IP Library › Granted Patent US 11,365,239

Granted Patent B2

US 11,365,239 · App. 16/953,304 · Granted Jun 21, 2022

Anti-SARS-COV-2 antibodies and uses thereof

Inventors: Zheng Zhang (Shenzhen, CN); Linqi Zhang (Beijing, CN); Lei Liu (Shenzhen, CN); Qi Zhang (Beijing, CN); Bin Ju (Shenzhen, CN); Xuanling Shi (Beijing, CN); Qing Zhu (Beijing, CN)

C07K16/10 A61K2039/505 A61K2039/545 C07K2317/31 C07K2317/52 C07K2317/76 C07K2317/94

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Patent No.: US 11,365,239
App. No.: 16/953,304
Granted: Jun 21, 2022
Kind: B2

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Abstract

Provided herein are modified anti-SARS-COV-2 antibodies or antigen binding fragments thereof having extended half life and optimized immune activities. Disclosed herein is also directed to pharmaceutical compositions comprising the same and a method for treating or preventing a disease in human patients that is caused by or related to the infection of SARS-COV-2.

Claims (75)

1. A modified antibody or an antigen-binding fragment thereof comprising at least an antigen-binding domain and a covalently linked modified human IgG constant domain, wherein the antigen-binding domain has a specific binding affinity to receptor binding domain (RBD) comprising the sequence of SEQ ID NO: 128 from the spike protein for SARS-CoV-2, wherein said modified human IgG constant domain comprises a substitution with tyrosine at amino acid residue 252, a substitution with threonine at amino acid residue 254, and a substitution with glutamic acid at amino acid residue 256, numbered according to the EU index as in Kabat, and wherein said antigen-binding domain comprises:

a. a heavy chain CDR1 (HCDR1) comprising the sequence of SEQ ID NO: 1, a heavy chain CDR2 (HCDR2) comprising the sequence of SEQ ID NO: 2, a heavy chain CDR3 (HCDR3) comprising the sequence of SEQ ID NO: 3; a light chain CDR1 (LCDR1) comprising the sequence of SEQ ID NO: 4, a light chain CDR2 (LCDR2) comprising the sequence of SEQ ID NO: 5, and a light chain CDR3 (LCDR3) comprising the sequence of SEQ ID NO: 6;

b. a HCDR1 comprising the sequence of SEQ ID NO: 11, a HCDR2 comprising the sequence of SEQ ID NO: 12, a HCDR3 comprising the sequence of SEQ ID NO: 13, a LCDR1 comprising the sequence of SEQ ID NO: 14, a LCDR2 comprising the sequence of SEQ ID NO: 15, and a LCDR3 comprising the sequence of SEQ ID NO: 16;

c. a HCDR1 comprising the sequence of SEQ ID NO: 21, a HCDR2 comprising the sequence of SEQ ID NO: 22, a HCDR3 comprising the sequence of SEQ ID NO: 23, a LCDR1 comprising the sequence of SEQ ID NO: 24, a LCDR2 comprising the sequence of SEQ ID NO: 25, and a LCDR3 comprising the sequence of SEQ ID NO: 26;

d. a HCDR1 comprising the sequence of SEQ ID NO: 31, a HCDR2 comprising the sequence of SEQ ID NO: 32, a HCDR3 comprising the sequence of SEQ ID NO: 33, a LCDR1 comprising the sequence of SEQ ID NO: 34, a LCDR2 comprising the sequence of SEQ ID NO: 35, and a LCDR3 comprising the sequence of SEQ ID NO: 36;

e. a HCDR1 comprising the sequence of SEQ ID NO: 41, a HCDR2 comprising the sequence of SEQ ID NO: 42, a HCDR3 comprising the sequence of SEQ ID NO: 43, a LCDR1 comprising the sequence of SEQ ID NO: 44, a LCDR2 comprising the sequence of SEQ ID NO: 45, and a LCDR3 comprising the sequence of SEQ ID NO: 46;

f. a HCDR1 comprising the sequence of SEQ ID NO: 51, a HCDR2 comprising the sequence of SEQ ID NO: 52, a HCDR3 comprising the sequence of SEQ ID NO: 53, a LCDR1 comprising the sequence of SEQ ID NO: 54, a LCDR2 comprising the sequence of SEQ ID NO: 55, and a LCDR3 comprising the sequence of SEQ ID NO: 56;

