Treatment of chronic spontaneous urticaria by administering (r)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-1-YL]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3- YL)piperazin-1-YL]pent-2-enenitrile

Abstract

Methods for treating patients with chronic spontaneous urticaria (CSU) comprising administering at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl) pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof are disclosed.

Description

Attorney Docket No.01183-0291-00PCT-PRN TREATMENT OF CHRONIC SPONTANEOUS URTICARIA BY ADMINISTERING (R)-2-[3-[4-AMINO-3-(2-FLUORO-4-PHENOXY-PHENYL)PYRAZOLO[3,4- D]PYRIMIDIN-1-YL]PIPERIDINE-1-CARBONYL]-4-METHYL-4-[4-(OXETAN-3- YL)PIPERAZIN-1-YL]PENT-2-ENENITRILE

[0001] Disclosed herein are methods for treating chronic spontaneous urticaria. BTKinhibitors and pharmaceutical compositions comprising the same are also disclosed.

[0002] Chronic spontaneous urticaria (CSU), formerly known as chronic idiopathic urticaria(CIU) is a common condition characterized by the spontaneous appearance of pruritic hives and wheals with or without angioedema for more than 6 weeks without a clear inciting factor. CSU has a prevalence between 0.5% and 1% (Maurer et al.2011). It more commonly affects females than males, and the peak incidence occurs between 20 and 40 years of age. Patients with CSU experience substantial disease burden, including sleep impairment, body image issues, diminished physical and emotional well-being, and impaired performance at school and work (Can et al.2023; Kolkhir et al.2022). CSU can thus have significant detrimental impacts on quality of life, productivity, and psychological health (Maurer et al.2017).

[0003] Although the molecular mechanisms are still being elucidated, CSU is thought to bedriven by pathogenic activation of mast cells and basophils leading to local release of degranulation products. Of these degranulation products, histamine is felt to play a central role in CSU pathogenesis, driving the pruritus and local vascular permeability (leading to urticaria / angioedema) characteristic of this disease. Of note, emerging data suggest that mast cell and basophil activation in CSU is mediated by activation of the high-affinity IgE receptor, FcεRI, either from development of IgE to autoantigens such as thyroid peroxidase (autoimmune Type I phenotype) or development of activating IgG autoantibodies to IgE or FcεRI (autoimmune Type IIb phenotype) (Bracken et al.2019; Giménez-Arnau et al.2021; Kolkhir et al.2017). Current approved treatments for CSU are targeted against either mast cell degranulation products or the IgE receptor. H1-antihistamines (H1-AH) are first-line therapy in most practice settings. However, approximately 50% of patients fail to achieve symptomatic control with H1-AH at a standard dose. Second-line treatment includes escalation up to four-fold the standard dose of H1-AHs; however, the success rate for patients remains around 45-55%, and dose escalation may be associated with increased somnolence compared to standard dosing of H1-AHs (Armstrong et al.2023; Kaplan et al.2023; Kolkhir et al.2022; Xiao et al.2023). Omalizumab, an anti-IgE monoclonal antibody which reducesAttorney Docket No.01183-0291-00PCT-PRN both serum IgE and cell-surface FcεRI, has emerged as an effective treatment for CSU with inadequate response to H1-AH. However, it has been reported that nearly 50% of patients who receive omalizumab have an inadequate response to this therapy (Metz et al.2017). In particular, patients with Type IIb autoimmunity are less likely to respond to treatment with H1-AH or omalizumab (Marcelino et al.2021). As such, there is a need for additional treatments for CSU.

[0004] Emerging evidence suggests that Bruton’s tyrosine kinase (BTK), a non-receptor-tyrosine kinase and a member of the TEC family of kinases, plays a role in signal amplification after FcεRI cross-linking, leading to enhanced activation of mast cells and basophils. Consistent with this observation, BTK antagonists have demonstrated an inhibitory effect on basophil activation by allergens or anti-IgE antibodies. Given its importance in both the generation of antibodies and signaling through FcεRI, BTK has great potential as a target in CSU therapy, as evidenced by multiple clinical studies investigating the effect of BTK inhibitors on patients with CSU who are refractory to treatment with H1-AH, and are omalizumab-naïve.

[0005] Compound (I) is a BTK inhibitor of the following structure:, wherein *C is a stereochemical center. See PCT Publication No. WO 2014 / 039899, which is incorporated herein by reference, e.g., Example 31. (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, having the following structure:Attorney Docket No.01183-0291-00PCT-PRN, is also known as rilzabrutinib. This compound has been disclosed in several patent publications, such as, e.g., PCT Publication Nos. WO 2014 / 039899, WO 2015 / 127310, WO 2016 / 100914, WO 2016 / 105531, WO 2018 / 005849, and WO 2021 / 150723, the contents of each of which are incorporated by reference herein.

[0006] Rilzabrutinib is a novel, highly selective, and potent small molecule inhibitor of non-T cell white blood cell signaling via B-cell receptor, FcɣR, and / or Fc^R signaling of the BTK pathway. In the context of ITP, rilzabrutinib has the potential to (1) inhibit B cell activation and (2) interrupt antibody-coated cell phagocytosis by FCγR in the spleen and liver (Bradshaw et al.2021, Langrish et al.2021, Owens et al.2022).

[0007] Rilzabrutinib functions as a reversible covalent BTK inhibitor and is capable of bothnon-covalently and covalently binding to its target; in particular, its reversible cysteine binding enables high selectivity and precise BTK inhibition without a permanent modification of proteins and peptides (Langrish et al.2021, Owens et al.2022, Smith PF et al.2017). Taken together, these properties allow for enhanced selectivity and extended inhibition with low systemic exposure. In comparison to first and second generation BTKi, rilzabrutinib has shown minimal cross-reactivity with other molecules and is low risk for off- target effects (Smith PF et al.2017). Importantly, rilzabrutinib’s reversible binding minimizes the likelihood of permanently modified peptides (Serafimova IM 2012). In addition, rilzabrutinib shows improved kinase selectivity relative to the covalent BTK inhibitor ibrutinib. Preclinical studies in a broad kinase enzyme inhibition panel showed that 1 µM rilzabrutinib achieved >90% inhibition of just 6 of 251 kinases sharing a common cysteine in their active site. By contrast, 1 µM ibrutinib inhibited 21 kinases. Rilzabrutinib’s IC50 values were 1.3 nM for BTK, 0.8 nM for tyrosine protein kinase TEC, 1.0 nM for bone marrow tyrosine kinase on chromosome X (BMX), 1.2 nM for receptor-like kinase (RLK), 6.3 nM forAttorney Docket No.01183-0291-00PCT-PRN B cell lymphocyte kinase (BLK), and 11 nM for ERBB4. Further preclinical assays with rilzabrutinib showed that binding to BTK persisted while that for other TEC family members decayed rapidly over time.

[0008] Rilzabrutinib has shown encouraging results for the treatment of immune-mediateddiseases. In humans, rilzabrutinib is rapidly absorbed following oral administration, with a fast half-life (3-4 h) and variable pharmacokinetics (Smith PF et al., 2017).

[0009] In Phase 1 studies of rilzabrutinib with 114 healthy volunteers, target BTK occupancylevels were safely and consistently exceeded, suggesting rilzabrutinib may be highly effective in treating autoimmune diseases. Moreover, preclinical and clinical pharmacokinetic and pharmacodynamic data showed that treatment effects endured even after the compound was cleared from circulation, consistent with an extended target residence time (Hill R et al., 2015) and high target occupancy rate (> 90% within four hours and high sustained occupancy over 24 h) (Smith PF et al., 2015).

[0010] Rilzabrutinib has also demonstrated a favorable safety profile in clinical studies. In contrast with non-selective, irreversible BTK inhibitors, rilzabrutinib does not alter platelet aggregation in healthy volunteers or patients with ITP and thus does not lead to bleeding problems (Langrish et al.2021, von Hundelshausen and Seiss 2021). As an additional point of contrast with irreversible BTK inhibitors, rilzabrutinib treatment does not exert clinically relevant effects on cardiac repolarization (electrocardiogram parameters including corrected QT interval) in healthy volunteers (N=51), even when administered at supratherapeutic doses (Lipsky and Lamanna 2020). Indeed, the most commonly reported adverse events in healthy volunteers were gastrointestinal adverse events, including nausea / vomiting and diarrhea. No serious adverse events or deaths were reported, and no participants discontinued treatment due to an adverse event (Smith PF 2017). Moreover, based on preclinical reproductive toxicity studies, rilzabrutinib is not expected to harm fetal development or male fertility.

[0011] The efficacy of rilzabrutinib has been evaluated in both nonclinical and clinical studies. Rilzabrutinib demonstrated blockade of the rat Arthus reaction, full disease reversal of a rat collagen-induced arthritis model, and reduction in platelet loss in a mouse model of immune thrombocytopenia. The therapeutic effects of rilzabrutinib in pemphigus was studied in dogs with newly diagnosed, naturally occurring pemphigus foliaceus (PF). The drug safely controlled disease without the need for corticosteroid (CS) in 4 of 4 cases. The clinical efficacy of rilzabrutinib was further demonstrated in an open-label, Phase 1 / 2 study inAttorney Docket No.01183-0291-00PCT-PRN immune thrombocytopenic purpura (ITP). In this trial, 50% of participants achieved the primary response endpoint after treatment with rilzabrutinib for at least 12 weeks. Furthermore, there were no treatment-emergent serious adverse events (TESAEs) observed. Collectively, these and other studies have shown rilzabrutinib to be a safe and effective inhibitor of BTK.

[0012] There is preliminary evidence to support the role of BTK inhibition in patients with CSU, including in patients with CSU who are both refractory to treatment with H1-AH and are omalizumab-naïve (Maurer et al.2021; Metz et al.2020). Notably, results from studies on the BTK inhibitor fenebrutinib suggest a differential response based on basophil histamine release assay (BHRA) status, wherein BHRA-positive patients may be more sensitive to BTK inhibition, especially at lower doses, compared to BHRA-negative patients (Metz et al.2020). Separately, studies suggest that CSU patients who are BHRA-positive are more likely to have a poorer response to omalizumab compared to those who are BHRA-negative. As patients with prior omalizumab use, including omalizumab-incomplete responders may be enriched for BHRA-positive CSU patients, who are in turn more likely to have Type IIb autoimmunity and be less responsive to available treatments, they may be best poised to benefit from BTK inhibition. Patients with prior omalizumab use, including omalizumab-incomplete responders who are BHRA-negative may also stand to benefit from BTK inhibition, although this benefit may be seen at higher doses compared to BHRA-positive patients (Gericke et al.2016). Accordingly, a dose-ranging Phase 2 study was initiated to assess the efficacy and safety of rilzabrutinib in patients with moderate-to-severe CSU.

[0013] Accordingly, disclosed herein are methods of treating chronic spontaneous urticaria (CSU) in a human patient in need thereof, comprising administering to the human patient in need thereof a therapeutically effective amount of at least one compound chosen from (R)-2- [3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof.

[0014] Further disclosed herein are methods of treating chronic spontaneous urticaria (CSU) in a human patient in need thereof, comprising administering to the human patient a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3- (2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-Attorney Docket No.01183-0291-00PCT-PRN 4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment.

[0015] Further disclosed herein is a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2- enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for use in treating chronic spontaneous urticaria (CSU) in a human patient in need thereof.

[0016] Further disclosed herein is a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2- enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for use in the manufacture of a medicament for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof.

[0017] Further disclosed herein is the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2- enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof.

[0018] Further disclosed herein is the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2- enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof.

[0019] Further disclosed herein is a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2- enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for use in treating chronic spontaneous urticaria (CSU) in a human patient in need thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment.Attorney Docket No.01183-0291-00PCT-PRN

[0020] Further disclosed herein is a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2- enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for use in the manufacture of a medicament for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment.

[0021] Further disclosed herein is the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2- enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment.

[0022] Further disclosed herein is the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2- enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment. BRIEF DESCRIPTION OF DRAWINGS

[0023] Fig.1A shows the graphical study design.

[0024] Fig.1B shows patient disposition up to Week 12.

[0025] Fig.2 shows a waterfall plot of UAS7 at Week 12 by treatment group (omalizumab- naïve population). Circles and triangles indicate scores for individual patients at baseline and Week 12, respectively.

[0026] Fig.3 shows a waterfall plot of UAS7 at Week 12 by treatment group (patients with prior omalizumab use, including omalizumab-incomplete responders in ITT population). Circles and triangles indicate scores for individual patients at baseline and Week 12, respectively.Attorney Docket No.01183-0291-00PCT-PRN

[0027] Fig.4 shows the cumulative probability function of change from baseline in UAS7 at Week 12 (omalizumab-naïve population).

[0028] Fig.5 shows a plot of LS mean change from baseline in UAS7 over time up to Week 12 (ITT population).

[0029] Fig.6 shows a plot of LS mean change from baseline in UAS7 over time up to Week 12 (omalizumab-naïve population).

[0030] Fig.7 shows a plot of LS mean change from baseline in UAS7 over time up to Week 12 (omalizumab-naïve population with outlier removed from analysis).

[0031] Fig.8 shows a plot of mean change from baseline in UAS7 over time up to Week 12 (patients with prior omalizumab use, including omalizumab-incomplete responders in ITT population).

[0032] Fig.9 shows a plot of the proportion of participants with UAS7 <=6 over time up to Week 12 (ITT population).

[0033] Fig.10 shows a plot of the proportion of participants with UAS7 <=6 over time up to Week 12 (omalizumab-naïve population).

[0034] Fig.11 shows a plot of the proportion of participants with UAS7 =0 over time up to Week 12 (ITT population).

[0035] Fig.12 shows a plot of the proportion of participants with UAS7 =0 over time up to Week 12 (omalizumab-naïve population).

[0036] Fig.13 shows a plot of the proportion of participants with UAS7 reduction from baseline of 10 points or more over time up to Week 12 (ITT population).

[0037] Fig.14 shows a plot of the proportion of participants with UAS7 reduction from baseline of 10 points or more over time up to Week 12 (omalizumab-naïve population).

[0038] Fig.15 shows a cumulative probability function of change from baseline in ISS7 at Week 12 (omalizumab-naïve population).

[0039] Fig.16 shows a waterfall plot of ISS7 at Week 12 by treatment group (omalizumab- naïve population). Circles and triangles indicate scores for individual patients at baseline and Week 12, respectively.

[0040] Fig.17 shows a waterfall plot of ISS7 at Week 12 by treatment group (patients with prior omalizumab use, including omalizumab-incomplete responders in the ITT population). Circles and triangles indicate scores for individual patients at baseline and Week 12, respectively.Attorney Docket No.01183-0291-00PCT-PRN

[0041] Fig.18 shows a plot of LS mean change from baseline in ISS7 over time up to Week 12 (ITT population).

[0042] Fig.19 shows a plot of LS mean change from baseline in ISS7 over time up to Week 12 (omalizumab-naïve population).

[0043] Fig.20 shows a plot of LS mean change from baseline in ISS7 over time up to Week 12 (omalizumab-naïve population with outlier removed from analysis).

[0044] Fig.21 shows a plot of mean change from baseline in ISS7 over time up to Week 12 (patients with prior omalizumab use, including omalizumab-incomplete responders in the ITT population).

[0045] Fig.22 shows a cumulative probability function of change from baseline in HSS7 at Week 12 (omalizumab-naïve population).

[0046] Fig.23 shows a waterfall plot of HSS7 at Week 12 by treatment group (omalizumab- naïve population). Circles and triangles indicate scores for individual patients at baseline and Week 12, respectively.

[0047] Fig.24 shows a waterfall plot of HSS7 at Week 12 by treatment group (patients with prior omalizumab use, including omalizumab-incomplete responders in the ITT population). Circles and triangles indicate scores for individual patients at baseline and Week 12, respectively.

[0048] Fig.25 shows a plot of LS mean change from baseline in HSS7 over time up to Week 12 (ITT population).

[0049] Fig.26 shows a plot of LS mean change from baseline in HSS7 over time up to Week 12 (omalizumab-naïve population).

[0050] Fig.27 shows a plot of LS mean change from baseline in HSS7 over time up to Week 12 (omalizumab-naïve population with outlier removed from analysis).

[0051] Fig.28 shows a plot of mean change from baseline in HSS7 over time up to Week 12 (patients with prior omalizumab use, including omalizumab-incomplete responders in the ITT population).

[0052] Fig.29 shows a plot of LS mean change from baseline in AAS7 over time up to Week 12 in participants with angioedema at baseline (ITT population).

[0053] Fig.30 shows a plot of LS mean change from baseline in AAS7 over time up to Week 12 in participants with angioedema at baseline (omalizumab-naïve population).Attorney Docket No.01183-0291-00PCT-PRN

[0054] Fig.31 shows a cumulative probability function of change from baseline in AAS7 at Week 12 in participants with angioedema at baseline (omalizumab-naïve population).

[0055] Fig.32 shows a waterfall plot of AAS7 at Week 12 by treatment group in participants with angioedema at baseline (omalizumab-naïve population). Circles and triangles indicate scores for individual patients at baseline and Week 12, respectively.

[0056] Fig.33 shows a plot of the proportion of participants with AAS7 =0 over time up to Week 12 (participants with angioedema at baseline in the omalizumab-naïve population).

[0057] Fig.34 shows a plot of proportion of participants with AAS7 =0 over time up to Week 12 (omalizumab-naïve population with outlier removed from the analysis).

[0058] Fig.35 shows a plot of LS mean change from baseline in UCT over time up to Week 12 (ITT population).

[0059] Fig.36 shows a plot of LS mean change from baseline in UCT over time up to Week 12 (omalizumab-naïve population).

[0060] Fig.37 shows a plot of proportion of participants with UCT ≥12 over time up to Week 12 (omalizumab-naïve population).

[0061] Fig.38 shows a plot of LS mean change from baseline in PGIS over time up to Week 12 (omalizumab-naïve population).

[0062] Fig.39 shows a plot of LS mean change from baseline in PGIC over time up to Week 12 (omalizumab-naïve population).

[0063] Fig.40A-E shows a plot of the median percentage change from baseline (with interquartile range) for (A) sMRGPRX2, (B) IL-31, (C) IgG anti-TPO, (D) IgG anti-FcεRI, and (E) IgG anti-IgE.

[0064] Fig.41 shows a plot of the median percentage change from baseline (with interquartile range) for eosinophils. Definitions:

[0065] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meanings. All undefined technical and scientific terms used in this Application have the meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0066] As used herein, “a” or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound unless statedAttorney Docket No.01183-0291-00PCT-PRN otherwise. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.

[0067] As used herein, the term “about” is used herein to mean approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 5%. With regard to specific values, it should be understood that specific values described herein for subject populations (e.g., the subject of the described clinical trial) represent median, mean, or statistical numbers, unless otherwise provided. Accordingly, aspects of the present disclosure requiring a particular value in a subject are supported herein by population data in which the relevant value is assessed to be a meaningful delimitation on the subject population.

[0068] As used herein, the term “active pharmaceutical ingredient” or “therapeutic agent” (“API”) refers to a biologically active compound.

[0069] As used herein, the term “approved treatment” refers to a medication that has received regulatory authorization, in any country, for its intended use.

[0070] As used herein, the terms “administer,” “administering,” or “administration” herein refer to providing, giving, dosing, and / or prescribing by either a health practitioner or an authorized agent and / or putting into, taking, or consuming by the patient or person himself or herself. For example, “administration” of an API to a patient refers to any route (e.g., oral delivery) of introducing or delivering the API to the patient. Administration includes self- administration and administration by another.

[0071] As used herein, the term “baseline” refers to a measurement or an average of measurements taken on or before day 1 (D1) of initiating rilzabrutinib treatment. By way of non-limiting example, baseline can be determined for, e.g., UAS7, ISS7, UCT, and AAS7.

[0072] As used herein, “BID” and “bid” are used interchangeably to refer to twice a day.

[0073] As used herein, the term “in combination with,” when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to the patient prior to, concurrent with, or subsequent to each other during a treatment period. Unless specified otherwise, the two or more compounds, agents, or active pharmaceutical ingredients may be administered on different schedules during the treatment period, such as, e.g., with one orAttorney Docket No.01183-0291-00PCT-PRN more compounds, agents, or active pharmaceutical ingredients being administered once a day and one or more other compounds, agents, or active pharmaceutical ingredients being administered twice a day.

[0074] As used herein, an amount expressed in terms of “mg of [X]” refers to the total amount in milligrams of [X], i.e., the free base. In some embodiments, rilzabrutinib may be administered as a pharmaceutically acceptable salt of rilzabrutinib, in which case an amount expressed in terms of “mg of rilzabrutinib” refers to the total amount in milligrams of rilzabrutinib, i.e., the free base, plus the equivalent amount of one or more pharmaceutically acceptable salts of rilzabrutinib based on the weight of free base therein. For example, “400 mg of at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof” includes 400 mg of rilzabrutinib and a concentration of one or more pharmaceutically acceptable salts of rilzabrutinib equivalent to 400 mg of rilzabrutinib.

[0075] As used herein, “moderate-to-severe” CSU encompasses both patients with moderate CSU and patients with severe CSU.

[0076] As used herein, the terms “prior use of omalizumab” “omalizumab- incomplete responder,” “omalizumab-incomplete responder,” “incomplete responder,” and “incomplete responders” refer to participants who were previously treated with omalizumab and / or exhibited inadequate control of CSU symptoms despite treatment with omalizumab as prescribed.

[0077] As used herein, a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, and neither biologically nor otherwise undesirable, such as, e.g., a carrier or an excipient that is acceptable for mammalian pharmaceutical use.

[0078] As used herein, the term “pharmaceutically acceptable salt” refers to a salt form, e.g., an acid addition salt, of an active pharmaceutical agent that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the API of which the salt is made. Pharmaceutically acceptable salts are well known in the art and include those derived from suitable inorganic and organic acids. Such salts include, but are not limited to, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonicAttorney Docket No.01183-0291-00PCT-PRN acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, and the like. S. M. Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0079] As used herein, the terms “rilzabrutinib,” “(R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-1-yl]pent-2-enenitrile;” “the compound of Formula (I);” and “2-[(3R)-3-[4- amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]-pyrimidin-1-yl]piperidine-1-carbonyl]- 4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile” are used interchangeably to refer to a compound having the structure:which is also referred to as 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-1-yl]piperdine-1-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-1-yl]-(E and Z)- pent-2-enenitrile; (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2- enenitrile; 1-piperidinepropanenitrile, 3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl]-α-[2-methyl-2-[4-(3-oxetanyl)-1-piperazinyl]propylidene]-β- oxo-, (3R)-; (EZ)-2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4- d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-1-yl]pent-2- enenitrile; and also by the International Nonproprietary Names for Pharmaceutical Substances (INN) as published by the World Health Organization (https: / / cdn.who.int / media / docs / default-source / international-nonproprietary-names- (inn) / pl121.pdf?sfvrsn=69617906_15&download=true) having the following structure:Attorney Docket No.01183-0291-00PCT-PRN. The compound of Formula (I) includes E and Z isomers, as indicated by the wavy bond in the structure shown above. The compound of Formula (I) may be present as a salt form.

[0080] A dose of the (E) isomer of rilzabrutinib may contain the corresponding (Z) isomer as an impurity in less than about 1% by weight; a dose of the (Z) isomer of rilzabrutinib may contain the corresponding (E) isomer as an impurity in less than about 1% by weight. When rilzabrutinib is denoted as a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro- 4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, it means that the amount of (E) or (Z) isomer in the mixture is greater than about 1% by weight. In some embodiments, the molar ratio of (E) to (Z) isomer is 9:1. rilzabrutinib or a pharmaceutically acceptable salt thereof may also be referred to herein as a “drug,” “active agent,” “a therapeutically active agent,” or “API.”

[0081] As used herein, “QD” and “qd” are used interchangeably to refer to once a day.

[0082] As used herein, the terms “refractory” or “refractory to H1 antihistamines” encompasses patients diagnosed with CSU who continue to exhibit symptoms despite treatment with up to 4 times the recommended dose of H1-AH, for example 2 times the recommended dose, 2.5 times the recommended dose, 3 times the recommended dose, 3.5 times the recommended dose, or 4 times the recommended dose.

[0083] As used herein, the term “therapeutically effective amount” refers to that of a compound that produces the desired effect for which it is administered (e.g., improvement in CSU or a symptom of CSU, or lessening the severity of CSU or a symptom of CSU). The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0084] As used herein, “TID” and “tid” are used interchangeably to refer to three times a day.

[0085] As used herein, the term “treat,” “treating,” or “treatment,” when used in connection with a disorder or condition, includes any effect, e.g., lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the disorder or condition.Attorney Docket No.01183-0291-00PCT-PRN Improvements in or lessening the severity of any symptom of the disorder or condition can be readily assessed according to standard methods and techniques known in the art.

[0086] The present disclosure provides methods of treating chronic spontaneous urticaria (CSU) in a human patient in need thereof. In some embodiments, the methods comprise administering to the human patient in need thereof a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof. In some embodiments, the methods comprise administering to the human patient a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3- (2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl- 4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment. In at least one embodiment, rilzabrutinib is administered to the human patient.

[0087] In some embodiments, the human patient has moderate-to-severe CSU. In some embodiments, the human patient has moderate CSU. In some embodiments, the human patient has severe CSU. In some embodiments, the human patient has CSU refractory to H1 antihistamine (H1-AH) treatment.

[0088] In some embodiments, the human patient has Type I autoimmune CSU. In some embodiments, the human patient has Type IIb autoimmune CSU.

[0089] In some embodiments, the human patient has angioedema. In some embodiments, the human patient does not have angioedema.

[0090] In some embodiments, the human patient achieves a Urticaria Activity Score (UAS7) that is lower than baseline UAS7. In some embodiments, the human patient achieves a UAS7 that is lower than baseline UAS7 within 52 weeks of initiating rilzabrutinib. In some embodiments, the human patient achieves a UAS7 that is lower than baseline UAS7 within 24 weeks of initiating rilzabrutinib. In some embodiments, the human patient achieves a UAS7 that is lower than baseline UAS7 within 12 weeks of initiating rilzabrutinib. In some embodiments, the human patient achieves a UAS7 that is lower than baseline UAS7 within 4 weeks of initiating rilzabrutinib. In some embodiments, the human patient achieves a UAS7Attorney Docket No.01183-0291-00PCT-PRN that is lower than baseline UAS7 within 3 weeks of initiating rilzabrutinib. In some embodiments, the human patient achieves a UAS7 that is lower than baseline UAS7 within 2 weeks of initiating rilzabrutinib. In some embodiments, the human patient achieves a UAS7 that is lower than baseline UAS7 within 1 week of initiating rilzabrutinib.

[0091] In some embodiments, the human patient achieves a UAS7 ≤6. In some embodiments, the human patient achieves a UAS7 ≤6 within 12 weeks of initiating rilzabrutinib treatment.

[0092] In some embodiments, the human patient achieves a UAS7 of 0. In some embodiments, the human patient achieves a UAS7 of 0 within 12 weeks of initiating rilzabrutinib treatment.

[0093] In some embodiments, the human patient achieves a UAS7 that is at least 10 points lower than baseline UAS7. In some embodiments, the human patient achieves a UAS7 that is at least 12 points lower than baseline UAS7.

[0094] In some embodiments, the human patient achieves an Itch Severity Score (ISS7) that is lower than baseline ISS7. In some embodiments, the human patient achieves an ISS7 that is lower than baseline ISS7 within 52 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves an ISS7 that is lower than baseline ISS7 within 24 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves an ISS7 that is lower than baseline ISS7 within 12 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves an ISS7 that is lower than baseline ISS7 within 4 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves an ISS7 that is lower than baseline ISS7 within 3 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves an ISS7 that is lower than baseline ISS7 within 2 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves an ISS7 that is lower than baseline ISS7 within 1 week of initiating rilzabrutinib treatment.

[0095] In some embodiments, the human patient achieves an ISS7 that is at least 5 points lower than a baseline ISS7. In some embodiments, the human patient achieves an ISS7 that is at least 6 points lower than a baseline ISS7.

[0096] In some embodiments, the human patient achieves a Hives Severity Score (HSS7) that is lower than baseline HSS7. In some embodiments, the human patient achieves a HSS7 that is lower than baseline HSS7 within 52 weeks of initiating rilzabrutinib treatment.Attorney Docket No.01183-0291-00PCT-PRN In some embodiments, the human patient achieves a HSS7 that is lower than baseline HSS7 within 24 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a HSS7 that is lower than baseline HSS7 within 12 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a HSS7 that is lower than baseline HSS7 within 4 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a HSS7 that is lower than baseline HSS7 within 3 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a HSS7 that is lower than baseline HSS7 within 2 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a HSS7 that is lower than baseline HSS7 within 1 week of initiating rilzabrutinib treatment.

[0097] In some embodiments, the human patient achieves an Angioedema Activity Score (AAS7) that is lower than baseline AAS7. In some embodiments, the human patient achieves an AAS7 that is lower than baseline AAS7 within 52 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves an AAS7 that is lower than baseline AAS7 within 24 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves an AAS7 that is lower than baseline AAS7 within 12 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves an AAS7 that is lower than baseline AAS7 within 4 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves an AAS7 that is lower than baseline AAS7 within 3 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves an AAS7 that is lower than baseline AAS7 within 2 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves an AAS7 that is lower than baseline AAS7 within 1 week of initiating rilzabrutinib treatment.

[0098] In some embodiments, the human patient achieves a Urticaria Control Test (UCT) score that is higher than baseline UCT score. In some embodiments, the human patient achieves a UCT score that is higher than baseline UCT score within 52 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a UCT score that is higher than baseline UCT score within 24 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a UCT score that is higher than baseline UCT score within 12 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a UCT score that is higher than baseline UCT score within 8 weeks of initiating rilzabrutinib treatment.Attorney Docket No.01183-0291-00PCT-PRN In some embodiments, the human patient achieves a UCT score that is higher than baseline UCT score within 4 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a UCT score that is higher than baseline UCT score within 3 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a UCT score that is higher than baseline UCT score within 2 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a UCT score that is higher than baseline UCT score within 1 week of initiating rilzabrutinib treatment.

[0099] In some embodiments, the human patient achieves a UCT score ≥12. In some embodiments, the human patient achieves a UCT score ≥12 within 12 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a UCT score ≥12 within 8 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a UCT score ≥12 within 4 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a UCT score ≥12 within 3 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a UCT score ≥12 within 2 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a UCT score ≥12 within 1 week of initiating rilzabrutinib treatment.

[0100] In some embodiments, the human patient achieves a change from baseline in health-related quality-of-life (HRQoL). In some embodiments, the human patient achieves a change from baseline in HRQoL as measured by the Patient Global Impression of Severity (PGIS). In some embodiments, the human patient achieves a change from baseline in HRQoL as measured by the PGIS within 12 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a change from baseline in HRQoL as measured by the PGIS within 8 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a change from baseline in HRQoL as measured by the PGIS within 4 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a change from baseline in HRQoL as measured by the PGIS within 3 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a change from baseline in HRQoL as measured by the PGIS within 2 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a change from baseline in HRQoL as measured by the PGIS within 1 week of initiating rilzabrutinib treatment.

[0101] In some embodiments, the human patient achieves a change from baseline in HRQoL as measured by the PGIC. In some embodiments, the human patient achieves aAttorney Docket No.01183-0291-00PCT-PRN change from baseline in HRQoL as measured by the PGIC within 12 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a change from baseline in HRQoL as measured by the PGIC within 8 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a change from baseline in HRQoL as measured by the PGIC within 4 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a change from baseline in HRQoL as measured by the PGIC within 3 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a change from baseline in HRQoL as measured by the PGIC within 2 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a change from baseline in HRQoL as measured by the PGIC within 1 week of initiating rilzabrutinib treatment.

[0102] In some embodiments, the human patient requires rescue therapy. In some embodiments, when the human patient requires rescue therapy, the total number of days for which the human patient requires rescue therapy is lower than the total number of days for which the human patient required rescue therapy during a baseline time period of the same length. In some embodiments, when the human patient requires rescue therapy, the human patient receives rescue therapy with an H1-AH.

[0103] In some embodiments, the human patient has a history of taking one or more anti-IgE therapy prior to the start of the treatment period, optionally wherein the one or more anti-IgE therapy is omalizumab. In some embodiments, the human patient has a history of taking omalizumab prior to the start of the treatment period.

[0104] In some embodiments, the human patient has had an incomplete response to omalizumab. In some embodiments, the human patient is omalizumab naïve.

[0105] In some embodiments, the human patient has a positive basophil histamine release assay (BHRA) status. In some embodiments, the human patient has a negative BHRA status.

[0106] In some embodiments, the human patient receives concomitant treatment with an H1-AH.

[0107] In some embodiments, the human patient has previously been identified as having increased sMRGPRX2 serum levels. In some embodiments, the human patient has previously been identified as having increased mast cell MRGPRX2 expression. In some embodiments, the human patient achieves a reduction from baseline in sMRGPRX2 serumAttorney Docket No.01183-0291-00PCT-PRN levels. In some embodiments, the human patient achieves a reduction from baseline in sMRGPRX2 serum levels within 12 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in sMRGPRX2 serum levels within 10 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in sMRGPRX2 serum levels within 8 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in sMRGPRX2 serum levels within 6 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in sMRGPRX2 serum levels within 4 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in sMRGPRX2 serum levels within 2 weeks of initiating rilzabrutinib treatment.

[0108] In some embodiments, the human patient has previously been identified as having increased IL-31 serum levels. In some embodiments, the human patient has previously been identified as having increased IL-31 serum levels as a result of increased mast cell or basophil activation. In some embodiments, the human patient achieves a reduction from baseline in IL-31 serum levels. In some embodiments, the human patient achieves a reduction from baseline in IL-31 serum levels within 12 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IL-31 serum levels within 10 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IL-31 serum levels within 8 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IL-31 serum levels within 6 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IL-31 serum levels within 4 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IL-31 serum levels within 2 weeks of initiating rilzabrutinib treatment.

[0109] In some embodiments, the human patient has previously been identified as having increased IgG anti-TPO serum levels. In some embodiments, the human patient achieves a reduction from baseline in IgG anti-TPO serum levels. In some embodiments, the human patient achieves a reduction from baseline in IgG anti-TPO serum levels within 12 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IgG anti-TPO serum levels within 10 weeks of initiatingAttorney Docket No.01183-0291-00PCT-PRN rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IgG anti-TPO serum levels within 8 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IgG anti-TPO serum levels within 6 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IgG anti-TPO serum levels within 4 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IgG anti-TPO serum levels within 2 weeks of initiating rilzabrutinib treatment.

[0110] In some embodiments, the human patient has previously been identified as having increased IgG anti-FCεRI serum levels. In some embodiments, the human patient has previously been identified as having increased mast cell or basophil activation as a result of increased IgG anti-FCεRI levels serum levels. In some embodiments, the human patient achieves a reduction from baseline in IgG anti-FCεRI serum levels. In some embodiments, the human patient achieves a reduction from baseline in IgG anti-FCεRI serum levels within 12 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IgG anti-FCεRI serum levels within 10 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IgG anti-FCεRI serum levels within 8 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IgG anti-FCεRI serum levels within 6 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IgG anti-FCεRI serum levels within 4 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in IgG anti-FCεRI serum levels within 2 weeks of initiating rilzabrutinib treatment.

[0111] In some embodiments, the human patient has previously been identified as having increased eosinophil levels. In some embodiments, the human patient has previously been identified as having increased mast cell activation as a result of increased eosinophil levels. In some embodiments, the human patient achieves a reduction from baseline in eosinophil levels. In some embodiments, the human patient achieves a reduction from baseline in eosinophil levels within 12 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in eosinophil levels within 10 weeks of initiating rilzabrutinib treatment. In some embodiments, the humanAttorney Docket No.01183-0291-00PCT-PRN patient achieves a reduction from baseline in eosinophil levels within 8 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in eosinophil levels within 6 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in eosinophil levels within 4 weeks of initiating rilzabrutinib treatment. In some embodiments, the human patient achieves a reduction from baseline in eosinophil levels within 2 weeks of initiating rilzabrutinib treatment.

[0112] In some embodiments, the human patient does not achieve a reduction in total serum IgG or IgE levels.

[0113] In some embodiments, the treatment period is at least 12 weeks. In some embodiments, the treatment period is at least 52 weeks.

[0114] In some embodiments, the at least one compound consists of at least one compound chosen from the (E) isomer of rilzabrutinib and pharmaceutically acceptable salts thereof. In some embodiments, the at least one compound consists of at least one compound chosen from the (Z) isomer of rilzabrutinib and pharmaceutically acceptable salts thereof. In some embodiments, the at least one compound consists of a mixture of (E) and (Z) isomers of rilzabrutinib or a pharmaceutically acceptable salt of the foregoing.

[0115] In some embodiments, the method comprises administering to the human patient about 400 mg of at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof once, twice, or thrice a day. In some embodiments, the method comprises administering to the human patient about 400 mg of at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof once a day. In some embodiments, the method comprises administering to the human patient about 400 mg of at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof twice a day. In some embodiments, the method comprises administering to the human patient about 400 mg of at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof thrice a day.

[0116] In some embodiments, the method comprises administering to the human patient rilzabrutinib once, twice, or thrice a day. In some embodiments, the method comprises administering to the human patient rilzabrutinib once a day. In some embodiments, the method comprises administering to the human patient rilzabrutinib twice a day. In someAttorney Docket No.01183-0291-00PCT-PRN embodiments, the method comprises administering to the human patient rilzabrutinib thrice a day.

[0117] In some embodiments, the method comprises administering to the human patient 400 mg of rilzabrutinib once, twice, or thrice a day. In some embodiments, the method comprises administering to the human patient 400 mg of rilzabrutinib once a day. In some embodiments, the method comprises administering to the human patient 400 mg of rilzabrutinib twice a day. In some embodiments, the method comprises administering to the human patient 400 mg of rilzabrutinib thrice a day.

[0118] In some embodiments, the at least one compound is the (E) isomer of rilzabrutinib. In some embodiments, the at least one compound is the (Z) isomer of rilzabrutinib. In some embodiments, the at least one compound consists of a mixture of (E) and (Z) isomers of rilzabrutinib.

[0119] In some embodiments, the at least one compound is orally administered to the human patient. In some embodiments, the at least one compound is administered to the human patient in the form of at least one tablet. In some embodiments, the at least one compound is administered with water.

[0120] In some embodiments, the at least one compound is rilzabrutinib.

[0121] In some embodiments, the present disclosure provides a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4- phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for use in treating chronic spontaneous urticaria (CSU) in a human patient in need thereof.

[0122] In some embodiments, the present disclosure provides a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4- phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for use in the manufacture of a medicament for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof.

[0123] In some embodiments, the present disclosure provides for the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3- (2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-Attorney Docket No.01183-0291-00PCT-PRN 4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof.

[0124] In some embodiments, the present disclosure provides for the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3- (2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl- 4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof.

[0125] In some embodiments, the present disclosure provides for a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4- phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for use in treating chronic spontaneous urticaria (CSU) in a human patient in need thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment.

[0126] In some embodiments, the present disclosure provides for a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4- phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for use in the manufacture of a medicament for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment.

[0127] In some embodiments, the present disclosure provides for the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3- (2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl- 4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment.

[0128] In some embodiments, the present disclosure provides for the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-Attorney Docket No.01183-0291-00PCT-PRN (2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl- 4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment. Pharmaceutical Compositions:

[0129] In some embodiments of the present disclosure, rilzabrutinib is administered as part of a pharmaceutical composition comprising: at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is in the form of at least one tablet.

[0130] In some embodiments, rilzabrutinib is administered in the form of a film- coated tablet.

[0131] In some embodiments of the present disclosure, rilzabrutinib is administered in the form of at least one tablet comprising: at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, rilzabrutinib is administered in the form of at least one tablet comprising: at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof; at least one filler; at least one disintegrant; at least one lubricant; and at least one film coating.

[0132] In some embodiments, rilzabrutinib is administered with a glass of water.

[0133] The proportion and nature of any pharmaceutically acceptable excipient may be determined by the chosen route of administration and standard pharmaceutical practice. Except insofar as any conventional pharmaceutically acceptable excipient is incompatible with rilzabrutinib, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically composition, its use is contemplated to be within the scope of this disclosure.

[0134] Some non-limiting examples of materials which may serve as pharmaceutically acceptable excipients include: (1) sugars, such as, e.g., lactose, glucose, and sucrose; (2) starches, such as, e.g., corn starch and potato starch; (3) cellulose and its derivatives, such as, e.g., sodium carboxymethyl cellulose, ethyl cellulose, and celluloseAttorney Docket No.01183-0291-00PCT-PRN acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as, e.g., cocoa butter and suppository waxes; (9) oils, such as, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as, e.g., propylene glycol; (11) polyols, such as, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as, e.g., ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as, e.g., magnesium hydroxide and aluminum hydroxide; (15) alginic acid;(16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol;(20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed inpharmaceutical formulations.

[0135] Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York also discloses additional non-limiting examples of pharmaceutically acceptable excipients, as well as known techniques for preparing and using the same.

[0136] One skilled in the art can readily select the proper form and route of administration depending upon the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. EXAMPLES

[0137] The following example is intended to be illustrative and is not meant in any way to limit the scope of the disclosure. Abbreviations: AAS7 Angioedema activity score over 7 days AE Adverse event AESI Adverse event of special interest API Active pharmaceutical ingredient ALP Alkaline phosphatase ALT Alanine aminotransferase aPTT Activated partial thromboplastin time AST Aspartate aminotransferaseAttorney Docket No.01183-0291-00PCT-PRN BHRA Basophil histamine release assay bid / BID Twice daily (morning and evening) BM Biomarker BMI Body mass index BTK Bruton’s Tyrosine Kinase CD Cluster of differentiation CIU Chronic idiopathic urticaria CMH Cochran-Mantel Haenzel test CPK Creatine phosphokinase D Day DB Double-blind DLQI Dermatology Life Quality Index ECG Electrocardiograme-diary Electronic diaryED Early discontinuation EOT End of treatment EOS End of study FU Follow-up HbA1c Glycated hemoglobin H1-AH H1 antihistamine HIV Human immunodeficiency virus HRQoL Health-related quality of life HSS Hives severity score IgE Immunoglobulin E IgG Immunoglobulin G IgM Immunoglobulin M IL Interleukin IMP Investigational medicinal product INR International normalized ratioAttorney Docket No.01183-0291-00PCT-PRN ISS Itch severity score ITP Immune thrombocytopenia LDH Lactate dehydrogenase LS Least squares MCID Minimal clinically important difference MI Multiple imputation Mas-related G-protein coupled receptor MRGPRX2 member X2 N Number OCS Oral corticosteroids OLE Open-label extension phase OR Odds ratio PBMC Peripheral blood mononuclear cells PGIC Patient global impression of change PGIS Patient global impression of severity PK Pharmacokinetic PRO Patient-reported outcome qd / QD Once a day QOL Quality of Life QPM Once each evening R Randomization RRD Response rate difference SAE Serious adverse event TEAE Treatment-emergent adverse event TB Tuberculosis TID Three times daily / thrice daily TPO Thyroperoxidase UAS7 Urticaria activity score over 7 days UCT Urticaria control testAttorney Docket No.01183-0291-00PCT-PRN ULN Upper limit of normal V Visit W Week WOCBP Woman of childbearing potential WOCF Worst observation carried forwardAttorney Docket No.01183-0291-00PCT-PRN Example 1: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Dose- Ranging Phase 2 Study of Rilzabrutinib Followed by an Open-Label Extension Phase in Patients with Moderate-to-Severe Chronic Spontaneous Urticaria (CSU) Who Remain Symptomatic Despite the Use of H1 Antihistamine Treatments Study Design

[0138] This study is a 52-week sequential Phase 2 study on the effects of rilzabrutinib in adult participants with moderate-to-severe CSU who remain symptomatic despite the use of H1 antihistamine (H1-AH) treatment. The study comprises a 12 week, randomized, double-blind, placebo-controlled, multi-center, dose-ranging efficacy and safety phase, followed by a 40 week open label extension (OLE) phase (see Figure 1).

[0139] Patients exhibited at least moderate disease activity (see inclusion criteria) despite the use of H1-AH. It was expected that ~40% of patients would have concomitant angioedema. Participants were to be randomized 1:1:1:1 to one of three doses of rilzabrutinib or placebo. The randomization was to be stratified by region and prior use of omalizumab.

[0140] The study is to evaluate the effect of rilzabrutinib on itch and hives, scored individually or as a composite score; on angioedema activity; on participant-reported urticaria control; and on HRQoL.

[0141] The study consists of three phases and an optional OLE phase. The phases are as follows: •Screening period (up to 4 weeks)• Double-blind IMP treatment period (12 weeks): participants were randomized1:1:1:1 to one of the following treatments: rilzabrutinib 400 mg TID; rilzabrutinib 400 mg BID with matched placebo; rilzabrutinib 400 mg QPM with matched placebo; or matched placebo •Optional OLE phase (40 weeks): for participants who completed the 12-weekdouble-blind phase, eligible participants were given the option to continue to an OLE phase of the study. Participants in the OLE will be given rilzabrutinib 400 mg TID (the dose may be modified based on the 12-week safety and efficacy data) (all non- Germany countries). In Germany, participants in the OLE will be administered rilzabrutinib 400 mg BID. •Follow-up period (4 weeks)Attorney Docket No.01183-0291-00PCT-PRN

[0142] During the double-blind IMP treatment phase of this study, participants were to continue their established standard of care background therapy with an approved long- acting H1-AH, at up to 4-fold the recommended dose. If a participant was on an H1-AH dose higher than 4-fold the recommended dose at the screening visit, the Investigator may have adjusted the participant’s dose to within the stipulated dose range at the screening visit. For participants on stable doses of nonstudy-approved H1-AH, Investigators may have switched participants to an equivalent dose of a study-approved H1-AH maintenance medication at the screening visit. Participants should have continued their screening dose of H1-AH throughout the double-blind phase of the study, unless they experienced a disease flare. Participants should also continue their baseline dose of H1-AH for the first 12 weeks of the OLE phase of the study. After 12 weeks in the OLE phase, Investigators may, at their discretion, reduce participants’ H1-AH dose, but the antihistamine daily dose still may not exceed 4-fold the recommended dose (all non-Japan countries) or 2-fold the recommended dose (Japan only).

[0143] In the case that participants are considered for rescue therapy, participants on 1-, 2- or 3-fold the recommended H1-AH may receive additional doses of their study- approved H1-AH as rescue medication, as long as their daily dose does not exceed 4-fold the recommended daily dose of the H1-AH (all non-Japan countries) or 2-fold the recommended daily dose of the H1-AH (Japan only). At the investigator’s discretion, participants may be prescribed a short course of oral corticosteroids (OCS) as rescue therapy during the treatment, OLE and follow up periods. Rescue therapy should start with an increase in H1-AH whenever possible, followed by a short course of OCS if needed. For analysis of urticaria activity (including itch and hives individually), angioedema activity, participant-reported urticaria control and HRQoL, data collected after OCS use will be set to missing and the worse post-baseline values before OCS therapy will be used.

[0144] The end of the study in the 12 week double-blind phase of the study is defined as the date of the last follow-up visit of the last participant in the double-blind phase of study. Participants were considered to have completed the 12 week double-blind phase of the study if they had completed the 12 week phase of the study, including the last follow-up visit.

[0145] The end of the study in the 40 week open-label phase of the study is defined as the date of the last follow-up visit of the last participant in the open-label phase of the study. Participants will be considered to have completed the 40 week open-label phase of theAttorney Docket No.01183-0291-00PCT-PRN study once they have completed the 40-week phase of the study including the last follow-up visit.

[0146] The assessments used in this study are standard endpoints in evaluation of disease activity and response to therapy in CSU. Clinically, CSU is characterized by the spontaneous and recurrent appearance of pruritic hives. The proposed primary endpoints were the UAS7 at Week 12 in EU and EU reference countries and the ISS7 in the US. Regardless of where a participant was from, all assessments were the same. The UAS7 score is a composite score containing both the HSS7 and the ISS7. This allowed a global assessment of the two key components of urticaria: hives and itch. The UAS7 score has been well- established as a prospective measure of CSU activity and has been used in a number of clinical studies as a primary outcome measure (Agache et al.2021; Hawro et al.2018; Maurer et al.2019). As an independent score, ISS7 has also been well established and widely accepted as a primary outcome measure for CSU activity (Maurer et al.2013).

[0147] Angioedema is present in up to 40.3% of patients with CSU and can have a significant negative impact on quality of life (Sussman et al.2018). This study aimed to assess the effect of rilzabrutinib on angioedema activity. The weekly angioedema activity score (AAS7) was proposed as a tertiary endpoint. The AAS7 score is a validated tool determine angioedema activity and has previously been used in CSU clinical studies (Maurer et al.2019; Weller et al.2013).

[0148] This study also aimed to assess disease control from the perspective of participants. To this end, the UCT was proposed as a tertiary endpoint in this study. The UCT is a validated tool which has become the standard Patient-Reported Outcome (PRO) tool to determine disease control in CSU and other forms of chronic urticaria (Weller et al.2014; Zuberbier et al.2018). In addition to disease activity scores, this study aimed to assess the impact of rilzabrutinib on HRQoL in CSU. The dermatology life quality index (DLQI) was proposed as a tertiary endpoint in this study. The DLQI is a standard well-studied HRQoL score which has been validated for use in chronic urticaria (Lennox et al.2004).

[0149] Blood samples were also collected through Week 12 to evaluate the change in baseline in various biomarkers, including sMRGPRX2, IgG anti-TPO, IgG anti-FCεRI, IgG anti-IgE, and IL-31.

[0150] In sum, the proposed primary, secondary and tertiary endpoints were intended to allow a determination of the efficacy of rilzabrutinib on disease activity, diseaseAttorney Docket No.01183-0291-00PCT-PRN symptoms, and HRQoL in participants with CSU.

[0151] Table 1. Objectives and Endpoints.Attorney Docket No.01183-0291-00PCT-PRNAttorney Docket No.01183-0291-00PCT-PRN Study Population

[0152] Inclusion criteria are summarized in Table 2. Participants were eligible to be included in the study only if they met all of the inclusion criteria.

[0153] Table 2. Inclusion Criteria.Attorney Docket No.01183-0291-00PCT-PRN

[0154] Exclusion criteria are summarized in Table 3. Participants were excluded from the study if any of the criteria applied.

[0155] Table 3. Exclusion Criteria.Attorney Docket No.01183-0291-00PCT-PRNScreen Failures

[0156] Screen failures are defined as participants who consent to participate in the clinical study but are not subsequently randomized. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, and any SAE.

[0157] If a participant failed to complete 2 or fewer days of their UAS7 evaluation at screening, or if their e-diary device failed, that participant may have been rescreened once.Attorney Docket No.01183-0291-00PCT-PRN However, if a participant did not meet the minimum UAS7 or ISS7 score in screening, that participant was not eligible for rescreening.

