`
`
`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 IPR2025-00948
`Patent US 9,943,515 B2
`————————————————
`
`PETITION FOR INTER PARTES REVIEW
`
`

`

`TABLE OF CONTENTS
`
`Page
`Introduction ...................................................................................................... 1
`I.
`Standing Certifications .................................................................................... 1
`II.
`III. Challenges and Precise Relief Requested ........................................................ 1
`IV. Trento’515 Patent ............................................................................................ 2
`A.
`Specification .......................................................................................... 3
`B.
`Challenged Claims ................................................................................ 5
`C.
`Prosecution History ............................................................................... 5
`Level of Ordinary Skill .................................................................................... 8
`V.
`VI. Claim Construction .......................................................................................... 9
`VII. Prior Art ......................................................................................................... 10
`A. Herrstedt .............................................................................................. 11
`B.
`Bös: Netupitant is a New Antiemetic NK1 Antagonist ....................... 12
`C.
`Hargreaves Links Receptor Occupancy to Effective Dose ................. 13
`D. Herrington Establishes Day-One Dosing ............................................ 13
`VIII. Legal Standards ............................................................................................. 14
`IX. Ground 1: Claims 11-17 and 19-23 Were Obvious Over Herrstedt,
`Bös, and Herrington ....................................................................................... 15
`A.
`Claim 11 is an obvious modification of the prior art .......................... 16
`B.
`Claim 12: “The method of claim 11, comprising orally
`administering from about 200 to about 400 mg of
`netupitant as the free base.” ................................................................. 22
`Claim 13: “The method of claim 11, comprising orally
`administering about 300 mg of netupitant as the free
`base.” ................................................................................................... 23
`Claim 14: “The method of claim 11, wherein when said
`emesis inducing event comprises highly emetic
`chemotherapy, and the chemotherapy is selected from the
`group consisting of carmustine, cisplatin,
`
`D.
`
`C.
`
`-i-
`
`

`

`
`
`E.
`
`F.
`
`G.
`
`cyclophosphamide≥1500 mg/m2, dacarbazine,
`dactinomycin, mechlorethamine, streptozotocin and
`combinations thereof.” ........................................................................ 24
`Claim 15: “The method of claim 11, wherein when said
`emesis inducing event comprises moderately emetic
`chemotherapy, and the chemotherapy is selected from the
`group consisting of carboplatin, cyclophosphamide<1500
`mg/m2, cytarabine>1 mg/m2, daunorubicin, doxorubicin,
`epirubicin, idarubicin, ifosfamide, irinotecan, oxaliplatin
`and combinations thereof.” ................................................................. 25
`Claim 16: “The method of claim 11, wherein said emesis
`inducing event comprises chemotherapy selected from
`the group consisting of carboplatin, cyclophosphamide,
`cytarabine>1 mg/m2, daunorubicin, doxorubicin,
`epirubicin, idarubicin, ifosfamide, irinotecan, carmustine,
`cisplatin, dacarbazine, dactinomycin, mechlorethamine,
`streptozotocin, oxaliplatin and combinations thereof.” ...................... 26
`Claim 17: “The method of claim 11, for the treatment of
`CINV defined as no emetic episodes and no use of rescue
`medication following chemotherapy.” ................................................ 26
`Claim 19: “The method of claim 11, wherein said emesis
`inducing event is highly emetogenic chemotherapy, and
`said regimen is effective to prevent or reduce the severity
`of nausea during the acute and delayed phases.” ................................ 26
`Claim 20: “The method of claim 11, wherein said emesis
`inducing event is moderately emetogenic chemotherapy,
`and said regimen is effective to prevent or reduce the
`severity of nausea during the acute and delayed phases.” .................. 27
`Claim 21: “The method of claim 11, wherein said emesis
`inducing event comprises cisplatin.” .................................................. 28
`Claim 22: “The method of claim 11, wherein said emesis
`inducing event comprises carboplatin, cisplatin,
`oxaliplatin, or doxorubicin.” ............................................................... 28
`Claim 23: “The method of claim 11, wherein said emesis
`inducing event comprises cyclophosphamide.” .................................. 29
`M. Reasons to Combine and Reasonably Expect Success ....................... 29
`-ii-
`
`H.
`
`I.
`
`J.
`
`K.
`
`L.
`
`

