`C.
`No Unexpected Synergy Between Netupitant and
`Palonosetron ........................................................................................ 66
`D. No Nexus Between Alleged Synergy and Claimed Effect ................. 68
`E.
`Single Dose of Netupitant Was Expected ........................................... 68
`F.
`Acute-Phase Treatment with Netupitant Was Expected ..................... 69
`G.
`Characteristics of Netupitant Were Expected ..................................... 69
`XVII. Conclusion ..................................................................................................... 70
`XVIII.
`Payment of Fees - §§42.15(a) and 42.103........................................... 71
`XIX. Mandatory Notices - §42.8 ............................................................................ 72
`A.
`Real Parties-In-Interest ........................................................................ 72
`B.
`Related Matters .................................................................................... 72
`C.
`Lead and Back-up Counsel ................................................................. 72
`D.
`Service Information ............................................................................. 73
`XX. Exhibit List - §42.63(e) ................................................................................. 74
`XXI. Certifications .................................................................................................. 82
`A.
`Rule 42.24(d) Certification ................................................................. 82
`B.
`Rule 42.6(e)(4) Certificate of Service ................................................. 82
`C.
`Declaration .......................................................................................... 82
`
`-v-
`
`

`

`
`
`
`
`TABLE OF AUTHORITIES
`
`Cases
`
`Beckson Marine v. FNM, Inc., 292 F.3d 718 (Fed. Cir. 2002) ................................31
`
`Bristol-Myers Squibb v. Teva Pharms., 752 F.3d 967 (Fed. Cir. 2014) ..................59
`
`Cytiva Bioprocess v. JSR Corp., 122 F.4th 876 (Fed. Cir. 2024) ..................... 17, 22
`
`Immunogen, Inc. v. Stewart, No. 23-1762 (Fed. Cir. 2025) ...................................... 8
`
`In re Baxter Travenol, 952 F.2d 388 (Fed. Cir. 1991) .............................................69
`
`In re Hyatt, 708 F.2d 712 (Fed. Cir. 1983) ................................................................ 9
`
`In re Skoll, 523 F.2d 1392 (CCPA 1975) ................................................................58
`
`In re Urbanski, 809 F.3d 1237 (Fed. Cir. 2016) ............................................... 27, 30
`
`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) ......................................... 17, 23
`
`UCB, Inc. v. Actavis Labs., 65 F.4th 679 (Fed. Cir. 2023) ......................................29
`
`Statutes
`
`35 U.S.C. §102 .....................................................................................................1, 10
`
`35 U.S.C. §103 .....................................................................................................1, 17
`
`
`
`
`-vi-
`
`

`

`I.
`
`INTRODUCTION
`Petitioner Azurity Pharmaceuticals, Inc. (“Azurity”) requests inter partes
`
`review (“IPR”) to cancel claims 1-25 of U.S. Patent 8,623,826 (“Trento’826”,
`
`EX1001), assigned to Patent Owner (Helsinn). The prior art shows the claimed
`
`method is a routine variation on the existing standard, yet the examiner allowed the
`
`claims expressly relying on interested, undeposed, and materially-flawed
`
`testimony. These claims were never patentable.
`
`II.
`
`STANDING CERTIFICATIONS
`Trento’826 is available for IPR. Azurity is not barred or estopped from
`
`requesting IPR.
`
`III. CHALLENGES AND PRECISE RELIEF REQUESTED
`Claims 1-25 should be cancelled under 35 U.S.C. §1031 over:
`
`
`
`1 All pre-AIA 35 U.S.C. §§102 and 103.
`
`-1-
`
`

