Phytochem Rev

DOI 10.1007/s11101-017-9498-0

A review from patents inspired by two plant genera:

Uncaria and Hamelia
Isvett Josefina Flores-Sanchez . Ana Carmela Ramos-Valdivia

Received: 30 September 2016 / Accepted: 28 February 2017

Ó Springer Science+Business Media Dordrecht 2017

Abstract Specialized or secondary metabolism of Keywords Hamelia  Monoterpenoid indole and

plants from two genera, Uncaria and Hamelia, has oxindole alkaloids  Uncaria
been widely studied generating a huge investment in
research and development of patents. This review
Abbreviations
highlights the most recent patents granted so far, with
CYP450 Cytochrome P450
some exceptions, covering different areas of knowl-
IgE Immunoglobulin E
edge including biotechnological aspects of plant
MIA Monoterpenoid indole alkaloid
specialized/secondary metabolism. Several patent
MOA Monoterpenoid oxindole alkaloid
databases were consulted in order to collect patent
HIV/ Human immunodeficiency virus infection
information. There are patents for specialized/sec-
AIDS and acquired immune deficiency
ondary metabolite isolation methods, synthesis, pro-
syndrome
duction, genes, development of medicaments, drug
HPLC High-performance liquid
delivery systems, equipment, machines, industrial
chromatography
processes, plant culture techniques, and new plant
varieties, among others. This review of the state-of-the
art about patents related to Uncaria and Hamelia, as
Introduction
well as their metabolites, can be a valuable source of
organized information for those researchers develop-
Up to date there is a huge and novel patent collection
ing projects in many aspects related to these two
that can be attributed to new developments in the plant
genera. Uncaria and Hamelia have an enormous
science field (Hefferon 2010). Plants can be used for
potential to become important economically crops.
phytoremediation purposes and for biofuel produc-
tion. Crops can be resistant to plant pathogens and
abiotic stresses. Moreover, crop plants can have
Electronic supplementary material The online version of
this article (doi:10.1007/s11101-017-9498-0) contains supple- improved nutritional qualities, as biofortified foods.
mentary material, which is available to authorized users. In addition, there are plant production platforms for
therapeutic proteins (molecular farming), and for
I. J. Flores-Sanchez  A. C. Ramos-Valdivia (&)
Departamento de Biotecnologı́a y Bioingenierı́a, Centro biodegradable plastics and polymers (Hefferon
de Investigación y de Estudios Avanzados del Instituto 2015a, b). A patent is a government-conferred right
Politécnico Nacional, Av. IPN 2508, Col. San Pedro to exclude others from making, using, selling, or
Zacatenco, 07360 Mexico City, Mexico importing the invention claimed. Usually, it has two
e-mail: aramos@cinvestav.mx

123

parts, the first one is a description (or specification) of
the invention and the second one is a set of claims
defining the boundaries of intellectual property.
Patents can comprise from products to methods and
applications. The main role of patents in any field, for
example in biotechnology and medical applications, is
to induce either public or private investment in
research and development (Cook-Deegan and Niehaus
2014). Many reviews from Uncaria and to a lesser
extent of Hamelia have been published covering
individual aspects on phytochemistry, pharmacology
and ethnobotany (Heitzman et al. 2005; Zhang et al.
2015; Martins and Nunez 2015); but there are no
reviews exploring different fields of patent applica-
tions from Uncaria and Hamelia specialized or
secondary metabolism. This review focuses on patents
generated on studying these two plant genera, which
belong to the family Rubiaceae. Both of them produce
important particular alkaloids, the monoterpenoid
indole alkaloids (MIAs) and monoterpenoid oxindole
alkaloids (MOAs), and other secondary metabolites
(Heitzman et al. 2005; Martins and Nunez 2015). It has
been generated a vast number of specialized patents
for metabolite isolation methods, synthesis, produc-
tion, genes, and improved plant varieties, among
others. All information was gathered, assessed and
structured in this review, which highlights the most
recent patents so far, with some exceptions. Databases
such as Google patents, Espacenet, Patentscope,
USPTO, Patents.com, and PatentStorm were referred
for patent searching.
Rubiaceae family
The Rubiaceae family is one of the largest in the
Magnoliopsida class, with 637 genera and 13,000
species that is characterized by the production of
bioactive alkaloids, being indole alkaloids its main
chemical markers. However, this family has a large
diversity of substances such as iridoids, anthraqui-
nones, terpenoids (diterpenes and triterpenes), flavo-
noids and other phenolic derivatives (Martins and
Nunez 2015). Based on Robbrecht’s classification this
family is divided into four subfamilies: Antirheoideae,
Cinchonoideae, Ixoroideae and Rubioideae (Rob-
brecht 1988). The subfamily Cinchonoideae is the
smallest one within Rubiaceae family; and plants
belonging to this subfamily are primarily distributed in
123
Phytochem Rev
America continent, Africa, South and Southern Asia
and Oceania. Species within Cinchonoideae are char-
acterized as small trees, shrubs, with imbricate or
valvate corolla aestivation and, often, dry capsular
fruits (Manns and Bremer 2010). Besides, this sub-
family is formed by nine tribes; i.e. Chiococceae,
Cinchoneae, Guettardeae, Hamelieae, Hillieae,
Hymenodictyeae, Isertiaea, Naucleeae and Ron-
deletieae (Bremer 2009). Uncaria and Hamelia are
two genera belonging to the subfamily Cinchonoideae.
Genus Uncaria
Based on a combination of molecular and morpho-
logical data, the genus Uncaria belongs to the tribe
Naucleeae (Manns and Bremer 2010) and contains 35
species; being the most known species U. tomentosa
(Will. Ex Schult) DC, U. rhynchophylla (Miq.) Jacks,
and U. attenuata Korth (Zhang et al. 2015). They are
woody lianas, climbing by hooks formed from
reduced, modified branches, having bivalve and
elongated (up to 6 mm in length) fruits (Ridsdale
1978). This genus has been widely studied from a
phytochemical point of view from 1990 to 2014
(Martins and Nunez 2015). The major groups of
secondary metabolites present in this genus are MIAs
and MOAs, terpenoids and flavonoids (Laus 2004;
Fig. 1). Uncaria has been widely used in traditional
medicines from China to South America in order to
treat wounds, ulcers, fever, headache, gastrointestinal
diseases, and microbial infections (Zhang et al. 2015).
Uncaria patents
Patents for isolation, synthesis, biosynthesis
of MIAs and MOAs
Methods for preparing extracts from Uncaria plant
material by water decoction (Bobrowski 2004; Pero
2004) or alcoholic extraction (Kano et al. 2013; Yao
et al. 2010) have been patented (Table 1). One hundred
and twenty-three alkaloids have been isolated and they
are classified as MIAs and MOAs (Zhang et al. 2015).
Isolation methods from plant material for the MIA
geissoschizine methyl ether (Duan et al. 2011) and for
the MOAs rhynchophylline, isorhynchophylline, pter-
opodine, isopteropodine, mitraphylline and isomitra-
phylline have been developed (Duan et al. 2011; Tang
Phytochem Rev

MIAs
Vincoside lactam Hirsune Corynantheine
O
N N N
H N
N O N H N N H
H H N H H H H N
N H H
N H O H
H H H HO
O H
OCH3 O
H O OH O
OCH3 OGlc
OCH3 O OCH3 OCH3
OCH3
Geissoschizine methyl ether OGlc Strictosamide OCH3 Yohimbine

MOAs
H H H H H H
N OCH3 N OCH3 N O N O N O N O

H H H H H H H H H H H H
CO2CH3 CO2CH3 CO2CH3 CO2CH3
N O N O N O N O N O N O
O OCH3 O OCH3
H H H H H H

Rhynchophylline Isorhynchophylline Pteropodine Isopteropodine Mitraphylline Isomitraphylline

Triterpenoids Cyclitol
HO COOH
H H H H OH

COOH COOH COOH HO

OH
H
OH
H H H COOH
HO Quinic acid OH
HO H HO HO
H H H OH OH
OH
OH
OH
Ursolic acid Oleanolic acid Betulin Quinovic acid OH
HO
HO O OH
O OH
Flavonoids OH OH
OH
OH
OH
HO

OH
O

OH OH OH OH
OH
HO O
HO O HO O HO O OH O O OH
OH HO OH OH
OH OH Gambiriin A1 Cinchonain Ib
OH OH OGlc Procyanidin B1 OH
OH OH OH
OH O OH O OH O
HO O OH
OH
Kaempferol Quercen Isoquercitrin HO O
HO
OH OH OH OH OH
OH OH OH OH OH OH
OH OH OH
O
HO O OH
HO O HO O HO O HO O
OH HO O OH

OH OH OGlc OGlcRha OH
OH O O OH
OH OH OH O OH O OH
OH
Epicatechin Catechin Hyperin Run Procyanidin B3 Gambiriin C Cinchonain Ia

Fig. 1 Chemical structures of some metabolites isolated or identified in Uncaria plant material

et al. 2012; Keplinger et al. 1990; Hashimoto 2013). Due (Stöckigt et al. 2008; Fig. 2a). Biotechnological pro-
to oxindole alkaloids have a spiro b-amino carboxyl duction of strictosidine and strictosidine derivatives is
system, which allows isomerization in polar solvents claimed by the use of nucleotide sequences encoding
(Kaiser et al. 2013), a process for production of specific strictosidine synthases (Alexandrov et al. 2014) or
isomer mixtures of oxindole alkaloids by controlling immobilized pure strictosidine synthase from plant cell
pH, temperature or solvent has been claimed (Keplinger cultures (Zou et al. 2014). Patent KR100392292B1
et al. 2001). On the other hand, patent CN102786568B developed synthetic methods for derivatives of the MIA
developed a cheap method for the synthesis of the MIA hirsutine, which were used as alternative medicaments
vincoside lactam from strictosamide in acidic condi- to treat hepatitis C, as well as, other alkaloids containing
tions, which is claimed that the method avoids using 5-membered fused aromatic heterocyclic rings for their
large amount of solvents and environment pollution is use as inhibitors of the proteases NS3/NS4 from
reduced (Xiao et al. 2015). Strictosamide, a MIA is hepatitis C virus (Ahn et al. 2003).
formed by intramolecular cyclization of strictosidine
and has been isolated from Uncaria (Qi et al. 2014). The Patents for pharmaceutical applications of MIAs
glucoindole alkaloid strictosidine is a central common and MOAs, and for other uses
precursor to MIAs and it is biosynthesized by the
enzyme strictosidine synthase from tryptamine and Regarding medical treatments (Table 1), different
secologanin through a Pictet-Spengler reaction patents for preventing or treating cardiac diseases

123
 Phytochem Rev

Table 1 Some patents related to Uncaria species and/or specialized metabolites/metabolism from 1990 to 2016
Patent number Title Issue date Family* Company/ Country Ref.
academy/
government

Extracts
US6797286B2 Methods and preparations Sep 28, 2004 - Rainforest Nutritionals US Bobrowski
of extracts of Uncaria Inc. (2004)
species with reduced
alkaloid content1
EP1096943B1 Method of preparation and Jun 2, 2004 ? CampaMed Corp. US Pero (2004)
pharmaceutical
composition of an
Uncaria water-soluble
extract2
CN101342259B Method for extracting Mar 20, 2013 - Shenyang CN Kano et al.
alkaloid valid parts from Pharmaceutical (2013)
hooked Uncaria leaf, with University
hooked stem branch or
full grass and uses
thereof3
CN1939453B Gambir plant extract and its Sep 8, 2010 - Fudan University CN Yao et al.
use in preparation of (2010)
target organ protective
medicine4
Compound isolation
CN101798306B Uncaria alkaloid monomer Dec 21, 2011 - Lanzhou University of CN Duan et al.
as well as preparation Technology (2011)
method and application
thereof5
CN102093359B Process for extracting Jul 4, 2012 - 2nd AF Hosp PLA 3rd CN Tang et al.
rhynchophylline Military Med Univ (2012)
monomers from Uncaria
rhynchophylla6
US4940725A Oxindole alkaloids having Jul 10, 1990 ? Immodal Pharmaka AT Keplinger
properties stimulating the Gesellschaft MBH et al. (1990)
immunologic system and
preparation containing the
same7
JP5334508B2 Method for producing Nov 6, 2013 - Towa Corp. JP Hashimoto
highly active POA8 (2013)
Synthesis
EP0741727B1 Process for isomerization of Mar 28, 2001 ? Enzymatic Therapy US Keplinger
spirocyclic compounds LLC et al. (2001)
with b-aminocarboxyl
and/or b-aminocarbonyl
systems9
CN102786568B Vincoside lactam Jul 01, 2015 - Jiangsu Kanion CN Xiao et al.
preparation method10 Pharmaceutical Co. (2015)
Ltd.
Genes
US8710201B2 Nucleic acid sequences Apr 29, 2014 ? Ceres Inc. US Alexandrov
encoding strictosidine et al. (2014)
synthase11

123
Phytochem Rev

Table 1 continued
Patent number Title Issue date Family* Company/ Country Ref.
academy/
government

