IP Library › Granted Patent US 12,281,339
Granted Patent B2
US 12,281,339 · App. 15/641,819 · Granted Apr 22, 2025

Combination cancer immunotherapies with arginine depletion agents

Inventors: Elena Brin (San Diego, CA); Wei He (San Diego, CA)
Assignee: POLARIS GROUP
C12N9/96A61K47/10C12Y305/03006
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,281,339
App. No.
15/641,819
Granted
Apr 22, 2025
Kind
B2
Abstract

Provided are arginine depletion agents such as ADI-PEG for use in combination with cancer immunotherapies, for example, immune checkpoint modulators and T-cell adoptive immunotherapies, for treating various cancers. Also provided are related methods, compositions, patient care kits, and cell cultures.

Claims (45)

1. A method of treating a cancer in a subject in need thereof, comprising administering to the subject

(a) an ADI polypeptide; and

(b) an immune checkpoint modulatory agent wherein said agent is a PD-1 antagonist or a PD-L1 antagonist; and

wherein (i) the cancer in the subject is one targeted for immunotherapy treatment and (ii) the ADI-polypeptide is administered to enhance the immune activity of the immune checkpoint modulatory agent.

2. The method of claim 1 , wherein the ADI polypeptide comprises, consists, or consists essentially of

(i) a sequence selected from SEQ ID NO: 1-56; or

(ii) a sequence that is at least 95%, identical to a sequence selected from SEQ ID NO: 1-56.

3. The method of claim 1 , wherein the ADI polypeptide is covalently bonded via an optional linker to at least one PEG molecule.

4. The method of claim 3 , wherein the ADI polypeptide is covalently bonded to more than one PEG molecule.

5. The method of claim 3 , wherein the ADI polypeptide is covalently bonded to about 1 to about 10 PEG molecules.

6. The method of claim 5 , wherein the ADI polypeptide is covalently bonded to about 2 to about 8 PEG molecules.

7. The method of claim 3 , wherein the PEG molecules are straight chain or branch chain PEG molecules.

8. The method of claim 3 , wherein the PEG has a total average molecular weight of from about 1,000 to about 40,000 Daltons.

9. The method of claim 3 , wherein the PEG has a total average molecular weight of from about 10,000 to about 30,000 Daltons.

10. The method of claim 9 , wherein the PEG has a total average molecular weight of about 20,000 Daltons.

11. The method of claim 3 , wherein the linker is a succinyl group, an amide group, an imide group, a carbamate group, an ester group, an epoxy group, a carboxyl group, a hydroxyl group, a carbohydrate, a tyrosine group, a cysteine group, a histidine group, a methylene group, or any combinations thereof.

12. The method of claim 11 , wherein the source of the succinyl group is succinimidyl succinate.

13. The method of claim 1 , wherein the ADI polypeptide is pegylated arginine deiminase (ADI-PEG).

14. The method of claim 13 , wherein the ADI-PEG is ADI-PEG 20.

15. The method of claim 1 , wherein the antagonist is a PD-LI antagonist selected from one or more of an antibody or antigen-binding fragment or small molecule that specifically binds thereto, atezolizumab (MPDL3280A), avelumab (MSB0010718C), and durvalumab (MEDI4736), and wherein the cancer is optionally selected from one or more of colorectal cancer, melanoma, breast cancer, non-small-cell lung carcinoma, bladder cancer, and renal cell carcinoma.

16. The method of claim 1 , wherein the PD-I antagonist selected from one or more of an antibody or antigen-binding fragment or small molecule that specifically binds thereto, nivolumab, pembrolizumab, PDR00I, and pidilizumab.

17. The method of claim 16 , wherein the PD-I antagonist is nivolumab and the cancer is optionally selected from one or more of Hodgkin's lymphoma, melanoma, non-small cell lung cancer, hepatocellular carcinoma, renal cell carcinoma, and ovarian cancer.

18. The method of claim 16 , wherein the PD-I antagonist is pembrolizumab and the cancer is optionally selected from one or more of melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, and urothelial cancer.

