MÉTODO PARA TRATAR ECZEMA CRÔNICO DAS MÃOS MODERADO A SEVERO EM UM PACIENTE HUMANO

Abstract

A method of treating moderate to severe chronic hand eczema in a human patient comprising twice daily administration to the skin of said human patient in need thereof of an acidified aqueous topical composition comprising comprises 20 mg / g delgocitinib on a free base basis or a pharmaceutically acceptable salt.

Description

106 USE OF AN ACIDIFIED AQUEOUS TOPICAL COMPOSITION

[001] The present invention relates to a method for treating chronic eczema of the hands in a human patient comprising administering to the skin of said human patient an acidified aqueous topical formulation comprising delgocitinib. Fundamentals

[002] Chronic hand eczema (CHE) is a serious inflammatory skin disorder located anywhere on the hands or wrists. It is clinically distinguished by erythema, infiltration, hyperkeratosis, edema, and vesicles. Secondary signs include scaling, cracking, and erosions, and the condition can be exacerbated by bacterial infections. Important symptoms include itching and pain, and the disease is often distinguished by chronic recurrences and a poor prognosis.

[003] CHE refers to eczema on the hands that persists for more than months or recurs two or more times within 12 months.

[004] Hand eczema is usually multifactorial and it is generally agreed that no simple relationship exists between clinical patterns and etiological diagnoses (J Eur Acad Dermatol Venereol. 2015;29(12):2417-2422).

[005] Several different classifications have been proposed (Diepgen et al., J Dtsch Dermatol Ges. 2015;13(1):e1-22, Cronin E et al., Contact Dermatitis. 1985;13(3):153-161, Johansen et al. Contact Dermatitis. 2011;65(1):13-21) and the most common subtypes of CHE are found to be irritant contact dermatitis, atopic hand eczema and hyperkeratotic eczema (Apfelbacher et al. Acta Derm Venereol. 2014;94(2):163-167).

[006] Other subtypes include allergic contact dermatitis, contact urticaria / protein contact dermatitis, and recurrent vesicular eczema of the hands (dyshidrosis). Petition 870250111574, dated 04 / 12 / 2025, page 6 / 220 / 106

[007] Reported prevalence and incidence rates of hand eczema vary considerably depending on the methodology used in data collection. In a review of available data from 1964 to 2007, the point prevalence of hand eczema in the general population was approximately 4%, the 1-year prevalence was about 10%, and the lifetime prevalence approached 15%, with approximately 7 to 10% of patients with hand eczema reporting symptoms 'almost all the time', implying a chronic disease state. Based on data from 7 studies, the incidence rate of hand eczema was 5.5 cases / 1000 person-years with a higher average incidence rate among women (Diepgen et al., J Dtsch Dermatol Ges. 2015;13(1):e122). Severe risk factors, such as pre-existing AD, female sex, work with water, and contact allergy have been identified (Thyssen et al., Contact Dermatitis. 2010;62(2):75-87, Mortz et al., Br J Dermatol. 2014;171(2):313-323).

[008] The prevalence of hand eczema differs across age groups (6) with a median first onset in the early or mid-20s (Anveden et al., Contact Dermatitis. 2006;54(5):272-277, Hald et al., Br J Dermatol. 2008;158(4):773-777, Lind et al., Occup Environ Med. 2007;64(3):191-195). However, approximately one third of men and women report their first hand eczema before the age of 20 (Meding B et al., J Invest Dermatol. 2004;122(4):873-877).

[009] Although the molecular mechanisms underlying CHL are not fully understood, a large panel of cytokine-mediated signaling cascades has been identified as part of the pathophysiology, including the Th2 pathway (IL-4, IL-13), Th22 pathway (IL-22), Th17 pathway (IL-17), Th1 pathway (interferon-γ), and the JAK / STAT pathway representing cytokine responses. Since JAK proteins are required for the signaling of most cytokines, blocking JAKs reduces cytokine signaling and thus reverses the vicious cycle that leads to the development of CHL Petition 870250111574, dated 12 / 04 / 2025, p. 7 / 220 / 106 (Pedersen et al., J Invest Dermatol. 2007;127(11):2585-2595, Brunner et al., J Allergy Clin Immunol. 2017;139(45):565S76, Gittler et al., Journal of Allergy and Clinical Immunology. 2013;131(2):300-313).

[0010] CHE is generally difficult to treat and presents with periods of exacerbation and periods of remission.

[0011] Treatment of hand eczema involves different disease control strategies such as trigger elimination, general skin care, and anti-inflammatory therapy in a step-by-step approach. General skin care in terms of emollients is widely used and recommended by physicians, but evidence of effectiveness is scarce. Elimination of triggers such as allergens and irritants can be effective and a necessary prerequisite for successful therapy over a longer duration, but elimination can in many circumstances be difficult to achieve. Although there is no documented treatment effect, TCS remains the mainstay of topical anti-inflammatory therapy for hand eczema. However, long-term use of TCS is restricted due to side effects such as skin atrophy and potential inhibition of skin barrier repair.

[0012] Considering that mild CH, to some extent, can be controlled by eliminating triggers and general skin care, the control of moderate to severe CH is more complicated. Alitretinoin is the only approved product specifically indicated for the treatment of CH, but it is only indicated for severe CH and approved only in some countries worldwide. Treatment with alitretinoin has several safety limitations and is therefore indicated only for use in adults who have severe CH that is unresponsive to treatment with potent TCS.

[0013] Considering the lack of approved therapies for the treatment of CHE, other therapeutic options are limited to those approved for other skin diseases with an inflammatory pathophysiology. These treatments Petition 870250111574, dated 04 / 12 / 2025, page 8 / 220 / 106 applied lack clinical documentation for use in CHE and are restricted to short-term use which is not suitable in a chronic disorder distinguished by recurrent traits frequently resulting in exposure to long-term treatment.

[0014] Given that currently available treatment options lack documented treatment effect or are limited by restrictions on long-term use due to safety concerns, there is a high unmet medical need for novel topical treatments for moderate to severe CH that are highly effective in combination with a good safety profile, especially for long-term use. New and improved treatments could potentially improve the daily lives of patients with moderate to severe CH. Delgocitinib has the potential to address the unmet medical need associated with this serious disease.

[0015] Delgocitinib is described in WO2011013785 and has the general formula and is suitably prepared by one of the methods described in WO2018117152.

[0016] Delgocitinib is a pan-JAK inhibitor that blocks several cytokine-mediated signaling pathways and broadly suppresses the activation of immune and inflammatory cells such as T cells, B cells, mastoids, and monocytes activated by these cytokines.

[0017] The efficacy and safety of delgocitinib in mild to severe HCE was demonstrated in a phase 2a trial with delgocitinib 30 mg / g and in a phase 2b dose-ranging trial with delgocitinib (1, 3, 8 and 20 Petition 870250111574, dated 04 / 12 / 2025, p. 9 / 220 / 106 mg / g) (Worm et al., British Journal of Dermatology (2022), 187, p-42-51 and British Journal of Dermatology (May 2020, 185, (5), 1103-1110).

[0018] There is a clear unmet need for new long-term treatment options in the treatment of patients suffering from moderate to severe CH.

[0019] It has now been verified that the acidified aqueous composition comprising delgocitinib has a significant effect in patients suffering from moderate to severe chronic hand eczema (CHE). Summary of the Invention

[0020] The present invention relates to a method for treating moderate to severe chronic hand eczema in a human patient in need thereof comprising administering twice daily to the skin of said human patient, an acidified aqueous topical composition comprising 20 mg / g of delgocitinib in a pharmaceutically acceptable freebase or salt thereof, wherein the patient has disease severity graded as moderate to severe at screening and baseline according to the IGA-CHE (i.e., an IGA-CHE score of 3 or 4).

[0021] In another aspect, the invention relates to said acidified aqueous topical composition for use in a method for treating moderate to severe chronic eczema of the hands. Detailed Description of the Invention Figures:

[0022] Figure 1: IGA-CHE TS respondents from week 0 to 16. a) IGA-CHE TS at the visit, b) TS defined as an IGA-CHE score of 0 (clear) or 1 (almost clear) with a 2-step improvement from baseline.

[0023] Figure 2A: HECSI75 as a percentage of responders from week 0 to week 16.

[0024] Figure 2B: HECSI90 and DLQI > 4 as a percentage of Petition 870250111574, dated 04 / 12 / 2025, page 10 / 220 / 106 respondents from week 0 to week 16.

[0025] Figure 2C: HECSI75, HECSI90 and DLQI > 4 as percentage of responders in week 16.

[0026] Figure 3. Change in HESD pain score (weekly average) from baseline to week 16 in DELTA 1 and DELTA 2 (complete analysis set, WOCF). The HESD pain score was reported daily by study participants and ranges from 0 ('no symptoms') to 10 ('severe symptoms').

[0027] Figure 4A: Proportion of patients achieving a > 4-point reduction in HESD pain (HESD pain reduction > 4 points) from baseline to week 16 among study participants with a corresponding baseline HESD pain score (weekly average) of > 4 points in DELTA 1 and DELTA 2 (complete analysis set, NRI).

[0028] Figure 4B: Proportion of patients achieving a > 4-point reduction in HESD itching (HESD itching reduction > 4 points) from baseline to week 16 among study participants with a corresponding baseline HESD itching score (weekly average) of > 4 points in DELTA 1 and DELTA 2 (complete analysis set, NRI). HESD itch and pain scores were reported daily by study participants and ranged from 0 ('no symptoms') to 10 ('severe symptoms').

[0029] Figure 5. Change in HESD itch score (weekly mean) from baseline to week 16 in DELTA 1 and DELTA 2 (complete analysis set, WOCF). The HESD itch score was reported daily by study participants and ranges from 0 ('no symptoms') to 10 ('severe symptoms').

[0030] Figure 6. Summary of adverse events in DELTA 1 and DELTA 2 (safety analysis set). AEs with onset date on or after the date of the first application of study treatment or with a Petition 870250111574, dated 04 / 12 / 2025, page 11 / 220 / 106. Information regarding worsening severity after the first application of the study treatment is included. The classification is in accordance with MedDRA version 24.0.aInformation on exacerbation or worsening of CH that exceeded normal fluctuation or appeared in areas not normally affected by CH.

[0031] Figure 7. Results and action taken with the study drug following the occurrence of adverse events in DELTA 1 and DELTA 2 (safety analysis set).

[0032] Figure 8. Individual and mean relative effect (% of positive control) of ointment and cream application to human skin explants (NativeSkin) 24 hours after treatment. Different colors represent the different donors for each treatment.

[0033] Figure 9. Open-flow microperfusion probe inserted into the dermis.

[0034] Figure 10. Changes from baseline in EQ-5D at week 16 in all patients and by response to treatment as assessed by HECSI, IGA-CHE, and HEDS itch and pain scores.

[0035] Figure 11. Changes from baseline in DLGQI at week 16 in all patients and by response to treatment as assessed by HECSI, IGE-CHE, and HEDS itch and pain scores.

[0036] Figure 12. Proportion of patients who achieved improvement > 4 points in HESD itching and improvement > 4 points in HESD pain over time - pooled data from DELTA 1 and DELTA 2. *Statistically significant versus vehicle with multiplicity adjustment **Statistically significant versus vehicle without multiplicity adjustment

[0037] Based on the number of patients whose baseline value was > 4 (scale of 0 to 10). Abbreviations

[0038] AE = adverse event; Petition 870250111574, dated 04 / 12 / 2025, page 12 / 220 / 106 CH = chronic hand eczema; cDLQI = Child Dermatology Life Quality Index; HECSI = Hand Eczema Severity Index; HECSI-75 = at least a 75% improvement in the HECSI score from baseline. HECSI-90 = at least a 90% improvement in HECSI score from baseline; HESD = Hand Eczema Daily Symptom©.

[0039] IE = intercurrent event; IGA-CHE = Researcher Global Assessment for chronic hand eczema; IGA-CHE TS = Treatment success on the IGA-CHE scale, i.e., an IGA-CHE score of 0 (clear) or 1 (almost clear) with an improvement > 2 steps from baseline; TS = treatment success.

[0040] DLQI = Dermatology Life Quality Index; EQ-5D-5L = EuroQol Level 5 5-Dimensional Health Questionnaire; HEIS = Hand Eczema Impact Scale; PDAL = Limitations of Nearby Daily Activities WPAI:CHE = Work Productivity and Activity Deterioration: Chronic Hand Eczema.

[0041] cDLQI = Child Dermatology Life Quality Index; AS = area score; SS = severity score; CI, confidence interval; LS, least squares; SE, standard error; WOCF, observation of worsening carried forward; Petition 870250111574, dated 04 / 12 / 2025, page 13 / 220 / 106 NRI, non-respondent charge; And, number of events; N, number of patients in the analysis set; n, number of patients under observation; PYO, patient observation years; R, rate calculated as (E / PYO)*100.

[0042] As used here in connection with a value or quantity approximately means ± 10% of the value or quantity. IGA-CHE Efficacy Measurements

[0043] The IGA-CHE classifies the severity of the subject's overall disease and is based on a 5-point scale ranging from 0 (mild) to 4 (severe) (Table 1). The assessment will be based on the disease condition at the time of evaluation and not on the condition at a previous visit. New lesions occurring in previously untreated areas will be included in the assessment. Table 1 IGA-CHE Severity IGA-CHE Score Sign and Intensity Clear 0 No signs of erythema, scaling, hyperkeratosis / lichenification, vesiculation, edema, or fissures Almost clear 1 Slightly perceptible erythema No signs of scaling, hyperkeratosis / lichenification, vesiculation, edema, or fissures Mild 2 At least one: • Mild but defined erythema (pink) • Mild but defined scaling (mostly fine scales) • Mild but defined hyperkeratosis / lichenification and at least one: • Scattered vesicles, without erosion • Slightly palpable edema • Superficial fissures Moderate 3 At least one: • Clearly perceptible erythema (dark red) • Clearly perceptible scaling (thick scales) • Clearly perceptible hyperkeratosis / lichenification and at least one: • Clustered vesicles, without visible erosion • Defined edema • Fissures defined Petition 870250111574, dated 04 / 12 / 2025, page 14 / 220 / 106 Severity of IGA-CHE IGA-CHE Score Sign and intensity Severe 4 At least one: • Marked erythema (deep or bright red) • Marked and thick scaling • Marked hyperkeratosis / lichenification and at least one: • High density of vesicles with erosions • Marked edema • One or more deep fissures Hand Eczema Severity Index (HECSI)

[0044] The HECSI is an instrument used in clinical trials to classify the severity of 6 clinical signs (erythema, infiltration / papulation, vesicles, fissures, scaling, and edema) and the degree of lesions in each of the 5 regions of the hand (fingertips, fingers [except fingertips], palms, backs of hands, and wrists) using standard scales (Held et al., Br J Dermatol. 2005;152(2):302-307).

[0045] For each hand region (total of both hands, e.g., 10 fingers), the researcher rates the average severity of each of the 6 clinical signs of hand eczema using a 4-point severity scale ranging from 0 (none / absent) to 3 (severe) (Table 2). The researcher also rates the degree of lesions by assessing the percentage of hand regions occupied by these lesions and converting them to a score based on a 5-point scale (the area score) (Table 2). For each hand region, the region score will be calculated by summing the severity scores for the 6 clinical signs of hand eczema and multiplying by the area score (Table 3). The HECSI score is equal to the sum of the region scores and will range from 0 (lowest possible score) to 360 (highest possible score).

[0046] The assessment will be based on the disease status at the time of the assessment and not on the status at a previous visit. New CHE lesions that occur in previously untreated areas will be included in the assessment. Table 2: HECSI severity scoring scale and scoring scale Petition 870250111574, dated 04 / 12 / 2025, page 15 / 220 / 106 area Severity Score Scale (SS) (based on both hands) Area Score Scale (AS) (based on the affected area of ​​both hands) 0 None / Absent 0 0% of the area affected 1 Mild 1 1% to 25% of the area affected 2 Moderate 2 26% to 50% of the area affected 3 Severe 3 51% to 75% of the area affected 4 76% to 100% of the area affected Table 3: Calculation of the total HECSI score. Hand Region Erythema Infiltration / papulation Vesicles Fissures Scaling Edema Area Score Fingertips (SS + +SS +SS +SS +SS +SS SS) x AS Fingers (except fingertips) (SS + SS + SS + SS + SS + SS) x AS Palms (SS + +SS +SS +SS +SS +SS SS) x AS Backs of hands (SS + +SS +SS +SS +SS +SS SS) x AS Wrists (SS + +SS +SS +SS +SS +SS SS) x AS The total HECSI score is equal to the sum of the 5 scores from the region above: (range 0360) Patient-reported results (effectiveness)

[0047] PRO HESD is considered an efficacy assessment. Daily Symptom of Hand Eczema (HESD)

[0048] The HESD is a 6-item PRO instrument designed to assess the severity of signs and symptoms of CH. Subjects will rate the worst severity of 6 individual signs and symptoms of CH (itching, pain, cracking, redness, dryness, and flocculation) in the past 24 hours using an 11-point numerical rating scale with anchors of 0 = 'none (symptom)' and 10 = 'severe (symptom)'. The HESD score is derived as an average of the 6 items. Safety assessments Patient-reported outcomes (health-related quality of life and work productivity) Patient Global Impression of Severity (PGI-S) Questionnaires

[0049] The PGI-S is a 1-item questionnaire designed to assess the subject's overall perception of their signs and symptoms of itching, pain, or Petition 870250111574, dated 04 / 12 / 2025, page 16 / 220 / 106 chronic eczema of the hands in the past week on a 4-point categorical response scale ('none', 'mild', 'moderate' or 'severe'), Table 4. Table 4: Patient Global Impression of Severity (PGIS) Questionnaires PGI-S Itching PGI-S Pain PGI-S HESD Please choose the answer below that best describes the severity of any itching on your hands in the past week Please choose the answer below that best describes the severity of any pain in your hands in the past week Please choose the answer below that best describes the severity of your signs and symptoms of hand eczema in the past week Response score: □ None □ Mild □ Moderate □ Severe Response score: □ None □ Mild □ Moderate □ Severe Response score: □ None □ Mild □ Moderate □ Severe Patient Global Impression of Change (PGI-C) Questionnaires

[0050] The PGI-C is a 1-item questionnaire designed to assess the subject's impression of changes (38). From 5 response options ('much better', 'somewhat better', 'no change', 'somewhat worse', or 'much worse'), subjects have to select the single response that best describes the overall change in their itching, pain, or signs and symptoms of chronic hand eczema since they started IMP treatment, Table 5. Table 5: Patient Global Impression of Change (PGIC) Questionnaires Itching PGI-C Pain PGI-C HESD PGI-C Please choose the response below that best describes the overall change in any itching on your hands since you started taking the study medication. Please choose the response below that best describes the overall change in any pain in your hands since you started taking the study medication. Please choose the response below that best describes the overall change in your signs and symptoms of hand eczema since you started taking the study medication. Response score: □ Much better □ Somewhat better □ No change □ Somewhat worse □ Much worse Response score: □ Much better □ Somewhat better □ No change □ Somewhat worse □ Much worse Response score: □ Much better □ Somewhat better □ No change □ Somewhat worse □ Much worse Hand Eczema Impact Scale (HEIS)

[0051] HEIS includes 9 items that address the subject's perception of the impact of hand eczema on their daily activities, embarrassment, frustration, sleep, work, and physical functioning in the previous 7 days. Each Petition 870250111574, dated 04 / 12 / 2025, page 17 / 220 / 106. The item is scored on a 5-point scale (0 = 'not at all', 1 = 'somewhat', 2 = 'moderately', 3 = 'quite a lot', 4 = 'extremely'). The HEIS score is the average of the 9 items. The highest possible score is 4, and a high score is indicative of a high impact. 6 domain scores can be calculated for HEIS: PDAL (average of 3 items), embarrassment with the appearance of hands (average of 2 items), frustration with CHE (1 item), sleep (1 item), work (1 item), and physical functioning (1 item). Patient Global Assessment of Disease Severity (PAGA)

[0052] Subjects will make a global assessment of the severity of their hand eczema. The assessment will be made using a 5-point scale (0 = 'mild', 1 = 'almost mild', 2 = 'mild', 3 = 'moderate', 4 = 'severe') and will be based on the severity of their hand eczema at the time of assessment, Table 6. Table 6: Patient Global Assessment of Disease Severity (PAGA) Assess the severity of your hand eczema now. When making your assessment, you should think about the severity of any hand eczema symptoms you currently have, including scaling, blistering, cracking, swelling, redness, or thickening of the skin on your hands. □ Clear (None of the symptoms of hand eczema) □ Almost clear (Only slight redness, no other symptoms of hand eczema) □ Mild □ Moderate □ Severe Dermatology Life Quality Index (DLQI)

[0053] The DLQI is a validated questionnaire with content specific to those with dermatological conditions. It consists of 10 items addressing the subject's perception of the impact of their skin disease on different aspects of their quality of life during the past week, such as symptoms and sensations related to dermatology, daily activities, laser, work or school, personal relationships, and treatment (39). Each item is scored on a 4-point Likert scale (0 = 'not at all / not relevant'; 1 = 'somewhat'; 2 = 'quite a bit'; 3 = 'very'). The DLQI score is the sum of the 10 items (scores ranging from 0 to 30); a high score is indicative of a poor quality of life. Petition 870250111574, dated 04 / 12 / 2025, page 18 / 220 / 106

[0054] The cDLQI is a validated questionnaire with specific content for those with dermatological conditions. It consists of 10 items that address the subject's perception of the impact of their skin disease on different aspects of their quality of life during the past week, such as symptoms and sensations related to dermatology, friendships, laser, school or holidays, adverse comments, sleep, and treatment (35). Each item is scored on a 4-point Likert scale (0 = 'not at all / not relevant'; 1 = 'somewhat'; 2 = 'quite a bit'; 3 = 'very'). The total score is the sum of the 10 items (0 to 30); a high score is indicative of a poor quality of life. EuroQol 5-Dimensional Health Questionnaire Level 5 (EQ-5D-5L)

[0055] The EQ-5D-5L is a standardized measure of health status developed by the EuroQol group to provide a simple, generic measure of health for clinical and economic evaluation (EuroQol-- a new facility for the measurement of health-related quality of life. Health Policy. 1990;16(3):199208).

