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Antimalarial patent landscape: A qualitative and quantitative analysis


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The present study attempts to capture the development in the technology sphere of antimalarial agents through patent landscaping. The study addresses patents describing novel technologies related to some of the new and promising antimalarial drug targets. It also attempts to cover the patent landscape of the existing antimalarial drugs and vaccines. Lastly, a quantitative patent analysis of global antimalarial agents has been presented to arrive at an evidence-based policymaking in order to eradicate malaria.
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Antimalarial patent landscape: a qualitative
and quantitative analysis
Tarakanta Jana*, Siddhartha Dulakakhoria, Deepak Bindal, Trina Mukherjee, Ankit Tripathi and
Nupur Wadia
The present study attempts to capture the development in the technology sphere of antimalarial
agents through patent landscaping. The study addresses patents describing novel technologies
related to some of the new and promising antimalarial drug targets. It also attempts to cover the
patent landscape of the existing antimalarial drugs and vaccines. Lastly, a quantitative patent
analysis of global antimalarial agents has been presented to arrive at an evidence-based policy-
making in order to eradicate malaria.
Keywords: Antimalarial drug resistance, antimalarial drug targets, antimalarial vaccines, patent landscape, Plasmodium.
MALARIA is a major global health problem. It is the lead-
ing cause of death in children, and directly and adversely
affects economic development1. The World Health
Organization (WHO) places 3.3 billion people of the
world at risk of contracting malaria, with 2.1 billion at
low risk and 1.2 billion at high risk2,3. Vaccination,
vector control and parasiticidal drugs are the three main
strategies which are presently being used to control the
disease. Currently parasiticidal drugs are the main line of
disease control until vaccination or mosquito control can
be implemented more successfully4. For decades, malaria
chemotherapy has relied on a limited number of drugs.
However, the acquisition and spread of drug resistance
has led to increase in morbidity and mortality rates in
many malaria endemic regions. Increasing burden caused
by drug-resistant parasites has stimulated scientist and
researchers to look for novel drug targets and inhibitors5.
For these reasons it is imperative that new lines of drugs
should be explored before existing drugs lose too much
Currently, malaria drug development is research prior-
ity. Vaccine development is one aspect of the efforts to
control malaria, but an effective vaccine should transform
prospects of reducing this disease. Malaria vaccines can
be the cornerstone of malaria eradication7. Worldwide
funding for malaria vaccines has increased recently from
US$ 50 million to around US$ 60–70 million, but
remains an order of magnitude below that for HIV vac-
cine development8. Exciting progress made over the past
decade has revived scientific attention and has attracted
public and private funding to pursue vaccine-based inter-
vention strategies9.
An attempt has been made in this study to present an
overview of the new line of drugs that are been currently
explored, through patent landscaping. A detailed descrip-
tion of a few novel and promising technologies (accord-
ing to the authors) is also presented. Additionally, we
have also made an attempt to summarize the patent land-
scape of the existing antimalarial drugs. A detailed over-
view of the current patent landscape of the malaria
vaccines is also included. Lastly, to summarize the trend
of global patenting activity in the field of malaria, a
quantitative analysis of the global antimalarial agents has
been presented.
The databases searched included subscription-based data-
base Derwent Innovation Index for the period 1966–2011.
The search methodology for obtaining patent publications
related to the area of malaria was mainly based on key-
word searches. The search strings used to collect the data
are provided in the supplementary material (Tables 1–4
available online). In addition, various search strategies
based on applicant, owner or assignee and country-wise
coverage queries were also used.
Patent landscape of new antimalarial drug targets
Cell cycle as drug targets
Cyclin-dependent kinases (CDK) play an important role
in cell cycle progression and are conserved in all
eukaryotic species10. CDKs are attractive drug targets in
numerous diseases and efforts have led to the identifica-
tion of novel CDK-selective inhibitors in the develop-
ment of treatments for infectious diseases like malaria.
The authors are in the CSIR-National Institute of Science Communica-
tion and Information Resources, 14 Satsang Vihar Marg, Qutub Institu-
tional Area, New Delhi 110 067, India.
*For correspondence. (e-mail:
CURRENT SCIENCE, VOL. 103, NO. 10, 25 NOVEMBER 2012 1163
CDK has become the focus of rational drug design pro-
grammes for the development of new antimalarial agents.
An initial search with the string ‘cdk inhibitor’ retrieved
241 patent publications claiming composition or formula-
tion related to CDK inhibitors. One-third of the retrieved
patent publications were disclosing compositions and
formulation related to antineoplastic agents. A manual
check of the retrieved data revealed that only 13 patent
publications have described technology, related to CDK
inhibition, to treat malaria.
Three CDKs have been identified in the Plasmodium
genome11, Pfmrk, PK5 and PK6. The use of quinazoli-
none compounds, such as febrifugine derivatives, as in-
hibitors of recombinant plasmodial cyclin-dependent
kinase (Pfmrk) for the treatment of protozoan infections
was described in WO2004000319. Chalcones, another
compound claimed as a potent inhibitor of Pfmrk, was
disclosed in WO9317671.
WO200296888, granted in 2004 and assigned to Bayer
Pharma AG, came out as the most dominant patent with
64 citations. The patent claimed a novel pyrimidine
derivative as a potent CDK inhibitor. It was further
claimed that the compound is effective at nanomolar con-
centrations and has much stronger CDK inhibiting acti-
vity than known agents such as olomoucine, roscovitine
and kenpaullone, and can be used for treating Plasmo-
dium infection. Cyclacel Limited came out as the top
assignee with 10 publications related to Plasmodium
CDK inhibitors. The most dominant patent (US2007/
0021419-A1) in the Cyclacel CDK inhibitor patent port-
folio describes a compound which can be used for treating
antifungal and antiparasitic disorders, particularly ma-
laria. It was further claimed that the compound is a potent
protein kinase inhibitor and may also inhibit formation of
the nuclear envelop, exit from the quiescent phase of the
cell cycle, G1 progression, chromosome decondensation,
nuclear envelope breakdown, START initiation of DNA
replication, etc.
It is well established that active pharmaceutical agents
can be often given in combination in order to optimize the
treatment regime. We recorded 8 patent publications which
described the use of a pharmaceutical combination of CDK
inhibitor and another pharmaceutical agent, e.g. ErbB in-
hibitor (US2010/0143380), histone deacetylase inhibitor
(EP1951307), vascular endothelial growth factor receptor
inhibitor (EP1568368), cytosine analogue (US7772207),
DNA topoisomerase-I inhibitor (US2006/0148828),
gemcitabine (US2005/0267066), docetaxel (US2005/
0277656), mitoxantrone (US2005/0261260), anthracycline
(US2005/0222054) and 5-flurouracil (US2005/0164976).
Metabolic pathways in the apicoplast as drug targets
The identification of apicoplast in P. falciparum provided
new targets for drug therapy12. The apicoplast contains
metabolic pathways and housekeeping processes that
differ from those of the host, thereby presenting ideal
strategies for drug therapy. Compounds targeting these
pathways are antimalarial and have favourable profiles
based on extensive knowledge from their use as antibac-
DNA replication: The genome of the Plasmodium plas-
tid is circular and a bacterial-type DNA gyrase is required
for replication of the apicoplast genome14,15. Ciproflox-
acin has been shown to inhibit apicoplast DNA replica-
tion but not nuclear replication in P. falciparum. Recent
studies validate these findings, that DNA replication is a
viable therapeutic target in the apicoplast and point
towards ciprofloxacin as a potential antimalarial16.
A new class of terpyridine platinum complexes,
claimed to be potent intercalators of DNA and to have
anti-parasitic activity was disclosed in WO9727202.
Similarly, WO2003059881 disclosed a new oligopeptide
compound useful for treating diseases which depend on
DNA replication. Not a single patent claiming the inhibi-
tion of apicoplast DNA replication, for treating malaria
was recorded.
Transcription: The first step in gene expression, tran-
scription of the information in the DNA genome into
messenger RNA, is carried out by RNA polymerases
(RNAPs). These enzymes have become attractive targets
in the development of antibiotics17. For instance, the
frontline antitubercular drugs, rifampin and rifampicin,
effectively inhibit bacterial RNAPs. A number of other
potent inhibitors that affect different stages of transcrip-
tion or target different regions of the bacterial RNAP
have been reported, such as streptolydigin, microcin and
myxopyronin. These proteins are attractive targets in the
search for new antimalarial antibiotics.
