Dr. Ravi Dhar reviews "IP Barriers in Generic Vaccines in 2014"

IP Barriers
in
Developing
Generic Vaccines
&
How to Tackle these!
(F)
Ravi Dhar, Ph.D.
(rdhar_in@yahoo.com)
(rdhar.birac@nic.in)
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

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

4/6/2014 RD_Vaccine Meet_2014 3
Part-I

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

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

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)

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 guide—available as a smart phone app or by mail—offers health
care professionals cross-referenced lists of brand name and generic medicines.

“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 it’s taken until
the body eliminates it
Strength and dosage
Route of administration—tablet, 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)

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)

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)

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

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.

Part-II

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

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)

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.

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

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. h.v.hogerzeil@umcg.nl
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]

Indian Strength

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“)

= = Chances of IP generation or Utilization or Circumventing IP

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.

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.

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

Part-III

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 thickets’severely 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”

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.

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)

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

Global Support
for Vaccine Development

Part-IV

IP Barriers for Vaccine Development
Technical
Legal
Regulatory
Ethical
Societal

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 WTO’s restriction on utilizing technology barrier on
international trade.
Ethical
Societal: depends on economic status, poverty, affordability etc??

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.

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

IP Barriers
Legal
Infringements of various
scales – has become a
subsidiary business for some

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 WTO’s restriction on utilizing technology barrier on
international trade.

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.”

IP Barriers
Societal: depends on unmet
medical needs, economic status,
poverty, affordability etc??

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

R&D spending has a direct relationship
with development of new essential products

Part-V

Multiple Layers
of
IP Protection
in
Vaccine
Development

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)

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

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

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

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

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.

Need for Effective databases
Lack of patent claim information in publicly available
Indian patent databases hampers pace of R&D.
Bharat Biotech’s 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

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): 671–678. doi: 10.1038/nbt0710-671 , PMCID:
PMC3138722, NIHMSID: NIHMS270118
MoHFW -
http://mohfw.nic.in/WriteReadData/l892s/1084811197NATIONAL%20VACCI
NE%20POLICY%20BOOK.pdf

Circumventing Patent Laws for affordable
Vaccines
Credits: S. Padmanabhan, Nature Biotechnology, 2010

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.

Local R&D Effort:
Success Stories: Rotavirus Vaccine
(2013)
•India’s 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

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

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

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

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)

(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.

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).

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

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.

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).

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

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]

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 ????

Platform processes
Very useful
Generate huge IP

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
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

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
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

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
6 6,310,045 Compositions and methods for cancer
immunotherapy
7 5,662,896 Compositions and methods for cancer
immunotherapy
Reference Reagents

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

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.

Issues related to Expression
systems
Axel Patent Story !!!! Columbia University

AXELPatentStorey:ColumbiaUniversity

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).

(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

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

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.

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 body’s
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 Publishing’s
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.

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

IP issues in Delivery Systems

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 latter’s 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 today’s exchange rate), Vaxxas’ platform was originally
developed by researchers at UQ’s Australian Institute for Bioengineering and
Nanotechnology.
http://www.genengnews.com/gen-news-
highlights/merck-co-to-evaluate-transdermal-
vaccine-delivery-system/81247449/

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-γ 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 1–specific 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.)

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.

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

Will Vaccines Derived from Plants be Classified
under Drugs or Foods?
Ans:
Both – so IP issues become more complex

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. BIO’s 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.

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%

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 vaccine’s 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
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RD_Vaccine Meet_2014

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

Bode C. et al. (2011) CpG DNA as a vaccine adjuvant. Expert Rev Vaccines. 2011 April; 10(4): 499–511

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.

IP issues in Excipient
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), Dulbecco’s
Modified Eagle’s 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

IP issues in Delivery Devices

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.

4/6/2014 RD_Vaccine Meet_2014 100

4/6/2014 RD_Vaccine Meet_2014 101
Indian Vaccine Strength
http://www.slideshare.net/fababioasia/vaccines-
indias-strength-8501392

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: don’t 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**

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?

4/6/2014 RD_Vaccine Meet_2014 104
Solutions to tackle barriers

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.

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.

4/6/2014 RD_Vaccine Meet_2014 107
Pool Data

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.

4/6/2014 RD_Vaccine Meet_2014 109
Balancing Act

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.

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

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. Thailand’s 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

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

4/6/2014 RD_Vaccine Meet_2014 114

4/6/2014 RD_Vaccine Meet_2014 115
Compulsory Licensing to get
Generic Vaccines going?

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

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.

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

4/6/2014 RD_Vaccine Meet_2014 119
Thanks
(rdhar_in@yahoo.com)

Dr. Ravi Dhar reviews "IP Barriers in Generic Vaccines in 2014"

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Dr. Ravi Dhar reviews "IP Barriers in Generic Vaccines in 2014"