Enzymes
CN102532218B Strictosidine-like alkaloids Feb 19, 2014 ? Zhejiang University CN Zou et al.
as well as preparation (2014)
method and application
thereof12
Derivative synthesis
KR100392292B1 Usage as HCV NS3/NS4 Jul 22, 2003 - Peptron Co. Ltd. KR Ahn et al.
protease inhibitor of (2003)
5-membered fused
aromatic heterocyclic
compound13
Medical treatments
CN101791342B Uncaria extract and May 23, 2012 - Fudan University CN Chen et al.
application thereof in (2012)
preparing medicines for
reducing blood fat and
resisting cardiac
hypertrophy14
CN101683338B Application of hirsutine in Sep 7, 2011 ? Fudan University CN Zhu et al.
preparing medicament for (2011a)
treating myocardial
damage15
CN101683337B Application of Dec 17, 2011 ? Fudan University CN Zhu et al.
corynantheine in (2011b)
preparing medicament for
treating heart disease
induced by myocardial
damage16
EP0989856B1 Method and substances for May 12, 2010 ? Enzymatic Therapy US Keplinger
releasing a growth factor LLC et al. (2010)
from endothelial cells,
growth factor released in
accordance with said
method and use of same17
EP1786446B1 Hydroalcoholic extract of Sep 30, 2015 ? Herbarium Laboratorio BR Trentini
Uncaria tomentosa for the Botanico Ltd. (2015)
treatment of herpes virus
infection18
US7754250B2 Composition and methods Jul 13, 2010 ? UW US Castillo and
for treating Alzheimer’s Snow (2010)
disease and other
amyloidoses19
US8486957B2 Chemotherapeutic for Jul 16, 2013 ? WFU Health Sciences US Salbury et al.
inducing an MSH2- (2013)
dependent apoptotic
pathway20
CN103446140B Application of Feb 3, 2016 - 2nd AF Hosp PLA 3rd CN Zhou et al.
rhynchophylline in Military Med Univ (2016)
preparation of drug with
anxiolytic effect and
antidepressant effect21

123
 Phytochem Rev

Table 1 continued
Patent number Title Issue date Family* Company/ Country Ref.
academy/
government

CN102008577B Drug for preventing and Mar 21, 2012 - Southern Medical CN Mo et al.
curing dependence of University (2012)
amphetamine and opiate
drugs22
CN101972251B Use of hirsutine in May 30, 2012 - Southern Medical CN Mo and Weng
preparing anti-addictive University (2012)
drug23
US8741359B2 Method for testing a Jan 3, 2014 ? BASF Beauty Care FR Perrier et al.
substance which is Solutions France (2014)
potentially active in the S.A.S.
field of lipolysis and its
mainly cosmetic use24
Delivery methods
CN101862304B Uncaria sustained-release Jul 4, 2012 - Guizhou Baihua CN Huang et al.
tablet and preparation Medical & (2012c)
method thereof25 Pharmaceutical Co.
Ltd.
CN101869556B Uncaria slow release Nov 25, 2015 - Guizhou Baihua CN Huang et al.
capsule preparation and Medical & (2015)
preparation method Pharmaceutical Co.
thereof26 Ltd.
Treatments and compositions using Uncaria spp as an ingredient thereof
RU2545765C1 Agent and method of Apr 10, 2015 - SRI Health-Preserving RU Maslov and
treating diabetes Tech Corp. Ltd. Borodulin
mellitus27 (2015)
EP1996176B1 Compositions to reduce May 19, 2010 ? Astrum Therapeutics AU Hayes and
blood glucose levels and Pty. Ltd. Zolotoy
treat diabetes28 (2010)
CN103417950B Traditional Chinese Nov 25, 2015 - GAM Hosp, CACMS CN Tong (2015)
medicine composition for
preventing and treating
obese type 2 diabetes
combined dyslipidemia29
US7416748B2 Arthritis phyto- Aug 26, 2008 - None US Olalde (2008a)
nutraceutical synergistic
composition30
CN104096221B Natural drug composition Sep 30, 2015 - None CN Du and Tao
for curing rheumatism (2015)
bone diseases and
preparation method31
US7390512B2 Multiple sclerosis Jun 24, 2008 - None US Olalde (2008b)
synergistic phyto-
nutraceutical
composition32
CN102091239B Uncaria abalone sour soup Jul 4, 2012 - None CN Sun et al.
for treating trigeminal (2012)
neuralgia33
CN103610795B Method for preparing Jan 01, 2016 - Baihua Pharmaceutical CN Huang et al.
Eucommia ulmoides step- Group Co. Ltd. (2016)
down oral preparation34

123
Phytochem Rev

Table 1 continued
Patent number Title Issue date Family* Company/ Country Ref.
academy/
government

CN102049010B Medicament for preventing Jul 4, 2012 - None CN Su (2012)

and treating ischemic
cerebrovascular
diseases35
CN103446458B Powder for treating Jan 20, 2016 - Fujian Liancheng CN Jiang (2016)
convulsion36 Guanjang
Dendrobium Co.Ltd.
CN102824484B Plaster for treating lumbar Feb 12, 2014 - None CN Wang and
disc herniation37 Wang (2014)
US8968801B1 Supplement composition Mar 3, 2015 - Cellhealth Technology US Giampapa
for supporting DNA Ltd. (2015a)
repair and method of
use38
US8974839B2 Dietary supplement system Mar 10, 2015 ? Cellhealth Technology US Giampapa
for multifunctional anti- Ltd. (2015b)
aging management and
method of use39
CN102078507B Uncaria-containing Jul 25, 2012 - Jiangsu Prov Acad CN Huang et al.
composition with anti- TCM (2012a)
aging function40
CN101411852B Capsule containing hooked May 18, 2011 - Ruzhou Chinese CN Gao et al.
Uncaria and Gastrodia41 Medicine Hospital (2011)
US7354570B2 Chinese preparation for Apr 8, 2008 ? Tianjin Kinsly CN Wang et al.
treating enteritis ulcer Pharmaceutical R&D (2008)
colitis and preparation Co. Ltd.
method thereof42
CN103446543B Traditional Chinese April 1, 2015 - HUTCM CN Yan et al.
medicine for treating (2015)
thyroid associated
ophthalmopathy in acute
stage43
US6893648B2 Composition and method May 17, 2005 - None US Mermelstein
for treatment of vaginal and
dryness44 Marchese
(2005)
EP2416794B1 Plant compositions for the Dec 25, 2015 ? None LB El Khatib and
treatment or prevention of El Kettany
viral blood-borne diseases (2015)
caused by the human
immunodeficiency virus
(HIV) or hepatitis C45
US7955624B2 Compositions and methods Jun 7, 2011 ? Northern Innovations CA Heuer and
for increasing adipose Holding Corp. Clement
metabolism, lipolysis or (2011)
lipolytic metabolism via
thermogenesis46
US6878378B1 External skin care Apr 12, 2005 ? Kao Corporation JP Yamaki et al.
composition47 (2005)
CN103385301B Pressure reduction milk tea Jul 15, 2015 - Anhui Washan Foods CN Fan (2015)
and preparation method Co. Ltd.
thereof48

123
 Phytochem Rev

Table 1 continued
Patent number Title Issue date Family* Company/ Country Ref.
academy/
government

CN103392886B Liver-clearing and lung- Dec 17, 2014 - None CN Lv (2014)

nourishing health-care
tea49
CN103461760B Preparation method of Jan 27, 2016 - None CN Chen (2016)
shrimp shell powder cold
noodles50
CN103461802B Five-vegetable blood Aug 5, 2015 - Dangtu County CN Wu (2015)
pressure-reducing sweet Ruilong FTPPC
rice flour and production
method thereof51
EP1720561B1 Botanical extract Apr 11, 2012 ? None NL Taal (2012)
composition52
Other applications
CN1182083C Complex fertilizer for Dec 29, 2004 - None CN Liao (2004)
killing insect and bacteria
and its production
method53
Identification methods
CN101772579B Method of identifying the Jun 5,l 2013 ? Tsumura & Co. JP Yamaji (2013)
species of plant belonging
to the genus Uncaria54
CN103869010B HPLC method for Dec 9, 2015 - Guangdong CN Zeng et al.
distinguishing different Pharmaceutical (2015)
varieties of Uncaria55 University
Machines
CN204134889U Stem branch and hook Feb 4, 2015 - None CN Zhang (2015)
separation device for
Uncaria56
* A set of patents from a same invention and registered in various countries; as applications or/and grants. Black numbers are
correlated with Fig. 4. 2nd AF Hosp PLA 3rd Military Med Univ, The Second Affiliated Hospital of The Third Military Medical
University of PLA; FTPPC, Fruit Tree Planting Professional Cooperatives; HUTCM, Henan University of traditional Chinese
Medicine; Jiangsu Prov Acad TCM, Jiangsu Province Academy of Traditional Chinese Medicine; SRI Health-Preserving Tech,
Scientific-Research Institute of Health-Preserving Technologies; UW, University of Washington; WFU, Wake Forest University;
GAM Hosp, CACMS, Guang An Men Hospital, China Academy of Chinese Medical Sciences

have been developed, using an Uncaria alkaloid
extract (Chen et al. 2012), hirsutine (Zhu et al.
2011a) or the MIA corynantheine, both of them are
from Uncaria plant material (Zhu et al. 2011b). In
order to stimulate the immunologic system the patent
EP0989856B1 claims use and biosynthesis of a
growth-factor from endothelial cells exposed to Un-
caria alkaloids in vitro; which stimulates immune
system (Keplinger et al. 2010). The patent
EP1786446B1 developed an efficient method to treat
Herpes simplex mucocutaneous infection by using a
70% hydroalcoholic extract, containing Uncaria alka-
loids (Trentini 2015). For treatment of Alzheimer’s
disease and other amyloid diseases, the patent
US7754250B2 claims administration of Uncaria inner
bark or root tissue in order to inhibit amyloid
formation, deposition, accumulation, amyloid pro-
tein-amyloid protein interactions, and/or dissolution/
disruption of preformed or pre-deposited amyloid
fibrils (Castillo and Snow 2010). In oncology field, an
effective method for treating neoplasms using deriva-
tives of the MIA yohimbine together with other known
chemotherapeutic agents has been patented (Salbury
et al. 2013). In the psychology and psychiatric fields,
the use of rhynchophylline as anxiolytic or anti-
depressant has been claimed (Zhou et al. 2016), while

123
Phytochem Rev

(a) MIA and MOA Biosynthesis (b) Triterpenoid Biosynthesis

CHO
NH2 OGlc 2,3-Oxidosqualene
O
N CH3OOC
H
Tryptamine Secologanin
O
STR Triterpene synthases

H
N
N
H
H OGlc
Strictosidine HO HO HO
O
H3CO2C Lupeol α-Amyrin β-Amyrin

MIAs
N O
N
H
MOAs
H H H
H
COOH COOH
H COOH
O
H H H
OGlc HO HO HO
H H H

Strictosamide Betulinic acid Ursolic acid Oleanolic acid

COOH

H COOH
HO
H
Quinovic acid

Fig. 2 Biosynthesis of alkaloids and triterpenoids in the genera
Uncaria and Hamelia. a Biosynthesis of MIAs and MOAs.
Strictosidine is the first common precursor formed by conden-
sation of tryptamine (derived from tryptophan decarboxylation)
and secologanin (from deoxyxylulose phosphate/methylerythri-
tol phosphate pathway) by the enzyme strictosidine synthase
(STR) (Flores-Sanchez et al. 2016). The dashed arrow means
several steps. b Biosynthesis of main triterpenoids detected in
both genera Uncaria and Hamelia. 2,3-Oxidosqualene is the first
common precursor formed by oxidation of squalene via the
precursor mevalonate (Flores-Sanchez et al. 2002), which is
cyclized by triterpene synthases or oxidosqualene synthases.
Three arrows imply successive oxidation steps

the use of rhynchophylline (Mo et al. 2012) and
hirsutine (Mo and Weng 2012) was claimed for
prevention or treatment of drug dependence. In
cosmetic field, the patent US8741359B2 developed a
method to treat cellulitis using a hydroethanolic
extract from U. tomentosa bark (Perrier et al. 2014).
In order to improve bioavailability and controlled
release of rhynchophylline or Uncaria alkaloids,
methods and formulations for a sustained-release
tablet, having an enteric coat (Huang et al. 2012c)
and capsules (Huang et al. 2015) were developed. One
very common use of Uncaria is as component of
polyherbal or polycomponent treatments for
management of a great variety of symptoms and
diseases in traditional medicine, especially from
China, Japan and Korea (Zhang et al. 2015; Heitzman
et al. 2005). The Uncaria component can be such as
plant material, extracts, pure metabolites or mixtures.
There are patents from polyherbal/polycomponent
medicaments for treating diabetes mellitus (Maslov
and Borodulin 2015; Hayes and Zolotoy 2010; Tong
2015), inflammatory diseases (Olalde 2008a; Du and
Tao 2015), multiple sclerosis (Olalde 2008b; Sun et al.
2012), vascular diseases (Huang et al. 2016; Su 2012),
convulsions (Jiang 2016), lumbar disc herniation
(Wang and Wang 2014), nuclear and mitochondrial

123
 Table 2 Some patents related to other secondary/specialized metabolites present in Uncaria species from 1988 to 2016
Patent number Title Issue date Family* Company/ Country Ref.
academy/