[0158] In cases where original screen failure was due to reasons expected to change at re-screening and based upon the Investigator’s clinical judgment, the participant may have been rescreened one time for this study after notification of the Sponsor. Rescreened participants were to be assigned a new participant number for the re-screening event. There was no requirement for a waiting period between the screen-failure and the re-screening. A new consent form must have been signed and Visit 1 procedures must have been repeated for re-screened participants. Study Intervention(s) Administered

[0159] Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol. Tables 4 and 5 provide an overview of interventions administered in the present study.

[0160] Consecutive doses were to be administered approximately 6 hours apart (and not less than 4 hours apart).Attorney Docket No.01183-0291-00PCT-PRN

[0161] Table 4. Overview of Study Interventions Administered Intervention label Rilzabrutinib Placebo Intervention name Rilzabrutinib Placebo ib

[0162] Table 5. Arms and Associated Interventions Arm name Placebo 400 mg QPM 400 mg BID 400 mg TID A i t d Ril b ti ib Ril b ti ib Ril b ti ib Ril b ti ib rNoninvestigational Medicinal Products

[0163] Participants were to continue their established standard of care background therapy with a long-acting, non-sedating H1-AH during the study. For participants on stable doses of non-study-approved H1-AH, investigators may have switched participants to an equivalent dose of a study-approved H1-AH maintenance medication. Only up to 4-fold (all non- Japan countries) or 2-fold (Japan only) the recommended dose was allowed. If participants wereAttorney Docket No.01183-0291-00PCT-PRN on dose higher than 4-fold the recommended dose at screening, the Investigator could have adjusted the participant dose to the stipulated range at the screening visit (Visit 1). Participants must have remained on this dose of antihistamine for at least 3 consecutive days before screening assessment of UAS7 and ISS7 is initiated. Participants were to continue to take the same daily dose throughout the study unless they experience a flare for which rescue therapy may have been initiated. During the OLE phase, participants are to also continue their baseline dose of H1-AH for the first 12 weeks of the OLE phase. After 12 weeks in the OLE phase, Investigators may, at their discretion, decide to reduce or discontinue participants’ maintenance antihistamines dose, but the antihistamine daily dose still may not exceed 4-fold the recommended dose; the dose of rilzabrutinib will remain the same.

[0164] Because rilzabrutinib is a mild inhibitor of CYP3A, only the following study- approved antihistamines and recommended were allowed as background therapy to minimize the possibility of rilzabrutinib altering their pharmacokinetics: cetirizine (10 mg QD); levocetirizine dihydrochloride (5 mg QD); fexofenadine (60 mg BID or 180 mg QD); desloratadine (5 mg QD); and bilastine (20 mg QD). Dose Modification

[0165] Rilzabrutinib dose modification was not allowed during the double-blind phase. For the OLE phase, the dose may be modified based on the 12 week safety and efficacy data. Concomitant Therapy

[0166] Any medication or vaccine (including over-the-counter or prescription medicines, recreational drugs, vitamins, and / or herbal supplements) that the participant was receiving at the time of enrollment or received during the study must have been recorded along with the reason for use, the dates of administration (including the start and end dates), and dosage information (including dose and frequency). The sponsor should have been contacted if there were any questions regarding concomitant or prior therapy.

[0167] Participants were to abstain from taking nonprescription drugs (including vitamins and dietary or herbal supplements) within 2 weeks or 5 half-lives (whichever was longer) before the start of study intervention until completion of the follow-up visit, unless, inAttorney Docket No.01183-0291-00PCT-PRN the opinion of the Investigator, the medication would not interfere with the study. New or chronic prescription medications could have been used if needed at the discretion of the Investigator. The Medical Monitor was to be contacted if there were any questions regarding new or chronic medications.

[0168] Clinically relevant drugs that are substrates of CYP3A, including those considered to be sensitive CYP3A substrates were permitted. Appropriate caution was to be used when co-administering sensitive CYP3A substrates with rilzabrutinib and a benefit-risk assessment was to be conducted for each medication. Consideration was also to have been given to avoidance of high doses, dose reduction, or replacement of sensitive and narrow therapeutic index CYP3A substrate drug. Systemic strong and moderate inhibitors (including foods such as grapefruit juice) and inducers of CYP3A were to be avoided.

[0169] Medications that have not been listed as exclusion criteria were permitted for use during the trial. These include the following: •Oral corticosteroid rinses (mouth washes) are allowed.• H2 antihistamine (H2-AH) receptor blocking drugs were permitted provided they weretaken once daily only and were taken 2-3 hours after administration of the evening rilzabrutinib or placebo dose. •Antacids were permitted provided they were given 2 hours or more apart fromrilzabrutinib or placebo dose. •COVID-19 vaccines

[0170] Participants were to continue their established standard of care background therapy with a long acting, non-sedating H1-AH (defined as noninvestigational medicinal product (NIMP)). During the OLE phase, participants should also continue their baseline dose of H1-AH for the first 12 weeks of the OLE phase. After 12 weeks in the OLE phase, Investigators may, at their discretion, decide to reduce or discontinue participants’ maintenance antihistamines dose; the dose of rilzabrutinib will remain the same. In addition, participants should continue to take only allowed concomitant therapy, as defined for the first phase of the study (i.e., 12-week double-blind period).

[0171] A list of prohibited concomitant therapies is provided in Table 6.Attorney Docket No.01183-0291-00PCT-PRN

[0172] Table 6. Prohibited Concomitant Therapy Drug Category Drug Name Immunosuppressants Mycophenolate mofetilAttorney Docket No.01183-0291-00PCT-PRN Esomeprazole Lansoprazole. Rescue Medicine

[0173] As rescue medication, up to 4-fold of the approved dose of the participants usual H1-AH could have been given on days where pruritus and wheal development were severe. The total daily H1-AH dose was not to exceed 4-fold the recommended dose during the screening, treatment and follow-up period.

[0174] The initial maintenance antihistamine dose should have remained stable throughout the 12-week double-blind phase and the first 12 weeks of the OLE phase, and participants were to continue their maintenance dose once rescue treatment is no longer required. After 12 weeks in the OLE phase, Investigators may, at their discretion, decide to reduce or discontinue participants’ maintenance antihistamines dose, but the antihistamine daily dose still may not exceed 4-fold the recommended dose.Attorney Docket No.01183-0291-00PCT-PRN

[0175] If needed, or if unable to increase H1-AH as an initial step for rescue therapy, participants may have been prescribed a short course of OCS. After any use of OCS, participants would have needed to seek immediate medical attention to ensure that the initial reaction had been successfully controlled and / or to evaluate for additional therapeutic steps. In order to ensure consistency, when possible, it was recommended to use OCS for 5 to 7 days with a starting dose of oral prednisone 40 mg (or clinically comparable OCS) followed by taper per the Investigator’s judgment. The use of OCS was to be delayed, if possible, for at least 8 weeks following the initiation of the investigational treatment. The date and time of OCS administration as well as the name and dosage regimen of the OCS was to be recorded.

[0176] Unless permanently discontinued from the study, all participants were to complete the scheduled study visits and assessments whether or not they completed study treatment and whether or not they received rescue treatment for CSU. Investigators were to make every attempt to conduct efficacy and safety assessments immediately before administering any rescue treatment. An unscheduled visit may have been used for this purpose, if necessary. Participants who received rescue therapy with OCS during the study treatment were considered “treatment failures” for the analysis of all efficacy endpoints. Efficacy Assessments

[0177] Efficacy data was to be collected via electronic devices. The e-diary was to be used for daily recording of PRO such as the UAS7 and AAS7 questionnaires, and use of H1-AH medication. This device was to be dispensed at Screening (Visit 1), including instructions for use. Additionally, participants were to be instructed on the use of the device.

[0178] Participants were to fill in UCT, DLQI, PGIC, and PGIS questionnaires during their site visit. Urticaria Activity Score

[0179] The UAS is a validated PRO measure. The daily UAS is the sum of the daily Hive Severity Score (HSS, ranging from 0 = None to 3 = more than 50 hives) and the daily Itch Severity Score (ISS, ranging from 0 = None to 3 = intense), the 2 key urticaria signs and symptoms which are wheals and itch. The daily UAS scores range from 0 to 6 point / day. DailyAttorney Docket No.01183-0291-00PCT-PRN UAS scores are summed over 7-day period to create the UAS7, ranging from 0 to 42, and are composed of the HSS7 and ISS7 components. The UAS7 is an established and widely accepted PRO tool to prospectively measure CSU activity (Młynek et al.2008). It has been used in most clinical trials in CSU in recent years as a main outcome parameter and medical practice (Maurer et al.2013; Metz et al.2020). A minimal important difference (MID) value ranging from 9.5 to 10.5 has been defined to help interpretation of the change in score in CSU participants (Hawro et al.2018; Hollis et al.2018; Mathias et al.2012). Patients were to complete the UAS using the e- diary. The e-diary was to be used once daily on the same time of each day recording of participant’s answers to the urticaria activity score over 7 days (UAS7) questionnaire. For participants who entered the OLE phase, their answers to the UAS7 questionnaire were also to be collected from Week 20 to Week24 and from Week 48 to Week 52. Angioedema Activity Score

[0180] The AAS is a validated PRO measure that assesses angioedema activity (Weller et al.2013). The AAS is a diary in which participants document on a daily basis the presence or absence of angioedema during the past 24 hours. If angioedema is present, participants answer 5 additional questions about the time of the day the swelling episode occurred, and the severity and impact on daily functioning and appearance this swelling episode has had. Each AAS item is scored between 0 and 3 points, that is, the minimum and maximum daily AASs are 0 and 15 points. The daily AASs are summed up to 7-day scores (AAS7), with 7-day scores ranging from 0 to 105 (Weller et al.2013). A MID of the AAS7 of around 8 points has been established (Weller et al.2013). Patients were to complete the AAS using the e-diary. The e-diary was to be used once daily on the same time of each day recording of participant’s answers to the angioedema activity score over 7 days (AAS7) questionnaire. For participants who entered the OLE phase, their answers to the AAS7 questionnaire were also to be collected from Week 20 to Week24 and from Week 48 to Week 52. Urticaria Control Test

[0181] The UCT is a validated PRO measure for assessing urticaria control (Weller et al.2014) based on 4 items (severity of pruritus and wheals urticaria symptoms; frequency ofAttorney Docket No.01183-0291-00PCT-PRN treatment being not sufficient; QoL impairment; overall urticarial control). Each item is rated on a 5-point Likert-type scale (scored with 0 to 4 points). Low scores indicate high disease activity and low disease control. The UCT total score is calculated by adding all 4 individual item scores. Accordingly, the minimum and maximum UCT scores are 0 and 16, with a score of 16 points indicating complete disease control (Weller et al.2014). The recall period is the previous 4 weeks. Patients were to complete the UCT questionnaire during their site visit. Dermatology Life Quality Index

[0182] The DLQI is a PRO developed to measure dermatology-specific HRQoL in adult participants (Finlay and Khan 1994). The instrument comprises 10 items assessing the impact of skin disease on participants’ HRQoL over the previous week with an average completion time of 126 seconds (Loo et al.2003). The items cover symptoms, leisure activities, work / school or holiday time, personal relationships including intimate, the side effects of treatment, and emotional reactions to having a skin disease. It is a validated questionnaire used in clinical practice and clinical trials (Chernyshov 2019). Response scale is a 4-point Likert scale (0 = “not at all” and 3 = “very much”) for 9 items. The remaining 1 item about work / studying asks whether work / study has been prevented and then (if “No”) to what degree the skin condition has been a problem at work / study; the item is rated on a 3-point Likert scale (“Not at all” to “A lot”). Overall scoring ranges from 0 to 30, with a high score indicative of a poor HRQoL. Using an integrated analysis of distribution and anchor-based approaches using the change in DLQI total score and participant-assessed itch severity scores, the MID for the DLQI in participants with CIU was reported to be in the range of 2.24 to 3.10 points (Shikiar et al.2005). The recall period is the previous week. Patients were to complete the DLQI questionnaire during their site visit. Patient Global Impression of Change of CSU Disease and Patient Global Impression of Severity of CSU Disease

[0183] The PGIS is a 1-item measure that asks participants to provide a self-assessment of their overall CSU severity for the past week on a 4 point scale. Response choices are: “None”, “Mild”, “Moderate” and “Severe”. The PGIC is a 1-item measure that asks the participant to provide a self-assessment of overall change in their CSU since the participant started taking theAttorney Docket No.01183-0291-00PCT-PRN study medication on a 7-point scale. The response options range from “Very Much Better” to “Very Much Worse.” Patients were to complete questionnaires for the 2 items during their site visit. Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reporting

[0184] An AE is defined as any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention1.

[0185] Events meeting the AE definition include any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen from baseline, considered clinically significant in the medical and scientific judgment of the Investigator (i.e., not related to progression of underlying disease), e.g., events that are symptomatic; events that require either corrective treatment or consultation; events that lead to IMP discontinuation or modification of dosing; events that fulfill a seriousness criterion; and / or events defined as an AESI. Events meeting the AE definition further include the exacerbation of a chronic or intermittent pre-existing condition, including either an increase in frequency and / or intensity of the condition; a new condition detected or diagnosed after study intervention administration even though it may have been present before the start of the study; signs, symptoms, or clinical sequelae of a suspected drug-drug interaction; and / or signs, symptoms, or clinical sequelae of a suspected overdose of either study intervention or a concomitant medication.

[0186] An SAE is defined as any AE that, at any dose, results in death, is life- threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, or is a congenital anomaly / birth defect.

[0187] The term “life-threatening” in the definition of “serious” refers to an event in which the participant was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death if it were more severe.1An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention.Attorney Docket No.01183-0291-00PCT-PRN

[0188] In general, hospitalization signifies that the participant has been admitted (usually involving at least an overnight stay) at the hospital or emergency ward for observation and / or treatment that would not have been appropriate in the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

[0189] The term “disability” means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not constitute a substantial disruption.

[0190] Other situations may also have been considered SAEs. Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that did not result in hospitalization, or development of drug dependency or drug abuse.

[0191] The Investigator was to make an assessment of intensity for each AE and SAE reported during the study and assign it to one of the following categories: •Mild: an event that was easily tolerated by the participant, causing minimaldiscomfort and not interfering with everyday activities. •Moderate: an event that caused sufficient discomfort to interfere with normaleveryday activities. •Severe: an event that prevented normal everyday activities. An AE that was assessedas severe should not have been confused with an SAE. “Severe” is a category used for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. An event is defined as “serious” when it meets at least one of the predefined outcomes as described in the definition of an SAE, and not when it is rated as severe.Attorney Docket No.01183-0291-00PCT-PRN Adverse Events of Special Interest

[0192] An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor is required. Such events may have required further investigation in order to characterize and understand them. AESIs may have been added, modified, or removed during a study by protocol amendment. Exemplary AESIs are listed below. •Pregnancy of a female participant entered in the study, or pregnancy occurring in afemale partner of a male participant entered in the clinical trial. Such a pregnancy was to be qualified as an SAE only if it fulfilled one of the seriousness criteria. In the event of pregnancy in a female participant, the IMP was to be discontinued. Follow- up of the pregnancy in a female participant or in a female partner of a male participant was mandatory until the outcome had been determined. •Symptomatic overdose (serious or nonserious) with an IMP or NIMP. An overdose(accidental or intentional) with the IMP was an event suspected by the Investigator or spontaneously notified by the participant (not based on systematic pills count) and defined as a single ingestion of a dose equal to or greater than 1,200 mg (≥3 times the indicated single dose of 400 mg), provided that it had been taken at once or over 2- hour period. An overdose (accidental or intentional) with the NIMP was an event suspected by the Investigator or spontaneously notified by the participant (not based on systematic pills count) and defined as at least twice the maximum allowed daily dose, within the intended therapeutic interval. For H1-AH only, an overdose is defined as any dose that exceeds the maximum allowed daily dose in this protocol. •Increase in ALT. For participants with an increase in ALT >3 x ULN, report the ALT>3 x ULN together with total bilirubin value including normal ranges and confirm the elevation within 72 hours. •Other project specific AESIs. This may have included severe infections, includingopportunistic infections; tuberculosis or initiation of medications for suspected tuberculosis; diagnosed and biologically proven SARS-CoV-2 infection; major hemorrhagic events, including symptomatic bleeding in a critical area or organ such as the central nervous system (CNS), or intraocular bleeding, resulting in an SAE;Attorney Docket No.01183-0291-00PCT-PRN severe or serious AEs (or non-serious AEs with a severity level consistent with Grade 3 Common Terminology Criteria for AE (CTCAE) of cytopenia v 5.0; and atrial fibrillation. Pharmacokinetics

[0193] Plasma samples were to be obtained for PK characterization of rilzabrutinib. Selected residual plasma samples may have been utilized to assess PK of relevant metabolites of rilzabrutinib. Concentrations at each time point were to be reported. Biomarkers

[0194] Collection of biological samples for other biomarker research was also part of this study. The following samples for biomarker research were required and were to be collected from all participants in this study: •Serum and plasma samples for soluble biomarkers and cellular tests. Analytesincluded IgG anti-IgE, IgG anti-FcεRI, IgG anti-TPO, IgE anti-TPO, IL-31, and sMRGPRX2. •Blood samples for immune cell phenotyping, including measurement of eosinophillevels •Blood samples for BTK occupancy in peripheral blood mononuclear cells (PBMCs)at selected sites

[0195] For each patient, serum samples were to be collected on each of four visits (Visits 2, 4, 6, and end of study / follow up).

[0196] Serum analyte testing was to be performed using the antibodies and antigens listed below: •hIgG anti-FcεRI (Cat. No. #130-122-308; Miltenyi)• hIgG anti-IgE-biotin (Cat. No. #130-117-938; Miltenyi)• Anti-IgE-HRP (Cat. No. #5220-0329; SeraCare)• Anti-hIgG HRP (Cat. No. #109-035-008; Jackson IR)• Purified TPO (Cat. No. #043 / 20; In.vent Diagnostica)Attorney Docket No.01183-0291-00PCT-PRN •Recombinant human FcεRIα (HIS-tag) (Cat. No. #FCA-H5228; AcroBiosystems)• Human IgE (myeloma) (Cat. No. #401152; Merck Millipore)• IvIg (Kiovig) (Cat. No. #LE-07-43020; Baxter AG / Shire)• IgE anti-TPO (SP1.4-IgE anti-TPO purified from hybridoma supernatants) (Guo et al.1996)

[0197] Serum analyte testing was to be performed using the following commercial assays: •sMRGPRX2 ELISA (Cat. No. #MBS933336; MyBioSource)• IL-31 HTRF assay (Cat. No. #62HIL31PEG; Cisbio / PerkinElmer)• IgG anti-TPO ELISA (Cat. No. #ORG503; Orgentec Diagnostica GmbH)

[0198] All chemical and biological reagents used for serum analyte testing were of analytical grade and were used without further purification. Any water used for dilution, e.g., for the washing buffer, was to be deionized and obtained directly from the facilities installation.

[0199] The following commercial reagents and consumables were to be used: •ECL prime (Cat. No. #10308449; Cytiva / FisherScientific)• Streptavidin HRP (Cat. No. #DY998; R&D Systems)• PBS (Cat. No. #14190094; Gibco)• Protein-free blocking buffer (Cat. No. #927-90001; LI-COR)• TritonX-100 (Cat. No. #T8532; SigmaAldrich)• Tween-20 (Cat. No. #M147; VWR LifeSciences)• NaCl• MaxiSorp 384 well plates (Cat. No. #P6491; Nunc / SigmaAldrich)

[0200] Assay buffer was to be prepared using PBS, Tween-20, TritonX-100, and NaCl. TBS was to comprise 10 mM Tris, 150 mM Nacl, pH 7.4. TBST was to comprise TBS and Tween-20.Attorney Docket No.01183-0291-00PCT-PRN

[0201] Laboratory equipment was to include a Multimode Plate Reader (VICTOR5; Perkin Elmer).

[0202] If dilutions were to be prepared, the same dilutions were to be prepared twice from each sample. These were to be measured on different plates. Each plate was to include a standard curve. Samples were to be measured twice for all biomarkers except for sMRGPRX2. Mean measurement values were to be calculated, and the concentration of the biomarker was to be calculated using GraphPad Prism 9 software (4-PL model).

[0203] Biomarker assays were performed as described below.

[0204] For the IgG anti-IgE ELISA, MaxiSorp plates were coated overnight with 1 μg / mL human IgE antigen and blocked with 10% protein-free blocking buffer diluted in assay buffer. Following the addition of serum samples (1:100 dilution in assay buffer) or the hIgG anti- IgE standard (1:2 serial dilution in assay buffer), the plates were incubated at room temperature. Next, the anti-IgG-HRP detection antibody was added to all samples. Development was performed using ECL-prime solution, and chemiluminescent signal intensity was measured on the Victor5 multimode plate reader.

[0205] For the IgG anti-FcεRI ELISA, MaxiSorp plates were coated overnight with 1 μg / mL recombinant human FcεRIα and blocked with 10% protein-free blocking buffer diluted in assay buffer. Following the addition of serum samples (1:100 in assay buffer) or the hIgG anti- FcεRI standard (1:2 serial dilution in assay buffer), the plates were incubated at room temperature. Next, the anti-IgG-HRP detection antibody was added to all samples. Development was performed using ECL-prime solution and chemiluminescent signal intensity was measured on the Victor5 multimode plate reader.

[0206] The IgG anti-TPO ELISA was performed according to the manufacturer’s instructions.

[0207] For the IgE anti-TPO ELISA, plates were coated with purified human TPO and blocked with 1% fetal bovine serum (FBS) diluted in TBST. Serum samples (1:5 in TBS) or the SP1.4-IgE anti-TPO standard (1:2 serial dilution in assay buffer) were incubated at room temperature. Next, the anti-IgE-HRP antibody was added to all samples. Development wasAttorney Docket No.01183-0291-00PCT-PRN performed using ECL-prime solution and chemiluminescent signal intensity was measured on the Victor5 multimode plate reader.

[0208] The IL-31 HTRF assay was performed according to the manufacturer’s instructions.

[0209] For the sMRGPRX2 ELISA, measurements were performed according to the manufacturer's instructions. Single measurements were obtained for all samples.

[0210] Assay data ranges are described below. •sMRGPRX2: 0.1 ng / mL-10 ng / mL• IgG anti-FCεRI: 0-10000 arbitrary units (AU)• IgG anti-TPO: 0-3000 international units (IU)• IgE anti-TPO: 0-500 AU• IgG anti-IgE: 0-100000 AU• IL-31: 0.1 ng / mL-20 ng / mLStatistical Considerations

[0211] In this study, the statistical hypotheses for comparing each of rilzabrutinib groups against placebo on the primary endpoint of change from baseline in ISS7 at Week 12 (for US and US reference countries), and the primary endpoint of change from baseline in UAS7 at Week 12 (for countries except US and US reference countries) were as follows: •Null hypothesis H0: there is no treatment difference between rilzabrutinib andplacebo. •Alternative hypothesis H1: there is a treatment difference between rilzabrutinib andplacebo.

[0212] The statistical hypotheses to be tested on secondary efficacy endpoints could be specified similarly as those on the primary endpoint.

[0213] Participants were randomized to the intervention group in a ratio of 1:1:1:1.

[0214] An absolute change of 5 in ISS7 score is considered the minimal clinically important difference (MCID) and an absolute change of 10 in UAS7 score is considered the MCID. Based upon an SD of 7, a change of 5 in the ISS7 would correspond to an effect size ofAttorney Docket No.01183-0291-00PCT-PRN approximately 0.71. Based upon a SD of 14, a change of 10 in the UAS7 would correspond to an effect size of approximately 0.71. Based on this assumption, plus the assumption of a 15% dropout rate before Week 12, it was estimated that 38 patients per group would provide approximate 80% power to detect an effect size of 0.71 or higher between the rilzabrutinib arm and placebo using a 2-sided t-test with alpha = 0.05. This sample size estimate applies to both ISS7 (primary endpoint for US and US reference countries) and UAS7 (primary endpoint for all countries except US and US reference countries).

[0215] The sample size calculations were performed using EAST 6.5.

[0216] The randomization was to be stratified by region and prior use of omalizumab (yes or no). Note: prior use of omalizumab = yes represents patients with prior omalizumab use, including omalizumab-incomplete responders, and prior use of omalizumab = no represents omalizumab-naïve patients. Patients with prior omalizumab use, including omalizumab- incomplete responders were only to be randomized to the 400 mg BID, 400 mg TID and placebo arms, and they were to be capped at up to 15% of the patients in that arm. Populations for Analyses

[0217] The populations for analyses are defined in Table 7. Table 7. Populations for Analyses Population Description S d All ti i t h i d th ICF e re tAttorney Docket No.01183-0291-00PCT-PRN were to be analyzed according to the intervention they actually received g[ ] e e cacy en po n s ana yses were o e pr mar y ase on e oma zumab- naïve population. The ITT population was to be used as the supplementary analysis for selected efficacy endpoints. Primary Endpoints

[0219] The primary endpoint was change from baseline in UAS7 at Week 12 (except US and US reference countries). For US and US reference countries, the primary endpoint was change from baseline in ISS7 at Week 12.

[0220] The summary of primary estimand for the primary endpoint is provided in Table 8. Table 8. Primary Estimand for the Primary Endpoint Treatment Rilzabrutinib 400 mg QPM, 400 mg BID, 400 mg TID, and S 2 lAttorney Docket No.01183-0291-00PCT-PRN the study intervention due to lack of efficacy prior to Week 12, WOCF approach was to be used to impute missing data if f nt .Supplementary Analysis

[0221] The primary endpoint was also to be analyzed on ITT population. In addition, descriptive statistics for patients with prior omalizumab use, including omalizumab-incomplete responders, were to be provided.

[0222] As-observed analysis (including all data after taking the prohibited and / or rescue medications) and other supplementary analyses were to be performed to provide additional insights into the understanding of the treatment effect.

[0223] In addition to the comparison between each dose level of rilzabrutinib and placebo in a pairwise manner, a pooled analysis of the BID and TID doses may have been performed as appropriate.Attorney Docket No.01183-0291-00PCT-PRN Secondary Endpoint(s)

[0224] The following secondary endpoints were to be analyzed using the same approach as for the primary endpoint: •Change from baseline in UAS7 at Week 4• Change from baseline in UAS7 at Week 12 (for US and US reference countries)• Change from baseline in ISS7 at Week 12 (except US and US reference countries)• Change from baseline in HSS7 at Week 12

[0225] The following responder secondary endpoints were to be analyzed using the Cochran-Mantel-Haenszel test adjusted by region: •Proportion of participants with UAS7 ≤6 at Week 12• Proportion of participants with UAS7 = 0 at Week 12

[0226] Participants who received selected prohibited medications and / or rescue medications were to be considered as non-responders for time points after the medication usage. For other participants, all available data including those collected during the off-treatment period were to be used to determine the responder / non-responder status. Missing data were to be considered as non-responders.

[0227] No multiplicity adjustment for the secondary efficacy endpoints was to be made. A pooled analysis of the BID and TID doses may have been performed as appropriate. Safety Analysis

[0228] All safety analysis was to be based on the safety population according to the intervention group to which the participants are exposed. The safety analysis was to be conducted separately for double-blind period and open-label period.Attorney Docket No.01183-0291-00PCT-PRN Example 2: Double-Blind Treatment Phase Results

[0229] A study was initiated to evaluate the effect of rilzabrutinib treatment in patients with moderate-to-severe chronic spontaneous urticaria (CSU) whose disease was not controlled with H1-antihistamines (H1-AH) alone. Over the course of this 12-week, double-blind, placebo- controlled study, N=160 patients were administered one of three doses of rilzabrutinib (400 mg QD, 400 mg BID, or 400 mg TID) or a placebo.

[0230] Patients exhibited significant improvement across all disease components, including urticaria activity, itch severity, and hives. These improvements, which were observed from Week 1, were sustained through Week 12. Moreover, improvements were observed in both the intent-to-treat (ITT) and omalizumab-naïve participant populations.

[0231] Primary endpoints for this study included the change from baseline in weekly urticaria activity score (UAS7) at Week 12 (all non-US countries) and the change from baseline in weekly itch severity score (ISS7) at Week 12 (US only). Secondary and tertiary endpoints are described in Table 1.

[0232] For patients receiving 400 mg TID rilzabrutinib, the study met the primary endpoints for both non-US countries and the US. Additionally, for patients receiving 400 mg TID rilzabrutinib, the study met several secondary endpoints, including the proportion of participants with well-controlled disease (UAS7 ≤6) at Week 12 and the percent change from baseline in weekly hives severity score (HSS7) at Week 12.

[0233] Evidence of a dose-response relationship was observed for patients treated with rilzabrutinib. While there was no difference between patients receiving 400 mg QPM rilzabrutinib and patients receiving the placebo, patients receiving 400 mg BID rilzabrutinib showed positive improvements across all endpoints when compared to patients receiving the placebo.

[0234] Moreover, rilzabrutinib was generally safe, with no evidence of new safety concerns or dose-related AEs.Attorney Docket No.01183-0291-00PCT-PRN Participant Demographics

[0235] The 160 patients enrolled in the phase 2 study were characterized by the demographic information provided in Tables 9-12. Of the 160 patients randomized, 142 (88.75%) completed the double-blind period. Baseline demographics and disease characteristics were generally well balanced across treatment arms (Tables 9 and 10). The omalizumab-naïve patient population was similar to the ITT population.

[0236] The median age of enrolled patients was 44. At enrollment, patients had CSU for a median duration of 3.0 years, and 11.6% had previously received omalizumab (patients with prior omalizumab use, including omalizumab-incomplete responders). Additionally, 36.9% of patients had a history of angioedema. Table 9. Demographics and Participant Characteristics at Baseline (Randomized Population) Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib All (N=40) 400mg QPM 400mg BID 400mg TID (N=160) (N=38) (N=41) (N=41)Median 39.5 41.0 43.0 49.0 44.0 Q1 ; Q3 27.0 ; 50.5 33.0 ; 50.0 34.0 ; 57.0 40.0 ; 56.0 33.0 ; 54.5 Min ; Max 19 ; 70 20 ; 66 24 ; 73 22 ; 77 19 ; 77 Age group (years) [n (%)] Number 40 38 41 41 160 18-39 20 (50.0) 16 (42.1) 17 (41.5) 10 (24.4) 63 (39.4)40-64 18 (45.0) 21 (55.3) 22 (53.7) 27 (65.9) 88 (55.0)≥65 2 (5.0) 1 (2.6) 2 (4.9) 4 (9.8) 9 (5.6)Age group (years) [n (%)] Number 40 38 41 41 160 < 44 (Median) 25 (62.5) 20 (52.6) 21 (51.2) 13 (31.7) 79 (49.4) ≥44 (Median) 15 (37.5) 18 (47.4) 20 (48.8) 28 (68.3) 81 (50.6)Regiona[n (%)] Number 40 38 41 41 160 Asia 9 (22.5) 10 (26.3) 8 (19.5) 8 (19.5) 35 (21.9) Latin America 14 (35.0) 14 (36.8) 11 (26.8) 9 (22.0) 48 (30.0) Eastern Europe 3 (7.5) 4 (10.5) 3 (7.3) 5 (12.2) 15 (9.4) Western Countries 14 (35.0) 10 (26.3) 19 (46.3) 19 (46.3) 62 (38.8) Sex [n (%)] Number 40 38 41 41 160 Male 14 (35.0) 10 (26.3) 16 (39.0) 8 (19.5) 48 (30.0)Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib All (N=40) 400mg QPM 400mg BID 400mg TID (N=160) (N=38) (N=41) (N=41) Female 26 (65.0) 28 (73.7) 25 (61.0) 33 (80.5) 112 (70.0) Race [n (%)] Number 40 38 41 41 160 White 31 (77.5) 27 (71.1) 33 (80.5) 30 (73.2) 121 (75.6) Black or African American 0 0 0 0 0 Asian 9 (22.5) 11 (28.9) 8 (19.5) 10 (24.4) 38 (23.8) Japanese 2 (5.0) 3 (7.9) 2 (4.9) 3 (7.3) 10 (6.3) Native Hawaiian or Other Pacific 0 0 0 0 0 Islander American Indian or Alaska Native 0 0 0 1 (2.4) 1 (0.6) Multiple 0 0 0 0 0 Not reported 0 0 0 0 0 Unknown 0 0 0 0 0 Ethnicity [n (%)] Number 40 38 41 41 160 Hispanic or Latino 13 (32.5) 17 (44.7) 12 (29.3) 11 (26.8) 53 (33.1) Not Hispanic or Latino 27 (67.5) 21 (55.3) 28 (68.3) 28 (68.3) 104 (65.0) Not reported 0 0 1 (2.4) 1 (2.4) 2 (1.3) Unknown 0 0 0 1 (2.4) 1 (0.6) Weight (kg) Number 40 38 41 41 160 Mean (SD) 74.86 72.31 (16.45) 75.68 (18.99) 74.52 (16.37) 74.38 (18.00) (17.38) Median 72.65 67.35 75.00 75.00 72.90 Q1 ; Q3 58.60 ; 60.50 ; 81.90 61.00 ; 87.00 64.00 ; 81.50 60.75 ; 87.40 85.00 Min ; Max 44.0 ; 110.6 48.9 ; 118.0 49.8 ; 141.5 43.4 ; 114.8 43.4 ; 141.5 Weight group (kg) [n (%)] Number 40 38 41 41 160 < 72.9 (Median) 21 (52.5) 23 (60.5) 20 (48.8) 16 (39.0) 80 (50.0) ≥72.9 (Median) 19 (47.5) 15 (39.5) 21 (51.2) 25 (61.0) 80 (50.0)Weight group (kg) [n (%)] Number 40 38 41 41 160 <60 11 (27.5) 7 (18.4) 9 (22.0) 8 (19.5) 35 (21.9) ≥60 - <90 20 (50.0) 28 (73.7) 24 (58.5) 28 (68.3) 100 (62.5)≥90 9 (22.5) 3 (7.9) 8 (19.5) 5 (12.2) 25 (15.6)BMI (kg / m2) Number 40 38 41 41 160 Mean (SD) 27.04 (5.73) 26.01 (5.48) 27.01 (6.18) 27.69 (5.25) 26.95 (5.65) Median 25.30 25.20 24.90 27.80 25.90 Q1 ; Q3 23.65 ; 21.70 ; 30.50 22.60 ; 30.10 24.50 ; 29.20 22.90 ; 31.00 29.95 Min ; Max 17.9 ; 42.4 18.4 ; 38.6 17.3 ; 43.2 17.6 ; 42.2 17.3 ; 43.2Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib All (N=40) 400mg QPM 400mg BID 400mg TID (N=160) (N=38) (N=41) (N=41) BMI≥25 - <30 12 (30.0) 10 (26.3) 9 (22.0) 21 (51.2) 52 (32.5)a≥30 11 (27.5) 10 (26.3) 11 (26.8) 8 (19.5) 40 (25.0)Asia: South Korea, Taiwan, Japan; Latin America: Argentina, Chile; Eastern Europe: Poland; Western Countries: Spain, Italy, Germany, Canada, Greece, Netherlands. Table 10. Demographics and Participant Characteristics at Baseline (Omalizumab-Naïve Population) Placebo Rilzabrutini Rilzabrutini Rilzabrutini All (N=36) b 400mg b 400mg b 400mg (N=143) QPM BID TIDMedian 38.0 41.0 44.0 49.0 43.0 Q1 ; Q3 27.0 ; 49.5 33.0 ; 50.0 33.0 ; 57.0 40.0 ; 59.0 31.0 ; 54.0 Min ; Max 19 ; 70 20 ; 66 24 ; 73 22 ; 77 19 ; 77 Age group (years) [n (%)] Number 36 37 35 35 143 18-39 19 (52.8) 16 (43.2) 15 (42.9) 8 (22.9) 58 (40.6)40-64 15 (41.7) 20 (54.1) 18 (51.4) 23 (65.7) 76 (53.1)≥65 2 (5.6) 1 (2.7) 2 (5.7) 4 (11.4) 9 (6.3)Age group (years) [n (%)] Number 36 37 35 35 143 < 44 (Median) 24 (66.7) 20 (54.1) 17 (48.6) 11 (31.4) 72 (50.3) ≥44 (Median) 12 (33.3) 17 (45.9) 18 (51.4) 24 (68.6) 71 (49.7)Regiona[n (%)] Number 36 37 35 35 143 Asia 9 (25.0) 10 (27.0) 8 (22.9) 8 (22.9) 35 (24.5) Latin America 13 (36.1) 14 (37.8) 10 (28.6) 8 (22.9) 45 (31.5) Eastern Europe 3 (8.3) 4 (10.8) 3 (8.6) 4 (11.4) 14 (9.8) Western Countries 11 (30.6) 9 (24.3) 14 (40.0) 15 (42.9) 49 (34.3) Sex [n (%)] Number 36 37 35 35 143 Male 13 (36.1) 9 (24.3) 13 (37.1) 7 (20.0) 42 (29.4) Female 23 (63.9) 28 (75.7) 22 (62.9) 28 (80.0) 101 (70.6) Race [n (%)] Number 36 37 35 35 143 White 27 (75.0) 26 (70.3) 27 (77.1) 25 (71.4) 105 (73.4) Black or African American 0 0 0 0 0Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutini Rilzabrutini Rilzabrutini All (N=36) b 400mg b 400mg b 400mg (N=143) QPM BID TIDIslander American Indian or Alaska Native 0 0 0 0 0 Multiple 0 0 0 0 0 Not reported 0 0 0 0 0 Unknown 0 0 0 0 0 Ethnicity [n (%)] Number 36 37 35 35 143 Hispanic or Latino 12 (33.3) 16 (43.2) 11 (31.4) 10 (28.6) 49 (34.3) Not Hispanic or Latino 24 (66.7) 21 (56.8) 23 (65.7) 23 (65.7) 91 (63.6) Not reported 0 0 1 (2.9) 1 (2.9) 2 (1.4) Unknown 0 0 0 1 (2.9) 1 (0.7) Weight (kg) Number 36 37 35 35 143 Mean (SD) 73.33 (17.55) 72.64 (16.55) 74.13 (19.95) 72.62 (15.08) 73.17 (17.19) Median 71.75 67.70 71.90 75.00 71.90 Q1 ; Q3 58.20 ; 84.6060.70 ; 81.9056.70 ; 84.0062.00 ; 81.5060.20 ; 82.70 Min ; Max 44.0 ; 110.6 48.9 ; 118.0 49.8 ; 141.5 43.4 ; 110.0 43.4 ; 141.5 Weight group (kg) [n (%)] Number 36 37 35 35 143 < 72.9 (Median) 20 (55.6) 22 (59.5) 19 (54.3) 15 (42.9) 76 (53.1) ≥72.9 (Median) 16 (44.4) 15 (40.5) 16 (45.7) 20 (57.1) 67 (46.9)Weight group (kg) [n (%)] Number 36 37 35 35 143 <60 11 (30.6) 7 (18.9) 9 (25.7) 8 (22.9) 35 (24.5) ≥60 - <90 18 (50.0) 27 (73.0) 19 (54.3) 24 (68.6) 88 (61.5)≥90 7 (19.4) 3 (8.1) 7 (20.0) 3 (8.6) 20 (14.0)BMI (kg / m2) Number 36 37 35 35 143 Mean (SD) 26.48 (5.32) 26.22 (5.41) 26.49 (6.07) 27.19 (4.82) 26.59 (5.38) Median 25.25 25.40 24.50 27.10 25.40 Q1 ; Q3 23.35 ; 30.0521.80 ; 30.5022.40 ; 31.3024.20 ; 29.1022.60 ; 29.60 Min ; Max 17.9 ; 39.7 18.4 ; 38.6 17.3 ; 43.2 17.6 ; 41.4 17.3 ; 43.2 BMI group (kg / m2) [n (%)] Number 36 37 35 35 143 <25 17 (47.2) 17 (45.9) 20 (57.1) 11 (31.4) 65 (45.5) ≥25 - <30 10 (27.8) 10 (27.0) 6 (17.1) 18 (51.4) 44 (30.8)≥30 9 (25.0) 10 (27.0) 9 (25.7) 6 (17.1) 34 (23.8)BMI: Body mass indexaAsia: South Korea, Taiwan, Japan; Latin America: Argentina, Chile; Eastern Europe: Poland; Western Countries: Spain, Italy, Germany, Canada, Greece, Netherlands.Attorney Docket No.01183-0291-00PCT-PRN Table 11. Demographics and Participant Characteristics at Baseline (Patients with Prior Omalizumab Use, Including Omalizumab-Incomplete Responders in ITT Population) Placebo Rilzabrutini Rilzabrutini Rilzabrutini All (N=4) b 400mg b 400mg b 400mg (N=17) QPM BID TIDMedian 53.0 48.0 41.5 50.0 47.0 Q1 ; Q3 36.0 ; 60.0 48.0 ; 48.0 34.0 ; 59.0 39.0 ; 54.0 39.0 ; 55.0 Min ; Max 25 ; 61 48 ; 48 34 ; 64 34 ; 55 25 ; 64 Age group (years) [n (%)] Number 4 1 6 6 17 18-39 1 (25.0) 0 2 (33.3) 2 (33.3) 5 (29.4)40-64 3 (75.0) 1 (100) 4 (66.7) 4 (66.7) 12 (70.6)≥65 0 0 0 0 0Age group (years) [n (%)] Number 4 1 6 6 17 < 44 (Median) 1 (25.0) 0 4 (66.7) 2 (33.3) 7 (41.2) ≥44 (Median) 3 (75.0) 1 (100) 2 (33.3) 4 (66.7) 10 (58.8)Regiona[n (%)] Number 4 1 6 6 17 Latin America 1 (25.0) 0 1 (16.7) 1 (16.7) 3 (17.6) Eastern Europe 0 0 0 1 (16.7) 1 (5.9) Western Countries 3 (75.0) 1 (100) 5 (83.3) 4 (66.7) 13 (76.5) Sex [n (%)] Number 4 1 6 6 17 Male 1 (25.0) 1 (100) 3 (50.0) 1 (16.7) 6 (35.3) Female 3 (75.0) 0 3 (50.0) 5 (83.3) 11 (64.7) Race [n (%)] Number 4 1 6 6 17 White 4 (100) 1 (100) 6 (100) 5 (83.3) 16 (94.1) Black or African American 0 0 0 0 0 Asian 0 0 0 0 0 Native Hawaiian or Other Pacific 0 0 0 0 0 Islander American Indian or Alaska Native 0 0 0 1 (16.7) 1 (5.9) Multiple 0 0 0 0 0 Not reported 0 0 0 0 0 Unknown 0 0 0 0 0 Ethnicity [n (%)] Number 4 1 6 6 17 Hispanic or Latino 1 (25.0) 1 (100) 1 (16.7) 1 (16.7) 4 (23.5) Not Hispanic or Latino 3 (75.0) 0 5 (83.3) 5 (83.3) 13 (76.5) Not reported 0 0 0 0 0Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutini Rilzabrutini Rilzabrutini All (N=4) b 400mg b 400mg b 400mg (N=17) QPM BID TIDNumber 4 1 6 6 17 Mean (SD) 88.55 (18.49) 60.10 (NC) 84.73 (8.01) 85.63 (20.59) 84.50 (16.08) Median 89.85 60.10 88.00 76.00 84.00 Q1 ; Q3 72.85 ; 60.10 ; 60.1084.00 ; 89.40 75.00 ; 75.00 ; 90.00 104.25 108.00 Min ; Max 68.7 ; 105.8 60.1 ; 60.1 69.0 ; 90.0 64.0 ; 114.8 60.1 ; 114.8 Weight group (kg) [n (%)] Number 4 1 6 6 17 < 72.9 (Median) 1 (25.0) 1 (100) 1 (16.7) 1 (16.7) 4 (23.5) ≥72.9 (Median) 3 (75.0) 0 5 (83.3) 5 (83.3) 13 (76.5)Weight group (kg) [n (%)] Number 4 1 6 6 17 <60 0 0 0 0 0 ≥60 - <90 2 (50.0) 1 (100) 5 (83.3) 4 (66.7) 12 (70.6)≥90 2 (50.0) 0 1 (16.7) 2 (33.3) 5 (29.4)BMI (kg / m2) Number 4 1 6 6 17 Mean (SD) 32.05 (7.69) 18.50 (NC) 30.03 (6.54) 30.60 (7.09) 30.03 (7.05) Median 30.35 18.50 28.70 28.60 28.70 Q1 ; Q3 26.30 ; 37.8018.50 ; 18.5026.90 ; 30.1025.00 ; 35.7025.10 ; 33.20 Min ; Max 25.1 ; 42.4 18.5 ; 18.5 23.3 ; 42.5 23.5 ; 42.2 18.5 ; 42.5 BMI group (kg / m2) [n (%)] Number 4 1 6 6 17 <25 0 1 (100) 1 (16.7) 1 (16.7) 3 (17.6) ≥25 - <30 2 (50.0) 0 3 (50.0) 3 (50.0) 8 (47.1)Spain, Italy, Germany, Canada, Greece, Netherlands. Table 12. Disease and Other Characteristics at Baseline (Randomized Population) Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib All (N=40) 400mg QPM 400mg BID 400mg TID (N=160)Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib All (N=40) 400mg QPM 400mg BID 400mg TID (N=160) (N=38) (N=41) (N=41) Number 40 38 41 41 160No 36 (90.0) 37 (97.4) 35 (85.4) 35 (85.4) 143 (89.4) History of allergybNumber 40 38 41 41 160 Allergic 6 (15.0) 10 (26.3) 13 (31.7) 12 (29.3) 41 (25.6) Non-Allergic 34 (85.0) 28 (73.7) 28 (68.3) 29 (70.7) 119 (74.4) History of atopic dermatitis Number 40 38 41 41 160 Yes 1 (2.5) 0 1 (2.4) 1 (2.4) 3 (1.9) No 39 (97.5) 38 (100) 40 (97.6) 40 (97.6) 157 (98.1) History of angioedema Number 40 38 41 41 160 Yes 18 (45.0) 16 (42.1) 12 (29.3) 13 (31.7) 59 (36.9) No 22 (55.0) 22 (57.9) 29 (70.7) 28 (68.3) 101 (63.1) Number of angioedema episodes in past 6 months Number 18 17 12 13 60 Mean (SD) 9.5 (14.6) 8.6 (14.4) 11.4 (20.3) 14.5 (16.0) 10.7 (15.9) Median 4.0 1.0 1.5 6.0 2.5 Q1 ; Q3 1.0 ; 10.0 0.0 ; 12.0 1.0 ; 17.5 3.0 ; 30.0 1.0 ; 16.5 Min ; Max 0 ; 60 0 ; 48 0 ; 70 0 ; 48 0 ; 70 Time since last angioedema episode (months) Number 18 16 12 13 59 Mean (SD) 7.14 (21.22) 6.62 (11.64) 21.31 (64.64) 10.39 (29.51) 10.60 (34.22) Median 1.41 2.83 1.81 1.87 1.58 Q1 ; Q3 0.92 ; 3.19 0.71 ; 8.20 0.76 ; 4.63 1.02 ; 3.29 0.76 ; 4.50 Min ; Max 0.5 ; 91.8 0.4 ; 48.2 0.5 ; 226.4 0.2 ; 108.4 0.2 ; 226.4 Baseline UAS7 score Number 40 38 41 41 160 Mean (SD) 30.0 (8.6) 31.4 (7.3) 30.2 (7.2) 29.9 (8.6) 30.3 (7.9) Median 29.0 30.0 28.0 29.0 29.0 Q1 ; Q3 23.0 ; 37.5 27.0 ; 38.0 25.0 ; 35.0 25.0 ; 36.0 25.0 ; 37.0 Min ; Max 16 ; 42 16 ; 42 18 ; 42 0 ; 42 0 ; 42 Baseline UAS7 score [n (%)] Number 40 38 41 41 160 <28 15 (37.5) 10 (26.3) 16 (39.0) 14 (34.1) 55 (34.4) ≥28 25 (62.5) 28 (73.7) 25 (61.0) 27 (65.9) 105 (65.6)Baseline ISS7 score Number 40 38 41 41 160 Mean (SD) 15.6 (4.2) 16.5 (3.5) 15.8 (3.7) 15.9 (4.4) 15.9 (4.0)Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib All (N=40) 400mg QPM 400mg BID 400mg TID (N=160) (N=38) (N=41) (N=41) Median 14.5 16.5 15.0 15.0 15.0≥13 29 (72.5) 33 (86.8) 34 (82.9) 37 (90.2) 133 (83.1)Baseline HSS7 score Number 40 38 41 41 160 Mean (SD) 14.4 (4.9) 14.9 (4.3) 14.4 (4.3) 14.0 (4.8) 14.4 (4.5) Median 14.0 14.0 14.0 14.0 14.0 Q1 ; Q3 11.0 ; 18.9 12.0 ; 18.0 12.0 ; 17.0 12.0 ; 17.0 12.0 ; 18.0 Min ; Max 7 ; 21 7 ; 21 7 ; 21 0 ; 21 0 ; 21 Baseline AAS7>0 [n (%)] Number 40 38 41 41 160 Yes 30 (75.0) 28 (73.7) 28 (68.3) 26 (63.4) 112 (70.0) No 10 (25.0) 10 (26.3) 13 (31.7) 15 (36.6) 48 (30.0) Baseline AAS7 score for participants with angioedemacNumber 30 28 28 26 112 Mean (SD) 59.7 (27.1) 54.0 (25.2) 46.1 (25.7) 46.0 (22.3) 51.7 (25.6) Median 61.5 56.0 44.5 50.5 51.0 Q1 ; Q3 42.0 ; 86.0 39.0 ; 71.0 24.0 ; 67.5 27.0 ; 61.0 32.0 ; 68.0 Min ; Max 8 ; 101 6 ; 99 2 ; 92 9 ; 91 2 ; 101 Baseline UCT score Number 35 36 41 40 152 Mean (SD) 4.2 (3.1) 4.0 (2.2) 4.2 (3.1) 4.5 (3.5) 4.3 (3.0) Median 4.0 4.0 4.0 4.0 4.0 Q1 ; Q3 2.0 ; 6.0 2.0 ; 5.5 2.0 ; 6.0 2.0 ; 6.5 2.0 ; 6.0 Min ; Max 0 ; 12 0 ; 9 0 ; 13 0 ; 15 0 ; 15 Baseline PGIS score Number 40 38 41 40 159 Mean (SD) 2.4 (0.6) 2.5 (0.6) 2.2 (0.6) 2.4 (0.7) 2.4 (0.6) Median 2.0 3.0 2.0 2.0 2.0 Q1 ; Q3 2.0 ; 3.0 2.0 ; 3.0 2.0 ; 3.0 2.0 ; 3.0 2.0 ; 3.0 Min ; Max 1 ; 3 1 ; 3 1 ; 3 0 ; 3 0 ; 3 Baseline Eosinophils (10ˆ9 / L) Number 40 38 41 41 160 Mean (SD) 0.194 (0.104) 0.189 (0.134) 0.192 (0.150) 0.200 (0.144) 0.194 (0.133) Median 0.180 0.155 0.160 0.180 0.165 Q1 ; Q3 0.115 ; 0.290 0.110 ; 0.250 0.090 ; 0.260 0.090 ; 0.290 0.090 ; 0.280 Min ; Max 0.03 ; 0.45 0.02 ; 0.67 0.02 ; 0.62 0.02 ; 0.64 0.02 ; 0.67 Baseline Eosinophils (10ˆ9 / L) [n (%)] Number 40 38 41 41 160 < 0.165 (Median) 19 (47.5) 20 (52.6) 22 (53.7) 19 (46.3) 80 (50.0) ≥0.165 (Median) 21 (52.5) 18 (47.4) 19 (46.3) 22 (53.7) 80 (50.0)Baseline Eosinophils (10ˆ9 / L) [n (%)]Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib All (N=40) 400mg QPM 400mg BID 400mg TID (N=160) (N=38) (N=41) (N=41) Number 40 38 41 41 160Median 0.040 0.040 0.040 0.040 0.040 Q1 ; Q3 (0.023; 0.050) (0.015; 0.070) (0.015; 0.060) (0.030; 0.050) (0.015; 0.060) Min ; Max N / A N / A N / A N / A N / A Baseline Total IgE (IU / mL) Number 39 37 41 40 157 Mean (SD) 319.6 (530.2) 433.3 (669.8) 275.7 (487.3) 389.0 (638.7) 352.6 (581.9) Median 142.6 158.0 111.1 116.8 123.8 Q1 ; Q3 40.4 ; 349.5 37.6 ; 533.6 38.7 ; 314.6 34.7 ; 407.9 37.6 ; 351.1 Min ; Max 0 ; 2608 3 ; 2843 1 ; 2634 1 ; 2882 0 ; 2882 Baseline Total IgE (IU / mL) [n (%)] Number 39 37 41 40 157 <300 27 (69.2) 25 (67.6) 29 (70.7) 28 (70.0) 109 (69.4) ≥300 12 (30.8) 12 (32.4) 12 (29.3) 12 (30.0) 48 (30.6)Baseline Total IgE (IU / mL) [n (%)] Number 39 37 41 40 157 <100 18 (46.2) 15 (40.5) 19 (46.3) 18 (45.0) 70 (44.6) ≥100 21 (53.8) 22 (59.5) 22 (53.7) 22 (55.0) 87 (55.4)Baseline Total IgG (g / L) Number 40 38 41 41 160 Mean (SD) 12.4 (3.2) 11.6 (2.0) 11.3 (2.3) 11.7 (2.1) 11.7 (2.5) Median 11.9 11.1 11.4 11.7 11.5 Q1 ; Q3 10.2 ; 14.0 9.9 ; 13.0 10.2 ; 12.4 10.4 ; 12.9 10.1 ; 13.0 Min ; Max 6 ; 24 8 ; 17 6 ; 19 7 ; 18 6 ; 24 Baseline Total IgG (g / L) [n (%)] Number 40 38 41 41 160 <7 1 (2.5) 0 1 (2.4) 0 2 (1.3) 7-16 33 (82.5) 37 (97.4) 39 (95.1) 40 (97.6) 149 (93.1)>16 6 (15.0) 1 (2.6) 1 (2.4) 1 (2.4) 9 (5.6)Baseline Total IgM (g / L) Number 39 37 41 41 158 Mean (SD) 1.1 (0.6) 1.1 (0.5) 1.2 (0.7) 1.3 (0.8) 1.2 (0.6) Median 1.0 1.1 1.1 1.1 1.1 Q1 ; Q3 0.7 ; 1.3 0.7 ; 1.5 0.7 ; 1.4 0.7 ; 1.6 0.7 ; 1.4 Min ; Max 0 ; 3 0 ; 2 0 ; 4 0 ; 4 0 ; 4 Baseline Total IgM (g / L) [n (%)] Number 39 37 41 41 158 <0.4 0 2 (5.4) 1 (2.4) 1 (2.4) 4 (2.5) 0.4-2.3 36 (92.3) 35 (94.6) 38 (92.7) 34 (82.9) 143 (90.5) >2.3 3 (7.7) 0 2 (4.9) 6 (14.6) 11 (7.0)Baseline IgG anti-IgE (Arbitrary U) Number 40 38 41 41 160Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib All (N=40) 400mg QPM 400mg BID 400mg TID (N=160) (N=38) (N=41) (N=41) Mean (SD) N / A N / A N / A N / A N / ABHRA- 35 (87.5) 32 (88.9) 34 (82.9) 35 (85.4) 136 (86.1) Baseline IgG anti-FceRI (Arbitrary U) Number 40 38 41 41 160 Mean (SD) 312.3 (530.0) 931.6 (4512.2) 1591.8 214.9 (298.3) 762.3 (4275.0) (7225.6) Median 141.6 174.7 208.2 134.2 160.1 Q1 ; Q3 56.1 ; 308.9 53.7 ; 250.0 99.8 ; 425.0 46.4 ; 308.9 53.5 ; 317.6 Min ; Max 0 ; 2762 0 ; 27990 0 ; 46369 0 ; 1695 0 ; 46369 Baseline IgE anti-TPO (Arbitrary U) Number 40 38 41 41 160 Mean (SD) 2.7 (0.6) 2.9 (1.3) 2.7 (0.5) 2.8 (0.7) 2.8 (0.8) Median 2.5 2.5 2.6 2.6 2.6 Q1 ; Q3 2.2 ; 3.2 2.4 ; 3.2 2.4 ; 2.9 2.2 ; 3.0 2.3 ; 3.1 Min ; Max 2 ; 4 2 ; 10 2 ; 4 2 ; 5 2 ; 10 Baseline IL-31 Number 40 38 41 41 160 Median 4.0 4.1 5.0 4.2 4.2 Q1 ; Q3 (2.9; 5.3) (3.2; 5.7) (3.8; 8.4) (3.3; 6.7) (3.3; 6.4) Baseline sMRGPRX2 (ng / mL) Number 40 38 41 41 160 Median 21.1 26.5 17.5 21.8 21.2 Q1 ; Q3 (13.1; 30.6) (17.5; 33.6) (10.4; 28.3) (14.3: 30.3) (13.6; 31.2) Baseline IgG anti-TPO (IU) Number 40 38 40 41 159 Mean (SD) 18.7 (50.0) 35.4 (107.4) 47.7 (182.1) 36.1 (80.7) 34.5 (115.2) Median 0.0 0.0 3.1 1.6 0.4 Q1 ; Q3 0.0 ; 6.8 0.0 ; 8.3 0.0 ; 9.7 0.0 ; 19.9 0.0 ; 10.3 Min ; Max 0 ; 205 0 ; 429 0 ; 1133 0 ; 338 0 ; 1133 Baseline H1-antihistamines dose [n (%)] Number 40 38 41 40 159Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib All (N=40) 400mg QPM 400mg BID 400mg TID (N=160) (N=38) (N=41) (N=41) At least weekly 2 (5.0) 5 (13.2) 1 (2.4) 2 (4.9) 10 (6.3)

[0237] Treatment with rilzabrutinib yielded significant improvements in UAS7. In particular, patients receiving 400 mg TID rilzabrutinib saw a significant reduction in UAS7 at Week 12, thereby meeting the primary endpoint in the non-United States countries (see Figures 2-4 and Tables 13-16). In the ITT population, participants receiving 400 mg TID rilzabrutinib showed a LS mean change from baseline at Week 12 of -17.95 (p=0.00116) points, while patients receiving the placebo showed a LS mean change of -11.20 from baseline to Week 12 (see Table 13). Consistent results were observed for omalizumab-naïve patients receiving 400 mg TID rilzabrutinib, both prior to (LS mean change of -16.89, p=0.0159; see Table 14) and following (LS mean reduction of -17.50, p=0.0079; see Table 15) the removal of a non- symptomatic outlier (UAS7 / ISS7=0 at baseline) who was erroneously randomized into the 400 mg TID rilzabrutinib arm.

