ISSN 1866-8836
Клеточная терапия и трансплантация

Genome Games: Market Challenges, Investment Opportunities and Patent Battles

Kristina A. Khodova
Skolkovo Foundation, Moscow, Russia
Dr. Kristina A. Khodova, Skolkovo Innovation Center, Nobel Street 5, 143026, Moscow, Russia
Phone: +7 (916) 438-29-54 E-mail:
doi 10.18620/ctt-1866-8836-2017-6-1-44-47
Submitted 19 December 2016
Accepted 19 December 2016
Published 10 March 2017

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Cellular Therapy and Transplantation (CTT)
Volume 6, Number 1


Recent improvements in targeted genome editing technologies have opened new potential therapeutic applications in different medical conditions. Despite the fact that most of these technologies are still at early implementation phase, they already demonstrate a high therapeutic potential which may change treatment methodology for many severe diseases, and exert a significant influence upon market landscape and human population in general. However, some major issues and risks remain in the field, i.e., whether appropriate products and results will meet expectations of scientists, engineers and investors, and what risks could be anticipated for the registration procedures and introduction of original products into clinical practice.


Genome editing, investment, startups, research & development, intellectual property.

It took millions of years for apes to evolve into humans.
It may take only a century for humans to change again.
Unknown author

Recent  advent  and  subsequent  improvements  in  genome editing  techniques  have  dramatically  changed  public  attitudes  towards  implementation  of  biotechnology  and  created  novel  opportunities  for  a  variety  of  technological  startup companies. None of the most influential publications in the world have overlooked growing interest for for genome editing  in  various  fields  of  medicine,  agriculture,  industrial biotech, etc. Booming headlines have announced future victories  over  severe  diseases,  comparing  recent  achievements in genetic engineering to invention of electricity, antibiotics, rocketry, and the Internet. A total of 1 billion US dollars has already  been  invested  into  these  studies,  including  venture capital and other funding sources. How reasonable could the high expectations of scientific, clinical and business communities be? What obstacles should researchers and industries anticipate on their way to the market? Is this potential really high, or is it another soap bubble from the modern biotech?

Since 2005, as the term ‘Genome editing’ was coined [1], the field has developed, both in academic and industrial circles, towards  the  more  efficient  targeted  nucleases  which  should possess  optimal  specificity,  cost  efficiency,  and  provide  reproducible results. These advances resulted in development of the three main groups of relevant enzymes, i.e., zinc finger nucleases (ZFN), Transcription activator-like effector nucleases (TALEN), and CRISPR/Сas enzyme systems (CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; Cas, a CRISPR-associated protein). High accuracy of specific genome  targeting  by  means  of  these  molecular  lancets  led to present-day discovery of a novel research area which was designated as ‘gene surgery’.

Broad outlooks of gene surgery have drawn immediate interest, first of all, in the medical field. Over the last decade, significant increase in the number of companies using different genome editing techniques has been observed. Their aim is to  develop  novel  therapies  for  inherited  monogenic,  oncological and viral diseases. For instance, Sangamo Biosciences has developed a proprietary genome editing technology using  ZFN  system,  and  succeeded  in  Phase  I  clinical  studies with HIV-infected patients, then extending potential indications  to  hemophilias,  hemoglobinopathies,  etc.  [2].  French company Cellectis  is  developing  TALEN  in  immuno-oncology.  The  idea  is  to  edit  immune  cells  for  treatment  of  hemato-oncological disorders and some solid tumors [3]. The Editas  Medicine activities  are  focused  on  genetic  diseases, e.g.  their  first  clinical  trial  scheduled  for  2017  will  concern Leber’s amaurosis, a rare clinical form of blindness [4]. Caribou Biosciences studies different options for CRISPR-based technologies in medicine, agriculture, biological studies and industry,  [5]  whereas Intellia  Therapeutics,  their  affiliated company, is seeking for ex vivo and in  vivo genome editing for a number of clinical conditions [6]. CRISPR Therapeutics are focused on three main topics, (1) ex vivo gene editing of hematopoietic  stem  cells;  (2) in  vivo gene  editing  for  liver diseases; (3) additional in vivo programs targeting other or gan systems, such as muscle and lung [7].

