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nature biotechnology volume 28 number 7 JulY 2010 671
improving vaccine access in LMCs. When
introduced in the early 1980s, the HBV vac-
cine was priced at $50–80 per dose, one of
the most expensive prophylactic vaccines
at that time21. However, developing coun-
try vaccine manufacturers (DCVMs), using
alternate expression platforms suitable for
low-cost development, successfully brought
inexpensive HBV vaccines to market in the
1990s. The ensuing competition reduced
market prices to less than $0.30 per dose21,22.
Procurement costs for large vaccination
programs consequently decreased, allow-
ing wider access to the vaccine in LMCs21.
DCVMs are therefore potentially important
suppliers of low-cost HPV vaccines.
For successful production, DCVMs require
access to relevant technology, which can be
protected by intellectual property (IP) rights.
Although DCVMs have faced few patent bar-
riers so far, changes adopted by developing
countries to comply with the World Trade
Organization’s Agreement on Trade Related
Aspects of Intellectual Property Rights might
create new obstacles for vaccine develop-
ment23. Before the agreement, many LMCs
did not award product patents for biopharma-
ceuticals, including vaccines. Now, however,
DCVMs must consider international phar-
maceutical companies’ product patent rights
on vaccines and related technologies. Patents
granted in developing countries might con-
strain the ability of manufacturers to develop
vaccines and/or to sell vaccines in local and
international LMC markets (Fig. 1), thereby
reducing their development incentives.
Two recent reports have suggested that
IP might be a barrier for DCVMs who are
interested in developing HPV vaccines24,25.
However, publicly available information about
the patenting and licensing of HPV vaccine tech-
nologies in developing countries is minimal.
such pricing enables middle-class access in
some emerging economies, the vaccine remains
unaffordable for most low- and middle-income
populations in LMCs. Prices must fall below
$2 per dose to make broad access possible in
low-income populations, especially in coun-
tries where gross domestic product per capita
is below $1,000 (refs. 9,10). It is unlikely that
Merck or GSK can reduce vaccine prices to
match these affordability targets because of the
high production costs associated with their vac-
cines11. Company donations can also improve
access12,13. Merck donated about 130,000 doses
to PATH for demonstration studies in India,
Peru and Vietnam14. Through the Gardasil
Access Program, Merck aims to extend its sup-
port to LMCs and has pledged to make 3 million
doses of vaccine available to eligible countries15.
However, reliance on pharmaceutical company
donations alone is unsustainable. Alternatively,
donor-aided vaccine purchase can significantly
increase vaccine access by facilitating distribu-
tion of highly discounted vaccines in eligible
LMCs16. The Global Alliance for Vaccines and
Immunization (GAVI) recently prioritized
HPV vaccines17. However, owing to a $4 bil-
lion deficit and existing financial commitments
to other vaccines, it might be unable to finance
HPV vaccines18. Donors often face tradeoffs,
and high prices limit the quantities of vaccines
or treatments they can subsidize19.
Vaccine manufacturing in LMCs can also
reduce prices. Over the past decade, manufac-
turers in India, Cuba, China and Brazil have
demonstrated their capacity to produce low-
cost vaccines that meet international quality
standards. They primarily serve low-income
markets, supplying 64% of childhood vac-
cines procured by UNICEF and 43% of vac-
cines procured by GAVI20,21. Recombinant
hepatitis B (HBV) vaccines illustrate the
potential impact of such manufacturers in
Cervical cancer, the leading cause of female
cancer mortality worldwide, dispropor-
tionately affects women in low- and middle-
income countries (LMCs). Four-fifths of the
nearly 275,000 annual cervical cancer–related
deaths occur in LMCs where routine gyne-
cological screening is minimal or absent1,2.
Two new prophylactic vaccines, Gardasil
from Merck (Whitehouse Station, New Jersey,
USA) and Cervarix from GlaxoSmithKline
(GSK; London) have proven effective in
preventing human papilloma virus (HPV)-
induced cervical lesions and some sequelae.
Both vaccines are composed of HPV-L1
major capsid antigen virus-like particles
(VLPs), and both prevent persistent infec-
tion from HPV-16 and HPV-18, which cause
nearly 70% of cervical cancers3. Gardasil also
contains L1 antigens from HPV strains 6 and
11, which are associated with genital warts.
Costing at least $300 for the three-dose regi-
men, Gardasil is one of the most expensive
vaccines introduced so far4. Its private market
price exceeds $500 in several developed and
developing countries5, which few can afford
in most LMCs1,6,7.
Price discrimination by pharmaceutical com-
panies could improve vaccine access in LMCs.
Merck introduced Gardasil in India at about
$171 for the three-dose regimen8. Although
Intellectual property, technology transfer and
manufacture of low-cost HPV vaccines in India
Swathi Padmanabhan, Tahir Amin, Bhaven Sampat, Robert Cook-Deegan & Subhashini Chandrasekharan
An empirical study of the impact of patenting and licensing on regional manufacturing of human papilloma virus
vaccines to help improve vaccine affordability and access.
Swathi Padmanabhan, Robert Cook-Deegan
and Subhashini Chandrasekharan are at
the Center for Genome Ethics, Law & Policy,
Institute for Genome Sciences & Policy, Duke
University, Durham, North Carolina, USA;
Tahir Amin is at the Initiative for Medicines
Access and Knowledge, New York, New York,
USA; and Bhaven Sampat is at the Mailman
School of Public Health, Columbia University,
New York, New York, USA.
e-mail: shubha.c@duke.edu
patents
npg © 2012 Nature America, Inc. All rights reserved.
