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Combination Comprising Palbociclib And 6 (2,4 Dichlorophenyl) 5 [4 [(3 S) 1 (3 Fluoropropyl)pyrrolidin 3 Yl]Oxyphenyl] 8,9 Dihydro 7 H Benzo[7] Annulene 2 Carboxylic Acid And Its Use For The Treatment Of Cancer

Abstract: Herein are provided a combination of palbociclib and of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2- carboxylic acid or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing such a combination, and the therapeutic uses thereof, in particular for the treatment of cancer, including breast cancer.

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Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
22 January 2020
Publication Number
09/2020
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
PATENTS@DPAHAUJA.COM
Parent Application

Applicants

SANOFI
54 rue La Boétie 75008 PARIS

Inventors

1. BOUABOULA, Monsif
c/o Sanofi Patent Department 54 rue La Boétie 75008 PARIS
2. SHOMALI, Maysoun
c/o Sanofi Patent Department 55 Corporate Drive Mail Code: 55A-505A BRIDGEWATER, New Jersey 08807
3. SUN, Fangxian
c/o Sanofi Patent Department 55 Corporate Drive Mail Code: 55A-505A BRIDGEWATER, New Jersey 08807

Specification

COMBINATION COMPRISING PALBOCICLIB AND 6-(2,4-DICHLOROPHENYL)-5-[4-[(3S)-1 -(3-FLUOROPROPYL)PYRROLIDIN-3-YL]OXYPHENYL]-8,9-DIHYDRO-7H-BENZO[7] ANNULENE-2-CARBOXYLIC ACID AND ITS USE FOR THE TREATMENT OF CANCER Herein are provided a combination of palbociclib and of 6-(2,4-dichlorophenyl)-5-[4- [(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, a pharmaceutical composition containing such a combination, and the therapeutic uses of such combination and pharmaceutical composition, in particular for the treatment of cancer. The estrogen receptor a (ESR1 ) is expressed in the majority of breast tumors, enabling them to respond to the mitogenic actions of estrogens. 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, hereafter designated as "compound (1 )", is a selective estrogen receptor degrader (SERD) which has complete estrogen receptor antagonist properties and accelerates the proteasomal degradation of the estrogen receptor. This compound is disclosed in the patent application PCT/EP2017/053282, published as WO 2017/140669. Palbociclib, also known as 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(1 -piperazinyl)pyridine-2-ylamino]pyrido[2,3-d]pyrimidin-7(8H)-one, is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. Palbociclib is marketed under the tradename Ibrance® and is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer, in combination with an aromatase inhibitor, or in combination with fulvestrant in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist. There is always a need to find new antitumoral treatments. Now, it has been shown that a combination of compound (1 ) with palbociclib is well tolerated, demonstrates strong anti-tumor efficacy and induces tumor regression, with a synergistic effect compared to each of the active ingredient alone. Herein is provided a combination comprising compound (1 ) and palbociclib. In the combination provided herein, compound (1 ) may exist not only in the form of a zwitterion (i.e. a globally neutral molecule having an acid group and a basic group), but also in the form of addition salts with acids or bases. Such addition salts may be used in the above combination. Hence, herein is provided a combination comprising compound (1 ), or a pharmaceutically acceptable salt thereof, and palbociclib. In an embodiment, the combination of compound (1 ), or a pharmaceutically acceptable salt thereof, with palbociclib shows therapeutic synergy. A combination demonstrates therapeutic synergy if its therapeutic effect is superior compared to the cumulative effect of either active agent of the combination alone. In another embodiment, compound (1 ), or a pharmaceutically acceptable salt thereof, and palbociclib are administered by the oral route. Provided herein is also a combination of compound (1 ), or a pharmaceutically acceptable salt thereof, and palbociclib for its use as a medicament. Provided herein is also a pharmaceutical composition comprising compound (1 ), or a pharmaceutically acceptable salt thereof, and palbociclib, as well as at least one pharmaceutically acceptable excipient. The excipients are selected from the customary excipients which are known to a person skilled in the art. More particularly, the excipients are selected from those useful for oral administration in whatever form (liquid solution, dispersion or suspension, tablets, capsules or the like). In another embodiment, compound (1 ), or a pharmaceutically acceptable salt thereof, and palbociclib may be administered simultaneously, separately, or spaced out over a period of time (sequential administration). Therefore, the combination provided herein is not exclusively limited to the one which is obtained by physical association of the constituents in a single pharmaceutical composition, but also to those which allow a separate administration, which can be simultaneous or spaced out (or "spread out") over time. Herein is also provided a pharmaceutical kit which comprises: (i) a first pharmaceutical composition comprising compound (1 ), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient; (ii) a second pharmaceutical composition comprising palbociclib, and at least one pharmaceutically acceptable excipient; both pharmaceutical compositions (i) and (ii) being in separate compartments and being intended to be independently administered, each administration with regards to the other one being simultaneous, separated or spread out (sequential) over time. In the combinations, pharmaceutical compositions and pharmaceutical kit described above, the compound (1 ) or pharmaceutically acceptable salt thereof and palbociclib are advantageously present at effective doses, adapted considering the treated pathology and the condition of the patient to which it is administered. In particular for palbociclib, the recommended starting dose for cancer treatment for adult patients is 125 mg once daily for 21 days followed by 7 days off treatment, along with dosing interruption and/or dose reductions based on individual safety and tolerability. Herein is also provided a combination comprising compound (1 ), or a pharmaceutically acceptable salt thereof, and palbociclib, as well as a pharmaceutical composition and kit as described above, for use in the treatment of cancer. Herein is also provided compound (1 ) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer by co-administration with palbociclib. Herein is also provided palbociclib for use in the treatment of cancer by coadministration with compound (1 ) or a pharmaceutically acceptable salt thereof. In another embodiment, the cancer is a hormone dependent cancer. In another embodiment, the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor a dependent cancer. In another embodiment, the cancer is resistant to anti-hormonal treatment. In another embodiment, the cancer is a cancer with wild type estrogen receptors. In another embodiment, the cancer is a cancer with deregulated function of estrogen receptors related to, but not limited to, at least one epigenetic and genetic alteration of estrogen receptors such us mutation, amplification, splice variant. In another embodiment, the cancer is a cancer with mutated estrogen receptors. In another embodiment, the mutations of estrogen receptors can include, but not limited to, new or known mutations such as Leu536Arg, Tyr537Ser, Tyr537Asn, or Asp538Gly. In another embodiment, the cancer is an estrogen-sensitive cancer. In another embodiment, the cancer is breast cancer, more particularly an estrogen receptor positive breast cancer (ERa positive breast cancer), or a metastasis thereof, such as a cerebral metastasis. Herein is also provided a method of treating the pathological conditions indicated above, particularly breast cancer, comprising administering to a subject in need thereof a therapeutically effective amount of compound (1 ), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of palbociclib. Herein is also provided a method of treating the pathological conditions indicated above, particularly breast cancer, comprising administering to a subject in need thereof a pharmaceutical composition as described above. Herein is also provided a method of treating the pathological conditions indicated above, particularly breast cancer, comprising administering to a subject in need thereof a combination as described above. Herein is also provided a method of treating the pathological conditions indicated above, particularly breast cancer, comprising co-administering to a subject in need thereof compound (1 ) or a pharmaceutically acceptable salt thereof and palbociclib. Herein is also provided a method of treating the pathological conditions indicated above, particularly breast cancer, comprising co-administering to a subject in need thereof palbociclib and compound (1 ) or a pharmaceutically acceptable salt thereof. In an embodiment of the methods described above, the subject is a human. Herein is also provided a combination comprising compound (1 ), or a pharmaceutically acceptable salt thereof, and palbociclib for the manufacture of a medicament useful in treating the pathological conditions indicated above, particularly breast cancer. Herein is also provided the use of compound (1 ), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament useful in treating the pathological conditions indicated above, particularly breast cancer, by co-administration with palbociclib. Herein is also provided the use of palbociclib in the manufacture of a medicament useful in treating the pathological conditions indicated above, particularly breast cancer, by co-administration with compound (1 ) or a pharmaceutically acceptable salt thereof. Herein is also provided an article of manufacture, a packaging, or an administration unit, comprising: - a packaging material; - the above defined combination, pharmaceutical composition or pharmaceutical kit; and - a label or package insert contained within said packaging material, indicating