8-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

WASHINGTON, D.C. 20549

FORM 8-K

CURRENT REPORT

Pursuant to Section 13 or 15(d) of the

Securities Exchange Act of 1934

Date of Report (Date of Earliest Event Reported): July 14, 2011

Marina Biotech, Inc.

(Exact name of registrant as specified in its charter)

Delaware	000-13789	11-2658569
(State or other jurisdiction of incorporation)	(Commission File Number)	(I.R.S. Employer Identification No.)
3830 Monte Villa Parkway, Bothell, Washington		98021
(Address of principal executive offices)		(Zip Code)

Registrant’s telephone number, including area code: 425-908-3600

N/A

Former name or former address, if changed since last report

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

¨ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

¨ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

¨ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

¨ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Item 5.02 Departure of Directors or Certain Officers; Election of Directors; Appointment of Certain Officers; Compensatory Arrangements of Certain Officers.

Amendment of 2008 Stock Incentive Plan

At the 2011 Annual Meeting of Stockholders (the “Annual Meeting”) of Marina Biotech, Inc. (the “Company”) held on July 14, 2011, the Company’s stockholders approved an amendment to the Company’s 2008 Stock Incentive Plan (as amended, the “2008 Plan”). The amendment was previously adopted by the Company’s Board of Directors on May 24, 2011. Pursuant to the amendment, the total number of shares of common stock, par value $0.006 per share, of the Company (“Common Stock”) that may be subject to the granting of awards under the 2008 Plan was increased from 2,125,000 shares to 8,125,000 shares.

Additional information regarding the 2008 Plan is summarized under the heading “Proposal No. 6 – Approval of an Amendment to our 2008 Stock Incentive Plan to Increase the Number of Shares Available Thereunder from 2,125,000 to 8,125,000” in the Company’s Definitive Proxy Statement on Schedule 14A in connection with the Annual Meeting (the “Proxy Statement”), which was filed with the Securities and Exchange Commission (the “SEC”) on June 7, 2011, and is incorporated herein by reference. The description of the 2008 Plan set forth in the Proxy Statement and in this Current Report on Form 8-K are qualified in their entirety by reference to the text of the 2008 Plan, which is filed as Exhibit 10.1 hereto and is incorporated herein by reference.

Amendment of Employee Stock Purchase Plan

At the Annual Meeting, the Company’s stockholders approved an amendment to the Company’s 2007 Employee Stock Purchase Plan (as amended, the “ESPP”). The amendment was previously adopted by the Company’s Board of Directors on May 24, 2011. Pursuant to the amendment, the total number of shares of Common Stock available for issuance under the ESPP was increased from 150,000 shares to 650,000 shares.

Additional information regarding the ESPP is summarized under the heading “Proposal No. 5 – Approval of an Amendment to our 2007 Employee Stock Purchase Plan to Increase the Number of Shares Available for Issuance Thereunder from 150,000 to 650,000” in the Proxy Statement, which was filed with the SEC on June 7, 2011, and is incorporated herein by reference. The description of the ESPP set forth in the Proxy Statement and in this Current Report on Form 8-K are qualified in their entirety by reference to the text of the ESPP, which is filed as Exhibit 10.2 hereto and is incorporated herein by reference.

Election of R. John Fletcher

On July 14, 2011, the Board of Directors of the Company, upon recommendation of the Nominating and Corporate Governance Committee of the Board, acting pursuant to Article II, Section 5 of the Amended and Restated By-Laws of the Company, elected R. John Fletcher to fill the vacancy in the Board of Directors created by the expiration of the term of Chiang J. Li, M.D., effective immediately, with a term expiring at the annual meeting of stockholders to be held in 2012. Mr. Fletcher was also appointed to serve as a member of each of the Board’s Audit Committee and Compensation Committee. Mr. Fletcher will be compensated as a director pursuant to the Company’s general compensation policy for non-employee directors. The Company announced the appointment of Mr. Fletcher in a press release dated July 18, 2011, which is attached hereto as Exhibit 99.1.

Item 5.03 Amendments to Articles of Incorporation or Bylaws; Change in Fiscal Year.

On July 18, 2011, the Company filed a Certificate of Amendment (the “Certificate of Amendment”) to the Restated Certificate of Incorporation of the Company (the “Restated Certificate”) with the Secretary of State of the State of Delaware to increase the number of authorized shares of Common Stock from 90,000,000 to 180,000,000. The holders of a majority of the outstanding shares of the Company’s capital stock approved the amendment to the Restated Certificate at the Annual Meeting pursuant to Section 242 of the Delaware General Corporation Law. A copy of the Certificate of Amendment is filed as Exhibit 3.1 hereto.

Item 5.07. Submission of Matters to a Vote of Security Holders.

