`
`
`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 IPR2025-00946
`Patent US 9,186,357 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’357 Patent ............................................................................................ 3
`A.
`Specification .......................................................................................... 3
`B.
`Challenged Claims ................................................................................ 5
`C.
`Prosecution History ............................................................................... 5
`Level of Ordinary Skill .................................................................................... 7
`V.
`VI. Claim Construction .......................................................................................... 8
`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
`B.
`Hargreaves Links Receptor Occupancy to Effective Dose ................. 12
`C.
`D. Herrington Establishes Day-One Dosing ............................................ 13
`VIII. Legal Standards ............................................................................................. 13
`IX. Ground 1: Claims 2-4, 11-16, 40, 52-54 and 56-62 Were Obvious
`Over Herrstedt and Bös ................................................................................. 14
`A.
`Claim 2 ................................................................................................ 15
`B.
`Claim 3: “The method of claim 2, wherein the sub-
`therapeutic dose of dexamethasone comprises from about
`50 to 70% of a minimum effective dose when
`administered alone against CINV.” ..................................................... 22
`Claim 4 ................................................................................................ 23
`Claims 11-16: highly or moderately emetic
`chemotherapy ...................................................................................... 28
`Claims 40 and 52: “The method of claim [2/4], wherein
`said treatment of CINV is defined as no emetic episodes
`and no use of rescue medication following said
`
`C.
`D.
`
`E.
`
`-i-
`
`

`

`
`
`H.
`
`F.
`G.
`
`chemotherapy.” .................................................................................... 30
`Claims 53-54: ...................................................................................... 31
`Claims 56-57: “The method of claim 54, wherein said
`chemotherapy is [highly/moderately] emetogenic
`chemotherapy, said netupitant blood levels are effective
`to treat said CINV during the acute and delayed phases of
`said CINV, and said palonosetron blood levels are
`effective to treat said CINV during the acute phase of
`said CINV.” ......................................................................................... 34
`Claims 58-59: “The method of claim 54, wherein said
`chemotherapy is [highly/moderately] emetogenic
`chemotherapy, and said regimen is effective to prevent or
`reduce the severity of nausea during the acute and
`delayed phases.” .................................................................................. 36
`Claims 60-62: specific chemotherapies .............................................. 37
`I.
`X. Ground 2: Claim 41-42 Were Obvious Over Herrstedt, Bös and
`Herrington ...................................................................................................... 38
`XI. Ground 4: Claim 55 Was Obvious Over Herrstedt, Bös, and
`Hargreaves ..................................................................................................... 44
`XII. No Secondary Considerations ....................................................................... 48
`A. Aprepitant Shows Efficacy for Nausea ............................................... 48
`B. Misrepresentation of data during examination .................................... 53
`C.
`No Unexpected Synergy Between Netupitant and
`Palonosetron ........................................................................................ 57
`D. No Nexus Between Alleged Synergy and Claimed Effect ................. 58
`E.
`Single Dose of Netupitant Was Expected ........................................... 58
`F.
`Acute Phase Treatment with Netupitant Was Expected ..................... 59
`G.
`Characteristics of Netupitant Were Expected ..................................... 60
`XIII. Conclusion ..................................................................................................... 60
`XIV. Payment of Fees - §§42.15(a) and 42.103 ..................................................... 61
`XV. Mandatory Notices - §42.8 ............................................................................ 62
`A.
`Real Parties-In-Interest ........................................................................ 62
`-ii-
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`

`

`
`
`Related Matters .................................................................................... 62
`B.
`Lead and Back-up Counsel ................................................................. 62
`C.
`Service Information ............................................................................. 63
`D.
`XVI. Exhibit List - §42.63(e) ................................................................................. 64
`XVII. Certifications .................................................................................................. 72
`A.
`Rule 42.24(d) Certification ................................................................. 72
`B.
`Rule 42.6(e)(4) Certificate of Service ................................................. 72
`C.
`Declaration .......................................................................................... 72
`
`
`
`
`
`
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`-iii-
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`
`
`TABLE OF AUTHORITIES
`
`Cases
`
`Page
`
`Bristol-Myers Squibb v. Teva Pharms., 752 F.3d 967 (Fed. Cir. 2014) ..................48
`
`Cytiva Bioprocess v. JSR Corp., 122 F.4th 876 (Fed. Cir. 2024) ............................14
`
`Immunogen, Inc. v. Stewart, No. 23-1762 (Fed. Cir. 2025) ...................................... 8
`
`In re Baxter Travenol, 952 F.2d 388 (Fed. Cir. 1991) .............................................60
`
`In re Skoll, 523 F.2d 1392 (CCPA 1975) ................................................................48
`
`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
`
`
`
`
`
`-iv-
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`