g. a HCDR1 comprising the sequence of SEQ ID NO: 65, a HCDR2 comprising the sequence of SEQ ID NO: 66, a HCDR3 comprising the sequence of SEQ ID NO: 67, a LCDR1 comprising the sequence of SEQ ID NO: 68, a LCDR2 comprising the sequence of SEQ ID NO: 69, and a LCDR3 comprising the sequence of SEQ ID NO: 70;

h. a HCDR1 comprising the sequence of SEQ ID NO: 75, a HCDR2 comprising the sequence of SEQ ID NO: 76, a HCDR3 comprising the sequence of SEQ ID NO: 77, a LCDR1 comprising the sequence of SEQ ID NO: 78, a LCDR2 comprising the sequence of SEQ ID NO: 79, and a LCDR3 comprising the sequence of SEQ ID NO: 80;

i. a HCDR1 comprising the sequence of SEQ ID NO: 85, a HCDR2 comprising the sequence of SEQ ID NO: 86, a HCDR3 comprising the sequence of SEQ ID NO: 87, a LCDR1 comprising the sequence of SEQ ID NO: 88, a LCDR2 comprising the sequence of SEQ ID NO: 89, and a LCDR3 comprising the sequence of SEQ ID NO: 90;

j. a HCDR1 comprising the sequence of SEQ ID NO: 95, a HCDR2 comprising the sequence of SEQ ID NO: 96, a HCDR3 comprising the sequence of SEQ ID NO: 97, a LCDR1 comprising the sequence of SEQ ID NO: 98, a LCDR2 comprising the sequence of SEQ ID NO: 99, and a LCDR3 comprising the sequence of SEQ ID NO: 100;

k. a HCDR1 comprising the sequence of SEQ ID NO: 105, a HCDR2 comprising the sequence of SEQ ID NO: 106, a HCDR3 comprising the sequence of SEQ ID NO: 107, a LCDR1 comprising the sequence of SEQ ID NO: 108, a LCDR2 comprising the sequence of SEQ ID NO: 109, and a LCDR3 comprising the sequence of SEQ ID NO: 110;

l. a HCDR1 comprising the sequence of SEQ ID NO: 136, a HCDR2 comprising the sequence of SEQ ID NO: 137, a HCDR3 comprising the sequence of SEQ ID NO: 138, a LCDR1 comprising the sequence of SEQ ID NO: 139, a LCDR2 comprising the sequence of SEQ ID NO: 140, and a LCDR3 comprising the sequence of SEQ ID NO: 141;

m. HCDR1 comprising the sequence of SEQ ID NO: 146, a HCDR2 comprising the sequence of SEQ ID NO: 147, a HCDR3 comprising the sequence of SEQ ID NO: 148, a LCDR1 comprising the sequence of SEQ ID NO: 149, a LCDR2 comprising the sequence of SEQ ID NO: 150, and a LCDR3 comprising the sequence of SEQ ID NO: 151;

n. HCDR1 comprising the sequence of SEQ ID NO: 156, a HCDR2 comprising the sequence of SEQ ID NO: 157, a HCDR3 comprising the sequence of SEQ ID NO: 158, a LCDR1 comprising the sequence of SEQ ID NO: 159, a LCDR2 comprising the sequence of SEQ ID NO: 160, and a LCDR3 comprising the sequence of SEQ ID NO: 161;

o. HCDR1 comprising the sequence of SEQ ID NO: 166, a HCDR2 comprising the sequence of SEQ ID NO: 167, a HCDR3 comprising the sequence of SEQ ID NO: 168, a LCDR1 comprising the sequence of SEQ ID NO: 169, a LCDR2 comprising the sequence of SEQ ID NO: 170, and a LCDR3 comprising the sequence of SEQ ID NO: 171;

p. HCDR1 comprising the sequence of SEQ ID NO: 176, a HCDR2 comprising the sequence of SEQ ID NO: 177, a HCDR3 comprising the sequence of SEQ ID NO: 178, a LCDR1 comprising the sequence of SEQ ID NO: 179, a LCDR2 comprising the sequence of SEQ ID NO: 180, and a LCDR3 comprising the sequence of SEQ ID NO: 181;