19. The method of claim 1 , wherein (a) and (b) are administered separately.

20. The method of claim 1 , wherein (a) and (b) are administered together as part of the same composition.

21. The method of claim 1 , wherein the cancer is selected from one or more of hepatocellular carcinoma, melanoma, pancreatic cancer, prostate cancer, small cell lung cancer, mesothelioma, lymphoma, hepatoma, sarcoma, leukemia, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, non-small cell lung cancer (NSCLC), kidney cancer, bladder cancer, uterine cancer, esophageal cancer, brain cancer, head and neck cancers, cervical cancer, and testicular cancer.

22. The method of claim 21 , wherein:

(i) the melanoma is metastatic melanoma;

(ii) the leukemia is selected from the group consisting of lymphocytic leukemia, chronic myelogenous leukemia, acute myeloid leukemia and relapsed acute myeloid leukemia;

(iii) the gastric cancer is stomach cancer; and

(iv) the brain cancer is selected from the group consisting of glioma and glioblastoma multiforme.

23. The method of claim 1 wherein the cancer is an argininosuccinate synthetase (ASS)- or argininosuccinate lyase (ASL)-deficient cancer.

24. A method of adoptive T-cell immunotherapy for treating a cancer in a subject in need thereof, comprising

(a) incubating ex vivo-derived T-cells (i) with or (ii) in arginine-free medium supplemented with citrulline;

(b) administering the ex vivo-derived T-cells to the subject.

25. The method of claim 24 , wherein the ADI polypeptide is pegylated arginine deiminase (ADI-PEG).

26. The method of claim 25 , wherein the ADI-PEG is ADI-PEG 20.

27. A method of increasing T-cell activation and/or regulatory T-cell (Treg) downregulation in vitro or ex vivo, comprising (a) incubating T-cells with an ADI polypeptide wherein said ADI polypeptide converts arginine to citrulline, (b) incubating T-cells in an arginine-free medium supplemented with citrulline, or both (a) and (b).

28. The method of claim 27 , wherein the arginine depletion agent is pegylated arginine deiminase (ADI-PEG).

29. The method of claim 28 , wherein the ADI-PEG is ADI-PEG 20.

30. A composition or patient care kit, comprising:

(a) an ADI polypeptide which converts arginine to citrulline; and

(b) an immune checkpoint modulatory agent wherein said agent is a PD-1 antagonist or a PD-L1 antagonist.

31. The composition or patient care kit of claim 30 , wherein the arginine depletion agent is pegylated arginine deiminase (ADI-PEG).