`

`
`
`Ground Claims
`
`Combined Teachings of
`
`1
`
`2
`
`3
`
`19, 22-23 & 25
`
`MASCC2 (EX1013) & Hoffmann3 (EX1011)
`
`19-20, 22-23 & 25
`
`MASCC & Bös4 (EX1014)
`
`19-23 & 25
`
`MASCC, Bös & ALOXI5 (EX1015)
`
`
`
`2 Antiemetic Subcommittee of the Multinational Association of Supportive Care in
`Cancer (MASCC), Prevention of chemotherapy- and radiotherapy-induced
`emesis: results of the 2004 Perugia International Antiemetic Consensus
`Conference, 17 Annals of Oncology 20 (2006).
`3 T. Hoffmann et al., Design and synthesis of a novel, achiral class of highly potent
`and selective, orally active neurokinin-1 receptor antagonists, 16 BIOORGANIC &
`MEDICINAL CHEMISTRY LETTERS 1362 (2006).
`4 M. Bös et al., 4-phenyl-pyridine derivatives, US 6,297,375 B1 (issued 2 Oct.
`2001).
`5 ALOXI (palonosetron HCl) Capsules, label (Revised 09/2008).
`
`-2-
`
`

`

`
`
`4
`
`5
`
`6
`
`7
`
`1-3, 8-10, 15-18 & 24
`
`Herrstedt6 (EX1010), Hoffmann & Hargreaves7
`
`(EX1012)
`
`1-3, 6-10, 15-18 & 24 Herrstedt, Bös & Hargreaves
`
`4-5
`
`10-14
`
`Herrstedt, Bös, Hargreaves & Herrington8
`
`(EX1016)
`
`Herrstedt, Bös, Hargreaves & ALOXI
`
`Exhibits, including a declaration from Stephen Peroutka, M.D., Ph.D. (EX1009),
`
`support these grounds.
`
`IV. TRENTO’826 PATENT
`
`Trento’826 purports to provide “methods for treating nausea and vomiting in
`
`
`
`6 J. Herrstedt & P. Dombernowsky, Anti-Emetic Therapy in Cancer
`Chemotherapy: Current Status, 101 BASIC & CLINICAL PHARMACOLOGY &
`TOXICOLOGY 143 (2007).
`7 R. Hargreaves, Imaging Substance P Receptors (NK1) in the Living Human Brain
`Using Positron Emission Tomography, 63(11) J. Clinical Psychiatry 18 (2002).
`8 J.D. Herrington et al., Randomized, Placebo-controlled, Pilot Study Evaluating
`Aprepitant Single Dose Plus Palonosetron and Dexamethasone for the Prevention
`of Acute and Delayed Chemotherapy-induced Nausea and Vomiting, 112 Cancer
`2080 (2008).
`
`-3-
`
`

`

`
`
`patients undergoing chemotherapy, radiotherapy, or surgery, comprising the co-
`
`administration of netupitant, palonosetron and dexamethasone.” EX1001, cover.
`
`A. Specification
`The specification “relates to the use of centrally acting NK1 antagonists to
`
`treat nausea and vomiting, particular[ly] nausea and vomiting induced by highly
`
`emetogenic chemotherapy, and to the treatment of such nausea and vomiting over
`
`multiple consecutive days[, and] also relates to combined oral dosage forms of
`
`palonosetron and netupitant.” EX1001, 1:19-25. Using a 5-HT3 antagonist (like
`
`palonosetron) with a steroid (like dexamethasone) “significantly improve[d] the
`
`standard of life for patients undergoing emetogenic medical procedures.” EX1001,
`
`1:29-39. Indeed, “[p]alonosetron hydrochloride ha[d] recently emerged as a highly
`
`efficacious anti-nauseant and anti-emetic agent.” EX1001, 1:40-41.
`
`NK1 antagonists aprepitant and casopitant had been tested—FDA had
`
`approved aprepitant for preventing “nausea and vomiting”—but Trento’826
`
`reported neither was effective. EX1001, 2:6-50. Nevertheless, Trento’826 reported
`
`NK1 antagonists, specifically including netupitant, continued to be “suggest[ed]…
`
`for a variety of conditions in which substance P (the natural ligand for the NK1
`
`receptor) is active.” Listed conditions included “vomiting [but not] nausea
`
`specifically.” EX1001, 3:21-60. Trento’826 reported discovering netupitant is
`
`active against nausea, binds to striatum NK1 receptors for 96 hours post-
`
`-4-
`
`

