Molecular Biotechnology (2021) 63:1223–1234

https://doi.org/10.1007/s12033-021-00373-0

ORIGINAL PAPER

Production of scFv, Fab, and IgG of CR3022 Antibodies Against

SARS‑CoV‑2 Using Silkworm‑Baculovirus Expression System
Takeru Ebihara1 · Akitsu Masuda1 · Daisuke Takahashi2 · Masato Hino3 · Hiroaki Mon4 · Kohei Kakino1 ·
Tsuguru Fujii5 · Ryosuke Fujita3 · Tadashi Ueda2 · Jae Man Lee5 · Takahiro Kusakabe4 

Received: 4 April 2021 / Accepted: 16 July 2021 / Published online: 25 July 2021
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

Abstract
COVID-19, caused by SARS-CoV-2, is currently spreading around the world and causing many casualties. Antibodies against
such emerging infectious diseases are one of the important tools for basic viral research and the development of diagnostic
and therapeutic agents. CR3022 is a monoclonal antibody against the receptor binding domain (RBD) of the spike protein
(S protein) of SARS-CoV found in SARS patients, but it was also shown to have strong affinity for that of SARS-CoV-2. In
this study, we produced large amounts of three formats of CR3022 antibodies (scFv, Fab and IgG) with high purity using a
silkworm-baculovirus expression vector system. Furthermore, SPR measurements showed that the affinity of those silkworm-
produced IgG antibodies to S protein was almost the same as that produced in mammalian expression system. These results
indicate that the silkworm-baculovirus expression system is an excellent expression system for emerging infectious diseases
that require urgent demand for diagnostic agents and therapeutic agents.

Keywords  Silkworm-baculovirus expression vector system · CR3022 antibody · scFv · Fab · IgG · SARS-CoV-2 · Spike
protein

Introduction
In December 2019, coronavirus disease 2019 (COVID-19)
caused by the severe acute respiratory syndrome corona-
virus 2 (SARS-CoV-2) broke out in Wuhan, China and
* Takahiro Kusakabe
kusakabe@agr.kyushu-u.ac.jp
1
Laboratory of Insect Genome Science, Graduate School
of Bioresource and Bioenvironmental Sciences, Kyushu
University, Motooka 744, Nishi‑ku, Fukuoka 819‑0395,
Japan
2 the previous studies [10] and revealed that its receptor bind-
Laboratory of Protein Structure, Function and Design,
Faculty of Pharmaceutical Sciences, Kyushu University,
Higashi‑ku, Fukuoka 812‑8582, Japan
3
Laboratory of Sanitary Entomology, Faculty
of Agriculture, Kyushu University, Motooka 744, Nishi‑ku,
Fukuoka 819‑0395, Japan
4
Laboratory of Insect Genome Science, Faculty
of Agriculture, Kyushu University, Motooka 744, Nishi‑ku,
Fukuoka 819‑0395, Japan
5
Laboratory of Creative Science for Insect Industries, Faculty
of Agriculture, Kyushu University, Motooka 744, Nishi‑ku,
Fukuoka 819‑0395, Japan
rapidly spread around the world [1]. In May 2020, the
WHO recognized it as a pandemic, more than 106 million
people infected and 2.3 million people dead as of February
10, 2020 [2]. In 2002 and 2012, two other human corona-
viruses, SARS-CoV [3] and MERS-CoV [4], have spread
wide area. These three coronaviruses belong to beta-cor-
onaviruses, probably originated from bats, and have viral
envelope with spike glycoprotein (S protein) [5–7]. The S
protein is the major viral antigen and binds the host receptors
and mediates virus-host membrane fusion when the virus
invades the host cells [8, 9]. The structure and function of
the SARS-CoV-2 S protein have been analyzed in detail by
ing domain (RBD) adopts receptor binding sensitive (open
or up) or insensitive (close or down) conformations within S
protein [11–13]. Both SARS-CoV-2 and SARS-CoV mainly
use human ACE2 membrane protein as a receptor [9] and
their amino acid sequences of RBD are highly conserved
73% [14].
The monoclonal antibody CR3022, a neutralizing anti-
body targeting the RBD domain of SARS-CoV, was iso-
lated by screening using a phage display library constructed
from blood of a convalescent SARS patient from Singapore

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Vol.:(0123456789)

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[15, 16]. Interestingly, the previous studies have shown that
CR3022 is capable of binding to the RBD of SARS-CoV-2
in which 24 of the CR3022 buried region (28 residues) are
conserved between SARS-CoV and SARS-CoV-2 [17].
Recent report also demonstrated that CR3022 neutralizes
SARS-CoV-2 through a neutralization mechanism that is
not detectable in some assays [18], although other studies
showed that CR3022 does not neutralize SARS-CoV-2 prob-
ably due to a single mutation, A384P, among the four uncon-
served residues [17, 19]. These studies suggest that CR3022
could be useful for therapeutic regent against COVID-19,
especially in combination with other neutralizing antibod-
ies. Structural and biochemical analyses revealed that the
binding epitope of CR3022 does not overlap with that of a
neutralizing antibody isolated from a SARS-CoV-2 patient,
thus the multiple antibodies are able to bind to the S protein
without competition [20, 21].
In therapeutic and serological applications of antibodies,
in addition to IgG, which has high detection sensitivity and
high affinity for antigens due to its avidity effect, scFv and
Fab are used because of their simple structure, high produc-
tivity, and small molecular weight, which makes it easy to
control chemical modification of proteins and fusion with
large enzymes [22, 23]. Post-translational modifications are
important for antibodies to have biological functions, espe-
cially glycosylation, and it has been reported that the lack of
glycosylation actually lowers the affinity of antibodies to Fcγ
receptors [24]. The E. coli expression system is simple and
capable of expressing a large amount of protein, but not suit-
able for IgG production due to lack of the post-translational
modifications such as disulfide bonds and glycosylation.
Hence, the IgG is typically produced by transfecting expres-
sion plasmids into mammalian cells, such as CHO cells or
HEK293 cells [25, 26]. However, the selection of stable cell
lines expressing high amount of IgG is time-consuming, and
transfection of large amount of plasmid is expensive when
the commercially available kits are used. The baculovirus
expression vector system (BEVS) using cultured insect cells
is suitable for expressing eukaryotic proteins because of its
post-translational modification is similar to that for mam-
malian cells. The BEVS using silkworm (silkworm-BEVS)
is a more efficient system than that using the insect cells
for expressing heterologous proteins. It is easy to scale up
without evaluating growth conditions; simply increasing the
number of silkworms rearing. In fact, our laboratory has
successfully used the silkworm-BEVS to produce a variety
of useful proteins [27–29].
In this study, we proposed that silkworm-BEVS is effec-
tive for rapid delivery of therapeutic and diagnostic agents
against emerging infectious diseases, using the production of
recombinant CR3022 antibody as an example. We produced
more than 1 mg of CR3022 in different formats, scFv, Fab,
and IgG, from silkworm serum and evaluated its binding
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Molecular Biotechnology (2021) 63:1223–1234
affinity to the S protein of SARS-CoV-2. The results showed
that silkworm-BEVS was effective in producing high quality
and functional CR3022 antibodies.
Materials and Methods
Cell Culture and Silkworm Strain
Insect culture cells, BmN (Bombyx mori-derived cells)
cells (Funakoshi Inc.), were cultured at 27 °C using IPL-41
insect medium (Sigma, St. Louis, MO) containing 10% Fatal
Bovine Serum (Gibco, Grand Island, NY). The f38 strain
of silkworm used in this study was provided by the Genetic
Resources Development Center, Faculty of Agriculture,
Kyushu University supported by the National BioResource
Project (NBRP). Silkworm larvae were reared by fresh mul-
berry leaves at 25 to 27 °C.
Construction of Recombinant Baculovirus
The single chain variable fragments (scFv) of CR3022 heavy
chain (Hc) (GenBank: ABA54613.1) and light chain (Lc)
(GenBank: ABA54614.1) linked by a flexible peptide linker
(GGGGS × 3) was chemically synthesized (Integrated DNA
Technologies Inc.). To construct gateway-based entry clones,
the coding region of scFvs (­ VHVL, ­VLVH) were amplified by
polymerase chain reaction (PCR) with KOD-Plus-Neo DNA
polymerase (TOYOBO, Tokyo, Japan) using the primer
sets (VHVL-F, R and VLVH-F, R, Table 1). The SalI and
XhoI-digested amplicons were inserted into the modified
pENTR11 (XhoI-digested pENTRL21c-TEV-H8S amplicon;
our laboratory stocks) vector by Ligation High (TOYOBO,
Tokyo, Japan). As described in our previous report [27], the
lobster L21 sequence (L21) was used to enhance transla-
tion, the silkworm 30 K-signal peptide (30 K) to secrete
CR3022 antibodies into silkworm sera, and the C-terminal
His8-STREP double tag is used to facilitate purification. The
resulting constructs were designated pENTR11-L21-30K-
VH(G4S)VL-TEV-H8S and pENTR11-L21-30K-VL(G4S)
VH-TEV-H8S, respectively. To generate the Fab (HFab and
Lc) expression vectors, ­CH1 and ­CL region were obtained
by PCR using the CH1-G-R, F and CL-G-R, F primer sets
(Table 1) from the vector of our previous study [30], and
then these regions were connected to V ­ H and V­ L gene by
the Gibson assembly method [31], respectively. Regarding
the Hc of IgG (HFab-Fc) expression vector, the Fc region
was connected to the HFab by PCR using Fc-G-F and Fc-
G-R primers in the same manner as above. The resulting
constructs were designated pENTR11-L21-30K-HFab-TEV-
H8S, pENTR11-L21-30K-Lc-TEV-H8S, and pENTR11-
L21-30K-Hc-TEV-H8S respectively. As illustrated in
Fig. 1b, the resulting constructs were then transferred to the
Molecular Biotechnology (2021) 63:1223–1234 1225

Table 1  List of primers used in Primer name Primer sequence (5ʹ–3ʹ)

this study
VHVL-F CAA​ATG​CAG​TTG​GTT​CAG​TCC​GGT​ACT​GAG​
VHVL-R ggggGTC​GAC​TTA​ATT​TCC​ACT​TTG​GTG​CCT​TGG​CCG​
VLVH-F GAT​ATA​CAA​CTG​ACG​CAG​TCC​CCA​GACAG​
VLVH-R ggggCTC​GAG​ACA​GTG​ACT​GTG​GTT​CCC​TGT​CCC​CATAC​
CH1-G-F AAG​GCA​CCC​TGG​TCA​CAG​TCT​CCT​CAG​CCT​CCA​CCA​AGG​GTC​CAT​CGG​TC
CH1-G-R AGT​ACA​GGT​TTT​CGC​CTG​CAC​TCG​AGG​CAC​AAG​ATT​TGG​GCT​CAA​CTT​TC
CL-G-F GCA​CCA​AAG​TGG​AAA​TTA​AAC​GTA​CGG​TGG​CTG​CAC​CAT​CTG​TCT​TCA​TC
CL-G-R GCT​TCA​ACA​GGG​GAG​AGT​GTT​AAG​CCT​CGA​GTG​CAG​GCG​AAA​ACC​TGT​ACTTC​
Fc-G-F AAG​TTG​AGC​CCA​AAT​CTT​GTG​ACA​AAA​CTC​ACA​CAT​GCC​CAC​CGT​GCC​CA
Fc-G-R GAG​CCT​CTC​CCT​GTC​TCC​GGG​TAA​GTC​GAG​TGC​AGG​CGA​AAA​CCT​GTA​CTTCC​

modified pDEST8/v-cath-EGFP vector (Invitrogen, Carls-
bad, CA, our laboratory stock) by the Gateway LR reaction
to generate baculovirus transfer plasmid following the manu-
facturer’s protocol. The five recombinant baculoviruses were
created using BmNPV/T3 bacmid DNA according to the
previous study [32]. The bacmid DNA was then transfected
into the BmN cell using Avalanche®-Everyday transfec-
tion reagent (EZ Biosystems, College Park, MD, USA) to
produce the recombinant virus particles. The culture super-
natant was harvested as the P1 virus on the 5th day after
cell transfection. The high-titer virus (P3) stock (~ 1 × ­107
plaque-forming unit/ml) was prepared through a serial infec-
tion of baculovirus in cultured cells. All viruses for silk-
worm infections were kept at 4 °C in the dark until use.
analysis. The samples were separated by 5–20% or 12%
SDS-PAGE under the reducing or non-reducing conditions
and transferred onto polyvinylidene difluoride (PVDF)
membrane (Millipore, Billerica, MA), and further blocked
in TBST buffer (20 mM Tris–HCl pH 7.6; 500 mM NaCl;
0.1% w/v Tween-20) with 5% w/v skim milk. The membrane
was incubated with HisProbe-HRP (1:5000) (Thermo Fisher
Scientific, Waltham, MA) at 4 °C. The specific protein bands
were visualized using the Super Signal West Pico Chemi-
luminescent Substrate (Thermo Fisher Scientific, Waltham,
MA).
Purification of Recombinant CR3022 Antibodies

Expression of Recombinant scFv, Fab and IgG
in Silkworm Hemolymph
The recombinant baculovirus expressing the scFv (~ 1 × ­105
plaque-forming unit per larvae) were injected into the 5th
instar silkworm larvae (day 3). In the case of Fab and IgG,
the two recombinant baculoviruses, expressing HFab and Lc
or Hc and Lc, respectively, in different ratio were infected
to BmN cells and all samples were prepared based on the
method according to the previous study [27]. After optimiz-
ing the co-infection ratio of two recombinant baculoviruses
using BmN cells, the recombinant baculoviruses expressing
HFab and Lc or Hc and Lc were injected into the 5th instar
silkworm larvae (day 3) at a ratio of 3:1. Silkworm hemo-
lymph was collected into a tube containing 20 mM 1-phenyl-
2-thiourea at 4 dpi and centrifuged at 9000 rpm for 10 min
at 4 °C to remove insoluble matter. The supernatant sample
was immediately frozen at − 80 °C.
SDS‑PAGE and Western Blotting Analysis
The expression of CR3022 antibodies in all samples was
analyzed using sodium dodecyl sulfate–polyacrylamide gel
electrophoresis (SDS-PAGE) followed by Western blotting
The purification procedure was performed using HisTrap
excel column (GE Healthcare Bioscience, Piscataway, NJ)
and Strep-Tactin HP column (IBA GmbH, Germany). This
protocol for two-step affinity chromatography was previ-
ously optimized in our laboratory [27]. The clarified silk-
worm serum was diluted up to 50 mL by binding buffer
(20 mM Tris–HCl pH 7.5; 0.5 M NaCl), and filtered through
0.45 μm filters (Millipore, Billerica, MA) after centrifuged
at 9000 rpm for 10 min at 4 °C. The sample was loaded onto
a 5 mL HisTrap excel column, and after washing with 25 mL
binding buffer containing 30 mM imidazole, the proteins
were eluted with 12 mL and 15 mL binding buffer contain-
ing 100 mM and 500 mM imidazole, respectively. The eluted
fractions containing antibodies were collected and concen-
trated to 5 mL by ultrafiltration using Amicon Ultra-15 10 K
filters (Millipore, Billerica, MA).
Then, the sample removing excess imidazole was further
diluted up to 50 mL by PBS and load onto a 5 mL Strep-
Tactin column. After the wash with 25 mL of PBS, the pro-
teins were eluted with 24 mL of PBS supplemented with
2.5 mM desthiobiotin, then the fractions containing antibod-
ies were collected and concentrated to 2 mL by ultrafiltra-
tion using Amicon Ultra-15 10 K filters. The concentrated
sample was dialyzed by PBS, and the final concentration of

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 Molecular Biotechnology (2021) 63:1223–1234 1227
◂Fig. 1  a Schematic diagram of the three formats of CR3022 antibod-
ies (Hc: heavy chain, Lc: light chain, HFab: N-terminal half of one
heavy chain). In the scFvs ­(VHVL and ­VLVH), the antibody regions of
the ­VH and ­VL are linked by a linker (3 × ­G4S). All three formats have
a purification tag for facilitating purification. b Construction of the
recombinant baculoviruses expressing the three formats of CR3022
antibodies (scFv, Fab and IgG). The expression of them were under
the control of the polyhedrin promoter (PH) and follow by an SV40
polyadenylation signal (SV40). B1 and B2: recombination sites for
Gateway cloning; L21: leader sequence for enhancing translation
efficiency; 30  K: signal peptide of silkworm 30  kDa protein; TEV:
tobacco etch virus protease cleavage site; 8xHis: 8 × Histidine tag;
Strep: Strep tag
the protein was quantified by ImageJ using bovine serum
albumin (BSA) as standard.
Spike‑Antibody Interaction Analysis by Surface
Plasmon Resonance (SPR) Experiments
SPR experiments were performed using a Biacore X100 (GE
Healthcare Bioscience, Piscataway, NJ) at 25 °C. SARS-
CoV-2 spike proteins were immobilized on a CM5 sensor
chip (Cytiva, Tokyo, Japan) using standard amine-coupling
chemistry. This SARS-CoV-2 Spike protein was expressed
using a silkworm-baculovirus expression vector system and
purified from silkworm serum using the two-step chroma-
tography as well as the recombinant antibodies. Immobiliza-
tion densities on flow cell 2 are ~ 2000 for CR3022 ­VHVL,
­VLVH, and Fab and ~ 1000 RU for IgG, respectively. Flow
cell 1 was left blank to serve as a reference surface. All the
surfaces were blocked with 1 M ethanolamine, pH 8.5. A
two-fold dilution series of the antibodies (15.6–250 nM of
­VHVL, ­VLVH and Fab, 0.63–10 nM of IgG) diluted in a run-
ning buffer (PBS with 0.005% Tween-20) was injected with
a flow rate of 30 μL/min for 3 min followed by 10 min of
dissociation step. The surfaces were regenerated with 30 s
injection of 10 mM Gly-HCl, pH 2.5 followed by 30 s injec-
tion of 3 M ­MgCl2. The data were fit to a simple 1:1 interac-
tion model using the global data analysis available within
Biacore X100 evaluation software.
ELISA
ELISA was performed to examine the binding affinity of
CR3022 IgG to S protein. The 96-well plate were coated
with four concentrations of S protein (0.1, 1, 10, 100 ng)
and incubated overnight at 4 °C. The plates were washed
four times with 300 μL PBST (PBS with 0.1% Tween-20),
blocked with 5% skim milk in PBST for 2 h at room temper-
ature, and then the four concentrations of purified CR3022
IgG (0.01, 0.1, 1, 10 μg/mL) were added to the wells and
incubated for 1 h at 37 °C. The plates were washed four
times and incubated with Anti-Human IgG Fc which con-
jected with HRP (1:10,000) (#ab98624, Abcam, Cambridge,
UK). After 1 h incubation at 37 °C, the plate was washed,
developed with TMB substrate and the reaction was stopped
by the addition of 2 N ­H2SO4. Then the absorbance read at
450 nm and 620 nm.
Results
Construction of the Recombinant Baculoviruses
and Expression of scFv, Fab and IgG
To establish the low cost and efficient expression system of
CR3022 scFv, Fab and IgG, we have generated 5 recombi-
nant baculoviruses shown in Fig. 1b as described under the
Materials and methods. The Heavy chain (Hc) and Light
chain (Lc) of CR3022 sequence were codon-optimized for B.
mori s and were chemically synthesized. A signal peptide of
a silkworm 30 kDa protein (30 K-signal peptide) was fused
to the N-termini of the target proteins, and a lobster L21
sequence was inserted upstream of the 30 K-signal peptide
to increase the amount of protein translation. In addition,
TEV cleavage site, His and STREP tag were fused to the
C-termini of all constructs for purification, except for the
Lc expression vector.
For scFvs (­ VHVL, ­VLVH) expression, the 5th instar silk-
worm larvae were infected with the corresponding recom-
binant baculoviruses. The expression of these antibodies
in silkworm hemolymph was then confirmed by Western
blotting analysis. As shown in Fig. 2a, b, V ­ HVL and V­ LVH
were expressed in silkworm hemolymph and their predicted
molecular weight were approximately 30 kDa regardless of
reducing or non-reducing conditions, respectively.
To optimize the expression of Fab and IgG as heterodi-
mer or heterotetramer, respectively, we varied the ratio of
two viruses co-infected into BmN cells and confirmed the
expression of them by Western blotting at 3 dpi (the virus
combinations to express Fab and IgG are shown in Fig. 1b).
Under the non-reducing conditions, it is demonstrated that
the optimal infection ratio of the two recombinant baculo-
viruses, HFab and Lc for Fab or Hc and Lc for IgG, was
3:1 in the medium of cultured BmN cells (Supplemental
Fig. S1a, b). Therefore, this 3:1 of recombinant baculovi-
ruses co-infection ratio was used for the efficient expression
of Fab and IgG in silkworm larvae. As shown in Fig. 2a,
Lanes 3 and 4, the expression of the HFab of Fab or Hc of
IgG with molecular weight of approximately 27 or 53 kDa,
respectively, were confirmed by Western blotting (reducing
conditions) in hemolymph of the 5th instar larvae at 4dpi.
Furthermore, the assembled Fab and IgG were observed in
the non-reducing conditions (Fig. 2b, Lanes 3 and 4). When
the hemolymph of silkworm f38 strain was subjected to
Western blotting analysis using His-probe, the non-specific
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1228 Molecular Biotechnology (2021) 63:1223–1234

the same elution fractions with HFab and Hc at a molecu-

a 1 2 3 4 lar ratio of approximately 1:1 (Fig. 3c, d), suggesting that
(kDa) disulfide bonds between Lc and HFab or Hc are correctly
formed. Moreover, in the Histidine affinity purification, the
* * * * scFvs and Fab begin to elute in the binding buffer contain-
100 ing 100 mM imidazole, whereas most of the IgG elutes in
the binding buffer containing 500 mM imidazole (Fig. 3d,
66
Lane 5 and 6). Since the IgG molecule forming homodimer
Hc
55.6 by disulfide bonds has two purification tags, it is expected
to have strong binding affinity to nickel conjected agarose
37 beads. These purified proteins were dialyzed against 1 × PBS
VHVL and quantified. As a result, 2.34 mg of ­VHVL, 2.64 mg of
29 VLVH ­VLVH, 1.44 mg of Fab, and 1.30 mg of IgG were purified
HFab from 10 ml of silkworm hemolymph, and the SDS-PAGE
verifications for each purified antibody demonstrated that
they were achieved in good purity, 95% for ­VHVL, 98%
b for ­VLVH, 93% for Fab, and 84% for IgG, respectively, as
1 2 3 4 judged by image analysis of gels.

(kDa) Hc2 + Lc2 (IgG) Binding Analysis of CR3022 Recombinant

Antibodies
* * * *
100
The binding affinity of CR3022 scFvs, Fab and IgG with
66 SARS-CoV-2 Spike (S) protein was measured using sur-
55.6 face plasmon resonance (SPR) analysis (Fig. 4). The dis-
HFab + Lc (Fab)
sociation constants (KD) of the ­VHVL, ­VLVH and Fab with
the ectodomain of SARS-CoV-2 S protein (a.a. 1–1208;
37
VHVL without furin cleavage site (residues 682–685) and proline
29 substitutions at residues 986 and 987) [33] were 20.1 nM,
VLVH
27.8  nM and 45.4  nM, respectively (Fig. 4a–c). On the
other hand, CR3022 exhibited a much higher affinity for S
protein with the KD of 0.21 nM, which was approximately
50–100 greater than Fab and scFvs (Fig. 4d). Furthermore,
to evaluate whether the CR3022 IgG produced in silkworm
Fig. 2  Expression of scFvs (­VHVL and ­VLVH), Fab and IgG in silk-
worm hemolymph at 4 dpi under the reducing condition (a) and non- are usable for ELISA, different amounts of S protein (0.1,
reducing condition (b), respectively (Lane 1: V
­ HVL, Lane 2: ­VLVH, 1, 10, and 100 ng) were immobilized on a 96-well plate and
Lane 3: Fab, Lane 4: IgG). These expressions were confirmed by its binding with CR3022 IgG was measured. As shown in
Western blotting using HisProbe
Fig. 5, the CR3022 IgG was able to detect SARS-CoV-2 S
protein in a dose-dependent manner. With 100 ng of S pro-
background signal was detected around 100 kDa in all lanes tein on the plate, the binding signal reached the plateau at a
(Fig. 2, asterisk). concentration of 1 μg/mL CR3022 IgG. In addition, when
using 10 μg/mL IgG, the detection limit was ~ 100 pg of S
Purification of CR3022 Recombinant Antibodies protein (Fig. 5, inlet).
from Silkworm Hemolymph

All four CR3022-derived antibodies successfully expressed Discussion

in silkworm hemolymph were purified by two-step affin-
ity chromatography. As shown in Fig. 3, the affinity puri-
fication through His tag and Strep tag chromatography is
simple and highly efficient; CBB staining of SDS-PAGE
gel clearly shows that the recombinant CR3022 antibod-
ies could be purified with high purity. In the cases of Fab
and IgG, the Lc without purification tags were detected in
Upon the emerging of infectious diseases spreading all over
the world, it is important to urgently proceed with basic sci-
entific research on such pathogenic the viruses and micro-
organisms. These basic studies are indispensable for the
development of diagnostic and therapeutic agents to prevent
the diseases and protect our health. In particular, antibodies

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Molecular Biotechnology (2021) 63:1223–1234 1229

a
(kDa) His affinity (kDa) Strep affinity

100 100
66 66
55.6 55.6

37 37
29 29 V HV L

IP FT WS 1 2 3 4 5 6 7 8 9 10 IP FT WS 11 12 13 14 15 16 17 18 19

b His affinity Strep affinity

(kDa) (kDa)
100 100
66 66
55.6 55.6

37 37
29 29 V LV H

IP FT WS 1 2 3 4 5 6 7 8 9 10 IP FT WS 11 12 13 14 15 16 17 18 19

c
(kDa) His affinity (kDa) Strep affinity

100 100
66 66
55.6 55.6
37 37
29 29 HFab
Lc

IP FT WS 1 2 3 4 5 6 7 8 9 10 IP FT WS 11 12 13 14 15 16 17 18 19

d
(kDa) His affinity Strep affinity
(kDa)
100
100
66
55.6 66
55.6 Hc
37 37
29 29
Lc

IP FT WS 1 2 3 4 5 6 7 8 9 10 IP FT WS 11 12 13 14 15 16 17 18 19

Fig. 3  Purification of the CR3022 antibodies from hemolymph of
silkworm larvae infected or co-infected with recombinant baculovi-
ruses using the two-step affinity chromatography (a ­VHVL, b ­VLVH,
c Fab, d IgG) as described in Materials and Methods. The arrows
indicate the each of recombinant antibodies. IP: input; FT: flow-
through; WS: wash fraction; lanes 1–4: elution fractions by 100 mM
imidazole; lanes 5–10: elution fractions by 500 mM imidazole; lanes
11–19: elution fractions by 2.5  mM desthiobiotin. Protein samples
from each step were resolved in 12% SDS-PAGE and visualized by
Coomassie Brilliant Blue (CBB) R-250 staining

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1230
Fig. 4  Binding affinity of CR3022 antibodies with S protein. The
binding affinity of CR3022 V ­ HVL (a), ­VLVH (b), Fab (c) and IgG
(d) with S protein were measured using surface plasmon resonance
specific for pathogenic microorganisms are one of the most
important tools in these studies.
Using a Silkworm-BEVS, we produced three formats of
CR3022 antibodies (scFvs, Fab and IgG) which have been
first reported as a neutralizing antibody against the RBD of
SARS-CoV and recently reported to bind strongly to that of
SARS-CoV-2. The S protein, the major antigen of SARS-
CoV-2, is very similar to that of the previously prevalent
SARS-CoV, with 73% homology in amino acid sequences
of RBD, a target for diagnostic and therapeutic agents [34].
In this study, we produced more than 1 mg of four dif-
ferent recombinant CR3022 antibodies from 10 mL of silk-
worm hemolymph within a month (Fig. 3). Several expres-
sion systems were used to produce human scFv [35–37] and
the E. coli expression system is one of the most suitable
13
Molecular Biotechnology (2021) 63:1223–1234
as described in Materials and Methods. The data were fit to a simple
1:1 interaction model using the global data analysis available within
Biacore X100 evaluation software
expression systems for mass production of scFv [38]. How-
ever, it is time-consuming to purify and refold the scFv
expressed in E. coli from the inclusion body [39], whereas
the silkworm-BEVS is capable of producing scFvs compa-
rable to the E. coli expression system without refolding. In
addition, it is very difficult to produce Fab or IgG in E. coli
which lacks post-translational modifications. Cultured mam-
malian cells also provide a platform for producing recom-
binant antibodies in large scale, but the screening of cell
lines with high-expression and the modulation of culture
conditions are time-consuming (minimum 12 months) [25].
Using silkworm-BEVS, it is possible to express and purify
the biologically active Fab and IgG with correct disulfide
bond formation in a much shorter time than mammalian cell
expression systems. For CR3022 IgG, it has been reported
Molecular Biotechnology (2021) 63:1223–1234 1231
Fig. 5  Binding affinity of
CR3022 IgG with S protein in
ELISA. The different concentra-
tions of CR3022 IgG (0.01, 0.1,
1, 10 μg/mL) were incubated
with the plates coated with the
different concentrations of S
protein (0.1, 1, 10, and 100 ng),
and then detected by an HRP-
conjugated Anti-Human IgG Fc
that an expression level of 130 μg per gram of fresh leaf
weight can be obtained using a transient expression system
in plants [40]. In this study, 130 μg of purified CR3022 IgG
was eventually purified and recovered from 1 mL of silk-
worm serum using silkworm-BEVS. Although it is difficult
to make a simple comparison, these results suggest that the
expression level is comparable or more equivalent to that
produced in plants.
The SPR measurement showed that CR3022 IgG has
higher affinity (KD = 0.21 nM) than ­VHVL, ­VLVH and Fab
(KD = 20.1 nM, 27.8 nM and 45.4 nM, respectively). The
previous study measuring the affinity of CR3022 antibod-
ies produced using the different expression system [14]
revealed that the CR3022 scFv produced by E. coli had a
KD of 6.3 nM with the RBD, which is higher than that pro-
duced by the silkworm-BEVS. This result may be caused by
the differences in the antigens or in coupling methods; the S
proteins were immobilized by amine-coupling in this study,
and RBD was enzymatic biotinylated and immobilized onto
a strept-avidin chip in the other studies. The ­VHVL and ­VLVH
of CR3022 produced using silkworm-BEVS showed almost
equivalent productivity of 2.34 mg and 2.64 mg per 10 mL
of silkworm serum, respectively, while the affinity of V ­ HV L
was slightly higher than that of V­ LVH. Previous studies have
shown that the productivity and affinity of ­VHVL and V ­ LVH
differ depending on the type of antibody [41, 42], and for
CR3022, ­VHVL was considered to be a more suitable form
of scFv for diagnostic and pharmaceutical applications than
­VLVH. It was also reported that the affinity of CR3022 Fab or
IgG produced in mammalian cells with the RBD is 115 nM
and < 0.1 nM, respectively [17]. The affinity of CR3022 IgG
produced using silkworm-BEVS was almost the same as that
in the mammalian cells at 0.21 nM. In contrast, the KD of
CR3022 Fab produced using silkworm-BEVS (45.4 nM)
is higher than that of produced using mammalian system
(115 nM). The CR3022 Fab and IgG used in this study were
designed to have two disulfide bonds (usually one) connect-
ing ­CH1 and C
­ L to enhance the productivity of the recombi-
nant antibodies. The KD of CR3022 Fab with two disulfide
bonds produced in this study was 2.5-fold lower than that of
mammalian cell-produced CR3022 Fab with single disulfide
bond, suggesting that an additional disulfide bond probably
contributes to increase the binding activity of CR3022 Fab
in the absence of Fc regions.
Dose-dependent binding of the CR3022 IgG produced
using silkworm-BEVS were shown by ELISA, but the reac-
tion plateaued at a concentration of 100 ng of S protein
per well (96-well plate). The detection limit in ELISA was
~ 100 pg (0.7 pM) of S protein, which is less sensitive than
other detection systems, as described in previous report
[43], and would not be enough to detect the virus protein in
sera with low viral titers in early infected patients. To use
the IgG as a diagnostic reagent to detect the SARS-CoV-2
from patient sera, the sensitivity of detection system such
as an immunochromatography system needs to be improved
further. Since several SARS-CoV-2 antibodies recognizing
the different regions of RBD were reported [20, 21], it is
possible to develop a highly sensitive detection system by
combining the multiple antibodies without competition for
epitope binding.
Recently, the antibody-dependent cellular cytotoxicity
(ADCC) activity of monoclonal antibodies against several
viruses-infected cells has been highlighted because of its
potential to decrease viral replication and reduce clinical
symptoms [44, 45]. ADCC is one of the antiviral activ-
ity that induces the cellular cytotoxicity through a natural
13

1232
killer (NK) cell expressing Fc receptors, which binds to Fc
region of IgG. [46]. Therefore, this ability of antibodies to
induce strong ADCC would be advantageous when used as
therapeutic agents. The induction of ADCC is enhanced by
the lack of α-1,6-fucose in the N-linked glycan (Asn-297 in
the ­CH2 domain) of the Fc region [47, 48]. Previous stud-
ies showed that the antibodies secreted form the transgenic
silkworm lack this fucose and is demonstrated to have the
ability to induce the strong ADCC [49]. Considering these
reports, it is highly likely that CR3022 IgG produced using
silkworm-BEVS can induce stronger ADCC than those pro-
duced by other expression systems, and is expected to be
highly effective in clinical applications.
Conclusion
In conclusion, we demonstrated that the silkworm-BEVS
can produce antibodies in three different formats of CR3022
easily in a short-term. Furthermore, the purified CR3022
antibodies showed almost the same affinity for the S pro-
tein as those produced in mammalian cells. Thus, our study
suggests that the silkworm-BEVS is suitable as an expres-
sion system for producing diagnostic and therapeutic agents
that can rapidly respond to emerging of infectious diseases
including COVID-19.
Supplementary Information  The online version contains supplemen-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 12033-0​ 21-0​ 0373-0.
Acknowledgements  This work was supported in part by Cabinet
Office, Government of Japan, Cross-ministerial Strategic Innovation
Promotion Program (SIP), “Technologies for Smart Bio-industry and
Agriculture” (funding agency: Bio-oriented Technology Research
Advancement Institution, NARO). This work was partially supported
by Platform Project for Supporting Drug Discovery and Life Science
Research (Basis for Supporting Innovative Drug Discovery and Life
Science Research (BINDS)) from Japan Agency for Medical Research
and Development (AMED) under Grant Number JP20am0101091.
Declarations  biological characterization of human monoclonal antibodies
Conflict of interest  The authors declare that they have no conflict of
interest.
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 No. 21-___

IN THE
Supreme Court of the United States

JUNO THERAPEUTICS, INC.; SLOAN KETTERING

INSTITUTE FOR CANCER RESEARCH,
Petitioners,
v.
KITE PHARMA, INC.,
Respondent.

On Petition For A Writ Of Certiorari

To The United States Court Of Appeals
For The Federal Circuit

PETITION FOR A WRIT OF CERTIORARI

HENRY HADAD GREGORY A. CASTANIAS

J. PATRICK ELSEVIER Counsel of Record
PETER NOH NOEL J. FRANCISCO
BRISTOL MYERS SQUIBB JENNIFER L. SWIZE
Route 206 & Province JONES DAY
Line Road 51 Louisiana Ave., NW
Princeton, NJ 08543 Washington, D.C. 20001
(202) 879-3939
gcastanias@jonesday.com

Counsel for Petitioners

(additional counsel listed on inside cover)
 (continued from front cover)

MORGAN CHU ANDREA W. JEFFRIES

ALAN J. HEINRICH JONES DAY
ELIZABETH C. TUAN 555 South Flower Street
IRELL & MANELLA LLP Los Angeles, CA 90071
1800 Avenue of the Stars
Suite 900 MATTHEW J. RUBENSTEIN
Los Angeles, CA 90067 JONES DAY
90 South Seventh Street
ANDREI IANCU Suite 4950
IRELL & MANELLA LLP Minneapolis, MN 55402
750 17th Street NW
Suite 850 LISA L. FURBY
Washington, DC 20006 JONES DAY
110 North Wacker Drive
Suite 4800
Chicago, IL 60606

Counsel for Petitioners

 QUESTION PRESENTED
Section 112(a) of Title 35, United States Code,
requires that a patent include a “specification,” which
“shall contain a written description of the invention,
and of the manner and process of making and using
it, in such full, clear, concise, and exact terms as to
enable any person skilled in the art to which it
pertains, or with which it is most nearly connected, to
make and use the same.”
The question presented is:
Is the adequacy of the “written description of the
invention” to be measured by the statutory standard
of “in such full, clear, concise, and exact terms as to
enable any person skilled in the art to make and use
the same,” or is it to be evaluated under the Federal
Circuit’s test, which demands that the “written
description of the invention” demonstrate the
inventor’s “possession” of “the full scope of the claimed
invention,” including all “known and unknown”
variations of each component?
 ii

PARTIES TO THE PROCEEDING

Petitioners Sloan Kettering Institute for Cancer
Research (“Sloan Kettering”) and Juno Therapeutics,
Inc. (“Juno”) were plaintiffs-appellees in the Federal
Circuit below. Respondent Kite Pharma, Inc. (“Kite”)
was a defendant-appellant in the Federal Circuit
below.
CORPORATE DISCLOSURE STATEMENT
Sloan Kettering does not issue stock and has no
corporate parent. Juno is a wholly owned subsidiary
of Celgene Corporation. Celgene Corporation is a
wholly owned subsidiary of Bristol Myers Squibb
Company. Other than the listed entities, no publicly
held corporation owns 10% or more of the stock of
Juno or its corporate parents.
STATEMENT OF RELATED PROCEEDINGS
Present Patent Infringement Litigation:
United States District Court for the Central District
of California:
Juno Therapeutics, Inc. v. Kite Pharma, Inc., No.
2:17-cv-7639 (judgment entered April 8, 2020)
United States Court of Appeals for the Federal
Circuit:
Juno Therapeutics, Inc. v. Kite Pharma, Inc., No.
20-1758 (judgment reversed August 26, 2021;
rehearing petition denied January 14, 2022)
Inter Partes Review:
Patent Trial and Appeal Board:
Kite Pharma, Inc. v. Sloan Kettering Institute for
Cancer Research, No. IPR2015-01719 (Final
Written Decision holding challenged claims of
 iii

U.S. Patent No. 7,446,190 not unpatentable

issued December 16, 2016)
United States Court of Appeals for the Federal
Circuit:
Kite Pharma, Inc. v. Sloan-Kettering Institute for
Cancer Research, No. 17-1647 (Board decision
summarily affirmed June 24, 2019)
 iv

TABLE OF CONTENTS

Page

QUESTION PRESENTED..........................................i
PARTIES TO THE PROCEEDING .......................... ii
CORPORATE DISCLOSURE STATEMENT .......... ii
STATEMENT OF RELATED PROCEEDINGS....... ii
TABLE OF AUTHORITIES .................................... vii
INTRODUCTION ....................................................... 1
OPINIONS BELOW ................................................... 5
JURISDICTION ......................................................... 5
STATUTORY PROVISION INVOLVED ................... 6
STATEMENT ............................................................. 7
A. The Patent System’s Fundamental
Quid Pro Quo .............................................. 7
B. Sloan Kettering’s Invention ....................... 9
C. Kite’s Willful Infringement ...................... 13
D. The Federal Circuit Applies Its
“Written Description” Test And
Overrides The Work Of The
Patent Office, The Jury, And
The District Court .................................... 14
REASONS FOR GRANTING THE WRIT ............... 18
I. THE FEDERAL CIRCUIT’S
PERSISTENT INTERPRETATION OF
§ 112 IS CONTRARY TO THE STATUTE
AND THIS COURT’S PRECEDENT ............... 18
 v

TABLE OF CONTENTS
(continued)
Page

A. The Federal Circuit’s Interpretation

Contradicts The Statute .......................... 18
B. The Federal Circuit’s Interpretation
of § 112 Conflicts With This Court’s
And Other Circuits’ Interpretations ........ 24
II. THE FEDERAL CIRCUIT’S
ERRONEOUS INTERPRETATION
PRESENTS SEVERE DANGERS TO
RESEARCH AND INNOVATION,
ESPECIALLY THE LIFE SCIENCES ............ 29
III. THIS CASE IS AN IDEAL VEHICLE ............ 36
CONCLUSION ......................................................... 37
 vi

TABLE OF CONTENTS
(continued)
Page

APPENDIX A: Opinion of the United States

Court of Appeals for the Federal Circuit
(Aug. 26, 2021).................................................. 1a
APPENDIX B: Final Judgment of the United
States District Court for the Central
District of California (Apr. 8, 2020) ............... 23a
APPENDIX C: Order of the United States
District Court for the Central District
of California (Mar. 24, 2020) .......................... 26a
APPENDIX D: Jury Verdict Form
(Dec. 13, 2019) ................................................ 82a
APPENDIX E: Order of the United States
Court of Appeals for the Federal Circuit
Denying Rehearing (Jan. 14, 2022) ............... 85a
APPENDIX F: Statutory Provisions...................... 87a

PATENT APPENDIX:
U.S. Patent No. 7,446,190 ................................ 1b
 vii

TABLE OF AUTHORITIES

Page(s)
CASES
AbbVie Deutschland GmbH & Co. v.
Janssen Biotech, Inc.,
759 F.3d 1285 (Fed. Cir. 2014) ...................... 15, 22
Amgen Inc. v. Sanofi,
872 F.3d 1367 (Fed. Cir. 2017) ............................ 35
Ariad Pharms., Inc. v. Eli Lilly & Co.,
598 F.3d 1336 (Fed. Cir. 2010)
(en banc) ................................ 15, 16, 19, 20, 22, 23,
26, 27, 28, 31, 33, 37
Artis v. District of Columbia,
138 S. Ct. 594 (2018) ............................................ 19
Ass’n for Molecular Pathology v. Myriad
Genetics, Inc.,
569 U.S. 576 (2013) ................................................ 9
Biogen Int’l GMBH v. Mylan Pharms. Inc.,
18 F.4th 1333 (Fed. Cir. 2021)............................... 6
Biogen Int’l GmbH v. Mylan Pharms Inc.,
28 F.4th 1194 (Fed. Cir. 2022)............................. 37
Donner v. Am. Sheet & Tin Plate Co.,
165 F. 199 (3d Cir. 1908) ..................................... 25
Evans v. Eaton,
20 U.S. 356 (1822) ................................................ 27
Facebook, Inc. v. Duguid,
141 S. Ct. 1163 (2021) .......................................... 20
 viii

TABLE OF AUTHORITIES
(continued)
Page(s)
Festo Corp. v. Shoketsu Kinzoku
Kogyo Kabushiki Co.
535 U.S. 722 (2002) .............................................. 28
Gill v. Wells,
89 U.S. (22 Wall.) 1 (1874) ................................... 27
Graver Tank & Mfg. Co. v. Linde Air
Prods. Co.,
339 U.S. 605 (1950) .............................................. 35
Gross v. FBL Fin. Servs., Inc.,
557 U.S. 167 (2009) .............................................. 19
Helsinn Healthcare S.A. v. Teva
Pharms. USA, Inc.,
139 S. Ct. 628 (2019) .............................................. 9
Ill. Tool Works, Inc. v. Foster Grant Co.,
547 F.2d 1300 (7th Cir. 1976) .............................. 25
In re Ruschig,
379 F.2d 990 (C.C.P.A. 1967)............................... 16
In re Wands,
858 F.2d 731 (Fed. Cir. 1988) ........................ 15, 21
J.E.M. Ag Supply, Inc. v. Pioneer Hi-
Bred Int’l, Inc.,
534 U.S. 124 (2001) .............................................. 26
KSR Int’l Co. v. Teleflex Inc.,
550 U.S. 398 (2007) ................................................ 9
Loving v. IRS,
742 F.3d 1013 (D.C. Cir. 2014) ............................ 23
 ix

TABLE OF AUTHORITIES
(continued)
Page(s)
Markman v. Westview Instruments,
517 U.S. 370 (1996) ...................................... 8, 9, 26
Mayo Collaborative Servs. v.
Prometheus Labs., Inc.,
566 U.S. 66 (2012) ...................................... 2, 26, 28
Pfaff v. Wells Elecs., Inc.,
525 U.S. 55 (1998) ............................................ 1, 30
Philip A. Hunt Co. v. Mallinckrodt
Chem. Works,
177 F.2d 583 (2d Cir. 1949) ................................. 25
Regents of the Univ. of Cal. v. Eli Lilly & Co.,
119 F.3d 1559 (Fed. Cir. 1997) ............................ 16
Rimini Street, Inc. v. Oracle USA, Inc.,
139 S. Ct. 873 (2019) ............................................ 23
SCA Hygiene Prods. Aktiebolag v. First
Quality Baby Prods., LLC,
137 S. Ct. 954 (2017) ............................................ 19
Schriber-Schroth Co. v. Cleveland Tr. Co.,
305 U.S. 47 (1938) ................................................ 27
The Telephone Cases,
126 U.S. 1 (1888) .............................................. 1, 24
United States v. Dubilier Condenser Corp.,
289 U.S. 178 (1933) .............................................. 25
Univ. of Rochester v. G.D. Searle & Co.,
375 F.3d 1303 (Fed. Cir. 2004) ............................ 31
 x

TABLE OF AUTHORITIES
(continued)
Page(s)
Universal Oil Prods. Co. v. Globe
Oil & Ref. Co.,
322 U.S. 471 (1944) ........................................ 25, 30
Vas-Cath Inc. v. Mahurkar,
935 F.2d 1555 (Fed. Cir. 1991) ............................ 16
CONSTITUTIONAL AND STATUTORY AUTHORITIES
U.S. Const. art. 1, § 8, cl. 8.................................... 7, 29
16 U.S.C. § 973c......................................................... 21
28 U.S.C. § 1254 .......................................................... 5
28 U.S.C. § 1295 .......................................................... 4
35 U.S.C. § 101 ...................................................... 9, 26
35 U.S.C. § 102 ............................................................ 9
35 U.S.C. § 103 ............................................................ 9
35 U.S.C. § 112 ........................... 1, 2, 6, 7, 8, 9, 15, 17,
18, 21, 22, 23, 24, 26,
27, 28, 29, 31, 32
35 U.S.C. § 132 .................................................... 16, 28
35 U.S.C. § 282 .......................................................... 17
35 U.S.C. § 285 .......................................................... 17
Patent Act of 1793, 1 Stat. 318 ............................... 7, 8
Patent Act of 1836, 5 Stat. 117 ................................... 8
 xi

TABLE OF AUTHORITIES
(continued)
Page(s)
OTHER AUTHORITIES
37 C.F.R. § 1.821 ......................................................... 9
Dmitry Karshtedt, Mark A. Lemley &
Sean B. Seymore, The Death of the
Genus Claim, 35 Harv. J. L. &
Tech. 1 (2021) ....................................... 2, 15, 31, 33
Jeffrey A. Lefstin, The Formal
Structure of Patent Law and the
Limits of Enablement, 23 Berkeley
Tech. L.J. 1141 (2008) .......................................... 35
Arti K. Rai, Intellectual Property Rights
in Biotechnology: Addressing New
Technology, 34 Wake Forest L. Rev.
827 (1999) ............................................................. 16
Allen K. Yu, The En Banc Federal
Circuit’s Written Description
Requirement: Time for the
Supreme Court to Reverse Again?,
33 Cardozo L. Rev. 895 (2012) ............................. 31
 INTRODUCTION
This case concerns a provision of American patent
law that has existed since the first Patent Act of 1790.
Now located in 35 U.S.C. § 112(a), this provision
prescribes what an inventor’s “specification” must
disclose to the public to obtain a patent: “a written
description of the invention, and of the manner and
process of making and using it, in such full, clear,
concise, and exact terms as to enable any person
skilled in the art to which it pertains, or with which it
is most nearly connected, to make and use the same,
and shall set forth the best mode contemplated by the
inventor or joint inventor of carrying out the
invention.” This provision embodies the “carefully
crafted bargain,” Pfaff v. Wells Elecs., Inc., 525 U.S.
55, 63 (1998), that lies at the core of patent law: In
exchange for a limited period of exclusivity, inventors
must disclose their invention to the public. The
question presented here is this: What scope of
disclosure does § 112(a) require?
No modern case of this Court has turned on this
question. But the Court has been consistent,
throughout its history, in understanding Congress’s
language to require exactly what it says: Inventors
must provide a written description of their invention
in a way that enables a skilled worker “to make and
use” it. Thus, “it is enough if [the inventor] describes
his method with sufficient clearness and precision to
enable those skilled in the matter to understand what
the process is, and if he points out some practicable
way of putting it into operation.” The Telephone
Cases, 126 U.S. 1, 535-36 (1888). More recently, the
Court has likewise stated that “Section 112 requires
only a ‘written description of the invention … in such
 2

full, clear, concise, and exact terms as to enable any

person skilled in the art … to make and use the
same.’” Mayo Collaborative Servs. v. Prometheus
Labs., Inc., 566 U.S. 66, 90 (2012) (ellipses in original;
quoting § 112).
The Federal Circuit, however, demands otherwise.
Even though the statute plainly says that the
measure of the “written description of the invention”
is whether it allows skilled workers to make and use
the invention, that court has burdened the
straightforward textual provision with convoluted,
judicially crafted requirements that the patent show
the inventor “possessed the full scope of the claimed
invention,” including all “known and unknown”
variations of individual components.
The consequences of this judicial embroidery have
been devastating for innovation. It has led the
Federal Circuit to invalidate numerous patents by
demanding the impossible. The effect has been
particularly lethal in the biological arts, where it
“represents both bad law and bad policy” and “may
threaten innovation.” Dmitry Karshtedt, Mark A.
Lemley & Sean B. Seymore, The Death of the Genus
Claim (“KLS”), 35 Harv. J. L. & Tech. 1, 1, 4 (2021).
This case is the poster child for those devastating
consequences. It involves the erasure of patent
protection for a lifesaving technology in the CAR-T
therapy field. In this field, the “T” is a “T-cell,” an
immune cell native to the human body. And the
“CAR” is a “chimeric antigen receptor,” made up of one
or more “signaling domains” that kill cancer cells,
along with a “binding element”—usually a “single
chain variable fragment” (“scFv”)—that attaches the
 3

CAR-T cell to the cancer cell so that the signaling

domains can kill it. In CAR-T therapy, T-cells are
extracted from a patient’s blood, the CAR is inserted,
and the newly formed CAR-T cells are replicated in
the laboratory and then returned to the patient’s body
to kill the targeted cancer cells.
Led by Dr. Michel Sadelain, a team of Sloan
Kettering inventors developed a CAR that did even
more. Their inventive advance was the addition of a
specific second signaling domain that allowed the
creation of CAR-T cells that not only kill cancer cells
in the body, but also replicate, building an army of
CAR-T cells inside the patient that will destroy even
more cancer cells. Sloan Kettering’s invention has
thus been hailed as the world’s first “living drug.”
No one disputes that the patent granted to the
Sloan Kettering team for this groundbreaking
invention adequately describes the two claimed
signaling domains—indeed, it discloses the precise
nucleotide sequence of each of them. The Sloan
Kettering patent also describes scFvs as “[k]nown
binding elements,” and their production as “routine.”
So routine, in fact, that the patent cited an article
published over a decade earlier by Orlandi et al. that
taught a process for creating these binding elements
for any target of interest, a process successfully
followed by a laboratory employee who had been hired
to wash dishes and wanted to try his hand at making
scFvs.
When Kite, a rival company, copied Dr. Sadelain’s
invention and rushed its product to market, Sloan
Kettering and its exclusive licensee, Juno, sued Kite
for infringement. At trial, Kite sought to avoid
 4

liability by challenging Sloan Kettering’s patent as

invalid, but the jury disagreed. The jury also found
Kite’s infringement willful, and awarded close to a
billion dollars in damages.
The Federal Circuit, however, reversed the
judgment as a matter of law on the ground that Sloan
Kettering’s patent failed that court’s atextual “written
description” requirement as to the well-known
“binding element” component of the claims. In the
Federal Circuit’s view, it was not enough for Sloan
Kettering’s patent to teach skilled workers to make
and use the binding element; the patent had to
additionally demonstrate that the inventors
“possessed,” in some amorphous sense, the “full scope”
of their claimed invention at the time of application,
including all possible binding elements, “known and
unknown.” Particularly for inventions in the
biological sciences, such a “possession” test is simply
impossible to meet. And, since the same statute
governs all patents, the problems with this atextual
interpretation affect all kinds of technologies.
The Court should grant certiorari. The Federal
Circuit’s approach contravenes the plain statutory
text and is erasing vast swaths of patents for failing
to satisfy a disclosure standard found nowhere in the
statute. And because the Federal Circuit has
exclusive jurisdiction over patent appeals, 28 U.S.C.
§ 1295, no other court of appeals will be able to
address this question.1

1In Amgen Inc. v. Sanofi (No. 21-757), this Court has called for
the Solicitor General’s views on the very same statute, albeit
with respect to the Federal Circuit’s distinct “enablement”
requirement. Because both cases involve the same sentence in
 5

OPINIONS BELOW
The Federal Circuit’s opinion (Pet.App.1a-22a) is
reported at 10 F.4th 1330. The opinion of the U.S.
District Court for the Central District of California
denying Kite’s post-trial motion for judgment as a
matter of law (Pet.App.26a-81a) is unreported but
available at 2020 WL 10460622. The jury verdict
(Pet.App.82a-84a) is unreported. The district court’s
judgment (Pet.App.23a-25a) is unreported. The
Federal Circuit’s order denying rehearing
(Pet.App.85a-86a) is unreported.
JURISDICTION
The Federal Circuit issued its opinion on August 26,
2021, and denied Plaintiffs’ timely rehearing petition
on January 14, 2022. On March 7, 2022, Chief Justice
Roberts granted an extension of time to file this
petition by June 13, 2022. No. 21A461 (U.S.).
Jurisdiction in this Court exists under 28 U.S.C.
§ 1254(1).

the statute, the Court may also wish to call for the Solicitor
General’s views here prior to granting review.
 6

STATUTORY PROVISION INVOLVED

35 U.S.C. § 112 states, in relevant part2:
(a) In General.—The specification shall
contain a written description of the invention,
and of the manner and process of making and
using it, in such full, clear, concise, and exact
terms as to enable any person skilled in the art
to which it pertains, or with which it is most
nearly connected, to make and use the same, and
shall set forth the best mode contemplated by the
inventor or joint inventor of carrying out the
invention.
(b) Conclusion.—The specification shall
conclude with one or more claims particularly
pointing out and distinctly claiming the subject
matter which the inventor or a joint inventor
regards as the invention.