32. The composition or patient care kit of claim 31 , wherein the ADI-PEG is ADI-PEG 20.

Assignments (2)
MERGER Recorded Mar 13, 2025
From: TDW GROUP
To: POLARIS GROUP
Reel/Frame 070502/0383 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 1, 2017
From: POLARIS GROUP
To: TDW GROUP
Reel/Frame 044011/0428 →
Continuity (3)
Provisional Application 62515807 · Jun 6, 2017
Provisional Application 62358479 · Jul 5, 2016
Related Publication 20180010114A1 · Jan 11, 2018
References Cited (122)
US 5658565A · Billiar · 1997 [cited by examiner]
US 5804183A · Filpula et al. · 1998 [cited by applicant]
US 6132713A · Fiipula et al. · 2000 [cited by applicant]
US 6180387B1 · Biswas et al. · 2001 [cited by applicant]
US 6183738B1 · Clark · 2001 [cited by applicant]
US 6635462B1 · Ensor et al. · 2003 [cited by applicant]
US 7204980B2 · Clark · 2007 [cited by applicant]
US 7323167B2 · Clark et al. · 2008 [cited by applicant]
US 7413735B2 · Min et al. · 2008 [cited by applicant]
US 9333268B2 · Bomalaski et al. · 2016 [cited by applicant]
US 9731028B2 · Bomalaski et al. · 2017 [cited by applicant]
US 9789170B2 · Showalter et al. · 2017 [cited by applicant]
US 20030215429A1 · de Simone · 2003 [cited by applicant]
US 20040258675A1 · Ensor et al. · 2004 [cited by applicant]
US 20050129706A1 · Clark · 2005 [cited by applicant]
US 20060002915A1 · Min et al. · 2006 [cited by applicant]
US 20070198198A1 · Burczynski et al. · 2007 [cited by applicant]
US 20070212311A1 · Burne et al. · 2007 [cited by applicant]
US 20090238813A1 · Georgiou et al. · 2009 [cited by applicant]
US 20100197944A1 · Palle et al. · 2010 [cited by applicant]
US 20100303893A1 · Luo et al. · 2010 [cited by applicant]
US 20110111403A1 · Petrauskene et al. · 2011 [cited by applicant]
US 20110268766A1 · Beech · 2011 [cited by examiner]
US 20110301189A1 · Hattar et al. · 2011 [cited by applicant]
US 20120015049A1 · Zhang · 2012 [cited by applicant]
US 20120148559A1 · Georgiou et al. · 2012 [cited by applicant]
US 20130022625A1 · Igawa et al. · 2013 [cited by applicant]
US 20130052179A1 · Huang et al. · 2013 [cited by applicant]
US 20140348814A1 · Almassy et al. · 2014 [cited by applicant]
US 20150132278A1 · Bomalaski et al. · 2015 [cited by applicant]
US 20150231272A1 · Bomalaski et al. · 2015 [cited by applicant]
US 20160074487A1 · Showalter et al. · 2016 [cited by applicant]
US 20170000862A1 · Wu et al. · 2017 [cited by applicant]
TW 201340979A · 2013 [cited by applicant]
WO WO2013151568A1 · 2013 [cited by examiner]
WO WO2016149562A2 · 2016 [cited by examiner]
Pinton et al (Oncotarget, 2015, vol. 7, pp. 1168-1184) (Year: 2015). [cited by examiner]
Pardoll (Nature Reviews Cancer, 2012, vol. 12, pp. 252-264) (Year: 2012). [cited by examiner]
Abstract of Besse et al (European Journal of Cancer, Sep. 2015, vol. 51, suppl. 3, pp. S717-S718) (Year: 2015). [cited by examiner]
Deeks (Drugs, 2014, vol. 74, pp. 1223-1239) (Year: 2014). [cited by examiner]
Khoja et al (Journal for the Immunotherapy of Cancer, 2015, vol. 3, 13 pages) (Year: 2015). [cited by examiner]
Raber et al (Oncotarget, Mar. 19, 2016, vol. 7, pp. 17565-17578) (Year: 2016). [cited by examiner]
Fultang et al (International Journal of Cancer, Feb. 23, 2016, vol. 139, pp. 501-509) (Year: 2016). [cited by examiner]
The abstract of Shim et al (Proc. Am Assoc. Cancer Res., 2009, Abstract No. LB-35) (Year: 2009). [cited by examiner]
Yoon et al (International Journal of Cancer, 2006, vol. 120, pp. 897-905). (Year: 2006). [cited by examiner]
Noh et al (Molecules and Cells, 2002, vol. 13, pp. 137-143) (Year: 2002). [cited by examiner]
Amin et al (Oncology, 2013, vol. 27, pp. 680-691). (Year: 2013). [cited by examiner]
Floros and Tarhini (Seminars in Oncology, 2015, vol. 42, pp. 539-548) (Year: 2016). [cited by examiner]