`

`
`
`administration, and makes both palonosetron and dexamethasone more effective,
`
`permitting subtherapeutic dexamethasone doses, and providing an effective 5-day
`
`combination therapy. EX1001, 4:37-5:20.
`
`Trento’826 Example 4 discloses administering netupitant alone to healthy
`
`human volunteers and determining brain NK1-receptor occupancy. As
`
`“anticipated” 90% or higher occupancy (“close to the expected Cmax”) of striatum
`
`receptors was reached for half the subjects with a single oral dose. Moreover, “[a]ll
`
`doses showed a relatively long duration of blockade of NK1 receptors and the
`
`decline over time was
`
`dose dependent.” The
`
`results were provided
`
`in Figure 5 (detail,
`
`right). EX1001,
`
`16:37-60.
`
`B. Challenged Claims
`Trento’826 has two independent claims. Claim 19 relates to treating acute-
`
`or delayed-phase chemotherapy-induced nausea and vomiting (CINV) with
`
`netupitant and palonosetron. Claim 1 relates to treating both nausea and vomiting
`
`for 5 days by administering (a) day-one netupitant, which occupies at least 70% of
`
`striatum NK1 receptors 72 hours later, (b) day-one palonosetron, and (c) day-one
`
`-5-
`
`

`

`
`
`dexamethasone at 50-70% of its effective dose when used without netupitant,
`
`where the treatment is effective for 5 days, and where the treatment is more
`
`effective than steps (b) and (c) alone. EX1001, 21:39-63, 23:8-15.
`
`C. Prosecution History
`Trento’826 issued from application 13/077,462 (EX1005), filed 31 March
`
`2011, which is a continuation of PCT/IB2010/003106,9 which claims priority to
`
`provisionals 61/382,70910 and 61/262,470.11 Its earliest possible effective filing
`
`date is 18 November 2009; however, the earlier provisional never discloses co-
`
`administration with dexamethasone, so claims encompassing co-administering
`
`dexamethasone are not entitled to priority before 14 September 2010.
`
`The examiner rejected claims over Reddy,12 which teaches treating CINV by
`
`administering an NK1 antagonist (aprepitant) with a 5-HT3 antagonist, and
`
`dexamethasone. Reddy teaches a 5-HT3 antagonist combined with dexamethasone
`
`was the “standard of care for highly emetic chemotherapy” and adding an NK1
`
`
`9 EX1055, filed 18 November 2010.
`10 EX1056, at 154-190, filed 14 September 2010.
`11 EX1057, at 192-219, filed 18 November 2009.
`12 EX1021, G.K. Reddy et al., Novel Neurokinin-1 Antagonists as Antiemetics for
`the Treatment of Chemotherapy-Induced Emesis, 3 Support Cancer Ther. 140-42
`(2006).
`
`-6-
`
`

`

`
`
`antagonist defined a new standard. EX1021, 141. Reddy also teaches netupitant
`
`was another NK1 antagonist under development for the same use. Id. The examiner
`
`found “Reddy teaches enhanced treatment of CINV with the addition of aprepitant
`
`or casopitant. Accordingly, the artisan would have reasonably expected enhanced
`
`treatment of CINV with netupitant”; however, Reddy was not “anticipatory insofar
`
`as netupitant is not a preferred species” but nonetheless “it would have been
`
`obvious to select netupitant given its plain enumeration in the prior art reference.”
`
`EX1005, 285; EX1009, ¶¶29-30.
`
`Helsinn responded with a declaration alleging unexpected results from
`
`combining netupitant with palonosetron. The declarants—a Trento’826 inventor
`
`and another Helsinn employee—argued using netupitant with palonosetron was
`
`synergistic because palonosetron inhibits the natural ligand for the NK1 receptor,
`
`even though it is a 5-HT3 antagonist, while other 5-HT3 antagonists do not.
`
`EX1009, ¶31.
`
`The examiner provided as reason for allowance: “132 Declaration, filed
`
`5/17/2013, affiant showing evidence of synergy (unexpected result) from the
`
`combination of netupitant and palonosetron in regard to the claimed method.”
`
`EX1009, ¶32. The examiner did not identify the precise unexpected result, but
`
`Helsinn had argued (EX1005, 331)—
`
`the combination of netupitant and palonosetron consistently reduced
`
`-7-
`
`