`

`I.
`
`INTRODUCTION
`Petitioner Azurity Pharmaceuticals, Inc. (“Azurity”) requests inter partes
`
`review (“IPR”) to cancel claims 2-4, 11-16, 40-42, and 52-62 of U.S. Patent
`
`9,186,357 (“Trento’357”, EX1002), 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, the claims challenged here 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 2-4, 11-16, 40-42, and 52-62 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-
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`

`

`
`
`
`
`Ground Claims
`
`Obvious from the Combined Teachings of
`
`1
`
`2
`
`4
`
`2-4, 11-16, 40, 52-54
`
`Herrstedt2 (EX1010) & Bös3 (EX1014)
`
`& 56-62
`
`
`
`41-42
`
`55
`
`Herrstedt, Bös & Herrington4 (EX1016)
`
`Herrstedt, Bös & Hargreaves5 (EX1012)
`
`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 grounds 3 and 5-8 are omitted from this IPR. Exhibits, including a declaration
`
`
`
`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-
`
`

`

`
`
`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-
`
`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
`
`-3-
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`

`
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`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.”
`
`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
`
`-4-
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`

`

`
`
`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, above). EX1002, 16:37-
`
`60.
`
`B. Challenged Claims
`Trento’357 has 62 claims; three (1, 2, 4) are independent. This petition
`
`addresses claims 2 and 4 and their dependent claims (3, 11-16, 40-42, and 52-62).
`
`Claim 2 relates to treating CINV by administering netupitant and a subtherapeutic
`
`dose of dexamethasone. EX1002, claim 2. Claim 4 relates to treating CINV by
`
`administering palonosetron and netupitant. EX1002, claim 4.
`
`C. Prosecution History
`Trento’357 issued from application 14/069,927 (EX1006), filed 1 November
`
`2013, which claims priority to PCT/IB2010/003106,6 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-
`
`administration with dexamethasone, so claims encompassing co-administering
`
`dexamethasone are not entitled to priority before 14 September 2010.
`
`
`
`6 EX1055, filed 18 November 2010.
`7 EX1056, at 154-190, filed 14 September 2010.
`8 EX1057, at 192-219, filed 18 November 2009.
`-5-
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`
`
`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,9 which 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 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
`
`
`
`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).
`
`-6-
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`

`

`
`
`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
`
`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
`-7-
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`

`
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`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.
`
`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
`
`The phrase inducing in a subject blood levels of palonosetron and
`
`netupitant effective to treat said CINV10 means administering therapeutically-
`
`effective amounts that reach the target receptors in the central nervous system
`
`(CNS) via the circulatory system—as would be necessary for orally- or
`
`intravenously-administered drugs. Trento’357 defines a therapeutically effective
`
`amount to mean “an amount sufficient to elicit the desired biological response”
`
`(EX1002, 7:55-57) but it does not discuss “blood levels” or define what constitutes
`
`
`
`10 Bold-italicized text indicates added emphasis.
`-8-
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`

`
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`“blood levels…effective to treat” or otherwise establish that blood levels have any
`
`criticality beyond delivering therapeutically-effective amounts of the claimed
`
`antagonists to their respective CNS receptors. EX1009, ¶¶874-78. During
`
`prosecution of a related patent, the examiner reached the same unrebutted
`
`conclusion. EX1008, 120 (examiner treating claimed blood level as equivalent to
`
`“effective amounts of each component to prevent acute and delayed emesis in
`
`patients receiving highly emetogenic cancer chemotherapy”), 165-66; EX1009,
`
`¶¶875-77; cf. EX1006, 461 (arguing administration of prodrug form of netupitant
`
`corresponded with inducing blood levels).
`
`
`
`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. EX1002,
`
`7:62-8:4 (“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, ¶863.
`
`Correspondingly, sub-therapeutic dose of dexamethasone means less than these
`
`defined minimum amounts.
`
`-9-
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`

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`
`
`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
`
`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
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`-10-
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`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
`
`(CNS) disorders[.]” EX1014, 1:15-56. Specifically, “neurokinin-1 receptor
`
`antagonists are further useful for the treatment of motion sickness and for
`
`-11-
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`

`
`
`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. 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.
`
`-12-
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`

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`
`
`
`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.
`
`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,
`
`-13-
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`

`

`
`
`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 2-4, 11-16, 40, 52-54 AND 56-62 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
`
`5-HT3 antagonist and dexamethasone. Id., 146-47; 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)”). Bös evaluated formula Ib’s affinity for human NK1
`
`receptors and determined it is “a potent and selective antagonist.” Id., 17:61-18:48;
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`
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`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).
`
`
`
`Netupitant
`EX1011, Table 4.
`
`Formula Ib
`EX1014, 14:9-30.
`A. Claim 2
`1. [preamble]: “A method of treating chemotherapy induced
`nausea and vomiting (CINV) in a subject receiving
`chemotherapy 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
`
`-15-
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`

