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of 14 Kyle Thompson 29/05/13

Intellectual Property Analysis of B O T O X ®

W ritten by: M r K yle Thompson ©

Thursday 29th May 2013


Allergan, Inc.

Company Vision includes two principles :

deep engagement with medical specialists

products that improve patient outcomes.

Allergan is a boutique pharmaceuticals company, with what some would consider a product

portfolio exhibiting diversity. In 2013 it has taken further action in reinforcing its market share

in Canada and the US, when it entered into merger agreement in January which acquired MAP

Pharmaceuticals, which was primarily to acquire its core technology Levadex® which treats

migraine (Pyott, 2012). Allergan distributes to approximately 85 countries and has its main

pharmaceutical manufacturing headquarters in Ireland, Texas and Brazil.

Its various Botox® applications are a high revenue earner for the company, where a significant

(Pyott, 2012). In 2012, therapeutic application of

Botox® constituted around 52% , of sales of Botox®, where it was responsible for 16% of

(Pyott, 2012).

Allergan, Inc. (Irvine, California, U.S.) utilizes the toxin produced by the Hall strain of

Clostridium botulinum serotype A in its product Botox® (Ting & Freiman, 2004). The toxin is a

protein and weighs approximately 150 KDa (Chaddock & Acharya, 2011). Botox® causes an

inhibition of release acetylcholine, at the neuromuscular junction resulting in flaccid muscle

paralysis and cranial nerve palsies (Caleo & Schiavo, 2009; Katona, 2012; Robertson & Garza,

2012; Turton, Chaddock, & Acharya, 2002).

Botox® targets soluble NSF-attachment protein receptors (SNARE), specifically Botox ®

functions as an endopeptidase that attacks and cleaves 9 amino acids from synaptosomal-

associated protein of 25kDa (SNAP-25) (Davletov, Bajohrs, & Binz, 2005). SNAP-25 is

responsible for vesicle formation of acetylcholine, which halts for a time after Botox®

treatments, but is reversed as new nerves are formed (Davletov et al., 2005).

Allergan became the proprietor of Botox®, previously known under the elicitable name -

of a license previously owned by the FDA, for the treatment of strabismus and blepharospasm


approved in 1989 (Scott, 2004; Ting & Freiman, 2004). Botox® was subsequently recognized as

a treatment for sever glabellar rhytid amelioration (wrinkles) in 2002 by the FDA, after the

Carruthers published the observation in 1992 (Berry & Stanek, 2012; Chaddock & Acharya,

2011)

Allergan has a significant advantage in the market, as it was first to manufacture a quality

product , the product continues to see success in clinical trials for various ailments (DuBois,

2011). The confidentiality with which Allergan manages their manufacturing of Botox®, ensures

that competitors find it difficult to replicate the product exactly (DuBois, 2011).

Intellectual Property

There is no patent owned by Allergan for the actual toxin, the API of, Botox® rather its modes

of treatment in the clinical setting. However, as it owns its own manufacturing facilities, it

instead relies on confidentiality agreements of its workers (DuBois, 2011). The actual

formulation of Botox® must therefore rely on trade secret to protect against competitors. As such

Botox

Within

company:

intellectual property rights that are important to the commercialization of our products and

product candidates. We cannot assure you that we will successfully obtain or preserve patent

(White, 2010)

Competitors

Ipsen, Inc. (Paris, France) Botox® treatments based

market, having filed 11 new therapeutic application patents. They have large European

Botox formulation under the brand

namesDysport ®/Azzalure® and Reloxin®(Pickett, 2012). Ipsen also has marketing approval in

Japan and China, for Dysport®, as of 2009.


A more recent market competitor in the European union, is the German company Merz (Pickett,

2012). Merz Pharma market their own formulation as Bocouture®/Xeomin® or Vistabel®

(Pickett, 2012). In 2010 Merz gained significant market share in the US with the launch of its

product, which had previously seen success in Canada in 2009 and Germany in 2005.

Other emerging competitors, include Neuronox® from Medytox, Inc. (Seoul, Korea). Their

product has seen success in its native Korean state, and continues to grow in the South East

Asian region, it has also been approved for treatment of hyperhidrosis (Wilson, 2011).

