- 1.IP Barriers in Developing Generic Vaccines & How to
Tackle these! (F) Ravi Dhar, Ph.D. ([email protected])
([email protected]) 5.3.2014 (Mobile: 987-162-0439) Affiliation:
BIRAC-DBT, GoI, India Past Affiliations: University of Kashmir,
India University of Delhi, India National Institute of Immunology,
India Johns Hopkins University, U.S.A. LSU, U.S.A. OTT, Boston
University, U.S.A. OTT, NIH, U.S.A. 4/6/2014 1RD_Vaccine Meet_2014
Protecting the bottom line: Tackling IP barriers in developing
generic vaccines. Vaccine World Summit-2014, Hyderabad, India
2. 4/6/2014 RD_Vaccine Meet_2014 Acknowledgements IMAPAC_2014,
Singapore NIH PubMed Scientific Community across world DBT, GoI
NII, India Dr. M.K. Bhan, India Dr. Gerald T. Keusch, BU, USA Dr.
Asley Stevens, BU, USA DELCON Library @BIRAC Various Websites
USPTO/EPO/IPO Nature Biotechnology & other Journals GHI &
OTT, Boston University, USA OTT, NIH, USA 2 3. 4/6/2014 RD_Vaccine
Meet_2014 3 Part-I 4. 4/6/2014 RD_Vaccine Meet_2014 4 Basic
Information: When a new product like drug or vaccine is developed,
it is patented. Generic drugs or vaccines can be legally produced
as drugs when: 1) the patent has expired, 2) the generic company
certifies the brand company's patents are either invalid,
unenforceable or will not be infringed, 3) for drugs which have
never held patents, or 4) in countries where a patent(s) is/are not
in force. The expiration of a patent removes the monopoly of the
patent holder on drug sales licensing. Patent lifetime differs from
country to country, and typically there is no way to renew a patent
after it expires. A new version of the drug/vaccine with
significant changes to the compound or structure could be patented,
but this requires new clinical trials. In addition, a patent on a
changed compound/ or component of vaccine does not prevent sales of
the generic versions of the original drug unless regulators take
the original drug off the market 5. 4/6/2014 RD_Vaccine Meet_2014 5
Issue on Generics Patented Medical interventions vs. Requirement of
wide range of affordable Medical interventions:
Drugs/vaccines/devices/ diagnostics Do we need to produce Generic
Products or Modify Intellectual Property Laws & Modify
International Treaties 6. 4/6/2014 RD_Vaccine Meet_2014 6 The first
task in developing a utilitarian theory of intellectual property is
translating the ideal of the "greatest good of the greatest number
(social welfare in mind), yet allowing the creator to maximize
wealth. (Source: Richard Posner, Economic Analysis of Law (3rd ed.,
Boston: Little, Brown, 1986), pp. 11-15) 7. 4/6/2014 RD_Vaccine
Meet_2014 7 Importance of Generics (U.S. example): In USA 80% of
U.S. prescriptions filled with a generic medicine Food and Drug
Administration (FDA): This agency must approve every generic
medicine before it can be sold in the United States Proving
Bio-equivalance 80-85% cost savings by consuming generic medicines
$1 Trillion! According to IMS Health, generic medications saved the
American health care system $1 trillion between 2002 and 2011 GBR
Generic Brand Reference Guide This easy-to-use guideavailable as a
smart phone app or by mailoffers health care professionals
cross-referenced lists of brand name and generic medicines. 8.
4/6/2014 RD_Vaccine Meet_2014 8 To gain FDA approval, generic
medicines must be proven to be bioequivalent to their brand name
counterparts. That means generic and brand name medicines are the
same in the following ways: Active ingredient Maximum amount of
medicine in the blood at any given time Total amount of medicine in
the blood from the time its taken until the body eliminates it
Strength and dosage Route of administrationtablet, injection, etc.
Expected safety and efficacy FDA evaluation of manufacturing
facilities Just because products have the same active ingredient
does not mean they are bioequivalent. Once generic bioequivalence
is proven, the FDA considers a generic medicine interchangeable
with the brand name medicine. (Source:
http://www.mylan.com/products/why-generics) 9. 4/6/2014 RD_Vaccine
Meet_2014 9 Tackling Patent Reforms (US Academia view point-2013)
Discourage weak claims of patent infringement brought at least in
part for nuisance value Limit the scope of discovery in patent
cases prior to the issuance of a claim construction order To
contain/address un-necessary litigations. To facilitate the early
adjudication of patent infringement suits, we recommend that
patentees be required to plead their infringement allegations with
greater specificity. To increase transparency and confidence in the
market for patent licensing: (a) Government should ask patentees to
disclose and keep up-to-date the identity of parties with an
ownership stake or other direct financial interest in their patent
rights. (b) Government should consider additional legislation
designed to deter fraudulent, misleading, or otherwise abusive
patent licensing demands made outside of court. (Source:
http://www.patentlyo.com/patent/2013/11/ip-law-professors-rise-up-against-patent-assertion-entities.html)
10. 4/6/2014 RD_Vaccine Meet_2014 10 11. An Interesting Article:
GLOBAL HEALTH: A NORMATIVE ANALYSIS OF INTELLECTUAL PROPERTY RIGHTS
AND GLOBAL DISTRIBUTIVE JUSTICE by Matthew Wayne DeCamp Department
of Philosophy Duke University Date: 25 April 2007
(http://dukespace.lib.duke.edu/dspace/bitstream/handle/10161/193/D_DeCamp_Matthew_Wayne_a_052007.pdf?sequence=1)
4/6/2014 11RD_Vaccine Meet_2014 12. VACCINE TECHNOLOGY TRANSFER:
SUMMARY CHART ERAS TECHNOLOGY ECONOMICS POLITICS REGULATION LEGAL
AND INTELLECTUAL PROPERTY TECHNOLOGY TRANSFER HEROIC Low Low cost
Colonial policy plus altruism Nearly absent Absent Institut Pasteur
MID-CENTURY Moving Increasing cost National health programs
Strengthening from a low base Absent WHO, national institutes,
meetings, education? ERADICATION PROGRAMS Moving Pressure by buyers
Altruism, global budget issues Strengthening, WHO prequalification
Nearly absent WHO, expert groups, donor funding CURRENT High High
cost/low margin, economies of scale Self-sufficiency,
biotechnology, donor politics, privatization -Very high domestic
and parallel -WHO prequalification Strengthening but mainly on
intermediates and processes WHO DCVMN, biotechnology programs,
corporate strategic alliances, donors education FUTURE? High
Globalization? Access? Financial sustainability? ICH? Research tool
issues? Bio-terrorism concerns? Global integration? 12 Source:
J.Barton@Stanford, U.S.A. 4/6/2014 RD_Vaccine Meet_2014 13.
4/6/2014 RD_Vaccine Meet_2014 13 On Generics: (1) A generic drug
has lower development costs because it can rely on the research
data from the originator product, As far as the generics are
concerned, all they have to show is bio-equivalency to the
innovators product and piggy-ride on the rest of the innovators
data. For challenging molecules, where bioavailability is an issue,
the generics have a tough time achieving bio- equivalency, due to
several factors, and are a cause for concern. (2) The patent life
of a new molecule in the United state is 17 years from first
discovery. It takes quite a few years in preclinical, pharmacology,
pharmacokinetics,/drug metabolism, toxicology and formulation
development, phase 1, 2 and 3 with longest time required in phase 3
depending on the diseases the drug is being targeted for. By this
time, in most instances, the time left for return, on about a
billion dollars invested to discover and develop a new molecule, is
about 10 years or less. 14. 4/6/2014 RD_Vaccine Meet_2014 14
Part-II 15. 4/6/2014 RD_Vaccine Meet_2014 15 We need to answer the
following critical questions! Q) Whether the current medical
innovation system works, and for whom. Answer: It works & has
delivered, however, generics are important & affordable for
economically weak sections of society Q) How best could governments
balance private commercial interests and public health in their IP
laws? Answer: Difficult question for any developing or
under-developed country due to financial constraints. However, to
balance these, both are equally important Barrier=Obstruction/
Issue=Important Topic for debate 16. 4/6/2014 RD_Vaccine Meet_2014
16 Vaccines& Biologics! Vaccine: A preparation of killed
microorganisms, living attenuated organisms, or living fully
virulent organisms that is administered to produce or artificially
increase immunity to a particular disease. (Merriam-Webester.com)
Biologic: A preparation, such as a drug, a vaccine, or an
antitoxin, that is synthesized from living organisms or their
products and used as a diagnostic, preventive, or therapeutic
agent. The American Heritage Medical Dictionary Copyright 2007,
2004 by Houghton Mifflin Company. Published by Houghton Mifflin
Company. All rights reserved. A vaccine is a biological preparation
that improves immunity to a particular disease. A vaccine typically
contains an agent that resembles a disease-causing microorganism
and is often made from weakened or killed forms of the microbe, its
toxins or one of its surface proteins. The agent stimulates the
body's immune system to recognize the agent as foreign, destroy it,
and keep a record of it, so that the immune system can more easily
recognize and destroy any of these microorganisms that it later
encounters. (Wikipedia) 17. 4/6/2014 RD_Vaccine Meet_2014 17 Are
there Generic Vaccines? There is no (?) such thing as a generic
vaccine. Even vaccines based as closely as possible on licensed
products must prove safety and efficacy in clinical trials,
although for many well-established classes of vaccines, these
trials can be smaller than the trials used to license the original
vaccine. Vaccines are also biologics, but are generally even more
complex than biologic drugs. Source: Expert Rev. Vaccines 8(10):
1439-49. 18. 4/6/2014 RD_Vaccine Meet_2014 22 Why Generic Vaccines?
