IP Library › Granted Patent US 12,357,692
Granted Patent B2
US 12,357,692 · App. 18/063,902 · Granted Jul 15, 2025

Method of treating influenza A

Inventors: Nicole Kallewaard-Lelay (Gaithersburg, MD); Raburn Mallory (Gaithersburg, MD); Gabriel Robbie (Gaithersburg, MD); Song Ren (Gaithersburg, MD)
Assignee: MEDIMMUNE, LLC
A61K39/42A61K31/13A61K31/215A61K31/7012A61P31/16C07K16/1018A61K2039/505A61K2039/545C07K2317/21C07K2317/33C07K2317/76C07K2317/94C12N2760/16111
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 12,357,692
App. No.
18/063,902
Granted
Jul 15, 2025
Kind
B2
Abstract

Provided herein are methods for treating, reducing or preventing influenza A virus infection in a patient, as well as compositions and articles of manufacture for treating, reducing or preventing influenza A virus infection in a patient.

Claims (13)

1. A method of preventing an influenza A virus symptom in a patient, the method comprising administering to the patient about 3000 mg anti-influenza A antibody or fragment thereof that is capable of binding to influenza A virus hemagglutinin and neutralizing at least one group 1 subtype and at least one group 2 subtype of influenza A virus, wherein the anti-influenza A antibody or fragment thereof comprises a HCDR1 of SEQ ID NO:3, HCDR2 of SEQ ID NO:4, and HCDR3 of SEQ ID NO:5 and a LCDR1 of SEQ ID NO:8, LCDR2 of SEQ ID NO:9 and LCDR3 of SEQ ID NO:10.

2. The method according to claim 1 , wherein the administering is selected from parenteral or intravenous administration.

3. The method according to claim 2 , wherein the anti-influenza A antibody or fragment thereof is administered as a single dose.

4. The method according to claim 1 , wherein the anti-influenza A antibody or fragment thereof is administered before the patient is exposed to influenza A virus or is infected with influenza A virus.

5. The method according to claim 1 , wherein the anti-influenza A antibody or fragment thereof is administered to a subject within 7 days of exposure to influenza A virus or infection with influenza A virus.

6. The method according to claim 1 , wherein the anti-influenza A antibody or fragment thereof is administered to a subject within 3 days of exposure to influenza A virus or infection with influenza A virus.

7. The method according to claim 1 , wherein the anti-influenza A antibody or fragment thereof is administered to a subject within 1 day of exposure to influenza A virus or infection with influenza A virus.

8. The method according to claim 1 , wherein the anti-influenza A antibody or fragment thereof is capable of neutralizing one or more influenza A virus group 1 subtype selected from: H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, H18, and variants thereof; and one or more influenza A virus group 2 subtypes selected from: H3, H4, H7, H10, H14 and H15 and variants thereof.

9. The method according to claim 1 , wherein the anti-influenza A antibody or fragment thereof comprises a VH having an amino acid sequence with at least 75% identity to the amino acid sequence of SEQ ID NO: 2 and a VL having an amino acid sequence with at least 75% identity to the amino acid sequence of SEQ ID NO:7.

10. The method according to claim 1 , wherein the anti-influenza A antibody or fragment thereof comprises a VH having an amino acid sequence shown in SEQ ID NO: 2 and a VL having an amino acid sequence shown in SEQ ID NO: 7.

11. The method according to claim 1 , wherein the anti-influenza A antibody comprises MEDI8852.

12. The method according to claim 1 , wherein the antibody or fragment thereof is administered in combination with one or more small molecule antiviral medications.

13. The method according to claim 12 , wherein the small molecule antiviral medication is selected from oseltamivir, zanamivir, amantadine and rimantadine.