We recorded about 20 patent publications, which de-
scribed technologies for the preparation of compositions
or pharmaceutical formulations, containing several anti-
biotics, which include transcription-inhibiting compounds
like rifampin and rifampicin, for the treatment of bacte-
rial and viral, including parasitic diseases like malaria.
US2011028385 disclosed a compound for treating bacte-
rial, viral and fungal, including parasitic diseases like
malaria and the mode of action of the compound involved
RNA transcription inhibition. The compound comprising
an immunomodulator, that must be combined or associ-
ated with at least one substance specifically targetted
against the pathogens that infected the host. Selected from
chemical groups and species such as bacterial nucleic
acid synthesis inhibitors (rifampicin, quinolones), and
substances with antibacterial, antiparasitic, antifungal and
antiviral properties, where a combination of substances
can be used in the treatment of infections caused by intra-
cellular microorganisms. A preparation containing active
substances 3-N-formyl-hydroxylaminopropyl phosphonic
acid derivative combined with other pharmaceutical
active agents like rifampin (a nucleic acid synthesis
inhibitor) is described in US2004235784. It was further
claimed that the pharmaceutical preparation can be used
in the therapeutic and prophylactic treatment of bacterial
and parasitic infections, especially malaria.
Fatty acid synthesis: It is one of the most attractive tar-
gets for malaria drug discovery. This pathway has been
found to be the target of several classes of antimicrobial
compounds, some of which have antimalarial activity18.
Among the enzymes of the FASII pathway in P. falcipa-
rum, FabI or enoyl-acyl carrier protein (ACP) reductase,
catalysing the final step in the chain elongation cycle, has
been studied in great detail from the viewpoint of identi-
fying potent inhibitors. Based on the potential of com-
pounds to inhibit the bacterial enoyl-ACP reductase,
inhibitory effects of triclosan, diazoborine, isoniazid and
ethionamide on the Plasmodium enzyme and growth in
culture have been studied19.
A total of seven patent publications were recorded
which disclosed technology related to fatty acid synthesis
(FAS) inhibition. The National Institute of Immunology
(NII) and Indian Institute of Science (IISc) with three
patent publications, WO200100138-A2, US2008051445-
A1 and US2008161247-A1, came out as the top assignee.
WO200100138-A2 described the use of hydroxydiphenyl
ether class of chemicals, e.g. triclosan to inhibit the elon-
gation in FAS in malaria parasite. US2008051445-A1
discloses a method for treating infectious diseases, such
as malaria using enoyl-ACP reductase inhibitor, i.e. an
inhibitor of the rate-limiting enzyme of type-II FAS path-
way that pulls the cycles of fatty acid elongation to com-
pletion, in microorganisms, including malarial parasites,
and which is different from the FAS I pathway in
humans. Thus, it provides a treatment method that acts on
a component of FAS pathway essential for growth; and
exhibits potent antimalarial, antibacterial and biocidal ac-
tivity. US2008161247-A1 claimed a synergistic composi-
tion for enhancing the effect of an inhibitor in inhibiting
nicotinamide adenine dinucleotide/nicotinamide adenine
dinucleotide phosphate (NAD+/NADP+) or reduced form
of NAD+/reduced form of NADP+ (NADH/NADPH)-
dependent enzymes and enoyl-ACP reductase for treating
malaria. The inhibitor for NAD+/NADP+-dependent
enzymes and enoyl-ACP reductase is triclosan.
A compound which inhibits the growth of liver stage
Plasmodium parasites and prevents malaria in a vertebrate
subject was disclosed in WO2008147826-A1. The inhibi-
tor of apicoplast FAS is a type-II FAS pathway inhibitor.
WO2009101345-A1, assigned to Seattle Biomedical
Research Centre, claimed a novel substituted bicyclic
compound useful as an anti-infective medicament for the
treatment and/or prevention of human/animal infections
related to a pathogen with enoyl-ACP reductase enzyme
or a structurally related enzyme. The compound acts as
an enoyl-ACP reductase inhibitor. US2005142204 de-
scribed the technology involved in manufacturing an oral
anti-malaria dosage form, comprising triclosan emulsion
and/or an oil solution.
Isoprenoid biosynthesis: The presence of a mevalonate-
independent pathway for isoprenoid biosynthesis in P.
falciparum has been discovered. 1-Deoxy-D-xylulose-5-
phosphate (DOXP) reducto isomerase plays an essential
role in the non-mevalonate pathway, which is absent in
A search with the string ‘DOXP malaria’ retrieved
seven patent publications, claiming novel compounds for
treating malaria by inhibition of DOXP reducto isomerase.
Among these, four patents (WO200278714, US2003144249,
WO200160829, WO200041473-A2) were assigned to
Jomaa Pharmaka GMBH, two patents (WO2005048715,
WO2005016942) to Bioagency AG and one patent
(US6638957) jointly assigned to Jomaa Pharmaka GMBH
and Bioagency AG.
Cytosolic targets
Folate pathway: The folate pathway has been a major
drug target. The combination of pyrimethamine, inhibit-
ing the dihydrofolate reductase (DHFR) and sulfadoxine,
inhibiting dihydropteroate synthase (DHPS), are provid-
ing to be an effective and cheap antimalarial. A method to
treat severe/multi-drug resistant cerebral malaria compris-
ing antimalarial agents
-arteether, sulfadoxin and pyri-
methamine is described in US2006141024. DE4009941
claimed the use of pteridines in combination with dhfr
inhibitors (pyrimethamine) and dhps inhibitors (sulfad-
oxine) for the treatment of malaria. We have recorded a
total of 44 publications claiming the use of dhfr-
inhibiting compounds. Six patent publications claimed
the use of P. falciparum DHFR (PfDHFR) inhibiting com-
pound as the primary drug for treating malaria. A few of
the disclosed PfDHFR inhibitors are new triazine deriva-
tives (WO2011018742-A1), new 2,4-diamine pyrimidine
(WO2009048957), new pyrimidine and quinazoline deri-
vatives (WO2004082613), new 2,4-diamino-5-phenyl-
pyrimidine derivatives (US2004180913) and new 2,4-
diaminopyrimidine (WO2003043979).
There has also been an effort to make methotrexate and
aminopterin, potent inhibitors of dhfr, in situ from non-
toxic precursors, in view of their toxicity to the host. We
recorded 20 patent publications which claimed the use of
methotrexate in combination with several other chemical
compounds for the treatment of malaria. In the case of
aminopterin we recorded only two patents mentioning the
use of the drug in methods for preparing monoclonal
antibody against malaria parasites.
Glycolysis: Plasmodium derives most of its energy
through glycolysis, hence inhibitors of this pathway have
CURRENT SCIENCE, VOL. 103, NO. 10, 25 NOVEMBER 2012 1165
been studied for antimalarial activity. One of the well-
studied targets is P. falciparum lactate dehydrogenase
(PfLDH). We recorded a single patent application which
(WO2011054525) claimed the use of compounds (substi-
tuted 5-membered heterocyclic) that inhibit lactate dehy-
drogenase (LDH) for treating malaria. It further claimed
to provide compounds that are selective inhibitors of the
LDH-A subunit of LDH enzymes. A large effort is
focused on developing PfLDH inhibitors such as gossy-
pol derivatives and naphthoic acid-based compounds. Not
a single patent claiming the use of gossypol or naphthoic
acid-based compound as a PfLDH inhibitor was recorded.
But we did record four patents mentioning the use of
gossypol in combination with several other chemical
compounds for treating malaria.
Salvage pathway: P. falciparum purine nucleoside
phosphorylase (PfPNP) is an enzyme of the salvage
pathway which has been studied as potential drug tar-
gets21. WO2009082247 discloses compounds comprising
PNP and purine phosphoribosyl transferase (PPRT) in-
hibitors which are useful for treating protozoan parasites,
e.g. malaria. 5-Methylthio-imucillin-H has been devel-
oped as a potent and selective inhibitor of PfPNP based
on the crystal structure of the inhibitor-bound compound.