Table 1 Evidence of products reverse engineerability

(Berry & Stanek, 2012; Chaddock & Acharya, 2011; Wilson, 2011)

Invention 1 - EP0758900: Botulinum toxin for reduction of migraine headache pain

(Binder)

Migraine prevalence of the world population has been estimated at approximately 6% for males

and 18% for females. (Ravishankar, 2010). Botox® for migraine is primarily targeted to service

neurologists and pain specialists Botox® as a treatment for headache pain was approved in

Australia and New Zealand, Hong Kong, India, Korea , Canada, and almost all states in the

European Union (Pyott, 2012). Botox® as acute migraine treatment saw approval by the US

Food and Drug Administration (FDA) and the Medicines and Healthcare products Regulatory

Agency (MHRA) in 2010 (Berry & Stanek, 2012; Park, 2012).

Allergan acquired an exclusive worldwide license for the treatment of migraine headaches from

Miotech, Inc (Llc, California) in 1998, (Tonyt, 1998). to which it pursue clinical trials (Park,

2012).

Brand Name Company API MW(kDa)Botox® Allergan, Inc. 900Xeomin® Merz Pharma 150Dysport® Ipsen, Inc. 750Azzalure® Ipsen, Inc. 750Neuronox® Medy-‐Tox 900


However the patent lifespan is almost at an end, where:

Patent Expiry: 5th of September, 2014

Priority Filing date: 5th of September 1994

The Patent is of high importance, along with trade secret and trademark, this is a reflection of

less important, as the invention is a method or process sold to medical professionals, not one

purchased at the supermarket.

Table.2 - Brief intellectual property portfolio, Botox® for migraine treatment

The invention is quite heavily reliant on the discretion of medical doctors in their selection of

treatment options for patients. Botox® in general is reliant on the medical procedure, which is

patentable subject matter in some countries. Therefore intellectual property was first focused on

patent protection; following this is the registered Botox® trademark. The invention is quite

novel, considering that the cause for headache pain is still not certain and in fact the Botox®

treatment recently has faced allegations that its treatment, granted regulatory approval in 2010 by

the FDA, with scientific supporting literature funded by Allergan, has less than claimed

effectiveness (Park, 2012). This is causing doctors to reevaluate the model of headache etiology,

which is an issue, as Botox® for migraine may have been too novel.

There is a potential world market for headache effective treatment (please see Index, figure 1 and

2). With a relatively large proportion of the population experience headache, approximately at

20%, with females seeing higher incidence than males s(Ravishankar, 2010). The proportion is

further divided into the young experiencing higher frequency in comparison to older people

(CDC, 2006). The commercialization could in theory target the younger population of emerging

Intellectual property rights ImportanceA. Patent ****B. Trade secret ****C. Plant breeders right *D. Registered design *E. Copyright *F. Trademark *****


markets such as india and South East Asian regions, as other brands such as Neuronox® are

already (Wilson, 2011).

The molecular biology behind the procedure is theory quite complex, the neurotoxin targeting

SNARE proteins and neurotransmitter vesicle formation for muscle stimulation negation

(Davletov et al., 2005; Pickett, 2012; Robertson & Garza, 2012). However, if in the hands of a

health professional the procedure is relatively straight forward.

Competitors have already formulated their own versions of the toxin, which included differences

in complexing protein content inter alia (Berry & Stanek, 2012; Chaddock & Acharya, 2011;

Wilson, 2011). However to our knowledge their has been no competition as yet in the migraine

market, something that may change in the future.

Table 3 Detailed intellectual property portfolio, Botox® for migraine treatment

C riteria Novelty *****

Commercial viability Complexity Re- engineer

Protection lifespan

Potential to keep a secret

Ability independent ar rive at same development

Rating **** *** ***** *** * ** ***

Reason Reducing headache pain and symptoms of headaches, comprises admin. of an invertebrate presynaptic neurotoxin into muscles, or extramusc.

There is a potential global market present for the alleviation of headache suffering of patients (~ 20% world population)

procedure must be administered by neurologists

Product solution and procedure are easily replicated. Regulatory approval required

the patent expires in 2015 (owing to its early filing date)

manufacture of product can be kept secret however a medical procedure cannot

competitors could gain market share if approval is granted

Decision May be too novel, as medical theory in headache etiology is not sound

Commense international jusrisdiction not allready pursued (india, south east asia)

health ramification if procedure is performed incorrectly

someone versed in the art, relatively easily re-engineer.

