Regulated Biocircuit Systems

  • Published: Dec 14, 2017
  • Earliest Priority: Apr 11 2016
  • Family: 5
  • Cited Works: 0
  • Cited by: 0
  • Cites: 5
  • Sequences: 213455
  • Additional Info: Full text

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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property

Organization
International Bureau

(10) International Publication Number

(43) International Publication Date

19 October 2017 (19.10.2017)

W !P O

(51) International Patent Classification:
C07K 14/705 (2006.01)
CI 2N 5/10 (2006.01)
C07K 19/00 (2006.01)
C12N 15/62 (2006.01)
C12N 5/0783 (2010.01)
(21) International Application Number:
PCT/US20 17/026950
(22) International Filing Date:
11 April 2017 ( 1 1.04.2017)

(25) Filing Language:

English

(26) Publication Langi

English

(30) Priority Data:
62/320,864
62/466,596

11 April 2016 ( 1 1.04.2016)
03 March 2017 (03.03.2017)

US
US

(71) Applicant: OBSIDIAN THERAPEUTICS,
INC.
[US/US]; 1030 Massachusetts Avenue, Fourth Floor, Cam
bridge, MA 02138 (US).
(72) Inventors: BARRETT, Peter; 400 Technology Square,
10th Floor, Cambridge, MA 02139 (US). GLADSTONE,
Michael, N.; 400 Technology Square, 10th Floor, Cam
bridge, MA 02139 (US). KASSUM, Tariq, A.; 1030 Mass
achusetts Avenue, Fourth Floor, Cambridge, MA 02138
(US). SURI, Vipin; 3 Coolidge Road, Belmont, MA
02478 (US). LI, Dan, Jun; 1030 Massachusetts Avenue,
Fourth Floor, Cambridge, MA 02138 (US). SUN, Dexue;
1030 Massachusetts Avenue, Fourth Floor, Cambridge, MA
02138 (US). DOLINSKI, Brian; 1030 Massachusetts Av
enue, Fourth Floor, Cambridge, MA 02138 (US).
(74) Agent: WARD, Donna, T. et al; DT Ward, P.C. 142A
Main Street, Groton, MA 01450 (US).
(81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,

(54) Title: REGULATED BIOCIRCUIT SYSTEMS

PCT

WO 2017/180587 A3
AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ,
CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO,
DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR,
KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM,
PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC,
SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.

(84) Designated States (unless otherwise indicated, for every
kind of regional protection available): ARIPO (BW, GH,
GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ,
UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
KM, ML, MR, NE, SN, TD, TG).
Published:
— with international search report (Art. 21(3))
— before the expiration of the time limit for amending the
claims and to be republished in the event of receipt of
amendments (Rule 48.2(h))
— with sequence listing part of description (Rule 5.2(a))
(88) Date of publication of the international search report:
14 December 2017 (14. 12.2017)

INTERNATIONAL SEARCH REPORT

International application No.
PCT/US20 17/026950

A.

CLASSIFICATION

O F SUBJECT

MATTER

IPC(8) - C07K 14/705; C07K 19/00; C 1 2 N 5/0783; C 1 2 N 5/1 0 ; C 1 2 N 15/62 (201 7.01 )
CPC -

C07K 14/705; C07K 231 9/00; C07K 231 9/03; C07K 2319/70; C 1 2 N 5/0636; C 1 2 N 251 0/00
(201 7.08)

According

to International

B.

Patent Classification

(IPC) o r to both national classification

and IPC

FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols)
See Search History document
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
USPC - 424/93.21; 435/375; 514/1 .1; 536/23.4 (keyword delimited)
Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
See Search History document
C.

DOCUMENTS CONSIDERED

Category*

I Further

TO BE RELEVANT

Citation of document, with indication, where appropriate, of the relevant passages

Relevant to claim No.

