IIPTA...A SWOT analsysis on BN technology is carried out. Allergan Inc., Merz Pharma and Galderma are indicated as the key-players in BN market and a competitive analysis is performed

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Patent Landscape onBotulinum Neuromodulator

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IIPTALaunch a Career. Be Awesome

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In order to investigate the recent drift of innovation on botulinum neuromodulator (BN), a technology landscape is performed. The structure

of botulinum toxin along with formulation, mechanism of actions, applications are discussed in the literature review. The keywords such as “botulinum”, “botulinum production”, “botulinum formulation”, “fermentation”, “botulinum delivery”, “botox” are primarily used to find out the patents from most commonly used databases such as USPTO, WIPO, EPO, PatentLens, IPO. Also the patents on the applications of botulinum are retrieved by using the keywords such as “hair”, “teeth”, “skin”, dystonia”, “blepharospasm”, “parkinson’s disease” in the same databases. Altogether, 223 relevant patents are retrieved and analyzed. The maximum number of fillings and publications were recorded in 2005 and a good correlation (r= 0.69) between priority year and publication year was observed. Patria Walker is known as the leading inventor followed by Gary Borodic, Aoki Roger, Elizabeth Moyer, Andrew Blumenfeld and Micheal Dake. Maximum patents are owned by the industrial organizations (84%) such as Allergan Inc., Merz Pharma, Galderma (a subsidiary of Q-Med) apart from the individual investors (11%), research unit (4%) and government body (1%), respectively. The United States

of America is known as the leading place of first filling of invention although this country is not specialized for BN technology. Japan is indicated as a specialized country for said technology through relative specialization index calculation. Allergan Inc. is found as the most frequent applicant, respectively among the top 10 patent families. A61k is the predominant international classification code (IPC) in the said field with low occurrence of C07K, C12N, A01N, and A61M. Most of the researches on botulinum product target the cosmetic application (24%) followed by reduction of muscle pain, treatment of dystonia, cerebral pulsy and blepharospam.. A SWOT analsysis on BN technology is carried out. Allergan Inc., Merz Pharma and Galderma are indicated as the key-players in BN market and a competitive analysis is performed among them. After the preliminary landscape, a “White Gap” analysis is carried out to find out the problerms associated with BN arena which are needed to be solved in future.

Keywords: botulinum, botulinum neuromodulator (BN), patent, invention, international patent classification (IPC), place of first filling, priority year, publication year, assignee, inventor, patent family, relative specialization index (RSI), SWOT, competitive intelligence, white gap.

Abstract

Patent Landscape on Botulinum Neuromodulator

1

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Chapter 1: Introduction ...................................................................................

Chapter 2: Literature review ............................................................................

• 2.1 Introduction on Botulinum neurotoxin ...................................

• 2.2 Structure of Botulinum neurotoxin ..........................................

• 2.3 Mechanism of action ..................................................................

• 2.4 Types .............................................................................................

• 2.5 Production ...................................................................................

• 2.6 Application ..................................................................................

Chapter 3: Methodology ....................................................................................

Chapter 4: Results and statistical analysis ........................................................

Chapter 5: SWOT analysis .................................................................................

Chapter 6: Competitive Intelligence .................................................................

Chapter 7: White Gap Analysis .........................................................................

Chapter 8: Standard botulinum products ........................................................

Chapter 9: Discussion .........................................................................................

References .............................................................................................................

Appendix ...............................................................................................................

TOPIC

TABLE OF CONTENTS

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Not only in America, botulinum neurotoxin has also leaded the European market4. Almost more than 1.5 million botulinum injections were used in Europe- a double digit increment with respect to 20114. The popularity of botulinum neurotoxin can not be evaluated with respect to the European or Asian markets as rare information on the Asian botulinum case studies are available.

However a study mentioned about the application of botulinum neurotoxin in 20 Asian patients in massester reduction5. So, observing the demand, a technology landscape is planned to perform which covers the detailed information on botulinum neurotoxin, methods of analysis, results and the recent information.

Medical Aesthetic is an approach in order to beautify the body with the help of medical knowledge through surgical or non-surgical procedure. The surgical procedure covers breast augmentation, liposuction, rhinoplasty, blepharoplasty, abdominoplasty1 whereas non-surgical approach includes microdermabarasion, chemical peel, and the application of dermal filler, botulinum neurotoxin and external emitting energy

devices1. According to a study (2008), patients usually preferred non-surgical procedure over surgical procedure as the patients were concerned about the risk of procedures and complications2. Another study (2012) conducted by the American Society of Aesthetic Plastic surgery, indicated botulinum neurotoxin technology as foremost medical aesthetic procedure among five non-surgical aspects3.

Chapter 1Introduction


Figure 1: top five non-surgical cases. Data collected fromhttp://www.surgery.org/sites/default/files/2012-p5.pdf

3

Number of American cases, 2012

0 500000 1000000 1500000 2000000 2500000 3000000 3500000

Botulinum neurotoxin

Microdermaabrasion

Chemical peel

Laser hair removal

Dermal filler

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2.1 Introduction

Botulinum neurotoxin (or toxin or modulator) is a protein and produced by bacterium Clostridium botulinum6. Although it was first recognized and isolated by Emile van Ermenge in 18857, the therapeutic use of

boulinum toxin was discovered by a physicist Krener in 18978.