Continuity (4)
Continuation 16984827 · Aug 4, 2020
Continuation 16068941
Provisional Application 62278068 · Jan 13, 2016
Related Publication 20230181735A1 · Jun 15, 2023
References Cited (177)
US 3766162A · Spector · 1973 [cited by applicant]
US 3791932A · Schuurs et al. · 1974 [cited by applicant]
US 3817837A · Rubenstein et al. · 1974 [cited by applicant]
US 4179337A · Davis et al. · 1979 [cited by applicant]
US 4233402A · Maggio et al. · 1980 [cited by applicant]
US 4495285A · Shimizu et al. · 1985 [cited by applicant]
US 4609546A · Hiratani · 1986 [cited by applicant]
US 4676980A · Segal et al. · 1987 [cited by applicant]
US 4766106A · Katre et al. · 1988 [cited by applicant]
US 4831175A · Gasnow et al. · 1989 [cited by applicant]
US 5595721A · Kaminski et al. · 1997 [cited by applicant]
US 5807715A · Morrison et al. · 1998 [cited by applicant]
US 6300064B1 · Knappik et al. · 2001 [cited by applicant]
US 6300104B1 · Morrison et al. · 2001 [cited by applicant]
US 8101553B1 · Kurosawa et al. · 2012 [cited by applicant]
US 8871207B2 · Lanzavecchia · 2014 [cited by applicant]
US 9243054B2 · Burioni et al. · 2016 [cited by applicant]
US 9340603B2 · Lanzavecchia · 2016 [cited by applicant]
US 10442854B2 · Kallewaard-Lelay et al. · 2019 [cited by applicant]
US 10494419B2 · Benjamin et al. · 2019 [cited by applicant]
US 10519221B2 · Kallewaard-Lelay et al. · 2019 [cited by applicant]
US 20070219149A1 · Hasegawa et al. · 2007 [cited by applicant]
US 20100080813A1 · Lanzavecchia · 2010 [cited by applicant]
US 20110014187A1 · Burioni et al. · 2011 [cited by applicant]
US 20120128684A1 · Marasco et al. · 2012 [cited by applicant]
US 20160257732A1 · Benjamin et al. · 2016 [cited by applicant]
US 20170218054A1 · Kallewaard-Lelay et al. · 2017 [cited by applicant]
US 20180155413A1 · Kallewaard-Lelay et al. · 2018 [cited by applicant]
US 20190015509A1 · Kallewaard-Lelay et al. · 2019 [cited by applicant]
US 20200109187A1 · Kallewaard-Lelay et al. · 2020 [cited by applicant]
EP 1167382A1 · 2002 [cited by applicant]
EP 2919813B1 · 2018 [cited by applicant]
JP 2014527403A · 2014 [cited by applicant]
JP 2015501815A · 2015 [cited by applicant]
RU 2536956C1 · 2014 [cited by applicant]
WO WO0052031A2 · 2000 [cited by applicant]
WO WO0052473A2 · 2000 [cited by applicant]
WO WO2004001007A1 · 2003 [cited by applicant]
WO WO2004007667A2 · 2004 [cited by applicant]
WO 2005007697A1 · 2005 [cited by applicant]
WO WO2006124269A2 · 2006 [cited by applicant]
WO WO2007045477A2 · 2007 [cited by applicant]
WO WO2007109742A2 · 2007 [cited by applicant]
WO WO2007117577A2 · 2007 [cited by applicant]
WO WO2007134327A2 · 2007 [cited by applicant]
WO WO2008028946A2 · 2008 [cited by applicant]
WO WO2008054606A2 · 2008 [cited by applicant]
WO WO2008066691A2 · 2008 [cited by applicant]
WO WO2008076379A2 · 2008 [cited by applicant]
WO WO2008084410A2 · 2008 [cited by applicant]
WO WO2008110937A2 · 2008 [cited by applicant]
WO WO2009115972A1 · 2009 [cited by applicant]
WO WO2010010466A2 · 2010 [cited by applicant]
WO WO2010010467A2 · 2010 [cited by applicant]
WO WO2010054007A1 · 2010 [cited by applicant]
WO WO2012082634A1 · 2012 [cited by applicant]
WO WO2013007770A1 · 2013 [cited by applicant]
WO WO2013011347A1 · 2013 [cited by applicant]
WO WO2013043729A1 · 2013 [cited by applicant]
WO WO2013044203A2 · 2013 [cited by applicant]
WO WO2013086052A2 · 2013 [cited by applicant]
WO WO2013132007A1 · 2013 [cited by applicant]
WO WO2014078268A1 · 2014 [cited by applicant]
WO WO2014158001A1 · 2014 [cited by applicant]
WO WO2015051010A1 · 2015 [cited by applicant]
WO WO2016011035A2 · 2016 [cited by applicant]
WO WO2016196470A1 · 2016 [cited by applicant]
WO WO2017123685A1 · 2017 [cited by applicant]