[0238] In the 400 mg TID arm, all patients except for one showed improvement in the weekly UAS7. Moreover, a clear separation was observed between patients receiving 400 mg TID rilzabrutinib and patients receiving the placebo across all response thresholds (see Figure 4).

[0239] Subgroup analysis of the omalizumab-naïve population further supports the efficacy of rilzabrutinib treatment in CSU (see Table 16). Overall, treatment with 400 mg TID rilzabrutinib was efficacious across subgroups, regardless of baseline demographic characteristics. Moreover, 400 mg TID rilzabrutinib treatment led to improvements in patientsAttorney Docket No.01183-0291-00PCT-PRN with a low IgE concentration, positive BHRA status, history of angioedema, or characteristics of difficult-to-treat CSU. Table 13. Supplementary Analysis: Change from Baseline in UAS7 at Week 12 (ITT Population) UAS7 Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=40) 400mg QPM 400mg BID 400mg TID (N=38) (N=41) (N=41) Baseline Number 40 38 41 41 Mean (SD) 29.97 (8.56) 31.37 (7.32) 30.21 (7.19) 29.88 (8.57) Median 29.00 30.00 28.00 29.00 Q1 ; Q3 23.00 ; 37.50 27.00 ; 38.00 25.00 ; 35.00 25.00 ; 36.00 Min ; Max 16.0 ; 42.0 16.0 ; 42.0 18.0 ; 42.0 0.0 ; 42.0 Week 12 Number (observed / imputed) 35 (33 / 2) 31 (28 / 3) 30 (27 / 3) 33 (30 / 3) Mean (SD) 19.27 (13.49) 21.80 (10.94) 14.70 (14.29) 10.52 (10.26) Median 17.50 22.40 12.00 9.00 Q1 ; Q3 7.00 ; 29.00 14.00 ; 28.00 0.00 ; 26.00 0.00 ; 16.80 Min ; Max 0.0 ; 42.0 0.0 ; 42.0 0.0 ; 42.0 0.0 ; 35.0 Change from baseline Number (observed / imputed) 35 (33 / 2) 31 (28 / 3) 30 (27 / 3) 33 (30 / 3) Mean (SD) -10.76 (13.99) -11.04 (9.56) -16.02 (13.29) -20.30 (12.41)Median -8.00 -9.40 -13.50 -20.33Q1 ; Q3 -21.00 ; -0.50 -17.50 ; -3.67 -27.00 ; -4.00 -31.00 ; -10.00Min ; Max -40.8 ; 20.5 -31.0 ; 3.3 -42.0 ; 1.0 -42.0 ; -1.0LS Mean (SE) a -11.20 (1.98) -10.22 (2.01) -14.82 (1.98) -17.95 (1.95)LS Mean Diff vs. placebo (95% CI)a0.97 (-4.40, 6.34) -3.62 (-8.87, 1.63) -6.76 (-12.01, - 1.51) P-value vs. placeboa0.7230 0.1763 0.0116aEach of the imputed complete data were analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group and regions as covariates. Note: Data collected after study intervention discontinuation were included. Data post selected prohibited / rescue medications (high / medium impact on efficacy confirmed through blinded medical review) were set to missing and imputed by WOCF. Missing data after study intervention discontinuation for lack of efficacy were imputed by WOCF; other missing data were imputed by MI. Descriptive statistics at Week 12 include participants with WOCF imputation at Week 12, and participants whose values were imputed by MI at Week 12 were excluded from the descriptive analysis. Table 14. Primary Analysis: Change from Baseline in UAS7 at Week 12 (Omalizumab- Naïve Population) UAS7 Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TIDAttorney Docket No.01183-0291-00PCT-PRN UAS7 Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) Mean (SD) 19.32 (13.04) 22.00 (11.07) 15.61 (13.91) 11.00 (9.90) Median 17.75 22.87 14.00 12.25 Q1 ; Q3 8.17 ; 28.50 14.00 ; 28.00 2.00 ; 26.00 1.00 ; 17.15 Min ; Max 0.0 ; 42.0 0.0 ; 42.0 0.0 ; 42.0 0.0 ; 35.0 Change from baseline Number (observed / imputed) 32 (31 / 1) 30 (27 / 3) 26 (24 / 2) 28 (27 / 1) Mean (SD) -9.71 (13.20) -10.57 (9.36) -14.49 (12.08) -19.04 (11.40) Median -8.00 -8.70 -12.80 -18.92 Q1 ; Q3 -18.50 ; -0.50 -17.33 ; -3.67 -22.00 ; -4.00 -28.50 ; -8.75 Min ; Max -35.0 ; 20.5 -31.0 ; 3.3 -40.8 ; 1.0 -42.0 ; -1.0 LS Mean (SE)a-10.14 (2.05) -9.74 (2.00) -14.24 (2.06) -16.89 (2.04) LS Mean Diff vs. placebo (95% CI)a0.40 (-5.08, 5.89) -4.09 (-9.59, 1.40) -6.75 (-12.23, - 1.26) P-value vs. placeboa0.8856 0.1441 0.0159aEach of the imputed complete data were analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group and regions as covariates. Note: Data collected after study intervention discontinuation were included. Data post selected prohibited / rescue medications (high / medium impact on efficacy confirmed through blinded medical review) were set to missing and imputed by WOCF. Missing data after study intervention discontinuation for lack of efficacy were imputed by WOCF; other missing data were imputed by MI. Descriptive statistics at Week 12 include participants with WOCF imputation at Week 12, and participants whose values were imputed by MI at Week 12 were excluded from the descriptive analysis. Table 15. Change from Baseline in UAS7 at Week 12 (Omalizumab-Naïve Population with Outlier Removed from Analysis) UAS7 Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=34)Mean (SD) 19.32 (13.04) 22.00 (11.07) 15.61 (13.91) 11.00 (9.90) Median 17.75 22.87 14.00 12.25 Q1 ; Q3 8.17 ; 28.50 14.00 ; 28.00 2.00 ; 26.00 1.00 ; 17.15 Min ; Max 0.0 ; 42.0 0.0 ; 42.0 0.0 ; 42.0 0.0 ; 35.0 Change from baseline Number (observed / imputed) 32 (31 / 1) 30 (27 / 3) 26 (24 / 2) 28 (27 / 1) Mean (SD) -9.71 (13.20) -10.57 (9.36) -14.49 (12.08) -19.04 (11.40)Median -8.00 -8.70 -12.80 -18.92Q1 ; Q3 -18.50 ; -0.50 -17.33 ; -3.67 -22.00 ; -4.00 -28.50 ; -8.75Min ; Max -35.0 ; 20.5 -31.0 ; 3.3 -40.8 ; 1.0 -42.0 ; -1.0LS Mean (SE) a -10.01 (2.01) -9.93 (1.96) -14.30 (2.06) -17.50 (2.06)LS Mean Diff vs. placebo (95% CI)a0.08 (-5.29, 5.46) -4.29 (-9.74, 1.16) -7.50 (-13.02, - 1.97) P-value vs. placeboa0.9759 0.1232 0.0079aEach of the imputed complete data were analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group and region as covariates.Attorney Docket No.01183-0291-00PCT-PRN Table 16. Subgroup Analysis: Change from Baseline in UAS7 at Week 12 by Subgroups (Omalizumab-Naïve Population) Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) Age group (years)Mean (SD) -11.71 (13.10) -10.71 (7.99) -16.63 (13.80) -19.17 (11.98) LS Mean (SE)a-11.56 (3.28) -8.84 (2.81) -15.12 (2.72) -17.54 (2.39) LS Mean Diff vs. placebo (95% CI)a2.72 (-5.76, -3.56 (-11.91, -5.98 (-13.92, 11.20) 4.80) 1.95) P-value vs. placeboa0.5296 0.4045 0.1393 Overall p-value for interactionb0.9595 Age group (years) < 65 Number (observed / imputed) 30 (29 / 1) 29 (26 / 3) 25 (23 / 2) 24 (23 / 1) Mean (SD) -10.62 (12.74) -10.37 (9.46) -13.91 (11.95) -18.19 (11.00) LS Mean (SE)a-10.41 (2.02) -9.12 (1.96) -13.99 (2.04) -16.30 (2.11) LS Mean Diff vs. placebo (95% CI)a1.30 (-4.27, 6.86) -3.58 (-9.19, 2.03) -5.88 (-11.58, - 0.19) P-value vs. placeboa0.6475 0.2106 0.0430 ≥ 65 Number (observed / imputed) 2 (2 / 0) 1 (1 / 0) 1 (1 / 0) 4 (4 / 0) Mean (SD) 4.00 (16.97) -16.33 (NC) -29.00 (NC) -24.13 (14.17) LS Mean (SE)a1.46 (10.15) -1.73 (17.36) -21.85 (10.98) -23.81 (7.07) LS Mean Diff vs. placebo (95% CI)a-3.19 (-44.28, -23.31 (-51.77, -25.27 (-49.57, - 37.89) 5.15) 0.97) P-value vs. placeboa0.8790 0.1084 0.0416 Overall p-value for interactionb0.2251 Gender Male Number (observed / imputed) 11 (11 / 0) 8 (8 / 0) 9 (8 / 1) 5 (5 / 0) Mean (SD) -6.91 (13.75) -9.58 (10.13) -16.87 (13.20) -12.72 (5.65) LS Mean (SE)a-6.70 (3.52) -8.84 (4.15) -16.67 (3.54) -11.21 (4.99) LS Mean Diff vs. placebo (95% CI)a-2.15 (-12.83, -9.97 (-19.70, - -4.51 (-16.53, 8.54) 0.25) 7.51) P-value vs. placeboa0.6937 0.0445 0.4622 Female Number (observed / imputed) 21 (20 / 1) 22 (19 / 3) 17 (16 / 1) 23 (22 / 1) Mean (SD) -11.17 (12.99) -10.93 (9.28) -13.23 (11.66) -20.41 (11.94) LS Mean (SE)a-11.39 (2.38) -9.27 (2.22) -12.97 (2.46) -18.51 (2.16) LS Mean Diff vs. placebo (95% CI)a2.13 (-4.34, 8.59) -1.57 (-8.27, 5.12) -7.12 (-13.39, - 0.85) P-value vs. placeboa0.5190 0.6450 0.0260Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35)< 72.9 (Median) Number (observed / imputed) 18 (18 / 0) 17 (16 / 1) 16 (15 / 1) 13 (13 / 0) Mean (SD) -11.18 (11.95) -7.98 (7.20) -12.97 (9.84) -20.83 (13.25) LS Mean (SE)a-10.84 (2.51) -7.76 (2.45) -13.03 (2.58) -18.62 (2.85) LS Mean Diff vs. placebo (95% CI)a3.08 (-3.85, -2.19 (-9.21, 4.84) -7.78 (-15.19, - 10.01) 0.37) P-value vs. placeboa0.3833 0.5418 0.0397 ≥ 72.9 (Median) Number (observed / imputed) 14 (13 / 1) 13 (11 / 2) 10 (9 / 1) 15 (14 / 1) Mean (SD) -7.82 (14.89) -13.96 (10.98) -16.91 (15.27) -17.48 (9.72) LS Mean (SE)a-7.93 (3.02) -11.30 (3.07) -15.67 (3.01) -16.27 (2.71) LS Mean Diff vs. placebo (95% CI)a-3.37 (-11.78, -7.75 (-16.17, -8.35 (-16.31, - 5.05) 0.68) 0.38) P-value vs. placeboa0.4330 0.0715 0.0400 Overall p-value for interactionb0.4144 Baseline weight (kg) < 60 Number (observed / imputed) 10 (10 / 0) 6 (5 / 1) 7 (7 / 0) 8 (8 / 0) Mean (SD) -8.75 (11.17) -7.82 (8.01) -10.00 (9.76) -19.50 (14.84) LS Mean (SE)a-8.01 (3.53) -6.74 (4.50) -11.36 (3.92) -19.90 (4.01) LS Mean Diff vs. placebo (95% CI)a1.28 (-9.97, -3.35 (-13.61, -11.88 (-22.36, - 12.52) 6.91) 1.40) P-value vs. placeboa0.8237 0.5222 0.0262 ≥ 60 - <90 Number (observed / imputed) 15 (14 / 1) 21 (19 / 2) 16 (14 / 2) 17 (17 / 0) Mean (SD) -10.84 (13.46) -10.49 (9.74) -15.04 (13.16) -18.74 (10.60) LS Mean (SE)a-11.19 (2.81) -9.11 (2.26) -13.31 (2.65) -15.74 (2.43) LS Mean Diff vs. placebo (95% CI)a2.08 (-5.04, 9.20) -2.12 (-9.70, 5.46) -4.55 (-11.84, 2.73) P-value vs. placeboa0.5666 0.5832 0.2205 ≥ 90 Number (observed / imputed) 7 (7 / 0) 3 (3 / 0) 3 (3 / 0) 3 (2 / 1) Mean (SD) -8.64 (16.85) -16.67 (9.07) -22.00 (9.00) -19.44 (9.03) LS Mean (SE)a-8.78 (4.74) -14.44 (7.38) -20.74 (5.01) -20.81 (7.30) LS Mean Diff vs. placebo (95% CI)a-5.66 (-22.88, -11.96 (-25.48, -12.03 (-29.07, 11.55) 1.56) 5.01) P-value vs. placeboa0.5190 0.0829 0.1663 Overall p-value for interactionb0.7259 Baseline BMI (kg / m2) < 25 Number (observed / imputed) 15 (15 / 0) 14 (13 / 1) 17 (16 / 1) 11 (11 / 0) Mean (SD) -8.97 (10.73) -7.00 (7.22) -14.44 (11.30) -17.02 (13.10) LS Mean (SE)a-8.65 (2.64) -6.27 (2.66) -14.48 (2.43) -17.23 (3.19) LS Mean Diff vs. placebo (95% CI)a2.37 (-4.98, 9.73) -5.83 (-12.83, -8.58 (-16.69, - 1.16) 0.47)Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) P-value vs. placeboa0.5266 0.1020 0.0381- - - - LS Mean (SE)a-9.33 (3.97) -7.48 (3.95) -11.34 (4.80) -14.99 (2.89) LS Mean Diff vs. placebo (95% CI)a1.85 (-9.71, -2.01 (-14.35, -5.67 (-15.50, 13.42) 10.33) 4.16) P-value vs. placeboa0.7535 0.7493 0.2585 ≥ 30 Number (observed / imputed) 8 (8 / 0) 9 (8 / 1) 4 (4 / 0) 4 (3 / 1) Mean (SD) -16.25 (12.62) -15.85 (8.40) -16.50 (13.23) -23.25 (10.60) LS Mean (SE)a-14.22 (4.23) -14.65 (3.89) -15.87 (4.21) -21.80 (5.17) LS Mean Diff vs. placebo (95% CI)a-0.43 (-11.59, -1.65 (-13.49, -7.58 (-20.66, 10.72) 10.19) 5.50) P-value vs. placeboa0.9391 0.7849 0.2561 Overall p-value for interactionb0.9352 RegioncAsia Number (observed / imputed) 8 (8 / 0) 9 (9 / 0) 8 (8 / 0) 6 (6 / 0) Mean (SD) -7.46 (11.36) -9.59 (9.91) -11.25 (10.32) -13.93 (11.07) LS Mean (SE)a-6.47 (3.67) -9.00 (3.50) -11.32 (3.76) -14.25 (3.99) LS Mean Diff vs. placebo (95% CI)a-2.53 (-12.50, -4.86 (-15.18, -7.78 (-18.32, 7.44) 5.46) 2.76) P-value vs. placeboa0.6187 0.3562 0.1479 Latin America Number (observed / imputed) 11 (10 / 1) 10 (7 / 3) 8 (6 / 2) 6 (6 / 0) Mean (SD) -13.32 (15.08) -13.28 (10.78) -10.23 (11.81) -14.07 (12.07) LS Mean (SE)a-11.88 (3.39) -10.74 (3.14) -9.26 (3.71) -11.50 (4.23) LS Mean Diff vs. placebo (95% CI)a1.14 (-7.86, 2.62 (-7.19, 0.38 (-10.12, 10.15) 12.43) 10.88) P-value vs. placeboa0.8035 0.6003 0.9434 Eastern Europe Number (observed / imputed) 2 (2 / 0) 4 (4 / 0) 3 (3 / 0) 4 (4 / 0) Mean (SD) -10.00 (18.38) -5.79 (5.45) -20.14 (18.13) -21.88 (11.40) LS Mean (SE)a-19.72 (8.80) -5.35 (5.65) -6.34 (10.64) -25.97 (6.17) LS Mean Diff vs. placebo (95% CI)a14.37 (-6.40, 13.37 (-19.79, -6.26 (-24.55, 35.15) 46.54) 12.03) P-value vs. placeboa0.1751 0.4292 0.5025 Western Countries Number (observed / imputed) 11 (11 / 0) 7 (7 / 0) 7 (7 / 0) 12 (11 / 1) Mean (SD) -7.68 (12.86) -10.70 (8.61) -20.62 (10.65) -23.13 (10.61) LS Mean (SE)a-7.98 (3.38) -8.74 (4.03) -20.19 (3.23) -19.49 (3.03) LS Mean Diff vs. placebo (95% CI)a-0.76 (-11.10, -12.21 (-21.37, - -11.51 (-20.42, - 9.58) 3.06) 2.61) P-value vs. placeboa0.8853 0.0090 0.0113 Overall p-value for interactionb0.4154 RaceAttorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) White -- - - - LS Mean (SE)a-6.51 (3.58) -8.43 (3.32) -11.33 (3.66) -14.94 (3.44) LS Mean Diff vs. placebo (95% CI)a-1.92 (-11.55, -4.82 (-14.87, -8.43 (-18.08, 7.72) 5.24) 1.23) P-value vs. placeboa0.6967 0.3477 0.0871 Overall p-value for interactionb0.9692 Ethnicity Hispanic Number (observed / imputed) 10 (10 / 0) 12 (10 / 2) 8 (6 / 2) 8 (8 / 0) Mean (SD) -14.65 (15.20) -10.26 (9.92) -10.23 (11.81) -15.49 (12.69) LS Mean (SE)a-12.54 (3.60) -8.80 (2.97) -10.31 (3.59) -13.76 (3.78) LS Mean Diff vs. placebo (95% CI)a3.74 (-5.35, 2.24 (-7.72, -1.22 (-11.34, 12.83) 12.19) 8.91) P-value vs. placeboa0.4198 0.6597 0.8139 Non-Hispanic Number (observed / imputed) 22 (21 / 1) 18 (17 / 1) 17 (17 / 0) 18 (17 / 1) Mean (SD) -7.46 (11.88) -10.78 (9.25) -16.52 (12.39) -22.02 (10.28) LS Mean (SE)a-8.25 (2.37) -9.79 (2.59) -16.16 (2.46) -19.24 (2.48) LS Mean Diff vs. placebo (95% CI)a-1.54 (-8.49, 5.41) -7.92 (-14.63, - -10.99 (-17.71, - 1.20) 4.28) P-value vs. placeboa0.6636 0.0209 0.0013 Overall p-value for interactionb0.2878 History of angioedema Yes Number (observed / imputed) 15 (14 / 1) 11 (8 / 3) 8 (6 / 2) 9 (8 / 1) Mean (SD) -10.17 (12.72) -13.08 (11.63) -8.60 (9.01) -16.58 (10.23) LS Mean (SE)a-9.67 (2.91) -11.20 (2.97) -11.58 (3.69) -15.33 (3.68) LS Mean Diff vs. placebo (95% CI)a-1.53 (-9.72, 6.65) -1.91 (-11.17, -5.66 (-14.82, 7.35) 3.50) P-value vs. placeboa0.7135 0.6863 0.2255 No Number (observed / imputed) 17 (17 / 0) 19 (19 / 0) 18 (18 / 0) 19 (19 / 0) Mean (SD) -9.30 (13.98) -9.12 (7.74) -17.10 (12.56) -20.20 (12.00) LS Mean (SE)a-9.88 (2.69) -7.72 (2.58) -15.01 (2.39) -17.97 (2.40) LS Mean Diff vs. placebo (95% CI)a2.16 (-5.19, 9.52) -5.13 (-12.18, -8.09 (-15.14, - 1.92) 1.03) P-value vs. placeboa0.5644 0.1538 0.0246 Overall p-value for interactionb0.7199Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) Baseline UAS7 scoreMean (SD) -13.28 (12.47) -11.12 (10.28) -16.73 (14.20) -22.66 (12.35) LS Mean (SE)a-13.11 (2.72) -11.17 (2.39) -17.23 (2.81) -19.91 (2.64) LS Mean Diff vs. placebo (95% CI)a1.94 (-5.16, 9.03) -4.13 (-11.78, -6.81 (-14.23, 3.52) 0.62) P-value vs. placeboa0.5925 0.2903 0.0722 Overall p-value for interactionb0.9282 Baseline ISS7 score < 13 Number (observed / imputed) 10 (10 / 0) 2 (2 / 0) 6 (5 / 1) 2 (2 / 0) Mean (SD) -5.50 (12.18) -5.83 (3.06) -10.78 (8.33) -10.75 (6.01) LS Mean (SE)a-4.91 (3.05) -3.27 (5.21) -9.30 (4.02) -9.24 (6.48) LS Mean Diff vs. placebo (95% CI)a1.64 (-10.30, -4.39 (-14.52, -4.33 (-18.30, 13.58) 5.74) 9.63) P-value vs. placeboa0.7870 0.3954 0.5433 ≥ 13 Number (observed / imputed) 22 (21 / 1) 28 (25 / 3) 20 (19 / 1) 26 (25 / 1) Mean (SD) -11.62 (13.46) -10.91 (9.59) -15.60 (12.97) -19.67 (11.53) LS Mean (SE)a-10.75 (2.45) -10.47 (2.13) -15.07 (2.33) -18.70 (2.15) LS Mean Diff vs. placebo (95% CI)a0.28 (-6.08, 6.64) -4.32 (-10.91, -7.95 (-14.32, - 2.27) 1.57) P-value vs. placeboa0.9304 0.1991 0.0145 Overall p-value for interactionb0.8561 Duration of disease (years) < 2 Number (observed / imputed) 14 (13 / 1) 10 (9 / 1) 14 (13 / 1) 12 (11 / 1) Mean (SD) -7.17 (10.41) -12.50 (9.27) -14.54 (10.00) -19.20 (11.00) LS Mean (SE)a-7.07 (2.94) -10.62 (3.36) -16.30 (2.66) -17.20 (3.03) LS Mean Diff vs. placebo (95% CI)a-3.55 (-12.28, -9.24 (-17.02, - -10.14 (-18.42, - 5.17) 1.46) 1.86) P-value vs. placeboa0.4248 0.0200 0.0164 2 - 10 Number (observed / imputed) 15 (15 / 0) 16 (16 / 0) 11 (10 / 1) 12 (12 / 0) Mean (SD) -13.42 (14.67) -10.83 (9.70) -15.56 (14.75) -17.51 (11.39) LS Mean (SE)a-12.83 (2.86) -9.73 (2.58) -12.88 (3.03) -16.44 (3.07) LS Mean Diff vs. placebo (95% CI)a3.11 (-4.51, -0.05 (-8.24, 8.14) -3.61 (-11.80, 10.72) 4.58) P-value vs. placeboa0.4239 0.9909 0.3878 > 10Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) Number (observed / imputed) 3 (3 / 0) 4 (2 / 2) 1 (1 / 0) 4 (4 / 0)1-fold Number (observed / imputed) 17 (17 / 0) 16 (14 / 2) 11 (10 / 1) 18 (17 / 1) Mean (SD) -12.60 (13.61) -8.61 (9.50) -18.22 (14.88) -15.87 (11.07) LS Mean (SE)a-12.27 (2.76) -7.64 (2.73) -15.75 (3.11) -14.92 (2.59) LS Mean Diff vs. placebo (95% CI)a4.64 (-2.96, -3.48 (-11.69, -2.65 (-10.05, 12.23) 4.73) 4.76) P-value vs. placeboa0.2316 0.4057 0.4837 2 to 4-fold standard dose Number (observed / imputed) 14 (13 / 1) 14 (13 / 1) 15 (14 / 1) 10 (10 / 0) Mean (SD) -6.32 (12.80) -12.81 (9.00) -11.75 (9.14) -24.73 (10.10) LS Mean (SE)a-6.56 (2.90) -10.93 (2.77) -12.98 (2.55) -20.96 (3.15) LS Mean Diff vs. placebo (95% CI)a-4.37 (-12.30, -6.42 (-13.94, -14.41 (-22.75, - 3.56) 1.10) 6.07) P-value vs. placeboa0.2798 0.0942 0.0007 Overall p-value for interactionb0.1610 Baseline Eosinophils (10^9 / L) <0.150 Number 16 N / A 11 14 Mean (SD) N / A N / A N / A N / A LS Mean (SE) -13.06 (2.87) N / A -13.60 (3.19) -20.09 (3.11) LS Mean Diff vs. placebo (95% CI) N / A -0.54 (-8.95, 7.87) -7.04 (-15.34, 1.27) P-value vs. placebo N / A N / A N / A ≥0.150 Number 16 N / A 15 14 Mean (SD) N / A N / A N / A N / A LS Mean (SE) -6.89 (2.77) N / A -14.57 (2.57) -14.80 (2.58) LS Mean Diff vs. placebo (95% CI) N / A -7.68 (-15.25, - -7.92 (-15.27, - 0.11) 0.56) P-value vs. placebo N / A N / A N / A Baseline Eosinophils (10ˆ9 / L) < 0.165 (Median) Number (observed / imputed) 17 (17 / 0) 16 (14 / 2) 13 (12 / 1) 14 (14 / 0) Mean (SD) -12.63 (13.99) -9.46 (8.63) -11.24 (8.98) -21.57 (13.01) LS Mean (SE)a-12.47 (2.71) -7.71 (2.71) -14.30 (2.83) -19.82 (2.96) LS Mean Diff vs. placebo (95% CI)a4.76 (-2.75, -1.83 (-9.50, 5.84) -7.36 (-15.23, 12.26) 0.52) P-value vs. placeboa0.2139 0.6397 0.0673 ≥ 0.165 (Median) Number (observed / imputed) 15 (14 / 1) 14 (13 / 1) 13 (12 / 1) 14 (13 / 1)Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) Mean (SD) -6.40 (11.83) -11.84 (10.30) -17.73 (14.16) -16.50 (9.30) LS Mean (SE)a-7.12 (2.93) -10.83 (2.83) -14.13 (2.87) -14.63 (2.71) LS Mean Diff vs. placebo (95% CI)a-3.71 (-11.80, -7.01 (-15.24, -7.52 (-15.32, 4.38) 1.22) 0.28) P-value vs. placeboa0.3686 0.0948 0.0590 Overall p-value for interactionb0.3253 Baseline Eosinophils (10ˆ9 / L) < 0.3 Number (observed / imputed) 29 (28 / 1) 25 (22 / 3) 20 (19 / 1) 23 (22 / 1) Mean (SD) -9.51 (13.70) -10.75 (8.91) -14.90 (12.30) -19.99 (12.00) LS Mean (SE)a-10.16 (2.13) -9.19 (2.15) -15.05 (2.31) -18.29 (2.31) LS Mean Diff vs. placebo (95% CI)a0.97 (-5.00, 6.93) -4.89 (-11.04, -8.14 (-14.29, - 1.26) 1.98) P-value vs. placeboa0.7505 0.1188 0.0096 ≥ 0.3 Number (observed / imputed) 3 (3 / 0) 5 (5 / 0) 6 (5 / 1) 5 (5 / 0) Mean (SD) -11.67 (8.14) -9.69 (12.55) -13.11 (12.32) -14.65 (7.48) LS Mean (SE)a-7.66 (5.36) -9.66 (4.84) -11.06 (3.93) -13.16 (4.09) LS Mean Diff vs. placebo (95% CI)a-2.00 (-16.22, -3.40 (-16.66, -5.51 (-18.58, 12.21) 9.86) 7.57) P-value vs. placeboa0.7820 0.6148 0.4085 Overall p-value for interactionb0.9380 Baseline Total IgE (IU / mL) < 300 Number (observed / imputed) 23 (22 / 1) 21 (18 / 3) 18 (16 / 2) 18 (18 / 0) Mean (SD) -7.80 (13.81) -10.61 (9.62) -15.35 (12.23) -20.66 (12.39) LS Mean (SE)a-8.06 (2.36) -9.07 (2.38) -14.78 (2.46) -18.19 (2.47) LS Mean Diff vs. placebo (95% CI)a-1.01 (-7.60, 5.59) -6.72 (-13.41, - -10.13 (-16.83, - 0.03) 3.44) P-value vs. placeboa0.7649 0.0490 0.0030 ≥ 300 Number (observed / imputed) 9 (9 / 0) 8 (8 / 0) 8 (8 / 0) 10 (9 / 1) Mean (SD) -14.59 (10.63) -9.60 (9.52) -12.53 (12.31) -16.12 (9.22) LS Mean (SE)a-12.46 (3.64) -8.04 (3.57) -14.22 (3.59) -14.94 (3.46) LS Mean Diff vs. placebo (95% CI)a4.42 (-5.58, -1.77 (-12.00, -2.48 (-12.37, 14.42) 8.47) 7.41) P-value vs. placeboa0.3860 0.7351 0.6230 Overall p-value for interactionb0.5123 Baseline Total IgE (IU / mL) < 100 Number (observed / imputed) 15 (14 / 1) 11 (10 / 1) 11 (10 / 1) 13 (13 / 0) Mean (SD) -6.59 (15.16) -11.05 (9.70) -16.26 (11.38) -21.03 (13.37) LS Mean (SE)a-7.30 (3.09) -8.49 (3.25) -15.72 (3.24) -17.40 (3.01) LS Mean Diff vs. placebo (95% CI)a-1.19 (-10.05, -8.43 (-17.18, -10.10 (-18.54, - 7.67) 0.33) 1.65) P-value vs. placeboa0.7926 0.0593 0.0191 ≥ 100Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) Number (observed / imputed) 17 (17 / 0) 18 (16 / 2) 15 (14 / 1) 15 (14 / 1)BHRA+ Number (observed / imputed) 3 (3 / 0) 3 (2 / 1) 6 (5 / 1) 4 (4 / 0) Mean (SD) -8.83 (8.78) -19.94 (5.28) -19.50 (10.03) -22.13 (16.40) LS Mean (SE)a-9.49 (6.28) -17.03 (6.45) -19.58 (5.46) -22.12 (5.72) LS Mean Diff vs. placebo (95% CI)a-7.53 (-24.53, -10.09 (-27.02, -12.63 (-29.25, 9.46) 6.84) 4.00) P-value vs. placeboa0.3849 0.2428 0.1365 BHRA- Number (observed / imputed) 29 (28 / 1) 26 (24 / 2) 20 (19 / 1) 24 (23 / 1) Mean (SD) -9.80 (13.68) -9.96 (9.08) -12.98 (12.46) -18.52 (10.75) LS Mean (SE)a-9.97 (2.05) -8.95 (2.08) -12.39 (2.21) -16.51 (2.11) LS Mean Diff vs. placebo (95% CI)a1.02 (-4.73, 6.78) -2.42 (-8.35, 3.52) -6.53 (-12.28, - 0.79) P-value vs. placeboa0.7271 0.4247 0.0258 Overall p-value for interactionb0.4945aEach of the imputed complete data were analyzed by fitting an ANCOVA model with the corresponding baseline value and intervention group as covariates. Analysis was based on the same imputed dataset using WOCF / MI from primary analysis of the primary endpoint.bEach of the imputed complete data were analyzed by fitting an ANCOVA model with the corresponding baseline value and intervention group as covariates, plus the subgroup variable and the subgroup-by-intervention interaction. Analysis was based on the same imputed dataset using WOCF / MI from primary analysis of the primary endpoint.cAsia: South Korea, Taiwan, Japan; Latin America: Argentina, Chile; Eastern Europe: Poland; Western Countries: Spain, Italy, Germany, Canada, Greece, Netherlands. Note: Descriptive statistics include participants with WOCF imputation at Week 12 and participants whose Week 12 values were imputed by MI were excluded from the descriptive analysis.

[0240] Additionally, participants exhibited a rapid and sustained improvement in symptoms, with significant reductions in UAS7 observed following one week of treatment (see Figures 5-8 and Tables 17-20). In the ITT population, participants receiving 400 mg BID rilzabrutinib had an LS mean change in UAS7 from baseline to Week 12 of -10.01 (p=0.0024; see Table 18). Consistent with rilzabrutinib’s dose-dependent effect on UAS7, participants receiving 400 mg TID showed an LS mean change in UAS7 from baseline to Week 12 of -12.72 (p<0.0001), reflecting a 40.18% decrease from baseline. Notably, the overall reduction in UAS7 observed in both the 400 mg BID and TID arms exceeded the minimal clinically important difference (MCID) of 10 points.Attorney Docket No.01183-0291-00PCT-PRN