Clostridium botulinum6 is an anaerobic, gram positive, rod shaped bacterium that produces several toxins6. Clostridium botulinum6 tolerates trace of oxygen due to enzyme superoxide dismutase which is an important antioxidant6.

2.2 Structure

The BN molecule consists of a sequence of ~1,300 amino acids - nearly 21,000 atoms9. They can be found as a single-chain polypeptide, but they are not very toxic in single chain polypeptide form9; but it becomes more toxic in two chains (one

large chain and one small change bonded by di-sulphide bond) formation9. The single chain polypeptide is cleaved into larger chain connected to a smaller chain associated with a single zinc atom (di-sulphide bond) in the first step within bacteria9. Later the toxin is activated by the reduction of di-sulphide bond which occurs in the body during neuro-toxic mechanism9.

Chapter 2Literature review


Scientific classification. Available online http://microbewiki.kenyon.edu/index.php/Clostridium_botulinum_neu2011 Last Access 19th Nov., 2013

4

domainclassorderfamilygenus

species

bacteriaclostridia

clostridialesclostridiaceae

clostridumc.botulinium

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2.3 Mechanism of Action

The mechanism of action of BN includes four steps: binding, internalization, membrane translocation and enzymatic target modification10. The toxins bind to cholinergic nerve endings rapidly- the binding sites for BTX is the carboxy-terminal domain in heavy chain. BTX crosses the membrane by endocytosis. When internalized BTX within the neurons, the light chain crosses the hydrophobic vesicle membrane to reach cytosol which lowers the pH of BTX (4.4- 4.6). Low pH makes a conformational change of BTX- from water soluble neutral form to acid form10,11. This is followed by the penetration of heavy and light chain into lipid bilayer and an ion channel is formed in the bilayer. Three substrate proteins are identified10: vesicle associated membrane protein, synaptosomal associated protein, and syntaxin and these three proteins together form a complex: a soluble N-ethylamide sensitive fusion attachment protein receptor (SNARE). The generation of SNARE intervenes the fusion of neurotransmitter

containing vesicle with synaptic membrane which releases the neurotransmitter into the synapse. The destruction of protein of SNARE resists the release of acetyl-choline and co-transmitter from the nerve ending10,11

2.4 Types

BN is usually classified into 8 types of neurotoxins (labeled as types A, B, C [C1, C2], D, E, F, G and H)12,13. Neurotoxins “A” to “G” are antigenically and serologically different but structurally similar6,12. Human botulism is caused mainly by types A, B, E, and rarely F12. Clostridium baratii and Clostridium butyricum generate only serotype F and E, respectively6. Types C and D causes disease in animals6. Type G is produced by Clostridium argentinese6. Recently (2013), two scientists of Public Health discovered new member of botulinum toxin (H) from a baby suffered from botulism13. According to the scientists, one would die by inhaling 13/1,000,000,000 of a gram of botulinum toxin H13. Two botulinum toxin gene clusters of Clostridium


Figure 2: Structure of Botulinum neurotoxin9

5

Basic structure of botulinum neurotoxin

3-d ribbon model of botulinum neurotoxin

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botulinum strain IBCA10-7060 type Bh were sequenced by the scientists of California Department of Public Health. The sequence of BN/H showed difference from the sequences of the 7 known genes for toxin types A-G13,14. The 5’ one-third terminus of BN/H that codes for the botulinum toxin light chain differed markedly from the light chain coding

sequences of toxin types A–G13,14. The 3’ two-thirds terminus of BN/H that codes for the botulinum toxin heavy chain contained a novel HN translocation domain coding sequence and a nonneutralizing type A–like HC binding domain coding sequence14.

2.5ProductionBotulinum neurotoxin is naturally produced by the Bacerium Clostridium botulinum6. But, the commercial production of botulinum toxin type includes two media which consist of an animal based product and protein product of soybean. Clostridium botulinum6 type A bacteria is cultured in the first medium which permits the growth of the bacterium which is followed by the inoculation of the second medium with first medium15. Clostridium botulinum6 type A is again produced in second medium under favorable condition and at last botulinum toxin type A is recovered from the solution15. Another patent also explained the production method of botulinum toxin which consists of two media but free of animal product15. The first medium is made up of protein derived

from yeast or vegetables at a concentration of 25- 200gil15 and Clostridium botulinum6 is cultured in first medium in 34 degree calcium. 2-4% of the first medium is required to inolcuate the second medium which is followed by further culturing of Clostridium botulinum6 in second medium15.

2.6ApplicationsBN is known to its application in cosmetology16. But apart from cosmetology, BN is used in treating excessive muscle contraction17 and treating diseases of excessive glandular secretion, specifically drooling and sweating18. Revolutionary information is found on the application of BN for treating Parkinson’s disease19, Dystonia20, and Blepharospasm21.


