Commercialization and transfer assistance program

PARTNER ORGANIZATION

1. Role, experience and qualifications of the partner organization in conjunction with the project

Gestion Univalor, Limited partnership ("Univalor") is a limited partnership whose mission is to commercialize discoveries made by researchers at the Université de Montréal, École Polytechnique de Montréal, CHU Sainte-Justine-Mother and Child University Hospital Center, HEC Montréal, Hôpital Maisonneuve-Rosemont, Hôpital du Sacré-Coeur de Montréal, Institut de recherches cliniques de Montréal and the Institut universitaire de gériatrie de Montréal. Univalor also provides commercialization services to the limited partnerships of the Montréal Heart Institute.

Univalor strives to develop profitable and long term business relationships with companies wishing to maintain or improve their competitive position in their industry by having access to cutting edge technologies developed by internationally acclaimed researchers.
Univalor's multidisciplinary team is made up of 12 professionals in business development and commercialization with expertise in life sciences, engineering, intellectual property, legal affairs, and finance.
Achievements

Between 2001 and 2008, about 520 discoveries from Université de Montréal and its affiliated institutions have been evaluated by Univalor and more than 900 patents applications have been filed. Univalor currently has approximately 265 patents and patents pending in its portfolio, has signed over 33 license agreements and has been involved in the creation of 23 spin-off companies over the years.

Since 2001, funding provided for commercial maturation from Valorisation-Recherche Québec and the Ministère du Développement Économique, de l’Innovation et de l’Exportation (“MDEIE”) have allowed many technologies to reach maturity and demonstrate operational capabilities. More than 8.2 million dollars have been invested in our most commercially promising technologies and 130 million dollars into our spin-off companies.

2. Description of the partner organization's project selection process

Over time, Univalor has developed its own methods and tools for evaluating technologies emerging from research laboratories and for helping researchers who wish to commercialize their inventions. Internal evaluation is conducted by the business development manager and the project leader using a 5-point criteria: scientific and technological quality, intellectual property, market size, business opportunity, and relevancy for Univalor. Different databases such as Dialog Pro Competitive Intelligence, Medtrack, and Delphion are used to accomplish this evaluation. Meetings with the inventor(s) and a literature review are also very important steps in order to thoroughly evaluate the technology on its scientific basis.

Results of the internal evaluations are discussed weekly during our evaluation committee, which is comprised of all of Univalor’s professionals. This allows us to take full advantage of our multidisciplinary team. Relevant questions regarding intellectual property, technical issues, time-to-market, etc. often arise. The manager of business development may either pursue the evaluation after this meeting or retain the services of one or more experts. These experts, skilled in the specific technology, are asked to give their opinion about the technology on both a scientific and commercial basis under a confidential agreement. If the technology is recommended for commercialization, a technology transfer strategy is then drawn up by the evaluation committee and rapidly implemented.
When a technology shows a real commercial potential, Univalor’s business development manager, along with the help of the researcher and the research administrator at the institution, looks for financial resources to perform proof of concept or validation when the development status of the technology is not mature enough to start licensing discussions with a company. Once a grant is procured and the maturation project is started, the manager of business development carefully follows the progression of the project. Results are communicated to potential partners if discussions have already been initiated and interest in the technology has been shown. Business development activities start (if they have not already started) once the maturation project begins and intensifies once the proof of principal is accomplished.

3. Professional who will support the valorization process

Anne-Marie Larose, Ph.D, MBA, Business Development Manager, is currently responsible of this technology at Univalor. Ms. Larose has more than ten years of experience in the life sciences industry. After having obtained her doctoral degree in cellular and molecular biology, she joined a young biotech company at the pre-startup stage. During the five years that followed, Ms. Larose was directly involved in the different aspects of the company's corporate and technological development, notably in the elaboration of business and commercial strategies, the protection of intellectual property, the planning and management of R&D projects, and the management of the quality control department. Afterwards, as commercial attaché for the British consulate in Montréal, Ms. Larose was responsible for commercial exchanges with the Canadian biopharmaceutical sector. More recently, Ms. Larose has contributed to the fulfillment of various industrial and institutional development mandates in the Life Sciences sector as main advisor in an advisory office. As of March 2004, Ms. Larose has been developing business relations with corporations in the Life Sciences field who wish to commercialize technologies with the greatest growth potential.