2 Although the pre-America Invents Act (“AIA”) version of § 112

governs this case, the AIA left the statute’s operative language
unchanged. Compare 35 U.S.C. § 112(a)-(b) (post-AIA), with 35
U.S.C. § 112, ¶¶ 1-2 (pre-AIA); see generally Biogen Int’l GMBH
v. Mylan Pharms. Inc., 18 F.4th 1333, 1341 n.5 (Fed. Cir. 2021)
(AIA’s amendments “bear no significance for purposes of [the
Federal Circuit’s] written-description analysis”). For ease of
reference, this petition generally refers to the AIA version’s
lettered sections.
 7

STATEMENT
A. The Patent System’s Fundamental
Quid Pro Quo
The American patent system rests on the
Constitution’s Intellectual Property Clause, which
gives Congress the “Power … To promote the Progress
of Science and useful Arts, by securing for limited
Times to Authors and Inventors the exclusive Right to
their respective Writings and Discoveries.” U.S.
Const. art. 1, § 8, cl. 8. The Framers’ insight that
incentives are essential to innovation underlies the
patent system’s fundamental quid pro quo: the
inventor teaches the public to make and use the
invention, and the public gives the inventor the
exclusive right to make, use, and profit from it for a
limited period of time.
To effectuate this bargain, Congress has
consistently required that a patent application
contain written disclosures allowing skilled artisans
to make and use the invention. This requirement,
which has existed in substantially the same form
since George Washington’s presidency, involves “a
written description of the invention, and of the
manner and process of making and using it, in such
full, clear, concise, and exact terms as to enable any
person skilled in the art to which it pertains … to
make and use the same.” 35 U.S.C. § 112(a); see
Patent Act of 1793 § 3, 1 Stat. 318, 321 (“written
description of his invention, and of the manner of
using, or process of compounding the same, in such
full, clear and exact terms, as to … enable any person
skilled in the art or science … to make, compound,
and use the same”).
 8

Initially, the patent statutes contained no separate

requirement for patent “claims” as that term is now
used, so the written description itself also
“distinguish[ed] the [invention] from all other things
before known” and set out the invention’s boundaries.
See Patent Act of 1793 § 3, 1 Stat. at 321. Over time,
though, the numbered “claim” format developed and
became cemented as a separate statutory
requirement.
Now housed in 35 U.S.C. § 112(b), the claim
requirement states: “The specification shall conclude
with one or more claims particularly pointing out and
distinctly claiming the subject matter which the
inventor or a joint inventor regards as the invention.”
That provision traces back to 1836. See Patent Act of
1836 § 6, 5 Stat. 117, 119 (directing inventors to
“particularly specify and point out the part,
improvement, or combination, which [they] claim[] as
[their] own invention or discovery”). Meanwhile,
§ 112(a) maintains essentially the same language
regarding an enabling written disclosure from the
pre-1836 Patent Act: “a written description of the
invention, and of the manner and process of making
and using it, in such full, clear, concise, and exact
terms as to enable any person skilled in the art to
which it pertains … to make and use the same.”
Thus, as this Court explained in a case involving
the claim requirement, “[u]nder the modern American
system,” these disclosure “objectives are served by two
distinct elements of a patent document.” Markman v.
Westview Instruments, 517 U.S. 370, 373 (1996). The
first is “a specification describing the invention ‘in
such full, clear, concise, and exact terms as to enable
any person skilled in the art … to make and use the
 9

same.’” Id. (quoting 35 U.S.C. § 112, ¶ 1 (pre-AIA),

now § 112(a)). And the second is “one or more ‘claims,’
which ‘particularly poin[t] out and distinctly clai[m]
the subject matter which the applicant regards as his
invention.’” Id. (quoting 35 U.S.C. § 112, ¶ 2 (pre-
AIA), now § 112(b)) (brackets in original). Patent
applications may also contain nucleotide or amino-
acid “sequence listings” relevant to an invention, 37
C.F.R. § 1.821. Although claims and sequence listings
are technically part of the “specification,” 35 U.S.C.
§ 112(b); 37 C.F.R. § 1.821(c), courts often use the
term “specification” to refer to just the inventor’s
written disclosure. E.g., Markman, 517 U.S. at 373
(distinguishing between the “specification” and the
“claims”).
In addition to § 112’s requirements, the Patent Act
defines the scope of patent-eligible inventions, 35
U.S.C. § 101, and requires that claimed inventions be
novel, id. § 102, and nonobvious, id. § 103. This Court
has recently interpreted each of these cornerstone
Patent Act provisions. E.g., Ass’n for Molecular
Pathology v. Myriad Genetics, Inc., 569 U.S. 576
(2013) (§ 101); Helsinn Healthcare S.A. v. Teva
Pharms. USA, Inc., 139 S. Ct. 628 (2019) (§ 102); KSR
Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) (§ 103).
So too has it interpreted the claim requirement now
found in § 112(b). Markman, 517 U.S. 370. But
§ 112(a) and its predecessors have escaped the Court’s
attention.
B. Sloan Kettering’s Invention
1. Dr. Michel Sadelain directs the Center for Cell
Engineering at Sloan Kettering and is the lead
 10

inventor on Sloan Kettering’s patent. He is a world-

recognized expert in CAR-T therapy.
Early CARs, which date to the 1990s, had two
components.

scFv

signaling
domain

The first component was a “signaling domain,”

which activates the cancer-bound T-cell to destroy the
cancer cell.
The second component in these early CARs was an
scFv, an antibody-derived component that pairs with
a protein called an antigen on the surface of cancer
cells and attaches—in CAR lingo, “binds”—the CAR-
T cell to the cancer cell. scFvs were well-known
biological tools, including as binding elements in
CARs, long before Sloan Kettering’s patent. E.g.,
C.A.App.33931-33935; C.A.App.35766-35768. For
example, a 1989 paper by Orlandi et al. provided the
“cookbook” or “recipe” to make scFvs that would bind
to any target antigen (the “Orlandi method”).
C.A.App.36185-36189.
Although these early CARs allowed T-cells to bind
to targeted antigens, the signaling domain failed to
produce sufficiently robust immune responses to
 11

successfully treat the cancer. Researchers, including

Dr. Sadelain and his co-inventors, sought to improve
upon the early CARs’ signaling domain by adding
another amino-acid sequence to stimulate a better
immune response. The original signaling sequence
became known as the “primary signaling domain,”
and the newly added signaling sequence became
known as the “costimulatory signaling domain,” with
both together called the “backbone.” The other
component—unchanged from earlier CARs—was the
scFv for binding.
2. Dr. Sadelain’s groundbreaking invention was
his use of a particular amino-acid sequence as the
backbone’s costimulatory domain. Although the field
believed this sequence would not work in this role,
Dr. Sadelain’s remarkable two-part backbone not only
killed the targeted cancer cells, but also caused the
CAR-T cells to replicate, creating a growing army of
CAR-T cells to kill even more cancer cells.
Dr. Sadelain’s invention was celebrated as the world’s
first “living drug” because its cancer-treating CAR-T
cells reproduce in the patient’s body, bolstering the
patient’s own immune system and creating a
sustained anti-cancer effect. C.A.App.32913-32914,
33930.
 12

In 2008, the Patent Office granted a patent to

Dr. Sadelain and his team; their employer, Sloan
Kettering, became the assignee. The claims at issue
recite three elements:
1. “a zeta chain portion comprising the
intracellular domain of human CD3 ζ chain”
(the primary signaling domain).
Pat.App.23b.
2. “a costimulatory signaling region” that
“comprises the amino acid sequence encoded
by SEQ ID NO:6.” Id.
3. “a single chain antibody” (i.e., scFv) “binding
element that specifically interacts with a
selected target,” further limited in two
asserted claims to an scFv that “binds to
CD19,” an antigen associated with blood
cancer. Id.
 13

This patent epitomizes the enabling of a skilled

artisan to make and use the invention. Its sequence
listings disclose the precise nucleotide sequence for
both signaling elements of the backbone. And
although the scFv binding element remained
unchanged from the prior art, and the patent
describes it as “known” and its making as “routine,”
the patent’s specification nevertheless provides
examples of scFvs, including one that binds to the
CD19 protein found on blood cancer cells.
Pat.App.12b, 14b. It also describes the Orlandi
method for making additional scFvs for binding the
inventive two-part backbone to other cancer-cell
antigens, and cites and incorporates Dr. Orlandi’s
article by reference. Pat.App.12b.
C. Kite’s Willful Infringement
Unbeknownst to Sloan Kettering, its invention was
being copied and exploited by Kite, a commercial
manufacturer. As scientists at nonprofit research
institutions often do, Dr. Sadelain had shared
information about the invention with the National
Cancer Institute (“NCI”). C.A.App.32929-32931,
32934. He was unaware that NCI would later share
his invention with Kite, and that Kite would pursue a
commercial embodiment of his invention. Kite,
though, knew it needed Dr. Sadelain’s inventive
backbone, and Kite’s product, Yescarta, copied it.
Kite eventually sought a license from Sloan
Kettering so that it could use the technology
legitimately. Sloan Kettering, however, chose to
exclusively license the patent to Juno, an entity
founded by experts affiliated with various research
institutions.
 14

When Kite’s licensing attempts failed, it tried to

avoid infringement liability by seeking to invalidate
the patent through the AIA’s inter partes review
mechanism. The Patent Office rejected Kite’s
challenge and reaffirmed the patent grant. The
Federal Circuit summarily affirmed the Patent
Office’s decision, and Kite did not seek this Court’s
review.
After it failed to license or invalidate the patent,
Kite barged ahead and “chose to accelerate [its
infringing product] YESCARTA® to market to its own
advantage and to Plaintiffs’ corresponding detriment,
all while knowing that Plaintiffs’ assertion of the
Patent in this litigation was … ‘inevitable.’”
C.A.App.42. Kite’s pirated use of Sloan Kettering’s
invention allowed it to exploit a first-mover advantage
in the market. Kite leveraged that advantage into a
lucrative $11.9 billion buyout from Gilead Sciences,
one of the world’s largest pharmaceutical companies.
D. The Federal Circuit Applies Its
“Written Description” Test And
Overrides The Work Of The Patent
Office, The Jury, And The District
Court
1. Once Kite commercially launched Yescarta,
Sloan Kettering and Juno sued Kite for infringement.
Kite stipulated that Yescarta literally infringes the
patent, C.A.App.7706-7709, but argued the patent
was invalid because, in Kite’s view, it did not satisfy
the Federal Circuit’s written-description standard.3

3 Kite also argued that it did not infringe if the “Certificate of

Correction” the Patent Office issued in 2013 to correct a
typographical or clerical error regarding the costimulatory
 15

As noted above, the Federal Circuit interprets

§ 112(a) to require not only an enabling written
description of the invention and manner and process
of making and using it, but also, as a “separate”
requirement, that the inventor demonstrate
“possession” of the “full scope” of the invention,
including every possible variation of each component.
Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336,
1351 (Fed. Cir. 2010) (en banc); AbbVie Deutschland
GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285,
1301 (Fed. Cir. 2014). For so-called “genus” claims,4
the Federal Circuit’s “possession” test asks whether
the patent “disclos[es] … either a representative
number of species falling within the scope of the genus
or structural features common to the members of the
genus so that one of skill in the art can ‘visualize or
recognize’ the members of the genus.” Ariad, 598 F.3d
at 1350.
The Federal Circuit’s inventor-possession test
originated in cases from the Court of Customs and
Patent Appeals, and then from the Federal Circuit
itself, involving questions of timing—for example, the

signaling domain was invalid, and that the patent did not satisfy
the Federal Circuit’s “enablement” test, which requires that “the
specification teach those in the art to make and use the invention
without undue experimentation.” In re Wands, 858 F.2d 731, 737
(Fed. Cir. 1988). The jury and district court rejected these
arguments, and the Federal Circuit did not reach them.
4 A “genus claim” “covers a group of structurally related products

that incorporate the basic advance of the patented invention.”

KLS, supra, 35 Harv. J. of L. & Tech. at 3. They are “[t]he central
feature of patent law in the chemical, biological, and
pharmaceutical industries” because they ensure “that no one can
copy the[] basic idea by making a small change to it to avoid
infringing the patent.” Id. at 1, 3.
 16

statutory bars on adding “new matter” to existing

patents via amendment or “reissue” patents, e.g., 35
U.S.C. § 132(a), and the question of an applicant’s
entitlement to the effective priority date of an earlier
application. See, e.g., In re Ruschig, 379 F.2d 990,
995-96 (C.C.P.A. 1967); Vas-Cath Inc. v. Mahurkar,
935 F.2d 1555, 1560-64 (Fed. Cir. 1991). But the
Federal Circuit then “broke new ground” by morphing
this timing question into a requirement applicable
“not only to later-filed claims but also to claims filed
in the original patent.” Arti K. Rai, Intellectual
Property Rights in Biotechnology: Addressing New
Technology, 34 Wake Forest L. Rev. 827, 834 (1999)—
first in a panel decision in Regents of the University of
California v. Eli Lilly & Co., 119 F.3d 1559, 1566 (Fed.
Cir. 1997), and, ultimately, in that court’s en banc
opinion in Ariad.
According to Kite, the Patent Office’s determination
that Sloan Kettering’s disclosure met this “inventor
possession” test was wrong. Kite did not argue that
the patent lacked written description for either part of
Dr. Sadelain’s revolutionary backbone, but instead
directed this attack solely at the old, well-known scFv
component of the CAR.
At trial, Sloan Kettering refuted this argument by
demonstrating that scFvs were well known, that they
had been used as CAR components for years, and that
skilled artisans would have no difficulty making and
using them with Dr. Sadelain’s two-part backbone. In
particular, Sloan Kettering established that public
scFv knowledge included Dr. Orlandi’s 1989 paper—
summarized, cited, and incorporated by reference in
the patent—that explained how to make scFvs that
would bind to any selected target antigen.
 17

C.A.App.36185-36189. As Kite’s own expert testified,

scientists using this method to obtain an scFv for a
specific target essentially reverse-engineer to the
scFv: they inject the target antigen into a mouse,
which makes corresponding antibodies from which
binding scFvs can be extracted. C.A.App.33678-
33679. This process was so routine that a self-taught
employee, hired as a dishwasher in a trial expert’s
research laboratory, successfully used it.
Pet.App.39a.
The jury rejected all of Kite’s theories for escaping
infringement liability, concluding that the inventors
had upheld their end of the bargain under § 112 and
that Kite failed to carry its burden of overcoming the
presumption that the Patent Office had validly issued
the patent. Pet.App.82a-84a; see 35 U.S.C. § 282. As
relevant here, the jury found Kite failed to establish
that the patent lacked adequate “written description.”
The jury also found Kite’s admitted infringement
willful and awarded damages to compensate Sloan
Kettering and Juno for Kite’s infringement.
2. The district court rejected all of Kite’s post-trial
motions challenging the jury’s verdict. As the court
reasoned, “[t]hat Defendant disputes Plaintiffs’
testimony and evidence, or presented its own
conflicting evidence, is not grounds for JMOL.”
Pet.App.39a-40a. Having upheld the verdict, the
court exercised its discretion to award enhanced
damages for Kite’s egregious piracy of Sloan
Kettering’s invention, see 35 U.S.C. § 285, and ordered
Kite to pay royalties on all sales of Yescarta and any
other infringing products until the patent’s expiration
in 2024. Pet.App.23a-25a.
 18

3. The Federal Circuit, however, reversed the

jury’s factual finding as a matter of law. That court
took no issue with the adequacy of the patent’s
description of the novel, two-part backbone that Kite
copied. Instead, it invalidated the patent based solely
on its remarkable conclusion that the patent’s
disclosure with respect to the old, standard, scFv
binding element did not satisfy its own “written
description” standard. Reaching even beyond its prior
articulations of that standard, it held that, in addition
to providing an enabling written description, “the
inventors needed to convey that they possessed the
claimed invention, which encompasses all scFvs,
known and unknown, as part of the claimed CAR that
bind to a selected target.” Pet.App.13a.
Without recorded dissent, the Federal Circuit
rejected the plaintiffs’ petition to reconsider its
interpretation of § 112 en banc. Pet.App.85a-86a.
REASONS FOR GRANTING THE WRIT
I. THE FEDERAL CIRCUIT’S PERSISTENT
INTERPRETATION OF § 112 IS
CONTRARY TO THE STATUTE AND THIS
COURT’S PRECEDENT.
A. The Federal Circuit’s Interpretation
Contradicts The Statute.
1. Section 112 states, in pertinent part: “The
specification shall contain a written description of the
invention, and of the manner and process of making
and using it, in such full, clear, concise, and exact
terms as to enable any person skilled in the art to
which it pertains … to make and use the same ….” 35
U.S.C. § 112(a).
 19

“Statutory construction must begin with the

language employed by Congress and the assumption
that the ordinary meaning of that language accurately
expresses the legislative purpose.” Gross v. FBL Fin.
Servs., Inc., 557 U.S. 167, 175 (2009). Accordingly,
there is a “basic and unexceptional rule that courts
must give effect to the clear meaning of statutes as
written, giving each word its ordinary, contemporary,
common meaning.” Artis v. District of Columbia, 138
S. Ct. 594, 603 n.8 (2018) (brackets, ellipses, and
internal quotation marks omitted). These principles
apply fully here because “[p]atent law is governed by
the same … methods of statutory interpretation … as
other areas of civil litigation.” SCA Hygiene Prods.
Aktiebolag v. First Quality Baby Prods., LLC, 137 S.
Ct. 954, 964 (2017) (brackets in original).
The statute’s plain language—both its syntax and
punctuation—compels the conclusion that both the
“written description of the invention” and the “written
description … of the manner and process of making
and using it” are subject to the same modifier: “in such
full, clear, concise, and exact terms as to enable any
person skilled in the art to which it pertains … to
make and use the same [i.e., the invention].” That—
not any “inventor possession” standard—is the test
Congress prescribed for an adequate “written
description.”
The Federal Circuit’s contrary, atextual reading
cannot be sustained. In its 2010 en banc decision in
Ariad (which was never presented to this Court for
review), that court parsed the statute’s language by
holding that the “in such full, clear, concise, and exact
terms as to enable” phrase “modifies only ‘the written
description … of the manner and process of making
 20

and using [the invention].’” Ariad, 598 F.3d at 1344

(ellipses and brackets in original). By so holding, the
Federal Circuit freed itself to maintain its
extratextual, judicially imposed “possession”
requirements for the “written description of the
invention.”
That was error. The comma in the statute following
“and of the manner and process of making and using
it” establishes that the “in such … terms as to enable”
modifier applies to both the “written description of the
invention” and the “written description … of the
manner and process of making and using it.” “As
several leading treatises explain, ‘a qualifying phrase
separated from antecedents by a comma is evidence
that the qualifier is supposed to apply to all the
antecedents instead of only to the immediately
preceding one.’” Facebook, Inc. v. Duguid, 141 S. Ct.
1163, 1170 (2021) (brackets omitted) (quoting
Eskridge and citing Singer & Singer; Sutherland; and
Scalia & Garner).
Here, the statute’s structure and punctuation
confirm that the “written description” of both “the
invention” and “the manner and process of making
and using it” are qualified by the language that
follows—“in such full, clear, concise, and exact terms
as to enable any person skilled in the art to which it
pertains … to make and use the same.” Congress
thereby supplied the standard by which the adequacy
of a patent’s written description should be measured.
Congress’s chosen language allows no room for
additional mandates. Requirements stated in this “in
such … as to” form—as the Patent Act’s specification
requirement has been since 1793—set out complete
 21

tests that do not permit additional, judicially crafted

encumbrances. When Congress makes it a crime, for
example, “to operate a vessel [in a particular area] in
such a way as to disrupt or in any other way adversely
affect the activities of traditional and locally based
fishermen and fishing vessels,” 16 U.S.C. § 973c(b)(5)
(emphasis added), a violation occurs if the vessel’s
operation “disrupt[s] or in any other way adversely
affect[s] the activities of traditional and locally based
fishermen and fishing vessels,” regardless of whether
it also disrupts other types of boats. Just so here. By
commanding that a “specification shall contain a
written description of the invention, and of the
manner and process of making and using it, in such
full, clear, concise, and exact terms as to enable any
person skilled in the art to which it pertains … to
make and use the same …,” 35 U.S.C. § 112(a)
(emphasis added), Congress provided not just the
requirement of “a written description of the
invention,” but the standard by which that description
is to be measured. The specification is adequate if its
written description of the invention (and “the manner
and process of making and using it”) fulfills the test
that the “in such … as to” language defines—that is,
if it enables the skilled artisan to make and use the
invention—regardless of whether it also demonstrates
the inventor’s “possession.”
2. The Federal Circuit, however, holds that
§ 112(a)’s “in such … terms as to enable” language
applies only to what it calls the “enablement
requirement,” which requires that “the specification
teach those in the art to make and use the invention
without undue experimentation.” Wands, 858 F.2d at
737. By parsing the statute in this odd fashion, the
 22

Federal Circuit cleaved “written description of the

invention” from the rest of § 112(a), and concluded
that the statute imposes an additional “written
description” requirement independent of the
remaining statutory text. Ariad, 598 F.3d at 1347.
Reading the statute as containing a separate,
standardless “written description of the invention”
requirement has allowed the Federal Circuit to pile
gloss after judicial gloss onto its atextual test. When
that court, en banc, entrenched this “separate”
“written description” requirement in Ariad, it framed
its test as whether the patent specification
“reasonably conveys to those skilled in the art that the
inventor had possession of the claimed subject matter
as of the filing date,” 598 F.3d at 1351—a “quixotic”
and “vague” test with “no statutory support,” see id. at
1362 (Rader, J., concurring in part and dissenting in
part). That court further suggested that, for “genus”
claims, its “possession” test requires “the disclosure of
either a representative number of species falling
within the scope of the genus or structural features
common to the members of the genus so that one of
skill in the art can ‘visualize or recognize’ the
members of the genus.” Id. at 1350 (majority op.).
That subsequently evolved into a requirement that
any such “representative” disclosures must “support
the full scope of the claims.” AbbVie Deutschland, 759
F.3d at 1301. And in this case, it arrived at the
astonishing conclusion that an inventor must
demonstrate “possession” of all possible variations of
each individual component of the invention—both
“known and unknown.” Pet.App.13a. These judicially
imposed requirements have nothing to do with § 112’s
 23

textual mandate that the ordinary worker be able to

pick up the patent, read it, and practice the invention.
In departing from the straightforward, textually
supported reading of § 112, the Federal Circuit
suggested that divorcing the “written description of
the invention” from the statutory measuring stick of
“such full, clear, concise, and exact terms as to enable
any person skilled in the art … to make and use the
same” is necessary to prevent the parallel clause set
off in commas—“and of the manner and process of
making and using it”—from being superfluous. See
Ariad, 598 F.3d at 1344-45. But there is both good
reason and a good explanation for why the statute
reads as it does. The parallel language—present in
the patent statutes for centuries—is readily
understandable as a continuation of the language
from the earliest versions of the Patent Act, when
“claims” were not required to separately define the
invention. That language in no way transforms the
“written description of the invention” into a super-
claiming requirement, as the Federal Circuit’s test
demands.
In any event, “[s]ometimes the better overall
reading of the statute contains some redundancy.”
Rimini Street, Inc. v. Oracle USA, Inc., 139 S. Ct. 873,
881 (2019); see also Loving v. IRS, 742 F.3d 1013, 1019
(D.C. Cir. 2014) (Kavanaugh, J.) (“[L]awmakers, like
Shakespeare characters, sometimes employ overlap or
redundancy so as to remove any doubt and make
doubly sure.”). To the degree § 112(a) contains any
redundancy, this is just such a case. Indeed, it is
unsurprising that, in setting forth the disclosure
requirement for how to make and use a thing,
 24

Congress would start with a reference to the thing

itself (“the invention”) to enhance clarity.
Having forsaken the statutory standard of an
enabling “written description of the invention, and of
the manner and process of making and using it,” the
Federal Circuit has crafted its “possession”
standard—with all of its subsequent mutations—out
of thin air. The statute makes no mention or even
suggestion of “possession,” let alone the inventor’s
clairvoyant demonstration of “possession” of all
possible variations, “known and unknown,” of each
individual component. See Pet.App.13a. Moreover,
the Federal Circuit’s interpretation of § 112
improperly shifts the statutory focus—from what “any
person skilled in the art” would understand, to the
atextual question of what the inventors demonstrate
in the specification that they “possessed.” These
deviations from the statute’s plain language are alone
ample reason to grant review and reject the Federal
Circuit’s interpretation of § 112.
B. The Federal Circuit’s Interpretation of
§ 112 Conflicts With This Court’s And
Other Circuits’ Interpretations.
1. Unsurprisingly given the statutory language’s
clarity, this Court has consistently understood it to
mean exactly what it says—even though it last
focused on the provision decades ago. Since
Congress’s adoption of a separate claim requirement,
this Court has repeatedly described the disclosure
required by § 112’s predecessors as turning entirely
on whether the written description of the invention
enables skilled workers to make and use the
invention. The Telephone Cases, 126 U.S. at 535-36
 25

(“[I]t is enough if [the inventor] describes his method

with sufficient clearness and precision to enable those
skilled in the matter to understand what the process
is, and if he points out some practicable way of putting
it into operation.”); United States v. Dubilier
Condenser Corp., 289 U.S. 178, 187 (1933) (“[U]pon
expiration of [the patent term], the knowledge of the
invention inures to the people, who are thus enabled
without restriction to practice it and profit by its use.
To this end the law requires such disclosure to be
made in the application for patent that others skilled
in the art may understand the invention and how to
put it to use.” (internal citations omitted)); Universal
Oil Prods. Co. v. Globe Oil & Ref. Co., 322 U.S. 471,
484 (1944) (“[T]he quid pro quo is disclosure of a
process or device in sufficient detail to enable one
skilled in the art to practice the invention once the
period of the monopoly has expired ….”).
Several regional circuits (before the Federal
Circuit’s creation) read the statute the same way.
Donner v. Am. Sheet & Tin Plate Co., 165 F. 199, 206
(3d Cir. 1908) (“statutory requirement that the
patentee shall make a written description of his
invention or discovery, ‘in such full, clear … and exact
terms as to enable any person skilled in the art … to
make, construct … and use the same’” (ellipses in
original)); Philip A. Hunt Co. v. Mallinckrodt Chem.
Works, 177 F.2d 583, 585 (2d Cir. 1949) (Hand, J.)
(same); Ill. Tool Works, Inc. v. Foster Grant Co., 547
F.2d 1300, 1309 (7th Cir. 1976) (same). No regional
circuit recognized a different standard governing the
“written description of the invention.”
In the course of addressing other aspects of the
Patent Act, this Court’s more recent decisions have
 26

likewise understood that § 112(a) requires only an

enabling written description, to complement the
claims’ precise definition of the invention. Thus, a
decade ago, while interpreting § 101’s patent-
eligibility language, this Court stated that “Section
112 requires only a ‘written description of the
invention … in such full, clear, concise, and exact
terms as to enable any person skilled in the art … to
make and use the same.” Mayo, 566 U.S. at 90
(ellipses in original; quoting § 112)). Before that, it
had similarly stated, in a case involving the claim
requirement, that patents must “contain[] a
specification describing the invention ‘in such full,
clear, concise, and exact terms as to enable any person
skilled in the art … to make and use the same.’”
Markman, 517 U.S. at 373 (ellipses in original;
quoting § 112). Likewise, when comparing the Patent
Act (which concerns “utility patents”) to the Plant
Patent Act, the Court explained: “[T]o obtain a utility
patent, a breeder must describe the plant with
sufficient specificity to enable others to ‘make and use’
the invention after the patent term expires.” J.E.M.
Ag Supply, Inc. v. Pioneer Hi-Bred Int’l, Inc., 534 U.S.
124, 142 (2001); see also id. at 154 (Breyer, J.,
dissenting) (describing § 112 as requiring “an
enabling written description of the invention”). All of
this language suggests that the Court understands
the phrase “written description of the invention” as
tied to and modified by the phrase “in such full, clear,
concise, and exact terms as to enable …”—an
understanding that matches the text, but that the
Federal Circuit says is wrong.
2. In Ariad, the Federal Circuit asserted that
other opinions from this Court support its reading of
 27

§ 112. See 598 F.3d at 1345-47. But none read § 112

or its predecessors as imposing the Federal Circuit’s
“possession” mandate for demonstrating a “written
description of the invention.” Indeed, in only one such
case, Evans v. Eaton, 20 U.S. 356 (1822), did this
Court use the word “possession” at all, and not in any
way supportive of the Federal Circuit’s approach.
Evans explained that the specification served “to put
the public in possession of what the party claims as
his own invention”—not to demonstrate the inventor’s
possession. Id. at 434 (emphasis added). By
“put[ting] the public in possession” of the invention,
the inventor, consistent with the statute, both
“enable[d] all persons to use [the invention]
beneficially” after the patent’s expiration and, in the
absence of a separate claim requirement, “enable[d]
them to avoid [inadvertently] making and using it”
during the patent’s term. Id. at 400. By contrast,
demonstrating the inventor’s own possession, as the
Federal Circuit requires, does neither.
Other cases the Federal Circuit cited involved
disputes over distinct issues—establishing whether
later-added claims related to original patent
applications or contained new matter. See Schriber-
Schroth Co. v. Cleveland Tr. Co., 305 U.S. 47, 57
(1938) (patent application “cannot be broadened by
amendment so as to embrace an invention not
described in the application as filed,” and the “object
of the statute is to require the patentee to describe his
invention so that others may construct and use it after
the expiration of the patent and ‘to inform the public
during the life of the patent of the limits of the
monopoly asserted’” (emphasis added)); Gill v. Wells,
89 U.S. (22 Wall.) 1, 25 (1874) (new claims in a reissue
 28

patent must sufficiently relate back to the original

patent). In these circumstances, the specification’s
written description could provide evidence of
compliance vel non with separate requirements
flowing from different portions of the Patent Act. E.g.,
35 U.S.C. § 132(a) (“No amendment shall introduce
new matter into the disclosure of the invention.”). But
these cases neither mention “possession” nor support
or reflect a standalone “written description”
requirement unrelated to the statutory enablement
test.
Finally, the Federal Circuit in Ariad pointed to
Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co.
535 U.S. 722 (2002), as support for its distinct “written
description of the invention” standard. See 598 F.3d
at 1346-47. But the Court’s general statement in
Festo that “[w]hat is claimed by the patent application
must be the same as what is disclosed in the
specification,” 535 U.S. at 736, does not support the
Federal Circuit’s judicially created “possession”
standard. Nothing about that basic observation of
concordance between claims and specification can be
read as mandating disclosure of the “full scope” of the
invention and each constituent component to show
“possession” by the inventor. Besides, Festo’s
statement came in the context of a case about different
issues—estoppel arising from claim amendment
during prosecution—and cannot compete with the
text and grammar of the statute itself, nor the weight
of this Court’s consistent description of § 112’s
requirements as turning simply on whether there is
an enabling disclosure. E.g., Mayo, 566 U.S. at 90
(“Section 112 requires only a ‘written description of
the invention … in such full, clear, concise, and exact
 29

terms as to enable any person skilled in the art … to

make and use the same.” (ellipses in original; quoting
§ 112)); see supra at 25-26.
***
At bottom, a “written description of the invention”
requirement, measured by a standard “separate from
enablement” using the Federal Circuit’s judicially
created “possession” inquiry, which that court has
further defined to apply to the “full scope” of all
“known and unknown” variations of all components
and embodiments, is nowhere in the statutory text.
Congress’s language is clear that the written
description of the invention and manner and process
of making and using it must enable a skilled artisan
to make and use the invention. Nothing more.
II. THE FEDERAL CIRCUIT’S ERRONEOUS
INTERPRETATION PRESENTS SEVERE
DANGERS TO RESEARCH AND
INNOVATION, ESPECIALLY THE LIFE
SCIENCES.
1. By undermining the incentive to innovate, the
Federal Circuit’s interpretation of § 112 has severe
consequences for society. Those consequences carry
special importance because they touch on the
constitutional underpinnings of the patent system.
See U.S. Const. art. 1, § 8, cl. 8. (permitting Congress
to “promote the Progress of Science and useful Arts,
by securing for limited Times to … Inventors the
exclusive Right to their respective … Discoveries”).
The Framers recognized the importance of offering
time-limited protections to spur scientific research
and the development of new technology. “[T]he patent
system represents a carefully crafted bargain that
 30

encourages both the creation and the public disclosure

of new and useful advances in technology, in return
for an exclusive monopoly for a limited period of time.”
Pfaff, 525 U.S. at 63. Accordingly, the constitutionally
grounded and statutorily defined “quid pro quo is
disclosure of a process or device in sufficient detail to
enable one skilled in the art to practice the invention
once the period of the monopoly has expired.”
Universal Oil Prods., 322 U.S. at 484.
2. Neither the public nor the skilled artisan
derives any advantage from the Federal Circuit’s
grafting of its atextual “possession” inquiry onto the
statutory mandate of a written description that
enables. So long as the claims serve as “the measure
of the grant” by clearly delimiting the boundaries of
what is protected, see id., and the written description
of the invention and how to make and use it permits
its practice by a skilled artisan, the inventors have
upheld their side of the bargain. Demanding more
prolixity, as the Federal Circuit’s rule does, fails to
“promote the progress of science and useful arts” in
any way.
Here, the claims pinpoint the boundaries of what is
protected—a CAR encompassing Dr. Sadelain’s
revolutionary backbone and an scFv (binding
element) that attaches the CAR to the CD19 antigen
(or, for the broader claims, a CAR encompassing the
backbone and an scFv that binds to a different
antigen). Kite’s own actions demonstrate as much.
Its furious attempts to license or invalidate the patent
show it knew its activities were covered. And its use
of the disclosed backbone with an off-the-shelf scFv
shows it had no trouble making and using the
invention. By contrast, the claims in no way prevent
 31

any member of the public from selecting, making, and

using any scFvs they want, except with Sloan
Kettering’s backbone.
3. While the Federal Circuit’s interpretation
yields no benefits, it imposes clear costs on innovation
and the incentives to develop new technology—costs
that are particularly stark in pharmaceutical and
other life sciences fields. That court has admitted that
its construction of § 112 has particular bite “in the
biological arts” because, in its view, the requirement
“ensures that when a patent claims a genus by its
function or result, the specification recites sufficient
materials to accomplish that function.” Ariad, 598
F.3d at 1352-53. But the Federal Circuit’s heavy-
handed demand for “sufficient materials” in the
written description of a “genus claim” is a bug, not a
feature. Because of inherent variability and the large
number of inconsequential modifications that can be
made to inventions, “[t]he central feature of patent
law in the chemical, biotechnology, and
pharmaceutical industries is the genus claim.” KLS,
supra, 35 Harv. J. L. & Tech. at 1. Indeed, “any patent
lawyer will tell you they are critical to effective patent
protection.” Id.
Accordingly, the Federal Circuit’s interpretation
“represents both bad law and bad policy” and “may
threaten innovation in an important sector of the
economy.” Id. at 1, 4; see also, e.g., Univ. of Rochester
v. G.D. Searle & Co., 375 F.3d 1303, 1314-25 (Fed. Cir.
2004) (Rader, J., dissenting from denial of rehearing
en banc) (listing more than 20 articles disagreeing
with the Federal Circuit’s interpretation); Allen K.
Yu, The En Banc Federal Circuit’s Written Description
 32

Requirement: Time for the Supreme Court to Reverse

Again?, 33 Cardozo L. Rev. 895 (2012).
The innovators most directly affected share these
concerns. As St. Jude Children’s Research Hospital,
the Albert Einstein College of Medicine, and the
University of Texas MD Anderson Cancer Center
explained in supporting Sloan Kettering’s
unsuccessful en banc petition, the Federal Circuit’s
interpretation of § 112 “catches [them] in an
impossible bind for their ongoing and future
innovation efforts with [CARs] and other lifesaving
biotechnologies” and “harm[s] innovation without any
corresponding benefit to the public.” C.A.Dkt. 93 at 4.
The Association of University Technology Managers
and Amgen, a leading biotechnology company, jointly
concurred, noting that the Federal Circuit’s
interpretation “harms first movers in the biologics
field and does not reward pathbreaking innovation.”
C.A.Dkt. 94 at 9. As City of Hope put it, the Federal
Circuit’s “interpretation of the written description
requirement will have the unintended effect of
jeopardizing the development of biopharmaceutical
therapies at City of Hope and other research
institutions,” and, ultimately, “patients will lose.”
C.A.Dkt. 95 at 1, 8.
Sloan Kettering and these other centers of
innovation serve society and promote the useful arts
more effectively by researching the next breakthrough
cancer treatment than by conducting rote work to,
e.g., characterize unnecessary, additional scFvs. But
if they forgo this unproductive path, they lose any
hope of meeting the Federal Circuit’s test, and cannot
secure the patent protection that the Framers and
Congress intended to spur innovation, and that, in
 33

turn, can produce funds for further groundbreaking

research.
Indeed, in situations like the one here, the Federal
Circuit’s test will frequently be impossible to meet.
Here, although only one functioning scFv against a
target antigen of interest, such as CD19, is needed to
practice the invention, Sloan Kettering would have to
waste years making and testing an essentially infinite
number of scFvs to try to demonstrate possession of
all scFvs that could be used with its inventive
backbone. For inventions that have components with
thousands, millions, or billions or more possible
formulations and inherent variability, “[n]o matter
how much testing the patentee does, there will always
be untested species, and because those species aren’t
tested, the [skilled artisan] won’t know whether they
are properly included in the genus, so the claim would
fail written description” under the Federal Circuit’s
test. KLS, supra, 35 Harv. J. L. & Tech. at 63. Large
and naturally occurring variation, which arises
frequently in the biological arts, also prevents
inventors from obtaining meaningful protection by
claiming only specific embodiments, since copyists
could easily use routine modifications from the
specific embodiments claimed. It also makes it
impossible to predict a priori all molecular structures
that may perform a particular biological function,
such as all scFv structures that bind to a particular
antigen, thus rendering cold comfort the Federal
Circuit’s assurances that representative examples are
unnecessary if the inventor provides a structure-
function relationship. See Ariad, 598 F.3d at 1350.
This case illustrates the peril inventors face.
Nobody disputes that Dr. Sadelain’s team discovered
 34

a groundbreaking cancer-fighting tool, nor that Sloan

Kettering disclosed this valuable tool and thereby
added to the store of human knowledge, nor that those
in the field would practice the invention by either
using an already-known scFv (as Kite did for its
conceded infringement) or employing the Orlandi
method to produce an appropriate, working scFv that
binds to the selected target antigen. Nor does
anybody dispute that Kite understood the patent and
copied Dr. Sadelain’s inventive backbone. Applying
the undisputed clear-and-convincing-evidence
standard to Kite’s challenge, the jury and district
court found no fault with the Patent Office’s
conclusion that the patent adequately described the
invention and permitted the person of skill in the art
to make and use it.
Kite, however, exploited the Federal Circuit’s
increasingly draconian glosses on its “separate”
“written description” requirement as a way to escape
liability for its willful infringement. In the process, it
destroyed Sloan Kettering’s patent—which was
supposed to be the reward for Sloan Kettering
upholding its end of the bargain by publicly disclosing
its invention. If the Federal Circuit were really right
to set aside the jury’s verdict as a matter of law
because the applicants failed to demonstrate
“possession” of all “known and unknown” variations of
the scFv component, see Pet.App.13a, inventors like
Dr. Sadelain and his team could never reliably secure
meaningful patent protection. To “deprive [the
inventor] of the benefit of his invention” in this way
“would foster concealment rather than disclosure of
inventions,” thereby undermining “one of the primary
 35

purposes of the patent system.” Graver Tank & Mfg.

Co. v. Linde Air Prods. Co., 339 U.S. 605, 607 (1950).
4. While the problem is currently most acute in
Federal Circuit jurisprudence involving the biological
arts, it threatens to metastasize to other fields as well.
The Federal Circuit has said it “eschew[s] judicial
exceptions to the written description requirement
based on the subject matter of the claims.” Amgen Inc.
v. Sanofi, 872 F.3d 1367, 1379 (Fed. Cir. 2017). And
the biological arts are far from the only field in which
inventions involve wide variability in some sense. For
example, Professor Lefstin points to the simple
example of a patent claim directed to a chair (“An
object for supporting a human body, comprising [¶] a
substantially flat surface sized to accommodate a
human posterior and [¶] four legs supporting said
surface.”), and observes that even that simple claim
encompasses an “infinite variety of embodiments,”
both known and unknown, because it does not account
for the possibility that the chair might be made of
specific materials not yet known or available. Jeffrey
A. Lefstin, The Formal Structure of Patent Law and
the Limits of Enablement, 23 Berkeley Tech. L.J.
1141, 1168-71 (2008). Under a “written description”
test requiring “possession” of all “known and
unknown” embodiments, see Pet.App.13a, that claim
would be invalid.
Or, consider a patent claim to an electronic device
that includes an “electrical charging cord” limitation,
and whose written description gives the twin
examples of a cord with (i) a two-prong connection to
a household electrical outlet and (ii) a USB-A
connection. Under the Federal Circuit’s approach,
that claim would be invalid for failure to describe
 36

existing but well-known and smaller USB-C plugs, let

alone for its failure to anticipate not-yet-available
(and therefore not-yet-known) electrical connections.
By its terms, the Federal Circuit’s “possession” test
would invalidate those claims, too.
Just as such a regime would stymie innovation in
the electrical arts, it does the same in the biological
arts. And just as that cannot be the law in the
electrical arts, it cannot be the law in the biological
arts.
III. THIS CASE IS AN IDEAL VEHICLE.
This case provides an excellent vehicle to take up
this legal question—whether a patent’s disclosure
must not only provide an enabling written
description, but also satisfy the Federal Circuit’s
“separate,” atextual “possession” requirement. And
this case is unburdened by the vehicle issues affecting
prior petitions. See Idenix Pharms. LLC v. Gilead
Scis., Inc. (No. 20-380) (Federal Circuit also found
enablement lacking); Amgen Inc. v. Sanofi (No. 18-
127) (questions regarding mootness and interlocutory
posture); Janssen Biotech, Inc. v. Abbott Labs. (No. 11-
596) (claims at issue were later-added).
Recent en banc practice in the Federal Circuit
confirms that further percolation of the issue in that
court will not solve the problem. Indeed, the addition
of gloss after gloss on the “written description”
requirement has produced disagreement over its
contours to such a degree that three judges recently
voted to grant en banc review of a decision that, in
their view, “imports extraneous considerations into
the written description analysis and blurs the
boundaries between the written description
 37

requirement and the other statutory requirements for

patentability,” thereby “muddying … the written
description requirement.” Biogen Int’l GmbH v.
Mylan Pharms Inc., 28 F.4th 1194, 1196 (Fed. Cir.
2022) (Lourie, J., joined by Moore, C.J. and Newman,
J., dissenting from denial of rehearing en banc). At
the same time, however, those three judges reiterated
their support for Ariad’s general rule. Id. at 1199. In
combination with the denial of rehearing en banc in
the present case, and the fact that this issue can arise
only in the Federal Circuit, that statement makes
clear that the needed course correction will have to
come from this Court.
In short, the numerous amici in this case, the
underlying substance of other petitions, and academic
and industry commentary all reflect the increasing
drumbeat of the need for this Court’s intervention.
Both the time and the vehicle are ripe for the Court to
take up this critically important issue.
CONCLUSION
The petition for a writ of certiorari should be
granted.
 38

June 13, 2022 Respectfully submitted,

HENRY HADAD GREGORY A. CASTANIAS

J. PATRICK ELSEVIER Counsel of Record
PETER NOH NOEL J. FRANCISCO
BRISTOL MYERS SQUIBB JENNIFER L. SWIZE
Route 206 & Province JONES DAY
Line Road 51 Louisiana Ave., NW
Princeton, NJ 08543 Washington, D.C. 20001
(202) 879-3939
MORGAN CHU gcastanias@jonesday.com
ALAN J. HEINRICH
ELIZABETH C. TUAN ANDREA W. JEFFRIES
IRELL & MANELLA LLP JONES DAY
1800 Avenue of the Stars 555 South Flower Street
Suite 900 Los Angeles, CA 90071
Los Angeles, CA 90067
MATTHEW J. RUBENSTEIN
ANDREI IANCU JONES DAY
IRELL & MANELLA LLP 90 South Seventh Street
750 17th Street NW Suite 4950
Suite 850 Minneapolis, MN 55402
Washington, DC 20006
LISA L. FURBY
JONES DAY
110 North Wacker Drive
Suite 4800
Chicago, IL 60606

Counsel for Petitioners

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1996 SCC OnLine Cal 145 : AIR 1996 Cal 367 : (1997) 1 Cal LT 123 : (1996) 2
AP LJ (DNC) 62 : (1997) 17 PTC 756 : (1996) 23 CLA (SN) 39 : (1995-96) 100
CWN 562

BEFORE NISITH KUMAR BATABYAL, J.

Hindusthan Lever Limited … Petitioner;

Versus
Godrej Soaps Limited and others … Respondents.
Suit No. 245 of 1993
Decided on April 11, 1996
ORDER
1. This hearing arises out of an application for temporary injunction filed on behalf
of the plaintiff. In the suit the plaintiff prays for leave under Clause 12 of the Letters
Patent. Decree for permanent injunction restraining the defendants, their servants,
agents, and assignees etc. from in any way in fringing or attempting to infringe Patent
No. 170171 of the plaintiff; Decree for permanent injunction restraining the
defendants, their servants, agents etc. from in any way manufacturing, selling or
offering for sale or advertising any toilet soap bearing the Trade Mark ‘VIGIL’ or any
other trade mark and having the composition that is covered under and or within the
range of Patent No. 170171 of the plaintiff. Delivery upon oath of all toilet soaps
already manufactured and in possession, power and custody of the defendant No. 1
and/or the defendants Nos. 2 and 3 and/or their agents and servants that in any way
infringe and/or have been manufactured in accordance with the Patent No. 170171 of
the plaintiff and marked under the trade mark ‘VIGIL’ or any other trade mark etc.
etc., a Decree directing the defendants to render a true and faithful account in respect
of the infringed soaps manufactured by the defendant No. 1 and sold by the
defendants that are in accordance with the Patent No. 170171; a Decree for Rs.
10,00,00,000/- and in the alternative, an enquiry into the loss and damage suffered
by the plaintiff and decree for the amount found due upon such enquiry etc. etc.
2. The petitioner/company is engaged in the manufacture of various kinds of soaps,
detergents, cleaning preparations, chemicals, fertilisers, etc. and is a leading
manufacturer in this country, of soaps and detergent and their products are sold under
different brands and enjoys considerable goodwill and reputation. The respondent No.
1 also carries on business of manufacture of various brands of soaps and detergent
and is one of the competitors of the plaintiff-company. The respondent

Page: 369

No. 2 is a Company which has been incorporated recently and is a collaboration of two
Companies, i.e., respondent No. 1 and Proctor and Gamble India Ltd. which is a
subsidiary of an American Company having its Headquarters in U.S.A. The respondent
No. 3 is one of the distributors of the respondents Nos. 1 and 2 for sale of their
products in an around the city of Calcutta. The plaintiff/petitioner holds and owns
more than one hundred and seventy active Patents granted by the Government of
India under the Patents Act for inventions in different fields including detergents,
soaps, their process of manufacture etc. etc.

3. On or about 21st September, 1988 the petitioner-company made two

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applications for Patent in respect of an invention relating to detergent bars suitable for
personal bathing or fabric washing under application No. 275/BOM/88 and the
improved process for preparing detergent bars suitable for personal or fabric washing
under application No. 274/BOM/88. The said two applications were accepted for grant
and the acceptances were notified in the Official Gazettes. The Patent Application No.
275/BOM/88 which was accepted under Serial No. 170171 was duly granted and
sealed by the Controller after the disposal of the proceedings under Sec. 27 of the
Patents Act, 1970 initiated at the instance of the defendant No. 1, before the Deputy
Controller of Patents, Bombay. The respondent No. 1 filed opposition proceedings
against the Patent Application No. 274/BOM/88 accepted and published under Serial
No. 170480 and the opposition was pending before the Dy. Controller of Patents,
Bombay. After hearing the parties the Dy. Controller of Patents, Bombay, directed the
Patent Application No. 170171 to proceed to sealing and accordingly the Patent was
granted and sealed on 23rd April, 1993. The petitioner has duly deposited the overdue
as well as current renewal fees upon the sealing of Patent No. 1701 and the Patent is
at present valid and subsisting. Upon acceptance of the said application, the
specification of other documents relating to the said two Patent Applications were laid
upon to public and thus, all the information relating to the inventions were made open
to the public.
4. The petitioner-company had at the material time and still has a Committee of
Senior Managers which review the quality of its product and also the quality of its
competitors' products on a regular basis. The respondent No. 1 is the manufacturer of
a bathing bar and/or a soap named ‘VIGIL’ which is marked by the respondent No. 2
and distributed by the respondent No. 3. The said Committee of the petitioner upon
finding that the said product ‘VIGIL’ had the legend ‘ALL NEW” and “THE LONGER
LASTING SOAP” caused the said product ‘VIGIL’ to be analysed to ascertain its
composition. The personal washing bar ‘VIGIL’ (also called a toilet soap) with
manufacturing dates of January, February and April, 1993 were analysed at the
petitioner's laboratories and the petitioner came to know that the composition of the
said bathing soap ‘VIGIL’ was within the range of all or some of the claims of Patent
No. 170171 of the petitioner which stands sealed and granted. A copy of the analysis
report has been annexed with the application of injunction and marked with the letter
“C”.
5. By reason of the Patent Specification No. 170131 of the petitioner, the patentee
enjoys exclusive right and monopoly in respect of the composition consisting of:—
(i) 25 to 60% by wt. detergent of which at least 50% by wt. is soap.
(ii) 40 to 55% water insoluble structurant including starch and having a particle
size of between 0.2 to 30 um. and,
(iii) 8 to 15% by wtc. water.
6. The respondents had access to the specification of Patent No. 170171 since the
notification after acceptance, i.e., on 15th February, 1992 and they have wrongfully
and illegally copied and materially utilised and reproduced the composition of the said
Patent No. 170171 and have thus wrongfully and illegally infringed the said Patent of
the petitioner.
7. The toilet soap of the respondents sold under the trade mark ‘VIGIL’ has a
wrapper

Page: 370

which also bears the words “ALL NEW” very prominently and distinctly together with
the words “The LONGER LASTING SOAP” is to make the trade and public believe that
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the toilet soap is an improved product. The said soap is available throughout the
country including Calcutta through almost all retail outlets and the respondents have
taken wrongful advantage of the publication of the invention of the petitioner under
Patent No. 170171 and Patent Application No. 274/BOM/88 in the Official Gazette
notified for opposition purposes. On examination of the wrappers of the aforesaid
samples of the toilet soap of the respondents, it is found that there is no mention of
the TFM (Total fatty matter) content of the soap. It is usual in the trade to mention the
TFM level and different soap manufacturers including the respondent No. 1 and the
petitioner indicate all TFM level of the TFM in the wrappers. The respondents Nos. 1
and 2 have deliberately and with a mala fide motive suppressed the use of the low
TFM in the impugned product in view of the consumer perception on high TFM level.
The respondents have not indicated the TFM level of the impugned toilet soaps in the
wrappers as the petitioner's said Patent No. 170171 is the invention of a composition
of detergent bars containing low TFM but having satisfactory properties.

8. By reason of the aforesaid wrongful and illegal acts of the respondents the
petitioner company has suffered an irreparable loss, damage, injury and prejudice.
There exists no standard for ascertaining the actual damage caused or likely to be
caused to the petitioner company and if the respondents are permitted to carry on and
continue with its wrongful and illegal acts, compensation in money could not be afford
adequate relief to the petitioner.
9. Hence the prayers for temporary injunction as follows:—
“(a) an order of injunction restraining the respondents, their servants, agents etc.
from in any way infringing the Patent No. 170131 of the petitioner;
(b) a temporary injunction restraining the respondents, their servants, agents etc.
from manufacturing, selling etc., the impugned bathing bar Vigil with the words
“ALL NEW” AND “THE LONGER LASTING SOAP” which uses and/or utilises the
composition of the Patent No. 170131 of the petitioner; and
(c) such further or other orders be made as the Court may deem fit and proper.
10. In the affidavit-in-opposition on behalf of the respondent No. 1, it has been
stated that the respondent No. 1 is a multinational company and a competitor to the
plaintiff in soap industry. The first respondent is a pioneer in the field of manufacture
and sale of Toilet Soaps in India for the last 60 years. Since 1987 the first respondent
has been manufacturing and selling the brand of low-priced popular Toilet Soap under
the Trade Mark “VIGIL”. Since November, 1991 they have been selling the Toilet Soap
under the same Trade Mark “VIGIL” with a variant ‘Pink’. The said product is sold in a
wrapper and bears the words “All New” and the words “The Longer Lasting Soap”. The
said soap is marketed all over India by the second respondent through a net-work of
2000 stockists.
11. Although the first respondent has been utilising various admixtures for various
soaps, they did not apply for or obtain any patent for such admixture as a substance
obtained by a mere admixture is not an invention within the meaning of Section 3(e)
of the Patents Act, 1970. According to the respondent No. 1, the alleged invention
under the Patent No. 170131 of the plaintiff is a mere admixtures and is not an
invention as claimed by them. The first respondent has challenged the order passed by
the Deputy Controller of Patents, Bombay by filing an appeal being Misc. Petition No.
24 of 1993 in the Bombay High Court, that matter is still pending.
12. It has been further stated that the plaintiff and the first respondent and second
respondent have then registered offices in Bombay, the impugned application No.
170131 of the plaintiff-petitioner for registration of their invention was filed in the
Patent Office at Bombay and the impugned order of the
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Deputy Controller of Patent was also passed in Bombay. The appeal from the said
order of the Deputy Controller of Patents, Bombay is now pending in the High Court of
Judicature at Bombay. Still the plaintiff-petitioner has filed the suit in Calcutta High
Court so that the respondents are embarrassed and are compelled to come over to this
place without any allegations that the petitioner or their agents had purchased any
sample of the soap ‘VIGIL’ at Calcutta. The next contention of the objector, respondent
is that the impugned Patent of the petitioner has been sealed recently. The law is well
settled that the Courts will refuse to grant injunction and at any rate interim injunction
when the patent in question is a new one the validity of which has not been
established in any legal proceedings and the validity whereof is under serious dispute
or challenge. When the patent which is sought to be enforced is a recent one, an
interlocutory injunction should not be granted. It has also been submitted that the
petitioner has not manufactured and marketed any low-priced popular soap using the
composition of the alleged patent. Whereas the respondent No. 1 has been
manufacturing and selling such low priced popular soap for a long time. If an order of
injunction as prayed for by the petitioner is passed, it would cause extreme hardship
on the first respondent leading to a situation of impossibility of compliance with the
order, keeping valuable labours and equipments of production idle.

13. It has been stated in the objection that purported expert opinions which have
been filed with affidavits in support of the petitioner for injunction by the plaintiff are
suspect. The purported expert opinion by way of three affidavits are guilty of making
false statements on oath. In the analysis report referred to in the affidavit of Mr.
Chittaranjan Mitra, “insoluble matter of alcohol” is mentioned. In the analysis report
annexed to the affidavit of Prof. Dr. Chakraborty, the very same matter is mentioned
as “Matter Insoluble” and in the report of Messrs. Jewel Metelochem Laboratories,
Bombay, the tests have been done for “alcoholic insoluble” matters and pot for “Water
Insoluble Matter”. It has been further ascertained that the plaintiff-petitioner has no
lawful right, title or interest to prohibit the respondent No. 1 from using their alleged
process or alleged composition of the impugned Patent No. 170131. The respondent
No. 1 has denied that the analysis of ‘Vigil’ soap in Annexures 2 and 3 to the
injunction petition indicate a detergent and soap combination level between 40.8%
and 42% as alleged or which includes soaps at a level which is more than 50% of the
soap and detergent combination as alleged. None of the four reports relied on by the
petitioner indicates “Water Insoluble” matter which is the term in the impugned
patent.
14. It has been lastly submitted that if the petitioner is granted an injunction at
this stage then it would enable the petitioner to appropriate a large chunk of the soap
industry to itself and would result in stifling trade competition.
15. In support of their objections the respondent No. 1 have filed affidavit sworn by
Dr. V.V.R. Subrahmanyam who is also an expert in the field of chemical technology. In
his opinion, making detergent bars containing varying amounts of percentages of soap
including non-soap detergent and water insoluble fillers, including starch and varying
ranges of moisture (water) by plodding, is not new, but is a state-of-art technology, so
also use of additives like water-soluble polymers to improve the quality of detergent
bars, which fall under the category of ‘Combo Bars’ is known and is not new.
16. In the affidavit-in-reply filed on behalf of the plaintiff-petitioner the material
allegations made in the objection have been denied. It has been stated further that
the respondent No. 1 in the opposition have not disclosed the composition of the
impugned ‘Vigil’ soap. If the respondent No. 1 are not infringing the petitioner's
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patent, the simplest thing to do for the respondents would be to disclose the
composition. It has further been submitted that the proposition of law as made out in
the objection petition is based upon the earlier Patent Act, 1911. The English law on
the subject as laid down in Smith v. Grig, (1924) 1 KB 655, has been expressly not

Page: 372

followed by English Courts and has been overruled by the decision of the House of
Lords in the case of American Cynamide, 1975 RPC 513 : 1975 AC 396.

17. It has been also stated that in the objection, attention has been drawn to the
fact that the analysis report mentioned “Water Insoluble” and “Alcohol Insoluble”
whereas the Patent is for “Water Insoluble Particulate Structurant”. It is well known
that the BIS method for ascertaining water/alcohol insoluble particulate structurant is
normally through the route of alcohol and as such wherever the analysis has been
done in alcohol, the report mentioned “Alcohol Insoluble” and whenever the matter
insoluble has been indicated, the method of analysis has been indicated in the report
itself. It has also been stated that it is common knowledge that to ascertain water-
soluble to toilets bar, it has to be done in alcohol in order to ensure that all the soap is
dissolved in alcohol and fully removed but the starch in the process is not destroyed.
It is well known that the expression matter ‘insoluble’ indicated in the various reports
are nothing but water insoluble particulate structurant as given in the specification.
18. In the reply it has also been submitted the contention of the respondent No. 1
that they will suffer considerable hardship and irreparable loss and prejudice by the
grant of injunction petition no prayer has been made for stopping of manufacture and
sale of ‘Vigil’ soap manufactured by the respondent No. 1 but the only prayer is that
the respondents should be restrained from using the plaintiffs patent in the
manufacture of the said soap. So there is no question of exploiting a monopolistic
situation. Whereas in the reply it has been stated that the report, of Dr.
Subramanayam suffers from contradiction and lack of reasoning. It has been stated
that Dr. Subramanayam has conceded that the composition is a “State-of-art
technology”. The composition which is a “State-of-art technology” meaning “today's
technology” cannot be thirty years old. It has also been stated that the water soluble
polymer is not an essential part of the petitioner's patent. It has been submitted that
no reliance should therefore be placed on the report of Dr. Subramanayam overriding
the opinion given by the expert of the petitioners.
19. On 12-7-1993, a learned Judge of this Court, on the petition for temporary
injunction, passed an interim order in terms of prayer (c) of the petition restraining
the respondents, their servants, etc. from manufacturing, selling or marketing or
advertising the impugned bathing soap ‘Vigil’ with the words “ALL NEW” AND “THE
LONGER LASTING SOAP” which utilises the process of composition of Patent No.
170131 of the plaintiff-petitioner or any composition which comes within the range
covered by the said patent.
20. On 21st July, 1993, the learned Judge on hearing the parties passed the
following order:—
“It has ordered that the defendants will be at liberty to sell soaps wherein TFM i.e.
total fatty matter percentage is mentioned but will not sell any soap infringing the
composition of the plaintiff's patent bearing No. 170131. Earlier interim order is
modified to this extent only. Defendants will file their affidavit-in-opposition by
26th July, 1993; plaintiff will file reply by 28th July, 1993 and the injunction matter
will come up for hearing as a ‘Specially Fixed Matter’ on 29th July, 1993.”
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21. Against that order two appeals were taken. One by Godrej Soaps Ltd. and the
other by Procter and Gamble Godrej Ltd. The learned Appellate Court on hearing the
parties was pleased to pass the following order:—
“We, therefore, allow this appeal and set aside the orders under appeal. However,
we direct that the appellants shall keep separate accounts of the manufacture and
sale of the impugned product and furnish monthly statements of such manufacture
and sale to the Advocate-on-Record of the plaintiff. We make it quite clear that we
have not expressed any opinion on the merits of the contentions. We were only
concerned to decide whether at this stage any temporary injunction should be
granted or not. The Court of the first instance

Page: 373

will decide the issues raised after completion of the affidavits.”

