`
`
`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 IPR2025-00947
`Patent US 9,186,357 B2
`————————————————
`
`PETITION FOR INTER PARTES REVIEW
`
`

`

`B.
`C.
`
`TABLE OF CONTENTS
`Introduction ...................................................................................................... 1
`I.
`Standing Certifications .................................................................................... 1
`II.
`III. Challenges and Precise Relief Requested ........................................................ 1
`IV. Trento’357 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. Herrstedt Teaches NK1 Antagonist/5-HT3
`Antagonist/Dexamethasone Antiemetic Prophylaxis .......................... 10
`Bös: Netupitant is a New Antiemetic NK1 Antagonist ....................... 11
`ALOXI Label Teaches FDA-Approved Palonosetron
`Dosing.................................................................................................. 12
`D. Hargreaves Links Receptor Occupancy to Effective Dose ................. 13
`E.
`Herrington Establishes Day-One Dosing ............................................ 13
`F.
`Bonadeo Teaches Single-Dose Form and Avoiding
`Palonosetron-Degradation Products .................................................... 14
`VIII. Legal Standards ............................................................................................. 15
`IX. Ground 1: Claims 1, 5-10, and 17 Were Obvious Over Herrstedt and
`Bös ................................................................................................................. 15
`A.
`Claim 1 ................................................................................................ 17
`B.
`Claim 5: “The method of claim 1, wherein the
`chemotherapy comprises moderately or highly
`emetogenic chemotherapy.” ................................................................ 20
`Claim 6: “The method of claim 1, wherein said
`chemotherapy comprises carboplatin.” ............................................... 21
`Claim 7: “The method of claim 1, wherein the netupitant
`-i-
`
`C.
`
`D.
`
`

`

`
`
`E.
`F.
`
`and palonosetron are administered no more than one hour
`prior to administration of the chemotherapy.” .................................... 21
`Claims 8-10: highly or moderately emetic chemotherapy .................. 22
`Claim 17: “The method of claim 1, wherein said
`treatment of CINV is defined as no emetic episodes and
`no use of rescue medication following said
`chemotherapy.” .................................................................................... 24
`G. Obvious to Combine and Reasonably Expect Success ....................... 24
`X. Ground 2: Claims 18-19, 25-27, and 30-32 Were Obvious Over
`Herrstedt, Bös and Herrington ....................................................................... 27
`A.
`Claims 18 and 19 ................................................................................. 27
`B.
`Claims 25-27 ....................................................................................... 30
`C.
`Claims 30-32 ....................................................................................... 32
`D. Obvious to Combine and Reasonably Expect Success ....................... 32
`XI. Ground 3: Claim 20 Was Obvious Over Herrstedt, Bös, Herrington,
`and ALOXI .................................................................................................... 33
`XII. Ground 5: Claims 24 and 29 Were Obvious Over Herrstedt, Bös,
`Hargreaves, and Herrington ........................................................................... 35
`XIII. Ground 6: Claim 28 Was Obvious Over Herrstedt, Bös, Bonadeo, and
`Herrington ...................................................................................................... 39
`XIV. Ground 7: Claims 21-23, 33-35, 37-39, 43-44, and 46-51 Were
`Obvious Over Herrstedt, Bös, Bonadeo, Herrington, and ALOXI ............... 42
`A.
`Claim 21: “The method of claim 19, wherein: a) said
`netupitant is administered orally as the free base in a dose
`of about 300 mg; b) said palonosetron is administered
`orally as palonosetron hydrochloride in a dose of about
`0.50 mg based on the weight of the free base; c) said
`netupitant and palonosetron are administered as a single
`unit dosage form less than 2 hours prior to said
`chemotherapy.” .................................................................................... 42
`Claim 22 .............................................................................................. 44
`Claim 23 .............................................................................................. 45
`Claims 33-35 ....................................................................................... 46
`-ii-
`
`B.
`C.
`D.
`
`