WO WO2017147248A1 · 2017 [cited by applicant]
Abed et al., “A Review of Clinical Influenza A and B Infections with Reduced Susceptibility to Both Oseltamivir and Zanamivir,” Open Forum Infectious Diseases 4(3): ofx105 (2017). [cited by applicant]
Ali et al., “Evaluation of MEDI8852, an Anti-Influenza A Monoclonal Antibody, in Treating Acute Uncomplicated Influenza,” Antimicrobial Agents and Chemotherapy 62(11): e00694-18 (2018). [cited by applicant]
Benjamin et al., “A Broadly Neutralizing Human Monoclonal Antibody Directed against a Novel Conserved Epitope on the Influenza Virus H3 Hemagglutinin Globular Head,” J Virol 88(12):6743-6750 (2014). [cited by applicant]
Biere et al., “Differentiation of Influenza B Virus Lineages Yamagata and Victoria by Real-Time PCR,” J Clin Microbiol 48:1425-1427 (2010). [cited by applicant]
Bouvier, “The Future of Influenza Vaccines: A Historical and Clinical Perspective,” Vaccines 6:58 (2018). [cited by applicant]
Centers for Disease Control and Prevention. “Influenza (Flu): Antiviral drugs for seasonal influenza: additional links and resources.” Jan. 7, 2021. [cited by applicant]
Chai et al., “A broadly protective therapeutic antibody against influenza B virus with two mechanisms of action,” Nature Comm 8:14234 (2017). [cited by applicant]
Corti et al., “Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine,” J Clin Invest 120:1663-1673 (2010). [cited by applicant]
Corti et al., “A Neutralizing Antibody Selected from Plasma Cells That Binds to Group 1 and Group 2 Influenza A Hemagglutinins,” Science 333(6044):850-856 (2011). [cited by applicant]
Corti et al., “Cross-neutralization of four paramyxoviruses by a human monoclonal antibody,” Nature 501(7467):439-443 (2013). [cited by applicant]
Corti et al., “Tackling influenza with broadly neutralizing antibodies,” Curr Opin Virol 24:60-69 (2017). [cited by applicant]
Davies and Riechmann. “Affinity improvement of single antibody VH domains: residues in all three hypervariable regions affect antigen binding.” Immunotechnology. 2:169-179 (1996). [cited by applicant]
Deyde et al. “Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide.” JID 196:249 (2007). [cited by applicant]
Deyev and Lebedenko. “Modern Technologies for Creating Synthetic Antibodies for Clinical Application.” Acta Naturae 1:32-50 (2009). [cited by applicant]
Dreyfus et al., “Highly Conserved Protective Epitopes on Influenza B Viruses,” Science 337(6100):1343-1348 (2012). [cited by applicant]
Duwe, S. “Influenza viruses—antiviral therapy and resistance.” GMS Infect Dis 5:ISSN 2195-8831 (2017). [cited by applicant]
Ekiert et al., “Antibody recognition of a highly conserved influenza virus epitope: implications for universal prevention and therapy,” Science 324(5924):246-251 (2009). [cited by applicant]
Ekiert et al., “A Highly Conserved Neutralizing Epitope on Group 2 Influenza A Viruses,” Science 333(6044):843-850 (2011). [cited by applicant]
Ekiert et al., “Cross-neutralization of influenza A viruses mediated by a single antibody loop,” Nature 489(7417):526-532 (2012). [cited by applicant]
Fan et al. “Bispecific antibodies and their applications.” J. Hematol. Oncol. 8:130 (2015). [cited by applicant]
Friesen et al., “A common solution to group 2 influenza virus neutralization,” Proc Natl Acad Sci USA 111(1):445-450 (2014). [cited by applicant]
Genbank Accession ID AAK94805.1, immunoglobulin light chain variable region, partial [ [cited by applicant]
Genbank Accession ID ACS95408.1, immunoglobulin heavy chain variable region, partial [ [cited by applicant]
Gerhard et al., “Prospects for Universal Influenza Virus Vaccine,” Emerg Infect Dis 12(4):569-574 (2006). [cited by applicant]