WO 2015/142675 A2 (NOVARTIS AG e t al) 24 September 2015 (24.09.2015) entire document

53, 55-57, 66, 67, 70

US 2014/0010791 A 1 (THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR
UNIVERSITY) 09 January 2014 (09.01.2014) entire document

1, 4 , 21, 36-40, 47-49, 53,
55-59, 66, 67, 69a, 69b,
70

WO 2016/012623 A 1 (THERAVECTYS e t al) 28 January 2016 (28.01.2016) entire document

1, 4 , 21, 36-40, 47-49, 53,
55-59, 66, 67, 69a, 69b,
70

WO 2015/150771 A 1 (UCL BUSINESS PLC) 08 October 2015 (08.10.2015) entire document

1, 4 , 21, 36-40, 47-49, 53,
55-59, 66, 67, 69a, 69b,
70

US 2012/0178168 A 1 (WANDLESS et al) 12 July 2012 (12.07.2012) entire document

1, 4 , 2 1 , 36-40, 47-49, 53,
55-59, 66, 67, 69a, 69b,
70

documents are listed in the continuation of Box C .

[

|

See patent family annex.

*
Special categories of cited documents:
"A" document defining the general state of the art which is not considered
to be of particular relevance
"E" earlier application or patent but published on or after the international
filing date
"L" document which may throw doubts on priority claim(s) or which is
cited to establish the publication date of another citation or other
special reason (as specified)
"O" document referring to an oral disclosure, use, exhibition or other
means
"P" document published prior to the international filing date but later than
the priority date claimed

"V

Date o f the actual completion o f the international search

Date of mailing o f the international search report

03 October 2017
Name and mailing address o f the ISA/US
Mail Stop PCT, Attn: ISA/US, Commissioner for Patents

P.O. Box 1450, Alexandria, VA 22313-1450
Facsimile No. 571-273-8300
Form PCT/lSA/2 10 (second sheet) (January 2015)

later document published after the international filing date or priority
date and not in conflict with the application but cited to understand
the principle or theory underlying the invention

"X" document of particular relevance; the claimed invention cannot be
considered novel or cannot be considered to involve an inventive
step when the document is taken alone
"Y" document of particular relevance; the claimed invention cannot be
considered to involve an inventive step when the document is
combined with one or more other such documents, such combination
being obvious to a person skilled in the art
"&" document member of the same patent family

2 4 OCT

2017

Authorized officer
Blaine R. Copenheaver

INTERNATIONAL SEARCH REPORT

International application No.
PCT/US201 7/026950

Box No. I

Nucleotide and/or amino acid sequence(s) (Continuation

of item l.c of the first sheet)

With regard to any nucleotide and/or amino acid sequence disclosed in the international application, the international search was
carried out on the basis of a sequence listing:
forming part of the international application as filed:
in the form of an Annex C/ST.25 text file.

on paper or in the form of an image file.

I I furnished together with the international application under PCT Rule ]3ler. 1(a) for the purposes of international search
only in the form of an Annex C/ST.25 text file.
furnished subsequent to the international filing date for the purposes of international search only:
in the form of an Annex C/ST.25 text file (Rule 3 r. 1(a)).

I I on paper or in the form of an image file (Rule 13

r . 1(b) and Administrative Instructions, Section 713).

In addition, in the case that more than one version or copy of a sequence listing has been filed or furnished, the required
statements that the information in the subsequent or additional copies is identical to that forming part of the application as
filed or does not go beyond the application as filed, as appropriate, were furnished.

3. Additional comments:

SEQ

ID NO:1 , 2,

102 5, and 102452 were searched.

Form PCT/lSA/2 10 (continuation of first sheet (1)) (January 201 5)

INTERNATIONAL SEARCH REPORT

International

application No.

PCT/US2017/026950
Box No. I I

Observations

where certain claims were found unsearchable

(Continuation

of item 2 of first sheet)

This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:
1.