Generic vaccines are cheaper A high percentage of vaccination would
drastically decrease the spread of disease Benefits the Governments
by complementing preventive health measures Employers have to deal
with healthy and productive workforce Families would benefit by
gaining workable man-days Benefits individuals because of good
health quality & loss of man days 19. 4/6/2014 RD_Vaccine
Meet_2014 19 Lancet. 2013 Feb 23;381(9867):680-9. doi:
10.1016/S0140-6736(12)62128-X. Epub 2013 Feb 12. Promotion of
access to essential medicines for non-communicable diseases:
practical implications of the UN political declaration. Hogerzeil
HV, Liberman J, Wirtz VJ, Kishore SP, Selvaraj S, Kiddell-Monroe R,
Mwangi-Powell FN, von Schoen-Angerer T; Lancet NCD Action Group.
Departmentof Global Health, University of Groningen, University
Medical Centre, Groningen, Netherlands. [email protected]
AAccess to medicines and vaccines to prevent and treat
non-communicable diseases (NCDs) is unacceptably low worldwide. In
the 2011 UN political declaration on the prevention and control of
NCDs, heads of government made several commitments related to
access to essential medicines, technologies, and vaccines for such
diseases. 30 years of experience with policies for essential
medicines and 10 years of scaling up of HIV treatment have provided
the knowledge needed to address barriers to long-term effective
treatment and prevention of NCDs. More medicines can be acquired
within existing budgets with efficient selection, procurement, and
use of generic medicines. Furthermore, low-income and middle-income
countries need to increase mobilisation of domestic resources to
cater for the many patients with NCDs who do not have access to
treatment. Existing initiatives for HIV treatment offer useful
lessons that can enhance access to pharmaceutical management of
NCDs and improve adherence to long-term treatment of chronic
illness; policy makers should also address unacceptable inequities
in access to controlled opioid analgesics. In addition to
off-patent medicines, governments can promote access to new and
future on-patent medicinal products through coherent and equitable
health and trade policies, particularly those for intellectual
property. Frequent conflicts of interest need to be identified and
managed, and indicators and targets for access to NCD medicines
should be used to monitor progress. Only with these approaches can
a difference be made to the lives of hundreds of millions of
current and future patients with NCDs. bstract Copyright 2013
Elsevier Ltd. All rights reserved. PMID: 23410612; [PubMed -
indexed for MEDLINE] 20. 4/6/2014 RD_Vaccine Meet_2014 20 Indian
Strength 21. 4/6/2014 RD_Vaccine Meet_2014 21 Recent Policy of
Indian Government The health ministry has revealed that Rs 16,000
crore have been earmarked for distribution of free generic
medicines under 12th five year plan through various schemes. "There
is an outlay of Rs 16,000 crore for this initiative in the 12th
Plan. The initiative is based on the Tamil Nadu model where free
medicines procured in bulk by the Tamil Nadu Medical Services
Corporation (TNMSC), in generic name, directly from the
manufacturers is supplied through an IT enabled supply chain
management system to the public (Indian Health minister-26.8.2013)
(http://www.biospectrumindia.com/biospecindia/news/194111/govt-free-generic-
medicines-priority#16387c;%20font-size:14px;%20display:block;%20text-
decoration:none;%20) 22. 4/6/2014 RD_Vaccine Meet_2014 22 23.
4/6/2014 RD_Vaccine Meet_2014 23 = = Chances of IP generation or
Utilization or Circumventing IP 24. 4/6/2014 RD_Vaccine Meet_2014
24 Vaccine Development The development cycle is quite different
from that of traditional pharmaceuticals: Exploratory stage: to
understand the disease, its epidemiological data and the right
proteins (antigens) to use in preventing or treating the disease;
Pre-clinical stage: to assess antigen safety and select the best
candidate vaccine; Clinical development: from 10 (Phase I) to 1,000
people (Phase III) are involved in clinical trials and the first
batches are produced (clinical batches and industrial batches for
compliance); Regulatory approval: all the data collected through
the preceding stages are submitted to the relevant health
authorities for approval; Manufacturing process: takes up to 22
months to produce a single batch of vaccine; Quality control:
approximately 70% of production time is dedicated to quality
control. 25. 4/6/2014 RD_Vaccine Meet_2014 25 CAUTION Once a
vaccine is ready, it needs to be preceded by Implementation
research (which is an important step toward achieving high vaccine
coverage and the uptake of desirable new vaccines) is a highly
complex and requires participation of stakeholders from diverse
backgrounds to ensure effective planning, execution,
interpretation, and adoption of research outcomes. Unlike other
scientific disciplines, implementation research is highly
contextual and depends on social, cultural, geographic, and
economic factors to make the findings useful for local, national,
and regional applications. 26. 4/6/2014 RD_Vaccine Meet_2014 26
Problem Actions required Inadequate preclinical data and lack of
detailed information on protective correlates of immunity
contribute to product failure in clinical trials Development of
more relevant animal models; more human samples to be collected and
analysed; increased use of experimental human challenge infections
Lack of information on the infectious exposures of intended vaccine
recipients More human samples to be collected and analysed Vaccines
are to be used in populations with less- responsive immune systems
Gain a greater understanding of the mechanisms of action of
currently used adjuvants; development of vaccine delivery systems
specifically for use in immunocompromised populations Antigenic
variation requires constant updating of vaccine formulations Seek
conserved antigens; monitor genetic variation of infectious
organisms in the community High costs of vaccine development result
in premature abandonment of potentially useful products More
investment in vaccine research Inadequate access to vaccines in
poorer countries, especially those for use against tropical
diseases More tiered pricing strategies; facilitate the development
of vaccines in developing countries The current challenges for
vaccine development J Med Microbiol July 2012 vol. 61 no. Pt 7
889-894 27. 4/6/2014 RD_Vaccine Meet_2014 27 Part-III 28. 4/6/2014
RD_Vaccine Meet_2014 28 The Contradiction in IP protection An
R&D system exclusively based on IP does not generate sufficient
economic incentives for pharmaceutical companies to develop
medicines needed predominantly in poor countries. In fact, many
pharmaceutical companies have downsized or shut down their
infectious-disease R&D divisions, the recent one being Astra
Zeneca closure in india. IP often by itself, acts as a barrier to
innovation : Patent thicketsseverely limit the ability of
researchers to develop new treatments and technologies.
Increasingly, the existing approach to R&D is failing rich
countries too, with few pharmaceutical companies successfully
replenishing their drug pipelines 29. 4/6/2014 RD_Vaccine Meet_2014
29 Possible Solution (Israeli experience) Takeda (10th largest
pharma company in the world), advances a very strong late-stage
pipeline to develop a successful vaccine business that has the
potential to be commercially attractive while at the same time
creating low-cost health solutions (i.e. vaccines) for some of the
poorest countries in the world (i.e. emerging markets). In order to
do so, the company is building its strong vaccine franchise network
to achieve this goal. 30. 4/6/2014 RD_Vaccine Meet_2014 30
Recommendation of Sixty-fifth (65th) WHA, 194 Member States
endorsed the GVAP's goals and the following six strategic
objectives (May 2012): (1) All countries commit to immunization as
a priority for all stakeholders in a country, and establish good
governance for effective, high-quality immunization services. (2)
Individuals and communities should demand immunization as both
their right and responsibility. (3) Equitable access to
immunization should be a core component of the Right to Health. (4)
Strong immunization systems should become integral parts of
well-functioning health systems so that it works in a coordinated
manner to achieve national-level goals. (5) Immunization programs
should have sustainable and appropriate level of funding,
management, and oversight to ensure the sustainability of
immunization programs. (6) A continuous improvement and innovation
in research and development is necessary in all aspects of
immunization, from communication to genomics at country, regional,
and global research levels to maximize the benefits of immunization
(Source :Alonso, P.L., deQudros C.A., Robert M. & Lal A.A.
(2013) Editorial in Vaccine 31(2), April 2013) 31. 4/6/2014
RD_Vaccine Meet_2014 31 Generic vaccines are highly regulated!
Being biological products, Governments are concerned about
regulating all aspects of vaccine development namely:- Product
safety Clinical trials Pricing Reimbursement Patent protection
R&D incentives Mode of administration Issues of
thermo-stability managed by generic manufacturers Concept of
differential pricing 32. 4/6/2014 RD_Vaccine Meet_2014 32 Global
Support for Vaccine Development 33. 4/6/2014 RD_Vaccine Meet_2014
33 Part-IV 34. 4/6/2014 RD_Vaccine Meet_2014 34 IP Barriers for
Vaccine Development Technical Legal Regulatory Ethical Societal 35.
4/6/2014 RD_Vaccine Meet_2014 35 IP Barriers Technical The term
Technology Barrier refers to the use of laws, directives,
regulations and standards to regulate trade between countries.
Utilizing certification, inspection and such process to impose new
requirements on import goods based on technology, health concern,
packaging and labelling. On the surface, it is to raise the quality
standard of the merchandize, but the ultimate is to limit import.
In this tariff verses non-tariff era, the standards set for
technology barriers are said to protect the welfare of the consumer
and thus favoured by all countries. Since it improves the quality
and protects consumer rights, it is therefore, accepted and
implemented in different countries Legal Regulation According to
article 20?(general exception) and article 21?(safety exception) of
GATT, nations have the right to protect the safety of its people
and its plants. When safety is threatened, they can take exceptions
from GATT in setting technical standards. This is outside the rules
that regulate import quota base on the national per capita income
rule. However, as mentioned, technical standards are usually
wrongfully used in international trade for self-protection. It has
become means to limit import. It has become barriers to free trade.