that said combination, pharmaceutical composition or pharmaceutical kit is administered to a patient for the treatment of cancer. The examples below show how to synthesize compound (1 ), and the pharmacological results obtained with compound (1 ), palbociclib and their combination against a breast cancer cell line xenograft in mice. 1 - Synthesis of 6-(2,4-dichlorophenyl)-5-r4-r(3S)-1 -(3-fluoropropyl) PVrrolidin-3-vnoxyphenvn-8,9-dihydro-7H-benzof71annulene-2-carboxylic acid The experimental protocol for synthesizing 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (compound (1 )), described in the patent application WO 2017/140669, is reproduced below, along with its analytical data. The synthetic scheme for the synthesis of compound (1 ) is found in Figure 1. The 1 H NMR spectra were performed on a Bruker Avance DRX-400 spectrometer, with the chemical shifts (δ in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz. The liquid chromatography/mass spectra (LC/MS) were obtained on a UPLC Acquity Waters instrument, light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210 40% is considered as therapeutically inactive. Percent tumor regression is defined as % (percentage) of tumor volume decrease in the treated group on a specified observation day compared to its volume when the study was initiated. At a specific time point (t) and for each animal, the regression percentage is calculated using the following formula: volumet0 - volumet % regression (at t) 100 volume t,o The median percent regression for a group on a given day is then calculated by taking the median of individual % regression values calculated for each animal in the group. The day of calculation is determined by the day when ΔΤ/ΔΟ is calculated, excepted if median percent regression is not representative of the activity of the group. In this case, the day is determined by the first day when the median percent regression is maximal. 2-1 -3: Statistical analysis A two-way Anova-Type analysis with factors treatment and day (repeated) is performed on tumor volume changes from baseline. It is followed by contrast analyses with Bonferroni-Holm correction for multiplicity to compare all treated groups to the control group and to compare the combination versus each single agent at the dose involved in the combination at each day from day 27 to 51. In the figures, the medians and Median Absolute Deviation (MAD) of each group are represented for each day of measurement. In the tables, the medians and Normalized MAD (nMAD = 1.4826*MAD) of each group are reported for each day of measurement. Tumor volume changes from baseline are calculated for each animal and each day by subtracting the tumor volume on the day of first treatment (day 21 ) from the tumor volume on the specified observation day. All statistical analyses were performed using SAS version 9.2 software. A probability of less than 5% (p<0.05) was considered as significant. 2-2: Results Compound (1 ) at 5 mg/kg BID, palbociclib 100 mg/kg QD and the combination of compound (1 ) and palbociclib at the doses and regime for 30 days were well tolerated in this study showing average body weight change in % per group at nadir (the lowest of body weight drop in the group) of -1 .7% (day 22), -2.0% (day 22) and -6.4% (day 26), respectively (Table 1 ). Compound (1 ) at a dose of 5 mg/kg BID for 30 days had minimal effect on tumor growth with ΔΤ/ΔΟ value of 59% (p = 0.41 13) on day 51 . Palbociclib at a dose of 100 mg/kg QD for 30 days achieved anti-tumor efficacy with ΔΤ/ΔΟ value of 27% (p<0.0001 ) on day 51 . When compound (1 ) at 5 mg/kg combined with palbociclib 100 mg/kg with the same dose regime as BID for compound (1 ) and QD for palbociclib, the combination treatment demonstrated strong anti-tumor efficacy with ΔΤ/ΔΟ value less than 0 (p < 0.0001 ) and induced tumor regression (median tumor regression 32%) on day 51 . The statistical analysis indicated the combination effect was significantly different when compared to either compound (1 ) alone or palbociclib alone on day 51 (p <0.0001 ). Detailed results are shown in Tables 1 , 2 and 3 below, as well as in Figures 2 and 3: - Figure 2: Antitumor activity of compound (1 ) combined with palbociclib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft in nude mice: tumor volume evolution. The curves represent medians + or - MAD (Median Absolute Deviation) at each day for each group; - Figure 3: Antitumor activity of compound (1 ) combined with palbociclib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft in nude mice: tumor volume changes from baseline on day 51 . Points represent individual tumor volume changes from baseline on day 51 , bars correspond to medians. From this experiment, we conclude that the compound (1 ) at 5 mg/kg twice a day combined with the CDK4 inhibitor palbociclib at 100 mg/kg once a day induced significant anti-tumor efficacy and tumor regression in MCF7-Y537S human breast cancer cell line xenograft model in nude mice that was superior to single agents alone. Table 1 : Efficacy of compound (1 ) combined