672 volume 28 number 7 JulY 2010 nature biotechnology
(Table 2). The universities and NIH have
not sought patent protection for technolo-
gies underlying L1-VLP vaccines in India.
However, Merck and GSK have applied for
patents on HPV vaccine compositions. GSK
alone has filed 13 of these applications. The
Indian Intellectual Property Office (IPO) has
awarded six patents, four to GSK and one each
to Wyeth Holdings (Wayne, New Jersey, USA)
and the University of Cape Town (Cape Town,
South Africa). Although the determination of
patent scope is complicated and sometimes the
subject of costly litigation, we offer our pre-
liminary analysis of patent claims based on our
understanding of these technologies and dis-
cussions with researchers who developed first-
generation vaccines. Patent 203333, awarded
to GSK, claims compositions of a prophylactic
vaccine that contains VLPs composed of L1
antigens from HPV-16, 18, 31 and 45. This is
detailed in Claim 1, the first independent claim
that technically confers the broadest scope of
protection and reads, “A vaccine composition
comprising virus like particles containing
L1 proteins or functional L1 protein deriva-
tives from human papilloma virus 16, human
papilloma virus 18, human papilloma virus
33 and human papilloma virus 45 genotypes
wherein the antibody response generated
by the vaccine is at a level similar to that for
each human papilloma virus, virus like par-
ticle formulated alone.” Our analysis suggests
that only a vaccine containing L1-VLPs from
all four HPV strains mentioned in Claim1
directly infringes the patent. Therefore, Indian
manufacturers are probably free to develop a
bivalent HPV vaccine containing L1-VLPs for
HPV-16 and HPV-18 only or a quadrivalent
vaccine containing any combination of three,
two or one of these four strains in addition
to other unclaimed oncogenic strains. Patent
209780, also awarded to GSK, claims a vac-
cine composition comprising L1-VLPs for
HPV-16, HPV-18 and an adjuvant contain-
ing aluminum hydroxide and 3-O-desacyl-
4’-monophosphoryl lipid A (3dMPL). Claim
1 specifically reads, “A vaccine comprising a
human papillomavirus 16 L1 virus like par-
ticles, human papillomavirus 18 L1 virus like
particle, aluminum hydroxide, and 3dMPL.”
Furthermore, Claim 4 reads, “The vaccine
consisting of an HPV 16 L1 VLP, an HPV 18
L1 VLP, aluminum hydroxide, and 3dMPL.”
However, our analysis suggests that a bivalent
(HPV-16, -18 L1-VLP) prophylactic vaccine
developed by an Indian manufacturer would
not infringe this patent if formulated with a
different adjuvant. Additional patents awarded
to GSK (Tab l e 2) claim nucleotide sequences
of HPV early antigens (214047) and compo-
sitions of combination vaccines containing
of Rochester (Rochester, New York, USA),
Georgetown University (Washington,
DC) and the University of Queensland
(Brisbane, Queensland, Australia) (Tabl e 1).
MedImmune (Gaithersburg, Maryland, USA),
Merck and GSK developed these technologies
further and performed safety and efficacy
clinical testing to bring the vaccines to mar-
ket28. The IP landscape for HPV vaccines is
complex, with 81 US patents granted so far,
linked to 86 specific Patent Cooperation
Treaty (PCT) applications. Eighteen enti-
ties—ten of which are nonprofit—own these
US patents. Nonprofit organizations own 20
of the 81 US patents, for-profits own 55, and
for-profit and nonprofit entities jointly own
6 (Supplementary Table 1). Merck owns the
most patents (24), followed by GSK and the
US Government (arising from the NCI), who
own 8 patents each.
As of December 2008, 19 of the 86 inter-
national PCT applications were filed in India
We therefore systematically investigated the
extent to which patents are a barrier to produc-
ing HPV vaccines in LMCs, focusing on India
for several reasons. India bears nearly 25% of
the global cervical cancer burden26,27 and its
growing middle class is a potentially large pri-
vate market for HPV vaccines. Including this
vaccine in national immunization programs
that target low-income populations will fur-
ther expand the market, creating strong incen-
tives for local manufacturing of inexpensive
alternatives. In addition, several Indian man-
ufacturers who are interested in developing
HPV vaccines have concerns about potential
patent impediments to such efforts.
The HPV vaccine patent landscape
First-generation prophylactic vaccines.
Technologies that enabled the development
of L1-VLP-based vaccines originated at the
US National Institutes of Health’s (NIH)
National Cancer Institute (NCI), University
Figure 1 Impact of patents on manufacturing, sale, and/or export of ‘bio-similar’ HPV vaccines by
developing country vaccine manufacturers. Patents existing in the country of the manufacturer that
claim the ‘composition of matter’ of necessary antigens (e.g., nucleic acid and/or amino acid sequences
of the L1 proteins) or the vaccine itself (e.g., VLPs made of L1 antigens) would prevent DCVMs from
developing and selling vaccines in their country without a license from the patent owner. If, however,
patents only claim specific methods or processes for producing the vaccine, manufacturers may have
freedom to operate if they use alternate processes to ‘work around’ those patents. Patents granted in
jurisdictions outside the manufacturing country—especially in potential export markets—might also
affect DCVM vaccine development plans. Manufacturers exporting vaccines to these countries would
infringe patents if their vaccines embodied the compositions or processes protected by such patents.