10. POTENTIAL MARKET

Why typing HPV in Canada now?
There are few distinct, but inter-related reasons why having “home”, provincial, or national HPV typing assay, presents advantageous situation over not having it. Commercial impact is for example one of the resons. In Canada, Roche is the only assay approved by Health Canada with prize of 80-100$CA per screening (material cost), while FDA approved HC2 assay is reaching value of 150-180$ per single patient (Qiagen, 2009, listing prices). Both assays are developed in US. In Europe, the situation is more complex and diversified with more small companies trying to get part of the market. On the contrary, to our knowledge, Canada does not have any force to address this challenge.

Another important factor is timing, as: 1) HPV vaccination era requires more rigorous screening activity with new and specific HPV typing tests, as suggested by Canadian and international authorities (see Franko et al, Vaccine 26S (2008) F46–F58). The urgent need for new HPV screening guidelines and new biomarkers is also documented by Feng et al. (JNCI Vol. 100, Issue 5, 2008). The current and future necessity and role of HPV screening in the era of HPV vaccination is also well described by Smirh et al., Gynecologic Oncology 109 (2008) S31–S39). All these arguments are pointing out that HPV screening has to be continued in the new form - if not inforsed by government, because of the following reasons:

1) Vaccine is not clinically tested on already infected women,

2) The mother-child frequency of transition is not known,

3) The vaccine protective time is not yet defined and

4) 30% of cervical cancer will not be protected by the vaccine.

Target market
Sugestion:I would make few comments about local Montreal-Quebec-Canada market, including private laboratories, clinics, hospitals and general public awareness for diagnostics of STD.

The US molecular diagnostics field is the most dynamic segment of the in vitro diagnostic (IVD) market, with an expected growth rate of approximately 17% through 2012. Infectious disease testing accounts for the bulk of this market, and HPV testing is one of the fastest growing. As the second most prevalent molecular test, HPV testing has been estimated in 2006 to have reached approximately 55 million tests that year alone, representing an IVD market size of $500 million (Frost & Sullivan, 2006). Recently, the company Third Wave Technologies has provided projections which suggest that the global market for HPV testing could reach $250 million in 2008 with a market penetration of only 28% but a growth rate in excess of 25%. This includes more than 10 million HPV tests being performed in the United States each year. Finally, the HPV testing market in the EU is just emerging, as studies are underway to evaluate the use of HPV tests as a primary screen for cervical cancer in women, replacing Pap testing.