[0241] Similar results were observed for the omalizumab-naïve population (see Table 19). Omalizumab-naïve participants in the 400 mg BID and TID rilzabrutinib arms experienced an LS mean reduction in UAS7 of -9.79 (p=0.0040) and -11.44 (p=0.0003) from baseline to Week 12, respectively. Similar data were obtained when these analyses were repeated following the removal of the asymptomatic outlier (see Table 20).Attorney Docket No.01183-0291-00PCT-PRNroirPhtiw bi )0 nD)I00.0.4 0)0)0.02.2 0 1.1.8)0stgitu)4.rT6 1 22) .5.0.0)8.03 10 044 0 / 80 0660 / 9(.01 - 8 -) .0 / 2258 .036 7 - 3 -)0 / 7. .0.09045neniitd bg= 6(.amN(38; ;6(370.(7.21 ; 2 ;661; ;6(9; ;6(.51 ; 2 ;6 a ulszli00.0 1.61.10 20. .0 (3 6.802- 0 0..02(56367. -52.(350 32.8 6.3 0. .00PcnIreR4 33 221 1 42- 0 - 18- 8 0d,d3-6-8- n) )0) )nesopbinD)aI7 0 .0.08 0 .04 .1.0.05 2 .5.5.07 0 Useit )6.082) .42000.5)2 20)7390) .630.80.5n b o aRurB6 7 bg= 6(0.034 1 / 1 5; ;5itme ( (.533; 3 1; / 510 -( (.5 ;0; 1 / 350.- . 5(0;7; 1 / 3 10 . 5(.032 ; 3 ;utealam zNlzilpl(30.0i 00.04 3.01 67 1.20 .00.3 7 1 63 .87- 10.8(62- 69 .52-6.6(6020 5 69-0. .00.0 am R 22 12 411-2-3-6- 91 5up mob0 0)0)2 0o OcninM)C0.0. )C0.0.C.06.06 C.09.0)9 C0.0.PrIeo-itP)ivrbaurQ1 N011)bg= 1(0.044 0 / N055)1;ï0;1((0.022 0 / N011)5;0;1((0.0 - - 0 / N233).06;0;1((2.0 - - 0 / N022 .09;2;1((0.0222;0;PmamN(0.4 a hu.00.10.2.00.11- .00.13-0.10.20.t zzli00 1 1 4 14 5 5 6 6 9 2 52161 3.099 3 22.0222Ni-iwla R 4 4 2 -1- - -3- -2bstm)3 2)0)2)3 4)7 0aneO mio t b)4.5 4.0.321 aec= 4( 9.42 4)45.0.0)69. / .090820 / .520. )3.1.70. )3.5. .072- 0 0 / 917- 0 0 / 5892z; ;4( 5.3 ; 4 ;4( 9.; ;4(.9 ; ;41( 5.3 ; 4uPaillPN(6 99 . 300.(01300.(65- 0.0 (25 10.2 (9928;85.4 45.5.1 44. .08 2145. - .96 144.2 0. .08a 3 633 13 4227-1- -9 1-3- -72 51mbi )0) )1 0)9)O nD( it IT)8.050.050. )6 20 / .20 000.70. )50 / .60.0030. )6 50 / .5 7.353.9)6 0 170 / .6004.20.8d)soir urbg3 58(.03451.023510.- ; ;439.- 1 ;51.023m= 348;0;3( (8; ;3( (7000.3( (50;3 34.( (4; ;reed az nli00N( .320.0.57100.5.51-0.6 4.03- 4 55100.4 92 50 3.77.080 31 13- 386.59- 3.65.070Po dpn R 2 11-2-3- 6 1 o nsitbil eailnD)I0))10.0. )2 0)0)- 9 9 .3 0. .0)1.00. ) .6 7.3.0)2)6 0 .8 0. .0B-RuitpuelerB51.0520 / 10820 / .804 g3 57 to(.03451.0 2458.0 - ; 3 ; 0 / 5339 .11- 1 ; 0 / 40108 .1 22 4eP b = 3 leam 38;zli00N( .720;3 9.5.0 ( (1;57 20;3 0.( (56 481 37.9.000 3.99- 0 0.0.3 9( (92- 516;3.042- 4.3 0( (8; ;49 10 5.5 0.10 35. .010bvï4 2 2 1 19-1-3-1- 91 1upa R6-omN-bi )0)0 0)3)0Deocba niM t P)4.00. )8.07.20820 / .709.0) )40.20 / .1.0)5 6.3.6. )7.001- 8 0 / 65370 / .909.02hnt I- muurQ3 77 bg= 3(10.3478 0; ;3 nbzilam( (10.25; 479 ; 3( (00.; ;72.9 -0.03( (7; 278 6;3( (40.23; 4 ;iaa zli0N(1.300.0 10.7820.076- .05 721- .35.7420.04 3 76 21 3.30.2 85 33.2 17-1-3- 37.1 67 23-8- 3.30.2 0 6 2kmm ReeuO -z )0)i 4 0) )0 o)9.0.0)4. .5.0)1 0 5..0.8)5 0 7)8 .3 7.0)0. .0.0Wla b ye6.3c3 68(05200 / 2 .3 ; 4 ;600 20 / 310.3 ; 46.938(0 5.1 ; 1 0 / ; 6464 7 0 / 0092 335.; ;5310.24bmal= 37800.( (070; (70- 00.( (71- 8.0 ( (95;0;PN(9.20.6 6.825. .061. .50 6 7O82 21 35 10 33 7-3- 3.1 1.100 53.42 30. .08 0Sg 2 2 2 -9-3-1- 2 1AniUd)d)de )d)fuolcete niedeyrnutultutu I p pesap pa,m mesi / dem enii / bmi / mi / eledemodedenilemU vrvub)essa rb)b esrfvrvbe)gerssab)esb)bSa.7mrD eSxao(DxSamoo(DSxanaoxoxm h(DSa(DSao b(n3M reb(n3M rfre(n3Mc1 uz tre(n3M re(n3M rfmnaaiedeQ ; ;naniimaedeQ ; ;enigb mnaaiedeQ ; ;ninbnaiQemaede; ;bnaniimaedeQ ; ;enigelil eba7niu 1 l N M M Q M1u 1 N M M Q Mnau 1 N M M Q Mcru 12u 1naamSek heN M M Q M k N M M Q M h As eeC PeeC T O UaB W WAttorney Docket No.01183-0291-00PCT-PRN gnI,UsbeB6 aRur1 / 10 0.0 ; 0 ; 1 / 344 4.0 ; ; 1 / 318.85 6001430bg=5(000.5(70.05(.582 ; 3 1; / 51( 0.5;0; 1 / 4705(.1; ; 1 / 9.04 metamN((01.0 (02.10(910(11.0.(74.80(uelz0 6.0- 77 6.5- 8 0 61.0.6.8- 42 6.4- 80 5 zilpli04 431 2- -0 48-1- 7.030 52-4- 48-1-am R- -11-4-mocbi )0 .0.0)4 .3.3)0)0 .0)6 OrnIo- niM t P)i1)C 99rbaurQ 0)C 6 6)C0.0. )C 2.02)C.63.73) / N0110 / N44 40N0990N0220N6550bg=1((0.09- ; - 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4 1 -3- 43.53- 0 5 1 5.0 0.5 0 0 1 - 37.7.000 3.01 22.9 1 2 -3- 53.1 3- 10.90 3 6 3 -1-a R3-511-4-N-bbi ) -a niM t P) ) )4 0)0)9 .0.5)4 3 0 .)0 0 .0) )80. )30.0. )mu Q70 / 7.88002 0 / .0.176270 9 0 / 7.0908.0220 / 7.72.080- 2 0 / 6.90 7527- 1 1 / 6 urzilbg3=3 am( (70.; ;5- 0.03( (.6 ; ;369.63( (10.2; 40;3( (00.; ;7- 3.03( (.696;5;8.3(a zli0N(736.0.32 3 - 732.1-3.0 7 3 98- 30.2 20. .07 5 5 31. .37 52- 730.2- 8.162 7 8 3 m 0 R47-1-2 3- 2 19-1-4- -O -2-) )4 0)0)0)3 0 ob) )1 00. )4. .0.00)9 8.0. )00. .0)2. .0.83)e6 c30 / 5.0 0.2 900 / 2 00 1538 30 ; 5 ; 0 / .5010000a.3204 / 5.890 l = 30 0 ; 7 ; 0 / 5730 00 ; 4 ; 0 / 4 N( (.;0;3 513-0.( (7.9 - 5 9. .03 0( (03;20;3(.0 .0 (03-0. .03(.7 3(19-6. .03 0(P(31.5.-082 5 -3- 32.6 0 0 53.6 5.0 530.23531.60 43 1 -3-1- 22 716-1- -9 1 -3-1-)d) ) ) ) )eetunidededeenided ple tsututuletuetu iap p psp p m / bmi / miemiabmimid d / dni / / / eme edmd dvov leeoe errrvrvrv vefe sarf r rsbegsbesb es egeseso()no)bo)mbo)nbo)bo r D eSxa an3hc(rD eSxa(n3rD eSxao(n3rfrDSx3a ahc(rDSx3a(rb( Mt( M ( Me(nMt e(nMenaiQu; ;nbnaiQ ;bnaiQ ;egbnaiQ ;nbnaiQ ;b maede1niecmaede; nimaede; nimaed ; nma d ; nm7ru 1 M3u 1 N M M Q Mnaue1ieN M M Q Mcruee1iN M M Q M4u N M M Q M N M M Q N Seh P k CeP kAeeeeU W WAttorney Docket No.01183-0291-00PCT-PRN bi ) ) ) ) )nDI2 6 0 4 0 .8. .00.5 5 7. .76.8)4 0 1 7 8. .6.02 7.gitniu) .rT600181.010)302 30 / 1.51 - 7 -)0 / 7283 .44 - 2 -)1 / .9.5000.010)401 31 / 1.510 - 1 -)1 / 720 .9d bg=(.5u amNl(88;3;6 .c szli00.0 3.0 ( (0 642; ;6 9.2- 7.02( (8; ;5 676- 4.0 (1 6(.525;0;5 26. .0 ( (0; ;5 612- 00.( (3 617- 14 0.71.00.9 0.01.40.27.0nIreR 4 01 22- 3 - -6- 391- 8 22- 044-7-,desno) )0)-)-)Upbisn eitDI5 0 2 ).5 0.80.5) .6 0.6001.00 2 0) .9 3. )5362.04 0 2 0 0)9.5.90. ) .4 5.8011.04 ).089baRurB6610 bg=( 0.2 1; 3 ; / 410( (.6- ; ; 1 / 440..4(1- ; ; 1 / 60 51 / 106..31- 0( 0.1 ; 3 ;3(9; ; 1 / 450..3(2meutelam zNl0(030 06. .00.1 50 .82- 01(539- 07(520 1.04- .3.39- 47. .00.(020 4.0- 0 .52(094--4.3zilpi4 31 1 23 2 69 9 0 5 83 1am R2-- 6-2-7-mcbi )0 0- -o) .0.0)0 .1.1)0)0 .0.0)OnnM C0.0.C 33 C 6 C0.0.C CrI-itP)i1N088)ra0N022)0N0565)0N099)N02222)N6oburQPbg=(0.01 1 / (8;.0 - - / (.1 - - / (.01 1 0 / (.0 - - 0 / (.60;1(03;0;1(06;0;1(09;0;1(02; ;1(63 mamN(0.10.1.02-0.1.1 5-1.10.10. .02- 00. .65-huzzli00 8.08 3.03 6.16 1 8 123 6 9.01 991 2.01 22 3tii1 - 22-5- 55- 12-2-5-wla R 4- -12-stm)0)7)8)4)8)n6 0.e68.3.4.62 73.12 Ot9 9.iob) . .0 1.21.211 0.3. .3.4 0572)ae 00518 -)6332) .1877)1.834 - 4 -)31 Pc= 1 al( 6.20; 3 / 1.3 - ; 0 / 2.9 - - 0 / 13.33 0 / (.3 ; ; 0 / 2.95;4( (37;0.04( (35; ;4( (8; ;4(410.04( (99 PN(3 .82.04197.16.1- 3 45.4- 76.42200.4.41- .59 46.2- 1 96.1 53- 95.64.5 0.6 1 8 68- 7 8111-1-1- 0 1 -2-4-i- 23- b nitD)I )1 0 6.0.0. ) )9 0)0) )0 / .7.580. )07.0.70.65)0 3 0.6 8.0. )7 0)0.6.090. )0 0.8u T539098 290 0- 2 / 2929 03- ; / 30098 / 3117- 2 / 3330 rbg=(.01am 54; 3 ;3(.4; ;3(.1;.031(.01 33( 1.5; ;3( 0.0 zli00N( .610(1 4 41.50.2 80 35.51- 0 5.0.5(29 1 23- 3.1 5- 9 13.00(3141;0; (4 31- 3.43.00.0 33.71- 0 60.0.2(44- 32 3.45- 4n R -2-5- 7 o - 1 51-2-5-itbi ) )nDI1 7)7 0). .00)9 2 5. .3) ))6 0)5 0).0.0)5alit ) .7.1.0 0 / 90 5.0 / .6801 / .3.0.0 1 / .5231 / .7uu B5311022 310 .0 - 3 ;3534 . 1- 133042 3117- 13939porg=(.02 ; 4 ;3(1;3( 91; ;31(.5243(.62; ;3(.80P beam 24 z0N(9.10(9 0.0.33.41- 0 5.0.8(35 3.54- 20..90(26 0 4 1;0; (6 32.0.0.4.51- 7 6. .83(47 .04-vïli04 5 0 3 23a R 1 61--2- 6 4- 61- 7 0 32 1 1 51-2-3- 34 4-N-bbinM)2 0 .0) ) )7- 0 5 40. )35. ) )8 0))2 8)8. )3aitP)7.808.021 / .201 -.01 1 / 5.684 -.43 1 / .1.537.021 / .5902 -.01 1 / 6.66mu Q38269;62.8 ;5925;52urz g=( 0.ilba 1; 4 ;3( 0.;0.3(1;3( 6.8; 4 ;3(55.;3(.87a zm li0N(2 9.20 0 10. .0 (87-30(122 72 731.9.0- 43- 739. -9 7.3.13(318(89- 636.02. .06 50 3.68- 3.00.31(53- 66 34.2- 2m R4 11-2 4- 2 11-1-3O- -)0 0) ) )o.0)7 0 .00. )3 6 b) .0 0. .7)6)2 0).5)5 0 0. .0)1 5.e62.c3 2109.05a.2204 / .14112 l =( 402 ;1 0 / 4143 .80 ; 6 ; 0 / 3.2934.0 03 / .904 .220438(.0 - ; 7 ; / 3928 .4PN3;( 9 .020;3 .0 ( (.443- 0;3 0.0.( (4436 51-5. .03 0( (16; ;3 33.10.0 (600 3.61- .0.03 3( (390 64- 20.40 3.6645 1 -3- 3.1 5 50 1 380.1 20 30.1 73- 35 2 1 -2- - -1 -1-3-)de) ) ) e)etunid letdetdetnid letpeesu ap up upesu ap m m m m m nii / b i id / d / denii / b i / leem savroevedv leemdvoev )b esrf r r rbee e sae rf reeo)gsb) sb)bsb)gsb)Dxam DxanaoDxaoxmox nao S o((n3rfreSn3hc(reS(D n3reS 3aorf(rDS 3ahc(rDS naaiedeQ M; ;eb( a1nig nmn uaiedeQ M; ;tb( a1ninecmn uaiedeQ M; ;b(n na1nimuaiedeQ M; ;eegb(n 1ninmnauaiMedeQ ; ;t enb(n 1niecmnauaiede7 M M Q Mah N M M Q MreN M M Q M5N M M Q Mah N M M Q MreN M MS C P k C PAeeU WAttorney Docket No.01183-0291-00PCT-PRN bi3)nDI6)0) ) ).6.5 86.1 0 9 2 8 9 0.0. .0.0 0.- 88.gitniu)rT65 - 2 -)1 / .4100.060)482 31 / 1.510 - 1 -)1 / 826;.6002)2.5- 1 / 010.054.0)40 101 / 1.0d bg=; ;5 u amNl(4.0 (1(.0 ;0 30;5(6; ;5(90. ..c s0 (32- 00.(08- 02;5(.1 0 6.0 (71; 30;5(6 .0 (61- rz eli002.0 4 5 0 6 1.-0 0.7 00 60.60.92 644.-81- 00 6.1 012.60 68.0nIR,d9-2-e)3-7- -1 )2-)snoUpbi )sn eitDI )- ;.05 3 1 0) .4 3.30.5) .80 80.00.38 2) .90 41.0 1. )9 0 8 0 1 1) .7 0.10. ) .590baRurBg609 =.0.5 ; 1 / 5131 / 102.04( 8.2 ; 3 ;4(.6;0; 1 / 5124(.6;0; 1 / 5 41(0 5 0.2 1; 3 ; / 41( 0.5meutb elam z0N(0040(350(720 0 50. .00.0 5.9- .0.56(6835.2- .3 0.(02 6 00 56.0(0 .00.20 5.4-zilpli41-1- 3 1 83- 49 11 0 0am R 11- -5- - -12-mocbi6 .6.7)0)0 .0. )4)0)OnnM0.0.C0C.5.5 0.0.CrI-itP)35 35)C 077)N04242)N485 85)C 077)N0oirbaurQ1- - 0 / NPbg=; ;1( 1 1 0 / ((0.07; ;1(0.04- ; - ; 0 / 1((4.58- ; - ; 0 / N 1(0.01 1 0 / (7; ;10.04 mazmN(6 .6 7.10.10 .00.1.042- 0 .00.1.55- 4 .5 5.(10.10 .00.(1.02-huli0 3 3 7 771 44 8 8 8 7 7 4tizil0 R 4 55- 1 12-22-5- 55- 1 7112-wa - -stm 6) )-1)n.e5.04 0)1 2 4 5.72 0)O 0 0t2 0.0. .0.3.0.8.0.1iob)1 1) .1052)2.826 ae4- - 1 / 10 - 0)35510)5.0072) .12 a.34 1 / (.9 ; ; 1 / 2.9 - ; 1 / 13.34 1 / 7 l6Pc=;3;3( (6;0;3(130.03( (44;.93( (1; ;3( (1.PN(8.9.4520.4.71- .09 4 0 2.2 5.5 1 74.3- 7 5 45308.46.8- 55-- 72 9111-1-1- 11.3- 745- .309.2618-3 2 - bi0 n3i. ) )tDI )0.38)3 0 0.2 0.0. )3 3)0 0.0.845. )69.5.0.77 2) ) )4 7 8 03.6.0. )0.4u T533- ; / 11010 / 1210- 3 / 15331- 1 / 09086 / 0010 rbg=;.031(.02am 4 0(04; 43( 0.5; ;3( 8.7; ;3(.01 33( 0.5 zli00N(1.0 1 17; (4 21- 3.14.60.1 40 3.91- 0 50.0.7(73- 17 3.04- 3023..0(44 1 0 0 1;0; (6 3.53.00.0 03.51- 6n R48- 11-2-5-8-1- 1 61-oitbi9 nDI .6.8) ))6 3)2 0).0)8 3) ).3.3)7 0)0alit )7 41 / .7.8.0 1 / .420.1 / .18 31.9.0.0 1.2uu B53- 4 ;321062 3118 .0 - 33936- 1 / 31862 / 3115porg=;3(.52 ; 4 ;3(1; ;3(.08; ;31(.82 ; 43(.72P beam 60.z0N(5.0(26 0 4 10(6 30.0.0.43.71- 0 0.0.2(49 .83- 3 3.0.0(54 0 45.10; (3 6.0.4.01-vïli04 0 a R8-1- 7 0 2 431 41- 3 -2- 3 3 3 4-8-1- 5 0 34 1 51-N-bbi2)0)6 7)0)0)M.0a nitP)24.2)2 14. .08.0)15.6.2.3)7.0.01 1.0 0)3 20. .08.0)6 0.muurQ71 z g3- ; ; / 0i.305 31( 2.22 / ;430 31(0 0.- ; 3 ; / 30 3301 (.3 - 1 / ;;100 31( 2.222 / ;410 31(0 0.lb = azm 0 0(18 0N(7.0 4 10; (99- 7.03.2 0. .047. .61(477 9.3- 2 1.0. 0(18 0 3.110; (02 ..039.9-ali8 R140 31 23- 35 8 3 0 30m 04 4 - 02 11 2-3 1- 12 411O -- -)5- -9 o.8.8))7 0))3 5 2.0. )1 9 3.0))4 0))7 b)e6 3 3 c3 1- 4 ; 1 / 9. .08.01010221 / .302 111 / 5. .1 51 / 8. .08.0 1.610- 11939 .5 - 7 ;201022 / 2010 al=;PN(0 0.03( 0..0(1; 4 ;3( 5.;0;3(6;7 3( 0.1; 4 ;3( 0.27 .620 5. .0 (267- .40.0(20 6.2- .0.00(38 .720 2. .0 (397- 0 0 3 00 3.34439 6 0 3 10 3.15-1- 91 19-1- -2-5-1- 91 19-)d)etd uee) ) )tnid letdetdetp upeup up up mi / emsia / bmi / mi / emid nid d d ni / evrleem vrorevevledeve saef r rsa rsx b ()bsbe)gesbesbb esb a oDSxamoo(DSxanao()Dxo)Sa(DSxamoo()D 3ren3rfre3hcr3r3rfrS QM; ;b(naiQ M1iue e; ;egb(n naiQ M1inuee; ;t enb(n naiQ Me1ieuee; ;b(n naiQ M ;eegb(n nanma d nma d nma d1nimuaede;1ninmuaiedeQ M6N Ma cr 7a7 M Q M N M M Q M N M M Q M N M M Q M NS k h eeCeh M M P keCAeU W WAttorney Docket No.01183-0291-00PCT-PRN bi7)4 nD) )0)5)I1.0.4 )4. .86.68)6 0 2 .0)5. .03.06 2)6. .26.18 7 0.0gitniurT)g68 = - 7 ;- ; 1 / 8932 52(.2 - -d b; ; 1 / .2100.0 51.07 ; 3 1 / 2811 51(.5 - ; - ; 1 / 5082 52(.9 - -);; 1 / .0100.0 51.07 ; 3amN(0.0 (51 5 - 1.0 ( (030; (35 2 - 00.(64 8 - 2.0 ( (943;ulc srz eli00.04 62 69.7.0 3 -4- 8 50 6 1.5 0. .07 20 65.50.52 694.-81.0 40 6 1.8 3. .07 2 0 nIR5- 8 -2-,d3 7- 9 - n)- -) ) )-eso UpbisnDI0 .0.01 0 .5.0.07 0 3 0 2 2 00.1.0.0.6 5. ).08 3 80beitB)aRurg600)=; ; 1 / 39045( 5.; 0) .65. .0; 1 / 095)902 41- 0)109- 0) .75. .01 3 1 / 095 41( 0.; ; 1 / 45( 3.; ; 1 / 411 3meutbm elaz0N(0 .00.(22.0.00( (0.1; ; (0600.(660 52 5.59- 00 50.0 .0.5.02-0.2 5.1 9- .0.00( (70.1; ;00 51.00.zli04- 8 01100 1 54- 1 011.00 ilp R 43-5- 1 - - 1 02-3-6- 1 - 1 0 am m Ocnbi0 i.tP)04.04 -o) )0)0)8)0 nM 4)C.58.58)C0.60. )C.05.05)C.90.01)C0.0.rI- 22 N455 N0 6 N022 N866 N088 oirbaurQ1 bg=- - 0 / 1(.5 - - 0 / 1(.01 1 0 / 1(.0 - - 0 / 1(.9 - - 0 / (.01 1N ;0;0 (4 .58;4; (06;0; (0 .05;0; (8 .90;8;1(08;0;Pmam( .15-5.10.10.12-0.16-0.10.10.a zli0 12- 3 - 3 71- 31 40 30 - 73- 3. -3 41- 30.40 m R42-3 5- 2 11-1-3 5- 2 1 O- -0) )o0.0 0 .0.0)9 0)7 049 8.3)1 0 b)5. )9.05) .4)5. . )6.2.3) .0e6 2 c3 - 21; 1 / 7817 1 / 9.109.021 / .7;2 100 33(.8 - -11 / 9116 1 / 2.108.02 ;;2310.2 ; 42310.; 1 ;233(.8 - ; ;1310.24al= 00.(61 2 - 0.00( (1810; ( (67- 00.(33 2 - 8.00( (50;20;PN( .040 3 1 37.0.0 33.3 5. .0-4- 9 0 33.6.087 330. .570 23.6 0. .00 2 - 5 5 -1- 91 019-1-3- 2 3 -5-1- 02 41 e)id) ) e) )n d d leetnd d suetet ieteap up uplesutp up bmi / mi / emia / bmi / miod d ni / m redmd dfvervrleesavrorefvervregeseses eesesxnbo)xbo)bmbo)g nbo)bo)3a a(DSa(Dxao(Dxa a(Dxa(DxaQM hc;;trenb(n3M reS 3 b(nM rfreS 3hb(nMctreS(n3M reS(n3MmnaaidQ ; ;mnaaiQ ; ;egmnaiQ ; ;nb mnaiQ ; ;b mnaiQ ; ;1niecuee1ni8uede1ninauaede1niecuaede1niuaede1ni7 Q MreN M M Q M k N M M Q M h N M M Q MreN M M Q M9k N M M Q M S P AeeC PeeU W WAttorney Docket No.01183-0291-00PCT-PRNcnI,UaPtiwiP noitbailnitDI ) )6 0 .4.040. )8 .3 3.5.04)6 .30 5. .0)9 0 .5.59 40. ) .1 - ;.02 upB51 / 110- 6 1 / 04712 1 / 40321 / 110- 8 1 / 149063ourP bg3 8 = 2( (.017; ;8 07.2( (.7 - ;71 79; 0.2( (.532 ; 47 ; 2( (.514; ;7 00.2( (.710.0.07;0.eam zli00N(92.51- 40.5 23- 92.25- 70 8210 3.60 22.0.0.0 82.01- 40.2 43- 88 2.85- 010 01- 0vï4 a R1-2-5- 19- 1- 51 01-2-5-1-N- )0)7) )0)4bbinM)90. .3)3 8.68. )9 0 .0)0 20. .3)9 7.3.0aitP)3 / .9053 / .7868 3 / 6.8.0 3 / .0033 / .9 0 0 mu Q73 19.0 - 3 ;12.51- ;101022 11.0 - 3 ;1201- 1urg= 3(51;l0.03(2; 0.3( 0.7; 4 ;3(0;3(.76; ;zibam a z0N((43.711- .08(46 32.3- 2 7.00(4710(3 3.2 0. .0437.1- 0 .5.04(45 31.3- 7 0.0. 00 mli0 73R41-1- -6 3 O - 1 51- 02 40 1 1 831--1- 6 3 21-)o) )0 5) - -1 / .0 2.07.3)8 9 1 / 0.3. .316)4 0)1)7 0)6-) / 2. .0 08.0 1. )0 0.3 / .5.041 / 2. .06 be6 c3 110- 11838 = 31( 0.;.8 - 5 ;221322 2100 ; 12243 .30 50;3(2;7.3( 8.9; 4 ;31( 0.3;3(3;3;alPN((257- 3.3.00.(028- 45 2 1 39. - .000(310(48-3-3- 6 90 33.7 5. .00 33.2.0.(8 65 339.3-3. .03 00 2 -4-1- 91 019-1-3- 0 3 -5-1-)dee) ) ) e)tunidetdetdetnidetpleup up upleup emsasanii / bmi / mi / emi / bmi / ledem s odedenil demdeavrrfvrvr es vrorfvrbesbegeses abes egesmoo rf()r Dxanb ao eS()b Dxao)Dxambo)Dxanb ao)Dxan3hcreS(n3reS o n3rf(reSn3hc(reSn3 eb(naiQ Mtb(naiQ Mb(naiQ Meb( aiQ Mtb( aiQ Mg namuaede; ;1ninemuaede; ;1ni0muaede; ;1nigmnaede; ;ninemnaede; ;niN M Mcr 1 nau 1cru 1 7 h Q MeN M M Q M k N M M Q M h N M M Q MeN M M Q M S C P C P AeeU WAttorney Docket No.01183-0291-00PCT-PRNstm 1 0 3 0 1.49 0 9 0 neOo) )2.70.09.02)5.060.90.0)6.05620. )3. .0.0)5.000.0.itb aePc4=1 / 10a.24 1 / 1 l 3(.5 - ; ; 1 / 4(.6 - 0 ; 1 / 120 0.2 42 41 / 2.00 ; 0 ;N(( (831;7;3(83 2 - 5.53(03;62.32( (741;0;2( (45 23 8. .8P 4.5.34371. . .78 44. -3.4 3.039. -0 1 62 1 332--3- 5 5- 489- .680.- 1 0 0 1 0 2-4-4- bi ) )3 0)2 3) )0 5 nitDI )4 0)T)50 / .5000.08.70 / .51.0088. )3.0. )0 5)90 / .24.7.0033 5 31 / 9.51.70.51 / .41281 urbg3 1 = 31(.02amN ( ; 3131( 0.- 7; ;133( 0.0- ; ;79 2(.21 3721( 9.- -8; ;16310;0.(131- 0 0.0.8(116- 90.0(02; ;8 100.(41- 0 5.0.zli00(4 3.13.040 3.17 7 23- 3.068.8 0 1 - 2.011.08.02 1 0 29 8 24- n R 11- -5- 8- 1- -oitbai ) )lnitDI ) )0 0)3 0)5) )0 51 / .830.02.021 / .8.01040. )00. .0)1 0)8.006 1 / .29412 4 22 / .93.0.0 2 / .0204.upourBg3 821.224821(.0 - ; ;823(.1 - ; ;4 062 21.02 4421(.8 - ; 1 ;P b = e am( (61 z 1;0;0 (69 1 - 0 80.8(27 5 - 90.0( (141;0;2 0(91- 08.0 vïli00N(9 4 20.50. .40 92.84.33- 92.81.16 5 0 26.0. .0 62.440.24- a R 11-2-5- 81- 51 21-2-)-N-biM))6 0))0 0 2))8.8 8. )7 0)6 7 ba nitP)3 / 1. .08.0 3 / .6 00.3.3 3 / 1.0 28 3 / 0. .08.0)3 / .3 6.3.3muurQ73 0110 0.22 4 09(.0 - ; 3 ;0391 z(.1 - ;7117 8.22 4 79(0 7.- ; 3 ;ilbg= 3(am liN((370;20;3 .0 (8 3.21 1 - 0 .0.03 1(344;30.3- 00.2 0( (002;20;2 .0 (7 0.58- 3 .3.01 a z0 3.1 0.0 31 6330.0 3.0 0.0 30 734 12 411-1- -5 3 01- 2 411-1- -m R -5- 2 O)2 0) )ob) )1 000 0.0)4 0)0 05e61 / 3.2.0.0)1 / .90.0.6)1 / 4.53.05)1 / 0. .5.0)1 / .2 5.0.0 c3 2310 0.8 22 4 211.20 ; 1 ;240 7(.3 ; ;1315 7.8 22 4 1310 0.- ; 2 ;al=( (912;3;3( (80 1 - 0 3 0.0.(93 3 - 1 1. .03 0( (271;7;3( (18- 00.PN(33.8.03 93.1 90 3.0985 36-1-3.2 - 39 1 2 -6- 0 1 - 3.3.02 91.0 3.7.585 1 89-1-3-)d)etde )d)d)deuetnietete nip upleutp u ulemi / emsap p m m ni / b i / i / emsia / bde idemded nidm vrlevovevleev o essa rrf r rsbb es eeses a resrfeo()xmbo)g xnbo)xbo)bxmbo)g xnrD eSao(D b(n3rfreSa an3hc(rD eSa(D n3reSao(D n3rfreSa an3hcnaiQ M; ;egb(naiQ M; ;tnb(naiQ M; ;b(naiQ M; ;egb(naiQ M ;tn 1 muaede1ninmuaede1niemuaede1ni2muaede1ninmuaede;1nie71N M M Q MaN M M Q McrN M M Q M1N M Ma crS k h e CeQ M h N M M Q M P k CeP AeeeU W WAttorney Docket No.01183-0291-00PCT-PRN hgu orht.96- 80.(0(0( tn 0 6.-90 0 1aoi66-cit)- daeun 6 0 mit6.0.0.0) ) eno 50 (.01 ; 0 ; 0) / 0 / 0 / uccsi040 0.0.0(0(0s(er / d7.6- 0 0 0 0 0 n 4 5 0 0 - 11-deoit)- ti9 2 .8 5.8. )4 0)0)7binhev 13043 2 -) .7.020.15.or ret1000.6) .620. .380.(0.- 6010)5520 pni; ; 2 / 31(.03 ; 3 2 / 3( 0.- ; ; 2 / 32( 9.- d ;; ety 20 .36- 4.00(0020;21.50.(0 4.4 1 - 00.7(45 4 - 07.6cedu 6- 7 0 91.-410.5 2 4 7 10.5 11- 411- .280.3 056-letssr)-- -- tset9 7f.8 6. ) ).2 0 9 0)4 3 3.opaa766912) .5 0. .0) .7.03020. ) .0.0858- 0atata3(.7 - ; 2 / 7022 07;31.02 4 2 / 31(.0 - ; 0 ; 2 / 4(.1 ; ;Ddg .24.-700( (041;0; (03 1 - 00.3(08 40 .0.00.ni0.60 50.5 5- 191 6.0.0.440.9 82- 5.3- 1 00d0edssi)- - 51 01-2-5- 11- u 0) ) )- lM 0cn.3.52 3 6 0 4iF 3.28.8 2. .0.3 3.0.1. eC 82718) . .3.0)60)6701 reO (.6 - ; 4 / 6001 39;313 4 4 / 3100(.0 ; ; 4 / 34(.6 ;0; w2.2- 50.0( (0.05;0; (48 2 - 0 4. .0 (26 80.0.0nWy 31.0 7.07 3- 8 4-1- .7 410.0.8 7 1 631 02-1. --3- 6 0 6 00 -1-1-oitabd unet)2 3.9)9 0)0)6 0.1 itu np 1.0.31.01.0.5 2. .06 m 862 1) .3 8.0) .20)05oci4(.7 - ; 1 ; 2 / 10 5.25 32 / 01.00 ; 6 ; 2 / 5.30 ; 3 ; sidn 16 260.3( (04;20;3( (01 10 0. .03( (22 33 3. .0 dna3. - .30 50.05 - 8 59. -0og 1 8 3 0.1.-6-1- 22 30.34 27-1-1- 5 30 2 -3-1-itn neissviretm)d)etde)nottuetp unid pleetiu y p desemsiautre / emi bmi sw deni / vrled / em v oderetf )w erssaesrfevraedei)b DSxao()bb Dxamo()gsbetveDxanao()Dxacerla( n3MyreS(n3 o MrfreS(n3M hctreS(n3llMoccinaiQdbnaiQebaiQbaiQ da ; ; utm; ;gmn; ;nmn; ;a eede1niSaedeM M Q Mfu 1ninauaede1nieca d n toN M M Q M h N M M Q Mruee1i aN M M Q MDmd CeP:dneetd on E NilbAttorney Docket No.01183-0291-00PCT-PRN r a oe 1 7 7 1 5 1 1 5 f 0 0 8 0 3 0 0 7 6 9 obuela 0 0.0 .08 .00 5 0 9 0 5 2 0.1 . 7 0 0.1 7 0 0 3 ec cv- 0 000.30.00.20.0.0.4na< < < 0 0 0 elp p r ef.sfivdebi ) ) )n -,-, ,-,-,5 -,-,2 -,-,6 gita 7 3 9..629 6 7 0 9.46 8 4.98 ) naunhrn ba)I .83) .77)6) .63) .90) ,0.52) .32) ,6.50) .45) ,0 aeC 4oC- 0 0.3- 4 1.2- 54- 6 9.3- 63.4- 3 1.3- 92.4- 8 73- 89.itzlM%(%irS 46( ( 8302.1(35( 56.0 32-(4( 2.2 42-(.0( 0.0 62- alL5 9( .91 9.91.21 3 2.89.27(214 2.3.3 (816 2.6.7 (7 u2-2-1-2-1- .38 2 8 1.95 2 0 2.9p6- - -7- -5ea- -o ). - . .A8a-6-8- - -7- - -6- - -U ) nim E o S)5)8) ) )0)3) ) )7)0) ) )4)7) )erf(n.41.40 8 15.4. .5.55 5.3 5. .5.63 6.2 6. .6.68 6.8 6.nee ilgna nile(2(1 1(1 1 ((1 6(2 1(1 1 ((1 5(3 1(1 1 ((1 8(1 1(1(esahesM.7aS 2.04 1 0 1.43 7.8.0.84 3 5 1 0 1.13 8.3.1.30 6 5 1 2 1.59 9.5.7.45 7 4 3.57 .0a C b L- - - - - - - - - - - -1-1-9-8- B e m n)3)5) )5)4)3) ) ) ) ) ) ) ) ) )oil )ersD1.3.63 7 15 1 5 7 2 0 9 8 0 7 0 2 3 6 9 f aS 01 116. . . .8 01 01 118. .8 017. .9 218. .17. .27. .1 eb-(n(5(8(4(7(8(0( ( ( (8(1(9(1(8(1(gtsa 0 8 2 3 3 7 3 2 2 5 oe.96.99.83.36.54.59.43.83.44.67.91.6.9.6.8.8n P M 1 1 2 2 1 1 2 2 1 1 2 22 31 51 12 12 ah C) )7)9)2)6) ) ) ) ) ) ) ) ) ) ) )tneD nS.5.1.3.57 .59 .12 .36 .57 .59 .12 .36 .57 .59 .12 .36 .5c(8(7(7(8(8(7 7 8 8 7 7 8 8 7 7 8 eileesna 8 8 1 2 7 3 7 9 8(81(27(37(98( ( ( ( ( ( (81 2 7 3 7 9 8 8 1 7 7 r ae.B M 9.2 0. . . . . . . . . . .2.3.9.3 13 92 92 03 13 9 9 0 1 9 9 0 1 9 P 2 2 3 3 2 2 3 3 2 dn n 14 14 83 04 14 04 83 93 14 14 83 93 83 83 83 83 a eD DIMD DMD DMD DM gIPI IPI IPI IP nTgBgQgTgBgQgTgBgQgTgBgQa g h m0 m0 m0 m0 m0 m0 m0 m0 m0 m0 m m C 0 0 0).40 0 0 0)0 0 0 0)0 0 0 0 0 0)0 b4b 4b44b 4b 4b44b 4 444 4 44 8i1 nitni=i i i=ibibi=bibibi= iiniN nininiN nininiN nin n N el1 utr )utr )ur )(toutr )ut)u)(tut t)u)u)(tiut)iut)u)(b kb1 b1 b8b2r ro aeeaz4az4az3eckb1 b1 b8b3r r ro eaz4az4az3eckba1 b1 b8b4rb1rb1rb8ob z4az4az3eckaz4az4az3ecTlWi=lRN( i=lRN( i= RN(al elP Wi=lRN( i=lRN( i= RN(aleelP Wi=lRN( i=lRN( i= RN(aleelP Wi=lRN( i=lRN( i= RN(alPAttorney Docket No.01183-0291-00PCT-PRNra oe 42 8 2 9 9 5 8 7 0 9 1 0 ofbuecelca 0 3 v- .03 2 .12 0 .90 6 .06 9 .07 0 .30 6 .00 0 .06 4 .30 7 .00 8 .07 .6nalp 0 0 0 0 0 0 0 0 0 0 0 0erpef.sfivdebign -, , ,-), ,1 -,-),7 -,-, ,nitna 8 0 .19 2 5..958.1, 0 4 8 4 8 1 auhr)I .5baeC6 51. ) .3)0.6) .2, .6.9 3. )3)-52- )45 1- 5 3 4- 33- )8 33.0 4- 95 3)8 - 84.8 3)-26 3)29 1- 6CazlM%( 8.7(83.7.1.3( (23(160.35.12-(0( 6.2 52 ( 9. -6( 8.5.5(2 %irS5 1.8 7.1 21.7 (016 -(8 0 8 3.1 L9( .22 0 2 -1-0.-27 4 4.62-1- .25.40 6.72.4137 2-2- .1- 72-2-ea- -) nES)0)7)0)0)9)2)2)5) ) ) ) ) ) ) )eil(n3 3 4 4 8 9 0 07 5 8 5 1 7 5 6 8 8 6 8 6 9 0 gesan.a 5.( 5.( 5.( 5.( 5.( 5. . . . . . . . .9.( 6(6(5(5(5(5(5(5(5 5 ahbe 1 .07 .62 .50 2 6 4 0 4 0 0 4 2 4(2(4 CmoM.8.1.6.1.9.9.8.5.3.6.2.2.8rS 4 5 2 4 2 3 1 3 4 5 1 4 4 3 6 2 7 4 7 4 3 5 1 %fL- - - - - - -2-5-4-3-2-5-5-3-3- a roe 34 30 19 22 14 51 71 07 17 23 50 42obuela 0 .05 .20 .90 .03 5 0 1 2 1 2 3fcv- 0 0 0 0.10.40.00.0.4.0.0.8ecalp 0 0 0 0 0nepr.sefv) ) ) ) ) ) ) )fibi3 .04 5 2) ).72 2 4 .78).97 9 6)7 den gtn).8.2.1. .2.8ia I2-,1,4,2-,10, 3,2-,0- .,72,1-,0- .,34,nura beC2 .96 7 5 .30 8 6 .82 . 5 6 6 3 ahaM0.07.72.4.7100.5.01.30.4CzlirS% L519- -4-(( ( 11(6 -8-6- (( 14(8 -( 1-6- (( 19 -( 1-5- ((3enil )3 s60 7)5)1 2 4 8 8 0)5 5)1 7 5 3 0 9 eD. .S 01 310.97. .9.2.1.9 11 21 01 113.3.9 219.1.11.02.34.09.1 a( ( ( ( ( ( (9 1 1 1 1 1 b- n 2( ( ( ( ( ( ( ( ( (tsa.74 .48 .50 .35 . 1 2 1 1 4 8 2 3 9 1 6 oe 2 6 09.5.1.5.3.0.9.9.3.5.0.7P M 1 1 2 91 21 61 02 02 31 51 02 02 21 31 12 91 ))7)9)2)6)7)9) ) ) ) ) ) ) ) ) )D.5.1.3.5.5.12 .36 .57 9 2 6 7 9 2 6 eS 8 7 7 8 8 7 7 8.58.17.3.5.5.1.3.5nil(n( ( ( ( ( ( ( ( ( (7(8(8(7(7(8(esa 8 8 1 2 7 3 7 9 8 8 1 2 7 3 7 9 8 8 1 7 7 8 1 7 7 ae.9.0. . . . . . .2.3.9.8.2.3.9.B M 2 3 13 92 92 03 13 92 92 03 13 92 92 03 13 92 n 93 83 73 73 73 93 53 63 63 93 43 73 43 83 43 73 DIDIMPDIDIMPDIDIMPD DIMP TB Q T B QIg g g g g gTgBgQgTgBgQg m0 m 0 0 m0 m0 m0 m0 m0 m0 m0 m0 m0 m0 4 0 4 0 4)0 0 4 0 4 0 4)0 0 4 0 0)0 0 0 0)0 bibibi4bibibi4bi4b 4b44b 4b 4b4 ntntn = itn =i i=i i i= iiNitniniN nininiN nininiN uu (t t(t t t(t t t(5rkb)eea1rb)1urb)8ob6urb)ur )ur )ob7ur )ur )ur )ob8ur )ur )ur )ob9z4 li=az4 li=az3eli=ckeea1 z4b li=a1 z4b li=a8 z3eli=ckb eea1 z4b li=a1 z4b li=a8 z3eli=ckb eea1 z4b li=a1 z4b l =a8 z3el=ckeeW RN(RN(RN(alP W RN(RN(RN(alP W RN(RN(RN(alP W RN( iRN( iRN(alP WAttorney Docket No.01183-0291-00PCT-PRNra ooefbul41 72 55 75 95 55 04 76 58 03 06 76ececa 0 v- .00 .00 .30 .03 .05 .60 .02 . 1 0 6 1.snaelp 0 0 0 0 0 0 000.50.00.00.80etrp aief.srafivvdebi )ogn - - 4 - - it , , .7, , ,- - 2, , ,-,9,0,c0san na)1 6 7,0 567 1 3.9sauraI .7) .9)9.7) .0) . ) .0.0 6. ) .538. )nhbeC25966944607 2)96)125 3)33- )891oiCazlM 4- %( 2.30-( 3. .43-( 7.3-( 1.2-( 9.42 -( 9.3-( 2.2-( 4.41 -( 9.( 0.1-( 6.5ge%irS L5 8 9 16 82-( .46.14(2 60 12 1 371 22 1 381 8.2.419 1rd 3.678.3.05.196. .26 60.n 2 -2- .48-2-1- -2-1-5-2-1-2-apu ea)oreniEgS)2)8)4)8)3)8)7)1)7)7)8)4)1)8) )n gl(nes0.9.0.9.1.2.2.2.2.3 3 3 4 66 6 6 4oitaana6 hbe(5 3(6 5 6 6 6 6 6.6.6.6.6.6.6.6ne.51(.23(.55(.05(.73(.15(.32(.50(.87(.89(.36(.76(.14(.33(.v03 .rCmoM%rfS4 L5- 2 5 - 6 3 - 8 2 - 6 5 - 1 5 - 7 3 - 3 3 - 5 5 - 9 4 - 6 3 - 0 3 - 9 5 - 9 4 - 593- 2et3 - ni,eu alae 0 9 5 3 4 6 vro obuf el5 7 1 0 6 3 0ea 0 9 2 5 7 4 8 6 4 1 6 3ec .01 .09 .41 .08 .07 .70 .07 .04 .81 7 2nilcalv- p 0 0 0 0 0 0 0 0 0.00.10.70esanep br.s ) ) ) )gefiv) ) ) )nifdbi4 2 1 1 5 3 1)8)1) )denitna.1.9).2.2.6.4.7.44 .6.53 .64 .I2-,0-,3,1-,0,4,1-,0,4,1-,13no 6 pgnuara beC4 ha CzlM.07 .78 .69 .37 .54 .98 .78 .57 .61,.07,.80serr% 2 0619 519 528 4.ocirS L519-(( 1- -( 1- -(-( 1- -(-( 1- -( 4-(e9(5 3 .(70 6 .46 .(74 5 .52 .(56 2 .67 h 9t0.87.-5-1-3.64-0-7.76 4-0- . .h 63- 0tia- - -)wlm E o S)r 2)5)5) )8)4) ) ) ) ) ) ) ) ) ) edo f(.een8.8.85.8.94 .92 .97 .82 .93 .90 5 8 1 8 a1 1 18.1 1 1 1 1 1 1.91.91.91.02.91mgne(9(5(3 1( (0(6(6(0(5(5(2(0(5(2( (A nil .6.4.30.2.3.6.9.1.9.9.4.9.82 . 