`

`
`
`significant nausea in response to HEC [highly-emetic chemotherapy],
`reduced nausea during the delayed phase in response to HEC, and
`reduced significant nausea during the overall phase in response to
`MEC [moderately-emetic chemotherapy]. These results were
`unexpected, and they plainly support the patentability of the claimed
`invention.
`Significantly, Helsinn’s response materially altered the data tables to remove
`
`unsupportive data. EX1009, ¶¶1360-79.
`
`V. LEVEL OF ORDINARY SKILL
`A POSA was skilled in one of “clinical medicine, medical oncology,
`
`radiation oncology, oncology nursing, statistics, pharmacy, medical policy and
`
`decision making, and pharmacology.” EX1013, 20. In 2009, such professionals had
`
`advanced degrees in pharmacology, medicine, or allied fields, and would have
`
`worked in consultation with other specialists in these fields, and had practical
`
`knowledge and experience about metabolism studies, in-vitro and in-vivo testing,
`
`formulation, and combination therapy. Dr. Peroutka is a pharmacologist familiar
`
`with the level of skill at the critical date. EX1009, ¶¶1-7, 57-60.
`
`Trento’826 itself notes the high level of skill in the art: “[t]he skilled artisan
`
`will be able to determine appropriate dosages[.]” EX1001, 7:57-61; 10:9-12
`
`(POSA can determine “suitable dosing regimen”). Cf. Immunogen, Inc. v. Stewart,
`
`No. 23-1762, slip 10 (Fed. Cir. 2025) (affirming obviousness where art showed
`
`physicians could determine the claimed dose).
`-8-
`
`

`

`
`
`VI. CLAIM CONSTRUCTION
`Trento’826 provides definitions of claim terms. EX1001, 7:3-9:5.
`
`The phrase therapeutically effective amount13 means “an amount sufficient
`
`to elicit the desired biological response.” EX1001, 7:55-57; EX1009, ¶140.
`
`The phrase minimum effective dose of dexamethasone means 20 mg on
`
`day-one and on subsequent days 16 mg for HEC and 0 mg for MEC. EX1001,
`
`7:62-8:4; EX1009, ¶¶147, 267. Correspondingly, sub-therapeutic dose of
`
`dexamethasone means less than these defined minimum amounts.
`
`Trento’826 does not disclose or define what synergistically effective to
`
`antagonize NK1 activity means. EX1001, EX1009, ¶153. Indeed, Trento’826 does
`
`not disclose any synergism; hence, synergy means only an effect greater than what
`
`the prior art would have suggested for the combination. Novo Nordisk v. Caraco
`
`Pharmaceutical, 719 F.3d 1346, 1352 (Fed. Cir. 2013) (“more effective than what
`
`would have been expected in view of the prior art”).
`
`For claim element 1(a)[2], “a therapeutically effective amount which”
`
`means the functions following “which” describe inherent properties rather than
`
`therapeutic effects that might further restrict a therapeutically-effective amount. In
`
`re Hyatt, 708 F.2d 712, 714 (Fed. Cir. 1983) (ordinary grammar applies); EX1009,
`
`
`13 Bold-italicized text indicates added emphasis.
`
`-9-
`
`