The Ecuador resolution results in the TBT treaty, , hereon referred
as SPS Treaty. Besides the treaty, there are also other conditions
that constituted WTOs restriction on utilizing technology barrier
on international trade. Ethical Societal: depends on economic
status, poverty, affordability etc?? 36. IP issues Virus genes,
gene sequences, treatments, and vaccines: These include proprietary
claims on viruses originating in developing countries and that were
shared with the international community for public health purposes
(H5N1 Vaccines) Synthetic consensus Antigens: The patent includes
claims that cover the synthetic consensus H1 antigen and DNA
constructs and vaccines that include this antigen, including
universal influenza vaccine INO-3510. This patent also covers
methods of treating a patient using the SynCon universal influenza
vaccine
(http://www.news-medical.net/news/20120326/USPTO-issues-patent-to-Inovios-SynCon-H1N1-
influenza-vaccine.aspx) Vaccine Stabilization Technology: The novel
technology could eliminate the need for cold-chain production,
transportation and storage for Alum adjuvanted vaccines. ThermoVax
is exclusively licensed to Soligenix by the University of Colorado.
The main patent claims describe methods to prepare an
immunologically-active adjuvant-bound, freeze-dried, thermostable
vaccine composition in which the vaccine uses Alum adjuvants. The
main patent also includes claims for the adjuvant-bound composition
itself. 4/6/2014 36RD_Vaccine Meet_2014 37. 4/6/2014 RD_Vaccine
Meet_2014 37 IP Barriers Technical The term Technology Barrier
refers to the use of laws, directives, regulations and standards to
regulate trade between countries. Utilizing certification,
inspection and such process to impose new requirements on import
goods based on technology, health concern, packaging and labelling.
On the surface, it is to raise the quality standard of the
merchandize, but the ultimate is to limit import. In this tariff
verses non-tariff era, the standards set for technology barriers
are said to protect the welfare of the consumer and thus favoured
by all countries. Since it improves the quality and protects
consumer rights, it is therefore, accepted and implemented in
different countries 38. 4/6/2014 RD_Vaccine Meet_2014 38 IP
Barriers Legal Infringements of various scales has become a
subsidiary business for some 39. 4/6/2014 RD_Vaccine Meet_2014 39
IP Barriers Regulation According to article 20?(general exception)
and article 21?(safety exception) of GATT, nations have the right
to protect the safety of its people and its plants. When safety is
threatened, they can take exceptions from GATT in setting technical
standards. This is outside the rules that regulate import quota
base on the national per capita income rule. However, as mentioned,
technical standards are usually wrongfully used in international
trade for self-protection. It has become means to limit import. It
has become barriers to free trade. The Ecuador resolution results
in the TBT treaty, , hereon referred as SPS Treaty. Besides the
treaty, there are also other conditions that constituted WTOs
restriction on utilizing technology barrier on international trade.
40. 4/6/2014 RD_Vaccine Meet_2014 40 IP Barriers Ethical READ this:
http://www.allergysa.org/journals/2009/november/vaccination-and-ethical-issues.pdf
???? Compulsory vaccination was originally introduced for smallpox,
and mandatory immunisation is still in force in some countries.
Vaccination is no longer compulsory in South Africa, but carries
significant benefits both for individuals and for the community. An
ethical dilemma is posed by the fact that the vaccine is
administered to a healthy child, with the intention of protecting
both the individual child and the community, but the risk has to be
borne by the child alone. The anti-vaccination lobby claims that
there is an association between measles-mumps-rubella (MMR) vaccine
and autism, but there are no data to support this. Parents
generally have the best interests of the child at heart, and
parental autonomy to refuse vaccination should be respected unless
the child is considered to be at significant risk from that
refusal. Equity of access to vaccinations is ensured by the public
health system in South Africa. The introduction of pneumococcal
conjugate vaccine and rotavirus vaccine into the immunisation
programme is in the interests of the public, but carries
significant cost implications. 41. 4/6/2014 RD_Vaccine Meet_2014 41
IP Barriers Societal: depends on unmet medical needs, economic
status, poverty, affordability etc?? 42. 4/6/2014 RD_Vaccine
Meet_2014 42 Inspite of all the issues, people need generic
vaccines even in developed countries. This has become more
important due to increase in poverty levels world wide 43. 4/6/2014
RD_Vaccine Meet_2014 43 R&D spending has a direct relationship
with development of new essential products 44. 4/6/2014 RD_Vaccine
Meet_2014 44 45. 4/6/2014 RD_Vaccine Meet_2014 45 Part-V 46.
4/6/2014 RD_Vaccine Meet_2014 46 Multiple Layers of IP Protection
in Vaccine Development 47. 4/6/2014 RD_Vaccine Meet_2014 47
Platform Processes DNA Sequences Cell Lines Antigen Bio-processing/
Production Expression of Cells used Vehicle Immunostim Formulations
& Excipients Animal Models Issues related to New Clinical
Trials Delivery Device Yield improvement Know-how & Trade
Secrets Fishing out new IP Mechatronics used for vaccine production
Reference Reagents Protocols Adjuvant VACCINES (Source:
http://www.wto.org/english/tratop_e/trips_e/techsymp_feb11_e/friede_18.2.11_e.pdf
) (modified) 48. 4/6/2014 RD_Vaccine Meet_2014 48 Do True Generic
Drugs Exist? True 'generic' vaccines do not exist Complex
biological drugs: equivalence can not be demonstrated by simple
tests. Full clinical safety and efficacy (or surrogate) testing of
'copy' required. Even in absence of patent barriers numerous
barriers to vaccine production Expertise, know how, previous
clinical data Cost (investment, production) Clinical studies
(possibly very large if comparing efficacy to existing vaccine)
http://www.who.int/phi/news/Presentation15.pdf 49. 4/6/2014
RD_Vaccine Meet_2014 49 Trade secrets/know-how Many critical
aspects of the operations of bio- processing facilities are
valuable knowledge. In some jurisdictions, this knowledge can be
protected under trade secret law. It is customary for any
pharmaceutical production plant to keep its standard operating
procedures as trade secrets, given the considerable time and
resources involved in fine tuning operations. SOPs & Business
Plans are also restricted By extension, employees of such plants
will need to be informed of procedures for keeping information
confidential and should have related clauses in their employment
contracts. Misappropriation: Merck vs SKB 1999 50. 4/6/2014
RD_Vaccine Meet_2014 50 Vaccines under development in India in
academic institutions Human vaccines under development Institutions
involved Status Cholera vaccine Dengue vaccine Hepatitis A HIV
vaccine Japanese encephalitis vaccine Leishmania vaccine Malaria
vaccine Rotavirus vaccine Tuberculosis vaccine Typhoid vaccine
IMTECH, Chandigarh; NICED, Kolkata ICGEB, N. Delhi NIV, Pune THSTI,
Gurgaon; IAVI NII, N. Delhi NIV and University of Pune, Pune IOP
and IMM, N. Delhi ICGEB, N. Delhi AIIMS, New Delhi; CDC and NIH,
USA THSTI and UDSC, N. Delhi AIIMS, N. Delhi Live oral cholera
vaccine candidate vaccine strain VA1.4 Phase II studies completed,
Phase III will begin soon. Efforts on developing safe, efficacious
and inexpensive tetravalent dengue vaccine candidate are underway.
An agreement for transfer has been signed with BBIL for further
development. Efforts are underway to design of candidate vaccines
to elicit neutralizing antibodies against HIV. (1) Vero
cell-derived inactivated JEV vaccine developed was transferred to
Panacea Biotech. (2) JE chimeric peptide based vaccine has been
transferred BBIL, Hyderabad. Use of live-attenuated Leishmania
donovani parasites as vaccine candidates against visceral
leishmaniasis is being tested at laboratory scale. PvDBPII for P.
vivax and JAIVAC-1 vaccine for P. falciparum has been transferred
to BBIL, Hyderabad. Phase I clinical trials completed. Phase III
clinical trial of rotavirus vaccine 116E underway at three sites:
SAS, N. Delhi; CMC, Vellore; KEM Hospital Pune. Recombinant BCG 85c
(rBCG85c), one of several candidates that showed promising results
in animals, is being developed as a TB vaccine. A Vi-conjugate
typhoid vaccine technology has been transferred to USV Ltd. Mumbai.
AIIMS, All India Institute of Medical Sciences; BBIL, Bharat
Biotech International Ltd.; CDC, US Centers for Disease Control and
Protection; HIV, Human immunodeficiency virus; IAVI, International
AIDS Vaccine Initiative; ICGEB, International Center for Genetic
Engineering and Biotechnology; IMM, Institute of Molecular
Medicine; IMTECH, Institute of Microbial Technology; IOP, Institute
of Pathology; JEV, Japanese encephalitis virus; NICED, National
Institute of Cholera and Infectious Diseases NII, National
Institute of Immunology; NIH, US National Institutes of Health;
NIV, National Institute of Virology; THSTI, Translational Health
Science Technology Institute; UDSC, University of Delhi, South
Campus. a Compiled from Annual reports of Department of
Biotechnology and Indian Council of Medical Research. Source: Sen
Gupta, Sanjukta, et al. (2013) Vaccine development and deployment:
Opportunities and challenges in India. Vaccine 31(2), B43-B53 51.