Patent IP is almost over, only seeing 5 years of viable commercialisation total

methods of procedure are known to the lamen

many companies are in market so it is possible


Invention 2: U .S. 6,974,578 Use of a botulinum toxin (preferably botulinum toxin type A)

to treat or reduce secretion of a sweat gland of a patient (Aoki, G rayston, Carlson, & L eon)

The first instance of treatment of hyperhidrosis in a patient was in 1996, by Bushara et al.

(Bushara, Park, Jones, & Schutta, 1996). In the United states approximately 2.8% of the

population, of which around half suffer from axillary hyperhidrosis (Strutton, Kowalski, Glaser,

& Stang, 2004). This increase in sweating observed in patients has been described as barely

tolerable in performance of daily activities , which have psychological and social consequences

(Strutton et al., 2004). Dysport® and Botox® are the market leaders in the treatment of axillary

hyperhidrosis utilizing botulinum toxin (Glaser, 2006). A limitation associated with both

products is that there can be no changing from one to the other as this could elicit

immunogenicity, due to differences in their bioequivalence (Glaser, 2006).

hyperhidrosis, is all but over where:

Patent expiry -12/28/2013

Priority filing date - 28-12-1993

As with observed in the patent for Botox® migraine treatment, the patent is of high importance,

along with trade secret and trademark. However, trade secret is less important with this invention

as its patent is nearing an end. Plant breeders rights, copyright and registered design are less

important, as with invention 1.

Table 4 - Brief intellectual property portfolio, Botox® for hyperhidrosis treatment

Intellectual property rights ImportanceA. Patent ****B. Trade secret **C. Plant breeders right *D. Registered design *E. Copyright *F. Trademark *****


The novelty of the invention is perhaps explained by the fact that Botox® seems to be applicable

in many different areas of medical treatment, or at least disorders which involve uncontrollable

muscle spasm (DuBois, 2011). Treatment of excessive sweating is a logical extension of

Botox®, however this does not detract from the novelty of a treatment that is reversible and

relatively noninvasive, when compared with other alternatives such a scaring from pain surgery

and skin irritating de-odorants, its novelty is realized (Glaser, 2006).

Commercial viability is perhaps less than the Botox® treatments for headache, due to the smaller

associated markets 2.8% compared with 20% (Ravishankar, 2010; Strutton et al., 2004). The

complexity, reverse engineerability, secret potential and independent development potential

remain similar to invention 1.

Table 5 Detailed intellectual property portfolio, Botox® for hyperhidrosis treatment

C riteria Novelty *****

Commercial viability Complexity Re- engineer

Protection lifespan

Potential to keep a secret

Ability independent ar rive at same development

Rating **** ** **** *** * * ***** Reason Treatment of

(sweat gland) of a patient comprising administration of a botulinum toxin to the gland to reduce the secretion of sweat

Approximately 2.8% of the USA population suffer from hyperhidrosis

Procedure must be admin. by at least a GP, preferably dermatologist

procedure is easily reversed however, regulatory approval is required, for sale.

Very low lifespan, as patent expires this year.

manufacture of product can be kept secret however a medical procedure cannot

competitors could gain market share if approval is granted or method altered

Decision Treatment increases life satisfaction dramatically

This market size should be reflected in other countries, thus large market possibility

highly qualified customer base

Possible reengineer, regulatory approval competitor protection

Has had 10 years of commercialisation, after Reg. approval

methods of procedure are known to the lamen

many companies are in market so it is possible


IP strategy

The products already have a brand name that is recognized internationally as a market leader in

the field of cosmetic application s of botulinum neurotoxin, however as the FY 2012, therapeutic

sales of Botox ® were higher than cosmetic sales, albeit by 1%. This is a reflection of the arena

Botox® products are entering, the migraine and sweating patents expire in 2015 and 2016

respectively, so that form of intellectual property has run its duration.

As the brand has a base, and is respected in the field of medical treatment, focus should now be

on registered designs, trademarks and brand awareness, which it is currently lacking. The brand

Botox® is synonymous with wrinkle removal and youthful appearance. However, it is lesser

known for its somewhat unique medical applications.