`

`
`
`Claims 37-39 and 49-51 ...................................................................... 46
`E.
`Claims 43-44 ....................................................................................... 47
`F.
`Claims 46-48 ....................................................................................... 47
`G.
`H. Obvious to Combine and Reasonably Expect Success ....................... 48
`XV. Ground 8: Claims 36 and 45 Were Obvious Over Herrstedt, Bös,
`Bonadeo, Hargreaves, Herrington and ALOXI ............................................. 49
`XVI. No Secondary Considerations ....................................................................... 50
`A. Aprepitant Shows Efficacy for Nausea ............................................... 50
`B. Misrepresentation of data during examination .................................... 55
`C.
`No Unexpected Synergy Between Netupitant and
`Palonosetron ........................................................................................ 59
`D. No Nexus Between Alleged Synergy and Claimed Effect ................. 60
`E.
`Single Dose of Netupitant Was Expected ........................................... 60
`F.
`Acute Phase Treatment with Netupitant Was Expected ..................... 61
`G.
`Characteristics of Netupitant Were Expected ..................................... 62
`XVII. Conclusion ..................................................................................................... 62
`XVIII.
`Payment of Fees - §§42.15(a) and 42.103........................................... 63
`XIX. Mandatory Notices - §42.8 ............................................................................ 64
`A.
`Real Parties-In-Interest ........................................................................ 64
`B.
`Related Matters .................................................................................... 64
`C.
`Lead and Back-up Counsel ................................................................. 64
`D.
`Service Information ............................................................................. 65
`XX. Exhibit List - §42.63(e) ................................................................................. 66
`XXI. Certifications .................................................................................................. 74
`A.
`Rule 42.24(d) Certification ................................................................. 74
`B.
`Rule 42.6(e)(4) Certificate of Service ................................................. 74
`C.
`Declaration .......................................................................................... 74
`
`
`
`-iii-
`
`

`

`
`
`
`
`Table of Authorities
`
`Cases
`
`Beckson Marine v. FNM, Inc., 292 F.3d 718 (Fed. Cir. 2002) ................................35
`
`Bristol-Myers Squibb v. Teva Pharms., 752 F.3d 967 (Fed. Cir. 2014) ..................50
`
`Cytiva Bioprocess v. JSR Corp., 122 F.4th 876 (Fed. Cir. 2024) ............................15
`
`Ex parte Tanksley, 26 USPQ2d 1384 (BPAI 1991) .................................................. 9
`
`Immunogen, Inc. v. Stewart, No. 23-1762 (Fed. Cir. 2025) ...................................... 9
`
`In re Baxter Travenol, 952 F.2d 388 (Fed. Cir. 1991) .............................................62
`
`In re Skoll, 523 F.2d 1392 (CCPA 1975) ................................................................50
`
`In re Urbanski, 809 F.3d 1237 (Fed. Cir. 2016) ......................................................34
`
`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) ................................................15
`
`Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co., 868 F.3d
`1013 (Fed. Cir. 2017) ............................................................................................ 9
`
`Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) (en banc) ........................... 9
`
`Richardson-Vicks Inc. v. Upjohn Co., 122 F.3d 1476 (Fed. Cir. 1997) ..................49
`
`Samsung Elecs. Am. v. Prisua Eng’g, 948 F.3d 1342 (Fed. Cir. 2020) ..................... 9
`
`Statutes
`
`35 U.S.C. §102 .....................................................................................................1, 10
`
`35 U.S.C. §103 ........................................................................................................... 1
`
`35 U.S.C. §112 ........................................................................................................... 9
`
`-iv-
`
`

`

`I.
`
`INTRODUCTION
`Petitioner Azurity Pharmaceuticals, Inc. (“Azurity”) requests inter partes
`
`review (“IPR”) to cancel claims 1, 5-10, 17-39, and 43-51 of U.S. Patent 9,186,357
`
`(“Trento’357”, EX1002), assigned to Patent Owner (Helsinn). This petition covers
`
`49 of 133 closely related claims spread over four patents. The prior art amply
`
`shows the claimed method is just a routine variation on the existing standard, yet
`
`the examiner allowed the claims, relying on interested, undeposed, irrelevant, and
`
`materially-flawed testimony. As this petition and accompanying exhibits with
`
`expert testimony show, these claims were never patentable.
`
`II.
`
`STANDING CERTIFICATIONS
`Trento’357 is available for IPR. Azurity is not barred or estopped from
`
`requesting IPR on these grounds.
`
`III. CHALLENGES AND PRECISE RELIEF REQUESTED
`Claims 1, 5-10, 17-39, and 43-51 should be cancelled as unpatentable under
`
`35 U.S.C. §1031 on these grounds:
`
`
`
`1 All references to §§102 and 103 are to the pre-AIA versions.
`-1-
`
`