4/6/2014 RD_Vaccine Meet_2014 51 Bolar Provision/Research Exemption
Implemented from 2003 in India Useful for Indian generic
manufacturers Technical consultations should be carried out to
examine the possibility of any alteration in vaccine formulation
(e.g. vaccines with or without preservative, with or without
adjuvant, liquid or lyophilized etc.) that could enable the use of
a vaccine in the existing schedule. Such a consultative process
should include scientists, program managers, cold chain managers
and representatives of the manufacturers. The combinations vaccines
have shown to improve coverage, and reduce non-program costs,
especially in countries with similar issues. These factors should
be considered before making a decision on the use of combination
vaccines Source: National Vaccine Policy, India, 2011 52. 4/6/2014
RD_Vaccine Meet_2014 52 Drug Applications and Current Good
Manufacturing Practice (cGMP) Regulations (US-FDA) FDA ensures the
quality of drug products by carefully monitoring drug
manufacturers' compliance with its Current Good Manufacturing
Practice (CGMP) regulations. The CGMP regulations for drugs contain
minimum requirements for the methods, facilities, and controls used
in manufacturing, processing, and packing of a drug product. The
regulations make sure that a product is safe for use, and that it
has the ingredients and strength it claims to have. The approval
process for new drug and generic drug marketing applications
includes a review of the manufacturer's compliance with the cGMP.
53. 4/6/2014 RD_Vaccine Meet_2014 53 Need for Effective databases
Lack of patent claim information in publicly available Indian
patent databases hampers pace of R&D. Bharat Biotechs R&D
was delayed due to uncertainty about the status of patent
protection for HPV antigens in India. Moreover, many countries in
Africa, Latin America and Southeast Asia potential markets for HPV
vaccines lack online patent databases, making it very difficult to
determine which LMCs have pending or granted patents. More
importantly, LMC companies generally lack the substantial financial
and human resources necessary to perform freedom to operate (FTO)
analyses using proprietary databases available in developed
countries. IPO database needs to be more robust?? Source: Serum
Institute of India & Bharat Biotech 54. 4/6/2014 RD_Vaccine
Meet_2014 54 Padmanabhan S. et al. (2010) Intellectual Property,
Technology Transfer and Developing Country Manufacture of Low-cost
HPV vaccines - A Case Study of India. Nat Biotechnol. 2010 July;
28(7): 671678. doi: 10.1038/nbt0710-671 , PMCID: PMC3138722,
NIHMSID: NIHMS270118 MoHFW -
http://mohfw.nic.in/WriteReadData/l892s/1084811197NATIONAL%20VACCI
NE%20POLICY%20BOOK.pdf 55. 4/6/2014 RD_Vaccine Meet_2014 55
Circumventing Patent Laws for affordable Vaccines Credits: S.
Padmanabhan, Nature Biotechnology, 2010 56. 4/6/2014 RD_Vaccine
Meet_2014 56
http://mohfw.nic.in/WriteReadData/l892s/1084811197NATIONAL%20VACCINE%20POLICY%20BOOK.pdf
MoHFW, GoI Improving the institutional capacity for intellectual
property (IP) management and technology transfer will help
investigators involved in the research to understand the patent
claims and will enable them to make sound judgments, during the
product development. There are a few steps needed in this arena:
Strengthening Indian patent office, reducing the time to examine
and grant a patent, and creation of more comprehensive IP databases
in India Encouraging technology transfer from multinational
companies to develop products and gaining access to technologies
and know-how Indian patent law may have provisions to permit
compulsory licensing in special situations like the H1N1 pandemic
or in situations, where a technology/intermediate is needed for
vaccine development. The country should develop/use expertise to
study the flexibilities enshrined in the Trade Related Aspects of
Intellectual Property rights (TRIPS) agreement to reduce the
negative impact of the patents. The arrangements like Bolar
provision which permits the manufacturers of generic
pharmaceuticals to begin product development, while the patent is
still in force. This could be particularly helpful in reducing the
lead-time to obtain regulatory clearances during vaccine
development. Collective management of IPR and open access
agreements should be resorted to improve innovation and access.
Innovations in ways to deal with IPR of new vaccines need to emerge
through innovative funding of R&D. It is suggested that a body
is created to acquire and hold IPR for technologies beneficial for
use in public health. This body could then license the technology
to emerging manufacturers on acceptable terms for development of
vaccines and related products. 57. 4/6/2014 RD_Vaccine Meet_2014 57
Local R&D Effort: Success Stories: Rotavirus Vaccine (2013)
Indias new rotavirus vaccine, promises to drastically reduce
diarrhoeal deaths Rotavac can be safely administered along with
oral polio drops When licensed, Rotavac will be available at a
dollar-per-dose and compares well with existing vaccines 58. IP
Coverage on Vaccine Patents Vaccine Methods of prophylaxis and
treatment Modified de-activated organism DNA, amino acid sequence
of antigens, modifications, fusion proteins Expression systems
Adjuvants Formulations, dosage, carriers, excipients, diluents etc.
Delivery device and dosing regimen Research tools and platform
technologies Processes conjugation technology, expression systems,
manufacturing and purification processes 4/6/2014 58RD_Vaccine
Meet_2014 59. What are the Implications? What is being patented?
Where are they patented? What obstacles does patent protection
present for the development and production of vaccines? How can one
legally manufacture and import/ export vaccines? What is the
timeline for IPR protection on the technologies? What obstacles
does patent protection present for rapid dissemination of vaccines
in time of public health need/crisis? Claim overlap periods Claim 1
Claim 7 Claim 10 Claim 11 4/6/2014 59RD_Vaccine Meet_2014 60.
4/6/2014 RD_Vaccine Meet_2014 60 IP Issues Related to Antigens
First-generation cervical cancer vaccines "do not seriously
inhibit" the efforts of developing country vaccine manufacturers
(DCVMs) to develop these vaccines The current vaccines do not
protect against several cancer-causing strains of HPV that present
in low-income countries, and suggest that DCVMs could make products
that include antigens missing in the patented versions 61. 4/6/2014
RD_Vaccine Meet_2014 61 Issues related to DNA sequences Poorly
designed analysis (H5N1 case): There are many techniques for filing
invention disclosures that render the searchability of DNA or
protein sequences very difficult & finding DNA or protein
sequences disclosed in or claimed In patents is extraordinarily
difficult. Claims on less variable conserved parts of genome Follow
one system of classification while doing FTOs or searches
Non-disclosure of sequences in less known but potent organisms
(Source: TWN-2011) 62.
(http://www.ipaustralia.gov.au/get-the-right-ip/patents/about-patents/what-can-be-patented/patents-for-biological-inventions/)
Patents for Expression Vectors & biological inventions A
standard patent can be obtained for isloated bacteria, cell lines,
hybridomas, related biological materials and their use, and
genetically manipulated organisms. Examples of patentable
inventions include: isolated bacteria and other prokaryotes, fungi
(including yeast), algae, protozoa, plasmids, viruses, prions cell
lines, cell organelles, hybridomas genetic vectors and expression
systems apparatus or processes for enzymology or microbiology
compositions of micro-organisms or enzymes propagating, preserving
or maintaining micro-organisms mutagenesis or genetic engineering
fermentation or enzyme using processes to synthesise a desired
compound or composition measuring or testing processes involving
enzymes or micro-organisms processes using enzymes or
micro-organisms to liberate, separate, purify or clean the use of
micro-organisms to produce food or beverages. 4/6/2014 62RD_Vaccine
Meet_2014 63. 4/6/2014 RD_Vaccine Meet_2014 63 Genetic inventions
and their patent claims (A) For genetic inventions, many different
types of patent can be found. They vary as to the kinds of claims
used and how the set of claims is structured. There are at least
three common categories of patent in this field. DNA coding for
industrially useful expression products. The cloning of a DNA
coding sequence can enable the commercial production of an
important therapeutic protein, such as a blood protein or a
vaccine. Such an achievement can represent a clear advance in
pharmaceutical technology and deserve legal protection, provided
the innovation meets standard criteria of patentability. Similarly,
the cloning of DNA coding sequences which leads to advances in
plant biotechnology, thereby improving agricultural Products like
plant derived vaccines, practices and productivity, is patentable.
A typical claims structure in such a therapeutic product patent
will cover the following: 1. DNA of specific function and/or
nucleotide sequence. 2. A recombinant vector (plasmid) containing
DNA of (1). 3. A genetically modified organism containing DNA of
(1). 4. A method of production of polypeptide expressed by DNA of
(1). 5. The expressed polypeptide per se (only if novel, i.e.
differing in some respect from the naturally occurring protein).