US7098334 discloses the usage of 5-methylthio-imucillin
as 5-methylthioadenosine phosphorylase (MTAP) inhibitor
and 5-methylthioadenosine nucleosidase (MTAN) inhibi-
Hypoxanthine–guanine–xanthine phosphoribosyl trans-
ferase (PfHGXPT) is another potential drug target from
the salvage pathway22. PfHGXPT catalyses the transfer
of phosphoribosyl group to hypoxanthine, xanthine or
guanine to give the corresponding nucleotide.
US2005123557 discloses an immunotherapeutic compo-
sition comprising the HGXPRT protein or one or more
isolated proteins each comprising at least one immuno-
genic fragment, or an isolated nucleic acid encoding the
protein, and a carrier, diluent or excipient. The patent fur-
ther claimed that the composition can be used to treat
protozoal diseases like malaria. CN1900274 provides the
recombinant protein (HGXPRT) of malignant malarial
parasite hypoxanthine–guanine–xanthine ribose phos-
phate transferase. It was claimed that the recombinant
protein HGXPRT has excellent immunogenicity and
excellent enzymic kinetic characteristic, and can induce
effective malarial parasite antagonizing immune response
in the immunized individual and produce efficient enzy-
mological activity.
Redox system: It is still a matter of debate whether com-
pounds directed at P. falciparum antioxidant defence
could be a valid chemotherapeutic approach23. However,
it is generally accepted that oxidative stress is an impor-
tant mechanism for destruction of malaria and other
intracellular parasites24,25. To prevent oxidative stress, the
parasite has its own battery of defence tactics and pro-
duces its own antioxidant enzymes. The malaria parasite
contains three antioxidant enzymes: superoxide dismutase
(SOD), glutathione peroxidase (GPx) and catalase. Func-
tional thioredoxin and glutathione systems have been
shown to participate in antioxidant defence in P. falcipa-
rum and both are considered as attractive targets. The
antioxidant defence of the parasite could therefore be a
potential target for antimalarial chemotherapeutics. We
did not record any patent claiming compounds or drug
combinations which target the parasitic redox system.
Shikimate pathway: The discovery of the Shikimate
pathway in the malaria parasite has shown the path for
the discovery of new drug targets. Absence of the Shiki-
mate pathway in mammals presents an excellent target
for the development of new chemotherapeutic agents26.
US6699654 claimed a composition that interferes with
the growth or survival of an apicomplexan parasite by
inhibiting enzymes involved in metabolic pathways of the
parasite. The patent further claimed that the compound
inhibits (i) the synthesis of chorismate from phosphoe-
nolpyruvate and erythrose 4 phosphate by the Shikimate
pathway, (ii) synthesis of tetrahydrofolate from choris-
mate by the Shikimate pathway, (iii) synthesis of
ubiquinone from chorismate by the Shikimate pathway,
(iv) synthesis of aromatic amino acids (phenylalanine,
tyrosine and tryptophan) from chorismate by the Shiki-
mate pathway and (v) synthesis of the menaquinone,
enterobactin and vitamins E and K1 from chorismate by
the Shikimate pathway.
Mitochondrial targets: There are two main functions of
mitochondria: electron transport and protein synthesis.
These appear to be essential for survival and constitute
potential targets for antimalarial chemotherapy.
WO2010142741, assigned to the GlaxoSmithKline (GSK)
group, discloses new phenylpyridylpyridone compounds
useful in the treatment of malaria caused by infection
with P. falciparum. It was further claimed that the com-
pound acts by inhibiting ubiquinol-cytochrome bc1
(cytbc1) oxidoreductase, inhibits electron transport and
collapses mitochondrial membrane potential, which is re-
quired for a number of parasite biochemical processes.
Orotidine decarboxylase catalysing the conversion of
orotidine monophosphate to uridine monophosphate has
also been studied as a unique drug target and novel
pyrimidine derivatives are also under consideration.
Food vacuoles: Haemoglobin is broken down into heme
and is converted to hemozoin in the food vacuole. This
pathway has been targeted by the currently available
aminoquinolones27. Falcipains and plasmepsin proteases
which break down haemoglobin are now considered as
potential drug targets for new antimalarial agents. We
recorded seven patents which claimed novel compounds
to treat malaria by inhibiting plasmepsin protease. The
claimed plasmepsin inhibiting novel compounds are
macrocyclic heterocyclic compound (US2010063121),
substituted piperazine compounds (US2009105251), new
pyrido (2,3-d)pyrimidine compounds (US2010137310),
7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene derivatives (US-
7427613), allophenylnorstatine-based compound (US-
2005037953) and hydroxyamino acid amide derivatives
Patent landscape of the existing antimalarial
Artemisinins: These are one of the most important
classes of antimalarials for reasons that include pharma-
cokinetic properties, pharmocodynamic properties and
activity against multi-drug resistant parasites28. We re-
corded a total of 203 patents claiming the use of artemisi-
nins and their derivatives (artemether, artesunate and
dihydroartemisinin) to treat malaria. The Council of
Scientific and Industrial Research (CSIR)-India with 13
patent publications was the main applicant. Analysis of
artemisinin-related patenting activity by country revealed
that the US was by far the most prolific innovator country.
After manual refining of the retrieved data, we recorded
81 patent publications which claimed new artemisinin de-
rivatives or artemisinins as the primary drug, whereas the
remaining patent publications claimed the use of artemis-
inins as a secondary drug in combination with several
other pharmaceutical agents for the treatment of malaria.
The demand for artemisinin derived from plants may
soon exceed the supply. A number of semi-synthetic
routes to prepare artemisinin analogues, such as arte-
mether and artesunate with changes to the
-lactone por-
tion have been developed with the goal of improving the
pharmacokinetic properties29. An approach to meet the
demands for artemisinin-based therapies is to develop a
totally synthetic artemisinin analogue that can be manu-
factured at a price competitive with that of the agricul-
tural process. US6486199 awarded to Medicine of
Malaria Venture discloses such a compound. The patent
claimed of a method for treating malaria, schistosomiasis,
and cancer using a spiro or dispiro 1,2,4-trioxolane. The
compound was developed by Vennerstrom et al.30 as a
potent antimalarial. The compound lacks chiral centres
and is synthesized in a short and economical fashion by
Griesbaum co-ozonolysis involving the joining of O-
methyl adamantanone oxime with a substituted cyclohex-
anone in the presence of ozone followed by post-
ozonolysis side-chain elaboration. US2009042821
assigned to Ranbaxy claimed of a compound comprising
spiro or dispiro 1,2,4-trioxolane antimalarials, or their
pharmaceutically acceptable salts, prodrugs and ana-
logues, and processes for their preparation. Another patent
assigned to Ranbaxy (US20090306091) discloses antima-
larial therapy using a synthetic artemisinin derivative and
bisquinoline derivative.
Similarly, US7667017 discloses another bioengineer-
ing method invented by Kielsing et al.31, who have trans-
planted plant biosynthetic genes into yeast to allow
production of the artemisinin precursor artemisinic acid
in yields that appear suitable for large-scale fermentation.
The patent claimed of a method synthesizing isopentenyl
pyrophosphate (IPP) in a host microorganism. The
method includes introduction of heterologous nucleic
acid sequences into the host microorganism. It was fur-
ther claimed that each nucleic acid sequence codes for a
different enzyme in the mevalonate pathway for produc-
ing IPP. WO2010109472 discloses a method for micro-
bial bioconversion of arteannuin B to artemisinins.
Lumefantrine: A total of 41 patent publications claiming
the use of lumefantrine as an antimalarial drug have
been recorded. Ten patent publications claim the use of
lumefantrine as the primary drug. WO2006117616
assigned to Ranbaxy claimed of a new polymorphic
form of lumefantrine useful for treating or preventing
malaria. IN200901437, IN200802503, IN200801677 and
IN200700012 claimed of new process for the preparation
of lumefantrine.
Coartem (US5677331) is a combination of artemisinin-
derivatives artemether and lumefantrine and is the first
fixed dose artemisinin-based combination therapy to meet
WHO pre-qualification criteria for efficacy, safety and
Amodiaquine: This belongs to the 4-aminoquinoline
chemical class. It is used in combination with artesunate.
We recorded 62 patent publications claiming the use of
amodiaquine in combination with artesunate. Eighteen
patent publications claimed the use of amodiaquine as the
primary drug. Searete LLC and CSIR-India were the
major applicants. ASAQ, a pharmaceutical combination
of artesunate and amodiaquine, is one of the currently
available antimalarial medications. The drug was devised
by Drug for Neglected Disease initiative (DNDi) in part-
nership with Sanofi-Aventis. ASAQ is patent-free.