`

`
`
`Ground Claims
`
`Obvious from the Combined Teachings of
`
`1
`
`2
`
`3
`
`5
`
`6
`
`7
`
`8
`
`1, 5-10 & 17
`
`Herrstedt2 (EX1010) & Bös3 (EX1014)
`
`
`
`18-19, 25-27 & 30-32 Herrstedt, Bös & Herrington4 (EX1016)
`
`Herrstedt, Bös, Herrington & ALOXI5
`
`(EX1015)
`
`Herrstedt, Bös, Hargreaves6 (EX1012) &
`
`Herrington
`
`Herrstedt, Bös, Bonadeo (EX1017)7 &
`
`Herrington
`
`Herrstedt, Bös, Bonadeo, Herrington & ALOXI
`
`Herrstedt, Bös, Bonadeo, Hargreaves,
`
`Herrington & ALOXI
`
`20
`
`24 & 29
`
`28
`
`21-23, 33-35, 37-39,
`
`43-44 & 46-51
`
`36 & 45
`
`
`
`2 J. Herrstedt & P. Dombernowsky, Anti-Emetic Therapy in Cancer
`Chemotherapy: Current Status, 101 BASIC & CLINICAL PHARMACOLOGY &
`TOXICOLOGY 143-150 (2007).
`
`
`-2-
`
`

`

`
`
`Azurity has also filed a second IPR petition challenging the remaining claims of
`
`Trento’357; the grounds are assigned numbers in parallel across these two IPRs,
`
`and ground 4 is omitted from this IPR. Exhibits, including a declaration from
`
`Stephen Peroutka, M.D., Ph.D. (EX1009), support these grounds. None of these
`
`references was applied in a rejection against these claims.
`
`IV. TRENTO’357 PATENT
`
`Trento’357 is entitled “Compositions and methods for treating centrally
`
`mediated nausea and vomiting”, claims priority to a provisional filed on November
`
`18, 2009, and purports to provide “methods for treating nausea and vomiting in
`
`patients undergoing chemotherapy, radiotherapy, or surgery, comprising the co-
`
`
`
`3 M. Bös et al., 4-phenyl-pyridine derivatives, US 6,297,375 B1 (issued 2 Oct.
`2001).
`4 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).
`5 ALOXI (palonosetron HCl) Capsules, label (Revised 09/2008).
`6 R. Hargreaves, Imaging Substance P Receptors (NK1) in the Living Human Brain
`Using Positron Emission Tomography, 63(11) J. Clinical Psychiatry 18-24 (2002).
`7 D. Bonadeo et al., Soft Capsules Comprising Palonosetron Hydrochloride
`Having Improved Stability and Bioavailability, WO 2008/049552 (published 2
`May 2008).
`
`-3-
`
`

`

`
`
`administration of netupitant, palonosetron and dexamethasone.” EX1002, 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. The present invention also relates to combined oral
`
`dosage forms of palonosetron and netupitant.” EX1002, 1:19-25. Treatment with a
`
`5-HT3 antagonist (like palonosetron) and a steroid (like dexamethasone) “ha[d]
`
`been demonstrated to significantly improve the standard of life for patients
`
`undergoing emetogenic medical procedures.” EX1002, 1:29-39. Indeed,
`
`“[p]alonosetron hydrochloride ha[d] recently emerged as a highly efficacious anti-
`
`nauseant and anti-emetic agent.” EX1002, 1:40-41.
`
`NK1 antagonists aprepitant and casopitant had been tested—FDA had even
`
`approved aprepitant “for the prevention of nausea and vomiting”—but Trento’357
`
`reported neither was effective. EX1002, 2:6-50. (Actually, Helsinn reported similar
`
`or better results for the standard “Aprepitant Regimen” versus netupitant regimens.
`
`EX1002, 19:Table 6; EX1009, ¶24.) Nevertheless, Trento’357 reported that 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.”
`
`-4-
`
`

