From a Discovery to Clinical Applications Worldwide. A discovery gives new hope to millions of people suffering from cancers, inborn genetic defects and to patients awaiting autotransplantation or regeneration of damaged or missing tissues. This is a new chapter in the development of effective genetic vaccines which, in the near future, will make it possible to fight malignancies, among others. A team from the University of Warsaw discovered universal analogous endings for mRNA molecules (so called 5’ caps) which guarantee higher mRNA stability in cell natural environment and enhance the production of desired proteins.

1. From a Discovery to Clinical
Applications Worldwide
A team from the University of Warsaw discovered universal analogous endings for mRNA
molecules (so called 5’ caps) which guarantee higher mRNA stability in cell natural environment
and enhance the production of desired proteins.
A discovery gives new hope to millions of people suffering from cancers, inborn genetic defects and
to patients awaiting autotransplantation or regeneration of damaged or missing tissues. This is a
new chapter in the development of effective genetic vaccines which, in the near future, will make it
possible to fight malignancies, among others.
Effective commercialization of discoveries
research & development results
Enhancing mRNA Stability
University Technology Transfer Centre
www.uott.uw.edu.pl

2. The scientific world have concluded that in order to induce certain effects in gene therapies it
is better to improve methods for specific mRNA molecule synthesis (several times less complex
compared to DNA molecules) rather than interfere in DNA itself.
In contrast to DNA, mRNA is outside the cell nucleus, hence it is
easier to introduce it to the cell as there is no need to interfere
in the nucleus. Various mRNA molecules present in cells serve
as “recipes” for production of particular proteins. These are
instructions based on which ribosomes, by decoding the information
there contained, produce a particular, specific protein. Together with
the rapid development in genetics, the interests of scientists and
pharmaceutical companies have focused on studying the role of mRNA
in treating diseases which result either from the overproduction of
certain proteins (e.g., in cancer cell formation processes), or from chronic
deficiency of some proteins in the body. In the scientific world, there is
a belief that the ability to “manage” the production of particular proteins
in practice will enable the development of highly effective therapies,
including these against cancers.
mRNA is a molecule of ribonucleic acid
(RNA) which functions as a messenger.
Its role is to transfer genetic information
from the cell nucleus (DNA) to cell
organelles that are responsible for protein
(polypeptide) synthesis. One of the ends
in mRNA molecule - called 5’ cap - shows
affinity towards the initiation factor
present in the cell. Upon their biding, the
synthesis of a particular type protein may
take place in the cell.
Polish Scientists Solve the Problem
For scientists, the main challenge in the development of genetic vaccines was to overcome the natural instability
of mRNA molecules which degrade rapidly in cell environment. Without removing this limitation high amounts of
mRNA dosed to the cells would be required to obtain a therapeutic effect. Thus, for the cells to produce much
higher amounts of desired proteins, mRNA-based therapies would have to ensure both the enhancement of
mRNA stability and the affinity to the initiation factor. Only in this way satisfactory therapeutic results might be
obtained. And this was achieved by Polish scientists.
mRNA plays an important role in innovative anti-cancer vaccines, cancer therapies, as well as in the treatment of
various genetic diseases. mRNA is also one of the foundations in the field of stem cells applications in restoring,
forming and treating tissues and organs.

3. The University of Warsaw cooperated with the Louisiana State University Health Sciences Center at
Shreveport (LSUHSC-S). In UW labs the 5’ cap analogues were designed and synthesised, while
in LSUHSC-S new mRNA molecules were tested for their stability and affinity in the cell environment.
A Two-in-One Breakthrough
In the cell, natural mRNA molecules are enzymatically degraded (destroyed).
Degradation process starts with detaching one of the mRNA molecule ends,
so called 5’ cap. The cap is a universal structure which is present in all mRNA
molecules of eukaryotic organisms. The scientists from UW focused on the
synthesis of 5’ cap analogues which could replace the naturally occurring cap
and become more resistant to degrading enzymes activity. Many alternative
solutions had been obtained and tested, but only after replacing one
of the oxygen atoms with a sulphur atom in a triphosphate bridge,
typical for the cap, it was found that the stability of this new mRNA
molecule in a living organism extends threefold and, additionally, its
affinity towards the factor initiating the protein synthesis increases
from 2 to 4 times. As a result, out of the same amount of mRNA over
5 times more protein is yielded. Such a spectacular effect was obtained
by exchanging a single atom in a molecule made of 80 thousand atoms. The
discovery was conventionally named S-ARCA. Being aware of the impact of
their discovery, the same team tested other 5’ end cap analogues and in a
short time they found another “effective” analogue, this time by replacing
an oxygen atom with a BH3 group. The discovery was conventionally named
B-ARCA. Both inventions became a basis to apply for the patent protection.
Solving the mRNA instability
issue and enhancing its productivity
The invention has
therapeutic applications:
• it is essential in
anti-cancer vaccines,
• it facilitates the supplementation
of proteins whose low levels cause
different diseases,
• it enables reprogramming
of stem cells for regenerative
medicine purposes.