[0056] The EQ-5D-5L is a self-administered questionnaire used to assess health status 'today' and is divided into 2 sections.

[0057] The first section includes 5 dimensions (mobility, self-care, usual activity, pain / discomfort, and anxiety / depression). Each dimension will be assessed by the subject using a 5-point scale ('no problem', 'mild problems', 'moderate problems', 'severe problems', and 'unable to / extreme problems'). The EQ-5D-5L index score is derived from the 5 dimensions and has been converted from the 5L system to the 3L system using the EQ-5D-5L crossover value set. The index score ranges from 0.594 to 1.0 (based on the UK country-specific value set), with a higher score indicating a better health status.

[0058] The second section consists of a vertical visual analog scale anchored at 0 ('the worst health you can imagine') and 100 ('the Petition 870250111574, dated 04 / 12 / 2025, page 19 / 220 / 106 better health than you can imagine'). Decreased Productivity and Activity at Work: Chronic Eczema of the Hands (WPAI:CHE)

[0059] The impact of CHE on the subject's ability to work and perform regular activities will be assessed by the WPAI:CHE, which is an instrument for measuring decreases in both paid and unpaid work (Reilly et al., Pharmacoeconomics. 1993;4(5):353-365). The WPAI:CHE consists of 6 items and scores can be calculated for 4 domains, each reflecting the percentage decrease due to CHE during the last 7 days, with higher numbers indicating a greater decrease and less productivity: • Absenteeism: percentage of work time lost due to CHE for those who were currently employed.

[0060] • Presenteeism: percentage of decrease in working hours due to CHE for those who were currently employed and actually worked in the last 7 days.

[0061] • Loss of productivity at work: percentage of overall decrease in work due to CHE for those who were currently employed.

[0062] • Decrease in activity: percentage of decrease in activity due to CHE for all respondents.

[0063] The endpoints to be investigated are shown in tables 7 and 8 below. Table 7: Final Points__________________________________________________ Primary endpoint: • IGA-CHE TS in Week 16. Key secondary endpoints: • HECSI-75 in Week 16. • HECSI-75 in Week 8. • HECSI-90 in Week 16. • IGA-CHE TS in Week 8. • IGA-CHE TS in Week 4.________________________________________________________ Key secondary endpoint: • Percentage change in HECSI score from baseline to week 16.______ Key secondary endpoints: • Reduction in HESD itch score (weekly average) of > 4 points from baseline at Week 16. Among subjects with a baseline HESD itch score Petition 870250111574, dated 04 / 12 / 2025, page 20 / 220 / 106 (weekly average) > 4 points. • Reduction in HESD itch score (weekly average) of > 4 points from baseline at Week 8. Among subjects with a baseline HESD itch score (weekly average) > 4 points. • Reduction in HESD itch score (weekly average) of > 4 points from baseline in Week 4. Among subjects with a baseline HESD itch score (weekly average) > 4 points. • Reduction in HESD itch score (weekly average) of > 4 points from baseline in Week 2. Among subjects with a baseline HESD itch score (weekly average) > 4 points. • Reduction in HESD score (weekly average) of > 4 points from baseline at Week 16. Among subjects with a baseline HESD score (weekly average) > 4 points. • Reduction in HESD score (weekly average) of > 4 points from baseline at Week 8. Among subjects with a baseline HESD score (weekly average) > 4 points. • Reduction in HESD score (weekly average) of > 4 points from baseline in Week 4. Among subjects with a baseline HESD score (weekly average) > 4 points. • Reduction in HESD pain score (weekly average) of > 4 points from baseline at Week 16. Among subjects with a baseline HESD pain score (weekly average) > 4 points. • Reduction in HESD pain score (weekly average) of > 4 points from baseline at Week 8. Among subjects with a baseline HESD pain score (weekly average) > 4 points. • Reduction in HESD pain score (weekly average) of > 4 points from baseline in Week 4. Among subjects with a baseline HESD pain score (weekly average) > 4 points. • Reduction in DLQI score of > 4 points from baseline at Week 16. Among subjects with a baseline DLQI score > 4 points______________________________ Key secondary endpoints: • Change in HESD itch score (weekly average) from baseline to week 16. • Change in HESD score (weekly average) from baseline to week 16. • Change in HESD pain score (weekly average) from baseline to week 16. • Change in HESD score from baseline to week 16. • Change in HEIS PDAL score from baseline to week 16. • Change in DLQI score from baseline to week 16. Table 8: Secondary and exploratory endpoints________________________ Secondary endpoint______________________________________________________________________________ • Number of treatment-emergent AEs from baseline to week 16 (Week 18 for non-LTE trial participants) per subject. An event will be considered treatment-emergent if it started after the first IMP application or if it started before the first IMP application and worsened in severity after the first IMP dose.___________________________ Exploratory endpoints__________________________________________________________________________ Efficacy • IGA-CHE TS at Weeks 1, 2, and 12. • HECSI-75 in Weeks 1, 2, 4, and 12. • HECSI-90 in Weeks 1, 2, 4, 8, and 12. • Percentage change in HECSI score from baseline to Weeks 1, 2, 4, 8, and 12. • Reduction in HESD itch score (weekly average) of > 4 points from baseline in Weeks 1 and 12. • Among subjects with a baseline HESD itch score (weekly average) > 4 points. • Reduction in HESD itch score (weekly average) of > 3 points from baseline in Weeks 1, 2, 4, 8, 12, and 16. Among subjects with a baseline HESD itch score (weekly average) > 3 points. • Time to reduction in HESD itch score (weekly average) of > 4 points. Among subjects with a baseline HESD itch score (weekly average) > 4 points. Petition 870250111574, dated 04 / 12 / 2025, page 21 / 220 / 106 • Change in HESD itch score (weekly average) from baseline to Weeks 1, 2, 4, 8 and 12. • Reduction in HESD score (weekly average) of > 4 points from baseline in Weeks 1, 2, and 12. Among subjects with a baseline HESD score (weekly average) > 4 points. • Reduction in HESD score (weekly average) of > 3 points from baseline in Weeks 1, 2, 4, 8, 12, and 16. Among subjects with a baseline HESD score (weekly average) > 3 points. • Time to reduction in HESD score (weekly average) of > 4 points. Among subjects with a baseline HESD score (weekly average) > 4 points. • Change in HESD score (weekly average) from baseline through Weeks 1, 2, 4, 8, and 12. • Reduction in HESD pain score (weekly average) of > 4 points from baseline in Weeks 1, 2, and 12. Among subjects with a baseline HESD pain score (weekly average) > 4 points. • Reduction in HESD pain score (weekly average) of > 3 points from baseline in Weeks 1, 2, 4, 8, 12, and 16. Among subjects with a baseline HESD pain score (weekly average) > 3 points. • Time to reduction in HESD pain score (weekly average) of > 4 points. Among subjects with a baseline HESD pain score (weekly average) > 4 points. • Change in HESD pain score (weekly average) from baseline to Weeks 1, 2, 4, 8, and 12. • Change in HESD (weekly average for each individual symptom score [excluding itching and pain]) from baseline to week 16. Quality of life and health-related effectiveness • Change in HESD score from baseline to Weeks 1, 2, 4, 8, and 12. • Reduction in HEIS score of > 1.5 points at Weeks 1, 2, 4, 8, 12, and 16. Among subjects with a baseline HEIS score > 1.5 points. • Change in HEIS PDAL score from baseline through Weeks 1, 2, 4, 8, and 12. • Reduction in HEIS PDAL score of > 1.5 points in Weeks 1, 2, 4, 8, 12, and 16. Among subjects with a baseline HEIS PDAL score > 1.5 points. • Change in HEIS (each individual domain score [excluding PDAL]) from baseline through Weeks 1, 2, 4, 8, 12, and 16. • Reduction in DLQI score of > 4 points at Weeks 1, 4, 8, and 12. Among subjects with a baseline DLQI score > 4 points. • Change in DLQI score from baseline through Weeks 1, 4, 8, and 12._______________ • Change in EQ-5D-5L index score from baseline through Weeks 1, 4, 8, 12, and 16. • Change in the EQ-5D-5L visual analog scale score from baseline to Weeks 1, 4, 8, 12, and 16. • Change in WPAI:CHE absenteeism score from baseline to weeks 4, 8, and 16. Among subjects with paid work at baseline. • Change in WPAI:CHE presenteeism score from baseline to weeks 4, 8, and 16. Among subjects with paid work at baseline. • Change in productivity loss score on the WPAI:CHE from baseline in Weeks 4, 8, and 16. Among subjects with paid work at baseline. • Change in activity decrease score on WPAI:CHE from baseline to weeks 4, 8, and 16.___________________________________________________________________________________ • Change in gene expression measured on skin tape strips from baseline to week 16. Table 9: Primary, secondary, key, and secondary endpoints_______ Final points________________________________________________________________________________________ Primary endpoint: • IGA-CHE TS in Week 16. (IGA-CHE TS refers to a score of 0 [clear] or 1 [almost clear] with a step > 2 improvement from baseline).__________________________________________________________________________________ Key secondary endpoint: • HECSI-90 in Week 16.__________________________________________________________________ Secondary endpoint: • IGA-CHE TS in Weeks 2, 4, 8 and 12. Petition 870250111574, dated 04 / 12 / 2025, page 22 / 220 / 106 Key secondary endpoints: • Reduction in HESD itch score (weekly average) of > 4 points from baseline at Week 16. Among subjects with a baseline HESD itch score (weekly average) > 4 points 1) Reduction in HESD pain score (weekly average) of > 4 points from baseline at Week 16. Among subjects with a baseline HESD pain score (weekly average) > 4 points. 2) Reduction in HESD score (weekly average) of > 4 points from baseline at Week 16. Among subjects with a baseline HESD score (weekly average) > 4 points.________ Secondary endpoint: • Change in DLQI score from baseline to week 16. Table 10: Secondary and Exploratory Endpoints_______________________ Secondary Endpoint___________________________________________________________________________ 1) Number of treatment-emergent AEs from baseline to week 18. An event will be considered treatment-emergent if it started after the first IMP application or if it started before the first IMP application and worsened in severity after the first IMP dose.____________ Exploratory Endpoints_______________________________________________________________________ Efficacy • HECSI-90 at Weeks 4 and 8. • HECSI-75 at Weeks 4, 8, and 16. • Percentage change in HECSI score from baseline to Weeks 4, 8, and 16. Quality of life and health-related effectiveness • Reduction in HESD itch score (weekly average) of > 4 points from baseline at Weeks 2, 4, and 8. Among subjects with a baseline HESD itch score (weekly average) > 4 points. • Reduction in HESD itch score (weekly average) of > 3 points from baseline at Weeks 2, 4, 8, and 16.4. Among subjects with a baseline HESD itch score (weekly average) > 3 points. • Change in HESD itch score (weekly average) from baseline to Weeks 2, 4, 8, and 16. • Reduction in HESD pain score (weekly average) of > 4 points from baseline in Weeks 2, 4, and 8. Among subjects with a baseline HESD pain score (weekly average) > 4 points. • Reduction in HESD pain score (weekly average) of > 3 points from baseline at Weeks 2, 4, 8, and 16. Among subjects with a baseline HESD pain score (weekly average) > 3 points • Change in HESD pain score (weekly average) from baseline to Weeks 2, 4, 8, and 16. • Reduction in HESD score (weekly average) of > 4 points from baseline in Weeks 2, 4, and 8. Among subjects with a baseline HESD score (weekly average) > 4 points. • Reduction in HESD score (weekly average) of > 3 points from baseline in Weeks 2, 4, 8, and 16. Among subjects with a baseline HESD score (weekly average) > 3 points. • Change in HESD score (weekly average) from baseline through Weeks 2, 4, 8, and 16. • Change in DLQI score from baseline through Week 4.

[0064] As described above, the invention relates to: A method for treating moderate to severe chronic hand eczema in a human patient comprising administering twice daily to the skin of said human patient in need thereof an acidified aqueous topical composition comprising 20 mg / g of delgocitinib in a pharmaceutically acceptable freebase or salt thereof, wherein the patient has disease severity classified as moderate to severe on screening and Petition 870250111574, dated 04 / 12 / 2025, page 23 / 220 / 106 baseline according to IGA-CHE (i.e., an IGA-CHE score of 3 or 4).

[0065] In a further embodiment, the invention relates to: The use of an acidified aqueous topical composition comprising 20 mg / g of delgocitinib in a pharmaceutically acceptable freebase or salt thereof for treating moderate to severe chronic hand eczema in a human patient, comprising twice-daily administration to the skin of said human patient in need thereof, wherein the patient has disease severity classified as moderate to severe at screening and baseline according to IGA-CHE (i.e., an IGACHE score of 3 or 4).

[0066] In a further embodiment, the invention relates to: The use of delgocitinib for the manufacture of an acidified aqueous topical composition comprising 20 mg / g of delgocitinib in a freebase or a salt thereof that is pharmaceutically acceptable for treating moderate to severe chronic hand eczema in a human patient, comprising twice-daily administration to the skin of said human patient in need thereof, wherein the patient has disease severity classified as moderate to severe at screening and baseline according to IGA-CHE (i.e., an IGA-CHE score of 3 or 4).

[0067] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a HESD itching score (weekly average) of > 4 points at baseline.

[0068] In a further embodiment, the invention relates to the above method, use or application, wherein the patient: is an adolescent aged 12 to 17 or an adult aged 18 or above; wherein the patient has eczema of the hands that has persisted for more than 3 months or has returned two or more times within the last 12 months.

[0069] In a further embodiment, the invention relates to Petition 870250111574, dated 04 / 12 / 2025, p. 24 / 220 / 106 method, use or the above use, where the patient has a recent documented history of inadequate response to treatment with topical corticosteroids (TCS) or for whom TCS are documented to be otherwise clinically inadvisable (e.g., due to significant side effects or safety risks).

[0070] In a further embodiment, the invention relates to the above method, use or application, wherein the patient achieves an IGACHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 16.

[0071] In a further embodiment, the invention relates to the above method, use or application, wherein the patient achieves an IGACHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 12.

[0072] In a further embodiment, the invention relates to the above method, use or application, wherein the patient achieves an IGACHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8.

[0073] In a further embodiment, the invention relates to the above method, use or application, wherein the patient achieves an IGACHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 4.

[0074] In a further embodiment, the invention relates to the above method, use or application, wherein the patient achieves an IGACHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 2.

[0075] In a further embodiment, the invention relates to the above method, use or application, wherein the patient achieves an IGACHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 1. Petition 870250111574, dated 04 / 12 / 2025, page 25 / 220 / 106

[0076] In a further embodiment, the invention relates to the above method, use or application, wherein the patient achieves at least a 90% improvement in HECSI score from baseline at week 16, or week 8, or week 4, week 2, or week 1.

[0077] In a further embodiment, the invention relates to the above method, use or application, wherein the patient achieves at least a 75% improvement in HECSI score from baseline at week 16, or week 8, or week 4, or week 2, or week 1.

[0078] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD score (weekly average) > 4 points and achieves a reduction in HESD score (weekly average) of > 4 points from baseline by week 16.

[0079] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD score (weekly average) > 4 points and achieves a reduction in HESD score (weekly average) of > 4 points from baseline by week 12.

[0080] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD score (weekly average) > 4 points at baseline and achieves a reduction in HESD score (weekly average) of > 4 points from baseline at week 8.

[0081] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD score (weekly average) > 4 points at baseline and achieves a reduction in HESD score (weekly average) of > 4 points from baseline in week 4.

[0082] In a further embodiment, the invention relates to Petition 870250111574, dated 04 / 12 / 2025, page 26 / 220 / 106 method, use or the use above, in which the patient has a baseline HESD score (weekly average > 4 points at baseline and achieves a reduction in HESD score (weekly average) of > 4 points from baseline in week 2.

[0083] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD score (weekly average) > 4 points at baseline and achieves a reduction in HESD score (weekly average) of > 4 points from baseline in week 1.

[0084] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD score (weekly average) > 3 points and achieves a reduction in HESD score (weekly average) of > 3 points from baseline by week 16.

[0085] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD score (weekly average) > 3 points and achieves a reduction in HESD score (weekly average) of > 3 points from baseline by week 12.

[0086] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD score (weekly average) > 3 points at baseline and achieves a reduction in HESD score (weekly average) of > 3 points from baseline at week 8.

[0087] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD score (weekly average) > 3 points at baseline and achieves a reduction in HESD score (weekly average) of > 3 points from baseline in week 4. Petition 870250111574, dated 04 / 12 / 2025, page 27 / 220 / 106

[0088] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD score (weekly average) > 3 points at baseline and achieves a reduction in HESD score (weekly average) of > 3 points from baseline in week 2.

[0089] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD score (weekly average) > 3 points at baseline and achieves a reduction in HESD score (weekly average) of > 3 points from baseline in week 1.