`

`
`
`EX1002, 3:21-60. Trento’357 reported discovering, however, that netupitant is
`
`active against nausea and binds to striatum NK1 receptors in the brain for 96 hours
`
`after administration, and that it makes both palonosetron and dexamethasone more
`
`effective, permitting the use of subtherapeutic dexamethasone doses, and providing
`
`a combination therapy that could be effective for 5 days. EX1002, 4:37-5:20.
`
`Example 4 in Trento’357 discloses the results administering netupitant alone
`
`to healthy human volunteers to determine occupancy of brain NK1 receptors. As
`
`“anticipated” 90% or higher occupancy (“close to the expected Cmax”) of the
`
`striatum receptors was reached with half of 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). EX1002,
`
`16:37-60.
`
`B. Challenged Claims
`Trento’357 has 62 claims; three (1, 2, 4) are independent. This petition
`
`addresses claim 1 and its dependent claims (5-10, 17-39, and 43-51). Claim 1
`
`-5-
`
`

`

`
`
`relates to treating chemotherapy-induced nausea and vomiting (“CINV”) by
`
`administering a regimen of netupitant, palonosetron, and dexamethasone. EX1002,
`
`claim 1.
`
`C. Prosecution History
`Trento’357 issued from application 14/069,927 (EX1006), filed 1 November
`
`2013, which claims priority to PCT/IB2010/003106,8 and to provisionals
`
`61/382,7099 and 61/262,470.10 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 only office action during prosecution was a double patenting rejection
`
`over U.S. Patent No. 8,623,826 (Trento’826), of which Trento’357 is a
`
`continuation. EX1006, 233-36. During prosecution of Trento’826, the examiner
`
`rejected claims over Reddy,11 which taught treating CINV by administering an
`
`
`
`8 EX1055, filed 18 November 2010.
`9 EX1056, at 154-190, filed 14 September 2010.
`10 EX1057, at 192-219, filed 18 November 2009.
`11 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-
`
`

`

`
`
`NK1 antagonist (aprepitant) with a 5-HT3 antagonist, and dexamethasone. Reddy
`
`taught a 5-HT3 antagonist combined with dexamethasone was the “standard of care
`
`for highly emetic chemotherapy” and adding an NK1 antagonist defined a new
`
`standard. EX1021, 141. Reddy also taught netupitant was an 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.
`
`In response, Helsinn submitted a declaration alleging unexpected results
`
`from combining netupitant with palonosetron. The declarants were a Trento’826
`
`inventor (Giorgia Rossi) and another Helsinn employee (Pietra) who argued the
`
`combination of netupitant and palonosetron provided a synergistic effect because
`
`palonosetron inhibits the natural ligand for the NK1 receptor, even though it is an
`
`5-HT3 antagonist, while other 5-HT3 antagonists do not. EX1009, ¶31.
`
`In allowing the claims, the examiner provided as reasons for allowance:
`
`“132 Declaration, filed 5/17/2013, affiant showing evidence of synergy
`
`(unexpected result) from the combination of netupitant and palonosetron in regard
`
`-7-
`
`

`

`
`
`to the claimed method.” EX1009, ¶32. While the examiner did not identify the
`
`precise unexpected result, Helsinn had argued (EX1005, 331) that—
`
`the combination of netupitant and palonosetron consistently reduced
`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 would be 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 would have
`
`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’357 itself notes the high level of skill in the art. For example, “[t]he
`
`skilled artisan will be able to determine appropriate dosages[.]” EX1002, 7:57-61.
`
`-8-
`
`