Figure 3: Mechanism of action of botulinum [11]

6

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The first step of our study was to retrieve the granted patents or published patent applications related BN technology. Patents were retrieved from most common databases- WIPO, USPTO, Espacenet, PatentLens, and IPO. The patents were found from the different combinations of keywords mentioned in title, abstract or claims of the databases. From the literature review of BN, we have found several keywords segregating the topic into several sections such as:

1. Botulinum production2. Botulinum formulation3. Botulinum delivery4. Application of botulinum in dermatology

such as in treatment of skin, hair , teeth5. Application of botulinum in other

than dermatology such as Dystonia, Blepharospasm, Parkinson’s disease.

So, from these above segregation, several keywords such as botulinum, production, formulation, delivery, skin, hair, teeth, parkinson’s, dystonia, blepharospasm etc. Table 1 demonstrates the names of the, corresponding search queries and number

of patents found on botulinum neurotoxin. Repetitions of patents or published applications were not considered and duplicate documents were removed. Altogether, 223 patents were retrieved for analysis and the number of patents from each database which were considered for analysis, were shown in Table 2 (appendix). After retrieval, the non-technical and technical information from the patents were collected and the raw data were represented in taxonomical manner. These raw data were analyzed to evaluate the patenting activities over time, the number of patents over geographical scope, types of assignees and international patent classifications. Also, further analysis was carried out to map the application areas, new products, process involved in the arena of BN research.

7

Chapter 3Methodology


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Table 1: Search query


8

En_Ti: (botulinum)

En_Ti: (botulinum production)

En_Ti: (botulinum formulation)

En_Ti: (botox)

En_Ti: (botulinum delivery)

En_Ti: (botulinum) and Cl: skin

En_Ti: (botulinum) and Cl: hair

En_Ti: (botulinum) and Cl: teeth

En_Ti: (botulinum) and Cl: dystonia

En_Ti: botulinum and cl: Blepharospasm

En_Ti: (botulinum) and Cl: parkinson's

ttl/"botulinum"

ttl/"botulinum" and aclm/"fermentation"

ttl/"botulinum" and aclm/"delivery"

ttl/"botulinum" and aclm/"dystonia"

ttl/"botulinum" and aclm/"blepharospasm"

ttl/"botulinum" and aclm/"production"

Title: botulinum

Title: botulinum and Claim: fermentation

Title: botulinum and claim: dystonia

Title: botulinum and claim: blepharospasm

Title: botulinum and Claim: Parkinson

Title: botulinum and claim: dystonia

Title: botulinum and claim: parkinson

Title: botulinum and claim: blepharospasm

Title: botulinum

1091

38

57

6

50

76

10

1

61

47

35

228

8

7

14

10

11

500

6

17

0

0

69

33

48

7

WIPO

WIPO

WIPO

WIPO

WIPO

WIPO

WIPO

WIPO

WIPO

WIPO

WIPO

USPTO

USPTO

USPTO

USPTO

USPTO

USPTO

Espacenet

Espacenet

Espacent

Espacenet

Espacent

Patent Lens

Patent Lens

PatenLens

IPO

Number of patents/patent applicationsAlgorithm Database

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Table 2: Patents/ patent applications considered for statistical analysis from each databas

9


USPTO

EPO

WIPO

PatentLens

IPO

44

22

125

30

2

Number of patents/patent applicationsPatent Database

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The above graph explains the number of patents filed and published in each year (2000 to present). A growth in the number of filling of inventions was observed after 2000 where maximum fillings were recorded in 2005 followed by a steady fall. Most recent trend shows further escalation of filling of inventions. However, the year- 2005 is found as a most successful year for BN technology inventions as highest number (45) of publications is occurred in 2005 although the trend of publication dropped after 2005

except 2010. Most noteworthy information is that there is a good positive correlation (r= 0.69) between the numbers of fillings and publications in each year (from 2000 to present) which concludes that there is a possibility for high numbers of fillings with high number of publications.

Number of patents by inventorsThis analysis (Figure 5) highlights on the topmost inventors who contributed into BN technology innovation.

10

Chapter 4Results and statistical analysis


Bibliographic analysis

Patenting activities over time: Patenting activities are generally evaluated through priority year (filing year where applicable) and publication year. Priority year is the year when inventors first disclose their invention to the government authorized body whereas

the publication year is the year when the contents of the patent applications are displayed through official website handled by the specific patent offices. Figure 4 shows the technology trends of botulinum neuromodulator on the basis of priority year and publication year.

Figure 4: graph on the basis of priority and publication year

num

ber

of fi

lling

Number of Patents based on priority year

Number of patents based on publication year

05

101520253035404550

1998 2000 2002 2004 2006 2008 2010 2012 2014

Year

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Patricia Walker is known for her extreme contribution (24) patents followed by Gary Borodic (22), Aoki Roger K (17), Elizabeth Moyer (15), Andrew Blumenfeld (13) and Micheal Dake (12), respectively. The nationality of those inventors is the United States except Aoki Roger K (no information about nationality).

Number of patents by assignee: We have segregated the number of assignees into company, individual investor, academic research unit and government body. Maximum patents (84%) on BN technology are owned by the industrial organizations or companies which are followed by individual investor (11%), research unit (4%) and government body (1%), respectively (Figure6).