64. Patents for genetic modification or manipulation A standard
patent can also be obtained for inventions involving: genotypically
or phenotypically modified living organisms, for example,
genetically modified bacteria, plants and non-human organisms
(patenting of plant varieties is described in Plant Breeder's
Rights) isolated DNA, RNA, chromosomes and genes (including human
DNA and genes) isolated products of such DNA, RNA and genes
including polypeptides and proteins. Examples of patentable
inventions include: synthetic genes or DNA sequences mutant forms
and fragments of gene sequences an isolated DNA coding sequence for
a gene an isolated protein expressed by a gene vectors (such as
plasmids or bacteriophage vectors or viruses) containing a
transgene methods of transformation using a gene host cells
carrying a transgene higher plants or animals carrying a transgene
organisms for expression of a protein from a transgene general
recombinant DNA methods such as PCR and expression systems 4/6/2014
64RD_Vaccine Meet_2014 65. Patents for DNA or gene sequences Human
beings and the biological processes for their generation are not
patentable. Although standard patents can be obtained for
biological material such as micro-organisms, nucleic acids,
peptides and organelles, this material is only patentable if it has
been isolated from its natural environment, or has been
synthetically or produced by recombinant mode, e.g., DNA or genes
in the human body are not patentable. A DNA or gene sequence that
has been isolated may be patentable. Patent specifications must
also describe a specific use for a biological material. For
example, if the invention relates to a gene, the specification must
disclose a specific use for the gene, such as its use in the
diagnosis or treatment of a specific disease, or its use in a
specific enzymatic reaction or industrial process. 4/6/2014
65RD_Vaccine Meet_2014 66. 4/6/2014 RD_Vaccine Meet_2014 66
Examples of genetic inventions and their patent claims (B) It
should be noted that these different forms of claims may not all be
present in a single patent; official patent regulations in certain
countries may require them to be divided into two or more separate
patent applications. The US patents on breast cancer genes (BRCA1
and BRCA2) and their use in diagnostic testing are illustrative
examples of this practice. Genes which control biological pathways.
Research continues to identify receptors and genes involved in
biological pathways. When such a gene is located, it may be
possible to correlate a malfunction in the pathway with a mutation
or loss of this gene. The cDNA and the encoded polypeptide would be
considered targets for diagnosis and drug discovery or vaccine
development. One type of invention in this category would be the
use of the target to discover substances which achieve some useful
effect by binding to the target. This would also include substances
which, by blocking the target, prevent entry of pathogens such as
viruses into the cell. Typical claims are: 1. The receptor peptide
or polypeptide (protein) of a defined sequence. 2. DNA coding for
the receptor (1). 3. A transformed cell expressing the receptor
(1). 4. An assay system comprising the transformed cell (3). 5. A
method of identifying an agonist or antagonist of the receptor. 6.
Agonists or antagonists of receptor (1) identified by method (5),
(a claim of this type is allowed with great difficulty). 67.
4/6/2014 67RD_Vaccine Meet_2014 Why China is a genetic powerhouse
with a problem - The Globe and ... www.theglobeandmail.com Dec 15,
2012 - But not just human DNA. Once known as the Beijing Genomics
Institute, BGI is on a mission to sequence the genomes of a vast
array of living. In the South China city of Shenzhen, a thriving
manufacturing hub known for cheap goods and high-tech electronics,
the genetic secrets of life roll off machines by the minute. Here
at the global headquarters of BGI-Shenzhen, housed in a former shoe
factory, the genomic revolution runs on an industrial scale.
Powered by an army of young lab technicians and banks of high-end,
U.S.-made sequencers that hum 24/7, the DNA of human kind is
decoded with conveyor-belt speed and brute force 68. 4/6/2014
RD_Vaccine Meet_2014 68 Recent Pat Drug Deliv Formul.
2008;2(1):68-82 Potential of nanocarriers in genetic immunization.
Khatri K, Goyal AK, Vyas SP. Source Drug Delivery Research
Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour
Vishwavidyalaya, Sagar, MP 470003, India. Abstract DNA vaccination
(or genetic immunization) strategies provide important
opportunities for improving immunization, since both humoral and
cell- mediated responses are induced. The use of genetic vaccines
for inducing immunity to infectious agents can eliminate or
significantly alleviate the pathology associated with a broad range
of infections. A requirement for efficient DNA vaccination is the
development of gene delivery systems capable of overcoming barriers
to gene transfection. Compared to viral systems, nonviral systems
are considered to be safe, cheap, multiple delivery is possible and
able to deliver larger pieces of DNA. Also, these nanocarriers
avoid DNA degradation and facilitate targeted delivery to antigen
presenting cells. This review describes the potential of non-viral
nanocarrier construct(s) in genetic immunization. Issued patents in
the field were retrieved from the US patent database. Various
carrier systems used to deliver plasmid DNA were reviewed in
detail. PMID:19075899 [PubMed - indexed for MEDLINE] 69. 4/6/2014
RD_Vaccine Meet_2014 69 Case History: IP Issues in Influenza
Vaccines Further IP Considerations: Reverse Genetics Patents and
WHO GISN H5N1 Vaccine Seed Strains Antisera Research: Emerging
Intellectual Property Claims Conflicting Priorities: Public
Research and Private Patents, Two ???? 70. Platform processes Very
useful Generate huge IP 4/6/2014 70RD_Vaccine Meet_2014 71.
4/6/2014 RD_Vaccine Meet_2014 71 72. 4/6/2014 RD_Vaccine Meet_2014
72 1 7,223,411 Herpesvirus replication defective mutants 2
7,186,559 Apparatus and method for electroporation of biological
samples 3 7,141,425 Apparatus and method for electroporation of
biological samples 4 7,141,408 Plasmid maintenance system for
antigen delivery 5 7,138,112 Plasmid maintenance system for antigen
delivery 6 7,125,720 Plasmid maintenance system for antigen
delivery 7 7,115,269 Attenuated Salmonella strain used as a vehicle
for oral immunization 8 7,078,218 Alphavirus particles and methods
for preparation 9 7,045,335 Alphavirus replicon vector systems 10
7,029,916 Apparatus and method for flow electroporation of
biological samples 11 7,026,155 Method of reducing bacterial
proliferation 12 6,995,008 Coordinate in vivo gene expression
Delivery Systems 73. 4/6/2014 RD_Vaccine Meet_2014 73
Bio-manufacturing of Vaccines PAT. NO Title 1 8,440,791 Thimerosal
removal device 2 8,388,955 Fc variants 3 8,367,805 Fc variants with
altered binding to FcRn 4 8,338,574 FC variants with altered
binding to FCRN 5 8,324,351 Fc variants with altered binding to
FcRn 6 8,318,907 Fc variants with altered binding to FcRn 7
8,101,720 Immunoglobulin insertions, deletions and substitutions 8
8,093,357 Optimized Fc variants and methods for their generation 9
8,034,335 High-titer retroviral packaging cells 10 8,030,071
Restoration of cholesterol independence and its use as a selectable
marker in NS0 cell culture 11 7,964,403 Preparation of vaccine
master cell lines using recombinant plant suspension cultures 12
7,901,921 Viral purification methods 13 7,879,338 Vectors and
methods for immunization against norovirus using transgenic plants
14 7,553,666 Preparation of vaccine master cell lines using
recombinant plant suspension cultures 15 6,395,538 Method and
system for providing real-time, in situ biomanufacturing process
monitoring and control in response to IR spectroscopy 16 6,266,569
Method and system of computing similar to a turing machine 74.
4/6/2014 RD_Vaccine Meet_2014 74 1 8,168,421 Microbial vaccine and
vaccine vector 2 7,704,491 Recombinant human metapneumovirus and
its use 3 7,169,396 Reference clones and sequences for non-subtype
B isolates of human immunodeficiency virus type 1 4 6,897,301
Reference clones and sequences for non-subtype B isolates of human
immunodeficiency virus type 1 5 6,492,110 Reference clones and
sequences for non-subtype B isolates of human immunodeficiency
virus type 1 6 6,310,045 Compositions and methods for cancer
immunotherapy 7 5,662,896 Compositions and methods for cancer
immunotherapy Reference Reagents 75. 4/6/2014 RD_Vaccine Meet_2014
75 1 8,507,658 Ex vivo animal or challenge model as method to
measure protective immunity directed against parasites and vaccines
shown to be protective in the method 2 8,507,445 Compositions and
methods of use of targeting peptides for diagnosis and therapy of
human cancer 3 8,507,206 Monoclonal antibodies that target
pathological assemblies of amyloid .beta. (Abeta) 4 8,506,969
Efficient cell culture system for hepatitis C virus genotype 7a 5
8,501,194 Vaccine for viruses that cause persistent or latent
infections 6 8,498,879 Automated systems and methods for obtaining,
storing, processing and utilizing immunologic information of
individuals and populations for various uses 7 8,497,351 Nucleic
acid and corresponding protein entitled 162P1E6 useful in treatment
and detection of cancer 8 8,497,292 Translational dysfunction based
therapeutics 9 8,491,909 Methods and compositions for dosing of
allergens 10 8,486,421 Antigen-norovirus P-domain monomers and
dimers, antigen- norovirus P-particle molecules, and methods for
their making and use 11 8,486,413 Immunological compositions as
cancer therapeutics Animal models for Vaccines 76. 4/6/2014
RD_Vaccine Meet_2014 76 Carriers for Vaccines United States Patent
# 8,506,968; Inventor: Akeefe, et al.; Eli Lilly and Company
(Indianapolis, IN); Filed December 28, 2009, Date of Grant: August
13, 2013 SARS vaccine compositions and methods of making and using
them Abstract Described is a composition and method for reducing
the occurrence and severity of infectious diseases, especially
infectious diseases such as SARS, in which lipid- containing
infectious viral organisms are found in biological fluids, such as
blood. The present invention employs solvents useful for extracting
lipids from the lipid- containing infectious viral organism thereby
creating immunogenic modified, partially delipidated viral
particles with reduced infectivity. The present invention provides
delipidated viral vaccine compositions, such as therapeutic vaccine
compositions, comprising these modified, partially delipidated
viral particles with reduced infectivity, optionally combined with
a pharmaceutically acceptable carrier or an immunostimulant. The
vaccine composition is administered to a patient to provide
protection against the lipid-containing infectious viral organism
or, in case of a therapeutic vaccine, to treat or alleviate
infection against the lipid-containing infections viral organism.
The vaccine compositions of the present invention include
combination vaccines of modified viral particles obtained from one
or more strains of a virus and/or one or more types of virus. 77.