`

`
`
`Similarly, the art can determine the “suitable dosing regimen”. EX1002, 10:9-12;
`
`cf. Immunogen, Inc. v. Stewart, No. 23-1762, slip 10 (Fed. Cir. 2025) (affirming
`
`obviousness where art showed physicians could determine the claimed dose).
`
`VI. CLAIM CONSTRUCTION
`No terms need be construed to find the claims unpatentable in view of the
`
`prior art. Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co., 868 F.3d
`
`1013, 1017 (Fed. Cir. 2017). In mapping the prior art to the claims, Petitioner has
`
`applied “the meaning that [a] term would have to a person of ordinary skill in the
`
`art in question at the time of the invention.” Phillips v. AWH Corp., 415 F.3d 1303,
`
`1313 (Fed. Cir. 2005) (en banc).
`
`In several instances, claims either lack or have inconsistent antecedent basis.
`
`For example, Claim 35 recites “moderately emetogenic” chemotherapy, but its
`
`dependent claim 37 is limited to cisplatin, a highly emetogenic chemo. Without
`
`conceding any question under 35 U.S.C. §112, Azurity has been able to apply the
`
`prior art to each claim by focusing on the limitation in the claim being analyzed.
`
`Under long-established precedent, if prior art may be applied, §112 defects will not
`
`prevent a determination of obviousness. Ex parte Tanksley, 26 USPQ2d 1384,
`
`1387 (BPAI 1991) (reaching merits where claim meaning was sufficiently clear to
`
`apply the prior art); accord Samsung Elecs. Am. v. Prisua Eng’g, 948 F.3d 1342,
`
`1355 (Fed. Cir. 2020) (“[T]hat the claim is subject to invalidation on the ground of
`
`-9-
`
`

`

`
`
`indefiniteness … does not speak to whether the claim is also invalid for
`
`obviousness”).
`
`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. Herrstedt Teaches NK1 Antagonist/5-HT3
`Antagonist/Dexamethasone Antiemetic Prophylaxis
`Herrstedt, a 2007 journal article, provides a summary of treatments in 2007
`
`
`
`for CINV. EX1010, Abstract. It describes the development of antiemetic therapy
`
`including serotonin receptor 5-HT3 antagonists (e.g., palonosetron) and the NK1
`
`antagonists (e.g., aprepitant). Id. Herrstedt taught adding an NK1 antagonist to the
`
`antiemetic combination of 5-HT3 antagonist plus corticosteroid (e.g.,
`
`dexamethasone). Id. (“Aprepitant increases the effect of a serotonin3-receptor
`
`antagonist plus a corticosteroid against acute emesis induced by highly or
`
`moderately emetogenic chemotherapy.”). Id., abstract. Herrstedt describes
`
`generally that antiemetic drugs should be administered in a combination therapy
`
`that includes a corticosteroid, a 5-HT3 antagonist, and an NK1 antagonist. EX1010,
`
`145; EX1009, ¶¶111-12.
`
`
`
`Herrstedt also taught palonosetron as an improved 5-HT3 antagonist.
`
`EX1010, 145-146. Palonosetron “has a very potent and specific binding at 5-HT3
`
`-10-
`
`

`

`
`
`receptors and a half-life around 40 hr as compared to less than 10 hr for the other
`
`agents (table 3).” EX1010, 145, Table 3. Moreover, while 5-HT3 antagonists had
`
`shown “limited or no efficacy in delayed emesis” (i.e., emesis occurring 24-120
`
`hours after chemotherapy), “[p]alonosetron might be an exception” because it had
`
`FDA approval “in the treatment of delayed emesis from MEC.” EX1010, 146;
`
`EX1009, ¶113.
`
`
`
`Herrstedt summarizes phase-III clinical trials evaluating a drug-dosing
`
`regimen including administering a 5-HT3 antagonist (e.g., palonosetron),
`
`dexamethasone, and an NK1 antagonist (e.g., aprepitant). EX1010, 146. These
`
`trials showed a statistical benefit for these combined therapeutics as prophylaxis
`
`for CINV. Id.; EX1009, ¶114. Moreover, using aprepitant “results in a two-time
`
`increase in the [area under curve] of dexamethasone indicating an inhibition of
`
`aprepitant on dexamethasone metabolism.” EX1010, 147. Thus, when
`
`dexamethasone is administered with an NK1 antagonist (aprepitant), the
`
`concentration of dexamethasone doubles due to decreased dexamethasone
`
`metabolism. EX1009, ¶115.
`
`B. Bös: Netupitant is a New Antiemetic NK1 Antagonist
`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
`
`-11-
`
`