Piperaquine: A total of 18 patent publications claiming
the use of piperaquine for treating malaria have been
recorded. Thirteen patent publications claim the use of
piperaquine as the primary drug. The mode of action of
piperaquine is based upon heme binding, with an anti-
malarial activity against both P. falciparum and P.
vivax. Piperaquine has been combined with dihydroar-
temisinin (CN1237416, CN101199489, CN101984970,
CN101129377) with a view to provide a cheap, well-
tolerated, short-course treatment regime with a high cure
rate against drug-resistant parasite.
CURRENT SCIENCE, VOL. 103, NO. 10, 25 NOVEMBER 2012 1167
Duocotecxin and artekin are two commercially avail-
able medications of piperquine and dihydroartemisinin
combination. Eurartesim is another piperaquine and dihy-
droartemisinin combination which has been recently
approved by the European Commission for the treatment
of uncomplicated malaria.
Pyronaridine: Twenty-five patent publications claiming
the use of pyronaridine as an antimalarial agent has been
recorded. Seven patent publications claimed the use of
pyronaridine as the primary drug. KR975895 discloses a
method for preparing pyronaridine. The method is
claimed to produce pyronaridine with high yield and high
purity and with improved antimalarial activity.
WO2006049391 (Pyramax) assigned to Shin Poong
Pharmaceuticals disclosed a pharmaceutical formulation
comprising artesunate and pyronaridine, which can be
administered orally and is effective against resistant
strains of malaria.
Mefloquine: We recorded 123 patent publications claim-
ing the use of mefloquine as an antimalarial drug. Only
nine patent publications were recorded which claimed the
use of mefloquine as the primary drug, whereas the re-
maining claimed the usage of mefloquine as a secondary
drug in combination with several other antimalarial com-
pounds. EP2233481 claimed of a novel method for pro-
ducing mefloquine. The method comprises of diastereo-
selective hydrogenation of dehydromefloquine in an inert
solvent and using novel metal catalysts. US2007078161
assigned to Arakis Limited claimed new crystalline forms
of (+)– and (–)–erythro mefloquine hydrochloride, useful
for treating malaria. WO9821323-A2 claimed of a new
synthetic oligonucleotide, which is complementary to the
P. falciparum multi drug resistance gene and useful for
restoring sensitivity to antimalarial drugs such as meflo-
Quinine/quinidine: Quinine was the first effective drug
use in the treatment of malaria caused by P. falciparum,
appearing in therapeutics in the 17th century. It remained
the antimalarial drug of choice until the 1940s, when
other drugs replaced it32. A search for patents claiming
the use of quinine as a antimalarial drug retrieved 153
patent publications. In the last ten years only 22 patent
publications were recorded which claim the use of qui-
nine as the primary drug. WO200146188 claimed of new
stereoisomerically purified forms of the compounds,
quinine and quinidine and a method for determining
the therapeutic profile of a compound by comparing the
effects of the compound on the first and second ion chan-
nels and gastrointestinal tissue samples. US2008039492
claimed a method of optimizing the safe use of quinine
and providing information that quinine affects the activity
of a cytochrome p450 isozyme. US2009163540 claimed a
new solid state form of quinine sulfate.
Atovaquone: A total of 61 patent publications claiming
the use of atovaquone for treating malaria have been re-
corded. Six patent publications claimed the use of atova-
quone as the primary antimalarial drug. WO2010001379
claimed of a new process for preparing atovaquone. The
process provides higher yields of pure atovaquone, using
reagents which are inexpensive while avoiding the use of
heavy metals. WO2010009492 claimed of a new method
for preparing atovaquone and its salt. WO2011021230
claimed of a new atovaquone–proguanil complex. Atova-
quone is available as a combination preparation with
proguanil that has been commercially available from
GSK since 2000 as malarone for the treatment and pre-
vention of malaria.
Chloroquine: This is a 4-aminoquinoline drug used in
the treatment or prevention of malaria. It was until
recently the most widely used antimalarial. Two hundred
and seventy-three patent publications claiming the use of
chloroquine have been recorded. Of these, 188 were
issued or published in the last 10 years. But the emer-
gence of drug-resistant parasitic strains is rapidly de-
creasing its effectiveness; however, it is still the first-line
drug of choice in most sub-Saharan African countries.
We recorded a total of 78 patent publications claiming
the use of new compounds against chloroquine-resistant
malaria. Forty-four of these were published or issued in
the last 10 years. The Hoffmann La Roche & Co and the
University of Namibia were the top applicants with 8 and
7 patent publications respectively. Hoffmann La Roche &
Co portfolio consisted of publications claiming new or
known compounds. University of Namibia patent portfo-
lio was mainly composed of publications claiming the
synthesis of metal complexes for treating chloroquine-
resistant malaria.
Pyrimethamine: This is a medication used for treating
protozoal infection, mainly malarial infection. It inter-
feres with tetrahydrofolic acid synthesis from folic acid
by inhibiting the enzyme DHFR. It is for intermittent
preventive treatment, combined with sulfadoxine. One
hundred and ten publications claiming the use of
pyrimethamine have been recorded. Fifty-eight publica-
tions claimed the use of pyrimethamine in combination
with sulfadoxine. We also observed that majority of the
publications claimed the use of pyrimethamine–sulfad-
oxine as secondary drugs in combination with several
other antimalarial agents.
Resistance to pyrimethamine is widespread. Mutations
in the malarial gene for DHFR may reduce the effective-
ness of pyrimethamine. In this context we recorded nine
publications which disclose new compounds for treating
pyrimethamine-resistant malaria.
Primaquine: A member of the 8-aminoquinoline group,
primaquine is a medication used for the treatment of
malaria. We recorded a total of 95 patent publications
claiming the use of primaquine as a primary or secondary
antimalarial drug. Thirteen patents claimed the use of
primaquine as the primary or major antimalarial drug.
CSIR-India with six patents was the main applicant.
US7183291, EP1055427 and WO200191535 from the
CSIR-India portfolio claimed of new primaquine deriva-
tives for treating malaria.
Pre-erythrocytic vaccines: Currently, pre-erythrocytic
stage (sporozoite and liver-stage) vaccines are the best
supported financially, perhaps because there is a potential
market in the more developed countries33. The ideal vac-
cine of this stage would induce high titres of functional
antibodies against sporozoite to prevent all parasites
entering the liver stage, and induce potent cytotoxic T-
lymphocytes immunogenicity against the liver stage to
kill infected hepatocytes, while not harming the human
host. WO9310152 describes a vaccine derived from the
circumsporozoite (CS) protein of P. falciparum. And it
seems that there has been some progress made towards
the vaccination against P. falciparum using the approach
described therein. To date the most advanced malaria
vaccine in the clinic is based on a lipoprotein particle re-
ferred to as RTS,S (WO200403718 and WO2004037189
assigned to GSK). It is a pre-erythrocytic stage particle
against P. falciparum, which inhibits the parasite entry
into liver cells. This particle contains a portion of the CS
protein of P. falciparum fused in frame via a linear linker
to the N-terminal of the S-antigen from hepatitis B.
The linker may comprise a portion of preS2 from the
A hybrid P. vivax CS protein is described in
WO2006088597; the publications claimed that the syn-
thetic nucleotide fragment encoding a PvCS-hybrid pro-
tein is useful as a diagnostic reagent, for antibody
production, and as a protective vaccine against infection
with any strain of P. vivax. The methods can be used for
diagnosing, preventing or treating malaria infection. A
fusion protein composed of the hybrid protein of
WO2006088597 and S-antigen of hepatitis B and lipopro-
tein particles comprising the same are described in
EP2007057301. A lipoprotein particle comprising the
fusion protein of EP2007057301, RTS and optionally S
units is described in EP2007057296.
ICC-1132 (WO200213765) is another pre-erythrocytic
candidate vaccine. It is a hepatitis B core particle, geneti-
cally engineered to include a region of the CS for high
titre antibody induction. The ME-TRAP vaccine
(WO2008122811) is entirely different from the other pre-
erythrocytic malaria vaccines. It is a DNA vaccine that
uses the prime boost approach for immunization. It uses a
malaria DNA sequence known as ME (multipurpose epi-
tope) TRAP (thombospondin-related protein). An anti-
gen-based vaccine against malaria comprising a fusion
protein derived from P. falciparum glutamate-rich protein
(GLURP) genetically coupled to at least one other P. fal-
ciparum derived protein or a homologue of the fusion
protein or comprising a recombinant BCG expressing the
nucleic acid is described in WO2004043488.