However, if vaccines had different formulations or were developed by using alternate processes, they
could still be sold in the importing country.
Do patents exist in
country of regional
manufacturer?
Can patents be
worked around?
Do these patents exist in
the importing country?
Manufacturing country free to
make and sell vaccines in local
and international markets
Manufacturing country free to make
vaccine and sell to countries in which
granted patents are not infringed
Manufacturing country has no
freedom to make and sell vaccine
without infringing patents
Do these patents
exist in the importing
country?
Manufacturing country free to
make and sell a vaccine developed
using alternate processes or
with alternate compositions
Manufacturing country free to make
and sell a vaccine developed using
alternate processes or with alternate
compositions as long as patents are
not infringed in the importing country
No
No
No
No
Ye s
Ye s
Ye s
Ye s
PATENTS
npg © 2012 Nature America, Inc. All rights reserved.
nature biotechnology volume 28 number 7 JulY 2010 673
HPV-16 and HPV-18 L1 antigens can induce
a strong immune response11,31. This technol-
ogy would allow oral or mucosal immuniza-
tion against HPV-16 and HPV-18 infection.
Lower development and implementation
costs associated with this oral vaccine make
it highly suitable for use in LMCs. To maxi-
mize the potential benefits of this technology
to LMCs, Nardelli-Haefliger and colleagues
assigned ownership of enabling IP to Indian
Immunologicals (Hyderabad) (D. Nardelli-
Haefliger, personal communication). Indian
Immunologicals has a memorandum of under-
standing with Lausanne and has received bio-
logical materials, know-how and training. It
from Johns Hopkins30. Using an Escherichia
coli expression system to purify L2 antigenic
peptides, Shantha hopes to lower develop-
ment costs, thereby making it possible to
reduce the price of vaccines significantly30
(A. Khar & R. Chaganti, Shantha Biotechnics;
personal communication).
Indian patent application 131/CHENP/2007
also bears on second-generation vaccine devel-
opment and is based on research performed
at the University of Lausanne (Lausanne,
Switzerland). Denise Nardelli-Haefliger and
colleagues showed that recombinant clones
of attenuated Salmonella enterica (serovar
Typhi and Typhimurium) strains expressing
HPV L1 antigens (202425) and other antigens,
respectively. These too are unlikely to con-
strain Indian vaccine manufacturers develop-
ing Gardasil or Cervarix ‘biosimilars’.
The University of Cape Town patent claims
methods to produce HPV-16 L1-VLPs in
tobacco plants and their use in a vaccine
composition. However, plant-based expres-
sion has so far been unsuccessful in yielding
high amounts of purified HPV-16 VLPs11,
thus limiting the commercial viability of
this technology. Patent 220842, awarded to
Wyeth, covers polypeptides of HPV early
antigens E6 and E7, which are likely to be
used in therapeutic cervical cancer vac-
cine compositions but are less relevant to
L1-VLP–based prophylactic vaccines. We
found no patents on HPV-16 and HPV-18
L1 nucleic acid sequences filed or awarded
in India. However, Merck has four pending
patent applications, claiming L1 nucleic acid
sequences of HPV subtypes 31, 45, 52 and
58, optimized for expression in several yeast
strains. Because the IPO can choose to sig-
nificantly narrow the scope of or deny some
claims during examination, it is difficult to
assess whether Merck’s applications will affect
vaccine development in India.
Second-generation prophylactic vaccines.
Currently, marketed first-generation vaccines
are costly to produce as they use expensive
expression systems to produce the L1 anti-
gens. Moreover, both miss several oncogenic
HPV strains that are present in India and
other LMCs29, which is particularly prob-
lematic when countries lack the screening
programs necessary to detect cancers not
prevented by current vaccines. Researchers
at the NCI and Johns Hopkins University
(Baltimore, Maryland, USA) have developed
an L2 (minor capsid antigen)-based vac-
cine. This approach would protect against
infection by all oncogenic strains and would
eliminate the costs of increasing the valency
of L1-based vaccines11.
NCI and Johns Hopkins have partnered
with Shantha Biotechnics (Hyderabad,
India) to commercialize this candidate. They
jointly filed Indian patent application 6219/
DELNP/2007 (Tab le 2) with the explicit ratio-
nale of preserving freedom to operate and
market exclusivity for Indian partners (J.T.