22. Against that order an SLP was filed in the Apex Court being SLP (Civil) No. (S)
13082/93. Their Lordships were pleased to record the following order:—
“We are not inclined to interfere with the impugned interim order passed by the
Division Bench of the High Court. We, therefore, request the learned trial Judge to
dispose of the original petition within three months from today. In case the petition
is not disposed of within the said period, then the further continuance of the interim
order shall be reconsidered by the trial Court on the basis of the affidavits already
placed on record, uninfluenced by any observations on fact or law made by the
Division Bench of the High Court. With this observation the Special Leave Petition is
disposed of.”
Matter has now come up before this Court for disposal of the petition for temporary
injunction.
23. The principles upon which an interlocutory injunction may be granted in a
patent case are the same as in a case under the provisions of Order 39, Rules 1 and 2
of the Civil Procedure Code, though interim injunction restraining the defendant from
infringing a patent does not come strictly within this scope of Order 39. The plaintiff in
a patent case must show a prima facie case of an infringement and further that the
balance of convenience and inconvenience is in his favour. In patent cases the onus of
showing a prima facie case justifying the grant of an injunction is a heavy one and it is
comparatively easy for the respondent to establish a defence sufficient to prevent the
grant of such an injunction. In Hubbard v. Vosper, (1972) 1 All ER 1023 : (1972) 2 QB
84 at 1029, Lord Denning observed:— “In considering whether to grant an
interlocutory injunction, the right course for a Judge is to look at the whole case. He
must have regard not only to the strength of the claimant but also to the strength, of
the defence, and then decide what is best to be done. Sometimes, it is best to grant
an injunction so as to maintain the status quo until the trial. At other times, it is best
not to impose a restraint on the defendant, but leave him free to go ahead. For
instance, in Frazer v. Evans, (1969) 1 All ER 8, although the plaintiff owned the
copyright, we did not grant an injunction, because the defendant might have a
defence of fair dealing. The remedy by interlocutory injunction is so useful that it
should be kept flexible and discretionary. It must not be made the subject of strict
rules.”
24. Mr. Chakraborty, Ld. Sr. Counsel, appearing on behalf of the plaintiff-petitioner
has submitted that the patent application No. 275/BOM/88 which was accepted under
SI. No. 170171 was duly granted and sealed by the Controller of Patents of Bombay.
According to the Ld. Lawyer, Patent Application No. 274/BOM/88 published under Sl.
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No. 170480 was considered along with the objection filed by the Respondent No. 1
thereto by the Dy. Controller of Patents of Bombay, who directed the Patent
application to proceed to sealing and accordingly, the patent was granted and sealed
on 23rd April, 1993. The petitioner/Company has duly deposited the entire dues upon
the sealing of Patent No. 170171 and the patent is still valid and subsisting. It has
accordingly been submitted by the Ld. Counsel that his client has been able to prove
that there is a prima facie case for granting of an interlocutory injunction in this case.
25. So far as infringement of patent and the balance of convenience are concerned,
it has been submitted on behalf of the petitioner/company that the respondent No. 1,
the manufacturer of a Bathing soap and/or a soap named ‘VIGIL’ which is marketed by
the respondent No. 2 and distributed by the Respondent No. 3 on chemical analysis
was found coming within the range of all or some of the claims of Patent No. 170171
of the petitioner. As a result of the wrongful and illegal acts of the respondents, the
petitioner-company has suffered irreparable loss, damage, injury and prejudice. There
exists no standard for ascertaining the actual damage caused or likely to be caused to
the petitioner and if the respondents are permitted to carry on or to continue with the
wrongful and

Page: 374

illegal acts, compensation in money would not afford adequate relief to the petitioner.
Therefore, the damage is irreparable and the balance of convenience or inconvenience
is definitely in favour of the petitioner.

26. Mr. Goutam Chakraborty, learned counsel for the petitioner-company has relied
upon the following cases in support of his contention. He has heavily relied upon the
principles laid down in American Cyanamid Company v. Ethicon Ltd., (1975) RPC
513 : 1975 AC 396 : 1975 (1) All ER 504. In that celebrated judgment, Lord Diplock
at p. 539 made the following observations:—
“The instant appeal arises in a patent case. Historically there was undoubtedly a
time when in an action for infringement of a patent that was not already “well
established”, whatever that may have meant, an interlocutory injunction to restrain
infringement would not be granted if counsel for the defendant stated that it was
intended to attack the validity of the patent.
“Relies of this reluctance to enforce a monopoly that was challenged, even though
the alleged grounds of invalidity were weak are to be found in the judgment of
Scutton L.J., as late as 1924 in Smith v. Grigg Ltd., (1924) KB 655; but the
elaborate procedure for the examination of patent specifications by expert
examiners before a patent is granted, the opportunity for opposition at that stage
and the provisions for appeal to the Patent Appeal Tribunal in the person of a Patent
Judge of the High Court, make the grant of a patent now-a-days a good prima facie
reason, in the true sense of the term, for supporting the patent to be valid and have
rendered absolute the former rule of practice as respects interlocutory injunctions in
action for infringement actions. In my view the grant of interlocutory injunctions in
actions for infringement of patents is governed by the same principles as in other
actions……”
27. Mr. Chakraborty, learned counsel has submitted that in view of the above
decision of the House of Lords, the view taken by a Division Bench of this Court in
Boots Pure Drug Co. v. May & Baker Ltd, (52 CWN 253) should be taken as not laying
down the correct principle of law. In that case, it was held that in order to get a
temporary injunction against the infringement of a patent right, it is necessary that
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the plaintiffs should prove three things:—

(a) that they have a prima facie right, that is to say, they have such evidence as
would lead the court to come to the conclusion that the patent is prima facie a
valid patent;
(b) they must prove by prima facie evidence that there has been an infringement
on the part of the defendant; and
(c) that the balance of convenience is in favour of the plaintiffs.
28. As regards condition (a) it is a rule of practice (emphasis added) that if a
patent is a new one, a mere challenge at the Bar would be quite sufficient for the
refusal of a temporary injunction, but if the patent is sufficiently old and has been
worked, the court would, for the purpose of a temporary injunction, presume the
patent to be a valid one. If the patent is more than 6 years old and there has been
actual user it would be safe for the court to proceed upon this presumption.
29. Mr. Chakraborty, learned counsel has also cited Continental Paper Bag Co. v.
Eastern Paper Bag Co., (1907) 210 US 1122 : 52 Law Ed 405, to show that even in
case of non-user of a patent, it is quite competent for the court to grant injunction. In
that case, the U.S. Supreme Court held, non-user of a patent, at least, if such non-use
is not unreasonable and does not involve its rights of the public, will not justify the
court of equity in withholding injunctive relief against infringement. Mr. Chakraborty,
learned counsel has referred to this case presumably because the petitioner company
in our case has not yet used the patent. The learned counsel in his inimitable style has
put the crux of the problem in the following way: I have kept my newly acquired
house vacant but you cannot trespass into it.
30. Mr. Chakraborty, learned counsel has cited Biswanath Prasad Radhey Shyam v.
H.M. Industries (AIR 1982 SC 1444). He has

Page: 375

drawn the attention of this court to para 15 at p. 1447 which runs as follows:

“15. As against this, Mr. Mehta, appearing for the respondent, submits that whether
the process got patented by the respondent involves a method of near manufacture
or improvement, is one purely of fact and should not as a matter of practice, be
disturbed by this court. Even in cases of doubt — proceeds the argument — the
court should uphold the patent. It is submitted that a patent is granted by the
controller after due inquiry and publication and unless the contrary is proved,
should be presumed to have been duly granted. In the instant case, it is urged,
that presumption is stronger because the trial Judge as well as the Appellate Bench
of the High Court have concurrently held that the process patented had utility.”
31. Mr. Chakraborty, learned counsel, in his usual fairness, has also drawn the
attention of this court to para 33 at p. 1450, of the reported judgment which runs as
follows:
“33. It is noteworthy that the grant and sealing of the patent, or the decision
rendered by the Controller in the case of opposition, does not guarantee the validity
of the patent which can be challenged before the High Court on various grounds in
revocation or infringement proceedings. It is pertinent to note that this proposition,
viz., the validity of a patent is not guaranteed by the grant, is now expressly
provided in S. 13(4) of the Patents Act, 1970. In the light of this principle, Mr.
Mehta's argument that there is a presumption in favour of the validity of the patent
cannot be accepted”.
32. Mr. S.B. Mukherjee, learned counsel appearing, on behalf of the Soaps Ltd. has
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opposed the contention of the learned counsel for the petitioner. He has first drawn
the attention of the Court to the meaning of the term ‘patent’ as given in standard
vocabularies and legal dictionaries. He has drawn the attention of the Court to
Halsbury's Laws of England, 4th Edition, Vol. 35 (1981), para 303 which runs as
follows:— The word ‘Patent’ as used in this title denotes, a monopoly right in respect
of an invention.”
33. Mr. Mukherjee, has then drawn the attention of the Court to page 329, under
the heading ‘Patent’ of ‘Words and Phrases’, Legally Defined, 3rd Edn., Vol. 3, K-Q,
edited by John B. Saunders (1989) which runs as follows:— “The truth is that letters
patent do not give the patentee any right to use the invention — they do not confer
upon him a right to manufacture according to his invention. That is a right which he
would have equally effectually if there were no letters patent at all; only in that case,
all the world would equally have the right. What the letters patent confer is the right
to exclude others from manufacturing in a particular way, and using a particular
invention”.
34. He has next drawn the attention of the Court to Black's ‘Law Dictionary’, 6th
Edition (1990), at p. 1125, where ‘Patent right’ has been defined as “a right secured
by patent; usually meaning a right to the exclusive manufacture, use and sale of an
invention or patented article”.
35. Mr. Mukherjee has also drawn the attention of the Court to the meaning of the
expression ‘privilege’ at page 1197 of the said Dictionary which runs as follows:— “A
particular and peculiar benefit or advantage enjoyed by a person, company or class,
beyond the common advantages of other citizens. An exceptional or extraordinary
power of exemption. A peculiar right, advantage, exemption, power, franchise or
immunity held by a person or class not, generally possessed by others”.
36. Mr. Mukherjee, has also drawn the attention of the Court to the meanings of the
expressions ‘Patent’ and ‘Privilege’ as given in ‘The New Shorter Oxford English
Dictionary’ edited by Lesley Brown, Vol. 2, N-Z (1993) at pp. 2121 and 2360. — In
this Dictionary, ‘patent’ ‘is a document constituting letters patent, especially a licence
from a government to an individual or organisation conferring for a set period, the sole
right to make, use, or sell some process or invention, a right conferred in this way’.
The term ‘privilege’ has been interpreted as meaning a right, advantage or immunity
granted to or enjoyed by a

Page: 376

person or a class of people beyond the usual right or advantages of others.

37. Mr. Mukherjee has drawn the attention of the Court to S. 48(1) of the Patents
Act, 1970, where the term ‘exclusive right’ has been substituted in place of the term
‘exclusive privilege’ used in S. 12(1) in the Indian Patents and Designs Act, 1911. It
has been submitted by him that the substitution of the expression ‘privilege’ by the
expression ‘right’ has not made much of a difference because a ‘privilege’ is nothing
more than a ‘right’ which is conferred by the crown. This aspect of right has been
explained in the Dictionary as stated above. This submission has been made by Mr.
Mukherjee, learned counsel, especially to meet the point raised by Mr. Goutam
Chakraborty, learned counsel, appearing on behalf of the petitioner that under the Act
of 1911, Patent was only a privilege and not a right.
38. Moreover, Mr. Mukherjee, relying upon the decision in Bishwanath Prasad
Radheshyam v. H.M. Industries (AIR 1982 SC 1444) has submitted that the fact that
the controller has granted patent does not give rise to a presumption in favour of the
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validity of the patent. The grant and sealing of the patent or the decision rendered by
the Controller in the case of opposition does not guarantee the validity of the patent
which can be challenged before the High Court on various grounds in revocation or
infringement proceedings. This position, i.e., the validity of a patent is not guaranteed
by the grant, is now expressly provided in S. 13(4) of the Patents Act, 1970.
39. Mr. Mukherjee has also submitted that the order of the Dy. Controller of Patents
at Bombay for registration of the invention filed in the Patent Office as per Application
No. 170131 has been challenged in appeal by the respondents Nos. 1 and 2 and the
said appeal is now pending before the Hon'ble High Court at Bombay.
40. Mr. Mukherjee, has further submitted that the impugned patent of the
petitioner has been sealed recently and that the law is well-settled that the Courts will
refuse to grant injunction and at any rate interim injunction when the patent in
question is a new one, the validity of which has not been established in any legal
proceeding and the validity of which is under serious dispute or challenge.
41. Mr. Mukherjee, learned counsel has first referred to the American Cyanamid
Company case, (1975) RPC 513 : 1975 (1) All ER 504 (supra) decided by the House of
Lords in 1974. In that case, the plaintiffs ware the owners of a patent covering sterile,
absorbable, surgical articles formed from PHAE, (Poly-hydroxyacetic ester). The
defendants manufactured a suture formed from a copolymer and were nearly ready to
launch it upon the British market. The plaintiff's alleged that it infringed their patent.
The trial Judge granted interlocutory relief. The Court of Appeal allowed the appeal
concluding simply that on the question of infringement, the plaintiff had not made a
strong prima facie case and that in consequence that was the end of any claim to
interlocutory relief. The question of balance of convenience was not considered.
42. Held, per Lord Diplock, the reminder of the House concurring:
(i) That there was no rule of law that precluded the grant of an interim injunction
unless upon the evidence adduced by both parties, the applicant had satisfied
the court that on the balance of probabilities the acts of the other party sought to
be enjoined, if committed, would violate the applicant's legal rights;
(ii) Unless the material available to the court at the hearing of the application for an
interlocutory injunction failed to disclose that the plaintiff had any real prospect
of succeeding in a claim for a permanent injunction at the trial, the Court should
go on to consider whether the balance of convenience lay in favour of granting or
refusing the relief that was sought;
(iii) That the grant of interlocutory injunctions in patent infringement actions was
governed by the same considerations as in other actions;

Page: 377

(iv)In contrast with former practice in relation to interlocutory relief in patent

infringement cases, the grant of a patent was in present times a good prima facie
reason for supposing a patent to be valid in this context.

43. Mr. Mukherjee has also relied upon the decision of our Apex Court in
Bishwanath Prasad Radhey Shyam's case, AIR 1982 SC 1444 (supra). According to
him, para 33 of the reported judgment lays down the Indian law. The last sentence of
para 33 takes the bottom out of the proposition that there is a presumption in favour
of the validity of a patent.
44. Mr. Mukherjee has drawn the attention of the Court to a single Bench decision
of the Delhi High Court in N.R.D. Corpn. of India v. D.I.C. & G. Mills Ltd. (AIR 1980
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Delhi 132). In that case, it has been held that for the grant of temporary injunction,
principles applicable to the infringement of patent actions are that there is a prima
facie case, that the patent is valid and infringed, that the balance of convenience is in
favour of grant of injunction and that the plaintiff will suffer an irreparable loss. The
learned Judge relied upon the same principles as laid down in Boots Pure Drug Co.'s,
52 CWN 253 (supra) though within the four corners of the judgment that decision is
not referred to.
45. Mr. Mukherjee has also referred to the decision of a Division Bench of Delhi High
Court is Niky Tasha India Pvt. Ltd. v. Faridabad Gas Gadgets Pvt. Ltd. (AIR 1985 Delhi
136). Their Lordships considered the American Cyanamid Company's case, (1975) RPC
513 : 1975 (1) All ER 504 (supra) and held, it is well-settled, both in India and in
England, that an interlocutory injunction will not normally be granted where damages
will provide an adequate remedy should the claim succeed. Furthermore, the Court will
not grant an interlocutory injunction unless satisfied that there is a real probability of
the plaintiff succeeding on the trial of the suit. Where the design is of a recent date,
no injunction should be granted. Moreso, when there is a serious question as to the
validity of the design to be tried in the suit and an application for cancellation has
been made.
46. Mr. Mukherjee has also cited Monsanto Company v. Coramandal Indag Products
(P) Ltd. (AIR 1986 SC 712). That was a case for revocation of a patent. Mr. Mukherjee
has presumably referred to the principles laid down in this case, as in our case, a point
has been raised by Godrej Co. that the plaintiff's patent suffers from lack of novelty
and from anticipation. In Monasanto's case, it has been held that to satisfy the
requirement of being publicly known as used in clauses (e) and (f) of S. 64(1) of the
Patents Act, 1970, it is not necessary that it should be widely used to the knowledge
of the consumer public. It is sufficient if it is known to the persons who are engaged in
the pursuit of the knowledge of the patented product or process either as men of
science or men of commerce or consumers. The section of the public who are men of
science or men of commerce were interested in knowing about herbicides which could
destroy weeds but not rice must have been aware of the discovery of the active agent.
There was no secret about the active agent as claimed by the plaintiffs since there was
no patent for the agent. The process was known, the product was known, the use was
known and then there was no invention.
47. Mr. Mukherjee has also referred to the following passage at p. 113 of Brain C.
Reid's “A Practical Guide to Patent Law”, 2nd Edition, (1993):
“Nevertheless, the grant of interlocutory relief is by no means automatic; it
remains, at the end of the day, an exceptional remedy given at the Court's direction
— for which exceptional cause has to be shown. The leading modern decision in this
area of the law generally, American Cyanamid v. Ethico (Interlocutory) was in fact
enunciated in a patent dispute in 1974.”
48. But the learned author at p. 116 of the same treatise has drawn the attention
to the danger inherent in mechanical application of the American Cyanamid approach:
“In particular, the Court will not allow the American Cyanamid approach (which in
principle is quite favourable to the patentee) to become by over-rigid application an
engine of oppression. This is highlighted by the

Page: 378

decision of the Court of Appeal in Brupat v. Sandford Masion Products (1983 RPC 61)
where a defendant of extremely modest financial standing (normally a good reason for
grant of relief since it gives rise to doubt as to their eventual capacity to pay damages
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if infringement is found at the trial) was allowed to continue provided that he pay in
the interim into an escrow account a reasonable royalty”.

49. Mr. Mukherjee has also referred to the treatise of Kerr on “Law and Practice of
Injunction” (6th Edn. 1981) where at p. 320 under the heading “Interlocutory Relief”
it has been pointed out as follows:—
“If one clear instance of infringement or a strong prima facie case of infringement is
made out and the plaintiff has not been guilty of laches, the court will generally
grant an interlocutory injunction in the following cases: (1) when the validity of the
patent has already been established in a previous action; (2) when the patent is of
old standing and the enjoyment under it has been uninterrupted; (3) when the
validity of the patent is not in issue; and notwithstanding that the defendant offers
to keep an account.
“Conversely, in general, if the patent is new, and its validity has not been
established, and endeavoured to be shown that it ought not to have been granted,
the Court will not interfere.”
50. Mr. P.K. Das, learned counsel appearing on behalf of the Proctor & Gamble
Godrej Ltd., defendant No. 2, has fully adopted the arguments of Mr. S.B. Mukherjee,
learned counsel for Godrej Soaps Ltd. Mr. Das has mainly argued on two new grounds
of attack.
51. The first point urged by Mr. Das is regarding forum inconvenience. Mr. Das has
drawn the attention of the Court to paras 30, 33, 35, 39 and 40 of the plaint and to
para 4 of the A.O. filed on behalf of respondent No. 2 and to para 7 of the affidavit-in-
reply at p. 352 of Vol. II of paper book. According to the learned counsel, the point to
be judged is whether the plaintiff would have more inconvenience in Bombay. He has
in support of his contention cited a number of cases.
52. The first case cited is Mac Shannon v. Rockware Glass Ltd., (1978) 1 All ER
625 : 1978 AC 795. Held, in order to obtain a stay of proceedings the defendant had
to show that there was another forum in which justice could be done between the
parties and to refuse a stay would produce injustice. He was under no duty to show
that the institution of the proceedings in England was vexatious or oppressive. Where
England was not the natural forum and the plaintiff offered no reasonable justification
for his choice of forum in the shape of some real personal or juridical advantage which
could be objectively demonstrated, the Court could grant a stay if the defendant
merely established that he would be involved in substantial inconvenience and
unnecessary expenses if the proceedings were allow in England.
53. He has next referred to In re Norton's Settlement, Norton v. Norton, (1908) 1
Ch D 471. Held, that the plaintiff had in fact brought the action in England instead of
in India, not for any bona fide purpose but in order to obtain an undue advantage over
the defendants and that the continuance of the proceedings in England would
necessarily be productive of injustice to the defendants. So the action ought to be
stopped.
54. He has also cited Saudi India Navigation Line v. Asteroid Maritime Ltd., (1985)
2 CHN 149; The Abidin Daver, (1984) 1 All ER 470 : 1984 AC 398; Logan v. Bank of
Scotland, (1906) 1 KB 141; Hansraj Bajaj v. The Indian Overseas Bank Ltd. (AIR 1956
Cal 33) and Jokai (Assam) Tea Co. Ltd. v. Bhawani Shankar (AIR 1976 Cal 18). In all
these cases, the same principle which is running like a thread is that the court would
stay a proceeding if it was not brought in the natural forum without any reasonable
justification and if the defendant merely established that he would be involved in
substantial inconvenience and unnecessary expenses if the proceeding was continued.
55. Mr. Das has next referred to the “Gillette” plea viz. that the alleged
infringement
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was not novel, at the date of the patent. In Gillette Safety Razor Co. v. Anglo-
American Trading Co. Ltd. (30 RPC 465) Lord Moulton observed: “I am of the opinion
that in this case the defendant's right to succeed can be established without an
examination of the terms of the specification of the plaintiffs letters patent. I am
aware that such a mode of deciding a patent case is unusual, but from the point of
view of the public it is important that this method of viewing their rights should not be
overlooked. In practical life, it is often the only safeguard to the manufacturer. It is
impossible for an ordinary member of the public to keep watch on all the numerous
patents which were taken out and to ascertain the validity and scope of their claims.
But he is entitled to feel secure if he knows that which he is doing differs from that
which has been done of old only in non-patentable variations. Such as, the
substitution of mechanical equipments or changes of material shape or size. The
defence that the alleged infringement was not novel at the date of the plaintiff's
letters patent was a good defence in law and it would sometimes obviate the great
length and expenses of patent cases if the defendant could and would put forth his
case in this form, and spare himself the trouble of demonstrating on which horn of the
well-known dilemma the plaintiff had impaled himself, invalidity or non-infringement”.

56. Mr. Das has cited the decision in Windsurfing International Inc. v. Tabur Marine
(Great Britain) Ltd., ((1985) RPC 59). In that case, the patent in suit claimed a wind-
propelled vehicle having an unstayed spar connected through a universal joint and sail
attached to the spar and held taut between a pair of arcuate booms mounted on the
spar at one end and joined together at the other. In an action for infringement, the
defendants claimed for its revocation on the grounds that what was claimed lacked
novelty over a prior user by C and was obvious in view either of the prior user or of a
printed publication D which described some basic concepts as that of the patent but
the said board had been fitted with a square-rigged sail. Held, upholding the
defendants' contention that (1) the philosophy behind obviousness must take into
account the same concept as anticipation, namely, that it would be wrong to prevent a
man from doing something which was known in the art before the priority date; (2)
the question of obviousness was not to be answered by looking with the benefit of
hindsight at what was now known and what had been known at the priority date and
asking whether the former flowed naturally and obviously from the latter, but by
hypothesising what would have been obvious at the priority date to a person skilled in
the art who had access to what was known in the art at that time. In that case, their
Lordships relied upon the principles laid down in Gillette case, 30 RPC 465 (supra).
57. Mr. Das then cited the decision in Hickman v. Andrews (1983 RPC 147). In that
case there were inconsistencies in the defendant's evidence as to how the prototype of
their product had come to be made. In addition, no contemporaneous corroborative
material had been put forward by the defendants to support their evidence on this
point. The balance of probabilities led to the conclusion that the defendant's product
had originated from use having been made of knowledge of the plaintiffs' “workmate”.
Since the standard of proof in a “Gillette” defence was steict, the defendants had
accordingly failed to make good their defence. Held that since approaching a patent
infringement action by means of the “Gillette” defence was unusual, it was justifiable
that the defence be strictly proved and accordingly the trial Judge had not misdirected
himself in this respect.
58. Mr. Das has also cited Page v. Brent Toy Products Ltd., (Vol. LXVII, Reports of
Patent, Design and Trade Mark Cases 4). In that action for infringement of patent, the
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defendants applied, after the case was set down for trial, for leave to amend their
defence so as to include a “Gillette” plea, viz. that the alleged infringement was not
novel, at the date of the patent, by reason of a foreign patent specification over 50
years old. It was stated on behalf of the plaintiff that the amendment was allowed and
the new plea disclosed a defence to the action, the action

Page: 380

would probably be discontinued. The learned Trial Judge held that the balance of
convenience required that the soundness in law of the proposed plea should be
decided upon the application to amend and not left to the trial. The learned Judge
decided the merits of the plea upon the application to amend. The learned Court of
Appeal upheld the view of the learned Trial Judge and explained the nature of
“Gillette” defence at page 12 as follows:—

“I think I should refer, not to the whole speech, but to certain passages in it, before
I add a few words of my own on the same line as Roxburgh, J's judgment. The
case, as may be judged from its title, was a case in which the Gillette Razor Co.
were alleging against the Anglo-American Trading Co. that the latter had infringed
the former's Latters Patent for a razor. It appears that one of the matters discussed
during the hearing was this, that there had previously been a razor handle,
invented by a gentleman called Burler; and as Lord Moulton points out, if you put a
blade into Butler's handle the article was indistinguishable for all practical purposes
from the defendants' allegedly infringing article. The noble Lord, having stated that,
goes on: “It follows, therefore, that no patent of date subsequent” to the
publication of Butler's specification could possibly interfere with the right of the
public to make the defendants' razor. If the claims of such a patent were so wide as
to include in it, the patent would be had, because it would include something which
differed by no patentable difference from that which was already in the possession
of the public. Such a patent would be bad for want of novelty. If the claims were
not sufficiently wide to include the defendants' razor, the patentee could hot
complain of the public making it. In other words, the defendants must succeed
either on invalidity or on non-infringement”.
59. From the submission made by the learned lawyer of the parties it is clear that
in order to get a temporary injunction against the infringement of a patent right, the
party claiming has to prove three things as in all cases for grant of temporary
injunction, namely, that the party has a prima facie case, that there is a prima facie
infringement and that the balance of convenience is in his favour. But right from
Smith v. Grigg Ltd., (1924 (1) KB 655), there was a practice that if a patent was new,
a mere challenge at the bar would be quite sufficient for refusal of temporary
injunction, but if the patent was sufficiently old and had been worked out, then the
Court would for the purpose of temporary injunction presume the patent to be a valid
one. This view as affirmed in a Division Bench decision of this Court in Boots Pure Drug
Co. (India) Ltd.'s case, 52 CWN 253 (supra). But this view received a jolt for the first
time in the American Cyanamid case, (1975) RPC 513 (supra). It was laid down by the
House of Lords that the grant of a patent now a days prima facie constitutes a good
ground for supposing the patent to be valid. But even the English Courts after about 8
years of the decision in this case (American Cyanamid case) have held that the Court
will not allow the American Cyanamid approach to become by over-rigid application an
engine of oppression. (Vide: ‘A Practical Guide to Patent Law’ by Brain C. Reid referred
to above). The learned author says that this is a leading modern decision in this area.
But the learned author has also drawn our attention to the decision of the Court of
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Appeal in 1983 in Brupat v. Sanford Marine Products, (1983) RPC 61 (supra)

highlighting this aspect of Lord Diplock's judgment.
60. Now let us have a look at the Indian Law on the matter. The Patents Act, 1970
has introduced some textual change in S. 12(1) of the Indian Patent and Designs Act,
1911. The term — “exclusive privilege” has been changed into “exclusive right” in S.
48 of the Act of 1970. A Division Bench of the Delhi High Court in Niky Tasha's case,
AIR 1985 Delhi 136 (supra) has observed as follows:
“In the leading case of American Cyanamid v. Ethicon, 1975 AC 396 : 1975 RPC
513 : 1975 (1) All ER 504, the House of Lords has stated the principles governing
the grant of injunction in patent litigation. According to

Page: 381

Lord Diplock, the correct approach is as follows: The Court must first be satisfied that
is a serious question to be tried. Then it should turn at once to the balance of
convenience. If it appears that damages awarded at the trial will adequately
compensate the plaintiff and the defendant is likely to be able to pay them,
interlocutory relief should not normally be granted. If damages will not be adequate to
compensate the plaintiff, becomes necessary to consider whether, on the other hand,
the defendant would be adequately compensated by damages upon the plaintiffs cross
-undertaking, should he not make good his claim at trial, if they would be adequate,
the injunction would be granted. If the balance remains substantially even, some
account can ultimately be taken of the relative strength of each party's case as
revealed by the Affidavit evidence”.

61. This Lordships took the view, “I take it to be well settled, both in India and
England, that an interlocutory injunction will not normally be granted where damages
will provide an adequate remedy, should the claim succeed. Furthermore, I have
always understood the rule to be that the Court will not grant an interlocutory
injunction unless satisfied that there is a real probability of the plaintiff succeeding on
the trial of the suit. When the design is of recent date, as in this case, no injunction
should be granted. More so, when there is a serious question as to the validity of the
design to be tried in that suit and an application for cancellation has been made”.
62. A Division Bench of this Court in Boots Pure Drug Co. case, 52 CWN 253 (supra)
also took the similar view in 1947. Since then the Indian Act was substituted by a new
Act in 1970. It has already been noted above that “exclusive privilege” in Section 12
(1) of the Act of 1911 has been changed into “exclusive right” in Section 48 of the Act
of 1970. The Apex Court of our land in Bishwanath Prasad Radhey Shyam, AIR 1982
SC 1444 (supra) at para 33, has held that there is no presumption in favour of the
validity of a patent by the mere grant or sealing of the patent. This is now expressly
provided in Section 13(4) of the Act of 1970.
63. This dictum of the Apex Court of our land clearly spells out the law in India on
the point and the ratio of the decision in American Cyanamid case, (1975) RPC 513 :
1975 AC 396 1975 (1) All ER 504 (supra) cannot govern the field here. Therefore the
contention of Mr. G. Chakraborty that the grant of patent in favour of his client shows
prima facie validity of the patent cannot be entertained.
64. The point which demands our active consideration next is which there is prima
facie infringement of plaintiffs patent. In para 23 of the petition for injunction it has
been stated as follows (at p. 78 of paper book No. I):—
“23. By reason of the aforesaid the petitioner as the patentee enjoy exclusive right
and monopoly in respect of the aforesaid composition consisting of.
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(i) 25 to 60% by wt. detergent of which at least 50% by wt. is soap;

(ii) 49 to 50% water-insoluble structurant including starch and having a particle
size of between 0.2 to 30m. and
(iii) 8 to 15% by wt. water.
The petitioner further states that no one else has any right to use the aforesaid
composition and/or to use a composition which comes within the scope and/or
range of the said Patent No. 170131 of the petitioner.”
65. In para 24 of the said petition, it has been stated as follows:
“24. The composition of the aforesaid patent of the petitioner according to claim 7
(when dependent on claims 1, 4 and 6) and that of the impugned toilet soap of the
respondent No. 1 bearing the trade-mark VIGIL are set out side by side for ready
composition:—
Composition according to claim 7 (when Composition of the impugned toilet soaps
dependent on claim 1, 4 and 6) of patent bearing the Trade-mark VIGIL (pkd.
No. 170131 1/93, 4/93) of the detergent
(i) 25 to 60% by wt. detergent of which (i) 44 to 52% detergent of which at least
at least 50% by wt. is soap. 75 to 89% by wt. in soap.
(ii) 40 to 55% water insoluble structurant (ii) 44 to 50% water insoluble including
including starch and having a particle strach and having particle size of
size of between 0.2 to 30m (microm) and between 6 to 10 in (microm) and
(iii) 8 to 15% by wt. water. (iii) About 8 to 13% by wt. water.

Page: 382

In this connection, the petitioner will crave leave to refer to expert opinion at the
hearing of the application.”

66. In para 26 of the said petition, it has been stated as follows:—

“26. The respondent No. 1 and/or the respondents had access to the specification of
Patent No. 170131 since the notification after acceptance, that is, on 15th Feb.
1992 and they have wrongfully and illegally copied and materially utilised and
reproduced the composition of the said Patent No. 170131 and have thus wrongfully
and illegally infringed Patent No. 170131 of the petitioner. The respondent No. 1
has no right to use the process and/or composition of the said Patent No. 170131 or
use any composition by utilising the same range and/or parameter of the said
Patent.”
67. The respondent No. 1 in the A.O. affirmed on 16-8-1993 at paras. 24 (page 35
of the Paper Book II), 25 to 27 (Pages 36 to 40 of Paper Book II) has covered the
allegation made in paras 23, 24 and 26 of the injunction petition. Lots of technical
expressions have been used in the paras 25A, 25B to 25C but the main conclusion is a
wholesale denial of the allegation made by the petitioner Company. The respondent
No. 1 has also raised the point, in this connection, that prima facie there is no
invention element in the alleged patent of the petitioner. Thus they have raised the
“plea of Gillette” defence indirectly. The main thrust of the respondent No. 2 is on this
point. There are expert, opinions both in favour and against the contention of the
petitioner. In this connection reference has already been made to the decisions laid
down in Gillette Safety Razor Co. v. Anglo-American Trading Co. Ltd. 30 RPC 465
(supra), Windsurfing International Inc. v. Tabur Marine (Great Britain) Ltd. 1985 RPC
59 (supra). Hickman v. Andrews (1983 RPC 147 (supra) and Page v. Brent Toy
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Products Ltd. Vol. LXVII Report of Patent, Design and Trade Mark Cases 4 (supra). The
most striking thing with respect to the case of the respondent No. 1 is that they have
not come with a chemical analysis report showing the composition of VIGIL Soap. They
have chosen to rely upon the Gillette plea indirectly. At the core of the plea is the
stand that the alleged infringement was not novel at the date of the patent. Thus
there is an implied stand that even if there is an infringement, temporary injunction
cannot be granted due to the Gillette plea. Narayanan in his treatise on “Patent Law”
2nd Edn., at para 1299 at p 528 has in connection with a discussion on Gillette
defence, observed: “This kind of defence has not so far been considered by High
Courts in India. But there is no reason why such a defence will not be considered when
properly pleaded.” In this case, in the affidavit sworn by Mr. V.V.R. Subrahmanyam on
12-8-1993 (Vide pages 148 to 158 of Paper Book II) which is annexure to the A.O. on
behalf of the respondent No. 1 sworn on 30-6-1993 (Vide: pp 147 of Paper Book II), it
has been stated at p 156 that “The composition of the pleaded bars of the invention is
mentioned in the claims of the U.S. Patent No. 2438169 as 5 — 40% starch, at least
6% non-soap detergent, remaining being soap and other fillers”.
68. Mr. S.B. Mukherjee, learned Counsel for respondent No. 1 has drawn the
attention of this Court to the United States Patent Office Publication in connection with
U.S. Patent No. 2438169 patented on 23-3-1948 (Vide p. 189 of Paper Book No. II).
He has also given a comparative Chart of the Hindusthan Lever Ltd.'s Patent No.
170131 and the U.S. Patent No. 2438169.
U.S. Patent No. 2438169

Page: 383

HLL Patent No. 170131

I(a) Total detergent (Soap + non-Soap I(a) Total detergent (Soap + non-Soap
detergent) 25% to 60% detergent) 30% to 80%
(b) Soap content at least 50% or above (b) Soap content at least 30%
(c) Non-Soap detergent 0% to 30% (c) Non-soap detergent 5% to 40%
II(a) Fillers including starch 30% to 60% II(a) Fillers including starch 10% to 60%
(b) Starch Trace to 60% (b) Starch 10% to 40%
(c) Sodium Sulphate 0% to 20%
III Water 8% to 35% III Water 5% to 15%
from a plain look at the comparative table it appears that the basic pattern in the
composition of the two are more or less the same, though the percentage are not
identical. But a mere arrangement or rearrangement of known devices each
functioning independently of one another in a known way is not prima facie an
invention under Section 3 of the Patent Act, 1970. So the plea of Gillette defence can
be considered in this case as it has been properly pleaded in this case.
69. The last question that is to be considered is whether the balance of convenience
and inconvenience is in favour of granting interlocutory injunction. It is obvious that
the patent has not yet been exploited by the petitioner. So there is no question of loss
of employment or fall in revenue of the plaintiff-company. They apprehend that they
will suffer an irreparable loss unless injunction is granted. But it is clear that in Para
39 of the plaint it has been averred that the damage suffered by the petitioner can be
provisionally quantified. The implied presumption is that there is some basis for
assessment of the damages though the exact figure cannot be arrived at the stage. So
it cannot be said that the balance of convenience is definitely in favour of granting
interlocutory injunction.
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70. Before winding up the matter a few words need be said about the plea of forum
inconveniens raised by Mr. Das, learned Counsel for the respondent No. 2. At this
stage, when this Court is considering the question of granting interlocutory injunction,
it is useless to raise the plea of forum inconvenience for staying this proceeding.
Certainly the respondent No. 2 can raise the plea at the appropriate stage. If this plea
is entertained at this stage, then there will be no chance of complying with the
direction of the apex Court. Moreover, this plea could be raised before the apex Court
but that was not raised. In the circumstances, it will not be proper to go into the
prima facie merits of the plea of forum inconveniens in this case.
71. In view of the above discussions, this court holds that there is no case for
granting interlocutory injunction in this case. The petition for temporary injunction is
accordingly dismissed on contest. But this cannot prevent this Court from passing an
order directing the respondents to keep monthly accounts of the sales of VIGIL Soap
and to furnish the same in court and also give a copy to the plaintiff an every quarter
till the disposal of this suit. The first such statement of account is to be filed within 30
-6-1996 positively.
Petition dismissed.
———
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 KSR International Co. v. Teleflex Inc. et al., 550 U.S. 398 (2007)

Prepared by UNCTAD’s Intellectual Property Unit

Summary

This case concerned the condition of non-obviousness as a prerequisite for

patentability. The Supreme Court of the United States (hereinafter: the Court)
reinforced the objective analysis approach for applying 35 U.S.C. §103 (i.e. the
domestic provision on non-obviousness) as it was established with the three
determining factors in Graham v. John Deere.1 It found that the Court of Appeals for
the Federal Circuit (hereinafter: the Federal Circuit) had erred in rigidly applying the
narrow teaching, suggestion and motivation test (1) for obviousness under § 103, (2)
for the narrow understanding of the use of hindsight and (3) for not considering
whether the invention was obvious to try. They found the above to be in conflict with
the broader understanding of obviousness established in Graham.

The facts

In order to accommodate smaller drivers of automobiles, inventors designed and

patented gas pedals whose locations could be adjusted. Two different patents, called
the Asano and the Redding patent existed and both addressed the problem in a
mechanical way. 2 When newer cars with computer-controlled throttles reacting to
electronic instead of mechanical signals emerged, inventors found and patented
various solutions on how to translate the mechanical operation of adjusting the
location of the gas pedal into digital data. Petitioner KSR International Co.
(hereinafter: KSR) had developed an adjustable pedal system for cars with cable-
actuated throttles. It was protected by patent '976. KSR supplied the above invention
to General Motors Corporation (hereinafter: GMC) for trucks using computer-
controlled throttles. KSR adjusted its invention to the use in trucks by adding a
modular sensor to the design. Respondents Teleflex Inc. et al. (hereinafter: Teleflex)
held the exclusive license for the Engelgau patent that included in claim No. 4 a
position-adjustable pedal assembly with an electric pedal position sensor attached to a
fixed pivot point. The U.S. Patent and Trademark Office (PTO) only granted this
patent because of the claim's limitation to devices "attached to a fixed pivot point",
which distinguished it from Redding's patent. Following KSR's design for GMC,
Teleflex sued KSR for infringement on its Engelgau patent and the described claim
No. 4. KSR argued that claim No. 4 was invalid pursuant to the rules on non-
obviousness set out in § 103 of the Patent Act. They argued that §103 forbade the
issuance of a patent in case "the differences between the subject matter sought to be
patented and the prior art are such that the subject matter as a whole would have been

1 In Graham v. John Deere the Court established that the element of non-obviousness as set out in §103
must be assessed with the help of the following factors: (1) the scope and content of prior art, (2) the
differences between the prior art and the claims at issue and (3) the level of ordinary skill in the
concerned art. Furthermore, secondary considerations may be commercial success, long felt but
unresolved needs or the failure of others to find a solution. See the summary in this database.
2 The Asano patent includes a support structure whereby, when the pedal's location is adjusted, one of

the pedal's pivot points stays fixed. The Redding patent reveals a sliding mechanism where both the
pedal and pivot point are adjusted.
obvious at the time the invention was made to a person having ordinary skill in the
art”.3 The District Court agreed with KSR, but the Federal Circuit reversed in January
2005. The Court reversed the judgment of the Federal Circuit and declared the patent
invalid due to the obviousness of the invention, §103 of the Patent Act.

The legal issues:

Teaching, Suggestion, or Motivation Test (TSM) and Graham factors

The Court reinforced the objective analysis for applying §103 as it was established
with the three determining factors in Graham v. John Deere.4 It found that the Federal
Circuit, in an effort to reach a more uniform and consistent test of obviousness than
the one established in Graham v. John Deere, had applied a "teaching, suggestion, or
motivation" (TSM) test. According to this test, a "patent claim is only proved obvious
if the prior art, the problem's nature, or the knowledge of a person having ordinary
skill in the art reveals some motivation or suggestion to combine the prior art
teachings". This test attempts to meet the problem that almost all inventions
essentially are new combinations of known elements by requiring proof that a certain
motivation or suggestion to combine those known elements to form the new invention
existed. It intends to prevent hindsight bias. For obviousness to be established, it is
therefore in general not sufficient to demonstrate that each element has formed a part
of the prior art before. In addition, according to the Federal Circuit, there needs to be a
clear TSM to combine prior art elements to the invention at issue. The District Court
and the Federal Circuit both applied the TSM test, but with different outcomes. The
District Court held that KSR satisfied it and invalidated the claim, whereas the
Federal Circuit chose a stricter application of the TSM test and found the invention to
be non-obvious and thus the patent to be valid. The Court, in turn, ruled that the
Federal Circuit had "addressed the obviousness question in a narrow, rigid manner
that is inconsistent with §103" and the Court's precedents.5 It agreed with KSR and
found that on the basis of the pedal as registered in the Asano patent "mounting an
available sensor on a fixed point" of that pedal was an obvious step.6 It stressed that
the Graham factors and the TSM test need not be inconsistent. For consistency of both
approaches, general principles as formulated in the TSM test must not be transformed
into rigid rules. However, the main test to non-obviousness seems to remain the
Graham test.

Obviousness according to the Graham factors

The Court established that the Graham ruling provided an expansive and flexible
approach to the question of obviousness. Once more, it restated the need for caution
when granting a patent based on the combination of elements existing in prior art. The
improvement must be more than just a predictable use of prior-art elements according
to their established functions. In order to determine whether the combination was
predictable and whether there was an apparent reason for it, the Court explained that
"it will often be necessary to look to interrelated teachings of multiple patents; to the
effects of demands known to the design community or present in the marketplace; and

3 See syllabus of the decision, p.2.

4 See footnote nr. 1.
5 See syllabus of the decision, p. 3 at the bottom.
6 See pp.11-24 of the judgment.
to the background knowledge possessed by a person having ordinary skill in the art."7
The teachings need not be precise and explicit, but lead a person of ordinary skill in
the direction of the new combination.

Points of significance:

• The Court restated the need for caution when granting a patent based on a
combination of elements existing in prior art: “Granting patent protection to
advances that would occur in the ordinary course without real innovation
retards progress and may, for patents combining previously known elements,
deprive prior inventions of their value or utility.”8
• A claimed invention may be obvious despite the absence of a clear teaching,
suggestion or motivation to combine various prior art references.
• The patent examiner should not overestimate the importance of published
articles and express prior art. The person skilled in the art is not to be
considered as a technical dumbbell with little initiative on its own, but as a
person that is capable of using common sense and taking into account the
particularities of the individual case (e.g. design needs and the demand in a
specific market).

Key words:
Patentability, non-obviousness, inventive step, ordinary skilled person, pre-grant
flexibilities, TSM test, "teaching, suggestion, or motivation test", mechanical skill.

Available at http://www.supremecourt.gov/opinions/06pdf/04-1350.pdf

7 See pp. 11-14 of the decision.

8 KSR Syllabus, p. 5.
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 US011034762B1

( 12 ) United States Patent ( 10 ) Patent No .: US 11,034,762 B1

Glanville et al . (45 ) Date of Patent : Jun . 15 , 2021

( 54 ) ANTI - SARS -COV - 2 ANTIBODIES DERIVED Beeman . Netflix's ‘ Pandemic ' Doctor Says He May Have Found a
FROM CR3022 Treatment for Coronavirus. Heavy (Apr. 10 , 2020 ) . Retrieved Sep.
18 , 2020 at URL : https://heavy.com/news/2020/04/jacob-glanville
( 71 ) Applicant: Centivax , Inc. , South San Francisco , netflix -pandemic -doctor -coronavirus /. 6 pages .
CA ( US ) Centivax Antibodies Neutralize the Pandemic Coronavirus, Inde
pendently Confirmed by Three Research Laboratories (USAMRIID ,
(72) Inventors: Jacob Glanville, San Francisco , CA Stanford , and UTMB/GNL ). Business Wire (May 18 , 2020 ) . Retrieved
(US ) ; Shahrad Daraeikia , San Jul. 27 , 2020 at URL : https://www.businesswire.com/news/home/
Francisco , CA (US ) ; I- Chieh Wang , 20200518005767/ en /Centivax -Antibodies -Neutralize- Pandemic
San Bruno , CA (US ); Sindy Andrea Coronavirus -Independently -Confirmed . 3 pages.
Liao Chan , San Jose , CA (US ); CNBC's Closing Bell . @CNBCClosingBell . . @ distributedbio is
Jean- Philippe Bürckert, Belmont, CA developing a COVID - 19 treatment using antibodies produced dur
(US ) ; Sawsan Youssef, Menlo Park , CA ing the 2002 SARS outbreak . Founder & CEO Dr. @CurleyJungle Jake
joined us to talk more about the timeline and potential effectiveness
(US) of the treatment. ( Tweet ). Twitter ( Apr. 21 , 2020 ) . Retrieved Jul. 30 ,
2020 from https://twitter.com/CNBCClosingBell/status/
( 73 ) Assignee : Centivax , Inc. , South San Francisco , 1252681883772694533 ? s = 20 . One page .
CA (US ) Cohen , J. @Sciencecohen . In parallel with vaccine race , 50+ groups
are making a boatload of SARS - CoV - 2 monoclonal antibodies from
( * ) Notice: Subject to any disclaimer, the term of this recovered patients like Dr. X , mice , SARS - CoV, and computer
patent is extended or adjusted under 35 programs. Yes, access , production, and safety will be issues . But
U.S.C. 154 ( b ) by 0 days. color me optimistic . https://sciencemag.org/news/2020/05/race
antibodies -stop -new - coronavirus ( Tweet ). Twitter (May 5 , 2020 ) .
( 21 ) Appl . No.: 15 /931,649 Retrieved Jul. 30 , 2020 from https://twitter.com/sciencecohen/status/
1257800751184633857 ? s = 20 . One page .
(22) Filed : May 14, 2020 Cohen . The race is on for antibodies that stop the new coronavirus.
Related U.S. Application Data Science (May 5 , 2020 ) . Retrieved Aug. 8 , 2020 at URL : https : //
www.sciencemag.org/news/2020/05/race-antibodies-stop-new
(60) Provisional application No. 63 / 014,546 , filed on Apr. coronavirus/. 10 pages.
23 , 2020 , provisional application No. 62 / 993,630 , Co -pending U.S. Appl. No. 15 /931,642 , filed May 14 , 2020 .
filed on Mar. 23 , 2020 . Co -pending U.S. Appl. No. 15 /931,643 , filed May 14 , 2020 .
Co -pending U.S. Appl. No. 15 /931,648 , filed May 14 , 2020 .
( 51 ) Int . Cl . Co -pending U.S. Appl. No. 15 /931,652 , filed May 14 , 2020 .
A61K 39/42 ( 2006.01 ) Co -pending U.S. Appl. No. 15 /931,654 , filed May 14 , 2020 .
CO7K 16/28 ( 2006.01 ) Coronavirus is ‘much worse than influenza : Doctor. Fox Business
GOIN 33/569 ( 2006.01 ) News . Video (transcript ). Transcribed Sep. 16 , 2020 from URL :
CO7K 16/10 ( 2006.01 ) https://video.foxbusiness.com/v/6142665270001/#sp=show-clips. Mar.
A61K 39/00 ( 2006.01 ) 18, 2020. 3 pages.
Distributed Bio CEO on developing therapeutic antibody treatment
( 52 ) U.S. CI .
against coronavirus. CNBC Squawk on the Street video ( transcript ).
??? CO7K 16/28 (2013.01 ) ; CO7K 16/10 Transcribed Sep. 16 , 2020 from URL : https://www.cnbc.com/video/
( 2013.01 ) ; GOIN 33/56983 (2013.01 ) ; A61K 2020/03/23/distributed -bio -ceo -on -developing-therapeutic -antibody
2039/505 (2013.01 ) ; CO7K 2317/55 ( 2013.01 ) ; treatment-against - coronavirus.html. Mar. 23 , 2020. 3 pages.
CO7K 2317/565 (2013.01) Distributed Bio . @Distributedbio . An update on our monoclonal
( 58 ) Field of Classification Search antibodies being engineered against # COVID19 from @CurlyJungle Jake
None on @SquawkCNBC this morning. ( Tweet). Twitter ( Mar. 23 , 2020 ) .
See application file for complete search history . Retrieved Jul. 30 , 2020 from https://twitter.com/distributedbio/status/
1242123582341181440 ? s = 20 . One page .
( 56) References Cited (Continued )
PUBLICATIONS
Primary Examiner Shanon A. Foley
Assistant Examiner — Myron G Hill
Rudikoff et al., Proc Natl Acad Sci USA 1982 vol . 79 (Year: 1982 ) . * (74 ) Attorney, Agent, or Firm Wilson Sonsini Goodrich
MacCallum et al. J. Mol . Biol . ( 1996 ) 262 , 732-745 ( Year: 1996 ) . * & Rosati
Tian et al . Emerging Microbes and Infections, 2020 , 9 : 382-385 .
Published online Feb. 17 , 2020 ) . ( Year: 2020 ) . * (57 ) ABSTRACT
Aiola , C. @Chrisaiola . Dr. Jake Glanville and I discuss what we can
expect in the coming weeks , why COVID - 19 is much more dan This disclosure provides antibodies that are derived from
gerous than seasonal influenza , and his team's continuing effort to CFR3022 and that can be administered to an individual that
bio -engineer antibodies. @Curly JungleJake #coronavirus # COVID19 is infected with a virus. Antibodies herein can be capable of
#pandemic ( Tweet ). Twitter (Mar. 16 , 2020 ) . Retrieved Jul. 30 , 2020 treating or curing the virus, and which may provide protec
from https://twitter.com/chrisaiola/status/1239707660896870402 ? tion against the virus for up to several weeks . Antibodies
s=20 . One page. herein can be used to diagnose a SARS COV 2 infection .
Aiola , Chris. Dr. Jake Glanville - Mar. 15 , 2020. YouTube video
( transcript ). Transcribed Sep. 16 , 2020 from URL : https : //www. 13 Claims , 1 Drawing Sheet
youtube.com/watch?v=bEjk-bLVW_8&feature=youtu.be. Mar. 16 ,
2020. 6 pages . Specification includes a Sequence Listing .
 US 11,034,762 B1
Page 2
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PUBLICATIONS
Distributed Bio . @Distributedbio . Hear more about our progress on
engineering our #monoclonal #antibodies to neutralize # COVID19
from @CurlyJungleJake on @TheStoryFNC with @ marthamaccal
lum ( Tweet ). Twitter (Mar. 19 , 2020 ) . Retrieved Jul. 30 , 2020 from
https://twitter.com/distributedbio/status/1240798648054591488?s=
20. One page .
Distributed Bio . @Distributedbio . It was a blast working with
@chrisaiola and @ZPZProduction re #influenza for #Pandemic on
# Netflix - hear more about #coronavirus here . ( Tweet). Twitter
(Mar. 3 , 2020 ) . Retrieved Jul. 30 , 2020 from https://twitter.com/
distributedbio / status/ 1234873874669547521 ? s = 20. One page .
Dr. Glanville: 3 to 4 weeks before completing engineering on drug
that neutralizes coronavirus. Fox News . Video ( transcript ). Tran
scribed Sep. 16 , 2020 from URL : https://video.foxnews.com/v/
6142979870001 # sp= show - clips . Mar. 19 , 2020. 3 pages.
Fighting the Pandemic : Potential COVID - 19 Treatment. CNBC
Closing Bell video ( transcript). Transcribed Sep. 16 , 2020 from
URL : https://twitter.com/CNBCClosingBell/status/
1252681883772694533 ? s = 20 . Apr. 21 , 2020. 2 pages .
Glanville, J. @Curly JungleJake. Interview on @FoxBusiness where
we discuss our #antibody therapeutics program for the #coronavirus.
( Tweet ). Twitter (Mar. 18 , 2020 ) . Retrieved Jul. 30 , 2020 from
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s= 20 . One page .
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2020-1 / a -discussion -with - jacob - glanville - from -netflix - s -pandemic ?
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jbc.M600697200 . Epub Apr. 5 , 2006. DOI : 10.1074 / jbc.
M600697200 .
Scientists begin their study of covid- 19 , looking for antibody. Radio
New Zealand ( RNZ ) broadcast ( transcript ). Transcribed Sep. 16 ,
2020 from URL : https://www.rnz.co.nz/national programmes/ first
up/audio / 2018736849 / scientists -begin -their -study -of -covid - 19
looking - for -antibody. Mar. 4 , 2020. 4 pages.
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says -he -discovered -potential-coronavirus - cure /. 6 pages.
* cited by examiner
U.S. Patent Jun . 15 , 2021 US 11,034,762 B1

Virus Antigen Sequence SEO ID

NO
MERS 5gma VECDFSPLLSGTPPQVYNFKRLVFTNCNYNLTKLLSL 453
FSVNDFTCSQISPAAIASNCYSSLILDYFSYPLSMKS
DLSVSSAGPISQFNYKQSFSNPTCLILATVPHNLTTI
TKPLKYSYINKCSRLLSDDRTEVPQLVNANQYSPCVS
IVPSTVWEDGDYYRKQLSPLEGGGWLVASGSTVAMTE
QLQMGFGITVQYGTDTNSVCPKL
2019 2019 RFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVAD 454
ncov Wuhan YSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFV
Hu - 1
IRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNS
NNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQA
GSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVV
LSFELLHAPATVCGP

SARS 2 dd8 S PNITNLCPFGEVFNATKFPSVYAWERKKISNCVADYS 455

spike VLYNSTFFSTFKCYGVSATKLNDLCFSNVYADSFVVK
glycopr
otein GDDVROIAPGOTGVIADYNYKLPDDFMGCVLAWNTRN
IDATSTGNYNYKYRYLRHGKLRPFERDISNVPFSPDG
KPCTPPALNCYWPLNDYGFYTTTGIGYQPYRVVVLSF
ELLNAPATVCGPKLSTD

