IP Library Granted Patent US 12,250,943
Granted Patent B2
US 12,250,943 · App. 17/602,207 · Granted Mar 18, 2025

Compositions and methods for the cryopreservation of immune cells

Inventors: Yosef Refaeli (Denver, CO); Brian C. Turner (Denver, CO); Thomas R. Payne (Aurora, CO)
Assignee: HTYR Acquisition LLC
A01N1/0221A01N1/0284C12N5/0634
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Quick Facts
Patent No.
US 12,250,943
App. No.
17/602,207
Granted
Mar 18, 2025
Kind
B2
Abstract

Provided herein are compositions and methods for the cryopreservation of immune cells, such as peripheral blood mononuclear cells (PBMCs) by pre-treating the cells with a PTD-MYC fusion protein (e.g., an HIV TAT-MYC fusion protein) prior to freezing. Kits for practicing the methods are also provided herein.

Claims (29)

1. A cryogenically frozen composition comprising:

(a) a MYC fusion polypeptide, comprising (i) a protein transduction domain; (ii) a MYC polypeptide sequence; and

(b) one or more peripheral blood mononuclear cells (PBMCs) isolated from a donor subject;

wherein the composition exhibits increased cell viability when thawed as compared to control PBMCs in the absence of the MYC fusion polypeptide after a freeze-thaw cycle.

2. The cryogenically frozen composition of claim 1 , wherein the protein transduction domain sequence is a TAT protein transduction domain sequence.

3. The cryogenically frozen composition of claim 1 , wherein the MYC fusion polypeptide comprises SEQ ID NO: 1.

4. The cryogenically frozen composition of claim 1 , wherein the one or more peripheral blood mononuclear cells comprises a T-cell, a B-cell, an NK cell, a monocyte, a granulocyte, a macrophage, or any combination thereof.

5. The cryogenically frozen composition of claim 1 , further comprising a cell suspension medium.

6. The cryogenically frozen composition of claim 5 , wherein the cell suspension medium comprises CHB media, CS5 media, or CS10 media.

7. The cryogenically frozen composition of claim 1 wherein the composition exhibits increased cell recovery when thawed as compared to control PBMCs in the absence of the MYC fusion polypeptide after a freeze-thaw cycle.

8. The cryogenically frozen composition of claim 1 , wherein the composition exhibits increased expression of CD25 after cell activation as compared to control PBMCs in the absence of the MYC fusion polypeptide after a freeze-thaw cycle.

9. A method of cryopreserving peripheral blood mononuclear cells (PBMCs), comprising:

(a) contacting a composition comprising one or more PBMCs isolated from a donor subject with an effective amount of a MYC fusion polypeptide, comprising (i) a protein transduction domain; (ii) a MYC polypeptide sequence; and

(b) cooling the PBMCs to a temperature sufficient to freeze the composition.

10. The method of claim 9 , wherein the protein transduction domain sequence is a TAT protein transduction domain sequence.

11. The method of claim 9 , wherein the MYC fusion polypeptide comprises SEQ ID NO: 1.

12. The method of claim 9 , wherein the one or more peripheral blood mononuclear cells comprises a T-cell, a B-cell, an NK cell, a monocyte, a granulocyte, or any combination thereof.

13. The method of claim 9 , further comprising suspending the PBMCs in a cell suspension medium.

14. The method of claim 13 , wherein the cell suspension medium comprises CHB media, CS5 media, or CS10 media.

15. The method of claim 9 , wherein the composition comprising one or more PBMCs is contacted with the MYC fusion polypeptide at a concentration of about 0.5 μg/mL to about 500 μg/mL.

16. The method of claim 9 , wherein the composition comprising one or more PBMCs is contacted with the MYC fusion polypeptide at a concentration of about 0.5 μg/mL to about 10 g/mL.

17. The method of claim 9 , wherein the composition comprising one or more PBMCs is contacted with the MYC fusion polypeptide for less than 24 hours prior to step (b).

18. The method of claim 9 , wherein the composition comprising one or more PBMCs is contacted with the MYC fusion polypeptide for about 1 hour prior to step (b).

19. The method of claim 9 , wherein the PBMCs are washed following step (a) and prior to step (b).

20. The method of claim 9 , wherein the PBMCs are cooled using a controlled-rate cryogenic freezer.

21. The method of claim 9 , wherein the PBMCs are cooled at a rate of about −1° C. per min.

22. The method of claim 9 , wherein the temperature sufficient to freeze the composition is about −80° C. to about −190° C.

23. The method of claim 9 , further comprising thawing of the cryopreserved cells, such that the cells exhibit one or more of increased cell viability, increased cell recovery, cell activation, or increased expression of CD25 after cell activation as compared to control PBMCs not contacted with an effective amount of the MYC fusion polypeptide.