q. HCDR1 comprising the sequence of SEQ ID NO: 186, a HCDR2 comprising the sequence of SEQ ID NO: 187, a HCDR3 comprising the sequence of SEQ ID NO: 188, a LCDR1 comprising the sequence of SEQ ID NO: 189, a LCDR2 comprising the sequence of SEQ ID NO: 190, and a LCDR3 comprising the sequence of SEQ ID NO: 191;

r. HCDR1 comprising the sequence of SEQ ID NO: 196, a HCDR2 comprising the sequence of SEQ ID NO: 197, a HCDR3 comprising the sequence of SEQ ID NO: 198, a LCDR1 comprising the sequence of SEQ ID NO: 199, a LCDR2 comprising the sequence of SEQ ID NO: 200, and a LCDR3 comprising the sequence of SEQ ID NO: 201;

s. HCDR1 comprising the sequence of SEQ ID NO: 206, a HCDR2 comprising the sequence of SEQ ID NO: 207, a HCDR3 comprising the sequence of SEQ ID NO: 208, a LCDR1 comprising the sequence of SEQ ID NO: 209, a LCDR2 comprising the sequence of SEQ ID NO: 210, and a LCDR3 comprising the sequence of SEQ ID NO: 211;

t. HCDR1 comprising the sequence of SEQ ID NO: 216, a HCDR2 comprising the sequence of SEQ ID NO: 217, a HCDR3 comprising the sequence of SEQ ID NO: 218, a LCDR1 comprising the sequence of SEQ ID NO: 219, a LCDR2 comprising the sequence of SEQ ID NO: 220, and a LCDR3 comprising the sequence of SEQ ID NO: 221;

u. HCDR1 comprising the sequence of SEQ ID NO: 226, a HCDR2 comprising the sequence of SEQ ID NO: 227, a HCDR3 comprising the sequence of SEQ ID NO: 228, a LCDR1 comprising the sequence of SEQ ID NO: 229, a LCDR2 comprising the sequence of SEQ ID NO: 230, and a LCDR3 comprising the sequence of SEQ ID NO: 231;

v. HCDR1 comprising the sequence of SEQ ID NO: 236, a HCDR2 comprising the sequence of SEQ ID NO: 237, a HCDR3 comprising the sequence of SEQ ID NO: 238, a LCDR1 comprising the sequence of SEQ ID NO: 239, a LCDR2 comprising the sequence of SEQ ID NO: 240, and a LCDR3 comprising the sequence of SEQ ID NO: 241;

w. HCDR1 comprising the sequence of SEQ ID NO: 246, a HCDR2 comprising the sequence of SEQ ID NO: 247, a HCDR3 comprising the sequence of SEQ ID NO: 248, a LCDR1 comprising the sequence of SEQ ID NO: 249, a LCDR2 comprising the sequence of SEQ ID NO: 250, and a LCDR3 comprising the sequence of SEQ ID NO: 251;

x. HCDR1 comprising the sequence of SEQ ID NO: 256, a HCDR2 comprising the sequence of SEQ ID NO: 257, a HCDR3 comprising the sequence of SEQ ID NO: 258, a LCDR1 comprising the sequence of SEQ ID NO: 259, a LCDR2 comprising the sequence of SEQ ID NO: 260, and a LCDR3 comprising the sequence of SEQ ID NO: 261;

y. HCDR1 comprising the sequence of SEQ ID NO: 266, a HCDR2 comprising the sequence of SEQ ID NO: 267, a HCDR3 comprising the sequence of SEQ ID NO: 268, a LCDR1 comprising the sequence of SEQ ID NO: 269, a LCDR2 comprising the sequence of SEQ ID NO: 270, and a LCDR3 comprising the sequence of SEQ ID NO: 271;

z. HCDR1 comprising the sequence of SEQ ID NO: 276, a HCDR2 comprising the sequence of SEQ ID NO: 277, a HCDR3 comprising the sequence of SEQ ID NO: 278, a LCDR1 comprising the sequence of SEQ ID NO: 279, a LCDR2 comprising the sequence of SEQ ID NO: 280, a LCDR3 comprising the sequence of SEQ ID NO: 281;

aa. HCDR1 comprising the sequence of SEQ ID NO: 286, a HCDR2 comprising the sequence of SEQ ID NO: 287, a HCDR3 comprising the sequence of SEQ ID NO: 288, a LCDR1 comprising the sequence of SEQ ID NO: 289, a LCDR2 comprising the sequence of SEQ ID NO: 290, a LCDR3 comprising the sequence of SEQ ID NO: 291;