Issues related to Expression systems Axel Patent Story !!!!
Columbia University 4/6/2014 77RD_Vaccine Meet_2014 78. 4/6/2014
RD_Vaccine Meet_2014 78 AXELPatentStorey:ColumbiaUniversity 79. IP
issues in cells used for Expression Cells Several of these cell
lines have been used for many years and hence are not covered by
patents and can be obtained from public sources. However, in order
to get regulatory approval for vaccines produced in a cell line
requires that Master and Working cell banks are established and
characterized, a very lengthy and costly process. Manufacturers who
have undertaken such processes are unlikely to share their
characterized cell line. Hence even in absence of IP on the cell
line, there is a significant barrier to the use of these cells. A
possible exception to this is the Vero cell line which can be
purchased with full characterization. There is IP on specific
variants of these strains (e.g. MDCK-B-702 described in US 6825036,
a MDCK line with higher susceptibility to infection described in WO
2005/113758), and on the new cell lines including the PerC6 cell
lines (e.g. US7192759) and avian embryonic lines (WO 2006/108846).
4/6/2014 79RD_Vaccine Meet_2014 80. (WO 2006/108846). Cell over
expressing a nucleic acid encoding WO 2003/048348 sialyltransferase
for production of virus Crucell WO 2005/113758 A MDCK cell with
higher susceptibility to viral infection than parenteral line ID
biomedical US 6825036 process for preparing MDCK cell in serum-free
suspension -specifically MDCK- B-702 line. Kumamoto-ken, JP US
7192759 human embryonic retinoblast cell encoding E1 gene of
adenovirus to produce influenza Crucell WO 2006/108846 avian
embryonic stem cell. Replicating virus in suspension Vivalis EP
1108787 method for producing flu virus or antigen in cell encoding
adenovirus E1 gene. Crucell In addition, as discussed below, there
is IP on using cell lines for producing influenza vaccines and also
processes involving these cell lines, including the
http://www.who.int/vaccine_research/diseases/influenza/Mapping_Intellectual_Property_Pandemic_Influenza_Vaccines.pdf
4/6/2014 80RD_Vaccine Meet_2014 81. IP on cell culture inactivated
vaccine production process US 7132271 method for enhancing
production using cell with targeted deletion in PKR or 2-5A gene U.
California US 6673591 use of cells with targeted deletion in PKR
gene to enhance virus production in cells U. California US 6686190
use of cells with targeted deletion in at least one ISG gene to
enhance production in cells U. California WO 1997/008292 process to
enhance virus production in cells by inhibiting PKR 2-5a synthetase
U. California US 6344354 Vaccine comprising flu virus produced on
cells (isolate not been passaged on eggs) St Judes US 6656720 MDCK
cell adapted to suspension growth for influenza virus production
Novartis US 6455298 use of MDCK 33016 for replication of influenza
virus in serum-free medium. EP 870508 process to reduce DNA content
in cell derived vaccine by use of DNAse and detergent Duphar US
4500513 influenza vaccine production in liquid cell culture Miles
Lab US 5698433 Producing flu vaccine in Avian embryo cells:
Infection prior to growth on monolayer. Baxter (Immuno ) US 5753489
producing virus in serum free monkey kidney cells Baxter (Immuno AG
US 6146873 producing virus in serum free monkey kidney cells Baxter
(Immuno AG US 5756341 producing in serum free monkey kidney cells,
with modified cleavage site in HA Baxter (Immuno AG US 5840565 Use
of PKR antisense polynucleotide to enhance production of influenza
virus in cells U. California WO 2005/024039 Replacing NS gene of
APR/8 with NS from A/England to produce high titer virus in cells
St Judes WO 2005/028658 two vectors, at least one containing a pol
II promotor linked to a ribozyme sequence Wisconsin alumni WO
2006/027698 tests to ensure that no pathogens other than influenza
virus are growing in cell culture Chiron Behring WO 2006/067211 use
of bacteriophage polymerase promoter to produce influenza antigen
in cells Solvay WO 2007/002008 expression vector containing canine
RNA polymerase regulatory sequence; MDCK MedImmune WO 2007/045674
method for producing flu virus or antigen in cell encoding
adenovirus E1 gene. Crucell US 7037707 method of making a
reassortant growing to high titer by using an alternative NS gene
St Judes 4/6/2014 81RD_Vaccine Meet_2014 82. 4/6/2014 RD_Vaccine
Meet_2014 82 IP Issues on Vehicles Injection Nanoparticles The
living epidermis and dermis are rich in antigen presenting cells
(APCs). Their activation can elicit a strong humoral and cellular
immune response as well as mucosal immunity. Therefore, the skin is
a very attractive site for vaccination, and an intradermal
application of antigen may be much more effective than a
subcutaneous or intramuscular injection. However, the stratum
corneum (SC) is a most effective barrier against the invasion of
topically applied vaccines. Products which have reached the stage
of clinical testing, avoid this problem by injecting the
nano-vaccine intradermally or by employing a barrier disrupting
method and applying the vaccine to a relatively large skin area.
Needle-free vaccination is desirable from a number of aspects: ease
of application, improved patient acceptance and less risk of
infection among them. Nanocarriers can be designed in a way that
they can overcome the SC. Also incorporation into nanocarriers
protects instable antigen from degradation, improves uptake and
processing by APCs, and facilitates endosomal escape and nuclear
delivery of DNA vaccines. In addition, sustained release systems
may build a depot in the tissue gradually releasing antigen which
may avoid booster doses. Therefore, nanoformulations of vaccines
for transcutaneous immunization are currently a very dynamic field
of research. Among the huge variety of nanocarrier systems that are
investigated hopes lie on ultra-flexible liposomes, superfine rigid
nanoparticles and nanocarriers, which are taken up by hair
follicles. The potential and pitfalls associated with these three
classes of carriers will be discussed. 83. 4/6/2014 RD_Vaccine
Meet_2014 83 IP Issues in Vaccination using gold nano- particles 26
June 2013 | Source: Nanotechnology Scientists in the US have
developed a novel vaccination method that uses tiny gold particles
to mimic a virus and carry specific proteins to the bodys
specialist immune cells. The technique differs from the traditional
approach of using dead or inactive viruses as a vaccine and was
demonstrated in the lab using a specific protein that sits on the
surface of the respiratory syncytial virus (RSV). The results have
been published today, 26 June 2013, in IOP Publishings journal
Nanotechnology by a team of researchers from Vanderbilt University.
RSV is the leading viral cause of lower respiration tract
infections, causing several hundred thousand deaths and an
estimated 65 million infections a year, mainly in children and the
elderly. The detrimental effects of RSV come, in part, from a
specific protein, called the F protein, which coats the surface of
the virus. The protein enables the virus to enter into the
cytoplasm of cells and also causes cells to stick together, making
the virus harder to eliminate. 84. 4/6/2014 RD_Vaccine Meet_2014 84
IP issues in Bio-manufacturing/NO COLD CHAIN VACCINES The nanopatch
is designed to place a tiny amount of vaccine just under the skin
without the need for a needle jab. Because it delivers the active
ingredient right to where it is needed, tests have shown it can
generate the same immune response with only a fraction of the dose
needed in a conventional vaccine. Among other potential advantages
of the nanopatch are that it is pain free, low cost it could be
made for under $1 a dose compared with more than $50 for many
current vaccines and easily transportable. Kendall (biotech company
given grant by Merck) even ponders whether it might be mailed to
remote places for people to administer it themselves 85. 4/6/2014
RD_Vaccine Meet_2014 85 IP issues in Delivery Systems 86. 4/6/2014
RD_Vaccine Meet_2014 86 Merck & Co. to Evaluate Transdermal
Vaccine Delivery System Merck & Co. and vaccine delivery
specialist Vaxxas started a research collaboration focused on
evaluating the use of the latters transdermal Nanopatch vaccine
delivery system with a Merck vaccine candidate. Under terms of the
deal Australian firm Vaxxas will receive an up-front fee, research
funding, and option fees if Merck exercises its option to the
platform for the development and commercialization of vaccine
candidates for up to two additional fields. Vaxxas will also be
eligible for development and regulatory milestone payments. Vaxxas
Nanopatch vaccine delivery technology consists of a 1 cm2 silicone
array that carries about 20,000 vaccine-coated microprojections
that painlessly perforate the outer layers of the skin when applied
with the associated applicator device, and deliver the vaccine
directly to key immune cells immediately below the skin surface.