24. An immune cell bank comprising the cryogenically frozen composition of claim 1 .

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 17, 2024
From: TAIGA BIOTECHNOLOGIES, INC.
To: TAIGA BIOTECHNOLOGIES (ABC), LLC
Reel/Frame 067133/0248 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 17, 2024
From: TAIGA BIOTECHNOLOGIES (ABC), LLC
To: HTYR ACQUISITION LLC
Reel/Frame 067133/0520 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 7, 2021
From: REFAELI, YOSEF; TURNER, BRIAN C.; PAYNE, THOMAS R.
To: TAIGA BIOTECHNOLOGIES, INC.
Reel/Frame 057735/0034 →
Continuity (2)
Provisional Application 62830950 · Apr 8, 2019
Related Publication 20220142149A1 · May 12, 2022
References Cited (400)
US 4900322A · Adams · 1990 [cited by applicant]
US 4963489A · Naughton et al. · 1990 [cited by applicant]
US 5289858A · Grabenkort · 1994 [cited by applicant]
US 5476996A · Wilson et al. · 1995 [cited by applicant]
US 5652122A · Frankel et al. · 1997 [cited by applicant]
US 5670617A · Frankel et al. · 1997 [cited by applicant]
US 5674980A · Frankel et al. · 1997 [cited by applicant]
US 5698767A · Wilson et al. · 1997 [cited by applicant]
US 5747641A · Frankel et al. · 1998 [cited by applicant]
US 5804604A · Frankel et al. · 1998 [cited by applicant]
US 5811301A · Cameron · 1998 [cited by applicant]
US 5824837A · Chen et al. · 1998 [cited by applicant]
US 5843728A · Seed et al. · 1998 [cited by applicant]
US 5847082A · Rother et al. · 1998 [cited by applicant]
US 5849288A · Reisner · 1998 [cited by applicant]
US 5851828A · Seed et al. · 1998 [cited by applicant]
US 5912170A · Seed et al. · 1999 [cited by applicant]
US 6004811A · Seed et al. · 1999 [cited by applicant]
US 6040177A · Riddell et al. · 2000 [cited by applicant]
US 6284240B1 · Seed et al. · 2001 [cited by applicant]
US 6358739B1 · Baetge et al. · 2002 [cited by applicant]
US 6392013B1 · Seed et al. · 2002 [cited by applicant]
US 6410014B1 · Seed et al. · 2002 [cited by applicant]
US 6451558B1 · Cooke et al. · 2002 [cited by applicant]
US 6451601B1 · Baetge et al. · 2002 [cited by applicant]
US 6645501B2 · Dowdy · 2003 [cited by applicant]
US 6753162B1 · Seed et al. · 2004 [cited by applicant]
US 7135287B1 · Lonberg et al. · 2006 [cited by applicant]
US 7311920B1 · Devico et al. · 2007 [cited by applicant]
US 7582745B2 · Sah et al. · 2009 [cited by applicant]
US 7767453B2 · Zhang · 2010 [cited by applicant]
US 8034334B2 · Dudley et al. · 2011 [cited by applicant]
US 8211422B2 · Eshhar et al. · 2012 [cited by applicant]
US 8481492B2 · Edenhofer et al. · 2013 [cited by applicant]
US 8637307B2 · June et al. · 2014 [cited by applicant]
US 8697854B2 · Schendel et al. · 2014 [cited by applicant]
US 8784825B2 · Refaeli et al. · 2014 [cited by applicant]
US 8828723B2 · Refaeli et al. · 2014 [cited by applicant]
US 8986702B2 · Refaeli et al. · 2015 [cited by applicant]
US 9150831B2 · Cambier et al. · 2015 [cited by applicant]
US 9169462B2 · Refaeli et al. · 2015 [cited by applicant]
US 9365825B2 · Turner et al. · 2016 [cited by applicant]
US 9775897B2 · Refaeli et al. · 2017 [cited by applicant]
US 9789135B2 · Turner et al. · 2017 [cited by applicant]
US 10087420B2 · Turner et al. · 2018 [cited by applicant]
US 10149898B2 · Refaeli et al. · 2018 [cited by applicant]
US 10442853B2 · Refaeli et al. · 2019 [cited by applicant]
US 10760055B2 · Cambier et al. · 2020 [cited by applicant]
US 10864259B2 · Refaeli et al. · 2020 [cited by applicant]
US 11116796B2 · Turner et al. · 2021 [cited by applicant]
US 11369678B2 · Refaeli et al. · 2022 [cited by applicant]
US 20010049393A1 · Coller et al. · 2001 [cited by applicant]
US 20020055478A1 · Faris et al. · 2002 [cited by applicant]
US 20020076787A1 · Baetge et al. · 2002 [cited by applicant]
US 20020098166A1 · Havemann et al. · 2002 [cited by applicant]
US 20020155502A1 · Balint et al. · 2002 [cited by applicant]
US 20030072794A1 · Boulikas · 2003 [cited by applicant]
US 20030138859A1 · Barbera-Guillem et al. · 2003 [cited by applicant]
US 20030220286A1 · Abruzzese et al. · 2003 [cited by applicant]
US 20040224402A1 · Bonyhadi et al. · 2004 [cited by applicant]
US 20050220705A1 · Brooks et al. · 2005 [cited by applicant]
US 20050281816A1 · Lamping et al. · 2005 [cited by applicant]
US 20060068369A1 · Coelho et al. · 2006 [cited by applicant]
US 20060068469A1 · Payne et al. · 2006 [cited by applicant]
US 20060115898A1 · Zhang et al. · 2006 [cited by applicant]
US 20060154331A1 · Avidan et al. · 2006 [cited by applicant]
US 20060156422A1 · Dalrymple et al. · 2006 [cited by applicant]
US 20060222657A1 · Dowdy et al. · 2006 [cited by applicant]
US 20070011753A1 · Ito et al. · 2007 [cited by applicant]
US 20070047583A1 · Assa et al. · 2007 [cited by applicant]
US 20070067854A1 · Habu et al. · 2007 [cited by applicant]
US 20070082397A1 · Hasson et al. · 2007 [cited by applicant]
US 20070093420A1 · Yeomans et al. · 2007 [cited by applicant]