Schiller & M. Schmilovich, NCI, NIH; per-
sonal communication). Shantha has signed
a Cooperative Research and Development
Agreement with the NIH, gaining access to
biological materials such as codon-optimized
plasmids as well as the expertise and training
necessary to develop this vaccine. Shantha
has nonexclusively licensed this technology
Table 1 Timeline of patenting and licensing of HPV L1-VLP–based prophylactic vaccines
Date Event
July 19, 1991 Frazer et al. (Queensland) file international patent application in Australia
June 25, 1992 Schlegel et al. (Georgetown) file patent application in US
September 3, 1992 Schiller and Lowy et al. (NCI, NIH) file patent application in US
March 9, 1993 Rose et al. (Rochester) file patent application in US
February 1995 University of Queensland’s commercial arm UniQuest licenses HPV vaccine
technology to CSL (Melbourne)
October 5, 1995 MedImmune acquires exclusive license to HPV vaccine technology from
University of Rochester
1995 Merck licenses HPV vaccine technology from CSL
June 26, 1996 MedImmune in-licenses key HPV IP from German Cancer Research Center
January 7, 1997 NCI non-exclusively licenses HPV vaccine technology to MedImmune
June 24, 1997 USPTO declares initial interference
December 1997 NCI nonexclusively licenses HPV vaccine technology to Merck
December 11, 1997 MedImmune and SmithKline Beecham form worldwide HPV vaccine alliance
January 16, 1998 MedImmune finalizes vaccine agreement with SmithKline Beecham
October 24, 2001 USPTO declares patent interference 104,771 between Rose and Lowy
USPTO declares patent interference 104,772 between Rose and Schlegel
USPTO declares patent interference 104,773 between Rose and Frazer
USPTO declares patent interference 104,774 between Lowy and Schlegel
USPTO declares patent interference 104,775 between Lowy and Frazer
USPTO declares patent interference 104,776 between Schlegel and Frazer
February 2005 Merck and GSK enter cross-license agreement for HPV patents
May 2005 NCI’s nonexclusive licenses convert to co-exclusive licenses
September 20, 2005 USPTO Board of Interference announces decision and awards priority to Schlegel
et al.
December 29, 2005 Frazer et al. appeal USPTO decision, case docketed in CAFC
August 20, 2007 CAFC reverses USPTO decision and awards priority to Frazer et al.
Technologies underlying the L1-VLP based prophylactic vaccines emerged from research conducted at the
University of Rochester, the NCI, Georgetown University and the University of Queensland. The NCI initially
nonexclusively licensed the technology to MedImmune and Merck. MedImmune also acquired worldwide exclusive
rights to IP from Georgetown University and the University of Rochester. The University of Queensland licensed
its patents to CSL, which in turn licensed the technology exclusively to Merck. GSK eventually acquired exclusive
rights to MedImmune’s entire IP portfolio for HPV vaccine development. Owing to a first-to-invent system in
the United States, patent interference proceedings were triggered at the USPTO when claims overlapped from
different patent applications filed by four different groups of inventors. The interference proceedings involved
various L1-antigen HPV-related claims. Six two-way patent interferences between the four parties continued for
nearly a decade, presumably at significant cost to the institutions or their primary licensees, and were partially
resolved in 2005. Given the uncertainty surrounding the ownership of enabling vaccine technologies and the
possibility of mutually blocking exclusive rights (that is, neither firm could be sure its products would not infringe
on patent rights held by the other), Merck and GSK cross-licensed their respective IP holdings in 2005 to ensure
unfettered access to these technologies. They consequently secured their market position in the United States
and Europe and other OECD nations such as Canada and Japan. As part of the financial settlement of the patent
interference, the nonexclusive licenses awarded by NCI, NIH to MedImmune and Merck were converted to co-
exclusive licenses, thus allowing both GSK and Merck access to this IP. Merck brought Gardasil to market in the
United States in 2006 and Cervarix was introduced in the United Kingdom in June 2008. USPTO, US Patent and
Trademark Office; CAFC, US Court of Appeals for the Federal Circuit.
PATENTS
npg © 2012 Nature America, Inc. All rights reserved.
674 volume 28 number 7 JulY 2010 nature biotechnology
Serum Institute of India (Pune) and Bharat
Biotech (Hyderabad) are both also develop-
ing L1 VLP-based vaccines. Serum’s candi-
date will probably be a bivalent HPV-16 and
HPV-18 vaccine. The company will seek a
nonexclusive license from the NIH for cell
lines optimized for high expression of L1
antigens and will nonexclusively license the
Hansenula polymorpha expression platform
of an oral HPV vaccine. Both the Shantha and
Indian Immunologicals vaccines are currently
in the preclinical phase. Shantha projects a
2015 market entry at an initial price of $15
per dose32. Both manufacturers believe,
however, that prices will drop further as vac-
cine adoption increases, eventually reaching
around $1–2 per dose, which would make
broad access feasible.
has also filed international patent applications
(Table2 ) but will not seek patent protection
in Organisation for Economic Co-operation
and Development (OECD) markets (R.
Sriraman, D. Thiagarajan & K. Kumar, Indian
Immunologicals; personal communication).
With assured access to essential patents
and know-how, Indian Immunologicals has
strong incentives to invest in the development
Table 2 Patent landscape for HPV vaccines in India
Assignee/
applicant
PCT application no./
international
publication no.
Indian application no.
& application date in
India
Publication date
(application date)
Granted Indian
patent no.