`

`
`
`F.
`
`G.
`
`C.
`D.
`E.
`
`X. Ground 2: Claims 1-10 and 18 Were Obvious Over Herrstedt, Bös,
`Hargreaves, and Herrington ........................................................................... 30
`A.
`Claim 1 ................................................................................................ 30
`B.
`Claim 2: “The method of claim 1, wherein said netupitant
`occupies 80% or more of NK1 receptors in the striatum
`seventy-two hours after said administration.” ..................................... 39
`Claim 3: “The method of claim 1, further comprising:” ..................... 41
`Claim 4: “The method of claim 1 wherein: ......................................... 45
`Claim 5: “The method of claim 1 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’).” .......................................................................... 47
`Claim 6: “The method of claim 1 wherein said nausea
`and vomiting is induced by moderately or highly
`emetogenic chemotherapy.” ................................................................ 48
`Claim 7: “The method of claim 1 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 8: “The method of claim 1 comprising treating
`nausea and vomiting in 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 9: “The method of claim 1, comprising
`administering from about 200 to about 400 mg of
`netupitant as the free base.” ................................................................. 50
`Claim 10: “The method of claim 1, comprising orally
`administering about 300 mg of netupitant as the free
`base.” ................................................................................................... 51
`
`H.
`
`I.
`
`J.
`
`-iii-
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`

`

`
`
`K.
`
`Claim 18: “The method of claim 17, wherein said
`netupitant occupies at least 70% of said patient's striatum
`NK1 receptors ninety-six hours after said administration.” ................ 52
`Reason to Combine and Reasonably Expect Success ......................... 54
`L.
`XI. No Secondary Considerations ....................................................................... 55
`A. Aprepitant Shows Efficacy for Nausea ............................................... 55
`B.
`Data misrepresented during examination ............................................ 60
`C.
`No Unexpected Synergy Between Netupitant and
`Palonosetron ........................................................................................ 63
`D. No Nexus Between Alleged Synergy and Claimed Effect ................. 65
`E.
`Single Dose of Netupitant Was Expected ........................................... 65
`F.
`Acute-Phase Treatment with Netupitant Was Expected ..................... 66
`G.
`Characteristics of Netupitant Were Expected ..................................... 66
`XII. Conclusion ..................................................................................................... 67
`XIII. Payment of Fees - §§42.15(a) and 42.103 ..................................................... 68
`XIV. Mandatory Notices - §42.8 ............................................................................ 69
`A.
`Real Parties-In-Interest ........................................................................ 69
`B.
`Related Matters .................................................................................... 69
`C.
`Lead and Back-up Counsel ................................................................. 69
`D.
`Service Information ............................................................................. 70
`XV. Exhibit List - §42.63(e) ................................................................................. 71
`XVI. Certifications .................................................................................................. 77
`A.
`Rule 42.24(d) Certification ................................................................. 77
`B.
`Rule 42.6(e)(4) Certificate of Service ................................................. 77
`C.
`Declaration .......................................................................................... 77
`
`
`
`-iv-
`
`

`

`
`
`TABLE OF AUTHORITIES
`
`Cases
`
`Page
`
`Bristol-Myers Squibb v. Teva Pharms., 752 F.3d 967 (Fed. Cir. 2014) ..................55
`
`Cytiva Bioprocess v. JSR Corp., 122 F.4th 876 (Fed. Cir. 2024) ..................... 14, 55
`
`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) .......................... 46, 47, 51, 66
`
`In re Hyatt, 708 F.2d 712 (Fed. Cir. 1983) ..............................................................10
`
`In re Skoll, 523 F.2d 1392 (CCPA 1975) ................................................................55
`
`In re Urbanski, 809 F.3d 1237 (Fed. Cir. 2016) ............................................... 23, 46
`
`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) ................................................14
`
`Statutes
`
`35 U.S.C. §102 .....................................................................................................1, 10
`
`35 U.S.C. §103 ........................................................................................................... 1
`
`-v-
`
`

`

`I. INTRODUCTION
`Petitioner Azurity Pharmaceuticals, Inc. (“Azurity”) requests inter partes
`
`review (“IPR”) to cancel claims 1-23 of U.S. Patent 9,943,515 (“Trento’515”,
`
`EX1003), assigned to Patent Owner (Helsinn). This petition covers 23 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, and materially-
`
`flawed testimony. As this petition and accompanying exhibits with expert
`
`testimony show, these claims were never patentable.
`
`II. STANDING CERTIFICATIONS
`Trento’515 is available for IPR. Azurity is not barred or estopped from
`
`requesting IPR on these grounds.
`
`III. CHALLENGES AND PRECISE RELIEF REQUESTED
`Claims 1-23 should be cancelled as unpatentable under 35 U.S.C. §1031 on
`
`these grounds:
`
`
`
`1 All references to 35 U.S.C. §§102 and 103 are to the pre-AIA versions.
`-1-
`
`