Gioia et al., “Cross-subtype Immunity against Avian Influenza in Persons Recently Vaccinated for Influenza,” Emerg Infect Dis 14(1):121-128 (2008). [cited by applicant]
Greenspan et al., “Defining epitopes: It's not as easy as it seems,” Nature Biotechnol 17:936-937 (1999). [cited by applicant]
Hassantoufighi et al., “A practical influenza neutralization assay to simultaneously quantify hemagglutinin and neuraminidase-inhibiting antibody responses,” Vaccine 28:790-797 (2010). [cited by applicant]
Holliger et al. “‘Diabodies’: small bivalent and bispecific antibody fragments.” 90:6444-6448 (1993). [cited by applicant]
Holt et al. “Domain antibodies: proteins for therapy.” Trends Biotech. 21(11):484 (2003). [cited by applicant]
Ignatiev, Anna Viktorovna, “Features of the antigenic structure of hemagglutinin recognized by antibodies against modern influenza A viruses of subtypes H5 and H1.” Virology (2012). [cited by applicant]
Kallewaard et al., “Structure and Function Analysis of an Antibody Recognizing All Influenza A Subtypes,” Cell 166: 596-608 (2016). [cited by applicant]
Kashyap et al., “Combinatorial antibody libraries from survivors of the Turkish H5N1 avian influenza outbreak reveal virus neutralization strategies,” Proc Natl Acad Sci USA 105(16):5986-5991 (2008). [cited by applicant]
Kaverin et al., “Epitope Mapping of the Hemagglutinin Molecule of a Highly Pathogenic H5N1 Influenza Virus by Using Monoclonal Antibodies,” J Virol 81(23):12911-12917 (2007). [cited by applicant]
Kozbor et al., “The production of monoclonal antibodies from human lymphocytes,” Immunol Today 4(3):72-79 (1983). [cited by applicant]
Krause et al., “A Broadly Neutralizing Human Monoclonal Antibody That Recognizes a Conserved, Novel Epitope on the Globular Head of the Influenza H1N1 Virus Hemagglutinin,” J Virol 85(20):10905-10908 (2011). [cited by applicant]
Lamepjo, T. “Influenza and antiviral resistance: an overview.” Eur. J. Clin. Microbiol. Infect. Dis. (2020) doi.org/10.1007/s10096-020-03840-9. [cited by applicant]
Lee et al., “Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced by avidity,” Proc Natl Acad Sci USA 109(42):17040-17045 (2012). [cited by applicant]
Li et al., “Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells,” Proc Natl Acad Sci USA 109(23):9047-9052 (2012). [cited by applicant]
Lin et al., “Recent changes among human influenza viruses.” Virus Res. 103:47-52 (2004). [cited by applicant]
Nakamura et al., “An In Vivo Human-Plasmablast Enrichment Technique Allows Rapid Identification of Therapeutic Influenza A Antibodies,” Cell Host Microbe 14:93-103 (2013). [cited by applicant]
Nguyen et al., “Heterosubtypic Immunity to Influenza A Virus Infection Requires B Cells but Not CD8+ Cytotoxic T Lymphocytes,” J Virol 183:368-376 (2001). [cited by applicant]
Okuno et al., “A Common Neutralizing Epitope Conserved between the Hemagglutinins of Influenza A Virus H1 and H2 Strains,” J Virol 67(5):2552-2558 (1993). [cited by applicant]
Pakula and Sauer, “Genetic Analysis of Protein Stability and Function,” Annu. Rev. Genet. 23:289-310 (1989). [cited by applicant]
Pan et al., “Weight-based Dosing in Medication Use: What Should We Know?” Patient Preference and Adherence 10: 549-560 (2016). [cited by applicant]
Pappas et al., “Rapid development of broadly influenza neutralizing antibodies through redundant mutations,” Nature 516(7531):418-422 (2014). [cited by applicant]
Paul et al., eds. Fundamental Immunology 3 [cited by applicant]
Prabhu et al., “Monoclonal Antibodies against the Fusion Peptide of Hemagglutinin Protect Mice from Lethal Influenza A Virus H5N1 Infection,” J Virol 83(6):2553-2562 (2009). [cited by applicant]