4. Before 2007 Studies on the properties of mRNA and 5’ cap analogues
2007
Filing the patent application in Poland and in the USA (S-ARCA); the beginning of work on
analogous solutions to protect against competition; publication in a renowned scientific journal
2008 Signing the contract on the co-ownership of the invention between UW and LSUHSC-S (S-ARCA)
2008
Filing the patent application in Poland and in the USA (B-ARCA); gaining the interest from research
teams seeking potential cooperation; establishing the relation
with University in Mainz and BioNTech company - the future investor
2010 Signing the contract on the co-ownership of the invention between UW and LSUHSC-S (B-ARCA)
2010
Agreement between UW and LSUHSC-S on the distribution of the revenue from selling the licence; negotiations
with the investor (BioNTech); supporting the invention’s credibility by the production and delivery of 5’ cap
analogue compound in the amount sufficient to start clinical trials
2010 Signing the licence contract between UW and LSUHSC-S with BioNTech company; first clinical trials set off
2013 Negotiations with BioNTech on the revision of the licence contract due to the global pharmaceutical company
interested in the invention which was attracted by BioNTech
2015 Granting by BioNTech the sub-licence to pharmaceutical company Sanofi which conducts clinical trials on a
broader scale – a contract worth 360 mln dollars
2016 Selling by BioNTech the sub-licence to Genentech company from Roche group –
a contract worth 310 mln dollars
Commercialisation of mRNA 5’ Cap - Timeline

5. Contract Between the Owners of the Invention
After the discovery of 5’-end caps S-ARCA i B-ARCA, UW / LSUHSC-S consortium established and secured with a mutual
agreement the co-ownership of the invention. The contract included, among others, the distribution of creative input
between institutions, method for managing applications in patent processing, commercialisation process. Due to its
considerable experience with the commercialisation process, LSUHSC-S was established a leader for contacting with
potential business partners. During next stages both partners also used contracts to regulate issues on the distribution
of the revenue from selling licences and sub-licences. The matter is quite relevant as usually in teamwork the business
value of patent applications differs, and so does the work contribution or number of co-authors in both applications. Early
established terms help to avoid future misunderstandings over the distribution of financial resources between the inventors.
Patent Protection – the Broader, the Better
The consortium did realise that in the procedure for patent application it is worth considering the broadest geographical
area possible. Applications for patent protection were submitted simultaneously in Poland and in the USA. For both
applications the international protection was extended within PCT.
Scientific Publication as an Effective Form of Promotion
Immediately after filing patent applications, the team published results of their work in a renowned scientific journal.
This was enough to gain the attention from other teams interested in designing and testing “vaccines of the future” which
could e.g. permanently treat malignancies. This way UW / LSUHSC-S started the co-operation with a research team from
the University in Mainz whose subsidiary, BioNTech company, specialised in research on gene therapies.
Finding a Business Partner
BioNTech company was genuinely interested in a licence for new efficient mRNA which would enable conducting the
research more effectively, as well as make it possible to introduce life-saving vaccines to clinical trials. BioNTech with their
experience in research on genetic vaccines seemed to be a perfect business partner who believed in the potential of the
invention and who would invest financial resources in it. For UW and LSUHSC-S it was clear that without such a partner
the invention would be of scientific value only. Thus, the negotiations with the future strategic partner began.
Negotiations and Selling the Licence
The leader of negotiations (LSUHSC-S) offered BioNTech to prepare a letter of intent outlining the preliminary financial
settlements and the strategy for invention protection. However, at the stage of signing the licence contract, a demand was
issued to produce 4 grams of the compound containing changed 5’ cap in UW laboratories.
Inventor’s Credibility – Show It Will Work on the Scale
BioNTech wanted to minimise the investment risk. By demanding 4 grams of the compound, that is the amount sufficient
to start clinical trials, the investor wanted to verify whether the invention, still being in a theoretical sphere, is transferable
to the sphere of practical applications. It is worth explaining that such compounds usually are obtained in the amount of
1 - 5 milligrams and the synthesis on the scale expected by BioNTech was about to take weeks. The scientists of UW took
on the challenge and after intensive work they proved that they can produce 4 grams of pure 5’ cap S-ARCA.
Gaining the Popularity – Sub-licence and Global Expansion
The invention by UW scientists turned out to be groundbreaking enough for the investor to gain the attention of a global
pharmaceutical concern and to start negotiations on granting a sub-licence for further clinical trials on a large scale. It required
a revision of the original licence contract, including benefits for the inventors and institution. The inventors realised that a bigger
player on the market was needed to achieve the implementation of their solution on the global market.
For investors, the full engagement of the inventors in further product development on its every
stage is of a great importance. Actually, it was inventors’ engagement and faith in the project that
eventually convinced BioNTech to conclude the licence contract.
Commercialisation of mRNA 5’ Cap –
Step by step