`

`
`
`Ground Claims
`
`Obvious from the Combined Teachings of
`
`1
`
`2
`
`11-17 & 19-23
`
`1-10 & 18
`
`Herrstedt2 (EX1010), Bös3 (EX1014) &
`
`optionally Herrington4 (EX1017)
`
`Herrstedt, Bös, Hargreaves5 (EX1012) &
`
`Herrington
`
`Exhibits, including a declaration from Stephen Peroutka, M.D., Ph.D. (EX1009),
`
`support these grounds.
`
`IV. TRENTO’515 PATENT
`Trento’515 is entitled “Compositions and methods for treating centrally
`
`
`
`mediated nausea and vomiting”, claims priority to a provisional filed on November
`
`
`
`2 J. Herrstedt & P. Dombernowsky, Anti-Emetic Therapy in Cancer
`Chemotherapy: Current Status, 101 BASIC & CLINICAL PHARMACOLOGY &
`TOXICOLOGY 143-150 (2007).
`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 R. Hargreaves, Imaging Substance P Receptors (NK1) in the Living Human Brain
`Using Positron Emission Tomography, 63(11) J. CLINICAL PSYCHIATRY 18-24
`(2002).
`
`-2-
`
`

`

`
`
`18, 2009, and purports to provide “compositions and methods for treating or
`
`preventing nausea and vomiting in patients undergoing chemotherapy,
`
`radiotherapy, or surgery.” EX1003, 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.” EX1003, 1:25-31. 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.” EX1003, 1:42-45. Indeed,
`
`“[p]alonosetron hydrochloride ha[d] recently emerged as a highly efficacious anti-
`
`nauseant and anti-emetic agent.” EX1003, 1:50-51.
`
`NK1 antagonists aprepitant and casopitant had been tested—FDA had even
`
`approved aprepitant “for the prevention of nausea and vomiting”—but Trento’515
`
`reported neither was effective. EX1003, 2:29-34. (Actually, Helsinn reported
`
`similar or better results for the standard “Aprepitant Regimen” versus netupitant
`
`regimens. EX1003, 19:Table 6; EX1009, ¶24.) Nevertheless, Trento’515 reported
`
`that NK1 antagonists, specifically including netupitant, continued to be
`
`-3-
`
`

`

`
`
`“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.” EX1003, 3:60-4:9. Trento’515 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. EX1003, 4:55-5:40.
`
`Example 4 in Trento’515 discloses the results of 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 in subjects receiving a single oral dose of 300 mg
`
`or more. 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). EX1003, 17:4-
`
`28.
`
`-4-
`
`

`

`
`
`B. Challenged Claims
`Trento’515 has 23 claims; two (1, 11) are independent. Claim 11 relates to
`
`treating acute- or delayed-phase nausea and vomiting for 5 days with a single dose
`
`of netupitant. Claim 1 relates to treating acute- or delayed-phase nausea and
`
`vomiting for 5 days by administering day-one netupitant. EX1003, 22:2-19, 23:1-
`
`14.
`
`C. Prosecution History
`Trento’515 issued from application 15/003,327 (EX1007), filed 19 May
`
`2016, which claims priority to PCT/IB2010/0031066 and to provisionals
`
`61/382,7097 and 61/262,470.8 Its earliest possible effective filing date is
`
`18 November 2009; however, the earlier provisional never discloses co-
`
`administering dexamethasone, so claims encompassing dexamethasone are not
`
`entitled to priority before 14 September 2010.
`
`During examination, the examiner rejected claims over Reddy,9 which
`
`
`
`6 EX1055, filed 18 November 2010.
`7 EX1056, at 154-190, filed 14 September 2010.
`8 EX1057, at 192-219, filed 18 November 2009.
`9 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).
`
`-5-
`
`