0V ahesMaS6 1 5 1 1 1.697 1 5 1 0 7 4 0 0 7 420.21 O C C b L- - - - -1-1-1-1-1-1-1-1-1-1-1- N e)Anil ) )e 5 3)sD4.0)1.0)3.5)1.4)2.5)5.8)6.1)8.6)8.0)0.5)6.6)2.9)2.4)9.9n 4.ag aS9.9 41 01 11 01 41 01 21 01 3 1 2 0 4 0 3nitb-(tsn(a 6(3(8( ( ( ( ( (1(1(1(1(1(1(1( tifoe.7P M 1.11 4.13 1 0.72 2 0.82 2 1.85 1 4.11 1 0.47 2 9.15 8 4 2 0 0 7y 1 2.51 4.01 1.62 9.51 0.71 4.81 1.22 91bdez) )7)9)2)6)7)9)2)6)7)9) ) ) ) ) )ylaeD.5.1.3.52 6 7 9 2 6nanS il(8 7 7 8.58.17.37.5.5.1.3.5.5.1.3.5eesn(a 8(81( ( ( ( (8(8(7(7(8(8(7(7(8( re2 7 3 7 9 8 8 1 2 7 3 7 9 8 8 1 2 7 3 7 9 8 8 1 2 7 3 7w ae.B M 9.2 0.3 1.3 9.2 9.2 0.3 1.3 9.2 9.2 0.3 1.3 9.2 9.2 0.9.3 13 92atad 5 4 5 6 6 3 5 7 7etn 3 3 3 3 3 3 3 3 3 43 43 73 33 03 13 53elp DIDIMPDIDIMPDIDIMPD DIMP m BgQgTgBIo Tcg gQgTgBgQgTgBgQg d m m m met0 0 0 0 m0 m0 m0 m0 m m m m u 0 0 0)0 0 0)0 0 0)0 0 0)p 44 404 4 404 40 4 0 0 0 0 0 binbibi4bibibi4bibibi44bi4bi4bi4mietn n = n n n = n n n = n n n = i ri iNi i iNi i iNi iNhtut tb)a1ur )ur )(o 0tututu(1tututu(2tutiutu(fz4b14b83b1r ) r ) r )o kb14b14b8b1r ) r ) r )o kb1 b1 b8b1r ) r ) r )o kb1 b1 b8boh li=azl=azel=ceeazl=azl=az3el=ceeaz4 l =az4 l =az3el=ceeaz4=az4=az3=eccaRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(allP WiRN(lilRN( iRN(alPaEAttorney Docket No.01183-0291-00PCT-PRN)nra oe 40 01 26 30 04 39 50 78 77 21 63 8oitofbuela 0al .00 .00 .10 .01 .06 0 0 3 0 0 89 ec cna.lv- p 0 0 0 0 030.00.00.20.00.00.20uperpoef.sPfivedebi- - - -)2 - -)3)8 gnita,7, ,6 8,3,6.8,3,3.9-,- 3,3.2vïn aauhrn)I .2baeC2) .9.9.9.87, .4.25, .2.87,89)66 2- )1)42)2 2)55)9 2)38)2N-Ca bzli M 4-( 9.31 -( 0.040( 6. -( 3.32- 10( 7. .14-( 9.31 - 08( 1. .34-( 4.3- 67( 5. .3a %rS% L5 3 9 11 19 (.1.12 318 32- 916 52- 301072- 7.05 2.17.28(0.17.1 (8.3.2 (2m2-2-1-2-1- .6uz6a-2- 0 2- .96 3 8.-2-2-28-ilae) nES)6)4)5) )1)0) ) ) ) ) ) ) ) ) )meigles(n6.56.54.7 5.5 5.55.9 52.4 54.9 56.6 56.8 54.2 56.2 59.8 58.6 56.6 58.5O n(aa hbae(0(.68(.47 5 .( (68 0(.95(.07(.36(.74(.11( ( ( ( ( (.13 .95 .95 .72 3 22Cm1oM%rfS 6 L34 3 142.4 6 4 7 7 0 8 9 6.63.68.40k- - -9-4-3-2-1-4-4-2-1-4-4-2-2-eeae 3 0 3 3 7 4 4 9 9 2 2 9Wro obuel0 4 8 0 2 8 2 5 1 5 3 9 a 0 .00 .09 .00 .03 .08 .30 .02 .03 . 0 1 6ot fcv- 0 0 0 0 0 0 0 030.00.00.30pecaluepp ner.sefv) ) ) ) ) ) ) )fbi1 8)0 4 7)1 5 1)7 2)mi idTenigtuna.8)I2.-1.,1-,5.5 31. .3.4 6.2 .2.9.27 .4,3-,0- 2,2-,0- 21-,1-,2rra 8 1 2 1,5, ,2 3,enabeCvhaM.9.3.5.92 3.38 6 3 % 2 18oCzli- 17. .9514. .56.21.40.66r S L51-1-( 1-8-(-( 1-9-(-( 1-1- -(79((9(4 1 S8.2.(53 5 1(5.80 4 7( (8 0.10 2.0A7.63-7. .74-1-9. .66 5-2- .86.52- a- - - - - -U)nim E o S)6) ) ) )6)7) ) )5)7) ) ) ) ) )erf(een.58 a 1( 5.2 6.5.52 56. .61 6 2 .73 .76 2 15.15.1 1(15.5.1 16.6.1 16.7.nilgn naile 4( ( (3(4 1(1( (3(6 1(1( (6(9 1(1(esM.49 .76 . 5.6.41 0.8.90 2.6.84 6eshaS 1 19 07.533 1 0 1.7.93 1.1.93 2.1.0a C b L- - - - - -7-5-1-1-9-6-1-1-9-7-Be) )m n) ) ) ) ) ) ) ) ) ) ) ) ) )oil )6 2 eD2.3.8 4 6 6 7rs .4.6.8.7 5fS 0 1 0 0 09.0.7 1 08.9.0 9 1 0 10.8.1 06.7.2 18.2.2 a 1 1 8 1 1 1 8 1 9 1 9 1 9 1 8 1eb-(tsn(a 7(.77(.71(.80(.85(.69(.54(.49(.47(.31(.71( ( ( ( (.00 .65 2 2 9gn oe 7 9 3 5 5 9.6.9.9.0P M 1 1 2 2 1 1 32 32 51 71 22 22 41 51 12 22ah Ct ) )8) ) ) ) ) ) ) ) ) ) ) ) ) ) )D ne .01 .14 .29 .38 .01 .14 .29 .38 . 1 4 9 8 1 4 9 nSc(8(7(7(8(8(7(7(80(8.1(7.2(7.3(8.0(8.1(7.27.38e iln 4 3 1 7 4 3 1 7 4 3( ( (reesa ae3.7.1.9.3.7.1.9 3 71 1 7 9 4 3 3 7 1 1 7 9 B M 92 92 1 8 9 9 1.8.9.9.1.8.9.9.1.8P3 2 2 2 3 2 2 2 3 2 2 2 3 2dn n 53 53 73 63 53 43 73 53 53 53 73 53 23 33 73 43aeD DIMD DIMD DIMD DMgIP TB QIP TB QIPI IP n g g g g g gTgBgQgTgB Qa g gh m0 m m m m m m m m m m mC 0 00 00)0 0 0)0 0 0)0 0 0).4 4 46 0 0 0 34 4 46 0 0 0 34 4 46 0 0 0 34 4 4639binbinbin =binbinbi=bibibi=bibibi=1 itiel1 utr )iutN r)iut)( iutn )iutN n )iutn )( iutn )iutN n )iutn )( iniN ut t)u)u)(b kb53b5r3b7o 3b2raeeazekb5r ro 3b53b73b3r r ro kb53b53b73b4r r ro kb53b53b73b5k Tl=azl=azl=ceeazl=azl=azel=ceeazl=azl=azel=ceeazl=azl=azel=ceeWiRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(alP WAttorney Docket No.01183-0291-00PCT-PRNra oe 64 02 64 85 18 68 43 63 25 22 3 8ofbuela 1 .06 .20 .90 .08 .02 0 2 8 2 80 75ec cna v- 0 0 0 0 0.40.00.00.40.00.00.60elprpef.sfivdebi ) )gn - 2 6 -)ni,7 - - t a,5.56.06,1 5. ,- -au.9, , , , ,5 9 6 3 0 6 5 9hrn ba)eI .5,1 C 4)8, .21, .6.4 6. ) .2.4 4. )9 1 1)03- )7 9 0)44)816 7)79)04CazlM 3-9.%( 7.3.2 4- 3 4( 0.( 4.81.34-( 0.3-( 4.2-( 2.30 -( 8.3- 2 (8.2-( 9.2 %irS5 72-( 1- 0 7.622-(586 271 723 581 L9( .19 3(.11- .73 4 4 5.32 1- .74.4286.15.-00.6227.23- 8 -9. - - - - -06-ea) nES)9)8)0)2)5)2)4)2)3)7)5)9)9)0) )eigl(nes6.6.5.7.3.3.1.3.1.9.8 9 4 32 2 4 2 ana5(5(5(5 6 6 6 6 6 5.5.5.6.6.6.6 ahbe2 .08 .52(.95(.85(.63(.20(.35(.51(.91(.03(.26(.50(.97(.41(.64 CmoMrS2 5 1 4 1 3 2 3 0 5 1 4 3 3 6 2 7 4 8 0 3 4.80 %fL- - - - - - -2-5-4-3-2-5-5-3-3- a oe 41 24 07 81 7 3 6 7 3 2 9 4rbul3 9 7 2 4 4 9 1 4 3 9 3oea.0.4.8.03 .21 .60 .06 .04 .65 .02 . 5fcv- 0 0 0 0 0 0 0 0 00.8ecalp 0 0 0nepr.sefv) )f)ibi5)8)0 7) ).87 0 5) ) ) ).2 3 7 4)2den4. .9.9.7 5 0. .5ia.9 0-1- .2.600.5gturna)I0-,2,4, ,1,3, ,0,3, , -4 0, ,n eC4 8 9 2 3 6 9 3 6.3 6ab ha ClM 7. .1 1. .01.0.2.11.2.8 30.50.4z% irS9 6-4 8-6-9-5-5- L5 9 -((0(-10(-.( ( ( 1-1( ( (-( 1-( (66 4 3 .08 7 1 2 1 4 7 1.3.9.2 3.5.1 1. .45-1- 0.53-1- .64-1-5-5.50- a- - -) m E o S) ) ) ) ) ) )rf(2 2 7 2 0 7 2) ) ) )n.7.7.6.7.9.8.88 0 .87 .74 .7) )7 6).97).83 .8)7 eea1(1(1(1(1(1(1( 8.1 1(1(17.1 1 18.gne nail4 4 8 4 2 1 6( (1 esM.5.0.0.4.1.2.48 0 4 5( ( ( (1 .1.8.9.53 4 .07 .40 .4 (3 haS5 1 2 1 0 1 0 1 5 1 2 1 0 195 1 3 1 0 1.45 5 0.9C b L- - - - - - - - - - -9-1-1-1-9- en)0)6) ) )3)6)2) ) ) ) ) ) ) ) )il )s6 38 2 7 4 7 3 4 1 6 2 9 eD. .S 01 31.2.2.17.24.09.03.9.10.08.08.0.35.09.1 a 1 9 9 1 1 1 1 9 1 1 1 9 1 1 1 b-(n(1(2(3(1(0(2(1(7(4(5(1(8( ( ( (tsa.4.2.6.3.1.0.2.6.5.5.1.76 8 6 1 oe 3 7 0 8 41 7.3.9.1.3P M 1 1 2 1 1 02 91 31 51 12 91 31 31 12 91 ))8)1) ) ) ) ) ) ) ) ) ) ) ) ) )D.0.14 .29 .38 .01 .14 .29 .38 . 1 4 9 8 1 4 9 eS 8 7 7 8 8 7 7 808.17.27.38.08.17.27.3nil(n(4(3(1(7(4(3(1(7(4(3( ( ( ( (8(esa ae3.97.91.19.3 83.7.1.9.3.7.1 1.7 9.4 3.3 7.1 1.7 9.B M 2 2 2 92 92 13 82 92 92 13 82 92 92 13 82 n 33 43 63 33 13 43 43 23 03 43 33 33 82 33 33 33 DIDIMPDIDIMPDIDIMPD DIMP TB Q T B Q TIg g g g g g gBgQgTgBgQg m0 m0 m0 m m m m m m m m m 0 4 0 0)0 0 0)0 0 0)0 0 0)i4 46 0 0 0 6 0 0 0 6 0 0 0 6 bnbinbi34 4 434 4 434 4 43 n =binbinbin =binbibi=bibibi= itititNitititNitnitnitN nitniniN ur )ur )u)( u)u)u)( u)u)u)( ut t)u)u)(ba5b5rb7ob6rb5rbrob7r r rob8r r rob9z3 3 3ek 3 53b73 kb53b53b73 kb53b53b73 k li=azl=azl=ceeazl=azl=azel=ceeazl=azl=azel=ceeazl=azl=azel=ceeRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(alP WAttorney Docket No.01183-0294-00PCT-PRNra ooefbul82 62 04 96 09 23 17 39 54 05 29 72ececa 0 v- .00 .07 .20 .01 .03 .40 .01 . 1 0 5 3.snaelp 0 0 0 0 0 0 000.40.00.00.60etrp aief.srafivdebi )vogn - - 9 - -,- -,-, ,csnit , , .3, ,na)4 6 7,5 5 2,3,8 1,0 9 .39asauraI .0) .6)6.8) .8 7. ) .6.7 4. ) .269. )nhbeC3428 218)840 3)99)257 5)13- )928oiCazlM 4-4-0.%( 9.( 9.64-( 8.3-( 4.2-( 6.40 -( 8.3-( 5.2-( 4.40 -( 0.( 6.2-( 9.3ge%irS L5 9 82 829-( .95.85(3 67 36 1 665 37 1 185 4.8.801 1rd 4.110.7.25.614. .66 75.n 2 -2- .39-2-2- -2-2-7-2-1-4-apu ea)oreniEgS)4)4)5)0)7)8)0)5)1)8)5)3)2)1) )n gl(nes3.3.1.3.6.6.4.6.8.7 6 7 9 90 8 9 8oitaana6 hbe(6 4(6 6 6 6 6 6 6.6.6.6.6.6.6.6ne.58(.39(.86(.50(.83(.13(.07(.97(.46(.87(.60(.29(.83(.19(.v78 .rCmoM%rfS2 L5- 2 5 - 5 3 - 6 2 - 4 5 - 1 5 - 7 3 - 9 2 - 3 5 - 9 4 - 5 3 - 8 2 - 6 5 - 8 4 - 423- 0et3 - ni,eu alae 7 3 9 9 3 2 vro 3 9 1 9 1 6obuf el6 7 0 4 2 9 4 7 9 5 4 5ea 0ec .01 .06 .31 .05 .04 .51 .04 .00 . 1 4 8nilcalv- 0 0 0 0 0 0 0 060.00.10.80eseppan br.s ) ) )gefiv) ) ) )nifdbi6 9)0 8 5)1 5)6) )deni.t9.0na).7.2 0.0 .6.3.06 .8.20 .49 .I1-,1-,2,1-,0,31-,0-,31-,18no 5 pgnuara beC9 ha CzlM.14 % 2.22 0 0,1.4.56 5 3,8 3,9,8serr7.81 0.76.81.50.56.22.5 0.ocirS L519-(( 1- -( 1-1- -( 1-1- -( 1-9-( 5-(e7(6 6 .( (34 2 8 .( (58 9 6 .(35 9 .00 h 4t0.17.56 2- .26.5 -1-5.26.75 1- .4- .0 htia- - - - -6- )wlm E o S)r 3) ) e) ) ) ) ) ) ) ) ) ) ) ) )do f(.een91 1.96 1.80 7 19. .90 1.02 2.95 6 19. .97 1.93 4 4 6 0 5 1.919. .02.020. .02mgnae(5(4(3 1( (0(9(5 1( (6(6(3 1( ( (2( (A nil .7.8.07.2.8.26.8.5.67 9 .84 .24 4 . V ahesMaS5 1 4 1 1 1.66 4 1.65 4 0.26 4.7 10O C C b L- - -8-1-1-1-9-1-1-1-9-1-1-9-1- N eAnil ) ) )3)5)1) )6)9)4)4)0)6)2) )1)7)4naesD 24.2.2.93.6.2.5.8.1.3.09.0.0.g aS7.9 41 01 118.9 41 01 21 01 3 1 29.3 1 3nitb-(tsn(a 7(4(5( ( ( ( ( (1(1(1(9(1(1(1( tifoe.5P M 2.61 4.25 1 0.61 2 0.62 2 2.27 1 5.23 1 0.76 2 9.16 7 9 0 1 0 2y 1 3.01 5.11 1.82 9.01 1.61 5.01 2.32 91bdez) )8)1)4)9)8)1)4)9)8)1) ) ) ) ) )ylaeD.0.1.2.34 9 8 1 4 9nanS il(8 7 7 8.08.17.27.3.0.1.2.3.0.1.2.3eesn(a 4(33( ( ( ( (8(8(7(7(8(8(7(7(8( re7 1 1 7 9 4 3 3 7 1 1 7 9 4 3 3 7 1 1 7 9 4 3 3 7 1 1 7w ae.B M 9.2 9.2 1.3 8.2 9.2 9.2 1.3 8.2 9.2 9.2 1.3 8.2 9.2 9.9.2 13 82atad 9 9 4 2 0 8 4 3 1etn 2 2 3 3 3 2 3 3 3 92 33 33 82 62 03 23elp DIDIMPDIDIMPDIDIMPD DIMP m BgQgTgBIo Tcg gQgTgBgQgTgBgQg d m m m met0 0 0 0 m0 m0 m0 m0 m m m m u 0 0 0)0 0 0)0 0 0)0 0 0)p 44 464 4 464 40 4 6 0 0 0 6 binbibi3bibibi3bibibi34bi4bi4bi3mietn n = n n n = n n n = n n n = i ri iNi i iNi i iNi iNhtut tb)a5ur )ur )(o 0tututu(1tututu(2tutiutu(fz3b53b73b1r ) r ) r )o kb53b53b7b1r ) r ) r )o kb5b5b7b1r ) r ) r )o kb5b5b7boh li=azl=azel=ceeazl=azl=az3el=ceeaz3 l =az3 l =az3el=ceeaz3=az3=az3=eccaRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(allP WiRN(lilRN( iRN(alPaEAttorney Docket No.01183-0291-00PCT-PRN htiwnra oe 60 31 86 30 12 21 50 2 1 2 1 8oitofbuela 0ala.l00 .00 . 0 1 6 0 90 54 10 40 41 ec cv- p 0 010.00.00.30.00.00.20.00.00.30u n perp.oef sPfivedebi )8)8)1 gn - it ,- 7, ,- 4 8,- 8, .6-,-, .0-,-, .5vïn a auhrna ba).6.1.1.87 .17,6 .33 .16,9 .92 . 7,eI5)3)0)1)73)7 2)35)9 1)578)3N-CCaz 4- 7 (9.4- 03( 9. -(8 6.4-( 4.3- 90( 0. .14-( 8.3- 77( 9. .34-( 2.3- 5 2.3.3bla %irMS% 282 65 5 723 42- 015 42- 30(872- L5 9( .37.0.21 5 2.1.6 (.11.0 (.11.8 (m1- 7 8 0 .77 0 6 6 2 1 2 -2-2-1-2 2.8 2 2.9uz6- - -8- - -7-ilaea) E) ) ) ) ) ) ) ) ) ) ) ) ) )enilS(5 n64 6 4 4)7 9 4 9 4 9 2 2 4 9 6 7 6 8 4 4 3 0 6m gesan.a 5.( 5.( 5(.5.5 5.( 5.( 5.( 5.5.5.56.59.59.56.5O abe 5 5 8( ( ( ( ( ( ( ( ((h.8.5.73 4 .90 .47 .47 .76 .21 .22 . 6 7 2 52Cm1oM%rfS 6 L3k - 4 3 - 152.-9- 4 4 - 6 3 - 4 2 - 7 1 - 7 4 - 004- 9.12- 0.82- 6.64- 3.64- 8 2 -eeaWroe obu30 14 17 20 12 00 60 70 95 91 61 44 ela 0 .00 .09 .00 .03 .07 .30 .02 6 0 1 2ot feccalv- p 0 0 0 0 0 0 0.00.20.00.00.30puneper.sefv) ) )b 3 6)3) ) ) )9)1)8)7 0)mifi i .8.19.74.36.2 dTenigtuna) 2- .,1-,4 313- . .,0-2 723- . .,0-8 6.312-1- .22rraI3 3, , , , , , , ,enabeCha.17 8 5 2 0 6 4 3 4 0 3.31.5.127. .0.124. .7.81.30.7voCzlMirS% L5179-(( 1-8-1-8-6-1-9-6-1-1-6- 8( (5 4 S9.2. .( ( ( ( ( ( ( ( (56 7 9 3.0 2 4 5 2 4A7 6-9.5.87 4-1-7.1.75.4-2-2.87. .25 2- a- - - - - -U)nim E o S) ) ) ) ) ) ) ) ) ) ) )erf(9 .een58 3 6 8 15.5.5. .58 1.52 6 4 15.5. .63 1.6)8)2 1 0)4 15.6. .71.716.nilgnae(n 9 1(1(1( (9(0 1(1( (5(1(1( ( (1(aileM.55 4 0.8.52 3.56 .98 4 1 .38 .80eshsaS 1 1.89.17.63 0.8.94 1.2.84 2.3a C b L- - -3-1-1-7-5-1-1-9-6-1-1-9-Be)m n oil ) )eD 3 2) ) ) )9rs .3.8 4 9 6) )faS7.4.5.8.7 5) )9.0.7 1) )9.9.0 9) )0.8.1 1)6.7.2 8eb-(9 1 n(1(8 0 ( 1 0 ( 1 0 ( 1(8 0 ( 1(9 1 ( 1(9 0 ( 1(9 1 ( 1.( 8(a 9 7 1 0 3 9 4 9 0 1 1 0 5 2 2gtsn oe.28.79.83.85.06.59.43.43.25.77.02.62.6.9.9P M 1 1 2 2 1 1 2 2 1 1 2 2 41 51 12ah Ct)si) )D 6)nscy.l e31).14).29).36).31).14) ) ) ) ) ) ) ).29 .36 .31 .14 .29 . 6 1 4 nS(6(7(7 8 6 7 7 8 6 7 738.36.17.27eailn 1 3(1(7(1(3(1(7(1(3(1(7(1(3(1renesa ae2.7.1.9.2.7.1.9.2.7.1.9.2.7 1B M 03 92 13 82 03 92 13 82 03 9 1 8 0.9.1P A2 3 2 3 2 3dm norn 43 53 73 63 43 43 73 53 43 53 73 53 23 33 73aef D DIMPD DIMPD DIMD DIMgde ITB QITB QIP TIP n g g g g g g gBgQgTgB Qav g gho m0 m0 m0 m m m m m m m m m ) 0 0 0)0 0 0)0 0 0C.me0 4 0 4 0 4 6 0 0 0 34 4 46 0 0 0 34 4 46 0 0 0 34 4 40Rbinbinbin =bibibi=bibibi=bibibi2eritileiblat1 utriutN niu (tniutniutN niu (tniutnitN(nitnitnit) ) ) ) ) ) )u)u)u)u)u)kb4rueeaz3b5r3b7o 3b2r r ro kb43b53b73b3r r ro kb43b53b73b4r r rkb4b5b7 T Ol=azl=azel=ceeazl=azl=azel=ceeazl=azl=azel=ceeaz3 l =az3=az3= WiRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN(liRN(liRN(Attorney Docket No.01183-0291-00PCT-PRNra ooe 2fbu4 99 11 76 37 20 43 81 83 22 60 58 ela 1 .04 .24 .90 .09 .06 .40 . 2 9 2 1 3ec cv-0.0.4.0.0.6nael0 0 0 0 0 0 0 0 0 0 0 0rppef.sfivdebi )gn -,6)9 -, , ,-,-, ,- -,nitauna)5.26.5, 51 6 4 .01 1.7 7 8, ,3 2 8 6 8hrbaeI .6C4 3)4, .460.6 0 4)1 93- ) ) .293 26 0) .474) . ) .701 21 7) .818) . )40 29CazlM- %( 8.4.4- 324( 4.6(25. -4.4- 2(0( 9.3- 7( 7. -3.3- 2(0( 9.3- 2( 1. -7.5(2 %irS5 6 .2-( 1- 8 ..23 3.1 2 9 3 5.1 1 1 3 0.1 L9(9 9( 44.1.5.3.01- .87 318-6- 4 85- 0 24--5.2-2-1-2-2- 0 ea) nES)2)3)9)0)9)5)0)2)4) ) ) ) ) ) ) )eil( 8 7 6 5 62 5 1 5 3 8 4 3 gnesan. . . . .3.3.1.3.0.9.8.9.4.2.1.3.a5(5(5(5(5(6(6(6(6(6(5(5(5(6 6 6 6 ahbe4 o.79 .92 .66 . 3 7 2 2 0 7 4 8 5(0(0(2(9 CmMrS0 2 1 5 11.7.5.3.4.1.7.2.1.6.4.1.1.042 3 2 3 0 5 1 4 3 3 7 2 2 5 7 4 4 3 8 2 1 5 3 5 5 1 %fL- - - - - - - - - - - - - - -3-3- ae 2 1 3 8 4 7 7 8 9roobul71 39 34 11 34 67 50 95 8 8 2 9 2 2 3 1 3 81f eca v- .00.40.9.0.2.5.0.0.6.0.0.8ecal0 0 0 0 0 0 0 0 0 0 p pner.sefv) ) ) ) ) ) ) ) )fibi9 .96)7 3 .41 5 6 . 9)2 6 3)7dn.9 9.5.4eigta0nu- 2.6 1- .02.531- .10.530-0- .34arna)beI ,3,4 3, ,5 6,2,8,0,9,3,0,0,4haC.20.1 3. .41.9.3.51.1.8.8.4.5CzlMirS% L519-6-4-(( ( ( 1-7-6-1-9-5- 0 1- 0 1-5- 1 9 .( ( ( ( ( ( ( ( (56 4 6 1 3 0 5 8 1 8 6.5 -1-1.04. .96 2.-41-7. .56 4.-11-6.45. .55 0- a- - - -) m E o S rf() ) ) ) ) ) ) )8 2 .een71 .75 .61 .78 .86 .81 .) ) ) ) ) ) ) )7 8 6 2)6 0 6 1 7 a6.1 1(1(1(1(1(18(18. .71.71.717. .91.81.81.81 gne(7(1( ( ( (1( ( ( ( (nil6 h.04 .09 .25 .49 .60 .26 . 4 4 1 6 1 0 3 0 2 aesM.06 2 0 0 5 260.2.26.0.6.5.7.4.6.0CaS b L7-1-1-1-1-1-1-1-9-1- 4 1 - 0 1 -9- 5 1 - 5 1 - 0 1 - 0 1 - en) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) )il )0 esD2.0 S 26.6 1 03.8 2 3 1 311.92.2.6 9 17.2 1 24.7 1 09.4 7 1 013.9.3 9 10.4 1 08.1 6 08.0.2 35.9 09.1 a( ( ( ( ( ( ( ( (1 1 9 1 1 1 b- n 9 1 2 3( ( ( ( ( ( ( ( (tsa.1 0 2 1 7 4 5 1 8 6 8 6 1 oe02.43.27.60.38.14.07.20.69.53.55.11.72 9.3.9.1.3P M 2 1 1 2 1 1 1 2 1 1 1 1 31 31 12 91 ))9)6)1)4)9)6)1)4) ) ) ) ) ) ) ) )D.3.3.1.2.3.3.1.29 .36 .31 .14 . 9 6 1 4 9 eS il8 6 72.3.3.1.2.3n(n(7 8 6 7 7 8 6 7 7 8 6 7 7 8 7(1(3(1(7(1(3(1(7(1(3(1(7(1( ( (esa ae9.82.07.91.19.82.2 07.1.9.2.7.1.9.2.3 7.1 1.7 9.B M 2 3 2 3 3 92 13 82 03 92 13 82 03 92 13 82 n 43 33 43 63 33 13 43 43 23 03 43 33 33 82 33 33 33 DIDIMPD DIMPD DIMPD DIMP TB QITB QITB QIg g g g g g g g gTgBgQg m0 m0 m0 m0 m0 m m m m m m m )6 0 0 0)0 0 0)0 0 0)0 0 0)34=bi4nbi46 nbi340 6 0 0 0 6 0 0 0 6 n =bi4 434 4 434 4 43 nbinbin =binbinbi=bibibi= N( itititNitititNititnitN nitnitniN our )ur )u)( u)u)u)( u)u)u)( ut)u)u)(b5ekb43b5r3b7o 3b6re kb4r3b5ro 3b73b7r r ro kb43b53b73b8r r ro kb43b53b73b c aleeazlP Wi=azl=azl=ceeazl=azl=azel=ceeazl=azl=azel=ceeazl=azl=azel=cRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(alPAttorney Docket No.01183-0291-00PCT-PRNra oe 44 9 9 9 9 0 6 4 7 9 5 9 ofbuecelca 0 3 v- .00 4 .09 8 .20 8 .01 1 .04 7 .40 1 .02 3 .00 5 .40 1 .05 6 .08 .6nalp 0 0 0 0 0 0 0 0 0 0 0 0erpef.sfivdebign -,-),6 -,-, ,-,-, ,-, ,nitna)8 3.87,9 6 3 3 4 7 4,1 7 0.08 auhrbaeI .6.3C2 1.6.1. ) .0.7. ) .179. )4)-92 4)-29.1 4)-99 3)4 - 22- 0 3 4)19 3)95 2- 6 5 4)13- )21 2- 8CazlM%( 8.7( 1.5 8( 9.5( 5.6. -3(0( 6. -6( 1.3. -3(0( 6.7(51.4.0(4 %irS5 8 22-(4 4 6 8.1 3 8 9 6 1 5.45 7 1 L9( .25.25 2.83.31.84.41. .36 8.2 -2- .09-2-2-6-2-2-7-2-1-3-ea) nES)5)1)6)4)9)4)7) ) ) ) ) ) ) ) )eil(n5 4 1 3 6 7 38 5 5 7 7 8 7 5 4 7 1 0 3 0 6 1 gesan.a 6.( 6.( 6.( 6.( 6. . . . . . . . .6.8.( 6(6(6(6(6(6(6(7(7 6 6 ahbe 1 .15 .05 . 3 1 2 4 7 4 9 0 1 1(0(0(5 CmoM 8.8.2.7.2.3.1.7.0.3.0.1.4.6rS 2 5 2 5 5 3 6 2 4 5 1 7 0 3 9 6 8 7 9 4 0 %fL- - - - -5-3-3-5-4-3-2-5-4-3-3- a oe 85 51 64 30 54 36 09 76 46 97 2 9rbul0 2 8 1 4 8 0 3 5oea.0.0.35 8 0 2 7fcv- 0 0 0.00.00.4.0.0.5.0.1.9ecal0 0 0 0 0 0 0 p pner.sefv) ) ) ) )f) )idbi4 .19).82 4 .63)3 6 5)7 7)6)6enigtna)I2-,0- .,82,1.-1,0- .,3.73,1-1.,0, .7.93.1.,1-,145 nuara be haC9 .55 2.12 9 9 0 0 4 1.3.12.60.0.32.47 2,4,9 0.6.03.7 2.CzlMirS% L519-(( 1-7- 6( ( 15 -( 1-7- (( 1 1-6-1 9-5- 4 -( ( (5 -( (9(8 3.2 0. .21 2 -9.1 4. .83 5 1 -0.1. .40 1 -5. .24-0.nb-(.(( ( ( ( ( ( ( ( ( ( wtsn 7 oe.54 .65 .25( ( ( ( (ra.61 .62 .27 .23 .76 .16 .07 .19 .80 1 0 2ofP M 21 41 02 02 21 51 02 91 31 51 12 9.01 1.61 5.01 2.32 91deirra) )6)1)4)9)6)1)4)9)6)1)4)9)6) ) )cn eD.3.1.2.3.3.1.2.3.3.1.1 4 9oinS il(6 7 7 8 6 7 7 8 6 727.38.36.1.2.3 tesn(a 1( ( ( ( ( ( ( ( ( ( ( (7(7(8(avrae2.3 7.1 1.7 9.1 2.3 7.1 1.7 9.1 2.3 7.1 1.7 9.1 2.3 7.1 1.7 9.esB M 03 92 13 82 03 92 13 82 03 92 13 82 03 92 13 82botn 92 92 43 23 03 82 43 33 13 92 33 33 82 62 03 2sr3o W DIDMDMDM M:F TIPDB QITIPDB QITIPD DB QI IP C g g g g g g g g gTgBgQg O m m m m m m m m m m W 00 0 4 0 00)00 00 00)00 00 0)0 m0 m0) ;sbi4nbi46 bi46 0 6 0 0 0 6e34 4=bibibi34 4 4=bibibi34 4 4=bibibi3rau t ntntntntntntntnitnitnin = ii iNi i iNi iNiNqs9uru u (0u (1(2t t(tkb)eea4rb)5rb)7ob1rb)4ur )ur )ob1 ur )ur )ur )ob1 ur )ur )ur )obsaz3 li=az3 li=az3eli=ckeeaz3b li=a5 z3b li=a7 z3eli=ckb eea4 z3b li=a5 z3b li=a7 z3eli=ckb eea4 z3b li=a5 z3b li=a7 z3el=cel:W RN(RN(RN(alP W RN(RN(RN(alP W RN(RN(RN(alP W RN(RN( iRN(alPS LAttorney Docket No.01183-0291-00PCT-PRN stnna ftrb o e hulo a.sbera o poostv- vcaleitiooc7c niP pfbuleaalfitS o ADIpcecv-.su.)n)Ibiaonapo raelrppeto no peeUT 0)3 o aei Cnitbeh1f.sair t 2t%5rour calfapivv debioeitv valïadatselalu 9(fbapncsïaupn-hni aelb pnRzli .sb v isttaa T ooitOrgnitna) a n- oban nfd P eal rofbioa auhrbaInCaeC oizlgebapriteion u e p)n l miuurta7a vï tb)Iao%urecaC%irMS% L5rm 9(dn u azilazil mlb p S 4 Pe(blaazleA i v1-N3 - bvïDap% aRzl.is5 v9(pasmr ïaU1 aN- Rru ea)ormao hfDIn- nisnembadreed)enilEgSno(oitdtnio baw %Tg moi rutuzilmt- uunn% zpoo 0 0 0 0 nps(gesn aacgiailmn nane,)0hbaevrTe.u u aIerCms0m0zioM ldFemm Ore ) ) ) )SetnTIae2,0aer eO- d)0 0 0 0 %rfLi,e eu ht si24mas(d non 0 0 0 0 o% 1 1 1 1 d1g of(en a Nps(n(5(5(7(6 alakne vhtdeeievo DIsah Ter3 3 3 3ro obul eof eecancalvi-leb lliWe% C ptTIred)psan ort tce0.0Mnnne(no% 0 0einr2(0 0 pbr.sgsefv ntA st2 am i noc1psnfi-l.)2nadn de takeR dbidneienitt le2- p na oi acnereee bo ) pap w 1ci treitdW ul.sbgnuraeIserf r2trohren o a v- vecabCros ao pilt alhaM oco f elp xbP p CzlirS% L5 9en ( ht oin otibaecvDIe-is elpu)Ibiao htror ïa tbeCnitb petiTdn- B e neiuomi%5rureca)wleorrcna baht tadT9o(fbalapm Ed o So rf( pe2 m n pefhtreRzl.sOirv een gnam lAaiv tit1- uizistofvrnaileV hesMOnaat9 CaSC b Ltsl neo geO ofbinoba Nsn)besear apatsu moicnr6 u≤n)iteoc ICi%( uralAusergi fitecoc7StalDbap% z.s5 en)naapeFo rapre eAupRl9Rirv(ilesD g aS nit ,yrgeb-( tidn e% 3. eplht Uo Prti ssnafy ut ti(4 v 03 ïaaitreh vtiTd TIeet- d)unno% 0 0 0 0 oebsn-nao wpo(P M demi fdt mnpsn ezyhtl-onba sd st Ierfn erab uen n )laooocbimusiaa pre) )0)0)0)0 eDnSa en snitzi a,ts i-ndn% 01 0 0 0 nil(eresnesara(7 w u6Surlauciaeao ≤b myllas tsroo Nps(n(1 1(1(1(a aer4 14 83 04 B MtadcfAazofn Pret e oU lio oiwtf e)nelh ptrea r ti aodn erog nDI% d h 3 dtn o o% p(0 0 0 0 m vcs iB.A)e isen ocO veg 41.nitrR det7S i ,0 up Ahcm0el floeo s p o)04 miU a is0h7abrPbinbDinDIbinM = eatfn 4 wnSot .it Iiu Ttiu BtP N uQ (hto]2de ag paAe1rbg)1rbg)1rbg)8ob c 4v icni eUv2a 2i iteene M.atbiazlelm04=azlm04=azlm03=echeviil iR04N( iR04N( iR04N(alP E 0hra c6 daalasaa0[caper ≤herT BAttorney Docket No.01183-0291-00PCT-PRN e b ulob 00 98 45 39 57 8 9 2 4 a.vs-vec6 al .07 0.19 .96 .09 6 .46 0 .52 9 .12 2 .17 .6P p 0 0 0 0 0 0 0 0 )I , , , , ,Cbia n 0 6 5 2 4, , , ,i o t b 9 8. )7 5. )2 1. )5 8. )0 2 3. )4 5 0. )3 3 7)1 2 7)0 1)%rec039 037 01 089 078 01.097.34.5 5oural( 9.( 5.(2( 2.( 0 (0( 20( 70(3 9(fbazlp9 . 5 37 4.953 7.2 9.79.4 4.1 6.3s 0 82 8 1 1 97 9 5 4 2 1 91 85 31 91 64nR oiitOrv.4.3.0.4.14.02.38.26.0al ruofbip noa, ,9,3,3, ,8,8,4,1o)itbec)IP%u C.1)5)2. )022.2 07.40)3 09. )58.1)3.72)7.53)90.4)9e(rbal%(.514-(.041-(.1- 0(.117-(.661-( 4. - .0- .0 16(0(0 -( 9.vïDap5.939.2 aRzl.s0v9(51 9.1.3340.1N- 57.63.3358 1 4.2 - 31 31.2 -- Rirbadre ) ) ) )met- d uunn%9.8.8.z 0 0 0 0 0 2 0 2 0 0 0 2ilpoo nps(n(1( (amIe1 1mrOre) )n.1).9) ) ) ) ) ) ) ) ) )- d ono% 7 2.64.44.17.68.37.4.1.1.6.7(7(8(9(9(7(8 4 7 7 4 1 ( 9 9 7 7 9 9 Npse n r 7 9 5 4( ( ( ( ( (2 2 3 3 72 13 63 43 72 72 53 33 red) ).9).1) ) ). ) ) ) ) ) ) )no% 2 74.56.92.417.6. .92.924.3.p e(2 1(5 2 1 2 5 2 2 5 8 s n(8(6 2(2(8( ( (4 1 2(8( ( (8 2 3 R e b ulob 28 73 4 8 7 2 7 3 2 a.vs-vec2 0.3 1 1.3 8 9.1 1 0.3 7 8 8 0 2.0 6.8 0.3 1.2 5.Palp 0 0 0 0 0 0 0 0 0 )I , ,Cbia n 1 8, , , , , , ,i o t b 1 1. )5 7 6. )3 2 1. )3 1 2. )1 3 5)4 5 0)4 0 2 8)3 7)9 0)%rec176 078 02 130.051.3.04.8.5 5oura (.9 (.2 (9(.7 (.0(3 0(0(3 0(2 9(fbla 38 98 9.799 475 7.25.04.93.3zlp.s7 .62 6 . 1 98 4 2 31 16 511 58 53 R Oirv 543.01.06.82.50.03.52.50 r ofbinoba),0,3,4,0, , , , ,5 1 6 7 1n)itoit%( urec IC.9)28.72)-7.1)91.2) )7.40.548 0)2.41) .-263)4.-9 5)3alDbal(ap%..362(.3- .0 (.6- .8 1-.3(0.44(9( 1. .2.6 1- 6(1(8( 6.7uRzl.s5 9(7332 1 04.1 0 9 3 17.1 73. .943.5229.p v 12o Rir -1 13-PTdrTIeet- d) )unn.4).9).5).4).5poo% 0 2 0 0 0 4 0 2 0 2 0 2 nps(n(1(2(1( (mIer1 1 re) )n.6).9).7).0) ) ) ) ) ) ) )- d ono% 5 2 4 5.23.45.47.05.23.65.74.0(7(8(9(9(7(8(9(9(7(7 9 09 Npse n r 1 4 6 8 0 5 7( ( (3 3 3 3 3 3 3 83 03 13 63 63 red) ).4) ) ) ).8) ) ) ).8).4) )n1.o% 42 73.50.6.5 6 46.0.6 43.0.0 pse(n(1 0( (1 7 2(2 2(1 1(2(5(2(2(5(1(1 6 1 2 11 01 2 4 R )0)0)0 binbinD bi4 nM =binbi4 4 nbinM =binbinbinM = itDIit IitP Ni DIi DIiP Ni DIi DIiP N urbTg)urBg)urQ (tg)ourTtg)urBtg)urQ (tg)ourTtg)urBtg)urQ (g)o 1a1 zm4ba1 zm4ba8 zm3beb 1 cazm4bam14bam83beb 1 cam4bam14bam83beckli00=li00=li00=ael2 li00=zli00=zli00=al3zli0=zli0=zli0=al4e R 4N(R 4N(R 4N(P keeR 4N(R 4N(R 4N(P k 0 eeR 4N(R04N(R04N(P keeW W W WAttorney Docket No.01183-0291-00PCT-PRN e b ulob 34 36 76 45 25 29 30 8 9 a.vs-vec2 al .89 0.03 0.42 0.01 0.08 0.90 7 0.76 8 .31 .3P p 0 0 0 )I , , , , , , , , ,Cbia nio8 t b7 4 0 6 4 8 4 2 1 e2. )1)8 6)8)2 8 3 1 88.20. )1.92.31. )3. )5. )1. )%r9oc(fbal0 09 02 19 5 6 0 8 3 5ur(4 a.0 ( 6.(6 1 0 .9 ( 0.( 1.(6 0 .5 (3 0 .2 (0 0 .7 (8 .0zlp5 .s85 0 1 50 6 91 8 2 3 4 20 5 93 23 6 53 8 7 4 9 7 4 345 182nR oi. . . . . .2.7.4.itOrv 1 2 0 5 6 0 1 1 0al rbia, , , , , , , , ,uofp nob)I2 o)it )9)9 2.9)2)6 4. )5)6)3 9.P%ue(recC.633.2.2 2- 1 .97)11.032.6.245 .60 12.8.343 .83.9- 0 2)20vïDbal1- ap%5(7(1.83 - 3( 3.(6(7 - 01- 2(.57 -4.aRzl.s07.73.13(11(28.2(87 v9( .81 51.5 91 12.0.73 8.N- Rir - -7-badre-ed) ) ) ) ) ) ) ) ) ) ) ) )mtnn6.7.7.6.7.7.4.3.4.17.8.09.uuoo%8 5 2 5 5 5 5 8 5 3zilp nps(n(3(2(1(2(2(2( (1( (1(1(amIe2 3 4 2 4 5mrOre) ).7).4).6).9).4).4).6).4). ) ) )-nd ono% 5 ( 8 1 ( 7 4 ( 9 8 ( 8 1 ( 7 11.3.9.3(7 4 4 7 4 1 3 ( 9 9 7 7 9 8 Npsn 0 5 5 2 5( ( ( ( ( (er3 2 3 3 2 52 53 43 72 62 43 03 redn) ) ).3 6. ) ) )6. )6. ) ) ) ) ) )o% 4 824. .15 1 82 84.6. .92.751. .76 p(1( (1(2(5 5 2 2 8 1 sen(5 01 2(4 01 0(1 2(2(8( (9 3(6 R e b ulo a.vsb 77 6 6 7 1 6 7 0 7 9 5 0 9 4 30 30 35 04 5 9 - vecal7.00.03.0.0.9.1.4 1.8 3.P p 0 0 0 0 0 0 0 )Ibia,0,4,5,2,0,6,5, ,C nio t b4 3)1 9)7 0)3 8)0)3)6 5 ) 5 8 ) 2)%rec .2.4.3.337.961.37.77.21.6 5oura0(6 0(1 0(8 1(1(0(1 0(4 0(8 0(7 9(fbla 7.38.52.48.83.55.33.79.1.2zlp.s14 .249 3 2 524 093 68 7 6 27 042 Rirv 1.92.4.8.2.0.2.3.5O 0 8 8 1 2 2 0 r ofbinoba), , ,I0 8 0 2,4,1, , , ,0 4 3 7n)ite.0) .6) . ) .9) .6) .4) .2) .0)6. )o%ucC350- 5 8 10 91 859- 94- 64- 4 0 23it(ralDbal1- .7 (.0-1.(.1 (.9 9.(.5 (.1-0.ap%5(71.743(6.02.39(9.22.61(8uzl.s9.460.64 4 33.3 3 0 4 33.pR o Rirv(2 16- 2 2 1 16-PTdreT) ) ) ) ) ) ) )Iet- d)unn.3.8.6.0).3 2. ).3)2. )5.0.poo%(7 9 2 5 7 2.51 5 7 2.81 9 01 51 m n Ipse n(r 3(4(1(2(3( ( (5 2 3( (5 4(4(6 re) ).9).3).7).5).9).3). ) ) ) ) )-nd ono% 2 ( 8 87.0.3.7.1.0(6 4 7 5 8 4 5 8 0 2 5 ( 9 8 6 6 9 9 6 7 9 8 Npsn 4( ( ( ( ( ( ( ( ( (er3 82 63 53 72 82 63 83 82 92 53 43 redn) ) ) ) ) )1. .7) )o%3 5. .1.7)3) )0.7.3) )0.pse(7 1.1 3 n( (5 2 4 1. .1 99.1 3 3 5 5 3 2 7 51 7 3( ( ( ( ( ( ( ( ( (1 2 5 41 31 2 2 3 2 3 6 R 1 1 )0) )i i i4 0 bibibi4 0 bb b bibibi4 nitDInDInM = P N nDnDInM = P N nDnDInM = P N urT)iturB)iturQ)( it IourT)iturB)iturQ)( it IititourT)u B)u Q)(bg azlim1 04bg =azlim1 04bg =azlim8 03b =ebg cam14bg am14bg am83bebg am1r4bgrg o a 14b 83beal5zli0=zli0=zli0=cal6zli0=zlim0=azlim0=cal7R04N(R04N(R04N(P k 0 eeR 4N(R04N(R04N(P k 0 eeR 4N(R04N(R04N(P keeW W WAttorney Docket No.01183-0291-00PCT-PRN e b ulob 22 65 47 36 99 96 18 89 1 a.vs-vec5 al .14 0.16 0.11 0.57 0.08 0.27 0.09 76 0.0.6P p 0 0 )Ia, , , , , , , , ,Cbinio4 t b0 e7. )41 9 47. )2 8 1 5 5 6 4 20. )4 44. )9 48. )0 8)9 5 21. )8.37. )1. )%r c04 0 0 0 0 03 04 0 9 5ur( (3(5 0 5 6 03 01 9o(fbalap52.80.6.1 (.1 (.4 (.9 ( 7.(.8 (.31 229 942 315 548 451 852 799 513nRzloiitOr.sv6.26.22.05.17.24.03.1 37.27.0al ruofbioa, , ,po)n 5, , ,5, , ,7 itb)I8 .1)3 .)1.7)5)5.1)0)9. )P%ue(recC4- 51.0 4- 2 .40)2- 2.128.5.6 1- 8 .53)28.21- 4.8.6 2- 2 .06 17 .8vïDbalap%(1(1( 5.1- 4(8 -( 7.