The Company held its Annual Meeting on July 14, 2011. Proxies were solicited for each of the six (6) proposals set forth below pursuant to the Proxy Statement. Each share of Common Stock was entitled to one vote with respect to matters submitted to a vote of stockholders, and the voting results reported below are final. Abstentions had the same effect as “Against” votes for all proposals except Proposal No. 1.

PROPOSAL No. 1

Stockholders elected five (5) persons to the Board of Directors, each to hold office until the 2012 annual meeting of stockholders and until their respective successors shall have been duly elected or appointed and qualified, as shown below. This proposal required the affirmative vote of a plurality of the votes cast.

Nominee	Votes “FOR”	Votes WITHHELD	Broker Non-Votes
J. Michael French	14,795,159	1,218,992	26,764,529
James M. Karis	14,855,231	1,158,920	26,764,529
Peter D. Parker	14,848,992	1,165,159	26,764,529
Gregory Sessler	14,861,371	1,152,780	26,764,529
Michael D. Taylor, Ph.D.	14,854,759	1,159,392	26,764,529

PROPOSAL No. 2

Stockholders ratified the appointment of KPMG LLP as the Company’s independent registered public accounting firm for the fiscal year ending December 31, 2011, as shown below. This proposal required the affirmative vote of a majority of the shares present at the Annual Meeting, either in person or by proxy, and entitled to vote.

Votes “FOR”	Votes AGAINST	Votes ABSTAINED	Broker Non-Votes
41,447,945	926,904	403,831	-0-

PROPOSAL No. 3

Stockholders approved an amendment to the Restated Certificate to increase the number of authorized shares of Common Stock from 90,000,000 to 180,000,000, as shown below. This proposal required the affirmative vote of a majority of the issued and outstanding shares of Common Stock entitled to vote as of the record date.

Votes “FOR”	Votes AGAINST	Votes ABSTAINED	Broker Non-Votes
34,635,588	7,788,108	354,984	-0-

PROPOSAL No. 4

Stockholders approved an amendment to the Restated Certificate to effect a reverse stock split, at a time in the future, and in such ratio between a one-for-two and one-for-ten reverse stock split, to be determined by our Board of Directors, to be in the best interest of the Company, as shown below. This proposal required the affirmative vote of a majority of the issued and outstanding shares of Common Stock entitled to vote as of the record date.

Votes “FOR”	Votes AGAINST	Votes ABSTAINED	Broker Non-Votes
34,878,303	7,802,041	98,336	-0-

PROPOSAL No. 5

Stockholders approved an amendment to the Company’s 2007 Employee Stock Purchase Plan to increase the number of shares available for issuance thereunder from 150,000 to 650,000, as shown below. This proposal required the affirmative vote of a majority of the shares present at the Annual Meeting, either in person or by proxy, and entitled to vote.

Votes “FOR”	Votes AGAINST	Votes ABSTAINED	Broker Non-Votes
13,862,551	2,053,716	97,884	26,764,529

PROPOSAL No. 6

Stockholders approved an amendment to the Company’s 2008 Stock Incentive Plan to increase the number of shares available for issuance thereunder from 2,125,000 to 8,125,000, as shown below. This proposal required the affirmative vote of a majority of the shares present at the Annual Meeting, either in person or by proxy, and entitled to vote.

Votes “FOR”	Votes AGAINST	Votes ABSTAINED	Broker Non-Votes
12,024,030	3,889,210	100,911	26,764,529

Item 8.01 Other Events.

Exercises of Series B Warrants

During the period beginning on June 7, 2011 and ending on July 12, 2011, holders of 22,293,500 Series B Warrants, each to purchase one unit consisting of one share of Common Stock and one Series A Warrant to purchase one share of Common Stock, exercised their Series B Warrants, resulting in aggregate gross proceeds to the Company of approximately $3.1 million. The Company issued the Series B Warrants on May 20, 2011 in connection with the underwritten public offering of the Company’s securities effected pursuant to that certain Underwriting Agreement, dated May 17, 2011, between the Company and Roth Capital Partners, LLC, as representative of the underwriters named therein. The remaining 25,000 Series B Warrants expired by their terms on July 12, 2011.

Investor Presentation

Attached to this Current Report on Form 8-K as Exhibit 99.2, and incorporated herein by reference, is a copy of a presentation about the Company that it used at the Annual Meeting.

Item 9.01. Financial Statements and Exhibits

(d) Exhibits:

Exhibit No.	Description
3.1	Certificate of Amendment.
10.1	2008 Stock Incentive Plan (filed as Appendix A to the Company’s Definitive Proxy Statement on Schedule 14A filed on April 29, 2008, and incorporated herein by reference).**
10.2	2007 Employee Stock Purchase Plan (filed as Exhibit 10.1 to the Company’s Registration Statement on Form S-8, File No. 333-146183, and incorporated herein by reference).**
99.1	Press release of Marina Biotech, Inc. dated July 18, 2011.
99.2	Investor Presentation of Marina Biotech, Inc.