123
government

Triterpenoids
Compound isolation
CN101643492B Method for extracting and Jun 8, 2011 - Shandong Prov Inst TCM CN Yang et al. (2011)
preparing ursolic acid from
Uncaria57
Synthesis
CA2705902C A method for producing May 14, 2013 ? Northeast Forestry University CN Yan et al. (2013)
betulinic acid58
Biosynthesis
CN102226213B Method for synthesizing Jan 2, 2013 - Zhejiang University CN Chen et al. (2013)
betulinic acid by catalyzing
botulin with laccase59
Derivative synthesis
CN104045678B Chemically modified ursolic Mar 2, 2016 - GDUT CN Zhao et al. (2016)
acid and its preparation
method and use60
US9120839B2 Ursolic acid derivative and Sep 1, 2015 ? Nexoligo Co. Ltd. KR Yoon (2015)
method for preparing
same61
CN103933048B Applications of ursolic acid Mar 9, 2016 - Fuzhou University CN Shao et al. (2016)
derivatives in preparation
of drug for preventing and
treating tumor metastasis62
CN103877097B Novel use of ursolic acid Jan 20, 2016 - GDUT CN Zhang et al. (2016b)
derivative63
US9090574B2 Antioxidant inflammation Jul 28, 2015 ? Reata Pharmaceuticals Inc. US Anderson et al. (2015)
modulators: oleanolic acid
derivatives with saturation
in the C-ring64
US9278912B2 C13-hydroxy derivatives of Mar 8, 2016 ? Reata Pharmaceuticals Inc. US Jiang et al. (2016a)
oleanolic acid and methods
of use thereof65
US9249089B2 Antioxidant inflammation Feb 2, 2016 ? Reata Pharmaceuticals Inc. US Jiang et al. (2016b)
modulators: C-17
homologated oleanolic acid
derivatives66
Phytochem Rev
 Table 2 continued
Patent number Title Issue date Family* Company/ Country Ref.
academy/
government
Phytochem Rev

US8987502B2 Oleanolic acid amidate Mar 24, 2015 ? Hangzhou Bensheng Pharmaceutical Co. Ltd. CN Rong et al. (2015)
derivatives, preparation
methods and uses thereof67
US9156801B2 2-substituted oleanolic acid Oct 13, 2015 ? Hangzhou Bensheng Pharmaceutical Co. Ltd. CN Xu et al. (2015)
derivative, method
preparing for same, and
application thereof68
CN103864882B Oleanolic acid-pyrimide Oct 28, 2015 - Guanxi Normal University CN Cheng et al. (2015)
conjugate as well as
preparation method and
application thereof69
CN103864881B Oleanolic acid-uridine Jan 13, 2016 - Guanxi Normal University CN Cheng et al. (2016)
conjugate as well as
preparation method and
application thereof70
PL217864B1 New O-acylated oximes of Aug 29, 2014 - PUMS PL Bednarczyk-Cwynar et al. (2014)
oleanolic acid derivatives
and process for the
preparation of acylated
oxime derivatives of
oleanolic acid71
CN102875630B Piperazine derivative of Nov 19, 2014 - TIPR CN Liu et al. (2014)
oleanolic acid, preparation
method and application of
piperazine derivative72
CN102690315B Oleanolic acid oxime ester Dec 24, 2014 - China Agricultural University CN Zhang et al. (2014)
derivate, preparation
method and application
thereof73
US6890533B2 Betulinol derivatives74 May 10, 2005 ? None US Bomshteyn et al. (2005)
US8088757B2 Betulinol derivatives as Jan 3, 2012 ? Saxena Research LLC US Saxena and Rathnam (2012)
anticancer agents75
US8008280B2 Betulinol derivatives as anti- Aug 30, 2011 ? Saxena Research LLC US Saxena and Rathnam (2011)
HIV agents76
Genes
CA2392435C An isolated plant gene May 10, 2011 ? Plant Biosciences Ltd.-TSL GB Osbourn et al. (2011)
encoding a b-amyrin
synthase77

123
 Table 2 continued
Patent number Title Issue date Family* Company/ Country Ref.
academy/

123
government

CN103088042B Optimized triterpenoid Mar 26, 2014 - IBCAS CN Xue et al. (2014)
synthase coding gene and
application thereof78
CN103509726B Method for producing b- Apr 15, 2015 - Beijing Institute of Technology CN Li et al. (2015)
amyrin with
Saccharomyces cerevisiae
engineering bacterium79
US8647875B2 Enzymes involved in Feb 11, 2014 ? Plant Biosciences Ltd. GB Osbourn and Qi (2014)
triterpene synthesis80
Medical treatments
US6629835B2 Combinations of diterpene Oct 7, 2003 - Bank of America (Meta Proteomics LLC) US Babish et al. (2003)
triepoxide lactones and
diterpene lactones or
triterpenes for synergistic
inhibition of
cyclooxygenase-281
EP1694320B1 Use of compositions Jul 9, 2008 ? Lipid Nutrition B.V. NL Cain et al. (2008)
comprising oleanic acid and
ursolic acid for the
prevention of a medicament
for the treatment of
hypersensitivity and hyper
reactivity82
CN103936814B Tryptophan hydroxylase-1 Nov 18, 2015 - Nanjing Huitelai Pharmaceutical Technology Co. Ltd. CN Li (2015)
inhibitor ursolic acid
derivatives as well as
preparation method and
application thereof83
US6689767B2 Triterpenes having Feb 10, 2004 ? UMN US Krasutsky et al. (2004)
antibacterial activity84
RU2519133C1 Ointment containing Jun 10, 2014 - None RU Klopotenko (2014)
encapsulated triterpenic
acid or derivatives thereof85
KR101478110B1 Ursolic acid having anti- Dec 31, 2014 - KRIBB KR Chun et al. (2014a)
bacterial activity against
causative bacteria of
porcine respiratory disease
complex and uses thereof86
Phytochem Rev
 Table 2 continued
Patent number Title Issue date Family* Company/ Country Ref.
academy/
government
Phytochem Rev

KR101478109B1 Oleanolic acid having Dec 31, 2014 - KRIBB KR Chun et al. (2014b)
antibacterial activity
against causative bacteria
of porcine respiratory
disease complex and uses
thereof87
JPS6326083B2 Composition for oral cavity May 27, 1988 ? Rohto Pharmaceutical Co. Ltd. JP Hayashi et al. (1988)
application88
MX2012006516A Vaccine adjuvant Dec 7, 2013 - IPN MX Herrera et al. (2013)
composition based on
ursolic acid89
CN103251944A Preparation method of ursolic Aug 21, 2013 - XTIPC CAS CN Li et al. (2013)
acid as immnunologic
adjuvant vaccine and use90
KR100954887B1 Dendritic cells matured by Apr 28, 2010 - Chonnam National University KR Lee et al. (2010)
uncarinic acid C,
compositions for
immunotheraphy
containing the dendritic
cells, and methods for
preparing mature dendritic
cells using uncarinic acid
C91
CN103585161B Medicinal composition, and Dec 2, 2015 - FMMU CN Wang and Hai (2015a)
its application in preparing
medicines for treating
obesity, insulin resistance
and diabetes92
CN103585158B Medicinal composition and Jul 22, 2015 - FMMU CN Wang and Hai (2015b)
its application in
preparation of liver cancer
treatment medicines93
US9289443B2 Pharmaceutical composition Mar 22, 2016 ? ITRI TW Lee et al. (2016)
and method for preventing
or treating hepatitis C94
US9278913B2 Therapeutic compounds and Mar 8, 2016 ? Dartmouth College US Gribble et al. (2016)
methods of use95

123
 Table 2 continued
Patent number Title Issue date Family* Company/ Country Ref.
academy/

123
government

Delivery methods
CN102329362B Ursolic acid derivative Nov 21, 2012 - Fuzhou University CN Bai et al. (2012)
chemically modified by
polyethylene glycol and
preparation method of
ursolic acid derivative96
CN103705939B Preparation of amphiphilic Mar 2, 2016 - CPU CN Yao et al. (2016)
ursolic acid-polysaccharide
coupled substance and
application thereof in
treating tumors97
CN103990145B Folic acid-polyamide Jan 27, 2016 - Fuzhou University CN Gao et al. (2016)
polyamidoamine
(PAMAM)-ursolic acid
nanodrug with tumor
targeting and preparation
method of drug98
Detection methods
CN102895678B Liver-targeted magnetic Jun 4, 2014 - ZJU CN Tang et al. (2014)
resonance imaging contrast
agent based on oleanolic
acid and preparation
method thereof99
Other applications
KR101542843B1 An insecticide comprising Aug 7, 2015 - KRIBB KR Kim et al. (2015a)
ursolic acid100
US6433010B2 Pentacyclic triterpenes101 Oct 1, 2002 ? Arista Lifescience North America LLC US Glinski and Branly (2002)
DE60114708D1 Blends of ursolic acid/ Jul 20, 2006 ? Loders Croklaan USA LLC US Beindorff et al. (2006)
oleanolic102
Flavonoids
Extracts
US9308216B2 Rutin-rich extract and method Apr 12, 2016 ? Alps Pharmaceutical Ind. Co. Ltd. JP Minami et al. (2016)
of making same103
Phytochem Rev
 Table 2 continued
Patent number Title Issue date Family* Company/ Country Ref.
academy/
government
Phytochem Rev

Compound isolation
CA2427661C Methods of isolating May 28, 2013 ? Cognitive Clarity Inc. US Castillo et al. (2013)
amyloid-inhibiting
compounds and use of
compounds isolated from
Uncaria tomentosa and
related plants104
Medical treatments
CA2441099C Proanthocyanidins for the Apr 19, 2011 ? Cognitive Clarity Inc. US Snow et al. (2011)
treatment of amyloid and a-
synuclein diseases105
US8945518B2 Formulation of dual Feb 3, 2015 - Unigen Inc. US Jia and Zhao (2015)
eicosanoid system and
cytokine system inhibitors
for use in the prevention or
treatment of oral diseases
and conditions106
CN101083981B Flavonoid composition for Mar 27, 2013 ? Unigen Inc. US Zhao and Jia (2013)
treating oral diseases107
KR101505175B1 A novel composition for Mar 24, 2015 - CHA University, School of Medicine KR Kim et al. (2015b)
suppressing metastasis of
cancer108
CN101889999B Novel pharmaceutical use of Jul 18, 2012 - None CN Yan (2012)
kaempferol109
US9198453B2 Methods of reducing blood Dec 1, 2015 ? Stokely-Van Camp Inc. US Zachwieja et al. (2015)
lactate concentration110
US9180184B2 Adjuvant compositions and Nov 10, 2015 ? EpitoGenesis Inc. US Vajdy and Padrah (2015)
method of use111
US8507548B2 Method for treating addition Aug 13, 2013 ? Quercegen Pharmaceuticals LLC US Lines (2013)
using quercetin-containing
compositions112
US8648059B2 Use of epicatechin and Feb 11, 2014 ? UC US Villarreal et al. (2014)
derivatives and salts thereof
for cardiac protection of
ischemic myocardium and
to ameliorate adverse
cardiac remodeling113

123
 Table 2 continued
Patent number Title Issue date Family* Company/ Country Ref.
academy/

123
government

Other metabolites
US8372449B2 Method for enhancing the Feb 12, 2013 ? Optigenex Inc. US Pero (2013)
DNA repair process,
treating disorders
associated with the DNA
repair process, enhancing
anti-tumor response and
treating disorders
associated with anti-tumor
response in mammals by
administering purified
quinic acid and/or carboxyl
alkyl ester114

* A set of patents from a same invention and registered in various countries; as applications or/and grants. Black numbers are correlated with Fig. 4. CPU, China Pharmaceutical
University; FMMU, the Fourth Military Medical University; GDUT, Guangdong University of Technology; IBCAS, Institute of Botany of the Chinese Academy of Sciences;
IPN, Instituto Politécnico Nacional (National Polytechnic Institute); ITRI, Industrial Technology Research Institute; KRIBB, Korea Research Institute of Bioscience and
Biotechnology; PUMS, Poznan University of Medical Sciences; Shandong Prov Inst TCM, Shandong Provincial Institute of Traditional Chinese Medicine; TIPR, Tianjin Institute
of Pharmaceutical Research; TSL, The Sainsbury Laboratory; UC, University of California; UMN, University of Minnesota; XTIPC CAS, Xinjiang Technical Institute of Physics
and Chemistry, Chinese Academy of Sciences; ZJU, Zhejiang University. Bold letters represent patents with assignment combined among industry, academy, government, and by
countries
Phytochem Rev
Phytochem Rev

Phenylpropanoids Triterpenoids
HO COOH OH
HO O OH
O O
H H H
O OH O OH
COOH COOH COOH
OH HO
HO HO
Rosmarinic acid H H
OH Chlorogenic acid H
OH
HO HO HO
H H H
Alkaloids HO
O
OH
Ursolic acid 2α-Hydroxyursolic acid Rotundic acid
OH
O OH
O O H Flavonoids
NHCH3 O O
RhaGlc
Ephedrine OH
N
GlcO O
MIAs Seneciphylline
Narirun
OH O
OH

H
Apigenin 7-glucoside
H HO O OH O
OH
N O N O
OGlcRha HO
H H H H OH O
N CO2CH3
H3CO N CO2CH3 Run OH O O
H RhaGlc OH
H OH
Tetrahydroalstonine Aricine
HO O
OH O
MOAs OH
5,7,2’,5’-Tetrahydroxy-
H H H H flavanone 7-runoside
N O N O N O N O
OH Catechin
OCH3 OH