(4(4 -(0aRzl.5.43.633.3(2.534.6.73.630.1N- Risrv9(31 318- .36 818- 61 513-badre-ed) )3) )2)1)0) )9) ) ) ) )mtnn.47. .6.1.06. .81.11.70.2.9.uuoo%il1 5 1 1 2 8 1 0 6 3zp m nps(n( (5 2(6( ( (3(1(1(2(1(1(aIe4 7 7 4 6 7 6 5mrOre) ).3).3).3).9).3).9).9).3) ) ) )-nd ono% 4 ( 7 4 ( 7 7 ( 9 8 ( 8 4.6.4.9.9(7 2 1 3 8 1 1 8 ( 6 9 8 6 7 9 8 Npsn 6 6 6 2 6( ( ( ( ( ( (er2 2 3 3 2 22 43 03 42 52 43 23 redn) ).7).7) ) ) ) ) )o% 5 57. .1.7 1. ) )2 1 5 731. .7 4.6. ) )6 1 81. .11 p(2 2(1 2(8(1 3 2 8 1 sen(9(9 1(4(9 31 3( (6 1( ( (1 01 3 4 R e b ulo a.vsb 19 5 6 6 1 4 8 3 9 4 1 9 5 9 66 72 64 51 0 7 - vecal0.00.01.01.0.3.0.3 0.3 7.P p 0 0 0 0 0 0 )Ibia,8,9,3,3,6,8,1,1,C nio t b9 8)8 9)3 0)2 7)2 1)1 1)1)6)96)%rec .064.36.9.3.6.83.900.401.0 5oura (.70(.0(3 0(4 1(5 0(3 1(1(0(4 9(fbla 71 581 8.37.07.62.10.70.83.5zlp.s4 .21 2 .41 72 57 9 9 02 861 411 73 R.2.2.2.5.6.5.7Oirv 3 3 0 2 3 0 4 3 0 r ofbi ,noba), ,I0 8 2,n)ite.4) .9)3.0, ,7 6 8) .9) .0)2,.5, ,8 9 1) .8) .0)3. )o%ur cC0- 0 .606 .154- 3 3628 46 25 5 12it(alDbal( ( 6-7.(.3 (.4-2.(.0 (.7- .9ap% . 5.123.843(3.3.703.804(0.7.093.463(0 2.1uRzl s9(6 71 2 12 2 9 po Rirv 17- 17- 2 12-PTdre ) ) ) ) ) ) ) ) ) ) )TIet- d)un6. )pono%4.8 8.5.5.2.4.5.1.0.8.0.1 9 51 21 91 21 81 21 71 22 51 5 m n Ips(en( (r 6 4(6(5(8(5(7(5(7(9(1 6(6 re) ).2).7).4).0).3). ) ) ) ) ) )-nd on0.1.0.4.3.1.0o% 3 0 7 0 8 1 2 5 3 8 2 0 ( 7 7 9 9 6 6 9 8 6 6 9 9 Nps( ( ( ( ( ( ( ( ( ( ( (en r 03 92 73 63 82 52 53 43 62 82 53 63 redn) ).8).3) ) ) )0. .7.0) ) ) )0. .6.7) )0.o% 6 p 2 926.2 0 1 99.1 3 3 7 5 6 19.1 3 3 7 01 se(n(1( ( ( ( ( ( ( ( ( ( (1 2 1 4 3 6 3 6 5 3 3 4 R 1 1 1 1 1 )0)0)bibibi4bibibi4 0 bb b4 nDnDInM = P N nDnDInM =i i iP N nDnDInM = it Ii i iIi i iIi iP N urTt)urBt)urQ)(tourTt t)urB)urQ)(tuTt t)u B)u Q)(bg azlim1 04bg =azlim1 04bg =azlim8 03b =ebg cam14bg am14bg am8o 3bre bgrgrg o a 14b 14b 83be0 al8zli0=zli0=zli0=cal9zlim0=azlim0=azlim0=ca1R04N(R04N(R04N(P k 0 eeR 4N(R04N(R04N(P k 0 eeR 4N(R04N(R04N( lP keeW W WAttorney Docket No.01183-0291-00PCT-PRN e bulo a.1 1 3 2 2 4 4 1vsb 11 69 6 6 7 3 9 6 15 - veca.2.22 .26 .20 .38 .23 .06 .35 .3Plp 0 0 0 0 0 0 0 0 0)Ibia,2,6,6,5,8,7,4, ,Cnio t b4 6)6 5)6 0)0 6)7 5)0 1)6)88 6 ) 7)%rec .04.00.00.00.09.060.1784.00.7 5ofural(2 a.8 (3 .5 (4(2(3(4( 8.0(3 0(2 9(bp17 36 7.91 1.46 3.95 6.91 04 4.47 8.5Rzlir.s4 2 5 7 5 5 81 0 3 2 v2.29.13.9.8.4.9.9.4.O 0 1 1 0 3 1 0rofbioa, , ,)n 1, , ,5, , ,7 itb)I6 %( urecC.36)1)2.2 .-64.3 2)018)9 .-488)7.6)1)8.-5 3)0.8156.4 8)2Dbal(.45 08-(.282-( 0.(.40(.492-( 8.(.788-(.441-6.ap%.13 2 5.2.36.3 (6Rzl.s9.6v9(21 9.1 3 025.03 29.2 71.Rir8- 1 18-6-dreed) ) ) ) ) ) ) ) ) ) ).4).0)t-unn3.poo%49.22.61.14.10.09.1.9.1 79.n(1(2(1(1(1(2 8 1 2 ( 1(1(2 3(2(31mIpse n r 5 8 6 4 4 7 7 4(8 11 0(1 5 re) )n.4).3).6).1).6) ) ) ) ) ) )- dono% 1.4.9.3.7.0.6.9(7 4 ( 7 4 6 8 1 1 3 5 0 4 8 ( 9(8 6 7 9 8 6 8 9 8 Npse n r 5 6( ( ( ( ( ( ( ( (.2 2 53 13 42 52 43 03 32 82 53 23 n oired) )6) ) ) )4)g6) ) ) ) ) ) ern.% 8.754. .9. .3 1 81. .7 3.6 4.004. .11 yope(2 2 5 1 3 2 8 1 3 2 5 1bsn(0( ( ( ( ( ( ( ( ( ( ( deR 1 9 2 5 11 01 3 6 21 7 2 4ifite baulor7 2 0 0tsa.sbe97 74 90 2 2 2 7 4 1 4 1 2 7 0 3 2 84 85,pv- vcPal1.p 03.01.01.02.02.00.02.02.u 0ror)Ibia,9,7,5,5,6,o 1, , ,tagnoCn%io t b0 7)6)5)9)7)0 1 ) 4)61 9 ) 6)miitn5ru9orec .035.30.77.26.21.91.76.00.2ts e( 6 0(9 0(0 0(8 0(6 0(3 1(3 0(3 07evr(fbalap4.09.09.4.7.8.7.1.9 (.0 leetRzl.76 95 71 226 195 811 122 7 1 6 6 872zsniOir sv.02.61.20.32.91.40.73.02.30 neadro,Hnafbioa, ,9, , ,)n 9, , ,7 -l sitbu%ec)I7 C.7( ur5)3 4.1) .73 1 5)4.73)0 1.4)41.1 4) )7)1.et t5.10.39 0)6naatsDbal -ap%(.519-(.4 2- -6( 0. .8 6- .0 2- 3.7 6- .3 2- 2(3(0( 3.5(.98(6( 0.5 MredRzl.s5.9v9(236.2.9.03.8341 8 1 5 1.03.02 2 06. ehtno Rir1- 1 19- 17- mpsedrret-ed) ) ).4) ) ) ) ) ) ).8).1).3)orfehunn1.poo%7 48.55.26.40.24.85.2 6 4 65.detmn(1Ips(2(1(1(1(2 1 1 2(3(2(71vineen r 7 01 6 5 6(9(7(5 11 41 0(1 7reed;w r-e)nd.95.70.7)4.5)2.4) ) ) ) ) ) )ecte) ) )nbn 3.38.12.52.43.65.74.57eroiono%(6(7(9(8(6(6(9(8(6(7(9(8eftaNpse n r 7 9 6 3 6 8 5( fiic2 2 3 3 2 2 3 33 62 13 63 53 deotssraed) ). ) ) ) ) ) ) ) ) ) ) )raes ehn1o% 4.393.5. .66.719.5. .66.443.5.ntnp(3(2(5(71 3(3(7(71 3(2(5(21 o psosen 4 2 2(5 3 3(5 0 2( deR 1 1 7 1 1 7 1 1 5er:Dmr)0) )RofbinbitDiIni DIbi4 0 nM =bibibi4 0 bb b4 R;rep P nDnDInM =inDinDiInM = oitsautrT)iutN rB)urQ)( it IititP N ourT)urB)u Q)( it Iiu Tt)iu BtP N )u Q)( arw bg1 bg1 bg8b bg1 bg1rbg8obrgrgrg obs tazlim04=azlim04=azlim03=ec1am4am4 3e2b 14b 14b 83edseal1zli0=zli0=azlim0=caa 1zlim0=azlim0=azlim0=ca dotR04N(R04N(R04N(P k 0 eeR 4N(R04N(R04N( lP k 0 eeR 4N(R04N(R04N( lP:H RM W WaO bCAttorney Docket No.01183-0291-00PCT-PRN e b ulo 5 7 4 6 3 4 a.vsb 1 1 9 3 9 9 - vec5 .92 .39 .29 .19 .59 .2Palp 0 0 0 0 0 0e)I , ,vïC bia nio 0a %tb 5 6 0. )0, , ,E 93 85,E 53. )9 N)4. )71. )5 NN5rurec0 -(7 0(6(E 03 04()E 9ofbal14.23.0 N(60.(49.0 Nb(ap142 443 0 a nRzl0oi.315 252 0 0.itOr.sv1.12.3 07.40.2 0muzal ruofbioa, , ,2, , ,2ilpo)nitbec)I6)6) .3)7)1) .3P%uralC 9.6- 50.6 45- .1 8- 03.75.8 63- .8 6- .5 8)-0a me(b vïDap%(.7(6(.2(9(1( 6.2 zl.s52.6.19.3.15.19.OaR9Rirv(0 52- 8 22-dN-n badread) )met- unn% 0 0 0 0 0 0 09.n u o zitilpoo np (0 0 2(0 amI se n 1almru Ore) )0)0) ) ) ) ) ) ) ) )p -nd 0 0 00 00.1.400.2.6.300o ono%(1(1 1 1 79 19 1 79 88 49 1PNpse n 5(5(7(6(r 3 3 3 3 4(3 2(3 7( ( ( (3 53 13 33 73TTIre(d) ) )n)2 o% p(0 0 0 09.26).8. .4)( 8 0 2 17.1 5 01 sen 1(3(1( (4 2keRee bW ulo a.sb 22 60 37 25 78 37ovvec6 9t- .4 3.1 3.8 0.8 3.1 3 Palp 0 0 0 0 0.0pu)Ibia, , , ,o 05 29,7 2,eCnb) )E 7)6)Emi%5riteour c0.9 a 0(62.0 N)6.22.9 N).30(7 .(E 0(1 0(7(ET9(fbla 43 253 00 N 2.82 3.900 NreRzlpi .s8 v.02 3 .130.2 6 913 0.5.8 0.0v Or1 3 6 2or0ofbioa, , ,4,1, ,=n)nitbe )I0 3) )1)4 o%ur cC.26) .-454- 3.5) .6.9 7- 60- 0.84- 6.57)-67it(bal( 5.( ( 3.(.6 (.1 ( 3.SalDap%526 31.62.022 31.62A uRzl.sv9( .07.42- 12.1 42-Upo RirhPtiTdreet- d) ).4)w TIunn% 0 0 0.9poo(0 0 2 0 0 0 4 0stmn nIpse n(r 1(2apir) ) ) ) ) )ci-e)0)0)0)0 ndn.6.7)0.5.4.7)0t% 01 01 01 01 7 2 01 7 5 2 01roo N aps(en(1( ( (9(9( (9(8(9( (r 4 14 83 04 04 83 83 93 53 83 83Pfo red) ) )n noio% p 0 0 04. )3. )5.6. )43.( 0 2(7(0 2(1 7 0trsen 1 3 1( (6 3o R por ) )Ps0)0 tbibibi4=bibibi4bibibi.n n 2aitDIniutDIn2 prT)iM utP N n rB)iutDIn rQ)( itDIniM = P N ni DIni DIniMP ourT)urBt)urQ)(tourTt)urBt)urQ)eilci ebg azm1 04bg =a1 zm04bg8 =azm03b =ebg1 c1 azm04bg1 =azm04bg8 =azm03b =ebg1 g g cazm04b 1 =azm04b 8 =azm03=batrnileli0 s R 4N(liR04N(liR04N(alP kliR04N(liR04N(li0N(al2kli0N(li0N(li0N(aeeR 4 PeeR 4 R 4 R 4 Ta P B W WAttorney Docket No.01183-0291-00PCT-PRN e b ulob 90 96 49 19 47 69 2 4 4 a.vs-vec1 al .35 0.39 0.29 0.65 .76 9 .16 1 .09 7 .15 .9P p 0 0 0 0 0 0 )I , , , , , , ,Cbia n %io 2 t b 1 3. )38 92. ) ,E 42 79,E 54 1 N)2. )1. )N7. )93 25 74. )10. )6 5rurec0(7 07(E 099 066()E 06 07 05 9o(fbal0.( 5.0 ap522 N(.4 (.50 N( 2.( 1.( 4.4 6323 0 069 279 0 1756 451 326 zl.s6 0 0.4 3 0.4 1nR oi. .0. .09.2.9.itOrv 3 3 1 1 6 4 0al ruofbioa, , , , , , , , ,)nitb)I3)4)2 . 2)3)1 7.3 .2)4)6poecPC 7.23.33)06.35.3 2)16.7.5)%ue(ral4- .3 5- .4 8-9- .5 9- .130-3-7- 5vïDbap% zl.s5(9 8.61(0.51( 69..2(5.41( 29.3 -0.(.61(3.2.26 32(.7 ( 1.1.912.7aR v(5 52- 2 151 80-N- Rir -badreet- d) )8)8)6) ) ) ) ) ) )muunn%.z 2 0 0 0.2.87.57.6.7.7.4.3.ilpoo nps(n(1( ( (2(5(5(5(5(8(amIe1 3 2 1 2 2 2 2 3mrOr) ) )-end) .2.4.4)0).2).4).4)0).4).9).6).3).2ono% 79 19 1 0 9 1 79 19 1 0 9 1 49 28 88 79 79 Nps(n(5(2(2(7(5(2(2(7(4(9( ( (er3 3 3 3 3 3 3 3 3 2 13 63 53 red) )o%8)6)6)8)6)6) ).1).4) )n. . . . . .6.7 17.8.pse(2(8 1(8 3(0 2 3(8 8 0 5 1 1 2 2 n 1(3(3(2(6( ( (4 1 1 R e b ulob 92 4 3 9 1 7 3 1 0 a.vs-vec1 7 2.3 7 2.1 7 3.0 9 1 2 7 0 5.0 8.9 1.5 0.7 0.0 0.Palp 0 0 0 0 0 0 0 0 1 )I , ,Cbia 3 7, , , , , , ,nio t b 1 4. )8 E 80 68 02 48 65 13. )03. )11. )E8. )96. )0. )%5r9o(furecbal0(8 .50(3 N .4 ()0E 0(1 .306 N ( 6 ap088 758 0 N 761 87.()09 054 015 7 0E(.5 (.0 (.78 0 N 600 43 07 Rzl.s .44.830. .81.2 0. .67 2 .05 0 . 1 Oirv 4 3 0 1 1 0 7 601 r ofbioa, , , , , , , , ,)nitb)I4)6)4 . 0)8)9 3.6)4 .6)3necC.10.665)6.30.76 1)9.85 9.9)o%ur3- .0 3- .2 7-7- .3 8- .3 10.0-6- 3it(bal(7(6( 3.(5(1 -8.( 45(.7 ( 9.alDap%59131.620131(1.22.12206upRzl.sv9( .6.62- .4.18.4 o Rir -31 1.1 0PTdrTIeet- d) )unn%.5) ) ) ) ) ) ) )2. ) )2 0.42 0.5.3.8.6.0.32.3.5poo( (2 7 9 2 5 7 1 5 7 npsn 1( ( ( ( ( ( ( ( ( (mIer1 1 3 4 1 2 3 5 2 3 re ) ) ) ) ) ) ) ) ) ) ) ) )-nd) .5ono% 7.20.20 00.5.2.700.0.9.4.4.5(9 9 9 1 79 09 29 1 59 28 58 79 79 Npsn(9(7(7(8(9(7(8(8(8(4(5(7(er3 3 3 3 3 3 3 3 3 3 3 3 93 red) ) ) ) ) ) ) ) ) ) )n)o%5.8.8.5.8.3.0.1.76.46.5.pse(2 9 9 0 2 9 7 0 5 1 1 2 2 n(1(4(4(1(4(3(2(7( ( (6 1 1 R )0) ) )4 0 0 0 =bi( nbinbi4 nM =binbi4 4 nbinM =binbinbinM = NitDIitDIiP Ni DIi DIiP Ni DIi DIiP N oburTebg)1urBtg)urQ (tg)ourTtg)urBtg)urQ (tg)ourTtg)urBt)urQ)(o cam4bam14bam83beb 1 al3zlcam4bam14bam83beb 1 bg1 bg8b cam4am4am3ecP ki00=zli00=zli0=ael4zli0=zli0=zli0=al5zli0=zli0=zli0=aleR 4N(R 4N(R04N(P k 0 eeR 4N(R04N(R04N(P k 0 eeR 4N(R04N(R04N(P W W WAttorney Docket No.01183-0291-00PCT-PRN e b ulob 51 18 47 90 41 44 99 2 0 a.vs-vec4 al .00 0.25 0.91 0.39 0.16 0.95 3 0.76 8 .16 .5P p 0 0 0 )I , , , , , , , , ,Cbia nio 7 t b 9 8. )32 14. )25 20. )21 63. )93 94. )37 40 70 93 10. )2. )6. )0. )%re9oc2 6 5 7 7 48 2 79 5 5 (furbal0( 8.0( 7.0( 4.0( 0.0( 1.0( 4.0(5 0 0 a.9 ( 3.(9 .8nRzlp2 .s82 8 0oi.7 48 3 0.3 26 5 9.1 22 4 6.4 51 1 2.4 65 1 8 46 75 0.1 5 3.5 1 1 7 4itOrv 8 4 0 3 4 1 1.3.0al rbia, , , ,uofp nob)I7,o)it )6)6,3, , ,)4)2 5)7)3 6.P%ue(recalC.411 (.98.3- 7.5).70 7- 5.4- 26.3- 77.7)-79. .99- 83- 5 1)16vïDbap%5.692(691( 12..7(.3861(.7191( 0.2 8(.63(.4-2.1.752(6aRzl.s5. . . .9.v9(1 70- 5 8 0 1 071.2NRir --badre-ed) )4) ) ) ) ) ) ) ) ) ) )mtnn.17.8.09.33.7.2.1.0.6.9.1.uuoo%ilps1 5 4 5 6 1 0 8 8 1zp n(n( (1 1 1 2( ( ( (1(1(2( (1(1(amIe4 4 5 5 2 6 4 7 3 7 4mrOre) ).0).6).3).2).4).6) ) ) ) ) )-nd ono% 0.3.2.4.9.3.4(8 8 7 7 1 8 7 7 1 2 7 4 ( 8 9 9 9 8 9 9 9 8 9 9 Npsn( ( ( ( ( ( ( ( ( ( (er82 13 63 53 23 13 63 53 23 92 63 43 redn) ).0).4)o% 0 17) ) ) ) ) ) ) ) ).28.6. .417.8.6. .177.6.p(2 1(2(8 1 2 2 8 1 2 5 sen(7(4 1 1(3( ( ( (4 1 1 3( ( (6 1 2 R e b ulo 3 a.vsb 8 6 1 2 0 4 0 9 0 2 1 5 6 5 5 1 77 50 38 27 4 - vecal0.01.00.12.0.9.5.0.2 6.P p 0 0 0 0 0 0 )Ibia,0,2,6,3,4,1,3,5,C nio t b 4 1)2 5)5 0)1 4)8 6)8)7)2)24)%rec .15.99.15.1.50.92.18.70.7 5oura1(.0(0(0(8 0(4 0(0 0(3 0(9 0(5 9(fblap961.40.70.54.07.77.53.17.5.418 244 071 884 235 661 901 802 26 Rzlir sv.69.84.01.44.06.1.6.0.5O 1 1 4 0 r ofbinoa),0,8,3, , , ,4 4, ,2 4n)itb oit%( urec IC.8)35.3)23.96)3.1) .6)5 300- 9.07)7)2.7.6)4.700- 2 0)2alDbal(ap%..6- 20(.29 -( 9. - .0.7- 6(7(.912(. - .2.3 1- 7(4( 1..47(6upRzl.s5 734.10.9.1 v9(1 8 0 6 124.2.1 1 0 3 3 221.2o Rir -PTdre ) ) ) ) ) ) )TIe- d)un2)5 0 6) ) ) )t . . . .8.5.5.2.4 5pono% 2.81 9 01 51 4.81 9 5 2 9 2.8.2 m n Ips(en( (r 5 4(4(6( (1 1 1 1 1 1 6 4(6(5(8(5(7(5 re) ).0).8). ) ) ) ) ) ) ) ) )-nd ono% 8 747.57.20.45.47.57.2.5.4.0(7(8(9(9(9(8(9(9 0 0 7 5 ( 9 8 9 9 Npse n r 2 6 7 9 7 5 7( ( ( (3 3 3 3 3 3 3 93 73 33 73 83 red) )0).2. )6)5) )6. ) ) ) )5. ) )no% 2. .8.6.5.8.6.0.p 2 2 2 2 9 4 2 2 9 9 2 5 se(n(1 9( ( ( (1( ( (1( (5 1 1 4(6 1 1 4(8 1 2 R )0) )i i i4 0 bibibi4 0 bb b bibibi4 nitDInDInM = P N nDnDInM = P N nDnDInM = P N urT)iturB)iturQ)( it IourT)iturB)iturQ)( it IititourT)u B)u Q)(bg 6azm14bg am14bg am83bebg am14bg am14bg am83bebg am1r4bgrg o a 14b 83bekli00=zli0=zli0=cael7zli0=zli0=zli0=cal8zli0=zlim0=azlim0=caleR 4N(R04N(R04N(P k 0 eeR 4N(R04N(R04N(P k 0 eeR 4N(R04N(R04N(P W W WAttorney Docket No.01183-0291-00PCT-PRN e b ulob 98 04 25 37 83 71 16 93 2 a.vs-vec9 al .89 0.20 0.31 0.84 0.25 0.11 0.59 98 0.2.9P p 0 0 )I , , , , , , , , ,Cbia nio 1 t b 6 2 e1. )0)92 3 8 4 4 4 8 15.30. )6 8 2 0)4)2 81. )5. )0. )3.34.01. )%r c0 06 0 00 09 2 2 4 6 5ur(7(6 2 1 01 0 0 06 9o(fbala.9 0.(.1 (.1 (.9 (.0 ( 2.( 6.(.5zlp3 .s94 9 8 40 5 21 03 9 3 1 4 9 8 57 9 1 12 6 2 41 1 81 54 6 51 8 7nR oiitOrv.0.2.0.0.2.0.1.29.0al rbioa,8, , , , , , , ,uofp nb)I8.o)it )6)0 0.5 5. )1)4 4.7)7)6 4.%urecC3 16 .81.6- 1 .76)13 5 11.9.1 6- 9 .00)327.8- 1 .00.6- 3 . 0)12Pe(vïDbal -ap%5(2(3 -aRzl.s914.2( 8. -2(8 -9.(7( 80- .30 64(71.62(723.14.2(11 v9( .0. .-85-1- 01.8.-4 70N- Rir -badre-ed) )1)0)2) ) ) ) ) ) ) ) )mtnn.7.0.69.33.49.2.1.4.0.9.1.uuoo%il1 2 1 2 6 1 1 0 8 1zp m nps(n( ( (1(1(2(1(1(1(2(1(1(aIe6 7 6 5 5 8 6 4 4 7 7 4mrOre) ).4).9).3).7).6).1) ) ) ) ) )-nd ono% 1.3.9.6.7.6.4(9 2 7 1 8 7 7 8 8 5 4 4 ( 8 9 9 8 7 9 8 8 8 9 9 Npsn 2( ( ( ( ( ( ( ( ( ( (er3 92 63 33 13 72 63 23 13 03 53 43 redn) ) ) ) )o%6. .1)8 77).3. .41.9) ) ) )27. .11.41.3)44).6.p( (1 2(8 1 2 2 1 1 1 5 5 sen 3(6 1(3(4( (8 1(4(4( ( (5 2 2 R e b ulo 1 6 a.vsb 89 2 3 4 9 4 3 8 3 0 0 1 0 2 9 9 07 33 41 35 - vecal8.01.03.08.01.1.1.2.9.P p 0 0 0 0 0 )ICbia,n 0,4,2,6,1,6,1,2,6 i o t b 2 2)9 6)3 0)7 2)5 6)2 0)6 6)3)3)%rec .00.034.09.4.3.4.205.011.3 5oura (7(.2 (0 0(0 0(8 0(3 0(.00(0(1 9(fbla 7.642 0.40.32.25.198 2.75 5.3zlp.s15 .11 .91 33 .31 5 28 32 41 91 6 8 Riv.2.3.2.4.8.0Or1 2 0 1 2 0 3 2 1 r ofbi , , ,noba)I2,)9 4, ,5.4 8 1,7, ,.2 0 0n)iteo%ur cC.216.1).8 3- 8 . 4) .5) .9)16 164- 1 8) .8)112- 8.3)4.-949)-9it(alDbal1-( 7-7.1- .9 (.8-0.(.5ap%(21.352(4(41.962(3.432(.609.2(9upRzl.s5 v9( .80 191.4.71 091.7 02.1 83.0o Rir - -PTdre ) ) ) ) ) ) ) ) ) ) ) )TIet- d)un1.0.8.0.1. .448.5.6.0.4.5.pono% 71 22 51 51 71 2 51 21 41 22 81 2 m n Ips(en(r 7(9(6(6( (7 0(1 6(5(6(9(1 7(5 re) ).2).5).4).5).4) ) ) ) ) ) )-nd ono% 09 08 79 29 5.08 8.47 7.09 0.99 2.48 5.78 4.09 59 Nps( ( ( ( ( ( ( ( ( ( ( ( (en r 73 33 73 73 53 23 73 63 43 53 63 83 red) ) )85. )6) ) )56.0. ) ) ) )60.1.6. )3)no%.pse(9 n(9. .1 2 7 41 2.2 2 01 71 4.0.1 5 5 4( ( (8 1 3(6( (9 1(4(7( ( (6 2 2 R )0)0)binbibi4 itDIni DIniM =bibibi4 0 P N nDInDInM =bibibi4= P N nDInDInMP N urbTtg)urBtig)urQ (tg)ourT)iturB)iturQ)( itourT)iturB)iturQ)(o 9azm14bam14bam83bebg1 bg1 bg8b bg1 bg1 bg8b c 0am4am4am3e1am4am4am3e2 kli00=zli00=zli00=ael1zli0=zli0=zli0=cal1zli0=zli0=zli0=cal1e R 4N(R 4N(R 4N(P k 0 eeR 4N(R04N(R04N(P k 0 eeR 4N(R04N(R04N(P keeW W W WAttrorney Docket No.01183-0291-00PCT-PRN e buloa.3 6 7.svbvsb 8 o 2 5 9 2 3 1eb 6 7 1 21 14- vecPal .45 .75 .1Tulec1 p 0 0 0 T0Ia v.4 -al00.3 04.0 00.1 00.0)Ia, , ,Cn- Pp bi4 8, , , , ,%rio t b4 ec4. )0 4 003. )2 080. )2bia no 86)70 53 13)70)021%5ritbe 2.90. )5. )9.73.95o(fural(0(2(1 k 9ofur c1 a(010 ( 406 ( 6 19199 bp0.38.19.0Rzl.s07 8.5 5 2.12 2.eest( )nRIbal0.121.02.(.6 (.3a Cap801681 4 5056 1801 Oirv 1 1 0 p Ozlir.sv.53.82.51.5.6rW ico,5,3fbioa, , ,)nitbec)I0 C4. )0 4.13)4 oit )bi24.tr 0)a noa,0,3 6 0,8 %itb 7 p P(rue )I .7) .9) .2) .4) .3)(r cC65 . 0221 71779%urbal9%-(.131-(.282-( 9.ueDo2evï fbal( 3 (.61- .6ap%.505.334(82(.50(.36.90Dap5 Rl92 1 R.s5 8 2.0.85 z.s .v9(6.6 72.a 8 -miRzlirv9(2 228 93 2 Rirdree ) )t N-t- d) )9. .4.0)9.rb e adremet- d) )unno% 0 0 0 0 0.92unn poo%(2 1 7 2 3(2(3 v u 1ozilpo m n Ips(n(1mnIpse n(r 8 1(ae1 01 5er ro mre) ).6).3) ) ) )r -e) ) ) ) )O m -nd on% 8.3.8.1.64 45 07 77 73 84nd on.0.7.3.9o(o% 0 5 7 8rNpsn(7(9(6(8(3(7 Nps(8 e n(8 r 8(9 8 2 0(3 6(3 2.o3 n oiste1 1 2 2 1 1 rred) )4)7)7) ) )re ) ) )genio n.o% 1.5.9.2 9.24.1 ( 5 4 2 22 6 5dn) .00.3)47. .1 r1 yppsen(8( ( ( ( (1 6 1 8 2 8o% 2b0 1 1 2 1pse(2 1 n( (1 7(5 1(4deif1fReb ulob 73 0 9 3 4 Rito.6 3 0 2 bar easvec0 .05 .00 0 1e o 5 1 6tsv-al0.3.0.0ul.b 5 5 7,nivlP p 0 0 0 0as- vec7 1 0 p Pal2.ubia, , , , ,p 05.01.0roresa %rnio 3 t b 8 .5)57 8 0 8 .9)1 .6)3 .2)0 .3)og5ofec1020306 224 1)Iba, , ,tanob9( )Iural( 1.(7 .9 (2 .( 0.1(7Cin %rio7 t b8 3 ec5. )4 2 004. )2 090. )mii08ttsnem o R bap6917062754 28688.78 r O Czli .sv1.1 46.26.9.13.5oura (8(5(9evr r1 5 39(fblap5.76 1.15 4.61leetf)bioa,9, , ,9,RzlOir.s9 v.91 1.59 1.1 zsnin nb)I0 n0edoin%(ritecC.2)2 5.1)2 6)4. )5)00.93 05.378rofbi , , anat5 H-s co uitalDofural1 R bap%(.8 (.9-.(.52 5250.93.503(.7 (.2.6068.84)no itba)I ,1)9 .4) .6l)etutatd%eup Rzl.is5 v9(2 0 3 2 01 0 7 4 2( urecC.05 05 1 2- 2nasorDbal7ap%-(.851-(.21( 6.1 Mrer7Pdre) ) )Rzl.s54.2 v9(9.42.05 0ed T htno SeTt- d I unono% 0.42 0 0 0.94 Rir1- mpsA p nps(n(1(2dree ) ) ) )orert-eU mIerd) .8.1.3 fh hr) ) ) ) ) )unn poo%62 4 65.7det ti-ed)9.1.4.5.7.3.mnIps( (3(2(1( vin re wnono% 34 65 86 77 13 64 e n r 11 41 01 7eed;wsetNps(n(8(3(6(1(3(9 cte1 2 2 3 1 b naer1 r -e) )ndn.6) ) )nnre ) ) )5.50.47.57eroipid)1.9.6. ) ) )5.3.7.oo% Nps(7 n(8(9(8( effitai cino% 65 34 13 2 8 3 2 6 5 r 1 3 7cetp( ( ( ( ( ( (e3 3 3 53 dotssrsen 3 8 2 8 2 a a R 2 1 1 9 2 2raerep dn) ).4)5. ) )5eshtfo% 4op(2(96. .1 2 non ( 2(1psonDIDIMPDIDIsen 0 8 1(5edeoiT B Q T BR 1r:mrtrg g g g g m m m m m ) D 0 Rofo 0 r 0 00 00)00 00 bi4 R; ep nb p oitDiInitDr4 4 4044 4IbiniM = o t P NitsaPnbinbiitnbii n =bii N nbii niu T u B u Q ( arw.out t(t trbg)1rbg)1rg)obs t3it r )ur )ur )obur )ur )azlim04=azlm04b =azlm8 03=ecddseot 2b R04N( iR04N( iR04N(alP:Helalu1 a1 z4b kli=a1 z4b l =a8 z3=eb1 c2 az4b1 =az4= RM bapeeRN( iRN(liRN(alP klieeRN(liRN(aO bCTo p W WAttorney Docket No.01183-0291-00PCT-PRN .svb eo ulb 3 e 6 1 1 8 3 7 6 9 6 3 9 0 c 2 52 84 11 80 85 19 2 9 4 4 3 v-1 0 1 3 0 1 56 0 5 5 7 7 2 1 aal .p 0.0.0.0.0.0.0.0.0.02.04.0 Pbia,0,4,1,4,6,2,7,1,5, , ,%5rn ofio t b 9 ec7. )2 31. )8 97. )2 86. )9)7 53.0)8)4)1 4 ) 5 0 ) 9 7 ) 7)57.04.89.55.03.76.95.5s9t( )nRIur0 bal(8 1 49.(30 97.(10 74.(4 1 54.(0 5.6 (20 64.(8 0 5.(00 7.(30 4.(7 0 1.(30 5.(2 8.a Capp Ozlir.s75 47556 4 50145223 216923772 074683 v.12.92.02.61.83.0.3.5.3.8.7.4icitr)bia noa,i b)I5, , ,2 .4)8)9 3, ,1 .4)2. )7)1,2 .7)5,1 .2)6,0 .4)5,1 5,1 .1)6. )4,.1)0)P%e(r turecavlC4- 5.8.638 .25- 40 .81- 1.8.085 .45- 8 .359 .1 0- 8 .166 .06 2- 5 .9 9- 7.4.234 .9ïDofaR bap%(7(Rzl.s5 9.(663.10(9(3(3(91- 7 5.2734.3.21 1 5.863(7(.02.451- 2 4(0 .03(9(81- 4.1.643(2 .83N-ibrv 1 2 1 1 3 1 6 2 73- 1 9adreet- d) ).8).8).6).7).7).6).7). ) ) ).4)muunn zilpoo% nps(0 2 n(0 0 0 27.4.31(8 1(5 3(2 5 5 5 5 8 1.71 5 2( ( ( ( ( ( ( (amIe1 2 2 2 2 3 4 2mrre) ).2).8).0).4).5).4).4).6).2).7).4).7) ) ) )O-nd ono% 2 ( 6 7 ( 7 0 ( 4 1 ( 5 9 ( 5 9 ( 6 1 ( 3 8.8.8.9.6(4 2 6 1 5 6 2 2 8 ( 6 6 3 4 5 5 4 4 Npsn 3 8 4 8 2 5 1( ( ( ( ( ( ( (er2 2 1 1 2 2 1 71 32 42 11 61 12 91 51 71 red) ) ) ) ) ) ) ) ) )n)8. )7.2 0.06.85.06.06.84.18.73.36. )83. )42. )32. )71. )74.o% p 3 2 6 4 4 3 6 5 3 3 6 5 4 4 5 15 se(n(2 4( ( ( ( ( ( ( ( ( ( ( ( ( ( (8 1 7 5 1 4 8 4 2 4 9 6 7 0 8 R 1 2 1 1 1 2 1 1 1 2 1 1 1 2 1 e b ulob 67 75 67 08 8 2 8 2 3 4 2 6 a.vs-vec1 al .10 0.00 0.18 7 0.20 9 .08 5 .18 5 .63 9 .03 8 .60 1 .90 7 .25 .6P p 0 0 0 0 0 0 0 0 0 bia,3,7,4,0,1,1,9,4,1,0,7,5 %rnob 1)8)5 5 7 5 6 6 1 9 2 0 5ite.8.3.8) .6) .3) .7) .4) .0) .5) .3) .7) .5)9ofuc058 184001065 193027009 1960303 0206 ()I ral(.7 (.5 (.2 (.2 (.0 (.5 (.1 (.8 (0(1(9(5 R b Caz p9 ir.s65 4 v.4 8953 4 0 9344 3 3 68.030.32 7.342.92 2.0 3.6 26.2 15.5 38.2 12.0 17.3 22.5 19.8 07.2 Ol1 4 1 2.)bioa 7, ,3,7, , , , , ,1 1 , 7, ,n nib)I8. )6)3. )5. )3)0 6)0 4)0)9 4)6. )9 5)4 8)o%it(r turecC3- 1.7.093 .03- 6 .39- 3.3.987..36- 0..168.4.123..669 .93 27..0 7- 4..964 .7alDofuR balap%(5.67(34.3(5.09(3.72(34.0(5.761- 3(5(25.41- 4(6- 2(1(51- 6 32.23(2p Rzl.soirv9(6 1 1 3 81 1 9 1 2 414.3 4 22.5.1 - 419.4PTdreet- d) ).5).4).5).3) ) ) ) ).2) ) ).2)TIun pono% 0 2 0 2 0 2 7.89.62.05.37 2.35.57 2.89 np ( ( ( ( ( ( ( ( (1( ( (1( (mI se n r 1 1 1 3 4 1 2 3 5 2 3 5 4 r -e) )nd on5) ) ) ) ) ) ) ) ) ) ) ) ) ) ).0.1.8 9 5 3 3 5 5 3 3 3 5 0 8o% 0 ( 6 5 ( 7 4.( 3 8. . . . . . . . . . . .( 4 75 76 92 64 06 26 92 64 55 25 93 84 Npsn 3 0( ( ( ( ( ( ( ( ( ( ( ( (er2 3 41 02 22 72 21 91 32 52 21 91 12 12 61 02 red) ) ) ) )n)590595211) ) ) ) ) ) ) ) ) ) ). . . . .25.27.07.35.95.77.7.7.5.0.2.o% 3 2 6 5 4 3 7 5 3 3 07 3 4 7 1 1 p e( ( ( ( ( ( ( ( ( ( ( (5(4 4 6 5 s n 51 01 72 12 61 31 92 22 51 51 92 2(2 7( ( (1 91 52 1 R 2 MPDIDIMPD DIMPD DIMPD DQIgTgBgQIgTgBgQIgTgBgQIgTgBg m0 m m m m m m 0 0 0 0 m m m m m 4)0 0 0 0)0 0 0 0 0 0 0 0 0 0 0 0)0 0 0 0)0 0 0 bi44n =bi4bi4bi44bi4bi4bi44bi4bi4bi44b 4bitnitn = = =i iNitnitN nininiN nininiN niniu (b8burb1urb1ur(tb8obutrb1utrb1ur(t t t(t tr )o) ) ) ) )b)8oburb)1urb)1urb)8obur )ur )az3 iecaz4a4a3eca4a4a3eca4a4a3eb1 ca4ba14 l =3l=zl=zl=4zl=zl=zl=5zl=zl=zl=6zl=zl= RN(alP kieeRN( iRN( iRN(alP kieeRN( iRN( iRN(alP kieeRN( iRN( iRN(alP kieeRN( iRN(W W W WAttorney Docket No.01183-0291-00PCT-PRN .svb eo ulb 28 4 9 6 7 2 8 4 2 3 2 9 6 35 62 94 03 94 06 11 68 7 8 4 aecv-al9.00.01.08.00.00.05.00.01.8 03.8 00.5 05.0 P p bia,2,2,9, , , , , , , , ,o 7 7 7 1 5 0 1 9 9 %5rn 9ofitb 8 ec3. )8 099. )1 028. )2 074. )5 040. )7 109. )1 085. )3 82. )2 87. )8 55. )5 58. )2 85. )5tu1 8 6 1 0 106 190208 000s (nR)I rbal(15.(57.(46.(68.(55.(43.(14.(06.(43.(29.(73.(5 22.a ap82 6 7559 2 7 6 3 9 4 3 6 3 O Czl.s .9.71 8 3 6 6 2 2 1pirv 0 2.12.01.82.4.3.4.7.5.3.3ic ,2 1 3 1 1 2 1it )bioa 0, , , , , , , , , , ,r nb)I9. )2)3 7 5 4 0 2 1 4 4 7a%itec2.4.2) .2) .6) .4) .5) .9) .6) .3) .8) .8)P(rurC28 .906 .1 4- 5 .105 210753 638- 1222- 563eofal -( ( 2- .6 (.8 (.41- .7 (.5 (.51- .7 (.41- .3vïD bap%(12.34.51(4.78.07(8.21.00(1.82(1aR Rzl.s5 9(5.2 4 4 2 2 8.25 444.62 9 56 4.73 9 4.23N-iv0- 1 2 2 2 6 2 1 9 1 7bradre ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) )met- d)n.8.9.3.7.2.1.0.6.9.1.1.0.2.9.3.9uun zilpoo%(01 31 41 5(61 11 02 8 81 11 71 02 61 31 41 22amn Ipse n(4(5(5 2(6(4( (7 3(7(4(6(7(6(5(5(8mrre) ).5).3).1).9).5).1).1). ) ) ) ) ) ) ) )O-nd on0.8.9.3.6.1.9.3.6o% 9 8 7 2 9 1 7 0 6 3 4 8 4 3 4 8 ( 5 5 3 4 5 6 3 4 5 6 3 4 5 6 3 4 Npsn( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (e2 r 2 12 31 51 22 22 31 41 12 32 21 71 02 32 21 71 red) ) ) )n)5.07.19.21. )75. )09. )89. )20. )02. )31. )7. )4. )9. )1. )7. )4.o% 4 4 6 5 4 3 6 6 4 63 56 1 5 6 5 1 p e( ( ( ( ( ( ( ( ( ( ( (5(4 3 6 5 s n 5 5 2 0 5 4 2 1 6 3 3 8(7(3( (R1 1 2 2 1 1 2 2 1 1 2 1 1 1 32 81 e b ulob 89 7 9 1 9 1 2 7 7 8 7 3 a.vs-vec2 3 al .98 8 0.06 7 .15 5 .73 2 .02 4 .13 4 .61 0 .05 9 .33 4 .44 5 .10 .8P p 0 0 0 0 0 0 0 0 0 0 0 bia,4,7,4,1,8,6,8,8,3,7,4,o 8 9 7 6 4 2 9 1 3 %rnb) )3 6 8 7 5ite.34.8.7) .4) .0) .8) .4) .2) .6) .5) .7) .4)9ofuc09 047016031 153096027 193091091 0403 ()I ral(.3 (.0 (.6 (.9 (.7 (.7 (.1 (.6 (.4 (.(9(2 R b Caz p952 436994952 75658473 3 81 3273 8.153.62 ir.5 4 7 5 1 1 Ol sv9.03.8.1.6.9.2.2.4.4.0.1.)bioa,2 1 1 2 1 1 3 1 8,1 2 1 ,3,9,5, ,5,0,1,4,5,n n%itb)I7. )9itu. )8. )1. )8)4. )2. )0)3. )7. )1. )5 6)rec2 a 9 2 5 6.81 5 3.62.o(ralC2- .7 1- .45- .08lDof1.01(.54- .56 1.853 4 (.71- .420 .7 5- 4 .698 .2uR bap%(0(9(7- . p Rzl s50.2.73.63(5 522.4(9- 3 4.53(6 322.6(31- 6 46.3(9(61- 52.73(5 8 2oirv9(1- 81 51.3 2 71.5 2 0.5.1 8 1 2P re ) ) )Tdet- d) .5.0).6) ).8).5).5).2).4). ) ) ) ) )4.TIun pono% 0 m n Ips(1 5 4.8 5.1.0.8.0.19 5 2 9 2 8 2 7 2 5 5 7 42 e n(1 1(1 1 1 1 1 1 1 2 1 1 1(4(6(4( ( ( ( ( ( ( ( ( ( (0 rr6 6 5 8 5 7 5 7 9 6 6 7 1 e) )n9)0)0) ) ) ) ) ) ) ) ) ) ) ) )- d.ono% 7.5.99.39.70.01.45.13.0.7.8.6.0.1.8.( 5(5(3(4(5(6(3(4 5 0 1 8 2 0 4 8 ( 5 6 3 4 5 6 3 4 Npse n r 2 2 6 8 2 4 4( ( ( ( ( ( ( (2 2 1 1 2 2 1 71 12 42 31 02 02 42 41 02 red) )1)0)0)1)1)0)9)5)7)0)3)2) ) ) )n.2.5.1.6.2.0.5.8. . . .4.0.9.2.o% 4 0 8 1 7 0 5 1 p e(4(4 6 5 4 4 6 5 4 4 6 5 4 4 6 5 s n 6(1 8(1 5( ( ( ( ( ( ( ( ( ( ( ( (2 32 61 6 7 4 7 6 8 1 8 6 7 1 R 1 2 2 1 1 2 2 1 1 2 2 MPDIDIMPDIDIMPD DIMPD DQ T BI I Ig g gQgTgBgQgTgBgQgTgBg m0 m0 m0 m0 m0 m0 m m m m m m 0)0 0 0)0 0 00)00 00 00)0 0 4 0 bi4n =bi40 0 0 0 0 4 t nbi4t nbi44t n =bi4t nbi4t nbi44t n =bi4bi4bi44=bi4bii Ni i iNi i itN nitn riniN niniu (b8obur( (t t(t t)b)1urb)1urb)8oburb)1urb)1urb)8oburb)1urb)ur )obur )ur )az3 iel=c7az4 l =az4 l =az3el=c8 az4 l =az4 l =az3el=c9az4 l =a1 z4b l =a8 z3e0b l =c1 a1 z4b =a1 z4= RN(alP kieeRN( iRN( iRN(alP kieeRN( iRN( iRN(alP kieeRN( iRN( iRN(alP klieeRN(liRN(W W W WAttorney Docket No.01183-0291-00PCT-PRN.svbeoulb 76 6 6 8 2e2 02 6 7 6 1 1 4 9 7reaecv-al7.02.07.1 09.3 02.8 08.1 06.w0 kPpeebia, , , , , , ,o 95 96 47 36 18 0 0w%5rnitb4. )6. )4. )3. )6. )2 4. )0 3. )ne9o(furec02 ( 8 045094056 048091092vigR)Ibalap090.(3 930.(5389.(264.(2 57.(497.(200.2eh O Czlir.sv.11.81.14 0 6 8t1.9.8.0.7 e)brinoa, , ,0,1 , 1 , 0,o%(ritb)I9 uecC.18)5 0.68)6 0 .)4. )9)7)1 9. )feb - 25973 24.88.-07127 27)Dof ral1- .36(.951- .3- .8 (.92- .1- .3wR bap%5(2.63(82(0 6 3.2.03(52(6 8 1eiRzl.isrv9( .14 31.441- 41.71.5-verdr leet- d) ).2).1).4). ) ) ) )4).0. ) aciun pono% 60.9.1.91 7.9 d1 11 11 0 8 1 2 3 2 3e.mnIps(en(6(4(2 4(1 1 2( (1 7(7(4(8 1 0( m2 rr1 1 5de1-e) )nd.4) ) ) ) ) ) ) ) )dk nileeono% 1.65 5.35 4.73 5.44 1.05 0.95 2.14 7.95 4.36 85bhWNps( ( ( ( ( ( ( ( ( ( (goten 9 r 1 02 21 61 91 81 51 02 42 12 ueopur. r sd) )6. )4. )7)3)6)0)1)9)1)7 nh oit ren 8 4.5.4. . . . . .dedo% 4 4 6 5 84 0 7 2 5 1genpe( ( ( ( ( (5(5 4 3 4r mosn 8 6 3 9 8 8(0( ( (yripR1 1 2 1 1 1 2 51 31 51bfseebo 9 7dn 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cbhst.05.79.57.30.5.1.9.8.5.nern oiotrnapo%p 5 4 0 2 6 3 6 2ef ap icse(6 5 5 5 5 4 3 4fn(9(9(7(2(9(1(3(8(4(i7 dicd osetitac raR 1 1 2 2 1 2 2 1 1 1et seraelepsd esh Mt dn eaPD DQI IMPD DTI IM n P onv,spsoi rgdeced g gBgQgTgBgQ er een m0 m m m m m m:Dmrroop 0 4)0 0 0 0 0)0 0 0)ofhsei40 0 0 0 0 0 0 Rrewr- b 4 n =bi4bi4bi44 4 4=bibibi4 R =;p stno itN nitnitnitN nitnitnio t Nitsanan u( u u u ( u u ( arwpic srb)8obrb)1rb)1rb)obr ) r )ur )obs titaaz3 ie1 l =c1 az4 l =az4 l =a8 z3e2b l =c1 a1 z4b l =a1 z4b l =a8 z3=ecddser deotaPreRN(alP kieeRN( iRN( iRN(alP kieeRN( iRN(liRN(alP:H R:d Metison W WaO bCNocAttorney Docket No.01183-0291-00PCT-PRN ISS7