(publication date
of grant) Expiry date Summary of claims
GlaxoSmithKline
Biologicals
PCT/EP2005/006461
(WO 05/123125)
3436/KOLNP/2006 6/15/2007
(11/20/2006)
Pending An immunogenic vaccine composition
containing VLPs, and/or capsomeres of
HPV-16, HPV-18 and at least one other
HPV genotype
GlaxoSmithKline
Biologicals
PCT/EP2003/02826
(WO 03/077942)
1351/KOLNP/2004 12/30/2005
(9/13/2004)
203333
(4/13/2007)
9/13/2024 An L1-VLP–based vaccine composition con-
taining VLPs of HPV-16, 18, 31 and 45
Vaccine composition further comprising
complete or immunologically active frag-
ments of HPV early antigens E1–E8
Vaccine composition further comprising
antigens of other STDs including HIV, HSV
and Chlamydia
Glaxo Group PCT/GB2001/03290
(WO 02/08435)
67/MUMNP/2003
1561/MUMNP/2007
(Divisional of 67/
MUMNP/2003)
2/4/2005
(1/16/2003)
11/9/2007
(9/27/2007)
214047
(1/24/2008)
Pending
1/16/2023 A synthetic polynucleotide sequence, analog
or fragment codon optimized for E. coli and
encoding the mutated amino acid sequences
of HPV early antigen E1, E2 for HPV types/
subtypes selected from HPV strains 1–4, 6,
7, 10, 11, 16, 18, 26–29, 31, 33, 35, 39,
49, 51, 52, 56, 59, 62 and 68
A p7313Plc backbone-based expression
vector capable of driving expression of
nucleotide sequences claimed in bacterial
cells
GlaxoSmithKline
Biologicals
PCT/EP2006/003918
(WO 06/114312)
3957/KOLNP/2007 6/20/2008
(10/15/2007)
Pending L1 proteins of HPV-31, 45 and 52
Method to boost immune response to HPV-
16, HPV-18 vaccine by using L1 proteins
of other HPV subtypes in composition
claimed
SmithKline
Beecham
Biologicals
PCT/EP/2000/08784
(WO 01/0117551)
1471/CHENP/2003
IN/PCT/2002/336/CHE
11/25/2005
(9/17/2003)
N/A
(3/5/2002)
209780
(9/6/2007)
202425
(4/13/2007)
9/17/2023
3/5/2022
A vaccine composition comprising HPV-
16 L1 VLPs, HPV-18 L1 VLPs, aluminum
hydroxide and 3dMPL
A vaccine composition for treating or pre-
venting HPV and HSV infections compris-
ing the HSV gsD2 antigen and an HPV-6,
11, 16 or 18 L1 antigen and an adjuvant
that stimulates the TH1 response
GlaxoSmithKline
Biologicals
PCT/EP2003/014562
(WO 04/056389)
1108/KOLNP/2005 7/21/2006
(6/9/2005)
Pending Use of a vaccine composition compris-
ing HPV-16 and HPV-18 VLPs to prevent
infection by other oncogenic types of HPV,
excluding HPV-16 and HPV-18
Glaxo Group PCT/EP2003/011158
(WO 04/031222)
506/KOLNP/2005 6/9/2003
(3/24/2005)
Pending Nucleotide sequence of HPV polypeptides:
E1 or E2 from oncogenic HPV subtypes
Expression vector with codon-optimized
polynucleotide sequence
Pharmaceutical composition comprising
polynucleotides or vector-encoding nucle-
otide sequence
GlaxoSmithKline
Biologicals
PCT/EP2002/04966
(WO 02/087614)
1336/KOLNP/2003 1/13/2006
(10/16/2003)
Pending A vaccine composition comprising: (i) at
least one HIV antigen; and either one or
both of (ii) at least one HSV antigen and (iii)
at least one (HPV) antigen selected from
L1, L2, E6, E7 or a combination thereof
(continued)
PATENTS
npg © 2012 Nature America, Inc. All rights reserved.
nature biotechnology volume 28 number 7 JulY 2010 675
from Rhein Biotech (Düsseldof, Germany).
Serum anticipates a market entry of three to
four years after project initiation (S. Singh,
Serum Institute; personal communication).
In addition to the L1-VLP vaccine, Bharat
scientists are exploring a chimeric L2-HPV
vaccine. They plan to express an L2-HBV
small surface antigen fusion protein in Picchea
pastoris to produce VLPs containing HPV-L2
antigens at high density. Because the HBV
surface antigen spontaneously assembles into
VLPs, Bharat hopes to reduce the price of the
vaccine by circumventing the high costs of
purifying and assembling VLPs. Bharat filed
a provisional patent application for this vac-
cine in India last year. Despite developing this
technology in-house, Bharat might seek a non-
exclusive license from the NIH for the cell lines
used in neutralizing assays (S. Kandaswamy,
Bharat Biotech; personal communication).
Freedom to operate
Despite considerable patenting activity, our
analysis suggests that IP will not preclude
Table 2 Patent landscape for HPV vaccines in India (continued)
Assignee/
applicant
PCT application no./
international
publication no.
Indian application no.
& application date in
India
Publication date
(application date)
Granted Indian
patent no.