Further analysis shows that Allergen Inc. and Merz Pharma GMBH shared similar involvements (40%) with entire contributions from companies. Apart from them- Revance Therapeutics Inc.(8%), Soltice neuroscience Inc. (7%), Elan Pharmaceutical Inc. (2.5%), and Ipsen Pharma (2.5%) made considerable contribution to the BN technology (Figure7).The information of the major assignees other than the companies is tabulated (Table 2). We have also analyzed the nationalities of assignees and the analysis gives provides that most of applicants are from United States (82%) followed by France (9%), Canada (2%), Germany (2%) and others (5%), respectively (Figure 8).

11


Figure 5 Contributions from inventors

Figure 6: Types of assignee

Inventor

Number of Patents24

Patricia Walker

12

MichaelDake

13

Andrew Blumenfeld

15

Elizabeth Moyer

17

AokiRoger K

22

Gary Borodic

11%

5%2.70% 0.30%

research unit

government body

individual investor

industrial organization

limited liability (law firm)

81%

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Table 3: Assignees (other than companies)

Figure 7: Contributions of each life-science industrial organization


Figure 8: Assignee Nationality Vs. Number of patents

82%

9%

5%2% 2%

United StatesFranceGermanyCanadaOthers

Louisiana State University; Mayo foundation; Societe de Conseils de Recherches et D’Applications Scientifiques; City University of New York, Botulinum Toxin Research Associates, Inc.; Wisconsin Alumni Research Foundation; University of Massachusetts

Stephen Donovan et al; Blanda Wendy M.; Aoki Kei Roger; Borodic Gary;

Government Of The United States Of America

Taylor, Porter, Brooks & Phillips LLP; Heenan Blaikie LLP; Milbank, Tweed, Hadley & McCloy LLP; Carter, Deluca, Farrell & Schmidt LLP; Sheppard, Mullin, Richter & Hampton LLP

Limited liability(law firm)

Government body

Individual investorResearch unit

40%

40%

8%

7%

2.50% 2.50%

Allergen Inc

Merz Pharma GMBH

Revance Therapeutics Inc.

Soltice neuroscience Inc.

Elan Pharmaceutical Inc

Ipsen Pharma

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Place of first filling: The place of first filling reflects the applicant’s preference to get patent protection in that specific territory considering the demand of his invention in this said territory. So, according to the place of applicant’s preference of first filling- the United States of America is the leading

country (143) followed by World Intellectual Property Organization (25), European Patent Organization (15), Great Britain (12), Germany (6), Austria (5), France (3), Japan (2), Russia (1) and Korea (1), respectively (Figure 9).

Figure 9: Place of first filling vs. number of patents

It is known that there is a greater tendency to patent in certain countries than others, and this picture may change if the figures are corrected for this difference in behavior. Therefore, the Relative Specialization Index (RSI)21 for each applicant country has been calculated to give an indication of the level of

invention in BN technology for each country compared to the overall level of invention in that country, and is shown in Figure 10. In the calculation of relative specialization index, we have excluded European Patent Organization and World Intellectual Property Organization as both of them are not the countries.

Figure 10: Relative Specialization Index for countries of first filling

No./of Patents

Place of first filling

143

US

25

WO

15

EP

12

GB

6

DE

5

AU

3

FR

2

JP

1

RU

1

KR

Pla

ce o

f fir

st fi

lling

KR

RU

JP

FR

AU

DE

GB

US

RSI

-1.2 -1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8

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Figure 9 and 10 are different; figure showed the United States as the leading place of first filling followed by Great Britain, Germany, Austria, Japan, France, Russia and Korea. But figure 10 shows Japan is specialized in BN technology, not the United States. Comparatively, Great Britain, France and Korea are better than the United States in BN technology.

Patent distribution under IPCs: An invention must belong to an international patent classification (IPC). This section analyzes the number of patents in each class (Figure 11)

Around 87% of the total patents are categorized under A61K which covers preparations of products for medical, dental purposes followed by C07K, C12N, A01N and A61M, respectively.

Top 10 patent families: A patent family is a set of either patent applications or publications taken in multiple countries to protect a single invention by a common inventor(s) and

then patented in more than one country22. A first application is made in one country – the priority – and is then extended to other offices. In this section, we have chosen top 10 international patent families (Figure 12).

Figure 11: Patent distribution Vs. IPC

A61KC07KC12NA01NA61M

4%3.7% 3.3% 2%

87%

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Table 4: Top patent families with inventor and assignees

15


Types of Patents: It is known that there are three types of patents- product, process and product-process patents. The analysis (Figure 13) indicates that maximum number

of patents belongs to product-process patents (41%) followed by product patents (34%) and process patents (25%), respectively

Figure 12: Top 10 international patent families

EP 1366770 B1

US 7758873

EP 1112082

US 6872397

EP 1594523

EP 1617862

US 8298550

EP 1521593 B1

EP 1820510

EP 1128844

Aoki K Roger et al

Terrence J Hunt

Elizabeth Moyer

Aoki K Roger et al

Gary Borodic

Alan Ackerman

J. Frevert and V. Specht

S. Donovan

E. R First

H. Gassner and D. Sherris

Allergan Inc.

Allergan Inc.

Elan Pharmaceuticals

Allergen Inc.

Botulinum Toxin Research

Associates Inc.

Allergan Inc.

Merz Pharma GMBH

Allergan Inc.

Allergan Inc.