`

`
`
`(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,
`
`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.
`
`C. ALOXI Label Teaches FDA-Approved Palonosetron Dosing
`ALOXI, a 2008 FDA label revision (available through the FDA website
`
`
`
`before the critical date), discloses palonosetron hydrochloride (“palonosetron
`
`HCl”) as a potent and selective 5-HT3 antagonist for “[m]oderately emetogenic
`
`cancer chemotherapy – prevention of acute nausea and vomiting associated with
`
`initial and repeat courses” and also for highly emetogenic chemotherapy (HEC),
`
`like cisplatin. EX1015, 1, 3; EX1009, ¶¶102-03, 107-10. ALOXI teaches an orally-
`
`administered capsule with 0.56 mg palonosetron HCl, corresponding to 0.5 mg of
`
`-12-
`
`

`

`
`
`palonosetron free base, which ALOXI also describes as a 0.5 mg capsule. EX1015,
`
`1-4; EX1009, ¶104. ALOXI teaches administering palonosetron HCl capsules one
`
`hour before chemotherapy. EX1015, 5; EX1009, ¶105. ALOXI also teaches
`
`administering palonosetron with chemotherapeutic agents, systemic corticosteroids
`
`(e.g., dexamethasone), and with other antiemetic and antinausea agents. EX1015,
`
`2; EX1009, ¶106. EX1015, 4, Table 3 (comparing 0.5 mg capsules to 0.25
`
`intravenous palonosetron.
`
`D. Hargreaves Links Receptor Occupancy to Effective Dose
`Hargreaves, a 2002 journal article, taught using positron emission
`
`
`
`tomography (PET) to study the NK1-receptor pathway and its association with
`
`Substance P, which is implicated in pathophysiology of emesis and depression.
`
`EX1012, Abstract. Using aprepitant, the study evaluated NK1-receptor occupancy
`
`within the brain and associated such occupancy with therapeutically-effective
`
`doses. Id. Hargreaves teaches a 75% or greater NK1-receptor occupancy was
`
`associated with therapeutic doses that blocked emesis. EX1012, 23; EX1009,
`
`¶¶116-17.
`
`E. Herrington Establishes Day-One Dosing
`Herrington, a 2008 journal article, discloses a clinical trial evaluating three
`
`
`
`different treatment arms for antiemetic therapeutic effect for patients receiving
`
`highly emetogenic chemotherapy, in which all treatment arms received day-one
`
`-13-
`
`

`

`
`
`0.25 mg palonosetron intravenously and dexamethasone on each of Days 1-4.
`
`EX1016, Abstract. Arm A also received day-one 125 mg oral aprepitant plus 80
`
`mg oral aprepitant on days 2-3. Arm B received day-one 125 mg oral aprepitant
`
`but received placebo rather than aprepitant on days 2-3. Arm C received placebos
`
`on days 1-3. Id.; EX1009, ¶¶118-19. Herrington reports that day-one oral
`
`administration of a therapeutically effective amount of NK1 antagonist is as
`
`effective as multi-day administration. EX1016, Abstract; EX1009, ¶120.
`
`Herrington concluded no significant difference exists between a single (Day 1, 125
`
`mg) NK1 antagonist dose and multiple-day NK1 antagonist doses for both the acute
`
`phase (i.e., 0-24 hours following chemotherapy) and the delayed phase (i.e., 24-
`
`120 hours following chemotherapy). EX1016, Table 3; EX1009, ¶121.
`
`F. Bonadeo Teaches Single-Dose Form and Avoiding
`Palonosetron-Degradation Products
`Bonadeo, a 2 May 2008 PCT publication, describes formulations of
`
`
`
`palonosetron hydrochloride for oral administration, “preferably in the form of
`
`liquid filled capsules.” EX1017, Abstract. Bonadeo identifies degradation products
`
`of palonosetron including a product called Cpd1 ((3S)-3-[(3aS)-1-oxo-2,3,3a,4,5,6-
`
`hexahydro-1H-benzo[de]isoquinoline-2-yl-1-azoniabicyclo[2.2.2]octan-1-olate).
`
`EX1017, 3, 11 (limiting maximum content). Bonadeo teaches capsules “for the
`
`treatment of emesis,” describes including multiple active ingredients in its
`
`capsules, and describes embodiments “wherein said palonosetron comprises Cpd1
`-14-
`
`