SARS QDF4382 PNITNLCPFGEVFNATTFPSVYAWERKRISNCVADYS 456

5.1
VLYNSTSFSTFKCYGVSATKLNDLCFSNVYADSFVVK

GDDVRQIAPGQTGVIADYNYKLPDDFMGCVLAWNTRN
IDATSTGNYNYKYRSLRHGKLRPFERDISNVPFSPDG

KPCTPPAFNCYWPLNDYGFFTTNGIGYQPYRVVVLSF
ELLNAPATVCGPKLSTD
 US 11,034,762 B1
1 2
ANTI- SARS - COV - 2 ANTIBODIES DERIVED prises a VH CDR3 having an amino acid sequence of
FROM CR3022 CAGX , X ,GISTPMDVW (SEQ ID NO : 256 ) , wherein X , is
G or S ; and X2 is S or W. In further embodiments , the
CROSS -REFERENCE CR3022 - derived antibody or antigen - binding fragment fur
5 ther comprises an amino acid sequence that is at least 90 % ,
This application claims the benefit of U.S. Provisional 95 % , 98 % , 99 % , or 100 % identical to one or more of a VH
Application No. 63 /014,546 , filed on Apr. 23 , 2020 , and CDR1 comprising an amino acid of any one of SEQ ID
NOS : 155-187 and a VH CDR2 comprising an amino acid
62 / 993,630 , filed Mar. 23 , 2020 , all of which are incorpo of any one of SEQ ID NOS : 191-250 . In further embodi
rated herein by reference in their entireties for all purposes. 10 ments , the CR3022 - derived antibody or antigen - binding
SEQUENCE LISTING fragment further comprises a VH CDR1 having an amino
acid sequence of X , X2FX3X4XzXIX , ( SEQ ID NO : 154 ) ,
The instant application contains a Sequence Listing which wherein X is G or Y ; X , is G or T; X3 is 1 , S , or T ; X4 is D ,
has been submitted electronically in ASCII format and is S , T, or N ; X , is H or Y ; X. is A , W , G , or H ; and X , is G ,
hereby incorporated by reference in its entirety. Said ASCII 15 H , or S ; and a VH CDR2 having an amino acid sequence of
copy, created on May 29 , 2020 , is named 44561- GX , X ,X2PX X X X X X , YX10 ( SEQ ID NO : 190 ) ,
723_201_SL.txt and is 237,988 bytes in size . wherein X , is G , I , or W ; X2 is I or M ; X3 is I , N , or Y; X4
is G , N , or R ; X , is D , G , or S ; X. is G or S ; X , is any amino
BACKGROUND OF THE INVENTION acid (Xaa ) or no amino acid ; X , is A or T; X , is G , N , or R ;
20 and X10 is A or S.
Viruses are small infectious agents that can enter a living In some embodiments, provided herein is a CR3022
cell of an organism . Genetic information from a virus can be derived antibody or antigen -binding fragment that com
injected into the living cell , and can replicate inside the prises a variable heavy chain (VH ) that comprises:
living cell , and be released . Viruses can cause disease in the a . a VH CDR1 having an amino acid sequence that is at
organism and can spread between organisms . The mecha- 25 least 90% , 95 % , 98 % , 99 % , or 100% identical to any
nism by which a virus can cause disease can vary between one of SEQ ID NOS : 155-187 ;
viruses and can include cell lysis and / or cell death . b . a VH CDR2 having an amino acid sequence that is at
Coronaviruses are a group of related viruses that can least 90% , 95 % , 98 % , 99 % , or 100% identical to any
cause disease , for example in mammals and birds . Corona one of SEQ ID NOS : 191-250 ; and
viruses can cause respiratory tract infections, such as those 30 c . a VH CDR3 having an amino acid sequence that is at
causing pneumonia -like diseases , that can range from mild least 90% , 95 % , 98 % , 99 % , or 100% identical to any
to lethal. one of SEQ ID NOS : 257-316 .
Severe acute respiratory syndrome coronavirus 2 (SARS- In some embodiments, provided herein is a CR3022
Cov - 2 ) is a coronavirus responsible for a pandemic of a derived antibody or antigen -binding fragment that com
respiratory disease, COVID19 . An outbreak ofthis virus was 35 prises a variable light chain (VL) that comprises :
first identified in Wuhan, Hubei, China, and a pandemic was a . a VL CDR1 having an amino acid sequence that is at
recognized by the World Health Organization on Mar. 11 , least 90% , 95 % , 98 % , 99 % , or 100% identical to any
2020. The range of the severity of COVID19 is large, and one of SEQ ID NOS : 3-62 ;
ranges from asymptomatic to death . Approximately 20 % of b . a VL CDR2 having an amino acid sequence that is at
infected individuals can require hospitalization . The mor- 40 least 90% , 95 % , 98 % , 99 % , or 100% identical to any
tality rate of COVID19 appears to be between 1 % and 4 % . one of SEQ ID NOS : 65-89 and 444 ; and
COVID19 is transmitted between people , for example c . a VL CDR3 having an amino acid sequence that is at
through respiratory droplets, and can be spread by symp least 90% , 95 % , 98 % , 99 % , or 100% identical to any
tomatic and asymptomatic individuals, including during an one of SEQ ID NOS : 92-151 .
extended incubation period. Social distancing has been 45 In some embodiments, provided herein is a CR3022
applied worldwide to decrease the spread of COVID19 . derived antibody or antigen -binding fragment that com
Currently, there is no vaccine or treatment for COVID19 . prises a VL CDR1 having an amino acid sequence of
There is an urgent need for new compositions that can be KSSQSX LYSSX NX NYLA ( SEQ ID NO : 2 ) , wherein X
used for treating or preventing SARS - Cov - 2 infection and is V or L ; X , is I or N ; and X2 is K or L ; a VL CDR2 having
for diagnosing an exposure to SARS - Cov - 2 virus . 50 an amino acid sequence of X X X3X4RX X6 ( SEQ ID NO :
64 ) , wherein X , is W or R ; X , is A , S , or G ; Xz is S , T, or
SUMMARY OF THE INVENTION N ; X4 is T, L , F , or N ; X , is E , A , G , or L ; and Xo is S , P ,
G , F , or A ; and a VL CDR3 having an amino acid sequence
Provided herein is an isolated or purified antibody or of CX QYX X X PX , TF ( SEQ ID NO : 91 ) , wherein X , is
antigen -binding fragment that is derived from CR3022 and 55 Q , R , or H ; X2 is Y , H , or S ; Xz is S or T; X4 is T or L , and
that selectively binds to a severe acute respiratory syndrome X , is L , W , or Y. In further embodiments, the CR3022
coronavirus 2 (SARS - CoV - 2 ). In some embodiments, the derived antibody or antigen -binding fragment described
antibody or antigen -binding fragment has a binding affinity herein comprises: (i ) a VH CDR3 having an amino acid
of less than 50 nanomolar (nM ). In further embodiments, the sequence that is at least 90% , 95 % , 98 % , 99 % , or 100 %
CR3022 -derived antibody or antigen -binding fragment 60 identical to SEQ ID NO : 291 ; ( ii ) a VH CDR1 having an
binds to a receptor binding domain (RBD ) of SARS - CoV - 2 . amino acid sequence that is at least 90 % , 95 % , 98 % , 99 % ,
In further embodiments, the CR3022 - derived antibody or or 100 % identical to SEQ ID NO : 176 ; (ii ) a VH CDR2
antigen -binding fragment comprises an amino acid sequence having an amino acid sequence that is at least 90 % , 95 % ,
that is at least 90 % , 95 % , 98 % , 99 % , or 100 % identical to 98 % , 99 % , or 100% identical to SEQ ID NO : 225 ; (iv) a VL
a VH CDR3 comprising an amino acid of any one of any one 65 CDR1 having an amino acid sequence that is at least 90 % ,
of SEQ ID NOS : 257-316 . In further embodiments, the 95 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 37 ; (v )
CR3022 - derived antibody or antigen -binding fragment com- a VL CDR2 having an amino acid sequence that is at least
 US 11,034,762 B1
3 4
90 % , 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 65 PM , 260 PM , 250 PM , 240 PM , 230 PM , 220 PM , 210 PM ,
or 444 ; and ( vi) a VL CDR3 having an amino acid sequence 200 PM , 190 PM , 180 PM , 170 PM , or any integer therebe
that is at least 90 % , 95 % , 98 % , 99 % , or 100 % identical to tween . In further embodiments, the CR3022 -derived anti
SEQ ID NO : 126. In further embodiments, the CR3022- gen -binding fragment comprises a Fab , a Fab ' , a F ( ab ' ) 2 , a
derived antibody or antigen - binding fragment described 5 variable fragment (Fv ) , a triabody, a tetrabody , a minibody,
herein comprises an amino acid sequence that is at least a bispecific F (ab ' ) 2 , a trispecific F ( ab ' ) 2 , a diabody, a bis
20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 50% , 55 % , 60% , 65 % , pecific diabody, a single chain variable fragment ( scFv) , a
70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100 % scFv - Fc , a Fab - Fc , a VHH , or a bispecific scFv.
identical to one or more of a FW -L1 comprising an amino Provided herein is a method of preventing or treating a
acid sequence of SEQ ID NO : 1 or 442 , a FW -L2 comprising 10 SARS -CoV -2 viral infection or COVID19 in a subject in
an amino acid of SEQ ID NO : 63 or 443 , a FW - L3
comprising an amino acid sequence of SEQ ID NO : 90 or need thereof. In some embodiments, the method comprises
445 , a FW- L4 comprising amino acid sequence of SEQ ID administering to the subject one or more of the antibodies or
NO : 152 a FW -H1 comprising an amino acid sequence of antigen -binding fragments described herein . In further
SEQ ID NO : 153, a FW -H2 comprising amino acid sequence 15 embodiments , the method further comprises administering
one or more additional therapies or drugs to the subject.
of SEQ ID NO : 188 , 446 , or 447 , a FW -H3 comprising an
amino acid sequence of any one of SEQ ID NOS : 251-254 Provided herein is a method of diagnosing a subject as
and 448-449 , and a FW- H4 comprising an amino acid having COVID19 or suspected of having COVID19 , the
sequence of SEQ ID NO : 317. In further embodiments, the method comprising contacting a sample obtained from the
CR3022-derived antibody or antigen - binding fragment 20 subject with a CR3022 - derived antibody or antigen - binding
described herein comprises a variable heavy chain (VH ) fragment described herein ; detecting the presence or absence
having an amino acid sequence that is at least 90% , 95 % , of the CR3022 -derived antibody or antigen -binding frag
98 % , 99 % , or 100 % identical to any one of SEQ ID NOS : ment; and diagnosing the subject as being infected with a
318-377 . In further embodiments, the CR3022 -derived anti- SARS -CoV - 2 virus when the presence of the CR3022
body or antigen -binding fragment described herein com- 25 derived antibody or antigen -binding fragment is detected .
prises a variable light chain (VL ) having an amino acid Further provided herein is a method, wherein the sample
sequence that is at least 90% , 95 % , 98 % , 99 % , or 100 % comprises a nasal swab, nasal swab , a tissue sample, saliva ,
identical to any one of SEQ ID NOS : 378-437 . In further or blood . Further provided herein is a method, wherein
embodiments, the CR3022 -derived antibody or antigen detecting the presence or absence of the antibody or antigen
binding fragment described herein comprises a VL having 30 binding fragment comprises an enzyme linked immunosor
an amino acid sequence that is at least 90 % , 95 % , 98 % , bent assay (ELISA) , an immunospot assay, a lateral flow
99 % , or 100 % identical to any one of SEQ ID NOS : assay, flow cytometry, immunohistochemistry, or a western
378-437 , and a VH having an amino acid sequence that is at blot .
least 70 % , 75 % , 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100 %
identical to any one of SEQ ID NOS : 318-377 . In further 35 INCORPORATION BY REFERENCE
embodiments , the CR3022 - derived antibody or antigen
binding fragment described herein comprises a VH having
an amino acid sequence that is at least 70 % , 75 % , 80 % , All publications, patents, and patent applications men
85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ IDtioned in this specification are herein incorporated by ref
NO : 352 and a VL having an amino acid sequence that is at 40 erence to the same extent as if each individual publication ,
least 70 % , 75 % , 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100 % patent, or patent application was specifically and individu
identical to SEQ ID NO : 412. In further embodiments, the ally indicated to be incorporated by reference .
CR3022 -derived antibody is an IgG , an IgM , an IgE , an IgA , BRIEF DISCLOSURE OF THE DRAWINGS
or an IgD , or is derived therefrom . In further embodiments,
the CR3022 - derived antibody comprises a monoclonal anti- 45
body, a grafted antibody, a chimeric antibody, a human The novel features of the invention are set forth with
antibody, or a humanized antibody. particularity in the appended claims . A better understanding
In further embodiments , provided herein is a CR3022- of the features and advantages of the present disclosure will
derived antibody or antigen -binding fragment wherein the be obtained by reference to the following detailed descrip
binding affinity is less than 50 nM , 49 nM , 48 nM , 47 nM , 50 tion that sets forth illustrative embodiments, in which the
46 nM , 45 nM , 44 nM , 43 nM , 42 nM , 41 nM , 40 nM , 39 principles of the disclosure are utilized , and the accompa
nM , 38 nM , 37 nM , 36 nM , 35 nM , 34 nM , 33 nM , 32 nM , nying drawings of which :
31 nM , 30 nM , 29 nM , 28 nM , 27 nM , 26 nM , 25 nM , 24 FIG . 1 provides representative viral antigen sequences for
nM , 23 nM , 22 nM , 21 nM , 20 nM , 19 nM , 18 nM , 17 nM , which antibodies can be generated .
16 nM , 15 nM , 14 nM , 13 nM , 12 nM , 11 nM , 10 nM , 9 nM , 55
8 nM , 7 nM , 6 nM , 5 nM , 4 nM , 3 nM , 2 nM , 1 nM , 990 PM , DETAILED DESCRIPTION OF THE
980 PM , 970 PM , 960 PM , 950 PM , 940 PM , 930 PM , 920 INVENTION
PM , 910 PM , 900 PM , 890 PM , 880 PM , 870 PM , 860 PM ,
850 PM , 840 PM , 830 PM , 820 PM , 810 PM , 800 PM , 790 In view of the ongoing pandemic , there is a great need for
PM , 780 PM , 770 PM , 760 PM , 750 PM , 740 PM , 730 PM , 60 therapeutic and diagnostic antibodies that selectively bind to
720 PM , 710 PM , 700 PM , 690 PM , 680 PM , 670 PM , 660 severe acute respiratory syndrome coronavirus 2 (SARS
PM , 650 PM , 640 PM , 630 PM , 620 PM , 610 PM , 600 PM , Cov - 2 ) .
590 PM , 580 PM , 570 pM , 560 pM , 550 PM , 540 PM , 530 " CR3022” as referenced herein refers to an antibody that
PM , 520 PM , 510 PM , 500 PM , 490 PM , 480 PM , 470 PM , selectively binds to SARS - Cov - 1 and which has the follow
460 PM , 450 PM , 440 PM , 430 PM , 420 PM , 410 PM , 400 65 ing combination of complementarity determining regions
PM , 390 PM , 380 PM , 370 PM , 360 PM , 350 PM , 340 PM , (CDRs ) , or the following variable heavy chain (VH ) , and
330 PM , 320 PM , 310 PM , 300 PM , 290 PM , 280 PM , 270 variable light chain (VL ) .
 US 11,034,762 B1
5 6
antibody or antigen -binding fragment and the antigen causes
CR3022 Parental CDR Sequences SEQ ID NO a proportional increase in the refractive index , which is
VH CDR1 YGFITYWIG 168 observed as a change in response . These changes are mea
VH CDR2 GIIYPGDSETRYS 213 sured as changes in the resonance angle ( 80 ) of refracted
VH CDR3 CAGGSGISTPMDV 450 5 light when the antigen, flowing in a microfluidic channel,
VL CDR1 KSSQSVLYSSINKNYLA 3
binds to the immobilized antibody and increases in density
VL CDR2 WASTRES 438
VL CDR3 CQQYYSTPYT 439 at the sensor chip . For antibody - antigen interactions, the
change in refractive index on the surface is linearly related
to the number of antigens bound to an immobilized antibody.

SEQ
Clone VH / VL Parental Clone Sequence ID NO
CR3022 VH QMQLVQSGTEVKKPGESLKISCKGSGYGFITYWIGW 440
VRQMPGKGLEWMGIIYPGDSETRYSPSFQGQVTISA
DKSINTAYLOWSSLKASDTAIYYCAGGSGISTPMDV
WGQGTTVTVSS
CR3022 VL DIQLTQSPDSLAVSLGERATINCKSSQSVLYSSINKN 441
YLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGS
GTDFTLTISSLQAEDVAVYYCQQYYSTPYTFGQGTK
VEIK

The present disclosure describes CR3022 -derived anti- The response signal ( the SPR signal) is quantified in reso
bodies and antigen -binding fragments herein that selectively nance units (RU ). When a steady - state is achieved ( all
bind to SARS - Cov - 2 . 25 binding sites occupied) , the maximum RU is determined (n :
A CR3022 - derived antibody or antigen -binding fragment number of binding sites in ligand ) . Monitoring the change in
herein that is derived from ” this parental clone refers to an the SPR signal over time produces a sensorgram , a plot of
antibody or antigen -binding fragment that does not comprise the binding response ( RU) versus time which allows differ
amino acid sequences that are 100 % identical to the com- ent stages of a binding event to be visualized and evaluated .
bination of CDRs of the parental clone , or that does not 30 During the injection of an antigen , the binding response
comprise amino acid sequences that are 100 % identical to increase is due to the formation of antigen - antibody com
the VH of SEQ ID NO : 440 and the VL of SEQ ID NO : 441 . plexes at the surface and the sensorgram is dominated by the
Instead , such CR3022 - derived antibodies or antibody-bind- association phase . After a certain time of injection , a steady
ing fragments can have some degree of sequence identity to state is reached , in which binding and dissociating mol
the parental clone CR3022 . 35 ecules are in equilibrium . The decrease in response after
As used herein , the terms “ CR3022 - derived antibody or analyte injection is terminated is due to dissociation of the
antigen -binding fragment " and " CR3022 -derived antibody complexes , defining the dissociation phase . Depending on
or antigen -binding fragment herein which selectively binds the dissociation rate of the tested antibody, some assays may
to SARS-Cov - 2 ” are synonymous. require a regeneration step in order to reach the baseline
A CR3022 - derived antibody or antigen -binding fragment 40 again . Fitting the sensorgram data to an appropriate kinetic
herein also refers to an antibody or antigen -binding fragment binding model allows calculation of kinetic parameters such
that selectively binds to SARS - Cov - 2 , and which has a as the association ( kq) and dissociation (ka) rate constants,
greater binding affinity for SARS - Cov - 2 than to SARS- Cov- and the binding affinity of the tested interactions.
1. A CR3022 - derived antibody or antigen -binding fragment Preferably, a CR3022 - derived antibody or antigen -bind
herein that is derived from the parental clone also refers to 45 ing fragment herein selectively binds to SARS - Cov - 2 with
a CR3022 -derived antibody or antigen -binding fragment a binding affinity of less than 50 nM . In one instance , a
that is capable of neutralizing the activity of SARS - Cov - 2 . CR3022 -derived antibody or antigen - binding fragment
A CR3022 - derived antibody or antigen -binding fragment herein that is derived from bnb6 can selectively bind to
herein can selectively bind to the receptor binding domain SARS - Cov - 2 with a binding affinity of from about 0.7 nM
( RBD ) of SARS - Cov - 2 . In one instance , a CR3022 - derived 50 (e.g. , 700 PM ) to about 50 nM . In one instance , a CR3022
antibody or antigen -binding fragment herein selectively derived antibody or antigen -binding fragment herein that is
binds solely to SARS - Cov - 2 , and not to SARSI , SARS2 , derived from 6nb6 can selectively bind to SARS - Cov - 2 with
and / or Middle East Respiratory Syndrome (MERS ) . a binding affinity of less than 50 nM , 49 nM , 48 nM , 47 nM ,
Binding affinity of a CR3022 -derived antibody or antigen- 46 nM , 45 nM , 44 nM , 43 nM , 42 nM , 41 nM , 40 nM , 39
binding fragment herein can be determined by any suitable 55 nM , 38 nM , 37 nM , 36 nM , 35 nM , 34 nM , 33 nM , 32 nM ,
means including, but not limited to , high -throughput surface 31 nM , 30 nM , 29 nM , 28 nM , 27 nM , 26 nM , 25 nM , 24
plasmon resonance ( SPR) kinetic experiments. Briefly, a nM , 23 nM , 22 nM , 21 nM , 20 nM , 19 nM , 18 nM , 17 nM ,
CR3022 -derived antibody or antigen -binding fragment 16 nM , 15 nM , 14 nM , 13 nM , 12 nM , 11 nM , 10 nM , 9 nM ,
herein is immobilized to a solid surface using an anti- V5 8 nM , 7 nM , 6 nM , 5 nM , 4 nM , 3 nM , 2 nM , 1 nM , 990 PM ,
antibody. Different concentrations of antigen ( SARS - Cov - 2 , 60 980 PM , 970 PM , 960 PM , 950 PM , 940 PM , 930 PM , 920
SARS - Cov - 1, SARS2 , or MERS RBD proteins) are flowed PM , 910 PM , 900 PM , 890 PM , 880 PM , 870 PM , 860 PM ,
over the immobilized CR3022 -derived antibodies or anti- 850 PM , 840 PM , 830 PM , 820 PM , 810 PM , 800 PM , 790
gen -binding fragments to characterize the interactions to the PM , 780 PM , 770 PM , 760 PM , 750 PM , 740 PM , 730 PM ,
immobilized CR3022 -derived antibodies or antigen -binding 720 PM , 710 PM , 700 PM , 690 PM , 680 PM , 670 PM , 660
fragments. The SPR signal originates from changes in the 65 PM , 650 PM , 640 PM , 630 PM , 620 PM , 610 PM , 600 PM ,
refractive index at the surface of a gold sensor chip . An 590 PM , 580 PM , 570 PM , 560 PM , 550 PM , 540 PM , 530
increase in mass associated with a binding event between an PM , 520 PM , 510 PM , 500 PM , 490 PM , 480 PM , 470 PM ,
 US 11,034,762 B1
7 8
460 PM , 450 PM , 440 PM , 430 PM , 420 PM , 410 PM , 400 In some instances, a CR3022 -derived antibody or antigen
PM , 390 PM , 380 PM , 370 PM , 360 PM , 350 PM , 340 PM , binding fragment herein that selectively binds to SARS
330 PM , 320 PM , 310 PM , 300 PM , 290 PM , 280 pM , 270 Cov - 2 can further comprise an amino acid sequence that is
PM , 260 PM , 250 PM , 240 PM , 230 PM , 220 PM , 210 PM , at least 20 % , 25 % , 30% , 35 % , 40% , 45 % , 50% , 55 % , 50 % ,
200 PM , 190 PM , 180 pM , or 170 PM . 5 65 % , 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100 %
In any of the embodiments herein , a CR3022 -derived identical to one or more of a VH CDR1 comprising an amino
antibody or antigen - binding fragment herein can neutralize acid of any one of SEQ ID NOS : 155-187 , and a VH CDR2
the activity of SARS - Cov - 2 . Neutralization ability of a comprising an amino acid sequence of any one of SEQ ID
CR3022 -derived antibody or antigen -binding fragment NOS : 191-250 . In some instances, a CR3022 -derived anti
herein can be assessed using any suitable means including , 10 binds
body or antigen -binding fragment herein that selectively
but not limited to , an in vitro pseudovirus assay. For havingtoanSARS - Cov - 2 can further comprise a VH CDR1
amino acid sequence of X , X2FX2X4X5X6IX ,
example, spike genes from a SARS - Cov - 2 virus are codon ( SEQ ID NO : 154 ) , wherein X , is G or Y ; X2 is G or T ; X3
optimized for human cells and cloned into eukaryotic is I , S , or T ; X4 is D , S , T, or N ; X , is H or Y ; X , is A , W ,
expression plasmids to generate envelope recombinant plas- 15 G, or H ; and X , is G, H , or S ; and a VH CDR2 having an
mids ; mammalian cells are then transfected with the plas
mids . The transfected mammalian cells are contacted with a
amino acid sequence of GX , XXX , PX X X X X X , YX10
,?

CR3022 -derived antibody or antigen -binding fragment

( SEQ ID NO : 190 ) , wherein X is G , I , or W ; X , is I or M ;
X2 is I , N , or Y ; X4 is G , N , or R ; X , is D , G , or S ; Xo is G
herein and trypsinization is determined as a measure of or S ; X , is any amino acid ( Xaa ) or no amino acid ; Xg is A
neutralization . In some instances , a CR3022 - derived anti- 20 or T ; X , is G , N , or R ; and X10 is A or S.
body or antigen -binding fragment herein neutralize SARS In some instances, a CR3022 - derived antibody or antigen
Cov - 2 by at least 5 % , 10 % , 15 % , 20% , 25 % , 35 % , 40 % , binding fragment herein that selectively binds to SARS
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , or Cov - 2 can further comprise an amino acid sequence that is
more compared to a non - specific antibody, or compared to at least 20 % , 25 % , 30% , 35 % , 40% , 45 % , 50% , 55 % , 60 % ,
an antibody that selectively binds to SARS - Cov - 1 or MERS . 25 65 % , 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100 %
Neutralization ability of a CR3022 -derived antibody or identical to one or more of a VL CDR1 comprising an amino
antigen -binding fragment herein can also be assessed using, acid sequence of any one of SEQ ID NOS : 2-62 , a VL CDR2
for example, an in vivo hamster animal model . For example, comprising an amino acid of any one of SEQ ID NOS : 65-89
hamsters can be injected with either saline or a CR3022- and 444 , and a VL CDR3 comprising an amino acid
derived antibody or antigen -binding fragment herein . Body 30 sequence of any one of SEQ ID NOS : 92-151 . In some
weight and viable signs ( e.g. , ruffled hair and movement) are instances, a CR3022 - derived antibody or antigen -binding
recorded . Viral titers are assessed in homogenates of lung fragment herein that selectively binds to SARS - Cov - 2 can
tissues and / or by immunohistochemistry of lung tissue . A further comprise a VL CDR1 having an amino acid sequence
CR3022 - derived antibody or antigen -binding fragment of KSSQSX LYSSX NX NYLA ( SEQ ID NO : 2 ) , wherein
herein reduces viral titers compared to controls. 35 X , is V or L ; X , is I or N ; and X2 is K or L ; a VL CDR2
Competition assay of the interaction of SARS - Cov - 2 with having an amino acid sequence of X X X3X4RX3X6 ( SEQ
angiotensin -converting enzyme 2 (ACE2) can be assessed ID NO : 64 ) , wherein X , is W or R ; X , is A , S , or G ; X2 is
using an assay including , but not limited to , a classical S , T, or N ; X4 is T , L , F, or N ; X , is E , A , G , or L ; and X.
sandwich and premix assay format. For example, anti- V5 is S , P, G , F, or A ; and a VL CDR3 having an amino acid
tag antibodies are biotinylated and loaded onto streptavidin 40 sequence of CX , QYX2X2X4PXzTF ( SEQ ID NO : 91 ) ,
sensor tips . For a classical sandwich assay format, a wherein X , is Q , R , or H ; X , is Y , H , or S ; X3 is S or T ; X4
CR3022 -derived antibody or antigen -binding fragment is T or L , and X , is L , W , or Y.
herein is loaded onto the anti - V5 sensor tips . Following In other instances , a CR3022 -derived antibody or antigen
establishment of a baseline , SARS - Cov - 2 is added , followed binding fragment that selectively binds to a Sars - Cov - 2
by sandwiching of ACE2 or buffer. Dissociation in buffer is 45 virus, can comprise an amino acid sequence that is at least
measured . Capture of biotinylated ACE2 is included as a 20% , 25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % ,
self -blocking control. Alternatively, for a premix assay for- 70% , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 %
mat , a CR3022 -derived antibody or antigen -binding frag- identical to a VH CDR1 , a VH CDR2 , a VH CDR3 , a VL
ment herein are loaded onto the anti- V5 sensor tips . Fol- CDR1 , a VL CDR2 , and a VL CDR3 ; wherein the VH CDR1
lowing establishment of a baseline , a premix complex of 50 has an amino acid sequence of any one of SEQ ID NOS :
SARS - Cov - 2 +ACE2 , or a SARS - Cov - 2 alone are added to 154-187 ; the VH CDR2 has an amino acid sequence of any
the antibodies or antigen -binding fragments. Dissociation in one of SEQ ID NOS : 190-250 ; the VH CDR3 has an amino
buffer is measured . Capture of biotinylated ACE2 is acid sequence of any one of SEQ ID NOS : 256-316 ; a VL
included as a self -blocking control. CDR1 has an amino acid sequence of any one of SEQ ID
Representative CDR Sequences that Selectively Bind to 55 NOS : 2-62 ; a VL CDR2 has an amino acid sequence of any
SARS - Cov - 2 one of SEQ ID NOS : 64-89 and 444 ; and a VL CDR3 has
A CR3022 -derived antibody or antigen -binding fragment an amino acid sequence of any one of SEQ ID NOS : 91-151 .
herein that selectively binds to SARS - Cov - 2 can comprise Representative VH CDR3 Sequences
an amino acid sequence that is at least 20 % , 25 % , 30 % , A CR3022 - derived antibody or antigen -binding fragment
35 % , 40 % , 45 % , 50 % , 55 % , 60 % , 65 % , 70% , 75 % , 80 % , 60 herein that selectively binds to SARS - CoV - 2 can comprise
85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to a VH a VII CDR3 having an amino acid sequence of
CDR3 comprising an amino acid sequence of any one of any CAGX X2GISTPMDVW ( SEQ ID NO : 256 ) , wherein X , is
one of SEQ ID NOS : 257-316 . A CR3022 -derived antibody G or S ; and X , is S or W. In one instance, the VII CDR3
or antigen -binding fragment herein that selectively binds to comprises an amino acid sequence that is at least 20 % , 24 % ,
SARS - Cov - 2 can comprise a VH CDR3 having an amino 65 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60 % , 65 % , 70% , 75 % ,
acid sequence of CAGX , X_GISTPMDVW ( SEQ ID NO : 80% , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical to any
256 ) , wherein X , is G or S ; and X , is S or W. one of the following sequences:
 US 11,034,762 B1
9 10
Clone ID VH CDR3 SEQ ID NO : Clone ID VH CDR1 SEQ ID NO :
COVID19_P09_A09 CYSGSGISTPMDVW 257 COVID19 P09_A09 GTFSSYAIS 155
COVID19_P09_C09 CAGGSGISTPMDVW 258 COVID19_P09_C09 GTFSSYAIS 155
COVID19 P09 E05 CYSGSGISTPMDVW 259 5 COVID19_P09_E05 GTFSSYAIS 155
COVID19 P09 E11 CAGGSGISTPMDVW 260 COVID19_P09_E11 GTFSNHAIS 156
COVID19_P09_G05 CAGGSGISTPMDVW 261 COVID19_P09_G05 YTFTGHYMH 157
COVID19 P09 HOS CAGEWGISTPMDVW 262 COVID19_P09_H08 GTFSSYAIS 155
COVID19_P09_H09 CAGSGGISTPMDVW 263 COVID19_P09_H09 GTFITYWIY 158
COVID19_P10_A09 CAGGSGISTAWDVW 264 COVID19_P10_A09 YTFTDYYIH 159
COVID19 P10 B10 CAGGSGISTPMDVW 265 10 COVID19_P10_B10 YSFSDYHVH 160
COVID19_P10_C05 CAGSGGISTPMDVW 266 COVID19_P10_C05 GTFITYWIG 161
COVID19_P10_D08 CAGGSGISTPVGVW 267 COVID19_P10_D08 GTFNSHAIS 162
COVID19_P10_G03 CAGGSGISTPMDVW 268 COVID19_P10_G03 GTFSNSSIN 163
COVID19_P21_A12 CAGEWGISTPMDVW 269 COVID19_P21_A12 GTFSSYAIS 155
COVID19_P21_B01 CAGGSGISTPMDVW 270
COVID19_P21_B01 YTFSTYWIG 164
15 COVID19_P21_BO2 YTFTNYGIN 165
COVID19_P21_B02 CAAVSGISTPMDVW 271
COVID19_P21_B09 YTFTGHYMH 166
COVID19_P21_B09 CAGGSGISTPMDVW 272 COVID19_P21_B12 GTFSSYAIS 155
COVID19_P21_B12 CAGEWGISTPMDVW 273 COVID19_P21_E04 YTFTNYGIN 167
COVID19_P21_E04 CAGGSGISTPMDVW 274 COVID19_P21_E08 YGFITYWIG 168
COVID19_P21_E08 CAGGSGISTPMDVW 275 COVID19_P21_F02 YTFTSYGIS 169
COVID19_P21_F02 CLPGSGISTPMDVW 276 COVID19_P21_F08 GTFSTYAFN 170
COVID19_P21_F08 CAGGSGISTPGAVW 277 20 COVID19_P21_HO2 YGFITYWIG 168
COVID19_P21_HO2 CAGGSGLYTPMDVW 278 COVID19_P22_D06 GGFITYWIG 171
COVID19_P22_D06 CAGGSGVLTPMDVW 279 COVID19_P22_E06 GGFITYWIG 171
COVID19_P22_E06 CAGGSGISSDMDVW 280 COVID19 P22_G12 GGFITYWIG 171
COVID19_P22_G12 CAGGSGISTPMDVW 281 COVID19_P22_H10 GGFSTYWIG 172
COVID19_P22_H10 CAGGSGISTPMDVW 282 COVID19_P09_B07 GTFSSYAIS 155
283 25 COVID19_P09_B09 YRFTDYHLH 173
COVID19_P09_B07 CAGSWGISTPMDVW
COVID19 P09 B09 CAGGSGETTPMDVW 284 COVID19_P09_B10 YSFTDYHIH 174
COVID19_P09_B10 CAGGSGISTPMDVW 285 COVID19_P09_C05 YSFSDYYIH 175
COVID19_P09_C05 CAGGSGISTPMDVW 286 COVID19_P09_C08 YGFITYWIG 168
COVID19_P09_D06 YGFITYWIG 168
COVID19_P09_C08 CAGGSGISTPMDVW 287
COVID19_P09_GO2 GTFSSYAIS 155
COVID19_P09_D06 CAGGSGIYVPMDVW 288 COVID19_P09_G04 YGFITYWIG 168
30
COVID19_P09_GO2 CAGHWGISTPMDVW 289
COVID19_P09_G12 YPFTNYGIS 176
COVID19_P09_G04 CAGGSGLFTPMDVW 290 COVID19_P10_B04 YGFISYWIG 177
COVID19_P09_G12 CATLSGISTPMDVW 291 COVID19_P10_B06 GTFSSYAIS 155
COVID19_P10_B04 CAGSDGISTPMDVW 292 COVID19_P10_B08 GGFITYWIG 171
COVID19_P10_B06 CYSGSGISTPMDVW 293 COVID19_P21_A03 GTFSNNGLS 178
COVID19_P10_B08 CAGGSGISTPIDVW 294 35 COVID19_P21_A04 YGFITYWIG 168
COVID19_P21_A03 CRMGSGISTPMDVW 295 COVID19_P21_A05 GGFITYWIG 171
COVID19_P21_A04 CAGGSGLLTPMDVW 296 COVID19_P21_A08 GTFITYWIG 179
COVID19 P21_A05 CAGGSGISTPMDVW 297 COVID19_P21_A10 YGFITYWIG 168
COVID19_P21_A08 CAGGSGISTPMDVW 298 COVID19_P21_B08 GTFSSYAIS 155
COVID19_P21_B11 YGFITYWIG 168
COVID19_P21_A10 CAGGSGISTPMDVW 299
COVID19_P21_C09 YGFISYWIG 180
COVID19_P21_B08 CAGHWGISTPMDVW 300 40 COVID19_P21_E07 YGFITYWIG 168
COVID19_P21_B11 CAGSDGISTPMDVW 301
COVID19_P21_E12 GTFISYAIS 181
COVID19_P21_C09 CAGGSGILEPMDVW 302
COVID19_P21_F04 GTFSSYAIS 155
COVID19_P21_E07 CAGGSGISTPMDVW 303
COVID19_P21_E12 CAGSWGISTPMDVW 304 COVID19_P21_F11 GTFSSYAIS 155
COVID19_P21_H01 YGFSTYWIG 182
COVID19_P21_F04 CAGGSGISTPMDVW 305
COVID19_P21_H03 YTFTNYGIN 183
COVID19_P21_F11 CAGGSGISTLYDVW 306
307
45 COVID19_P22_B04 YGFITYWIG 168
COVID19_P21_H01 CAGGSGISTPMDVW
COVID19 P22 B12 GTLSSYAIS 184
COVID19_P21_HO3 CAVLSGISTPMDVW 308
COVID19_P22_C09 YNFTDYHIQ 185
COVID19_P22_B04 CAGGEGISTPMDVW 309
COVID19_P22_E10 GGFITYWIG 171
COVID19 P22 B12 CAGGSGISTPRSVW 310
COVID19_P22_C09 CAGGSGLTTPMDVW 311 COVID19_P22_E12 GTFSSYAIN 186
COVID19_P22_F04 GGFITYWIG 171
COVID19_P22_E10 CAGGSGISTPMDVW 312 50
COVID19_P22_F07 GTFSSYAIS 155
COVID19 P22 E12 CAGEWGISTPMDVW 313
COVID19_P22_F04 CAGGSGISTPMDVW 314
COVID19_P22_F11 GGFITYWIS 187

COVID19_P22_F07 CAGEWGISTPMDVW 315

COVID19_P22_F11 CAGGSGIIQPMDVW 316
Representative VH CDR1 Sequences
A CR3022 -derived antibody or antigen -binding fragment
herein that selectively binds to SARS - CoV - 2 can comprise
a VII CDR1 having an amino acid sequence of
X X FX X X X IX , ( SEQ ID NO : 154 ) , wherein X , is G
or Y ; X , is G or T ; X , is I , S , or T ; X , is D , S , T, or N ; X ,
is H or Y ; X. is A , W , G , or H ; and X , is G , H , or S. In one
instance, the VII CDR1 comprises an amino acid sequence
that is at least 20 % , 24 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 65 35 % , 40% , 45 % , 50 % , 55 % , 60 % , 65 % , 70% , 75 % , 80% ,
60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or
100% identical to any one of the following sequences :
Representative VH CDR2 Sequences
55
A CR3022 -derived antibody or antigen - binding fragment
herein that selectively binds to SARS -CoV - 2 can comprise
a VII CDR2 having an amino acid sequence of
GX X X3PX4X2XGX , X X , YX10 ( SEQ ID NO : 190) ,
60 wherein X , is G , I , or W ; X , is I or M ; X , is 1 , N , or Y ; X4
is G , N , or R ; X , is D , G , or S ; X is G or S ; X , is any amino
acid (Xaa ) or no amino acid ; X , is A or T; X , is G , N , or R ;
and X10 is A or S. In one instance, the VII CDR2 comprises
an amino acid sequence that is at least 20 % , 24 % , 30 % ,
85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to any one
of the following sequences:
 US 11,034,762 B1
11 12
-continued
Clone ID VH CDR2 SEQ ID NO :
COVID19_P09_A09 GIIYPGDSTTRYS 191
Clone ID VL CDR1 SEQ ID NO :
COVID19_P09_C09 GIIDPSGGSTSYA 192
COVID19 P09_E05 GIIYPGDSTTRYS 193 5 COVID19_P09_E05 KSSQSVLYSSINKNYLA 5
COVID19 P09 E11
COVID19_P09_G05
COVID19 P09_HOS
GIIYPGDGTTRYS
GIIYPGDSEARYS
GGIIPIFGTTNYA
194
195
196
COVID19_P09_E11
COVID19_P09_G05
COVID19_P09_H08
KSSQSVLYTSNNNNYLA
KSSQSVLYTSNNNNYLA
KSSQSVLYSSINKNYLA
oinna
6

8
COVID19_P09_H09 GIIYPGDGEARYS 197 COVID19_P09_H09 KSSQNVLYSSINKNYLA 9
COVID19_P10_A09 GWMNPNSGNTGYA 198 COVID19_P10_A09 TSSLSLQDRSNNKNYLT 10
COVID19_P10_B10 GMIIPRHGGTAYA 199 10 COVID19_P10_B10 KSSQSVLYSSNNKNYLA 11
COVID19_P10_C05 GIIYPGDGEARYS 200 COVID19_P10_C05 KSSQNVLYSSINKNYLA 12
COVID19_P10_D08 GWINPNSGATNYA 201 COVID19_P10_DOS KSSQSVLYSSINKNYLA 13
COVID19_P10_GO3 GRINPNSGGTNYA 202 COVID19_P10_G03 KSSQSVLYSSNNINYLA 14
COVID19_P21_A12 GSVIPVFGRPNYA 203 COVID19_P21_A12 KSSQSVLYSSINKNYLA 15
COVID19_P21_B01 GWIDPNSGGTNYA 204 COVID19_P21_B01 KSSQSVLYSSNKNNYLA 16
COVID19_P21_B02 GWMNPNSGNTGYA 205 15 COVID19_P21_B02 RSSQTVLYRSNNYNYLA 17
COVID19 P21_B09 GIIYPGDSEARYS 206
COVID19_P21_B09 KSSQSVLYSSNNLNYLA 18
COVID19 P21_B12 GMINPGGGNTNYA 207
COVID19_P21_B12 KSSQSVLYSSINKNYLA 19
COVID19 P21_E04 GWMNPNSGNTGYA 208
COVID19_P21_E08 GIIYPGDGETRYS 209 COVID19_P21_E04 KSSQSVLYSSNNKNYLA 20
COVID19_P21_F02 GIIYPGDGTTRYS 210 COVID19_P21_E08 KSSQSVLYSSINKNYLA 21
COVID19_P21_F08 GVINTGGGSVTYA 211 COVID19_P21_F02 KSSQRVLYSSNNLNYLA 22
COVID19 P21 HO2 GIIYPGDSETRYA 212 20 COVID19_P21_F08 KSSQSVLYSSNNINYLA 23
COVID19_P22_D06 GIIYPGDSETRYS 213 COVID19_P21_H02 KSSQSVLYSSINKNYLA 24
COVID19_P22_E06 GIIYPGDSETRYS 214 COVID19_P22_D06 KSSQSVLYSSINKNYLA 25
COVID19_P22_G12 GIIYPGDSETRYS 215 COVID19_P22_E06 KSSQSVLYSSINKNYLA 26
COVID19 P22 H10 GWINPNSGATKYA 216 COVID19_P22_G12 KSSQSVLYSSINKNYLA 27
COVID19_P09_B07 GGIIPTLGTANYA 217 COVID19_P22_H10 KSSQSVFHSSNNKNHLA 28
COVID19_P09_B09 GGIVPFSGTTNFA 218 25 COVID19_P09_B07 KSSQSVLYSSINKNYLA 29
COVID19_P09_B10 AMIVPRGGSTTYA 219 COVID19_P09_B09 KSSQSVLYSSINKNYLA 30
COVID19_P09_C05 GWIDPNSGGTNYA 220 COVID19_P09_B10 KSSQSVLYSSNNKNYLA 31
COVID19_P09_C08 GIIYPGDSETRYA 221 COVID19_P09_C05 KSSQSVLYSSNNHNYLA 32
COVID19_P09_D06 GIIYPGDSETRYA 222 COVID19_P09_C08 KSSQSVLHSAINKNYLA 33
COVID19_P09_G02 GIIYPGDSTTNYS 223
COVID19_P09_D06 KSSQSVLYSSINKNYLA 34
COVID19_P09_G04 GIIYPGDSETNYS 224 30 COVID19_P09_G02 KSSQSVLYSSINKNYLA 35
COVID19_P09_G12 GWMNPNSGNTGYA 225
COVID19_P10_B04 GIIYPGDGETRYS 226
COVID19_P09_G04 KSSQSVLYSSINKNYLA 36
COVID19_P10_B06 GIIYPGDSTTRYS 227 COVID19_P09_G12 RSSQSVLYSSNNKNYFA 37
COVID19_P10_B08 GWINPNSGGTKYA 228 COVID19_P10_B04 KSSQSVLYSSINKNYLA 38
COVID19_P21_A03 GGIIPIFGTANYA 229 COVID19_P10_B06 KSSQSVLYSSINKNYLA 39
COVID19_P21_A04 GIIYPGDSETRYS 230 35
COVID19 P10 BO8 KSSQSVLYSSNNKNYLA 40
COVID19_P21_A05 GIIYPGDGETRYS 231 COVID19_P21_A03 KSSQTISYSSDNKNYLA 41
COVID19_P21_A08 GWINPNSGGTNYA 232 COVID19_P21 A04 KSSQSVLYSSINKNYLA 42
COVID19_P21_A10 GIIYPGDGEARYS 233 COVID19_P21_A05 KSSQSVLYSSINKNYLA 43
COVID19_P21_B08 GVINTGGGSVTYA 234 COVID19_P21_A08 KSSQSVLYSSNNHNYLA 44
COVID19_P21_B11 GIIYPGDSETRYS 235 COVID19 P21 A10 KSSQSVLYSSINKNYLA 45
COVID19_P21_C09 GIIYPGDSETRYS 236
40
COVID19_P21_B08 KSSQSVLYSSINKNYLA 46
COVID19_P21_E07 GIIYPGDSETRYS 237 COVID19_P21_B11 KSSQSVLYSSINKNYLA 47
COVID19_P21_E12 GGIIPTLGTYNYA 238 COVID19_P21_C09 KSSQSVLYSSINKNYLA 48
COVID19_P21_F04 GQINPSGDSTRYA 239 COVID19_P21_E07 KSTQSVLYSSINKNYVA 49
COVID19_P21_F11 GIIYPGDSTARYS 240 COVID P21 KSSQSVLYSSINKNYLA 50
COVID19_P21_H01 GWINPNSGGTNYA 241
COVID19_P21_HO3 GWMNPYSGNTGYA 242
COVID19_P21_F04 KSSQSVLHSSNNLNYFA 51

COVID19_P22_B04 GIIYPGDSETRYA 243 45 COVID19_P21_F11 TSSQSVLHS SNNLNYLA 52

COVID19_P22_B12 GIIYPGDSETRYS 244 COVID19_P21_H01 KSSQSVLYRSNNLHYLA 53
COVID19_P22_C09 GMIIPRHGGTAYA 245 COVID19_P21_H03 KSSQSVLYSSNNKNYLA 54
COVID19 P22 E10 GIIYPGDGETRYS 246
COVID19 P22 B04 KSSQSVLYSSINKNYLA 55
COVID19_P22_E12 GGIIPVLHTVDYA 247 COVID19 P22 B12 KSSRILSYSPDNKNYLA 56
COVID19_P22_F04 GIIYPGDGEARYS 248 COVID19_P22_C09 KSSQSVLYSSNNKNYLA 57
COVID19_P22_F07 GGIIPIFGSTASYA 249 50 COVID19_P22_E10 KSSQSVLYSSINKNYLA 58
COVID19_P22_F11 GIIYPGDGEARYS 250 COVID19 P22 E12 KSSQSVLYSSINKNYLA 59
COVID19_P22_F04 KSSQSVLYSSINKNYLA 60
Representative VL CDR1 Sequences COVID19_P22_F07 KSSQSVLYSSINKNYLA 61

A CR3022 - derived antibody or antigen -binding fragment COVID19_P22_F11 KSSQSVLYSSINKNYLA 62

herein that selectively binds to SARS -CoV - 2 can comprise 55

a VL CDR1 having an amino acid sequence of
KSSQSX LYSSX NX NYLA ( SEQ ID NO : 2 ) , wherein X Representative VL CDR2 Sequences
is Vor L ; X , is I or N ; and X2 is K or L. In one instance, the A CR3022 - derived antibody or antigen -binding fragment
VL CDR1 comprises an amino acid sequence that is at least herein that selectively binds to SARS - CoV - 2 can comprise
20 % , 24 % , 30 % , 35 % , 40 % , 45 % , 50% , 55 % , 60% , 65 % , a VL CDR2 having an amino acid sequence of
70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100 % 60 X X X X RX X ( SEQ ID NO : 64 ) , wherein X , is W or R ;
identical to any one of the following sequences:
X , is A , S , or G ; X2 is S , T, or N ; X4 is T, L , F, or N ; X , is
E , A , G , or L ; and X , is S , P, G , F, or A. In one instance, the
Clone ID VL CDR1 SEQ ID NO : VL CDR2 comprises an amino acid sequence that is at least
COVID19_P09_A09 KSSQSVLYSSINKNYLA 3 65 20% , 24 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % ,
COVID19_P09_C09 KSSQSVLYSSNNYLA 4 70% , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 %
identical to any one of the following sequences :
 US 11,034,762 B1
13 14
Clone ID VL CDR2 SEQ ID NO : Clone ID VL CDR3 SEQ ID NO :
COVID19_P09_A09 WASTRES 65 COVID19_P09_A09 CRQYYSTPWTF 92
COVID19_P09_C09 WASTRES 65 COVID19_P09_C09 CRQYYSTPWTF 93
COVID19_P09_E05 WASTRES 65 5 COVID19_P09_E05 CRQYYSTPWTF 94
COVID19_P09_E11 WASTRES 65 COVID19_P09_E11 CRQYYSTPWTF 95
COVID19_P09_G05 WGSTRGS 66 COVID19_P09_G05 CRQYYSTPWTF 96
COVID19_P09_HOS WANIRES 67 COVID19_P09_H08 CQQYYSTPLTF 97
COVID19_P09_H09 WASTRES 65 COVID19_P09_H09 CQQYYTTPYTF 98
COVID19_P10_A09 WASTRES 65 COVID19_P10_A09 CQQHYSAPLTF 99
COVID19 P10 B10 WASTRDF 68 10 COVID19_P10_B10 CQQYYALPLTF 100
COVID19_P10_C05 WASTRES 65 COVID19_P10_C05 CQQYYTTPYTF 101
COVID19 P10_D08 WASTRES 65 COVID19_P10_D08 CRQYYSTPWTF 102
COVID19_P10_G03 WASTRAS 69 COVID19_P10_GO3 CRQYYSTPWTF 103
COVID19_P21_A12 WASLREG 70 COVID19_P21_A12 CQQYYYAPWTF 104
COVID19_P21_B01 CRQYYSTPWTF 105
COVID19_P21_B01 WASTRLS 71
15 COVID19_P21_B02 CQQYYSTPPTF 106
COVID19_P21_B02 WASTRES 65
COVID19_P21_B09 WGSTRGS 72
COVID19_P21_B09 CRQYYSTPWTF 107