OH OH
H H H H H H
CO2CH3 CO2CH3 H H
N O CO2CH3 N O COOH + +
N O N O HO O
HO O OCH3
H H H OCH3
Isopteropodine Pteropodine Speciophylline H Maruquine
OH OH
H H H OH OH
HO H OH Petunidin
N O H3CO N O N O Malvidin OH
N O
+
HO O
H H H H H H H
H COOH
CO2CH3 CO2CH3 CO2CH3 N O
N O N O N O
OH
Cyanidin
H H H H
Rumberine Palmirine Uncarine F Isomaruquine OH

Fig. 3 Chemical structures of specialized or secondary metabolites identified in the genus Hamelia

DNA mutations (Giampapa 2015a), cellular and organ agriculture field, an insecticide-bactericide coordi-
aging (Giampapa 2015b), for improvement memory nated fertilizer, which includes rhynchophylline,
(Huang et al. 2012a), for headache, insomnia, dizzi- polyphenols, minerals, rare earths, among others
ness (Gao et al. 2011), non-specific colitis (Wang et al. components, has been developed (Liao 2004).
2008), thyroid disorders (Yan et al. 2015), vaginal
dryness (Mermelstein and Marchese 2005), hepatitis Patents for identification from Uncaria plant
C, HIV/AIDS (El Khatib and El Kettany 2015), material and for development of devices
obesity (Heuer and Clement 2011), and for stimulating
ceramide production on skin (Yamaki et al. 2005). In Two identification methods have been patented
addition, there are different ways for the administra- (Table 1); one for identification of species of the
tion of these polyherbal/polycomponent treatments as genus Uncaria by genetic methods, using plant
nutraceutical foods such as teas (Fan 2015; Lv 2014), ribosomal DNA internal transcribed spacer regions
noodles (Chen 2016) or sweet rice flour for preparing and 45 nucleotide sequences (Yamaji 2013). The
meals (Wu 2015). Besides, there are also treatments other one is through alkaloid profiles as fingerprints
not only for human use, but for animals; for example, by a HPLC method (Zeng et al. 2015). On the other
patent EP1720561B1 claims the use of a six-compo- hand, a device to cut and separate hooks and stem
nent herbal extract for inflammation diseases in branches from Uncaria plants (Table 1) was devel-
humans, pets and farm animals; which includes oped to give a fine finishing to the plant material
Uncaria roots (Taal 2012). On the other hand, in the (Zhang 2015).

123
 Phytochem Rev

Table 3 Some patents related to the genus Hamelia and/or specialized metabolites/metabolism from 1979 to 2016
Patent number Title Issue date Family* Company/ Country Ref.
academy/
government

Extracts
US8652534B2 Compositions and methods Feb 18, 2014 ? Berry US Berry (2014)
for treatment of Pharmaceuticals
mammalian skin115 LLC
Alkaloids
DE2439523C2 Pharmaceutical Mar 22, 1979 ? Meto-International DE Poignant
compositions containing Gmbh (1979)
tetrahydroalstonine and
method for treating
circulation disorders116
Derivatives
EP0017525B1 Derivatives of Sep 28, 1983 ? Pierre Fabre S.A. FR Hatinguais
tetrahydroalstonine, their et al.
preparation and their (1983)
application as
medicaments117
Triterpenoids
Derivatives
CN102140126B Rotundic acid derivative Sep 26, 2012 - None CN Zhao et al.
and synthesis method (2012)
thereof as well as
application of rotundic
acid derivative in
preparing medicament for
preventing and curing
cardiovascular disease118
CN102391352B Amino acid derivatives of Sep 26, 2012 - None CN He et al.
rotundic acid and (2012)
application of derivatives
in preparation of
antitumor medicines119
Flavonoids
Flavanones
JP5311357B1 Carbonated beverage Oct 9, 2013 ? ITO EN Ltd. JP Awano et al.
packed in container and (2013)
manufacturing method
therefor120
KR101268325B1 Composition for preventing May 31, 2013 - KFRI KR Choi et al.
and treating alcoholic (2013)
liver disease comprising
flavonoid121
Flavones
CN103819438B Novel technology for Jan 20, 2016 - None CN Li (2016)
preparing apigenin from
by one-step method122
US8377918B2 Apigenin for Feb 19, 2013 - ACC Therapeutics US Jiang and
chemoprevention, and Inc. Fang
chemotherapy combined (2013)
with therapeutic
reagents123

123
Phytochem Rev

Table 3 continued
Patent number Title Issue date Family* Company/ Country Ref.
academy/
government

CN102441168B Medicine composition May 7, 2014 - Dinghong CN Zhao (2014)

containing apigenin, International
apigenin derivant and Investment Hong
Bc1-2 inhibitor and Kong Co. Ltd.
application thereof in
preparation of medicines
capable of treating
cancer124
TWI507527B Method of manufacturing Nov 11, 2015 - CNU TW Chang and
6-hydroxyapigenin by Ding
biotransformation125 (2015)
HRPK20130487B3 Probiotic formulation with Jul 31, 2015 ? Pharmas D.O.O. HR Cepanee and
apigenin and peppermint Knezevic
extract126 (2015)
US9056209B2 Apigenin-containing Jun 16, 2015 ? Kao Corporation JP Sugiyama
composition127 and
Kasamutsu
(2015)
CN103585113B Apigenin polylactic Apr 22, 2015 - TYUT CN Wang et al.
sustained release (2015a)
microsphere and
preparation method
thereof128
Anthocyanidins
US9308231B2 Anti-inflammatory Apr 12, 2016 ? Universite FR Renard et al.
composition comprising Bordeaux (2016)
malvidin-3-O-b-glucoside Segalen-
and a propolis extract129 Nutrivercell
US6967032B2 Product130 Nov 22, 2005 - Medpalett NO Slimestad
Pharmaceuticals (2005)
As
US8449927B2 Stabilized anthocyanin May 28, 2013 ? Omnica Gmbh DE Eidenberger
compositions131 (2013)
EP2831122B1 Anthocyanidin complex132 Feb 3, 2016 ? SapioTec Gmbh DE Roewer and
Broscheit
(2016)
CA2573510C Insulin secretion by Sep 6, 2011 ? MSU US Nair et al.
anthocyanins and (2011)
anthocyanidins133
US8420398B2 Estrous cycle monitoring by Apr 16, 2013 ? Oratel Diagnostics US Goldman
color response134 LLC (2013)
Other metabolites
CN102476997B Method for preparing Apr 2, 2014 - SUT-Hanzhong CN Chen et al.
chlorogenic acid by TRG Biotech Co. (2014)
freezing, concentrating ad Ltd.
crystallizing135
EP2592064B1 Process for production of Jun 24, 2015 ? Kao Corporation JP Sugiyama
purified chlorogenic acid- et al.
containing (2015)
pharmaceutical
preparation136

123
 Phytochem Rev

Table 3 continued
Patent number Title Issue date Family* Company/ Country Ref.
academy/
government

CN104496815B Preparation method of Jan 6, 2016 - Sichuan J.Z. CN Zhang et al.

medicinal chlorogenic Biochemical (2016a)
acid137 Science and
Technology
Development Co.
Ltd.
US7288271B2 Chlorogenic acid and an Oct 30, 2007 ? General Nutrition US Graus et al.
analog thereof for Investment Co. (2007)
immune system
stimulation138
US9259410B2 Methods of treating Feb 16, 2016 ? Advocos LLC US Schutz
polycystic ovarian (2016)
syndrome using
chlorogenic acid and
inositol139
US8197875B2 Taste modifiers comprising Jun 12, 2012 ? Givaudan SA CH Chien et al.
a chlorogenic acid140 (2012)
CN101095668B Application of rosmarinic Sep 8, 2010 ? Shandong Luye CN Qu et al.
acid in the preparation of Pharmaceutical Co. (2010)
medicines for treating or Ltd.
preventing liver fibrosis
and kidney fibrosis141
US9060985B2 Use of rosmarinic acid and Jan 23, 2015 ? IRD-ILM FR-FP Laurent et al.
the derivatives thereof to (2015)
treat ciguatera142
US9314490B2 Biological effects of Apr 19, 2016 ? Nestec S.A.- CH-FR Crespy et al.
compositions of L’Oreal (2016)
rosmarinic acid143
Variety/cultivar
USPP26247P2 Hamelia plant named Dec 22, 2015 - Greenleaf Nursery US Polanco
‘Grelmsiz’144 Co. (2015)
* A set of patents from a same invention and registered in various countries; as applications or/and grants. Black numbers are
correlated with Fig. 4. CNU, Chia Nan University of Pharmacy and Science; ILM, Institut Louis Maladarde; IRD, Institut de
Recherche Pour le Developpment; KFRI, Korea Food Research Institute; MSU, Michigan State University; SUT, Shaanxi University
of Technology; TYUT, Tai Yuan University of Technology. Bold letters represent patents with assignment combined among
industry, academy, government, and by countries

Patents for isolation, synthesis and biosynthesis
of triterpenoids in the genus Uncaria
Regarding to triterpenoids from Uncaria plants, 82
triterpenoids have been isolated from this genus.
Ursan- and oleanan-type pentacyclic triterpenes con-
stitute the main triterpenoids in Uncaria, which are
usually found in their glycosylated forms (Zhang et al.
2015). On Table 2, some patents related to these
important triterpenoids are presented. The patent
CN101643492B claims a method for extraction of
the triterpenoid ursolic acid from Uncaria plant
material, which is suitable for industrial production,
low cost and friendly to environment (Yang et al.
2011). Other triterpenoid isolated from Uncaria is
betulin or betulinol, a lupeol-type pentacyclic triter-
pene (Zhang et al. 2015); which is precursor of the
potent antitumor triterpene betulinic acid (Ali-Sayed
et al. 2016). Patents for chemical synthesis (Yan et al.
2013) or biosynthesis of betulinic acid from betulin
using a laccase enzyme (Chen et al. 2013) have been
reported. In addition, there are patents for synthesis of
ursolic acid derivatives (Zhao et al. 2016), ursolic acid
prodrugs (Yoon 2015), and their derivatives for

123
Phytochem Rev
Methods for preparing Uncaria extracts1-4
Alkaloid isolaon and detecon methods 5-8, 54-55
Synthesis/semi-synthesis/ biosynthesis methods9-12
MIAs and MOAs Derivave synthesis13
Pharmaceucal formulaons and presentaons 25-26
Medical treatments: Cardiac diseases, Hepas C,
Immunologic system smulaon, Herpes simplex mucocutaneus
infecon, Alzheimer’s disease, Amyloid diseases, Neoplasms,
Depression, Anxiety, Drug dependence, cellulis14-24
Polyherbal treatments with Uncaria plant material27-52
Others: Inseccide-bactericide coordinate ferlizer, Idenficaon methods
for Uncaria plant material, plant cung devices 53,56
Extracon/Isolaon methods57
Biosynthesis, Genes58-59,77-80
Triterpenoid derivave synthesis methods60-76
Triterpenoids Medical treatments: Inflammatory diseases,
Allergies, Microbial/Parasic infecons,
Dental caries, Obesity, Diabetes,
Hepas C infecon, Neoplasms,
Alzheimer’s disease, Parkinson’s disease,
Mulple sclerosis, Vaccine adjuvant,
Immunological system smulaon81-95
U. tomentosa
Pharmaceucal formulaons/presentaons 96-98
Liver diseases detecon methods99
Insect/ microbial pathogens control100-101
Taste enhancers102
Isolaon methods, Flavonoid-rich extract preparaon methods103-104
Flavonoids Medical treatments: Alzheimer’s disease, Parkinson’s disease,
Inflammaon, Neoplasms, Skin whitener, Drug dependence,
Ischemic organ injury, Vaccine adjuvant, exercise/athlec
performance105-113
Other metabolites Isolaon methods for quinic acid and derivaves 114
Fig. 4 General overview of patents from products, methods and applications created in the genera Uncaria and Hamelia. Black
numbers are correlated with patents in tables
treatment of tumor metastasis (Shao et al. 2016), and
for diabetes (Zhang et al. 2016b). Also, patents for the
synthesis of novel oleanolic acid derivatives have been
published to treat oxidative stress and inflammation
(Anderson et al. 2015; Jiang et al. 2016a, b), neo-
plasms (Rong et al. 2015; Xu et al. 2015; Cheng et al.
2015, 2016; Bednarczyk-Cwynar et al. 2014), pain
(Liu et al. 2014) and plant microbial infections (Zhang
et al. 2014). Furthermore, methods for the synthesis of
betulin derivative compounds, such as butyloxycar-
bonyl, carbobenzoxy, dialcohols, diethers and
immunoconjugated, for treatment of neoplasms
(Bomshteyn et al. 2005; Saxena and Rathnam 2012)
and as anti-HIV agents (Saxena and Rathnam 2011)
have been patented. Regards to pentacyclic triterpene
biosynthesis, this route has a common intermediate
precursor, 2,3-oxidosqualene, which is cyclized by
enzymes known as oxidosqualene cyclases or triter-
pene synthases to different cyclization products.
Lupeol, a-amyrin and b-amyrin are precursors of
betulinic acid, ursolic acid and oleanolic acid; respec-
tively. Their biosynthesis includes successive steps of
cyclization and oxidations by oxidosqualene synthases
and P450 oxidases from 2,3-oxidosqualene; as well as
Methods for preparing Hamelia extracts115
Pharmaceucal formulaons and presentaons116
MIAs and MOAs Derivave synthesis117
Medical treatments: Neoplasms, Skin disorders,
Vascular disorders 115-117
Derivave synthesis118-119
Triterpenoids Medical treatments: Neoplasms, Cardiovascular diseases118-119
Isolaon /Detecon methods122, 134-138
Semi-synthesis/Biosynthesis125
Pharmaceucal formulaons and Presentaons 120,126-
Flavonoids 128,131-132,140
Medical treatments: Neoplasms,
and Vascular diseases,
Anoxidants, Arthris,
Phenylpropanoids Liver/Renal diseases,
Diabetes,
Nutraceucals,
H. patens Polycysc ovarian syndrome
Skin improvement
Ciguatoxin poisoning 121,123-124,
129- 130,133,139,141-143
Hamelia plant variees144
glycosylation steps for glycosylated triterpenes
(Thimmappa et al. 2014; Huang et al. 2012b; Fig. 2b).
Patents protecting the use of genes participating on the
biosynthesis of triterpenoids have been granted
(Table 2). Thus, patent CA2392435C claims the use
of cDNA and genomic DNA sequences of b-amyrin
synthase, a triterpene synthase, vectors, transformed
host cells and methods for influencing or affecting
triterpene synthesis in plants giving resistance to
fungal pathogens (Osbourn et al. 2011). For biotech-
nological production of a-amyrin or b-amyrin, the
patents CN103088042B (Xue et al. 2014) and
CN103509726B (Li et al. 2015) developed production
methods using nucleotide sequences encoding triter-
pene synthases, plasmids, cassettes, transformed host
cells and engineered Pichia pastoris and Saccha-
romyces cerevisiae (Table 2). Furthermore, the use of
nucleotide sequences of a tailoring enzyme of b-
amyrin has been granted in the patent US8647875B2.
These sequences encode cytochrome P450s
(CYP51H), with sterol demethylase activity; but
capable of modifying both C and D rings of b-amyrin
to add hydroxylations and epoxidations. Vectors,
transformed plants, methods of producing plants with
123