US 20070098715A1 · Ettenberg et al. · 2007 [cited by applicant]
US 20070116691A1 · Cambier et al. · 2007 [cited by applicant]
US 20070130628A1 · Brown · 2007 [cited by applicant]
US 20070248618A1 · Cohen · 2007 [cited by applicant]
US 20080050396A1 · Andersen et al. · 2008 [cited by applicant]
US 20090291094A1 · Refaeli et al. · 2009 [cited by applicant]
US 20100047217A1 · Refaeli et al. · 2010 [cited by applicant]
US 20100055129A1 · Refaeli et al. · 2010 [cited by applicant]
US 20100233804A1 · Zhou et al. · 2010 [cited by applicant]
US 20100279351A1 · Refaeli · 2010 [cited by applicant]
US 20100297763A1 · Cambier et al. · 2010 [cited by applicant]
US 20110218210A1 · Refaeli et al. · 2011 [cited by applicant]
US 20120003189A1 · Pelus et al. · 2012 [cited by applicant]
US 20120027792A1 · Pavlakis et al. · 2012 [cited by applicant]
US 20120244133A1 · Rosenberg et al. · 2012 [cited by applicant]
US 20120251563A1 · Nicchitta et al. · 2012 [cited by applicant]
US 20130177586A1 · Refaeli et al. · 2013 [cited by applicant]
US 20140109246A1 · Jimeno et al. · 2014 [cited by applicant]
US 20140255369A1 · Turner et al. · 2014 [cited by applicant]
US 20140356392A1 · Refaeli · 2014 [cited by examiner]
US 20150164950A1 · Turner et al. · 2015 [cited by applicant]
US 20150218515A1 · Altrichter et al. · 2015 [cited by applicant]
US 20170044500A1 · Cooper et al. · 2017 [cited by applicant]
US 20180036396A1 · Refaeli · 2018 [cited by examiner]
US 20190060434A1 · Refaeli et al. · 2019 [cited by applicant]
US 20200215188A1 · Refaeli et al. · 2020 [cited by applicant]
US 20210121550A1 · Refaeli et al. · 2021 [cited by applicant]
AU 2762802A1 · 2002 [cited by applicant]
AU 2006304392A1 · 2007 [cited by applicant]
CA 2584738A1 · 2006 [cited by applicant]
CA 2626525A1 · 2007 [cited by applicant]
CN 1206044 · 1999 [cited by applicant]
CN 1357620A · 2002 [cited by applicant]
CN 1659187 · 2005 [cited by applicant]
CN 101045914A · 2007 [cited by applicant]
CN 101330830A · 2008 [cited by applicant]
CN 102027105A · 2011 [cited by applicant]
CN 102083960A · 2011 [cited by applicant]
CN 102083970 · 2011 [cited by applicant]
CN 103998604 · 2014 [cited by applicant]
CN 104353066A · 2015 [cited by applicant]
CN 104640551 · 2015 [cited by applicant]
EP 036776A2 · 1981 [cited by applicant]
EP 0213469A2 · 1987 [cited by applicant]
EP 1103615A1 · 2001 [cited by applicant]
EP 1357184 · 2003 [cited by applicant]
EP 1792627 · 2007 [cited by applicant]
GB 2387599 · 2003 [cited by applicant]
JP 2000175692 · 2000 [cited by applicant]
JP 2000189157 · 2000 [cited by applicant]
JP 2001501909 · 2001 [cited by applicant]
JP 2001518300 · 2001 [cited by applicant]
JP 2002541786A · 2002 [cited by applicant]
JP 2003513672A · 2003 [cited by applicant]
JP 2003514565 · 2003 [cited by applicant]
JP 2003265189 · 2003 [cited by applicant]
JP 2004519245A · 2004 [cited by applicant]
JP 2005523012 · 2005 [cited by applicant]
JP 2005525085 · 2005 [cited by applicant]
JP 2005232148 · 2005 [cited by applicant]
JP 2005527211 · 2005 [cited by applicant]
JP 2006519781A · 2006 [cited by applicant]
JP 2009511081A · 2009 [cited by applicant]
JP 2011528567A · 2011 [cited by applicant]
JP 2012501347A · 2012 [cited by applicant]
JP 2014527980A · 2014 [cited by applicant]
JP 2015524415A · 2015 [cited by applicant]
JP 6167130B2 · 2015 [cited by applicant]
JP 2015525209A · 2015 [cited by applicant]
JP 2016510996A · 2016 [cited by applicant]
JP 2017513498 · 2017 [cited by applicant]
JP 6484293B2 · 2019 [cited by applicant]
JP 6655050B2 · 2020 [cited by applicant]
WO WO8603780A1 · 1986 [cited by applicant]
WO WO9215322 · 1992 [cited by applicant]
WO WO9404686 · 1994 [cited by applicant]
WO WO9419465 · 1994 [cited by applicant]
WO WO9514078 · 1995 [cited by applicant]
WO WO9810058 · 1998 [cited by applicant]
WO WO9852614 · 1998 [cited by applicant]
WO WO9916884 · 1999 [cited by applicant]
WO WO9945962 · 1999 [cited by applicant]
WO WO9953023 · 1999 [cited by applicant]
WO WO9953028 · 1999 [cited by applicant]
WO WO0009669 · 2000 [cited by applicant]
WO WO0061617A2 · 2000 [cited by applicant]
WO WO0062067 · 2000 [cited by applicant]
WO WO0134824A2 · 2001 [cited by applicant]
WO WO0138548 · 2001 [cited by applicant]
WO WO02057436 · 2002 [cited by applicant]
WO WO02074968A1 · 2002 [cited by applicant]
WO WO03008630 · 2003 [cited by applicant]
WO WO03020763 · 2003 [cited by applicant]
WO WO03033701 · 2003 [cited by applicant]
WO WO03038057 · 2003 [cited by applicant]
WO WO03039462 · 2003 [cited by applicant]
WO WO03057171A2 · 2003 [cited by applicant]
WO WO03089580 · 2003 [cited by applicant]
WO WO03089630 · 2003 [cited by applicant]
WO WO03094849 · 2003 [cited by applicant]
WO WO03097675 · 2003 [cited by applicant]
WO WO2004033685A1 · 2004 [cited by applicant]
WO WO2004035535 · 2004 [cited by applicant]
WO WO2004044004A2 · 2004 [cited by applicant]