COVID19 P21 B12 WASYRES 73

COVID19_P21_B12 CQQYYGFPLTF 108
COVID19_P21_E04 CHQYYSTPPTF 109
COVID19_P21_E04 WASNREP 74 COVID19_P21_E08 CQQYYSTPYTF 110
COVID19_P21_E08 WAYTREP 75 COVID19_P21_F02 CRQYYSTPWTF 111
COVID19_P21_F02 WASTRGS 76 COVID19_P21_F08 CRQYYSTPWTF 112
COVID19_P21_F08 WASTRAA 77 20 COVID19 P21 HO2 CQQYHTIPYTF 113
COVID19_P21_HO2 WASTRES 65 COVID19_P22_D06 CQQYYATPYTF 114
COVID19_P22_D06 WASTRES 65 COVID19_P22_E06 CQQYYKIPYTF 115
COVID19_P22_E06 WASTREF 78 COVID19_P22_G12 CQQYYTTPYTF 116
COVID19_P22_G12 WASMRES 79 COVID19_P22_H10 CRQYYSTPWTF 117
COVID19_P22_H10 WASTRES 65 COVID19_P09_B07 CQQYHSTPLTF 118
70 25 COVID19_P09_B09 CQQYYSLPLTF 119
COVID19_P09_B07 WASLREG
COVID19_P09_B09 WASSRES 80 COVID19_P09_B10 CQQYYSTPVTF 120
65 COVID19_P09_C05 CRQYYSTPWTF 121
COVID19_P09_B10 WASTRES
COVID19_P09_C08 CQQYSTTPYTF 122
COVID19_P09_C05 WASTRES 65
COVID19_P09_D06 CQQYYKIPYTF 123
COVID19_P09_C08 WASTRES 65
COVID19 P09 GO2 CQQYHSTPWTF 124
COVID19_P09_D06 WASTRES 65 COVID19_P09_G04 CQQYSTTPYTF 125
30
COVID19_P09_G02 WASYRES 73
COVID19_P09_G12 CHQYYTTPPTF 126
COVID19_P09_G04 WASTRES 65 COVID19_P10_B04 CQQYYSTPYTF 127
COVID19_P09_G12 WASIRGS 444 COVID19_P10_B06 CRQYYSTPWTF 128
COVI P10_B WASTRES 65 COVID19_P10_B08 CQQYYSTVITE 129
COVID19_P10_B06 WASTRES 65 COVID19_P21_A03 CRQYYSTPWTF 130
COVID19_P10_B08 RASTRAS 81 35 COVID19 P21 A04 CQQYYSTPYTF 131
COVID19_P21_A03 WASTRLS 82 COVID19_P21_A05 CQQYYSTPYTF 132
COVID19_P21_A04 WASTRES 65 COVID19_P21_A08 CRQYYSTPWTF 133
COVID19_P21_A05 WASSRES 80 COVID19_P21_A10 CQQYHSTPYTF 134
COVID19 P21_A08 WASTRGS 83 COVID19_P21_B08 CQQYYGTPFTF 135
COVID19_P21_A10 WASTREP 84 COVID19_P21_B11 CQQYYSTPYTF 136
COVID19_P21_B08 WASFRES 88 40
COVID19_P21_C09 CQQYSSTPYTF 137
COVID19_P21_B11 WASTRES 65 COVID19_P21_E07 CQQYYSTPYTF 138
COVID19_P21_E12 CQQYHSTPLTF 139
COVID19_P21_C09 WASTRES 65
COVID19_P21_E07 WASTRES 65
COVID19_P21_F04 CRQYYSTPWTF 140
COVID19_P21_E12 WASLREG 70
COVID19_P21_F11 CRQYYSTPWTF 141
COVID19_P21_H01 CRQYYSTPWTF 142
COVID19_P21_F04 WASTRLS 85 COVID19_P21_H03 CHQYYNTPPTF 143
COVID19_P21_F11 WASTRES 65 45 COVID19 P22 B04 CQQYYSTPYTF 144
COVID19_P21_H01 WASTRSS 86 COVID19 P22 B12 CQQSYITPYTF 145
COVID19_P21_HO3 WATNRES 87 COVID19_P22_C09 CQHYYNTPLTF 146
COVID19_P22_B04 WASTRES 65 COVID19_P22_E10 CQQYYGIPYTF 147
COVID19 P22 B12 WASTRES 65 COVID19_P22_E12 CQQYLSTPLTF 148
COVID19_P22_C09 WASTRES 65 COVID19_P22_F04 CQQYHSTPYTF 149
COVID19_P22_E10 WASTRES 65 50 COVID19_P22_F07 CQQYYTAPFTF 150
COVID19_P22_E12 WASFRES 88 COVID19_P22_F11 CQQYLSTPLTF 151
COVID19_P22_F04 WASTRES 65
COVID19_P22_F07 WSSLRES 89
COVID19_P22_F11 WASTRES 65 Representative CDR Combinations
In one instance , the antibody or antigen -binding fragment
55 that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
Representative VL CDR3 Sequences CDR3 having an amino acid sequence that is at least 20 % ,
A CR3022 - derived antibody or antigen -binding fragment 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
herein that selectively binds to SARS - CoV - 2 can comprise to SEQ ID NO : 257 ; (ii ) a VH CDR1 having an amino acid
a VL CDR3 having an amino acid sequence of
60 sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CX ,QYX X X4PXzTF ( SEQ ID NO : 91 ) , wherein X , is Q , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
R , or H ; X , is Y, H , or S ; X2 is S or T; X4 is T or L , and X , 98 % , 99 % , or 100% identical to SEQ ID NO : 155 ; ( ii ) a VH
is L , W , or Y. In one instance , the VL CDR3 comprises an CDR2 having an amino acid sequence that is at least 20 % ,
amino acid sequence that is at least 20 % , 24 % , 30 % , 35 % , 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
40 % , 45 % , 50 % , 55 % , 60 % , 65 % , 70% , 75 % , 80% , 85 % , 65 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
90 % , 95 % , 98 % , 99 % , or 100 % identical to any one of the to SEQ ID NO : 191 ; ( iv ) a VL CDR1 having an amino acid
following sequences: sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
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50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 194 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100% identical to SEQ ID NO : 3 ; (v) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 6 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 5 CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 92 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen - binding fragment 10 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 95 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen - binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 258 ; (ii ) a VH CDR1 having an amino acid 15 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 261 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 155 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 20 98 % , 99 % , or 100% identical to SEQ ID NO : 157 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 192 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 195 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100% identical to SEQ ID NO : 4 ; (v) a VL 25 sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 7 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 30 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 66 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 93 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen -binding fragment 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 96 .
CDR3 having an amino acid sequence that is at least 20 % , 35 In one instance, the antibody or antigen - binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 259 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 40 to SEQ ID NO : 262 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 155 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 155 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 193 ; (iv ) a VL CDR1 having an amino acid 45 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 196 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100% identical to SEQ ID NO : 5 ; (v) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 50 98 % , 99 % , or 100% identical to SEQ ID NO : 8 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 67 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 94 . 55 acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance , the antibody or antigen - binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 97 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen - binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 60 CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 260 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 263 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 156 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 65 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 158 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
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25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 161 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 197 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 5 to SEQ ID NO : 200 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100% identical to SEQ ID NO : 9 ; (v) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 12 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino 10 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 98 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 15 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 101 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance , the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 264 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 20 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 267 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 159 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 162 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 25 CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 198 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 201 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 10 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 30 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 13 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , 35 to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 99 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 102 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 40 that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 265 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 268 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 160 ; ( ii ) a VH 45 sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 163 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 199 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 50 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 202 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 11 ; (v) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 14 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 55 CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 68 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 69 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 100 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen -binding fragment 60 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 103 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 50% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 266 ; (ii ) a VH CDR1 having an amino acid 65 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 269 ; (ii ) a VH CDR1 having an amino acid
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sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 272 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 155 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 5 98 % , 99 % , or 100% identical to SEQ ID NO : 166 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 203 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 206 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 15 ; (v ) a VL 10 sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 18 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 70 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 15 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 72 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 104 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 107 .
CDR3 having an amino acid sequence that is at least 20 % , 20 In one instance, the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 270 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 25 to SEQ ID NO : 273 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 164 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 50% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 155 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 204 ; (iv ) a VL CDR1 having an amino acid 30 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 207 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 16 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 35 98 % , 99 % , or 100 % identical to SEQ ID NO : 19 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 71 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % ,
to SEQ ID NO : 73 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 105 . 40 acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 108 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance , the antibody or antigen - binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 45 CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 271 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 274 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 165 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 167 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 205 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 55 to SEQ ID NO : 208 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 17 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 20 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino 60 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 74 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 106 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance , the antibody or antigen - binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 65 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 109 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen - binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
 US 11,034,762 B1
21 22
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 275 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 5 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 278 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 168 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 168 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 10 CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 209 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 212 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 21 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 15 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 24 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 75 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , 20 to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 110 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 113 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 25 that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 276 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 279 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 169 ; ( ii ) a VH 30 sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 171 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 210 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 35 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 213 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 22 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 25 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 40 CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 76 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 111 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen -binding fragment 45 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 114 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 277 ; (ii ) a VH CDR1 having an amino acid 50 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 280 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 170 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 55 98 % , 99 % , or 100% identical to SEQ ID NO : 171 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 211 ; (iv) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 214 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 23 ; (v ) a VL 60 sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 26 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 77 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 65 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 78 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 112 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
 US 11,034,762 B1
23 24
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 70 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 115 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 118 .
CDR3 having an amino acid sequence that is at least 20 % , 5 In one instance, the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 281 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 10 to SEQ ID NO : 284 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 171 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 173 ; ( ii ) a VH
75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 215 ; (iv ) a VL CDR1 having an amino acid 15 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 218 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 27 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 20 98 % , 99 % , or 100 % identical to SEQ ID NO : 30 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 79 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 80 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 116 . 25 acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance , the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 119 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen - binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 30 CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 282 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , to SEQ ID NO : 285 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 172 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 35 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 174 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 216 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 40 to SEQ ID NO : 219 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 28 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 31 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino 45 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 117 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 50 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 120 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 283 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 55 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 286 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 155 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 175 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 60 CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 217 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 220 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 29 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 65 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 32 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
 US 11,034,762 B1
25
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , 5 to SEQ ID NO : 73 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 121 .
In one instance, the antibody or antigen -binding fragment
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
CDR3 having an amino acid sequence that is at least 20 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 10 that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical
to SEQ ID NO : 287 ; (ii ) a VH CDR1 having an amino acid
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % ,
98 % , 99 % , or 100 % identical to SEQ ID NO : 168 ; ( ii ) a VH 15
CDR2 having an amino acid sequence that is at least 20 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical
to SEQ ID NO : 221 ; (iv ) a VL CDR1 having an amino acid
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 20
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % ,
98 % , 99 % , or 100 % identical to SEQ ID NO : 33 ; (v ) a VL
CDR2 having an amino acid sequence that is at least 20 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 25
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % ,
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 122 .
In one instance , the antibody or antigen - binding fragment 30
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
CDR3 having an amino acid sequence that is at least 20 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical
to SEQ ID NO : 288 ; (ii ) a VH CDR1 having an amino acid 35
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % ,
98 % , 99 % , or 100 % identical to SEQ ID NO : 168 ; ( ii ) a VH
CDR2 having an amino acid sequence that is at least 20 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 40
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical
to SEQ ID NO : 222 ; (iv ) a VL CDR1 having an amino acid
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % ,
98 % , 99 % , or 100 % identical to SEQ ID NO : 34 ; (v ) a VL 45
CDR2 having an amino acid sequence that is at least 20 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 50
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % ,
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 123 .
In one instance, the antibody or antigen -binding fragment
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
CDR3 having an amino acid sequence that is at least 20 % , 55
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical
to SEQ ID NO : 289 ; (ii ) a VH CDR1 having an amino acid
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 60
98 % , 99 % , or 100 % identical to SEQ ID NO : 155 ; ( ii ) a VH
CDR2 having an amino acid sequence that is at least 20 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical
to SEQ ID NO : 223 ; (iv ) a VL CDR1 having an amino acid 65
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % ,
26
98 % , 99 % , or 100 % identical to SEQ ID NO : 35 ; (v) a VL
CDR2 having an amino acid sequence that is at least 20 % ,
25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 124 .
In one instance, the antibody or antigen -binding fragment
CDR3 having an amino acid sequence that is at least 20 % ,
25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
to SEQ ID NO : 290 ; (ii ) a VH CDR1 having an amino acid
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
98 % , 99 % , or 100% identical to SEQ ID NO : 168 ; ( ii ) a VH
CDR2 having an amino acid sequence that is at least 20 % ,
25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
to SEQ ID NO : 224 ; ( iv ) a VL CDR1 having an amino acid
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
98 % , 99 % , or 100 % identical to SEQ ID NO : 36 ; (v) a VL
CDR2 having an amino acid sequence that is at least 20 % ,
25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 125 .
In one instance, the antibody or antigen -binding fragment
that selectively binds SARS - Cov - 2 can comprise (i ) a VH
CDR3 having an amino acid sequence that is at least 20 % ,
25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
to SEQ ID NO : 291 ; (ii ) a VH CDR1 having an amino acid
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
98 % , 99 % , or 100% identical to SEQ ID NO : 176 ; ( ii ) a VH
CDR2 having an amino acid sequence that is at least 20 % ,
25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
to SEQ ID NO : 225 ; ( iv ) a VL CDR1 having an amino acid
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
98 % , 99 % , or 100 % identical to SEQ ID NO : 37 ; (v) a VL
CDR2 having an amino acid sequence that is at least 20 % ,
25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
to SEQ ID NO : 444 ; and ( vi) a VL CDR3 having an amino
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 126 .
In one instance, the antibody or antigen -binding fragment
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
CDR3 having an amino acid sequence that is at least 20 % ,
25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
to SEQ ID NO : 292 ; (ii ) a VH CDR1 having an amino acid
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
98 % , 99 % , or 100% identical to SEQ ID NO : 177 ; ( ii ) a VH
CDR2 having an amino acid sequence that is at least 20 % ,
25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
to SEQ ID NO : 226 ; ( iv ) a VL CDR1 having an amino acid
 US 11,034,762 B1
27 28
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 229 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 38 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 5 98 % , 99 % , or 100 % identical to SEQ ID NO : 41 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 82 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 127 . 10 acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 130 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen - binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 15 CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 293 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 296 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 155 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 20 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 168 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 227 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 25 to SEQ ID NO : 230 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 39 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 42 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino 30 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 128 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance , the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 35 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 131 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 294 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 40 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 297 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 177 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 171 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 45 CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 228 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 231 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 40 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 43 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 81 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , 55 to SEQ ID NO : 80 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 129 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance , the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 132 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 60 that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 295 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 298 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 178 ; ( ii ) a VH 65 sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 179 ; ( ii ) a VH
 US 11,034,762 B1
29 30
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 168 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 232 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 5 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 235 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 44 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 47 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 10 CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 83 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 133 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen -binding fragment 15 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 136 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 299 ; (ii ) a VH CDR1 having an amino acid 20 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 302 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 168 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 25 98 % , 99 % , or 100% identical to SEQ ID NO : 180 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 233 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 236 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 45 ; (v ) a VL 30 sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 48 ; (v) a VL
75 % , 80 % , % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 84 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 35 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 134 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 137 .
CDR3 having an amino acid sequence that is at least 20 % , 40 In one instance, the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 300 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 45 to SEQ ID NO : 303 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 155 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 168 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 234 ; (iv ) a VL CDR1 having an amino acid 50 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 237 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 46 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 55 98 % , 99 % , or 100 % identical to SEQ ID NO : 49 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 88 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 135 . 60 acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance , the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 138 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen - binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 65 CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 301 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
 US 11,034,762 B1
31 32
to SEQ ID NO : 304 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 307 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 181 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 5 50% , 55 % , 50 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 182 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 238 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 10 to SEQ ID NO : 241 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 50 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 98 % , 99 % , or 100 % identical to SEQ ID NO : 53 ; (v) a VL
to SEQ ID NO : 70; and (vi) a VL CDR3 having an amino 15 25CDR2 having an amino acid sequence that is at least 20 % ,
% , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 139 . to SEQ ID NO : 86 ; and (vi ) a VL CDR3 having an amino
In one instance, the antibody or antigen -binding fragment acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
that selectively binds to SARS-Cov- 2 can comprise (i) a VH 20 4595 %% ,, 9850%% ,, 9955%%,, or60%100, 65%%identical
CDR3 having an amino acid sequence that is at least 20 % ,
, 70% , 75to %SEQ
, 80%ID, 85NO%: , 142
90%. ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , In one instance, the antibody or antigen -binding fragment
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
to SEQ ID NO : 305 ; (ii ) a VH CDR1 having an amino acid CDR3 having an amino acid sequence that is at least 20 % ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 25 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
98 % , 99 % , or 100 % identical to SEQ ID NO : 155 ; ( ii ) a VH to SEQ ID NO : 308 ; (ii ) a VH CDR1 having an amino acid
CDR2 having an amino acid sequence that is at least 20 % , sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 30 98 % , 99 % , or 100% identical to SEQ ID NO : 183 ; ( ii ) a VH
to SEQ ID NO : 239 ; (iv ) a VL CDR1 having an amino acid CDR2 having an amino acid sequence that is at least 20 % ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
50 % , 55 % , 60 % , 65 % , 0 % , 75 % , 80% , 5 % , 90% , 95 % , 75 % , 0% , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
98 % , 99 % , or 100 % identical to SEQ ID NO : 51 ; (v ) a VL to SEQ ID NO : 242 ; ( iv ) a VL CDR1 having an amino acid
CDR2 having an amino acid sequence that is at least 20 % , 35 sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 98 % , 99 % , or 100 % identical to SEQ ID NO : 54 ; (v) a VL
to SEQ ID NO : 85 ; and (vi ) a VL CDR3 having an amino CDR2 having an amino acid sequence that is at least 20 % ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , 40 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 140 . to SEQ ID NO : 87 ; and (vi ) a VL CDR3 having an amino
In one instance, the antibody or antigen - binding fragment acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
CDR3 having an amino acid sequence that is at least 20 % , 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 143 .
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 45 In one instance, the antibody or antigen - binding fragment
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
to SEQ ID NO : 306 ; (ii ) a VH CDR1 having an amino acid CDR3 having an amino acid sequence that is at least 20 % ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
98 % , 99 % , or 100 % identical to SEQ ID NO : 155 ; ( ii ) a VH 50 to SEQ ID NO : 309 ; (ii ) a VH CDR1 having an amino acid
CDR2 having an amino acid sequence that is at least 20 % , sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 98 % , 99 % , or 100% identical to SEQ ID NO : 168 ; ( ii ) a VH
to SEQ ID NO : 240 ; (iv ) a VL CDR1 having an amino acid CDR2 having an amino acid sequence that is at least 20 % ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 55 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
98 % , 99 % , or 100 % identical to SEQ ID NO : 52 ; (v ) a VL to SEQ ID NO : 243 ; ( iv ) a VL CDR1 having an amino acid
CDR2 having an amino acid sequence that is at least 20 % , sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 60 98 % , 99 % , or 100 % identical to SEQ ID NO : 55 ; (v) a VL
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino CDR2 having an amino acid sequence that is at least 20 % ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 141 . to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
In one instance, the antibody or antigen -binding fragment 65 acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
CDR3 having an amino acid sequence that is at least 20 % , 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 144 .
 US 11,034,762 B1
33 34
In one instance , the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 147 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 5 CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 310 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 313 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 184 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 10 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 186 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 244 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 15 to SEQ ID NO : 247 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 56 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 59 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino 20 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , to SEQ ID NO : 88 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 145 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance , the antibody or antigen - binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 25 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 148 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen - binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 311 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 30 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 314 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 185 ; ( ii ) a VH sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 171 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 35 CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 245 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 248 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 57 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 40 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 60 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , 45 to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 146 . acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
In one instance, the antibody or antigen -binding fragment 45 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% ,
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH 95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 149 .
CDR3 having an amino acid sequence that is at least 20 % , In one instance, the antibody or antigen -binding fragment
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 50 that selectively binds to SARS - Cov - 2 can comprise (i ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR3 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 312 ; (ii ) a VH CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 315 ; (ii ) a VH CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 171 ; ( ii ) a VH 55 sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100% identical to SEQ ID NO : 155 ; ( ii ) a VH
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 246 ; (iv ) a VL CDR1 having an amino acid 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 60 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to SEQ ID NO : 249 ; ( iv ) a VL CDR1 having an amino acid
98 % , 99 % , or 100 % identical to SEQ ID NO : 58 ; (v ) a VL sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,
CDR2 having an amino acid sequence that is at least 20 % , 50% , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90% , 95 % ,
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 61 ; (v) a VL
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 65 CDR2 having an amino acid sequence that is at least 20 % ,
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino 25 % , 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70% ,
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
 US 11,034,762 B1
35 36
to SEQ ID NO : 89 ; and (vi ) a VL CDR3 having an amino -continued
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % ,
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , Clone ID FW -L1 SEQ ID NO :
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 150 . COVID19_P10_D08 DIVMTQSPDSLAVSLGERATINC 1
In one instance, the antibody or antigen -binding fragment 5
COVID19_P10_G03 DIVMTQSPDSLAVSLGERATINC 1
that selectively binds to SARS - Cov - 2 can comprise (i ) a VH COVID19_P21_A12 DIVMTQSPDSLAVSLGERATINC 1

CDR3 having an amino acid sequence that is at least 20 % , COVID19_P21_B01 DIVMTQSPDSLAVSLGERATINO 1

COVID19_P21_B02 DIVMTQSPDSLAVSLGERATINC 1
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , COVID19_P21_B09 DIVMTQSPDSLAVSLGERATINC 1
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical COVID19_P21_B12 DIVMTQSPDSLAVSLGERATINC 1

to SEQ ID NO : 316 ; (ii ) a VH CDR1 having an amino acid 10 COVID19_P21_E04 DIVMTQSPDSLAVSLGERATINO 1

sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % ,

COVID19_P21_E08 DIVMTQSPDSLAVSLGERATINC 1
COVID19_P21_F02 DIVMTQSPDSLAVSLGERATINC 1
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , COVID19_P21_F08 DIVMTQSPDSLAVSLGERATINC 1
98 % , 99 % , or 100 % identical to SEQ ID NO : 187 ; ( ii ) a VH COVID19 P21 HO2 DIVMTQSPDSLAVSLGERATINC 1
COVID19 P22 D06
CDR2 having an amino acid sequence that is at least 20 % , 15 COVID19_P22_E06 DIVMTQSPDSLAVSLGERATINC 1

25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , DIVMTQSPDSLAVSLGERATINC 1
COVID19_P22_G12 DIVMTQSPDSLAVSLGERATINC 1
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical COVID19_P22_H10 DIVMTQSPDSLAVSLGERATINC 1
to SEQ ID NO : 250 ; (iv ) a VL CDR1 having an amino acid COVID19_P09_B07 DIVMTQSPDSLAVSLGERATINC 1
sequence that is at least 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , COVID19_P09_B09 DIVMTQSPDSLAVSLGERATINC
COVID19_P09_B10 DIVMTQSPDSLAVSLGERATINC 1
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , 20 COVID19_P09_C05 DIVMTQSPDSLAVSLGERATINC 1
98 % , 99 % , or 100 % identical to SEQ ID NO : 62 ; (v ) a VL COVID19_P09_C08 DIVMTQSPDSLAVSLGERATINC 1
CDR2 having an amino acid sequence that is at least 20 % , COVID19_P09_D06 DIVMTQSPDSLAVSLGERATINC 1
25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , COVID19_P09_G02 DIVMTQSPDSLAVSLGERATINC 1
COVID19_P09_G04 DIVMTQSPDSLAVSLGERATINC 1
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical COVID19 P09 G12 DIVMTQSPDSLAVSLGERATINC 1
to SEQ ID NO : 65 ; and (vi ) a VL CDR3 having an amino 25
COVID19_P10_B04 DIVMTQSPDSLAVSLGERATINC 1
acid sequence that is at least 20 % , 25 % , 30% , 35 % , 40 % , COVID19 P10 B06 DIVMTQSPDSLAVSLGERATINO 1
45 % , 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90 % , COVID19_P10_BOX DIVMTQSPDSLAVSLGERATINC 1
COVID19 P21 A03 DIVMTQSPDSLAVSLGERATINC 1
95 % , 98 % , 99 % , or 100 % identical to SEQ ID NO : 151 . COVID19 P21 A04 DIVMTQSPDSLAVSLGERATINC 1
Representative Frameworks (FW ) of Antibodies and Anti- COVID19 P21 A05 DIVMTQSPDSLAVSLGERATINC 1
gen - Binding Fragments that Selectively Bind to SARS- COVID19 P21 A08 DIVMTQSPDSLAVSLGERATINC 1
COV - 2 30 COVID19_P21_A10 DIVMTQSPDSLAVSLGERATINC 1
COVID19 P21 B08 DIVMTQSPDSLAVSLGERATINC 1
A CR3022 -derived antibody or antigen -binding fragment COVID19_P21_B11 DIVMTQSPDSLAVSLGERATINC 1
herein that selectively binds to SARS - Cov - 2 can comprise COVID19_P21_C09 DIVMTQSPDSLAVSLGERATINC 1
an amino acid sequence that is at least 20 % , 25 % , 30 % , COVID19_P21_E07 DIVMTQSPDSLAVSLGERATINC 1
COVID19 P21 E12 DIVMTQSPDSLAVSLGERATINC 1
35 % , 40 % , 45 % , 50 % , 55 % , 60 % , 65 % , 70% , 75 % , 80 % , 35 COVID19_P21_F04 DIVMTQSPDSLAVSLGERATINC 1
85 % , 90 % , 95 % , 98 % , 99 % , or 100 % identical to one or COVID19_P21_F11 DIVMTQSPDSLAVSLGERATINC 1
more of a FW- L1 comprising an amino acid sequence of COVID19_P21_H01 DIVMTQSPDSLAVSLGERATINC 1
SEQ ID NO : 1 or 442 , a FW- L2 comprising an amino acid COVID19 P21 HO3 DIVMTQSPDSLAVSLGERATINO 1

of SEQ ID NO : 63 or 443 , a FW -L3 comprising an amino COVID19 P22 B04 DIVMTQSPDSLAVSLGERATINC 1

COVID19_P22_B12 DIVMTQSPDSLAVSLGERATINC 1
acid sequence of any one of SEQ ID NO : 90 or 445 , a 40 COVID19_P22_C09 DIVMTQSPDSLAVSLGERATINC 1
FW - L4 comprising amino acid sequence of SEQ ID NO : COVID19_P22_E10 DIVMTQSPDSLAVSLGERATINC 1
152 a FW -H1 comprising an amino acid sequence of SEQ ID COVID19_P22_E12 DIVMTQSPDSLAVSLGERATINC
COVID19_P22_F04 DIVMTQSPDSLAVSLGERATINC
1
1
NO : 153 , a FW -H2 comprising amino acid sequence of SEQ COVID19_P22_F07 DIVMTQSPDSLAVSLGERATINC
ID NO : 188 , 446 , or 447 , a FW- H3 comprising an amino COVID19_P22_F11 DIVMTQSPDSLAVSLGERATINC 1
acid sequence of any one of SEQ ID NOS : 251-254 and 45
448-449 , and a FW- H4 comprising an amino acid sequence Representative FW -L2 Sequences
of SEQ ID NO : 317 . A CR3022 - derived antibody or antigen -binding fragment
Representative FW -L1 Sequences
A CR3022 - derived antibody or antigen -binding fragment herein that selectively binds to SARS - CoV - 2 can comprise
herein that selectively binds to a Sars - Cov - 2 can comprise a a FW- L2 having an amino acid sequence that is at least 20 % ,
VL framework (FW ) 1 (FW -L1) having an amino acid 50 2475%% ,, 30 % , 35%, 40 % , 45%, 50%, 55 %, 60%, 65%, 70%,
80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
sequence that is at least 20 % , 24 % , 30 % , 35 % , 40 % , 45 % ,
50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80% , 85 % , 90% , 95 % , to any one of the following sequences :
98 % , 99 % , or 100 % identical to any one of the following
sequences:
55 Clone ID FW - L2 SEQ ID NO :
COVID19_P09_A09 WYQQKPGQPPKLLIS 63
Clone ID FW - L1 SEQ ID NO : COVID19_P09_C09 WYQQKPGQPPKLLIS 63
COVID19_P09_E05 WYQQKPGQPPKLLIS 63
COVID19_P09_A09 DIVMTQSPDSLAVSLGERATINC 1 COVID19_P09_E11 WYQQKPGQPPKLLIS 63
COVID19_P09_C09 DIVMTQSPDSLAVSLGERATINC 1
60
COVID19_P09_G05 WYQQKPGQPPKLLIY 443
COVID19_P09_E05 DIVMTQSPDSLAVSLGERATINC 1 COVID19_P09_HOS WYQQKPGQPPKLLIY 443
COVID19_P09_E11 DIVMTQSPDSLAVSLGERATINC 1 COVID19_P09_H09 WYQQKPGQPPKLLIY 443
COVID19_P09_G05 DIVMTQSPDSLAVSLGERATINC 1 COVID19_P10_A09 WYQQKPGQPPKLLIY 443
COVID19_P09_HOS DIVMTQSPDSLAVSLGERATINC 1 COVID19_P10_B10 WYQQKPGQPPKLLIY 443
COVID19_P09_H09 DIVMTQSPDSLAVSLGERATINC 1 COVID19_P10_C05 WYQQKPGQPPKLLIY 443
COVID19_P10_A09 DIVMTQSPDSLAVSLGERATIRO 442
65
COVID19_P10_D08 WYQQKPGQPPKLLIS 63
COVID19_P10_B10 DIVMTQSPDSLAVSLGERATINC 1 COVID19_P10_G03 WYQQKPGQPPKLLIY 443
COVID19_P10_C05 DIVMTQSPDSLAVSLGERATINC 1 COVID19_P21_A12 WYQQKPGQPPKLLIY 443
 US 11,034,762 B1
37 38
-continued -continued
Clone ID FW -L2 SEQ ID NO : Clone ID FW - L2 SEQ ID NO :
COVID19_P21_B01 WYQQKPGQPPKLLIY 443 COVID19_P21_A08 WYQQKPGQPPKLLIY 443
5 443
COVID19_P21_B02 WYQQKPGQPPKLLIY 443 COVID19_P21_A10 WYQQKPGQPPKLLIY
COVID19_P21_B09 WYQQKPGQPPKLLIY 443 COVID19_P21_B08 WYQQKPGQPPKLLIY 443
COVID19_P21_B12 WYQQKPGQPPKLLIY 443 COVID19_P21_B11 WYQQKPGQPPKLLIY 443
COVID19_P21_E04 WYQQKPGQPPKLLIY 443 COVID19_P21_C09 WYQQKPGQPPKLLIY 443
COVID19_P21_E08 WYQQKPGQPPKLLIY 443 COVID19_P21_E07 WYQQKPGQPPKLLIY 443
COVID19_P21_F02 WYQQKPGQPPKLLIY 443 COVID19_P21_E12 WYQQKPGQPPKLLIY 443
COVID19_P21_F08 WYQQKPGQPPKLLIY 443 10 COVID19_P21_F04 WYQQKPGQPPKLLIY 443
COVID19_P21_H02 WYQQKPGQPPKLLIY 443 COVID19 P21 F11 WYQQKPGQPPKLLIS 63
COVID19_P22_D06 WYQQKPGQPPKLLIY 443 COVID19_P21_H01 WYQQKPGQPPKLLIY 443
COVID19 P22_E06 WYQQKPGQPPKLLIY 443 COVID19_P21_HO3 WYQQKPGQPPKLLIY 443
COVID19_P22_G12 WYQQKPGQPPKLLIY 443 COVID19_P22_B04 WYQQKPGQPPKLLIY 443
COVID19_P22_H10 WYQQKPGQPPKLLIY 443 COVID19_P22_B12 WYQQKPGQPPKLLIY 443
COVID19_P09_B07 WYQQKPGQPPKLLIY 443 15 COVID19_P22_C09 WYQQKPGQPPKLLIY 443
COVID19_P09_B09 WYQQKPGQPPKLLIY 443 COVID19_P22_E10 WYQQKPGQPPKLLIY 443
COVID19_P09_B10 WYQQKPGQPPKLLIY 443 COVID19_P22_E12 WYQQKPGQPPKLLIY 443
COVID19_P09_C05 WYQQKPGQPPKLLIS 63 COVID19_P22_F04 WYQQKPGQPPKLLIY 443
COVID19_P09_C08 WYQQKPGQPPKLLIY 443 COVID19_P22_F07 WYQQKPGQPPKLLIY 443
COVID19_P09_D06 WYQQKPGQPPKLLIY 443 COVID19_P22_F11 WYQQKPGQPPKLLIY 443
COVID19_P09_G02 WYQQKPGQPPKLLIY 443
20
COVID19_P09_G04 WYQQKPGQPPKLLIY 443
COVID19_P09_G12 WYQQKPGQPPKLLIY 443 Representative FW -L3 Sequences
COVID19_P10_B04
COVID19_P10_B06
WYQQKPGQPPKLLIY 443
63
A CR3022 - derived antibody or antigen -binding fragment
WYQQKPGQPPKLLIS herein that selectively binds to SARS - CoV - 2 can comprise
COVID19 P10 B08 WYQQKPGQPPKLLIY 443
COVID19_P21_A03 WYQQKPGQPPKLLIY 443
25
a FW - L3 having an amino acid sequence of that is at least
COVID19_P21_A04 WYQQKPGQPPKLLIY 443 20% , 24 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % ,
COVID19_P21_A05 WYQQKPGQPPKLLIY 443 70% , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 %
identical to any one of the following sequences:
Clone ID FW - L3 SEQ ID NO :
COVID19_P09_A09 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P09_C09 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P09_E05 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P09_E11 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P09_G05 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P09_H08 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19 P09 H09 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P10_A09 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19 P10 B10 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P10_C05 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P10_D08 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P10_G03 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_A12 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_B01 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_B02 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_B09 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_B12 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_E04 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYF 445
COVID19 P21 E08 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_F02 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_F08 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_H02 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P22_D06 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P22_E06 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P22_G12 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P22_H10 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P09_B07 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P09_B09 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P09_B10 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P09_C05 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P09_C08 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P09_D06 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P09_G02 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P09_G04 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P09_G12 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P10_B04 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19 P10 B06 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19 P10 B08 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_A03 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_A04 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_A05 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19 P21_A08 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_A10 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_B08 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
 US 11,034,762 B1
39 40
-continued
Clone ID FW - L3 SEQ ID NO :
COVID19_P21_B11 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_C09 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_E07 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_E12 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_F04 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19 P21 F11 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_H01 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P21_H03 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P22_B04 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P22_B12 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P22_C09 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P22_E10 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P22_E12 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P22_F04 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P22_F07 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90
COVID19_P22_F11 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 90

Representative FW - L4 Sequences 20 -continued

A CR3022 - derived antibody or antigen -binding fragment
herein that selectively binds to SARS - CoV - 2 can comprise Clone ID FW - L4 SEQ ID NO :
FW -L4 having an amino acid sequence that is at least 20 % , COVID19_P09_C08 GGGTKVEIKR 152
24 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % , 70 % , COVID19_P09_D06 GGGTKVEIKR 152
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical 25 COVID19_P09_GO2 GGGTKVEIKR 152
to any one of the following sequences: COVID19_P09_G04 GGGTKVEIKR 152
COVID19_P09_G12 GGGTKVEIKR 152
COVID19_P10_B04 GGGTKVEIKR 152
COVID19_P10_B06 GGGTKVEIKR 152
Clone ID FW - L4 SEQ ID NO : COVID19_P10_B08 GGGTKVEIKR 152
30 COVID19_P21_A03 GGGTKVEIKR 152
COVID19_P09_A09 GGGTKVEIKR 152 COVID19_P21_A04 GGGTKVEIKR 152
COVID19_P09_C09 GGGTKVEIKR 152 COVID19_P21_A05 GGGTKVEIKR 152
COVID19_P09_E05 GGGTKVEIKR 152 COVID19_P21_A08 GGGTKVEIKR 152
COVID19_P09_E11 GGGTKVEIKR 152 COVID19_P21_A10 GGGTKVEIKR 152
COVID19_P09_G05 GGGTKVEIKR 152 COVID19_P21_B08 GGGTKVEIKR 152
COVID19_P09_H08 GGGTKVEIKR 152 COVID19_P21_B11 GGGTKVEIKR 152
COVID19_P09_H09 GGGTKVEIKR 152 35
COVID19_P21_C09 GGGTKVEIKR 152
COVID19_P10_A09 GGGTKVEIKR 152 COVID19_P21_E07 GGGTKVEIKR 152
COVID19_P10_B10 GGGTKVEIKR 152 COVID19_P21_E12 GGGTKVEIKR 152
COVID19_P10_C05 GGGTKVEIKR 152 COVID19_P21_F04 GGGTKVEIKR 152
COVID19_P10_D08 GGGTKVEIKR 152 COVID19_P21_F11 GGGTKVEIKR 152
COVID19_P10_G03 GGGTKVEIKR 152 COVID19_P21_H01 GGGTKVEIKR 152
COVID19_P21_A12 GGGTKVEIKR
GGGTKVEIKR
152
152
40 COVID19_P21_HO3 GGGTKVEIKR 152
COVID19_P21_B01 COVID19 P22 B04 GGGTKVEIKR 152
COVID19 P21 BO2 GGGTKVEIKR 152 COVID19_P22_B12 GGGTKVEIKR 152
COVID19_P21_B09 GGGTKVEIKR 152 COVID19_P22_C09 GGGTKVEIKR 152
COVID19_P21_B12 GGGTKVEIKR 152 COVID19_P22_E10 GGGTKVEIKR 152
COVID19_P21_E04 GGGTKVEIKR 152 COVID19_P22_E12 GGGTKVEIKR 152
COVID19_P21_E08 GGGTKVEIKR 152
COVID19_P21_F02 GGGTKVEIKR 152
45 COVID19_P22_F04 GGGTKVEIKR 152
COVID19_P22_F07 GGGTKVEIKR 152
COVID19_P21_F08 GGGTKVEIKR 152 COVID19_P22_F11 GGGTKVEIKR 152
COVID19_P21_H02 GGGTKVEIKR 152
COVID19 P22 D06 GGGTKVEIKR 152
COVID19 P22 E06 GGGTKVEIKR 152 Representative FW - H1 Sequences
152
COVID19_P22_G12
COVID19_P22_H10
GGGTKVEIKR
GGGTKVEIKR 152 50 A CR3022 - derived antibody or antigen -binding fragment
COVID19_P09_B07 GGGTKVEIKR 152 herein can comprise a VH framework ( FW ) 1 (FW- H1 )
COVID19_P09_B09 GGGTKVEIKR 152 having an amino acid sequence that is at least 20 % , 24 % ,
COVID19 P09 B10 GGGTKVEIKR 152 30% , 35 % , 40 % , 45 % , 50 % , 55 % , 60 % , 65 % , 70% , 75 % ,
COVID19_P09_C05 GGGTKVEIKR 152 80% , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical to any
one of the following sequences:
Clone ID FW - H1 SEQ ID NO :
COVID19_P09_A09 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_C09 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_E05 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_E11 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_G05 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_HOS QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_H09 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P10_A09 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P10_B10 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P10_C05 QVQLVQSGAEVKKPGSSVKVSCKASG 153
 US 11,034,762 B1
41 42
-continued
Clone ID FW - H1 SEQ ID NO :
COVID19_P10_D08 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P10_G03 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_A12 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_B01 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_B02 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19 P21 B09 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_B12 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19 P21 E04 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21 E08 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_F02 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_F08 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_H02 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P22_D06 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P22_E06 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P22_G12 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P22_H10 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_B07 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_B09 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_B10 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_C05 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_C08 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_D06 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_GO2 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_G04 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P09_G12 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P10_B04 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P10_B06 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P10_B08 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_A03 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_A04 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_A05 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_A08 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_A10 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_B08 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_B11 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_C09 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_E07 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_E12 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_F04 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_F11 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_H01 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P21_H03 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P22_B04 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P22_B12 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P22_C09 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P22_E10 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P22_E12 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P22_F04 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P22_F07 QVQLVQSGAEVKKPGSSVKVSCKASG 153
COVID19_P22_F11 QVQLVQSGAEVKKPGSSVKVSCKASG 153

Representative FW -H2 Sequences -continued

A CR3022 -derived antibody or antigen -binding fragment
herein that selectively binds to SARS - CoV - 2 can comprise Clone ID FW - H2 SEQ ID NO :
a FW - 112 having an amino acid sequence that is at least 50 COVID19_P21_A12 WVRQAPGQGLEWM 188
20 % , 24 % , 30 % , 35 % , 40 % , 45 % , 50% , 55 % , 60% , 65 % , COVID19_P21_B01 WVRQAPGQGLEWM 188
70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100 % COVID19_P21_B02 WVRQAPGQGLEWM 188
identical to any one of the following sequences: COVID19_P21_B09 WVRQAPGQGLEWM 188
COVID19_P21_B12 WVRQAPGQGLEWM 188
55
COVID19_P21_E04
COVID19 P21 E08
WMRQAPGQGLEWM 447
188
Clone ID FW - H2 SEQ ID NO : WVRQAPGQGLEWM
COVID19_P21_FO2 WVRQAPGQGLEWM 188
COVID19_P21_F08 WVRQAPGQGLEWM 188
COVID19_P09_A09 WVRQAPGQGLEWM 188
COVID19_P21_HO2 188
COVID19_P09_C09 WVRQAPGQGLEWM 188 WVRQAPGQGLEWM
188 COVID19_P22_D06 WVRQAPGQGLEWM 188
COVID19_P09_E05 WVRQAPGQGLEWM COVID19_P22_E06 WVRQAPGQGLEWM 188
COVID19 P09 E11 WVRQAYGQGLEWM 446
COVID19_P09_G05 WVRQAPGQGLEWM 188 60 COVID19_P22_G12 WVRQAPGQGLEWM 188
COVID19_P22_H10 WVRQAPGQGLEWV 189
COVID19_P09_HOS WVRQAPGQGLEWM 188
188
COVID19_P09_H09 WVRQAPGQGLEWM 188 COVID19_P09_B07 WVRQAPGQGLEWM
COVID19_P10_A09 WVRQAPGQGLEWM 188 COVID19_P09_B09 WVRQAPGQGLEWM 188
COVID19_P10_B10 WVRQAPGQGLEWV 189 COVID19_P09_B10 WVRQAPGQGLEWM 188
COVID19_P10_C05 WVRQAPGQGLEWM 188 COVID19_P09_C05 WVRQAPGQGLEWM 188
COVID19_P10_D08 WVRQAPGQGLEWM 188 65 COVID19_P09_C08 WVRQAPGQGLEWM 188
COVID19_P10_GO3 WVRQAPGQGLEWM 188 COVID19_P09_D06 WVRQAPGQGLEWM 188
 US 11,034,762 B1
43 44
-continued -continued
Clone ID FW -H2 SEQ ID NO : Clone ID FW -H2 SEQ ID NO :
COVID19_P09_GO2 WVRQAPGQGLEWM 188 COVID19_P21_H03 WVRQAPGQGLEWM 188
5 188
COVID19_P09_G04 WVRQAPGQGLEWM 188 COVID19_P22_B04 WVRQAPGQGLEWM
COVID19_P09_G12 WVRQAPGQGLEWM 188 COVID19_P22_B12 WVRQAPGQGLEWM 188
COVID19_P10_B04 WVRQAPGQGLEWM 188 COVID19_P22_C09 WVRQAPGQGLEWV 189
COVID19_P10_B06 WVRQAPGQGLEWM 188 COVID19 P22 E10 WVRQAPGQGLEWM 188
COVID19 P10 BOS WVRQAPGQGLEWM 188 COVID19_P22_E12 WVRQAPGQGLEWM 188
COVID19_P21_A03 WVRQAPGQGLEWM 188 COVID19_P22_F04 WVRQAPGQGLEWM 188
COVID19_P21_A04 WVRQAPGQGLEWM 188 10 COVID19_P22_F07 WVRQAPGQGLEWM 188
COVID19_P21_A05 WVRQAPGQGLEWM 188 COVID19_P22_F11 WVRQAPGQGLEWM 188
COVID19_P21_A08 WVRQAPGQGLEWM 188
COVID19_P21_A10 WVRQAPGQGLEWM 188
COVID19_P21_B08 WVRQAPGQGLEWM 188
COVID19_P21_B11 WVRQAPGQGLEWM 188
Representative FW - H3 Sequences
COVID19_P21_C09 WVRQAPGQGLEWM 188 15 A CR3022 - derived antibody or antigen -binding fragment
COVID19_P21_E07 WVRQAPGQGLEWM 188
herein that selectively binds to SARS - CoV - 2 can comprise
COVID19_P21_E12 WVRQAPGQGLEWM 188
a FW - 113 having an amino acid sequence that is at least
COVID19_P21_F04 WVRQAPGQGLEWM 188
COVID19_P21_F11 WVRQAPGQGLEWM 188 20% , 24 % , 30 % , 35 % , 40 % , 45 % , 50 % , 55 % , 60% , 65 % ,
COVID19_P21_H01 WVRQAPGQGLEWM 188 70% , 75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 %
identical to any one of the following sequences :
Clone ID FW - H3 SEQ ID NO :
COVID19_P09_A09 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P09_C09 QQFQGRVTITADESTSTAYMELSSLRSEDTAVYY 252
COVID19_P09_E05 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P09_E11 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P09_G05 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P09_H08 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P09_H09 QKFYGRVTITADESTSTAYMELSSLRSEDTAVYY 448
COVID19_P10_A09 QNFOGRVTITADESTSTAYMELSSLRSEDTAVYY 449
COVID19_P10_B10 QKFCGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P10_C05 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P10_D08 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P10_603 QKFCGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_A12 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_B01 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_B02 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_B09 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_B12 EKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 253
COVID19_P21_E04 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_E08 QKFCGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_F02 QKFCGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_F08 QKFCGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_H02 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P22_D06 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P22_E06 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P22_G12 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P22_H10 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P09_B07 QKFCGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P09_B09 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P09_B10 QKFCGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P09_C05 QKFCGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P09_C08 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P09_D06 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P09_G02 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P09_G04 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P09_G12 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P10_B04 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P10_B06 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P10_B08 QKFCGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_A03 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_A04 QKFCGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_A05 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_A08 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_A10 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_B08 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_B11 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_C09 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_E07 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_E12 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_F04 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_F11 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_H01 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P21_H03 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P22_B04 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
 US 11,034,762 B1
45 46
-continued
Clone ID FW - H3 SEQ ID NO :
COVID19_P22_B12 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P22_C09 QRFQGRVTITADESTSTAYMELSSLRSEDTAVYY 254
COVID19_P22_E10 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P22_E12 QRLQGRVTITADESTSTAYMELSSLRSEDTAVYY 255
COVID19_P22_F04 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P22_F07 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251
COVID19_P22_F11 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 251

Representative FW -H4 Sequences - continued

A CR3022 - derived antibody or antigen -binding fragment
herein that selectively binds to SARS - CoV - 2 can comprise 15
Clone ID FW - H4 SEQ ID NO :
a FW - 114 having an amino acid sequence that is at least
20 % , 24 % , 30 % , 35 % , 40 % , 45 % , 50% , 55 % , 60% , 65 % , COVID19 P09 B10 GQGTLVTVSS 317
70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100 %
identical to any one of the following sequences: COVID19 P09 C05 GQGTLVTVSS 317

20 COVID19_P09_C08 GQGTLVTVSS 317

Clone ID FW - H4 SEQ ID NO : COVID19 PO9 D06 GQGTLVTVSS 317

COVID19_P09_A09 GQGTLVTVSS 317

COVID19_P09_GO2 GQGTLVTVSS 317
COVID19_P09_C09 GQGTLVTVSS 317
25 COVID19 P09 GO4 GQGTLVTVSS 317
COVID19 PO9 E05 GOGTLVTVSS 317
COVID19_P09_G12 GQGTLVTVSS 317
COVID19 P09 E11 GQGTLVTVSS 317
COVID19 P10 B04 GQGTLVTVSS 317
COVID19_P09_G05 GQGTLVTVSS 317
30 COVID19 P10 B06 GQGTLVTVSS 317
COVID19 PO9 HOS GQGTLVTVSS 317

COVID19 P09 H09 GQGTLVTVSS 317

COVID19 P10 B08 GQGTLVTVSS 317

COVID19_P10_A09 GQGTLVTVSS 317 COVID19_P21_A03 GQGTLVTVSS 317

35
COVID19 P10 B10 GQGTLVTVSS 317 COVID19 P21 A04 GQGTLVTVSS 317

COVID19_P10_C05 GQGTLVTVSS 317 COVID19 P21 A05 GQGTLVTVSS 317

COVID19 P10 DOS GQGTLVTVSS 317 COVID19 P21 A08 GQGTLVTVSS 317

40
COVID19 P10 G03 GQGTLVTVSS 317 COVID19 P21 A10 GQGTLVTVSS 317

COVID19 P21 A12 GQGTLVTVSS 317 COVID19 P21 B08 GQGTLVTVSS 317

COVID19_P21_B01 GQGTLVTVSS 317 COVID19 P21 B11 GQGTLVTVSS 317

GQGTLVTVSS 45
COVID19_P21_B02 317
COVID19_P21_c09 GQGTLVTVSS 317

COVID19 P21 B09 GQGTLVTVSS 317

COVID19 P21 E07 GQGTLVTVSS 317
COVID19 P21 B12 GQGTLVTVSS 317
COVID19 P21 El2 GQGTLVTVSS 317
COVID19 P21 E04 GQGTLVTVSS 317 50
COVID19 P21 F04 GQGTLVTVSS 317
COVID19 P21 E08 GQGTLVTVSS 317
COVID19 P21 F11 GQGTLVTVSS 317
COVID19_P21_F02 GQGTLVTVSS 317
COVID19 P21 HO1 GQGTLVTVSS 317
COVID19_P21_F08 GQGTLVTVSS 317 55
COVID19 P21 HO3 GQGTLVTVSS 317
COVID19 P21 HO2 GQGTLVTVSS 317
COVID19 P22 B04 GQGTLVTVSS 317
COVID19 P22 D06 GQGTLVTVSS 317

COVID19 P22 E06 GQGTLVTVSS 317

COVID19 P22 B12 GQGTLVTVSS 317
60
COVID19_P22_G12 GQGTLVTVSS 317 COVID19_P22_C09 GQGTLVTVSS 317

COVID19 P22 H10 GQGTLVTVSS 317 COVID19 P22 E10 GQGTLVTVSS 317

COVID19_P09_B07 GQGTLVTVSS 317 COVID19 P22 E12 GQGTLVTVSS 317

65
COVID19 PO9 B09 GQGTLVTVSS 317 COVID19 P22 F04 GQGTLVTVSS 317
 US 11,034,762 B1
47 48
- continued Representative VH and VL Sequences that Bind to SARS
COV - 2
Clone ID FW - H4 SEQ ID NO :

5
A CR3022 - derived antibody or antigen -binding fragment
COVID19_P22_F07 GQGTLVTVSS 317
herein that selectively binds to SARS - CoV - 2 can comprise
COVID19_P22_F11 GQGTLVTVSS 317 an VH having an amino acid sequence that is at least 70 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100% identical
to any one of the following sequences:
SEQ ID
Clone ID VH NO :

COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGGTFSSYAI SWVRQAPGQGLEWMG 318

P09_A09 ITYPGDSTTRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCYSGSG
ISTPMDVWGQGTLVTVSS

COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGGTFSSYAI SWVRQAPGQGLEWMG 319

P09 C09 IIDPSGGSTSYAQQFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGGSG
ISTPMDVWGQGTLVTVSS

COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMG 320

P09 E05 ITYPGDSTTRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCYSGSG
ISTPMDVWGQGTLVTVSS

COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGGTFSNHAISWVRQAYGQGLEWM 321

P09 E11 GIIYPGDGTTRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGISTPMDVWGQGTLVTVSS

COVID19 QVQLVOSGAEVKKPGSSVKVSCKASGYTFTGHYMHWVRQAPGQGLEWM 322

P09_G05 GIIYPGDSEARYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGISTPMDVWGQGTLVTVSS

COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGGTFSSYAI SWVRQAPGQGLEWMG 323

P09_H08 GIIPIFGTTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGEW
GISTPMDVWGQGTLVTVSS

COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGGTFITYWIYWVRQAPGQGLEWMG 324

P09 H09 HYPGDGEARYSQKFYGRVTITADESTSTAYMELSSLRSEDTAVYYCAGSG
GISTPMDVWGQGTLVTVSS

COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGYTFTDYYIHWVRQAPGQGLEWM 325

P10_A09 GWMNPNSGNTGYAQNFOGRVTITADESTSTAYMELSSLRSEDTAVYYCA
GGSGISTAWDVWGQGTLVTVSS

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGYSFSDYHVHWVRQAPGQGLEWV 326

P10 B10 GMIIPRHGGTAYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAG
GSGISTPMDVWGQGTLVTVSS

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGGTFITYWIGWVRQAPGQGLEWMG 327

P10_C05 HYPGDGEARYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGSG
GISTPMDVWGQGTLVTVSS
COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGGTFNSHAI SWVRQAPGQGLEWMG 328
P10 D08 WINPNSGATNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGISTPVGVWGQGTLVTVSS

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNSSINWVRQAPGQGLEWMG 329

P10 G03 RINPNSGGTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGGS
GISTPMDVWGQGTLVTVSS

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMG 330

P21 A12 SVIPVFGRPNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGEW
GISTPMDVWGQGTLVTVSS

COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGYTFSTYWIGWVRQAPGQGLEWM 331

P21 B01 GWIDPNSGGTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAG
GSGISTPMDVWGQGTLVTVSS

COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGYTFTNYGINWVRQAPGQGLEWM 332

P21_B02 GWMNPNSGNTGYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCA
AVSGISTPMDVWGQGTLVTVSS
COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGYTFTGHYMHWVRQAPGQGLEWM 333
P21 B09 GIIYPGDSEARYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGISTPMDVWGQGTLVTVSS
 US 11,034,762 B1
49 50
- continued

SEQ ID
Clone ID VH NO :

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMG 334

P21 B12 MINPGGGNTNYAEKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGE
WGISTPMDVWGQGTLVTVSS

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGINWMRQAPGQGLEWM 335

P21_E04 GWMNPNSGNTGYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCA
GGSGISTPMDVWGQGTLVTVSS

COVID19 QVQLVOSGAEVKKPGSSVKVSCKASGYGFITYWIGWVRQAPGQGLEWM 336

P21 E08 GIIYPGDGETRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGISTPMDVWGQGTLVTVSS

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYGISWVRQAPGQGLEWMG 337

P21 F02 ITYPGDGTTRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCLPGSG
ISTPMDVWGQGTLVTVSS

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSTYAFNWVRQAPGQGLEWM 338

P21_F08 GVINTGGGSVTYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAG
GSGISTPGAVWGQGTLVTVSS

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGYGFITYWIGWVRQAPGQGLEWM 339

P21 HO2 GIIYPGDSETRYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGLYTPMDVWGQGTLVTVSS

COVID19 QVQLVOSGAEVKKPGSSVKVSCKASGGGFITYWIGWVRQAPGQGLEWM 340

P22 D06 GIIYPGDSETRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGGS
GVLTPMDVWGQGTLVTVSS
COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGGGFITYWIGWVRQAPGQGLEWM 341
P22 E06 GIIYPGDSETRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGGS
GISSDMDVWGQGTLVTVSS

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGGGFITYWIGWVRQAPGQGLEWM 342

P22 G12 GIIYPGDSETRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGGS
GISTPMDVWGQGTLVTVSS

COVID19 QVQLVOSGAEVKKPGSSVKVSCKASGGGFSTYWIGWVRQAPGQGLEWV 343

P22 H10 GWINPNSGATKYAQKFOGRVTITADESTSTAYMELSSLRSEDTAVYYCAG
GSGISTPMDVWGQGTLVTVSS
COVID19 QVQLVOSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMG 344
P09 B07 GIIPTLGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGSW
GISTPMDVWGQGTLVTVSS
COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGYRFTDYHLHWVRQAPGQGLEWM 345
P09 B09 GGIVPFSGTTNFAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGETTPMDVWGQGTLVTVSS

COVID19 QVOLVOSGAEVKKPGSSVKVSCKASGYSFTDYHIHWVRQAPGQGLEWM 346

PO9 B10 AMIVPRGGSTTYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAG
GSGISTPMDVWGQGTLVTVSS

COVID19 QVOLVOSGAEVKKPGSSVKVSCKASGYSFSDYYIHWVRQAPGQGLEWM 347

P09_C05 GWIDPNSGGTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAG
GSGISTPMDVWGQGTLVTVSS

COVID19 QVOLVOSGAEVKKPGSSVKVSCKASGYGFITYWIGWVRQAPGQGLEWM 348

P09_C08 GIIYPGDSETRYAQKFOGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGISTPMDVWGQGTLVTVSS

COVID19 QVOLVOSGAEVKKPGSSVKVSCKASGYGFITYWIGWVRQAPGQGLEWM 349

P09 D06 GIIYPGDSETRYAQKFOGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGIYVPMDVWGQGTLVTVSS

COVID19 QVQLVOSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMG 350

P09 GO2 ITYPGDSTTNYSOKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGHW
GISTPMDVWGQGTLVTVSS
COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGYGFI TYWIGWVRQAPGQGLEWM 351
P09 G04 GIIYPGDSETNYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGLFTPMDVWGQGTLVTVSS

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGYPFTNYGISWVRQAPGQGLEWMG 352

P09 G12 WMNPNSGNTGYAQKFOGRVTITADESTSTAYMELSSLRSEDTAVYYCATL
SGISTPMDVWGQGTLVTVSS
 US 11,034,762 B1
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- continued

SEQ ID
Clone ID VH NO :

COVID19 QVQLVOSGAEVKKPGSSVKVSCKASGYGFISYWIGWVRQAPGQGLEWM 353

P10 B04 GIIYPGDGETRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGS
DGISTPMDVWGQGTLVTVSS

COVID19 QVQLVOSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMG 354

P10 BO6 ITYPGDSTTRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCYSGSG
ISTPMDVWGQGTLVTVSS

COVID19 QVQLVOSGAEVKKPGSSVKVSCKASGGGFITYWIGWVRQAPGQGLEWM 355

P10 BOS GWINPNSGGTKYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAG
GSGISTPIDVWGQGTLVTVSS
COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNNGLSWVRQAPGQGLEWM 356
P21 A03 GGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCRMG
SGISTPMDVWGQGTLVTVSS

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGYGFI TYWIGWVRQAPGQGLEWM 357

P21 A04 GIIYPGDSETRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGGS
GLLTPMDVWGQGTLVTVSS
COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGGGFITYWIGWVRQAPGQGLEWM 358
P21 A05 GIIYPGDGETRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGISTPMDVWGQGTLVTVSS

COVID19 QVQLVOSGAEVKKPGSSVKVSCKASGGTFITYWIGWVRQAPGQGLEWMG 359

P21 A08 WINPNSGGTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGISTPMDVWGQGTLVTVSS
COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGYGFITYWIGWVRQAPGQGLEWM 360
P21 A10 GIIYPGDGEARYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGISTPMDVWGQGTLVTVSS

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMG 361

P21 B08 VINTGGGSVTYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGH
WGISTPMDVWGQGTLVTVSS

COVID19 QVQLVOSGAEVKKPGSSVKVSCKASGYGFITYWIGWVRQAPGQGLEWM 362

P21 B11 GIIYPGDSETRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGSD
GISTPMDVWGQGTLVTVSS

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGYGFISYWIGWVRQAPGQGLEWM 363

P21 C09 GIIYPGDSETRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGGS
GILEPMDVWGQGTLVTVSS
COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGYGFITYWIGWVRQAPGQGLEWM 364
P21 E07 GIIYPGDSETRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGGS
GISTPMDVWGQGTLVTVSS
COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGGTFISYAISWVRQAPGQGLEWMG 365
P21 E12 GIIPTLGTYNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGSW
GISTPMDVWGQGTLVTVSS

COVID19 QVOLVOSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMG 366

P21 F04 QINPSGDSTRYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGGS
GISTPMDVWGQGTLVTVSS

COVID19 QVOLVOSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMG 367

P21 F11 ITYPGDSTARYSQKFOGRVTITADESTSTAYMELSSLRSEDTAVYYCAGGS
GISTLYDVWGQGTLVTVSS
COVID19 QVOLVOSGAEVKKPGSSVKVSCKASGYGFSTYWIGWVRQAPGQGLEWM 368
P21 H01 GWINPNSGGTNYAQKFOGRVTITADESTSTAYMELSSLRSEDTAVYYCAG
GSGISTPMDVWGQGTLVTVSS

COVID19 QVQLVOSGAEVKKPGSSVKVSCKASGYTFTNYGINWVRQAPGQGLEWM 369

P21 HO3 GWMNPYSGNTGYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCA
VLSGISTPMDVWGQGTLVTVSS

COVID19 QVOLVOSGAEVKKPGSSVKVSCKASGYGFITYWIGWVRQAPGQGLEWM 370

P22 B04 GIIYPGDSETRYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
EGISTPMDVWGQGTLVTVSS

COVID19 QVOLVOSGAEVKKPGSSVKVSCKASGGTLSSYAISWVRQAPGQGLEWMG 371

P22 B12 ITYPGDSETRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGGSG
ISTPRSVWGQGTLVTVSS
 US 11,034,762 B1
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- continued

SEQ ID
Clone ID VH NO :

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGYNFTDYHIQWVRQAPGQGLEWV 372

P22 C09 GMIIPRHGGTAYAQRFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGLTTPMDVWGQGTLVTVSS

COVID19 QVQLVQSGAEVKKPGSSVKVSCKASGGGFITYWIGWVRQAPGQGLEWM 373

P22_E10 GIIYPGDGETRYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGISTPMDVWGQGTLVTVSS

COVID19 QVQLVOSGAEVKKPGSSVKVSCKASGGTFSSYAINWVRQAPGQGLEWMG 374

P22 E12 GIIPVLHTVDYAQRLQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGEW
GISTPMDVWGQGTLVTVSS

COVID19 QVOLVOSGAEVKKPGSSVKVSCKASGGGFITYWIGWVRQAPGQGLEWM 375

P22 F04 GIIYPGDGEARYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGG
SGISTPMDVWGQGTLVTVSS

COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMG 376

P22_F07 GIIPIFGSTASYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGEW
GISTPMDVWGQGTLVTVSS
COVID19 QVOLVQSGAEVKKPGSSVKVSCKASGGGFITYWISWVRQAPGQGLEWMG 377
P22 F11 HYPGDGEARYSQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAGGS
GIIQPMDVWGQGTLVTVSS

A CR3022 -derived antibody or antigen -binding fragment

herein that selectively binds to SARS -CoV -2 can comprise
an VL having an amino acid sequence that is at least 70 % ,
75 % , 80 % , 85 % , 90% , 95 % , 98 % , 99 % , or 100 % identical
to any one of the following sequences:
SEQ ID
Clone ID VL NO :

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 378

P09_A09 LLISWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTPW
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNYLAWYOQKPGQPPKLL 379

PO9 C09 ISWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTPWTF
GGGTKVEIKR
COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 380
P09 E05 LLISWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTPW
TFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYTSNNNNYLAWYOQKPGQPP 381

P09 E11 KLLISWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTP
WTFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYTSNNNNYLAWYOQKPGQPP 382