bb. HCDR1 comprising the sequence of SEQ ID NO: 296, a HCDR2 comprising the sequence of SEQ ID NO: 297, a HCDR3 comprising the sequence of SEQ ID NO: 298, a LCDR1 comprising the sequence of SEQ ID NO: 299, a LCDR2 comprising the sequence of SEQ ID NO: 300, a LCDR3 comprising the sequence of SEQ ID NO: 301;

cc. HCDR1 comprising the sequence of SEQ ID NO: 306, a HCDR2 comprising the sequence of SEQ ID NO: 307, a HCDR3 comprising the sequence of SEQ ID NO: 308, a LCDR1 comprising the sequence of SEQ ID NO: 309, a LCDR2 comprising the sequence of SEQ ID NO: 310, a LCDR3 comprising the sequence of SEQ ID NO: 311;

dd. HCDR1 comprising the sequence of SEQ ID NO: 316, a HCDR2 comprising the sequence of SEQ ID NO: 317, a HCDR3 comprising the sequence of SEQ ID NO: 318, a LCDR1 comprising the sequence of SEQ ID NO: 319, a LCDR2 comprising the sequence of SEQ ID NO: 320, a LCDR3 comprising the sequence of SEQ ID NO: 321;

ee. HCDR1 comprising the sequence of SEQ ID NO: 326, a HCDR2 comprising the sequence of SEQ ID NO: 327, a HCDR3 comprising the sequence of SEQ ID NO: 328, a LCDR1 comprising the sequence of SEQ ID NO: 329, a LCDR2 comprising the sequence of SEQ ID NO: 330, a LCDR3 comprising the sequence of SEQ ID NO: 331;

ff. HCDR1 comprising the sequence of SEQ ID NO: 336, a HCDR2 comprising the sequence of SEQ ID NO: 337, a HCDR3 comprising the sequence of SEQ ID NO: 338, a LCDR1 comprising the sequence of SEQ ID NO: 339, a LCDR2 comprising the sequence of SEQ ID NO: 340, a LCDR3 comprising the sequence of SEQ ID NO: 341;

gg. HCDR1 comprising the sequence of SEQ ID NO: 346, a HCDR2 comprising the sequence of SEQ ID NO: 347, a HCDR3 comprising the sequence of SEQ ID NO: 348, a LCDR1 comprising the sequence of SEQ ID NO: 349, a LCDR2 comprising the sequence of SEQ ID NO: 350, a LCDR3 comprising the sequence of SEQ ID NO: 351;

hh. HCDR1 comprising the sequence of SEQ ID NO: 356, a HCDR2 comprising the sequence of SEQ ID NO: 357, a HCDR3 comprising the sequence of SEQ ID NO: 358, a LCDR1 comprising the sequence of SEQ ID NO: 359, a LCDR2 comprising the sequence of SEQ ID NO: 360, a LCDR3 comprising the sequence of SEQ ID NO: 361;

ii. HCDR1 comprising the sequence of SEQ ID NO: 366, a HCDR2 comprising the sequence of SEQ ID NO: 367, a HCDR3 comprising the sequence of SEQ ID NO: 368, a LCDR1 comprising the sequence of SEQ ID NO: 369, a LCDR2 comprising the sequence of SEQ ID NO: 370, a LCDR3 comprising the sequence of SEQ ID NO: 371;

jj. HCDR1 comprising the sequence of SEQ ID NO: 376, a HCDR2 comprising the sequence of SEQ ID NO: 377, a HCDR3 comprising the sequence of SEQ ID NO: 378, a LCDR1 comprising the sequence of SEQ ID NO: 379, a LCDR2 comprising the sequence of SEQ ID NO: 380, a LCDR3 comprising the sequence of SEQ ID NO: 381;

kk. HCDR1 comprising the sequence of SEQ ID NO: 386, a HCDR2 comprising the sequence of SEQ ID NO: 387, a HCDR3 comprising the sequence of SEQ ID NO: 388, a LCDR1 comprising the sequence of SEQ ID NO: 389, a LCDR2 comprising the sequence of SEQ ID NO: 390, a LCDR3 comprising the sequence of SEQ ID NO: 391;