The firm believes the system can significantly enhance the
therapeutic potential of both existing and new vaccine candidates
by amplifying efficacy, reducing the required dose, and obviating
the need for adjuvants, as well as preventing needlestick injuries
and cross-contamination. Preclinical in vivo studies showed that
use of Nanopatch allowed a 100-fold reduction in the required dose
of Fluvax influenza vaccine. The applicator device used with the
Nanopatch array has in addition been designed to achieve uniform
penetration and delivery across the range of natural variations in
skin structure associated with age, gender, and health, and
overcome the inconsistencies associated with other transdermal
vaccine delivery approaches, Vaxxas claims. Founded in August 2011
with a Aus$15 million venture capital investment (about $15.3
million at todays exchange rate), Vaxxas platform was originally
developed by researchers at UQs Australian Institute for
Bioengineering and Nanotechnology.
http://www.genengnews.com/gen-news-
highlights/merck-co-to-evaluate-transdermal-
vaccine-delivery-system/81247449/ 87. Issues related to
Immuno-stimulatory sequences Background: Recent studies have
demonstrated that bacterially derived immunostimulatory sequences
(ISSs) of DNA can activate the mammalian innate immune system and
promote the development of TH1 cells. Promotion of TH1 immunity by
means of immunotherapy in allergic patients has led to the
alleviation of symptoms that result from allergen-specific TH2
responses. Objective: Our purpose was to investigate whether the
TH1- enhancing properties of ISSs could be used to alter the
TH2-dominated immune response of allergic PBMCs in vitro. Methods:
Ragweed protein-linked ISS (PLI) was generated from a specific,
highly active 22-base ISS and Amb a 1, the immunodominant allergen
in ragweed pollen, to combine the TH1-enhancing properties of ISSs
with allergen selectivity, and its activity was investigated in
PBMC cultures from subjects with ragweed allergy. Results: PLI was
markedly successful at reversing the dominant allergen-induced TH2
profile while greatly enhancing IFN- production. Delivering ISSs in
a linked form proved to be much more effective at modulating the
resulting cytokine profile than delivering free ISSs in a mixture
with unlinked Amb a 1. PLI also demonstrated cytokine-modulating
properties, even when used to stimulate cells that had already been
primed for 6 days with Amb a 1. The antigen specificity of the
action of PLI was confirmed by the observations that PLI enhances
Amb a 1specific T-cell proliferation. Conclusion: These data
indicate that delivery of ISSs within an antigen-specific context
exhibits potent cytokine-modulating activity and, combined with its
reduced allergenicity, makes this molecule a strong candidate for
use in improved immunotherapy applications. (J Allergy Clin Immunol
2001;108:191-7.) 4/6/2014 87RD_Vaccine Meet_2014 88. 4/6/2014
RD_Vaccine Meet_2014 88 Plant Derived vaccines A new category of
technology which may confound existing IP regimes is plant derived
vaccines (PDVs). The make-up of this innovation is just as its name
suggests a vaccination product derived from plants. Although there
is no trick to understanding the nature of PDVs, deciding which IP
regime may be utilized to protect this invention can prove to be
troublesome. Due to the fact that the technology ties together
several elements which have previously stood alone as distinct
technological categories, PDVs fit simultaneously within several
existing categories, each of which offers unique aspects of
protection. In basic terms, a PDV is a plant variety, a drug, a
biotechnological innovation and a developing nation- focused
product all-in-one. It is therefore difficult to categorize PDVs
for the purpose of IP protection. 89. What will happen, if vaccines
will be derived from proprietary variety?? The decision of the
Supreme Court of the United States on Merck v. Integra Life
Sciences in 2005, analysts contend that, with the broadened
definition by the Supreme Court of the Hatch-Waxman Act as it
relates to data exclusivity, research in preparation of FDA
approval is exempt from the requirement for research licenses
4/6/2014 89RD_Vaccine Meet_2014 90. 4/6/2014 RD_Vaccine Meet_2014
90 Will Vaccines Derived from Plants be Classified under Drugs or
Foods? Ans: Both so IP issues become more complex 91. 4/6/2014
RD_Vaccine Meet_2014 91 Biotechnology products can benefit from
both trade secret and patent protection. Each of these forms of IP
are haunted by considerations beyond the bounds of pure science,
which arise in conjunction with the clinical trials and
commercialization stages in particular. These include ethical,
social and cultural concerns. In the words of E. Richard Gold and
Wendy A. Adams, the health benefits to individual recipients of the
products of biotechnological innovation are self evident, although
far from uncontroversial. Others have voiced concerns as to whether
extending strong IP rights to biotechnological innovation is
ethical, or even legally defensible. Specific issues raised by PDVs
include liabilities related to the growth of transgenic plants and
the production of drugs from these materials. BIO has acknowledged
that steps must be taken to minimize the risks associated with the
production of plant based genetically modified health technologies,
including control of exposure to transgenic plants and their
expression products. BIOs caution is the type of issue that will
likely be addressed through regulation or policy initiatives to
restrict the growth of plants to confined facilities and to ensure
that processing, milling and extraction of transgenic plant
materials is undertaken separate from commercial food and feed
channels. These represent physical protections which may be
achieved. Recent case law has examined the legal protections
available, through a review of the validity and scope of claims
which form the basis of patent rights held in biotechnology
inventions. 92. Issues of IP on Antigens VACCINE COMPONENT ROYALTY
ON SALES OF VACCINE Antigen A, Proprietary to Company A 2% Antigen
B, Discovered with proprietary tool of Company B 2% Antigen C,
Nonproprietary 0% Proprietary assembly technique of Company C 2%
Proprietary adjuvant 2% 4/6/2014 92RD_Vaccine Meet_2014 93. IP
Issues: Vaccine composition Component Purpose Example Adjuvants
enhance the immune response to a vaccine aluminium salts
Preservatives prevent bacterial or fungal contamination of vaccine
thiomersal Additives stabilise vaccines from adverse conditions
such as freeze-drying or heat, thereby maintaining a vaccines
potency gelatine Residuals from manufacturing process Inactivating
agents Antibiotics - prevent bacterial contamination during
manufacturing process Egg proteins- some vaccine viruses are grown
in chick embryo cells Yeast proteins formaldehyde neomycin,
streptomycin, polymyxin B influenza, yellow fever HepB vaccine
4/6/2014 93 RD_Vaccine Meet_2014 94. cDNA clones Methods of
treatment Human monoclonal antibodies Compounds genetic variants
Agonist and antagonist peptides Method for production and
purification Highly active glycoproteins-process conditions and an
efficient method for their production Nucleic-acid programmable
protein arrays Detection of adventitious agents Compositions and
methods for extracting and using vaccines composition containing
synthetic adjuvant Antibodies as vaccines Vaccine formulations
Combinations of clades as in pneumococcal treatment Compositions of
PD-1 antagonists and methods of use Inhibitors of angiopoietin-like
4 protein, combinations, and their use Chemically programmable
immunity use in gene modulation in vaccine development Compositions
and methods of enhancing immune responses Humanized antibody
compositions and methods Influenza inhibiting compositions and
methods Compositions and methods modulating MG29 for the treatment
of diabetes Methods of generating libraries and uses thereof
Process for improved protein expression by strain engineering
Process for large scale production of plasmid DNA by fermentation
Method for producing storage stable viruses and immunogenic
compositions thereof Prostate carcinogenesis predictor Antigen
surrogates in autoimmune disease Anti-avian influenza virus agent,
and product containing anti-avian influenza virus agent
Compositions and methods for frozen particle compositions
Immunoconjugates, methods and uses Simian adenovirus nucleic acid
and amino acid sequences, vectors containing same, and methods of
use Genetic adjuvants for immunotherapy Composition for prevention
of influenza viral infection comprising tannic acid, air filter
comprising the same and air cleaning device comprising the
filter4/6/2014 94RD_Vaccine Meet_2014 95. 4/6/2014 RD_Vaccine
Meet_2014 95 Bode C. et al. (2011) CpG DNA as a vaccine adjuvant.
Expert Rev Vaccines. 2011 April; 10(4): 499511 96. R&D Efforts
in Adjuvants The project of extracting a new vaccine adjuvant from
'Ashwagandha' (Withania somnifera), a medicinal plant used in
Ayurveda as an immunity enhancer, was sponsored by the Department
of Science and Technology and was jointly executed by the
researchers from Pune based Serum Institute of India (SII) and
University of Pune's Inter-disciplinary School of Health Sciences
(ISHS). The researchers already received a patent on this in India
in 2007, but the US patent was granted on August 6, 2013. The
adjuvant extracted from Ashwagandha is believed to improve vaccine
efficacy. Further, the adjuvant showed properties where it could be
useful in new vaccine development such as the pentavalent vaccine
targeting meningitis, or those against dengue, pneumococcal
diseases, polio, diphtheria, tetanus and hepatitis and also holds
promise against HIV, tuberculosis and malaria. The researchers have
clarified that unlike earlier instances where companies tried to
patent turmeric, for example, the patent here was in an area not
claimed by Ayurveda. 4/6/2014 96RD_Vaccine Meet_2014 97. IP issues
in Excipient 4/6/2014 97RD_Vaccine Meet_2014 Adenovirus sucrose,
D-mannose, D-fructose, dextrose, potassium phosphate, plasdone C,
anhydrous lactose, micro crystalline cellulose, polacrilin
potassium, magnesium stearate, cellulose acetate phthalate,
alcohol, acetone, castor oil, FD&C Yellow #6 aluminum lake dye,
human serum albumin, fetal bovine serum, sodium bicarbonate,
human-diploid fibroblast cell cultures (WI-38), Dulbeccos Modified
Eagles Medium March, 2011 Anthrax (Biothrax) aluminum hydroxide,
benzethonium chloride, formaldehyde, amino acids, vitamins,
inorganic salts and sugars December, 2008 BCG (Tice) glycerin,
asparagine, citric acid, potassium phosphate, magnesium sulfate,
Iron ammonium citrate, lactose February, 2009 DT (Sanofi) aluminum
potassium sulfate, peptone, bovine extract, formaldehyde,
thimerosal (trace), modified Mueller and Miller medium December,
2005
http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/b/excipient-table-2.pdf
98. IP issues in Delivery Devices 4/6/2014 98RD_Vaccine Meet_2014
99. 4/6/2014 RD_Vaccine Meet_2014 99 Strategy : Contribution by
PATH Advancing novel vaccine formulations and processing methods.
Evaluating the technical and commercial feasibility of improving
vaccine thermo-stability. Reducing needle stick injuries by
developing immunization devices that shield or eliminate needles.