All  things  considered,  there  is  a  new  ‘gold  rush’,  this  time centered on gene therapy. Investments to each of these companies  are  estimated  in  dozens  and  hundreds  millions  US dollars,  whereas  capitalization  of  the  most  advanced  firms exceeds a billion USD. Meanwhile, appropriate clinical studies  with  different  targeted  nucleases  enrolled  less  than  100 patients  with  viral  and  oncological  diseases  [8,  9].  To  date, several other clinical studies are endorsed [10], and vast majority  of  companies  are  only  in  the  process  of  approaching clinical  phase.  Moreover,  big  industry,  e.g., Novartis, Astra Zeneca, Bayer, has also entered the game.

Several start-ups involved in genome editing have emerged in Russia. They are employed for medical applications of genome editing technologies. For instance, two Skolkovo resident companies are performing these activities, i.e., AGCT with a flagship project of hematopoietic stem cells gene editing aimed for the treatment of HIV-associated tumors [11], and the Gene Therapy Centre.

It is commonly known that intellectual property is the main asset of any company active in biotechnology and largely determines  its  market  price  and  value.  Proprietary  rights  for ZFN and TALEN are already established by the main players, thus  forcing  emerging  companies  to  license  the  main  patents, or to create new inventive solutions. Meanwhile, an uncertainty with intellectual property for CRISPR is characterized as a “patent battle” by most experts in the field. In May 2012,  Jennifer  Doudna,  employed  at  the  UC  Berkeley  filed a  provisional  patent  application  describing  a  new in  vitro gene editing technique, jointly with Emmanuelle Charpentier (University of Vienna at that time) and other colleagues. In December 2012, Feng Zhang from the Broad Institute in Boston  filed  a  provisional  patent  application  for  the  specific use of CRISPR/Cas system exclusively in eukaryotic cells. Results  of  the  both  studies  were  reported  in Science in  August 2012 and February 2013, respectively [12, 13].

The first patent was finalized in March 2013, and the second one was finalized seven months later. However, the Broad Institute and MIT’s joint patent was granted first in April 2014, due to the fast track requested by Zhang at the United States Patent and Trademark Office (USPTO). A year later, the UC Berkeley  claimed  to  the  USPTO  on  the  patent  interference right,  demanding,  at  least,  partial  edition  of  the  patent  applied  by  Zhang,  based  upon  the  evidence  that  CRISPR  use in eukaryotic cells presumed an obvious extension of the in vitro studies  by  Doudna  and  Charpentier.  Over  2016,  a  big investigation has proceeded including analysis of a thousand of relevant documents offered by the both sides. The discussion is still ongoing, and appropriate decision is expected not earlier that in 2017.

However,  despite  the  lack  of  clear-cut  rights  for  intellectual  property,  and  uncertainty  of patent  landscape,  about  ten emerging biotechnological companies based on CRISPR/Cas techniques  have  raised  significant  funding  over  last  years. Some  of  them  have  already  licensed  intellectual  property from  their  current  owners  while  others  are  awaiting  decisions on the legal conflicts. It is still unknown whether these decisions  will  influence  the  marketing  processes  and  if  the CRISPR-based genome editing will be widely available in the future. Currently three companies are leading in the field of CRISPR/Cas-based  technologies  applications  in  medicine, i.e., Editas  Medicine,  with  Zhang  as  a  co-founder, CRISPR Therapeutics,  co-founded  by  Charpentier,  and Intellia  Therapeutics,  an  affiliated  company  by Caribou  Biosciences,  with Doudna as a co-founder. Great expectations placed on these technologies are counterpoised by many open questions of the novel therapies efficacy  and  safety.  Definite  answers  will  be  obtained  only  in  the course of clinical trials which will determine successfulness of either research team.