** Indicates management contract.

SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the Registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

	Marina Biotech, Inc.
July 18, 2011	By:	/s/ Peter S. Garcia
	Name:	Peter S. Garcia
	Title:	Chief Financial Officer

EXHIBIT INDEX

Exhibit No.	Description
3.1	Certificate of Amendment.
10.1	2008 Stock Incentive Plan (filed as Appendix A to the Company’s Definitive Proxy Statement on Schedule 14A filed on April 29, 2008, and incorporated herein by reference).**
10.2	2007 Employee Stock Purchase Plan (filed as Exhibit 10.1 to the Company’s Registration Statement on Form S-8, File No. 333-146183, and incorporated herein by reference).**
99.1	Press release of Marina Biotech, Inc. dated July 18, 2011.
99.2	Investor Presentation of Marina Biotech, Inc.

** Indicates management contract.

EX-3.1

CERTIFICATE OF AMENDMENT

OF THE

RESTATED CERTIFICATE OF INCORPORATION

OF

MARINA BIOTECH, INC.

Pursuant to Section 242 of the

Delaware General Corporation Law

The undersigned, a duly authorized officer of Marina Biotech, Inc. (the “Corporation”), a corporation organized and existing under the General Corporation Law of the State of Delaware (the “DGCL”), does hereby certify in accordance with the provisions of the DGCL as follows:

1.        The name of the Corporation is Marina Biotech, Inc. The Corporation was originally incorporated under the name Nastech Pharmaceutical Company Inc. The original Certificate of Incorporation of the Corporation (the “Original Certificate”) was filed with the Secretary of State of the State of Delaware on September 23, 1983, and the Original Certificate was amended and restated in its entirety by the filing of a Restated Certificate of Incorporation of the Corporation (the “Restated Certificate”) with the Secretary of State of the State of Delaware on July 20, 2005.

2.        This Certificate of Amendment amends the provisions of the Restated Certificate as set forth herein, and was adopted by the Corporation’s Board of Directors and authorized by a majority of the holders of the outstanding shares of common stock entitled to vote thereon at an annual meeting of stockholders pursuant to Section 242 of the DGCL.

3.        Article FOURTH, paragraph (a) of the Restated Certificate is hereby deleted and replaced in its entirety to read as follows:

“(a) The total number of shares of stock which the Corporation shall have authority to issue is 180,000,000 shares of Common Stock, $0.006 par value per share, and 100,000 shares of Preferred Stock, $0.01 par value per share.”

IN WITNESS WHEREOF, the undersigned, being the Secretary and Chief Financial Officer of the Corporation, does hereby execute this Certificate of Amendment as of July 18, 2011.

/s/ Peter S. Garcia
Name:	Peter S. Garcia
Title:	Secretary and Chief Financial Officer

EX-99.1

Exhibit 99.1

Marina Biotech Announces Changes to Board of Directors

Appoints John Fletcher to Board of Directors and James Karis as Chairman

Bothell, WA, July 18, 2011 – Marina Biotech, Inc. (Nasdaq: MRNA), a leading nucleic acid-based drug discovery and development company, today announced that R. John Fletcher was elected to the Company’s Board of Directors effective July 14, 2011, replacing Board member Chiang Li, Ph.D., M.D., who announced his retirement from the Marina Biotech board prior to the 2011 annual meeting of shareholders. The Company also announced the appointment of James Karis, who has served as a Board member since 2009, as Chairman of the Board, effective July 14, 2011, replacing co-chairmen Gregory Sessler and Peter Parker, both of whom will continue as board members of Marina Biotech.

“I am pleased to welcome John Fletcher to Marina Biotech’s Board of Directors,” stated James Karis, Chairman of the Board of Directors of Marina Biotech. “John brings extensive corporate strategy and financing experience that is characterized by a strong understanding of the commercial potential of new technologies and the options for developing, funding, and acquiring new businesses. We would also like to thank Dr. Li for his service to our company and his contributions to our wholly owned subsidiary, Cequent Pharmaceuticals. In addition, I want to thank Greg and Peter for their outstanding efforts as co-Chairmen in effectively integrating the MDRNA and Cequent Boards and then leading the new Marina Biotech Board throughout this past year.”

Mr. Fletcher is an independent director for purposes of the Sarbanes Oxley Act of 2002 and NASDAQ stock exchange regulations. He is a Founding Partner of Fletcher Spaght Ventures, a venture capital firm investing in emerging growth healthcare and high technology companies. He also serves as the CEO of Fletcher Spaght Inc., a management consulting firm he founded to provide strategy and financing assistance to new companies. Mr. Fletcher has over twenty-five years providing strategy and financing assistance to new companies. Prior to launching Fletcher Spaght Inc. in 1983, he served as a Senior Manager at The Boston Consulting Group, managing client relationships in healthcare and high technology companies. Mr. Fletcher attended the Wharton School of Business at the University of Pennsylvania and completed all coursework for a Ph.D. He holds an MA in International Finance from Central Michigan University, an MBA from Southern Illinois University, and a BBA from George Washington University. He is a current or past board member for many companies, including Axcelis, GlycoFi and Spectranetics.