WO2011138251 describes a lentiviral vector particle
comprising in its genome at least one recombinant
polynucleotide encoding at least one polypeptide(s) carry-
ing epitope(s) of a pre-erythrocytic stage antigen of a
Plasmodium parasite capable of infecting a mammalian
host and useful for treating malaria. US6066623,
US6268160, WO2006023593, WO2007027860 and
WO2010062859 also claimed new compounds to be used
as pre-erythrocytic vaccines.
Anti-cytoadhesion and placental malaria vaccine: The
PfEMP-1 antigen, the main ligand for cytoadhesion of
P. falciparum, is also being researched as a vaccine can-
didate. A bivalent vaccine described in WO2011061848,
is comprised of proteins, one of which is chosen from the
P. falciparum erythrocyte membrane proteins (PfEMP).
WO2009080715, WO2008039390 and WO200212292
are some of the other patent publications claiming the use
of PfEMP antigen.
VAR2CSA, a PfEMP variant is thought to mediate se-
questration specifically to the placenta. High VAR2CSA-
specific antibody titres correlate with a reduced risk of
malaria-induced low birth weight. The central role of
VAR2CSA in adhesion to the major ligand of placental
syncytiotrophoblasts is highlighted by the loss of cytoad-
hesive capacity in mutant parasites that contain targeted
deletion of the corresponding gene. These findings
together make placental cytoadhesion a leading target for
antibody-mediated vaccine strategies. WO2004067559
discloses a VAR2CSA polypeptide comprising a
sequence of 3056 amino acids. It was further claimed that
the polypeptide or nucleotide sequence is useful for
manufacturing a composition that prophylactically or thera-
peutically reduces the incidence, prevalence or severity of
pregnancy-associated malaria in a female subject. US77-
45580 discloses a VAR2CSA sequence for the use in
vaccine against pregnancy-associated malaria (PAM).
Blood-stage vaccines: The blood-stage vaccines are
directed against the merozoite surface protein (MSP) and
apical membrane protein (AMP). A vaccine that could
prevent invasion of red blood cells by merozoites would
prevent malaria disease34. Merozoite surface protein is the
most well-characterized antigen involved in invasion, and
is the basis for several candidate vaccines. US7488489,
US2009214635 and US2010291095 described a hybrid
protein comprising the peptide and an exogenous poly-
peptide sequence of MSP-3. The hybrid protein is
claimed to be a good blood-stage vaccine candidate.
CURRENT SCIENCE, VOL. 103, NO. 10, 25 NOVEMBER 2012 1169
Another blood-stage vaccine candidate is GLURP
(WO2004043488). It is an antigen-based vaccine against
malaria comprising a fusion protein derived from P. fal-
ciparum GLURP, genetically coupled to at least one other
P. falciparum-derived protein or a homologue of the
fusion protein or comprising a recombinant BCG express-
ing the nucleic acid. Both GLURP and MSP-3 blood-
stage candidate vaccines have been clinically assessed in
Europe. WO2005040203 disclosed novel MSP-3-like
family genes located on chromosome 10 of P. falciparum,
which encode proteins useful for preparing vaccine com-
positions against malaria. An anti-invasion vaccine based
on MSP-1 known as falciparum malaria protein-1 (FMP-1)
is being clinically assessed (WO200258727, WO200-
3004525, WO2003084472).
The P. falciparum glycosyl phosphatidyl inositol (GPI)
is another lead candidate for antimalarial vaccines. The
glycoproteins are often attached to the cell surface via a
GPI-anchor assembly. GPI-anchored proteins are ubiqui-
tous throughout the animal kingdom and play an impor-
tant role in orchestration of host–pathogen interactions
during the infective process. WO200015254 describes a
method of eliciting or inducing, in a mammal, an immune
response by administering a composition containing a
compound that induces a response to the inositol glycans
domain of a GPI, but not to the lipid domain of GPI. A
recombinant polypeptide showing enhanced immuno-
genicity, comprising a GPI structure was claimed in
WO9634105. WO200024406 describes a method for
treatment of mammalian diseases by activation of T-cells
using GPI. WO200113923 claimed of a method which
involves administration of GPI-inhibiting compounds for
treating malaria. Similarly, a method for identifying
inhibitors of GPI is described in WO200200919.
WO2004005532 discloses a method for the preparation of
glycosyl phosphatidyl linositol glycans, useful for the
treatment of malaria. An heterocyclic antimalarial agent
which can inhibit GPI by inhibiting the activity of the
GWT1 gene product of Plasmodium is disclosed in
WO2006016548. WO2009102717, WO2004048567 and
WO2004011026 are some of the other publications
claiming the use of GPI for treating malaria.
Sexual stage vaccine: There is little commercial funding
for sexual stage vaccine candidates, since they have no
market in developed countries. But sexual stage vaccine
could contribute to malaria control if linked with other in-
terventions. The US National Institute of Allergy and
Infectious Diseases Malaria Vaccine Development Unit
plans clinical assessment of a P. falciparum gametocyte
candidate vaccine, Pfs25, a recombinant protein. The US
Department of Health and Human Services has the
strongest patent portfolio concerned with sexual stage
vaccines. WO9219758 was the earliest patent recorded;
claiming the use of Pfs25. WO9814472, US2003049278
and US5853739 disclosed immunogenic compositions
comprising Pfs28 fusion proteins. An immunogenic con-
jugate comprising at least one Plasmodium sexual stage
surface protein (Pfs25) covalently linked to at least one
Plasmodium CS protein, where the conjugate elicits
an immune response to the sexual stage surface protein
and the CS protein in a subject is described in
Adjuvants for malaria vaccines
Till date vaccination has been the most cost-effective
health intervention for a range of infectious diseases, and
one day this will include malaria. Vaccines for malaria will
require adjuvant to induce protective immune responses.
Successful vaccine development requires knowing which
adjuvants to use and also how to formulate adjuvants and
antigens to achieve stable, safe and immunogenic vaccines.
Adjuvants and delivery systems which have been approved
for clinical trial testing or are components of licensed
vaccines, and have been used in malaria vaccines include
aluminium salts (alum), MF59TM and MPLTM (ref. 35).
Aluminium-based adjuvants, including aluminium hydro-
xide, aluminium phosphate and a combination of the two
have been evaluated by numerous groups. The use of
alum-based adjuvants for vaccines appears attractive
since there are only minimal intellectual property barriers.
However, the variable response, as well as formulation
and characterization challenges suggest that other adju-
vants should be considered.
MP59TM (US6299884 and US6451325) is an adjuvant
produced by Novartis (Chiron) comprising squalene, sor-
bitan rioleate and Tween 80, and is approved for use in
many European countries. MP59TM has also been tested
in candidate vaccines against malaria. MP59 is proprie-
tary and its use in vaccines produced by others would re-
quire a license. The original patent on MF59 emulsions
(EP0399843) has been revoked in the European Patent
Office. However, it may still be valid in other parts of the
world. Whereas the owners of the technology have pub-
licly indicated that in the event of a pandemic they
would permit their adjuvants to be used by others, pre-
negotiated licenses and supply agreements need to be
MPLTM (EP0971739, EP1194166 and US6491919),
patented by Croxia Corporation, is a nontoxic derivative
of LPS from Salmonella minnesota and is a potent stimu-
lator of TH1 response. The patents claimed an attenuated
form of the lipid-A component of bacterial lipopoly-
saccharide (LPS). LPS and lipid-A are potent immu-
nostimulators but have deleterious side effects, such as
pyrogenicity (fever). The modifications described in
Corixa’s patents abate the side effects but do not disable the
immunostimulatory effects of lipid-A. France patent
FR2824279 (Montanides) describes water-in-oil emul-
sions containing squalene and mannide-monooleate as an
emulsifier and known as Montanides have been exten-
sively used in malaria, HIV and cancer vaccine clinical
Quil A (US6352697) is a saponin preparation based on
defined compositions of purified saponin fractions
derived from the bark of Quillaja saponaria Molina. The
saponin preparations are useful in immunostimulating
complex (iscom) matrices. The saponin preparations and
iscom matrices prepared using them have particular acti-
vity as adjuvants. QS-21 is a purified component of Quil
A that demonstrates low toxicity and maximum adjuvant
activity. Patents that claim QS-21 are US5057540
(expired in 2008), US5583112, EP0362279 (expired in
2008) and EP0606317. AS02 (EP1126876B1 and
US7357936) and AS04 (EP0671948, EP0761231 and
US5750110) are proprietary adjuvants of GSK. AS02
contains MPLTM and QS-21 in an oil-in-water emulsion.