Ren et al., “Epitope-focused vaccine design against influenza A and B viruses,” Curr Opin Immunol 42:83-90 (2016). [cited by applicant]
Roit, Ivan M. (1991) [cited by applicant]
Rowe et al., “Detection of Antibody to Avian Influenza A (H5N1) Virus in Human Serum by Using a Combination of Serologic Assays,” J Clin Microbiol 37(4):937-943 (1999). [cited by applicant]
Rudikoff et al., “Single amino acid substitution altering antigen-binding specificity,” Proc Natl Acad Sci USA 79(6):1979-1983 (1982). [cited by applicant]
Simmons et al., “Prophylactic and Therapeutic Efficacy of Human Monoclonal Antibodies against H5N1 Influenza,” PLOS Med 4(5):e178 (2007). [cited by applicant]
Smirnov et al., “Prevention and treatment of bronchopneumonia in mice caused by mouse-adapted variant of avian H5N2 influenza A virus using monoclonal antibody against conserved epitope in the HA stem region,” Arch Viro… [cited by applicant]
Sui et al., “Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses,” Nature Struct Mol Biol 16(3):265-273 (2009). [cited by applicant]
Temperton et al., “Longitudinally Profiling Neutralizing Antibody Response to SARS Coronavirus with Pseudotypes,” Emerg Infect Dis 11(3):411-416 (2005). [cited by applicant]
Thompson et al., “Influenza-Associated Hospitalizations in the United States,” JAMA 292:1333-1340 (2004). [cited by applicant]
Throsby et al., “Heterosubtypic Neutralizing Monoclonal Antibodies Cross-Protective against H5N1 and H1N1 Recovered from Human IgM+ Memory B Cells,” PLOS One 3(12):e3942 (2008). [cited by applicant]
Traggiai et al., “An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus,” Nature Med 10:871-875 (2004). [cited by applicant]
Vareckova et al., “HA2-specific monoclonal antibodies as tools for differential recognition of influenza A virus antigenic subtypes,” Virus Res 132(1-2):181-186 (2008). [cited by applicant]
Wagner et al., “Bispecific antibody generated with sortase and click chemistry has broad antiinfluenza activity,” Proc Natl Acad Sci USA 111(47):16820-16825 (2014). [cited by applicant]
Wang, Qinghua et al., “Crystal Structure of Unliganded Influenza B Virus Hemagglutinin,” J Virol 82(6):3011-3020 (2008). [cited by applicant]
Wang, Taia T. et al., “Broadly Protective Monoclonal Antibodies against H3 Influenza Viruses following Sequential Immunization with Different Hemagglutinins,” PLOS Pathog 6(2):e1000796 (2010). [cited by applicant]
Whittle et al., “Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin,” Proc Natl Acad Sci USA 108(34):14216-14221 (2011). [cited by applicant]
Wilson et al., “Structure of the hemagglutinin membrane glycoprotein of influenza virus at 3 Å resolution,” Nature 289:366-373 (1981). [cited by applicant]
Wrammert et al., “Rapid Cloning of High Affinity Human Monoclonal Antibodies Against Influenza Virus,” Nature 453(7195):667-671 (2008). [cited by applicant]
Wrammert et al., “Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection,” J Exp Med 208(1):181-193 (2011). [cited by applicant]
Xiang et al., “Framework Residues 71 and 93 of the Chimeric B72.3 Antibody are Major Determinants of the Conformation of Heavy-chain Hypervariable Loops,” J Mol Biol 253:385-390 (1995). [cited by applicant]
Yasugi et al., “Human Monoclonal Antibodies Broadly Neutralizing against Influenza B Virus,” PLOS Pathog 9(2):e1003150 (2013). [cited by applicant]
Yoshida et al., “Cross-Protective Potential of a Novel Monoclonal Antibody Directed against Antigenic Site B of the Hemagglutinin of Influenza A Viruses,” PLOS Pathog 5(3):e1000350 (2009). [cited by applicant]
Zabetakis et al., “Contributions of the Complementarity Determining Regions to the Thermal Stability of a Single-Domain Antibody,” PLoS ONE 8(10):e77678 (2013). [cited by applicant]