P09 G05 KLLIYWGSTRGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTP
WTFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 383

P09 HO8 LLIYWANIRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCOQYYSTPLT
FGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSONVLYSSINKNYLAWYQQKPGQPPK 384

P09 HO9 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCOQYYTTPY
TFGGGTKVEIKR

COVID19 DIVMTQS PDSLAVSLGERATIRCTSSLSLODRSNNKNYLTWYOQKPGQPPK 385

P10 A09 LLIYWAS TRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCOQHYSAPL
TFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPP 386

P10 B10 KLLIYWASTRDFGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYALP
LTFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQNVLYSSINKNYLAWYQQKPGQPPK 387

P10 C05 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTTPY
TFGGGTKVEIKR
 US 11,034,762 B1
55 56
- continued

SEQ ID
Clone ID VL NO :

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYOQKPGQPPK 388

P10 DOS LLISWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTPW
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNINYLAWYOQKPGQPPK 389

P10_G03 LLIYWASTRASGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTPW
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 390

P21 A12 LLIYWASLREGGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYYAP
WTFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNKNNYLAWYQQKPGQPP 391

P21 B01 KLLIYWASTRLSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTP
WTFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCRSSQTVLYRSNNYNYLAWYOQKPGQPP 392

P21 B02 KLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTP
PTFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSNNLNYLAWYOQKPGQPP 393

P21 B09 KLLIYWGSTRGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTP
WTFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 394

P21 B12 LLIYWASYRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYGFPL
TFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPP 395

P21 E04 KLLIYWASNREPGVPDRFSGSGSGTDFTLTISSLQAEDVAVYFCHQYYSTP
PTFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYOQKPGQPPK 396

P21 E08 LLIYWAYTREPGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPY
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSORVLYSSNNLNYLAWYQQKPGQPP 397

P21 F02 KLLIYWASTRGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTP
WTFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNINYLAWYOQKPGQPPK 398

P21 F08 LLIYWASTRAAGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTPW
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 399

P21 HO2 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCOQYHTIPYT
FGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 400

P22 D06 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCOQYYATPY
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 401

P22 E06 LLIYWASTREFGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCOQYYKIPY
TFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 402

P22_G12 LLIYWASMRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTTPY
TFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVFHSSNNKNHLAWYOQKPGQPP 403

P22 H10 KLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTP
WTFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYOQKPGQPPK 404

P09 B07 LLIYWASLREGGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYHSTPL
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 405

P09 B09 LLIYWASSRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSLPLT
FGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPP 406

P09 B10 KLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTP
VTFGGGTKVEIKR
 US 11,034,762 B1
57 58
- continued

SEQ ID
Clone ID VL NO :

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSNNHNYLAWYQQKPGQPP 407

P09 C05 KLLISWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTP
WTFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLHSAINKNYLAWYOQKPGQPPK 408

P09 C08 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYSTTPY
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 409

P09_D06 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYKIPY
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 410

PO9 GO2 LLIYWASYRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCOQYHSTPW
TFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 411

P09_G04 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYSTTPY
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCRSSQSVLYSSNNKNYFAWYOQKPGQPP 412

P09 G12 KLLIYWASIRGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCHQYYTTPP
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYOQKPGQPPK 413

P10_B04 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPY
TFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 414

P10 B06 LLISWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTPW
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPP 415

P10 B08 KLLIYRASTRASGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTVI
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQTISYSSDNKNYLAWYQQKPGQPPK 416

P21 A03 LLIYWASTRLSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTPW
TFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 417

P21 A04 LLIYWAS TRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPY
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 418

P21 A05 LLIYWASSRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPY
TFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSNNHNYLAWYOQKPGQPP 419

P21 A08 KLLIYWASTRGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTP
WTFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 420

P21 A10 LLIYWAS TREPGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCOQYHSTPY
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYOQKPGQPPK 421

P21 BO8 LLIYWASFRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYGTPF
TFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 422

P21 B11 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCOQYYSTPY
TFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYOQKPGQPPK 423

P21 C09 LLIYWAS TRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYSSTPYT
FGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSTQSVLYSSINKNYVAWYOQKPGQPPK 424

P21 E07 LLIYWAS TRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCOQYYSTPY
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 425

P21 E12 LLIYWASLREGGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYHSTPL
TFGGGTKVEIKR
 US 11,034,762 B1
59 60
- continued

SEQ ID
Clone ID VL NO :

COVID19 DIVMTQS PDSLAVSLGERATINCKSSQSVLHSSNNLNYFAWYQQKPGQPP 426

P21 F04 KLLIYWASTRLSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTP
WTFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCTSSQSVLHSSNNLNYLAWYQQKPGQPPK 427

P21 F11 LLISWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTPW
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYRSNNLHYLAWYQQKPGQPP 428

P21 H01 KLLIYWASTRSSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCRQYYSTP
WTFGGGTKVEIKR
COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPP 429
P21 HO3 KLLIYWATNRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCHQYYNTP
PTFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYOQKPGQPPK 430

P22 B04 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPY
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSRILSYSPDNKNYLAWYQQKPGQPPK 431

P22 B12 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSYITPYT
FGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPP 432

P22_C09 KLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQHYYNTP
LTFGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 433

P22 E10 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYGIPY
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYOQKPGQPPK 434

P22 E12 LLIYWASFRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYLSTPLT
FGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 435

P22 F04 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCOQYHSTPY
TFGGGTKVEIKR

COVID19 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 436

P22 F07 LLIYWSSLRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTAPFT
FGGGTKVEIKR