AS02 is used in a malaria vaccine of GSK. AS04 also is
composed of MPL, but in combination with alum. This
adjuvant is used in GSK’s HSV and HPV vaccine.
US2011282061 discloses adjuvant molecules that com-
prise of an imidazoquinoline molecule covalently linked
to a phospho- or phosphonolipid group. The compounds
of the invention have been shown to be inducers of inter-
feron-a, IL-12 and other immunostimulatory cytokines
and possess an improved activity profile in comparison to
known cytokine inducers when used as adjuvants for
vaccine antigens.
Quantitative patent analysis of global
antimalarial agents
Geographical distribution of patent publications
Figure 1 demonstrates the worldwide distribution of
antimalarial patent publications which show the interest
of the assignees and inventors in a particular geographical
location for protecting their technology to lead in market.
The highest number of patents were published through
Patent Cooperation Treaty also termed as WIPO publica-
tions (PCT/WO) followed by USA (US) and Europe (EP)
with 1975, 1677 and 1529 patent publications respec-
tively. Australia (AU) leads Japan (JP) in patent publica-
tions followed by China (CN) and Germany (DE). India
(IN) placed at the eighth position in patent publications
showed its position in technological and research advan-
ces in antimalarials.
Patent publication distribution based on assignee
Figure 2 depicts the prominent players in the market of
antimalaria agents. The top-10 assignees are compara-
tively shown, in which GSK emerges as the top applicant
with 101 patents followed by CSIR-India with 56 patents
and US Health (the United States of America as Repre-
sented by the Secretary Department of Health and Human
Services) with 55 patents. India is a high malaria burden
country and delivers good efforts in research and deve-
lopment through CSIR.
Patent publication based on top technologies area
Figure 3 represents the segregation of antimalarial patents
on the basis of the International Patent Classification
(IPC). A61P-033/06 (therapeutic activity of antimalari-
als), A61P-033/00 (antiparasitic agents), A61K-039/015
(plasmodium antigens), A61K-000/00 (preparation for
medical purposes), A61P-035/00 (antineoplastic agents),
C07K-014/445 (peptides from plasmodium), A61P-031/
00 (anti infectives i.e. antibiotics, antiseptics, chemot-
herapeutics, etc.), A61K-039/002 (protozoa antigens),
A61K-039/00 (medicinal preparations containing anti-
gens or antibodies), C07H-021/04 (compounds having
deoxyribosyl as saccharide radical), A61P-043/00 (drugs
for specific purposes), C07K-014/435 (peptides from
animals and humans), A61P-033/02 (antiprotozoals),
C12N-015/30 (genes encoding protozoal proteins) and
C12N-015/09 (recombinant DNA-technology) are the IPC
classes which cover majority of the antimalarial patents.
Patent publication distribution based on inventor
Figure 4 shows the contribution of the top-10 inventors,
with the top inventor being Joseph D. Cohen, who
marked a significant milestone in research and develop-
ment of diagnosis and treatment methods of malaria.
Joseph has the highest number of patent publications (24)
followed by S. Hoffman (19), Pierre Druilhe (18), S. K.
Puri (16) and S. Singh (15).
Figure 1. Country-wise distribution of antimalarial patent publications.
Figure 2. Assignee-wise distribution of antimalarial patent publications.
CURRENT SCIENCE, VOL. 103, NO. 10, 25 NOVEMBER 2012 1171
Figure 3. Technology-wise distribution of patent publications.
Figure 4. Inventor-wise distribution of patent publication.
Figure 5. Trends of patent filed in United States Patent & Trademark
Summary of the antimalarial patent landscape
Malaria control has so far relied largely on a compara-
tively small number of chemically related drugs belong-
ing to four classes of compounds, four aminoquinoline
(chloroquine, quinine, mefloquine, amodiaquine) or eight
aminoquinoline (primaquine), artemisinins and deriva-
tives (artemisinin, artesunate, artemether, artemether,
dihydroartemisinin), the antifolate compounds (pyrim-
ethamine) and most recently naphthoquinone (atova-
quone)37. We recorded a total of 1164 patents claiming
the use of the four aforementioned compounds. The exist-
ing antimalarial drug patents cover half of the patented
technologies against malaria. Six hundred and seventy-
two patent publications claiming new compounds were
recorded. Three hundred and eight-seven patent publica-
tions describing new antimalarial compounds were filed
between 2005 and 2011. In case of malaria vaccine a rise
in patenting activity can be seen, especially in the last 5
years. From 1961 to 1999, a total of 276 patent publica-
tions were recorded, while from 2000 to 2004, 103 patent
publications and from 2005 to 2011, 227 publications
were recorded.
Already a substantial number of patents have been
granted within this field (Figures 5 and 6). A large num-
ber has been filed since 2001. The technical content of
the antimalarial patent landscape is complex. New anti-
malarial compounds and their methods of preparation,
combination therapies of existing pharmaceutical agents
and pre-erythrocytic vaccines showed the most intense
patenting activity. If grant rate follows these trends, there
will soon be a significant mass of patent claims through
which commercial products have to navigate through to
reach the market.
The United States clearly dominates most aspects of
antimalarial research, invention and patenting. This may
be because most of the assignees/applicants and/or inven-
tors are located in USA. The top public sector organiza-
tions by patent assignee are all in USA. Europe seems to
be closing the gap with USA. The top two assignees Pas-
teur Institute and GSK are located in Europe. Ownership
of antimalarial patents seems to be quite fragmented
across multiple organizations. A majority of the key pat-
ented technologies which are currently undergoing deve-
lopment or technologies which show promise of being
commercially applicable are assigned or owned by more
than one organization. Majority of the drugs currently
under clinical trial are sponsored or developed in collabo-
ration with more than one organization. Under such con-
ditions of fragmentation, the task of coordinating access
to complex technologies could involve an intense and
costly process.
Patenting activity in antimalarial elements has
increased. In spite of having patented products and a
good provision of compulsory licensing of these patented
products, successful commercial applications in this field
are subtle. So what are the reasons behind this – whether
the money needed to conduct research is scarce, that has
hampered research in developing new drugs or is there
unavailability of background data pertaining to clinical
trial phases, as clinical trial research is costly, lengthy
and pertaining to high risk?
Drug resistance
Drug resistance is a recurring theme in the history of in-
fectious disease control. From a public health perspective,
Figure 6. Trends of patent filed in European Patent Office.
Figure 7. Trends of patent publications disclosing compounds against drug-resistant malaria.
drug resistance is a critical factor that undermines malaria
control. The clinical consequences of such resistance are
well described in terms of increased morbidity and mor-
tality38,39. A search for patents disclosing technologies to
treat drug-resistant malaria and manual refining of the re-
trieved data resulted in 230 publications. Hoffman la
Roche and CSIR with 7 and 6 patent publications respec-
tively in their portfolio were the top applicants. The
Hoffman la Roche portfolio consisted of publications
disclosing compounds – piperidine derivatives (WO991-
2532), beta-alkoxy-acrylate derivatives (WO9902150),
aralkyl quinolin-4-yl-diamine derivatives (WO9718193),
bis-quinoline diamine derivatives (WO9535288), amino-
quinoline derivatives (US5596002) and dithiane deriva-
tives (US5302727) against chloroquine-resistant and
chloroquine-sensitive pathogens.
Poor-quality antimalarial drug is another menace which
is threatening to jeopardize the progress and investment
in combating malaria. Nayyar et al.40 point out that
around 36% of antimalarial drugs analysed in Southeast
Asia were fake, whereas a third of the samples in sub-
Saharan Africa failed chemical testing for containing too
much or too little of the active ingredient, potentially en-
couraging drug resistance. Antimalarial drug resistance
poses a real threat to the impact of most of the malaria
control programmes. Figure 7 shows trends of patent pub-
lications disclosing compounds against drug-resistant
malaria. Intensive monitoring of drug resistance along
with the strategies to reduce its future emergence and
spread is needed.