ll. HCDR1 comprising the sequence of SEQ ID NO: 396, a HCDR2 comprising the sequence of SEQ ID NO: 397, a HCDR3 comprising the sequence of SEQ ID NO: 398, a LCDR1 comprising the sequence of SEQ ID NO: 399, a LCDR2 comprising the sequence of SEQ ID NO: 400, a LCDR3 comprising the sequence of SEQ ID NO: 401;

mm. HCDR1 comprising the sequence of SEQ ID NO: 406, a HCDR2 comprising the sequence of SEQ ID NO: 407, a HCDR3 comprising the sequence of SEQ ID NO: 408, a LCDR1 comprising the sequence of SEQ ID NO: 409, a LCDR2 comprising the sequence of SEQ ID NO: 410, a LCDR3 comprising the sequence of SEQ ID NO: 411;

nn. HCDR1 comprising the sequence of SEQ ID NO: 416, a HCDR2 comprising the sequence of SEQ ID NO: 417, a HCDR3 comprising the sequence of SEQ ID NO: 418, a LCDR1 comprising the sequence of SEQ ID NO: 419, a LCDR2 comprising the sequence of SEQ ID NO: 420, a LCDR3 comprising the sequence of SEQ ID NO: 421;

oo. HCDR1 comprising the sequence of SEQ ID NO: 426, a HCDR2 comprising the sequence of SEQ ID NO: 427, a HCDR3 comprising the sequence of SEQ ID NO: 428, a LCDR1 comprising the sequence of SEQ ID NO: 429, a LCDR2 comprising the sequence of SEQ ID NO: 430, a LCDR3 comprising the sequence of SEQ ID NO: 431;

or a combination thereof.

2. The modified antibody or an antigen-binding fragment thereof of claim 1 , comprising:

a) binding affinity to RBD of said spike protein of SARS-CoV comprising the amino acid sequence of SEQ ID NO: 124 at a level that is non-detectable or that is no more than 50% of said binding affinity to said RBD of said spike protein of SARS-CoV-2;

b) binding affinity to RBD of said spike protein of MERS-CoV comprising the amino acid sequence of SEQ ID NO: 126 at a level that is non-detectable or that is no more than 50% of said binding affinity to said RBD of the spike protein of SARS-CoV-2;

c) binding affinity to said RBD of said spike protein of SARS-CoV-2 at a K d value of no more than 1×10 −7 M as measured by Surface Plasmon Resonance (SPR);

d) binding affinity to said RBD of said spike protein of SARS-CoV or the RBD of spike protein of MERS-CoV at a K d value of at least 1×10 −6 M as measured by SPR;

e) exhibiting at least 30% competition at 1 μM, with 2 μM angiotensin converting enzyme 2 (ACE2) receptor, for binding to said RBD of said spike protein of SARS-CoV-2 immobilized at a resonance unit (RU) of 250, as measured by SPR;

f) binding affinity to said RBD of said spike protein of SARS-CoV-2 at a neutralizing activity at an IC 50 value of no more than 100 μg/ml, as measured by pseudovirus, live virus microneutralization, inactivated virus neutralization assay, or a combination thereof; or

a combination thereof.

3. The modified antibody or an antigen-binding fragment thereof of claim 1 , wherein said antigen-binding domain comprises:

a HCDR1 comprising the sequence of SEQ ID NO: 105, a HCDR2 comprising the sequence of SEQ ID NO: 106, a HCDR3 comprising the sequence of SEQ ID NO: 107, a LCDR1 comprising the sequence of SEQ ID NO: 108, a LCDR2 comprising the sequence of SEQ ID NO: 109, and a LCDR3 comprising the sequence of SEQ ID NO: 110;

a HCDR1 comprising the sequence of SEQ ID NO: 136, a HCDR2 comprising the sequence of SEQ ID NO: 137, a HCDR3 comprising the sequence of SEQ ID NO: 138, a LCDR1 comprising the sequence of SEQ ID NO: 139, a LCDR2 comprising the sequence of SEQ ID NO: 140, and a LCDR3 comprising the sequence of SEQ ID NO: 141;

a combination thereof.

4. The modified antibody or an antigen-binding fragment thereof of claim 3 , wherein said modified antibody or an antigen-binding fragment thereof is bispecific and comprises a first antigen binding domain comprising:

and a second antigen binding domain comprising:

5. The modified antibody or an antigen-binding fragment thereof of claim 1 , wherein said modified antibody or said antigen-binding fragment has a half-life (T 1/2 ) in a range of from 50 to 120 days in vivo.