1. Business opportunity: Cervical cancer prevention program and HPV screening.

Cervical cancer is the second largest cause of cancer deaths in women worldwide. The estimated prevalence of HPV infection in women is 10.5%. Persistent infection with HPV is a trigger for cervical cancer, and preventing this infection can avert this deadly disease. The tests used in routine screening and clinical prevention of cervical cancer are so far based mostly on a cytological examination known as the Papanicolaou (Pap) smear. In 2005, more than 60 million Pap smears were performed in the US, and it is estimated that such screening programs and interventions have reduced the incidence of cervical cancer by ~80% in the United States, but at a cost of more than $6 billion US a year (Wu et al., 2006). Although the application of the conventional Pap test led to a dramatic reduction in the incidence rate of cervical carcinoma in the last fifty years, this test has significant limitations, including a sensitivity of only 50% to 60% in a routine screening setting (Fahey et al., 1995; Nanda et al., 2000). Because of this, an improved cytological test has been developed called the thin-layer liquid based cytology, or ThinPrep Pap test. This new test is far from infallible, failing to detect from 15% to 35% of cervical intraepithelial neoplasia (CIN) or cancer (Kulasingam et al., 2002). Recently published results of ASCUS/LSIL Triage Study for Cervical Cancer (ALTS) underline the importance of HPV DNA testing to improve specificity and reduce costs (ALTS, 2000; Sherman et al., 2001; Solomon et al., 2002a; Solomon et al., 2001; Solomon et al., 2002b; and http://www.cancer.gov/prevention/alts/results.html). Likewise, accurate and affordable HPV genotyping will be in high demand for the next few decades for ongoing HPV vaccination studies. The US Food and Drug Administration (FDA) approved the first preventive HPV vaccine on June 8, 2006 for the immunization of women between 9–26 years of age (Merck's quadrivalent vaccine Gardasil, targeting HPV 6, 11, 16 and 18 ). A second vaccine, Cervarix from GlaxoSmithKline (targeting HPV 16 and 18), is already available in Australia and in Europe. So far, these vaccines have shown to offer 100% protection against persistent homologous HPV infections (Stanley et al, 2006). In the current experimental phase of vaccine trials, HPV screenings are needed to: i) identify HPV status of individuals before vaccination and ii) monitor the efficacy of vaccines. Furthermore, the Advisory Committee of Immunization Practices (ACIP) recommends continuation of HPV screening protocols until other type-dependent vaccines are developed and until the protective time period of the vaccines has been fully characterized. In spite of the above recommendations and the introduction of a number of commercial HPV genotyping kits (see table 1), a DNA test of satisfactory specificity and sensitivity to detect HPV types is still unavailable.

2. Technological competition and benchmarking

Available HPV DNA tests, sensitivity and specificity.

Key industry participants in the molecular infectious disease diagnostics market in North America are Roche, Gen-Probe, QIAGEN (QIAGEN-Digene), bioMerieux, and Becton Dickinson. QIAGEN-Digene is the sole provider of molecular HPV tests in the US. The company offers two HPV tests which distinguish two groups of HPV subtypes (benign and malignant) and offers no subtypes differentiation. The Roche HPV genotyping test (LA) and the new Genomica CLART® HPV2 test, are the only commercially available test kits for the detection of 35 or more variants of HPV. The Roche test was expected to hit the US market in 2008, but is still unavailable to date (Frost & Sullivan, 2006).

A recent WHO international collaborative study (Quint et al., 2006) addressed the question of standardization of HPV molecular typing and detection. The methodology used in this study was performed by twenty-four participating laboratories included QIAGEN-Digene Hybrid Capture II, and by a variety of PCR/hybridization typing systems. The results demonstrate that the sensitivity of detection and the specificity of typing varied considerably among participating laboratories working with the eight most frequent high-risk types (16, 18, 31, 33, 35, 45, 52 and 58) and one low risk HPV 6. The sensitivity and specificity of the detection of HPV 16 and HPV 18 was only 62% and 74% respectively. For the other seven types, the adequate assessment varied from 95% (HPV 33 and 45) to 43% (HPV 31). Some false positive results were also reported. Clearly, an alternative approach to HPV typing is needed. Existing HPV DNA analyses rely either on hybridization techniques using type-specific HPV DNA probes, or are based on direct identification of HPV DNA PCR-products (see table 7). Several hybridization based tests and their prototypes have been developed that either require the viral DNA to be pre-amplified by PCR (Innogenetics, Roche Diagnostics, Genomica, Greiner Bio One) or do not require it (QIAGEN-Digene and Ventana). The main difficulty of hybridization approaches that use “classical probes” in these tests, is obtaining specific results when multiple similar targets have to be assayed simultaneously (note that here we use the term “classical” to distinguish from probes obtained by our method of iterative hybridization). Probes that fully match their targets (Roche, Genomica, Greiner Bio One) compromise accurate detection of multiple targets because they cross-hybridize ((Sandri et al, 2006) and our unpublished observations). Another group of hybridization-based tests that does not require prior amplification of HPV DNA include QIAGEN-Digene’s Hybrid Capture 2 (HC2) assay and Ventana’s Inform HPV. QIAGEN-Digene’s FDA-approved assay is widely used in clinical studies due to its relative simplicity and sensitivity. However, several recent reports pointed out two main disadvantages with HC2, questioning its use as a screening tool. First, it lacks individual HPV type identification. Second, there is a significant degree of cross-reactivity between the oncogenic and non-oncogenic types that leads to false-positive results 10% to 20% of the time (Cox et al., 2000; Gravitt et al., 1998; Poljak et al., 2002; Schneede et al., 2001; Terry et al., 2001; Yamazaki et al., 2001). In brief, the Ventana Inform HPV in situ hybridization assay seems to be more specific and sensitive than HC2, but its efficacy in predicting cervical lesions (positive predictive value) is no more than 48% (Qureshi et al., 2003). Several companies offer PCR-based kits (see table 3) like GenoID which became a small participant in the European molecular diagnostics market (Frost & Sullivan, 2006).