altered levels of CYP51H, transformation methods,
overexpression, mutants and production and uses of b-
amyrin derivatives are also claimed (Geisler et al.
2013; Osbourn and Qi 2014).
Patents for pharmaceutical applications
of triterpenoids in the genus Uncaria
For medical treatments (Table 2), some patents have
been developed in order to use of oleanolic acid,
ursolic acid, betulin, quinovic acid (an ursan-type
pentacyclic triterpenoid present in Uncaria material)
and/or their derivatives as anti-inflammatories (Babish
et al. 2003), to treat allergies in order to decrease
immunoglobulin E (IgE) levels (Cain et al. 2008), as
antibacterials (Li 2015; Krasutsky et al. 2004), anti-
parasitics (Klopotenko 2014), as alternative antibi-
otics for treatment of porcine respiratory diseases
(Chun et al. 2014a, b) and for prevention of dental
caries (Hayashi et al. 1988). A novel application of
ursolic acid or its derivatives as immunologic adjuvant
of vaccines has been claimed (Herrera et al. 2013; Li
et al. 2013). In the field of cell-based immunotherapy,
the patent KR100954887B1 developed a method for
production of cell compositions and/or cell products
(immunomodulators, such as cytokines or inter-
leukins) by adding the ursan-type pentacyclic triter-
penoid uncarinic acid C to immature dendritic cell
cultures (Lee et al. 2010). For treatment of obesity,
diabetes (Wang and Hai 2015a), liver cancer (Wang
and Hai 2015b), hepatitis C (Lee et al. 2016),
Alzheimer’s disease, Parkinson’s disease and multiple
sclerosis (Gribble et al. 2016), the use and application
methods of oleanolic acid and/or its derivatives have
been patented. Different methods to improve solubil-
ity, pharmacokinetics or target delivery of ursolic acid
or its derivatives to treat neoplasms have been claimed
for producing polyethylene glycol conjugates (Bai
et al. 2012), nanomicelles of polysaccharide conju-
gates (Yao et al. 2016), and dendrimers of folic acid-
polyamide polyamidoamine conjugates (Gao et al.
2016). A dendrimer is a highly branched macro-
molecule used as carrier of nanodrugs (Onoue et al.
2014). For detection of human liver cancer or other
liver diseases, the patent CN102895678B claims
synthesis methods for magnetic resonance imaging
contrast agents from oleanolic acid derivatives cou-
pled with diethylenetriaminepentaacetic acid dianhy-
dride and gadolinium(III) chloride (Tang et al. 2014).
123
Phytochem Rev
Other patent applications of triterpenoids
in the genus Uncaria
In the agriculture field (Table 2), the use of ursolic
acid and/or its salts as inhibitors of diacyl coenzyme
A:diacylglycerol acyl transferase for insect control has
been reported (Kim et al. 2015b), while the patent
US6433010B2 claims a plant protection composition
against microbial pathogens; which includes a mixture
of ursolic/oleanolic acids, betulin and their derivatives
(Glinski and Branly 2002). On the other hand,
compositions and preparing methods for mixtures
conformed by ursolic acid and oleanolic acid with
glycerides and edible fats/oils in order to improve the
taste of natural extracts or isolated metabolites have
been developed. This patent has applications in
nutraceutical and food products (Beindorff et al.
2006).
Patents for isolation methods and pharmaceutical
applications from flavonoids and other metabolites
in the genus Uncaria
In the genus Uncaria, forty flavonoids have been
identified, which are classified as flavan-3-ols and
flavonols. Some flavonols isolated from Uncaria are
kaempferol, quercetin, hyperin, rutin and iso-
quercitrin; while catechin, epicatechin, procyanidins,
gambiriins and cinchonains are flavan-3-ols (Zhang
et al. 2015). Table 2 also lists patents associated to the
extraction and uses of this important group of
metabolites, including a patented method for obtaining
a rutin-rich extract from U. elliptica stems and leaves
(Minami et al. 2016). Also, patents for isolation
methods of unique procyanidins from U. tomentosa
plant material have been published (Castillo et al.
2013). Furthermore, the use of these procyanidins for
the treatment of Alzheimer’s and Parkinson’s diseases
was patented a few years ago (Snow et al. 2011). In the
dental care field, the use of flavonoid compositions
from Uncaria, Scutellaria and Acacia extracts has
been claimed in order to inhibit inflammation caused
by periodontal diseases (Table 2), since it is known
that flavonoids are inhibitors of the enzymes lipoxy-
genase and cyclooxygenase belonging to the eicosa-
noid and cytokine systems (Jia and Zhao 2015; Zhao
and Jia 2013). In the oncology field, the patent
KR101505175B1 claims the use of kaempferol in
Phytochem Rev
order to suppress metastasis of cancer (Kim et al.
2015a), while patent CN101889999B was granted for
the use of kaempferol as a tyrosinase inhibitor and
therefore a melanogenesis inhibitor; i.e. a skin white-
ner (Yan 2012). In the sports field, a method for
reducing blood lactate concentration during exercise,
physical activity or athletic performance by adminis-
tration of quercetin and/or rutin, kaempferol and
isoquercitrin was developed (Zachwieja et al. 2015).
In the immunology field, the patent US9180184B2
declares the use of a composition of catechin, allyl
isothiocyanate and vitamins A, E, D and C as
adjuvants in order to increase immunogenicity of
vaccines administered via mucoses; i.e. intranasal,
buccal, or ocular (Vajdy and Padrah 2015), while in
the psychology field, a method for treating addictions
using a composition of quercetin and vitamins niacin
(B3) and C is claimed in the patent US8507548B2.
This patent declares that quercetin can alleviate
withdrawal symptoms accompanied with addiction
(Lines 2013). In the physiopathology field, a treatment
for avoiding organ deterioration and failure after
ischemic organ injury has been patented, claiming the
application of epicatechin and/or derivatives and salts
in combination with the antibiotic doxycycline (Vil-
larreal et al. 2014). Regarding other metabolites
(Table 2), the patent US8372449B2 developed meth-
ods of isolation and purification of quinic acid, quinic
acid ester and quinic acid lactone from water-soluble
extracts from U. tomentosa. Pharmaceutical composi-
tions for enhance immune competency, inhibit inflam-
matory responses, and treat disorders associated with
the response to tumor formation and growth are also
claimed (Pero 2013).
Genus Hamelia
The genus Hamelia belongs to the tribe Hamelieae
and 17 species have been accepted in this genus: H.
axillaris Sw., H. barbata Standl., H. calycosa Donn.
Sw., H. chrysantha Sw., H. cuprea Griseb., H.
longipes Standl., H. macrantha Little, H. magnifolia
Wernham, H. ovate Wernham, H. papillosa Urb., H.
patens Jacq., H. rostrata Bartl. Ex DC., H. rovirosae
Wernham, H. sanguinea Elias, H. ventricosa Sw., H.
xenocarpa Kuntze, and H. xorullensis Kunth (Mar-
tins and Nunez 2015; The Plant List 2016). In
general, they are shrubs or small trees native in
Mexico, Central America and South America.
Species of Hamelia have been introduced and
cultivated as ornamental plants in Southeastern
United States, Southern Africa and Southeastern
Asia (Elias and Pooler 2004). Leaves are light to dark
green, whorled and often with wavy margins and
reddish-pink midveins. This species is a perennial
plant, but in colder regions grows as annual plant. Its
flowers are arranged in a 3–5 rayed terminal cyme
and are tubular with color shades from yellow, orange
to scarlet red. The fruits are oval to elliptic berries
filled in seeds (Croat 1978). Besides, Hamelia has an
ecological role in some insect-plant and animal-plant
interactions, such as a nectar source for humming-
birds, bees, butterflies, hummingbird flower mites,
and as leaf and fruit source for moth caterpillars and
birds; respectively (Velazquez and Ornelas 2010;
Whitehead and Poveda 2011). In this genus, monoter-
penoid indole and oxindole alkaloids, terpenoids and
flavonoids (Fig. 3) have been detected and identified
as specialized/secondary metabolites; some of them
are also present in the genus Uncaria (Fig. 1). In H.
patents plants, some hydroxylated and methoxylated
MOAs as rumberine and palmirine (Fig. 3) are
accumulated in the aerial parts (Flores-Sanchez
et al. 2016; Rios and Aguilar-Guadarrama 2006).
Interestingly, these peculiar substituted patterns in
MOAs could be giving them new chemical and
biological characteristics that should be explored in
detail. It is noteworthy that some uses of Hamelia
such as analgesic, anti-inflammatory, antipyretic,
cicatrizant, antioxidant, antiseptic, cytotoxic, diure-
tic, fungicide, uterotonic and antiparasitic have been
detected in folk medicine (Duke 2002; Reyes-Chilpa
et al. 2004; Suarez et al. 2008).
Hamelia patents
Patents for isolation methods, synthesis
and pharmaceutical applications of alkaloids
and triterpenoids in the genus Hamelia
On Table 3, some patents related to Hamelia and some
metabolites identified in this genus are presented. It is
worth to mention that some patents for specific
secondary/specialized metabolites present in both
Uncaria and Hamelia were previously described in
the Uncaria section of this manuscript. Regarding
123