COVID19 DIVMTOS PDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPK 437

P22 F11 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYLSTPLT
FGGGTKVEIKR

In one instance , the antibody or antigen - binding fragment
that selectively binds to SARS - Cov - 2 can comprise VH
having an amino acid sequence that is at least 70% , 75 % ,
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
ID NO : 318 and a VL having an amino acid sequence that
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
100% identical to SEQ ID NO : 378 .
In one instance , the antibody or antigen -binding fragment
that selectively binds to SARS - Cov - 2 can comprise a VH
having an amino acid sequence that is at least 70% , 75 % ,
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
ID NO : 319 and a VL having an amino acid sequence that
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
100% identical to SEQ ID NO : 379 .
In one instance, the antibody or antigen -binding fragment
that selectively binds to SARS - Cov - 2 can comprise a VH
having an amino acid sequence that is at least 70% , 75 % ,
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
ID NO : 320 and a VL having an amino acid sequence that 65 ID NO : 323 and a VL having an amino acid sequence that
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 9 % , or
100% identical to SEQ ID NO : 380 .
45
In one instance, the antibody or antigen -binding fragment
that selectively binds to SARS - Cov - 2 can comprise a VH
having an amino acid sequence that is at least 70 % , 75 % ,
50
80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
ID NO : 321 and a VL having an amino acid sequence that
is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
100 % identical to SEQ ID NO : 381 .
In one instance , the antibody or antigen - binding fragment
55 that selectively binds to SARS - Cov - 2 can comprise a VH
having an amino acid sequence that is at least 70 % , 75 % ,
80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
ID NO : 322 and a VL having an amino acid sequence that
is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
60 100 % identical to SEQ ID NO : 382 .
In one instance, the antibody or antigen -binding fragment
that selectively binds to SARS - Cov - 2 can comprise a VH
having an amino acid sequence that is at least 70 % , 75 % ,
80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
100 % identical to SEQ ID NO : 383 .
 US 11,034,762 B1
61 62
In one instance, the antibody or antigen -binding fragment ID NO : 333 and a VL having an amino acid sequence that
that selectively binds to SARS - Cov - 2 can comprise a VH is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
having an amino acid sequence that is at least 70% , 75 % , 100 % identical to SEQ ID NO : 393 .
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ In one instance, the antibody or antigen - binding fragment
ID NO : 324 and a VL having an amino acid sequence that 5 that selectively binds to SARS - Cov - 2 can comprise a VH
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or having an amino acid sequence that is at least 70 % , 75 % ,
100% identical to SEQ ID NO : 384 . 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
In one instance , the antibody or antigen - binding fragment ID NO : 334 and a VL having an amino acid sequence that
that selectively binds to SARS - Cov - 2 can comprise a VH is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
having an amino acid sequence that is at least 70% , 75 % , 10 100 % identical to SEQ ID NO : 394 .
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
ID NO : 325 and a VL having an amino acid sequence that thatIn selectively one instance, the antibody or antigen -binding fragment
binds to SARS - Cov - 2 can comprise a VH
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
100% identical to SEQ ID NO : 385 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance, the antibody or antigen- binding fragment 15 ID80 %NO
, 85: %335,90and
%, 95a VL
%, 98having
% , 99an%, amino
or 100%acididentical to SEQ
sequence that
that selectively binds to SARS - Cov - 2 can comprise a VH
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 395 .
ID NO : 326 and a VL having an amino acid sequence that In one instance, the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 20 that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 386 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance , the antibody or antigen - binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH ID NO : 336 and a VL having an amino acid seq ce that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 25 100 % identical to SEQ ID NO : 396 .
ID NO : 327 and a VL having an amino acid sequence that In one instance, the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 387 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance , the antibody or antigen - binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH 30 ID NO : 337 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 397 .
ID NO : 328 and a VL having an amino acid sequence that In one instance, the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 388 . 35 having an amino acid sequence that is at least 70 % , 75 % ,
In one instance, the antibody or antigen -binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH ID NO : 338 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 398 .
ID NO : 329 and a VL having an amino acid sequence that 40 In one instance, the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 389 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance, the antibody or antigen -binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH ID NO : 339 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , 45 is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 399 .
ID NO : 330 and a VL having an amino acid sequence that In one instance , the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 390 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance, the antibody or antigen -binding fragment 50 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH ID NO : 340 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 400 .
ID NO : 331 and a VL having an amino acid sequence that In one instance, the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 55 having
that selectively binds to SARS - Cov - 2 can comprise a VH
an amino acid sequence that is at least 70 % , 75 % ,
100% identical to SEQ ID NO : 391 .
In one instance, the antibody or antigen -binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH ID NO : 341 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100 % identical to SEQ 60 100 % identical to SEQ ID NO : 401 .
ID NO : 332 and a VL having an amino acid sequence that In one instance, the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 392 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance , the antibody or antigen - binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH 65 ID NO : 342 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 402 .
 US 11,034,762 B1
63 64
In one instance, the antibody or antigen -binding fragment ID NO : 352 and a VL having an amino acid sequence that
that selectively binds to SARS - Cov - 2 can comprise a VH is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
having an amino acid sequence that is at least 70% , 75 % , 100 % identical to SEQ ID NO : 412 .
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ In one instance, the antibody or antigen - binding fragment
ID NO : 343 and a VL having an amino acid sequence that 5 that selectively binds to SARS - Cov - 2 can comprise a VH
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or having an amino acid sequence that is at least 70 % , 75 % ,
100% identical to SEQ ID NO : 403 . 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
In one instance , the antibody or antigen - binding fragment ID NO : 353 and a VL having an amino acid sequence that
that selectively binds to SARS - Cov - 2 can comprise a VH is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
having an amino acid sequence that is at least 70% , 75 % , 10 100 % identical to SEQ ID NO : 413 .
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
ID NO : 344 and a VL having an amino acid sequence that thatIn selectively one instance, the antibody or antigen -binding fragment
binds to SARS - Cov - 2 can comprise a VH
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
100% identical to SEQ ID NO : 404 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance, the antibody or antigen - binding fragment 15 ID80 %NO, 85: %354, 90and
%, 95a VL
%, 98having
%, 99an%, amino
or 100%acididentical to SEQ
sequence that
that selectively binds to SARS - Cov - 2 can comprise a VH
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 414 .
ID NO : 345 and a VL having an amino acid sequence that In one instance, the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 20 that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 405 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance , the antibody or antigen - binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH ID NO : 355 and a VL having an amino acid seq ce that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 25 100 % identical to SEQ ID NO : 415 .
ID NO : 346 and a VL having an amino acid sequence that In one instance , the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 406 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance , the antibody or antigen - binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH 30 ID NO : 356 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 416 .
ID NO : 347 and a VL having an amino acid sequence that In one instance, the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 407 . 35 having an amino acid sequence that is at least 70 % , 75 % ,
In one instance, the antibody or antigen -binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH ID NO : 357 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 417 .
ID NO : 348 and a VL having an amino acid sequence that 40 In one instance, the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 408 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance, the antibody or antigen -binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH ID NO : 358 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , 45 is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 418 .
ID NO : 349 and a VL having an amino acid sequence that In one instance , the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 409 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance, the antibody or antigen -binding fragment 50 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH ID NO : 359 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 419 .
ID NO : 350 and a VL having an amino acid sequence that In one instance, the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 55 having
that selectively binds to SARS - Cov - 2 can comprise a VH
an amino acid sequence that is at least 70 % , 75 % ,
100% identical to SEQ ID NO : 410 .
In one instance, the antibody or antigen -binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH ID NO : 360 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 60 100 % identical to SEQ ID NO : 420 .
ID NO : 351 and a VL having an amino acid sequence that In one instance , the antibody or antigen - binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 411 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance , the antibody or antigen - binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH 65 ID NO : 361 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 421 .
 US 11,034,762 B1
65 66
In one instance, the antibody or antigen -binding fragment ID NO : 371 and a VL having an amino acid sequence that
that selectively binds to SARS - Cov - 2 can comprise a VH is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
having an amino acid sequence that is at least 70% , 75 % , 100 % identical to SEQ ID NO : 431 .
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ In one instance, the antibody or antigen - binding fragment
ID NO : 362 and a VL having an amino acid sequence that 5 that selectively binds to SARS - Cov - 2 can comprise a VH
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or having an amino acid sequence that is at least 70 % , 75 % ,
100% identical to SEQ ID NO : 422 . 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
In one instance , the antibody or antigen - binding fragment ID NO : 372 and a VL having an amino acid sequence that
that selectively binds to SARS - Cov - 2 can comprise a VH is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
having an amino acid sequence that is at least 70% , 75 % , 10 100 % identical to SEQ ID NO : 432 .
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
ID NO : 363 and a VL having an amino acid sequence that thatIn selectively one instance, the antibody or antigen -binding fragment
binds to SARS - Cov - 2 can comprise a VH
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
100% identical to SEQ ID NO : 423 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance, the antibody or antigen- binding fragment 15 ID80 %NO
, 85: %373,90and
%, 95a VL
%, 98having
% , 99an%, amino
or 100%acididentical to SEQ
sequence that
that selectively binds to SARS - Cov - 2 can comprise a VH
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 433 .
ID NO : 364 and a VL having an amino acid sequence that In one instance, the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 20 that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 424 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance , the antibody or antigen - binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH ID NO : 374 and a VL having an amino acid seq ce that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 25 100 % identical to SEQ ID NO : 434 .
ID NO : 365 and a VL having an amino acid sequence that In one instance , the antibody or antigen - binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 425 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance , the antibody or antigen - binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH 30 ID NO : 375 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99% , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 435 .
ID NO : 366 and a VL having an amino acid sequence that In one instance, the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 426 . 35 having an amino acid sequence that is at least 70 % , 75 % ,
In one instance, the antibody or antigen -binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH ID NO : 376 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 436 .
ID NO : 367 and a VL having an amino acid sequence that 40 In one instance, the antibody or antigen -binding fragment
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or that selectively binds to SARS - Cov - 2 can comprise a VH
100% identical to SEQ ID NO : 427 . having an amino acid sequence that is at least 70 % , 75 % ,
In one instance, the antibody or antigen -binding fragment 80% , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ
that selectively binds to SARS - Cov - 2 can comprise a VH ID NO : 377 and a VL having an amino acid sequence that
having an amino acid sequence that is at least 70% , 75 % , 45 is at least 70% , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 100 % identical to SEQ ID NO : 437 .
ID NO : 368 and a VL having an amino acid sequence that Modified Antibodies
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or The present disclosure provides for modified antibodies .
100% identical to SEQ ID NO : 428 . Modified antibodies can comprise antibodies which have
In one instance, the antibody or antigen -binding fragment 50 one or more modifications which can enhance their activity,
that selectively binds to SARS - Cov - 2 can comprise a VH binding, specificity, selectivity , or another feature . In one
having an amino acid sequence that is at least 70% , 75 % , aspect , the present disclosure provides for modified anti
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ bodies (which can be heteromultimers ) that comprise a
ID NO : 369 and a VL having an amino acid sequence that CR3022 -derived antibody as described herein . Reference to
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 55 binding
a modifiedfragment
antibody
.
herein also refers to a modified antigen
100% identical to SEQ ID NO : 429 .
In one instance , the antibody or antigen - binding fragment A modified antibody can comprise a bispecific modified
that selectively binds to SARS - Cov - 2 can comprise a VH antibody, a trispecific modified antibody or antigen -binding
having an amino acid sequence that is at least 70% , 75 % , fragment, or a tetraspecific modified antibody or antigen
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ 60 binding fragment. A bispecific modified antibody can be
ID NO : 370 and a VL having an amino acid sequence that able to specifically bind to 2 targets. In some cases , one of
is at least 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or the targets a bispecific modified antibody can specifically
100% identical to SEQ ID NO : 430 . bind to can be a SARS - CoV - 2 . A trispecific modified anti
In one instance , the antibody or antigen - binding fragment body can be able to specifically bind to 3 targets. In some
that selectively binds to SARS - Cov - 2 can comprise a VH 65 cases , one of the targets a trispecific modified antibody can
having an amino acid sequence that is at least 70% , 75 % , specifically bind to can be a SARS - CoV - 2 . A tetraspecific
80 % , 85 % , 90 % , 95 % , 98 % , 99 % , or 100% identical to SEQ modified antibody can be able to specifically bind to 4
 US 11,034,762 B1
67 68
targets. In some cases , one of the targets a tetraspecific modification of the modified antibody polypeptide can com
modified antibody can specifically bind to can be a SARS-prise altering the native glycosylation pattern of the poly
CoV - 2 . peptide. Herein , “ altering” can mean deleting one or more
A modified antibody can comprise a human modified carbohydrate moieties found in the original modified anti
antibody. Also included herein are amino acid sequence 5 body, and / or adding one or more glycosylation sites that are
variants of the modified antibody which can be prepared by not present in the original modified antibody. Addition of
introducing appropriate nucleotide changes into the modi- glycosylation sites to the modified antibody polypeptide can
fied antibody DNA, or by synthesis of the desired modified be accomplished by altering the amino acid sequence such
antibody polypeptide. Such variants include, for example, that it contains one or more N - linked glycosylation sites .
deletions from , or insertions or substitutions of, residues 10 The alteration may also be made by the addition of, or
substitution by, one or more serine or threonine residues to
within the amino acid sequences of the first and second the original modified antibody sequence ( for O - linked gly
polypeptides forming the modified antibody. Any combina cosylation sites ) . For ease , the modified antibody amino acid
tion of deletion, insertion , and substitution is made to arrive sequence can be altered through changes at the DNA level ,
at the final construct, provided that the final construct
possesses the desired antigen -binding characteristics . The 15 particularly by mutating the DNA encoding the modified
antibody polypeptide at preselected bases such that codons
amino acid changes also may alter post- translational pro are generated that will translate into the desired amino acids .
cesses of the modified antibody, such as changing the Another means of increasing the number of carbohydrate
number or position of glycosylation sites . moieties on the modified antibody polypeptide is by chemi
" Alanine scanning mutagenesis
residues” orcanregions
be a useful
ofthemethod
modi- 20 Removal
cal orenzymatic coupling of glycosides to the polypeptide.
forfiedidentification of certain
antibody polypeptides that might be preferred locations of carbohydrate moieties present on the modified
antibody can be accomplished chemically or enzymatically.
for mutagenesis. Here , a residue or group of target residues Another type of covalent modification of modified anti
are identified (e.g. , charged residues such as Arg, Asp , His ,
body comprises linking the modified antibody polypeptide
Lys , and Glu ) and replaced by a neutral or negatively 25 to one of a variety of non -proteinaceous polymers, e.g. ,
charged amino acid ( for example, alanine or polyalanine) to polyethylene glycol , polypropylene glycol , or polyoxyal
affect the interaction of the amino acids with the surrounding kylenes.
aqueous environment in or outside the cell . Those domains Methods for complexing binding agents or the antibody or
demonstrating functional sensitivity to the substitutions then antigen -binding fragments thereof herein with another agent
are refined by introducing further or other variants at or for 30 are known in the art. Such methods may utilize one of
the sites of substitution. Thus, while the site for introducing
an amino acid sequence variation is predetermined , the several available heterobifunctional reagents used for cou
nature of the mutation per se need not be predetermined.
pling or linking molecules .
Normally the mutations can involve conservative amino
In one instance , Fc portions of antibodies can be modified
to increase half - life of the molecule in the circulation in
acid replacements in non - functional regions of the modified 35 blood when administered to a subject.
antibody. Exemplary mutations are shown below . Additionally, antibodies may be produced or expressed so
that they do not contain fucose on their complex N -glyco
Original Residue Exemplary Substitutions Preferred Substitutions side - linked sugar chains to increase effector functions. Simi
larly, antibodies can be attached at their C - terminal end to all
Ala ( A ) Val; Leu ; Ile Val 40 or part of an immunoglobulin heavy chain derived from any
Arg (R) Lys; Gln ; Asn Lys antibody isotype, e.g. , IgG , IgA , IgE , IgD , and IgM , and any
Asn ( N ) Gln ; His ; Lys; Arg Gin
of the isotype subclasses, e.g. , IgG1 , IgG2b , IgG2a , IgG3 ,
Asp (D) Glu Glu
Cys ( C ) Ser Ser and IgG4 .
Gln (Q) Asn
Asp
Asn
Asp
Glycosylation of immunoglobulins has been shown to
Glu (E) 45 have significant effects on their effector functions, structural
Gly ( G) Pro; Ala Ala
His (H) Asn ; Gln ; Lys; Arg Arg stability, and rate of secretion from antibody -producing
Ile (I) Leu ; Val; Met ; Ala ; Leu cells . Antibodies and antigen -binding fragments herein may
Leu ( L)
Phe ; Norleucine
Ile
be glycosylated . Glycosylation at a variable domain frame
Norleucine; Ile ; Val;
Met ; Ala ; Phe work residue can alter the binding interaction of the anti
Lys ( K ) Arg; Gln; Asn Arg 50 body with antigen . The present disclosure includes criteria
Met ( M ) Leu ; Phe ; Ile Leu by which a limited number of amino acids in the framework
Phe (F) Leu ; Val; Ile ; Ala ; Tyr Leu or CDRs of an immunoglobulin chain can be chosen to be
Pro (P) Ala Ala mutated (e.g. , by substitution , deletion , and /or addition of
Ser (S) Thr Thr
Thr (T ) Ser Ser residues ) in order to increase the affinity of an antibody.
Trp ( W ) Tyr; Phe Tyr 55 Linkers for conjugating antibodies to other moieties are
Tyr ( Y ) Trp ; Phe ; Thr; Ser Phe within the scope of the present disclosure . Associations
Val (V ) Ile ; Leu ; Met ; Phe ; Leu
(binding ) between antibodies and labels include, but are not
Ala ; Norleucine limited to , covalent and non -covalent interactions, chemical
conjugation, as well as recombinant techniques .
Covalent modifications of antibody, antigen - binding frag- 60 Antibodies, or antigen -binding fragments thereof, can be
ment, or modified antibody polypeptides are included within modified for various purposes such as , for example, by
the scope of this disclosure. Covalent modifications of the addition of polyethylene glycol ( PEG) . PEG modification
modified antibody can be introduced into the molecule by (PEGylation ) can lead to one or more of improved circula
reacting targeted amino acid residues of the modified anti- tion time , improved solubility, improved resistance to pro
body or fragments thereof with an organic derivatizing agent 65 teolysis, reduced antigenicity and immunogenicity ,
that can be capable of reacting with selected side chains or improved bioavailability, reduced toxicity, improved stabil
the N- or C - terminal residues. Another type of covalent ity, and easier formulation.
 US 11,034,762 B1
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A CR3022 - derived antibody or antigen -binding fragment include , but are not limited to , viral vectors ; naked DNA or
can be conjugated to , or recombinantly engineered with , an RNA expression vectors ; plasmid , cosmid , or phage vectors ;
affinity tag (e.g. , a purification tag ) . Affinity tags such as , for DNA or RNA expression vectors associated with cationic
example , His6 tags (His - His - His - His - His - His ) ( SEQ ID NO : condensing agents; DNA or RNA expression vectors encap
451 ) have been described . 5 sulated in liposomes ; and certain eukaryotic cells , such as
Since it is often difficult to predict in advance the char- producer cells .
acteristics of a variant modified antibody, it will be appre- As used herein , “ expression control sequence” means a
ciated that some screening of the recovered variants may be nucleic acid sequence that directs transcription of a nucleic
needed to select an optimal variant. Exemplary methods of acid . An expression control sequence can be a promoter,
screening the recovered variants are described below in the 10 such as a constitutive or an inducible promoter, or an
Examples enhancer. The expression control sequence is operably
Methods of Expressing Antibodies linked to the nucleic acid sequence to be transcribed . An
Also provided herein are methods of making any of these expression vector can be used to direct expression of an
antibodies or polypeptides . The polypeptides can be pro- antibody. Expression vectors can be administered to obtain
duced by proteolytic or other degradation of the antibodies, 15 expression of an exogenous protein in vivo.
by recombinant methods (i.e. , single or fusion polypeptides ) For high level production, a widely used mammalian
as described above, or by chemical synthesis . Polypeptides expression system is one which utilizes Lonza's GS Gene
of the antibodies, especially shorter polypeptides up to about Expression SystemTM This system uses a viral promoter and
50 amino acids , can be made by chemical synthesis. Meth- selection via glutamine metabolism to provide development
ods of chemical synthesis are commercially available . For 20 of high -yielding and stable mammalian cell lines.
example , an antibody could be produced by an automated For alternative high -level production, a widely used mam
polypeptide synthesizer employing a solid phase method . malian expression system is one which utilizes gene ampli
Antibodies may be made recombinantly by first isolating fication by dihydrofolate reductase deficient ( “ dhfr ”) Chi
the antibodies and antibody producing cells from host ani- nese hamster ovary cells . The system is based upon the
mals , obtaining the gene sequence, and using the gene 25 dihydrofolate reductase “ dhfr” gene, which encodes the
sequence to express the antibody recombinantly in host cells DHFR enzyme, which catalyzes conversion of dihydrofolate
( e.g. , CHO cells ) . Another method which may be employed to tetrahydrofolate. In order to achieve high production,
is to express the antibody sequence in plants ( e.g. , tobacco ) dhfr - CHO cells are transfected with an expression vector
or transgenic milk . Methods for expressing antibodies containing a functional DHFR gene , together with a gene
recombinantly in plants or milk have been disclosed . Meth- 30 that encodes a desired protein . In this case , the desired
ods for making derivatives of antibodies, e.g. , single chain , protein is recombinant antibody heavy chain and / or light
etc. are also within the scope of the present disclosure . chain .
As used herein , " host cell ” includes an individual cell or By increasing the amount of the competitive DHFR
cell culture that can be or has been a recipient for vector ( s ) inhibitor methotrexate ( MTX ) , the recombinant cells
for incorporation of polynucleotide inserts . Host cells 35 develop resistance by amplifying the dhfr gene. In standard
include progeny of a single host cell , and the progeny may cases , the amplification unit employed is much larger than
not necessarily be completely identical (in morphology or in the size of the dhfr gene , and as a result the antibody heavy
genomic DNA complement) to the original parent cell due to chain is co - amplified.
natural, accidental, or deliberate mutation . A host cell When large scale production of the protein, such as the
includes cells transfected with a polynucleotide ( s) of this 40 antibody chain , is desired, both the expression level and the
disclosure . stability of the cells being employed are taken into account.
DNA encoding an antibody may be readily isolated and The present application provides one or more isolated
sequenced using conventional procedures ( e.g. , by using polynucleotides ( nucleic acids ) encoding an antibody or an
oligonucleotide probes that are capable of binding specifi- antigen -binding fragment herein , vectors containing such
cally to genes encoding the heavy and light chains of the 45 polynucleotides, and host cells and expression systems for
monoclonal antibodies ). Hybridoma cells may serve as a transcribing and translating such polynucleotides into poly
source of such DNA . Once isolated , the DNA may be placed peptides.
into one or more expression vectors ( such as expression The present application also provides constructs in the
vectors disclosed in PCT Publication No. WO 87/04462 ) , form of plasmids , vectors , transcription or expression cas
which are then transfected into host cells such as E. coli 50 settes which comprise at least one polynucleotide as above .
cells , simian COS cells , Chinese hamster ovary (CHO ) cells , The present application also provides a recombinant host
or myeloma cells that do not otherwise produce immuno- cell which comprises one or more constructs as above . A
globulin protein , to obtain the synthesis of monoclonal nucleic acid encoding any antibody or antigen - binding frag
antibodies in the recombinant host cells . The DNA also may ment herein forms an aspect of the present application , as
be modified , for example, by substituting the coding 55 does a method of production of the antibody, which method
sequence for human heavy and light chain constant domains comprises expression from encoding nucleic acid therefrom .
in place of the homologous murine sequences, or by cova- Expression can be achieved by culturing under appropriate
lently joining to the immunoglobulin coding sequence all or conditions recombinant host cells containing the nucleic
part of the coding sequence for a non - immunoglobulin acid . Following production by expression , an antibody or a
polypeptide . In that manner, “ chimeric ” or “ hybrid ” anti- 60 portion thereof can be isolated and / or purified using any
bodies are prepared that have the binding specificity of an suitable technique, then used as appropriate.
antibody herein . Systems for cloning and expression of a polypeptide in a
Contemplated herein are vectors that encode the one or variety of different host cells are contemplated for use
more antibodies or antigen -binding fragments herein . As herein .
used herein , “ vector” means a construct, which is capable of 65 A further aspect provides a host cell containing nucleic
delivering, and possibly expressing, one or more gene (s ) or acid as disclosed herein using any suitable method . A still
sequence ( s) of interest in a host cell . Examples of vectors further aspect provides a method comprising introducing
 US 11,034,762 B1
71 72
such nucleic acid into a host cell . The introduction can be thesized at least in part by using the subject's cellular
followed by causing or allowing expression from the nucleic transcription and / or translation machinery. In some cases ,
acid , e.g. , by culturing host cells under conditions for for example where the polynucleotide is an mRNA mol
expression of the gene . ecule , the antibody or antigen -binding fragment can be
One or more polynucleotides encoding an antibody or an 5 synthesized at least in part by using the subject's cellular
antigen -binding fragment can be prepared recombinantly / translation machinery (e.g. , ribosomes , tRNA , etc. ) . In some
synthetically in addition to , or rather than , cloned . In a cases , antibody or antigen -binding fragments can be trans
further embodiment, the full DNA sequence of the recom- ported from a cell to the plasma of the subject after trans
binant DNA molecule or cloned gene ( s ) of an antibody or lation .
antigen - binding fragment herein can be operatively linked to 10 Compositions
an expression control sequence which can be introduced into Compositions comprising a CR3022 - derived antibody or
an appropriate host using any suitable method . antigen - binding fragment herein may be prepared for stor
Nucleic acid sequences can be expressed by operatively age by mixing an antibody or antigen -binding fragment
linking them to an expression control sequence in an appro- having the desired degree of purity with optional pharma
priate expression vector and employing that expression 15 ceutically acceptable carriers, excipients or stabilizers
vector to transform an appropriate host cell . Any of a wide (Remington , The Science and Practice of Pharmacy 20th Ed .
variety of expression control sequences — sequences that Mack Publishing ( 2000 ) ), in the form of lyophilized formu
control the expression of a nucleic acid sequence operatively lations or aqueous solutions .
linked to it can be used in these vectors to express the As used herein , " pharmaceutically acceptable carrier ” or
nucleic acid sequences. 20 “ pharmaceutical acceptable excipient ” includes any material
A wide variety of host / expression vector combinations which, when combined with an active ingredient, allows the
can be employed in expressing the nucleic acid sequences of ingredient to retain biological activity and is non - reactive
this disclosure . It will be understood that not all vectors , with the subject's immune system . Examples include, but
expression control sequences , and hosts will function are not limited to , any of the standard pharmaceutical
equally well to express the nucleic acid sequences. Neither 25 carriers such as a phosphate buffered saline solution , water,
will all hosts function equally well with the same expression emulsions such as oil /water emulsion , and various types of
system . In some embodiments, in selecting a vector, the host wetting agents. Preferred diluents for aerosol or parenteral
is considered such that the vector can function in it . The administration are phosphate buffered saline or normal
vector's copy number, the ability to control that copy (0.9 % ) saline . Compositions comprising such carriers are
number, and the expression of any other proteins encoded by 30 formulated by well-known conventional methods ( see , for
the vector, such as antibiotic markers , may also be consid- example , Remington's Pharmaceutical Sciences, 18th edi
ered . In certain embodiments , in selecting a vector, the host tion , A. Gennaro , Ed . , Mack Publishing Co. , Easton, Pa . ,
is considered such that the vector functions in it . The 1990 ; and Remington, The Science and Practice of Phar
vector's copy number, the ability to control that copy macy 20th Ed . Mack Publishing , 2000 ) .
number, and the expression of any other proteins encoded by 35 Acceptable carriers, excipients, or stabilizers are nontoxic
the vector, such as antibiotic markers, can also be consid- to recipients at the dosages and concentrations employed,
ered . and may comprise buffers such as phosphate , citrate, and
The present application also provides a method which other organic acids ; salts such as sodium chloride ; antioxi
comprises using a construct as stated above in an expression dants including ascorbic acid and methionine; preservatives
system order to express the antibodies (or portions 40 ( such as octadecyldimethylbenzyl ammonium chloride ; hex
thereof) as above . Considering these and other factors, a amethonium chloride ; benzalkonium chloride, benzetho
variety of vector /expression control sequence /host combi- nium chloride; phenol, butyl or benzyl alcohol ; alkyl para
nations can be constructed that can express the nucleic acid bens, such as methyl or propyl paraben; catechol; resorcinol ;
sequences on fermentation or in large scale animal culture . cyclohexanol; 3-pentanol; and m -cresol); low molecular
Simultaneous incorporation of the antibody ( or portion 45 weight ( less than about 10 residues ) polypeptides; proteins,
thereof) -encoding nucleic acids and the selected amino acid such as serum albumin , gelatin, or immunoglobulins; hydro
position changes can be accomplished by a variety of philic polymers such as polyvinylpyrrolidone; amino acids
suitable methods including, for example, recombinant and such as glycine, glutamine , asparagine, histidine, arginine,
chemical synthesis. or lysine ; monosaccharides , disaccharides , and other carbo
Provided herein are methods of expressing a CR3022- 50 hydrates including glucose , mannose, or dextrins; chelating
derived antibody or antigen -binding fragment (e.g. , an anti- agents such as EDTA ; sugars such as sucrose , mannitol,
body or antigen -binding fragment) that can selectively bind trehalose or sorbitol; salt -forming counter - ions such as
to SARS - Cov - 2 in a subject comprising administering to the sodium ; metal complexes ( e.g. , Zn- protein complexes ); and /
subject a composition comprising a polynucleotide ( e.g. , or non - ionic surfactants such as TWEENTM , PLURON
mRNA ) encoding the antibody or antigen -binding fragment. 55 ICSTM or polyethylene glycol (PEG) .
In some cases , administering the polynucleotide to the The compositions to be used for in vivo administration
subject can comprise enteral, gastroenteral, oral , transder- may be sterilized . This may be accomplished by, for
mal , epicutaneous , intradermal, subcutaneous , nasal admin- example , filtration through sterile filtration membranes, or
istration , intravenous, intraperitoneal, intraarterial, intra- any other art -recognized method for sterilization . Antibody
muscular, intraosseous infusion, transmucosal, insufflation , 60 compositions are generally placed into a container having a
or sublingual administration . In some cases , a polynucle- sterile access port, for example, an intravenous solution bag
otide can be administered via more than one route . or vial having a stopper pierceable by a hypodermic injec
Antibodies or antigen -binding fragments can be synthe- tion needle . Other methods for sterilization and filtration are
sized in the subject based at least in part on the polynucle- known in the art and are contemplated herein .
otide encoding the antibody or antigen -binding fragment. 65 In one embodiment of the present invention , the compo
For example, a polynucleotide can enter a cell of the subject, sitions are formulated to be free of pyrogens such that they
and the antibody or antigen -binding fragment can be syn- are acceptable for administration to a subject.
 US 11,034,762 B1
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The compositions according to the present invention may The present disclosure provides methods of prophylacti
be in unit dosage forms such as solutions or suspensions, cally treating (e.g. , preventing ) a subject having one or more
tablets , pills , capsules , powders, granules, or suppositories, co -morbidities or having an increased or high risk of infec
etc. , for intravenous, oral , parenteral or rectal administra- 5
tion .
tion, or administration by inhalation or insufflation . A “ subject ” as described herein , includes, but is not
The phrase " pharmaceutically acceptable” refers to limited to , a human , a rodent, a primate, etc. In some
molecular entities and compositions that are physiologically instances, the subject to be treated exhibits one or more
tolerable and do not typically produce an allergic or similar underlying conditions that exacerbate the infection such as ,
untoward reaction , such as gastric upset, dizziness and the 10
for example, high blood pressure, heart problems, diabetes,
like , when administered to a subject. immunocompromised, lung disease , cancer, clots , thrombo
In some instances, a CR3022 - derived antibody or antigen- sis , or a combination thereof.
binding fragment can be bound to one or more carriers. A subject can be administered a CR3022 -derived antibody
Carriers can be active and / or inert. Examples of well -known or antigen -binding fragment herein in an amount that
carriers include polypropylene, polystyrene, polyethylene, is achieves at least partially a partial or complete reduction of
dextran, nylon, amylases, glass , natural and modified cellu- one or more symptoms. Reduction can be , for example, a
loses , polyacrylamides, agaroses and magnetite . The nature decrease of one or more symptoms by about 5 % or more
of the carrier can be either soluble or insoluble for purposes compared to prior to treatment. For the administration to
of the invention . Those skilled in the art will know of other human patients, the compositions can be formulated by
suitable carriers for binding antibodies, or will be able to 20 methodology known by one in the art. The amount of an
ascertain such , using routine experimentation . antibody necessary to bring about therapeutic treatment of
One embodiment contemplates the use of the antibodies COVID19 is not fixed per se . The amount of antibody
and antigen -binding fragments to manufacture a medica- administered may vary with the extensiveness of the disease ,
ment for treating a condition, disease or disorder described and size of the human suffering from COVID19 . Treatment,
herein . Medicaments can be formulated based on the physi- 25 in one instance, lowers infection rates in a population of
cal characteristics of the subject needing treatment, and can subjects. Treatment may also result in a shortened recovery
be formulated in single or multiple formulations based on time , in fewer symptoms, or in less severe symptoms, or a
the stage of the condition, disease or disorder. Medicaments combination thereof compared to an untreated subject who
can be packaged in a suitable package with appropriate has COVID19 .
labels for the distribution to hospitals and clinics wherein the 30 The CR3022 -derived antibodies and antigen -binding
label is for the indication of treating a subject having a fragments herein may be used to treat a COVID19 infection
disease described herein . Medicaments can be packaged as (an infection caused by SARS - Cov - 2 ) in a subject in need
a single or multiple units. Instructions for the dosage and ther of , thereby reducing one or more symptoms of the
administration of the compositions can be included with the infection . The one or more symptoms to be treated include ,
packages as described below. The invention is further 35 but are not limited to , a fever of over 100.4 ° F. , fatigue,
directed to medicaments of an antibody or antigen -binding coughing ( e.g. , a dry cough ), aches , pains , runny nose , stuffy
fragment and a pharmaceutically acceptable carrier. nose , sore throat, diarrhea, headaches, shortness of breath , or
Kits any combination thereof. In some instances, treatment of a
Provided herein are kits that comprise one or more subject includes a reduction by at least 5 % in 1 symptom , 2
anti -SARS - Cov - 2 antibodies or antigen -binding fragments 40 symptoms, 3 symptoms, 4 symptoms, 5 symptoms, 6 symp
herein . Provided herein is a container means comprising one toms , 7 symptoms, 8 symptoms, 9 symptoms, 10 symptoms,
or more anti- SARS - Cov - 2 antibodies or antigen -binding or 11 symptoms. During at least a portion of this time period
fragments herein . The container means may be any suitable the antibody or antigen -binding fragment can protect the
container which may house a liquid or lyophilized compo- subject from infection by SARS - Cov - 2 . Protecting can
sition including, but not limited to , a vial , a syringe, a bottle, 45 comprise for example reducing an infection rate of SARS
an intravenous ( IV) bag , an ampoule, or any other suitable Cov - 2 or reducing or preventing reproduction of SARS
container. A syringe may be able to hold any volume of Cov - 2 . Treatment can comprise for example reducing symp
liquid suitable for injection into a subject including, but not toms of COVID - 19 , reducing a death rate , or reducing or
limited to , 0.5 cc , 1 cc , 2 cc , 5 cc , 10 cc or more . In some preventing reproduction of SARS - Cov - 2.
embodiments , the antibody or antigen -binding fragment is 50 “ Administering” is referred to herein as providing one or
lyophilized, and the kit comprises one or more suitable more compositions to a patient in a manner that results in the
buffers for reconstitution prior to injection . composition being inside the patient's body. Such an admin
The kit may comprise one or more instruction sheets istration can be by any route including, without limitation ,
describing the use of the one or more antibodies or antigen- locally, regionally, or systemically, by subcutaneous, intra
binding fragments . The kit may include one or more labels 55 dermal, intravenous, intra -arterial, intraperitoneal, or intra
describing the contents and use of the one or more antibod- muscular administration ( e.g. , injection ). In one instance ,
ies . administration is via intradermal injection. In another
Methods of Treatment instance, administration is via subcutaneous injection. In one
The present disclosure provides methods of preventing or embodiment, a subject is administered one of the antibodies
treating a subject infected with SARS - Cov - 2 ( COVID ) or 60 or antigen -binding fragments herein one or more times . In
suspected of being infected with SARS - Cov - 2 in a subject in another embodiment, a subject is administered two of the
need thereof, comprising administering to the subject a antibodies or antigen -binding fragments herein one or more
CR3022 -derived antibody or antigen -binding fragment times . In another embodiment, a subject is administered
herein . In one instance, the subject to be treated is symp- three of the antibodies or antigen -binding fragments herein
tomatic prior to administration of the antibody. In another 65 one or more times . In another embodiment, a subject is
instance, the subject to be treated is asymptomatic prior to administered four of the antibodies or antigen -binding frag
administration of the antibody. ments herein one or more times . A CR3022 -derived anti
 US 11,034,762 B1
75 76
body or antigen -binding fragment herein to be administered sion electron microscopy, tunable resistive pulse sensing ,
to the subject exhibits a nM or a PM binding affinity, e.g. , flow cytometry, qPCR , ELISA , or another acceptable
between 170 PM and 50 nM . method . An assay can be performed on a whole sample or a
The present disclosure provides methods of reducing the fraction of a sample, or SARS - Cov - 2 can be isolated from
death rate of infection by SARS - Cov - 2 by administering to 5 the sample prior to performing an assay. In some cases , the
a subject in need thereof a composition comprising one or reproduction of SARS - CoV - 2 can be slowed compared with
more polynucleotides ( e.g. , mRNA ) encoding a CR3022- subjects not administered a composition comprising an
derived antibody or antigen -binding fragment that can spe- mRNA molecule herein by at least 5 % , at least 10 % , at least
cifically bind to SARS - Cov - 2 . Reduction in death rate can 20% , at least 30% , at least 40 % , at least 50 % , at least 60 % ,
be determined for example by comparing the rate of death of 10 at least 70 % , at least 80 % , or at least 90 % . In some cases ,
subjects infected by SARS - Cov - 2 between a cohort that the reproduction of SARS - Cov - 2 can be slowed compared
receives the composition and a cohort that does not receive with subjects not administered a composition comprising an
the composition. Death rate can be determined for example mRNA molecule herein by about 10 % , about 20 % , about
by determining the number of infected subjects of a cohort 30% , about 40 % , about 50 % , about 60% , about 70 % , about
wherein infection by SARS - Cov - 2 results in death . In some 15 80% , about 90% , or a range between any two foregoing
cases , the death rate can be reduced compared with subjects values .
not administered a composition comprising an mRNA mol- The present disclosure also provides methods of activat
ecule herein by at least 5 % , at least 10 % , at least 20 % , at ing T cells in a subject comprising administering to a subject
least 30% , at least 40 % , at least 50% , at least 60 % , at least a composition comprising one or more polynucleotides ( e.g. ,
70 % , at least 80% , or at least 90 % . In some cases , the death 20 mRNA ) encoding a CR3022 - derived antibody or antigen
rate can be reduced compared with subjects not administered binding fragment that can specifically bind to SARS - CoV - 2 .
a composition comprising an mRNA molecule herein by In some cases , T cell activation can be elevated compared
about 10 % , about 20 % , about 30% , about 40 % , about 50 % , with subjects not administered the composition. Activation
about 60 % , about 70 % , about 80% , about 90 % , or a range of T cells can be determined for example by comparing the
between any two foregoing values . 25 activation of T cells in subjects infected SARS - Cov - 2
The present disclosure also provides methods for reducing between a cohort that receives the composition and a cohort
the infection rate of SARS - Cov - 2 by administering to a that does not receive the composition . In one aspect , the
subject non infected with SARS - Cov - 2 a composition com- activation of T cells in the subject can be directed to an
prising one or more polynucleotides ( e.g. , mRNA ) encoding anti - SARS - Cov - 2 response in the subject. Activated T cells
a CR3022 - derived antibody or antigen -binding fragment 30 in the subject can reduce severity of COVID - 19 symptoms,
that can specifically bind to SARS - CoV - 2 . Reduction in death rate, time to recovery, or viral reproduction in the
infection rate can be determined for example by comparing subject. Activation of T cells can be measured for example
the rate of infection of subjects exposed to SARS - Cov - 2 by measuring T cell proliferation, measuring cytokine pro
between a cohort that receives the composition and a cohort duction (e.g. , via enzyme - linked immunosorbent assays or
that does not receive the composition. Infection of a subject 35 enzyme -linked immunospot assays) , or detection of cell
can be determined by analyzing a sample from the subject surface markers associated with T cell activation ( e.g. ,
for the presence or absence of SARS - Cov - 2 after suspected CD69 , CD40L , CD137 , CD25 , CD71 , CD26 , CD27 , CD28 ,
or confirmed exposure to SARS - Cov - 2 , or after an elapsed CD30 , CD154 , or CD134 ) for example by flow cytometry .
time in which exposure to SARS - CoV - 2 is likely. In some In some cases , the T cell activation can be elevated com
cases , the infection rate can be reduced compared with 40 pared with subjects not administered a composition com
subjects not administered a composition comprising an prising an mRNA molecule herein by at least 5 % , at least
mRNA molecule herein by at least 5 % , at least 10 % , at least 10% , at least 20% , at least 30 % , at least 40 % , at least 50 % ,
20 % , at least 30 % , at least 40 % , at least 50 % , at least 60 % , at least 60 % , at least 70 % , at least 80% , or at least 90 % . In
at least 70 % , at least 80% , or at least 90% . In some cases , some cases , the T cell activation can be elevated compared
the infection rate can be reduced compared with subjects not 45 with subjects not administered a composition comprising an
administered a composition comprising an mRNA molecule mRNA molecule herein by about 10 % , about 20 % , about
herein by about 10 % , about 20 % , about 30% , about 40 % , 30% , about 40 % , about 50 % , about 60% , about 70 % , about
about 50 % , about 60 % , about 70% , about 80 % , about 90 % , 80% , about 90% , or a range between any two foregoing
or a range between any two foregoing values . values .
The present disclosure also provides methods for slowing 50 The present disclosure also provides methods for inducing
or preventing reproduction of SARS - Cov - 2 in a subject by T cell proliferation in a subject comprising administering to
administering to a subject infected with SARS - Cov - 2 a a subject a composition comprising one or more polynucle
composition comprising one or more polynucleotides ( e.g. , otides ( e.g. , mRNA ) encoding a CR3022 -derived antibody
mRNA ) encoding a CR3022 -derived antibody or antigen- or antigen -binding fragment that can specifically bind to
binding fragment that can specifically bind to SARS - Cov - 2 . 55 SARS -CoV - 2 . In some cases , T cell proliferation can be
Slowing or preventing reproduction of SARS - Cov - 2 can be elevated compared with subjects not administered the com
determined for example by comparing the rate of reproduc- position . In some cases , T cell proliferation can be directed
tion of the virus in subjects infected SARS - Cov - 2 between to an anti -SARS - Cov - 2 response in the subject. In some
a cohort that receives the composition and a cohort that does cases , T cell proliferation in the subject can reduce or
not receive the composition . Replication of SARS - Cov - 2 60 decrease severity of COVID - 19 symptoms, death rate , time
can be determine for example by determining ( directly or to recovery, or viral reproduction in the subject. cell
indirectly ) the amount of SARS - Cov - 2 in a sample acquired proliferation can be determined for example by cell count
from the subject at different time points. Assays that can be ing , viability staining , optical density assays, or detection of
used to determine amount of SARS - Cov - 2 in a sample can cell- surface markers associated with T cell activation ( e.g. ,
include a plaque assay, a focus forming assay, an endpoint 65 CD69 , CD40L , CD137 , CD25 , CD71 , CD26 , CD27 , CD28 ,
dilution assay , a protein assay ( e.g. , a bicinchoninic acid CD30 , CD154 , or CD134 ) for example by flow cytometry .
assay or a single radial immunodiffusion assay ) , transmis- In some cases , T cell proliferation can be elevated compared
 US 11,034,762 B1
77 78
with subjects not administered a composition comprising an A physician or veterinarian can readily determine and
mRNA molecule herein by at least 5 % , at least 10 % , at least prescribe the effective amount (ED50 ) of the antibody
20 % , at least 30 % , at least 40 % , at least 50 % , at least 60 % , required. For example, the physician or veterinarian could
at least 70 % , at least 80% , or at least 90% . In some cases , start doses of the antibody employed in the composition at
T cell proliferation can be elevated compared with subjects 5 levels lower than that required in order to achieve the desired
not administered a composition comprising an mRNA mol therapeutic effect and gradually increase the dosage until the
ecule herein by about 10 % , about 20 % , about 30 % , about desired effect is achieved . Alternatively, a dose can remain
constant.
40 % , about 50 % , about 60 % , about 70 % , about 80% , about
90 % , or a range between any two foregoing values . The antibody can be administered to a patient by any
The present disclosure also provides methods for inducing 10 convenient route such as described above. Regardless of the
a memory T cell response in a subject comprising admin ent invention , which canselected
route of administration , the antibodies of the pres
be used in a suitable hydrated form ,
istering to a subject a composition comprising one or more and / or the compositions, are formulated into acceptable
polynucleotides ( e.g. , mRNA ) encoding a CR3022 - derived dosage forms.
antibody or antigen -binding fragment that can specifically 15 Toxicity and therapeutic efficacy of compounds can be
bind to SARS - CoV - 2 . In some cases , a memory T cell determined by standard procedures in cell cultures or experi
response can be elevated compared with subjects not admin mental animals, e.g. , for determining the LD50 ( the dose
istered the composition . In some cases , a memory T cell lethal to 50 % of the population) and the ED50 (the dose
response in the subject can reduce or decrease i severity of therapeutically effective in 50 % of the population) . The dose
COVID - 19 symptoms, death rate, time to recovery, or viral 20 ratio between toxic and therapeutic effects is the therapeutic
reproduction in the subject. A memory T cell response can index and it can be expressed as the ratio LD50/ED50 .While
be directed to an anti - SARS - Cov - 2 response in the subject.
compounds that exhibit toxic side effects may be used , care
A memory T cell response can be determined for example by should be taken to design a delivery system that targets such
measuring T cell markers associated with memory T cells , compounds to the site of affected tissue in order to minimize
measuring local cytokine production related to memory 25 potential damage to healthy cells and, thereby, reduce side
immune response , or detecting memory T cell -surface mark- effects .
ers for example by flow cytometry. In some cases , the Data obtained from cell culture assays and / or animal
memory T cell response can be elevated compared with studies can be used in formulating a range of dosage for use
subjects not administered a composition comprising an in humans. The dosage of such compounds lies preferably
mRNA molecule herein by at least 5 % , at least 10 % , at least 30 within a range of circulating concentrations that include the
20 % , at least 30 % , at least 40 % , at least 50 % , at least 60 % , ED50 with little or no toxicity. The dosage may vary within
at least 70 % , at least 80% , or at least 90% . In some cases , this range depending upon the dosage form employed and
the memory T cell response can be elevated compared with the route of administration utilized . For any compound, a
subjects not administered a composition comprising an therapeutically effective dose can be estimated initially from
mRNA molecule herein by about 10 % , about 20 % , about 35 cell culture assays . A dose can be formulated in animal
30 % , about 40 % , about 50 % , about 60 % , about 70% , about models to achieve a circulating plasma concentration
80 % , about 90% , or a range between any two foregoing arrange that includes the IC50 (i.e. , the concentration of the
values . test compound which achieves a half -maximal inhibition ) as
A polynucleotide (e.g. , mRNA ) herein can be adminis- determined in cell culture . Levels in plasma can be mea
tered in any route available, including , but not limited to , 40 sured , for example , by high performance liquid chromatog
enteral, gastroenteral, oral, transdermal, epicutaneous, intra- raphy. Such information can be used to more accurately
dermal, subcutaneous, nasal administration , intravenous , determine useful doses in humans.
intraperitoneal, intraarterial, intramuscular, intraosseous It will be understood that administration of one or more of
infusion , transmucosal, insufflation, or sublingual adminis- the antibodies or antigen -binding fragments herein can be
tration . In some cases , mRNA of the present disclosure can 45 supplemented by one or more additional therapies or drugs
be administered parenterally ( e.g. , includes subcutaneous, such as , for example, respiratory therapy ; one or more blood
intravenous, intraperitoneal, intratumoral, intramuscular, thinners or anti - coagulants; statins , intubation ; hydroxy
intra - articular, intra -synovial, intrasternal, intrathecal, intra- chloroquine; one or more antibiotics (e.g. , doxycycline ,
hepatic, intralesional and injection or infusion techniques ), Azithromycin , etc.); one or more decongestants ( e.g. , Muci
intraventricularly, orally , by inhalation spray, topically, rec- 50 nex , Sudafed, etc. ) ; one or more anti- histamines and / or
tally, nasally, buccally, or via an implanted reservoir. glucocorticoids (e.g. , Zyrtec , Claritin, Allegra , fluticasone
Actual dosage levels of antibody can be varied so as to luroate , etc. ) ; one or more pain relievers ( e.g. , acetomino
obtain an amount of the active ingredient that is effective to phen ); one or more zinc -containing medications ( e.g. ,
achieve the desired therapeutic response without being toxic Zycam , etc. ) ; Azithromycin, hydroquinolone, or a combina
to the patient. The selected dosage level will depend upon a 55 tion thereof; one or more integrase inhibitors (e.g. , Bictegra
variety of factors including the activity of the particular vir, dolutegravir ( Tivicay ), elvitegravir, raltegravir, or a
antibody employed , the route of administration , the time of combination thereof); one or more nucleoside /nucleotide
administration, the rate of excretion of the particular anti- reverse transcriptase inhibitors (NRTIs ; e.g. , abacavir (Zia
body being employed, the duration of the treatment, other gen ), emtricitabine ( Emtriva ), lamivudine (Epivir ), tenofo
drugs, compounds and / or materials used in combination 60 vir alafenamide fumarate ( Vemlidy ), tenofovir disoproxil
with the particular composition employed , the age , sex , fumarate ( Viread ), zidovudine (Retrovir ), didanosine (Vi
weight, condition , general health and prior medical history dex , Videx EC ) , stavudine (Zerit ), or a combination thereof);
of the patient being treated , and like factors well known in a combination of NRTIs (e.g. , ( i ) abacavir, lamivudine, and
the medical arts . zidovudine ( Trizivir ), (ii ) abacavir and lamivudine ( Epzi
The antibodies and antigen -binding fragments herein can 65 com) , (iii ) emtricitabine and tenofovir alafenamide fumarate
be administered to a subject in various dosing amounts and (Descovy) , (iv) emtricitabine and tenofovir disoproxil
over various time frames. fumarate ( Truvada ), (v) lamivudine and tenofovir disoproxil
 US 11,034,762 B1
79 80
fumarate (Cimduo, Temixys ), (vi ) lamivudine and zidovu- such as , for example, Edoxaban (SAVAYSA® ), Fonda
dine (Combivir ), etc. ) ; a combination of Descovy and Tru- parinux ( ARIXTRA® ); and combinations thereof.
vada ; one or more non -nucleoside reverse transcriptase Diagnostics
inhibitors (NNRTIs; e.g. , doravirine ( Pifeltro ), efavirenz Provided herein are methods of diagnosing a subject
( Sustiva ) , etravirine ( Intelence ), nevirapine ( Viramune, 5 suspected of being infected with SARS - Cov - 2 by contacting
Viramune XR) , rilpivirine ( Edurant), delavirdine (Rescrip- a sample obtained from the subject with one or more
tor) , or a combination thereof); one or more Cytochrome antibodies or antigen -binding fragments herein .
P4503A (CYP3A) inhibitors ( e.g. , cobicistat ( Tybost), rito A " sample” from a subject to be tested utilizing one or
navir (Norvir ), etc. ); one or more protease inhibitors (PIs ; more of the assays described herein includes , but is not
e.g. , atazanavir (Reyataz ) , darunavir (Prezista ), fosampre 10 In
limited to , a nasal swab , a tissue sample , saliva , blood , etc.
some instances , the sample is treated prior to use in a
navir ( Lexiva ), lopinavir, ritonavir (Norvir ), tipranavir (Ap diagnostic assay. For example , a nasal swab may be flushed
tivus ) , etc.); one or PIs in combination with cobicistat , with phosphate buffered saline ( PBS ) ; a fluid sample may be
ritonavir, Lopinavir, Tipranavir, Atazanavir, fosamprenavir, centrifuged to concentrate the sample components; blood
indinavir ( Crixivan ), nelfinavir (Viracept), saquinavir ( Invi- 15 may be treated with heparin to prevent coagulation, etc.
rase) , or a combination thereof; Atazanavir; fosamprenavir; Samples may be tested in any suitable assay including , but
a combination of Atazanavir, darunavir and cobicistat ; one not limited to , an enzyme linked immunosorbent assay
or more fusion inhibitors ( e.g. , enfuvirtide ( Fuzeon) ; one or (ELISA ) , an immunospot assay, a lateral flow assay , immu
more post - attachment inhibitors (e.g. , ibalizumab -uiyk nohistochemistry (IHC ) , western blot , flow cytometry, etc.
( Trogarzo ) ); one or more Chemokine coreceptor antagonists 20 The sample is contacted with a CR3022 - derived antibody or
( CCR5 antagonists; e.g. , maraviroc ( Selzentry ) ); and one or antigen - binding fragment herein , and when the presence of
more viral entry inhibitors ( e.g. , enfuvirtide ( Fuzeon) , ibali- the antibody bound to a SARS - CoV - 2 is detected , the
zumab -uiyk ( Trogarzo ), maraviroc ( Selzentry ), etc. ) ; or a subject is diagnosed as being infected with SARS - Cov - 2
combination thereof. and / or having a COVID - 19 infection .
Non - limiting examples of combinations include one or 25 In one instance, a sample obtained from a subject is
more of the antibodies or antigen -binding fragments herein contacted with a CR3022 - derived antibody or antigen -bind
to be administered with one or more of the following: ( 1 ) ing fragment herein that selectively binds to SARS - Cov - 2
Azithromycin, hydroquinolone, or a combination thereof, and the presence or absence of the antibody or antigen
( 2 ) darunavir and cobicistat ( Prezcobix ), (3 ) lopinavir and binding fragment is determined . The subject is diagnosed as
ritonavir (Kaletra ), (4 ) abacavir, lamivudine, and zidovudine 30 being infected with SARS - Cov - 2 when the presence of the
( Trizivir ), ( 5 ) abacavir and lamivudine (Epzicom) , ( 6 ) antibody or antigen -binding fragment is detected .
emtricitabine and tenofovir alafenamide fumarate (Des
covy ) , ( 7 ) emtricitabine and tenofovir disoproxil fumarate Exemplary Definitions
( Truvada ), ( 8 ) lamivudine and tenofovir disoproxil fumarate
( Cimduo , Temixys ), ( 9 ) lamivudine and zidovudine (Com- 35 The term “ about ” as used herein , generally refers to a
bivir) , ( 10) , atazanavir and cobicistat ( Evotaz ) , ( 11 ) dora- range that is 2 % , 5 % , 10 % , 15 % greater than or less than ( + )
virine , lamivudine, and tenofovir disoproxil fumarate (Del- a stated numerical value within the context of the particular
strigo ), ( 12 ) efavirenz , lamivudine, and tenofovir disoproxil usage . For example, “ about 10 " would include a range from
fumarate (Symfi), ( 13 ) efavirenz, lamivudine , and tenofovir 8.5 to 11.5 . As used herein, the terms “ about” and “ approxi
disoproxil fumarate ( Symfi Lo ) , ( 14 ) efavirenz, emtricit- 40 mately , ” when used to modify a numeric value or numeric
abine , and tenofovir disoproxil fumarate ( Atripla ), ( 15 ) range, indicate that deviations of up to about 0.2 % , about
emtricitabine , rilpivirine, and tenofovir alafenamide 0.5 % , about 1 % , about 2 % , about 5 % , about 7.5 % , or about
fumarate (Odefsey ), ( 16 ) emtricitabine, rilpivirine, and teno- 10% (or any integer between about 1 % and 10 % ) above or
fovir disoproxil fumarate (Complera ), ( 17 ) elvitegravir , below the value or range remain within the intended mean
cobicistat , emtricitabine, and tenofovir disoproxil fumarate 45 ing of the recited value or range.
(Stribild ), ( 18 ) elvitegravir, cobicistat , emtricitabine, and As used in this specification and the appended claims , the
tenofovir alafenamide fumarate (Genvoya ), ( 19 ) abacavir, singular forms “ a , ” “ an , ” and “ the ” include plural references
dolutegravir, and lamivudine ( Triumeq ), ( 20 ) bictegravir, unless the context clearly dictates otherwise . Thus, for
emtricitabine, and tenofovir alafenamide fumarate (Bik- example, references to “ a method ” include one or more
tarvy ), (21 ) dolutegravir and lamivudine ( Dovato ), (22 ) 50 methods, and / or steps of the type described herein and / or
dolutegravir and rilpivirine ( Juluca ), ( 23 ) darunavir, cobi- which will become apparent to those persons skilled in the
cistat , emtricitabine, and tenofovir alafenamide fumarate art upon reading this disclosure .
( Symtuza ). Polypeptides (e.g. , proteins ) and polynucleotides ( e.g. ,
Non -limiting examples of combinations include one or nucleic acids ) described herein can be isolated and / or puri
more of the antibodies or antigen -binding fragments herein 55 homogeneous
to be administered with one or more blood thinners . Blood
fied from their form
natural. Methods
environment in substantially pure or
of purifying proteins and
thinners to be co - administered include, but are not limited nucleic acids are contemplated for use herein . “ Isolated ”
to , anti- platelet, and anti -coagulation medications . Anti- ( used interchangeably with " substantially pure " ) when
platelet medications are those such as , for example, aspirin , applied to polypeptides means a polypeptide or a portion
clopidogrel (PLAVIX® ); prasugrel ( EFFIENT® ); ticlopi- 60 thereof which , by virtue of its origin or manipulation : (i ) is
dine ( TICLID® ) ; ticagrelor (BRILINTA? ); and combina- present in a host cell as the expression product of a portion
tions thereof. Anticoagulants include, but are not limited to , of an expression vector ; (ii ) is linked to a protein or other
Warfarin (COUMADIN® , JANTOVEN® ); Heparin ( e.g. , chemical moiety other than that to which it is linked in
FRAGMIN® , INNOHEP® , and LOVENOX® ); Eabigatran nature; or (iii ) does not occur in nature, for example, a
(PRADAXA? ); Epixaban ( ELIQUIS? ); Non - vitamin K 65 protein that is chemically manipulated by appending, or
antagonist oral anticoagulants (NOACs) such as , for adding at least one hydrophobic moiety to the protein so that
example , Rivaroxaban (XARELTO? ); Factor Xa inhibitors the protein is in a form not found in nature. By “ isolated ” it
 US 11,034,762 B1
81 82
is further meant a protein that is : (i ) synthesized chemically
or protein having a binding domain which can be , or can be
or ( ii ) expressed in a host cell and purified away from homologous to , an antigen binding domain . In one instance ,
associated and contaminating proteins . The term generally an antibody or an antigen - binding fragment can be produced
means a polypeptide that has been separated from other in an appropriate in vivo animal model and then isolated
proteins and nucleic acids with which it naturally occurs . 5 and / or purified . It would be understood that the antibodies or
The polypeptide may also be separated from substances such antigen -binding fragments herein can be modified as
as antibodies or gel matrices ( polyacrylamide) which are described below or as known in the art.
used to purify it. As used herein , substantially pure, iso- Antibodies useful in the present invention encompass, but
lated ,” or purified refers to material which is at least 50% are not limited to , monoclonal antibodies, polyclonal anti
pure (e.g. , free from contaminants ), at least 60 % pure , at 10 bodies , antibody fragments ( e.g. , Fab , Fab ' , F (ab ' ) 2 , Fv, Fc ,
least 70% pure, at least 80 % pure, at least 85 % pure , at least
90 % pure, at least 91 % pure , at least 92 % pure , at least 93 % scFv, scFv - Fc , Fab - Fc , scFv -zipper, scFab , crossFab , cam
pure , at least 94 % pure , at least 95 % pure , at least 96 % pure , elids (VHH ) , etc. ) , chimeric antibodies, bispecific antibod
at least 97 % pure , at least 98 % pure, or at least 99 % pure . ies , multispecific antibodies, heteroconjugate antibodies,
Polypeptides can be isolated and purified from culture 15 single chain ( ScFv ) , mutants thereof, fusion proteins com
supernatant or ascites by saturated ammonium sulfate pre prising an antibody portion ( e.g. , a domain antibody),
cipitation, an euglobulin precipitation method , a caproic acid humanized antibodies, human antibodies, and any other
method, a caprylic acid method, ion exchange chromatog modified configuration of the immunoglobulin molecule that
raphy ( DEAE or DE52 ) , or affinity chromatography using comprises an antigen recognition site of the required speci
anti -Ig column or a protein A , protein G , or protein L column 20 ficity, including glycosylation variants of antibodies, amino
such as described in more detail below . In one aspect , acid sequence variants of antibodies, and covalently modi
reference to a binding agent, an antibody or an antigen- fied antibodies.
binding fragment also refers to an " isolated binding agent,” Depending on the amino acid sequence of the constant
an “ isolated antibody , " or an “ isolated antigen -binding frag- domain of its heavy chains , immunoglobulins ( Igs ) can be
ment . ” In another aspect , reference to a binding agent, an 25 assigned to different classes . There are five major classes of
antibody, or an antigen -binding fragment also refers to a immunoglobulins: IgA , IgD , IgE , IgG , and IgM , and several
“ purified binding agent,” a “ purified antibody , " or a “ puri- of these may be further divided into subclasses ( isotypes ) ,
fied antigen - binding fragment." e.g. , IgG1 , IgG2 , IgG3 , IgG4 , IgA1 and IgA2 . An Ig or
Antibodies can be “ isolated ” and “ purified ” from the portion thereof can , in some cases , be a human Ig . In some
culture supernatant or ascites mentioned above by saturated 30 instances, a CH3 domain can be from an immunoglobulin. In
ammonium sulfate precipitation , euglobulin precipitation some cases , a chain or a part of an antibody or antigen
method, caproic acid method, caprylic acid method , ion binding fragment, a modified antibody or antigen -binding
exchange chromatography ( DEAE or DE52 ) , or affinity fragment, or a binding agent can be from an Ig . In such
chromatography using anti - Ig column or a protein A , G or L cases , an Ig can be IgG , an IgA , an IgD , an IgE , or an IgM .
column using art -recognized conventional methods. 35 In cases where the Ig is an IgG , it can be a subtype of IgG ,
As used herein , the term “ antibody” refers to an immu- wherein subtypes of IgG can include IgG1 , an IgG2a , an
noglobulin ( Ig ) , polypeptide, or a protein having a binding IgG2b , an IgG3 , and an IgG4 . In some cases , a Ch3 domain
domain which is , or is homologous to , an antigen -binding can be from an immunoglobulin selected from the group
domain . The term further includes “ antigen -binding frag- consisting of an IgG , an IgA , an IgD , an IgE , and an IgM .
ments ” and other interchangeable terms for similar binding 40 The “ light chains” of antibodies ( immunoglobulins) from
fragments as described below. Native antibodies and native any vertebrate species can be assigned to one of two clearly
immunoglobulins ( Igs ) are generally heterotetrameric gly- distinct types, called kappa or ( “ K ” or “ K ” ) and lambda or
coproteins of about 150,000 Daltons , composed of two ( " 2 " ), based on the amino acid sequences of their constant
identical light chains and two identical heavy chains . Each domains .
light chain is typically linked to a heavy chain by one 45 As used herein , a “ monoclonal antibody ” refers to an
covalent disulfide bond , while the number of disulfide antibody obtained from a population of substantially homo
linkages varies among the heavy chains of different immu geneous antibodies, e.g. , the individual antibodies compris
noglobulin isotypes. Each heavy and light chain also has ing the population are identical except for possible naturally
regularly spaced intrachain disulfide bridges . Each heavy occurring mutations that may be present in minor amounts.
chain has at one end a variable domain (“ V + ) followed by 50 In contrast to polyclonal antibody preparations, which typi
a number of constant domains ( “ Ch ” ) . Each light chain has cally include different antibodies directed against different
a variable domain at one end (“ V ” ) and a constant domain determinants ( epitopes ), each monoclonal antibody is
( “ C ” ) at its other end; the constant domain of the light chain directed against a single determinant on the antigen
is aligned with the first constant domain of the heavy chain , (epitope ) . The modifier “ monoclonal” indicates the charac
and the light-chain variable domain is aligned with the 55 ter of the antibody as being obtained from a substantially
variable domain of the heavy chain . Particular amino acid homogeneous population of antibodies, and is not to be
residues are believed to form an interface between the light- construed as requiring production of the antibody by any
and heavy -chain variable domains. In some instances , an particular method . For example, the monoclonal antibodies
antibody or an antigen -binding fragment comprises an iso- to be used in accordance with the present invention may be
lated antibody or antigen -binding fragment, a purified anti- 60 made by the hybridoma method first described by Kohler
body or antigen -binding fragment, a recombinant antibody and Milstein, 1975 , Nature , 256 : 495 , or may be made by
or antigen - binding fragment, a modified antibody or anti- recombinant DNA methods such as described in U.S. Pat .
gen - binding fragment, or a synthetic antibody or antigen- No. 4,816,567 . The monoclonal antibodies may also be
binding fragment. isolated from phage libraries generated using the techniques
Antibodies and antigen -binding fragments herein can be 65 described in McCafferty et al . , 1990 , Nature, 348 :552-554 ,
partly or wholly synthetically produced. A CR3022 - derived for example. Other methods are known in the art and are
antibody or antigen -binding fragment can be a polypeptide contemplated for use herein .
 US 11,034,762 B1
83 84
A “ variable region ” of an antibody refers to the variable usually defined to stretch from an amino acid residue at
region of the antibody light chain or the variable region of position Cys226 , or from Pro230 , to the carboxyl - terminus
the antibody heavy chain , either alone or in combination . thereof. The Fc region of an immunoglobulin generally
The variable regions of the heavy and light chain each comprises two constant domains , CH2 and CH3 .
consist of four framework regions ( FR ) connected by three 5 The terms “ hypervariable region ” and “ CDR ” when used
complementarity determining regions (CDRs ) also known herein , refer to the amino acid residues of an antibody which
as hypervariable regions . The CDRs in each chain are held are responsible for antigen -binding. The CDRs comprise
together in close proximity by the FRs and, with the CDRs amino acid residues from three sequence regions which bind
from the other chain, contribute to the formation of the in a complementary manner to an antigen and are known as
antigen -binding site of antibodies. Amino acid residues of 10 CDR1 , CDR2 , and CDR3 for each of the VH and Vi chains.
CDRs and framework regions are as described herein for the It is understood that the CDRs of different antibodies may
provided sequences. contain insertions, thus the amino acid numbering may
With respect to antibodies, the term “ variable domain ” differ. CDR sequences of the antibodies and antigen -binding
refers to the variable domains of antibodies that are used in fragments thereof have been provided herein below .
the binding and specificity of each particular antibody for its 15 As used herein , “ framework region ” or “ FR ” or “ FW ”
particular antigen . However, the variability is not evenly refers to framework amino acid residues that form a part of
distributed throughout the variable domains of antibodies. the antigen binding pocket or groove. In some embodiments,
Rather, it is concentrated in three segments called hyper- the framework residues form a loop that is a part of the
variable regions (also known as CDRs ) in both the light antigen binding pocket or groove and the amino acids
chain and the heavy chain variable domains . More highly 20 residues in the loop may or may not contact the antigen.
conserved portions of variable domains are called the Framework regions generally comprise the regions between
" framework regions , ” “ FWs, ” or “ FRs. ” The variable the CDRs . Framework regions of the antibodies and antigen
domains of unmodified heavy and light chains each contain binding fragments thereof have been provided herein below .
four FRs ( FR1 , FR2 , FR3, and FR4 ) , largely adopting a The loop amino acids of a FR can be assessed and
B - sheet configuration interspersed with three CDRs which 25 determined by inspection of the three - dimensional structure
form loops connecting and, in some cases , part ofthe B - sheet of an antibody heavy chain and / or antibody light chain . The
structure . The CDRs in each chain are held together in close three -dimensional structure can be analyzed for solvent
proximity by the FRs and, with the CDRs from the other accessible amino acid positions as such positions are likely
chain , contribute to the formation of the antigen -binding site to form a loop and / or provide antigen contact in an antibody
of antibodies . 30 variable domain. Some of the solvent accessible positions
A “ constant region ” of an antibody refers to the constant can tolerate amino acid sequence diversity and others ( e.g. ,
region of the antibody light chain or the constant region of structural positions ) are , generally, less diversified . The
the antibody heavy chain , either alone or in combination . three -dimensional structure of the antibody variable domain
“ Epitope ” refers to that portion of an antigen or other can be derived from a crystal structure or protein modeling .
macromolecule capable of forming a binding interaction 35 In the present disclosure , the following abbreviations in
with the variable region binding pocket of an antibody. Such the parentheses ) are used in accordance with the customs , as
binding interactions can be manifested as an intermolecular necessary : heavy chain (H chain ), light chain ( L chain ),
contact with one or more amino acid residues of one or more heavy chain variable region (VH ), light chain variable
CDRs . Antigen binding can involve, for example, a CDR3 region ( VL ), complementarity determining region (CDR) ,
or a CDR3 pair or, in some cases , interactions of up to all six 40 first complementarity determining region ( CDR1 ) , second
CDRs of the Vh and V? chains . An epitope can be a linear complementarity determining region (CDR2 ) , third comple
peptide sequence (“ continuous ” ) or can be composed of mentarity determining region (CDR3 ) , heavy chain first
noncontiguous amino acid sequences (" conformational ” or complementarity determining region ( VH CDR1 ) , heavy
" discontinuous ” ). An antibody can recognize one or more chain second complementarity determining region ( VH
amino acid sequences; therefore, an epitope can define more 45 CDR2 ) , heavy chain third complementarity determining
than one distinct amino acid sequence . Epitopes recognized region ( VH CDR3 ) , light chain first complementarity deter
by antibodies can be determined by peptide mapping and mining region (VL CDR1 ) , light chain second complemen
sequence analysis techniques well known to one of skill in tarity determining region (VL CDR2 ) , and light chain third
the art . Binding interactions are manifested as intermolecu- complementarity determining region (VL CDR3).
lar contacts between an epitope on an antigen and one or 50 In some instances, an anti - SARS - Cov - 2 antibody is a
more amino acid residues of a CDR . An epitope herein can monoclonal antibody. As used herein , a “ monoclonal anti
refer to an amino acid sequence on a receptor binding body ” refers to an antibody obtained from a population of
domain or a spike domain . substantially homogeneous antibodies , i.e. , the individual
An antibody selectively binds to a target if it binds with antibodies comprising the population are identical except for
greater affinity, avidity, more readily, and / or with greater 55 possible naturally -occurring mutations that may be present
duration than it binds to other substances. For example, a in minor amounts. In contrast to polyclonal antibody prepa
CR3022 - derived antibody or antigen -binding fragment that rations, which typically include different antibodies directed
selectively binds to a SARS - Cov - 2 epitope is a CR3022- against different determinants (epitopes ) , each monoclonal
derived antibody or antigen -binding fragment that binds this antibody is directed against a single determinant on the
epitope with greater affinity, avidity, more readily, and /or 60 antigen (epitope) . The modifier “ monoclonal ” indicates the
with greater duration than it binds to SARS - Cov - 1 or character of the antibody as being obtained from a substan
MERS . tially homogeneous population of antibodies and is not to be
The term “ Fc region ” is used to define a C -terminal region construed as requiring production of the antibody by any
of an immunoglobulin heavy chain . The “ Fc region ” may be particular method, including the Tumbler methods described
a native sequence Fc region or a variant Fc region . Although 65 below .
the boundaries of the Fc region of an immunoglobulin heavy In some instances, an anti - SARS - Cov - 2 antibody or anti
chain might vary, the human IgG heavy chain Fc region is gen -binding fragment is a humanized antibody or a human
 US 11,034,762 B1
85 86
ized antigen -binding fragment. As used herein , “ humanized " amino acid residue changes, substitutions, additions, and / or
antibodies refer to forms of non -human ( e.g. , murine) anti- deletions can be introduced to remove the identified T -cell
bodies that are specific chimeric immunoglobulins, immu- epitope . Such changes can be made so as to preserve
noglobulin chains , or fragments thereof that contain minimal antibody structure and function while still removing the
sequence derived from non -human immunoglobulin. For the 5 identified epitope. Exemplary changes can include , but are
most part, humanized antibodies are human immunoglobu- not limited to , conservative amino acid changes.
lins ( recipient antibody ) in which residues from a comple- An anti - SARS - Cov - 2 antibody or antigen -binding frag
mentarity determining region ( CDR ) of the recipient are ment can be a human antibody or human antigen -binding
replaced by residues from a CDR of a non -human species fragment. As used herein , a “ human antibody” means an
( donor antibody ) such as mouse , rat, or rabbit having the 10 antibody having an amino acid sequence corresponding to
desired specificity , affinity, and biological activity. In some that of an antibody produced by a human and / or that has
instances, Fv framework region ( FR) residues of the human been made using any suitable technique for making human
immunoglobulin are replaced by corresponding non - human antibodies . This definition of a human antibody includes
residues . Furthermore, the humanized antibody may com- antibodies comprising at least one human heavy chain
prise residues that are found neither in the recipient antibody 15 polypeptide or at least one human light chain polypeptide .
nor in the imported CDR or framework sequences, but are One such example is an antibody comprising murine light
included to further refine and optimize antibody perfor- chain and human heavy chain polypeptides. In one embodi
mance . In general, a humanized antibody comprises sub- ment, the human antibody is selected from a phage library,
stantially all of at least one , and typically two , variable where that phage library expresses human antibodies
domains , in which all or substantially all of the CDR regions 20 ( Vaughan et al . , 1996 , Nature Biotechnology, 14 : 309-314 ;
correspond to those of a non - human immunoglobulin and all Sheets et al . , 1998 , PNAS USA, 95 : 6157-6162 ; Hoogen
or substantially all of the FR regions are those of a human boom and Winter, 1991 , J. Mol. Biol., 227 : 381 ; Marks et al . ,
immunoglobulin consensus sequence . The humanized anti- 1991 , J. Mol. Biol., 222 : 581 ) . Human antibodies can also be
body optimally also will comprise at least a portion of an made by introducing human immunoglobulin loci into trans
immunoglobulin constant region or domain (Fc ) , typically 25 genic animals, e.g. , mice in which the endogenous immu
that of a human immunoglobulin . Antibodies may have Fc noglobulin genes have been partially or completely inacti
regions modified as described in , for example, WO vated . This approach is described in U.S. Pat. Nos . 5,545 ,
99/58572 . Other forms of humanized antibodies have one or 807 ; 5,545,806 ; 5,569,825 ; 5,625,126 ; 5,633,425 ; and
more CDRs ( one , two, three, four, five, or six ) which are 5,661,016 . Alternatively, the human antibody may be pre
altered with respect to the original antibody, which are also 30 pared by immortalizing human B lymphocytes that produce
termed one or more CDRs " derived from ” one or more an antibody directed against a target antigen ( such B lym
CDRs from the original antibody . phocytes may be recovered from an individual or may have
If needed , an antibody or an antigen -binding fragment been immunized in vitro ). See , e.g. , Cole et al . , Monoclonal
herein can be assessed for immunogenicity and, as needed , Antibodies and Cancer Therapy, Alan R. Liss , p . 77 ( 1985 ) ;
be deimmunized (i.e. , the antibody is made less immunore- 35 Boerner et al . , 1991 , J. Immunol., 147 ( 1 ) : 86-95 ; and U.S.
active by altering one or more T cell epitopes ). As used Pat. No. 5,750,373 .
herein , a “ deimmunized antibody ” means that one or more Any of the anti-SARS -Cov - 2 antibodies or antigen -bind
T cell epitopes in an antibody sequence have been modified ing fragments herein can be bispecific . Bispecific antibodies
such that a T cell response after administration of the are antibodies that have binding specificities for at least two
antibody to a subject is reduced compared to an antibody 40 different antigens or different affinities for the same antigen.
that has not been deimmunized . Analysis of immunogenicity Bispecific antibodies can be prepared using the antibodies or
and T -cell epitopes present in the antibodies and antigen- antigen -binding fragments disclosed herein . Methods for
binding fragments herein can be carried out via the use of making bispecific antibodies are described ( see , e.g. , Suresh
software and specific databases. Exemplary software and et al . , 1986 , Methods in Enzymology 121 : 210 ) . Traditionally,
databases include iTopeTM developed by Antitope of Cam- 45 the recombinant production of bispecific antibodies was
bridge, England. iTopeTM, is an in silico technology for based on the co -expression of two immunoglobulin heavy
analysis of peptide binding to human MEW class II alleles . chain - light chain pairs , with the two heavy chains having
The iTopeTM software predicts peptide binding to human different specificities ( Millstein and Cuello , 1983 , Nature,
MEW class II alleles and thereby provides an initial screen 305 , 537-539 ) . Bispecific antibodies can be composed of a
for the location of such “ potential T cell epitopes.” iTopeTM 50 hybrid immunoglobulin heavy chain with a first binding
software predicts favorable interactions between amino acid specificity in one arm , and a hybrid immunoglobulin heavy
side chains of a peptide and specific binding pockets within chain - light chain pair ( providing a second binding specific
the binding grooves of 34 human MHC class II alleles . The ity) in the other arm . This asymmetric structure, with an
location of key binding residues is achieved by the in silico immunoglobulin light chain in only one half of the bispecific
generation of Imer peptides that overlap by one amino acid 55 molecule , facilitates the separation of the desired bispecific
spanning the test antibody variable region sequence. Each compound from unwanted immunoglobulin chain combina
9mer peptide can be tested against each of the 34 MHC class tions . Bispecific antibody fragments may be connected via a
II allotypes and scored based on their potential “ fit ” and linker. This approach is described in PCT Publication No.
interactions with the MHC class II binding groove. Peptides WO 94/04690 .
that produce a high mean binding score ( >0.55 in the 60 According to one approach to making bispecific antibod
iTopeTM scoring function ) against > 50 % of the MHC class ies , antibody variable domains with the desired binding
II alleles are considered as potential T cell epitopes. In such specificities ( antibody -antigen combining sites ) are fused to
regions , the core 9 amino acid sequence for peptide binding immunoglobulin constant domain sequences . The fusion can
within the MHC class II groove is analyzed to determine the be with an immunoglobulin heavy chain constant domain ,
MHC class II pocket residues ( P1 , P4 , P6 , P7 , and P9 ) and 65 comprising at least part of the hinge , CH2 and CH3 regions.
the possible T cell receptor ( TCR) contact residues (P - 1 , P2 , The first heavy chain constant region (CH1 ) , containing the
P3 , P5 , P8 ) . After identification of any T - cell epitopes , site necessary for light chain binding, can be present in at
 US 11,034,762 B1
87 88
least one of the fusions. DNAs encoding the immunoglobu- near the disulfide bonds existing between the hinge regions
lin heavy chain fusions and, if desired , the immunoglobulin in each of the two heavy chains . For example, papain cleaves
light chain , are inserted into separate expression vectors , and IgG upstream of the disulfide bonds existing between the
are co -transfected into a suitable host organism . This pro- hinge regions in each of the two heavy chains to generate
vides for great flexibility in adjusting the mutual proportions 5 two homologous antibody fragments in which an light chain
of the three polypeptide fragments in embodiments when composed of V , and CZ ( light chain constant region) , and a
unequal ratios of the three polypeptide chains used in the heavy chain fragment composed of V , and Chyi ( yl ) region
construction provide the optimum yields . It is , however, in the constant region of the heavy chain) are connected at
possible to insert the coding sequences for two or all three their C terminal regions through a disulfide bond . Each of
polypeptide chains in one expression vector when the 10 these two homologous antibody fragments is called Fab.'
expression of at least two polypeptide chains in equal ratios
results in high yields or when the ratios are of no particular Pepsin also cleaves IgG downstream of the disulfide bonds
significance . existing between the hinge regions in each of the two heavy
Heteroconjugate antibodies, comprising two covalently chains to generate an antibody fragment slightly larger than
joined antibodies, are also within the scope of the disclosure . 15 the fragment in which the two above -mentioned Fab ' are
Such antibodies have been used to target immune system connected at the hinge region . This antibody fragment is
cells to unwanted cells (U.S. Pat . No. 4,676,980 ) . Hetero called F ( ab ') 2.
conjugate antibodies may be made using any suitable cross The Fab fragment also contains the constant domain of
linking methods. Suitable cross - linking agents and tech- the light chain and the first constant domain (Chl) of the
niques are described , for example, in U.S. Pat . No. 4,676 , 20 heavy chain . Fab ' fragments differ from Fab fragments by
980 . the addition of a few residues at the carboxyl terminus of the
In some instances, a CR3022 -derived antibody described heavy chain Cyl domain including one or more cysteine ( s )
herein is a chimeric antibody. “ Chimeric” forms of non- from the antibody hinge region. Fab ' - SH is the designation
human (e.g. , murine ) antibodies include chimeric antibodies herein for Fab ' in which the cysteine residue ( s) of the
which contain minimal sequence derived from a non -human 25 constant domains bear a free thiol group . F (ab ' ) 2 antibody
Ig . For the most part, chimeric antibodies are murine anti- fragments originally were produced as pairs of Fab ' frag
bodies in which at least a portion of an immunoglobulin ments which have hinge cysteines between them . Other
constant region ( Fc ) , typically that of a human immuno- chemical couplings of antibody fragments are also known .
globulin , is inserted in place of the murine Fc . Chimeric or A “ Fv ” as used herein refers to an antibody fragment
hybrid antibodies also may be prepared in vitro using 30 which contains a complete antigen -recognition and antigen
suitable methods of synthetic protein chemistry, including binding site . This region consists of a dimer of one heavy
those involving cross -linking agents. For example , immu- chain and one light chain variable domain in tight, non
notoxins may be constructed using a disulfide exchange covalent or covalent association ( disulfide linked Fvs have
reaction or by forming a thioether bond . Examples of been described , see , e.g. , Reiter et al . ( 1996 ) Nature Bio
suitable reagents for this purpose include iminothiolate and 35 technology 14 : 1239-1245 ) . It is in this configuration that the
methyl - 4 -mercaptobutyrimidate . three CDRs of each variable domain interact to define an
Provided herein are antibodies and antigen - binding frag- antigen -binding site on the surface of the VH - V , dimer.
ments thereof, modified antibodies and antigen - binding Collectively, a combination of one or more of the CDRs
fragments thereof, and binding agents that specifically bind from each of the Vy and V , chains confer antigen -binding
to one or more epitopes on one or more target antigens. In 40 specificity to the antibody. For example, it would be under
one instance , a binding agent selectively binds to an epitope stood that, for example, the CDRH3 and CDRL3 could be
on a single antigen. In another instance , a binding agent is sufficient to confer antigen -binding specificity to an anti
bivalent and either selectively binds to two distinct epitopes body when transferred to Vh and V chains of a recipient
on a single antigen or binds to two distinct epitopes on two antibody or antigen -binding fragment and this combination
distinct antigens. In another instance, a binding agent is 45 of CDRs can be tested for binding, specificity, affinity, etc.
multivalent ( i.e. , trivalent, quatravalent, etc. ) and the binding using any of the techniques described herein . Even a single
agent binds to three or more distinct epitopes on a single variable domain ( or half of an Fv comprising only three
antigen or binds to three or more distinct epitopes on two or CDRs specific for an antigen ) has the ability to recognize
more (multiple ) antigens. and bind antigen , although likely at a lower specificity or
Functional fragments of any of the antibodies herein are 50 affinity than when combined with a second variable domain .
also contemplated . The terms “ antigen -binding portion of an Furthermore, although the two domains of a Fv fragment
antibody," " antigen -binding fragment," " antigen -binding (V , and Vw ) are coded for by separate genes , they can be
domain , ” “ antibody fragment,” or a “ functional fragment of joined using recombinant methods by a synthetic linker that
an antibody ” are used interchangeably herein to refer to one enables them to be made as a single protein chain in which
or more fragments of an antibody that retain the ability to 55 the V2 and Vh regions pair to form monovalent molecules
specifically bind to an antigen . Representative antigen- ( known as single chain Fv ( scFv ) ; Bird et al . ( 1988 ) Science
binding fragments include, but are not limited to , a Fab , a 242 : 423-426 ; Huston et al . ( 1988 ) Proc. Natl . Acad . Sci.
Fab ' , a F (ab ' ) 2 , a Fv, a scFv, a dsFv, a variable heavy domain , USA 85 : 5879-5883 ; and Osbourn et al . ( 1998 ) Nat. Biotech
a variable light domain , a variable NAR domain, bi- specific nol. 16 : 778 ) . Such scFvs are also intended to be encom
scFv, a bi -specific Fab2, a tri- specific Fabz , an AVIMER®, 60 passed within the term “ antigen -binding portion ” of an
a minibody, a diabody, a maxibody, a camelid , a VHH , an antibody. Any Vh and V? sequences of specific scFv can be
intrabody, fusion proteins comprising an antibody portion linked to an Fc region cDNA or genomic sequences in order
( e.g. , a domain antibody ), a single chain binding polypep- to generate expression vectors encoding complete Ig ( e.g. ,
tide , a scFv - Fc , or a Fab - Fc . IgG) molecules or other isotypes . Vh and V , can also be
“ F (ab')2” and “ Fab?” moieties can be produced by treating 65 used in the generation of Fab , Fv, or other fragments of Igs
an Ig with a protease such as pepsin and papain , and include using either protein chemistry or recombinant DNA tech
antibody fragments generated by digesting immunoglobulin nology
 US 11,034,762 B1
89 90
“ Single -chain Fv” or “ sFv ” antibody fragments comprise and the light chain variable region by a disulfide bond . The
the Vh and V , domains of an antibody, wherein these site in each chain , into which the Cys residue is to be
domains are present in a single polypeptide chain . In some introduced, can be determined based on a conformation
embodiments , the Fv polypeptide further comprises a poly- predicted by molecular modeling . In the present disclosure ,
peptide linker between the Vh and V , domains which 5 for example , a conformation is predicted from the amino
enables the sFv to form the desired structure for antigen acid sequences of the heavy chain variable region and light
binding . For a review of sFvs , see , e.g. , Pluckthun in The chain variable region of the above - described antibody, and
Pharmacology of Monoclonal Antibodies, Vol. 113 , Rosen- DNA encoding each of the heavy chain variable region and
burg and Moore eds . Springer - Verlag, New York , pp . 269- the light chain variable region, into which a mutation has
315 ( 1994). 10 been introduced based on such prediction , is then con
The term “ AVIMER® ” refers to a class of therapeutic structed . The DNA construct is incorporated then into a
proteins of human origin , which are unrelated to antibodies suitable vector and prepared from a transformant obtained
and antibody fragments, and are composed of several modu- by transformation with the aforementioned vector.
lar and reusable binding domains , referred to as A -domains Single chain variable region fragments ( “ scFv ” ) of anti
( also referred to as class A module , complement type repeat, 15 bodies are herein . Single chain variable region fragments
or LDL - receptor class A domain ). They were developed may be made by linking light and / or heavy chain variable
from human extracellular receptor domains by in vitro exon regions by using a short linking peptide. Bird et al . ( 1988 )
shuffling and phage display ( Silverman et al . , 2005 , Nat. Science 242 : 423-426 . The single chain variants can be
Biotechnol. 23 : 1493-1494 ; Silverman et al . , 2006, Nat. produced either recombinantly or synthetically . For syn
Biotechnol. 24 :220 ). The resulting proteins can contain 20 thetic production of scFv, an automated synthesizer can be
multiple independent binding domains that can exhibit used . For recombinant production of scFv, a suitable plas
improved affinity and / or specificity compared with single- mid containing polynucleotide that encodes the scFv can be
epitope binding proteins . Each of the known 217 human introduced into a suitable host cell , either eukaryotic , such as
A - domains comprises ~ 35 amino acids (~ 4 kDa ) ; and these yeast , plant, insect , or mammalian cells , or prokaryotic, such
domains are separated by linkers that average five amino 25 as E. coli . Polynucleotides encoding the scFv of interest can
acids in length . Native A - domains fold quickly and effi- be made by routine manipulations such as ligation of poly
ciently to a uniform , stable structure mediated primarily by nucleotides. The resultant scFv can be isolated using any
calcium binding and disulfide formation . A conserved scaf- suitable protein purification techniques.
fold motif of only 12 amino acids is required for this Diabodies can be single chain antibodies. Diabodies can
common structure . The end result is a single protein chain 30 be bivalent, bispecific antibodies in which Vy and V
containing multiple domains , each of which represents a domains are expressed on a single polypeptide chain , but
separate function . Each domain of the proteins binds inde- using a linker that is too short to allow for pairing between
pendently, and the energetic contributions of each domain the two domains on the same ain , thereby forcing the
are additive. domains to pair with complementary domains of another
Antigen -binding polypeptides also include heavy chain 35 chain and creating two antigen binding sites ( see , e.g. ,
dimers such as , for example, antibodies from camelids and Holliger, P., et al . , Proc. Natl. Acad . Sci. USA , 90 : 6444-6448
sharks. Camelid and shark antibodies comprise a homodi- ( 1993 ) ; and Poljak , R. J. , et al . , Structure, 2 : 1121-1123
meric pair of two chains of V - like and C - like domains ( 1994) ) .
(neither has a light chain) . Since the Vh region of a heavy As used herein , a “ minibody” refers to a scFv fused to
chain dimer IgG in a camelid does not have to make 40 CH3 via a peptide linker ( hingeless) or via an IgG hinge has
hydrophobic interactions with a light chain , the region in the been described in Olafsen, et al . , Protein Eng. Des. Sel.,
heavy chain that normally contacts a light chain is changed April 2004 ; 17 ( 4 ) : 315-23 .
to hydrophilic amino acid residues in a camelid . Vh domains As used herein , an “ intrabody ” refers to a single chain
of heavy -chain dimer IgGs are called Vrh domains. Shark antibody which demonstrates intracellular expression and
Ig - NARs comprise a homodimer of one variable domain 45 can manipulate intracellular protein function (Biocca , et al . ,
( termed a V -NAR domain ) and five C - like constant domains EMBO J. 9 : 101-108 , 1990 ; Colby et al . , Proc Natl Acad . Sci.
( C -NAR domains ) . In camelids, the diversity of antibody USA . 101 : 17616-21 , 2004 ) . Intrabodies, which comprise
repertoire is determined by the CDRs 1 , 2 , and 3 in the VH cell signal sequences which retain the antibody construct in
or Vhh regions . The CDR3 in the camel VHH , region is intracellular regions, may be produced as described in
characterized by its relatively long length , averaging 16 50 Mhashilkar et al . , ( EMBO 1 , 14 : 1542-51 , 1995 ) and Wheeler
amino acids (Muyldermans et al . , 1994 , Protein Engineering et al . (FASEB J. 17 : 1733-5 . 2003 ) . Transbodies are cell
7 ( 9 ) : 1129 ) . This is in contrast to CDR3 regions of antibod- permeable antibodies in which a protein transduction
ies of many other species . For example , the CDR3 of mouse domains ( PTD ) is fused with single chain variable fragment
Vh has an average of 9 amino acids . Libraries of camelid- ( scFv ) antibodies Heng et al . (Med Hypotheses. 64 : 1105-8 ,
derived antibody variable regions , which maintain the in 55 2005 ) .
vivo diversity of the variable regions of a camelid , can be A “ scFv - Fc ” fragment as herein refers to an scFv attached
made by, for example, the methods disclosed in U.S. Patent to an Fc domain . For example, an Fc domain may be
Application Ser. No. 20050037421 . attached to the C - terminal of the scFv. The Fc domain may
As used herein , a “ maxibody ” refers to a bivalent scFv follow the VH or VL , depending on the orientation of the
covalently attached to the Fc region of an immunoglobulin , 60 variable domains in the scFv ( i.e. , VH -VL or VL ) . Any
see , e.g. , Fredericks et al . , Protein Engineering, Design & suitable Fc domain known in the art or described herein may
Selection, 17 : 95-106 (2004 ) and Powers et al . , Journal of be used . In some cases , the Fc domain comprises an IgG1 Fc
Immunological Methods, 251 : 123-135 ( 2001 ) . domain or an IgG4 Fc domain . A scFv - Fc format allows for
As used herein , a “ dsFv” can be a Fv fragment obtained rapid characterization of candidate scFvs isolated from
by introducing a Cys residue into a suitable site in each of 65 phage display libraries before conversion into a full - length
a heavy chain variable region and a light chain variable IgG . This format offers several advantages over the phage
region , and then stabilizing the heavy chain variable region display -derived scFv, including bivalent binding, longer
 US 11,034,762 B1
91 92
half - life, and Fc -mediated effector functions . Here, a single - domain antibodies are much smaller than common
detailed method is presented , which describes the cloning, antibodies ( 150-160 kDa ), and even smaller than Fab frag
expression , and purification of an scFv - Fc fragment, starting ments ( which consist of one light chain and half a heavy
from scFv fragments obtained from a phage display library . chain and have a molecular weight of about 50 kDa) and
This method facilitates the rapid screening of candidate 5 single - chain variable fragments (which consist of two vari
antibodies, prior to a more time - consuming conversion into able domains , one from a light and one from a heavy chain ,
a full IgG format. In one instance, a single -chain Fv ( scFv ) and have a molecular weight of about 25 kDa) .
includes the heavy and light chains in the Fv of an anti- Suitable linkers may be used to link various parts of
SARS - Cov - 2 antibody herein joined with a flexible peptide recombinant or synthetic antibodies or antigen - binding frag
linker (e.g. , of about 10, 12 , 15 or more amino acid residues) 10 ments
in a single peptide chain . The single chain antibody may be
thereof or to multimerize binding agents . Annon
limiting example of a linking peptide is ( GGGGS )n , where
monovalent, if only a single VH and VL are used , bivalent, n=3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ,
if two VH and VL are used, or polyvalent, if more than two 20 , or more ( SEQ ID NO : 452 ) and which bridges approxi
VH and VL are used . In some instances , the entire Fc region mately 3.5 nm between the carboxy terminus ofone variable
is attached to the scFv. In other instances , only the CH3 15 region and the amino terminus of the other variable region .
region of a Fc is attached to the scFv ( a “ scFv - CH ). Linkers of other sequences have been designed and used .
A “ scFab ” as described herein refers to an antigen binding Methods of producing such antibodies are described in for
domain that specifically binds to SARS - Cov - 2 is fused via instance U.S. Pat. No. 4,946,778 , Pluckthun in The Phar
a peptide linker to the C - terminus to one of the heavy chains . macology of Monoclonal Antibodies, vol . 113 , Rosenburg
A “ scFv zipper” as described herein refers to constructs of 20 and Moore eds . Springer - Verlag, New York , pp . 269-315
leucine zipper-based dimerization cassettes for the conver- ( 1994 ) , Bird et al . , Science 242 , 423-426 ( 1988 ) , Huston et
sion of recombinant monomeric scFv antibody fragments to al . , PNAS USA 85 , 5879-5883 ( 1988 ) and McCafferty et al . ,
bivalent and bispecific dimers . A truncated murine IgG3 Nature 348 , 552-554 ( 1990 ) . Linkers can in turn be modified
hinge region and a Fos or Jun leucine zipper are cloned into for additional functions, such as attachment of drugs or
four scFv fragments. Cysteine residues flanking the zipper 25 attachment to solid supports. Fab and scFab fragments may
region are introduced to covalently link dimerized scFv be stabilized via natural disulfide bonds between the CL
fragments. The secreted fusion proteins form stable Fos •Fos domain and the CH1 domain . Antigen -binding fragments
or Jun Jun homodimers. comprising a heavy chain variable domain (VH ) and a light
A “ cross - Fab fragment” or “ xFab fragment” or “ crossover chain variable domain (VL ) , such as the Fab , crossFab , scFv
Fab fragment” as described herein refers to a Fab fragment, 30 and scFab fragments as described herein might be further
wherein either the variable regions or the constant regions of stabilized by introducing interchain disulfide bridges
the heavy and light chain are exchanged . Two different chain between the VH and the VL domain . Accordingly, one
compositions of a crossover Fab molecule are possible and embodir nt, the Fab fragment ( s ), the crossFab fragment( s ),
comprised within the scope of bispecific antibodies and the scFv fragment ( s) and / or the scFab fragment ( s) com
antigen -binding fragments described herein . On the one 35 prised in the antigen binding receptors according to the
hand , the variable regions of the Fab heavy and light chain invention might be further stabilized by generation of inter
are exchanged, i.e. the crossover Fab molecule comprises a chain disulfide bonds via insertion of cysteine residues. Such
peptide chain composed of the light chain variable region stabilized antigen binding moieties are referred to by the
(VL) and the heavy chain constant region (CH1 ) , and a term “ ds ” . Cysteine engineered antibodies, in some embodi
peptide chain composed of the heavy chain variable region 40 ments, are made reactive for conjugation with linker-de
(VH ) and the light chain constant region ( CL) . This cross- grader intermediates described herein , by treatment with a
over Fab molecule is also referred to as CrossFab VLVH . On reducing agent such as DTT ( Cleland's reagent, dithiothrei
the other hand, when the constant regions of the Fab heavy tol ) or TEP ( tris ( 2 - carboxyethyl )phosphine hydrochloride;
and light chain are exchanged , the crossover Fab molecule Getz et al . ( 1999 ) Anal. Biochem . Vol 273 : 73-80 ; Soltec
comprises a peptide chain composed of the heavy chain 45 Ventures, Beverly, Mass . ) followed by re - formation of the
variable region ( VH ) and the light chain constant region inter - chain disulfide bonds ( re -oxidation ) with a mild oxi
( CL) , and a peptide chain composed of the light chain dant such as dehydroascorbic acid .
variable region (VL ) and the heavy chain constant region Also provided herein are affinity matured antibodies. For
(CH1 ) . This crossover Fab molecule is also referred to as example , affinity matured antibodies can be produced by any
CrossFab CLCH1 . 50 suitable procedure ( see , e.g. , Marks et al . , 1992 , Bio / Tech
A “ Fab -Fc ” fragment as described herein refers to a Fab nology, 10 : 779-783 ; Barbas et al . , 1994, Proc Nat. Acad . Sci,
fragment that is attached to a CH1 , CH2 , and / or a CH3 USA 91 : 3809-3813 ; Schier et al . , 1995 , Gene, 169 : 147-155 ;
region of a Fc , where the molecule does not contain all of a Yelton et al . , 1995 , J. Immunol., 155 : 1994-2004 ; Jackson et
CH1 , CH2 , and CH3 . al . , 1995 , J. Immunol., 154 ( 7 ) : 3310-9 ; Hawkins et al , 1992 ,
The terms " single domain antibody ” and “ sdAb ” refer to 55 J. Mol. Biol., 226 : 889-896 ; and WO2004 /058184 ) . The
a single - chain antibody polypeptide consisting of a single following methods may be used for adjusting the affinity of
monomeric variable antibody domain . The term “ VHH ” as an antibody and for characterizing a CDR . One way of
used herein refers to molecules engineered from heavy- characterizing a CDR of an antibody and / or altering ( such as
chain antibodies found in camelids . The terms “ shark new improving ) the binding affinity of a polypeptide, such as an
antigen receptor ” , “ VNAR ” and “ IgNAR ” as used herein 60 antibody, is termed “ library scanning mutagenesis . ” Gener
refer to molecules obtained from the heavy - chain antibodies ally , library scanning mutagenesis works as follows. One or
of cartilaginous fish , such as sharks. Single -domain antibod- more amino acid position in the CDR is replaced with two
ies can also be obtained by splitting dimeric variable or more ( such as 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ,
domains from common immunoglobulin G (IgG) into 17 , 18 , 19 , or 20) amino acids . This generates small libraries
monomers . Single - domain antibodies are typically about 65 of clones (in some embodiments, one for every amino acid
110 amino acids long and have a typical molecular weight position that is analyzed ), each with a complexity of two or
in the region of from about 12 to about 15 kDa. As such , more members (if two or more amino acids are substituted
 US 11,034,762 B1
93 94
at every position) . Generally, the library also includes a amino acid sequence using a conservative or a non -conser
clone comprising the native ( unsubstituted) amino acid . A vative substitution such that the resulting modified antibody
small number of clones, for example, about 20-80 clones exhibits about 80 % homology to a sequence described
(depending on the complexity of the library ), from each herein .
library can be screened for binding specificity or affinity to 5 The phrase " conservative amino acid substitution ” refers
the target polypeptide ( or other binding target ), and candi- to grouping of amino acids on the basis of certain common
dates with increased , the same , decreased , or no binding are properties. A functional way to define common properties
identified . Binding affinity may be determined using Biacore between individual amino acids is to analyze the normalized
surface plasmon resonance analysis, which detects differ- frequencies of amino acid changes between corresponding
ences in binding affinity of about 2 - fold or greater. Biacore 10 proteins of homologous organisms (Schulz, G. E. and R. H.
can be particularly useful when the starting antibody already Schirmer, Principles of Protein Structure, Springer - Verlag).
binds with a relatively high affinity, for example , a Ky of According to such analyses, groups of amino acids may be
about 10 nM or lower . defined where amino acids within a group exchange pref
In some instances , an antibody or antigen -binding frag- erentially with each other, and therefore resemble each other
ment is bi - specific or multi- specific and can specifically bind 15 most in their impact on the overall protein structure.
to more than one antigen. In some cases , such a bi -specific Examples of amino acid groups defined in this manner
or multi - specific antibody or antigen -binding fragment can include :
specifically bind to 2 or more different antigens. In some (i ) a charged group , consisting of Glu and Asp , Lys, Arg
cases , a bi - specific antibody or antigen -binding fragment and His ;
can be a bivalent antibody or antigen -binding fragment. In 20 ( ii ) a positively - charged group , consisting of Lys, Arg and
some cases , a multi specific antibody or antigen -binding His ;
fragment can be a bivalent antibody or antigen - binding (iii ) a negatively - charged group , consisting of Glu and
fragment, a trivalent antibody or antigen -binding fragment, Asp ;
or a quatravalent antibody or antigen -binding fragment. ( iv ) an aromatic group , consisting of Phe, Tyr and Trp ;
An antibody or antigen -binding fragment herein can be an 25 (v ) a nitrogen ring group , consisting of His and Trp ;
isolated, purified , recombinant, or synthetic. (vi ) a large aliphatic non -polar group , consisting of Val,
As used herein , the term “ affinity ” refers to the equilib Leu and Ile ;
rium constant for the reversible binding of two agents and is (vii ) a slightly -polar group , consisting of Met and Cys;
expressed as K ) . The binding affinity (KD) of a CR3022- (viii ) a small- residue group , consisting of Ser, Thr, Asp ,
derived antibody or antigen -binding fragment herein can be 30 Asn , Gly, Ala , Glu , Gln and Pro ;
less than 50 nM , 49 nM , 48 nM , 47 nM , 46 nM , 45 nM , 44 (ix ) an aliphatic group consisting of Val, Leu , Ile , Met and
nM , 43 nM , 42 nM , 41 nM , 40 nM , 39 nM , 38 nM , 37 nM , Cys ; and
36 nM , 35 nM , 34 nM , 33 nM , 32 nM , 31 nM , 30 nM , 29 (x ) a small hydroxyl group consisting of Ser and Thr.
nM , 28 nM , 27 nM , 26 nM , 25 nM , 24 nM , 23 nM , 22 nM , In addition to the groups presented above, each amino
21 nM , 20 nM , 19 nM , 18 nM , 17 nM , 16 nM , 15 nM , 14 35 acid residue may form its own group , and the group formed
nM , 13 nM , 12 nM , 11 nM , 10 nM , 9 nM , 8 nM , 7 nM , 6 by an individual amino acid may be referred to simply by the
nM , 5 nM , 4 nM , 3 nM , 2 nM , 1 nM , 990 PM , 980 PM , 970 one and / or three letter abbreviation for that amino acid
PM , 960 PM , 950 PM , 940 PM , 930 PM , 920 PM , 910 PM , commonly used in the art as described above .
900 PM , 890 PM , 880 PM , 870 PM , 860 PM , 850 PM , 840 A " conserved residue ” is an amino acid that is relatively
PM , 830 PM , 820 PM , 810 PM , 800 PM , 790 PM , 780 PM , 40 invariant across a range of similar proteins. Often conserved
770 PM , 760 PM , 750 PM , 740 PM , 730 PM , 720 PM , 710 residues will vary only by being replaced with a similar
PM , 700 PM , 690 PM , 680 PM , 670 PM , 660 PM , 650 PM , amino acid , as described above for " conservative amino acid
640 PM , 630 PM , 620 PM , 610 PM , 600 PM , 590 PM , 580 substitution ."
PM , 570 PM , 560 PM , 550 PM , 540 PM , 530 PM , 520 PM , The letter “ x ” or “ xaa ” as used in amino acid sequences
510 PM , 500 PM , 490 PM , 480 PM , 470 PM , 460 PM , 450 45 herein is intended to indicate that any of the twenty standard
PM , 440 PM , 430 PM , 420 PM , 410 PM , 400 PM , 390 PM , amino acids may be placed at this position unless specifi
380 PM , 370 PM , 360 PM , 350 PM , 340 PM , 330 PM , 320 cally noted otherwise .
PM , 310 PM , 300 PM , 290 PM , 280 PM , 270 PM , 260 PM , As used herein , “ identity” means the percentage of iden
250 PM , 240 PM , 230 PM , 220 PM , 210 PM , 200 PM , 190 tical nucleotide or amino acid residues at corresponding
PM , 180 PM , 170 pM , or any integer therebetween . 50 positions in two or more sequences when the sequences are
Binding affinity may be determined using surface plas- aligned to maximize sequence matching, i.e. , taking into
mon resonance ( SPR) , Kinexa Biocensor, scintillation prox- account gaps and insertions . Identity can be readily calcu
imity assays , enzyme linked immunosorbent assay ( ELISA) , lated by known methods, including but not limited to those
ORIGEN immunoassay (IGEN) , fluorescence quenching, described in Computational Molecular Biology, Lesk , A. M. ,
fluorescence transfer, yeast display, or any combination 55 ed . , Oxford University Press, New York , 1988 ; Biocomput
thereof. Binding affinity may also be screened using a ing : Informatics and Genome Projects, Smith, D. W., ed . ,
suitable bioassay. Academic Press, New York , 1993 ; Computer Analysis of
As used herein , the term “ avidity ” refers to the resistance
Sequence Data , Part 1 , Griffin , A. M. , and Griffin , H. G. , eds . ,
of a complex of two or more agents to dissociation after Humana Press, New Jersey , 1994 ; Sequence Analysis in
dilution. Apparent affinities can be determined by methods 60 Molecular Biology , von Heinje , G. , Academic Press, 1987 ;
such as an enzyme linked immunosorbent assay (ELISA) or and Sequence Analysis Primer, Gribskov, M. and Devereux ,
any other technique familiar to one of skill in the art. J. , eds . , M Stockton Press, New York , 1991 ; and Carillo , H. ,
Avidities can be determined by methods such as a Scatchard and Lipman , D. , SIAM J. Applied Math ., 48 : 1073 ( 1988 ) .
analysis or any other technique familiar to one of skill in the Methods to determine identity are designed to give the
art . 65 largest match between the sequences tested . Moreover,
A CR3022 - derived antibody or antigen -binding fragment methods to determine identity are codified in publicly avail
can be modified by making one or more substitutions in the able computer programs. Computer program methods to
 US 11,034,762 B1
95 96
determine identity between two sequences include , but are antigen -binding fragments herein . Such one or more RNA
not limited to , the GCG program package (Devereux, J. , et molecules may be present in a vector for administration to
al . , Nucleic Acids Research 12 ( 1 ) : 387 ( 1984 ) ) , BLASTP , a subject.
BLASTN , and FASTA ( Altschul, S. F. et al . , J. Molec. Biol. Provide herein are polynucleotides ( such as RNA, for
215 : 403-410 ( 1990 ) and Altschul et al . Nuc . Acids Res. 25 : 5 example mRNA ) encoding antibodies or antigen - binding
3389-3402 ( 1997 ) ) . The BLAST X program is publicly fragments that can specifically bind to SARS - CoV - 2 . Anti
available from NCBI and other sources (BLAST Manual, body or antigen -binding fragments encoded by polynucle
Altschul, S. , et al . , NCBI NLM NIH Bethesda, Md . 20894 ; otides can include antibodies or antigen -binding fragments.
Altschul, S. , et al . , J. Mol. Biol. 215 : 403-410 ( 1990) . The 10 Polynucleotides
infection of the
can be administered to a subject to prevent
subject by SARS - Cov - 2 or to treat a subject
well -known Smith Waterman algorithm may also be used to
determine identity. “ Polynucleotide” or “ nucleic acid , ” as antigen -binding fragments- 2 .canIn besome
infected by SARS -CoV cases , antibodies or
produced in a subject that
used interchangeably herein , refer to polymers of nucleo has been administered a polynucleotide herein .
tides of any length , and include DNA and RNA . The Polynucleotides can comprise genetic material encoding a
nucleotides can be deoxyribonucleotides, ribonucleotides, 15 CR3022-derived antibody or antigen -binding fragment ( e.g.,
modified nucleotides or bases , and / or their analogs , or any DNA or mRNA ). In some cases , polynucleotides can be in
substrate that can be incorporated into a polymer by DNA or a vector, such as a viral vector or an artificial chromosome
RNA polymerase. A polynucleotide may comprise modified such as a human artificial chromosome. In some cases ,
nucleotides, such as methylated nucleotides and their ana- polynucleotides can additionally comprise a promoter, a
logs . If present, modification to the nucleotide structure may 20 terminator, a sequence encoding a tag , a sequence encoding
be imparted before or after assembly of the polymer. The a second antibody or antigen -binding fragment, or
sequence of nucleotides may be interrupted by non -nucleo- sequence encoding a molecule that can aid in folding or
tide components. A polynucleotide may be further modified function of the antibody or antigen -binding fragment.
after polymerization , such as by conjugation with a labeling In some cases , polynucleotides can be used to prevent
component. Other types of modifications include , for 25 and / or treat disease caused by SARS - Cov - 2 or a similar
example , " caps,” substitution of one or more of the natu- virus ( e.g. , COVID - 19 ) ; i.e. , polynucleotides can have pro
rally occurring nucleotides with an analog , internucleotide phylactic or therapeutic uses , or both prophylactic and
modifications such as , for example , those with uncharged therapeutic uses . Accordingly, the present disclosure pro
linkages ( e.g. , methyl phosphonates, phosphotriesters, phos- vides methods to prevent and / or treat infection by SARS
phoamidates , carbamates, etc. ) and with charged linkages 30 CoV - 2 . In some cases , such methods can comprise admin
( e.g. , phosphorothioates , phosphorodithioates, etc. ), those istering to a subject one or more mRNA molecules encoding
containing pendant moieties, such as , for example, proteins a CR3022 -derived antibody or antigen -binding fragment
( e.g. , nucleases, toxins, antibodies , signal peptides, ply -L- that can specifically bind to SARS - CoV - 2 .
lysine , etc. ) , those with intercalators (e.g. , acridine , psoralen , An antibody library herein can comprise a plurality of
etc. ) , those containing chelators ( e.g. , metals , radioactive 35 antibodies and / or antigen -binding fragments. The plurality
metals, boron , oxidative metals, etc. ) , those containing alky- of antibodies and / or antigen -binding fragments can be at
lators , those with modified linkages (e.g. , alpha anomeric least 1.0x10 " , 1.0x107 , 1.0x10 % , 1.0x10 ° , 1.0x1010 , 2.0x
nucleic acids , etc. ), as well as unmodified forms of the 1010 , 3.0x1010 , 4.0x1010 , 5.0x1010 , 6.0x1010 , 7.0x1010 ,
polynucleotide (s ). Further, any of the hydroxyl groups ordi- 8.0x1010, 9.0x1010 , or 10.0x1010 .
narily present in the sugars may be replaced, for example , by 40 The practices of the present invention will employ, unless
phosphonate groups , phosphate groups, protected by stan- otherwise indicated, conventional techniques of molecular
dard protecting groups , or activated to prepare additional biology (including recombinant techniques ), microbiology,
linkages to additional nucleotides, or may be conjugated to cell biology, biochemistry and immunology, which are
solid supports . The 5 ' and 3 ' terminal OH can be phospho- within the skill of the art. Such techniques are explained
rylated or substituted with amines or organic capping group 45 fully in the literature, such as , Molecular Cloning : A Labo
moieties of from 1 to 20 carbon atoms . Other hydroxyls may ratory Manual, second edition (Sambrook et al . , 1989 ) Cold
also be derivatized to standard protecting groups. Polynucle- Spring Harbor Press ; Oligonucleotide Synthesis (M. J. Gait ,
otides can also contain analogous forms of ribose or deoxy- ed . , 1984 ) ; Methods in Molecular Biology, Humana Press ;
ribose sugars including , for example, 2 '- O -methyl-, 2-0- Cell Biology : A Laboratory Notebook (J. E. Cellis , ed . ,
allyl , 2 ' - fluoro- or 2 '- azido - ribose, carbocyclic sugar 50 1998 ) Academic Press ; Animal Cell Culture (R. I. Freshney ,
analogs, alpha -anomeric sugars , epimeric sugars such as ed . , 1987 ) ; Introduction to Cell and Tissue Culture (J. P.
arabinose, xyloses , or lyxoses , pyranose sugars , furanose Mather and P. E. Roberts, 1998 ) Plenum Press ; Cell and
sugars , sedoheptuloses, acyclic analogs, and abasic nucleo- Tissue Culture: Laboratory Procedures (A. Doyle , J. B.
side analogs such as methyl riboside . One or more phos- Griffiths , and D. G. Newell , eds . , 1993-1998 ) J. Wiley and
phodiester linkages may be replaced by alternative linking 55 Sons ; Methods in Enzymology (Academic Press, Inc. );
groups. These alternative linking groups include , but are not Handbook of Experimental Immunology (D. M. Weir and C.
limited to , embodiments wherein phosphate is replaced by C. Blackwell, eds . ) ; Gene Transfer Vectors for Mammalian
P (O ) S ( “ thioate ” ), P ( S ) S ( “ dithioate” ), (O ) NR2 ( “ amidate ” ) , Cells (J. M. Miller and M. P. Cabs, eds . , 1987 ) ; Current
P (O ) R , P (O ) OR' , CO , or CH2 ( “ formacetal ” ) , in which each Protocols in Molecular Biology ( F. M. Ausubel et al . , eds . ,
R or R' is independently H or substituted or unsubstituted 60 1987 ) ; PCR : The Polymerase Chain Reaction , (Mullis et al . ,
alkyl ( 1-20 C ) optionally containing an ether ( 0– ) link- eds ., 1994 ) ; Current Protocols in Immunology ( J. E. Coligan
age , aryl, alkenyl, cycloalkyl, cycloalkenyl, or araldyl. Not et al . , eds . , 1991 ) ; Short Protocols in Molecular Biology
all linkages in a polynucleotide need be identical. The ( Wiley and Sons , 1999 ) ; Immunobiology ( C. A. Janeway
preceding description applies to all polynucleotides referred and P. Travers, 1997 ) ; Antibodies ( P. Finch , 1997 ) ; Antibod
to herein , including RNA and DNA . 65 ies : a practical approach (D. Catty, ed . , IRL Press, 1988
In one aspect , provided herein is one or more RNA 1989 ) ; Monoclonal antibodies: a practical approach ( P.
molecules that encode one or more of the antibodies or Shepherd and C. Dean , eds . , Oxford University Press ,
 US 11,034,762 B1
97 98
2000 ) ; Using antibodies: a laboratory manual (E. Harlow -continued
and D. Lane (Cold Spring Harbor Laboratory Press, 1999 ) ;
and The Antibodies ( M. Zanetti and J. D. Capra, eds . , Captures ka kd KD Rmax
Harwood Academic Publishers, 1995 ) . RL (RU ) (M- 1 s- 1 ) (S - 1 ) (NM ) (RU )
5
1387 2.30E + 05 5.80E - 03 25.29 16
Examples 1577 1.30E + 05 5.70E - 03 42.72 22
1464 4.10E + 05 1.60E - 02 38.26 30
The application may be better understood by reference to 1361
2355
4.10E + 05
5.27E + 05
1.20E - 02 30.52
41.26
37
20
the following non - limiting examples , which are provided as 1377 4.00E + 05
2.17E - 02
9.30E - 03 23.26 21
exemplary embodiments of the application . The following 10 1997 7.50E + 04 5.70E - 04 7.59 28
examples are presented in order to more fully illustrate 1161 6.65E + 04 5.86E - 04 8.82 19.21
embodiments and should in no way be construed , however, 1436 4.62E + 05 1.56E - 02 33.76 75
as limiting the broad scope of the application . 1228 3.73E + 04 4.96E - 04 13.3 15.48
1169 4.38E + 05 1.54E - 02 35.2 50.56
Example 1 : Kinetics and Affinity Determination of 15 1763
1684
7.07E + 04
1.26E + 05
1.07E - 03
1.18E - 04
15.17
0.94
41.6
12.17
an Anti -SARS - Cov - 2 scFv by Surface Plasmon 1501 2.49E + 05 1.23E - 04 0.49 50
Resonance 1627 4.17E + 04 8.58E - 04 20.57 23.43
1820 4.38E + 04 1.77E - 03 40.37 51.3
High - throughput surface plasmon resonance (SPR) 1515 2.00E + 05 8.90E - 03 43.99 69
kinetic experiments were performed on Carterra LSA Array 20 1346 6.30E + 04 4.10E - 04 6.58 17
SPR instrument ( Carterra, Salt Lake City, Utah ) equipped 1470 1.20E + 05 3.90E - 04 3.25 37
1293 1.46E + 05 5.33E - 04 3.66 67
with HC200M sensor chip ( catalog No. 4287 , Carterra, Salt 1435 2.64E + 05 2.61E - 04 0.99 19
Lake City, Utah ) at 25 ° C. Anti -SARS - Cov - 2 scFv con 1340 5.23E + 04 5.70E - 05 1.1 6.33
structs were expressed with a V5 epitope tag to enable 1432 1.36E + 05 2.62E - 04 1.92 34
capture via immobilized anti - V5 antibody. Surfaces were 25 1679 3.05E + 05 5.70E - 05 0.2 45
prepared in HBSTE ( 10 mM HEPES pH 7.4 , 150 mM NaCl , 1689
975
2.00E + 05
2.76E + 05
5.70E - 05
1.04E - 02
0.29
37.56
32.6
130.65
3 mM EDTA , 0.01 % ( v / v ) Tween - 20 ) as running buffer. The 1598 4.19E + 04 3.70E - 04 8.81 21.86
capture surface was prepared by standard amine - coupling of 1035 1.52E + 05 9.11E - 04 6.01 13.91
anti - V5 tag antibody ( catalog No. ab27671 , Abcam , Cam 859 1.17E + 05 3.44E - 04 2.95 19.7
bridge, Mass . ) on the entire chip surface as follows. The chip 30 1471 5.49E + 04 8.93E - 04 16.27 28.08
was activated with a 10 - min injection of a freshly prepared 1609 1.09E + 05 5.70E - 05 0.5 33
1 : 1 : 1 ( v / v / v ) mixture of 0.4 M 1 -Ethyl-3-(3 -Dimethylami 1278 8.50E + 04 3.60E - 04 4.24 17
nopropyl ) carbodiimide hydrochloride ( EDC) +0.1 M N -hy 1265
1447
6.14E + 05
2.47E + 05
2.23E - 02
1.37E - 03
36.25
5.56
69
71.8
droxysulfosuccinimide ( SNHS ) +0.1 M 2- ( N -morpholino ) 836 5.51E + 05 1.57E - 02 28.51 39.43
ethanesulfonic acid (MES ) pH 5.5 . Then , anti - V5 tag anti- 35 792 4.34E + 05 1.42E - 02 32.83 19.62
body was diluted to 50 ug /ml in 10 mM sodium acetate pH 1149 6.16E + 05 3.81E - 03 6.18 90.69
4.3 and coupled for 14 min . Excess reactive esters were 1028 5.70E + 05 1.50E - 02 26.08 23
blocked with a 10 -min injection of 1 M ethanolamine HCl 1088 4.58E + 05 1.31E - 02 28.73 67.81
pH 8.5 . library of anti - COVID - 19 scFv clones was sup 1155 3.28E + 05 5.38E - 03 16.41 41.62
plied as plates of crude bacterial periplasmic extracts (PPE ) 40 785 3.08E + 05 1.24E - 02 40.33 28.35
and diluted 2 - fold in running buffer. ScFv samples were flow 881 8.60E + 05 2.31E - 02 26.9 36
printed for 15 - min in batches of 96 PPE’s in parallel using 808 3.78E + 05 1.55E - 02 40.96 48.96
703 4.09E + 05 1.43E - 02 34.97 41.34
the 96 channel printhead to generate a 384 - ligand array 745 6.31E + 05 1.66E - 02 26.34 43.14
comprising 1 spot per scFv . For the interaction analysis, the 1493 1.60E + 05 2.20E - 04 1.38 14.59
running buffer HBST ( 10 mM HEPES pH 7.4 , 150 mM 45 1497 2.50E + 05 8.30E - 03 32.81 25
NaCl , 0.01 % ( v / v ) Tween - 20 ) was supplemented with 0.5 1324 8.28E + 05 3.63E - 04 0.4 148
mg/ml BSA . Surfaces were stabilized with seven to eight 1531 1.20E + 04 2.80E - 04 22.54 70
buffer analyte injections. SARS - CoV - 2, SARS - CoV - 1, and 1409 2.21E + 04 5.07E - 04 22.95 62
MERS Receptor Binding Domain (RBD ) proteins were 1388 3.02E + 05 1.40E - 02 46.2 59
prepared at concentrations of 0 , 3.7 , 11.1 , 33.3 , 100 , 37 , and 50 1343 1.57E + 05 1.85E - 04 1.18
39.69
18
116
300 nM and these samples were injected as analyte for 5 1347
1380
8.14E + 04
6.24E + 04
3.23E - 03
5.70E - 05 0.91 15.7
min, allowing a 15 - min dissociation time . Samples were 1361 5.48E + 04 1.12E - 03 20.47 23.3
injected in ascending concentration without any regenera 1464 5.59E + 04 2.07E - 04 3.71 12.18
tion in between them . Binding data from the local reference 2137 4.26E + 04 4.82E - 04 11.32 45
spots were subtracted from the active spots and the nearest 55 1074 2.78E + 05 1.27E - 02 45.52 24.98
buffer blank analyte responses were subtracted to double 1050 2.73E + 05 5.88E - 04 2.15 26.91
reference the data . The double - referenced data were fitted to 1028 9.72E + 04 1.13E - 03 11.58 55.68
a simple 1 : 1 Langmuir binding model in Carterra's Kinetic 1723 2.54E + 04 6.79E - 04 26.77 30.71
Inspection Tool to give kinetics (k?, ka), affinity (KD ), and 819 1.58E + 05 7.29E - 03 46.24 20.81
Rmax value for each interaction . 60