WO WO2004050885 · 2004 [cited by applicant]
WO WO2004050895A2 · 2004 [cited by applicant]
WO WO2004074322A1 · 2004 [cited by applicant]
WO WO2004084805 · 2004 [cited by applicant]
WO WO2005014785 · 2005 [cited by applicant]
WO WO2005049073A2 · 2005 [cited by applicant]
WO WO2005084158 · 2005 [cited by applicant]
WO WO2005113595A2 · 2005 [cited by applicant]
WO WO2005114215A2 · 2005 [cited by applicant]
WO WO2006000830A2 · 2006 [cited by applicant]
WO WO2006032876 · 2006 [cited by applicant]
WO WO2006116512 · 2006 [cited by applicant]
WO WO2006125962A2 · 2006 [cited by applicant]
WO WO2007047583A2 · 2007 [cited by applicant]
WO WO2007067183 · 2007 [cited by applicant]
WO WO2008038002A2 · 2008 [cited by applicant]
WO WO2008039818A2 · 2008 [cited by applicant]
WO WO2008112922 · 2008 [cited by applicant]
WO WO2009059304 · 2009 [cited by applicant]
WO WO2009139930A2 · 2009 [cited by applicant]
WO WO2010011644 · 2010 [cited by applicant]
WO WO2010025421A2 · 2010 [cited by applicant]
WO WO2011100477A2 · 2011 [cited by applicant]
WO WO2012055170 · 2012 [cited by applicant]
WO WO2013039889A1 · 2013 [cited by applicant]
WO WO2013166321A1 · 2013 [cited by applicant]
WO WO2014018863A1 · 2014 [cited by applicant]
WO WO2014039908A1 · 2014 [cited by applicant]
WO WO2014083173A1 · 2014 [cited by applicant]
WO WO2014133567A1 · 2014 [cited by applicant]
WO WO2014133568A1 · 2014 [cited by applicant]
WO WO2014164606A1 · 2014 [cited by applicant]
WO WO2016105542A2 · 2016 [cited by applicant]
WO WO2017059319A2 · 2017 [cited by applicant]
WO WO2017123978A1 · 2017 [cited by applicant]
WO WO2018104909A2 · 2018 [cited by applicant]
De Clercq, E., “New Nucleotide Analogues for the Treatment of Hemorrhagic Fever Virus Infections.” Chem. Asian J., 2019, vol. 14, pp. 3962-3968. [cited by applicant]
Duraffour, et al., “How to treat Ebola virus infections? A lesson from the field.” Current Opinion in Virology, 2017, vol. 24, pp. 9-15. [cited by applicant]
Fanale, et al., “Monoclonal Antibodies in the Treatment of Non-Hodgkin's Lymphoma.” Drugs, 2007, vol. 3, pp. 333-350. [cited by applicant]
Foreign Action other than Search Report on CN 201910023181.2 Dtd Sep. 15, 2022. [cited by applicant]
Foreign Action other than Search Report on CN 201910848417.6 Dtd Nov. 3, 2022, 15 pages. [cited by applicant]
Foreign Action other than Search Report on EP 20212922.7 Dtd Sep. 1, 2022. [cited by applicant]
Gibson, et al., “How we evaluate and treat neutropenia in adults.” Blood, 2014, vol. 124, No. 8, pp. 1251-1258. [cited by applicant]
Jacobson, et al., “How I treat Burkitt lymphoma in adults.” Blood, 2014, vol. 124, No. 19, pp. 2913-2920. [cited by applicant]
Namikawa, et al., “A case of ABO-incompatible blood transfusion treated by plasma exchange therapy and continuous hemodiafiltration.” CEN Case Reports, 2018, vol. 7, pp. 114-120. [cited by applicant]
Non-Final Office Action on U.S. Appl. No. 17/009,279 Dtd Oct. 27, 2022. [cited by applicant]
Yu, et al., “Chapter 1: Clinical Overview of Cancer,” Clinical References for Cancers (Chinese), May 31, 2004, pp. 151 and 152. [cited by applicant]
“myc proto-oncogene protein [ [cited by applicant]
“Stem Cell”, Wikipedia, 2008, retrieved Nov. 13 from URL: http//en.wikipedia.org/wiki/Stem_cell (11 pages). [cited by applicant]
Altman et al., “Phenotypic Analysis of Antigen-Specific T Lymphocytes”, Science, vol. 274, 1996, pp. 94-96 (4 pages). [cited by applicant]
Amino Acid, NCBI, 2018 (8 pages). [cited by applicant]
Andersen et al., “Parallel detection of antigen-specific T cell responses by combinatiorial encoding of MHC multimers”, Nature Protocols, vol. 7, No. 5, 2012, pp. 891-902, DOI: 10.1038/nprot.2012.037 (12 pages). [cited by applicant]
Application for U.S. Appl. No. 12/048,148, filed Mar. 13, 2008 (50 pages). [cited by applicant]
Application for U.S. Appl. No. 12/506,894, filed Jul. 21, 2009 (59 pages). [cited by applicant]
Aubry et al., “N-Myc Shares Cellular Functions with c-Myc”, DNA and Cell Biology, vol. 19, No. 6, Jun. 2000, pp. 353-364 (12 pages). [cited by applicant]
Austrian Search Report and Written Opinion SG 201101367-9 dated Mar. 23, 2012 (17 pages). [cited by applicant]
Baum, Christopher, “Insertional Mutagenesis in Gene Therapy and Stem Cell Biology”, Current Opinion in Hematology, vol. 14, Jul. 2007, pp. 337-342 (6 pages). [cited by applicant]
Beerens et al., “Protein Transduction Domains and their Utility in Gene Therapy”, Current Gene Therapy, vol. 3, No. 5, 2003, pp. 486-494 (9 pages). [cited by applicant]
Benassayag et al., “Human c-Myc Isoforms Differentially Regulate Cell Growth and Apoptosis in [cited by applicant]
Berkson et al., “Pilot Screening Programme for Small Molecule Activators of p53”, International Journal of Cancer, vol. 115, 2005, pp. 701-710, DOI: 10.1002/ijc.20968 (10 pages). [cited by applicant]