1 Claims

Nos.:
because they relate to subject matter not required to be searched by this Authority, namely:

□

Claims Nos.:
because they relate to parts of the international application that do not comply with the prescribed requirements
extent that no meaningful international search can be carried out, specifically:

3. 12SI Claims Nos.: 8-20, 50-52, 68
because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule
Box No. Ill

Observations

where unity of invention

is lacking (Continuation

to such an

6 .4(a).

of item 3 of first sheet)

This International Searching Authority found multiple inventions in this international application, as follows:
See extra sheet(s).

As all required additional search fees were timely paid by the applicant, this international search report covers all searchable
claims.
As all searchable claims could be searched without effort justifying additional fees, this Authority did not invite payment o f
additional fees.
A s only some o f the required additional search fees were timely paid by the applicant, this international search report covers
only those claims for which fees were paid, specifically claims Nos.:

No required additional search fees were timely paid by the applicant. Consequently,
restricted to the invention first mentioned in the claims; it is covered by claims Nos.:

this international

search report is

1, 4 , 21, 36-40, 47-49, 53, 55-59, 66, 67, 69a, 69b, and 70 to the extent that they read on a n effector module comprising a first
component and a second component, wherein the first component is a stimulus response element selected to be SEQ ID NO:1
(encoded by SEQ ID NO: 102451); wherein the second component is a payload construct selected to be SEQ ID NO:2
(encoded by SEQ ID NO: 102452).
Remark o n Protest

□
□
□

Form PCT/ISA/2 10 (continuation

The additional search fees were accompanied by the applicant's
payment of a protest fee.

protest and, where applicable, the

The additional search fees were accompanied by the applicant's protest but the applicable protest
fee was not paid within the time limit specified in the invitation.
No protest accompanied the payment o f additional search fees.

o f first sheet (2)) (January 201 5)

INTERNATIONAL SEARCH REPORT

International application No.
PCT/US201 7/026950

Continued from Box No. Ill Observations where unity of invention is lacking

This application contains the following inventions or groups of inventions which are not so linked as to form a single general inventive
concept under PCT Rule 13.1. In order for all inventions to be examined, the appropriate additional examination fees need to be paid.
Group l+: claims 1-7, 21-49, 53-67, 69a, 69b, and 70 are drawn to effector modules, and biocircuit systems, polynucleotides, methods,
and T cells comprising the same.

The first invention of Group l+ is restricted to an effector modules, and biocircuit systems, polynucleotides, methods, and T cells
comprising the same, wherein the effector module comprises a first component and a second component, wherein the first component is
a stimulus response element selected to be SEQ ID NO:1 (encoded by SEQ ID NO: 102 51); wherein the second component is a
payload construct selected to be SEQ ID NO:2 (encoded by SEQ ID NO: 102452). It is believed that claims 1, 4 , 2 1 , 36-40, 47-49, 53,
55-59, 66, 67, 69a, 69b, and 70 read on this first named invention and thus these claims will be searched without fee to the extent that
they read on an effector module comprising SEQ ID NO:1, SEQ D NO:2, SEQ ID NO:102451 and/or SEQ ID NO:102452.
Applicant is invited to elect additional stimulus response elements and/or payload constructs and/or targets of a ligand binding partner
pairs and/or antibody regions, each with a specified SEQ ID NO to be searched in a specific combination for each effector module by
paying an additional fee for each set of election. An exemplary election would be an effector modules, and biocircuit systems,
polynucleotides, methods, and T cells comprising the same, wherein the effector module comprises a first component and a second
component, wherein the first component is a stimulus response element selected to be SEQ ID NO:3 (encoded by SEQ ID NO: 102453);
wherein the second component is a payload construct selected to be SEQ ID NO:4 (encoded by SEQ ID NO: 102454). Additional
effector modules will be searched upon the payment of additional fees. Applicants must specify the claims that read on any additional
elected inventions. Applicants must further indicate, if applicable, the claims which read on the first named invention if different than
what was indicated above for this group. Failure to clearly identify how any paid additional invention fees are to be applied to the "+"
group(s) will result in only the first claimed invention to be searched/examined.