[0090] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has an HESD itch score (weekly average) > 4 points and achieves a reduction in HESD itch score (weekly average) of > points from baseline at week 16.

[0091] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD itching score (weekly average) > 4 points and the patient achieves a reduction in HESD itching (weekly average) of > 4 points from baseline at week 12.

[0092] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD itching score (weekly average) > 4 points and the patient achieves a reduction in HESD itching (weekly average) of > 4 points from baseline at week 8.

[0093] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD itching score (weekly average) > 4 points and the patient achieves a reduction in HESD itching (weekly average) of > 4 points from the Petition 870250111574, dated 04 / 12 / 2025, page 28 / 220 / 106 baseline in week 4.

[0094] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline in week 2.

[0095] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD itching score (weekly average) > 4 points and the patient achieves a reduction in HESD itching (weekly average) of > 4 points from baseline in week 1.

[0096] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD itch score (weekly average) > 3 points and achieves a HESD itch reduction score (weekly average) of > 3 points from baseline at week 16.

[0097] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD itch score (weekly average) > 3 points and achieves a HESD itch reduction score (weekly average) of > 3 points from baseline at week 12.

[0098] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD itch score (weekly average) > 3 points and achieves a HESD itch reduction score (weekly average) of > 3 points from baseline at week 8.

[0099] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline (weekly average) HESD itch score > 3 points and achieves a Petition 870250111574, dated 04 / 12 / 2025, page 29 / 220 / 106 score on the reduction of itching in the HESD (weekly average) of > 3 points from baseline in week 4.

[00100] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD itch score (weekly average) > 3 points and achieves a HESD itch reduction score (weekly average) of > 3 points from baseline in week 2.

[00101] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD itch score (weekly average) > 3 points and achieves a HESD itch reduction score (weekly average) of > 3 points from baseline in week 1.

[00102] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD itch score (weekly average) > 3 points and achieves a HESD itch reduction score (weekly average) of > 3 points from baseline on Day 6, Day 5, Day 4, Day 3, Day 2 or within 36 hours or on Day 1 or within 24 hours.

[00103] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD pain score (weekly average) > 4 points and achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline by week 16.

[00104] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD pain score (weekly average) > 4 points and achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline by week 12.

[00105] In a further embodiment, the invention relates to Petition 870250111574, dated 04 / 12 / 2025, page 30 / 220 / 106 method, use or the use above, in which the patient has a baseline HESD pain score (weekly average) > 4 points and achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline in week 8.

[00106] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD pain score (weekly average) > 4 points and achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline in week 4.

[00107] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD pain score (weekly average) > 4 points and achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline in week 2.

[00108] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD pain score (weekly average) > 4 points and achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline in week 1.

[00109] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD pain score (weekly average) > 3 points and achieves a reduction in HESD pain score (weekly average) of > 3 points from baseline by week 16.

[00110] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD pain score (weekly average) > 3 points and achieves a reduction in HESD pain score (weekly average) of > 3 points from baseline by week 12. Petition 870250111574, dated 04 / 12 / 2025, page 31 / 220 / 106

[00111] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD pain score (weekly average) > 3 points and achieves a reduction in HESD pain score (weekly average) of > 3 points from baseline by week 8.

[00112] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD pain score (weekly average) > 3 points and achieves a reduction in HESD pain score (weekly average) of > 3 points from baseline in week 4.

[00113] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD pain score (weekly average) > 3 points and achieves a reduction in HESD pain score (weekly average) of > 3 points from baseline in week 2.

[00114] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD pain score (weekly average) > 3 points and achieves a reduction in HESD pain score (weekly average) of > 3 points from baseline in week 1.

[00115] In a further embodiment, the invention relates to the above method, use or application, wherein the patient has a baseline HESD pain score (weekly average) > 3 points and achieves a reduction in HESD pain score (weekly average) of > 3 points from baseline on Day 6, Day 5, Day 4, Day 3, Day 2 or within 36 hours or on Day 1 or within 24 hours.

[00116] In a further embodiment, the invention relates to the above method, use or application, wherein the patient achieves a reduction in DLQI score of > 4 points from baseline at week 16. Petition 870250111574, dated 04 / 12 / 2025, page 32 / 220 / 106

[00117] In a further embodiment, the invention relates to the above method, use or application, wherein the patient achieves a reduction in DLQI score of > 4 points from baseline at week 12.

[00118] In a further embodiment, the invention relates to the above method, use or application, wherein the patient achieves a reduction in DLQI score of > 4 points from baseline at week 8.

[00119] In a further embodiment, the invention relates to the above method, use or application, wherein the patient achieves a reduction in DLQI score of > 4 points from baseline in week 4.

[00120] In a further embodiment, the invention relates to the above method, use or application, wherein the patient achieves a reduction in DLQI score of > 4 points from baseline in week 2.

[00121] In a further embodiment, the invention relates to the above method, use or application, wherein the patient achieves a reduction in DLQI score of > 4 points from baseline in week 1.

[00122] In a further embodiment, the invention relates to the above method, use or application, in which no accumulation of delgocitinib in the body is observed.

[00123] In a further embodiment, the invention relates to the above method, use or application, in which the treatment is continued until the patient achieves clear or nearly clear skin.

[00124] In a further embodiment, the invention relates to the above method, use or application, wherein in the event of recurrence of signs and symptoms of (rashes), twice-daily treatment of the affected areas is restarted as needed.

[00125] In a further embodiment, the invention relates to the above method, use or application, wherein delgocitinib is dissolved in the aqueous phase of the topical formulation.

[00126] In a further embodiment, the invention relates to Petition 870250111574, dated 04 / 12 / 2025, page 33 / 220 / 106 method, use or the above use, in which the aqueous topical formulation has a pH below approximately 4.6.

[00127] In a further embodiment, the invention relates to the above method, use or application, wherein the aqueous topical formulation has a pH between about 3.8 and about 4.6.

[00128] In a further embodiment, the invention relates to the above method, use or application, wherein the aqueous topical formulation has a pH of about 4.3 or below.

[00129] In a further embodiment, the invention relates to the above method, use or application, wherein the aqueous topical formulation has a pH of about 4.2 or below.

[00130] In a further embodiment, the invention relates to the above method, use or application, wherein the aqueous cream comprises a lipid base.

[00131] In a further embodiment, the invention relates to the above method, use or application, wherein the lipid base is liquid paraffin.

[00132] In some embodiments, the acidified aqueous topical composition or aqueous cream is an oil-in-water emulsion as described in WO2020 / 229622.

[00133] In some embodiments, the acidified topical composition or aqueous cream used in accordance with the invention comprises a large amount of water and is acidified to a pH between 3.8 and 4.6, more preferably a pH around 4.2 using a pharmaceutically acceptable acid such as hydrochloric acid.

[00134] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises one or more bases selected from medium-chain triglycerides, safflower oil, castor oil, liquid paraffin, or mixtures thereof. In some embodiments, the base is liquid paraffin. Petition 870250111574, dated 04 / 12 / 2025, page 34 / 220 / 106

[00135] The base is typically present in an amount of about 50 mg / g to about 500 mg / g, about 200 mg / g to about 400 mg / g, about 75 mg / g to about 125 mg / g, or in an amount of about 100 mg / g. Properly the base is liquid paraffin.

[00136] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises a surfactant, emulsifier or stabilizer, and the surfactant, emulsifier or stabilizer is selected from one or more fatty alcohols such as one or more cetyl alcohols, stearyl alcohols, cetostearyl alcohols, sorbitan esters, sucrose esters, macrogol cetostearyl ether or mixtures thereof.

[00137] Typically, the surfactant, emulsifier, or stabilizer is present in an amount of 40 to 150 mg / g, 60 to 120 mg / g, or in an amount of about 80 to 100 mg / g.

[00138] Typically, a surfactant, emulsifier or stabilizer may be selected from fatty alcohols, such as cetostearyl alcohol, and is present in amounts of about 30 mg / g to about 120 mg / g, for example, about 50 mg / g to about 90 mg / g, or in an amount of about 70 to 75 mg / g. Typically, the surfactant, emulsifier or stabilizer may be selected from cetostearyl alcohol and is present in an amount of about 70 to 75 mg / g, or in an amount of about 72 mg / g.

[00139] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises a surfactant, emulsifier or stabilizer, and the surfactant, emulsifier or stabilizer is selected from sorbitan esters, sucrose esters, macrogol fatty acid ethers or mixtures thereof. For example, the surfactant or emulsifier is macrogol cetearyl ether.

[00140] Typically, the surfactant, emulsifier or stabilizer Petition 870250111574, dated 04 / 12 / 2025, p. 35 / 220 / 106 selected from sorbitan esters, sucrose esters, macrogol cetoaryl ether or mixtures thereof is present in amounts of about 10 mg / g to about 30 mg / g, about 14 mg / g to about 22 mg / g, or in an amount of about 20 to 22 mg / g. Typically, a surfactant, emulsifier or stabilizer is macrogol cetostearyl or another fatty alcohol ether in an amount of about 20 to 22 mg / g or in an amount of about 18 mg / g.

[00141] In some embodiments, the acidified aqueous topical composition or aqueous cream used according to the invention comprises a buffer or pH regulator. The pharmaceutically acceptable buffer or pH regulator may be one or more of a phosphate or citrate salt, sodium acetate, sodium carbonate, sodium citrate dihydrate, hydrochloric acid, or mixtures thereof. For example, the buffer or pH regulator would be one or more of citric acid monohydrate and sodium citrate dihydrate. Typically, a buffer selected from a phosphate, citrate, or acetate buffer is used.

[00142] The pH buffer or regulator would be present in varying amounts of about 0.5 mg / g to about 4 mg / g, or about 0.7 mg / g to about 2 mg / g, or about 1 g / g.

[00143] Typically, the buffer is a citric acid buffer comprising citric acid monohydrate and sodium citrate dihydrate, and the sodium citrate dihydrate is present in amounts of about 0.5 mg / g to about 4 mg / g, about 0.7 mg / g to about 2 mg / g, or in an amount of about 1 g / g, or the sodium citrate dihydrate is present in amounts of 0 mg / g to about 1 mg / g, 0 mg / g to about 0.5 mg / g, or is absent.

[00144] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises a pharmaceutically acceptable preservative such as a preservative Petition 870250111574, dated 04 / 12 / 2025, p. 36 / 220 / 106 selected from benzyl alcohol, sodium dehydroacetate, sorbic acid / salts or mixtures thereof. In one embodiment the preservative is benzyl alcohol.

[00145] The preservative may be present in varying amounts of about 5 mg / g to about 20 mg / g, about 7 mg / g to about 13 mg / g, or in an amount of about 10 mg / g. Typically, the preservative is benzyl alcohol and is present in an amount of about 5 mg / g to about 20 mg / g, about 7 mg / g to about 13 mg / g, or in an amount of about 10 mg / g.

[00146] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises a pharmaceutically acceptable antioxidant, such as an antioxidant selected from sodium sulfite, disodium edetate, trisodium edetate, butylhydroxyanisole, or mixtures thereof. In one embodiment, the antioxidant is butylhydroxyanisole.

[00147] The antioxidant may be present in varying amounts of about 0.05 mg / g to about 0.3 mg / g, about 0.1 mg / g to about 0.25 mg / g, or in an amount of about 0.2 mg / g. Typically, the antioxidant is butylated hydroxyanisole and is present in amounts of about 0.05 mg / g to about 0.3 mg / g, about 0.1 mg / g to about 0.25 mg / g, or in an amount of about 0.2 mg / g.

[00148] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises a pharmaceutically acceptable chelating agent such as EDTA, disodium edetate, EGTA, or ethylenediamine. In one embodiment, the chelating agent is disodium edetate.

[00149] Typically, the chelating agent is present in varying amounts from about 0.05 mg / g to about 1.5 mg / g, from about 0.5 mg / g to about 1 mg / g, or in an amount of about 0.6 mg / g. Typically, the Petition 870250111574, dated 04 / 12 / 2025, p. 37 / 220 / 106 The chelating agent is EDTA, present in an amount of approximately 0.05 mg / g, approximately 1.5 mg / g, approximately 0.5 mg / g, approximately 1 mg / g, or in an amount of approximately 0.6 mg / g.

[00150] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises a pharmaceutically acceptable acidifying agent which may be one or more of a strong acid such as hydrochloric acid or citric acid.

[00151] In one embodiment the acidifying agent is hydrochloric acid.

[00152] The acidifying agent may be present in an amount of 1 mg / ga approximately 25 mg / g, approximately 10 mg / ga approximately 20 mg / g, or in an amount of approximately 17.7 mg / g. Typically, the acidifying agent is hydrochloric acid present in an amount of 1 mg / ga approximately 25 mg / g, approximately 10 mg / ga approximately 20 mg / g, or in an amount of approximately 17.7 mg / g.

[00153] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention contains purified water, which may be present in various amounts of about 500 mg / g, about 900 mg / g, and for example, 760 mg / g.

[00154] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises 50 to 500 mg / g of an oily base and 40 to 150 mg / g of a surfactant, emulsifier or stabilizer.

[00155] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises 50 to 500 mg / g of liquid paraffin, 30 to 120 mg / g of cetostearyl alcohol or another fatty alcohol, and 10 to 30 mg / g of a macrogol cetoaryl ether or another fatty alcohol ether.

[00156] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises Petition 870250111574, dated 04 / 12 / 2025, page 38 / 220 / 106 200 to 400 mg / g of an oil base and 60 to 120 mg / g of a surfactant, emulsifier or stabilizer.

[00157] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises 200 to 400 mg / g of liquid paraffin, 50 to 90 mg / g of cetostearyl alcohol or another fatty alcohol, and 14 to 22 mg / g of a macrogol cetoaryl ether or another fatty alcohol ether.

[00158] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises 75 to 125 mg / g of an oily base and 80 to 100 mg / g of a surfactant, emulsifier or stabilizer.

[00159] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises 75 to 125 mg / g of liquid paraffin, 70 to 75 mg / g of cetostearyl alcohol or another fatty alcohol, and 14 to 22 mg / g of a macrogol cetoaryl ether or another fatty alcohol ether.

[00160] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises 50 to 500 mg / g of an oily base, 40 to 150 mg / g of a surfactant, emulsifier or stabilizer and 0.5 to 4 mg / g of a buffer (total acid and base).

[00161] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises 50 to 500 mg / g of liquid paraffin, 30 to 120 mg / g of cetostearyl alcohol or another fatty alcohol and 10 to 30 mg / g of a macrogol cetoaryl ether or another fatty alcohol ether and 0.5 to 4 mg / g of a buffer (total base and acid).

[00162] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises 200 to 400 mg / g of an oily base, 60 to 120 mg / g of a surfactant, Petition 870250111574, dated 04 / 12 / 2025, page 39 / 220 / 106 emulsifier or stabilizer and 0.7 to 2 mg / g of citric acid buffer (total base and acid) or another suitable buffer.

[00163] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises 200 to 400 mg / g of liquid paraffin, 50 to 90 mg / g of cetostearyl alcohol or another fatty alcohol and 14 to 22 mg / g of a macrogol cetoaryl ether or another fatty alcohol ether and 0.7 to 2 mg / g of a citric acid buffer (total base and acid) or another suitable buffer.

[00164] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises 75 to 125 mg / g of an oily base, 80 to 100 mg / g of a surfactant, emulsifier or stabilizer and about 1 mg / g of a buffer (total base and acid).

[00165] In some embodiments, the acidified aqueous topical composition or aqueous cream used according to the invention comprises 75 to 125 mg / g of liquid paraffin, 70 to 75 mg / g of cetostearyl alcohol or another fatty alcohol and 14 to 22 mg / g of a macrogol cetoaryl ether or another fatty alcohol ether and about 1 mg / g of a citric acid buffer (total base and acid) or another suitable buffer.

[00166] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises 50 to 500 mg / g of liquid paraffin, 30 to 120 mg / g of cetostearyl alcohol or another fatty alcohol and 10 to 30 mg / g of a macrogol cetoaryl ether or other fatty alcohol ether, 0.5 to 4 mg / g of a buffer (total base and acid) and 1 to 25 mg / g of an acidifying agent.

[00167] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises 200 to 400 mg / g of an oily base, 60 to 120 mg / g of a surfactant, emulsifier or stabilizer, 0.7 to 2 mg / g of a buffer (total base and Petition 870250111574, dated 04 / 12 / 2025, page 40 / 220 / 106 acid) or another suitable buffer and 1 to 25 mg / g of an acidifying agent.

[00168] In some embodiments, the acidified aqueous topical composition or aqueous cream used according to the invention comprises 200 to 400 mg / g of liquid paraffin, 50 to 90 mg / g of cetostearyl alcohol or another fatty alcohol and 14 to 22 mg / g of a macrogol cetoaryl ether or another fatty alcohol ether and 0.7 to 2 mg / g of a citric acid buffer (total base and acid) or another suitable buffer and 10 to 20 mg / g of hydrochloric acid or another pharmaceutically acceptable acidifying agent.

[00169] In some embodiments, the acidified aqueous topical composition or aqueous cream used in accordance with the invention comprises 75 to 125 mg / g of an oily base, 80 to 100 mg / g of a surfactant, emulsifier or stabilizer and about 1 mg / g of a buffer (total base and acid) and 10 to 20 mg / g of an acidifying agent.

[00170] In some embodiments, the acidified aqueous topical composition or aqueous cream used according to the invention comprises 75 to 125 mg / g of liquid paraffin, 70 to 75 mg / g of cetostearyl alcohol or another fatty alcohol and 14 to 22 mg / g of a macrogol cetoaryl ether or another fatty alcohol ether and about 1 mg / g of a citric acid buffer (total base and acid) or another suitable buffer and 10 to 20 mg / g of hydrochloric acid or another pharmaceutically acceptable acidifying agent.

[00171] According to any of the above embodiments, the acidified aqueous topical composition or aqueous cream comprising various amounts of oil base, surfactant, emulsifier or stabilizer, buffer, pH regulator and / or acidifying agent also contains a preservative, an antioxidant and / or an acidifying agent.

[00172] The acidified aqueous topical composition or aqueous cream used according to the invention can be prepared by separately preparing the aqueous and oily phases and then adding the oily phase to the aqueous phase and mixing them. Petition 870250111574, dated 04 / 12 / 2025, page 41 / 220 / 106

[00173] The aqueous phase: Purified water, pH regulators, buffers, acidifying agents, preservatives, and chelating agents were mixed together.

[00174] Delgocitinib was added and dissolved in the aqueous phase.

[00175] The pH was adjusted

[00176] The aqueous phase was heated

[00177] The oil phase: Liquid paraffin, surfactants, emulsifiers, stabilizers, and antioxidants were mixed together.

[00178] The oil phase was heated

[00179] The oil phase was added to the aqueous phase and mixed.

[00180] The mixture was homogenized and cooled. The acidified aqueous topical composition or aqueous cream was subsequently filled into the container with a closure.

[00181] Exemplary pharmaceutical formulations used in accordance with the invention: Quantity of Component (mg / g): Delgocitinib 20; liquid paraffin 100; cetostearyl alcohol 72; macrogol cetoaryl ether 18; benzyl alcohol 10; citric acid monohydrate 1.0; butylhydroxyanisole 0.2; disodium edetate 0.6; 3 M hydrochloric acid 17.7 and purified water 760.