Bird et al., “Expansion of Human and Murine Hematopoietic Stem and Progenitor Cells Ex Vivo without Genetic Modification Using MYC and Bcl-2 Fusion Proteins”, PLOS ONE, vol. 9, No. 8, e105525, 2014, pp. 1-20, DOI: 10.13… [cited by applicant]
Bissonnette et al., “Apoptotic cell death induced by c-myc is inhibited by bcl-2”, Nature, vol. 359, Oct. 8, 1992, pp. 552-554 (3 pages). [cited by applicant]
Bouchard et al., “Control of cell proliferation by Myc”, Trends in Cell Biology, vol. 8, 1998, pp. 202-206 (5 pages). [cited by applicant]
Bunting et al., “Restoration of lymphocyte function in Janus kinase 3-deficient mice by retroviral-mediated gene transfer,” Nature Medicine, vol. 4, No. 1, 1998, pp. 58-64 (7 pages). [cited by applicant]
Buske et al., “Deregulated expression of HOXB4 enhances the primitive growth activity of human hematopoietic cells”, Blood, vol. 100, No. 3, Aug. 1, 2002, pp. 862-868 (7 pages). [cited by applicant]
Capecchi, Mario R., “Altering the Genome by Homologous Recombination”, Science, vol. 244, No. 4910, Jun. 16, 1989, pp. 1288-1292 (5 pages). [cited by applicant]
Caron et al., “Endosome disruption enhances the functional nuclear delivery of Tat-fusion proteins”, Biochemical and Biophysical Research Communications, vol. 319, No. 1, Jun. 18, 2004, pp. 12-20 (9 pages). [cited by applicant]
Carotta et al., “Directed differentiation and mass cultivation of pure erythroid progenitors from mouse embryonic stem cells”, Blood, vol. 104, No. 6, Sep. 15, 2004, pp. 1873-1880, DOI: 10.1182/blood-2004-02-0570 (8 pag… [cited by applicant]
Chadwick et al., “Notch Signaling Induces Apoptosis in Primary Human CD34+ Hematopoietic Progenitor Cells”, Stem Cells, vol. 25, 2007, pp. 203-210, DOI: 10.1634/stemcells.2005-0303 (10 pages). [cited by applicant]
Chandran et al., “Tumor-Specific Effector CD8+ T Cells That Can Establish Immunological Memory in Humans after Adoptive Transfer are Marked by Expression of IL7 Receptor and c-myc”, Cancer Research, vol. 75, No. 16, 201… [cited by applicant]
Chang et al., “Phenotypic expression in [cited by applicant]
Chen et al., “Small-Molecule Anthracene-Induced Cytotoxicity and Induction of Apoptosis through Generation of Reactive Oxygen Species”, Biological & Pharmaceutical Bulletin, vol. 27, No. 6, Jun. 2004, pp. 838-845 (8 pag… [cited by applicant]
Cheng et al., “BCL-2, BCL-XL, Sequester BH3 Domain-Only Molecules Preventing BAX- and BAK-Mediated Mitochondrial Apoptosis”, Molecular Cell, vol. 8, Sep. 2001, pp. 705-711 (7 pages). [cited by applicant]
Chi et al., “Physical Stability of Proteins in Aqueous Solution: Mechanism and Driving Forces in Nonnative Protein Aggregation,” Pharmaceutical Research, vol. 20, No. 9, Sep. 2003, pp. 1325-1336 (2 pages). [cited by applicant]
Chin et al., “Essential role for oncogenic Ras in tumour maintenance”, Nature, vol. 400, Jul. 29, 1999, pp. 468-472 (5 pages). [cited by applicant]
Choi et al., “Myc protein is stabilized by suppression of a novel E3 ligase complex in cancer cells”, Genes & Development, vol. 24, 2010, pp. 1236-1241, DOI: 10.1101/gad.1920310 (6 pages). [cited by applicant]
Choi et al., “Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase”, Journal of Neuroscience, vol. 27, No. 11, Mar. 14, 2007, pp. 299… [cited by applicant]
Cleland et al., “The Development of Stable Protein Formulations: A Close Look at Protein Aggregation, Deamidation, and Oxidation,” Critical Reviews in Therapeutic Drug Carrier Systems, vol. 10, No. 4, Jan. 1, 1993, pp. … [cited by applicant]
Coeytaux et al., “The Cationic Amphipathic alpha-Helix of HIV-1 Viral Protein R (Vpr) Binds to Nucleic Acids, Permeabilizes Membranes, and Efficiently Transfects Cells”, The Journal of Biological Chemistry, vol. 278, No… [cited by applicant]
Coller et al., “Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion”, Proceedings of the National Academy of Sciences USA, vol. 9… [cited by applicant]
Communication pursuant to Rules 161(2) and 162 EPC for EP 17876016.1 dated Jul. 9, 2019 (3 pages). [cited by applicant]
Conti, et al., “Gene Therapy Using Neural Stem Cells”, Methods in Molecular Biology, vol. 198, 2002, pp. 233-244, XP009120658 (12 pages). [cited by applicant]
Coppola et al., “Constitutive c-myc oncogene expression blocks mouse erythroleukaemia cell differentiation but not commitment”, Nature, vol. 320, Apr. 24, 1986, pp. 760-763 (4 pages). [cited by applicant]
Corrected Notice of Allowability for U.S. Appl. No. 15/179,735 dated Jun. 15, 2018 (2 pages). [cited by applicant]
Corrected Notice of Allowability for U.S. Appl. No. 15/179,735 dated Jun. 8, 2018 (2 pages). [cited by applicant]
Corrected Notice of Allowability for U.S. Appl. No. 16/042,904 dated Mar. 6, 2020 (4 pages). [cited by applicant]
Corrected Notice of Allowance for U.S. Appl. No. 15/643,133 dated Jun. 8, 2020 (2 pages). [cited by applicant]
Corrected Notice of Allowance for U.S. Appl. No. 15/717,675 dated Jan. 10, 2020 (2 pages). [cited by applicant]