`

`
`
`taught treating CINV by administering an 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 treating chemotherapy-induced nausea and
`
`vomiting (CINV) with an NK1 antagonist, a 5-HT3 antagonist, and dexamethasone,
`
`where the NK1 antagonist could be aprepitant or netupitant. The examiner also
`
`rejected the claims for double patenting over Helsinn’s 8,623,826 (EX1001) and
`
`9,186,357 (EX1002) patents.10 EX1007; EX1009, ¶¶36-37. The examiner found
`
`netupitant’s NK1-receptor occupancy in the striatum of at least 80% was an
`
`inherent property. EX1007, 150; EX1009, ¶38.
`
`In response, Helsinn amended its independent claims and argued “Reddy
`
`does not anticipate or render obvious independent claims 16 and 54 because Reddy
`
`does not teach or suggest the prevention of emesis during the acute phase by
`
`netupitant” because aprepitant allegedly had a lesser effect based on Table 6 of the
`
`applicant’s specification. EX1007, 196, 201-02. Helsinn also argued Reddy “does
`
`not describe or suggest the administration of a single dose of netupitant over a five-
`
`
`
`10 The objects of IPR2025-00945 and IPR2025-00946 and -00947, respectively.
`-6-
`
`

`

`
`
`day period” and asserted “[a] tremendous amount of work was required to discover
`
`[the] dosing limitations” of the claims. Id., 200-02. Helsinn then argued treating
`
`acute and delayed CINV with a single netupitant dose, especially its acute-phase
`
`effectiveness, were unexpected results. Id., 203; EX1009, ¶39. Helsinn did not
`
`contest the inherency of netupitant’s receptor occupancy; instead, Helsinn relied on
`
`this inherency to support its claim to an unexpected result. Id., 203; EX1009, ¶40.
`
`In a final Office action, the examiner maintained the rejection over Reddy.
`
`EX1007, 211-213. The examiner found (1) “[t]he familiarity of working with an
`
`NK-1 antagonist and its intended use make obvious the administration of
`
`netupitant, as claimed, based on the administration of other NK-1 antagonists, e.g.
`
`aprepitant” made it “obvious to administer netupitant on day one of five
`
`consecutive days;” (2) the specification’s Table 5 failed “to distinguish over
`
`aprepitant, especially since numbers were fairly similar;” (3) the “binding habit of
`
`netupitant is an inherent property of netupitant” and the other purported benefits
`
`were known in the art; and (4) Helsinn failed to establish unexpected results and
`
`that “administration of a single dose…may also be construed as an inherent
`
`property of netupitant especially since the prior art teaches administration to
`
`patients for treatment of chemotherapy-induced nausea and vomiting.” Id., 215-18;
`
`EX1009, ¶40. In response, Helsinn canceled claims and amended then-pending
`
`independent claims to require a single dose of netupitant. EX1007, 281-82. Helsinn
`
`-7-
`
`

`

`
`
`argued the single-dose requirement without further doses to treat delayed nausea
`
`distinguished over the prior art. Id., 286-87. Helsinn also continued to argue that
`
`“Netupitant’s efficacy during the acute phase is unexpected.” Id., 288-89. Helsinn
`
`did not contest the examiner’s finding that the claimed features of netupitant were
`
`inherent. EX1009, ¶41.
`
`Following the after-final rejection response, the examiner issued an advisory
`
`action, stating that the amendments would raise new issues and thus the
`
`amendments would not be entered. EX1007, 312. The applicant then filed a
`
`Request for Continued Examination and amended the independent claims to recite
`
`“no further netupitant or pharmaceutically acceptable salt thereof is administered
`
`during said five consecutive days, and said single dose of netupitant or
`
`pharmaceutically acceptable salt thereof if [sic] effective to treat said nausea and
`
`vomiting for said five consecutive days.” Id., 324, 326. The applicant also
`
`reiterated that its “position is that it is unexpected that a single dose of netupitant
`
`would be effective against nausea and vomiting during the acute and delayed
`
`phases of emesis.” Id., 328-29. Following after-final prosecution to enter
`
`amendments and terminal disclaimers, the examiner allowed the claims without
`
`further substantive examination. EX1009, ¶¶41-49.
`
`V. LEVEL OF ORDINARY SKILL
`A POSA would be skilled in one of “clinical medicine, medical oncology,
`
`-8-
`
`

`

`
`
`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’515 itself notes the high level of skill in the art. For example, “[t]he
`
`skilled artisan will be able to determine appropriate dosages[.]” EX1003, 8:17-19.
`
`Similarly, the art can determine the “suitable dosing regimen”. EX1003, 10:37-40.
`
`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
`Trento’515 provides definitions of claim terms. EX1003, 7:26-8:31.
`
`The phrase therapeutically effective amount11 means “an amount sufficient
`
`to elicit the desired biological response.” EX1003, 8:13-15.
`
`The word if in claims 1 and 11 appears from context to mean “is”. Ex parte
`
`Tanksley, 26 USPQ2d 1384, 1387 (BPAI 1991) (reaching merits where claim
`
`
`
`11 Bold-italicized text indicates added emphasis.
`-9-
`
`