[00182] The acidified aqueous topical composition or aqueous cream used according to the invention can be prepared as follows: The aqueous phase: Purified water, pH regulators, buffers, acidifying agents, preservatives, and chelating agents were mixed together.

[00183] The pharmacological substance was added and dissolved in the aqueous phase at a temperature of around 15 to 25 °C.

[00184] The pH was adjusted to 4.0 to 4.4. Petition 870250111574, dated 04 / 12 / 2025, page 42 / 220 / 106

[00185] The aqueous phase was heated to around 65 to 75 °C. The oil phase:

[00186] Liquid paraffin, surfactants, emulsifiers, stabilizers, and antioxidants were mixed.

[00187] The oil phase was heated to around 65 to 75 °C.

[00188] The oil phase was added to the aqueous phase and mixed.

[00189] The mixture was homogenized for approximately 20 min. and subsequently cooled to approximately 30°C. The cream was then filled into a sealed container. Additional options

[00190] 1. A method for treating moderate to severe chronic hand eczema in a human patient in need thereof comprising administering twice daily to the skin of said human patient, an acidified aqueous topical composition comprising 20 mg / g of delgocitinib in a pharmaceutically acceptable freebase or salt thereof, wherein the patient has disease severity classified as moderate to severe at screening and baseline according to IGA-CHE.

[00191] 2. The modality 1 method, in which the patient has a HESD itch score (weekly average) of > 4 points at baseline.

[00192] 3. The method of any of the modalities 1 to 2, in which the patient: is an adolescent aged 12 to 17 or an adult aged 18 or over; in which the patient has eczema of the hands that has persisted for more than 3 months or has returned two or more times within the last 12 months.

[00193] 4. The method of any of the modalities 1 to 3, in which the patient has a recent documented history of inadequate response to treatment with topical corticosteroids (TCS) or for whom TCS are Petition 870250111574, dated 04 / 12 / 2025, p. 43 / 220 / 106 documented as otherwise clinically inadvisable (e.g., due to significant side effects or safety risks).

[00194] 5. The method of any of the modalities 1 to 4, in which delgocitinib is dissolved in the aqueous phase of the acidified aqueous topical formulation.

[00195] 6. The method of embodiment 5, in which the acidified aqueous topical formulation has a pH below about 4.6 or below about 4.4.

[00196] 7. The method of embodiment 6, in which the acidified aqueous topical formulation has a pH between about 3.8 and about 4.6.

[00197] 8. The method of embodiment 7, in which the aqueous topical formulation has a pH of about 4.3 or below.

[00198] 9. The method of embodiment 8, in which the aqueous topical formulation has a pH of about 4.2 or below.

[00199] 10. The method of any of the modalities 5 to 9, in which the aqueous cream comprises a lipid base.

[00200] 11. The method of modality 10, in which the lipid base is liquid paraffin.

[00201] 12. The method of any of the modalities 1 to 11, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 16.

[00202] 13. The modality 12 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8.

[00203] 14. The modality 12 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 4.

[00204] 15. The modality 12 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 2. Petition 870250111574, dated 04 / 12 / 2025, page 44 / 220 / 106

[00205] 16. The modality 12 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 1.

[00206] 17. The modality 12 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 5 or 6.

[00207] 18. The modality 12 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 4.

[00208] 19. The modality 12 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 3.

[00209] 20. The modality 12 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 2 or within 36 hours.

[00210] 21. The modality 12 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 1 or within 24 hours.

[00211] 22. The method of any of the modalities 1 to 21, in which the patient achieves at least a 90% improvement in the HECSI score from baseline at week 16.

[00212] 23. The modality 22 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline at week 8.

[00213] 24. The modality 22 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline at week 4.

[00214] 25. The modality 22 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline. Petition 870250111574, dated 04 / 12 / 2025, page 45 / 220 / 106 in week 2.

[00215] 25. The modality 22 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline in week 1.

[00216] 26. The modality 22 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 6.

[00217] 27. The modality 22 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 5.

[00218] 28. The modality 22 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 4.

[00219] 29. The modality 22 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 3.

[00220] 30. The modality 22 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 2 or within 36 hours.

[00221] 31. The modality 22 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 1 or within 24 hours.

[00222] 32. The method of any of the modalities 1 to 31, in which the patient achieves at least a 75% improvement in the HECSI score from baseline at week 16.

[00223] 33. The modality 32 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline at week 8.

[00224] 34. The method of modality 32, in which the patient achieves Petition 870250111574, dated 04 / 12 / 2025, page 46 / 220 / 106, at least a 75% improvement in the HECSI score from baseline in week 4.

[00225] 35. The modality 32 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline at week 2.

[00226] 36. The modality 32 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline in week 1.

[00227] 37. The modality 32 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 6.

[00228] 38. The modality 32 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 5.

[00229] 39. The modality 32 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 4.

[00230] 40. The modality 32 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 3.

[00231] 41. The modality 32 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 2 or within 36 hours.

[00232] 42. The modality 32 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 1 or within 24 hours.

[00233] 43. The method of any of the modalities 1 to 42, in which the patient has a baseline HESD score (weekly average) > 4 points and achieves a reduction in HESD score (average Petition 870250111574, dated 04 / 12 / 2025, page 47 / 220 / 106 weekly) of > 4 points from the baseline in week 16.

[00234] 44. The modality 43 method, in which the patient has a baseline HESD score (weekly average) > 4 points and achieves a reduction in HESD score (weekly average) of > 4 points from baseline in week 12.

[00235] 45. The modality 43 method, in which the patient has a baseline HESD score (weekly average) > 4 points at baseline and achieves a reduction in HESD score (weekly average) of > 4 points from baseline at week 8.

[00236] 46. The modality 43 method, in which the patient has a baseline HESD score (weekly average) > 4 points at baseline and achieves a reduction in HESD score (weekly average) of > 4 points from baseline in week 4.

[00237] 47. The modality 43 method, in which the patient has a baseline HESD score (weekly average) > 4 points at baseline and achieves a reduction in HESD score (weekly average) of > 4 points from baseline in week 2.

[00238] 48. The modality 43 method, in which the patient has a baseline HESD score (weekly average) > 4 points at baseline and achieves a reduction in HESD score (weekly average) of > 4 points from baseline in week 1.

[00239] 49. The method of any of the modalities 1 to 48, in which the patient has a baseline HESD itch score (weekly average) > 4 points and achieves a reduction in HESD itch score (weekly average) of > 4 points from baseline at week 16.

[00240] 50. The modality 49 method, in which the patient has a baseline HESD itching score (weekly average) > 4 points and the patient achieves a reduction in HESD itching (weekly average) of > 4 Petition 870250111574, dated 04 / 12 / 2025, page 48 / 220 / 106 points from the baseline in week 8.

[00241] 51. The modality 49 method, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline in week 4.

[00242] 52. The modality 49 method, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline in week 2.

[00243] 53. The modality 49 method, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline in week 1.

[00244] 54. The modality 49 method, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline on day 6.

[00245] 55. The modality 49 method, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline on day 5.

[00246] 56. The modality 49 method, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline on day 4.

[00247] 57. The modality 49 method, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline on day 3. Petition 870250111574, dated 04 / 12 / 2025, page 49 / 220 / 106

[00248] 58. The modality 49 method, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline on day 2 or within 36 hours.

[00249] 59. The modality 49 method, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline on day 1 or within 24 hours.

[00250] 60. The method of any of the modalities 1 to 59, in which the patient has a baseline HESD pain score (weekly average) > 4 points and achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline at week 16.

[00251] 61. The modality 60 method, in which the patient has a baseline HESD pain score (weekly average) > 4 points and achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline in week 8.

[00252] 62. The modality 60 method, in which the patient has a baseline HESD pain score (weekly average) > 4 points and achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline in week 4.

[00253] 63. The modality 60 method, in which the patient has a baseline HESD pain score (weekly average) > 4 points and achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline in week 2.

[00254] 64. The modality 60 method, in which the patient has a baseline HESD pain score (weekly average) > 4 points and achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline in week 1.

[00255] 65. The method of modality 60, in which the patient has a Petition 870250111574, dated 04 / 12 / 2025, page 50 / 220 / 106 HESD pain score at baseline (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline on day 6.

[00256] 66. The modality 60 method, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline on day 5.

[00257] 67. The modality 60 method, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline on day 4.

[00258] 68. The modality 60 method, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline on day 3.

[00259] 69. The modality 60 method, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline on day 2 or within 36 hours.

[00260] 70. The modality 60 method, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline on day 1 or within 24 hours.

[00261] 71. The method of any of claims 1 to 70, in which the patient achieves a reduction in DLQI score of > 4 points from baseline at week 16.

[00262] 72. The method of claim 71, in which the patient achieves a reduction in DLQI score of > 4 points from baseline at week 8. Petition 870250111574, dated 04 / 12 / 2025, page 51 / 220 / 106

[00263] 73. The method of claim 71, in which the patient achieves a reduction in DLQI score of > 4 points from baseline at week 4.

[00264] 74. The method of claim 71, in which the patient achieves a reduction in DLQI score of > 4 points from baseline in week 2.

[00265] 75. The method of claim 71, in which the patient achieves a reduction in DLQI score of > 4 points from baseline in week 1.

[00266] 77. The method of any of the modalities 1 to 75, in which treatment is continued until the patient achieves clear or nearly clear skin.

[00267] 78. The method of modality 77, in which administration is maintained for at least 2 weeks.

[00268] 79. The method of modality 77, in which administration is maintained for at least 4 weeks.

[00269] 80. The method of modality 77, in which administration is maintained for at least 8 weeks.

[00270] 81. The method of modality 77, in which administration is maintained for at least 12 weeks.

[00271] 82. A method for reducing itching in a human patient with moderate to severe chronic hand eczema, comprising administering twice daily to the skin of said human patient in need thereof, of an acidified aqueous topical composition comprising 20 mg / g of delgocitinib in a pharmaceutically acceptable freebase or salt thereof, wherein the patient has a baseline (weekly average) HESD itch score > 4 points.

[00272] 83. The method of modality 82, in which the patient: is an adolescent aged 12 to 17 or an adult aged 18 or Petition 870250111574, dated 04 / 12 / 2025, p. 52 / 220 / 106 above; wherein the patient has eczema of the hands that has persisted for more than 3 months or has returned two or more times within the last 12 months.

[00273] 84. The method of either of the modalities 82 and 83, wherein the patient has a recent documented history of inadequate response to treatment with topical corticosteroids (TCS) or for whom TCS are documented to be otherwise clinically inadvisable (e.g., due to significant side effects or safety risks).

[00274] 85. The method of any of the modalities 82 to 84, in which delgocitinib is dissolved in the aqueous phase of the acidified aqueous topical formulation.

[00275] 86. The method of embodiment 85, in which the acidified aqueous topical formulation has a pH below about 4.6 or below about 4.4.

[00276] 87. The method of embodiment 86, in which the acidified aqueous topical formulation has a pH between about 3.8 and about 4.6.

[00277] 88. The method of embodiment 87, in which the aqueous topical formulation has a pH of about 4.3 or below.

[00278] 89. The method of embodiment 88, in which the aqueous topical formulation has a pH of about 4.2 or below.

[00279] 90. The method of any of the modalities 83 to 89, in which the aqueous cream comprises a lipid base.

[00280] 91. The method of any of the modalities 82 to 90, in which the patient achieves a reduction in itching on the HESD (weekly average) of > 4 points from baseline in week 8.

[00281] 92. The method of modality 91, in which the patient achieves a reduction in itching on the HESD (weekly average) of > 4 points from baseline in week 4.

[00282] 93. The modality 91 method, in which the patient achieves a reduction in itching on the HESD (weekly average) of > 4 points from baseline in week 2. Petition 870250111574, dated 04 / 12 / 2025, page 53 / 220 / 106

[00283] 94. The modality 91 method, in which the patient achieves a reduction in itching on the HESD (weekly average) of > 4 points from baseline in week 1.

[00284] 95. In modality 91, the patient achieves a reduction in itching on the HESD (weekly average) of > 4 points from baseline on day 6.

[00285] 96. The modality 91 method, in which the patient achieves a reduction in itching on the HESD (weekly average) of > 4 points from baseline on day 5.

[00286] 97. The method of modality 91, in which the patient achieves a reduction in itching on the HESD (weekly average) of > 4 points from baseline on day 4.

[00287] 98. The method of modality 91, in which the patient achieves a reduction in itching on the HESD (weekly average) of > 4 points from baseline on day 3.

[00288] 99. The modality 91 method, in which the patient achieves a reduction in itching on the HESD (weekly average) of > 4 points from baseline on day 2 or within 36 hours.

[00289] 100. The modality 91 method, in which the patient achieves a reduction in itching on the HESD (weekly average) of > 4 points from baseline on day 1 or within 24 hours.

[00290] 101. The method of modality 82, in which the patient achieves an immediate reduction in itching.

[00291] 102. The method of any of the modalities 82 to 101, in which the patient achieves a statistically relevant reduction in the HEDS itch score from baseline on day 1 or within 24 hours compared to a patient administered placebo.

[00292] 103. The method of any of the modalities 82 to 101, in which the patient achieves a 1-point reduction in the itching score of Petition 870250111574, dated 04 / 12 / 2025, page 54 / 220 / 106 HEDS from baseline on day 1 or within 24 hours.

[00293] 104. The method of any of the modalities 82 to 101, in which the patient achieves a statistically relevant reduction in the HEDS itch score from baseline on day 2 or within 36 hours compared to a patient administered placebo.

[00294] 105. The method of any of the modalities 82 to 101, in which the patient achieves a 2-point reduction in the HEDS itch score from baseline on day 2 or within 36 hours.

[00295] 106. The method of any of the modalities 82 to 101, in which the patient achieves a 3-point reduction in the HEDS itch score from baseline at week 8.

[00296] 107. The method of any of the modalities 82 to 101, in which the patient achieves a 3-point reduction in the HEDS itch score from baseline at week 4.

[00297] 108. The method of any of the modalities 82 to 101, in which the patient achieves a 3-point reduction in the HEDS itch score from baseline at week 2.

[00298] 109. The method of any of the modalities 82 to 101, in which the patient achieves a 3-point reduction in the HEDS itch score from baseline in week 1.

[00299] 110. The method of modalities 82 to 101, in which the patient achieves a 4-point reduction in the HEDS itch score from baseline at week 8.

[00300] 111. The method of any of the modalities 82 to 101, in which the patient achieves a 4-point reduction in the HEDS itch score from baseline at week 4.

[00301] 113. The method of any of the modalities 82 to 112, in which the patient achieves a significant improvement in the IGA CHE score from baseline compared to placebo. Petition 870250111574, dated 04 / 12 / 2025, page 55 / 220 / 106

[00302] 114. The method of any of the modalities 82 to 113, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8.

[00303] 115. The modality 114 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 4.

[00304] 116. The modality 114 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 2.

[00305] 117. The modality 114 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 1.

[00306] 118. The method of modality 114, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 5 or 6.

[00307] 119. The method of modality 114, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 4.

[00308] 120. The modality 114 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 3.

[00309] 121. The modality 114 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 1 or within 24 hours.

[00310] 122. The modality 114 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 2 or within 36 hours.

[00311] 123. The method of any of the modalities 82 to 122, in which the patient achieves at least a 90% improvement in the HECSI score. Petition 870250111574, dated 04 / 12 / 2025, page 56 / 220 / 106 starting from the baseline in week 16.

[00312] 124. The modality 123 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline at week 8.

[00313] 125. The modality 123 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline at week 4.

[00314] 126. The modality 123 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline at week 2.

[00315] 127. The modality 123 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline in week 1.

[00316] 128. The modality 123 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 6.

[00317] 129. The modality 123 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 5.

[00318] 130. The modality 123 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 4.

[00319] 131. The modality 123 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 3.

[00320] 132 The modality 123 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 2 or within 36 hours.

[00321] 133. The method of modality 123, in which the patient achieves Petition 870250111574, dated 04 / 12 / 2025, page 57 / 220 / 106 at least 90% improvement in HECSI score from baseline on day 1 or within 24 hours.

[00322] 134. The method of any of the modalities 82 to 122, in which the patient achieves at least a 75% improvement in the HECSI score from baseline at week 16.

[00323] 135. The modality 134 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline at week 8.

[00324] 136. The modality 134 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline at week 4.

[00325] 137. The method of modality 134, in which the patient achieves at least a 75% improvement in the HECSI score from baseline at week 2.

[00326] 138. The modality 134 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline in week 1.

[00327] 139. The modality 134 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 6.

[00328] 140. The modality 134 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 5.

[00329] 141. The modality 134 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 4.

[00330] 143. The modality 134 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 3. Petition 870250111574, dated 04 / 12 / 2025, page 58 / 220 / 106

[00331] 144. The modality 134 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 2 or within 36 hours.

[00332] 145. The modality 134 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 1 or within 24 hours.

[00333] 146. The method of any of the modalities 82 to 145, in which treatment is continued until the patient achieves clear or nearly clear skin.

[00334] 147. The method of any of the modalities 82 to 146, in which administration is maintained for at least 2 weeks.

[00335] 148. The method of modality 147, in which administration is maintained for at least 4 weeks.

[00336] 149. The method of modality 147, in which administration is maintained for at least 8 weeks.

[00337] 150. The method of modality 147, in which administration is maintained for at least 12 weeks.

[00338] 151. The method of any of the modalities 82 to 150, in which the patient is not administered with other therapeutic agents used to treat chronic eczema of the hands.

[00339] 152. The method of any of the modalities 82 to 150, in which the administration of said acidified aqueous formulation does not cause burning at the site of administration.

[00340] 153. A method for reducing pain in a human patient with moderate to severe chronic hand eczema, comprising administering twice daily to the skin of said human patient in need thereof, of an acidified aqueous topical composition comprising 20 mg / g of delgocitinib in a pharmaceutically acceptable freebase or salt thereof, wherein the patient has a Petition 870250111574, dated 04 / 12 / 2025, page 59 / 220 / 106 HESD pain score at baseline (weekly average) > 4 points.

[00341] 154. The method of modality 153, in which the patient: is an adolescent aged 12 to 17 or an adult aged 18 or over; in which the patient has eczema of the hands that has persisted for more than 3 months or has returned two or more times within the last 12 months.

[00342] 155. The method of either modality 153 or 154, in which the patient has a recent documented history of inadequate response to treatment with topical corticosteroids (TCS) or for whom TCS are documented to be otherwise clinically inadvisable (e.g., due to significant side effects or safety risks).

[00343] 156. The method of any of the modalities 153 to 155, in which delgocitinib is dissolved in the aqueous phase of the acidified aqueous topical formulation.

[00344] 157. The method of embodiment 156, in which the acidified aqueous topical formulation has a pH below about 4.6 or below about 4.4.

[00345] 158. The method of embodiment 157, in which the acidified aqueous topical formulation has a pH between about 3.8 and about 4.6.

[00346] 159. The method of embodiment 158 ​​in which the aqueous topical formulation has a pH of about 4.3 or below.

[00347] 160. The method of embodiment 159, in which the aqueous topical formulation has a pH of about 4.2 or below.

[00348] 161. The method of any of the modalities 156 to 160, in which the aqueous topical formulation comprises a lipid base.

[00349] 162. The method of any of the modalities 153 to 161, in which the patient achieves a reduction in HEDS pain score (weekly average) of > 4 points from baseline in week 8.

[00350] 163. The method of modality 162, in which the patient achieves Petition 870250111574, dated 04 / 12 / 2025, p. 60 / 220 / 106 a reduction in HEDS pain score (weekly average) of > 4 points from baseline in week 4.