“I’m very excited to join the board of Marina Biotech and look forward to contributing strategically to the Company as it works to develop and commercialize therapeutic products based on RNA interference,” said Mr. Fletcher.

With the resignation of Dr. Li and the addition of Mr. Fletcher, there remain six members on the Marina Biotech Board of Directors.

About Marina Biotech, Inc.

Marina Biotech is a biotechnology company, focused on the development and commercialization of RNA interference- (RNAi) and RNA-based therapeutics. The Marina Biotech pipeline currently includes a clinical program in Familial Adenomatous Polyposis (a precancerous syndrome) and two preclinical programs — in bladder cancer and malignant ascites. Marina Biotech entered into an exclusive agreement with Debiopharm Group for the development and commercialization of the bladder cancer program. Marina Biotech’s goal is to improve human health through the development of RNAi and RNA-based compounds and drug delivery technologies that together provide superior therapeutic options for patients. Additional information about Marina Biotech is available at http://www.marinabio.com.

Forward-Looking Statements

Statements made in this news release may be forward-looking statements within the meaning of Federal Securities laws that are subject to certain risks and uncertainties and involve factors that may cause actual results to differ materially from those projected or suggested. Factors that could cause actual results to differ materially from those in forward-looking statements include, but are not limited to: (i) the ability of Marina Biotech to obtain additional funding; (ii) the ability of Marina Biotech to attract and/or maintain manufacturing, research, development and commercialization partners; (iii) the ability of Marina Biotech and/or a partner to successfully complete product research and development, including preclinical and clinical studies and commercialization; (iv) the ability of Marina Biotech and/or a partner to obtain required governmental approvals; and (v) the ability of Marina Biotech and/or a partner to develop and commercialize products that can compete favorably with those of competitors. Additional factors that could cause actual results to differ materially from those projected or suggested in any forward-looking statements are contained in Marina Biotech’s most recent periodic reports on Form 10-K and Form 10-Q that are filed with the Securities and Exchange Commission. Marina Biotech assumes no obligation to update and supplement forward-looking statements because of subsequent events.

Contact:

Marina Biotech, Inc.

Peter Garcia

Chief Financial Officer

(425) 908-3603

pgarcia@marinabio.com

EX-99.2

Annual Shareholders Meeting

Company Update

14 July 2011

Exhibit 99.2

Forward Looking Statement

Statements made in this presentation may be forward-looking statements within the

meaning of Federal Securities laws that are subject to certain risks and uncertainties and

involve factors that may cause actual results to differ materially from those projected or

suggested. Factors that could cause actual results to differ materially from those in

forward-looking statements include, but are not limited to: (i) the ability of Marina Biotech to

obtain

additional

funding;

(ii)

the

ability

of

Marina

Biotech

to

attract

and/or

maintain

manufacturing, research, development and commercialization partners; (iii) the ability of

Marina

Biotech

and/or

a

partner

to

successfully

complete

product

research

and

development, including preclinical and clinical studies and commercialization; (iv) the ability

of Marina Biotech and/or a partner to obtain required governmental approvals; and (v) the

ability of Marina Biotech and/or a partner to develop and commercialize products that can

compete favorably with those of competitors. Additional factors that could cause actual

results to differ materially from those projected or suggested in any forward-looking

statements are contained in Marina Biotech’s most recent periodic reports on Form 10-K

and Form 10-Q which are filed with the Securities and Exchange Commission. Marina

Biotech assumes no obligation to update and supplement forward-looking statements

because of subsequent events.

2

Broad Nucleic Acid-Based Platform

Provides a Superior Drug Discovery Engine

Appropriate

therapeutic

approach

to

targets

not

typically

suited

to

small

molecule or monoclonal antibody therapeutics

Capitalizes on distinct endogenous intracellular processes for protein

down-regulation

Allows for a scientific and risk adjusted pursuit of a specific nucleic acid-

based therapeutic modality

Established regulatory path through FDA and EMA

Multiple nucleic acid-based therapeutics are in clinical development

Two such therapeutics have been approved

3

4

Pfizer and Nucleic Acid-based Therapeutics

Tacere

shRNA

(TT-033):  Three separate, expressed RNAi elements targeting the

conserved regions of the Hepatitis C virus entrapped in an AAV protein coat

$145 MM deal (upfront and milestone payments have been made through Feb

2010)

Quark

siRNA

(PF-04523655):  Chemically-modified, unformulated siRNA compound

targeting proprietary target, RTP-801, for the treatment of wet age-related

macular degeneration (wet-AMD) and diabetic macular edema (DME)

Terms

not

disclosed

but

Pfizer

upped

milestone

payments

in

March

2011

to

support extended Phase II trials

Santaris

:

LNA

chemistry

for

single-stranded

RNA-targeted

therapies

$17 MM upfront (included $10 MM in equity) in 2010; $14 MM in 2011 and up

to $600 MM in downstream milestones

ssRNA

Nucleic Acid Therapeutic “Toolbox”

Constructs

Dicer length siRNA

RISC length siRNA

microRNA mimetics

microRNA antagonists

miniRNAs

Single-stranded RNA/DNA

5

Chemistries

UNA –

Non-nucleotide acyclic

monomers –

greater flexibility

CRN –

nucleotide analogs with a

linker connecting the C2’

and C4’

Delivery

DiLA

2

–

Combinations of amino acid head-groups, spacers, and

alkyl chains (tails)

SMARTICLES –

Combinations of anionic and cationic lipids

E. Coli –

Non-pathogenic bacteria engineered to produce, deliver

and release interfering RNA mediators (shRNA) to targeted tissue

Conjugation –

Peptides, etc. (phage display library)

Critical Needs for a Broad Nucleic Acid-

Based Therapeutics Discovery Engine

Multiple

chemistries to construct single and double-stranded

oligonucleotides with suitable affinity, stability and minimization of off-

target activity

Unlocked Nucleotide Analogs (UNA)

Conformationally Restricted Nucleotides (CRN)

With

multiple

delivery

approaches

Multiple carriers ranging from saline to bacteria to liposomal

(DiLA

2

/SMARTICLES

®

)

Multiple routes of administration (oral, local and systemic)

Leading to multiple nucleic acid-based therapeutic approaches

Double-stranded RNAi-based therapeutics

Single-stranded oligonucleotide therapeutics

MicroRNA-based therapeutics

6

RNAi

RDNA+

/chi

Marina Biotech’s Nucleic Acid-based

Therapeutic Platform

7

“undruggable target”

for a specific

indication

ssRNA/DNA

dsRNA

antagomir

mimetic

CRN/RNA

+ delivery

CRN/RNA

UNA/CRN

+ delivery

CRN/RNA

+ delivery

CRN/RNA

Plasmid +

bacteria

UNA +

delivery

Molecular Target

Local/Systemic

Oral

mRNA

microRNA

tk

tau

muRNA/muRNA+

RNAi

RDNA

RNA

RNA+

chi

/mu

mu

Selection of a Nucleic Acid-based

Therapeutic Approach

Target, indication and patient phenotype determine the most appropriate

combination of technologies and thus the specific nucleic acid-based

modality(ies) to pursue in preclinical proof-of-concept

Determine target and intended biology

Specific mRNA(s) to down-regulate a specific protein(s)

microRNA to up-/down-regulate multiple mRNAs/proteins

For down-regulation, use a mimetic

For up-regulation, use an antagomir

Select delivery approach based on construct and site (tissue/organ)

tkRNAi

tauRNAi

DNA+

–

delivery

of

ssDNA/RNA

A

When appropriate, multiple technologies can be evaluated to determine

the best approach

8

–

delivery

of

shRNA

to

mucosal

epithelium

RNAi

–

delivery

of

dsRNA

in

a

liposomal

formulation

RNAi

RDNA

RNA+

–

delivery

of

ssDNA/RNA

or

dsRNA

RNA

/mu

RDNA+

–

delivery

of

ssDNA/RNA

chi

/chi

mu

transKingdom

RNAi Platform

9

“undruggable target”

for a specific

indication

Molecular Target

mRNA

(protein)

ssDNA/RNA

dsRNA

antagomir

mimetic

microRNA

CRN-RNA

+ delivery

CRN-RNA

UNA/CRN

+ delivery

CRN-RNA

+ delivery

CRN/RNA

Plasmid +

bacteria

UNA +

delivery

Local/Systemic

Oral

tk

RNAi

About transKingdom

RNA interference (tkRNAi™)

10

Non-pathogenic bacteria engineered to produce, deliver and release

interfering RNA mediators (shRNA) to targeted tissue

Efficient delivery to the epithelium of the gastrointestinal tract via oral

administration

Safe

and

well

tolerated

daily

dosing

of

up

to

10

11

cfu

(colony

forming

units) in non-human primates for 9 months

Phase 1b/2a clinical trial to treat Familial Adenomatous Polyposis

(FAP) –

a genetic pre-cancerous polyposis disease with orphan drug

status

Exclusive worldwide license from Beth Israel Deaconess Medical

Center/Harvard

Familial Adenomatous Polyposis (FAP)

Rare hereditary disease

Mutation in Adenomatous Polyposis Coli (APC) gene

Causes

dysregulation

and

accumulation

of

-catenin

Results in numerous colon polyps appearing in early

adolescence with potential for rapid disease progression

Clinical

drug

product,

CEQ508,

targets

-catenin

oncogene

Unmet medical need

~80,000 worldwide (orphan status)

Near 100% risk of colon cancer if untreated

Treatment options:

Surgical intervention (colectomy) is the only available treatment

to prevent colon cancer progression

No generally accepted pharmaceutical approach is available

U.S. FAP Market Potential: >$100 MM

Opportunities to expand into sporadic CRC, other polyposis syndromes and other

GI cancers

Potential for 4Q2014 launch and first RNAi drug to market

11

Actual and Potential Clinical, Regulatory

and Commercial Timelines

12

December 2009 –

IND granted in U.S.