[0243] Rilzabrutinib treatment led to significant improvements in ISS7. Notably, participants receiving 400 mg TID rilzabrutinib exhibited a significant reduction in ISS7 at Week 12, thereby meeting the primary endpoint in the United States and United States Reference Countries (see Figures 15-17 and Tables 24-26). In the ITT population, participants receiving 400 mg TID rilzabrutinib exhibited a LS mean change from baseline at Week 12 of -9.58 (p=0.0181) points, while patients receiving the placebo exhibited a LS mean change of -6.31 points (see Table 24). Similar results were observed for the omalizumab-naïve population, both prior to (LS mean change from baseline of -9.21, p=0.0168; see Table 25) and following (LS mean change from baseline of -9.57, p=0.0078; see Table 26) the removal of the asymptomatic outlier (UAS7 / ISS7=0 at baseline) who was erroneously randomized into the 400 mg TID rilzabrutinib arm.

[0244] In the 400 mg TID arm, all patients except one showed improvement in the weekly ISS7. Moreover, a clear separation was observed between patients receiving 400 mg TID rilzabrutinib and patients receiving the placebo across all response thresholds (see Figure 15).

[0245] Further analysis of the omalizumab-naïve population supports the efficacy of rilzabrutinib treatment in CSU (see Table 27). Overall, baseline participant demographics did not appear to affect the efficacy of 400 mg TID rilzabrutinib Moreover, 400 mg TID rilzabrutinib treatment was efficacious in patients with characteristics such as low IgE, a positive BHRA status, and a history of angioedema. Table 24. Change from baseline in ISS7 at Week 12 (ITT population) ISS7 Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=40) 400mg QPM 400mg BID 400mg TID (N=38) (N=41) (N=41)Number (observed / imputed) 35 (33 / 2) 31 (28 / 3) 30 (27 / 3) 33 (30 / 3) Mean (SD) 9.96 (7.02) 11.37 (5.51) 7.61 (7.18) 5.59 (5.58) Median 8.00 11.20 7.00 6.00 Q1 ; Q3 4.67 ; 14.00 7.00 ; 15.17 0.00 ; 13.00 0.00 ; 8.75 Min ; Max 0.0 ; 21.0 0.0 ; 21.0 0.0 ; 21.0 0.0 ; 21.0Attorney Docket No.01183-0291-00PCT-PRN ISS7 Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=40) 400mg QPM 400mg BID 400mg TID (N=38) (N=41) (N=41) Change from baseline -Population) ISS7 Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) Baseline Number 36 37 35 35 Mean (SD) 15.14 (4.16) 16.38 (3.50) 15.45 (3.72) 15.69 (4.26) Median 14.00 16.00 14.00 14.00 Q1 ; Q3 12.00 ; 19.50 14.00 ; 20.00 13.00 ; 19.00 14.00 ; 19.00 Min ; Max 8.0 ; 21.0 9.0 ; 21.0 8.0 ; 21.0 0.0 ; 21.0 Week 12 Number (observed / imputed) 32 (31 / 1) 30 (27 / 3) 26 (24 / 2) 28 (27 / 1) Mean (SD) 10.02 (6.82) 11.51 (5.54) 8.09 (6.95) 5.77 (5.26) Median 8.50 11.60 7.00 7.00 Q1 ; Q3 4.83 ; 14.00 7.00 ; 15.17 1.17 ; 13.00 0.00 ; 8.88 Min ; Max 0.0 ; 21.0 0.0 ; 21.0 0.0 ; 21.0 0.0 ; 21.0 Change from baseline Number (observed / imputed) 32 (31 / 1) 30 (27 / 3) 26 (24 / 2) 28 (27 / 1) Mean (SD) -5.11 (6.70) -5.69 (4.72) -7.40 (6.12) -10.27 (6.02)Median -5.50 -5.33 -7.00 -10.33Q1 ; Q3 -9.00 ; -0.25 -8.17 ; -1.40 -11.00 ; -3.00 -14.50 ; -4.63Min ; Max -17.5 ; 9.8 -19.0 ; 1.0 -20.0 ; 2.0 -21.0 ; 0.0LS Mean (SE) a -5.77 (1.05) -5.19 (1.02) -7.73 (1.06) -9.21 (1.05)LS Mean Diff vs. placebo (95% CI)a0.58 (-2.24, 3.40) -1.96 (-4.77, 0.86) -3.44 (-6.25, - 0.62) P-value vs. placeboa0.6869 0.1728 0.0168aEach of the imputed complete data were analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group and regions as covariates.Attorney Docket No.01183-0291-00PCT-PRN ISS7 Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) Note: Data collected after study intervention discontinuation were included. Data post selected prohibited / rescue medications (high / medium impact on efficacy confirmed through blinded medical review) were set to missing and imputed by WOCF. Missing data after study intervention discontinuation for lack of efficacy were imputed by WOCF; other missing data were imputed by MI. Descriptive statistics at Week 12 include participants with WOCF imputation at Week 12, and participants whose values were imputed by MI at Week 12 were excluded from the descriptive analysis. Table 26. Change from Baseline in ISS7 at Week 12 (Omalizumab-Naïve Population with Outlier Removed from Analysis) ISS7 Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=34)Mean (SD) 10.02 (6.82) 11.51 (5.54) 8.09 (6.95) 5.77 (5.26) Median 8.50 11.60 7.00 7.00 Q1 ; Q3 4.83 ; 14.00 7.00 ; 15.17 1.17 ; 13.00 0.00 ; 8.88 Min ; Max 0.0 ; 21.0 0.0 ; 21.0 0.0 ; 21.0 0.0 ; 21.0 Change from baseline Number (observed / imputed) 32 (31 / 1) 30 (27 / 3) 26 (24 / 2) 28 (27 / 1) Mean (SD) -5.11 (6.70) -5.69 (4.72) -7.40 (6.12) -10.27 (6.02)Median -5.50 -5.33 -7.00 -10.33Q1 ; Q3 -9.00 ; -0.25 -8.17 ; -1.40 -11.00 ; -3.00 -14.50 ; -4.63Min ; Max -17.5 ; 9.8 -19.0 ; 1.0 -20.0 ; 2.0 -21.0 ; 0.0LS Mean (SE) a -5.71 (1.02) -5.29 (1.01) -7.76 (1.06) -9.57 (1.06)LS Mean Diff vs. placebo (95% CI)a0.42 (-2.33, 3.18) -2.05 (-4.84, 0.74) -3.86 (-6.71, - 1.02) P-value vs. placeboa0.7634 0.1491 0.0078aEach of the imputed complete data were analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group and region as covariates. Note: Data collected after study intervention discontinuation were included. Data post selected prohibited / rescue medications (high / medium impact on efficacy confirmed through blinded medical review) were set to missing and imputed by WOCF. Missing data after study intervention discontinuation for lack of efficacy were imputed by WOCF; other missing data were imputed by MI. Descriptive statistics at Week 12 include participants with WOCF imputation at Week 12, and participants whose values were imputed by MI at Week 12 were excluded from the descriptive analysis. One patient was randomized to Rilzabrutinib 400mg TID group by mistake (baseline ISS7 / UAS7=0). Removed this participant from the analysis.Attorney Docket No.01183-0291-00PCT-PRN Table 27. Subgroup Analysis: Change from Baseline in ISS7 at Week 12 by Subgroups (Omalizumab-naïve population) Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) Age group (years) -Mean (SD) -6.64 (6.75) -5.95 (3.70) -8.62 (7.08) -10.16 (6.20)LS Mean (SE) a -6.60 (1.68) -4.77 (1.45) -8.10 (1.40) -9.26 (1.23)LS Mean Diff vs. placebo (95% CI)a1.83 (-2.53, 6.19) -1.50 (-5.80, 2.80) -2.66 (-6.72, 1.41) P-value vs. placeboa0.4100 0.4943 0.2007 Overall p-value for interactionb0.9294 Age group (years) < 65 Number (observed / imputed) 30 (29 / 1) 29 (26 / 3) 25 (23 / 2) 24 (23 / 1) Mean (SD) -5.52 (6.47) -5.68 (4.80) -7.17 (6.13) -9.73 (5.71)LS Mean (SE) a -5.66 (1.04) -4.78 (1.01) -7.37 (1.05) -8.63 (1.09)LS Mean Diff vs. placebo (95% CI)a0.88 (-2.00, 3.75) -1.71 (-4.59, 1.18) -2.97 (-5.90, - 0.03) P-value vs. placeboa0.5497 0.2453 0.0478 ≥ 65 Number (observed / imputed) 2 (2 / 0) 1 (1 / 0) 1 (1 / 0) 4 (4 / 0) Mean (SD) 1.00 (9.90) -5.83 (NC) -13.00 (NC) -13.50 (7.71)LS Mean (SE) a 0.90 (3.84) 2.48 (6.23) -13.32 (4.62) -12.67 (2.73)LS Mean Diff vs. placebo (95% CI)a1.58 (-12.80, -14.22 (-25.98, - -13.57 (-22.81, - 15.96) 2.46) 4.32) P-value vs. placeboa0.8295 0.0178 0.0040 Overall p-value for interactionb0.1940 Gender Male Number (observed / imputed) 11 (11 / 0) 8 (8 / 0) 9 (8 / 1) 5 (5 / 0) Mean (SD) -3.50 (7.05) -5.20 (5.77) -8.17 (6.82) -7.08 (3.25)LS Mean (SE) a -3.55 (1.87) -4.68 (2.21) -8.42 (1.87) -6.50 (2.65)LS Mean Diff vs. placebo (95% CI)a-1.14 (-6.82, 4.55) -4.88 (-9.99, 0.23) -2.95 (-9.38, 3.48) P-value vs. placeboa0.6946 0.0613 0.3683 Female Number (observed / imputed) 21 (20 / 1) 22 (19 / 3) 17 (16 / 1) 23 (22 / 1) Mean (SD) -5.95 (6.52) -5.86 (4.42) -6.99 (5.89) -10.96 (6.30)LS Mean (SE) a -6.30 (1.20) -4.77 (1.12) -6.92 (1.24) -9.80 (1.09)LS Mean Diff vs. placebo (95% CI)a1.52 (-1.76, 4.81) -0.62 (-4.00, 2.75) -3.50 (-6.68, - 0.33) P-value vs. placeboa0.3627 0.7173 0.0305 Overall p-value for interactionb0.3883Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35)Mean (SD) -5.88 (6.08) -4.51 (3.00) -6.55 (5.45) -11.22 (7.22)LS Mean (SE) a -5.75 (1.29) -3.98 (1.27) -6.60 (1.34) -9.97 (1.47)LS Mean Diff vs. placebo (95% CI)a1.77 (-1.80, 5.35) -0.84 (-4.46, 2.77) -4.22 (-8.04, - 0.39) P-value vs. placeboa0.3311 0.6472 0.0306 ≥ 72.9 (Median) Number (observed / imputed) 14 (13 / 1) 13 (11 / 2) 10 (9 / 1) 15 (14 / 1) Mean (SD) -4.12 (7.53) -7.22 (6.10) -8.75 (7.15) -9.44 (4.85)LS Mean (SE) a -4.65 (1.54) -5.86 (1.55) -8.28 (1.53) -8.80 (1.38)LS Mean Diff vs. placebo (95% CI)a-1.21 (-5.49, 3.07) -3.62 (-7.92, 0.67) -4.15 (-8.21, - 0.09) P-value vs. placeboa0.5791 0.0983 0.0451 Overall p-value for interactionb0.4436 Baseline weight (kg) < 60 Number (observed / imputed) 10 (10 / 0) 6 (5 / 1) 7 (7 / 0) 8 (8 / 0) Mean (SD) -4.70 (5.59) -4.71 (2.89) -5.29 (4.80) -11.17 (7.60)LS Mean (SE) a -4.34 (1.79) -4.12 (2.29) -5.70 (2.01) -11.07 (2.04)LS Mean Diff vs. placebo (95% CI)a0.22 (-5.52, 5.95) -1.37 (-6.59, 3.86) -6.74 (-12.06, - 1.41) P-value vs. placeboa0.9410 0.6083 0.0131 ≥ 60 - <90 Number (observed / imputed) 15 (14 / 1) 21 (19 / 2) 16 (14 / 2) 17 (17 / 0) Mean (SD) -5.69 (7.04) -5.28 (4.97) -7.71 (6.96) -9.91 (5.71)LS Mean (SE) a -6.06 (1.42) -4.36 (1.15) -7.08 (1.35) -8.41 (1.24)LS Mean Diff vs. placebo (95% CI)a1.71 (-1.90, 5.31) -1.01 (-4.85, 2.82) -2.35 (-6.03, 1.34) P-value vs. placeboa0.3530 0.6049 0.2123 ≥ 90 Number (observed / imputed) 7 (7 / 0) 3 (3 / 0) 3 (3 / 0) 3 (2 / 1) Mean (SD) -4.45 (8.22) -10.47 (4.01) -10.67 (1.53) -9.89 (4.55)LS Mean (SE) a -5.14 (2.38) -8.76 (3.75) -10.60 (2.52) -10.90 (3.63)LS Mean Diff vs. placebo (95% CI)a-3.62 (-12.56, -5.46 (-12.33, -5.76 (-14.13, 5.32) 1.40) 2.61) P-value vs. placeboa0.4278 0.1187 0.1775 Overall p-value for interactionb0.7163 Baseline BMI (kg / m2) < 25 Number (observed / imputed) 15 (15 / 0) 14 (13 / 1) 17 (16 / 1) 11 (11 / 0) Mean (SD) -4.50 (5.63) -4.18 (3.14) -7.34 (6.20) -9.13 (7.05)LS Mean (SE) a -4.42 (1.40) -3.64 (1.42) -7.22 (1.29) -9.17 (1.68)LS Mean Diff vs. placebo (95% CI)a0.77 (-3.14, 4.68) -2.81 (-6.51, 0.90) -4.75 (-9.04, - 0.47) P-value vs. placeboa0.6983 0.1382 0.0297 ≥ 25 - <30Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) Number (observed / imputed) 9 (8 / 1) 7 (6 / 1) 5 (4 / 1) 13 (13 / 0)-- - -LS Mean (SE) a -7.67 (2.06) -7.49 (1.92) -8.24 (2.10) -10.85 (2.59)LS Mean Diff vs. placebo (95% CI)a0.17 (-5.29, 5.63) -0.57 (-6.35, 5.21) -3.19 (-9.64, 3.26) P-value vs. placeboa0.9508 0.8467 0.3327 Overall p-value for interactionb0.9842 RegioncAsia Number (observed / imputed) 8 (8 / 0) 9 (9 / 0) 8 (8 / 0) 6 (6 / 0) Mean (SD) -3.46 (5.86) -5.66 (5.13) -6.86 (5.22) -8.21 (6.23)LS Mean (SE) a -3.45 (1.91) -5.17 (1.81) -6.99 (1.97) -8.33 (2.09)LS Mean Diff vs. placebo (95% CI)a-1.72 (-6.88, 3.45) -3.54 (-8.93, 1.85) -4.87 (-10.41, 0.67) P-value vs. placeboa0.5148 0.1978 0.0848 Latin America Number (observed / imputed) 11 (10 / 1) 10 (7 / 3) 8 (6 / 2) 6 (6 / 0) Mean (SD) -7.29 (7.65) -6.51 (5.89) -4.42 (6.21) -7.34 (5.81)LS Mean (SE) a -6.59 (1.75) -5.19 (1.62) -4.75 (1.94) -6.07 (2.20)LS Mean Diff vs. placebo (95% CI)a1.40 (-3.23, 6.04) 1.84 (-3.27, 6.94) 0.52 (-4.93, 5.96) P-value vs. placeboa0.5532 0.4802 0.8521 Eastern Europe Number (observed / imputed) 2 (2 / 0) 4 (4 / 0) 3 (3 / 0) 4 (4 / 0) Mean (SD) -6.00 (8.49) -5.54 (3.34) -10.81 (7.84) -13.17 (6.21)LS Mean (SE) a -12.67 (4.21) -4.74 (2.49) -4.38 (4.01) -14.02 (2.49)LS Mean Diff vs. placebo (95% CI)a7.93 (-2.07, 8.28 (-5.64, -1.35 (-10.49, 17.93) 22.21) 7.79) P-value vs. placeboa0.1201 0.2436 0.7720 Western Countries Number (observed / imputed) 11 (11 / 0) 7 (7 / 0) 7 (7 / 0) 12 (11 / 1) Mean (SD) -3.97 (6.35) -4.61 (3.50) -9.95 (5.74) -11.79 (5.72)LS Mean (SE) a -4.55 (1.70) -3.02 (2.04) -10.12 (1.65) -9.58 (1.54)LS Mean Diff vs. placebo (95% CI)a1.53 (-3.74, 6.79) -5.57 (-10.21, - -5.03 (-9.55, - 0.93) 0.51) P-value vs. placeboa0.5697 0.0186 0.0293 Overall p-value for interactionb0.3768 Race White Number (observed / imputed) 24 (23 / 1) 21 (18 / 3) 18 (16 / 2) 20 (19 / 1) Mean (SD) -5.66 (6.98) -5.70 (4.66) -7.64 (6.60) -10.88 (6.28)LS Mean (SE) a -6.01 (1.20) -4.41 (1.21) -7.91 (1.21) -9.18 (1.24)LS Mean Diff vs. placebo (95% CI)a1.60 (-1.77, 4.97) -1.90 (-5.24, 1.43) -3.17 (-6.56, 0.21) P-value vs. placeboa0.3527 0.2635 0.0663Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35)-- - -LS Mean (SE) a -3.47 (1.86) -4.94 (1.72) -6.99 (1.92) -8.74 (1.80)LS Mean Diff vs. placebo (95% CI)a-1.48 (-6.47, 3.52) -3.52 (-8.76, 1.71) -5.27 (-10.33, - 0.21) P-value vs. placeboa0.5627 0.1874 0.0414 Overall p-value for interactionb0.8028 Ethnicity Hispanic Number (observed / imputed) 10 (10 / 0) 12 (10 / 2) 8 (6 / 2) 8 (8 / 0) Mean (SD) -8.02 (7.65) -5.04 (5.25) -4.42 (6.21) -8.13 (6.19)LS Mean (SE) a -7.01 (1.85) -4.19 (1.52) -5.19 (1.87) -7.36 (1.94)LS Mean Diff vs. placebo (95% CI)a2.82 (-1.84, 7.47) 1.82 (-3.35, 6.98) -0.35 (-5.55, 4.84) P-value vs. placeboa0.2356 0.4911 0.8936 Non-Hispanic Number (observed / imputed) 22 (21 / 1) 18 (17 / 1) 17 (17 / 0) 18 (17 / 1) Mean (SD) -3.79 (5.94) -6.12 (4.43) -8.59 (5.90) -11.83 (5.76)LS Mean (SE) a -4.47 (1.21) -5.29 (1.31) -8.43 (1.26) -10.16 (1.27)LS Mean Diff vs. placebo (95% CI)a-0.82 (-4.37, 2.73) -3.96 (-7.39, - -5.69 (-9.13, - 0.53) 2.25) P-value vs. placeboa0.6503 0.0236 0.0012 Overall p-value for interactionb0.2235 History of angioedema Yes Number (observed / imputed) 15 (14 / 1) 11 (8 / 3) 8 (6 / 2) 9 (8 / 1) Mean (SD) -5.34 (6.25) -6.31 (5.88) -4.04 (5.66) -9.01 (5.02)LS Mean (SE) a -5.25 (1.51) -5.00 (1.53) -6.26 (1.90) -8.24 (1.90)LS Mean Diff vs. placebo (95% CI)a0.25 (-3.98, 4.47) -1.01 (-5.77, 3.76) -2.99 (-7.72, 1.75) P-value vs. placeboa0.9094 0.6793 0.2160 No Number (observed / imputed) 17 (17 / 0) 19 (19 / 0) 18 (18 / 0) 19 (19 / 0) Mean (SD) -4.90 (7.26) -5.32 (4.04) -8.89 (5.85) -10.86 (6.47)LS Mean (SE) a -5.34 (1.39) -4.56 (1.34) -7.93 (1.24) -9.56 (1.25)LS Mean Diff vs. placebo (95% CI)a0.78 (-3.03, 4.59) -2.59 (-6.23, 1.05) -4.22 (-7.88, - 0.56) P-value vs. placeboa0.6884 0.1626 0.0239 Overall p-value for interactionb0.9105 Baseline UAS7 score < 28 Number (observed / imputed) 12 (12 / 0) 6 (6 / 0) 11 (9 / 2) 11 (11 / 0) Mean (SD) -2.68 (6.50) -5.32 (3.03) -6.29 (4.93) -7.61 (4.20)LS Mean (SE) a -3.17 (1.42) -3.33 (1.83) -5.40 (1.42) -6.43 (1.53)LS Mean Diff vs. placebo (95% CI)a-0.15 (-4.72, 4.41) -2.22 (-6.23, 1.79) -3.26 (-7.39, 0.88) P-value vs. placeboa0.9472 0.2773 0.1225 ≥ 28Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) Number (observed / imputed) 20 (19 / 1) 24 (21 / 3) 15 (15 / 0) 17 (16 / 1) -score < 13 Number (observed / imputed) 10 (10 / 0) 2 (2 / 0) 6 (5 / 1) 2 (2 / 0) Mean (SD) -3.42 (6.10) -4.42 (0.82) -5.28 (5.01) -3.50 (0.71)LS Mean (SE) a -2.72 (1.55) -1.87 (2.70) -5.14 (1.96) -3.73 (3.33)LS Mean Diff vs. placebo (95% CI)a0.85 (-5.28, 6.98) -2.42 (-7.37, 2.52) -1.01 (-8.29, 6.27) P-value vs. placeboa0.7852 0.3369 0.7855 ≥ 13 Number (observed / imputed) 22 (21 / 1) 28 (25 / 3) 20 (19 / 1) 26 (25 / 1) Mean (SD) -5.88 (6.95) -5.78 (4.87) -8.03 (6.38) -10.79 (5.93)LS Mean (SE) a -5.74 (1.24) -5.38 (1.08) -7.87 (1.19) -10.18 (1.09)LS Mean Diff vs. placebo (95% CI)a0.36 (-2.88, 3.59) -2.14 (-5.49, 1.22) -4.45 (-7.66, - 1.23) P-value vs. placeboa0.8293 0.2124 0.0068 Overall p-value for interactionb0.5628 Duration of disease (years) < 2 Number (observed / imputed) 14 (13 / 1) 10 (9 / 1) 14 (13 / 1) 12 (11 / 1) Mean (SD) -3.63 (5.63) -5.46 (4.49) -7.53 (5.34) -10.93 (5.46)LS Mean (SE) a -3.65 (1.54) -4.83 (1.76) -8.54 (1.41) -9.77 (1.60)LS Mean Diff vs. placebo (95% CI)a-1.18 (-5.77, 3.41) -4.89 (-8.99, - -6.12 (-10.48, - 0.80) 1.75) P-value vs. placeboa0.6138 0.0191 0.0060 2 - 10 Number (observed / imputed) 15 (15 / 0) 16 (16 / 0) 11 (10 / 1) 12 (12 / 0) Mean (SD) -7.08 (7.11) -6.43 (5.07) -8.05 (6.91) -9.37 (5.98)LS Mean (SE) a -7.03 (1.42) -5.24 (1.27) -6.89 (1.50) -8.84 (1.51)LS Mean Diff vs. placebo (95% CI)a1.79 (-1.98, 5.56) 0.14 (-3.91, 4.18) -1.82 (-5.85, 2.22) P-value vs. placeboa0.3512 0.9476 0.3780 >10Number (observed / imputed) 3 (3 / 0) 4 (2 / 2) 1 (1 / 0) 4 (4 / 0)Mean (SD) -2.17 (8.81) -3.29 (3.90) 1.67 (NC) -11.00 (8.91)LS Mean (SE) a -3.68 (3.26) -0.20 (2.96) 5.36 (5.71) -9.33 (2.48)LS Mean Diff vs. placebo (95% CI)a3.49 (-5.35, 9.04 (-4.01, -5.64 (-13.66, 12.33) 22.09) 2.38) P-value vs. placeboa0.4391 0.1743 0.1678 Overall p-value for interactionb0.4674 Baseline H1-antihistamines dose 1-fold Number (observed / imputed) 17 (17 / 0) 16 (14 / 2) 11 (10 / 1) 18 (17 / 1)Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) Mean (SD) -6.94 (6.90) -5.09 (4.87) -9.03 (7.91) -8.88 (5.91)LS Mean (SE) a -6.83 (1.42) -4.24 (1.40) -8.44 (1.60) -8.05 (1.33)LS Mean Diff vs. placebo (95% CI)a2.59 (-1.31, 6.49) -1.60 (-5.81, 2.60) -1.22 (-5.04, 2.59) P-value vs. placeboa0.1928 0.4541 0.5295 2 to 4-fold standard dose Number (observed / imputed) 14 (13 / 1) 14 (13 / 1) 15 (14 / 1) 10 (10 / 0) Mean (SD) -2.96 (6.24) -6.37 (4.61) -6.20 (4.30) -12.76 (5.65)LS Mean (SE) a -3.48 (1.49) -5.28 (1.43) -6.73 (1.31) -11.00 (1.62)LS Mean Diff vs. placebo (95% CI)a-1.80 (-5.90, 2.30) -3.25 (-7.13, 0.62) -7.52 (-11.82, - 3.22) P-value vs. placeboa0.3893 0.1001 0.0006 Overall p-value for interactionb0.1602 Baseline Eosinophils (10ˆ9 / L) <0.150 Number 16 N / A 11 14 Mean (SD) N / A N / A N / A N / A LS Mean (SE) -6.78 (1.51) N / A -6.93 (1.69) -10.28 (1.64)LS Mean Diff vs. placebo (95% CI) N / A -0.15 (-4.60, 4.29) -3.50 (-7.87, 0.87) P-value vs. placebo N / A N / A N / A≥0.150 Number 16 N / A 15 14 Mean (SD) N / A N / A N / A N / A LS Mean (SE) -3.99 (1.42) N / A -7.91 (1.29) -8.30 (1.31)LS Mean Diff vs. placebo (95% CI) N / A -3.92 (-7.74, - -4.31 (-8.09, - 0.10) 0.53) P-value vs. placebo N / A N / A N / ABaseline Eosinophils (10ˆ9 / L) < 0.165 (Median) Number (observed / imputed) 17 (17 / 0) 16 (14 / 2) 13 (12 / 1) 14 (14 / 0) Mean (SD) -6.64 (7.14) -4.93 (4.13) -5.92 (5.31) -10.99 (6.77)LS Mean (SE) a -6.51 (1.42) -4.00 (1.41) -7.37 (1.49) -10.22 (1.54)LS Mean Diff vs. placebo (95% CI)a2.51 (-1.40, 6.42) -0.86 (-4.88, 3.15) -3.71 (-7.81, 0.40) P-value vs. placeboa0.2080 0.6742 0.0767 ≥ 0.165 (Median) Number (observed / imputed) 15 (14 / 1) 14 (13 / 1) 13 (12 / 1) 14 (13 / 1) Mean (SD) -3.38 (5.91) -6.55 (5.33) -8.88 (6.71) -9.55 (5.32)LS Mean (SE) a -4.08 (1.51) -5.54 (1.44) -7.62 (1.45) -8.24 (1.39)LS Mean Diff vs. placebo (95% CI)a-1.46 (-5.64, 2.72) -3.53 (-7.69, 0.63) -4.16 (-8.20, - 0.11) P-value vs. placeboa0.4941 0.0959 0.0440 Overall p-value for interactionb0.4740 Baseline Eosinophils (10ˆ9 / L) < 0.3 Number (observed / imputed) 29 (28 / 1) 25 (22 / 3) 20 (19 / 1) 23 (22 / 1) Mean (SD) -4.98 (7.03) -5.66 (4.16) -7.62 (6.27) -10.61 (6.31)LS Mean (SE) a -5.46 (1.09) -4.64 (1.10) -7.78 (1.19) -9.46 (1.18)LS Mean Diff vs. placebo (95% CI)a0.83 (-2.24, 3.89) -2.31 (-5.47, 0.85) -3.99 (-7.15, - 0.84)Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35) P-value vs. placeboa0.5966 0.1514 0.0132-- - -LS Mean (SE) a -4.85 (2.85) -5.53 (2.57) -6.15 (2.12) -8.12 (2.13)LS Mean Diff vs. placebo (95% CI)a-0.68 (-8.12, 6.76) -1.29 (-8.43, 5.85) -3.27 (-10.21, 3.67) P-value vs. placeboa0.8580 0.7219 0.3547 Overall p-value for interactionb0.9753 Baseline Total IgE (IU / mL) < 300 Number (observed / imputed) 23 (22 / 1) 21 (18 / 3) 18 (16 / 2) 18 (18 / 0) Mean (SD) -4.45 (6.94) -5.41 (4.78) -7.93 (6.60) -11.12 (6.60)LS Mean (SE) a -4.51 (1.21) -4.46 (1.23) -7.94 (1.28) -9.55 (1.28)LS Mean Diff vs. placebo (95% CI)a0.05 (-3.34, 3.44) -3.43 (-6.90, 0.04) -5.04 (-8.49, - 1.58) P-value vs. placeboa0.9766 0.0524 0.0043 ≥ 300 Number (observed / imputed) 9 (9 / 0) 8 (8 / 0) 8 (8 / 0) 10 (9 / 1) Mean (SD) -6.80 (6.07) -6.11 (5.05) -6.20 (5.04) -8.74 (4.73)LS Mean (SE) a -6.54 (1.94) -4.90 (1.83) -7.17 (1.88) -8.12 (1.78)LS Mean Diff vs. placebo (95% CI)a1.64 (-3.67, 6.95) -0.62 (-6.16, 4.91) -1.58 (-6.77, 3.62) P-value vs. placeboa0.5443 0.8249 0.5523 Overall p-value for interactionb0.5546 Baseline Total IgE (IU / mL) < 100 Number (observed / imputed) 15 (14 / 1) 11 (10 / 1) 11 (10 / 1) 13 (13 / 0) Mean (SD) -4.06 (7.77) -4.48 (4.37) -8.52 (6.05) -11.17 (7.09)LS Mean (SE) a -4.24 (1.58) -3.37 (1.66) -8.29 (1.67) -9.19 (1.55)LS Mean Diff vs. placebo (95% CI)a0.87 (-3.65, 5.38) -4.06 (-8.57, 0.46) -4.95 (-9.29, - 0.61) P-value vs. placeboa0.7062 0.0780 0.0253 ≥ 100 Number (observed / imputed) 17 (17 / 0) 18 (16 / 2) 15 (14 / 1) 15 (14 / 1) Mean (SD) -6.04 (5.66) -6.28 (5.01) -6.57 (6.24) -9.49 (5.03)LS Mean (SE) a -6.03 (1.33) -5.51 (1.28) -6.91 (1.31) -9.13 (1.38)LS Mean Diff vs. placebo (95% CI)a0.52 (-3.13, 4.18) -0.88 (-4.57, 2.80) -3.10 (-6.85, 0.65) P-value vs. placeboa0.7797 0.6380 0.1053 Overall p-value for interactionb0.6170 Baseline BHRA BHRA+ Number (observed / imputed) 3 (3 / 0) 3 (2 / 1) 6 (5 / 1) 4 (4 / 0) Mean (SD) -4.39 (5.43) -9.13 (3.87) -9.57 (4.88) -12.42 (9.12)LS Mean (SE) a -5.38 (3.35) -8.50 (3.41) -8.42 (3.14) -12.96 (3.21)LS Mean Diff vs. placebo (95% CI)a-3.12 (-12.22, -3.03 (-12.35, -7.58 (-16.53, 5.98) 6.28) 1.37) P-value vs. placeboa0.5015 0.5234 0.0967Attorney Docket No.01183-0291-00PCT-PRN Placebo Rilzabrutinib Rilzabrutinib Rilzabrutinib (N=36) 400mg QPM 400mg BID 400mg TID (N=37) (N=35) (N=35)-- - -LS Mean (SE) a -5.49 (1.04) -4.66 (1.06) -6.59 (1.13) -8.82 (1.08)LS Mean Diff vs. placebo (95% CI)a0.83 (-2.10, 3.77) -1.10 (-4.12, 1.91) -3.33 (-6.25, - 0.41) P-value vs. placeboa0.5791 0.4730 0.0256 Overall p-value for interactionb0.5253aEach of the imputed complete data were analyzed by fitting an ANCOVA model with the corresponding baseline value and intervention group as covariates. Analysis was based on the same imputed dataset using WOCF / MI from primary analysis of the primary endpoint.bEach of the imputed complete data were analyzed by fitting an ANCOVA model with the corresponding baseline value and intervention group as covariates, plus the subgroup variable and the subgroup-by-intervention interaction. Analysis was based on the same imputed dataset using WOCF / MI from primary analysis of the primary endpoint.cAsia: South Korea, Taiwan, Japan; Latin America: Argentina, Chile; Eastern Europe: Poland; Western Countries: Spain, Italy, Germany, Canada, Greece, Netherlands. Note: Descriptive statistics include participants with WOCF imputation at Week 12 and participants whose Week 12 values were imputed by MI were excluded from the descriptive analysis.