In  2016,  the  story  with  CAR-T  (Т  lymphocytes  with  chimeric  antigen  receptors)  has  forced  the market  players  and general  public  to  realize  potential  serious  consequences of  novel  over-estimated  approaches.  A  clinical  trial  performed  by Juno  Therapeutics was  discontinued  in  July,  due to severe neurotoxicity (i.e. cerebral edema) and lethal outcomes in three patients with acute lymphoblastic leukemia. This  event  caused  immediate  reaction  among  investors,  researchers  and  society.  The  questions  were  raised  on  ethics and design of clinical studies by sponsors keeping the novel production  technologies  as  a  commercial  secret,  as  well  as claims for transparency from all the stakeholders, especially, in advanced fields of medicine [14]. The reasons were soon specified, the study protocol was amended appropriately, and so the trial was resumed. In November, however, two more lethal  outcomes  were  reported  by  similar  reasons,  with  repeated  discontinuation  of  the  clinical  trial.  Despite  certain concerns,  the  challenges  were  only  transient,  both  for Juno Therapeutics,  and  their  competitors  developing  CAR-T  for other applications (Kite Pharma, for non-Hodgkin lymphoma, Novartis), and the first approval of this technology is expected in the US in early 2017. Outlooks for the CRISPR technology application for CAR-T production resulted into several joint R&D programs: Editas Medicine in cooperation with Juno Therapeutics are developing  novel  gene-engineered  Т  cells  for  cancer  immunotherapy,  whereas Novartis combined  their  efforts  with Intellia Therapeutics,  with  a  purpose  of  editing  hematopoietic  stem cells and design of novel CAR-T cells. Complex  approval  procedures  represent  additional  barriers for commercialization of new technologies, due to high-degree regulation in medicine and legal specifications in different  countries.  Moreover,  some  open  questions  remain,  e.g., the  issues  of  pricing,  optimized  manufacturing  and  quality control  for  the  personalized  products.  Advances  in  technologies  definitely  result  into  changes  and  improvement  of regulatory  standards.  This  is  already  true  for  gene  therapy legislation in the USA and the EU [15, 16]. Moreover, some special procedures for registration of breakthrough technologies are available in these countries, e.g., Prime in European Medical Agency (EMA), and Breakthrough Designation and Fast  Track in  Food  and  Drug  Administration  (FDA,  USA). In  Russian  Federation,  the  Federal  Law On  Biomedical  Cellular  Products was  issued  in  2016  [17],  which  has  fixed  the regulatory frames for ex vivo gene editing technologies. Regulations for in vivo gene therapeutic techniques are generally determined in the Federal Law On Medicinal Drug Controls [18].  Emergence  of  novel  technologies  poses  questions  not only to the researchers but for the regulatory bodies as well. Certainly,  a  dialogue  between  the  industry  and  regulators may  accelerate  clinical  implementation  of  novel  promising technologies  aimed  for  the  future  treatment  of  serious  and life-threatening diseases.

Rapid development and growing interest in genome editing have  drawn  attention  of  the  community  to  this  technology, both in the view of potential treatment advances of many severe disorders, as well as a source of numerous ethical dilemmas. The main aspect may concern opportunities for germinal  cell  and  embryos  editing  at  the  preimplantation  stage. Just  in  February  2016,  Kathy  Niakan  from  Francis  Crick Institute obtained the first British licence for editing human embryos  limited  by  research  purposes  only,  in  order  to  investigate fundamental mechanisms of normal and disturbed embryogenesis [19]. Quite recently, two research teams from China  have  reported  the  first  successful  cases  of  human embryo  editing  [20].  In  the  first  case,  the  gene  editing  was performed  due  to  an  inherited  blood  disorder,  and,  in  the second  case,  the  procedure  induced  resistance  against  HIV. In both cases, the embryos were non-viable and were eliminated within several days. These events caused vivid discussions on rationale and relevance of human genome editing. On  the  one  hand,  such  approach  may  potentially  cure  the child of an inherited disease, or make him non-susceptible to many infections. On the other hand, it may result in severe complications, since long-term effects of such interventions are still unknown. Moreover, there are concerns that in the future these procedures could be used for the consumer purposes,  e.g.  choice  of  eye  color,  or  mental  characteristics  of the subject.