September 2010 –

Patent grant in the EP protecting tkRNAi

December 2010 –

Received FDA Orphan Drug Designation

January 2011 –

Completed LTT study in Non-Human Primates

June 2011 –

Completed dosing in Cohort 1

1Q2012 –

Complete dose escalating phase of 1b/2a

Delayed dosing of Cohort 2 until 4Q2011

Remedying GMP-related issues not a safety issue

Informed the FDA of our decision to delay dosing

2Q2012 –

Complete stable dose phase of 1b/2a

4Q2013 –

Complete Pivotal Phase 2

3Q2014 –

Expedited/accelerated FDA review and approval

4Q2014 –

Launch –

first RNAi drug to market

RNAi Platform

13

“undruggable target”

for a specific

indication

ssDNA/RNA

dsRNA

mRNA

antagomir

mimetic

microRNA

CRN/RNA

+ delivery

CRN/RNA

UNA/CRN

+ delivery

CRN/RNA

+ delivery

CRN/RNA

Plasmid +

bacteria

UNA +

delivery

Molecular Target

RNAi

tau

Local/Systemic

Oral

tau

About tauRNA interference (tauRNAi)

14

Combination of highly active UsiRNA constructs and liposomal

delivery systems

UsiRNA –

Substitution of unlocked nucleobase analogs (UNA) within

siRNA; therapeutic use proprietary to Marina Biotech

DiLA

-

Di-Alkylated

Amino

Acids

for

liposomal-based

delivery;

novel

compounds proprietary to Marina Biotech

Smarticles -

Lipid-based amphoteric liposomes for oligonucleotide delivery

(in Phase I Clinical Trial by ProNAi via systemic delivery)

Pairing of the UsiRNA with the most appropriate liposomal delivery

system provides greater efficacy and specificity for RNAi

2

Publications on UsiRNAs and Systemic

and

Local

Delivery

with

DiLA

15

Mol Ther. 2011 Apr 19. (PMID:21505423)

An Amino Acid-based Amphoteric Liposomal Delivery System for Systemic Administration of

siRNA.

Adami RC, Seth S, Harvie P, Johns R, Fam R, Fosnaugh K, Zhu T, Farber K, McCutcheon M, Goodman TT, Liu Y, Chen Y, Kwang E,

Templin MV, Severson G, Brown T, Vaish N, Chen F, Charmley P, Polisky B, Houston ME Jr.

Marina Biotech, Inc., Bothell, Washington, USA.

Nucleic Acids Res. 2011 Mar 1;39(5):1823-32.

Improved specificity of gene silencing by siRNAs containing unlocked nucleobase analogs.

Vaish N, Chen F, Seth S, Fosnaugh K, Liu Y, Adami R, Brown T, Chen Y, Harvie P, Johns R, Severson G, Granger B, Charmley P,

Houston M, Templin MV, Polisky B.

Marina Biotech Inc., 3830 Monte Villa Parkway, Bothell, WA 98021, USA

Mol Ther. 2011 Mar 1. (PMID: 21364537)

RNAi-based Therapeutics Targeting Survivin and PLK1 for Treatment of Bladder Cancer.

Seth

S,

Matsui

Y,

Fosnaugh

K,

Liu

Y,

Vaish

N,

Adami

R,

Harvie

P,

Johns

R,

Severson

G,

Brown

T,

Takagi

A,

Bell

S,

Chen

Y,

Chen

F,

Zhu T, Fam R, Maciagiewicz I, Kwang E, McCutcheon M, Farber K, Charmley P, Houston Jr ME, So A, Templin MV, Polisky B.

Discovery Research and Pharmaceutical Development, Marina Biotech Inc., Bothell, Washington, USA

2

Marina Biotech/Debiopharm:

Bladder Cancer R&D Collaboration

Exclusive agreement for the research, development and

commercialization of Marina Biotech’s pre-clinical program

in bladder cancer

First agreement to license an RNAi-based therapeutic,

delivered with a lipid-

or liposomal-based formulation, to a

pharma company

Debiopharm is responsible for development and

commercialization of any products

Debiopharm will pay:

All research and development costs for the program

Up to $24 million based on predefined research and development

milestones

Royalties on sales of products

16

ssDNA/RNA Technology

17

“undruggable target”

for a specific

indication

ssDNA/RNA

dsRNA

mRNA

antagomir

mimetic

microRNA

CRN/RNA

+ delivery

CRN/RNA

UNA/CRN

+ delivery

CRN/RNA

+ delivery

CRN/RNA

Plasmid +

bacteria

UNA +

delivery

RDNA/     RDNA+

Molecular Target

Local/Systemic

Oral

chi

chi

Conformationally Restricted

Nucleotides (CRN)

CRNs

are

nucleotide

analogs

with

a

linker

connecting

the

C2’

and

C4’

carbons of ribose

CRN and LNA lock the ribose ring into a stable conformation and increase

the hybridization affinity to the mRNA or microRNA target

Distinguished

from

LNA

by

a

longer

linker

and

different

location

of

the

oxygen atom

Places the oxygen in an optimal position for stability and affinity

RNA                                        CRN               

LNA

18

CRN-Substitution Results in Less

Ribose Ring Puckering

19

CRNs are distinguished by a linker whose length results in less ribose

ring puckering

Conformation of CRN more closely resembles that found in RNA

CRN

LNA

Puckering of the ribose

ring at the 2’

carbon

Less Ribose Ring Puckering May Result

in Lower Structural Distortion

20

CRN substitution within an oligo may result in lower structural distortion

when hybridized to a complementary mRNA

Figure Adapted from Eichert et al.,

Nucleic Acid res. 2010 Oct 1 38(19):6729-36

RNA/CRN

Distortion of

Duplex Structure

The rigid structure imparted by multiple

LNA

substitutions

“stretches”

the

duplex

CRNs have greater flexibility by virtue of

the longer linker and would be expected

to maintain an overall structure similar to

an all-RNA structure

Therefore CRN substituted single-

stranded RNA/DNA may have promising

drug-like properties

Therapeutic Approaches Using CRN

Technology

21

mRNA Translational Blockers

Substitute CRN at ends of DNA-RNA hybrid compounds thus preserving

DNA in the interior and allowing interaction with RNAse H

microRNA Antagonists

Substitute CRN throughout strand to maximize hybridization affinity

Additional modifications (e.g., 2’O-methyl) can be included within the

construct for increased affinity and greater nuclease stability

= CRN

Advantages of CRN Technology

22

Increased affinity with CRN substitution maintains structural orientation

thus allowing for variable lengths

Standard 19-

to 22-mers

Greater number of substitutions in 14-

to 16-mers

Fully substituted 7-

to 9-mers targeting microRNA seed region

Delivery can be achieved with multiple formulations

Simple formulations (e.g., saline) can be used in many situations (liver,

lung, kidney, some tumors)

If

appropriate,

encapsulation

within

a

liposomal

formulation

for

systemic

or

local administration to certain tissues/organs

CRN-Related Therapeutic Modalities

Aptamers

Therapeutics

Diagnostics

Delivery/cell surface ligands

Exon skipping oligonucleotide

Minor/Major Groove Binders/Triplex forming oligonucleotides

Ribozymes

Splice junction inhibitors

Steric blockers

tRNA/tRNA suppressors

bridge (adapter molecule) between the mRNA and the protein

“Suppress”

the phenotypic effect of a coding mutation

23

Other Uses for CRN technology

Primer/Probes for PCR

qRT-PCR

5’

and 3’

RACE

Single, multiplex and allele specific PCR

Capture Probes

In

situ

hybridization/Fluorescence

in

situ

hybridization

SNP genotyping

Expression analysis

Monitor/identify exon skipping

Monitor/identify splice variants

Research/Diagnostics agents

Aptamers

Bacterial strain/virus identification

Single cell miRNA analysis

24

microRNA (miRNA) Technology

Local/Systemic

Oral

“undruggable target”

for a specific

indication

microRNA

mimetic

antagomir

UNA/CRN

+ delivery

CRN-RNA

+ delivery

CRN/RNA

mRNA

dsRNA

ssDNA/RNA

Plasmid +

bacteria

UNA +

delivery

CRN-RNA

+ Delivery

CRN-RNA

25

microRNA Mimetic Approach

Molecular Target

Local/Systemic

Oral

“undruggable target”

for a specific

indication

microRNA

mimetic

antagomir

UNA/CRN

+ delivery

CRN-RNA

+ delivery

CRN-RNA

mRNA

dsRNA

ssDNA/RNA

Plasmid +

bacteria

UNA +

delivery

CRN-RNA

+ delivery

CRN-RNA

26

mu

RNA+

microRNA Mimetic using UNA & CRN

27

MicroRNA mimetic -

dsRNA

Substitute with UNA and CRN

UNA –

increase nuclease resistance and decrease cytokine induction;

inhibition of passenger strand activity

CRN –

increase hybridization affinity; nuclease resistance

Additional modifications (e.g., 2’O-methyl) can be included within the

construct for nuclease stability

Duplex

construct

–

likely

to

require

delivery

for

most

indications

DiLA

2

-based

liposomes

or

Smarticles

(amphoteric

liposomes)