with palbociclib against subcutaneous MCF7-Y537S human breast cancer xenograft i nude mice. Table 2: Efficacy of compound (1 ) combined with palbociclib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft model in nude mice. Comparison of each group to the control group at each day. Tumor volume changes from baseline mm3 : Median (nMAD)*, n and p-value* # p-values obtained with a contrast analysis versus control at each day with Bonferroni-Holm adjustment for multiplicity after a two-way Anova-Type on tumor volume changes from baseline. * MAD= Median Absolute Deviation; nMAD= normalized MAD; nMAD= 1.4826*MAD. For palbociclib at 100 mg/kg, the effect on tumor volume changes from baseline is significant compared to the control group from day 30 to day 51. For the combination compound (1 ) at 5 mg/kg + palbociclib at 100 mg/kg, the effect on tumor volume changes from baseline is significant compared to the control group from day 27 to day 51. n = number of animals. 3 mice were excluded from statistical analysis because those mice corresponded to non- drug related death or terminations during the study. Table 3: Efficacy of compound (1 ) combined with palbociclib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft model in nude mice. Comparison of compound (1 ) 5 mg/kg and palbociclib 100 mg/kg as single agents versus the combination at each day. Tumor volume changes from baseline mm3 : Median (nMAD)*, n and p-value* Treatment Global Day 27 Day 30 Day 34 Day 37 Day 41 Day 44 Day 49 Day 51 Group Compound (1) 5 mg/kg -8.0 -17.0 -35.0 -30.0 -43.0 -63.0 -53.0 -52.0 - + (63.75) (97.85) (74.13) (57.82) (60.79) (45.96) (72.65) (72.65) n=9 n=9 n=9 n=9 n=9 n=9 n=9 n=9 Palbociclib 100 mg/kg 68.5 98.0 121.5 132.0 193.5 249.5 298.5 363.5 Palbociclib (31.88) (25.20) (34.10) (31.88) (52.63) (43.74) (97.11) (108.23) 100 mg/kg n=10 n=10 n=10 n=10 n=10 n=10 n=10 n=10 O.0001 0.2417 0.0736 0.0026 0.0002 <0.0001 <0.0001 <0.0001 <0.0001 114.0 171.5 270.5 336.0 440.0 498.5 727.5 782.0 Compound (19.27) (31.13) (112.68) (112.68) (39.29) (91.18) (160.86) (112.68) (1) n=8 n=8 n=8 n=8 n=8 n=8 n=8 n=8 5 mg/kg O.0001 0.0342 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 # p-values obtained with a contrast analysis to compare the combinations of compound (1) and palbociclib versus each single agent at the dose involved in the combination at each day with Bonferroni-Holm adjustment for multiplicity after a two-way Anova-Type on tumor volume changes from baseline. * MAD= Median Absolute Deviation; nMAD= normalized MAD ; nMAD= 1.4826*MAD The effect of the combination of compound (1) at 5 mg/kg + palbociclib at 100 mg/kg is significantly greater than the effect of palbociclib at 100 mg/kg alone on day 34 to day 51. The effect of the combination of compound (1) at 5 mg/kg + palbociclib at 100 mg/kg is significantly greater than the effect of compound (1) at 5 mg/kg alone on day 27 to day 51. n = number of animals. 3 mice were excluded from statistical analysis because those mice corresponded to non-drug related death or terminations during the study. CLAIMS 1 . A combination comprising 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, or a pharmaceutically acceptable salt thereof, and palbociclib. 2. The combination according to claim 1 , showing therapeutic synergy. 3. The combination according to claim 1 or claim 2, for use in the treatment of cancer. 4. The combination according to claim 4, wherein the cancer is breast cancer. 5. A pharmaceutical composition comprising 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, or a pharmaceutically acceptable salt thereof, and palbociclib, and at least one pharmaceutically acceptable excipient. 6. The pharmaceutical composition according to claim 5, wherein 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, or a pharmaceutically acceptable salt thereof, and palbociclib are administered simultaneously, separately, or spaced out over a period of time. 7. The pharmaceutical composition according to claim 5 or claim 6, for use in the treatment of cancer. 8. The pharmaceutical composition according to claim 7, wherein the cancer is breast cancer. 9. Compound 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid or a pharmaceutically acceptable salt thereof for use in the treatment of cancer by co-administration with palbociclib. 10. Palbociclib for use in the treatment of cancer by co-administration with compound 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 1 1 . A pharmaceutical kit comprising: (i) a first pharmaceutical composition comprising 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 - (3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2- carboxylic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient; (ii) a second pharmaceutical composition comprising palbociclib, and at least one pharmaceutically acceptable excipient; both pharmaceutical compositions (i) and (ii) being in separate compartments and being intended to be independently administered, each administration with regards to the other one being simultaneous, separated or spread out over time.