Kryczek et al (Journal of Experimental Medicine, 2006, vol. 203, pp. 871-881) (Year: 2006). [cited by examiner]
Smith et al (Gynecologic Oncology, 2014, vol. 134, pp. 181-189). (Year: 2014). [cited by examiner]
Wheatley et al, Anti-Cancer Drugs, 2004, vol. 15, pp. 825-833 (Year: 2004). [cited by examiner]
Murad, Rambam Maimonides Medical Journal, 2011, vol. 2, No. 2, e0038, 1-9 pages (Year: 2011). [cited by examiner]
Garon et al (Seminars in Oncology, 2015, vol. 42, No. 5, suppl.2, pp. S11-S18) (Year: 2015). [cited by examiner]
International Search Report and Written Opinion for International Application No. PCT/US2017/040700, mailed Nov. 17, 2017, 11 pages. [cited by applicant]
Kuo, et al., “Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes.” Oncotarget (2010); 1(4): 246-251. [cited by applicant]
Albina, et al., “Regulation of macrophage functions by L-arginine.” J Exp Med. (1989); 169(3): 1021-1029. [cited by applicant]
Ascierto, et al., “Pegylated arginine deiminase treatment of patients with metastatic melanoma: results from phase I and II studies.” J Clin Oncol. (2005); 23(30): 7660-7668. [cited by applicant]
Aulak, et al., “Molecular sites of regulation of expression of the rat cationic amino acid transporter gene.” J Biol Chem. (1996); 271(47): 29799-29806. [cited by applicant]
Bansal, et al., “Citrulline can preserve proliferation and prevent the loss of CD3 zeta chain under conditions of low arginine.” JPEN J Parenter Enteral Nutr. (2004); 28(6): 423-430. [cited by applicant]
Bomalaski, et al., “Comparative toxicity of arginine deiminase formulated with polyethylene glycol 5000 or 20,000 and the effects of arginine.” Preclinica (2003); 1:284: 293. [cited by applicant]
Bottino, et al., “Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule.” J Exp Med. (2003); 198(4): 557-567. [cited by applicant]
Bronte, et al., “Regulation of immune responses by L-arginine metabolism.” Nat Rev Immunol. (2005); 5(8): 641-654. [cited by applicant]
De Graaf, et al., “Nonnatural amino acids for site-specific protein conjugation.” Bioconjug Chem. (2009); 20(7): 1281-1295. [cited by applicant]
Delage, B. et al., “Arginine Deprivation and Argininosuccinate Synthetase Expression in the Treatment of Cancer,” International Journal of Cancer, 126: 2762-2772 (2010). [cited by applicant]
Derre, et al., “BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination.” J Clin Invest. (2010); 120(1): 157-167. [cited by applicant]
Extended European Search Report for European Application No. 15765975.6, dated Oct. 27, 2017, 6 pages. [cited by applicant]
Feun, et al., “Arginine deprivation in cancer therapy.” Curr Opin Clin Nutr Metab Care (2015); 18(1): 78-82. [cited by applicant]
Fletcher, et al., “l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells.” Cancer Res. (2015); 75(2): 275-283. [cited by applicant]
Gazzola, et al., “Regulation of amino acid transport in chick embryo heart cells. I. Adaptive system of mediation for neutral amino acids.” Biochim Biophys Acta. (1972); 266(2): 407-421. [cited by applicant]
He, et al., “Agonist anti-human CD27 monoclonal antibody induces T cell activation and tumor immunity in human CD27-transgenic mice.” J Immunol. (2013); 191(8): 4174-4183. [cited by applicant]
Holtsberg, F. W. et al., “Poly(ethylene glycol) (PEG) Conjugated Arginine Deiminase: Effects of PEG Formulations on its Pharmacological Properties,” Journal of Controlled Release, 80:259-271 (2002). [cited by applicant]
Huang, et al., “Role of LAG-3 in regulatory T cells.” Immunity (2004); 21(4): 503-513. [cited by applicant]
Hyatt, et al., “Adaptive regulation of the cationic amino acid transporter-1 (Cat-1) in Fao cells.” J Biol Chem. (1997); 272(32): 19951-19957. [cited by applicant]
Izzo, F., et al., “Pegylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: results from phase I/II studies.” J Clin Oncol. (2004); 22(10): 1815-1822. [cited by applicant]