= CRN

= UNA

Delivery of a miR-34 Mimetic in a Smarticles

Formulation Inhibits Tumor Growth

Inhibition of Liver Cancer Biomarker

Alpha Feto Protein Levels

Inhibition of Tumor Growth

Tumor Weight (g)

miR-NC

miR-34

Untreat. Cont.           miR-NC                  miR-34

Smarticles

formulation

provided

effective

delivery

to

orthotopic

liver

tumors

Significant reduction in tumor growth and liver tumor specific biomarker

28

Local/Systemic

Oral

Molecular Target

“undruggable target”

for a specific

indication

microRNA

mimetic

antagomir

UNA/CRN

+ delivery

CRN-RNA

+ delivery

CRN/RNA

mRNA

dsRNA

ssDNA/RNA

Plasmid +

bacteria

UNA +

delivery

CRN-RNA

+ delivery

CRN-RNA

29

mu

RNA/

mu

RNA+

microRNA Antagonist using CRN

30

MicroRNA antagonists (Antimir) therapeutics

Substitute CRN throughout the strand to maximize the hybridization affinity

between antimir and the target microRNA

Allows for use of shorter length sequences

Additional modifications (e.g., phosphorothioate and 2’O-methyl) can be

included within the construct for nuclease stability and increase affinity

Delivery formulation

Simple formulations (e.g., saline) can be used as the vehicle for and can

be used as the vehicle in many situations

Encapsulation within a liposomal formulation for systemic or local

administration may be required for some tissues/organs

= CRN

CRNs Increase Antimir Activity

CRN substitution increases the activity of an Antimir with >90%

inhibition of luciferase activity

No activity against a scrambled target sequence (not shown)

31

Dual luciferase assay; Average of triplicate; HeLa cells co-transfected with psiCHECK2-miR21plasmid

% Luciferase (Renilla) Activity Remaining

Construct

0%

20%

40%

60%

80%

100%

miR-21

Antimir-21

Unmodified

Antimir-21

(CRN)

Antimir-21

(LNA)

5 nM

25 nM

5 nM

25 nM

5 nM

25 nM

5 nM

25 nM

Antimir Conc. (nM)

CRN-substituted Antimir

LNA-substituted Antimir

Unmodified Antimir

CRN-substituted

Antimir

is

highly

potent,

with

an

IC

50

of

0.2

nM

Similar potency for CRN-

and LNA-substituted versions

50% Inhibition

Dual luciferase assay; HeLa cells co-transfected with psiCHECK2-miR21plasmid;

Unmodified Antimir all RNA; CRN-substituted Antimir has DNA and P=S backbone

CRNs Increase Antimir Potency

32

Molecular Target

Local/Systemic

Oral

“undruggable target”

for a specific

indication

microRNA

mimetic

antagomir

UNA/CRN

+ delivery

CRN/RNA

+ delivery

CRN/RNA

mRNA

dsRNA

ssRNA/DNA

Plasmid +

bacteria

UNA +

delivery

CRN/RNA

+ delivery

CRN/RNA

Marina Biotech’s Nucleic Acid-based

Therapeutic Platform

33

tk

RNAi

tau

RNAi

chi

RDNA/

chi

RDNA+

mu

RNA+

mu

RNA/

Resourcing a Broad Discovery Engine

–

Funded

by

Marina

Biotech

Includes funding CEQ508 Phase 1b/2a Trial

–

Funded by outside sources

siRNA in liposomal delivery for local administration funded by Debiopharm

(Marina Biotech UsiRNA and liposomal delivery)

–

Funded

by

Marina

Biotech

and

outside

sources

ssDNA in liposomal delivery for systemic administration funded by ProNAi (ProNAi DNA

decoy in Marina Biotech delivery)

ssRNA/DNA in saline/liposomal delivery for systemic administration funded by Marina

Biotech

–

Funded

by

Marina

Biotech

and

outside

sources

microRNA mimetic in liposomal delivery for systemic administration funded by

Mirna Therapeutics (Mirna mimetic in Marina Biotech delivery)

microRNA antagonists in saline for systemic administration funded by Marina

Biotech

34

tk

RNAi

tau

RNAi

chi

RDNA/

chi

RDNA+

mu

RNA/

mu

RNA+

2010-2011 Achievements

Initiated patient dosing in an FAP Phase 1b/2a Clinical Trial and

completed dosing the first cohort

Established first ever partnership around a liposomal delivered

RNAi compound with Debiopharm for the development and

commercialization a bladder cancer therapeutic

Established use of CRNs within single-stranded oligonucleotides

including microRNA antagonists

Established broadest single-company nucleic acid-based drug

discovery engine in the industry

Published three scientific manuscripts in peer-reviewed journals

describing UsiRNA platform, DiLA2 delivery technology and pre-

clinical data from the bladder cancer program

35

Thank You

36