Documents

Application Documents

# Name Date
1 202037002932-US(14)-ExtendedHearingNotice-(HearingDate-21-12-2023).pdf 2023-12-06
1 202037002932.pdf 2020-01-22
2 202037002932-TRANSLATIOIN OF PRIOIRTY DOCUMENTS ETC. [22-01-2020(online)].pdf 2020-01-22
2 202037002932-US(14)-HearingNotice-(HearingDate-04-12-2023).pdf 2023-10-18
3 202037002932-STATEMENT OF UNDERTAKING (FORM 3) [22-01-2020(online)].pdf 2020-01-22
3 202037002932-Information under section 8(2) [04-11-2022(online)].pdf 2022-11-04
4 202037002932-POWER OF AUTHORITY [22-01-2020(online)].pdf 2020-01-22
4 202037002932-FER.pdf 2021-10-18
5 202037002932-FORM 1 [22-01-2020(online)].pdf 2020-01-22
5 202037002932-ABSTRACT [30-09-2021(online)].pdf 2021-09-30
6 202037002932-DRAWINGS [22-01-2020(online)].pdf 2020-01-22
6 202037002932-CLAIMS [30-09-2021(online)].pdf 2021-09-30
7 202037002932-DECLARATION OF INVENTORSHIP (FORM 5) [22-01-2020(online)].pdf 2020-01-22
7 202037002932-CORRESPONDENCE [30-09-2021(online)].pdf 2021-09-30
8 202037002932-DRAWING [30-09-2021(online)].pdf 2021-09-30
8 202037002932-COMPLETE SPECIFICATION [22-01-2020(online)].pdf 2020-01-22
9 202037002932-FER_SER_REPLY [30-09-2021(online)].pdf 2021-09-30
9 202037002932-Proof of Right [21-07-2020(online)].pdf 2020-07-21
10 202037002932-FORM 3 [21-07-2020(online)].pdf 2020-07-21
10 202037002932-OTHERS [30-09-2021(online)].pdf 2021-09-30
11 202037002932-FORM 18 [17-06-2021(online)].pdf 2021-06-17
12 202037002932-FORM 3 [21-07-2020(online)].pdf 2020-07-21
12 202037002932-OTHERS [30-09-2021(online)].pdf 2021-09-30
13 202037002932-FER_SER_REPLY [30-09-2021(online)].pdf 2021-09-30
13 202037002932-Proof of Right [21-07-2020(online)].pdf 2020-07-21
14 202037002932-COMPLETE SPECIFICATION [22-01-2020(online)].pdf 2020-01-22
14 202037002932-DRAWING [30-09-2021(online)].pdf 2021-09-30
15 202037002932-CORRESPONDENCE [30-09-2021(online)].pdf 2021-09-30
15 202037002932-DECLARATION OF INVENTORSHIP (FORM 5) [22-01-2020(online)].pdf 2020-01-22
16 202037002932-CLAIMS [30-09-2021(online)].pdf 2021-09-30
16 202037002932-DRAWINGS [22-01-2020(online)].pdf 2020-01-22
17 202037002932-ABSTRACT [30-09-2021(online)].pdf 2021-09-30
17 202037002932-FORM 1 [22-01-2020(online)].pdf 2020-01-22
18 202037002932-FER.pdf 2021-10-18
18 202037002932-POWER OF AUTHORITY [22-01-2020(online)].pdf 2020-01-22
19 202037002932-STATEMENT OF UNDERTAKING (FORM 3) [22-01-2020(online)].pdf 2020-01-22
19 202037002932-Information under section 8(2) [04-11-2022(online)].pdf 2022-11-04
20 202037002932-US(14)-HearingNotice-(HearingDate-04-12-2023).pdf 2023-10-18
20 202037002932-TRANSLATIOIN OF PRIOIRTY DOCUMENTS ETC. [22-01-2020(online)].pdf 2020-01-22
21 202037002932.pdf 2020-01-22
21 202037002932-US(14)-ExtendedHearingNotice-(HearingDate-21-12-2023).pdf 2023-12-06

Search Strategy

1 SearchStrategyE_25-06-2021.pdf