The inventions listed in Groups l+ do not relate to a single general inventive concept under PCT Rule 13.1, because under PCT Rule
13.2 they lack the same or corresponding special technical features for the following reasons:
The Groups l+ formulas do not share a significant structural element for treating a disease or disorder in a subject, requiring the
selection of alternatives for the stimulus response elements and/or payload constructs and/or targets of a ligand binding partner pairs
and/or antibody regions, where "said payload having a sequence selected from the group consisting of SEQ ID NO: 1-102450, and
212852-213270; one or more regions derived from a Target of a ligand binding partner pair listed in Table 2 or Table 3; one or more
regions derived from an antibody listed in Table 5; or an SRE listed in Table 4".
The Groups l+ share the technical features of a biocircuit system comprising an effector module, said effector module comprising (a) a
first component and a second component wherein each of said first said second component is independently selected from the group
consisting of a peptide, peptide complex, peptide-protein complex, protein, fusion protein, protein complex, protein-protein complex, and
wherein said first component is a stimulus response element (SRE) comprising (i) one or more regions derived from a payload, said
payload having a sequence (ii) one or more regions derived from a Target of a ligand binding partner pair (iii) one or more regions
derived from an antibody; or (iv) an SRE, and wherein said second component is a payload construct comprising ( ') a payload, said
payload having a sequence or functional fragment thereof; ( ') a Target of a ligand binding partner pair or functional fragment thereof; or
(iii') an antibody or a functional fragment thereof; and wherein said effector module is responsive to at least one stimulus; a
polynucleotide comprising: (a) a first region encoding a stimulus response element (SRE) selected from the group consisting of a
peptide, a peptide complex, a peptide-protein complex, a protein, a fusion protein, a protein complex, and a protein-protein complex,
said SRE comprising; (i) one or more regions derived from a payload, said payload having a sequence; (ii) one or more regions derived
from a Target of a ligand binding partner pair; or (iii) an SRE and (b) a second region encoding one or more payload constructs and
wherein said a payload construct comprises ( ') a payload, said payload having a sequence or ( ') an antibody or a functional fragment
thereof; and (c) optionally, a third region encoding at least one member of the group consisting of a linker, modifier, signal sequence;
binding domain, regulatory motif, dimerization domain, and cleavage site; a regulatable human T cell or T cell population engineered to
express an effector module; a method of producing a regulatable human T-cell or population thereof, the method comprising, (a)
contacting an isolated population of T-cells with a polynucleotide encoding one or more effector modules such that the effector module
can be expressed in the contacted population; (b) causing the level of the payload encoded by said one or more effector modules to be
modulated upon exposure of the expressed effector module with one or more stimuli; a multi-tuned effector module comprising, (a) a first
component and a second component wherein each of said first said second component is independently selected from the group
consisting of a peptide, peptide complex, peptide-protein complex, protein, fusion protein, protein complex, protein-protein complex, and
wherein said first component is a stimulus response element (SRE) comprising (i) one or more regions derived from a payload, said
payload having a sequence (ii) one or more regions derived from a Target of a ligand binding partner pair; (iii) one or more regions
derived from an antibody; or (iv) an SRE, and wherein said second component is a payload construct comprising ( ') a payload, said
payload having a sequence or functional fragment thereof; ( ') a Target of a ligand binding partner pair or functional fragment thereof; or
(iii') an antibody or a functional fragment thereof; wherein said payload construct comprises a polypeptide variant which comprises (1) a
cleavage motif; or (2) one or more insertions, deletions, substitutions, additions, or covalent modifications; and wherein said multi-tuned
effector module is responsive to at least one stimulus; a biocircuit system having an effector module comprising an organizational
pattern. However, these shared technical features do not represent a contribution over the prior art.
Specifically, US 20140010791 A1, to The Board of Trustees of the Leland Stanford Junior University discloses a biocircuit system
comprising an effector module (Methods and compositions for the rapid and reversible destabilizing of specific proteins in vivo using
cell-permeable, synthetic molecules are described, Abstract), said effector module comprising (a) a first component and a second