Hamelia extracts, methods to prepare alcohol-, oil- or
petrolatum-based H. patens plant extracts and com-
position uses for treatment or prevention of a wide
range of skin disorders, such as pre-cancerous lesions,
keratotic lesions, carcinomas, melanomas, and radia-
tion-induced burns, are claimed in the patent
US8625534B2 (Table 3). The compositions of struc-
turally complex molecules (Fig. 3) can consist of the
alkaloids ephedrine, seneciphylline (seneciophylline);
of the MIA aricine; of the MOAs rumberine, specio-
phylline, palmirine, pteropodine, isopteropodine,
maruquine, isomaruquine, uncarine F; of the ursan-
type pentacyclic triterpenoids ursolic acid, 2a-hy-
droxyursolic acid, rotundic acid; of the flavonoids
catechin, narirutin, 5,7,20 ,50 -tetrahydroxyflavanone
7-rutinoside, apigenin-7-O-b-D-glucuronide, rutin;
of phytosterols stigmasterol, b-sitosterol,
24-methylenecycloartene-3b-ol, 24-methylcycloart-
24-ene-3b-ol, stigmast-4-ene-3,6-dione, stigmast-4-
ene-3,3-dione, of the phenylpropanoid rosmarinic
acid; and of the alcohol 2E-3,7,11,15,19-pen-
tamethyl-2-eicosane-1-ol (Berry 2014). About some
specific metabolites, tetrahydroalstonine is a MIA
isolated from H. patens (Martinez et al. 1996), which
has been proposed as biosynthetically precursor of
hydroxylated and methoxylated MIA and MAO
(Flores-Sanchez et al. 2016) and the former patent
DE2439523C2 described its use as adrenolytic agent
for treating vascular disorders (Poignant 1979). A
method to prepare tetrahydroalstonine derivatives for
treatment of hypertension is described in the patent
EP0017525B1 (Hatinguais et al. 1983). For the ursan-
type pentacyclic triterpenoid rotundic acid (Fig. 3),
there are patents for synthetic methods for the
preparation of rotundic acid derivatives of succinyl
and amino acids to treat cardiovascular diseases (Zhao
et al. 2012) or to use them as antineoplastic drugs (He
et al. 2012), respectively.
Patents for synthesis, biosynthesis
and pharmaceutical applications of flavonoids
and phenylpropanoids in the genus Hamelia
Patents for the flavonoids narirutin and apigenin
(Fig. 3), identified in Hamelia plant material, are
described in Table 3. In the beverage industry field,
the patent JP5311357B1 claims that the narirutin and
carotenoid contents should have a ratio in the range of
13–85 in order to improve flavor, suppress acidity and
123
Phytochem Rev
bitterness from beverages containing flavonoids
(Awano et al. 2013). In the medical field, a novel
composition of glycosylated or hydrolyzed flavonoids
such as narirutin, naringenin, naringin, herperetin, and
hesperidin for preventing and treating alcohol liver
diseases has been patented. In such patent, the
enzymatic glycosylation with b-cyclodextrin by a
cyclodextrin glycosyltransferase is claimed (Choi
et al. 2013). The use of apigenin and/or its derivatives
for treatment or prevention of neoplasms have been
also patented (Jiang and Fang 2013; Zhao 2014). Due
to the relevance of this flavone, the patent
CN103819438B developed a novel and efficient
method to obtain apigenin from its precursor narin-
genin using iodine or bromine water as dehydrogena-
tion reagent (Li 2016). A biotechnological production
of 6-hydroxyapigenin, an inhibitor of human intestinal
a-glucosidases (Kawabata et al. 2003), that can
suppress glucose absorption by a Pichia pastoris
expression system has been granted (Chang and Ding
2015). The developed process uses apigenin as
substrate and a fusion gene vector with a cytochrome
P450 monooxygenase of Aspergillium oryzae and an
oxidoreductase of S. cerevisiae.
An enriched formulation of probiotic cultures of
lactic acid bacteria with apigenin and peppermint
extract which can be used as food, pharmaceutical or
veterinary product was patented (Cepanee and Kneze-
vic 2015). On the other hand, in order to improve
apigenin stability for storage conditions, the patent
US906209B2 developed a synthesis method of api-
genin adducts with dibutylhydroxytoluene, without
affecting any pharmacological property (Sugiyama
and Kasamutsu 2015). A novel sustained apigenin
delivery system in the form of microsphere particles,
using poly-DL-lactic acid and soybean lecithin as
substrate materials, is claimed in the patent
CN103585113B (Wang et al. 2015a). Regarding to
the group of anthocyanidins, three anthocyanidins,
malvidin, petunidin and cyanidin, have been identified
in Hamelia (Forsyth and Simmonds 1954; Ronquillo
et al. 1988). In the medicine area, an anti-inflamma-
tory composition for treating arthritis, which contains
malvidin-3-O-b-glucoside and propolis has been
patented (Table 3, Renard et al. 2016). While a
composition containing a mixture of anthocyanins in
which the aglycones are petunidin, malvidin, del-
phinidin, cyanidin, peonidin and pelargonidin, work-
ing in synergistic form as antioxidant composition for
Phytochem Rev
treatment of vascular system has been claimed
(Slimestad 2005). It is also noteworthy that a method
for stimulating insulin secretion by anthocyanidins
and anthocyanins, such as petunidin, has been pub-
lished (Nair et al. 2011). Likewise, in order to improve
stability for storage and/or exposition to aqueous
environment of the anthocyanins malvidin and petu-
nidin, among others, two effective methods have been
developed by addition of glutathione (Eidenberger
2013) or by complexing with sulfobutyl ether b-
cyclodextrin (Roewer and Broscheit 2016). In the
veterinary field, a quick and simple method of
determining by color response the estrous cycle from
cattle, livestock or farm animals for breeding or
artificial insemination was developed. Different test
kits, which include the use of anthocyanin pigments
such as diglycosides of petunidin, malvidin, cyanidin,
hirsutidin and pelargonidin, are claimed (Goldman
2013). Chlorogenic acid was detected in H. patens
plants (Flores-Sanchez et al. 2016) among other
metabolites. This finding resulted of relevance in
connection with several patents developed for efficient
purification methods of this compound for pharma-
ceutical compositions (Table 3, Chen et al. 2014;
Sugiyama et al. 2015; Zhang et al. 2016a). In addition,
patents for stimulating the immune system (Graus
et al. 2007) or treat polycystic ovarian syndrome
(Schutz 2016) using high quality chlorogenic acid
were developed. On the other hand, patent
US8197875B2 claims the utilization of chlorogenic
acid in order to modify taste profiles of food products,
beverages and pharmaceuticals to decrease or remov-
ing bitterness (Chien et al. 2012). Some patented uses
of the phenylpropanoid rosmarinic acid are for the
treatment or prevention of liver or renal fibrosis (Qu
et al. 2010), of ciguatoxin poisoning (fish food
poisoning) (Laurent et al. 2015), and for skin, coat,
hair or health improvement (Crespy et al. 2016,
Table 3).
Patents for Hamelia plant varieties
Finally, a patented new cultivar denominated Grelm-
siz from H. patens has been developed. The plant has
dark and light yellow green variegated leaves and
orange red to red color flowers (Polanco 2015). In
general, most countries, except The United States,
exclude agriculture-related inventions from utility
patent protection, giving an alternative form of
intellectual property called Plant Breeder’s Rights.
The plant breeder’s rights or referred to as plant
variety protection provide protection against the
unauthorized use of the protected varieties (Brenner
1998).
Discussion and conclusions
There is a huge amount of patents inspired on different
aspects of specialized/secondary metabolism from the
genus Uncaria, which reflects the enormous invest-
ment in research and development, but much less from
the genus Hamelia. A general overview of patents
created for different aspects from these two genera is
presented in Fig. 4, which shows that although
Uncaria has a greater number of patents, the possibil-
ity that many of the compounds are present also in
Hamelia (Figs. 1, 3) enriches the accessibility for such
products, methods or applications. A few patent
applications were mentioned by their novelty; how-
ever, they are still waiting for being granted. Also, it
has been observed that many patents have been lapsed
because they failed to pay maintenance fees. It is
significant to mention that a patent can be reinstated
every time that is granted in a different country;
forming a patent family (Parisi et al. 2013). In this
review, as show in Supplementary Fig. 1a for the
genus Uncaria, industry had a 45% of patent produc-
tion, while universities and research institutes hold
35%. Besides, it was found that participation of
researchers as owners themselves was only 12%. Also,
it is remarkable that 6% of patent inventions belong to
governments. Furthermore, the contribution by coun-
try was as follows: China had 48%, followed by
United States (28%), South Korea (6.1%) and Japan
(4.4%). The rest of contributions were from Europe,
Australia, Canada, Mexico, Brazil, Lebanon, and
Taiwan (Supplementary Fig. 1b). Moreover, it was
found that only one patent (CA2392435C) was
developed by a contribution between a company and
academy, representing only 0.9% from the total of
patents (Table 2). However, only a few of them
become commercial products/processes. For example,
the patent EP1096943B1 (Pero 2004) became into the
commercial product C-Med-100Ò. Although U.
tomentosa has been marketed worldwide in different
presentations, such as extracts, capsules or pills (these
last ones containing powdered stem or root bark), the
123

assessment report from European Medicines Agency
(2015) indicated that it is difficult to draw a clear
conclusion from documented scientific evidence from
in vitro studies and to lesser extent in animal studies,
about the medicinal uses of U. tomentosa, including
C-Med-100Ò. However, in Spain and Hungary, prod-
ucts containing U. tomentosa have been accepted and
used traditionally for medicinal purposes. Neverthe-
less, it is not possible to determine the success or
failure of a patent. In the case of Hamelia, it was found
that industry had a 67% of participation on patent
production, followed by 23% from academy and 10%
from researchers as owners themselves. Contrary to
the government participation in patent development in
the genus Uncaria, no participation from any govern-
ment was found in the genus Hamelia (Supplementary
Fig. 2a). The contribution by countries was as follows:
China and United States had a higher participation,
with 25% and 21.9%, respectively; followed by France
(12.5%), Germany (9.4%), Japan (9.4%) and Switzer-
land (6.3%). The rest of contributions were for South
Korea, Taiwan, Croatia, Norway and French Polyne-
sia (Supplementary Fig. 2b). Furthermore, it was
observed that 13% from the total patent development
was by contributions between academy–company,
academy–academy, and company–company, or by
contributions between countries (Table 3). The per-
centage of contributions in the genus Hamelia was
higher than that of the genus Uncaria (0.9%). In
general, the main development of patents for alkaloids
in the genus Uncaria was focused on polyherbal or
polycomponent treatments for management of a great
variety of symptoms and diseases in traditional
medicine (46%), followed by applications on specific
medical treatment (20%), methods for alkaloid isola-
tion (7%), and plant extract production (7%) (Supple-
mentary Fig. 3). In the case of triterpenoids identified
in the genus Uncaria, the main developments of
patents were on synthetic methods for triterpenoid
derivatives (37%) and applications for specific med-
ical treatments (33%), followed by biotechnological
applications from triterpenoid synthase genes (9%)
and drug delivery systems (8%) (Supplementary
Fig. 4). Regarding flavonoids and quinic acid, both
of them identified in Uncaria plant material, the main
patent production was focused on their application on
medical treatments (75%), followed by manufacture
of plant extracts enriched on these metabolites (9%),
methods for compound isolation (8%) and medical
123
Phytochem Rev
application of the cyclitol (8%) (Supplementary
Fig. 5). On the other hand, the patent production in
the genus Hamelia was focused on different applica-
tions of the phenylpropanoid chlorogenic acid (30%),
followed by the specialized metabolite groups of
flavones (24%) and anthocyanidins (20%) (Supple-
mentary Fig. 6). Synthetic methods for triterpenoid
derivatives and different applications for flavanones
had similar contribution of 7%, each. Up to date, there
is one patent (US8652534B2) about production and
medical uses of Hamelia plant extracts (Table 3); this
patent has also been published as US9345736B2
(Berry 2016a) and US9345737B2 (Berry 2016b). In
the same way, there is only one patent for a new
variety or cultivar from the genus Hamelia
(USPP26247P2). There is an enormous potential in
the ornamental field for the development of new
Hamelia varieties, as well as for research and devel-
opment on medicine field from MIAs, MOAs and
other specialized/secondary metabolites of this plant
genus, but also for the genus Uncaria. A large amount
of patent applications are waiting to be granted every
day. Some examples for the genus Uncaria are the
patent applications for in vitro methods of Uncaria
seed germination (Yang et al. 2015) and Uncaria
explant culture (Wei et al. 2015). Also, a method for
Uncaria planting for easy plant harvest (Qui 2015a),
and Uncaria cutter/shearing machines (Qui 2015b, c).
There are applications for Uncaria alkaloid composi-
tions for treatment of prostatic hyperplasia (Wang
et al. 2015b) and the use of Uncaria phenolic extracts
(Monagas et al. 2014), among others.
In conclusion, the specialized/secondary metabo-
lism of plants from the genera Uncaria and Hamelia
have stimulated research and development of medica-
ments, drug delivery systems, equipment, machines,
industrial processes, and plant culture techniques, in
order to be able to access their important metabolites,
such as MIAs, MOAs, triterpenoids and flavonoids.
Since several species of Uncaria and Hamelia have a
broad potential to become economically important
crops, this review with the state-of-the-art about
patents on these members of the Rubiaceae family,
can be a valuable source of organized information for
those researchers developing projects in many aspects
related to these two plant genera.
Acknowledgements I.J.F.S. received a postdoctoral
fellowship from CONACYT (Mexico). We thank to
Phytochem Rev
Prof.em.dr. Robert Verpoorte (IBL, Leiden University, The
Netherlands) and Dr. Carlos M. Cerda-Garcı́a-Rojas
(Department of Chemistry, Cinvestav-IPN, Mexico) for their
helpful suggestions and discussions.
References
Ahn SY, Ban JG, Choi HI et al (2003) Usage as HCV NS3/NS4
protease inhibitor of 5-membered fused aromatic hetero-
cyclic compound. KR Patent 100392292B1
Alexandrov N, Brover V, Feldmann K (2014) Nucleic acid
sequences encoding strictosidine synthase. US Patent
8710201B2
Ali-Sayed M, Jantan I, Vijayaraghavan K et al (2016) Betulinic
acid: recent advances in chemical modifications, effective
delivery, and molecular mechanisms of a promising anti-
cancer therapy. Chem Biol Drug Res 87:517–536
Anderson E, Jiang X, Liu X et al (2015) Antioxidant inflam-
mation modulators: oleanolic acid derivatives with satu-
ration in the C-ring. US Patent 9090574B2
Awano I, Takihara T, Araki Y et al (2013) Carbonated beverage
packed in container and manufacturing method therefor. JP
Patent 5311357B1
Babish JG, Howell T, Pacioretty L (2003) Combinations of
diterpene triepoxide lactones and diterpene lactones or
triterpenes for synergistic inhibition of cyclooxygenase-2.
US Patent 6629835B2
Bai K, Guo Y, Zheng Y (2012) Ursolic acid derivative
chemically modified by polyethylene glycol and prepa-
ration method of ursolic acid derivative. CN Patent
102329362B
Bednarczyk-Cwynar B, Zaprutko L, Atamanyuk D et al (2014)
New O-acylated oximes of oleanolic acid derivatives and
process for the preparation of acylated oximes derivatives
of oleanolic acid. PL Patent 217864B1
Beindorff C, Cain FW, Pierce JH et al (2006) Blends of ursolic
acid/oleanolic acid. DE Patent 60114708B1
Berry DW (2014) Compositions and methods for treatment of
mammalian skin. US Patent 8652534B2
Berry DW (2016a) Topical treatment of radiation dermatitis
using Hamelia patens. US Patent 9345736B2
Berry DW (2016b) Topical treatment of keratotic lesions using
Hamelia patens. US Patent 9345737B2
Bobrowski PJ (2004) Methods and preparations of extracts of
Uncaria species with reduced alkaloid content. US Patent
6797286B2
Bomshteyn AL, Rathnam P, Saxena BB (2005) Betulinol
derivatives. US Patent 6890533B2
Bremer BA (2009) A review of molecular phylogenetic studies
of Rubiaceae 1. Ann Mo Bot Gard 96:4–26
Brenner C (1998) Intellectual property rights and technology
transfer in developing country agriculture: rhetoric and
reality. Working paper 133, OECD, Paris, pp 1–53
Cain FW, Stam W, Schmid U et al. (2008) Use of compositions
comprising oleanic acid and ursolic acid for the preparation
of a medicament for the treatment of hypersensitivity and
hyperreactivity. E Patent 1694320B1
Castillo GM, Snow AD (2010) Composition and methods for
treating Alzheimer’s disease and other amyloidosis. US
Patent 7754250B2
Castillo G, Choi PY, Nguyen B et al (2013) Methods of isolating
amyloid-inhibiting compounds and use of compounds
isolated from Uncaria tomentosa and related plants. CA
Patent 2427661C
Cepanee I, Knezevic Z (2015) Probiotic formulation with api-
genin and peppermint extract, HR Patent K20130487B3
Chang TS, Ding HY (2015) Method of manufacturing 6-hy-
droxyapigenin by biotransformation. TW Patent I507527B
Chen R (2016) Preparation method of shrimp shell cold noodles.
CN Patent 10341760B
Chen Y, Zhu Y, Zhu Y (2012) Uncaria extract and application
thereof in preparing medicines for reducing blood fat and
resisting cardiac hypertrophy. CN Patent 101791342B,
Chen Q, Liu J, Fu M et al (2013) Method for synthesizing
betulinic acid by catalyzing botulin with laccase. CN
Patent 102226213B
Chen D, Li X, Ji X et al (2014) Method for preparing chloro-
genic acid by freezing, concentrating and crystallizing. CN
Patent 102476997B
Cheng K, Liang H, Su C et al (2015) Oleanolic acid-pyrimide
conjugate as well as preparation method and application
thereof. CN103864882B
Cheng K, Liang H, Su C et al (2016) Oleanolic acid-uridine
conjugate as well as preparation method and application
thereof. CN103864881B
Chien M, Hausler A, van Leersum H (2012) Taste modifiers
comprising a chlorogenic acid. US Patent 8197875B2
Choi IW, Park YK, Kim YS et al (2013) Composition for pre-
venting and treating alcoholic liver disease comprising
flavonoid. KR Patent 101268325B1
Chun HK, Park TH, Choung DH et al (2014a) Ursolic acid
having anti-bacterial activity against causative bacteria of
porcine respiratory disease complex and uses thereof. KR
Patent 101478110B1
Chun HK, Park TH, Choung DH (2014b) Oleanolic acid having
antibacterial activity against causative bacteria of porcine
respiratory disease complex and uses thereof. KR Patent
101478109B1
Cook-Deegan R, Niehaus A (2014) After myriad: genetic testing
in the wake of recent Supreme Court decisions about gene
patents. Curr Genet Med Rep 2:223–241
Crespy V, Castiel I, Bel-Rhlid R et al (2016) Biological effects
of compositions of rosmarinic acid. US Patent 9314490B2
Croat TB (1978) Flora of Barro Colorado Island. Standford
University Press, USA, pp 809–810
Du Z, Tao Y (2015) Natural drug composition for curing
rheumatism bone diseases and preparation method thereof.
CN 104096221B
Duan D, Ren J, Yang Z et al (2011) Uncaria alkaloid monomer
as well as preparation method and application thereof. CN
Patent 101798306B
Duke JA (2002) Handbook of medicinal herbs, 2nd edn, CRC
Press LLC, USA p 615-616
Eidenberger T (2013) Stabilized anthocyanin compositions.
US8449927B2
El Khatib N, El Kettany S (2015) Plant composition for the
treatment or prevention of viral blood-borne diseases
123