(publication date
of grant) Expiry date Summary of claims
SmithKline
Beecham
Biologicals
PCT/EP1998/05285
(WO 99/10375)
1903/MAS/1998 3/4/2005
(8/24/1998)
Pending HPV-16 or HPV-18 E6 or E7 HPV pro-
tein in fusion with Hib, lipoprotein D, or
NS I or fragment thereof from influenza
virus, and LYTA or fragment thereof from
Streptococcus pneumoniae
SmithKline
Beecham
Biologicals
PCT/EP2000/08728
(WO 01/17550)
IN/PCT2002/335/CHE 3/4/2005
(3/5/2002)
Pending Multivalent combination vaccine including
HPV (L1, L2, E6, E7) antigens, EBV (gp
350), HBV (Sag), hepatitis A (HM-175
strain), HSV-2 gD VZV antigen (gpl), HCMV
antigen (gB685, pp65), Toxoplasma gondii
antigen (SAG1 or TG34)
SmithKline
Beecham
Biologicals
PCT/EP1998/08563
(WO 99/33868)
IN/PCT2000/116/CHE 3/4/2005
(6/13/2000)
Pending A vaccine composition of HPV E6 or
E7 proteins or fusion of above antigens
with others including Hib, lipoprotein D,
NS I, influenza virus and LYTA of
S. pneumoniae
Merck & Co. PCT/EP2004/008677
(WO 04/084831)
4036/DELNP/2005 8/31/2007
(9/8/2005)
Pending Codon-optimized nucleic acid sequence
encoding HPV 31 L1 and codon-optimized
for expression in yeast strains including
Saccharomyces cerevisiae and Pichia
pastoris
Vector and host expressing nucleic acid
claimed
VLPs of recombinant HPV-31 L1 or L2 pro-
teins or combinations produced in yeast
Methods for producing VLPs in yeast using
above nucleotide sequences
Merck & Co. PCT/US2005/009199
(WO 05/097821)
5998/DELNP/2006 8/24/2007
(10/16/2006)
Pending Codon-optimized nucleic acid of HPV-52
L1 for expression in yeast including S. cer-
evisiae and P. pastoris
VLPs of HPV-52 L1, L2 or combination
produced in yeast
Method of producing HPV-52 L1 or L2 or
combination VLPs in yeast
Merck & Co. PCT/US2004/037372
(WO 05/047315)
2930/DELNP/2006 8/10/2007
(5/22/2006)
Pending Codon-optimized nucleic acid of HPV-58
L1 for expression in yeast (S. cerevisiae,
Hansenula polymorpha, P. pastoris,
Kluyveromyces fragilis, Kluyveromyces lac-
tis, Saccharomyces pombe)
VLPs of HPV-58 L1, L2 or combination
Method of producing HPV-58 L1 or L2 or
combination VLPs in yeast
Indian
Immunologicals
PCT/IB2005/001725
(WO 05/123762)
131/CHENP/2007 8/24/2007
(1/12/2007)
Pending HPV-16 L1 nucleic acid sequence codon-
optimized for expression in prokaryotic
organisms E. coli, Shigella, Lactobacillus,
Mycobacteria, Listeria, or Salmonella-
attenuated strains S. enterica serovar,
S. typhimurium, S. typhi
Attenuated strain of microorganism
expressing codon-optimized HPV capsid
protein from HPV-16, 18, 31, 45
Method for improving immunogenicity of
a prokaryotic microorganism, specifically
Salmonella against HPV 16
(continued)
PATENTS
npg © 2012 Nature America, Inc. All rights reserved.
676 volume 28 number 7 JulY 2010 nature biotechnology
Initiative for Vaccine Research or other agen-
cies could help coordinate FTO and patent
landscaping services to advise regional manu-
facturers on potential IP barriers for HPV vac-
cine development. The creation of resources
to map and update the IP landscape for novel
HPV vaccines could facilitate regional manu-
facturing efforts. This could be developed in
partnership with the DCVM network.
Potential roles for universities
and funders
Universities and nonprofit research institu-
tions exploring new HPV vaccines can expe-
dite access to technology in LMCs. The IP
management practices of academic institu-
tions, who are the primary generators and
gatekeepers of IP for vaccine technologies,
will greatly affect regional vaccine manufac-
turing. The Lausanne-Indian Immunologicals
partnership, for example, harnesses the
capacity of a DCVM to commercialize a vac-
cine candidate with potentially high public
expensive. Our experience mirrored those
of Serum (Y. Dalvi, Serum Institute; per-
sonal communication) and Bharat. Indeed,
Bharat’s R&D was delayed owing to uncer-
tainty about the status of patent protection
for HPV antigens in India (S. Kandaswamy,
Bharat Biotech; personal communication).
Moreover, many countries in Africa, Latin
America and Southeast Asia—potential mar-
kets for HPV vaccines—lack online patent
databases, making it very difficult to deter-
mine which LMCs have pending or granted
patents. More importantly, LMC companies
generally lack the substantial financial and
human resources necessary to perform FTO
analyses using proprietary databases available
in developed countries.
Shantha, Indian Immunologicals and Bharat
often rely on researchers to conduct in-house
patent searches (R. Chaganti, A. Khar, Shantha;
R. Sriraman, D. Thiagarajan, K. Kumar,
Indian Immunologicals; S. Kandaswamy,
Bharat; personal communication). The WHO
manufacturing of first-generation L1-VLP–
based vaccines unless they are identical in
formulation or strain coverage to those com-
positions claimed in granted Indian patents.
We cannot, however, make this claim defini-
tively owing to uncertainties in interpreting
claims and the fate of pending applications.
The claims analysis we present is therefore not
legal advice but rather a starting point for inde-
pendent freedom to operate (FTO) analyses by
interested parties. Although there are several
patents and pending applications on promising
second-generation technologies (e.g., L2-based
vaccines or oral L1 vaccines), they so far appear
to preserve freedom for DCVMs.