`

`
`
`meaning was sufficiently clear to apply the prior art).
`
`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. EX1003,
`
`8:20-30 (“The minimum effective dose of dexamethasone, when used to treat
`
`CINV induced by [HEC], has been demonstrated to be 20 mg. administered orally
`
`or by injection on day one, and sixteen mg. administered orally or by injection on
`
`days two, three and four. * * * When used to treat CINV induced by [MEC], the
`
`minimum effective dose of dexamethasone is 20 mg. administered orally or by
`
`injection on day one, and zero mg. on days two, three and four.”); EX1009, ¶635.
`
`For claim element 1[b], the plain and ordinary meaning of “which” in the
`
`phrase beginning “which enters…” is that 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) (“A claim must be read in accordance with the precepts of English
`
`grammar.”); EX1009, ¶¶614-17 (explaining the 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 35 U.S.C. 102(b) prior art. No ground
`
`reference was applied in a rejection during examination.
`
`-10-
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`

`

`
`
`
`
`A. Herrstedt
`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
`
`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.
`
`-11-
`
`

`

`
`
`
`
`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
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`“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
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`by a selective neurokinin-1-receptor antagonist.” EX1014, 1:59-67; EX1009, ¶¶95-
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`96. Bös expressly identifies netupitant (“formula Ib”) as “characterized by valuable
`
`therapeutic properties as a highly selective antagonist of the Neurokinin 1”.
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`-12-
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`

`

`
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`EX1014, 14:32-38; EX1009, ¶¶97-98. Bös tested netupitant in model animals,
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`including a test of antiemetic effects in ferrets that showed pre-exposure netupitant
`
`administration “completely blocked the emesis induced by the emetogens.”
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`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
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`range of 10-1000 mg. EX1014, 42:5-11; EX1009, ¶¶100-01.
`
`C. 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
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`doses. Id. Hargreaves teaches a 75% or greater NK1-receptor occupancy was
`
`associated with therapeutic doses that blocked emesis. EX1012, 23; EX1009,
`
`¶¶116-17.
`
`D. 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
`
`0.25 mg palonosetron intravenously and dexamethasone on each of Days 1-4.
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`-13-
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`

`

`
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`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.
`
`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.,
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`122 F.4th 876, 886-87 (Fed. Cir. 2024).
`
`-14-
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`

`

`
`
`IX. GROUND 1: CLAIMS 11-17 AND 19-23 WERE OBVIOUS
`OVER HERRSTEDT, BÖS, AND HERRINGTON
`These claims were unpatentably obvious variants on a then-state-of-the-art
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`professional recommended 3-drug regimen with a newer NK1 antagonist
`
`(netupitant) substituted for an older NK1 antagonist (aprepitant), with routine
`
`choices about dosage form, amount, and timing. Herrstedt teaches methods of
`
`treating both nausea and vomiting for five consecutive days after chemotherapy.
`
`EX1010, 143, 146. Herrstedt teaches administering a day-one NK1 antagonist
`
`(aprepitant) in a therapeutically effective amount. Id., 146. Herrstedt describes that
`
`the above steps are effective to treat both nausea and vomiting during a 5-day
`
`period. Id., 146. EX1009, ¶¶504-06.
`
`Bös teaches its “Formula Ib” is an improved NK1 antagonist. EX1014,
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`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)”), 17:61-18:48 (“a potent and selective antagonist.”), 18:60-
`
`63 (“a competitive antagonist at human recombinant NK1 receptors”), 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. EX1009, ¶507 (comparing structures).
`
`Herrington teaches administering an NK1 antagonist (aprepitant) on day
`
`one—and only on day one—of a five-day treatment period was effective at
`-15-
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`

`

`
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`preventing nausea and vomiting from chemotherapy-induced emesis. EX1017,
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`Abstract; EX1009, ¶508.
`
`A. Claim 11 is an obvious modification of the prior art
`1. [preamble]: “A method of treating nausea and
`vomiting in response to an emesis-inducing event for a
`period of five consecutive days in a patient in need
`thereof, comprising”
`
`
`
`To the extent the preamble is limiting, Herrstedt teaches it. Herrstedt teaches
`
`methods for treating “[c]hemotherapy-induced nausea and vomiting” in a patient.
`
`EX1010, 143. Herrstedt explains chemotherapy is an e