caused by the human immunodeficiency virus (HIV) or
hepatitis C. E Patent 2416794B1
Elias TS, Pooler MR (2004) The identity of the African firebush
(Hamelia) in the ornamental nursery trade. HortoScience
39:1224–1226
European Medicines Agency (2015) Assessment report on Un-
caria tomentosa (Wild. ex Schult.) DC., cortex. Committee
on Herbal Medicinal Product, United Kingdom, pp 1-78
Fan Q (2015) Pressure reduction milk tea and preparation
method thereof. CN Patent 103385301B
Flores-Sanchez IJ, Ortega-Lopez M-HM et al (2002) Biosyn-
thesis of sterols and triterpenes in cell suspension cultures
of U. tomentosa. Plant Cell Physiol 43:1502–1509
Flores-Sanchez IJ, Paniagua-Vega D, Vera-Reyes I et al (2016)
Alkaloid biosynthesis and metabolic profiling responses to
jasmonic acid elicitation in Hamelia patens by NMR-based
metabolomics. Metabolomics 12:66
Forsyth WGC, Simmonds NW (1954) A survey of the antho-
cyanins of some tropical plants. Proc R Soc Lond B Biol
Sci 142:549–564
Gao X, Dong X, Liu Z et al (2011) Capsule containing hooked
Uncaria and Gastrodia. CN Patent 101411852B
Gao Y, Li Z, Wang C et al (2016) Folic acid-polyamide
polyamidoamine (PAMAM)-ursolic acid nanodrug with
tumor targeting and preparation method of drug. CN Patent
103990145B
Geisler K, Hughes RK, Sainsbury F et al (2013) Biochemical
analysis of a multifunctional cytochrome P450 (CYP51)
enzyme required for synthesis of antimicrobial triterpenes
in plants. Proc Natl Acad Sci USA 110:E3360–E3367
Giampapa VC (2015a) Supplement composition for supporting
DNA repair and method of use. US Patent 8968801B1
Giampapa VC (2015b) Dietary supplement system for multi-
functional anti-aging management and method of use. US
Patent 8974839B2
Glinski J, Branly KL (2002) Pentacyclic triterpenes. US Patent
6433010B2
Goldman D (2013) Estrous cycle monitoring by color response.
US Patent 8420398B2
Graus YMF, Smit HF, Osterhaus ADME, Hageman RJJ (2007)
Chlorogenic acid and analog thereof for immune system
stimulation. US Patent 7288271B2
Gribble GW, Honda T, Sporn MB et al (2016) Therapeutic
compounds and methods of use. US Patent 9278913B2
Hashimoto A (2013) Method for producing highly active POA.
JP Patent 5334508B2
Hatinguais P, Cousse H, Vilain P (1983) Derivatives of
tetrahydroalstonine, their preparation and their application
as medicaments. E Patent 0017525B1
Hayashi S, Yoshida A, Kametaka S et al (1988) Composition for
oral cavity application. JP Patent S6326083B2
Hayes E, Zolotoy A (2010) Compositions to reduce blood glu-
cose levels and treat diabetes. E Patent 1996176B1
He Y, Nan M, Zhao Q et al (2012) Amino acid derivatives of
rotundic acid and application of derivatives in preparation
of antitumor medicines. CN Patent 102391352B
Hefferon K (2010) Plant biotechnology patents; applications in
agriculture and medicine. Recent Pat Biotechnol
4:136–152
Hefferon K (2015a) Agricultural biotechnology. In: Rapley R,
Whitehouse D (eds) Molecular biology and biotechnology,
123
Phytochem Rev
6th edn. The Royal Society of Chemistry, Cambridge,
pp 483–507
Hefferon KL (2015b) Nutritionally enhanced food crops; pro-
gress and perspectives. Int J Mol Sci 16:3895–3914
Heitzman ME, Neto CC, Winiarz E et al (2005) Ethnobotany,
phytochemistry and pharmacology of Uncaria (Rubi-
aceae). Phytochemistry 66:5–29
Herrera JL, Perez BEG, Lopez MLD et al (2013) Vaccine
adjuvant composition based on ursolic acid.
MX2012006516A
Heuer MA, Clement K (2011) Compositions and methods for
increasing adipose metabolism, lipolysis or lipolytic
metabolism via thermogenesis. US Patent 7955624B2
Huang H, Zhong R, Jia X et al (2012) Uncaria-containing
composition with anti-aging function. CN Patent
102078507B
Huang L, Li J, Ye H et al (2012b) Molecular characterization of
the pentacyclic triterpenoid biosynthetic pathway in
Catharanthus roseus. Planta 236:1571–1581
Huang W, Li J, Zhou F (2012) Uncaria sustained-release tablet
and preparation method thereof. CN Patent 101862304B
Huang W, Li J, Zhou F (2015) Uncaria slow release capsule
preparation and preparation method. CN Patent
101869556B
Huang W, Ma J, Zhou F (2016) Method for preparing Eucommia
ulmoides step-down oral presentation. CN Patent
103610795B
Jia Q, Zhao Y (2015) Formulation of dual eicosanoid system and
cytokine system inhibitors for use in the prevention or
treatment of oral diseases and conditions. US Patent
8945518B2
Jiang R (2016) Powder for treating convulsion. CN Patent
103446458B
Jiang BH, Fang J (2013) Apigenin for chemoprevention, and
chemotherapy combined with therapeutic reagents. US
Patent 8377918B2
Jiang X, Bender CF, Visnick M (2016a) C13-hydroxy deriva-
tives of oleanolic acid and methods of use thereof. US
Patent 9278912B2
Jiang X, Liu X, Greiner J et al (2016b) Antioxidant inflamma-
tion modulators: C-17 homologated oleanolic acid
derivatives. US Patent 9249089B2
Kaiser S, Verza SG, Moraes RC (2013) Cat’s claw oxindole
alkaloid isomerization induced by common extraction
methods. Quim Nova 36:808–814
Kano Y, Wu C, Ma B et al (2013) Method for extracting alkaloid
valid parts from hooked Uncaria leaf, with hooked stem
branch or full grass and uses thereof. CN Patent
101342259B
Kawabata J, Mizuhata K, Sato E et al (2003) 6-hydrox-
yflavonoids as a-glucosidase inhibitors from Marjoram
(Origanum majorana) leaves. Biosci Biotechnol Biochem
67:445–447
Keplinger K, Wagner H, Kreutzkamp B (1990) Oxindole alka-
loids having properties stimulating the immunologic sys-
tem and preparation containing the same. US Patent
4940725A
Keplinger D, Keplinger K, Laus G (2001) Process for isomer-
ization of spirocyclic compounds with b-aminocarboxyl
and/or b-aminocarbonyl systems. E Patent 0741727B1
Phytochem Rev
Keplinger K, Laus G, Wurm M (2010) Method and substances
for releasing a growth factor from endothelial cells, growth
factor released in accordance with said method and use of
same. E Patent 0989856B1
Kim BC, Jo EJ, Kim SJ (2015a) A novel composition for sup-
pressing metastasis of cancer. KR Patent 101505175B1
Kim YH, Kim HC, Nam KH et al (2015b) An insecticide
comprising ursolic acid. KR Patent 101542843B1
Klopotenko LL (2014) Ointment containing encapsulated
triterpenic acid or derivatives thereof. RU Patent
2519133C1
Krasutsky PA, Carlson RM, Karim R (2004) Triterpenes having
antibacterial activity. US Patent 6689767B2
Laurent D, Pauilac S, Chinain M et al (2015) Use of rosmarinic
acid and the derivatives thereof to treat ciguatera. US
Patent 9060985B2
Laus G (2004) Advances in chemistry and bioactivity of the
genus Uncaria. Phytother Res 18:259–274
Lee JJ, Takei M, Akemi U et al (2010) Dendritic cells matured
by uncarinic acid C, compositions for immunotheraphy
containing the dendritic cells, and methods for preparing
mature dendritic cells using uncarinic acid C. KR Patent
100954887B1
Lee LT, Chang SF, Kuo ZK et al (2016) Pharmaceutical com-
position and method for preventing or treating hepatitis C.
US Patent 9289443B2
Li J (2015) Tryptophan hydroxylase-1 inhibitor ursolic acid
derivatives as well as preparation method and application
thereof. CN Patent 103936814B
Li Y (2016) Novel technology for preparing apigenin from by
one-step method. CN Patent 103819438B
Li X, Li Y, Lu X et al (2013) Preparation method of ursolic acid
as immunologic adjuvant vaccine and use.
CN103251944A
Li C, Zhang G, Zhou X (2015) Method for producing b-amyrin
with Saccharomyces cerevisiae engineering bacterium. CN
Patent 103509726B
Liao Y (2004) Complex fertilizer for killing insect and bacteria
and its production method. CN Patent 1182083C
Lines TC (2013) Method for treating addiction using quercetin-
containing compositions. US Patent 8507548B2
Liu Y, Liu D, Xie X et al (2014) Piperazine derivative of
oleanolic acid, preparation method and application of
piperazine derivative. CN 102875630B
Lv Y (2014) Liver-clearing and lung-nourishing health-care tea.
CN 103392886B
Manns U, Bremer B (2010) Towards a better understanding of
intertribal relationships and stable tribal delimitations
within Cinchonoideae s.s. (Rubiaceae). Mol Phylogenet
Evol 56:21–39
Martinez JA, Durand E, Viamontes AJ et al (1996) Alkaloids of
Hamelia patens growing in Cuba. Rev Cubana Quim
8:75–79
Martins D, Nunez CV (2015) Secondary metabolites from
Rubiaceae species. Molecules 20:13422–13495
Maslov LI, Borodulin VV (2015) Agent and method of treating
diabetes mellitus. RU patent 2545765C1
Mermelstein H, Marchese FP (2005) Composition and method
for treatment of vaginal dryness. US Patent 6893648B2
Minami K, Taniwaki S, Katsumata A (2016) Rutin-rich extract
and method of making same. US Patent 9308216B2
Mo Z, Weng J (2012) Use of hirsutine in preparing anti-addic-
tive drug. CN Patent 101972251B
Mo Z, Weng J, Cai H et al (2012) Drug for preventing and curing
dependence of amphetamine and opiate drugs. CN Patent
102008577B
Monagas JM, Sanchez FP, Quintanilla JEL et al (2014) Phenolic
extracts from Uncaria tomentosa L. (cat’s claw) containing
procyanidins, propelargonidins and flavonolignans,
method for the production thereof. WO2014096488A1
Nair MG, Jayaprakasam B, Olson LK et al (2011) Insulin
secretion by anthocyanins and anthocyanidins. CA Patent
2573510C
Olalde JAR (2008a) Arthritis phyto-nutraceutical synergistic
composition. US Patent 7416748B2
Olalde JAR (2008b) Multiple sclerosis synergistic phyto-nu-
traceutical composition. US Patent 7390512B2
Onoue S, Yamada S, Chan HK (2014) Nanodrugs: pharma-
cokinetics and safety. Int J Nanomedicine 9:1025–1037
Osbourn A, Qi X (2014) Enzymes involved in triterpene syn-
thesis. US Patent 8647875B2
Osbourn AE, Haralampidis K, Bryan GT (2011) An isolated
plant gene encoding a b-amyrin synthase. CA Patent
2392435C
Parisi C, Rodriguez-Cerezo E, Thangaraj H (2013) Analysing
patent landscapes in plant biotechnology and new plant
breeding techniques. Transgenic Res 22:15–29
Pero RW (2004) Method of preparation and pharmaceutical
composition of an Uncaria water-soluble extract. E Patent
1096943B1
Pero RW (2013) Method for enhancing the DNA repair process,
treating disorders associated with the DNA repair process,
enhancing anti-tumor response and treating disorders
associated with anti-tumor response in mammals by
administering purified quinic acid and/or carboxyl alkyl
ester. US Patent 8372449B2
Perrier E, Rival D, Lamy V (2014) Method for testing a sub-
stance which is potentially active in the field of lipolysis
and its mainly cosmetic use. US Patent 8741359B2
Poignant JC (1979) Pharmaceutical compositions containing
tetrahydroalstonine and method for treating circulation
disorders. DE Patent 2439523C2
Polanco MA (2015) Hamelia plant named ‘Grelmsiz’. US Patent
PP26247P2
Qi W, Yue SJ, Sun JH et al (2014) Alkaloids from the hook-
bearing branch of Uncaria rhynchophylla and their neu-
roprotective effects against glutamate-induced HT22 cell
death. J Asian Nat Prod Res 16:876–883
Qu G, Tian J, Jian W (2010) Application of rosmarinic acid
in the preparation of medicines for treating or preventing
liver fibrosis and kidney fibrosis. CN Patent 1010956
68B
Qui Y (2015a) Uncaria planting method. CN105027932A
Qui Y (2015b) Uncaria shearing machine. CN105171862A
Qui Y (2015c) Uncaria cutter. CN105034047A
Renard L, Massalyai DM, Merillon JM (2016) Anti-inflamma-
tory composition comprising malvidin-3-O-b-glucoside
and a propolis extract. US Patent 9308231B2
Reyes-Chilpa R, Rivera J, Oropeza M et al (2004) Methanol
extracts of Hamelia patens containing oxindole alkaloids
relax KCl-induced contraction in rat myometrium. Biol
Pharm Bull 27:1617–1620
123