Form PCT/ISA/210 (extra sheet) (January 2015)

INTERNATIONAL SEARCH REPORT

International application No.
PCT/US20 17/026950

component wherein each of said first said second component is independently selected from the group consisting of a peptide, peptide
complex, peptide-protein complex, protein, fusion protein, protein complex, protein-protein complex (a protein of interest fused to a
single-polypeptide chain, ligand-dependent, stability-affecting protein derived from a naturally-occurring ligand binding protein, and a
ligand that binds to the stability-affecting protein to modulate stability of the stability-affecting protein, Para. [0013]), and wherein said first
component is a stimulus response element (SRE) (levels of fluorescence of various YFP-FKBP fusion proteins (i.e., C-terminal FKBP
mutants) in response to different concentrations of Shield 1, Para. [0082]) comprising (i) one or more regions derived from a payload,
said payload having a sequence (targeted-delivery of a conditionally stabilized protein, Para. [0095]) and wherein said second
component is a payload construct comprising ( ') a payload, said payload having a sequence or functional fragment thereof (introducing
into a eukaryotic cell a nucleic acid comprising a polynucleotide which encodes a fusion protein wherein the fusion protein comprises a
secreted protein fused to a single-polypeptide chain, ligand-dependent, stability-affecting FKBP variant protein, Claim 1; These
observations suggested that Shieldl addition produced a tunable, dose-dependent secretion of a cytokine in vivo, Para. [0163]); and
wherein said effector module is responsive to at least one stimulus (levels of fluorescence of various YFP-FKBP fusion proteins (i.e.,
C-terminal FKBP mutants) in response to different concentrations of Shieldl, Para. [0082]), a polynucleotide (polynucleotide, Para.
[0154]) comprising: (a) a first region encoding a stimulus response element (SRE) selected from the group consisting of a peptide, a
peptide complex, a peptide-protein complex, a protein, a fusion protein, a protein complex, and a protein protein complex (polynucleotide
sequences encoding the FKBP L106P stability-affecting protein were fused to polynucleotides corresponding to the N-terminus of a
thermostable luciferase to obtain the chimeric gene L106P-tsLuc, which was stably integrated into HCT1 16 colon cancer cell, Para.
[0154]), said SRE comprising; (i) one or more regions derived from a payload, said payload having a sequence (introducing into a
eukaryotic cell a nucleic acid comprising a polynucleotide which encodes a fusion protein wherein the fusion protein comprises a
secreted protein fused to a single-polypeptide chain, ligand-dependent, stability-affecting FKBP variant protein, Claim 1; These
observations suggested that Shieldl addition produced a tunable, dose-dependent secretion of a cytokine in vivo, Para. [0163]); a
multi-tuned effector module (Methods and compositions for the rapid and reversible destabilizing of specific proteins in vivo using
cell-permeable, synthetic molecules are described, Abstract) comprising, (a) a first component and a second component wherein each of
said first said second component is independently selected from the group consisting of a peptide, peptide complex, peptide-protein
complex, protein, fusion protein, protein complex, protein-protein complex (a protein of interest fused to a single-polypeptide chain,
ligand-dependent, stability-affecting protein derived from a naturally-occurring ligand binding protein, and a ligand that binds to the
stability-affecting protein to modulate stability of the stability-affecting protein, Para. [0013]), and wherein said first component is a
stimulus response element (SRE) (levels of fluorescence of various YFP-FKBP fusion proteins (i.e., C-terminal FKBP mutants) in
response to different concentrations of Shieldl, Para. [0082]) comprising (i) one or more regions derived from a payload
(targeted-delivery of a conditionally stabilized protein, Para. [0095]), said payload having a sequence (introducing into a eukaryotic cell a