6. Head of Gene Expression Laboratory at the Faculty of
Physics and Head of Interdisciplinary Laboratory of
Molecular Biology and Biophysics at the Centre of New
Technologies UW
Since 1980, Prof. Edward Darżynkiewicz has conducted research on the function of 5’ end (so
called cap) in eukaryotic mRNA based on synthetic cap analogues; he is a pioneer in this field not
only in Poland, but in the world as well (over 170 scientific publications in high level journals, e.g.
in Cell. Science, Nature Comm. and the like). In the second half of the 1980s, he initiated synthetic
studies on chemically modified dinucleotide cap analogues and on their enzymatic introduction
to mRNA in the search for highly translationally active transcripts. His discovery of so called “Anti
Reverse Cap Analog”, known as “ARCA”, together with Janusz Stępiński i Robert E. Rhoads (USA) in
2001,occurredtobeagroundbreakinginventionandhasbeenpatented,commercialisedandhas
found a broad application in biotechnological production of proteins. These events have become
an inspiration to search for even more effective analogues (beta S-ARCA and beta B-ARCA). In
2014, he was awarded the Leon Marchlewski Medal for outstanding achievements in the field of
biochemistry and biophysics.
Edward Darżynkiewicz, Prof.
Head of Laboratory of Bioorganic Chemistry
at the Centre of New Technologies UW
He works on the synthesis of nucleotides and their analogues of biological and therapeutic
importance. For the last 10 years he has specialised in 5’-end mRNA analogue (cap) synthesis
to develop “stable mRNA”, i.e. resistant to cell degradation mechanisms, as well as “effective
mRNA” with molecules which stimulate cells to produce certain proteins more efficiently
than natural ones. Presently, he is the head of an advanced laboratory at the Centre of New
Technologies, University of Warsaw. He has authored and co-authored nearly 100 scientific
publications. In his professional career, he has filed 5 patent applications. He is a co-inventor
and initiator of two inventions (beta S-ARCA and beta B-ARCA) protected with international
patents. Fellow of the Rector Scholarship for years 2004 - 2007, fellow of the Polityka magazine,
winner of the UW Rector’s Award for scientific achievements as well as of the Faculty of Physics
UW Award.
Jacek Jemielity, Prof. UW
Joanna Kowalska, Ph.D.
Associate Professor at the Division of Biophysics,
Institute of Experimental Physics UW
She specialised in the chemical synthesis and studying properties of modified nucleotides of
biological importance. For the last few years she has worked on the design and synthesis of 5’-
end (cap) mRNA analogues to apply in biotechnology and medicine. She has authored and co-
authored more than 50 scientific works. Fellow of, among others, the Minister of Science and
Higher Education Scholarship, Foundation for Polish Science. Many times awarded for scientific
achievements, e.g. with the UW Rector’s Second Degree Award, the Faculty of Physics UW Award,
Prof. Pieńskowski Award. She is a co-inventor of two inventions (beta S-ARCA and beta B-ARCA)
protected with international patents.
Co-inventors
of beta S-ARCA and beta B-ARCA from UW
Co-authors of the invention from UW
Co-authors of the invention from LSUHSC-S
Joanna Żuberek, Ph.D., Assistant Professor at the Division of Biophysics, Institute of Experimental Physics
UW, co-inventor of beta B-ARCA.
Maciej Łukaszewicz, Ph.D., Assistant Professor at the Division of Biophysics, Institute of Experimental
Physics UW, co-inventor of beta B-ARCA.
Ewa M. Grudzień-Nogalska, Doctor of Philosophy (PhD), Biochemistry, Biophysics and Molecular Biology.
Robert E. Rhoads, Professor, Head of the Department of Biochemistry & Molecular Biology.

7. What you should know about UOTT
University Technology Transfer Centre is a part of University of Warsaw and it helps scientists to
commercialise their work (discoveries and inventions). UOTT supports scientists throughout the
whole commercialisation path – from the idea, through filing a patent application, to establishing
a spin-off company, selling a licence or a single disposal of rights.
photo:GrzegorzKrzyżewski

8. Science Commercialisation
Patent Protection
Commercialisation Process Consulting
Establishing Spin-off Companies
Sales and Marketing Support
University Technology Transfer Centre
ul. Żwirki i Wigury 101 (building CNBCh UW), 02-089 Warsaw
tel./ fax (+48 22) 55 40 730
uott@uott.uw.edu.pl
www.uott.uw.edu.pl