[0246] Additionally, participants exhibited a rapid, clinically meaningful improvement in symptoms, with significant reductions in ISS7 observed following one week of treatment (see Figures 18-21 and Tables 28-31). In the ITT population, participants receiving 400 mg BID rilzabrutinib had an LS mean change in ISS7 of -5.23 points from baseline (p=0.0024; see Table 29). Consistent with rilzabrutinib’s dose-dependent effect on ISS7, participants receiving 400 mg TID showed an LS mean change in ISS7 of -6.65 points (p<0.0001), reflecting a 40.41% decrease from baseline. Notably, the overall reduction in ISS7 observed in both the 400 mg BID and TID arms exceeded the minimal clinically important difference (MCID) of 5 points.

[0247] Similar results were observed for the omalizumab-naïve population. Omalizumab-naïve participants in the 400 mg BID and TID rilzabrutinib arms experienced an LS mean reduction in ISS7 of -5.06 (p=0.0060) and -6.13 (p=0.0003), respectively (see Table 30). Similar data were obtained when these analyses were repeated following the removal of the asymptomatic outlier (see Table 31).

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2 1 -1- 39.2 40 3.2a R4-8.-1- 8820 32.7 - 2 1 -1- N- bbiM.0)0 ) 0)2 0 0. .7)0 ) 7 a n) )6.0.0)5.00. ) .50)4.0)5.1 0.mitP uQ75 ; 1 / 32.55411 / 3.43 50- 1 1 / 39272- 6 ; 2 / 13. .050412 / .11 50- 1zur3 ilbg=.03( (7.201 ; 2 ;3(.0 ; ;00.3(.61;.03(88.1 ; 21 ; 3(.2 ; ;00.a azmN(00 4.2100.(49 .55-0.9(40 .23- 1 .700(3.6900.(31 .1 5-0.4 mli001- 3010.60 36- 11- 38 41300.0 3 21- O R 41-3-6- -1 76-1-)) 5)5 7)) o) .5)5 0 1) ) .5)0 0)3 7 / .8.0.0 1 / 5 .5 2. .0 1 / .2 2.221.7.0.0 18 .4 8. .0be6 c33 ;15(0 6.4 11 2 15(00 0.- 6 ;1830 (.0 - ; 6 ; / 25(34 11 2 / 2500 2.- 5 ;al= PN( .03 0(81 0 25.1;0;3;.0 (24 5.4- 0..03 5 40(20 7.2- 4 .7.03 0(13.9;- 0 35.0;3 .0 ( (38 5.4-;0..000 1 3015.50 34-7-2- 38 7 2 -5-1- 3010.70 34-7-2-)d) ) )etd ueetnid letd)etdetp upeup up up mi / emsia / bmi / mi / emid nid ni / evrleemodedeledeessavrrfvrvrs vrbes eeses abesx b a o()b r DSxamoo)g xnb r(rDSa ao)xbo)xmbo)xh (rDSa(rDSaor (rDSaM;e(n3Mf e(n3Mc e(n3Me(n3Mf e(n3 bnaniimQebnaiQtbnaiQbnaiQebnaiQ Muaede; ;g 1ninmuaede; ;n 1niemuaede; ;1nimuaede; ;1nigmaede; ;niN M M Q M h N M M Q MeN M M Q M N M M Q Mnu 1 M6a cr 7ah N M M Q M 7 k SeC P k C SeeeIW WAttorney Docket No.01183-0291-00PCT-PRN -bbi )3 n3)0)5a 1.3. )0 1 mitDI .09.93. )7 T)6)9.34 12631 -)3 18.00. .08)71.607.0-3 -)4.04 11181 -)2 17. .006.8)uzurg= / 53(.18- ; ; / 56(.54 ; 1 / 5(7.04; ; / 53(.66- ; ; / 56(.04 ; 1 1 / 5 aOgnidUauziln amitP)mocurQ1)C 11 =0) / N C 1(0 .96 - 6- 0 / 1 N0.0.0)C 44 0)C 66)C / N0110 / N7660 / N00.0)0 / O( 0771(.0 - -1(.6 - -1( 0.1 1rnIbg a(01;0; (0.7;0; (04; ; (76; ; (00; ;1(zmNl0(19.16- .99.1 1.0 0.0.1- 00.6.6- 77.0100.7.07 14.04 16.66 1.0.00 1 oir i0 R46- 1 6 -6- 71- 4 1 -1-6- 6 6 -6- 1 011Phti)7 0 99. ).05 0)0 ) 5.0.00 1 28. ).09 0wostb)4) .1n / 917110)1 / 4.0.0.6061)1 / 2.585- 0) .1 / 828320)1 / 0.7.0.7041)1 / eec= 3italN ( ( 5.- ;68; 5.3( (1.401 ; 2 ;3( ( 0.40;8;2.3( ( 4.- ;20; 5.3( (0.71 27; ;3(a P(4.1 2- 27 4 64. .9128.41-6.1 45- 43 4 06.4 04- 1.85.801- .114.6- .50.35 P2-4- 1 77-1-4- 8 5 - 1 6 bi )nitDI4 8 )) .6 7.75.2) )1 0 ) 0)4 3 60)3.00. ) .8 3. .1) )1 00)urT530 / 0136 .63- 1 ; 0 / 8.5. .50110 / 84.6 53- 1 ; 0 / 81393 . 3- 9 ; 0 / 9.30.0.910 / 9 bg= 3(2;2( 0.1 22(.3 ;2( 43;.025( 0.; 22 am(4510.(47;0; (19- 00.(9580(870; (zli00N(03.2- 5.20 80.8 40.0 5.1 8.5- 1 22.75.0 29- 32- 25.70 9 11- 26.6.00.9 20 2 R45-8- -21-5-8-noitbi )alni DI1 9 ))5. .242.2) )5 0 ) 7)1 5 00)51. .0)6. .02.2) )1 0)utpurB5 g31 / 3735 31- 2 1 / 25. . .60111 / 2.12 60- 2 1 / 28309 01- 2 1 / 0.0.81.0111 / 8 o b 3 P am=( (.36; ;1.03( (3.01 26; ;3( (50.; ;90.03( (.10; ;0.027 ((.01 27; ;2(ezli00N(439.5- 0 3 0 67.0 3.3.0.00 331. - .01 22- 331.6- 0 93 7 30.0 2.6.1.00 92vï4 a R4- 5 8 -1- 7 28-1-5- 0 9 -1- 7 1N- )3)3bbia niM t P) )9 2.0.38.77) )36 0 2. .0.0)) 39 0 .9 0.0. )93.3.73.77) )35 0 1. .0.0)mQ7 / 1928- ; / 5041 / 4021 / 8281; / 55413 / uur3i3l(.7 ;0(.51 20(.0 - ;0(.6 -1(.21 21 z bg= amN (70.03 323-0.0(20; ;3 3 100.( ;336- 70.3 9(43;3.-303 0(601;0;3 0.(a z0(mli0 3.26 00 3.7 0.3.0.133.1.30 43.4 0.43 43-6-1- 01 706-9-1- 6 3 - 81- 01 80 O R5-)o)6 1 2. .5) )3 0))7 3))3 5 7. .0) )4 0)b)e61 / .457 c3 2736- 5 1 / 2.2.0.060511 / .1 3. .06007 1 / .31 14 43- 5 1 / .9.0.055411 / al3(.7 ; ;3( 1 22( 0.- ;2(.3 ; ;1( 7.1 21 =(750.0 (50.; ;3(4;.03(30.03(50; ;3(PN(335.2- 8.00 00 331.90 2 00. .00 35- 0 39. .08 -5-1- 1 74-9-1- 37 31.3- 1.00 00 2 10 35.3 00. .00 23 -5-1- 1 7 e)d)d)de) ) )nileetsuetetnidededeap up upletut tp u u mi / msiap p b / emi bmimiemid ni / / / ni / moredfevervrledemdvederor vrvrledevrgesnb ao()essab)b es fbe)gesbessabb esb Dxao(Dxamo(Dxanao()Dxao)Dxamo hctreS nb(n3raiMeS o b(n3rafiMereS 3hb(na MctreS 3(rS 3 o b(nra Meb(na Mf(ereb ecmnQruaede; ;1nimn uaedeQ ; ;1nigmnaiedeQ ; ;ninemnaiedeQ ; ;nimnaiedeQ ; ;nigm N M M Q M8N M M Q Mnau 1 N M Mcru 19u 1nau e h Q M N M M Q M N M M Q M h N 7S P keCeP k CSeeeIW WAttorney Docket No.01183-0291-00PCT-PRN -b)0 abi )0 nDI2.0.09 0 8.03.4)0)6 0).0.085.73.4)miutzu T)67.6263) .i.l rg=(69 - - 1 / 0315 3;.07 - 1 -)5 2 / 8.0. .0)2.033)3.6631)9 60582 / 8.0 - - 2 / 3.7 - - 2 / 9.65 3;5(3; ;4(.0 ; 1 ;4(73;0;4(9; ;4(.7a bamN( .31- . .0 (98- 7.0 (330(.1 1- .0 (57- 0.0 (21 li031 64.0 6.06.01 65.00 6m z0 2 41- 66.12- 4 10.8 0.1 4 00 2 1 - 02- .8 000.44OR -7-9-2-6 1-g- -1-nid) )ulc sbi )rnI enitDI3 7 )5. .1010.4 3 0) .7 3. .0)148- 0)1 0)5 0 .1 0.0. )5.00.00.5 0) .00 030. .0)0)4 .1,denurBg69 =(so 3.0 -5; ; 1 / 5 pb04(.25;0;.0 1 / 48(048 0.1 1; 1 ; / 49(.01;0; 1 / 45(.30 ; 1 / 0 3;4.048( 0.Usam z0N(0.801- 0 0. .0(19.00(040(01 0825.7- 00 54.0.0.0 5.8- .0.(1 80 2 5.77-2.0(72 50 57.beli41- 0 01- 7 19-1- 391- 6aRR -1-6-1- -5- -metuelbi )0l .0.0)8 .3. )0)0 zipnM C C4)0 C.0.0C.9.9)amimotP curQ)1N(01 .011 - 1 -)0 / N(82 .352 - 5 -)0 / C N0.08.08)0 / N(03 .013 - 1 -)0 / N(0161 - 6 -)0 / C N0OrnIbg=01; ;1 amN(0.1- 00.(8 3.2; ;1 584.( (00.8;0;1 0.(0 0.3; ;10.9100.( 9.1; ;1( 0609..(09o zirli00 1.01 - 11 2.32 1.08.08 13- .03 11- .91 1.09 R 41-1-1-5- 2 55- 81- 3 11-6- 1 66-P- - -hti )0 ) 5)) 5w4.8.17. )0 9 0 .877. )o0 1.3.057stb) .0. .0 0.3.01 40.03- 0)13820)19.041) .2903- 0)3120)6.0neec= 7( 8.italN(50;0; / .421-7. .33 5( ( 0.- ; / 81 2 1 / ( 8.487;.385- 0.3 3( (.7 ; ; 1 / 4 495;8;3 2.(622 43.1-9.8.3 9( ( 6.- ; 1 / 8 416;6- 84.3 4( (.549 6a P 4 P9-1-1- 60.4 - 077- .3- 8.021 1 1 - 8 1 -1- .960.5 - 099- .7- 8 bin ) 0)6 3 ) 0)3 itDI )7 5. .067. )3.0. / .6316) )0 0) )73. . / 50.0.00) ) / 7 3. .050.0.830 03 urT5 0 bg35 =(.0 - 090303 0; ;2(.05- ; ;.00.2001 35( 0.1 20350 (.0 - ; 0 ; / 00 3393 (.1 - ; ; / .01.50 35( 0.am 01l- 00.1(66- 10(57;0; (50 1 - 00.(77 5 - 20(97 zi00N( .7 0.9 49- 4 1 2.5.70 037.-2- 8 51- 60.0.0 20 3.5 09.1 0 - 4 12- 3.28.60 1 41- 39.6 R5-8- -5-8-noitbi0)7 0)9 nD)40. )7.61. ) )0))80. )7.335. ) )alit I ) .13.0 1 / 7.631 / 95.0.1 / .52.0 1 / 2.181 / 4uu B5360- 38043 31- 272.7011 768- 57340 1- 389.60prg o b =( 0.;P am 78- 0;.02(.3; ;2(.010(75- 7.00(77; 20;2( (75.; ;7- 0.02(.8; ;2(.00(04- 0.00(37ez0N(5. .0925.6.0 82.1.0.0820. .5821. .00 9.9vïli0 R47- 1 1 -2- 1 5 - 1 91- 8 007- 2 1 -2- 7 0 2 4 - 01- 7a -1-N-bbia n miM ) t P)7 0).2 5.0. )6 3 2.3. / .0905) )30 0)) / 3. .0.0 36 0).2 0.2. )2 1 1. .43.674) )35 5.zu Q7522- 118231- ;15041 / 1503- 2 / 19231- 2 / 050urilbg3=(.4 ; ;3(.33;.03( 5.1 23(.0 ; ;3(.29; ;3(.0a azm 950N( .3- 00..(0 09 4.03- 3 .300(3 4.49;0; (360- 00.(5 .0.4.4.09 4.23- 40..(31 100 3.01mli0146-9- -37 3 - 31- 301 70 36-9-1- 37 3 - 71- 311 O R5-5- ))o 7 00. )8 .60 .0.5) )9 0)))9 0.0)5 . 0.5) )1 b)e6 c3.7.050 50 8 ; 1 / 1933 .301 ;6 ; 1 / 2.4.0.0634111 2 / 2.8.05008 ; 1 / 92143.01 .30 ; 6 ; 1 / 2.360 0a.l=(.;PN(8 5.4- 0 ..03 7( (80 292-0. .03(0(03.; ;3( 0.;3095.0 (395- 7.03(39 7(393-7. .03(0(41 321 -04 8-1- 33.8 50 3.2 02.0 30.-5-1- 1 55.-18-1- 35.3 50 3.3 0 -5-1- 1 e) ) )id leee) )ntdetdetnidedesu u ultutu ap p pesap p bmi / mi / em nii / bmi / mi / modredfvedrvrleemd dvrorefvervre)gesbessaeee eo)bo)bsbo)gsb) sb)DxanaDxaDxam Dxanaoxo S(n3ha Mc(reS(n3reS o(n3rfreSn3hc(rD eSa(D n3reS atb( Mb( Mb( Mtb( Mb(n niedeQ ; ;na1niinecmuaedeQ ; ;na1ni0muaiedeQ ; ;ea1nigmnaidQ ; ; annmnaidQ ; ;nanmaid N M M Q M N M M Q Mnuee1ieuee1i1 ueeM M Q Mr 1aN M M Q McrN M M Q M17eh N M MS P keCekSePeeIW WAttorney Docket No.01183-0291-00PCT-PRN -b)0 0abi )0 nDI0.0.0 0 573)0)6 9. .4)1 0 0 7.0.0 5.73.4mit )0. .0z8)3.533) .7031)8.0. .0)2.033)4.1031u u T65 2i / 8l rbg=; 1 ;4(8.7 - - 2 / 3 3;.5 - - 2 / 70582 / 9 0;4(7;0;3(.0 ; 1 ;3(0.0 - - 2 / 4.0 - -7;0;3(0;0;a amN(0.0 (.51- .0.0 (38- .0.0 (000(.01- .0 (60.0l0 6 1 61.0 5.05.01 531.00m z00.0 2 1 00.6 0.0 3 1. -00OiR4 01-2-2- 1 7 - 01- 4 01-2-2- 0 7 - 01-g1-1-nid) )0ulc sbirnI enitDI3)6 7 )8.0. )3. .1010.1 3 0) .5.3.0) )9780)0 0 3 0 ..50.00. )3.070.0 0) .0 0.0.00050,denurBg628 =1 1sopbamN(; 10; / 9 4((3.0 -3; ; 1 / 4 0 4(.6 - ; 1 / 6;.039(0 0.98 ;1 1; / 9 3(0.5 - 1 / 50.- ;6; ;03(0;.0U.41- 0.0(58- 40(000(.51- 0.1(0000 sz00.0.0 500.825.0 2.50 45. .00.435.24.01-0.0beli04 11- 81- 4 00 9 - 5 001-aRR -1-5-9-1-1-7-1-metuelbii )0l .0.0)4 .)0)7zpnM 0 C C1.1)0 C.0.0.6.7amimotP curQ)1.0=9.09)0 / N(02 .012 - 1 -)0 / N(47 . 57 - 5 -)0 / C N0.07.07)0 / N(0414 - 1 -)C 0 / N(7666 - 6 -OrnI; ;1; ;111( 01.01.6bg amN(0 .00.(0 10.2 1 - 0 .00.(4 11.7 -; ;54 .1 1..(10 .07;0;.0.(0 10.4 -; ;7 100.(16.6 -; ;677.o zli0 9 2 2 7 7 707 4.04 6.66ir04 91- 2 11-5- 7 55- 71- 4 11-6- 6 66-PR- - - -hti) 0)0))wo501 0 .0.05 0.0. )5.09 0 9 0 2 0 00 6. .0.0 9.0.0.stb) . .ec4 41) .8804 =1 2 1 / ( 0.- ; 0);1 / 14020)6. . .(1.- ; 1 / 0101 21)00 21 / 100)070 0( 0.; ; 1 / 56.; ;ne; ;3(6228.3(63; 4.2( (.07; ;2(7400.2( (660.0italN(82.49.1-9.9 4.1 6- 24 33 00.31- .01 36-0.0a P P.031 0 1 - 7 1 -1- 53.5 - 598-3.-9.0.61.500 00 1 1 -2-2- 5 5 0 -1-1- bin 0 itDI )0.0. )) 0)3 urT5010 / 2 9. .252. )03.0.0.630) )) 6 8 .80. )2 3)2 0. .640. )2 .7 5.43.00bg3 150- 4 / 13303 =1 23(.0 ; ;3(.00- 3 1 / ;;7.20 25( 0.811 / ;2763 2(.3 - 0 1 / 7139- ;0; ;2(.17;.0am;3; (39- 00.1(86l- 10.(770; (7 .i0 021- 00.(65- 00 z0N(3.0.13.2 0.13.0.700 827. .00.805.1 8.6 0.0 R4 29- 4 1 -2- 6 5 - 5 8 -1- 5 00 21- 4 1 -2- 22 0 6 - 011--noitbiD0)) 0)88. )8 0 .05. ) )0)) 0)20. )5 7 .62.alnit I )0.0.1 / .12.0 1 / 1.53250.0.2.13.0 28.62uu B5301 860- 48044 12- 2 / 49.031 / 460- 2 / 48302- 2prg=1 ; 2 ;2( 0.; ;2(.7; ;26(.01 ; 22( 0.; ;2( 0.5; ;o b P am 0(18- 0.08(55- 5.00(977; (07- 0.00(64- 7.00ez0N( .0.0925. .0927.9.0 62.0.1.064. .060.6.0vïli04 307- 2 1 -1- 9 a R4- 0 8 -1- 8 10 27- 1 1 -2- 29 4 - 1 9 -1-N-bbia nmiM 0 t P) .0.0)) 3 / 3 0).8 0.0. )2 3 3.3. / .1805) )34 7 5. .1.0)) 32 0).7 4.0. )4 3 3.9.38.05uzurQ7ilbg341 0403 =1 - 1am; 20;3( (7.06-; ;08 3201 00.(.00- ; ; / .075051 / 2(.61 2724(31 .3 - 1 / ;;76 224 (.6 - ;2;.09(23- 00(111;0; (95- 70.(13- 00a z0N(0.0.33.0.033.1.00 03.5 0.0.0.6.19 0.8 0.0mli0 0 R 4 76-8-1- 6 3 - 0 51- 11 70 35-8-1- 33 0 3 -5-1- O - 0 o)))5 0.0)0 .70 .0.5)1)2 0))0 5)b) .0.0 2.8)9 7 .6 2. .3ec31 22.0.060.8.0.0. .28 6 411 / 008 ; 1 / 2343 .30 ; 6 ; 1 / 161 / 701 / 67 ( 04 11 2 160 5- 9 ;14.6 - ; 9 ;al=; ;3 PN(0 0. .0 ( (0 35.;38.6- 0 4.-0.03 7( (35 303-2. .03 0(25.; ;3 209.83.-1- 36.0 60 ( (.;215- 0.53 7( (13 253- .2.00 50 1 308.0 31.5- .0 691- 3.2 60 63- - -1 4 -3-6-1-)dee) ) ) e )tunid pleetdetdetnid letesu ap up upesup m m m manii / b i id / d / enii / bmi / leem v oedvedv leemdvoesa rbesrf r r ree e sae rfevrexb gs sbsgsamo)b)b)b)b)DxanaoDxaoxmox naox3 orf(reSn3hc(reS(D n3reS 3aorf(rDS 3ahc(rDS 3aQMeb( aiQ Mtb( aiQ Mb(naiQ Meeb(naiQ Mt eb(naiQ M; ;ngmna d ; ;nnmna d ; ;n n ma d ; ;ngmna d ; ;nnmna d ; ;1iMnuee1ieh N M M Q Mcuee1i2uee1ieN M M Q Mnuee1iecuee1niQar 1ak N M M Q M h N M M Q MreN M M Q M7S C PeC PSeIWAttorney Docket No.01183-0291-00PCT-PRN - h bb)g ainDI )0)2 0 2 0 00u mit ) )6z3. .04.0) .1.0.0)5.65. .oru uil rT6=2 / 060 .514 12 / 020 5.00 ; 2 / 02(.708; 00;htae armOnidc W ef.susbiyy Dcab fivlcrniI ) ) )cd dbi-nI e,dtuB)60 / 0 / 0 / iffetuegnita,8ensorpbg= 0 0 0 mN ( ( ( enp naurna)I .0)Usa bezli0(0 0 0 0 o 4tmi )hbaeC4 4- 1 8.aRRca eprenoCi zlirMS%5(551metuzelmwt% L9( .99ilpbinMi ycal2-amitP) ) ) )macu mocurQ1=0 / 00 / 00 / uii0dffepoea) OnIbg N( ( (e fPnE)ram(0 0 0m / eilS 4o zirli00 hoT ges( 2.PR 4gikhcn ( ana 5(salrTI(ahbe 1htinof2CmoMS.40wos) ) )ointb)40 1%rfL4-n / 0 / 0 / taoieec= 0 0 0citakitalN ea P((0(0(0deu mnit ea oe Penul10 ucoscWrobea 0 siot feca.lv-0< bi )) 0 )8 7eri / dcpp ntDI1 0 0.5.0n pne.urT)5)2 / 1.0.0.6050)2 / 7.0.0. )7306- 0 2 / 42782.d- 0etioitU rsefv)bg3 3(.01 23 am=(00; ; ( (0.0z7-; ;3 0.0 ( (.357; ;03.binehefvidbi5 n1.li00N(5.410 10.0.5 5.26.09- 5.04- 4r8.006-oretmi eigtna a)I2-,R 4 1 7 -9-3-5-pdniyTrnuarbe 4 aC 1.noitbi )) 0)et5 0cedueh v CzlMiS%57-(alniutDI )6 0 3 5)7.0.10.1) .3.00.02)2.0.2.6302l2etss rrOL9(5 6.purB32 / 80 bg= 3( (.01 2; 2 ; / 37(0 0.;0; 2 / 5 .303(.;30; tset.0ofa7S4-oP amez00N(50 .870 .0.0 (08- 0 56. .034(251- 52. -0.00 pa00at taSI a) EvïliR4 7 06-1- 6 4 -1-1- am Ddgno S()aN.- nirf6 bi) 0)0deis e een7.gnae 0ba niM)tP) )3 0 6 .0.0.0)4.00.0.6 ).9.0.0d 5300usil n cMilnail(esM5 m zu Q734 / 80404 / 8.00 4 / 4; ;.ehaS.6urilbg= 3( (40.1 22;3( 0 ; ;3(.30 0; (04 10 00.(93 8.0.0 niFsC b L6- 0eC a a azm0N(77.0.7.4- .90 7.1- 00reO e mli0 O R 4 50.00 1 1 -1-2- 6 6 0 -1-1-wnW Bni) )oy molesD 0 ) 0 )) itabdrfaS(.65 ob)90.9 0 6) .504.01) .3.0.81 2) .00 83.0.308 uet2 nitueb-tsna(e 0 ec32= / 7 3( (70.13; 2 2; / 3500 ; 2 / 4 (( 0.;.3 ; ;np g o P2.0.03(30.0 omin M 9 alPN(51.13 2.8.0537- 1 202.14.-00(503-0.0cd a 7 -1-0.8 5 2 -3- 0si1 -dnah) )dn r og C D 7 aitnis tne .3nS(4 wrnesiecil(ena 8 o )f vretms8o rae.5 d) e)dentt eB M 1 etd uetunidetiri e Pplprydspeuaut erd n 14 mi / emsia / bmcien / nseorw a dnidmditetvf ) eDIrleev oevaaw gTessa rbb esrf reesvresdeeitvena g m o)bo)gbo)bc rh 0 ( D y Sxamo(DSxana(DSxaot elllaC 0 4 dreutb(n3rfrenaiQ M ;eb(n3hcrenaiQ M ;tb(n3sronaiQ M ;occiade .9bin Smaede;f u 1nigmaede; ninma d ; nWt itN M M Q Mnau 1eh N M M Q Mcruee1iN M M Q M: aF Dm 27oCeP C:deel1 ur )kba14 S d Oetdn baeezli=SIn E o W Nilb T W RN(Attorney Docket No.01183-0291-00PCT-PRN r a oe 90 5 10 2 0 1 5 5 7 7 9 3 ofbul2 9 6 0 9 2 2 4 0 3 a 0 2 0 1 3 0 0 1 0 1 1 0 ececv- .0.2 0. .0.4.0.0.3.0.0.5.0na0 0 < 0 0 0 0 0 0 0 0 0 elp rpef.sfivdebign -),8 -,-),6 -,-),0 -,-, ,-,nitna)2.35,2 4.58,2 8.96,7 3 6 4 auraI .52.9) .54.7) .3.3.4 2. ) .1hbeC7)C 9 390)1 132)7 0 8)43)08 6)azlM 3-1.4- %( 5 63-8.4-3-5.3-3- 42-3- 3 %irS5 5.3 9 .25-(.( 15( 7.813.9 2 .16-( 5.( 33( 5.614.1 4 .24-( 0(0.8( 6.3( 0..24 . 90( 2.7 0.1 9 L9(3 7 - 9 6 4 7 8 45.62.88-2-1- .65 2-1- .33 85- 1 72-1-2-ea- -) nES)8)5)0)1)6)2)8)1)6)3)0)7)2)4)6)eiglnes(an2.a53.53.52.52.53.52.52.52.53.53.55.56.56.56.2 3.h( ( ( ( ( ( ( ( (5 5 abe2 .03 .36 .49( ( ( ( ( ( (.21 .13 .19 .47 . 8 8 4 7 0 6 7 6 CmM4 9 0 9 6 5 900.80.79.42.98.34.80.75.9g - nu, , -, -, , -, -, , -, -, , -,ara beC2 0 .05 9 3 .00 3 5 .20 8 7 . 9 haM%7.4-6.3.3-0.8.3-5.9.03 6.CzlirS L559-((3( 6-4- 7( ( ( 6-4-( 5-4- -( 5- 2.3.41 7 6( (.86 0 7(3(2 7(6 -1-5.4 -2.2 -0-7.3 -6.2.9-0-1.3 -6.2.6-0-3.3 - a) m E o S r) ) ) ) ) ) )f(een8 a7.9 07.8 07.9 07.0 08.1 08.1)8.3)8.4)8.5)8.5)8.8)8.9)8.0)9.0)9.6 8.gne 0 0 0 0 0 0 0 0 0 0 0 nil(3(7(0(2(8(7(1(4(8( ( ( ( ( ( (aesM.2.4.0.9.6.2.4.86 8 5 4 9 2 3 haS5 3 2 7 5 4 3 7.66.0.0.7.2.2.6.9C b L- - - - - - - - -5-4-7-7-5-4-8- enil ) )e 6)6)6) )5)0)1) ) )3)2) ) )6) )sD aS8(.54.2.97.7.3.6 76.4.1 87.1 0 1 ( 4 5.95 4 5.4.14 5.2.24.6.9b-tsna 5(.68(.01 5 .( (97 0( (5 .(6( ( (5(6( ( (5(44 .41 .63 1 4 . 4 4 2 0 4 0 oe P M 01 31 319.7 01 21 219.72.5.99 11 115.71. .3.38 11 117.6 ))8) ) ) ) ).63 .54) ) ) ) ) ) ) ) ) )D.27 .38 .63 .54 .27 .38 .63 .54 .27 .38 .63 .54 7 eS il3 3 4 4 3 3 4 4.2.3n(n(0(0(0(3 3 4 4 3 3 4 4 8(0(0(0(8(0(0(0(8(0( ( (esa ae8.B M 55.1 66.1 58.1 58.1 55.1 66.1 58.1 58.1 55.1 66.1 58.1 58.0 1 55.0 1 66.8 1 58.1 51 n 14 83 04 14 04 83 93 14 14 83 93 83 83 83 83 93 DIMPD DIMPD DIMD DIMDQIP P BT B QITB QI Ig g g g g g g gTgBgQgTg m0 m m m m m m m m m m m 0 0 4 0 i4)0 0 0 0 4 0 0 4 0 4)0 0 0 0 4 0 0 4 0 4)0 0 0 0 4 0 0 4 0)0 0 0 bnbi4 n =binbinbi4 n =binbinbi4444n =bibibi=biititNitititNitititN nininiN niurbur(o a1 z4b li=a8 z3b2 ururur(o e kb li=ceea1 z4b li=a1 z4b li=a8 z3b3ur r r(t t to(t) ) ) ) ) )u)u)e kb li=ceea1 z4b li=a1 z4b li=a8 z3b4ur )ur )ur )o e kb li=ceea1 z4b l =a1 z4b l =a8 z3b5ur )e kb l =ceea1 z4 l = RN(RN(alP W RN(RN(RN(alP W RN(RN(RN(alP WiRN( iRN( iRN(alP WiRN(Attorney Docket No.01183-0291-00PCT-PRN r a oe 96 97 90 1 2 4 8 9 3 7 3 0 ofbucela 7 0 0 48 98 10 31 62 70 21 69 30 ecv- .1.9.0.0.2.0.0.2.0.0.4.0na0 0 0 0 0 0 0 0 0 0 0 0 elp rpef.sfivd)ebi )gn 5 0 .4-), ,4 -,-),1 -,-, ,-,nit .4na 4,51 1 5..337 1 0.06 2 3 2 0 aura)I4, .8)9,2.3.0,3.0.7 7. ) .8hb CaeC 1z.8 2 l.6 4- 5 9.2- )( 56.0 4)-24 3)-63.8 3)-15 3)-61 2- 3 0)5.4- 3 %irM4 S% L529- 3(808.4 15 12-( 66.9( 83.5 32-( 97.5( 20.4(001( 37.8 (( 14 -(.8.73(.9.9 (.9.0 6. .5.86 6 9 -8.2-1- 4 .64 8 -2- 8 6 1- .61 92- 0 2 -5- 4 2 -ea0 - ) nES)9)2)2)3)4)6)9)9) ) ) ) ) ) ) )eil( 3 4 48 4 6 5 2 3 5 1 gnes . . .8.8.9.9.6.6.8.7.9.9.0.9.0ana5(5(5(5(5 5 5 5 5 5 5 5 5 6 5.6 ahbe2 .12 .47 .21(.38(.17(.03(.43(.89(.72(.56(.86(.70(9(0(3 CmoMrS3 4 - 2 - 3 - 5 - 2 4 - 7 - 8 2 - 3 - 7 4 - 8 - 8 2 - 4.8- 2.3- 8.8- 2.4- 5 -g- - - -nuara be,C 5,ha.67,2.0,7,5,6. .4.95,1.8,6, -, , -8,1. .81 6.4 3.13 9 CzlM%3i-rS2-6-4-3-6-5 3-5.53- .5 L5 9((2( ( (.38 9(- 9( ( (- -7( ( (- 1(1-0.9 00.4.9.31 -1-1-7.7 37. .35 -2-1-0.6 38. .65 -2-0-3.3 - a) m E o S rf()n8)8 8)8 8)8 3) )9 3 9 5) )9 5 9 1) ) ) ) ) ) ) )9 1 9 3 9 2 9 5 9 3 9 6 9 4 9 5 eea.0.0.0.0.0.0.0.0. . . . . . .9.gn naile( ( ( ( ( ( ( (0(0(0(0(0(0(0(0(esM9 .88 .47 .57 . 7 8 9 1 7 7 0 6 7 2 1 5 haS9.8.2.8.7.7.3.0.6.4.2.6.8C b L6-5-5-8-6-6-4-8-7-6-5-8-8-6-5-8- enil )e) ) ) ) ) ) ) ) ) ) ) ) ) ) ) )sD aS 5 1 (.9 6.2 6 48.0 8 9 ( 4(.26.5 1.2 6 58.2 9 7 ( 5(.45.3 2.4 57.6 5.79 2 .6 2.9 51.2 6 b.5- n( ( (6( (5 6( (5 tsa 3 0 .04 .11 2 3 . 7(3(3 0 8(2(8 1 4(3 oe P M5.8 11 018.66.2.88 01 011.70. .6.98 01 017.61. .6.37 01 013.6 ))8)3)4)7)8)3)4)7)8)3)4)7) ) ) )D.6.5.2.3.6.5.2.3.6.5.2.8 3 4 7 eS il(3 3 43.6.5.2.3n 4 3 3 4 4 3 3 4 4 3 3 4 4 n(0(0(0(8(0(0(0(8( ( ( ( ( ( ( (esa ae8.55.66.58.58.55.66.58.0 58.0 55.0 66.8 58.0 58.0 5.0 6.8 8.B M 1 1 1 1 1 1 1 1 1 1 1 1 51 61 51 51 n 83 73 73 73 93 53 63 63 93 43 73 43 83 43 73 53 DIMPDIDIMPDIDIMPD DIMPDB Q T B QI Ig g g g gTgBgQgTgBgQgTg m0 m0 m0 m0 m0 m0 m0 m0 m0 m0 m0 m 0 0)0 0 0)0 0 0)0)0 4 i404 4 404 40 0 0 0 0 bnbi4 n =binbinbi4444 4 444n =bibibi=bibibi=biititNitititN nitniniN nininiN niurbur(o a1 z4b li=a8 z3b6 urur r(t to(t t t(t) ) ) )u)e kb li=ceea1 z4b li=a1 z4b li=a8 z3b7ur )ur )ur )o8ur )ur )ur )o9ur )e kb li=ceea1 z4b li=a1 z4b li=a8 z3bekb l =ceea1 z4b l =a1 z4b l =a8 z3bekb14 l =ceeazl= RN(RN(alP W RN(RN(RN(alP W RN(RN( iRN(alP WiRN( iRN( iRN(alP WiRN(Attorney Docket No.01183-0291-00PCT-PRN N R hgP- u orrW a hteTroe 19 02 39 93 53 49 1 7 0 6 0dehto 0 o0-fbula 0 9 2 9 8 0 06 79 70 71 97.;F 1ecec9 na.lv-0.3.0.1.8.0.0.6.0.1.8smrp 0 0 0 0 0 0 0 0 0 0 0etifC 2erp ainO r0ao -ef.sc Wvvyy 3fi8 dbi-)2)o -1eni,-,-,6c ct, .1,6,5,2,6,3.7 sabacid ffet1 gn na)9 9,8.4 1.2.3 91.881seu0.auraI .6)6.97) .82. ) .10,nnp hbe 6 4)o2)82 8)3)96 0)3)5oiomCaC 3- 0 2iN zli.2.33- 6 8. -(7 5.1-6.3- 4 4-(7 61-3.4- 5 3-(6 4.0 get etrMS%5(452-(215(5(.e% L9( .9.9561 3 52.0(031(3.69.36 1rdcarek0(7.4 2. .1.8 3. .2.6- npc2- .08 0 1 -1-1- 2 5 2 -1-3- 3 3 2 -1-(5 3am pi wyco7- .1 u om uiacDyea)rEe ) ) ) ) ) ) ) ) ) ) ) ) )g deiffenenilSrg(4 o nes9.2 0.7 9.4 1 1 3 9 2 3 2 5 1 3 2 3 2 8 1 8 2 4)5 5)5 0n 3oitm / fhoana5ttahbe(6 0(5.( 6.( 6.( 6.( 6.( 6. . . . . . .( 6(6(6 6 6 6 6negikc.83 .96 .83 .25 .77 .01 .85 .75 . 2(2(1(7(3(8vrh(salrACmoMrfS1 5 - 7 3 - 0 3 - 6 5 - 84.9.6.8.2.2.5 etno 4 - 9 3 - 7 3 - 5 5 - 9 4 - 6 3 - 3 3 - 9 5 - 0 5 - 5 3 - 6 3 - ni oifn f CesD 0 aS0b-(.2.9.8 92.6 6 14.48 852gnny 7 5(5(.45.27 5(.66.75.0.7 5(6(.55.1.7 5(.0 ittioit bd sn( ( ( ( ( ( ( (7at a 5 4 6 7 9 7( fuetoe 4 4. .40.53 6 04.0. .32 7 6 08.5.7. .9.09 5.1 6. .36 9.y bnitup P M 7 1 1 6 8 1 9 6 7 01 01 5 7 11 9dn ezomi)) ) ) ) ) ) ) ) ) )ycasid )) ) ) )l dnaeD 8 .63 .54 .27 .38 .63 .54 .27 .38 .63 .54 .27 .38 .63 .54 .2 nanog nS il(3 3 4 4 3 3 4 4 3 3 4 4 3 3 4er itnisesn(a 0(ae8.0(5.0( ( ( ( ( ( ( ( ( ( ( (enesi6.8 8.0 8.0 5.0 6.8 8.0 8.0 5.0 6.8 8.0 8.0 5.0 6.w 1 1 1 1 1 1 1 1 1 1 1 1avrmB M 51 61 51 5 5 6 5 5 5 6 5 5 5 6 5taetotdnit.eI4ety 3 3 3 3 3 3 3 3 dsMn 3 53 63 63 33 53 73 7 4 4 7 3 0 1 5el ey putrebDIMPDBIDIMPDIDIMPDIDIMP msorcewd tf )etwu gQgTgBgQgTgBgQgTgBgQg da eip m m m m m m metdvmi00 00)00 0 m m m m uet e0 00)00 00 00)00 00 0)pcerer4bi40 bi40 0 0 0lblla e4i4bi4bi44bi4bi4bi44bi4b 4b4mieociw nitn = ritN nitnitn = itN nitnitn = itN niitniitn = itNht cadeatau b)1urb)(0 8ob1 urb)1urb)1ur(1 b)8ob1 urb)1urb)1ur(2 b)8ob1 urb)1ur )ur )(oftam dboDdg az4 li=az3elckaz4az4az3eckaz4az4a3ecka4ba14ba83echc: ednisRN( i= RN(aleelP Wi=lRN( i=lRN( i= RN(aleelP Wi=lRN( i=zlRN( i= RN(aleezlP Wi=zlRN( i=zlRN( i=aetnsRN(alPaEoiNilb mAttorney Docket No.01183-0291-00PCT-PRN ehtmraorefoofbuldeececa d v- ulnacelrppxeef.s efiv redebinwikgntnaeeaura)IwhbaeCeCzlMh %t%irS L5t9( aIMy b ea) detenilESu gnes(p nm aaa hbeie CmoMre%rfS Lwseulaaroevobulesf eeca ohcalv-wneppstr.sneafvpfidbiiceniitgtnaranua)IparbeCdhaM naCzlirS% L5,9(keewea)htEtmo San rf(o eenitgnaaitle n u ahesMp m CaS b LiF e C n O il )esDWS h atbi-(tsnawoestP Mnapicit)raeD p nSeil(d esn u alcae n B Mikeenwhcaetascit.ssiistaylts aenavietv piitrcpisercsDedAttorney Docket No.01183-0291-00PCT-PRN) ra oe 50 12 72 3 9 5 4 6 9 0 1 7 nooitfbul0 1 6 0 7 5 3 1 1 eeca 0 0 8 0 2 7 0 0 6 0 1 8 v.0.0.2.0.0.4.0.0.2.0.0.3ac -nalp 0 0 0 0 0 0 0 0 0 0 0 0luerp.pef sofivPdbi) ) ) )eegn -,- 0 - - 2 - - 8 - - 1vïnitauna)I8,.79.8.96,,0,.76.3,.09,3,.39.3,.16,4,.77.7.38,ahrbaeC2)N-CazlM 4- 78 3)0 - 03.2)4- 62 3)6 - 09.2)485 3)4 11.0 4)66 3)6 97.%( 8.631(0.35.82-(2( 5.9 -0. -21-(2( 4.3 - 52-( 3. -8( 6.2 42-b %irS L5 9 a( .31 7.82- 3(3 5.618 .2 (010(5 3(2- .27 2 7 2.2.31.37 2 0 8.5.52.34 2 0 2 2.0m8- - -5- - -8- - -7-u(1kWob of eca 0 v.00 .03 .20 .04 9 0 1 3 1 2 5t ecal -p 0 0 0 0.00.40.00.00.30.00.00.40 pnepur.seefvfibi)2 ) ) ) ) ) )mi e57 ) 4 1 4 9 7 ) 0 1 4 2 9 )8 5 )0 )0 dnitna.)1.0.3.1.0.4.14. .1 7.4. .5TgI -nu, -,1, -, -1, -0- 1,0-0- 1,ara beC9 0 7,.95 6 2,3,5 3,1,2 6reha v CzlM 8.8.i S%56-5-3-3.4. .9( 6-4-2-9.5-1.5.4-3-7.5-3.5.3-3-orL9((1(72.4 3(1. .34(6(6(8(2(2(3( (3 S4-3-1-1.4 -2.2.7-0-5.3 -8.2.16 -1-2.3 -8.2.9-0-SI a)im Eno Serf()2 )3 )0 )2 )2 )3 )0 )2 ) ) ) ) ) ) ) )2 eena8.08.08.08.08.08.08.08.7 08.7 08.5 08.7 8.2 9.3 9.9 8.9.nilgne nail( ( ( ( ( ( ( ( ( (0(0(0(0(0(0(esM3 .16 .05 .23 . 7 9 9 3 9 2 2 0 3 6 3 0eshaS a C b L6-5-3-91.-37.-45.-93.-23.-27.-56.-84.-73.-37.-96.-05.-14-Be m nil )eD) ) ) )4 8 8 2 5 1 3) ) ) )2 4 6 3 7 7 1)2) ) ) ) )9 8 6 0)3)2 9 4 orsfaS(.6. . .5 5eb-(4(5(.8. . .5 5(4(5(.45.0.4.6 4(5(.05.0 7.1.6 4(6(gtsna(1 1 8 7(0 2 3 8(4(6 0 8(9(2 9 1 n oe P M5. .5.0.59 01 31 314. .3.5.38 01 21 213.81. .6.99 11 117.73. .3.58 11 11 ah C) )6) ) ) ) ) ) ) ) ) ) ) ) ) ) )tneDS.22 4.70 3.56 3.16 4.22 4.70 3.56 6 2 0 6 6 2 0 6 3.1.2.7.5.1.2.7.5.1encil( ( ( ( ( ( ( (4(4(3(3(4(4(3(3(4(esna 9 6 5 4 8 3 4 1 9 6 5 8 4 9 5 8 4 9 5 8 4reae. . . . .4.3.1.6.4.3.1.6.4.3.1.B M 51 51 61 51 51 51 61 51 51 5 6 5 5 5 6 5P1 1 1 1 1 1 1 dn n 53 53 73 63 53 43 73 53 53 53 73 53 23 33 73 43 aeD DMD DMD DMD DM gITIPI IPI IPI IP n gBgQ T B Q T B Q T B Qa g g g g g g g g g g h m0 m0 m0 m0 m0 m0 m m m m m m C 0 0 0).46 0 0 0)0 0 0 6 0 0 0)0 0 0 6 0 0 0)6 b4b 4b34b 4b 4b34b 4b 4b34b 4b 4b3 0i3ninin =ininin =ininin =ininin = itititNel( itititNitititNitititN 1urb)5ur )ur )ob2 ur )ur )ur )(ob3ur )ur )ur )(ob4ur )ur )ur )(ob5b ka3ba53ba73eckba53ba53ba73eckba53ba53ba73ekba53ba53ba73ek aee zTlWi=zlRN( i=zlRN( i=ee zlRN(alP Wi=zlRN( i=zlRN( i=eezlRN(alP Wi=zlRN( i=zlRN( i=ceezl=zl=zl=ceeRN(alP WiRN( iRN( iRN(alP WAttorney Docket No.01183-0291-00PCT-PRNra oe 14 55 15 24 28 06 83 40 7 6 7 2ofbuela 1 .00 .37 .70 .00 0 0 4 50 03 61 21ec cv- 0 0 0 0.10.30.00.00.30.00.0.5nael0 0rppef.sfivdebi))) ) - 4 5 - 0 - - 7gn nit ,0.3.5,, 2 5.9,9,- 3.7,- 7,1 ,1auhrna)I .17,71.6.27, .3.37, .5.6 5.baeC5)3,3 8 1)0 3- )6 1)3)8 6)7)2)3CazlM 3-4.%( 9.3.0 4- 9 01( 7.( 0. .54- 9 (9.3- 57( 7. .43- 0 (8.3- 4 (7.2-( 2.1 %irS L5 2 329- 3 (.5 1- 0 73 .632- 974 02- 818 341 9(4(.74 3(3.64.07(1.19.6 6.1- .03 8 -2.2-1- .68-2-1- .505- 81-2- a 2 -e) eniES)5 )3 )6 )8 )8 )3 )7 ) ) ) ) ) ) ) ) ) glnes(an7.a57.55.57.52.62.60.3 62.9 62.8 60.8 69.0 51.7 65.4 63.9 2.8 2.h( ( ( ( ( ( ( ( (6 6 6 abe4 .67 .19 .82 .16 .38( ( ( ( ( ( (.29 .26 .62 .47 .73 3 9 8 4 0 CmoM%rfS3 L5- 2 4 - 1 3 - 4 3 - 2 5 - 1 4 - 6 3 - 7 2 - 4 5 - 6.24- 8.73- 9.02- 1.55- 2.55- 7.93- 1 3 - a oe 61 16 49 30 43 40 19 46 44 7 3 2rbul2 5 8 1 8 6 0 6 9 6 9oea.0.4.7.0.1 6 3 7feccalv- 0 0 0 010.30.00.00.40.00.00.60 p pner.sefvfibi)2 ) 4 0)) 3 2 ) ) ) 8 3 9 5 ) ) ) ) 8 6 8 0 8 ) 1 6dn. .5. .8.3. .1.4.eigturna a)I0-,1.,720- 0 3, , ,1,0-,0,1.2, 0,0- .0, 2,nabeC4 7 2 6 1 1 8 9 5 1 7haM 3. .33 0.1. .34.83 0. .84.5.2 4. .1CzlirS% L559- -((8( 2-6- -2( ( (-( 6- -( 3-( 5-5-3-.93 7 6 .71(.23 6( ( (. 6 2 9 5 8.2 -0-3.04.3 -1-1-4.33-2.-01.-52-7.2.5-0- a) m E o S r ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) f(n1 9 1 9 8 8 1 9 9 9 7 9 5 9 8 9 7 9 4 9 3 9 5 3 8 6 8 eea.0.0.0.0.0.0.0. . . .9.0.9.9.9.gne( ( (0 0 0 0 0 1 0 0 0 nil( ( ( ( ( ( ( ( ( ( ( ( (aesM1 .55 .50 .33 .67 .27 . 2 0 4 7 6 1 3 0 6 1 haS8 6 5 5 8 56.06.8.5.4.1.1.9.2.9.4C b L- - - - - - -4-8-7-6-5-7-8-5-5- enil ) ) )esD)aS 7)(.81 8)5.8 6.5)6 4(.75) )4.00 6 5) ) )4)0) ) )6)3 6.4 2.8.5 63.7.1 52.2.6 5(5(.35.16 5(5(.55.56 5 6 b-sn( (0( ( ( ( ( ( ( ( (ta 2 8 5 2 5 7 8 4 1 8 1 4 2 5 oe9.8. .0 7.3.8.2.5 1 2.6.5 23 3.7.1P M 6 8 11 9 7.8 01 01.7.8 01 01.7.7 01 01 ))6)2)0)6)6)2)0)6)6)2)0)6)6)2)0)D.2.7.5.1.2.7.5.1.2.7.5.1.2.7.6 eS il4 3 3 4 4 3 3 4 4 35.1n(n(9(5(8(4( ( ( ( ( (3(4(4(3(3(4(esa69 5 8 4 9 5 8 4 9 5 8 4 ae.4.3.1.6.4.3.1.6.4.3.1.6.4.3.1.B M 51 51 61 51 51 51 61 51 51 51 61 51 51 51 61 51 n 33 43 63 33 13 43 43 23 03 43 33 33 82 33 33 33 DIDIMPDIDIMPDIDIMPDIDIMP TgBgQgTgBgQgTgBgQgTgBgQg m0 m0 m0 m0 m0 m0 m0 m0 m0 m0 m m 0 4 0 0)0 0 0)0 0 0)0 0 0)i4 464 4 464 4 46 0 0 6 bnbinbi3 n =binbinbi3 n =binbinbi34 4 43 n =binbinbin = itititN( itititN( itititN( itititN ur )ur )ur )our )ur )u)u)u)u)u)u)u)(ba5b5b7b6b5b5rb7ob7rbr rob8r r rob9z3 3 3ek 3 3 3ek 53b53b73ekb53b53b73ek li=azli=azl=ceeazl=azl=azl=ceeazl=azl=azl=ceeazl=azl=azl=ceeRN(RN( iRN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(alP WAttorney Docket No.01183-0291-00PCT-PRN r a oe 8 4 4 3 7 4 7 8 5 0 f 4 9 0 8 6 5 3 8 1 9 obuecelca 0 v- .00 0.06 0.32 8 0 8 2 0.02 0.14 0.61 4 8 1 2 5.0.00.00.50.00.10.90see 4 2 2 v ro 1 8 0 5 6 4 0 8 8 8 9eobuf ela 1 ec .02 0 .02 0 .44 0 .04 8 .17 2 .62 9 .07 2 .06 6 .71 27 68nilcalv- p 0 0 0 0 0 0 0 0 0.00.10.60esanepr.sbg efv) ) ) ) ) )nifidbi7 2 enit7.3.4 3 ) na0-0- .5 11.9 ) 0- .65 5 ) 0.1 42.8 ) 0- .28 2 ) 0.2 62.6)0- .80 dno 0.4p gnuara)I , , ,beC9 7 0, ,.78 6,.81, ,.32 5, , ,3,se.12 .15 7 4rrha CzlM 0.5.3 6.4 3 9.5 3 2. .74 2.ocirS%6-5- -5- - -5- - -6- -2- L5 9e((3( (8( (9(8( (3(2( (6(h 4.4 3 -9.2.01 -1-9.2.0-2.-59 0 -1.3.4-2.-44 0 -4.3.98t-1-5.0 htia)wlEemo S d rf()0 )9 )6 )8 )3 ) o 5 )1 )2 )2 )2 )0 )1 )5 ) ) ) een gna0.e19.( 09.( 09.( 00.( 10.( 10.( 10.0.0.0.0.0.6 0.2 0.5 0.m(1(1(1(1(1(1 1 1 1 A nail5 6 0 2 9 7 6 8 0 5 3 2(1(3(9(7V hesMO aS.48.97.16.05.58.77.26.65.58.7.7.3.2.7.1.7C C b L- - - - - - - - -7-5-5-9-7-5-5- N eAnil )e) ) ) ) ) ) ) ) ) ) ) )n )) )asD aS 1 b.31 5 .1 1.4 9.5 .29 0 .2 3.9 4.3 4 5 5.1 3.6)5 4 5.2 8.gnit-(tsn 5 a(7 5 8( (5 3 6(5 5 6.5.95 6.2.95 6 ( 7( ( (5(6( ( (5(6( ( ( tifoe6.6. .45 .55 7.7 3 1. .40 .09 9 3 3 4 9.0.27 7 9 1 2 0.5.0y P M 6 7 01 01 6 8 01 01.6.7 11 01.5.8 11 01bdez) )6) ) ) ) ) ) ) ) ) ) ) )yle.2 .70 .56 .16 .22 .70) ) ) aD2.56 .16 .22 .70 .56 .16 .22 0 6nanS il(4 3 3 4 4 3 3 4 4 3 3 4 4.73.53.1eesn(a 9( ( ( ( ( ( ( ( ( ( ( ( ( (4( re6.5 4.8 3.4 1.9 6.5 4.8 3.4 1.9 6.5 4.8 3.4 1.9 6.5 4.8 3 4 1 w ae B M 51 51 61 51 51 51 61 51 51 51 61 51 51 5.1 6.1 51atad 9 9 4 2 0etn 2 2 3 3 3 82 43 33 13 92 33 33 82 62 03 23elp DIDIMPDIDIMPDIDIMPDIDIMP mo TB Q T cg g g gBgQgTgBgQgTgBgQg d met0 m m m m m m m m m m m u 0 00 00)00 00 00)00 00 0)0 0 0)p 4bi4 4634 4 46 0 34 4 46 0 0 0 34 4 46minbitnbirin =binbinbin =bibibi=bibibi3=ei N N n n n N n n n Nhtutb)i5utrb)5urb)(0iti7ob1 utrb)i5utrb)5urb)(1iti7ob1 utrb)i5utrib)5ur(2tib)7ob1 utrib)5utr )ur )(ofboaz3 li=az3 li=az3eli=ckaa eez3 li=az3 li=az3eli=ckaa eez3 li=az3 li=az3eli=cka3ba53ba73ea eezli=zli=zli=chcaRN(RN(RN( lP W RN(RN(RN( lP W RN(RN(RN( lP W RN(RN(RN(alPaEAttorney Docket No.01183-0291-00PCT-PRN heg h utorrm h otira he roetdfbehtfodewa nroe 60 6 7 3 9 2 5 oul ;ul2 0 0 8 9 0 ceamrF du oiofbea 0 0 8 0 1 6 0 ecv-ltecv.0.0.2.0.0.4.0nalpifCcal cal -p 0 0 0 0 0 0 0 e n rpoOxeu ne pef.sc Wepre.sfivyyreoff vdbicab wibi) ) egncidek P den -,-,3 -,-,9 -,nitaunaf)f teupee egnitna)6 .23.9.29,9 .57.1.39,6 .2hrbaeIC n w omi evïa auhrbaeIC 6)22)6 95.2)82)6)2924 CazlM%tceht N CazlM 4-( 8.4-( 3.64-( 6.32-( 9. .94-( 9.1 %irS5apretaI -b %irS%5 48 .515 .28-(3 .6142 .16-(0 .11 L9(mi wyca L9(7 3 2 .37 7 8 .37 mMuiacy ibm2-2-8-2-1-5-2-ea)dffduza) eniEeeSfetuil ea nES )6 )3 )4 )7 )7 )6 )6 )9 )4 glnes( m / anhop gikeilcmim gnes(an7.57.55.56.55.55.53.54.56.5 a a a hbeh(ale O abe(3(0(0(9(7(8(2(4(4n n ailesMdulp cM milnailesM1 .20 .10 .36 .93 .52 .55 .04 . 7 h CaS b Lni .ieFeC Fsh CaS b L6-5-3-1-7-5-4-23.-77- r C a eneO O il )w W Ben esD nyWmil )aSeD) ) ) )7 8 8 2 5 1 3) ) ) )0 4 6 3 7 7)1 b-( oit bh dtio rsaS(.4. . .5 5(4(5(.8. .1.5 5(4(5(.45 tsnaa unetuwsft eb-tsna(9 1 .58 .07 .(59 2 .33 .58 .(38 oeitP M npnoag oe7.0 3 35.0 2 21.cmip n P M 9 1 1 1 8 1 1 1 8 sidica )dniatrah)s ) ) ) ) ) ) ) ) ) )D nog p CiD 2 .32 .70 .56 . 2 2 0 6 2 eSiitn lie t s eS 31.3.7.5.1.3n(sd nnesiu ne ylnil(n(3 5(3 5(4 8(3 4(3 5(3 4 3 5(8(4(esa aevrlcemnca r nesa ae1.64.53.61.51.64.53.61.5 1.B Mtnoitt.IikeB M 1 1 1 1 1 1 1 51 61 yesMeeP An d ut esrey bwhdm 4 5 7 6 4 4 7 5 4 rcnorn 3 3 3 3 3 3 3 3 3 ewd tf )etaea wut efgd DIDIMPDIDIMPDIaepaeT B Q T B Q Tdeitvmisc.sn ceereitlllaresiisav g g g g g g g t ylah o m0 m0 m0 m0 m0 m0 m0 cm0 0 0)6 0 0 0)6 0 ociwatsnC adteaat. e4aeab 4b 4b34 4 434ve1 Riniitni=bibibi=biitnitN nitnitniN niDm dgitv pit3rei1 ur )ur )ur )(o2 ur )utr )ur )(to3ur ):deen t diircpir elltkba43ba53ba73bekba43b53b73bekb43 onssscbuee zli=zli=zli=cee zli=azli=azl=ceeazl= Nil i esb m Dea d T O W RN(RN(RN(alP W RN(RN( iRN(alP WiRN(Attorney Docket No.01183-0291-00PCT-PRNra oe 08 64 23 52 82 04 02 78 25 1 3 9ofbuela 0 .07 .20 .01 .00 . 1 9 0 0 02 23 30ec cv- 0 0 0 040.00.20.80.00.10.30.0nael0 p pref.sfivdebi) ) ))) - 5 - - 8 6 5 0gnit ,9.5,4,- 6.9,1.0.0-,, - 9 4.4,nauna)I .06, .4.08, .17,71.7.78,5 .9hrbaeC5)4 6 0)66)5 5)8,0 0)9 2- )4 0)CazlM 3-0.%( 2.34-3- 53.23- 64. .3 4- 5 5( 1.8( 3.( 9.3 3( 1.(38.4- 5 64.4( 8.%irS5 82-(0 042-(432-( 1- 77.132- 07 L9( .10 5.32- .24.20 9.59 1(.9 (.47 3 3 18- 2 4 -2-2- .66-1- .28-8.2- .2 2- 18-ea) eniES)1 )2 )8 )2 )8 )4 )1 )8 )3 ) ) ) ) ) ) ) glnes(an6.a54.55.50.69.57.59.57.57.4 55.4 57.8 52.2 62.5 60.7 62.6 61.h( ( ( ( ( ( ( ( ( ( (6 abe2 .09 .04 .86 .66 .55 .06 .39( ( ( ( (.56 .28 .16 .09 8 5 3 2 CmoM%rfS1 L4- 9 2 - 0 2 - 7 4 - 3 4 - 0 3 - 3 2 - 3 5 - 2 4 - 2 3 - 4.13- 2.35- 1.44- 6.23- 8.22- 4 5 - a oe 72 44 13 39 14 00 35 36 74 82 99 6rbul1 5 0 1 8 1 5 6 0 9 4oea.0.2.0.0.3.2 0fec0.4.8.0.1.3.0calv- p 0 0 0 0 0 0 0 0 0 0 0 0nepr.sefvfidbi)1 ) )5 )6 ) )7 )))5 ) ) )3 n6.4 .9 2.4.2 .3 7.8 .481.7 .801.eigtna)I0- 0,1-0- 1,0- 1.521- 0.311-nuara,beC2 4,3,6 2,5,1,7,9,0,8,4haM 1. .53 1.2. .43 6. .33 1.3. .34.8 2.CzlirS% L559- -((7( 6-5- -0( ( ( 5- -( 2-6- -( 3-( 6- 8.2.39 6 5(1.-6.01 1( (3 8.21.-2.90 7 2(0.9 9 -2.07.71.-21-6.- - -3-3-3- a) m E o S r ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) f(n5 8 2 8 4 8 1 9 1 9 7 8 9 8 1 9 0 9 7 8 0 9 8 7 4 8 5 eea.0.0.0.0.0.0.0. . . .9.9.9.9.9.gne( ( (0 0 0 0 0 0 0 0 0 nil( ( ( ( ( ( ( ( ( ( ( ( (aesM1 .54 .94 .68 .76 .94 . 9 5 5 4 4 1 6 3 4 3 haS6 4 3 7 6 15.04.8.5.4.6.6.5.1.8.8C b L- - - - - - -8-6-5-5-8-6-6-4-8- enil ) ) )esD)S 9 8 0).0 6.4.3) ) ).02 9 4).0 7.1.7) ).81 8) ) ) )6)5).8 6.5 5 02.8.5 a(6 4(5(5 6 4(6(5 6 4(.74.06.46 5(5.3b-tsna(6 0 .68 .(99(2 9 .31 .(52(8 0 .(05(2( (5 5 7 .28 .(4 oe P M1.9 11 117.73.8 11 119.68.8 117.93.78.58 01 011.7 ))2)0)6)2)2)0)6)2)2)0)6)2)2)0)6)D.7.5.1.3.7.5.1.3.7.5.1.3.7.5.2 eS il3 3 4 3 3 3 4 3 3 31.3n(n(5(8(4(5( ( ( ( ( (4(3(3(3(4(3(esa45 8 4 5 5 8 4 5 5 8 4 5 ae.3.1.1.4.3.1.1.4.3.1.1.4.3.1.1.B M 51 61 51 61 51 61 51 61 51 61 51 61 51 61 51 61 n 53 73 53 23 33 73 43 33 43 63 33 13 43 43 23 03 DIMPDBIDIMPDIDIMPDIDIMPDIgQgTgBgQgTgBgQgTgBgQgTg m0 m0 m0 m0 m0 m0 m0 m0 m0 m0 m m 0 0)0 0 0)0 0 0)0 0 0)0 4 i464 4 464 4 4640 6 0 bnbi3 itn =bii nbinbi3 n =binbinbi3 n =bi4 434nbinbin =bin utN rb)a5urb)( itititN 7ob4 urb)4urb)5urb)( iti7ob5utrb)i4utN rb)ur )( itiob6utr ) riutN )riut)(ob7ur )z3 3ek 3 3 3ek 3 53b73ekb43b53b73ekb43 li=azli=ceeazl=azl=azl=ceeazl=azl=azl=ceeazl=azl=azl=ceeazl= RN(RN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN(Attorney Docket No.01183-0291-00PCT-PRNra oe 27 92 59 10 78 08 33 51 66 4 0 2ofbuela 3 .01 .32 .02 .08 . 0 1 9 3 62 65 51ec cv- 0 0 0 040.00.00.30.00.10.60.0nael0 p pref.sfivdebi) ) gn - 6 - - - - 8 -nit, - a,0.87,5,1 ,6,1,0.49,1 1 ,,aurn)I .4, .0.1 9. ) .9.5, .2.97 9 15. ) .9hbaeC3)6 2 7)57)628 0)68)0 7)3- )18 9)CazlM 3-5( 0. .43-( 9.3-( 1.2-( 9.4-( 1.3- 72( 4. .43- 0 5 (2.( 9.2-( 5.3- 6 (2.%irS% L5 1129- 013 3901 368 42- 018 3931 24 (.27(5.5.1 9. .5.4 (6.2.939. .11- .39 05- 3 1 8 -1-2-2-2- .39 7 -1-1-3- 2 2 -ea) eniES)6 )4 )7 )9 )3 )0 ) ) ) ) ) ) ) ) ) ) glnes(an0.a69.50.64.63.62.6 63.2 65.7 63.3 61.1 63.3 67.8 67.0 64.1 6.1 6.h( ( ( ( ( ( ( ( (6 6 6 abe3 .07 .12 .84 .68 .24( ( ( ( ( ( (.14 .15 .40 .48 .22 6 4 6 6 0 CmoM%rfS7 L4- 8 3 - 9 2 - 1 5 - 2 5 - 8 3 - 2 3 - 3 5 - 1 5 - 7.93- 9.22- 4.05- 9.04- 9.03- 5.63- 3 5 - a oe 04 92 34 49 34 97 44 55 03 8 1 6rbul6 9 3 3 3 0 3 3 9 9 1oea.0.3.0.0.2 1 8 1feccalv- p 0 0 0 060.00.00.40.00.10.50.00nepr.sefvfibi)4 ) ) 1 1 ) 2 3 ) ) 1 6 6 ) 9 1 ) ) 2 8 4 ) ) ) 4 7 6 8dn.1.4. . .9. . . .7.eigtna)I0,10-0- 10-0-510- .50.910-nuara, , , , , , , , , , ,beC5 8 7 3 2 8 1 7 8 5 5 1haM.84.53 5.3. .23 3.5. .6 9. .9.4 2.CzlirS% L5 - 9((- 6( 5-5- -( 6-5-3-( 5-4-3-6-.39( (.09 3 3( ( ( ( ( (.67 6 4 1 9 5 9 2 -1-8.27.0-6.8. .01-2. .12.-70-4.-2-3-2-3-3- a) m E o S r ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) f(n3 9 1 9 4 9 9 9 7 9 5 9 7 9 2 0 9 9 5 9 8 4 4 8 2 0 eea.0.0.0.0.0.0. . . .9.0.0.9.0.0.gn naile( ( ( ( ( (0(1(0(0(0(1(1(0(1(1(esM0 .53 .24 .14 .38 .18 5 9 8 6 2 8 6 1 7 2 haS7 6 5 8 8.06.4.7.9.1.1.8.8.4.6.8C b L- - - - - -5-8-7-6-5-8-7-6-5-8- enil ) )esD) )S 6 4 0).1 3.7.1) ) ).55 6 3) ) )5)4) ) )0)9).5 2.2.1 .311.9.5 93.4.3 a(6 5(5(5 6 5(6(5.17 5(5(.25.27 5 6.5b-tsna(1 8 .61 .(54(3 2 .75 .(18(3 6 .45 .(55( ( (5 7 3 . 0(9 oe P M2.8 01 012.73.7 01 016.66.7 01 017.61.4.08 01 019.6 ))2)0)6)2)2)0)6)2)2)0)6)2)2)0) )D.7.5.1.3.7.5.1.3.7.5.1.3.7.56 2 eS il3 3 4 3 3 3 4 3 3.1.3n(n(5(8(4(5( ( ( ( (3(4(3(3(3(4(3(esa45 8 4 5 5 8 4 5 5 8 4 5 ae.3.1.1.4.3.1.1.4.3.1.1.4.3.1.1.B M 51 61 51 61 51 61 51 61 51 61 51 61 51 61 51 61 n 43 33 33 82 33 33 33 92 92 43 23 03 82 43 33 13 DIMPDBIDIMPDIDIMPDIDIMPDIgQgTgBgQgTgBgQgTgBgQgTg m0 m0 m0 m0 m0 m0 m0 m0 m0 m0 m m 0 0)0 0 0)0 0 0)0 0 0)0 4 i464 4 464 4 4640 6 0 bnbi3 itn =bii nbinbi3 n =bibibi3=bi4bi4bi34=biN n n n n n n n utrb)a5urb)( itititN 7ob8 urb)4urb)5urb)( iti7ob9utrb)i4utN r)ur )(o 0itib1 utr ) riutN )ur )(o 1itb1 ur )z3 3ek 3 3 3ek 3b53b73ekb43b53b73 kb43 li=azl=ceeazl=azl=azl=ceeazl=azl=azl=ceeazl=azl=azel=ceeazl= RN( iRN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN( iRN( iRN(alP WiRN(Attorney Docket No.01183-0291-00PCT-PRN heg h utormra hreore 3 5 0t htfoofbul1 8 2 90 64deodeea 5 7 1 1 7cecv- .0 m;F dana0.50.00.1.9 .s rifC ulc( .elp 0 0etnO)rp xef.esaiDroI2fac WeCiv 3debi )vycy breel, - , 1oc acidw Mbgnita 7 ,,.69 6 2.18saffetk ueead anauhrn ba)I5)7.2) .9.81 1)2) ,nenp we TCaeC 3- 02zlM- 24- 73- 83oio %(tmi ehc91.( 7.2( 1.(23. .57gecetnee%irSs(L5 9( .7031 75 70. .5.731-rdapreta.si ei1 -5- 3 4 2 -1-(n 9 2.am pi wyI syrepes0 u ea)omcMylaxaruiacifb naehp eniEg defed S) ) ) ) ) ) ) nfeeth ntutongl(4 nes76 4 8 5 5 8 9 8 2 5 2 6oitm / hop mit ean.6.6.6.6.6.6.6n gikcm or alm ahbae(6(1(7(0(6(5(evh(alieftutaCmoM.2.5.4.2.3.34 .6ret s rrenaper%rfS9 L4- 6 3 - 1 3 - 8 5 - 9 4 - 4 3 - 4 3 - nino ,eoifnwp sio c ptd utaoiteuitrev n alacie 1 7 8 1 4 vdaeula anv psiïailbro -obul58 70 70 94 3e6nf eimeitnesht n-elecacalv- .0.7.0.1.7 leup 0 0 0 0 0sa coscoh siw debvabunep ber / d sto mr.sgdenonameu o z defvfidbi) ) )ni2 ))dtiitpiileen 3 8 ita.3 00.12.4 8 nbine citR.) aht1- .70.1oph ovrra0= mfgnuarna)beI ,0,1, ,3 4,serpetnpd 7Soo ehaC.1.21 7. .83 3.rrodiynaA dnsCzlMirS% L55-3-69-4-2- ceet(( cdu,kU / 8( aru .31(6(5(2 htelets7 reeS To2. c-50-8.3.0-2-4.0 htistsetwSITI ea)wo lepfa em Ea ahtt eni eh atleh o S dt trrf()2 ) ) ) ) )1 ) otaDd ansoabht ev eena0.8 19.0 00.6 10.6 10.0.2 0.m.g Adnisit (at eoogne n( ( ( (1(1 1eu kb dailhesM1 4 2 7 6(9(1 VdsiOuM patCaS.7 sinen b L7.-85.-35.-59.-77.-25.-75- Clc .m NniFi m is iaAeC FtC y b ntsenil ) ) )5)1) ) )4)nraeO w O peWuitu asesD aS 45b-(.9.3.6 55.2 8.gnn 6 5(6(.25.96 5(6( ittioiyWhortabdtigpfsatsna( w3 3 4(7(9 1 2foe P M9. .0yunetws7 1.21 017.50. .58 1.01 01b ituptDIo tdnnaaTg n ezocmip moihtdic00tr )) )2)0)6)y 2) ) )lasidniatra4opstnieD.7.5.1.32 .70 .56 .1 nanog pbinonS il(3(3(4(3(3(3(4(er itnis edit rp o pesna 5 ae4.8 4 5 5 8 4enwesviuurB M 53.1 61.1 51.1 64.1 53.1 61.1 51a rm lct n b aetoti atzl na5tsdnit.Ikiciae9ety 3 3 2 2 3 3 desMeeRofiln 2 3 3 8 6 0 2el eyw tn putreb tDIMPDIDIMh dP msorewdc e)etaezigi asfBgQgTgBgQ c tfwu g daptm Ao7 m0 m0 m0 m0 metdeia0 uetvemieso cit.sd isnaSS 0 4 0)0 0)pcer r siyr Ibi46 0 bi34bi4bi46 bi3millla eeociwtalts asnaaw n nitn = i n n n =cdeateetin utN rb)ur )( itititN o 2( ht1ur )ur )ur )of atoa av Dm dgitvn iteit]a5a9oitz3b7 li=az3b kb4 li=ecaleeaz3b li=a5 z3b li=a7b z3eli=ch alc:denpiaetdisrcpironicp 4clsisese2 u n 0 d RN(RN(P W RN(RN(RN(PaE N b m Ded O0[erAttorney Docket No.01183-0291-00PCT-PRN e b ulob 9 7 8 3 0 9 3 0 6 4 9 0 a.vs0 - vec0 6 .02 1 .02 2 .30 2 .04 8 .03 5 .30 7 .07 8 .06 8 .13 7 .02 7 .46 .6Palp 0 , 0 , 0 , 0 , 0 , 0 , 0 , 0 , 0 , 0 , 0 0 bia 6 9 0 2 2 3 1 1 9, ,o 2 3 0 2 4 0 1 1 4 15 7 2 %5rnitbe 0. )91. )56. )87. )70. )96. )94. )49. )67. )00. )7 5. )8 4. )9ofuc291106 101103 170 0 130906 ()I ral( 8.(.( ( 8.( ( ( (1(7(3(7(4 R b Cazlp1 .s56104291 2 9.74 673163.7773.44 73.3981.460.84 7.376.731.13 4 1 7 7 7 4 3p e(6(4(3(2 6(5(3(2(6 5 4 3 6 5 4 4 s n 22 71 2( ( ( ( ( ( ( ( (1 8 32 81 41 01 32 81 71 11 42 81 71 5 R 1 e b ulob 20 08 12 31 94 67 11 94 8 9 7 9 a.vs-vec0 al .01 0.02 0.20 3 0 0 5 85 39 22 77 0.00.00.3.0.0.1.0.6.8P p 0 0 0 0 0 0 0 )Ibia,9, , , , , , , , , , ,C no 6)22 68 60)37 43 17 18 66 57 12 03 %itb.3.2) .6) .8.0) .6) .6) ) ) ) ) )5re9oc14 3 9 01 1 6 80.99.78.80.51.41 (furbal2(.41(10 a7 (1 1 1 0(.6 (60 7(5 1 0 3(.1 (10 1(1 0 6(10 3(10 0(9 6z p8 . 272.5.2 16 85 5 723.2.0 19 66 4 101.1.5.2.6.15 68 4 555 37 2 Rl s .4.2.8.7.6.6.1.4.8.1.2.0Oirv 6 3 1 4 2 1 4 2 1 2 1 1 r ofbi , , , , , , , , ,)no itba)I8,.4)5)6 .4)0,.4)0)8 .6)3,.7)6)6 .2)0 .9)1 .3)9 .9)%urecC2294..158 .47- 2 .85106..326 .69- 0 .75153.046- 12- 46694 ( Dbalap%(2(.53.6.55( (47.23(9.65.64(.9 (.640.13(3.85.52(.149.8(.538.01- 4(.571- 2(.432 Rzl sv9(2 52 2 3 1 5 2 1 1 1 7 2 51 81.6.7Rir4 3 3 5 1 dreet- d) ).4) ) ) ) ) ) ) )unn% 0 2 0 0 0.94 0.52.4.5.3.8.6.0poo( ( (0 2 0 2 7 9 2 5 npsn 1 2(1( ( ( ( ( (mIer1 1 3 4 1 2 re ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) )-)nd on1.2.8.5.7.3.5.0.3.3.6 5 7 3 6 5o% 4 ( 3 1 5 7 1 6 0 0 9 6.2.7.1.6.2.2 ( 5(6(7(3(4(6(7(2(4 5 6 3 4 5 5 Npse n r 4 12 5( ( ( ( ( ( (1 2 13 31 91 32 82 21 91 02 72 31 91 02 12 red) ).9).8).2) ).3).7).5).0).7).7) ) ) ) ) )n 5 8 45.8 3 9 0 0 3.47.52.38.73.4.5o% p 6 4 3 2 6 5 3 3 7 5 7 7 se(n(7( (2( ( (4 3 6 5 4 4 2 02 3(1 9 82 22 5(1 2(1 9(2 2(2 8(1 3(1 8(2(8(9 R 2 2 1 1 g g g g g g g g g g g g m0 m 0 0 m0 m0 m0 m0 m0 m0 m0 m0 m0 m0 4 0 4 0 4)0 0 4 0 4 0 4)0 0 4 0 4 0)0 0 0 0)0 bin)bi )it14nit1bi )84=bi )bi )4nit3N nit14nit1bi )84=bi )bi )4)44 44nit3N nit14nit1bi8=bi )bi )4bi )84= 4nit3N nit14nit14ni3N ur= b 1aNur= Nu= r N((our=ur= Nu= r N(our=ur= Nu= r N(our=ur=t=(NurNo z(baz(bab bNb zecaz( az(ba (bebNb ca ( a (ba (bebNb ca ( a (ba (beckliDliDIliMP2 liDliDI zliMP3zliDzliDI zliMP4zliDzliDI zliMP eeRIT R B R QalP keeRIT R B R QalP kIaelkIaleR T R B R Q PeeR T R B R Q P W W W WAttorney Docket No.01183-0291-00PCT-PRN e b ulo a.vsb 99 8 2 6 3 9 5 2 6 0 9 1 5 74 79 55 95 3 8 4 4 7 9 1 - vec .0.5.5.3.56 .84 .09 .33 .77 .15 .21 .7Palp 0 , 0 , 0 0 0 0 0 0 0 0 0 0 bia 1 5,0,1,0,7, , , , , ,o 5 2 2 1 2 2 59 68 76 03 17 9 %5rnitbe 9. )45. )03. )86. )85. )04. )39. )45. )14. )27. )16. )3 83. )9ofur c050903 090807 000106 0005000t . . . . .al rv 2 1 0 1 1 1.2.1.1.1.1 bioa, , , , , , , , , , ,0,u)p nb)o%itec I5 1. )0 42. )6 7.78 9)5.32)2 73. )9 45. )0 9 50. )9.52)0 29. )0 3 4. ) .09 0) .57)P(rurC 0-56722 1-06406191-083 97- 1 61- 628eDofbal(.1- . - .(.1- .2- .(.(.1- .(.( 3. -8.vïR ap.%57.54(03(7 .31.353(03(425.5 34.233(621.93.773(8 .41 a Rzl s923.11.0.00.6 3N-irv(2 76- 1 7 2 2 1 4 1 14-badreemt- d) )7. )7. )4. ) ) ) ) ) ) ) ) ) )3.4. )78.9.3. )72.1.0. )69.1.uunn zpoo%(5 5 5 8 1.1 5 01 31 4.1 5 61 11 0.2 8 81 11ilmnpsn(2(2(2(3( (4 2(4(5( (5 2(6( ( (3( (aIer4 7 7 4mre) )n6)9)8)0)9)6)1)6)4) ) ) ) ) ) )O- d.ono% 8.2.6.0.2.8.4.5.17.54.16.3.1.1.0.( 2(4(5(5(4(4(5(5(3(4 5 4 7 4 0 ( 5 5 3 3 5 5 Npse n r 0 5 1 8 5 7 0 ...

Claims

Attorney Docket No.01183-0291-00PCT-PRN What is claimed is:

1. A method of treating chronic spontaneous urticaria (CSU) in a human patient in needthereof, comprising administering to the human patient in need thereof a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4- amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof.

2. The method of claim 1, wherein the human patient has moderate-to-severe CSU.

3. The method of claim 1 or 2, wherein the human patient has moderate CSU.

4. The method of claim 1 or 2, wherein the human patient has severe CSU.

5. The method of any one of the preceding claims, wherein the human patient has CSUrefractory to H1 antihistamine (H1-AH) treatment.

6. The method of any one of claims 1-5, wherein the human patient has Type Iautoimmune CSU.

7. The method of any one of claims 1-5, wherein the human patient has Type IIbautoimmune CSU.

8. The method of any one of the preceding claims, wherein the human patient hasangioedema.

9. The method of any one of the preceding claims, wherein the human patient achieves aUrticaria Activity Score (UAS7) that is lower than baseline UAS7.

10. The method of any one of the preceding claims, wherein the human patient achieves aUAS7 that is lower than baseline UAS7 within 52 weeks of initiating rilzabrutinibAttorney Docket No.01183-0291-00PCT-PRN treatment.

11. The method of any one of the preceding claims, wherein the human patient achieves aUAS7 that is lower than baseline UAS7 within 24 weeks of initiating rilzabrutinib treatment.

12. The method of any one of the preceding claims, wherein the human patient achieves aUAS7 that is lower than baseline UAS7 within 12 weeks of initiating rilzabrutinib treatment.

13. The method of any one of the preceding claims, wherein the human patient achieves aUAS7 that is lower than baseline UAS7 within 4 weeks of initiating rilzabrutinib treatment.

14. The method of any one of the preceding claims, wherein the human patient achieves aUAS7 ≤6.

15. The method of any one of the preceding claims, wherein the human patient achieves aUAS7 ≤6 within 12 weeks of initiating rilzabrutinib treatment.

16. The method of any one of the preceding claims, wherein the human patient achieves aUAS7 of 0.

17. The method of any one of the preceding claims, wherein the human patient achieves aUAS7 of 0 within 12 weeks of initiating rilzabrutinib treatment.

18. The method of any one of the preceding claims, wherein the human patient achieves aUAS7 that is at least 10 points lower than baseline UAS7.

19. The method of any one of the preceding claims, wherein the human patient achievesan Itch Severity Score (ISS7) that is lower than baseline ISS7.Attorney Docket No.01183-0291-00PCT-PRN20. The method of any one of the preceding claims, wherein the human patient achievesan ISS7 that is lower than baseline ISS7 within 52 weeks of initiating rilzabrutinib treatment.

21. The method of any one of the preceding claims, wherein the human patient achievesan ISS7 that is lower than baseline ISS7 within 24 weeks of initiating rilzabrutinib treatment.

22. The method of any one of the preceding claims, wherein the human patient achievesan ISS7 that is lower than baseline ISS7 within 12 weeks of initiating rilzabrutinib treatment.

23. The method of any one of the preceding claims, wherein the human patient achievesan ISS7 that is at least 5 points lower than baseline ISS7.

24. The method of any one of the preceding claims, wherein the human patient achieves aHives Severity Score (HSS7) that is lower than baseline HSS7.

25. The method of any one of the preceding claims, wherein the human patient achieves aHSS7 that is lower than baseline HSS7 within 52 weeks of initiating rilzabrutinib treatment.

26. The method of any one of the preceding claims, wherein the human patient achieves aHSS7 that is lower than baseline HSS7 within 24 weeks of initiating rilzabrutinib treatment.

27. The method of any one of the preceding claims, wherein the human patient achieves aHSS7 that is lower than baseline HSS7 within 12 weeks of initiating rilzabrutinib treatment.Attorney Docket No.01183-0291-00PCT-PRN28. The method of any one of the preceding claims, wherein the human patient achievesan Angioedema Activity Score (AAS7) that is lower than baseline AAS7.

29. The method of any one of the preceding claims, wherein the human patient achievesan AAS7 that is lower than baseline AAS7 within 52 weeks of initiating rilzabrutinib treatment.

30. The method of any one of the preceding claims, wherein the human patient achievesan AAS7 that is lower than baseline AAS7 within 24 weeks of initiating rilzabrutinib treatment.

31. The method of any one of the preceding claims, wherein the human patient achievesan AAS7 that is lower than baseline AAS7 within 12 weeks of initiating rilzabrutinib treatment.

32. The method of any one of the preceding claims, wherein the human patient achieves aUrticaria Control Test (UCT) score that is higher than baseline UCT score.

33. The method of any one of the preceding claims, wherein the human patient achieves aUCT score that is higher than baseline UCT score within 52 weeks of initiating rilzabrutinib treatment.

34. The method of any one of the preceding claims, wherein the human patient achieves aUCT score that is higher than baseline UCT score within 24 weeks of initiating rilzabrutinib treatment.

35. The method of any one of the preceding claims, wherein the human patient achieves aUCT score that is higher than baseline UCT score within 12 weeks of initiating rilzabrutinib treatment.

36. The method of any one of the preceding claims, wherein the human patient achieves aUCT score that is higher than baseline UCT score within 8 weeks of initiatingAttorney Docket No.01183-0291-00PCT-PRN rilzabrutinib treatment.

37. The method of any one of the preceding claims, wherein the human patient achieves aUCT score that is higher than baseline UCT score within 4 weeks of initiating rilzabrutinib treatment.

38. The method of any one of the preceding claims, wherein the human patient achieves aUCT score ≥12.

39. The method of any one of the preceding claims, wherein the human patient achieves aUCT score ≥12 within 12 weeks of initiating rilzabrutinib treatment.

40. The method of any one of the preceding claims, wherein the human patient achieves aUCT score ≥12 within 8 weeks of initiating rilzabrutinib treatment.

41. The method of any one of the preceding claims, wherein the human patient achieves aUCT score ≥12 within 4 weeks of initiating rilzabrutinib treatment.

42. The method of any one of the preceding claims, wherein the human patient achieves achange from baseline in health-related quality-of-life (HRQoL).

43. The method of any one of the preceding claims, wherein the human patient achieves achange from baseline in HRQoL as measured by the Patient Global Impression of Severity (PGIS).

44. The method of any one of the preceding claims, wherein the human patient achieves achange from baseline in HRQoL as measured by the PGIS within 12 weeks of initiating rilzabrutinib treatment.

45. The method of any one of the preceding claims, wherein the human patient achieves achange from baseline in HRQoL as measured by the PGIS within 8 weeks of initiating rilzabrutinib treatment.Attorney Docket No.01183-0291-00PCT-PRN46. The method of any one of the preceding claims, wherein the human patient achieves achange from baseline in HRQoL as measured by the PGIS within 4 weeks of initiating rilzabrutinib treatment.

47. The method of any one of the preceding claims, wherein the human patient achieves achange from baseline in HRQoL as measured by the PGIS within 2 weeks of initiating rilzabrutinib treatment.

48. The method of any one of the preceding claims, wherein the human patient achieves achange from baseline in HRQoL as measured by the PGIC.

49. The method of any one of the preceding claims, wherein the human patient achieves achange from baseline in HRQoL as measured by the PGIC within 12 weeks of initiating rilzabrutinib treatment.

50. The method of any one of the preceding claims, wherein the human patient achieves achange from baseline in HRQoL as measured by the PGIC within 8 weeks of initiating rilzabrutinib treatment.

51. The method of any one of the preceding claims, wherein the human patient achieves achange from baseline in HRQoL as measured by the PGIC within 4 weeks of initiating rilzabrutinib treatment.

52. The method of any one of the preceding claims, wherein the human patient achieves achange from baseline in HRQoL as measured by the PGIC within 2 weeks of initiating rilzabrutinib treatment.

53. The method of any one of the preceding claims, wherein the human patient requiresrescue therapy.Attorney Docket No.01183-0291-00PCT-PRN54. The method of claim 53, wherein the total number of days for which the humanpatient requires rescue therapy is lower than the total number of days for which the human patient required rescue therapy during a baseline time period of the same length.

55. The method of any one of the preceding claims, wherein the human patient has ahistory of taking omalizumab prior to the start of the treatment period.

56. The method of any one of the preceding claims, wherein the human patient has had anincomplete response to omalizumab.

57. The method of any one of claims 1-55, wherein the human patient is omalizumabnaïve.

58. The method of any one of the preceding claims, wherein the human patient has apositive basophil histamine release assay (BHRA) status.

59. The method of any one of the preceding claims, wherein the human patient receivesconcomitant treatment with an H1-AH.

60. A method of treating chronic spontaneous urticaria (CSU) in a human patient in needthereof, comprising administering to the human patient a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4- phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4- [4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment.

61. The method of any one of the preceding claims, wherein the treatment period is atleast 12 weeks.Attorney Docket No.01183-0291-00PCT-PRN62. The method of any one of the preceding claims, wherein the treatment period is atleast 52 weeks.

63. The method of any one of the preceding claims, wherein the at least one compoundconsists of at least one compound chosen from the (E) isomer of rilzabrutinib and pharmaceutically acceptable salts thereof.

64. The method of any one of claims 1-62, wherein the at least one compound consists ofat least one compound chosen from the (Z) isomer of rilzabrutinib and pharmaceutically acceptable salts thereof.

65. The method of any one of claims 1-62, wherein the at least one compound consists ofa mixture of (E) and (Z) isomers of rilzabrutinib or a pharmaceutically acceptable salt of the foregoing.

66. The method of any one of the preceding claims, comprising administering to thehuman patient rilzabrutinib once, twice, or thrice a day.

67. The method of any one of the preceding claims, comprising administering to thehuman patient 400 mg of rilzabrutinib once, twice, or thrice a day.

68. The method of any one of the preceding claims, comprising administering to thehuman patient 400 mg of rilzabrutinib once a day.

69. The method of any one of claims 1-67, comprising administering to the human patient400 mg of rilzabrutinib twice a day.

70. The method of any one of claims 1-67, comprising administering to the human patient400 mg of rilzabrutinib thrice a day.

71. The method of any one of claims 1-63 and 66-70 wherein the at least one compoundis the (E) isomer of rilzabrutinib.Attorney Docket No.01183-0291-00PCT-PRN72. The method of any one of claims 1-62, 64, and 66-70, wherein the at least onecompound is the (Z) isomer of rilzabrutinib.

73. The method of any one of claims 1-62 and 65-70, wherein the at least one compoundconsists of a mixture of (E) and (Z) isomers of rilzabrutinib.

74. The method of any one of the preceding claims, wherein the at least one compound isorally administered to the human patient.

75. The method of any one of the preceding claims, wherein the at least one compound isadministered to the human patient in the form of at least one tablet.

76. The method of any one of the preceding claims, wherein the at least one compound isadministered with water.

77. The method of any one of claims 1-65 and 74-76, wherein the at least one compoundis rilzabrutinib.

78. A therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for use in treating chronic spontaneous urticaria (CSU) in a human patient in need thereof.

79. A therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for use in the manufacture of a medicament for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof.Attorney Docket No.01183-0291-00PCT-PRN80. Use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof.

81. Use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof.

82. A therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for use in treating chronic spontaneous urticaria (CSU) in a human patient in need thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment.

83. A therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for use in the manufacture of a medicament for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment.

84. Use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, for treating chronicAttorney Docket No.01183-0291-00PCT-PRN spontaneous urticaria (CSU) in a human patient in need thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment.

85. Use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating chronic spontaneous urticaria (CSU) in a human patient in need thereof, wherein the human patient in need thereof has CSU refractory to H1 antihistamines (H1-AH) treatment.

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