[00351] 164. The method of modality 163, in which the patient achieves a reduction in HEDS pain score (weekly average) of > 4 points from baseline in week 2.

[00352] 165. The method of modality 164, in which the patient achieves a reduction in HEDS pain score (weekly average) of > 4 points from baseline in week 1.

[00353] 166. In modality 165, the patient achieves a reduction in HEDS pain score (weekly average) of > 4 points from baseline on day 6.

[00354] 167. The method of modality 166, in which the patient achieves a reduction in HEDS pain score (weekly average) of > 4 points from baseline on day 5.

[00355] 168. The method of modality 167, in which the patient achieves a reduction in HEDS pain score (weekly average) of > 4 points from baseline on day 4.

[00356] 169. The method of modality 168, in which the patient achieves a reduction in HEDS pain score (weekly average) of > 4 points from baseline on day 3.

[00357] 170. The method of modality 169, in which the patient achieves a reduction in HEDS pain score (weekly average) of > 4 points from baseline on day 2 or within 36 hours.

[00358] 171. The modality 170 method, in which the patient achieves a reduction in HEDS pain score (weekly average) of > 4 points from baseline on day 1 or within 24 hours.

[00359] 172. The method of modality 153, in which the patient achieves an immediate reduction in pain.

[00360] 173. The method of any of the modalities 153 to 172, Petition 870250111574, dated 04 / 12 / 2025, page 61 / 220 / 106, in which the patient achieves a statistically relevant reduction in HEDS pain score from baseline on day 1 or within 24 hours compared to a patient administered placebo.

[00361] 174. The method of any of the modalities 153 to 172, in which the patient achieves a 1-point reduction in the HEDS pain score from baseline on day 1 or within 24 hours.

[00362] 175. The method of any of the modalities 153 to 172, in which the patient achieves a statistically relevant reduction in HEDS pain score from baseline on day 2 or within 36 hours compared to a patient administered placebo.

[00363] 176. The method of any of the modalities 153 to 172, in which the patient achieves a 2-point reduction in the HEDS pain score from baseline on day 2 or within 36 hours.

[00364] 177. The method of any of the modalities 153 to 172, in which the patient achieves a 3-point reduction in the HEDS pain score from baseline at week 8.

[00365] 178. The method of any of the modalities 153 to 172, in which the patient achieves a 3-point reduction in the HEDS pain score from baseline at week 4.

[00366] 179. The method of any of the modalities 153 to 172, in which the patient achieves a 3-point reduction in the HEDS pain score from baseline in week 2.

[00367] 180. The method of any of the modalities 153 to 172, in which the patient achieves a 3-point reduction in the HEDS pain score from baseline in week 1.

[00368] 181. The method of any of the modalities 153 to 172, in which the patient achieves a 4-point reduction in the HEDS pain score from baseline at week 8.

[00369] 182. The method of any of the modalities 153 to 172, Petition 870250111574, dated 04 / 12 / 2025, page 62 / 220 / 106, in which the patient achieves a 4-point reduction in the HEDS pain score from baseline in week 4.

[00370] 183. The method of any of the modalities 153 to 182, in which the patient achieves a significant improvement in the IGA CHE score from baseline compared to placebo.

[00371] 184. The method of any of the modalities 153 to 182, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8.

[00372] 185. The modality 184 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 4.

[00373] 186. The method of modality 184, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 2.

[00374] 187. The method of modality 184, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 1.

[00375] 188. The method of modality 184, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 5 or 6.

[00376] 189. The method of modality 184, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 4.

[00377] 190. The method of modality 184, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 3.

[00378] 191. The modality 184 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 1 or within 24 hours. Petition 870250111574, dated 04 / 12 / 2025, page 63 / 220 / 106

[00379] 192. The modality 184 method, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline on day 2 or within 36 hours.

[00380] 193. The method of any of the modalities 153 to 192, in which the patient achieves at least a 90% improvement in the HECSI score from baseline at week 16.

[00381] 194. The modality 193 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline at week 8.

[00382] 195. The modality 193 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline at week 4.

[00383] 196. The modality 193 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline at week 2.

[00384] 197. The modality 193 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline in week 1.

[00385] 198. The modality 193 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 6.

[00386] 199. The modality 193 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 5.

[00387] 200. The modality 193 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 4.

[00388] 201. The modality 193 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline. Petition 870250111574, dated 04 / 12 / 2025, page 64 / 220 / 106 on the 3rd.

[00389] 202. The modality 193 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 2 or within 36 hours.

[00390] 203. The modality 193 method, in which the patient achieves at least a 90% improvement in the HECSI score from baseline on day 1 or within 24 hours.

[00391] 204. The method of any of the modalities 153 to 203, in which the patient achieves at least a 75% improvement in the HECSI score from baseline at week 16.

[00392] 205. The modality 204 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline at week 8.

[00393] 206. The modality 204 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline at week 4.

[00394] 207. The modality 204 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline at week 2.

[00395] 208. The modality 204 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline in week 1.

[00396] 209. The modality 204 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 6.

[00397] 210. The 204 modality method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 5.

[00398] 211. The method of modality 204, in which the patient achieves Petition 870250111574, dated 04 / 12 / 2025, page 65 / 220 / 106, at least a 75% improvement in the HECSI score from the baseline on day 4.

[00399] 213. The modality 204 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 3.

[00400] 214. The modality 204 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 2 or within 36 hours.

[00401] 215. The modality 204 method, in which the patient achieves at least a 75% improvement in the HECSI score from baseline on day 1 or within 24 hours.

[00402] 216. The method of any of the modalities 153 to 215, in which treatment is continued until the patient achieves clear or nearly clear skin.

[00403] 217. The method of any of the modalities 82 to 146, in which administration is maintained for at least 2 weeks.

[00404] 218. The method of modality 217, in which administration is maintained for at least 4 weeks.

[00405] 219. The method of modality 217, in which administration is maintained for at least 8 weeks.

[00406] 220. The method of modality 217, in which administration is maintained for at least 12 weeks.

[00407] 221. The method of any of the modalities 153 to 220, in which the patient is not administered with other therapeutic agents used to treat chronic eczema of the hands.

[00408] 222. The method of any of the modalities 153 to 220, in which the administration of said acidified aqueous formulation does not cause burning at the site of administration.

[00409] 223. A method for treating chronic eczema of the hands Petition 870250111574, dated 04 / 12 / 2025, page 66 / 220 / 106 moderate to severe in a human patient comprising the twice-daily administration to the skin of said human patient in need thereof, of an acidified aqueous topical composition comprising 20 mg / g of delgocitinib in a pharmaceutically acceptable freebase or salt thereof, wherein said administration is maintained for at least 12 weeks, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 12 and wherein the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline at week 12.

[00410] 224. The method of modality 223, in which the patient is an adult aged 18 years or older and in which the patient has eczema of the hands that has persisted for more than 3 months or has returned two or more times within the last 12 months.

[00411] 225. A method for treating moderate to severe chronic hand eczema in a human patient comprising administering twice daily to the skin of said human patient in need thereof, of an acidified aqueous topical composition comprising 20 mg / g of delgocitinib in a pharmaceutically acceptable freebase or salt thereof, wherein said administration is maintained for at least 8 weeks, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8 and wherein the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline at week 8.

[00412] 226. The method of modality 224, in which the patient is an adult aged 18 years or older and in which the patient has eczema of the hands that Petition 870250111574, dated 04 / 12 / 2025, page 67 / 220 / 106 has persisted for more than 3 months or returned two or more times within the last 12 months.

[00413] 227. A method for treating moderate to severe chronic hand eczema in a human patient comprising administering twice daily to the skin of said human patient in need thereof, of an acidified aqueous topical composition comprising 20 mg / g of delgocitinib in a pharmaceutically acceptable freebase or salt thereof, wherein said administration is maintained for at least 6 weeks, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 6 and wherein the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline at week 6.

[00414] 228. The method of modality 224, in which the patient is an adult aged 18 years or older and in which the patient has eczema of the hands that has persisted for more than 3 months or has returned two or more times within the last 12 months.

[00415] 229. A method for treating moderate chronic eczema of the hands in a human patient comprising administering twice daily to the skin of said human patient in need thereof, of a topical formulation comprising 20 mg / g of delgocitinib in a pharmaceutically acceptable freebase or salt thereof.

[00416] 230. A method for treating severe chronic hand eczema in a human patient comprising administering twice daily to the skin of said human patient in need thereof, of a topical formulation comprising 20 mg / g of delgocitinib in a pharmaceutically acceptable freebase or salt thereof.

[00417] 231. The method of any of the modalities 229 to 230, Petition 870250111574, dated 04 / 12 / 2025, p. 68 / 220 / 106 where the patient has a baseline HESD itch score (weekly average) > 4 points.

[00418] 232. The method according to any of the modalities 229 to 231, where the patient has an IGA-CHE score of 3 or 4.

[00419] 233. The method of any of the modalities 229 to 232, in which the patient has a recent documented history of inadequate response to treatment with topical corticosteroids (TCS) or for whom TCS are documented to be otherwise clinically inadvisable (for example, due to significant side effects or safety risks).

[00420] 234. The method of modality 233, in which the patient has a recent documented history of inadequate response to treatment with topical corticosteroids (TCS).

[00421] 235. The method of modality 233, in which topical corticosteroids (TCS) are documented to be clinically inadvisable for the patient.

[00422] 236. The method of any of the modalities 229 to 235, in which the patient is an adult 18 years of age or older.

[00423] 237. The method of modalities 229 to 235, in which the patient is an adolescent aged 12 to 17 years.

[00424] 238. The method of any of the modalities 229 to 237, in which the topical formulation is administered for at least 2 weeks.

[00425] 239. The method of modality 238, in which the topical formulation is administered for at least 4 weeks.

[00426] 240. The method of modality 239, in which the topical formulation is administered for at least 8 weeks.

[00427] 241. The method of modality 240, in which the topical formulation is administered for at least 12 weeks.

[00428] 242. The method of modality 241, in which the formulation Petition 870250111574, dated 04 / 12 / 2025, page 69 / 220 / 106 topical is administered for at least 16 weeks or more.

[00429] 243. The method of any of the modalities 229 to 242, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8.

[00430] 244. The method of any of the modalities 229 to 242, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 6.

[00431] 245. The method of any of the modalities 229 to 242, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 4.

[00432] 246. The method of any of the modalities 229 to 242, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 2.

[00433] 247. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline at week 8 and in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8.

[00434] 248. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline at week 6 and in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 6.

[00435] 249. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score (weekly average) > 4 points and in which the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline in Petition 870250111574, dated 04 / 12 / 2025, page 70 / 220 / 106 week 4 and in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 4.

[00436] 250. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline in week 2 and in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 2.

[00437] 251. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline in week 1 and in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 1.

[00438] 252. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline at week 8 and in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8.

[00439] 253. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline at week 6 and in which the patient achieves an IGA-CHÉ score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 6. Petition 870250111574, dated 04 / 12 / 2025, page 71 / 220 / 106

[00440] 254. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and in which the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline in week 4 and in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 4.

[00441] 255. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline in week 2 and in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 2.

[00442] 256. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline in week 1 and in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 1.

[00443] 257. The method of any of the modalities 229 to 242, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8 and ultimately a 90% improvement in the HECSI score from baseline at week 8.

[00444] 258. The method of any of the modalities 229 to 242, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 6 and by Petition 870250111574, dated 04 / 12 / 2025, page 72 / 220 / 106 last 90% improvement in HECSI score from baseline in week 6.

[00445] 259. The method of any of the modalities 229 to 242, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 4 and ultimately a 90% improvement in the HECSI score from baseline at week 4.

[00446] 260. The method of any of the modalities 229 to 242, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 2 and ultimately a 90% improvement in the HECSI score from baseline in week 2.

[00447] 261. The method of any of the modalities 229 to 242, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 1 and ultimately a 90% improvement in the HECSI score from baseline in week 1.

[00448] 262. The method of any of the modalities 229 to 242, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8 and ultimately a 75% improvement in the HECSI score from baseline at week 8.

[00449] 263. The method of any of the modalities 229 to 242, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 6 and ultimately a 90% improvement in the HECSI score from baseline at week 6.

[00450] 264. The method of any of the modalities 229 to 242, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near Petition 870250111574, dated 04 / 12 / 2025, page 73 / 220 / 106 clear) with an improvement > 2 steps from baseline in week 4 and finally a 75% improvement in HECSI score from baseline in week 4.

[00451] 265. The method of any of the modalities 229 to 242, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 2 and ultimately a 75% improvement in the HECSI score from baseline in week 2.

[00452] 266. The method of any of the modalities 229 to 242, in which the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline in week 1 and ultimately a 75% improvement in the HECSI score from baseline in week 1.

[00453] 267. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline, and lastly a 75% improvement in HECSI score from baseline at week 8.

[00454] 268. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline, and lastly a 75% improvement in HECSI score from baseline at week 6.

[00455] 269. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score. Petition 870250111574, dated 04 / 12 / 2025, page 74 / 220 / 106 (weekly average) > 4 points and the patient achieves a reduction in itching on the HESD (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline and finally a 75% improvement in the HECSI score from baseline in week 4.

[00456] 270. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline, and lastly a 75% improvement in HECSI score from baseline at week 2.

[00457] 271. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline, and lastly a 75% improvement in HECSI score from baseline in week 1.

[00458] 272. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8 and finally a 90% improvement in HECSI score from baseline at week 8.

[00459] 273. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in itching in Petition 870250111574, dated 04 / 12 / 2025, page 75 / 220 / 106 HESD (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of > 2 steps from baseline at week 8, and finally a 90% improvement in HECSI score from baseline at week 6.

[00460] 274. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8 and finally a 90% improvement in HECSI score from baseline at week 4.

[00461] 275. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8 and finally a 90% improvement in HECSI score from baseline at week 2.

[00462] 276. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD itch score (weekly average) > 4 points and the patient achieves a reduction in HESD itch (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8 and finally a 90% improvement in HECSI score from baseline at week 1.

[00463] 277. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline, a Petition 870250111574, dated 04 / 12 / 2025, page 76 / 220 / 106 IGA-CHE score of 0 (clear) or 1 (almost clear) with an improvement > 2 steps from baseline and lastly 75% improvement in HECSI score from baseline at week 8.

[00464] 278. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline, and lastly a 75% improvement in HECSI score from baseline at week 6.

[00465] 279. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline, and lastly a 75% improvement in HECSI score from baseline at week 4.

[00466] 280. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline, and lastly a 75% improvement in HECSI score from baseline in week 2.

[00467] 281. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 Petition 870250111574, dated 04 / 12 / 2025, page 77 / 220 / 106 steps from baseline and finally 75% improvement in HECSI score from baseline in week 1.

[00468] 282. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8 and lastly a 90% improvement in HECSI score from baseline at week 8.

[00469] 283. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8 and finally a 90% improvement in HECSI score from baseline at week 6.

[00470] 284. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8 and finally a 90% improvement in HECSI score from baseline at week 4.

[00471] 285. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8 and finally 90% improvement at Petition 870250111574, dated 04 / 12 / 2025, page 78 / 220 / 106 HECSI score from baseline in week 2.

[00472] 286. The method of any of the modalities 229 to 242, in which the patient has a baseline HESD pain score (weekly average) > 4 points and the patient achieves a reduction in HESD pain score (weekly average) of > 4 points from baseline, an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 8 and finally a 90% improvement in HECSI score from baseline at week 1.

[00473] 287. The method of any of the modalities 229 to 286, in which the patient: is an adolescent aged 12 to 17 or an adult aged 18 or over; in which the patient has eczema of the hands that has persisted for more than 3 months or has returned two or more times within the last 12 months.

[00474] 288. The method of any of the modalities 229 to 286, in which the patient has a recent documented history of inadequate response to treatment with topical corticosteroids (TCS) or for whom TCS are documented to be otherwise clinically inadvisable (e.g., due to significant side effects or safety risks).

[00475] 289. The method of any of the modalities 229 to 286, in which the topical formulation is an aqueous cream.

[00476] 290. The method of embodiment 289, in which delgocitinib is dissolved in the aqueous phase of the aqueous cream.

[00477] 291. The method of embodiment 290, in which the aqueous cream is acidified and has a pH below about 4.6.

[00478] 292. The method of embodiment 291, in which the aqueous cream has a pH between about 3.8 and about 4.6.

[00479] 293. The method of embodiment 292, in which the aqueous topical formulation has a pH of about 4.3 or below. Petition 870250111574, dated 04 / 12 / 2025, page 79 / 220 / 106

[00480] 294. The method of embodiment 293 in which the aqueous topical formulation has a pH of about 4.2 or below.

[00481] 295. The method of any of the embodiments 291 to 294, in which the aqueous cream comprises a lipid base.

[00482] 296. The method of modality 295, in which the lipid base is liquid paraffin.

[00483] 297. The method according to any of the embodiments in 296, wherein the acidified aqueous topical composition or aqueous cream comprises surfactants, emulsifiers or stabilizers.

[00484] 298. The method according to claim 297, wherein the surfactants, emulsifiers or stabilizers are selected from one or more cetostearyl alcohols and macrogol cetoaryl ethers.

[00485] 299. The method of embodiment 298, in which the surfactants, emulsifiers or stabilizers are selected from at least about 30 mg / g to about 80 mg / g of cetostearyl alcohol.

[00486] 300. The method according to any of the modalities 298 to 299, the surfactants, emulsifiers or stabilizers are selected from at least about 12 mg / g to about 22 mg / g of macrogol cetostearyl ether.

[00487] 301. The method according to embodiment 296, wherein the aqueous cream or acidified aqueous topical composition comprises liquid paraffin present in an amount of about 60 mg / g or about 140 mg / g, cetostearyl alcohol in an amount of about 60 mg / g or about 90 mg / g and macrogol cetoaryl ether present in an amount of about 14 mg / g or about 22 mg / g.

[00488] 302. The method according to embodiment 301, wherein the aqueous cream or acidified aqueous topical composition comprises liquid paraffin in an amount of about 100 mg / g, cetostearyl alcohol in an amount of about 72 mg / g and macrogol ether Petition 870250111574, dated 04 / 12 / 2025, page 80 / 220 / 106 ketoaryl in an amount of approximately 18 mg / g.

[00489] 303. The method according to any of the modalities 296 to 302, wherein the aqueous cream or acidified aqueous topical composition comprises a pH buffer or regulator.

[00490] 304. The method of embodiment 303, in which the buffer is a phosphate, citrate or acetate buffer.

[00491] 305. The method of embodiment 304, wherein the aqueous cream or acidified aqueous topical composition comprises citric acid monohydrate in an amount of about 0.5 mg / g to about 4 mg / g.

[00492] 306. The method according to embodiment 305, wherein the aqueous cream or acidified aqueous topical composition comprises sodium citrate dihydrate in an amount of 0 mg / g to approximately 1 mg / g.

[00493] 307. The method according to any of the modalities 296 to 306, wherein the aqueous cream or acidified aqueous topical composition comprises benzyl alcohol in an amount of about 7 mg / g to about 13 mg / g.

[00494] 308. The method according to embodiment 307, wherein benzyl alcohol in an amount of about 9 mg / g or about 11 mg / g.

[00495] 309. The method according to any of the modalities 296 to 308, wherein the aqueous cream or acidified aqueous topical composition comprises butylhydroxyanisole in an amount of about 0.05 mg / g to about 0.3 mg / g.

[00496] 310. The method according to embodiment 309, wherein the aqueous cream or acidified aqueous topical composition comprises disodium edetate in an amount of about 0.05 mg / g to about 1.5 mg / g.