Mayo Foundation

AssigneeInventorTop Patent families

155

6555

34

29

25

23

23

2114 14 EP1366770

US 7758873

EP1112082

US 6872397

EP1594523

EP 1617862

US 8298550

EP 1521593 B1

EP 1820510

EP 1128844

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Figure 13: Types of Patents

Figure 14: Applications of botulinum researches

16


ProductProcessProduct-Process

25%

34%41%

Enhancing Wound healing

Stabilizing &

preservative agents

Removing impurities ofRecombinant anti-

botulinum toxin Antibody

Immuno diagnostic agents &

vaccine components

Aesthetic &

cosmetic Purposes

Hypervolemic lip

deformity

Autonomic Nerve dysfunction

Cerebral Palsy

GastrointestinalDisorder

Dystonia

NeurologicBlepharaspasm

SpasticMuscle Pain

Laryngeal

Cervical

Focal

ApplicationIn

Treatmentof

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Figure 16 : New products generated from BN technology research

Enterotoxin

New Products

Liquidbotulinum

toxinTransdermal botulinum

toxin

Botulinumtoxin A

Botulinumtoxin B

Album free

botulinum

Anti-botulinum

toxin

Chemodenervating agent

Figure 15 : Occurrences of medical applications of Botulinum product

This figure illustrates about the occurrences of the useful application oif botulinum product in medical fields. The detailed analysis explains that most of the researches (24%) on botulinum product target the medical aesthetic field followed by reduction of muscle pain, treatment of dystonia, cerebral

pulsy and blepharospam. The production of preservative agent, immunodiagnostic agent are rarely focused in the researches on BN technology. However, cervical dystonia (61%) is the most focused field of dystonia research followed by laryngeal (25%) and focal dystonia (14%), respectively

Improvement of wound healing

Production of preservative agent

Anti-botulinum toxin production

Immunodiagnostic agent

Aesthetic application

Nerve dyfunction

Cerebral Pulsy

Gastrointestinal disorder

Dystonia

Blepharospasm

Musclepain

17%

14%11%

11%

9%

9%

0.50%0.25%

0.25%

24%

4%

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Figure 17: Records of inventions (%) in each category of new products

Most of the BN researches generate botulinum toxin A (68%) followed by the production of botulinum toxin B (10%), transdermal botulinum toxin (7%), albumin

free botulinum (6%), enterotoxin (3%), liquid botulinum toxin (3%), anti-botulinum toxin (2%), and chemodenervating agent (1%) respectively.

18


Figure 18: Processes involved in BN technology

Centrifugation

ProcessInvolved

FiltrationFermentation

Lyophilization

FreezeDrying

VacuumDrying

Microinjection

UltraFiltrationInjecting

Botulinum toxin though

various modesPurification

Sedimentation

Centrifugation

ChromatographyMethods

Botulinum Toxin A

Botulinum Toxin B

Anti-Botulinum Toxin

Liquid Botulinum Toxin

Enterotoxin

Albumin Free Botulinum

Transdermal Botulinum Toxin

Chemodenervating Agent68%

10%

2%

3%3%

6%

7%

1%

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Figure 20: Types of enzymes useful in BN technology

Temperature

PH

PK Values

Viscosity

Dosage

Molecular Weight

of Final compound

Time Period

Texture of the component

Lotion

Ointment

Spray

Gel,oil,etc.

SpecificConditions

Figure 19: Occurrences of different types of processes involved in BN technology

Micro injection

Other injection method

Freeze drying

Fermentation

Ultra filtration

SedimentationLyophilization

ChromatographyPurification

Filtration

65%

9%9%

4%4%

3%2% 1.5%1.5% 1%

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Figure 21: Specific condition adopted in BN researches

Hydrolyzed soybean

Endopeptidases

Cellulases

Heamagglutin Protein

Polypeptides

EnzymesInvolved

Sequestring agent

Ribonuclease

Protease

Hyaluronidase

Neurotoxin polypeptide

20


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Chapter 5Swot Analysis


• Application of botulinum as cosmetics is accepted in USA and Europe and the demand is growing in those said places24- the demand of botulinum in US is highest followed by dermal filler25.

• Applications not restricted with in the medical aesthetic field, also to treat Parkinson’s disease, Dystonia18,19,20,21

• within 24 hours of application, toxin starts to work to provide desirous result26

• Strength of customers- desire to maintain young appearance will never die24

• High entry barriers such as high R&D investment, high patent costs, long time clinical examination24

• Expensive branded products24,27.• Toxin production is highly sensitive in

laboratory condition24.

Strength Weakness

• several botulinum products are in pipeline, waiting to be released in the market28,29, 30

• Information about botulinum gradually spread across low income countries such as China, India, Russia and Brazil24

• botlinum toxin is known as most deadly substance; every country carefully scrutinizes each botulinum products before giving the permission of commercialization in their market24,31

• Competition with dermal filler as beauty products, serum, some other toxins such as tetanus toxin, saxitoxin, tetrodoxin24,32

• Sudden loss of supply of raw materials may interrupt the production of botlinum toxin in laboratory24

• botulinum products may cause several side effects such as double vision, blurred vision and drooping eyelids, hoarseness or change or loss of voice (dysphonia), trouble saying words clearly (dysarthria), loss of bladder control

Opportunity Threat:

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Chapter 6Competitive Intelligence


Allergan Inc.