`

`
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`studies.”). EX1009, ¶¶857-58.
`
`2. “administering to a subject receiving chemotherapy a
`regimen of netupitant and a sub-therapeutic dose of
`dexamethasone.”
`Herrstedt teaches treating highly-emetogenic chemotherapy with a triple-
`
`
`
`drug combination administered to patients on day 1 including a 5-HT3 antagonist,
`
`an NK1 antagonist (aprepitant), and dexamethasone. EX1010, 146 (“Two of the
`
`HEC studies used an identical design…ondansetron [NK1 antagonist],
`
`dexamethasone and aprepitant day 1 followed by dexamethasone days 2-4 plus
`
`aprepitant days 2-3.”). Herrstedt describes patients benefiting from the triple-drug
`
`antiemetic combination (including NK1 antagonist) administered on day one. Id.
`
`(“a complete response of 72.7% in the aprepitant arm versus 52.3% in the control
`
`arm” and “complete response rates were 62.7% versus 43.3%” in another study);
`
`id. (“Again a statistical[] benefit favouring aprepitant was seen, resulting in a
`
`complete response in the aprepitant arm of 72.0% versus 60.6% in the control
`
`arm.”). Based on Herrstedt’s teachings, as POSAs had good reason to employ a
`
`therapeutically effective amount of an NK1 antagonist in combination with
`
`dexamethasone. EX1009, ¶¶¶859-60.
`
`
`
`Herrstedt uses aprepitant, not netupitant, but teaches aprepitant was merely
`
`“the first drug” in a class of selective NK1 antagonists. EX1010, Abstract. Bös
`
`discloses netupitant is a potent and selective NK1 antagonist that is useful for
`
`-16-
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`
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`treating emesis. EX1014, 14:31-38 (“valuable therapeutic properties as a highly
`
`selective antagonist of the Neurokinin 1”); 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.”), 4:15-24
`
`(“the most preferred indications … are those which include disorders of the central
`
`nervous system, for example indications for the treatment or prevention of …
`
`emesis by the administration of NK-1 receptor antagonists”), 39:42-48
`
`(“pharmacological activity of the compounds of this invention as NK-1 receptor
`
`antagonists” have activity “correlated with treatment of” CNS disorders), 9:22-29
`
`(“particularly useful for treating CNS disorders, such as … emesis.”), 19:10-30
`
`(netupitant effective for treating emesis); EX1009, ¶861.
`
`
`
`Bös teaches a therapeutically-effective amount of its NK1 antagonists
`
`(including netupitant) for a patient to be in the range of about 10 mg to 1000 mg.
`
`EX1014, 42:5-11 (“The effective amount for the dosage can vary within wide
`
`limits and will, of course, be fitted to the individual requirements in each particular
`
`case. In general, in the case of oral administration a daily dosage of about 10 to
`
`1000 mg per person of a compound of this invention should be appropriate,
`
`although the above upper limit can also be exceeded when necessary.”); EX1009,
`
`¶861.
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`
`
`Bös provides ample reason to replace Herrstedt’s NK1 antagonist aprepitant
`
`with a therapeutically-effective amount of Bös’ new and improved NK1 antagonist
`
`netupitant. Indeed, Herrstedt taught aprepitant was just the first species of this new
`
`class, while Bös suggests netupitant is an attractive oral replacement for aprepitant,
`
`particularly because its good CNS penetration described would allow netupitant to
`
`reach NK1 receptors in the CNS to treat emesis with a reasonable expectation of
`
`success. EX1009, ¶861; see also EX1012, 18 (explaining importance of entering
`
`the CNS for antagonism of Substance P receptors in the brain).
`
`
`
`Moreover, Bös taught netupitant works well when administered before
`
`emetogenic chemotherapy (e.g., cisplatin). EX1014, 19:10-30 (“Emesis was
`
`induced in ferrets by various emetogens (apomorphine, morphine, ipecauanha,
`
`cisplatin and CuSO4. Pretreatment of this compound [netupitant] (0.3 mg/kg, p.o.)
`
`2 hours before the emet[o]gen, completely blocked the emesis induced by all
`
`emetogens.”); EX1009, ¶¶861-62.
`
`
`
`Regarding claim 2’s requirement of a “sub-therapeutic dose of
`
`dexamethasone,” as noted above, Trento’357 defines the standard minimum
`
`effective dose of dexamethasone as 20 mg on day 1 and 16 mg (for HEC) or 0 mg
`
`(for MEC) on each of days 2-4. EX1002, 7:62-8:4; EX1009, ¶863; §VI above.
`
`Based on this definition, Herrstedt teaches administering a day-1 first dose of
`
`dexamethasone that is 50% to 70% of the minimum effective dose for CINV when
`
`-18-
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`administered alone, but effe