`

`
`
`in an amount of less than 1.0 wt%.” EX1013, 3, 5, 16; EX1009, ¶¶123-24.
`
`VIII. LEGAL STANDARDS
`An obviousness analysis involves (1) determining the scope and content of
`
`the prior art, (2) ascertaining the differences between the prior art and the claims at
`
`issue, (3) resolving the level of ordinary skill in the art, and (4) evaluating any
`
`evidence of secondary considerations. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
`
`406 (2007). “[T]he fact that a combination was obvious to try might show that it
`
`was obvious under §103.” Id. at 421. If a property of a composition is inherent,
`
`reasonable expectation of success is assured. Cytiva Bioprocess v. JSR Corp.,
`
`122 F.4th 876, 886-87 (Fed. Cir. 2024).
`
`IX. GROUND 1: CLAIMS 1, 5-10, AND 17 WERE OBVIOUS OVER
`HERRSTEDT AND BÖS
`Herrstedt teaches treating both nausea and vomiting. Herrstedt describes
`
`administering therapeutically-effective amounts of an NK1 antagonist (aprepitant),
`
`a 5-HT3 antagonist (e.g., palonosetron), and a first (sub-therapeutic) dose of
`
`dexamethasone on day 1. EX1010, 143, 146-147. Herrstedt reports dexamethasone
`
`has twice the AUC concentration in this combination therapy, and teaches
`
`decreasing the first dose of dexamethasone by about 50% compared to the standard
`
`minimum-effective dose. EX1010, 147. Herrstedt teaches these steps effectively
`
`treat both nausea and vomiting during a 5-day period, and treat both nausea and
`
`vomiting to a greater extent during the 5-day period than a combination of just the
`
`-15-
`
`

`

`
`
`5-HT3 antagonist and dexamethasone. Id., 146-147; EX1009, ¶¶247, 843-45.
`
`Bös teaches its “Formula Ib” (netupitant) is an improved NK1 antagonist.
`
`Bös, 14:31-38 (“The compound of formula Ib and its salts is also characterized by
`
`valuable therapeutic properties as a highly selective antagonist of the Neurokinin
`
`1 (NK-1, substance P)”).12 Bös evaluated formula Ib’s affinity for human NK1
`
`receptors and determined it is “a potent and selective antagonist.” Id., 17:61-18:48;
`
`see also id., 18:60-63 (“a competitive antagonist at human recombinant NK1
`
`receptors”); id., 19:26-30 (“a potent antagonist of NK1 induced behaviours in
`
`gerbil and blocks emesis in ferrets and [S]ancus murinus with similar potency.”). A
`
`POSA would have known Bös formula Ib was netupitant. See EX1009, ¶¶845-46
`
`(comparing Bös’ formula Ib to the formula identified as netupitant by Hoffmann,
`
`as shown below).
`
`
`
`12 Bold-italicized text indicates added emphasis.
`-16-
`
`

`

`
`
`
`
`
`
`Netupitant
`EX1011, Table 4.
`
`Formula Ib
`EX1014, 14:9-30.
`A. Claim 1
`1. [preamble]: “A method of treating chemotherapy induced
`nausea and vomiting (CINV) comprising”
`To the extent it is limiting, Herrstedt teaches the preamble terms, for
`
`
`
`example, methods for prophylactically treating “[c]hemotherapy-induced nausea
`
`and vomiting” in a patient. EX1010, 143. Herrstedt’s primary therapeutic endpoint
`
`was no emesis for five consecutive days after chemotherapy with cisplatin (i.e.,
`
`five days “postcisplatin”). Id., 146 (“Complete response, defined as ‘no emesis and
`
`no rescue therapy on days 1-5 postcisplatin’, was the primary end-point in all
`
`studies.”). EX1009, ¶¶847-48.
`
`2. [a]: “administering to a subject receiving chemotherapy a
`regimen of palonosetron, netupitant and dexamethasone.”
`Herrstedt teaches treating highly-emeto