6. The modified antibody or an antigen-binding fragment thereof of claim 1 , wherein said modified antibody or said antigen-binding fragment comprises at least one amino acid subsequent substitutions in said human IgG constant domain, at least one amino acid substitution in a light chain of said modified antibody, at least one amino acid substitution in a heavy chain of said modified antibody, or a combination thereof.

7. The modified antibody or an antigen-binding fragment thereof of claim 6 , wherein said subsequent substitution comprises substituting a cysteine residue to a non-cysteine residue.

8. The modified antibody or an antigen-binding fragment thereof of claim 1 , wherein said modified antibody or said antigen-binding fragment thereof is a diabody, a Fab, a Fab′, a F(ab′)2, a Fd, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a bispecific dsFv, a disulfide stabilized diabody, a single-chain antibody molecule (scFv), an scFv dimer, a bispecific scFv dimer, or a multispecific antibody.

9. The modified antibody or an antigen-binding fragment thereof of claim 1 , wherein said SARS-CoV-2-binding affinity comprises at least 50% less or non-detectable binding affinity to SARS-CoV or MERS-CoV compared to said SARS-CoV-2 binding affinity, and said modified antibody has an increased affinity for FcRn compared to the affinity to FcRn of an antibody having a wild type human IgG constant domain.

10. A pharmaceutical composition comprising at least one said modified antibody or an antigen-binding fragment thereof of claim 1 , at least one nucleic acid encoding said modified antibody or said antigen-binding fragment thereof, or a combination thereof, and one or more pharmaceutically acceptable carriers.

11. The pharmaceutical composition of claim 10 , wherein said pharmaceutical composition comprises said modified antibody or an antigen-binding fragment thereof at a concentration in a range of from 10 mg/mL to 150 mg/mL.

12. The pharmaceutical composition of claim 10 , wherein said pharmaceutical composition is formulated to be administered to a subject via intravenous injection (IV), intramuscular injection (IM), subcutaneous (SC) injection, or a combination thereof.

13. The pharmaceutical composition of claim 10 , wherein said pharmaceutical composition is formulated for treatment of a person being one of:

a) a symptomatic, non-hospitalized adult with COVID-19 caused by SARS-CoV-2 infection; or

b) an hospitalized adult inpatient requiring supportive management of complications of severe infection of said SARS-CoV-2 selected from pneumonia, hypoxemic respiratory failure/ARDS, sepsis and septic shock, cardiomyopathy and arrhythmia, acute kidney injury, and complications from prolonged hospitalization including secondary bacterial and fungal infections, thromboembolism, gastrointestinal bleeding, critical illness polyneuropathy/myopathy, or a combination thereof.

14. The pharmaceutical composition of claim 10 , wherein said pharmaceutical composition comprises a first modified antibody or an antigen-binding fragment thereof comprising:

a second modified antibody or an antigen-binding fragment thereof, comprising a HCDR1 comprising the sequence of SEQ ID NO: 136, a HCDR2 comprising the sequence of SEQ ID NO: 137, a HCDR3 comprising the sequence of SEQ ID NO: 138, a LCDR1 comprising the sequence of SEQ ID NO: 139, a LCDR2 comprising the sequence of SEQ ID NO: 140, and a LCDR3 comprising the sequence of SEQ ID NO: 141.

15. The pharmaceutical composition of claim 13 , wherein said person is a person 60 years and older.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 22, 2021

From: ZHANG, ZHENG; ZHANG, LINQI; LIU, LEI; ZHANG, QI; JU, BIN; SHI, XUANLING; ZHU, QING

To: TSB THERAPEUTICS (BEIJING) CO., LTD.

Reel/Frame 058904/0445 →

Priority Claims (5)

CN 202010203065.1 · Mar 20, 2020 · national

WO PCT/CN2020/080532 · Mar 21, 2020 · international

WO PCT/CN2020/084097 · Apr 10, 2020 · international

WO PCT/CN2020/084805 · Apr 14, 2020 · international

WO PCT/CN2020/108718 · Aug 12, 2020 · international

Continuity (1)

Related Publication 20210292392A1 · Sep 23, 2021