Marketing challenges
The antimalarial market is one of the biggest markets with
around half a billion treatments needed per year, but
majority of the patients are located in low-income countries
and are unable to pay for their treatment. Norrby et al.41
have suggested that the main reason why the pharmaceu-
tical industry has been unwilling to invest in antibiotic
research development is because of the poor returns on
investment owing to increasing cost of drug development,
caused, in part, by increasing demands from regulatory
authorities and stricter pricing controls imposed by gov-
ernments. They further suggest that another problem for
the industry is that if it is able to achieve a high sales
figure, the result is likely to be more rapid emergence of
resistance which would have an effect on future sales.
CURRENT SCIENCE, VOL. 103, NO. 10, 25 NOVEMBER 2012 1173
The major cost in developing new drugs arises during the
clinical development programme, especially during the
phase-II and phase-III clinical trials designed to docu-
ment clinical efficacy and safety. The total cost for
development of a new anti-infective drugs is estimated to
be 500–600 million Euros, and is rarely completed in less
than 4–6 years after the first administration to human
Most of the developing nations license and make avail-
able only antimalarial drugs that are provided through
national health programmes. Baird42 has mentioned that
this approach often excludes relatively expensive or risky
therapies, even for patients who may be able to afford a
given drug and have access to medical supervision. He
further observes that the main factor affecting antimalar-
ial drug availability is economic. The developing world
requires distribution strategies for effective therapies that
overcome the availability of cheap but ineffective drugs.
IP challenges
Commercializing an antimalarial technology raises signi-
ficant IP challenges. Overlapping claims of different pat-
ents may cover antimalarial compounds and antigens that
may be needed for drug or vaccine development. Such
concentration of patents with potentially overlapping
claims results in patent thicket. Such a patent thicket is
daunting because it is likely that more than one com-
pound or antigen would be needed for an effective vac-
cine or drug. A solution to patent thicket is through
traditional licensing or partnering, which will tie up
resources needed to develop and deliver the drugs and
vaccines. The Malaria Vaccine Initiative (MVI) used this
solution to circumvent a patent thicket associated with
the primary malaria antigen vaccine candidate P. falcipa-
rum MSP-1. MVI contracted Alta Biomedical Group LlC
to identify potential patent roadblocks associated with
MSP-1. Up to 39 patent families, owned by 21 organiza-
tions (80% private sector, 20% public sector) were identi-
fied, of which researchers will need to negotiate with at
least eight entities for access. Although these patents
were an early disincentive for vaccine manufacturers to
invest in malaria vaccine development, early identifica-
tion facilitated informed decision making for strategic IP
A drawback of this method is that the negotiation re-
quired to access the key patents could delay the delivery
of the antimalarial agents. Another possibility is that
access to key patents may not be available, which would
affect investment decision upstream in the development
pipeline. As a result, it may not be possible to pursue the
effective drug or vaccine candidate, if companies holding
valuable malaria-drug/vaccine IP are unwilling to license
to others even if they are not developing a malaria
drug/vaccine themselves. Accessing the availability to
key patents becomes a priority44.
Concluding remarks
Malaria is an extremely difficult disease that has eluded
modern science for a long time. Recent advances, how-
ever, are promising. A difficult situation has arisen in
view of the development of resistance of the parasite to
antimalarials and unavailability of a vaccine. But by
working around these problems we can achieve suitable
and acceptable solutions to these situations. Resistance to
single-drug therapies can be overcome by using them in a
combination therapy. Mathematical modelling predicts
that existing drugs should be used in combination if their
effectiveness is to be safeguarded45. The precise choice of
combinations and formulation requires an immediate
research effort. The formulation, packaging, deployment
and adherence to these new compounds should be stud-
ied. Such studies require only a small investment com-
pared with the cost of developing new drugs46. IP
challenges should be addressed and resolved so that
access to the drugs, to be used in combination, is avail-
able. Lastly, initiatives like patent pool should be consid-
ered as complements to a broad set of other policies that
are needed to ensure access to medicine for all; patent
pools are only one way of addressing the issue.
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Received 6 July 2012; accepted 24 September 2012
... Patent data and indicators are collected and analysed on the basis of quantitative analysis to yield a conclusion 22,23 . Patent quantities are used as the basis to collect information. ...
... Table 2 and Figure 3 clearly show the annual development of LED bulb patent technology in each country. According to the statistics of LED bulb patent quantity, the five leading countries for producing LED bulb patents are the US (174), Japan (22), Taiwan (74), China (47) and the Netherlands (23). Of these 340 patents, the percentage of patents used in this study is 93.9 and they are mostly from the US. ...
There is an increasing demand for LED (light-emitting diode) bulbs, and technological development has become extremely significant, especially pertaining to patents. In this article, relevant LED bulb patents from the database of the United States Patent and Trademark Office (USPTO) from 1976 to 2014 have been examined and analysed. The applied patent indicator tools include patent analysis, technology life-cycle analysis, R&D ability analysis and patent classification analysis. The analysis was completed at the national, company and technology levels. At the national level, the US has the best performance. At the company level, the Switch Bulb Company, Inc. has obtained the most number of patents. According to the technological field of US Patent Classification, green LED light bulb patents mainly focus on D26/2, 362/249.n and 313/46 - especially D26/2. American companies in general have maximum success in patenting green LED light bulbs, but the Hon Hai Group, Taiwan is the only company covering these three technology fields. We demonstrate the development trend and operation of green LED light bulbs from different aspects to show that the technology gap is an important reference for other relevant LED bulb companies that plan to develop new technologies and increase their competitiveness in the future.
... Additionally, due to novel, user friendly data visualization technologies and publicly accessible patent databases, patent landscape analysis has become an available tool for researchers and stakeholders to investigate emerging areas and also to identify economically attractive research gaps [16]. Considering the wide variety of contents available in patents, they are essential source of information for technological analysis [17,18]. Although, technical possibilities for creating patent landscapes improved a lot in the last years, today only a limited number of patent landscapes are addressing comprehensive questions on health topics [19]. ...
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Background “Neglected Tropical Diseases” (NTDs) affect millions of people in Africa, Asia and South America. The two primary ways of strategic interventions are “preventive chemotherapy and transmission control” (PCT), and “innovative and intensified disease management” (IDM). In the last 5 years, phenomenal progress has been achieved. However, it is crucial to intensify research effort into NTDs, because of the emerging drug resistance. According to the World Health Organization (WHO), the term NTDs covers 17 diseases, namely buruli ulcer, Chagas disease, dengue, dracunculiasis, echinococcosis, trematodiasis, human African trypanosomiasis, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, rabies, schistosomiasis, soil-transmitted helminthes, taeniasis, trachoma, and yaws. The aim of this study is to map out research and development (R&D) landscape through patent analysis of these identified NTDs. To achieve this, analysis and evaluation have been conducted on patenting trends, current legal status of patent families, priority countries by earliest priority years and their assignee types, technological fields of patent families over time, and original and current patent assignees. Main body Patent families were extracted from Patseer, an international database of patents from over 100 patent issuing authorities worldwide. Evaluation of the patents was carried out using the combination of different search terms related to each identified NTD. In this paper, a total number of 12,350 patent families were analyzed. The main countries with sources of inventions were identified to be the United States (US) and China. The main technological fields covered by NTDs patent landscape are pharmaceuticals, biotechnology, organic fine chemistry, analysis of biological materials, basic materials chemistry, and medical technology. Governmental institutions and universities are the primary original assignees. Among the NTDs, leishmaniasis, dengue, and rabies received the highest number of patent families, while human African trypanosomiasis (sleeping sickness), taeniasis, and dracunciliasis received the least. The overall trend of patent families shows an increase between 1985 and 2008, and followed by at least 6 years of stagnation. Conclusion The filing pattern of patent families analyzed undoubtedly reveals slow progress on research and development of NTDs. Involving new players, such as non-governmental organizations may help to mitigate and reduce the burden of NTDs. Electronic supplementary material The online version of this article (10.1186/s12992-017-0306-9) contains supplementary material, which is available to authorized users.