Corrected Notice of Allowance for U.S. Appl. No. 15/717,675 dated Nov. 6, 2019 (4 pages). [cited by applicant]
Corrected Notice of Allowance for U.S. Appl. No. 16/042,904 dated Jan. 29, 2020 (2 pages). [cited by applicant]
Corrected Notice of Allowance for U.S. Appl. No. 16/042,904 dated Jun. 2, 2020 (4 pages). [cited by applicant]
Corrected Notice of Allowance for U.S. Appl. No. 16/042,904 dated Jun. 22, 2020 (4 pages). [cited by applicant]
Corrected Notice of Allowance for U.S. Appl. No. 16/261,207 dated Feb. 1, 2021 (4 pages). [cited by applicant]
D'Alessandro et al., “Red blood cell storage: the story so far”, Blood transfusion = Trasfusione del sangue, vol. 8, 2010, pp. 82-88, DOI: 10.2450/2009.0122-09 (7 pages). [cited by applicant]
Dang et al., “Identification of the Human c-myc Protein Nuclear Translocation Signal”, Molecular and Cellular Biology, vol. 8, No. 10, Oct. 1988, pp. 4048-4054 (7 pages). [cited by applicant]
Dang et al., “Nuclear and Nucleolar Targeting Sequences of c-erb-A, c-myb, N-myc, p53, HSP70, and HIV tat Proteins”, Journal of Biological Chemistry, vol. 264, No. 30, Oct. 25, 1989, pp. 18019-18023 (5 pages). [cited by applicant]
Dang, Chi V., “c-Myc Target Genes Involved in Cell Growth, Apoptosis, and Metabolism”, Molecular and Cellular Biology, vol. 19, No. 1, Jan. 1999, pp. 1-11 (11 pages). [cited by applicant]
Daugas et al., “Erythrocytes: Death of a mummy”, Cell Death and Differentiation, vol. 8, No. 12, 2001, pp. 1131-1133 (3 pages). [cited by applicant]
De Boer et al., “The tac promoter: A functional hybrid derived from the trp and lac promoters”, Proceedings of the National Academy of Sciences USA, Biochemistry, vol. 80, 1983, pp. 21-25 (5 pages). [cited by applicant]
De Korte, D. “New additive solutions for red cells”, ISBT Science Series, vol. 11, Suppl. 1, 2016, pp. 165-170 (6 pages). [cited by applicant]
Decision of Rejection for CN 200580031545.8 dated Jul. 3, 2012, English Translation Only (11 pages). [cited by applicant]
Decision of Rejection for CN 201380048261.4 dated Apr. 16, 2019 (15 pages). [cited by applicant]
Decision of Rejection for JP 2008-536713 dated Aug. 5, 2013, English Translation Only (2 pages). [cited by applicant]
Decision of Rejection for JP 2011-520133 dated Nov. 26, 2014 (9 pages). [cited by applicant]
Decision of Rejection for JP 2011-525258 date Dec. 3, 2014 (11 pages). [cited by applicant]
Decision of Rejection for JP 2014-108137 dated Jun. 2, 2016 (25 pages). [cited by applicant]
Decision of Rejection for JP 2018-153567 dated Mar. 18, 2020 (7 pages). [cited by applicant]
Delgado et al., “Myc Roles in Hematopoiesis and Leukemia”, Genes and Cancer, vol. 1, No. 6, 2010, pp. 605-616, DOI: 10.1177/1947601910377495 (12 pages). [cited by applicant]
Deocampo, et al., “Cooperation of bcl-2 and myc in the neoplastic transformation of normal rat liver epithelial cells is related to the down-regulation of gap junction-mediated intercellular communication”, Carcinogenes… [cited by applicant]
Derossi et al., “Trojan peptides: the penetratin system for intracellular delivery”, Cell Biology, vol. 8, Feb. 1998, pp. 84-87 (4 pages). [cited by applicant]
Dmitrovsky et al., “A Transfected c-myc Oncogene Inhibits Mouse Erytholeukemic Differentiation”, Current Topics in Microbiology and Immunology, vol. 132, 1986 (4 pages). [cited by applicant]
Domashenko et al., “TAT-mediated transduction of NF-Ya peptide induces the ex vivo proliferation and egraftment potential of human hematopoietic progenitor cells,” Blood, vol. 116, No. 15, Oct. 14, 2010, pp. 2676-2683 (… [cited by applicant]
Domen et al., “The Role of Apoptosis in the Regulation of Hematopoietic Stem Cells: Overexpression of BCL-2 Increase Both Their Number and Repopulation Potential”, Journal of Experimental Medicine, vol. 191, No. 2, 2000… [cited by applicant]
Dudley et al., “Adoptive Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for the Treatment of Patients with Refractory Metastatic Melanoma”, Journal of Clinical Oncology, vol. 23, No. … [cited by applicant]
Dvorak et al., “Cytochemical Localization of Peroxidase Activity in the Developing Erythrocyte”, American Journal of Pathology, vol. 67, No. 2, 1972, pp. 303-326 (24 pages). [cited by applicant]
Eilers et al., “Chimaeras of Myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells”, Nature, vol. 340, No. 6228, Jul. 6, 1989, pp. 66-68 (3 pages). [cited by applicant]
Eischen et al., “Apoptosis Triggered by Myc-Induced Suppression of Bcl-XL or Bcl-2 Is Bypassed during Lymphomagenesis”, Molecular and Cellular Biology, vol. 21, No. 15, Aug. 2001, pp. 5063-5070, DOI: 10.1128/MCB.21.15.5… [cited by applicant]
Elliot et al., “Intercellular Trafficking and Protein Delivery by a Herpesvirus Structural Protein”, Cell, vol. 88, Jan. 24, 1997, pp. 223-233 (11 pages). [cited by applicant]