Merz pharmaceutical

Galderma

$1,391.1 million total product net sales- 6.1 % compared to total product net sales in 2011; revenue $ 5.7

billion (in 2012) with a growth of 9% than

201134

Total revenue 980.2

million Euro in 2012 (913.1 million Euro in

2011).35

Sales figure was around 735 million Euros in 2007 while it touches

more than double- (1591 millions Euros) in

2012 sales of aesthetic and corrective products (268.6 million Euros)36

Ophthalmic, neuroscience, medical dermatology, urology- product of our interest-

Botox34

Neurology, dermatology, hairloss,

liver related brain impairment- product of our interest- Xeomin35

Most products are on skin based. Product

of our interest is Azzulure36

has invested $ 1 billion in research and development

in 2012; Research going on the application of

Botox in Juvenile Cerebral Palsy, Osteoarthritis Pain,

Premature Ejaculation apart from cosmetic use34

Spent 112.8 million Euro in R & D in 2012 than 125.3 million Euro in

2011; research focused on tinnitus- hearing

abnormality35

Approximately 19% of the revenues of each year

invested in R & D; focused on these following areas; Acne, Onychomycosis, Psoriasis and, Medical

solutions for skin senescence, Pigmentary

disorders36

CompanyFinancial

informationProduct ranges Research

and development

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Ipsen

Solstice neurosciences;

fully owned subsidiary of US

WorldMeds

Group sales 292.8 million euros in 2012;

Somatuline® and Dysport presented a solid growth rates of

8.4% in the first quarter of 201337

Total sales 75 million Euros in 201238

Eurology, oncology, endocrinology,

neurology, cognitive impairement-product of

our interest Dysport37

Products for the treatment of malignant

hyperthermia, cervical dystonia

in adults, the acute, intermittent treatment of hypomobility- product

of our interest Myobloc38

R&D expenditure totaled close to 250 million

Euro; working on the application of Dysport in Muscle spasticity of upper limbs in adults, children,

Temporary correction of moderate to severe

glabellar lines in adults and Cervical dystonia37

Research on MYOBLOC Injections into the salivary

glands to Treat Sialorrhea38

Research and developmentProduct rangesFinancial

informationCompany

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White gap analysis is performed after primary landscape study. It incorporates identification of gaps and making strategy how the gaps can be abridged39. White gap analysis is must to pinpoint an area where future researches on a specific technology can be performed or design a strategy to identify market which is useful for a specific technology So, landscape analysis on BN technology identifies following disadvantages;


Chapter 7White Gap Analysis

a) Repetition of doses to maintain the efficacy of botulinum toxin; so future research must be concentrated to find out the botulinum toxin with higher effectiveness in order to avoid repetition of administration of botulinum toxin.

b) Temporary side effects after the administration of botulinum toxin is unavoidable; next generation toxin is expected to be found without any side-effect or any additional medication is recommended to save the patients from side effects.

c) Asian market- especially Indian market is immature for BN technology; knowledge on botulinum toxin as medical aesthetic product should be spread across Asian market followed by the distribution of said products in less expense.

d) Complicated formulations of BN

technology- so the applications as aesthetic tool still not widely accepted.

e) Expensive doses- less expense materials are needed in low income countries.

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Chapter 8Standard Botulinum products

BOTOX®(onabotulinumtoxinA)

Myobloc(rimabotulinumtoxinB)

Dysport(abobotulinumtoxin A)

Xeomin (incobotulinumtoxin A)

Azzure(botulinumtoxin A)

Vistabel(botulinumtoxin A)

Neuronox(botulinumtoxin A)

Allergan Inc.

Solstice Neuroscience

Inc

Ipsen pharmaceutical

Merz pharmaceutical

Galderma

Allergan

Medytox

Cosmetic application-improve the look of moderate to severe

frown lines between the eyebrows (glabellar lines) Overactive

Bladder, Upper Limb Spasticity40

cervical dystonia to reduce the severity of abnormal head position

and neck pain associated with cervical dystonia41

Cervical dystonia & improve the look of moderate to severe frown

lines between the eyebrows42

abnormal spasm of the eyelids; the look of moderate to severe frown

lines between the eyebrows43

temporary improvement in the appearance of moderate to severe

glabellar lines44

appearance of moderate to severe vertical lines between the

eyebrows seen at frown46

Improvement of moderate- to-severe frown lines between brows, cerebral pulsy and

blepharopspam47

temporary improvement of

glabellar lines approved in 200240

crow’s feet lines approved in 201340

2000- approved by FDA41

April 2009- approved by FDA42

Aug, 2010- approved by FDA43

No information about FDA

approval but commercialization

approval in 15 European countries45

Approved in UK46

KFDA approved in 2011; global

commercialization started in 200547

Product name Comapny IndicationRegulatory

Approval Status

Table 5: Available products

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RT002- Nest Gen Neurotoxin

BOTOX®

BOTOX®

BOTOX®

DYSPORT®

DYSPORT®

DYSPORT®

DYSPORT®

DYSPORT®

DYSPORT® NEXT GENERATION

Revance Therapeutics48

Allergan

Allergan

Allergan

Ipsen Pharmaceutical






lateral canthal lines; hyperhidrosis48

Juvenile Cerebral Palsy33

Osteoarthritis Pain33

Premature Ejaculation33

Muscle spasticity of upper limbs in adults42

Muscle spasticity of lower limbs in children42

Muscle spasticity of upper limbs in children42

Neurogenic detrusor overactivity42

Temporary correction of moderate to severe glabellar

lines in adults (China)42

Cervical dystonia42

Phase 1; no information on marketing approval or FDA

approval

Phase 333

Phase 233

Phase 233

Phase 342

Phase 342

Phase 342

Phase 242

Phase 342

Phase 342

Product Development StatusIndicationComapnyProduct name

Product Pipeline:

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The innovation on BN technology has started after the year 2000 and the rate of patent filings increase gradually up to 2005. Maximum numbers of patent filings (44) were recorded in 2005 followed by a steady decline up to 2012 although a probability of higher number of patent filings is expected in future. The similar trend is also maintained by the number of patent publications. Highest number (44) of publications was occurred in 2005 although current trend exhibited limited publication records. The number of patent filings and the number of publications show a good positive correlation (r = 0.69) between them which means the tendency of the higher number of filing of patents with the higher number of publications.

Patricia Walker, Gary Borodic, Aoki Roger K, Elizabeth Moyer, Andrew Blumenfield, Micheal Dake are known as the leading inventors in BN technology. The name of Patricia Walker was come to know for her maximum contributions (24) followed Gary Borodic (22), Aoki Roger K (17), Elizabeth Moyer (15), Andrew Blumenfield (13), and Michael Dake (12), respectively. The noteworthy information is the nationality of leading inventors is the United States. The headquarters of the top industrial

organizations are in the US except Merz Pharma (Germany) and Ipsen (France). Apart from this, most of the research units and limited liability companies are based in the US. The nationality of the individual investors and the direct contribution of the government of United States of America reflected that the technologists are encouraged and facilitated by the government to take part within the research environment49.

A set of either patent applications or publications considered in several countries to protect a single invention by a common inventor and then patented in more than one country, then the set of the patent applications or publications are called patent family. Patent- EP 1366770 has 155 patent families where Aoki Roger K is the common inventor which means the Aoki Roger has filed EP 1366770 in several countries due to the global demand of the particular patent. Apart from this, Allergan is found as the assignee of six patent families among the top ten patent families- which explains

1. the presence of Allergan Inc. across the world,

2. Allergan Inc. is familiar with the patent laws of most of the countries.

Chapter 9Discussion


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The United States is found as the leading place of first filling of the inventions. Also, the nationality of most of the inventors and assignees is the United States. The reason behind the higher occurrences of the United States is that the demand of the technology in the American market. But, that does not mean America is specialized in BN technology- there is a huge difference between marketing of a product and the research on a product. To clarify, a statistical analysis- relative specialization index for the countries in our dataset is calculated. The relative specialization

index is an indication for the level of invention of each country in the dataset on BN technology compared to the overall level of invention in that country. However, the relative specialization index gives a reverse scenario- the negative index for the United States explains low levels of specialization in BN technology whereas the positive index for Japan shows greater levels of patenting in BN technology.

Most of the inventions (87%) are categorized under A61K- preparation of medical and dental preparations. In addition, inventions are also categorized under C07K which means the presence of peptides in botulinum. Also, the processes of making of botulinum products with delivery systems are described in some researches.

The application of Botulinum product is not restricted in aesthetic and cosmetic purposes, it is useful for improvement of wound healing process, removal of impurities of recombinant anti-botulinum toxin, to

generate immunodiagnostic agents etc. To treat cerebral pulsy, gastrointestinal disorder, dystonia, neurologic blepharaspasm, spastic muscle pain- the application of botulinum product is found handy. Botulinum toxin type A & B, recombinant anti botulinum toxin antibody, botulinum neurotoxin protein, enterotoxins, albumin free botulinum toxin, transdermal boulinum toxin, botulinum nanoemulsions, stable liquid formulations of botulinum toxin, PEGylated mutated Clostridium botulinum toxin from several researches.

Botulinum toxin in currently the stronghold of the US and Europe and the supremacy is likely to carry on over the next few years. Maximum numbers of approvals for botulinum toxin products have been received in these regions which provide a strong future market. The United States alone emerges as the single largest regional market. This region is also estimated to maintain a rapid growth pace, estimating compound annual growth rate of 10.7% through 201850. In Europe, Asia-Pacific, Latin America, Eastern Europe, the zeal for beauty is continuously raising the demands of botulinum products though these markets are not matured enough. The cosmetic application section for botulinum toxin recommends powerful growth assurance as well50.


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1. Cosmetic Procedures Increase in 2012, Available Online http://www.surgery.org/media/news-releases/cosmetic-procedures-increase-in-2012 Last Access 25th Nov., 2013.

2. D Amico RA et al, (2008), Risks and opportunities for plastic surgeons in a widening cosmetic medicine market: future demand, consumer preferences, and trends in practitioners’ services, Plast Reconstr Surg, 121(5):1787-92.