`

`
`
`¶¶257-60 (prior art identifies these functions as inherent in a therapeutic amount).
`
`VII. PRIOR ART
`All the applied and background references were publicly available over one
`
`year before the critical date and are thus section 102(b) prior art. No ground
`
`reference was applied in a rejection during examination.
`
`A. MASCC
`MASCC promulgates formal antiemetic recommendations of a multinational
`
`
`
`professional association on supportive care for cancer, updating the standard of
`
`care to the 2006 state-of-the-art. EX1013, 20.
`
`1. Recognized benefit from NK1-antagonist/5-HT3-
`antagonist/dexamethasone combination
`
`Two decades ago, antiemetic treatments received renewed attention,
`
`resulting in updated recommendations from the Multinational Association of
`
`Supportive Care (MASCC) “on antiemetic regimens to prevent emesis induced by
`
`high, moderate, low and minimal risk chemotherapy”. EX1013, 20. The state of the
`
`art had been—
`
`a 5-HT3-receptor antagonist plus dexamethasone as the regimen of
`choice for the prevention of acute emesis in cisplatin-treated patients[.
`However, a]prepitant is the first of a new class of drugs that
`selectively block the neurokinin-1 (NK1) neurotransmitter receptor,
`the binding site of the regulatory peptide Substance P. Aprepitant
`has been studied extensively for the prevention of cisplatin-induced
`
`-10-
`
`

`

`
`
`emesis. Several phase II double-blind studies showed added
`antiemetic activity when combined with a 5-HT3-receptor antagonist
`plus dexamethasone[].
`EX1013, 22. Moreover, a “reduced dose of dexamethasone was given in
`
`combination with aprepitant because a prior pharmacokinetic study found that
`
`aprepitant increased dexamethasone levels approximately two-fold.” Using a
`
`“primary endpoint [of] complete response (no emesis, no use of rescue
`
`antiemetics) over the 5-day study period”, this triple therapy was superior to the
`
`standard 5-HT3-antagonist/dexamethasone treatment. Id.
`
`[T]o prevent acute vomiting and nausea following [HEC], a three-
`drug regimen including single doses of a 5-HT3-receptor antagonist,
`dexamethasone and aprepitant given before chemotherapy is
`recommended (MASCC level of consensus: high; MASCC level of
`confidence: high).
`Id. Similarly, for HEC-induced delayed emesis, and despite studies with the then-
`
`current standard,
`
`the panel recommended that given the dependence of delayed emesis
`and nausea on acute antiemetic outcome, optimal acute antiemetic
`prophylaxis should be employed. For cisplatin, this includes a three-
`drug combination of aprepitant, a 5-HT3-receptor antagonist and
`dexamethasone.
`
`-11-
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`

`

`
`
`EX1013, 23. MASCC disclosed both oral and intravenous administration of the 5-
`
`HT3 antagonist14 and dexamethasone, and oral administration of the NK1
`
`antagonist. EX1013, 23-24; EX1009, ¶¶87-90.
`
`2. Palonosetron was a known, better 5-HT3 antagonist
`
`
`
`MASCC reported (EX1013, 24):
`
`Palonosetron is a 5-HT3-receptor antagonist that has a longer half-life
`and more avid receptor binding than the other 5-HT3 receptor
`antagonists. Two studies in patients treated with [MEC] demonstrated
`efficacy with a single intravenous dose of palonosetron 0.25 mg that
`was equal or better to a single intravenous dose of dolasetron or
`ondansetron in both the acute and delayed phases[.]
`MASCC also reported using palonosetron for HEC. EX1013, 22 (Table 3);
`
`EX1009, ¶91.
`
`B. Hoffmann
`Hoffmann, a 2006 journal article, teaches potent, orally-active NK1 antagonists
`
`
`
`to control CINV, as well as treat mood disorders like anxiety and depression.
`
`EX1011, Abstract. Hoffmann explains:
`
`[R]ecent clinical trials have demonstrated an important therapeutic
`application for NK1 receptor antagonists in the control of cancer
`
`
`14 Reportedly palonosetron was only then-available intravenously.
`
`-12-
`
`