IP transparency
Recent studies suggest that the lack of IP
transparency could be an important impedi-
ment for DCVMs exploring new vaccine
candidates33. Lack of patent claim infor-
mation in publicly available Indian patent
databases made our own research slow and
Table 2 Patent landscape for HPV vaccines in India (continued)
Assignee/
applicant
PCT application no./
international
publication no.
Indian application no.
& application date in
India
Publication date
(application date)
Granted Indian
patent no.
(publication date
of grant) Expiry date Summary of claims
University of
Cape Town,
South Africa
PCT/IB2002/03531
(WO 03/018623)
00831/DELNP/2004 4/27/2007
(3/31/2004)
221817
(7/7/2008)
3/31/2024 Modified nucleotide sequences encoding
HPV-16 and HPV-11 L1 proteins for pro-
ducing VLPs in plant cells where the plant
is Nicotiana benthamiana
VLPs produced by this method for use in a
vaccine to treat or prevent HPV infections
in humans
Wyeth Holdings PCT/US2003/031726
(WO 04/030636)
505/KOLNP/2005 2/24/2006
(3/24/2005)
220842
(6/6/2008)
3/24/2025 A fusion polypeptide comprising HPV E6
and E7 antigen polypeptides where the E6
antigen has mutations in amino acids 63
or 106 and the E7 antigen has mutations
in amino acids 24, 26 or 91
A nucleotide sequence encoding the above
polypeptide
Active Biotech PCT/SE2000/001808
(WO 01/023422)
IN/PCT/2002/00438/
CHE
3/4/2005
(3/21/2002)
Pending A carrier for introducing HPV major capsid
Ll protein that has been intentionally
modified to remove major type-specific
epitope(s) that cause production of neu-
tralizing antibodies and which raises a
protective immune response cross-reactive
toward two or more of the group of HPV-Ll
proteins comprising Ll proteins of HPV-16,
18, 31 and 45
Government of
the US (NIH);
Johns Hopkins
University
PCT/US2006/003601
(WO 06/083984)
6219/DELNP/2007 8/31/2007
(8/9/2007)
Pending A method for inducing broadly cross-
neutralizing antibodies against cutane-
ous and mucosal HPV types in humans by
administering immunogenic N-terminal
peptides of L2 protein
The Delphion patent database was searched for HPV vaccine–related patents and patent applications published on or before December 31, 2008, using ‘inventor’ and ‘assignee’
names. These results were supplemented with searches of other databases (Derwent Patent Index and the World Intellectual Property Office patent database) to find corresponding
international applications filed under the PCT and national phase information. Indian patent filings were identified using two freely available resources, the BigPatents42 and IPO
databases. As neither of the Indian electronic databases included patent claims, we obtained certified hard copies of all granted patents from the four Indian patent offices for claims
analysis. For pending Indian applications, we analyzed claims published in corresponding PCT filings. However, there might be pending patent applications not yet published by the
IPO that therefore could not be analyzed. We collected information about the licensing status of patents and applications from the US Securities and Exchange Commission filings,
and where necessary, directly from patent owners. We identified other legal and/or technological barriers through interviews conducted with HPV vaccine researchers, who developed
first- and second-generation vaccines, and technologies relevant to vaccine development in India. We also interviewed researchers and business leaders at four Indian companies—
Shantha Biotechnics, Indian Immunologicals, Bharat Biotech and Serum Institute of India—that are developing HPV vaccines. STDs, sexually transmitted diseases; HSV, herpes
simplex virus; Hib, Haemophilus influenzae type B; EBV, Epstein-Barr virus; HBV (sAg), hepatitis B surface antigen; HCMV, human cytomegalovirus.
PATENTS
npg © 2012 Nature America, Inc. All rights reserved.
nature biotechnology volume 28 number 7 JulY 2010 677
suggests that patents on first-generation vac-
cines do not seriously inhibit the development
efforts of DCVMs. Regional manufacturers,
national governments and international agen-
cies should consider this an opportunity and
take the necessary steps to make low-cost vac-
cine production a possibility.
Academic research institutions, from
which most HPV vaccine technologies
emerged, can play an important role in
supporting regional manufacturing. Their
technology transfer practices can promote
new channels for regional manufacturing
while ensuring that licensing does not block
pathways to low-cost regional manufactur-
ing of existing vaccines. Improving access to
know-how and creating IP transparency can
further facilitate regional manufacturing. By
participating in technology transfer partner-
ships and adopting favorable IP management
practices, universities can expedite access to
new generations of life-saving HPV vaccines
and increase the public health impact of these
vaccines in LMCs.
Note: Supplementary information is available on the
Nature Biotechnology website.
ACKNOWLEDGMENTS
We thank all the interviewees for their voluntary
participation in this study, and J.T. Schiller and M.
Angrist for helpful discussion and comments. S.P.
was supported by travel awards from the Alice M.
Baldwin Scholars program at Duke University, the Janet
B. Chiang grant from the Asian and Pacific Studies
Institute at Duke University, the Dannenberg Awards,
the Stay In Focus grant from the Focus Program and the
Public Policy Studies Department at Duke University.
S.C. and R.C.-D. gratefully acknowledge the support of
the National Human Genome Research Institute and
the Department of Energy (CEER grant P50 HG003391,
Duke University, Center of Excellence for ELSI
Research). S.C. and R.C.-D. also received a grant from
the Charles M. Josiah Trent Foundation that supported
travel for S.C. T.A. gratefully acknowledges the support
of the Echoing Green Fellowship.