Modern  legislation  on  the  embryo  editing  varies  in  different countries, from total ban to biased interpretation of legal standards  [21].  Hence,  there  is  no  answer  to  a  question  on the birthplace of the first “edited” child. The opinion leaders in this field have already replied to the social challenges and provided their comments, with respect to prospects of gene editing in germinal cells and embryos [22].

Technological breakthroughs, especially, in the field of biology  and  medicine,  reveal  a  number  of attractive  outlooks, along  with  potential  hazards.  Only  long-term  studies  may answer many current questions concerning human genome editing and we are lucky to live at the moment when we can observe and influence these changes.

Conflict of interests

The author has no conflicts of interest to be declared.


  1. Urnov  FD,  Miller  JC,  Lee  YL,  Beausejour  CM,  Rock JM,  Augustus  S,  Jamieson  AC,  Porteus  MH,  Gregory  PD, Holmes   MC.   Highly   efficient   endogenous   human   gene  correction  using  designed  zinc-finger  nucleases.  Nature. 2005;435(7042):646-651.
  8. Tebas  P,  Stein  D,  Tang  WW,  Frank  I,  Wang  SQ,  Lee  G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang WT, Levine BL, June CH. Gene editing of CCR5  in  autologous  CD4  T  cells  of  persons  infected  with HIV. N Engl J Med  2014; 370(10):901-910.
  9. Cyranoski D. CRISPR gene-editing tested in a person for the first time. Nature. 2016; 539:479.
  10. Reardon  S.  First  CRISPR  clinical  trial  gets  green  light from US panel. Nature News. Jun 22, 2016.
  12. Jinek  M,  Chylinski  K,  Fonfara  I,  Hauer  M,  Doudna  JA, Charpentier  E.  A  programmable  dual-RNA-guided  DNA endonuclease in adaptive bacterial immunity. Science. 2012; 337(6096):816-21.
  13. Cong  L,  Ran  FA,  Cox  D,  Lin  S,  Barretto  R,  Habib  N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F. Multiplex Genome  Engineering  Using  CRISPR/Cas  Systems.  Science 2013; 339(6121):819-23.
  14. Hey SP, Kesselheim AS. The FDA, Juno Therapeutics, and the ethical imperative of transparency. BMJ. 2016;354:i4435.
  15. EMA: Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products, 2015
  16. FDA Guidance: Preclinical assessment of investigational cellular  and  gene  therapy  products,  2013;  Potency  tests  for cellular and gene therapy products, 2014.
  17. Russian Federal Law On Biomedical Cellular Products of 23/06/2016, No.180-ФЗ (as amended for 2016, in Russian).
  18. Russian  Federal  Law  On  Medicinal  Drug  Controls  of 12/04/2010, No.61-ФЗ (as amended for 2016, in Russian).
  20. Callawey E. Second Chinese team reports gene editing in human embryos. Nature News. Apr 8, 2016.
  21. Araki M., Ishii T. International regulatory landscape and integration of corrective genome editing into in vitro fertilization. Reprod. Biol. Endocrinol. 2014; 12:108.
  22. Bosley KS, Botchan M, Bredenoord AL, Carroll D, Charo RA, Charpentier E, Cohen R, Corn J, Doudna J, Feng G, Greely  HT,  Isasi  R,  Ji  W,  Kim  J-S,  Knoppers  B,  Lanphier  E, Li  J,  Lovell-Badge  R,  Martin  GS,  Moreno  J,  Naldini  L,  Pera M,  Perry  ACF,  Venter  JC,  Zhang  F,  et  al.  CRISPR  germline engineering—the community speaks. Nature Biotechnology. 2015; 33:478–486.

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