Ridsdale CE (1978) A revision of Mitragyna and Uncaria
(Rubiaceae). Blumea 24:43–100
Rios MY, Aguilar-Guadarrama AB (2006) Alcaloides indolicos,
terpenos, esteroles y flavonoides de las hojas de Hamelia
patens Jacquin (Rubiaceae). Rev Cubana Plant Med 11:1–5
Robbrecht E (1988) Tropical woody Rubiaceae. Oper Bot Belg
1:599–602
Roewer N, Broscheit J (2016) Anthocyanidin complex. E Patent
2831122B1
Rong F, Xu R, Xie F et al (2015) Oleanolic acid amidate
derivatives, preparation methods and uses thereof. US
Patent 8987502B2
Ronquillo FA, Melgar MF, Carrillo JE et al (1988) Especies
vegetales de uso actual y potencial en alimentación y
medicina de las zonas semiáridas del nororiente de Gua-
temala. Cuadernos DIGI 159:7–88
Salbury Jr FR, Scorpinato KD, King SB (2013) Chemothera-
peutic for inducing an MSH2-dependent apoptotic path-
way. US Patent 8486957B2
Saxena BB, Rathnam P (2011) Betulinol derivatives as anti-HIV
agents. US Patent 8008280B2
Saxena BB, Rathnam P (2012) Betulinol derivatives as anti-
cancer agents. US Patent 8088757B2
Schutz J (2016) Methods of treating polycystic ovarian syn-
drome using chlorogenic acid and inositol. US Patent
9259410B2
Shao J, Xiang L, Yang X et al (2016) Applications of ursolic
acid derivatives in preparation of drug for preventing and
treating tumor metastasis. CN Patent 103933048B
Slimestad R (2005) Product. US Patent 6967032B2
Snow AD, Castillo GM, Choi PY et al (2011) Proanthocyanidins
for the treatment of amyloid and a-synuclein diseases. CA
Patent 2441099C
Stöckigt J, Barleben L, Panjikar S (2008) 3D-structure and
function of strictosidine synthase—the key enzyme of
monoterpenoid indole alkaloid biosynthesis. Plant Physiol
Biochem 46:340–355
Su F (2012) Medicament for preventing and treating ischemic
cerebrovascular diseases. CN Patent 102049010B
Suarez AI, Diaz B, Tillet S et al (2008) Leishmanicidal activity
of alkaloids from Hamelia patens. Ciencia 16:148–155
Sugiyama M, Kasamutsu S (2015) Apigenin-containing com-
position. US Patent 9056209B2
Sugiyama Y, Yamawaki K, Kubo Y (2015) Process for pro-
duction of purified chlorogenic acid-containing pharma-
ceutical preparation. E Patent 2592064B1
Sun Y, Yu H, Zhang Y (2012) Uncaria abalone sour soup for
treating trigeminal neuralgia. CN Patent 102091239B
Taal L (2012) Botanical extract composition. E Patent
1720561B1
Tang J, Liu M, Zhou S et al (2012) Process for extracting
rhynchophylline monomers from Uncaria rhynchophylla.
CN Patent 102093359B
Tang J, Shen Y, Liu S et al (2014) Liver-targeted magnetic
resonance imaging contrast agent based on oleanolic acid
and preparation method thereof. CN Patent 102895678B
The Plant List (2016) Version 1.1. Published on the internet.
http://www.theplantlist.org/. Accessed 4 May 2016
Thimmappa R, Geisler K, Louveau T et al (2014) Triterpene
biosynthesis in plants. Ann Rev Plant Biol 65:225–257
123
Phytochem Rev
Tong X (2015) Traditional Chinese medicine composition for
preventing and treating obese type 2 diabetes combined
dyslipidemia. CN Patent 103417950B
Trentini AMM (2015) Hydroalcoholic extract of Uncaria
tomentosa for the treatment of herpes virus infection.
E Patent 1786446B1
Vajdy M, Padrah S (2015) Adjuvant compositions and method
of use. US Patent 9180184B2
Velazquez T, Ornelas JF (2010) Pollen consumption by flower
mites in three hummingbird-pollinated plant species. Exp
Appl Acarol 50:97–105
Villarreal F, Yamazake KG, Taub PR et al (2014) Adverse
cardiac remodeling. US Patent 8648059B2
Wang X, Hai C (2015a) Medicinal composition, and its
application in preparation of medicines for treating
obesity, insulin resistance and diabetes. CN Patent
103585161B
Wang X, Hai C (2015b) Medicinal composition and its appli-
cation in preparation of liver cancer treatment medicines.
CN Patent 103585158B
Wang H, Wang X (2014) Plaster for treating lumbar disc her-
niation. CN Patent 102824484B
Wang B, Guo Z, Ye Z et al (2008) Chinese preparation for
treating enteritis ulcer colitis and preparation method
thereof. US Patent 7354570B2
Wang H, Niu B, Yan H et al (2015a) Apigenin polylactic sus-
tained release microsphere and preparation method thereof.
CN Patent 103585113B
Wang S, He J, Li T et al (2015b) Application of Uncaria active
alkaloid to preparation of prostatic medicament.
CN105012441A
Wei S, Ma X, Pan L et al (2015) Rapid propagation method of
Uncaria macrophylla Wall. CN105028202A
Whitehead SR, Poveda K (2011) Herbivore-induced changes in
fruit-frugivore interactions. J Ecol 99:964–969
Wu X (2015) Five-vegetable blood pressure-reducing sweet rice
flour and production method thereof. CN Patent
103461802B
Xiao W, Wang Z, Meng Z et al (2015) Vincoside lactam
preparation method. CN Patent 102786568B
Xu R, Rong F, Lai H (2015) 2-substituted oleanolic acid
derivative, method preparing for same, and application
thereof. US Patent 9156801B2
Xue Z, Qi X, Sun J et al (2014) Optimized triterpenoid synthase
coding gene and application thereof. CN Patent
103088042B
Yamaji H (2013) Method of identifying the species of plant
belonging to the genus Uncaria. CN Patent 101772579B
Yamaki K, Sano T, Hori K et al (2005) External skin care
application. US Patent 6878378B1
Yan X (2012) Novel pharmaceutical use of kaempferol. CN
Patent 101889999B
Yan X, Wang Y, Ding W et al (2013) A method for producing
betulinic acid. CA Patent 2705902C
Yan S, Wang Y, Bao H et al (2015) Traditional Chinese medi-
cine for treating thyroid associated ophthalmopathy in
acute stage. CN Patent 103446543B
Yang X, Zhou J, Yu Z et al (2011) Method for extracting and
preparing ursolic acid from Uncaria. CN Patent
101643492B
Phytochem Rev
Yang Q, Huo K, Zhang C et al (2015) Method for shortening
seedling raising time limit of Uncaria rhynchophylla seeds.
CN104996138A
Yao T, Zhu Y, Zhu Y (2010) Gambir plant extract and its use in
preparation of target organ protective medicine. CN Patent
1939453B
Yao J, Li Y, Zhou J (2016) Preparation of amphiphilic ursolic
acid-polysaccharide coupled substance and application
thereof in treating tumors. CN Patent 103705939B
Yoon YH (2015) Ursolic acid derivative and methods for
preparing same. US Patent 9120839B2
Zachwieja JJ, Pirner MA, Smith JE (2015) Methods of reducing
blood lactate concentration. US Patent 9198453B2
Zeng C, Huang Y, Chen Q (2015) HPLC method for distin-
guishing different varieties of Uncaria. CN Patent
103869010B
Zhang L (2015) Stem and hook separation device for Uncaria.
CN Patent 204134889U
Zhang J, Zhao H, Zheng L (2014) Oleanolic acid oxime ester
derivative, preparation method and application thereof. CN
Patent 102690315B
Zhang Q, Zhao JJ, Xu J et al (2015) Medicinal uses, phyto-
chemistry and pharmacology of the genus Uncaria.
J Ethnopharmacol 173:48–80
Zhang J, Zhang L, Huang W (2016a) Preparation method of
medicinal chlorogenic acid. CN Patent 104496815B
Zhang K, He Ping, Zhao S et al (2016b) Novel use of ursolic acid
derivative. CN 103877097B
Zhao L (2014) Medicine composition containing apigenin,
apigenin derivant and Bc1-2 inhibitor and application
thereof in preparation of medicines capable of treating
cancer. CN Patent 102441168B
Zhao Y, Jia Q (2013) Flavonoid composition for treating oral
diseases. CN Patent 101083981B
Zhao Q, He Y, Nan M et al (2012) Rotundic acid derivative and
synthesis method thereof as well as application of rotundic
acid derivative in preparing medicament for preventing and
curing cardiovascular disease. CN Patent 102140126B
Zhao S, Wu P, Zhang K et al (2016) Chemically modified ursolic
acid and its preparation method and use. CN Patent
104045678B
Zhou Y, Zhou S, Mo Z et al (2016) Application of rhyn-
chophylline in preparation of drug with anxiolytic effect
and antidepressant effect. CN Patent 103446140B
Zhu Y, Wu L, Zhu Y (2011a) Application of hirsutine in
preparing medicament for treating myocardial damage. CN
Patent 101683338B
Zhu Y, Wu L, Zhu Y (2011b) Application of corynantheine in
preparing medicament for treating heart disease induced by
myocardial damage. CN Patent 101683337B
Zou H, Zhu H, Stöckigt J et al (2014) Strictosidine-like alkaloids
as well as preparation method and application thereof. CN
Patent 102532218B
123