Johnson, et al. “Clinical and biological effects of an agonist anti-CD40 antibody: a Cancer Research UK phase I study.” Clin Cancer Res. (2015); 21(6): 1321-1328. [cited by applicant]
Johnston, et al., “The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function.” Cancer Cell (2014); 26(6): 923-937. [cited by applicant]
June, C.H. “Adoptive T cell therapy for cancer in the clinic.” J Clin Invest. (2007); 117(6): 1466-1476. [cited by applicant]
Kelly, M. P. et al., “Arginine Deiminase PEG20 Inhibits Growth of Small Cell Lung Cancers Lacking Expression of Argininosuccinate Synthetase,” British Journal of Cancer, 106(2):324-332 (2012). [cited by applicant]
Kurtulus, et al., “TIGIT predominantly regulates the immune response via regulatory T cells.” J Clin Invest. (2015); 125(11): 4053-4062. [cited by applicant]
Li, et al., “Emerging immune checkpoints for cancer therapy.” Acta Oncol. (2015); 54(10): 1706-1713. [cited by applicant]
Lines, et al., “VISTA is an immune checkpoint molecule for human T cells.” Cancer Res. (2014); 74(7): 1924-1932. [cited by applicant]
Lorentzen, et al., CD19-Chimeric Antigen Receptor T Cells for Treatment of Chronic Lymphocytic Leukaemia and Acute Lymphoblastic Leukaemia. Scand J Immunol. (2015); 82(4): 307-319. [cited by applicant]
Maude, et al., “CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia.” Blood (2015); 125(26): 4017-4023. [cited by applicant]
Park, et al., “Pharmacology of [cited by applicant]
Peranzoni, et al., “Role of arginine metabolism in immunity and immunopathology.” Immunobiology (2007); 212(9-10): 795-812. [cited by applicant]
Philips, et al., “Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies.” Int Immunol. (2015); 27(1): 39-46. [cited by applicant]
Phillips, et al., “Targeting arginine-dependent cancers with arginine-degrading enzymes: opportunities and challenges.” Cancer Res Treat. (2013); 45(4): 251-262. [cited by applicant]
Pilotte, et al., “Reversal of tumoral Immune resistance by inhibition of tryptophan 2,3-dioxygenase.” Proc Natl Acad Sci U S A. (2012);109(7): 2497-2502. [cited by applicant]
Platten, et al., “Cancer Immunotherapy by Targeting IDO1/TDO and Their Downstream Effectors.” Front Immunol. (2015); 5: 673. [cited by applicant]
Qiu, et al., “Targeting arginine metabolism pathway to treat arginine-dependent cancers.” Cancer Lett. (2015); 364(1): 1-7. [cited by applicant]
Rath, et al., “Metabolism via Arginase or Nitric Oxide Synthase: Two Competing Arginine Pathways in Macrophages.” Front Immunol. (2014); 5: 532. [cited by applicant]
Rodriguez, et al., “L-arginine availability regulates T-lymphocyte cell-cycle progression.” Blood (2007); 109(4): 1568-1573. [cited by applicant]
Rodriguez, et al., “L-arginine consumption by macrophages modulates the expression of CD3zeta chain in T lymphocytes.” J Immunol. (2003); 171(3): 1232-1239. [cited by applicant]
Rosenberg, et al., “Adoptive cell transfer as personalized immunotherapy for human cancer.” Science (2015); 348(6230): 62-68. [cited by applicant]
Schaer, et al., “GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability.” Cancer Immunol Res. (2013); 1(5): 320-331. [cited by applicant]
Shao, et al., CD137 ligand, a member of the tumor necrosis factor family, regulates immune responses via reverse signal transduction. J Leukoc Biol. (2011); 89(1): 21-29. [cited by applicant]
Sharma, et al., “The future of immune checkpoint therapy.” Science. (2015); 348(6230): 56-61. [cited by applicant]
Sheridan, C. “Ido inhibitors move center stage in immuno-oncology.” Nat Biotechnol. (2015); 33(4): 321-322. [cited by applicant]
Tahara-Hanaoka, et al., “Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR (CD155) and nectin-2 (PRR-2/CD112).” Int Immunol. (2004); 16(4): 533-538. [cited by applicant]