The described clones each had a superior binding affinity

Captures ka kd KD Rmax of less than 50 nM . The majority of the clones were
RL (RU ) (M- 1 s- 1 ) (S - 1 ) (nM) ( RU ) identified as binding solely to Sars - Cov - 2 (COV2 ) , however,
1328 2.80E + 05 8.50E - 03 30.63 17 65 a few clones were found to not only bind to Sars - Cov - 2 , but
685 4.19E + 05 1.73E - 02 41.23 21.85 also to Middle East Respiratory Syndrome ( MERS ) virus,
SARS - Cov - 1 , and /or SARS2 .
 US 11,034,762 B1
99 100
are transfected with Pseudo virus vector using Lipo
Clone ID Binding Affinity For : fectamine system ( ThermoFisher) following the manufac
COVID19_P22_F04 COV2 turer's instruction. Twenty - four hours later, new media is
COVID19_P21_A05 COV2 + SARS1 + SARS2 replaced and after 48 h from the beginning of transfection
COVID19_P22_E10 COV2 + SARS2
COV2
SARS - CoV - 2 pseudoviruses containing culture supernatants
COVID19_P22_E06
COVID19_P22_G12 COV2 are harvested, filtered ( 0.45 -um pore size , Millipore,
COVID19_P22_D06 COV2 + SARS1 + SARS2 SLHP033RB ) and stored at -80 ° C. in aliquots until use . The
COVID19_P10_B08
COVID19 P22 F11
COV2 + MERS
COV2
50% tissue culture infectious dose ( TCID50) of SARS
COVID19 P22_H10 COV2 10
CoV - 2 pseudovirus is determined using a single - use aliquot
COVID19 P21 E12 COV2 from the pseudovirus bank; all stocks are used only once to
COVID19_P10_C05 COV2 avoid inconsistencies that could have resulted from repeated
COVID19_P21_A08 COV2 freezing - thawing cycles . For titration of the SARS - CoV - 2
COVID19_P09_H09 COV2
COVID19_P10_D08 COV2 pseudovirus, a 2 - fold initial dilution is made in triplicates
COVID19_P21_E03 COV2
15 wells of 96 - well culture plates followed by serial 3 - fold
COVID19_P09_E11 COV2
COVID19_P21_A03 COV2 + SARS2
dilutions ( 8 dilutions in total ) . The last column served as the
COVID19_P10_GO3 COV2 cell control without the addition of pseudovirus. Then, the
COVID19 P22 E12 COV2 96 - well plates are seeded with trypsin - treated Vero E6
COVID19_P22_F07
COVID19_P09_HOS
COV2
COV2
mammalian transfectable cells adjusted to a pre -defined
COVID19_P09_B07 COV2 20 concentration . After 24 h incubation in a 5 % CO2 environ
COVID19_P09_C09 COV2 ment at 37 ° C. , the culture supernatant is aspirated gently to
COVID19_P21_F11 COV2 leave 100 ul in each well ; then , 100 ul of luciferase substrate
COVID19_P09_GO2 COV2 is added to each well . Two min after incubation at room
COVID19_P09_E05 COV2
COVID19_P10_B06 COV2 temperature , 150 ul of lysate is transferred to white solid
COVID19_P21_B12
COVID19 P21 F04
COV2 + SARS1 + SARS2
COV2
25 96 - well plates for the detection of luminescence using a
COVID19_P21_A12 COV2
microplate luminometer (PerkinElmer ). The positive well is
COVID19 P21 B08 COV2 determined as ten - fold relative luminescence unit ( RLU)
COVID19_P21_F08 COV2 values higher than the cell background. The 50 % tissue
COVID19_P09_A09 COV2
COVID19_P22_B12 COV2 30
culture infectious dose (TCID50 ) is calculated using the
COVID19_P10_B04 COV2 + SARS1 + SARS2 Reed - Muench method , as described in Nie J et al . Id . In
COVID19_P10_D09 COV2 some cases the pseudovirus included a GFP reporter instead
COVID19_P21_C09 COV2 + SARS1 + SARS2
of Luciferase ; in these cases , GFP fluorescence is measured
COVID19 P21 E08 COV2 + SARS1 + SARS2
COVID19_P09_G04 COV2 + SARS1 by flow cytometry.
COVID19 P22 B04 COV2 35 Pseudovirus Based Neutralization Assay
COVID19_P09_C08 COV2 + SARS1 + SARS2
Neutralization is measured by the reduction in luciferase
COVID19_P09_D06 COV2
COVID19_P21_H02 COV2 + SARS1 + SARS2 gene expression or GFP gene expression as described pre
COVID19_P19_A02 COV2 + SARS1 + SARS2 viously Nie J et al . Id . The 50 % inhibitory dilution (EC50 )
COVID19_P21_E07 COV2 + SARS1 + SARS2 is defined as the dilution of the tested antibodies at which the
COVID19_P21_A04 COV2 + SARS1 + SARS2
COVID19 P21 B11 COV2 + SARS1 + SARS2 40 relative light units (RLUs ) were reduced by 50 % compared
COVID19_P21_H01 COV2 with the virus control wells ( virus + cells ) after subtraction of
COVID19_P22_C09 COV2 the background RLUs in the control groups with cells only .
COVID19_P09_G12 COV2
In brief, pseudovirus in the TCID50 determined above is
COVID19_P22_H05 COV2
COVID19_P09_B09 COV2 incubated with serial dilutions of the test samples ( six
COVID19_P10_B10 COV2 45 dilutions in a 3 - fold step -wise manner ) in duplicate for 1 h
COVID19_P09_C05 COV2
at 37 ° C. , together with the virus control and cell control
COVID19_P09_B10 COV2
COVID19_P21_B01 COV2 wells in triplicate . Then , freshly trypsinized cells were added
COVID19_P10_A09 COV2 to each well . Following 24 h of incubation in a 5 % CO2
COVID19_P21_B09
COVID19_P09_G05
COV2
COV2 + SARS1 + SARS2 50
environment at 37 ° C. , the luminescence or fluoresce (de
COVID19 P21 B02 COV2 pending on the reporter gene used) is measured as described
COVID19_P21_E04 COV2 above ( relating to pseudovirus titration ). The EC50 values
COVID19_P21_H03 COV2
were calculated with non - linear regression, i.e. , log (inhibi
COVID19 P21 FO2
COVID19_P21_A10
COV2 + SARS2
COV2 + SARS1 + SARS2 + MERS
tor) vs. response ( four parameters ), using GraphPad Prism 8
55
(GraphPad Software, Inc. , San Diego , Calif., USA) .
Results
Neutralization was observable for the following clones :
Example 2 : In Vitro Neutralization Assay for Average Tm1 ( ° C . ) and IC50 data for a subset of the clones
Sars - Cov - 2 Virus is provided below :
Production and Titration of Pseudoviruses 60
For pseudovirus construction , spike genes from a SARS Average IC50 IC50 [ug /mL] IC50
COV 2 virus strain , a specific are codon - optimized for Tm1 [ug mL
/ ] pseudotyped [ug /mL ]
human cells and cloned into eukaryotic expression plasmid CloneID (° C. ) plaque lenti neut neut
to generate the envelope recombinant plasmids . The COVID19_P09_E05 61.9
pseudoviruses are produced and titrated using methods 65 COVID19_P09_G12
similar, as described previously in Nie J. et al . (Emerg
72.1 <3 0.053 < 1:16

Microbes Infect. 2020 December; 9 ( 1 ) : 680-686 ) , 293T cells

 US 11,034,762 B1
101 102
Example 3 : Competition of SARS -CoV - 2 / ACE2 Capture of biotinylated ACE2 at 10 ug /mL is included as a
Interaction with Anti- SARS - Cov - 2 scFv by self -blocking control in both assays.
Biolayer Interferometry
Example 4 : In Vivo Hamster Model for Sars -COV2
Competition assay of the interaction of SARS - CoV - 2 with 5 Infections
ACE2 is conducted in a classical sandwich and a premix
assay format using a ForteBio Octet HTX biolayer interfer- Competent 6-8 weeks old Syrian golden hamsters females
ometry instrument (Molecular Devices ForteBio LLC , Fre- ( Charles River Laboratories or Harlan Laboratories ) are
mont, Calif .) at 25 ° C. with running buffer HBST ( 10 mM housed three per cage in a biosafety level 3-4 animal facility
HEPES PH 7.4 , 150 mM NaCl , 0.01 % ( v / v ) Tween -20 , pH 10 in UTMB Galveston . Animals will be acclimatized in the
7.4 ) supplemented with 1 mg /mL BSA . BSL - 3-4 biosafety containment 3-5 days before the experi
An Anti - V5 tag antibody (catalog No. ab27671 , Abcam , ment begins . Animal will be housed and treated as recom
Cambridge, Mass . ) is biotinylated with a 5 : 1 molar ratio of mended by Institutional Biosafety and the Institutional Ani
sulfo -NHS -LC - LC -biotin ( catalog No. 21338 , Ther- mal Care and Use Committees.
moFisher Scientific , Waltham , Mass . ) and buffer exchanged 15 Animals are injected IP with 0.5-1 mL of either saline, a
into PBS using ThermoFisher Zeba 7K MWCO columns therapeutic antibody at 10 mg /Kg ( as disclosed herein ), or an
( catalog No. 89883 , ThermoFisher Scientific , Waltham , isotype control antibody at 10 mg/Kg, 24 h before viral
Mass . ) . infection . Animals are acclimatized in the ABSL - 3 biosafety
Streptavidin sensor tips (catalog no . 18-5021 , Molecular containment. On the day of infection, hamsters ( 5 per group )
Devices ForteBio LLC , Fremont, Calif.) are equilibrated in 20 will be inoculated with PBS or 10E5 ( 1x10 ) virus load via
buffer for 10 -min before the run . Sample plates are agitated nasal cavity in a total volume of 100 uL ( 50 uL into each
at 1000 rpm . At the start of the run , sensors are exposed to naris ).
buffer for 60 sec to establish a baseline . The biotinylated Hamsters ' bodyweight and viable signs ( such as ruffled
anti- V5 tag antibody at 7 ug /mL are loaded onto the sensors hair and lack of movement) will be monitored and recorded
for 5 -min to prepare an anti - V5 surface. To block remaining 25 twice daily for 3 days and virus titers will be measured from
free biotin binding sites , all sensors are exposed for 5 -min a nasal swab on day 2. Hamsters will be sacrificed on day 3
with 20 uM amine - PEG2 - biotin (catalog No. 21346 , Ther- and virus titers in homogenates of lung tissues will be
moFisher Scientific , Waltham , Mass . ) followed by two alter- determined .
nating 30 - sec cycles of 10 mM glycine - HCl pH1.7 and H & E - stained lung tissues will be evaluated by a suitable
buffer to precondition the sensors . 30 scientist, medical professional, or veterinary professional
For the classical sandwich assay format, a baseline in (e.g. , trained in pathology ) to determine the severity of
buffer is established for 60 - sec and anti -SARS -Cov - 2 scFv infection and amount of protection provided by the neutral
clones as PPE undiluted are captured for 2 -min onto the izing antibodies . To determine the TCID50 in the lungs,
anti - V5 sensor tips . Baseline in buffer is recorded for 60 - sec tissues will be homogenized and spun down and the super
followed by association of SARS - Cov - 2 at 100 nM for 35 natants will be removed and analyzed by a TCID50 assay as
2 -min, a quick wash in buffer for 15 - sec , and sandwiching described in a previous Example, above .
of 500 nM ACE2 or buffer for 2 - min . After each classical While preferred embodiments of the present invention
sandwich cycle , sensors are regenerated with two alternating have been shown and described herein , it will be obvious to
30 - sec cycles of 10 mM glycine - HCI PH1.7 and buffer. those skilled in the art that such embodiments are provided
For the premix assay format, a baseline in buffer is 40 by way of example only. Numerous variations, changes, and
established for 60 - sec and anti -SARS -Cov - 2 scFv clones as substitutions will now occur to those skilled in the art
PPE undiluted are captured for 2 -min onto the anti- V5 without departing from the invention . It should be under
sensor tips . Baseline in buffer is recorded for 60 - sec fol- stood that various alternatives to the embodiments of the
lowed by association of buffer, a premixed complex of 100 invention described herein may be employed in practicing
nM SARS - Cov - 2 + 500 nM ACE2 , or 100 nM SARS - Cov - 2 . 45 the invention . It is intended that the following claims define
Dissociation in buffer is measured for 30 - sec . After each the scope of the invention and that methods and structures
binding cycle , sensors are regenerated with two alternating within the scope of these claims and their equivalents be
30 - sec cycles of 10 mM glycine -HCI pH1.7 and buffer. covered thereby.
SEQUENCE LISTING

< 160 > NUMBE OF SEQ ID NOS : 456

< 210 > SEQ ID NO 1

< 211 > LENGTH : 23
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 1

Asp Ile Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15

Glu Arg Ala Thr Ile Asn Cys

20
 US 11,034,762 B1
103 104
- continued

< 210 > SEQ ID NO 2

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 6 ) .. ( 6 )
< 223 > OTHER INFORMATION : Vor L
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 11 ) .. ( 11 )
< 223 > OTHER INFORMATION : I or N
< 220 > FEATURE :
< 221 > NAME /KEY : MOD_RES
< 222 > LOCATION : ( 13 ) .. ( 13 )
< 223 > OTHER INFORMATION : Kor L

< 400 > SEQUENCE : 2

Lys Ser Ser Gln Ser Xaa Leu Tyr Ser Ser Xaa Asn Xaa Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 3

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 3

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 4

< 211 > LENGTH : 15
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 4

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Asn Asn Tyr Leu Ala
1 5 10 15

< 210 > SEQ ID NO 5

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 5

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 6

< 211 > LENGTH : 17
< 212 > TYPE : PRT
 US 11,034,762 B1
105 106
- continued
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 6

Lys Ser Ser Gin Ser Val Leu Tyr Thr Ser Asn Asn Asn Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 7

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 7

Lys Ser Ser Gin Ser Val Leu Tyr Thr Ser Asn Asn Asn Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 8

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 8

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 9

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of tificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 9

Lys Ser Ser Gln Asn Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 10

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 10

Thr Ser Ser Leu Ser Leu Gin Asp Arg Ser Asn Asn Lys Asn Tyr Leu
1 5 10 15

Thr

< 210 > SEQ ID NO 11

< 211 > LENGTH : 17
 US 11,034,762 B1
107 108
- continued
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 11

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 12

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 12

Lys Ser Ser Gin Asn Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 13

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 13

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 14

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 14

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Asn Asn Ile Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 15

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 15

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 16

 US 11,034,762 B1
109 110
- continued
< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 16

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Asn Lys Asn Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 17

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 17
Arg Ser Ser Gin Thr Val Leu Tyr Arg Ser Asn Asn Tyr Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 18

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 18

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Asn Asn Leu Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 19

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 19

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 20

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 20

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu
1 5 10 15

Ala
 US 11,034,762 B1
111 112
- continued
< 210 > SEQ ID NO 21
< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 21

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 22

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 22

Lys Ser Ser Gln Arg Val Leu Tyr Ser Ser Asn Asn Leu Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 23

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 23

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Asn Asn Ile Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 24

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 24

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 25

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 25

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala
 US 11,034,762 B1
113 114
- continued

< 210 > SEQ ID NO 26

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 26

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 27

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 27

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 28

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 28

Lys Ser Ser Gln Ser Val Phe His Ser Ser Asn Asn Lys Asn His Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 29

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 29

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 30

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 30

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala
 US 11,034,762 B1
115 116
- continued

< 210 > SEQ ID NO 31

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 31
Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 32

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 32

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn His Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 33

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 33

Lys Ser Ser Gin Ser Val Leu His Ser Ala Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 34

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 34

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 35

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 35

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15
 US 11.034.762 B1
117 118
- continued
Ala

< 210 > SEQ ID NO 36

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 36
Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 1 15

Ala

< 210 > SEQ ID NO 37

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 37

Arg Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Phe
1 1 15

Ala

< 210 > SEQ ID NO 38

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 38

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 39

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 39

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 1 15

Ala

< 210 > SEQ ID NO 40

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 40

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu
1 5 1 15
 US 11.034.762 B1
119 120
- continued

Ala

< 210 > SEQ ID NO 41

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 41

Lys Ser Ser Gin Thr Ile Ser Tyr Ser Ser Asp Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 42

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 42

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 43

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 43

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 44

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 44

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Asn Asn His Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 45

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 45

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
 US 11,034,762 B1
121 122
- continued
1 5 10 15

Ala

< 210 > SEQ ID NO 46

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 46

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 47

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 47

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 48

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 48

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 49

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 49
Lys Ser Thr Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Val
1 5 10 15

Ala

< 210 > SEQ ID NO 50

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 50
 US 11,034,762 B1
123 124
- continued
Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 51

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 51

Lys Ser Ser Gin Ser Val Leu His Ser Ser Asn Asn Leu Asn Tyr Phe
1 5 10 15

Ala

< 210 > SEQ ID NO 52

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 52

Thr Ser Ser Gin Ser Val Leu His Ser Ser Asn Asn Leu Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 53

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 53

Lys Ser Ser Gin Ser Val Leu Tyr Arg Ser Asn Asn Leu His Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 54

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 54

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 55

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 55
 US 11.034.762 B1
125 126
- continued

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 56

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 56
Lys Ser Ser Arg Ile Leu Ser Tyr Ser Pro Asp Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 57

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 57

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 58

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 58

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 10 15

Ala

< 210 > SEQ ID NO 59

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 59

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 60

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
 US 11,034,762 B1
127 128
- continued
< 400 > SEQUENCE : 60

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 61

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 61
Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 62

< 211 > LENGTH : 17
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 62

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu
1 5 10 15

Ala

< 210 > SEQ ID NO 63

< 211 > LENGTH : 15
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 63

Trp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Lys eu Ile Ser
1 5 10 15

< 210 > SEQ ID NO 64

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 1 ) .. ( 1 )
< 223 > OTHER INFORMATION : W or R
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 2 ) .. ( 2 )
< 223 > OTHER INFORMATION : A , S , or G
< 220 > FEATURE :
< 221 > NAME /KEY : MOD_RES
< 222 > LOCATION : ( 3 ) .. ( 3 )
< 223 > OTHER INFORMATION : S , T , or N
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 4 ) .. ( 4 )
< 223 > OTHER INFORMATION : T , L , F , or N
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
 US 11,034,762 B1
129 130
- continued
< 222 > LOCATION : ( 6 ) .. ( 6 )
< 223 > OTHER INFORMATION : E , A , G , or L
< 220 > FEATURE :
< 221 > NAME / KEY : MOD RES
< 222 > LOCATION : ( 7 ) .. ( 7 )
< 223 > OTHER INFORMATION : S , P , G , F , or A

< 400 > SEQUENCE : 64

Xaa Xaa Xaa Xaa Arg Xaa Xaa

1 5

< 210 > SEQ ID NO 65

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 65

Trp Ala Ser Thr Arg Glu Ser

1 5

< 210 > SEQ ID NO 66

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 66

Trp Gly Ser Thr Arg Gly Ser

1 5

< 210 > SEQ ID NO 67

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 67

Trp Ala Asn Ile Arg Glu Ser

1 5

< 210 > SEQ ID NO 68

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 68

Trp Ala Ser Thr Arg Asp Phe

1 5

< 210 > SEQ ID NO 69

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 69
 US 11.034.762 B1
131 132
- continued
Trp Ala Ser Thr Arg Ala Ser
1 5

< 210 > SEQ ID NO 70

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 70

Trp Ala Ser Leu Arg Glu Gly

1 5

< 210 > SEQ ID NO 71

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 71

Trp Ala Ser Thr Arg Leu Ser

1 5

< 210 > SEQ ID NO 72

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 72
Trp Gly Ser Thr Arg Gly Ser
1 5

< 210 > SEQ ID NO 73

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 73

Trp Ala Ser Tyr Arg Glu Ser

1 5

< 210 > SEQ ID NO 74

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 74

Trp Ala Ser Asn Arg Glu Pro

1 5

< 210 > SEQ ID NO 75

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 » ORGANISM : Artificial Sequence
< 220 > FEATURE :
 US 11,034,762 B1
133 134
- continued
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 75

Trp Ala Tyr Thr Arg Glu Pro

1 5

< 210 > SEQ ID NO 76

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 76

Trp Ala Ser Thr Arg Gly Ser

1 5

< 210 > SEQ ID NO 77

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 77

Trp Ala Ser Thr Arg Ala Ala

1 5

< 210 > SEQ ID NO 78

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 78

Trp Ala Ser Thr Arg Glu Phe

1 5

< 210 > SEQ ID NO 79

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 79

Trp Ala Ser Met Arg Glu Ser

1 5

< 210 > SEQ ID NO 80

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 80

Trp Ala Ser Ser Arg Glu Ser

1 5
 US 11,034,762 B1
135 136
- continued
< 210 > SEQ ID NO 81
< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 81
Arg Ala Ser Thr Arg Ala Ser
1 5

< 210 > SEQ ID NO 82

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 82

Trp Ala Ser Thr Arg Leu Ser

1 5

< 210 > SEQ ID NO 83

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 83

Trp Ala Ser Thr Arg Gly Ser

1 5

< 210 > SEQ ID NO 84

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 84

Trp Ala Ser Thr Arg Glu Pro

1 5

< 210 > SEQ ID NO 85

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 85

Trp Ala Ser Thr Arg Leu Ser

1 5

< 210 > SEQ ID NO 86

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 86
 US 11.034.762 B1
137 138
- continued

Trp Ala Ser Thr Arg Ser Ser

1 5

< 210 > SEQ ID NO 87

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 87

Trp Ala Thr Asn Arg Glu Ser

1 5

< 210 > SEQ ID NO 88

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 88

Trp Ala Ser Phe Arg Glu Ser

1 5

< 210 > SEQ ID NO 89

< 211 > LENGTH : 7
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 89

Trp Ser Ser Leu Arg Glu Ser

1 5

< 210 > SEQ ID NO 90

< 211 > LENGTH : 31
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
polypeptide
< 400 > SEQUENCE : 90

Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15

Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr
20 25 30

< 210 > SEQ ID NO 91

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 220 > FEATURE :
< 221 > NAME /KEY : MOD_RES
< 222 > LOCATION : ( 2 ) .. ( 2 )
< 223 > OTHER INFORMATION : Q , R , or H
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 5 ) .. ( 5 )
< 223 > OTHER INFORMATION : Y , H , or s
 US 11.034.762 B1
139 140
- continued
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 6 ) .. ( 6 )
< 223 > OTHER INFORMATION : S or T
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 7 ) .. ( 7 )
< 223 > OTHER INFORMATION : Tor L
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 9 ) .. ( 9 )
< 223 > OTHER INFORMATION : L , W , or Y

< 400 > SEQUENCE : 91

Cys Xaa Gin Tyr Xaa Xaa Xaa Pro Xaa Thr Phe
1 5 10

< 210 > SEQ ID NO 92

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 92

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 93

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 93

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 94

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 94

Cys Arg Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 95

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 95

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 96

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
 US 11.034.762 B1
141 142
- continued
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 96
Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 97

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 97

Cys Gin Gin Tyr Tyr Ser Thr Pro Leu Thr Phe
1 5 10

< 210 > SEQ ID NO 98

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 98

Cys Gin Gin Tyr Tyr Thr Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 99

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 99

Cys Gin Gin His Tyr Ser Ala Pro Leu Thr Phe
1 5 10

< 210 > SEQ ID NO 100

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 100

Cys Gin Gin Tyr Tyr Ala Leu Pro Leu Thr Phe
1 5 10

< 210 > SEQ ID NO 101

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 101

Cys Gin Gin Tyr Tyr Thr Thr Pro Tyr Thr Phe
1 5 10
 US 11,034,762 B1
143 144
- continued

< 210 > SEQ ID NO 102

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 102

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 103

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 103

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 104

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 104

Cys Gin Gin Tyr Tyr Tyr Ala Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 105

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 105

Cys Arg Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 106

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 106

Cys Gin Gin Tyr Tyr Ser Thr Pro Pro Thr Phe
1 5 10

< 210 > SEQ ID NO 107

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
 US 11.034.762 B1
145 146
- continued
< 400 > SEQUENCE : 107

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 108

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 108

Cys Gin Gin Tyr Tyr Gly Phe Pro Leu Thr Phe
1 5 10

< 210 > SEQ ID NO 109

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 109

Cys His Gin Tyr Tyr Ser Thr Pro Pro Thr Phe
1 5 10

< 210 > SEQ ID NO 110

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 110

Cys Gin Gin Tyr Tyr Ser Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 111

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 111

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 112

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 112

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 113

< 211 > LENGTH : 11
< 212 > TYPE : PRT
 US 11,034,762 B1
147 148
- continued
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 113

Cys Gin Gin Tyr His Thr Ile Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 114

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 114

Cys Gin Gin Tyr Tyr Ala Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 115

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 115

Cys Gin Gin Tyr Tyr Lys Ile Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 116

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 116

Cys Gin Gin Tyr Tyr Thr Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 117

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 117

Cys Arg Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 118

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 118

Cys Gin Gin Tyr His Ser Thr Pro Leu Thr Phe
1 5 10
 US 11,034,762 B1
149 150
- continued

< 210 > SEQ ID NO 119

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 119

Cys Gin Gin Tyr Tyr Ser Leu Pro Leu Thr Phe
1 5 10

< 210 > SEQ ID NO 120

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 120

Cys Gin Gin Tyr Tyr Ser Thr Pro Val Thr Phe
1 5 10

< 210 > SEQ ID NO 121

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 121

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 122

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 122

Cys Gin Gin Tyr Ser Thr Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 123

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 123

Cys Gin Gin Tyr Tyr Lys Ile Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 124

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
 US 11,034,762 B1
151 152
- continued

< 400 > SEQUENCE : 124

Cys Gin Gin Tyr His Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 125

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 125

Cys Gin Gin Tyr Ser Thr Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 126

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 126

Cys His Gin Tyr Tyr Thr Thr Pro Pro Thr Phe
1 5 10

< 210 > SEQ ID NO 127

5211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 127

Cys Gin Gin Tyr Tyr Ser Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 128

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 128

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 129

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 129

Cys Gin Gin Tyr Tyr Ser Thr Val Ile Thr Phe
1 5 10

< 210 > SEQ ID NO 130

< 211 > LENGTH : 11
 US 11,034,762 B1
153 154
- continued
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 130

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 131

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 131

Cys Gin Gin Tyr Tyr Ser Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 132

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 132

Cys Gin Gin Tyr Tyr Ser Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 133

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 133

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Ti Phe
1 5 10

< 210 > SEQ ID NO 134

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 134

Cys Gin Gin Tyr His Ser Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 135

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 135

Cys Gin Gin Tyr Tyr Gly Thr Pro Phe Thr Phe
 US 11.034.762 B1
155 156
- continued
1 5 10

< 210 > SEQ ID NO 136

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 136

Cys Gin Gin Tyr Tyr Ser Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 137

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 137

Cys Gin Gin Tyr Ser Ser Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 138

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 138

Cys Gin Gin Tyr Tyr Ser Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 139

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of tificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 139

Cys Gin Gin Tyr His Ser Thr Pro Leu Thr Phe
1 5 10

< 210 > SEQ ID NO 140

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 140

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 141

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
 US 11,034,762 B1
157 158
- continued
peptide
< 400 > SEQUENCE : 141

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 142

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 142

Cys Arg Gin Tyr Tyr Ser Thr Pro Trp Thr Phe
1 5 10

< 210 > SEQ ID NO 143

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 143

Cys His Gin Tyr Tyr Asn Thr Pro Pro Thr Phe
1 5 10

< 210 > SEQ ID NO 144

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 144

Cys Gin Gin Tyr Tyr Ser Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 145

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 145

Cys Gin Gin Ser Tyr Ile Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 146

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 146

Cys Gin His Tyr Tyr Asn Thr Pro Leu Thr Phe
1 5 10

< 210 > SEQ ID NO 147

 US 11,034,762 B1
159 160
- continued
< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 147

Cys Gin Gin Tyr Tyr Gly Ile Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 148

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 148

Cys Gin Gin Tyr Leu Ser Thr Pro Leu Thr Phe
1 5 10

< 210 > SEQ ID NO 149

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 149

Cys Gin Gin Tyr His Ser Thr Pro Tyr Thr Phe
1 5 10

< 210 > SEQ ID NO 150

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 150

Cys Gin Gin Tyr Tyr Thr Ala Pro Phe Thr Phe
1 5 10

< 210 > SEQ ID NO 151

< 211 > LENGTH : 11
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 151

Cys Gin Gin Tyr Leu Ser Thr Pro Leu Thr Phe
1 5 10

< 210 > SEQ ID NO 152

< 211 > LENGTH : 10
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 152
 US 11,034,762 B1
161 162
- continued
Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
1 5 10

< 210 > SEQ ID NO 153

< 211 > LENGTH : 26
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 153

Gin Val Gin Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly
20 25

< 210 > SEQ ID NO 154

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 1 ) .. ( 1 )
< 223 > OTHER INFORMATION : Gor Y
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 2 ) .. ( 2 )
< 223 > OTHER INFORMATION : Gor T
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 4 ) .. ( 4 )
< 223 > OTHER INFORMATION : I , S , or T
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 5 ) .. ( 5 )
< 223 > OTHER INFORMATION : D , S , T , or N
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 6 ) .. (6 )
< 223 > OTHER INFORMATION : H or Y
< 220 > FEATURE :
< 221 > NAME /KEY : MOD_RES
< 222 > LOCATION : ( 7 ) .. ( 7 )
< 223 > OTHER INFORMATION : A , W , G , or H
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 9 ) .. ( 9 )
< 223 > OTHER INFORMATION : G , H , or s

< 400 > SEQUENCE : 154

Xaa Xaa Phe Xaa Xaa Xaa Xaa Ile Xaa

1 5

< 210 > SEQ ID NO 155

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 155

Gly Thr Phe Ser Ser Tyr Ala Ile Ser

1 5

< 210 > SEQ ID NO 156

< 211 > LENGTH : 9
 US 11,034,762 B1
163 164
- continued
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 156

Gly Thr Phe Ser Asn His Ala Ile Ser

1 5

< 210 > SEQ ID NO 157

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 157

Tyr Thr Phe Thr Gly His Tyr Met His

1 5

< 210 > SEQ ID NO 158

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 158

Gly Thr Phe Ile Thr Tyr Trp Ile Tyr

1 5

< 210 > SEQ ID NO 159

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 159

Tyr Thr Phe Thr Asp Tyr Tyr is

1 5

< 210 > SEQ ID NO 160

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 160

Tyr Ser Phe Ser Asp Tyr His Val His

1 5

< 210 > SEQ ID NO 161

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 161

Gly Thr Phe Ile Thr Tyr Trp Ile Gly

 US 11.034.762 B1
165 166
- continued
1 5

< 210 > SEQ ID NO 162

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 162

Gly Thr Phe Asn Ser His Ala Ile Ser

1 5

< 210 > SEQ ID NO 163

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 163

Gly Thr Phe Ser Asn Ser Ser Ile Asn

1 5

< 210 > SEQ ID NO 164

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 164

Tyr Thr Phe Ser Thr Tyr Trp Ile Gly

1 5

< 210 > SEQ ID NO 165

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of tificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 165

Tyr Thr Phe Thr Asn Tyr Gly Ile Asn

1 5

< 210 > SEQ ID NO 166

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 166

Tyr Thr Phe Thr Gly His Tyr Met His

1 5

< 210 > SEQ ID NO 167

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
 US 11,034,762 B1
167 168
- continued
peptide
< 400 > SEQUENCE : 167

Tyr Thr Phe Thr Asn Tyr Gly Ile Asn

1 5

< 210 > SEQ ID NO 168

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 168

Tyr Gly Phe Ile Thr Tyr Trp Ile Gly

1 5

< 210 > SEQ ID NO 169

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 169

Tyr Thr Phe Thr Ser Tyr Gly Ile Ser

1 5

< 210 > SEQ ID NO 170

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 170

Gly Thr Phe Ser Thr Tyr Ala Phe Asn

1 5

< 210 > SEQ ID NO 171

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 171

Gly Gly Phe Ile Thr Tyr Trp Ile Gly

1 5

< 210 > SEQ ID NO 172

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 172

Gly Gly Phe Ser Thr Tyr Trp Ile Gly

1 5

< 210 > SEQ ID NO 173

 US 11,034,762 B1
169 170
- continued
< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 173

Tyr Arg Phe Thr Asp Tyr His Leu His

1 5

< 210 > SEQ ID NO 174

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 174

Tyr Ser Phe Thr Asp Tyr His Ile His

1 5

< 210 > SEQ ID NO 175

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 175

Tyr Ser Phe Ser Asp Tyr Tyr Ile His

1 5

< 210 > SEQ ID NO 176

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 176

Tyr Pro Phe Thr Asn Tyr Gly Ile Ser

1 5

< 210 > SEQ ID NO 177

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 177

Tyr Gly Phe Ile Ser Tyr Trp Ile Gly

1 5

< 210 > SEQ ID NO 178

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 178
 US 11.034.762 B1
171 172
- continued
Gly Thr Phe Ser Asn Asn Gly Leu Ser
1 5

< 210 > SEQ ID NO 179

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 179

Gly Thr Phe Ile Thr Tyr Trp Ile Gly

1 5

< 210 > SEQ ID NO 180

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 180

Tyr Gly Phe Ile Ser Tyr Trp Ile Gly

1 5

< 210 > SEQ ID NO 181

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 181

Gly Thr Phe Ile Ser Tyr Ala Ile Ser

1 5

< 210 > SEQ ID NO 182

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 182

Tyr Gly Phe Ser Thr Tyr Trp Ile Gly

1 5

< 210 > SEQ ID NO 183

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 183

Tyr Thr Phe Thr Asn Tyr Gly Ile Asn

1 5

< 210 > SEQ ID NO 184

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 » ORGANISM : Artificial Sequence
< 220 > FEATURE :
 US 11.034.762 B1
173 174
- continued
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 184

Gly Thr Leu Ser Ser Tyr Ala Ile Ser

1 5

< 210 > SEQ ID NO 185

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 185

Tyr Asn Phe Thr Asp Tyr His Ile Gln

1 5

< 210 > SEQ ID NO 186

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 186

Gly Thr Phe Ser Ser Tyr Ala Ile Asn

1 5

< 210 > SEQ ID NO 187

< 211 > LENGTH : 9
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 187

Gly Gly Phe Ile Thr Tyr Trp Ile Ser

1 5

< 210 > SEQ ID NO 188

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 188

Trp Val Arg Gln Ala Pro Gly Gin Gly Leu Glu Trp Met
1 5 10

< 210 > SEQ ID NO 189

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 189

Trp Val Arg Gln Ala Pro Gly Gin Gly Leu Glu Trp Val
1 5 10
 US 11,034,762 B1
175 176
- continued
< 210 > SEQ ID NO 190
< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 220 > FEATURE :
< 221 > NAME /KEY : MOD_RES
< 222 > LOCATION : ( 2 ) .. ( 2 )
< 223 > OTHER INFORMATION : G , I , or W
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 3 ) .. ( 3 )
< 223 > OTHER INFORMATION : I or M
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 4 ) .. ( 4 )
< 223 > OTHER INFORMATION : I , N , or Y
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 6 ) .. ( 6 )
< 223 > OTHER INFORMATION : G , N , or R
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 7 ) .. ( 7 )
< 223 > OTHER INFORMATION : D , G , or s
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 8 ) .. ( 8 )
< 223 > OTHER INFORMATION : G or S
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 9 ) .. ( 9 )
< 223 > OTHER INFORMATION : Any amino acid or not present
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 10 ) .. ( 10 )
< 223 > OTHER INFORMATION : A or T
< 220 > FEATURE :
< 221 > NAME /KEY : MOD_RES
< 222 > LOCATION : ( 11 ) .. ( 11 )
< 223 > OTHER INFORMATION : G , N , or R
< 220 > FEATURE :
< 221 > NAME / KEY : MOD_RES
< 222 > LOCATION : ( 13 ) .. ( 13 )
< 223 > OTHER INFORMATION : A or S

< 400 > SEQUENCE : 190

Gly Xaa Xaa Xaa Pro Xaa Xaa Xaa Xaa Xaa Xaa Tyr Xaa
1 5 10

< 210 > SEQ ID NO 191

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 191

Gly Ile Ile Tyr Pro Gly Asp Ser Thr Thr Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 192

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 192

Gly Ile Ile Asp Pro Ser Gly Gly Ser Thr Ser Tyr Ala
 US 11.034.762 B1
177 178
- continued
1 5 10

< 210 > SEQ ID NO 193

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 193

Gly Ile Ile Tyr Pro Gly Asp Ser Thr Thr Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 194

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 194

Gly Ile Ile Tyr Pro Gly Asp Gly Thr Thr Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 195

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 195

Gly Ile Ile Tyr Pro Gly Asp Ser Glu Ala Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 196

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of tificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 196

Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Asn Tyr Ala
1 5 10

< 210 > SEQ ID NO 197

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 197

Gly Ile Ile Tyr Pro Gly Asp Gly Glu Ala Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 198

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
 US 11,034,762 B1
179 180
- continued
peptide
< 400 > SEQUENCE : 198
Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala
1 5 10

< 210 > SEQ ID NO 199

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 199

Gly Met Ile Ile Pro Arg His Gly Gly Thr Ala Tyr Ala
1 5 10

< 210 > SEQ ID NO 200

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 200

Gly Ile Ile Tyr Pro Gly Asp Gly Glu Ala Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 201

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 201

Gly Trp Ile Asn Pro Asn Ser Gly Ala Thr Asn Tyr Ala
1 5 10

< 210 > SEQ ID NO 202

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 202

Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala
1 5 10

< 210 > SEQ ID NO 203

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 203

Gly Ser Val Ile Pro Val Phe Gly Arg Pro Asn Tyr Ala
1 5 10

< 210 > SEQ ID NO 204

 US 11,034,762 B1
181 182
- continued
< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 204

Gly Trp Ile Asp Pro Asn Ser Gly Gly Thr Asn Tyr Ala
1 5 10

< 210 > SEQ ID NO 205

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 205

Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala
1 5 10

< 210 > SEQ ID NO 206

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 206

Gly Ile Ile Tyr Pro Gly Asp Ser Glu Ala Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 207

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 207

Gly Met Ile Asn Pro Gly Gly Gly Asn Thr Asn Tyr Ala
1 5 10

< 210 > SEQ ID NO 208

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 208

Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala
1 5 10

< 210 > SEQ ID NO 209

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 209
 US 11,034,762 B1
183 184
- continued
Gly Ile Ile Tyr Pro Gly Asp Gly Glu Thr Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 210

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 210

Gly Ile Ile Tyr Pro Gly Asp Gly Thr Thr Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 211

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 211

Gly Val Ile Asn Thr Gly Gly Gly Ser Val Thr Tyr Ala
1 5 10

< 210 > SEQ ID NO 212

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 212

Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ala
1 5 10

< 210 > SEQ ID NO 213

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 213

Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 214

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 214

Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 215

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 » ORGANISM : Artificial Sequence
< 220 > FEATURE :
 US 11,034,762 B1
185 186
- continued
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 215

Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 216

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 216

Gly Trp Ile Asn Pro Asn Ser Gly Ala Thr Lys Tyr Ala
1 5 10

< 210 > SEQ ID NO 217

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 217

Gly Gly Ile Ile Pro Thr Leu Gly Thr Ala Asn Tyr Ala
1 5 10

< 210 > SEQ ID NO 218

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 218

Gly Gly Ile Val Pro Phe Ser Gly Thr Thr Asn Phe Ala
1 5 10

< 210 > SEQ ID NO 219

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 219

Ala Met Ile Val Pro Arg Gly Gly Ser Thr Thr Tyr Ala
1 5 10

< 210 > SEQ ID NO 220

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 220

Gly Trp Ile Asp Pro Asn Ser Gly Gly Thr Asn Tyr Ala
1 5 10
 US 11,034,762 B1
187 188
- continued
< 210 > SEQ ID NO 221
< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 221

Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ala
1 5 10

< 210 > SEQ ID NO 222

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 222

Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ala
1 5 10

< 210 > SEQ ID NO 223

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 223

Gly Ile Ile Tyr Pro Gly Asp Ser Thr Thr Asn Tyr Ser
1 5 10

< 210 > SEQ ID NO 224

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 224

Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Asn Tyr Ser
1 5 10

< 210 > SEQ ID NO 225

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 225

Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala
1 5 10

< 210 > SEQ ID NO 226

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 226
 US 11,034,762 B1
189 190
- continued

Gly Ile Ile Tyr Pro Gly Asp Gly Glu Thr Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 227

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 227

Gly Ile Ile Tyr Pro Gly Asp Ser Thr Thr Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 228

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 228

Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala
1 5 10

< 210 > SEQ ID NO 229

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 229

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala
1 5 10

< 210 > SEQ ID NO 230

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 230

Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 231

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 231

Gly Ile Ile Tyr Pro Gly Asp Gly Glu Thr Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 232

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
 US 11,034,762 B1
191 192
- continued
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 232

Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala
1 5 10

< 210 > SEQ ID NO 233

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 233

Gly Ile Ile Tyr Pro Gly Asp Gly Glu Ala Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 234

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 234

Gly Val Ile Asn Thr Gly Gly Gly Ser Val Thr Tyr Ala
1 5 10

< 210 > SEQ ID NO 235

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 235

Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 236

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 236

Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 237

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 237

Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ser
1 5 10
 US 11,034,762 B1
193 194
- continued

< 210 > SEQ ID NO 238

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 238

Gly Gly Ile Ile Pro Thr Leu Gly Thr Tyr Asn Tyr Ala
1 5 10

< 210 > SEQ ID NO 239

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 239

Gly Gin Ile Asn Pro Ser Gly Asp Ser Thr Arg Tyr Ala
1 5 10

< 210 > SEQ ID NO 240

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 240

Gly Ile Ile Tyr Pro Gly Asp Ser Thr Ala Arg Tyr Ser
1 5 10

< 210 > SEQ ID NO 241

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 241

Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala
1 5 10

< 210 > SEQ ID NO 242

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide
< 400 > SEQUENCE : 242

Gly Trp Met Asn Pro Tyr Ser Gly Asn Thr Gly Tyr Ala
1 5 10

< 210 > SEQ ID NO 243

< 211 > LENGTH : 13
< 212 > TYPE : PRT
< 213 > ORGANISM : Artificial Sequence
< 220 > FEATURE :
< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic
peptide