nucleic acid comprising a polynucleotide which encodes a fusion protein wherein the fusion protein comprises a secreted protein fused
to a single-polypeptide chain, ligand-dependent, stability-affecting FKBP variant protein, Claim 1; These observations suggested that
Shieldl addition produced a tunable, dose-dependent secretion of a cytokine in vivo, Para. [0163]), and wherein said second component
is a payload construct comprising (i') a payload, said payload having a sequence or functional fragment thereof (introducing into a
eukaryotic cell a nucleic acid comprising a polynucleotide which encodes a fusion protein wherein the fusion protein comprises a
secreted protein fused to a single-polypeptide chain, ligand-dependent, stability-affecting FKBP variant protein, Claim 1; These
observations suggested that Shieldl addition produced a tunable, dose-dependent secretion of a cytokine in vivo, Para. [0163]) wherein
said payload construct comprises a polypeptide variant (levels of fluorescence of various YFP-FKBP fusion proteins (i.e., C-terminal
FKBP mutants) in response to different concentrations of Shieldl , Para. [0082]) which comprises ( 1 ) a cleavage motif; or (2) one or more
insertions, deletions, substitutions, additions, or covalent modifications; and wherein said multi-tuned effector module is responsive to at
least one stimulus (wDD was used to deliver a conditionally stable interleukin-2 (IL-2) protein. A n L-L106P-IL-2 chimeric gene was
inserted into a strain of wDD constitutively expressing luciferase, Para. [01 70]; levels of fluorescence of various YFP-FKBP fusion
proteins (i.e., C-terminal FKBP mutants) in response to different concentrations of Shieldl, Para. [0082]); a biocircuit system having an
effector module comprising an organizational pattern (Methods and compositions for the rapid and reversible destabilizing of specific
proteins in vivo using cell-permeable, synthetic molecules are described, Abstract; ideally reproducing the spatial and temporal
expression patterns of the unmodified gene, Para. [0202]).
Further, WO 2016/012623 A 1 to Theravectys et al. discloses a regulatable human T cell or T cell population engineered to express an
effector module (The invention relates to the regulated expression of a chimeric antigen receptor (CAR) within a lentiviral vector,
Abstract; CARs have been shown to have T cell-proliferating and activating potential on their own, Pg. 7, Lns. 7-8; Human T cells have
been genetically modified with a lentiviral vector to express a CD20-CAR, Pag. 7 , Lns. 18-19) a method of producing a regulatable
human T-cell or population thereof (Human T cells have been genetically modified with a lentiviral vector to express a CD20-CAR, Pag.
7, Lns. 18-19; the cell produces lentiviral vector particles encoding the CAR, Pg. 52, Lns. 1-3), the method comprising, (a) contacting an
isolated population of T-cells with a polynucleotide encoding one or more effector modules such that the effector module can be
expressed in the contacted population (the cell contains the vector integrated into the cellular genome. In one embodiment, the cell
contains the vector transiently expressing the CAR. In one embodiment, Pg. 52, Lns. 1-3; the lentivector particles are obtained in a host
cell transformed with a DNA plasmid, Pg. 52, Lns. 16-17); (b) causing the level of the payload encoded by said one or more effector
modules to be modulated upon exposure of the expressed effector module with one or more stimuli (a chimeric antigen receptor
comprising a binding domain; a transmembrane domain; a hook-binding domain, preferably comprising a streptavidin binding peptide,
Pg. 56, Lns. 20-22; Circulating APCs present the peptide-MHC complexes to T cells in the draining lymph nodes, where they interact
with T cell receptors, and, in conjunction with co-stimulatory signals, activate the T cells, Pg. 3, Lns. 8-10).

The inventions listed in Groups l+ therefore lack unity under Rule 13 because they do not share a same or corresponding special
technical features.

Form PCT/ISA/210 (extra sheet) (January 2015)



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