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4. Botulinum Toxin A Leads Europe Market - Cosmetic Surgery, Facial Aesthetics & Medical Laser Devices, Says New Research Report at ReportsnReports.com. Available Online http://www.prweb.com/releases/botulinum-toxin-a-leads/european-market/prweb10888914.htm Last Access 19th Nov., 2013.

5. J Ahn et al, (2004), Botulinum Toxin for Masseter Reduction in Asian Patients, Arch Asian Plast Surg, 6(3): 188-191.

6. Z. Dembek, L. Smith, J Rusnak. “BOTULINUM TOXIN” Medical Aspects of Biological Warfare. Online Available http://www.hsdl.org/?view&did=19851 Last Access 8th Nov., 2013.

7. EP van Ermengem, (1897), Ueber einen neuen anaëroben Bacillus und seine Beziehungen zum Botulismus, Zeitschrift für Hygiene und Infektionskrankheiten (in German) 26 (1): 1–56. doi:10.1007/BF02220526.

8. F J. Erbguth, (2004), Historical notes on botulism, Clostridium botulinum6, botulinum toxin, and the idea of the therapeutic use of the toxin, Movement Disorders (John Wiley & Sons on behalf of the Movement Disorder Society) 19 (S8): S2–S6. doi:10.1002/mds.20003. PMID 15027048.

9. GG Sedano, BOTULINUM TOXIN Available Online http://www.chm.bris.ac.uk/motm/botulism/botjm.htm Last Access 8th Nov., 2013.

10. Blockade of Neurotransmitter Relase by Botulinum Toxin Available Online http://www.biocarta.com/pathfiles/h_BOTULINPATHWAY.asp Last Access 8th Nov., 2013.

Reference


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11. A. Rystedt (2012). “Botulinum Toxin- Formulation, Concentration and Treatment” Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine

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13. F Diep (2013). “New, Incurable Botulinum Strain Has Top Secret DNA” Available Online http://www.popsci.com/article/science/new-incurable-botulinum-strain-has-top-secret-dna Last access 4th Nov., 2013.

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17. RL Rosales, D Dressler, (2010), On muscle spindles, dystonia and botulinum toxin, Eur J Neurol, 17:71-80.

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19. M Rezak, THE USE OF BOTULINUM TOXIN IN PARKINSON’S DISEASE, Available Online http://www.youngparkinsons.org/what-you-should-know-about-early-onset-parkinsons-disease/articles/the-use-of-botulinum-toxin-in-parkinsons-disease Last Access 19th Nov., 2013.

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23. Horwarth- Winter et al, (2003), Botulinum toxin A treatment in patients suffering from blepharospasm and dry eye, Br J Ophthalmol, 87(1): 54–56.

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URN:NBN:no-bibsys_brage_24428/1/Salopek%202009.pdf Last Access 19th Nov., 2013

25. Available Online http://www.plasticsurgery.org/Documents/news-resources/statistics/2012-Plastic-Surgery-Statistics/cosmetic-surgery-regional-statistics.pdf, Last Access 25th Nov., 2013.

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2013.

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29. Available Online http://www.allergan.com/research_and_development/pipeline.htm Last Access 25th Nov., 2013.

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31. B Liang,, TK Mackey, K Lovett, 2012, Emerging Dangers from Direct Botulinum Access and Use, Journal of Homeland Security and Emergency Management,9(1): 1-5.

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33. Available Online http://www.botoxcosmetic.com/botox-safety.aspx Last Access 25th Nov., 2013.

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35. Available Online http://www.merz.com/ Last Access 17th Oct., 2013


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36. Available Online http://www.galderma.com/ Last Access 17th Oct., 2013.

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42. Available Online http://www.dysport.co.nz/ Last Access 8th Nov., 2013

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44. Available Online http://www.galderma.com/Medical-Solutions/Major-Brands/Azzalure Last Access 25th Nov., 2013.

45. Available Online http://www.galderma.com/Media/Press-releases/articleType/ArticleView/articleId/22/Azzalure-approved-in-the-UK-for-aesthetic-use-in-the-treatment-of-glabellar-lines Last Access 25th Nov., 2013.

46. Available Online http://www.medicines.org.uk/EMC/medicine/17580/SPC/Vistabel/ Last Access 25th Nov., 2013.

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48. Avilable Online http://www.revance.com/products.html Last Access 25th Nov., 2013.

49. P Whoriskey, 2012, Innovation and competitiveness: How to encourage the next great U.S. inventions, Available Online http://www.washingtonpost.com/business/innovation-and-competitiveness-how-to-encourage-the-next-great-us-inventions/gJQALlfyNX_topic.html Last Access 27th Nov., 2013

50. http://www.prweb.com/releases/botulinum_toxin_botox/BTX/prweb9305891.htm Last Access 25th Nov., 2013.


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Relative Specialization Index (RSI) was measured to correct to absolute numbers of patent families to address that some countries file more patent applications than others in all fields of technology [27]. RSI evaluates the fraction of botulinum neuromodulator patents found in each country to the fraction of patents found in that country overall. The formula of relative specialization index is shown below [27]:

Whereni= number of patents on botulinum in country i; ntotal= total number of patents on botulinum in dataset; Ni= total number of patents in country i; Ntotal= total number of patents from all of the countries

Appendix


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