Allergan previously has focused on the diversification of its patent portfolio, catering to low

prevalence health disorders such as strabismus, or cataracts. Their recent movement into the

mainstream health disorders such as obesity and headaches, is a reflection of the growth of the

company. While this response is somewhat expected as a result, of such large multinational

companies s he company

should focus its strategy towards consolidation of market, as in its recent merger to MAP, which

owned a patent and product that targeted the same market as Botox® for chronic migraine.

The Botox® trademark is renewable every 10 years, which is administered by the World

Intellectual Property Organisation (WIPO), specifically the Madrid system. The Madrid system

is governed by 2 protocols, the Madrid Protocol and the Madrid Agreement, these allow a

company to file once and receive, in theory, an international registered trademark, such as

Botox®(Gurry, n.d.)

Patent protection is at an end within the borders of the US, and as PCT and EP patents were filed

for headache treatment in 1999, this forms prior art in all the countries belonging to these. It is

possible that an improvement to the method of application for both of these procedures could be

considered as a patentable subject matter Alternatively Allergan could seek partnerships with

open innovation with emerging companies like Meddy-tox, and therefore commercialize of the

emerging Southeast Asian markets, however whether a direct product competitor would

acquiesce to such demands is unknown.


References

Aoki, K. R., Grayston, M. W., Carlson, S. R., & Leon, J. M. US6974578-‐B1. Berry, M. G., & Stanek, Jan J. (2012). Botulinum neurotoxin A: A review. Journal of Plastic,

Reconstructive & Aesthetic Surgery, 65(10), 1283-‐1291. doi: http://dx.doi.org/10.1016/j.bjps.2012.04.016

Bushara, K. O., Park, D. M., Jones, J. C., & Schutta, H. S. (1996). Botulinum toxin -‐ A possible new treatment for axillary hyperhidrosis. Clinical and Experimental Dermatology, 21(4), 276-‐278.

Caleo, Matteo, & Schiavo, Giampietro. (2009). Central effects of tetanus and botulinum neurotoxins. Toxicon, 54(5), 593-‐599. doi: http://dx.doi.org/10.1016/j.toxicon.2008.12.026

CDC. (2006). QuickStats: Percentage of Persons Aged >18 Years Reporting Severe Headache or Migraine During the Preceding 3 Months, by Sex and Age Group -‐-‐-‐ United States, 2004 Morbidity and Mortality Weekly Report (Vol. 55).

Chaddock, John A., & Acharya, K. Ravi. (2011). Engineering toxins for 21st century therapies. FEBS Journal, 278(6), 899-‐904. doi: 10.1111/j.1742-‐4658.2011.08013.x

Davletov, B., Bajohrs, M., & Binz, T. (2005). Beyond BOTOX: advantages and limitations of individual botulinum neurotoxins TRENDS in Neurosciences 28(8), 1-‐7. doi: 10.1016/j.tins.2005.06.001

DuBois, S. (2011). Allergan's survival strategy: Botox everlasting. from http://money.cnn.com/2011/06/09/magazones/fortune/botox_allergan_patent_cliff_big_pharma.fortune/index.htm

Glaser, D. A. (2006). The use of botulinum toxins to treat hyperhidrosis and gustatory sweating syndrome. Neurotoxicity Research, 9(2-‐3), 173-‐178.

Gurry, Francis. (n.d.). Madrid System. from http://www.wipo.int/madrid/en/faq/madrid_system.html Jefferson, Richard A. (n.d.-‐a). Method For Reduction Of Migraine Headache Pain. Jefferson, Richard A. (n.d.-‐b). Method For Treating Secretions And Glands Using Botulinum Toxin. Katona, Peter. (2012). Botulinum toxin: Therapeutic agent to cosmetic enhancement to lethal biothreat.