It should be noted that another option exists for the sequencing of HPV PCR products. This is performed by Visible Genetics (Toronto) (Mahony et al., 2003) and is also an in-house test at the Hôpital Hôtel-Dieu de Montréal and at the Hôpital Sainte-Justine de Montréal. Although these sequencing tests are highly specific, they require trained personnel, expensive technology, and most significantly, are rendered useless when multiple variants of the virus are present in the same patient. Numerous other typing systems have been described (Hwang et al., 2003; Klaassen et al., 2004; Kleter et al., 1999; Schmitt et al., 2006; van den Brule et al., 2002, Schmitt et al., 2006) and they await a detailed clinical evaluation.

Competitive advantages

The main advantage of our method resides in its enhanced power of identification and discrimination of multiple short nucleic acid sequences that differ by a few mutations, as with the different HPV types in a multiplex hybridization assay. Because we select the most specific probes in predefined hybridization conditions we considerably reduce cross-hybridization problems inherent to the conventional hybridization approach used by Roche and Genomica (such as requiring a 52^oC (+/-2) special hybridization buffer). Other important benefits are described below:

• 
  Market need: The American Cancer Society (ACS) and the American Society of Colposcopy and Cervical Pathology (ASCCP) have issued new guidelines which incorporate DNA testing for high-risk HPV types, along with Pap tests, as a primary screen for women aged 30 and over. The capacity of our probes to detect and also to identify HPV types is clearly an asset if we consider that prevention by vaccine will address only specific HPV types.
  

• 
  Multiplex detection: Finding universal experimental conditions for hybridization becomes problematic in multiplex applications where many DNA targets are considered simultaneously. Our method overcomes this problem. Instead of adjusting the hybridization conditions to the probes, a set of probes is selected in such a way as to function under the intended hybridization conditions.
  

• 
  Detection of different types in the same patient: According to GeneticLab, the frequency of HPV patient superinfection is 28%, where 71% are infected with 2 subtypes, 21% with 3 subtypes, and 8% with 4 subtypes. Kits that can not discriminate HPV types are unable to differentiate new and persistent infections and have poor diagnostic potential in regard to superinfection.
  

• 
  Low production cost and ease of use: A kit based on our technology would require neither expensive instrumentation nor skilled personnel to use. Production of our diagnostic is not expected to be expensive, which would allow the licensor to get a high profit margin. This is crucial for commercial success in the diagnostic field.
  

Even though QIAGEN-Digene presently dominates the HPV DNA diagnostic market and there will be strong competition between new kits—such as the ones from Roche and Genomica—we strongly believe there is an opportunity for these innovative kits to enter this large, underpenetrated, growing market. By fulfilling all the main requirements of the clinical and market needs, our superior kit could quickly become the test of choice for HPV detection.