[00497] 311. The method according to any of the modalities 296 to 308, wherein the aqueous cream or acidified aqueous topical composition comprises hydrochloric acid in an amount of 0.1 mg / g approximately 25 mg / g. Petition 870250111574, dated 04 / 12 / 2025, page 81 / 220 / 106

[00498] 312. The method according to embodiment 311, wherein the aqueous cream or acidified aqueous topical composition comprises hydrochloric acid in an amount of 10 mg / g approximately 20 mg / g.

[00499] 313. The method according to any of the modalities 296 to 308, wherein the aqueous cream or acidified aqueous topical composition comprises purified water present in an amount of about 500 mg / g to about 900 mg / g.

[00500] 314. The method according to any of the modalities 296 to 313, wherein the aqueous cream or acidified aqueous topical composition comprises delgocitinib 20 mg / g; liquid paraffin, cetostearyl alcohol, macrogol cetoaryl ether, benzyl alcohol, citric acid, butylhydroxyanisole, disodium edetate, hydrochloric acid and purified water.

[00501] 315. The method according to embodiment 314, wherein the aqueous cream or acidified aqueous topical composition comprises delgocitinib 20 mg / g; liquid paraffin, 100 mg / g; cetostearyl alcohol, 72 mg / g; macrogol cetoaryl ether, 18 mg / g; benzyl alcohol, 10 mg / g; citric acid monohydrate, 1 mg / g; butylhydroxyanisole, 0.2 mg / g; disodium edetate, 0.6 mg / g; 3 M hydrochloric acid, 17.7 mg / g; and purified water, 760 mg / g.

[00502] 316. The method according to any of the modalities 296 to 315, wherein the skin permeability of the aqueous cream or acidified aqueous topical composition is approximately the same or improved compared to a 30 mg ointment comprising 30 mg / g delgocitinib, 820 mg / g white soft paraffin, 50 mg / g hard paraffin and 100 mg / g squalene as measured in the open flow microperfusion test in pigs.

[00503] 317. The method of any of the embodiments 1 to 316, wherein in the event of recurrence of signs and symptoms (rashes), twice-daily treatment of the affected areas is restarted as necessary.

[00504] 318. The method of any of the modalities 1 to 317, in Petition 870250111574, dated 04 / 12 / 2025, page 82 / 220 / 106, stating that administration to the skin of a human patient is the same as administration to the hands and wrists of a human patient.

[00505] 319. An acidified aqueous topical composition comprising 20 mg / g of delgocitinib in a pharmaceutically acceptable freebase or salt thereof according to any one of embodiments 1 to 318 for use in a method according to any one of embodiments 1 to 318.

[00506] 320. The use of delgocitinib for the manufacture of an acidified aqueous topical composition comprising 20 mg / g of delgocitinib in a pharmaceutically acceptable freebase or salt thereof according to any of the embodiments 1 to 318 for use in a method according to any of claims 1 to 318. Example 1

[00507] Delta 1 and Delta 2, two phase 3 clinical trials to confirm efficacy and evaluate safety of delgocitinib cream 20 mg / g twice daily compared to vehicle cream over a 16-week treatment period in adult subjects with moderate to severe chronic hand eczema (Delta 1).

[00508] The primary endpoint of the primary objective was IGA-CHE TS in week 16.

[00509] The secondary endpoint of the primary objective was HECSI-75 at week 16, HECSI-75 at week 8, HECSI-90 at week 16, IGA-CHE TS at week 8, IGA-CHE TS at week 4, and percentage change in HECSI score from baseline to week 16.

[00510] Other endpoints are described in tables 7 and 8 above.

[00511] For DELTA 1, 487 patients were randomized to delgocitinib cream (n = 325; 66.7%) and vehicle cream (n = 162; 33.3%) from 6 countries (Canada [n = 97], France [n = 81], Germany [n = 135], Italy [n = 45], Petition 870250111574, dated 04 / 12 / 2025, page 83 / 220 / 106 Poland [n = 105] and the United Kingdom [n = 24]). For DELTA 2, 473 patients were randomized from 7 countries (Belgium [n = 22], Canada [n = 97], Denmark [n = 22], Germany [n = 147], Netherlands [n = 24], Poland [n = 96], and Spain [n = 65]), with 314 (66.4%) receiving delgocitinib cream and 159 (33.6%) receiving vehicle cream. In total, 487 (DELTA 1) and 472 (DELTA 2) patients were included in the complete analysis set and safety analysis set. In total, 459 (94.3%) and 420 (88.8%) patients completed DELTA 1 and DELTA 2, respectively. In total, 6.2% (DELTA 1) and 7.0% (DELTA 2) of patients treated with delgocitinib cream and 13.0% (DELTA 1) and 23.3% (DELTA 2) of those in the cream vehicle groups discontinued study treatment. For both studies, baseline demographics and patient characteristics were comparable between patients treated with delgocitinib cream and patients treated with cream vehicle (Table 11).Overall, 99.4% (DELTA 1) and 98.5% (DELTA 1) of patients had a recent history of inadequate response to TCS treatment (Table 12). Demographic data and baseline characteristics: Table 11. Patient demographic data and baseline characteristics in DELTA 1 and DELTA 2 DELTA 1 DELTA 2 Total (N = 487) Delgocitinib cream 20 mg / g (N = 325) Creamy vehicle (N = 162) Total (N = 473) Delgocitinib cream 20 mg / g (N = 314) Creamy vehicle (N = 159) Age, median in years (min-max) 44.0 (19 to 87) 45.0 (19 to 87) 42.5 (20 to 73) 44.0 (18-86) 46.0 (18 to 83) 42.0 (18-86) Sex, n (%) Male Female 181 (37.2) 306 (62.8) 123 (37.8) 202 (62.2) 58 (35.8) 104 (64.2) 161 (34.0) 312 (66.0) 110 (35.0) 204 (65.0) 51 (32.1) 108 (67.9) Race, n (%) White Black or African American Asian Other / No information 427 (87.7) 4 (0.8) 19 (3.9) 37 (7.6) 283 (87.1) 3 (0.9) 14 (4.3) 25 (7.7) 144 (88.9) 1 (0.6) 5 (3.1) 12 (7.4) 441 (93.2) 3 (0.6) 15 (3.2) 14 (3.0) 295 (93.9) 2 (0.6) 8 (2.5) 9 (2.9) 146 (91.8) 1 (0.6) 7 (4.4) 5 (3.1) Region, n (%) Europe North America 390 (80.1) 97 (19.9) 260 (80.0) 65 (20.0) 130 (80.2) 32 (19.8) 376 (79.5) 97 (20.5) 250 (79.6) 64 (20.4) 126 (79.2) 33 (20.8) Petition 870250111574, dated 04 / 12 / 2025, page 84 / 220 / 106 DELTA 1 DELTA 2 DelgocitinibVehicle0 Total cream 20 Vehicle ... to-,·. / creamy (N = 487) Λ (N = 162) Total Delgocitinib Vehicle tN -47^3 cream 20 mg / g creamy (N = 3) (N = 314) (N = 159) Age at Onset of CHE, median (03 min- 3 to 2.0) years (0.3 min- 8.0). to 87) 30.0(0 to 72) 34.0(0 to 35.0 (0 to 83) 32.0 (0 to 77) 83) Duration of CHE, median (min- max.) years (min- max.) 6.0 (0 to 61) 6.0 to (0 to 5.51) 59) 4.0 (0 to 59) 5.0 (0 to 52) IGA-CHE, n (%) Moderately Severe 327 (67.1) 218 ​​(67.1) 109 (67.3) 160 (32.9) 107 (39.9) (756.32.32) (76.1) 121 (76.1) 113 (23.9) 75 (23.9) 38 (23.9) HECSI n Median (min-max.) 487 162 65.0 (10 to 325 61.5 (12 to 280) 121°2 660 59.0 (8 to 5927(7 to 59.0 (7 to 272) 213) DLQI n Median (min-max.) > 4, n (%) 479 321 158 12.0 (0 to 30) 12.0 (0 to 30) 12302 to 453 (94.6) 305 (95.0) 148 (93.7) 469 159 11.0 (1 to 310) 11.0 (2 to 30) 11.0 (1 to 28) 30) 452 (96.4) 299 (96.5) 153 (96.2) HESD Itching (weekly average) 486 162 469 157 n 7.3 (1.9 to 324) 7.6 (3.3 to 7.1 (2.3 to 312) 7.1 (2.6 to Median (min-max) 10.0) 7.2 (1.9 to 10.0) 10.0) 10.0) 7.1 (2.3 to 10.0) 10.0) > 4, n (%) 484 (99.6) 323 (99.7) 161 (99.4) 465 (99.1) 309 (99.0) 156 (99.4) HESD Pain (weekly average) 486 162 469 157 n 7.1 (0.8 to 324 7.2 (0.9 to 6.7 (0.0 to 312 6.7 (1.0 to Median (min-max) 10.0) 7.1 (0.8 to 10.0) 10.0) 10.0) 6.7 (0.0 to 10.0) 10.0) > 4, n (%) 440 (90.5) 291 (89.8) 149 (92.0) 435 (92.8) 294 (94.2) 141 (89.8) HESD (weekly average) 486 162 469 157 n 7.3 (1.4 to 324 7.3 (2.6 to 7.0 (2.1 to 312 7.1 (2.1 to Median (min-max.) 10.0) 7.2 (1.4 to 10.0) 10.0) 10.0) 7.0 (2.8 to 10.0) 10.0) > 4, n (%) 465 (95.7) 309 (95.4) 156 (96.3) 461 (98.3) 308 (98.7) 153 (97.5) Subtype of CH, an (%) Atopic hand eczema 217 (44.6) 143 (44.0) 74 (45.7) 128 (27.1) 82 (26.1) 46 (28.9) Allergic contact dermatitis 84 (17.2) 51 (15.7) 33 (20.4) 49 (10.4) 27 (8.6) 22 (13.8) Hyperkeratotic eczema 77 (15.8) 57 (17.5) 20 (12.3) 129 (27.3) 86 (27.4) 43 (27.0) Irritant contact dermatitis 75 (15.4) 49 (15.1) 26 (16.0) 113(23.9) 75(23.9) 38(23.9) Vesicular hand eczema (dyshidrosis) 34 (7.0) 25 (7.7) 9 (5.6) 53(11.2) 44(14.0) 9 (5.7). Note: Discrepancies in patient numbers for some assessments are due to some patients missing baseline assessments; HESD itching, HESD pain, and HESD scores range from 0 to 10; HEIS and HEIS PDAL range from 0 to 4. At baseline, one patient also presented with CHE subtype contact urticaria / contact dermatitis with protein. Petition 870250111574, dated 04 / 12 / 2025, page 85 / 220 / 106 Table 12. Summary of additional baseline characteristics and prior CHE treatments in DELTA 1 and DELTA 2 DELTA 1 DELTA 2 Total Delgocitinib Vehicle Cream 20 mg / g Creamy (N = 487) (n = 325) (N = 162) Total Delgocitinib Vehicle Cream 20 mg / g Creamy (N = 473) (N = 314) (N = 159) Number of eruptions experienced during the past year, n 0 1 to 2 3 to 5 6 to 10 11 to 20 >20 59 (12.3) 36 (11.1) 23 (14.6) 81 (16.8) 56 (17.3) 25 (15.8) 104 (2046) 70 (21.7) 34 (21.5) 95 (19.8) 64 (19.8) 31 (19.6) 98 (20.4) 65 (20.1) 33 (20.9) 44 (9.1) 32 (9.9) 12 (7.6) (%) 61 (13.0) 43 (13.7) 18 (11.4) 91 (19.3) 57 (18.2) 34 (21.5) 112 (23.8) 78 (24.9) 34 (21.5) 97 (20.6) 64 (20.4) 33 (20.9) 86 (18.3) 54 (17.3) 32 (20.3) 24 (5.1) 17 (5.4) 7 (4.4) HEIS n Median (min-max) 479 321 158 2.6 (0.0 to 2.7 (0.0 to 4.0) 2.6 (0.0 to 4.0) 4.0) 159 469 310 2.4 (0.2- 2 4 (0 2- 4.0) 2.4 (0.4-4.0) 4.0) HEIS PDAL n Median (min-max) 479 321 158 2.7 (0.0 to 2.7 (0.0 to 4.0) 2.7 (0.0 to 4.0) 4.0) 159 469 310 2.7 (0.0 to 2.74(00 to 2.7 (0.0 to 4.0) 4.0) Previous CHE treatments TCS, n (%) Inadequate response in the last 12 months 484 (99.4) 323 (99.4) 161 (99.4) 466 (98.5) 311 (99.0) 155 (97.5) Clinically inadvisable 118 (24.2) 79 (24.3) 39 (24.1) 77 (16.3) 48 (15.3) 29 (18.2) TCI, n (%) 174 (35.7) 121 (37.2) 53 (32.7) 175 (37.0) 113 (36.0) 62 (39.0) Phototherapy and other procedures, n (%) 92 (18.9) 65 (20.0) 27 (16.7) 99 (20.9) Oral retinoids, n (%) 60 (19.1) 39 (24.5) 67 (13.8) 45 (13.8) 22 (13.6) 76 (16.1) 52 (16.6) 24 (15.1) Oral corticosteroids, n (%) 59 (12.1) 46 (14.2) 13 (8.0) 78 (16.5) 50 (15.9) 28 (17.6) Oral methotrexate, n (%) 14 (2.9) 9 (2.8) 5 (3.1) 36 (7.6) 26 (8.3) 10 (6.3) Oral cyclosporine, n (%) 9 (1.8) 5 (1.5) 4 (2.5) 22 (4.7) 15 (4.8) 7(4,4) Other previous treatments of CHEa, n (%) 132(27,1) 91(28,0) 41(25,3) 80(16,9) 53(16,9) 27(17,0) Note: Discrepancies in patient numbers for some assessments are due to some patients who missed their baseline assessments. The most frequently reported (>2% of patients) included antihistamines, selected emollients and protectants, and antibiotics. CHE, Chronic Hand Eczema; HEIS, Hand Eczema Impact Scale; N, number of patients in the analysis set; n, number of patients under observation; PDAL: Limitations of Proximal Activities of Daily Living; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids. Investigational medicinal product (IMP)

[00512] Active IMP and placebo are presented in the table below: Petition 870250111574, dated 04 / 12 / 2025, page 86 / 220 / 106 Table 13. Investigational medicinal product Dosage form Active ingredient and concentration Package size Delgocitinib cream 20 mg / g Cream Delgocitinib, 20 mg / g 15 g Creamy vehicle Cream Vehicle 15 g

[00513] Delgocitinib cream 20 mg / g comprises: Delgocitinib 20 mg / g; liquid paraffin, 100 mg / g; cetostearyl alcohol, 72 mg / g; macrogol cetoaryl ether, 18 mg / g; benzyl alcohol, 10 mg / g; citric acid monohydrate, 1 mg / g; butylhydroxyanisole, 0.2 mg / g; disodium edetate, 0.6 mg / g; 3 M hydrochloric acid, 17.7 mg / g; and purified water, 760 mg / g.

[00514] The creamy vehicle comprises the same excipients in corresponding amounts. IMP Administration

[00515] IMP (delgocitinib cream 20 mg / g or cream vehicle) was applied as a topical application approximately 12 hours apart twice daily for 16 weeks. Inclusion criteria:

[00516] Subjects must meet all of the following criteria to be eligible for the test: 1. Signed and dated informed consent was obtained before any procedure related to the protocol.

[00517] 2. Age 18 or above at screening.

[00518] 3. Diagnosis of CHE, defined as eczema of the hands that has persisted for more than 3 months or has recurred two or more times within the last 12 months.

[00519] 4. Disease severity classified as moderate to severe at screening and baseline according to the IGA-CHE (i.e., an IGA-CHE score of 3 or 4).

[00520] 5. HESD itch score (weekly average) of > 4 points at baseline. The baseline weekly average will be calculated from Petition 870250111574, dated 04 / 12 / 2025, p. 87 / 220 / 106 daily assessments of itching severity during the 7 days immediately preceding the baseline visit (Day -7 to Day -1). A minimum of 4 itching scores from the 7 days is required to calculate the average baseline score.

[00521] 6. Subjects who have a recent documented history of inadequate response to TCS treatment (at any time within 1 year prior to the screening visit) or for whom TCS are documented to be otherwise clinically inadvisable (e.g., due to significant side effects or safety risks).

[00522] • Inadequate response is defined as a history of failure to achieve and maintain a low disease activity state (comparable to an IGA-CHE score of >2) despite treatment with a daily regimen of Class III to IV (potent to very potent) TCS for Europe and Class IV to I (medium to very / ultra-high potency) for Canada, applied for at least 28 days or for the maximum duration recommended by the product information, whichever is shorter.

[00523] • Important side effects or safety risks are those that outweigh the potential benefits of treatment and include treatment intolerance, hypersensitivity reactions, and significant skin atrophy as assessed by the physician.

[00524] 7. Subjects who adhered to standard non-medicated skin care including avoidance of known and relevant irritants and allergens.

[00525] 8. A woman of childbearing potential should use an acceptable method of birth control throughout the trial until the last IMP application. Exclusion criteria:

[00526] Subjects are not eligible for the test if they meet Petition 870250111574, dated 04 / 12 / 2025, page 88 / 220 / 106 any of the following criteria: 1. Concurrent skin diseases on the hands, for example, tinea manuum.

[00527] 2. Active AD requiring medical treatment in regions other than the hands and feet.

[00528] 3. Active psoriasis on any part of the body.

[00529] 4. Hyperkeratotic eczema of the hands in combination with a history of psoriasis anywhere on the body.

[00530] 5. Clinically significant infection (e.g., impetiginized hand eczema) on the hands.

[00531] 6. Systemic treatment with immunosuppressive drugs (e.g., methotrexate, cyclosporine, azathioprine), immunomodulatory drugs, retinoids (e.g., alitretinoin) or corticosteroids within 28 days before baseline (steroid eye drops and inhaled or intranasal steroids matching up to 1 mg of prednisolone for allergic conjunctivitis, asthma or rhinitis are permitted).

[00532] 7. Use of tanning beds, phototherapy (e.g., UVB, UVA1, PUVA), or hand bleaching baths within 28 days prior to baseline.

[00533] 8. Prior or current treatment with JAK inhibitors (including delgocitinib / LEO 124249), systemic or topical.

[00534] 9. Topical treatment with immunomodulators (e.g., PDE-4 inhibitors, pimecrolimus, tacrolimus) or TCS on the hands within 14 days prior to baseline.

[00535] 10. Use of systemic antibiotics or topical antibiotics applied to the hands within 14 days prior to baseline.

[00536] 11. Other therapy applied transdermally or cutaneously to the hands (except for the use of emollients of the subject's own) within 7 days prior to baseline. Petition 870250111574, dated 04 / 12 / 2025, pages 89 / 220 / 106

[00537] 12. Cutaneous treatments applied to areas other than the hands that would interfere with clinical trial assessments or present a safety concern within 7 days prior to baseline.

[00538] 13. Treatment with any marketed biological therapy or investigational biological agents (including immunoglobulin, anti-IgE, and dupilumab): • Any agents that deplete lymphocytes, including but not limited to rituximab: within 6 months before baseline or until lymphocyte counts return to normal, whichever is longer.

[00539] • Other biological products: within 3 months or 5 half-lives, whichever is longer, before baseline.

[00540] 14. Treatment with any unmarketed pharmacological substance (i.e., an agent that is not yet available for clinical use following registration) within the last 28 days before baseline or 5 half-lives, whichever is longer.