`

`
`
`chemotherapy-induced nausea and vomiting and in the treatment of
`mood disorders such as anxiety and depression.[ Aprepitant] was the
`first NK1 receptor antagonist to receive marketing approval. In March
`2003, it was approved by the FDA for [CINV].
`EX1011, 1362; EX1009, ¶¶92-93. This class includes netupitant, which Hoffmann
`
`teaches has favorable characteristics including high affinity, excellent penetration into
`
`the central nervous system (CNS), and excellent oral NK1-antagonist activity.
`
`EX1011, 1364; EX1009, ¶94. Hoffmann tested its NK1-antagonists (including
`
`netupitant) in vivo and showed they potently inhibit NK1 agonist-induced foot-tapping
`
`behavior in gerbils. EX1011, 1365.
`
`C. Bös
`Bös, a 2001 patent, describes using NK1 antagonists to inhibit conditions
`
`
`
`including chemotherapy-induced emesis. Bös teaches using NK1 antagonists for
`
`“mediation of the emetic reflex and the modulation of central nervous system
`
`(CNS) disorders[.]” EX1014, 1:15-56. Specifically, “neurokinin-1 receptor
`
`antagonists are further useful for the treatment of motion sickness and for
`
`treatment induced vomiting” such as in “the reduction of cisplatin-induced emesis
`
`by a selective neurokinin-1-receptor antagonist.” EX1014, 1:59-67; EX1009, ¶¶95-
`
`96. Bös expressly identifies netupitant (“formula Ib”) as “characterized by valuable
`
`therapeutic properties as a highly selective antagonist of the Neurokinin 1”.
`
`EX1014, 14:32-38; EX1009, ¶¶97-98. Bös tested netupitant in model animals,
`
`-13-
`
`

`

`
`
`including a test of antiemetic effects in ferrets that showed pre-exposure netupitant
`
`administration “completely blocked the emesis induced by the emetogens.”
`
`EX1014, 19:10-20; EX1009, ¶99. Bös disclosed that a POSA would be able to
`
`determine appropriate dosage “within wide limits”, particularly within a daily
`
`range of 10-1000 mg. EX1014, 42:5-11; EX1009, ¶¶100-01.
`
`D. ALOXI
`ALOXI, a 2008 FDA label revision, discloses “palonosetron HCl” as a
`
`
`
`potent, selective 5-HT3 antagonist for MEC and HEC. EX1015, 1, 3; EX1009,
`
`¶¶102-03, 107-10. ALOXI teaches a 0.56 mg palonosetron HCl capsule,
`
`corresponding to 0.5 mg palonosetron free base. EX1015, 1-4; EX1009, ¶104.
`
`ALOXI teaches administering these capsules one hour before chemotherapy.
`
`EX1015, 5; EX1009, ¶105. ALOXI also teaches administering palonosetron with
`
`chemotherapeutic agents, systemic corticosteroids (e.g., dexamethasone), and other
`
`antiemetic and antinausea agents. EX1015, 2; EX1009, ¶106. EX1015, 4, Table 3.
`
`E. Herrstedt
`Herrstedt, a 2007 journal article, summarizes 2007 CINV treatments,
`
`
`
`including antiemetic therapy with serotonin-receptor 5-HT3 antagonists (e.g.,
`
`palonosetron) and NK1 antagonists (e.g., aprepitant). EX1010, Abstract. Herrstedt
`
`teaches adding a NK1 antagonist to an antiemetic combination of 5-HT3 antagonist
`
`plus corticosteroid (e.g., dexamethasone). Id. (“Aprepitant increases the effect…
`
`-14-
`
`

`

`
`
`against acute emesis induced by” HEC or MEC). Id. Herrstedt teaches antiemetic
`
`drugs should be administered in a combination therapy including a corticosteroid,
`
`5-HT3 antagonist, and NK1 antagonist. EX1010, 145; EX1009, ¶111-12.
`
`
`
`Herrstedt also teaches palonosetron as an improved 5-HT3 antagonist.
`
`EX1010, 145-146 (palonosetron “has a very potent and specific binding at 5-HT3
`
`receptors and a half-life aroun