Company	Test Name	Technology	Total number of subtypes detected	Detection of multiple subtypes in same patient	Comments	Market
QIAGEN (Digene)	Hybrid Capture 2	RNA-DNA hybridization	2	No	The HC2 test uses specific antibodies and chemiluminescent signal amplification to measure the presence of RNA (DNA hybrids formed between a specific RNA probe and the viral DNA). Cross-reactivity of probes; No individual identification of HPV type; Detects only high risk HPV	US, Canada, Brazil, Europe, Asia, Australia
Ventana Medical Systems	Ventana Inform	PCR+ In situ hybridization	2	No	Cytogenetic HPV testing; Allows choice of sample types; No individual identification of HPV type; Poor accuracy	US, Canada, Europe, Japan, Asia, Australia
Genomica	CLART® HPV 2	low density microarray	35	Yes	Cross-reactivity of probes	Europe
Greiner Bio One	PapilloCheck®	DNA-Chip (microarray)	18 high-risk and 6 low-risk types of HPV	Yes	Cross-reactivity of probes	Europe
GenoID	Reveal HPV	PCR+ Molecular beacons	19	not in one assay	Semi-quantitative analysis; Very complex and requires RealTime PCR	Europe
Roche	Amplicor	PCR + hybridization	13 high-risk types	No	No individual identification of HPV type; Detects only high risk cases.	Europe
Roche (LA)	Linear Array	PCR + hybridization	37	Yes	Involves amplification of a portion of the L1 gene by PCR, coding for the major capsid protein, and a subsequent hybridization of the amplification products with the HPV type-specific probes; Unable to distinguish hr-HPV 52 from other high-risk genotypes (33, 35, and 58) presenting 2.2% of all cervical cancers; Less sensitive if a sample has a single infection with some specific HPV genotypes that are poorly amplified by PGMY (HPV 33 and 52); Hybridization probe for HPV 51 not sensitive enough; Requires very controlled temperature of hybridization 52+/-2°C; Presently the most accurate typing kit on the market.	Europe
BioMerieux	Protect HPV-Proofer assay (based on NucliSens Easy Q platform of bioMerieux)	Detection of oncogenic HPV gene expression	5 high risk types	n/d	Aims at the early detection of cervical carcinogenesis. Technology licensed from the company NorChip in January 2007.	Europe
Innogenetics	Inno-LiPA HPV Genotyping CE	PCR + hybridization	25	Yes, but have problems with sensitivity, due to the bias induced by 'universal' primers	Involves amplification of a portion of the L1 gene by PCR, coding for the major capsid protein, and a subsequent hybridization of the amplification products with the HPV type-specific probes; Problems detecting multiple infections reported, related to type-specific sensitivity of amplification; Full set of HPV types not included; Cross-hybridization reported; Requires controlled temperature of hybridization.	Europe
QIAGEN (through acquisition of Shenzhen P.G. Biotech Co.)	HPV detection kit	PCR -based	only 4 most common types (6, 11, 16 and 18)	n/d	n/d	China
Third Wave Technologies	HPV screening test (14 high-risk types of HPV)	n/d	14	No	n/d	FDA application for approval expected in 2008-2009
Third Wave Technologies	HPV genotyping test (HPV—16 and 18)	n/d	2	Yes	n/d
GeneticLab	PapiPlex^TM	Multiplex PCR	16	Yes	Multiplex detection; Complex handling and assay performance, (requires gel manipulation); Only 16 types; not clear how non-including types will perform	Japan
SensiGen	AttoSense ™ HPV Test	MassArray assay (mass spectrometry coupled with competitive PCR)	15 high risk types	n/d	Ultrasensitive detection kit (1 to 3 copies of HPV DNA in blood or tissue sample). The test is still in development. Licensed from University of Michigan in February 2007	Not on the market

Table 7. HPV molecular diagnostic kits

11.