Esdar et al., “Differentiation-associated apoptosis of neural stem cells is effected by Bcl-2 overexpression: impact on cell lineage determination” European Journal of Cell Biology, vol. 80, No. 8, Aug. 2001, pp. 539-55… [cited by applicant]
Examination Report for AU 2018247295 dated Dec. 6, 2019 (2 pages). [cited by applicant]
Examination Report for CA 2626525 dated Apr. 17, 2013 (4 pages). [cited by applicant]
Examination Report for CA 2626525 dated Apr. 8, 2014 (4 pages). [cited by applicant]
Examination Report for CA 2626525 dated Jul. 4, 2018 (3 pages). [cited by applicant]
Examination Report for CA 2626525 dated Jun. 13, 2017 (3 pages). [cited by applicant]
Examination Report for CA 2626525 dated Jun. 6, 2016 (3 pages). [cited by applicant]
Examination Report for CA 2626525 dated May 8, 2015 (3 pages). [cited by applicant]
Examination Report for CA 2680613 dated Nov. 21, 2013 (3 pages). [cited by applicant]
Examination Report for CA 2680613 dated Nov. 28, 2014 (4 pages). [cited by applicant]
Examination Report for CA 2723114 dated Apr. 21, 2015 (4 pages). [cited by applicant]
Examination Report for CA 2723114 dated Jul. 7, 2016 (3 pages). [cited by applicant]
Examination Report for CA 2731767 dated Jul. 25, 2012 (3 pages). [cited by applicant]
Examination Report for CA 2731767 dated Oct. 5, 2015 (3 pages). [cited by applicant]
Examination Report for CA 2731767 dated Sep. 5, 2014 (2 pages). [cited by applicant]
Examination Report for CA 2735522 dated Nov. 16, 2015 (4 pages). [cited by applicant]
Examination Report for CA 2735522 dated Oct. 2, 2014 (2 pages). [cited by applicant]
Examination Report for CA 2735522 dated Sep. 10, 2012 (3 pages). [cited by applicant]
Examination Report for CA 2879667 dated Jun. 18, 2019 (4 pages). [cited by applicant]
Examination Report for CA 2879667 dated May 25, 2020 (4 pages). [cited by applicant]
Examination Report for CA 2905285 dated Jan. 30, 2020 (5 pages). [cited by applicant]
Examination Report for CA 2905296 dated Feb. 11, 2021 (7 pages). [cited by applicant]
Examination Report for CA 2905296 dated Jan. 31, 2020 (4 pages). [cited by applicant]
Examination Report for CA 3035209 dated Feb. 3, 2020 (4 pages). [cited by applicant]
Examination Report for CA 3035209 dated Feb. 4, 2021 (4 pages). [cited by applicant]
Examination Report for CA 3065947 dated Nov. 4, 2020 (4 pages). [cited by applicant]
Examination Report for CA 3065947 dated Oct. 13, 2021 (4 pages). [cited by applicant]
Examination Report for EP 06826025.6 dated Sep. 22, 2009 (1 page). [cited by applicant]
Examination Report for EP 08743862.8 dated Sep. 23, 2010 (6 pages). [cited by applicant]
Examination Report for EP 08743862.8 dated on May 14, 2010 (6 pages). [cited by applicant]
Examination Report for EP 09747016.5 dated Apr. 9, 2013 (6 pages). [cited by applicant]
Examination Report for EP 09747016.5 dated Jul. 26, 2016 (5 pages). [cited by applicant]
Examination Report for EP 09747016.5 dated Jun. 12, 2017 (6 pages). [cited by applicant]
Examination Report for EP 09747016.5 dated Mar. 19, 2015 (5 pages). [cited by applicant]
Examination Report for EP 09747016.5 dated May 15, 2018 (7 pages). [cited by applicant]
Examination Report for EP 09810692.5 dated Mar. 28, 2012 (3 pages). [cited by applicant]
Examination Report for EP 09810692.5 dated Oct. 22, 2014 (3 pages). [cited by applicant]
Examination Report for EP 12187097.6 dated Jan. 22, 2015 (6 pages). [cited by applicant]
Examination Report for EP 13820331.0 dated Apr. 24, 2018 (4 pages). [cited by applicant]
Examination Report for EP 13820331.0 dated Jul. 29, 2019 (3 pages). [cited by applicant]
Examination Report for EP 14778538.0 dated Apr. 16, 2018 (4 pages). [cited by applicant]
Examination Report for EP 14779483.8 dated Apr. 28, 2021 (3 pages). [cited by applicant]
Examination Report for EP 14779483.8 dated Aug. 11, 2020 (3 pages). [cited by applicant]
Examination Report for EP 14779483.8 dated Jan. 14, 2019 (4 pages). [cited by applicant]
Examination Report for EP 14779483.8 dated Jun. 28, 2019 (4 pages). [cited by applicant]
Examination Report for EP 14779483.8 dated Jun. 29, 2018 (4 pages). [cited by applicant]
Examination Report for EP 14779483.8 dated Oct. 16, 2017 (4 pages). [cited by applicant]
Examination Report for EP 17876016.1 dated Apr. 12, 2021 (5 pages). [cited by applicant]
Examination Report for EP 17920607.3 dated Aug. 26, 2020 (5 pages). [cited by applicant]
Examination Report for EP 18154875.1 dated Sep. 6, 2019 (4 pages). [cited by applicant]
Examination Report for IN 2048/DELNP/2011 dated Sep. 15, 2016 (9 pages). [cited by applicant]
Examination Report for IN 3332/DELNP/2008 dated Aug. 23, 2013 (6 pages). [cited by applicant]
Examination Report for IN 634/DELNP/2011 dated Jun. 8, 2017 (10 pages). [cited by applicant]
Examination Report for IN 6624/DELNP/2014 dated Sep. 27, 2018 (4 pages). [cited by applicant]
Examination Report for IN 9033/DELNP/2010 dated May 19, 2017 (11 pages). [cited by applicant]