For the past several decades, considerable efforts have been made to roll back malaria, but contributions in this field have not been clearly investigated thus far. In this context, this paper explores research topics of malaria patents and compares their time-series trends. In particular, we compare the dynamics of antimalarial patent topics between the United States Patent and Trademark Office (USPTO) and the State Intellectual Property Office (SIPO) of the People’s Republic of China using a dynamic topic modeling (DTM) approach. Thus far, more patents have been applied in the USPTO with a drastic increase in the number of malarial patents. Eventually, patent application in the SIPO has become more frequent in comparison to that of the USPTO after 2013. In addition to the two different patenting trends between the USPTO and SIPO, topics of technological fields identified by the DTM approach are rather different for the two patent offices. Topics of mosquito prevention methods, such as a net and diagnostic tool, were found only in the SIPO, while in the USPTO, topics for specific vaccines in different stages were identified. In both, the SIPO and USPTO, topics of malarial medicine were common, and interestingly, two topics related to malarial medicines made using natural resources were observed in the SIPO. As such, our findings confirm that despite the common goals to eliminate malaria, different technological fields have evolved in the two major patent offices, based on the interests of the applicants and environmental conditions. Such distinctions shed light on necessity and effect complementary cooperation between the developed and developing worlds.
Efforts that have been made to find efficient and affordable antimalarials through recycling, rescuing, or repurposing classical drugs are discussed. Three main approaches were distinguished, the chemical recycling of classical drugs once considered as firstline antimalarials but which became useless for malaria chemotherapy, the rescuing, for malaria, of known bioactive molecules currently lacking clinical application, and the repurposing, for malaria, of therapeutic agents in clinical use or development against other diseases. In order to test the hypothesis that impairment of CD36 function could directly affect Plasmodium parasites and host interactions, Nathoo and co-workers evaluated antiretroviral drugs on nonopsonic phagocytosis by human macrophages and CD36-mediated cytoadherence of parasitized erythrocytes. The results showed that the protease-inhibitor class of antiretrovirals particularly impaired both processes. Skinner-Adams and co-workers reported that the HIV-1 protease inhibitors ritonavir, saquinavir and indinavir were effective against P. falciparum Dd2 in vitro at clinically relevant concentrations. Andrews and co-researchers further investigated the effect of combining some of the HIV-1 protease inhibitors in a murine model of malaria.
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Emerging resistance to existing antimalarial drugs could nullify efforts to eliminate this deadly disease. The discovery of thousands of agents active against malaria parasites offers hope for developing new drugs.
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Poor-quality antimalarial drugs lead to drug resistance and inadequate treatment, which pose an urgent threat to vulnerable populations and jeopardise progress and investments in combating malaria. Emergence of artemisinin resistance or tolerance in Plasmodium falciparum on the Thailand-Cambodia border makes protection of the effectiveness of the drug supply imperative. We reviewed published and unpublished studies reporting chemical analyses and assessments of packaging of antimalarial drugs. Of 1437 samples of drugs in five classes from seven countries in southeast Asia, 497 (35%) failed chemical analysis, 423 (46%) of 919 failed packaging analysis, and 450 (36%) of 1260 were classified as falsified. In 21 surveys of drugs from six classes from 21 countries in sub-Saharan Africa, 796 (35%) of 2297 failed chemical analysis, 28 (36%) of 77 failed packaging analysis, and 79 (20%) of 389 were classified as falsified. Data were insufficient to identify the frequency of substandard (products resulting from poor manufacturing) antimalarial drugs, and packaging analysis data were scarce. Concurrent interventions and a multifaceted approach are needed to define and eliminate criminal production, distribution, and poor manufacturing of antimalarial drugs. Empowering of national medicine regulatory authorities to protect the global drug supply is more important than ever.
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Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented. However, its continued use is challenged by its poor tolerability, poor compliance with complex dosing regimens, and the availability of more efficacious anti-malarial drugs. This article reviews the historical role of quinine, considers its current usage and provides insight into its appropriate future use in the treatment of malaria. In light of recent research findings intravenous artesunate should be the first-line drug for severe malaria, with quinine as an alternative. The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but it remains a promising intervention. In pregnancy, quinine continues to play a critical role in the management of malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available. For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option than quinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapid withdrawal of quinine for uncomplicated malaria cases risky. The best approach would be to identify solutions to ACT stock-outs, maintain quinine in case of ACT stock-outs, and evaluate strategies for improving quinine treatment outcomes by combining it with antibiotics. In HIV and TB infected populations, concerns about potential interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and these will need further research and pharmacovigilance.
The development of resistance by the parasite against first line and second line antimalarial drugs, has under-scored the importance to develop new drug targets and pharmacophores to treat the disease. The absence of a vaccine for protection and the availability of artemisinin and its derivatives as the only option has made the situation rather serious. With the availability of increased support for malaria research, a variety of drug targets and candidate molecules are now available for further development. However, the success rate of a candidate molecule to become a drug is very low and it does become necessary to start with a large basket, identified on a rational basis. This review focuses on the present efforts to identify a variety of drug targets in the malaria parasite and to develop candidate drug molecules.
One of the big success stories in synthetic biology is the re-engineering of an existing organism to produce the anti-malarial drug artemisinin. The drug is also found naturally in extracts of the plant Artemisia annua (Wormwood), but demand is far oustripping supply and extracting the drug from the plants is complex, time-consuming and expensive. In this lecture, Jay Keasling describes how he and his laboratory re-designed yeast microbes into living mini anti-malaria drug factories producing artemisinin more cheaply and efficiently. The lecture was given at the 12 May 2009 launch of the Imperial-based Centre for Synthetic Biology and Innovation—established in partnership with the London School of Economics and funded by the Engineering and Physical Sciences Research Council (EPSRC) as part of a science and innovation award.
Malaria is the third leading cause of death due to infectious diseases affecting around 243 million people, causing 863,000 deaths each year, and is a major public health problem. Most of the malarial deaths occur in children below 5 years and is a major contributor of under-five mortality. As a result of environmental and climatic changes, there is a change in vector population and distribution, leading to resurgence of malaria at numerous foci. Resistance to antimalarials is a major challenge to malaria control and there are new drug developments, new approaches to treatment strategies, combination therapy to overcome resistance and progress in vaccine development. Now, artemisinin-based combination therapy is the first-line therapy as the malarial parasite has developed resistance to other antimalarials. Reports of artemisinin resistance are appearing and identification of new drug targets gains utmost importance. As there is a shift from malaria control to malaria eradication, more research is focused on malaria vaccine development. A malaria vaccine, RTS,S, is in phase III of development and may become the first successful one. Due to resistance to insecticides and lack of environmental sanitation, the conventional methods of vector control are turning out to be futile. To overcome this, novel strategies like sterile insect technique and transgenic mosquitoes are pursued for effective vector control. As a result of the global organizations stepping up their efforts with continued research, eradication of malaria can turn out to be a reality.
Global access to advanced vaccine technologies is challenged by the interrelated components of intellectual property (IP) management strategies, technology transfer (legal and technical) capabilities and the capacity necessary for accelerating R&D, commercialization and delivery of vaccines. Due to a negative association with the management of IP, patents are often overlooked as a vast resource of freely available, information akin to scientific journals as well as business and technological information and trends fundamental for formulating policies and IP management strategies. Therefore, a fundamental step towards facilitating global vaccine access will be the assembly, organization and analysis of patent landscapes, to identify the amount of patenting, ownership (assignees) and fields of technology covered. This is critical for making informed decisions (e.g., identifying licensees, building research and product development collaborations, and ascertaining freedom to operate). Such information is of particular interest to the HIV vaccine community where the HIV Vaccine Enterprise, have voiced concern that IP rights (particularly patents and trade secrets) may prevent data and materials sharing, delaying progress in research and development of a HIV vaccine. We have compiled and analyzed a representative HIV vaccine patent landscape for a prime-boost, DNA/adenoviral vaccine platform, as an example for identifying obstacles, maximizing opportunities and making informed IP management strategy decisions towards the development and deployment of an efficacious HIV vaccine.
This brief review provides an overview of the pathogenesis of malaria, the human immune response to malaria, current methodology for malaria diagnosis, and current antimalarial drug regimens. The review also provides a critical evaluation of the research directions in the areas of drug design and vaccine design.