[00541] 15. Clinically significant infection within 28 days prior to baseline that, in the researcher's opinion, could compromise the subject's safety in the trial, interfere with IMP assessment, or reduce the subject's ability to participate in the trial.

[00542] Clinically significant infections are defined as: • A systemic infection.

[00543] • A serious skin infection requiring parenteral (intravenous or intramuscular) antibiotics, antiviral or antifungal medication.

[00544] 16. History of any known primary immunodeficiency disorder including a positive HIV virus test at screening, or the subject taking antiretroviral medications as determined by medical history and / or verbal information from the subject. Petition 870250111574, dated 04 / 12 / 2025, pages 90 / 220 / 106

[00545] 17. Major surgery within 8 weeks prior to screening, or surgery or hospitalization planned for the patient admitted during the trial period.

[00546] 18. History of cancer: • Subjects who have had basal cell carcinoma, localized squamous cell carcinoma of the skin, or carcinoma in situ of the cervix are eligible provided that the subject is in remission and curative therapy has been completed at least 12 months prior to screening.

[00547] • Subjects who have had other malignancies are eligible provided that the subject is in remission and curative therapy was completed at least 5 years prior to screening.

[00548] 19. Any disturbance that was not stable and: • It affected the subject's safety throughout the entire test.

[00549] • It prevented the subject from completing the test.

[00550] Examples include, but are not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, immunological, and psychiatric disorders and severe physical disability.

[00551] 20. Any abnormal findings that may: • To put the subject at risk because of their participation in the test.

[00552] • To influence the subject's ability to complete the test.

[00553] Abnormal findings must be clinically significant and observed during the screening period. Examples include abnormal findings on physical examination, vital signs, ECG, hematology, clinical chemistry, or urinalysis.

[00554] 21. Positive hepatitis B surface antigen or hepatitis C virus antibody serology on screening.

[00555] 22. ALT or AST level > 2.0 x ULN on screening. Petition 870250111574, dated 04 / 12 / 2025, pages 91 / 220 / 106

[00556] 23. Known or suspected hypersensitivity to any of the components of IMP

[00557] 24. Current participation in any other interventional clinical trial.

[00558] 25. Previously randomized in this clinical trial.

[00559] 26. Current or recent chronic alcohol or drug abuse, or any other condition associated with insufficient acceptance as judged by the investigator.

[00560] 27. Employees of the testing site or any other individual directly involved with the planning or conduct of the test or immediate family members of such individuals.

[00561] 28. Subjects who are legally institutionalized. Women who are pregnant or breastfeeding. Test outline Screening period (Week -4 to week 0)

[00562] The screening period had a minimum duration of 1 week and a maximum duration of 4 weeks (i.e., the screening visit occurred between Week -4 and Week -1). For subjects using treatments that are listed as exclusion criteria, the duration of the screening period depends on the required elimination period. In view of a 28-day elimination period for some of these treatments, the screening period may be extended to 31 days. Only subjects who are considered capable of stopping prohibited treatment during the screening period without experiencing intolerable worsening of CHE symptoms will be included in the trial.

[00563] During the screening visit, the subjects' eligibility to participate in the trial was checked.

[00564] The subject's CHE subtype(s) was / were classified according to standard clinical practice in Canada and Europe. Treatment period (Week 0 to week 16) Petition 870250111574, dated 04 / 12 / 2025, page 92 / 220 / 106

[00565] At baseline (Day 1), the eligibility of subjects to enter the trial was confirmed. Eligible subjects were randomized 2:1 to delgocitinib cream 20 mg / g or vehicle cream.

[00566] The IMP (delgocitinib cream 20 mg / g or creamy vehicle) was applied twice daily for 16 weeks. The first IMP application occurred at the test site on Day 1 after all baseline assessments were performed. All subsequent IMP applications were performed by subjects at home.

[00567] During the 16-week treatment period, subjects returned to the testing sites for efficacy and safety assessments. The final IMP application occurs at the subject's home before the subject attends the scheduled visit in week 16. Efficacy and safety assessments were conducted throughout the treatment period.

[00568] All eligible subjects who did not permanently discontinue IMP before week 16 were invited to participate in the LTE trial. Follow-up period (Week 16 to week 18)

[00569] These subjects who do not participate in the LTE trial will have a follow-up visit (conducted by telephone, but may be an on-site visit if necessary) approximately 2 weeks after the last IMP application for safety assessment. Note that for subjects who have permanently discontinued IMP, the 2-week follow-up period will begin at the time of the last IMP application.

[00570] Subjects participating in the LTE trial will not be required to complete the follow-up period, as safety data collection and safety monitoring will continue in the LTE trial. Effectiveness in weeks 4, 8, and 16:

[00571] For DELTA 1 and DELTA 2, the endpoint of the primary study (IGA-CHE score of 0 [clear] or 1 [almost clear] with at least one Petition 870250111574, dated 04 / 12 / 2025, page 93 / 220 / 106 2-step improvement at week 16) was achieved in 19.7% (n = 64; DELTA 1) and 29.1% (n = 91; DELTA 2) of patients in the delgocitinib cream groups and 9.9% (n = 16; DELTA 1) and 6.9% (n = 11; DELTA 2) of those in the corresponding cream vehicle groups (Figure 1). The proportion of patients achieving IGH-CHE TS at week 16 was statistically significantly higher in the delgocitinib cream groups compared with the cream vehicle groups (P > 0.006 for both studies). Across all 16-week DELTA 1 and DELTA 2 treatment periods, the proportion of patients achieving IGA-CHE treatment success was higher with delgocitinib cream treatment compared with the cream vehicle, with a statistically significant number of patients treated with delgocitinib achieving IGA-CHE treatment success versus those treated with the cream vehicle at Weeks 4 (P >0.043) and 8 (P >0.001) (Figure 1).

[00572] At week 16, the percentage of patients achieving HECSI-75 and HECSI-90 scores and a >4 point reduction in DLQI score from baseline was statistically significantly higher in the DELTA 1 and DELTA 2 delgocitinib cream groups compared with their corresponding cream vehicle groups (P<0.001; Figures 2A to C).

[00573] In the DELTA 1 trial, the least squares (LS) meaning change in HESD pain score from baseline to week 16 was -3.4 in patients treated with delgocitinib cream and -1.8 in those treated with cream vehicle (P<0.001; Figure 3). In the DELTA 2 study, the corresponding mean LS changes were -3.3 in the delgocitinib cream group and -1.3 in the cream vehicle group (P<0.001).Among patients with a baseline HESD pain score > 4 points, the proportion of patients treated with delgocitinib cream achieving a reduction > 4 points in HESD pain score from baseline to week 16 was statistically significantly higher (DELTA 1: Petition 870250111574, dated 04 / 12 / 2025, page 94 / 220 / 106 49.1%; DELTA 2: 48.6%) compared with those treated with creamy vehicle (DELTA 1: 27.5%; DELTA 2: 22.7%; P<0.001; Figures 4A to B).

[00574] A similar reduction in HESD itch score was observed in DELTA 1, with the mean change in LS from baseline to week 16 being -3.6 in the delgocitinib cream group and -1.9 in the vehicle cream group (P<0.001; Figure 5). In the DELTA 2 study, corresponding mean changes in LS were -3.4 for patients treated with delgocitinib cream and -1.4 for those treated with vehicle cream (P<0.001). Consequently, among study participants with a baseline HESD itch score of > 4 points, the proportion of patients treated with delgocitinib cream achieving a > 4-point reduction in HESD itch score from baseline to week 16 was statistically significantly higher (DELTA 1: 47.1%; DELTA 2: 47.2%) compared with those treated with vehicle cream (DELTA 1: 23.0%; DELTA 2: 19.9%; delgocitinib cream vs vehicle cream: P<0.001; Figure 4B).

[00575] In DELTA 1 and DELTA 2, patients treated with delgocitinib achieved significantly higher mean LS reductions in pain and itch scores from baseline versus those receiving creamy vehicle at Weeks 1–4 (P>0.002; Figures 3 and 5). Similarly, among patients with >4 points in HESD pain and itch scores at baseline, the proportion of patients treated with delgocitinib cream who achieved a >4 point reduction in HESD pain and itch scores from baseline at Weeks 2–4 was significantly higher than those treated with creamy vehicle (P >0.031; Figure 4A–B).

[00576] Among patients with a baseline HESD score of > 4 points, the proportion of patients treated with delgocitinib cream achieving a > 4 point reduction in HESD score from baseline to week 16 was statistically significantly higher (DELTA Petition 870250111574, dated 04 / 12 / 2025, pages 95 / 220 / 106 Delta 1: 47.2%; Delta 2: 44.5%) compared to those treated with creamy vehicle (Delta 1: 24.4%; Delta 2: 20.9%; P<0.001). The differences for the vehicle were 22.8% for Delta 1 and 23.6% for Delta 2. Security:

[00577] In DELTA 1 and DELTA 2, a comparable percentage of patients treated with delgocitinib cream and vehicle cream reported AEs (delgocitinib cream: 45.2% [DELTA 1] and 45.7% [DELTA 2]; vehicle cream: 50.6% [DELTA 1] and 44.7% [DELTA 2]; Figure 6). Most AEs were mild to moderate and not considered related to the study treatment. In both trials, the most frequently reported AEs were COVID-19 and nasopharyngitis, as well as headache. The proportion of patients who reported AEs leading to discontinuation of study treatment was lower in the delgocitinib cream treatment groups (DELTA 1: 0.6%; DELTA 2: 0.3%) compared with their corresponding vehicle cream groups (DELTA 1: 3.7%; DELTA 2: 3.1%). The results and action taken with the study drug following the occurrence of AEs were similar across all study groups in DELTA 1 and DELTA 2 (Figure 7).In both studies, few serious AEs (1.9% of patients) were reported, and all were assessed as unrelated to the study drug by both the investigator and the study sponsor; none led to any safety issues. No treatment-specific emergent safety issues were identified in DELTA 1 and DELTA 2. No AEs of special interest (eczema herpeticum, deep vein thrombosis, or pulmonary embolism) were reported in DELTA 1 and DELTA 2. No major adverse cardiac events were reported in the delgocitinib treatment arms for either study. There were no changes or differences between treatment groups in hematology, biochemistry, vital signs, physical examination, or ECG that were assessed to be clinically relevant. Petition 870250111574, dated 04 / 12 / 2025, pages 96 / 220 / 106

[00578] In DELTA 1 and DELTA 2, 41.9 to 47.2% of patients treated with delgocitinib cream and 36.9 to 41.2% of those treated with vehicle cream experienced no burning or stinging in week 1, with the proportion of patients increasing to 90.0 to 91.7% (delgocitinib cream) and 88.6 to 91.8% (vehicle cream) in week 16 (Table 14). Table 14. Assessment of local tolerability for worsening burning or stinging in connection with the application of study drug as assessed by study participants over selected weeks (safety analysis set) n (%) DELTA 1 DELTA 2 Delgocitinib 20 mg / g (N = 325) Creamy vehicle (N = 162) Delgocitinib 20 mg / g (N = 313) Creamy vehicle (N = 159) Week 1 288 (100.0) 141 (100.0) 248 (100.0) 136 (100.0) None 136 (47.2) 52 (36.9) 104 (41.9) 56 (41.2) Mild 94 (32.6) 46 (32.6) 93 (37.5) 44 (32.4) Moderate 43 (14.9) 23 (16.3) 39 (15.7) 22 (16.2) Severe 15 (5.2) 20 (14.2) 12 (4.8) 14 (10.3) Week 4 295 (100.0) 143 (100.0) 264 (100.0) 137 (100.0) None 173 (58.6) 61 (42.7) 149 (56.4) 64 (48.9) Mild 86 (29.2) 50 (35.0) 82 (31.1) 38 (29.0) Moderate 30 (10.2) 26 (18.2) 25 (9.5) 20 (15.3) Severe 6 (2.0) 6 (4.2) 8 (3.0) 9 (6.9) Week 8 293 (100.0) 136 (100.0) 252 (100.0) 124 (100.0) None 207 (70.6) 69 (50.7) 154 (61.1) 66 (53.2) Mild 58 (19.8) 36 (26.5) 71 (28.2) 36 (29.0) Moderate 24 (8.2) 28 (20.6) 25 (9.9) 14 (11.3) Severe 4 (1.4) 3 (2.2) 2 (0.8) 8 (6.5) c „ 28 Week 12 3 (100.0) 134 (100.0) 252 (100.0) 119 (100.0) * u _ 20 None 0 (70.7) 70 (52.2) 161 (63.9) 73 (61.3) Soft 59 (20.8) 41 (30.6) 66 (26.2) 28 (23.5) Moderate 21 (7.4) 19 (14.2) 22 (8.7) 13 (10.9) Severe 3 (1.1) 4 (3.0) 3 (1.2) 5 (4.2) c 14 30 Week 16 3 (100.0) 140 (100.0) 291 (100.0) 122 (100.0) , 27 None 8 (91.7) 124 (88.6) 262 (90.0) 112 (91.8) Mild 18 (5.9) 12 (8.6) 22 (7.6) 8 (6.6) Moderate 6 (2.0) 4 (2.9) 7 (2,4) 2 (1,6) Severe 1 (0,3) 0 0 0 a Assessed weekly in eDiary. N, number of patients in the analysis set; n, number of patients under observation.

[00579] A numerically higher proportion of patients treated with delgocitinib cream reported no tolerability or mild problems compared to those in the Week 1 cream vehicle group. Petition 870250111574, dated 04 / 12 / 2025, pp. 97 / 220 / 106 onwards. According to the researcher's assessment of local tolerability, delgocitinib cream was well tolerated by all subjects in both tests (Table 15). Few subjects had a patch test performed during the study (DELTA 1: n = 2 [delgocitinib cream] en = 4 [creamy vehicle]; DELTA 2: n = 1 [delgocitinib cream] en = 4 [creamy vehicle]). Table 15. Researcher's assessment of local tolerability based on suspected local skin reaction related to the study drug at the visit (safety analysis set) DELTA 1 DELTA 2 Delgocitinib Creamy vehicle Delgocitinib Creamy vehicle n (%) 20 mg / g (N = 325) (N = 162) 20 mg / g (N = 313) (N = 159) Week 1 318 (100.0) 157 (100.0) 303 (100.0) 150 (100.0) Yes 1 (0.3) 3 (1.9) 0 2 (1.3) No 317 (99.7) 154 (98.1) 303 (100.0) 148 (98.7) Week 2 311 (100.0) 153 (100.0) 294 (100.0) 148 (100.0) Yes 0 0 0 1 (0.7) No 311 (100.0) 153 (100) 294 (100.0) 147 (99.3) Week 4 308 (100.0) 152 (100.0) 295 (100.0) 136 (100.0) Yes 0 0 0 2 (1.5) No 308 (100.0) 152 (100) 295 (100.0) 134 (98.5) Week 8 308 (100.0) 142 (100.0) 289 (100.0) 126 (100.0) Yes 0 1 (0.7) 0 0 No 308 (100.0) 141 (99.3) 289 (100.0) 126 (100,0) Week 12 305 (100,0) 143 (100,0) 292 (100,0) 123 (100,0) Yes 0 0 0 0 No 305 (100,0) 143 (100) 292 (100,0) 123 (100,0) Week 16 305 (100,0) 141 (100,0) 291 (100,0) 122 (100,0) Yes 0 0 0 0 No 305 (100,0) 141 (100) 291 (100,0) 122 (100,0) Early termination 18 (100,0) 14 (100,0) 17 (100,0) 27 (100,0) Yes 0 1 (7,1) 1 (5,9) 3 (11,1) No 18 (100,0) 13 (92,9) 16 (94.1) 24 (88.9) End of treatment 324 (100.0) 157 (100.0) 310 (100.0) 150 (100.0) Yes 0 2 (1.3) 1 (0.3) 3 (2.0) No 324 (100) 155 (98.7) 309 (99.7) 147 (98.0)

[00580] The classification of all AEs, AEs related to the study drug, and AEs leading to discontinuation of the study drug were numerically higher with the creamy vehicle compared with delgocitinib from baseline to the end of the trial.

[00581] In general, delgocitinib cream provided the greatest improvements in Petition 870250111574, dated 04 / 12 / 2025, page 98 / 220 / 106 efficacy results both patient-reported and clinical versus creamy vehicle and was well tolerated over 16 weeks. Example 2

[00582] A randomized, double-blind, vehicle-controlled, parallel-group, multi-site, phase 3-phase clinical trial to confirm the efficacy and evaluate the safety of delgocitinib cream 20 mg / g twice daily compared with vehicle cream during a 16-week treatment period in adult subjects with moderate to severe chronic hand eczema (DELTA 2) Subjects

[00583] A total of 473 subjects were randomized 2:1 to delgocitinib cream 20 mg / g (314) or creamy vehicle (159).

[00584] The inclusion and exclusion criteria are the same as in example 1.

[00585] The investigational medicinal product (IMP) and the administration of IMP are the same as in example 1.

[00586] The test project is the same as in example 1.

[00587] Results: At week 16, a significantly higher proportion of patients treated with delgocitinib, compared to the cream vehicle, achieved IGA-CHE TS (29.1% vs. 6.9%; p<0.001), HECSI75 (49.5% vs. 18.2%; p<0.001), HECSI-90 (31.0% vs. 8.8%; p<0.001) and > 4 points improvement in DLQI (72.2% vs. 45.8%; p<0.001). There was no difference between delgocitinib and cream vehicle in the proportion of patients reporting adverse events (AEs; 45.7% vs. 44.7%) and serious AEs (1.6% vs. 1.9%). The classification of AEs assessed as likely or possibly related to the study drug was consistent between delgocitinib (31.29 per 100 patient observation years [PYO]) and creamy vehicle (30.87 per 100 PYO). The classification of AEs leading to discontinuation of the study drug was numerically higher. Petition 870250111574, dated 04 / 12 / 2025, page 99 / 220 / 106 high levels with creamy vehicle (11.02 per 100 PYO) compared to delgocitinib (1.04 per 100 PYO).

[00588] Overall, delgocitinib cream demonstrated the greatest improvements in both patient-reported and clinical efficacy outcomes versus vehicle cream and was well tolerated at 16 weeks. These results were consistent with those previously reported from the identically designed DELTA 1 study (example 1). Systemic exposure investigation:

[00589] Blood samples collected 2 to 6 hours after administration of the investigational medicinal product at Weeks 1, 4, and 16 were used to analyze plasma concentrations of delgocitinib using a liquid chromatography / mass spectrometry-based method with a lower limit of quantification of 5 pg / ml. The 50% inhibitory concentration (IC50) of delgocitinib was assessed using an in vitro IL-4 release assay in whole blood from healthy volunteers (n = 4). In the Phase 1 trial, single oral doses of delgocitinib (1.5, 3, 6, and 12 mg) were tested in healthy volunteers (n = 40). Data are reported as geometric means.

[00590] Results: The DELTA 2 analysis included samples from 313 subjects on active treatment. Plasma delgocitinib concentrations were 0.21, 0.20, and 0.12 ng / ml at Weeks 1, 4, and 16, respectively. The IC50 for delgocitinib was 17.2 ng / ml. In the Phase 1 study, the lowest oral dose of delgocitinib tested (1.5 mg) was perceived as a subtherapeutic dose. The peak systemic exposure (Cmax) of orally dosed delgocitinib at 1.5 mg was 7.2 ng / ml, meaning that systemic exposure after topical application in the DELTA 2 test was > 30 times lower (7.2 ng / ml divided by 0.21 ng / ml).