Examination Report for IN 9205/DELNP/2015 dated Nov. 28, 2019 (8 pages). [cited by applicant]
Examination Report for IN 9206/DELNP/2015 dated Dec. 26, 2019 (6 pages). [cited by applicant]
Examination Report No. 1 for AU 2009285547 dated Jul. 25, 2011 (2 pages). [cited by applicant]
Examination Report No. 1 for AU 2013292330 dated Sep. 6, 2017 (3 pages). [cited by applicant]
Examination Report No. 1 for AU 2014202016 dated May 12, 2015 (3 pages). [cited by applicant]
Examination Report No. 1 for AU 2014249200 dated Mar. 15, 2019 (4 pages). [cited by applicant]
Examination Report No. 1 for AU 2016203892 dated Apr. 12, 2017 (3 pages). [cited by applicant]
Extended European Search Report for EP 06826025.6 dated Aug. 13, 2009 (8 pages). [cited by applicant]
Extended European Search Report for EP 09747016.5 dated May 30, 2012 (8 pages). [cited by applicant]
Extended European Search Report for EP 09800871.7 dated Jun. 24, 2011 (5 pages). [cited by applicant]
Extended European Search Report for EP 09810692.5 dated Jul. 11, 2011 (5 pages). [cited by applicant]
Extended European Search Report for EP 12187077.8 dated Mar. 25, 2013 (7 pages). [cited by applicant]
Extended European Search Report for EP 12187097.6 dated Mar. 27, 2013 (8 pages). [cited by applicant]
Extended European Search Report for EP 13188850.0 dated May 27, 2014 (8 pages). [cited by applicant]
Extended European Search Report for EP 13820331.0 dated Oct. 10, 2016 (9 pages). [cited by applicant]
Extended European Search Report for EP 14778538.0 dated Sep. 29, 2016 (17 pages). [cited by applicant]
Extended European Search Report for EP 14779483.8 dated Dec. 23, 2016 (5 pages). [cited by applicant]
Extended European Search Report for EP 15175802.6 dated Dec. 14, 2015 (7 pages). [cited by applicant]
Extended European Search Report for EP 17876016.1 dated Jun. 26, 2020 (7 pages). [cited by applicant]
Extended European Search Report for EP 18154875.1 dated Apr. 24, 2018 (8 pages). [cited by applicant]
Extended European Search Report for EP 18841366.0 dated Mar. 16, 2021 (7 pages). [cited by applicant]
Extended European Search Report for EP 20212922.7 dated May 26, 2021 (7 pages). [cited by applicant]
Extended European Search Report for EP 21170329.3 dated Oct. 22, 2021 (10 pages). [cited by applicant]
Extended Search Report for EP 17920607.3 dated Dec. 11, 2019 (7 pages). [cited by applicant]
Extended Search Report for EP 19157513.3 dated Apr. 1, 2019 (13 pages). [cited by applicant]
Fanidi et al., “Cooperative interaction between c-myc and bcl-2 proto-oncogenes”, Nature, vol. 359, Oct. 8, 1992, pp. 554-556 (3 pages). [cited by applicant]
Felsher et al., “Reversible Tumorigenesis by MYC in Hematopoietic Lineages”, Molecular Cell, vol. 4, Aug. 1999, pp. 199-207 (9 pages). [cited by applicant]
Fifth Office Action for CN 200980126312.4 dated Jan. 22, 2014, English Translation Only (3 pages). [cited by applicant]
Filing Receipt for IL 265409 dated Oct. 19, 2021 (2 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 11/583,970 dated Apr. 9, 2014 (20 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 11/583,970 dated Nov. 17, 2011 (16 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 11/583,970 dated Nov. 26, 2008 (14 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 11/583,970 dated Nov. 4, 2009 (10 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 12/048,148 dated Feb. 15, 2013 (17 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 12/467,957 dated Feb. 28, 2011 (8 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 12/467,957 dated Sep. 17, 2014 (9 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 12/506,894 dated Oct. 9, 2014 (15 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 12/550,166 dated May 11, 2012 (12 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 12/701,383 dated Nov. 13, 2014 (18 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 12/701,383 dated Nov. 16, 2011 (14 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 13/795,659 dated Jul. 11, 2014 (16 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 13/795,659 dated Mar. 26, 2015 (18 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 13/797,648 dated Apr. 1, 2015 (12 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 13/797,648 dated Feb. 8, 2017 (18 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 14/461,105 dated Sep. 15, 2016 (6 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 14/509,870 dated Feb. 3, 2017 (16 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 14/873,296 dated Jan. 24, 2018 (17 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 15/244,138 dated Jun. 4, 2018 (15 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 15/244,138 dated Mar. 14, 2019 (14 pages). [cited by applicant]
Final Office Action for U.S. Appl. No. 15/668,451 dated May 24, 2018 (10 pages). [cited by applicant]