Creating inherently simple and easy-to-use devices and user aids
that improve safety and ease immunization logistics. Addressing
issues of cost by developing and testing effective devices that
enable delivery of a reduced dosage of vaccine and help to decrease
vaccine wastage. Improving vaccine presentations and packaging to
meet user needs and minimize environmental impact. Developing and
facilitating access to new equipment that stores, monitors, and
transports vaccines at appropriate temperatures. Analyzing the
cost-effectiveness of various immunization strategies and
interventions to facilitate decision-making. 100. 4/6/2014
RD_Vaccine Meet_2014 100 101. 4/6/2014 RD_Vaccine Meet_2014 101
Indian Vaccine Strength
http://www.slideshare.net/fababioasia/vaccines-
indias-strength-8501392 102. 4/6/2014 RD_Vaccine Meet_2014 102 Work
Around to break Barriers to Existing Vaccines for development of
Generic Vaccines w.r.t. basic vaccines Use of pertactin/69K in
acellular pertussis vaccine GSK / Medeva Work-around: dont include
it (FHA/PT) Combination vaccines containing low doses of T,P, etc
Use higher doses etc. Stick to 'old' formulation or develop work-
arounds Requires R&D capacity (Source: WHO) Repositioning in
Drugs** 103. 4/6/2014 RD_Vaccine Meet_2014 103 Original Drug
Repositioned Development Product Development Approved Repositioned
Product Subject to Generic/Modified Competition Original API Patent
(20 years) New Use Indication Patent (20 years) 5 yr NCE
Exclusivity 14 years extended Patent Life 30 month stay Approval of
Repositioning Product (Source: Drug Discovery Today: Therapeutic
Strategies Vol.8(3-4), 135, (2011) Subject to ANDA/505(b)2 Patent
Challenge Upto 5yr Ext Shelved API Never Previously Approved NCE
New Indication Illustration of exclusivities for repositioned
product based on shelved API
CanthisStrategybetriedforVaccines&Biologics? 104. 4/6/2014
RD_Vaccine Meet_2014 104 Solutions to tackle barriers 105. 4/6/2014
RD_Vaccine Meet_2014 105 Solutions Benchmarks on benefit sharing in
the Nagoya protocol (not verbatim) 1. Monetary benefits may
include, but not be limited to: Access fees/fee per sample
collected or otherwise acquired; Up-front, milestone, royalty
payments; Licence fees in case of commercialization; Special fees
to be paid to trust funds supporting conservation and sustainable
use of biodiversity; Salaries and preferential terms where mutually
agreed; Research funding; Joint ventures and joint ownership of
relevant intellectual property rights. 2. Non-monetary benefits may
include, but not be limited to: Sharing research and development
results and contribution to local economy; food and livelihoods;
Social recognition; Joint ownership of relevant intellectual
property rights. 106. 4/6/2014 RD_Vaccine Meet_2014 106 Disruptive
Innovations to tackle IP barriers in generic vaccines Generic drug
formulators tend toward what is tried and true, patents are built
on a foundation of the unexpected, and planning for the unplanned
requires special talents. Our scientists should exhibit success as
inventors as a result of combination of extensive experience,
out-of-the-box creativity, attention to the details of experimental
outcomes, and perseverance. India should look at every problem in
the drug development pathway as a potential opportunity to invent
and protect. 107. 4/6/2014 RD_Vaccine Meet_2014 107 Pool Data 108.
4/6/2014 RD_Vaccine Meet_2014 108 Indian Capacity to deliver
Complex Vaccines Starting with a few public-sector manufacturers in
the late 1960s India has emerged as the major supplier of basic
Expanded Programme on Immunization vaccines to the United Nations
Children's Fund (UNICEF) because of substantial private-sector
investment in the area. The Indian vaccine industry is now able to
produce new and more complex vaccines such as the Meningitis,
Haemophilus influenzae type b, and Pneumococcal conjugate vaccines,
Rotavirus vaccine and Influenza A (H1N1) vaccines. 109. 4/6/2014
RD_Vaccine Meet_2014 109 Balancing Act 110. 4/6/2014 RD_Vaccine
Meet_2014 110 We need to balance IP issues with Purchasing Power of
the sick & needy?? India needs to further strengthen its IP
protection mechanism and speed up examination process. However,
when it comes to development of new interventions for Type II and
III diseases, it is suggested that these be registered with the
appropriate government body, and not much emphasis be placed on
complete IP protection before an intervention is produced. This
process would ensure that it acknowledges the inventors or funding
agencies for their inventions yet reaches the needy quickly. It
also needs to be borne in mind that for public interest, choices of
IP management should be accordingly exercised, and should not be in
conflict with public good. 111. 4/6/2014 RD_Vaccine Meet_2014 111
Policy Issues The American Association of Universities, for
example, has sought to create further barriers to access by
encouraging 12 years of data exclusivity for follow-on biologics as
part of legislation under consideration in Congress. This is in
contrast to the five years of data exclusivity in place for small
molecule drugs, and despite the facts that the mean development
time for biologics is only 7.4 months longer, and the break-even
lifetimes are virtually identical. This stance, which would bolster
companies bottom lines, threatens to unduly delay the onset of
cheaper follow-on biologics after patent expiration.
http://www.med4all.org/fileadmin/med/pdf/2_Crager_
Formatted_June3_HPV-Impfung.pdf 112. 4/6/2014 RD_Vaccine Meet_2014
112 TRIPS Compliance INDIA: At the start of the Uruguay Round
negotiations in 1986, over fifty countries did not recognize
product patents on pharmaceuticals. The adoption of TRIPS caused a
seismic shift in the global IPR regime, raising barriers to generic
entry by blocking producers from finding alternative, lower-cost
means of producing the same drug. Patent protection of the end
product could trump inventions over the process of manufacturing
generic versions of the drug. Nowhere has this been of greater
concern than in India, which came into TRIPS compliance in 2005.
For low- and middle income countries, Indian generic manufacturers
supply more than eighty percent of antiretroviral drugs and nearly
ninety percent of the pediatric market for such drugs. However,
since several key second- and third- line antiretroviral drugs
(ARVs) have recently come under patent protection in India, it is
not likely that Indian generic competition will be able to reduce
the global prices for ARVs at the rates seen for the first-line
drugs. THAILAND: The use of the TRIPS flexibilities, such as
compulsory licenses, can lead to significant cost savings and
increases in coverage. Thailands compulsory license on efavirenz
was expected to halve the drug price and provide an additional
20,000 patients with the drug under the same budget. Generic
imports of the second-line ARV, Kaletra (lopinavir/ritonavir),
under compulsory license were also expected to cut the price by
over eighty percent, allowing an additional 8,000 patients to
access the drug. A comparison of the market prices for the branded
originator drugs at the time of the compulsory licenses with the
prices of the imported generic equivalents demonstrate a sixty-six
percent reduction in price for efavirenz and seventy percent for
lopinavir/ritonavir. It is expected that the prices of the cancer
drugs will be between three percent and twenty-five percent of the
prices for the patented drugs 113. 4/6/2014 RD_Vaccine Meet_2014
113 Reduction of Complexity by Sharing Information Even in presence
of patents, the emergence of markets for technology is not
straightforward because there are still major obstacles to such
markets (Teece, 1986). To respond to a need for lower transaction
costs on technology markets, new actors have recently emerged such
as Innocentive, Yet2.com, and Ocean Tomo - often assisted by new
information and communication technologies. The role of those
patent brokers is to organize and facilitate exchanges between
technology sellers and buyers. To do so, they provide technical
assistance, audit, and perform diagnostic tests to assess the value
of a given technology. Most importantly, they facilitate the
circulation of information (Yanagisawa and Guellec, 2009;
Dushnitsky and Klueter, 2011).
http://timreview.ca/article/502#sthash.LNJdhZ1s.dpuf 114. 4/6/2014
RD_Vaccine Meet_2014 114 115. 4/6/2014 RD_Vaccine Meet_2014 115
Compulsory Licensing to get Generic Vaccines going? 116. 4/6/2014
RD_Vaccine Meet_2014 116
https://www-935.ibm.com/services/uk/igs/pdf/g510-6342-00-5barriers-etr.pdf
(modified) Breaking Innovation to access Barriers Techno-scientific
Barriers: Human Resource Barriers Organizational barriers:
Inadequate funding, Risk avoidance, Siloing, Time commitments
Incorrect measures Bad Business Practices 117. 4/6/2014 RD_Vaccine
Meet_2014 117 Summary of R&D challenges The current,
market-based R&D system has failed to develop vaccines for
diseases such as TB and malaria that affect large numbers of people
as well as vaccines for smaller markets such as dengue or
Meningitis A. In addition to new vaccines, there is also a need for
improved, cheaper, and more suitable versions of existing vaccines.
Although there has been progress and a number of promising
initiatives, these efforts still depend too much on the established
multinational firms, who fund and conduct most late-stage vaccine
R&D. There is a great opportunity to exploit and expand
developing country capacity to develop needed vaccines. Much
vaccine technology is initially developed in government and
academic institutions, but these inventions are typically licensed
to big pharma for rich-world applications. New mechanisms are
needed to support technology transfer and fund vaccine development.
118. 4/6/2014 RD_Vaccine Meet_2014 118 With all this background,
contribution of Industry, Academia, NGOs, Governments, and health
care professionals should not be underestimated We need to be
tolerant and do the balancing act between various stake-holders for
global health issues RD-2014 119. 4/6/2014 RD_Vaccine Meet_2014 119
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