Anaerobe, 18(2), 240-‐243. doi: http://dx.doi.org/10.1016/j.anaerobe.2011.12.001 Park, Alice. (2012). Botox Treatments Not So Effective for Migraine Headache Relief. from

http://healthland.time.com/2012/04/25/botox-‐treatments-‐not-‐so-‐effective-‐for-‐migraine-‐headache-‐relief/

Pickett, A. (2012). Re-‐Engineering Clostridial Neurotoxins for the Treatment of Chronic Pain. BioDrugs, 24(3), 173-‐182. doi: 10.2165/11534510-‐000000000-‐00000

Pyott, David E.I. (2012). Allergans summary report 2012. from http://agn.client.shareholder.com/financials.cfm

Ravishankar, K. (2010). Migraine -‐ The New Understanding. Supplement of JapI, 58, 30-‐33. Robertson, C., & Garza, I. (2012). Critical analysis of the use of onabotulinumtoxinA (botulinum toxin

type A) in migraine. Neuropsychiatric Disease and Treatment, 8. doi: http://dx.doi.org/10.2147/NDT.S17923

Scott, A. (2004). Development of botulinum toxin therapy. Dermatologic Clinics, 22. doi: 10.1016/S0733-‐8635(03)00019-‐6

Strutton, D. R., Kowalski, J. W., Glaser, D. A., & Stang, P. E. (2004). US prevalence of hyperhidrosis and impact on individuals with axillary hyperhidrosis: results from a national survey. Journal of the American Academy of Dermatology, 51(2), 241-‐248.

Ting, P., & Freiman, A. (2004). The Story of Clostridium botulinum: from food poisoning to Botox. CLinical Medicine, 4(3), 258-‐261.

Tonyt. (1998). Biotech / Medical : Ligand (LGND) Breakout! , from http://www.siliconinvestor.com/readmsg.aspx?msgid=3274935

http://dx.doi.org/10.1016/j.bjps.2012.04.016

http://dx.doi.org/10.1016/j.toxicon.2008.12.026

http://money.cnn.com/2011/06/09/magazones/fortune/botox_allergan_patent_cliff_big_pharma.fortune/index.htm

http://money.cnn.com/2011/06/09/magazones/fortune/botox_allergan_patent_cliff_big_pharma.fortune/index.htm

http://www.wipo.int/madrid/en/faq/madrid_system.html

http://dx.doi.org/10.1016/j.anaerobe.2011.12.001

http://healthland.time.com/2012/04/25/botox-treatments-not-so-effective-for-migraine-headache-relief/

http://healthland.time.com/2012/04/25/botox-treatments-not-so-effective-for-migraine-headache-relief/

http://agn.client.shareholder.com/financials.cfm

http://dx.doi.org/10.2147/NDT.S17923

http://www.siliconinvestor.com/readmsg.aspx?msgid=3274935


Turton, K., Chaddock, J., & Acharya, R. (2002). Botulinum and tetanus neurotoxins: structure, function and therapeutic utility. Trends in Biochemical Sciences, 27(11), 552-‐558.

White, Mary Jo (2010). US securities and exchange commision. from http://www.sec.gov/Archives/edgar/data/850693/000085069312000003/agn10-‐k.htm#s4F4D1AAAF3790B3CAB713ABC85D05C4B

Wilson, Kevin A. (2011). Asian Neurotoxin Alternative Compares Favorably With Competitor. from http://digital.miinews.com/article/Asian+Neurotoxin+Alternative+Compares+Favorably+With+Competitor/728686/69901/article.html

http://www.sec.gov/Archives/edgar/data/850693/000085069312000003/agn10-k.htm#s4F4D1AAAF3790B3CAB713ABC85D05C4B

http://www.sec.gov/Archives/edgar/data/850693/000085069312000003/agn10-k.htm#s4F4D1AAAF3790B3CAB713ABC85D05C4B

http://digital.miinews.com/article/Asian+Neurotoxin+Alternative+Compares+Favorably+With+Competitor/728686/69901/article.html

http://digital.miinews.com/article/Asian+Neurotoxin+Alternative+Compares+Favorably+With+Competitor/728686/69901/article.html


Index

Fig 1 -‐ QuickStats: Percentage of Persons Aged >18 Years Reporting Severe Headache or Migraine During the Preceding 3 Months, by Sex and Age Group -‐-‐-‐ United States, 2004. Reprinted from: United States Centers for Disease Control and Prevention (CDC, 2006)

Fig 2. -‐ EP0758900: patent family jurisdictions (Jefferson, n.d.-‐a)


Fig. 3 -‐Invention 2: US6,974,578 patent family jusrisdictions (Jefferson, n.d.-‐b)

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