Zhou et al., “Hospitalizations Associated With Influenza and Respiratory Syncytial Virus in the United States, 1993-2008,” Clin Infect Dis 54(10):1427-1436. [cited by applicant]
Non-final Office Action issued in U.S. Appl. No. 15/026,276, dated Apr. 6, 2018. [cited by applicant]
Non-final Office Action issued in U.S. Appl. No. 15/026,276, dated Oct. 19, 2018. [cited by applicant]
Non-final Office Action issued in U.S. Appl. No. 15/026,276, dated Apr. 17, 2019. [cited by applicant]
Non-final Office Action issued in U.S. Appl. No. 15/325,603, dated Jun. 27, 2017. [cited by applicant]
Final Office Action issued in U.S. Appl. No. 15/325,603, dated Mar. 8, 2018. [cited by applicant]
Non-final Office Action issued in U.S. Appl. No. 15/325,603, dated Sep. 7, 2018. [cited by applicant]
Non-final Office Action issued in U.S. Appl. No. 15/577,799, dated Feb. 21, 2019. [cited by applicant]
Non-final Office Action issued in U.S. Appl. No. 16/068,941, dated Oct. 21, 2019. [cited by applicant]
Office Action in U.S. Appl. No. 16/068,941 issued Feb. 5, 2020. [cited by applicant]
Office Action in U.S. Appl. No. 16/560,040 issued Apr. 16, 2020. [cited by applicant]
Office Action in Australian Application No. 2014329609 issued Mar. 8, 2019. [cited by applicant]
Office Action in Australian Application No. 2015289805 issued Feb. 19, 2020. [cited by applicant]
Office Action in Chinese Application No. 201580038244.1 issued Jan. 17, 2020. [cited by applicant]
Office Action in Chinese Application No. 2014800539693.3 issued May 7, 2019. [cited by applicant]
Office Action in Chinese Application No. 201480053969.3 issued Feb. 3, 2020. [cited by applicant]
European Search Report in Application No. 14850550.6 issued Jul. 28, 2017. [cited by applicant]
European Search Report in Application No. 15821645.7 issued Mar. 26, 2018. [cited by applicant]
Office Action in European Application No. 15821645.7 issued Jul. 9, 2020. [cited by applicant]
Extended European Search Report dated Sep. 19, 2019. [cited by applicant]
Office Action in Japanese Application No. 2016-546872 issued Aug. 28, 2018. [cited by applicant]
Office Action in Japanese Application No. 2017-561892 issued Jun. 2, 2020. [cited by applicant]
Office Action in Japanese Application No. 2017-523183 issued Aug. 20, 2019. [cited by applicant]
Office Action in Mexican Application No. MX/a/2016/004067 issued Jul. 3, 2019. [cited by applicant]
Office Action in Russian Application No. 2016117053 issued Jun. 9, 2016. [cited by applicant]
Office Action in Russian Application No. 2016117053 issued Aug. 14, 2018. [cited by applicant]
Search Report in Russian Application No. 2020100073 issued May 28, 2020. [cited by applicant]
Office Action in Russian Application No. 2020100073 issued Jun. 10, 2020. [cited by applicant]
Russian Office Action Search Report dated Jul. 1, 2019. [cited by applicant]
Russian Office Action dated Nov. 6, 2019. [cited by applicant]
Office Action in Taiwanese Application No. 103134457 issued Apr. 11, 2018. [cited by applicant]
Office Action in Taiwanese Application No. 107146861 issued Feb. 6, 2020. [cited by applicant]
International Search Report issued in PCT/US2014/058652 on Jan. 29, 2015. [cited by applicant]
Preliminary Report on Patentability issued in PCT/US2014/058652 issued Apr. 5, 2016. [cited by applicant]
International Search Report issued in PCT/US2015/040385 on Dec. 23, 2015. [cited by applicant]
Preliminary Report on Patentability issued in PCT/US2015/040385 on Jan. 17, 2017. [cited by applicant]
International Search Report issued in PCT/US2016/035026 on Aug. 18, 2016. [cited by applicant]
International Search Report and Written Opinion issued in corresponding PCT/US2017/013086, dated Mar. 31, 2017. [cited by applicant]