[00591] Conclusion: Twice-daily application of delgocitinib cream resulted in minimal systemic exposure, at least 80 times lower Petition 870250111574, dated 04 / 12 / 2025, pp. 100 / 220 / 106 of the IC50 of whole blood at 16 weeks (17.2 ng / ml divided by 0.21 ng / ml) and at least 30 times lower than the oral dose of delgocitinib at 1.5 mg with no overlap in plasma exposure between oral and topical administration. These data further support the favorable safety profile of delgocitinib topical cream and suggest that no systemic pharmacological effects are expected with a 20 mg / g dose in patients with moderate to severe CH. Example 3

[00592] DELTA 1 and DELTA 2 were identically designed multicenter phase 3 trials in which adult patients with moderate-to-severe CHE were randomized (2:1) to double-blind treatment with delgocitinib 20 mg / g cream or vehicle cream twice daily for 16 weeks. In a pooled analysis of both trials, changes in EQ-5D scores from baseline to week 16 were assessed in all patients and in a post-hoc analysis of patients achieving clinical responses (defined as Hand Eczema Area and Severity Index (HECSI) -50, -75, and -90, Researcher Global Assessment for CHE treatment success [IGA-CHE TS; clear or near-clear skin with an improvement > 2 steps from baseline] and improvements > 4 points in Hand Eczema Daily Symptom (HESD) itch and pain scores). Results:

[00593] A total of 639 patients were randomized to delgocitinib cream 20 mg / g and 321 to vehicle cream through both tests. The majority of patients were white (90%), female (64%), with moderate CHE disease severity at baseline (72%). Mean ± SD of the EQ-5D score at baseline was 0.65 ± 0.23 in the delgocitinib group and 0.64 ± 0.24 in the vehicle cream group. Treatment with delgocitinib resulted in a significantly greater improvement in EQ-5D from baseline. Petition 870250111574, dated 04 / 12 / 2025, pp. 101 / 220 / 106 baseline compared with creamy vehicle at week 16 (least squares mean change [SE] 0.17 ± 0.01 vs. 0.06 ± 0.01; difference [95% CI] 0.11 (0.08, 0.13), p<0.001) (Figure 10). Improvements in the EQ-5D were significantly greater with delgocitinib versus creamy vehicle across all five EQ-5D dimensions (mobility, self-care, usual activities, pain / discomfort, and anxiety / depression). When analyzed by clinical response, there were clinically significant changes in EQ-5D (minimally important difference >0.082) across different responder thresholds, suggesting that improvements in HRQoL are likely associated with clinical response. Furthermore, improvements in EQ-5D were consistently higher with delgocitinib compared with creamy vehicle within each clinical responder group, all of which were statistically significant except for the IGA-CHE TS category.This is in addition to significantly more patients treated with delgocitinib achieving a clinical response across different clinical responder thresholds. Conclusion:

[00594] In patients with moderate to severe CHF with a substantial decrease in HRQoL, 16 weeks of twice-daily treatment with delgocitinib cream 20 mg / g resulted in a statistically significantly greater improvement than the creamy vehicle not only in clinical outcomes but also in HRQoL as measured by the EQ5D score. Among patients achieving a clinical response across multiple responder thresholds, treatment with delgocitinib resulted in an even greater HRQoL benefit than the creamy vehicle. This HRQoL improvement was considered clinically significant. Example 4

[00595] DELTA 1 and DELTA 2 were identically designed phase 3 trials. In both trials, adult patients with moderate to severe CHE Petition 870250111574, dated 04 / 12 / 2025, pp. 102 / 220 / 106 were randomized (2:1) to double-blind treatment with delgocitinib cream 20 mg / g or vehicle cream twice daily for 16 weeks. Data were pooled from both trials, and changes in DLQI scores were assessed from baseline to week 16 in all patients and in a post-hoc analysis of patients achieving clinical responses, defined as Hand Eczema Area and Severity Index (HECSI) -50, -75, and -90, Researcher Global Assessment of Treatment Success for CHS (IGA-CHE TS; a score of 0 / 1 with an improvement > 2 steps from baseline), and improvements of > 4 points in Hand Eczema Daily Symptom (HESD) itching and pain scores. Results:

[00596] Through two trials, 639 patients were randomized to delgocitinib cream 20 mg / g and 321 to vehicle cream. Most patients were white (90%), female (64%), and had a mean duration of CHE of approximately 10 years. The mean ± SD of the DLQI score at baseline was 12.4 ± 6.1 in the delgocitinib group and 12.4 ± 6.7 in the vehicle cream group. Delgocitinib resulted in a significantly greater improvement (i.e., reduction) in the DLQI from baseline compared with creamy vehicle at week 16 (least squares mean change [SE] -7.25 ± 0.22 vs. -3.46 ± 0.31; difference [95% CI] -3.79 (-4.55, -3.04), p<0.001) (Figure 11). DLQI improvements at week 16 were significantly greater (p<0.001) with delgocitinib versus creamy vehicle across all ten DLQI items, particularly those concerning embarrassment or self-consciousness related to skin and effects on work, social and leisure, and other daily activities.When analyzed by clinical response, greater improvements in DLQI with delgocitinib versus creamy vehicle were observed across all clinical responder categories, with these differences statistically significant for all except HECSI-90 and IGA-CHE TS. This is in addition to a larger proportion. Petition 870250111574, dated 04 / 12 / 2025, page 103 / 220 / 106 discharge of patients treated with delgocitinib than creamy vehicle achieving a clinical response as assessed through all responder thresholds (all p<0.001). Conclusion:

[00597] Twice-daily application of delgocitinib cream 20 mg / g resulted in a significant improvement in HRQoL versus cream vehicle as measured by the DLQI in patients with moderate to severe CH. In patients with a clinical response, the HRQoL benefit was greater with delgocitinib than with cream vehicle. Example 5

[00598] A phase 3 clinical trial to evaluate the efficacy and safety of twice-daily applications of delgocitinib cream 20 mg / g compared to vehicle cream during a 16-week treatment period in adolescents aged 12 to 17 years with moderate to severe chronic hand eczema (DELTA TEEN). Subjects

[00599] Approximately 92 subjects were randomized 3:1 to delgocitinib cream 20 mg / g or creamy vehicle. Inclusion criteria

[00600] The same as in example 2, except for the following inclusion criteria: 1. A signed and dated IC (Informed Consent Form) was obtained prior to any protocol-related procedure. The signed and dated IC must be provided by the subject's relative / guardian and / or by the subject in the form of a signed and dated IC / IA (as applicable according to national laws or regulations).

[00601] 2. Age 12 to 17 years at screening and baseline.

[00602] 3. HESD itch score (weekly average) of > 4 points at baseline. The weekly average baseline will be calculated from Petition 870250111574, dated 04 / 12 / 2025, page 104 / 220 100 / 106 daily assessments of itching severity during the 7 days immediately preceding the baseline visit (Day -7 to Day -1). A minimum of 4 itching scores from the 7 days is required to calculate the average baseline score. Exclusion criteria

[00603] Same as in example 1 except: Subjects or relatives / guardians who have current or recent chronic alcohol or drug abuse, or any other condition associated with poor adherence as judged by the researcher. IMP Investigational medicinal product (IMP)

[00604] Active IMP and placebo are presented in the table below: Table 16. Investigational medicinal product Dosage form Active ingredient and concentration Packaging size Manufacturer responsible for batch release Delgocitinib cream 20 mg / g Cream Delgocitinib, 20 mg / g 30 g LEO Pharma A / S Creamy vehicle Cream Vehicle 30 g LEO Pharma A / S

[00605] The excipients of delgocitinib cream 20 mg / g e creamy vehicle are the same as in example 1.

[00606] IMP (delgocitinib cream 20 mg / g or cream vehicle) was applied as a topical application approximately 12 hours apart twice daily for 16 weeks. Test outline

[00607] The test is a phase 3, randomized, double-blind, vehicle-controlled, parallel-group, multi-site trial. The trial is designed to evaluate the efficacy and safety of delgocitinib cream 20 mg / g applied twice daily for 16 weeks in adolescents aged 12 to 17 years with moderate to severe chronic hand eczema. Screening period (Week -4 to week 0)

[00608] The screening period has a minimum duration of 1 week and Petition 870250111574, dated 04 / 12 / 2025, page 105 / 220 101 / 106 a maximum duration of 4 weeks (i.e., screening visit should occur between Week -4 and Week -1). For subjects using treatments that are listed as exclusion criteria, the duration of the screening period will depend on the required elimination period. In view of a 28-day elimination for some of these treatments and the permitted visit window (+3 days), the screening period was extended to 31 days. Only subjects who are considered capable of discontinuing the prohibited treatment during the screening period without experiencing intolerable worsening of signs and symptoms of CH will be included in the trial.

[00609] During the screening visit, the subjects' eligibility to participate in the test was checked. The specific test measurements will be performed as outlined in the test procedures program.

[00610] The CHE subtype(s) of the subjects will be classified according to standard clinical practice in Europe, Canada and Australia. Treatment period (Weeks 0 to 16)

[00611] At baseline (Day 1), the eligibility of subjects to enter was confirmed. Eligible subjects were randomized 3:1 to delgocitinib cream 20 mg / g or vehicle cream.

[00612] Subjects / caregivers applied the IMP (delgocitinib cream 20 mg / g or creamy vehicle) twice daily for 16 weeks. The first IMP application occurred at the test site at baseline (Day 1) after all baseline assessments were performed. All subsequent IMP applications were performed by the subjects / caregivers at home.

[00613] During the 16-week treatment period, subjects returned to the testing sites for efficacy and safety assessments. Follow-up period (Weeks 16 to 18)

[00614] Subjects were followed up by telephone (or a site visit) approximately 2 weeks after the last IMP application for safety assessment. Note that for subjects who Petition 870250111574, dated 04 / 12 / 2025, page 106 / 220 102 / 106 discontinued IMP treatment prematurely; the 2-week follow-up period began at the time of the last IMP application. Final points

[00615] The endpoints for the test are described in tables 9 and 10 above. Example 6

[00616] Two different formulations comprising Delgocitinib were tested in I) Biomarker test in human skin explant (NativeSkin) and II) Open Flow Microperfusion (OFM) in vivo in pigs, to explore the PKPD profiles of delgocitinib in different test systems. Formulations tested.

[00617] Ointment: Delgocitinib ointment at 30 mg / g as described in D1 (WO2017 / 125523)

[00618] Cream: Delgocitinib 20 mg / g cream formulation as described in the patent application as filed (WO2020229622) Biomarker test in human skin explant

[00619] The two formulations were tested on NativeSkin models from Genoskin, France (LEO Pharma A / S experiment number EXP-20176909). The biomarkers for JAK inhibition, phosphorylated STAT3 / total STAT3 ratio (pY-STAT3 / STAT3), were measured 24 hours after application of ointment (30 mg delgocitinib / g) or cream (20 mg delgocitinib / g), compared to control and blank cream (3 different donors for each treatment).

[00620] The results are shown in Figure 8.

[00621] The Delgocitinib cream formulation inhibited the upregulation of the pY-STAT3 / STAT3 ratio significantly more Petition 870250111574, dated 04 / 12 / 2025, page 107 / 220 103 / 106 compared to the ointment (Figure 3) showing that significantly more Delgocitinib permeates into the skin from 20 mg / g of the cream of the invention compared to the 30 mg / g of ointment described in WO2017 / 125523. Open flow microperfusion

[00622] The two formulations were tested in vivo in pigs of the local variety at the Joanneum Research Institute, Austria (LEO Pharma A / S report number REP-DJR-2018-01). Delgocitinib concentrations were measured in the dermis up to 12 hours after application of ointment (30 mg delgocitinib / g) or cream (20 mg delgocitinib / g), using OFM (Figure 9).

[00623] The unbound concentration of delgocitinib in dermal interstitial fluid was calculated from the perfused concentration compensated for relative recovery in configuration and protein binding measured in vitro. Two pigs with two test fields for each formulation were treated and three probes were inserted into each test field (n = 12 individual probes per treatment).

[00624] The concentration of unbound dermal interstitial fluid (dISF) of delgocitinib was higher after application of the cream formulation compared to the ointment (Figure 3). The dISF concentration after cream application was clearly higher compared to the unbound potency, showing that more delgocitinib permeates into the skin from the 20 mg / g cream compared to the 30 mg / g ointment, which was in line with the inhibitory effect on the biomarker observed in the human skin explant experiment. Example 7

[00625] Itching and pain are two of the most common and bothersome symptoms of chronic hand eczema. Delgocitinib cream, a topical panJanus kinase inhibitor, was well tolerated and demonstrated significant improvement in all primary and secondary efficacy endpoints in DELTA-1 and DELTAPetition 870250111574, dated 04 / 12 / 2025, page 108 / 220 104 / 106 2.

[00626] This analysis includes pooled data from DELTA-1 and -2 (delgocitinib cream 20 mg / g [n = 639]; creamy vehicle [n = 321]; twice daily). The Hand Eczema Symptom eDiary (HESD) captured patient-reported severity of itching and pain over the past 24 hours on an 11-point numerical score scale (0 = no itching / pain to 10 = severe itching / pain). Changes in itching and pain from baseline were assessed daily during Week (W)1 and weekly from W1 to W16.

[00627] For itching, the mean least squares (LS) reduction from baseline was 0.22 to 1.32 in the delgocitinib cream group and 0.21 to 0.68 in the cream vehicle group between Day (D)17. For pain, a mean LS reduction from baseline of 0.13 to 1.43 versus 0.26 to 0.81 was observed, respectively. From W1 to 16, patients treated with delgocitinib achieved higher mean LS reductions from baseline in the itching score (1.0 to 3.5) versus those who received cream vehicle (0.4 to 1.7; P<0.001). Similar results were observed for mean LS pain reduction (delgocitinib cream: 0.9 to 3.3; cream vehicle: 0.4 to 1.5; P<0.001).Among patients with > 4 HESD itch / pain score points at baseline, the proportion of patients treated with delgocitinib cream achieving a > 4 HESD itch / pain score reduction from baseline on W2 to 16 was higher than those treated with vehicle cream (P > 0.001).

[00628] Early onset of itching and pain reduction was observed within W1 for patients treated with delgocitinib, with reductions remaining significantly greater versus patients treated with creamy vehicle from W1 to W16. Example 8

[00629] In the phase 3 DELTA 2 trial, delgocitinib cream 20 mg / g, one Petition 870250111574, dated 04 / 12 / 2025, pp. 109 / 220 105 / 106 topical pan-Janus kinase inhibitor was well tolerated and demonstrated significant improvement in all efficacy endpoints versus vehicle cream in adults with moderate to severe chronic hand eczema (CHE).

[00630] Pharmacokinetic blood sampling in DELTA 2 was performed 2 to 6 hours after delgocitinib administration at Weeks 1, 4, and 16 using a liquid chromatography / mass spectrometry-based method (lower limit of quantification: 5 pg / ml). In the phase 1 trial (NCT05050279), single oral doses of delgocitinib were tested in healthy volunteers with sampling performed up to 24 hours after administration.

[00631] In Delta 2, the geometric mean + / - SD of the maximum plasma concentration (Cmax) and area under the concentration curve from time 0 to 12 hours (AUC0-12) on day 8 was 0.46 ng / ml ± 0.28 and 3.7 ng*h / ml ± 1.88, respectively. Steady state was reached on Day 8. Systemic exposure (AUC and Cmax) between day 1 and day 8 was similar and negligible.

[00632] In DELTA 2, minimal systemic exposure was recorded in 313 patients treated with delgocitinib, with the highest geometric mean plasma concentration being 0.21 ng / ml at week 1 (n = 286). At week 16, systemic absorption was detected in only a few patients, and detectable absorption decreased by 48% to an average of 0.11 ng / ml in the remaining subjects. In the Phase 1 trial, the lowest oral delgocitinib dose tested (1.5 mg; n = 8) is considered subtherapeutic and showed a peak systemic exposure (geometric mean Cmax) of 7.2 ng / ml. In DELTA 2, adverse events (AEs) were reported by 45.7% (n = 143 / 313; delgocitinib cream) and 44.7% (n = 71 / 159; vehicle cream) of patients, with COVID-19 being the most common (11.5% vs 12.6%, respectively). The likelihood rate related to AEs was low and similar between delgocitinib cream and vehicle cream. None Petition 870250111574, dated 04 / 12 / 2025, pages 110 / 220 106 / 106 deaths were reported. Few SAES were reported without any being assessed as related to the study drug.

[00633] The plasma protein binding of delgocitinib is 22 to 29%.

[00634] Following repeated topical administration of delgocitinib cream, the mean half-life of delgocitinib was estimated to be 20.3 hours.

[00635] The DELTA 2 trial demonstrated minimal systemic exposure associated with a favorable safety profile, supporting a lack of significant systemic effect from twice-daily applications of delgocitinib cream in patients with moderate to severe CH. Petition 870250111574, dated 04 / 12 / 2025, pages 111 / 220

Claims

1 / 2 CLAIMS 1. Use of an acidified aqueous topical composition comprising 20 mg / g of delgocitinib in a pharmaceutically acceptable freebase or salt thereof, characterized in that it is for the manufacture of a medicament for treating moderate to severe chronic hand eczema in a human patient in need thereof, comprising twice-daily administration to the skin of said human patient, wherein the patient has disease severity classified as moderate to severe at screening and baseline according to IGA-CHE (i.e., an IGA-CHE score of 3 or 4).

2. Use according to claim 1, characterized in that the patient has a baseline HESD itch score (weekly average) of > 4 points.

3. Use according to claim 1 or 2, characterized in that the patient is an adolescent aged 12 to 17 or an adult aged 18 or above; wherein the patient has eczema of the hands that has persisted for more than 3 months or has returned two or more times within the last 12 months.

4. Use in accordance with any of claims 1 to 3, characterized in that the patient has a recent documented history of inadequate response to treatment with topical corticosteroids (TCS) or for whom TCS are documented to be otherwise clinically inadvisable (due to significant side effects or safety risks).

5. Use in accordance with any of claims 1 to 4, characterized in that the patient achieves an IGA-CHE score of 0 (clear) or 1 (near clear) with an improvement > 2 steps from baseline at week 16, or week 8, or week 4, or week 2, or week 1. Petition 870250083402, dated 09 / 16 / 2025, pp. 249 / 251 2 / 2 6. Use in accordance with any one of claims 1 to 5, characterized in that the patient achieves at least a 75% improvement in the HECSI score from baseline at week 16, or week 8, or week 4, or week 2, or week 1.

7. Use in accordance with any of claims 1 to 6, characterized in that the patient achieves a reduction in DLQI score of > 4 points from baseline at week 16, or week 8, or week 4, or week 2, or week 1.

8. Use in accordance with any of claims 1 to 7, characterized in that no accumulation of delgocitinib in the body is observed, wherein administration to the skin of a human patient is administration to the hands and wrists of a human patient.

9. Use according to any one of claims 1 to 8, characterized in that delgocitinib is dissolved in the aqueous phase of the topical formulation, and wherein the aqueous topical formulation has a pH below about 4.6 or below about 4.4, or the aqueous topical formulation has a pH between about 3.8 and about 4.6, or the aqueous topical formulation has a pH of about 4.3 or below, or the aqueous topical formulation has a pH of about 4.2 or below.

10. Use in accordance with any of claims 1 to 9, characterized in that the aqueous cream comprises a lipid base, and in that the lipid base is liquid paraffin. Petition 870250083402, dated 09 / 16 / 2025, pp. 250 / 251

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