COMPETING FINANCIAL INTERESTS
The authors declare no competing financial interests.
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vaccines will probably reduce prices.
Conclusions
Experiences with introducing new vac-
cines suggest that 20 years could pass before
women in LMCs gain access to HPV vac-
cines41. Meanwhile, every five-year delay in
vaccine introduction could result in nearly
1.5 to 2 million more HPV-related deaths1.
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income markets.
University licensing terms are generally
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Rochester, Queensland and Georgetown
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MedImmune. However, the licensing of vac-
cine technologies underlying Gardasil and
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sity technology transfer practice guidelines
to maximize benefit for the global poor34,35.
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limited recombinant vaccine production
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licensing largely unnecessary at the time.
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practice guidelines deserve attention, espe-
cially as new technologies for prophylactic
or therapeutic vaccines emerge.
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options for DCVMs. Preferred practices
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tantly, illuminating unblocked pathways can
create incentives to commercialize vaccines
that are of little interest to OECD manufac-
turers. Universities owning upstream tech-
nologies can promote and compel disclosure
of licensing terms as part of licensure to
improve transparency. Alternatively, sponsors
of university research can make transparency
a condition of funding by stipulating (i) dis-
closure of what geographic regions and fields
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nature biotechnology volume 30 number 2 february 2012 193
Erratum: Factors influencing agbiotech adoption and development in
sub-Saharan Africa
Obidimma C Ezezika, Abdallah S Daar, Kathryn Barber, Justin Mabeya, Fiona Thomas, Jennifer Deadman, Debbie Wang & Peter A Singer
Nat. Biotechnol. 30, 38–40 (2012); published online 9 January 2012
In the version of this article published in print, the affiliations were omitted. The error was corrected before online publication in the HTML and
PDF versions of the article.
Erratum: Amelioration of sepsis by inhibiting sialidase-mediated disruption
of the CD24-SiglecG interaction
Guo-Yun Chen, Xi Chen, Samantha King, Karen A Cavassani, Jiansong Cheng, Xincheng Zheng, Hongzhi Cao, Hai Yu, Jingyao Qu,
Dexing Fang, Wei Wu, Xue-Feng Bai, Jin-Qing Liu, Shireen A Woodiga, Chong Chen, Lei Sun, Cory M Hogaboam, Steven L Kunkel,
Pan Zheng & Yang Liu
Nat. Biotechnol. 29, 428–435 (2011); published online 6 May 2011; corrected after print 18 January 2012
In the version of this article initially published, a line in the abstract read, “repressed by the t interaction….” It should have read, “repressed by the
interaction….” The error has been corrected in the HTML and PDF versions of the article.
Corrigendum: Industry continues dabbling with open innovation models
Cormac Sheridan
Nat. Biotechnol. 29, 1063–1065 (2011); published online 8 December 2011; corrected after print 8 February 2012
In the version of this article initially published, Richard Anderson is named incorrectly and so is his affiliation as director of the Initiative for Open
Innovation. The source’s correct name is Richard Jefferson and he is founder and CEO of Cambia, a not-for-profit biotech research institute based
at the Queensland University of Technology, in Brisbane, Australia. The error has been corrected in the HTML and PDF versions of the article.
Corrigendum: FDA panel votes to pull Avastin in breast cancer, again
Mark Ratner
Nat. Biotechnol. 29, 676 (2011); published online 5 August 2011; corrected after print 8 February 2012
In the version of this article initially published, only “ovarian and small cell lung cancer” were said to be among Avastin’s current FDA-approved
uses. In the US, Avastin is currently approved for advanced colon, non-small cell lung, glioblastoma and kidney cancers. FDA withdrew Avastin’s
breast cancer approval in November 2011 (Nat. Biotechnol. 30, 6 (2012). The error has been corrected in the HTML and PDF versions of the article.
Corrigendum: Chinese vaccine developers gain WHO imprimatur
Hepeng Jia & Karen Carey
Nat. Biotechnol. 29, 471–472 (2011); published online 7 June 2011; corrected after print 8 February 2012
In the version of this article originally published, in Table 1, Sinovac Biotech was described as having been acquired by Novartis in March. Novartis
acquired a different company, Tianyuan, as stated later in the article.
Corrigendum: Intellectual property, technology transfer and manufacture of
low-cost HPV vaccines in India
Swathi Padmanabhan, Tahir Amin, Bhaven Sampat, Robert Cook-Deegan & Subhashini Chandrasekharan
Nat. Biotechnol. 28, 671–678 (2010); published online 8 July 2010; corrected after print 8 February 2012
In the version of this article initially published, on p. 671, column 2, the authors state: “Merck has donated three million doses of Gardasil to the
Program for Appropriate Technology in Health (PATH) for demonstration trials14. Its Gardasil Access Program aims to extend this support to eight
LMCs15.” It should have read: “Merck donated about 130,000 doses to PATH for demonstration studies in India, Peru and Vietnam14. Through
the Gardasil Access Program, Merck aims to extend its support to LMCs and has pledged to make 3 million doses of vaccine available to eligible
countries15.” In addition, reference 14 should have been Tsu, V. PATH/Seattle, personal communication (2011), rather than Harner-Jay et al.
J. Pharm. Sci. (2008).
errata, corrigenda and addenda
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