Tarasenko, et al., “Impaired T cell function in argininosuccinate synthetase deficiency.” J Leukoc Biol. (2015); 97(2): 273-278. [cited by applicant]
Thomas, et al., “Targeting human CD27 with an agonist antibody stimulates T-cell activation and antitumor immunity.” Oncoimmunology (2014); 3(1): e27255. [cited by applicant]
Topalian, et al., “Immune checkpoint blockade: a common denominator approach to cancer therapy.” Cancer Cell. (2015); 27(4): 450-461. [cited by applicant]
Vonderheide, et al., “Agonistic CD40 antibodies and cancer therapy.” Clin Cancer Res. (2013); 19(5): 1035-43. [cited by applicant]
Workman, et al., “Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo.” J Immunol. (2004); 172(9): 5450-5455. [cited by applicant]
Workman, et al., “The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells.” Eur J Immunol. (2003); 33(4): 970-979. [cited by applicant]
English translation of Chinese Office Action dated Jan. 7, 2021, corresponding to counterpart Chinese Application No. 201780042314.X; 7 pages. [cited by applicant]
English translation of Chinese Office Action issued May 29, 2020, corresponding to counterpart Chinese Application No. 201780042314.X; 6 pages. [cited by applicant]
English translation of Taiwanese Search Report dated Sep. 24, 2021, corresponding to counterpart Taiwanese application No. 106122601; 1 page. [cited by applicant]
Bononi et al. “Latest Developments in our Understanding of the Pathogenesis of Mesothelioma and the Design of Targeted Therapies,” Expert Rev. Respir Med., Oct. 2015; vol. 9, No. 5; pp. 633-654. [cited by applicant]
English translation of Chinese Office Action dated Sep. 28, 2021, corresponding to counterpart Chinese Application No. 201780042314.X; 6 pages. [cited by applicant]
English Translation of Taiwanese Office Action for application No. 106122601, Jun. 27, 2023, 11 pages. [cited by applicant]
English translation of Chinese Notification of Reexamination for application No. 201780042314.X, Nov. 14, 2023, 10 pages. [cited by applicant]
Yu, Boafa, “Interventional Oncology & Chemoimmunotherapy,” Military Medical Science Press, 1st edition, 1st printing, Sep. 2014, pp. 44-53. Machine translation. [cited by applicant]
Shi, Yuankai, “Advances in Medical Oncology in China: Education for Chinese Oncologists,” Peking Union Medical College Press, 1st edition, 1st printing, Jun. 2013, pp. 407-409. Machine Translation. [cited by applicant]
Croft, Michael, et al., “The significance of OX40 and OX40L to T-cell biology and immune disease,” Immunological reviews, May 2009, pp. 173-191, 229.1. [cited by applicant]
Doherty, Daniel H., et al., “Site-specific PEGylation of engineered cysteine analogues of recombinant human granulocyte-macrophage colony-stimulating factor,” Bioconjugate chemistry, Sep. 2005, pp. 1291-1298, 16.5. [cited by applicant]
Feun, Lynn, and Niramol Savaraj, “Pegylated arginine deiminase: a novel anticancer enzyme agent,” Expert opinion on investigational drugs, Jul. 2006, pp. 815-822, 15.7. [cited by applicant]
Ramos, Carlos A., Barbara Savoldo, and Gianpietro Dotti, “CD19-CAR trials,” The Cancer Journal, Mar. 2014, pp. 112-118, 20.2. [cited by applicant]
Raber, Patrick, Augusto C. Ochoa, and Paulo C. Rodriguez, “Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives,” Immunological investigat… [cited by applicant]
Rodríguez, Paulo C., and Augusto C. Ochoa, “Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives,” Immunological reviews, Apr. 2008, pp. 180-191, 222.1. [cited by applicant]
Feun, L., et al., “Arginine deprivation as a targeted therapy for cancer,” Current pharmaceutical design, Apr. 2008, pp. 1049-1057, 14.11. [cited by applicant]
English translation of Chinese Office Action for application No. 201780042314X, Mar. 13, 2024, 8 pages. [cited by applicant]