Alopecia - Hair Loss

Rationale

• “Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [1]

• “An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries.” February 16, 2006 – [2]

Introduction

Hair Basics

• Hair is a complex and delicate part of the body
• Keeping it healthy and beautiful is a challenge
• Structure of Hair root - [3]
• Structure of Hair bulb - [4]

Structure of Hair root and Hair bulb

Reasons for Hair loss

Survey results from Japan

Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss which has been termed “Male Pattern Baldness” (Androgenetic Alopecia).

Main reasons

• Hormonal effect of androgen
• Reduction of blood circulation around hair follicle
• Deactivation of hair matrix cells

Some facts from Japan

• Market size: ¥ 30 Billion
• Number of products: more than 100

(JICST-EPlus - Japanese Science & Technology)

Goals

• Summarize IP activity over the years
• Identify major players
• Conduct patent analysis

a) Composition b) Nature c) Action

Alopecia occurs due to

• Hormonal effects of androgens
• Reduction of blood circulation around hair follicle
• Deactivation of hair matrix cells

And then

• Analyze patents pertaining to high sebum activity

Approach

Broad search conducted on hair loss patents.

Patent information sourced through SIP.

Patents selected randomly for analysis.

Composition of treatment for causes are identified and categorized as follows:

• Anti-androgen
• Minoxidil
• Double action (Anti-androgen + Mindoxidil)
• Hair matrix cells activator
• Sebum production inhibitor

IP activity over years

The graph indicates: -

• Number of patents filed every 5 years (except for first 7 years).
• First solution proposed in 1973
• Filing trend indicates steep rise in activity recently.

IP Activity over years

Major Players

• Assignees with more than 20 patents to their credit

Assignees with more than 20 patents

• Assignees with less than 20 patents to their credit

Assignees with less than 20 patents

• Active Assignees

Assignees currently active with more than 5 patents to their credit during 2000-2005, among them following are the leaders of 2005-

WARNER with 9 patents,

BRISTOL with 6 and

ABBOTT with 5.

Active Assignees

Anti-androgens

• Anti-androgen is a substance that inhibits biological effects of androgenic hormones
• 5-alpha reductase + Testosterone = Dihydrotestosterone (DHT)
• DHT attaches to an Androgen Receptor.
• DHT causes increase in hair loss and gradual miniaturization of the follicle, which eventually dies resulting hair loss

=== Functions of Anti-androgen === [5]

Functions of Anti-androgen

IP Map for Anti-androgen

Pat/Pub#	Nature	Composition	Composition action
US20060009430 BLOTECH (2004) [6]	Natural extracts	Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)	Fatty acids – Inhibit testosterone Sterols - Mechanism of action unknown. Quercetin results in cell growth cycle. Beta-sitosterol reduce inflammation on scalp
US20060009427 WARNER LAMBERT(2004)[7]	Organic compound	New class of 4-cycloalkoxy benzonitrile derivatives and salts	Acts as androgen receptor modulators and blocks formation of DHT.
US20050085467 WARNER LAMBERT(2004) [8]	Organic compound	New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.	The compounds inhibit, or decrease, activation of androgen receptor by androgens.
US20050118282 APHIOS Corp (2003) [9]	Natural extracts	Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.	Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.
US20060009429 Fundacion Pablo Cassara (2003) [10]	Nucleotide	Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)	Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle
US20030007941 PFIZER INC (2001) [11]	Organic compound	Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate	Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle
US20030073616 N/A (1995) [12]	Peptides/nucleic acid	Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)	Inhibit synthesis of bradykinin receptors or compounds by binding to B2 receptor
EP0279010 KAO Corp (1987) [13]	Natural extracts	Walnut extract (leaves/pericarps) with an organic solvent	Blocks formation of DHT

Minoxidil

• A thick network of tiny veins and arteries lines the outer wall of the follicle. Blood pumps through the bulb and hair via this network
• Minoxidil dilates blood vessels; which is also called as “potassium channel opener”
• Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.

=== Functions of Monoxidil === [14]

Functions of Monoxidil

IP Map for Minoxidil

Pat/Pub#	Nature	Composition	Composition action
US20040157856 WARNER LAMBERT(2002) [15]	Organic compound	Benzopyran compounds	Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers
US20050053572 LG HOUSEHOLD & HEALTH CARE(2001) [16]	Natural extracts	Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)	Promotes function of cell activity and dilates blood vessels

Double action (Anti-androgen + Minoxidil)

• Combination of Minoxidil + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness

=== Functions of (Anti-androgen + Minoxidil) === [17]and [18]

Functions of (Anti-androgen + Minoxidil)

IP Map for (Anti-androgen + Minoxidil)

Pat/Pub#	Nature	Composition	Composition action
US20060052405 N/A(2000) [19]	Peptides	Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhance and sunscreen	Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp
US20050123577 L'OREAL(2000) [20]	Peptides	Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP	Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP
US6447762 COLOMER GROUP(1999) [21]	Natural extract	Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)	Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp

Hair matrix cell activator

• Stem cells of the hair follicle are gathered in the basal layer of the outer root sheath bulge.
• It is from these cells that matrix cells are formed.
• Growth and differentiation of the matrix cells are under the influence of substances produced by cells of the dermal papilla.

=== Functions of Hair matrix cell activator === [22]

Functions of Hair matrix cell activator

IP Map for Hair matrix cell activator

Pat/Pub#	Nature	Composition	Composition action
US20020052498 SHISEIDO(1999) [23]	Organic compound	(2-substituted oxyphenyl) alkanamide derivative and its salt	Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect
US20040071647 L'OREAL(1998) [24]	Peptides	Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions	Reducing the expression of MMPs (Metalloproteases) in the scalp - slow down or inhibit the degradation of the perifollicular matrix (extracellular matrix surround the hair follicle)

Sebum Production Inhibitor

• Sebum, a complex mixture of lipid substances, is secreted from sebaceous glands associated with hair follicles.
• The inhibitor blocks the excessive sebum production produces greasy effect on hair and scalp and also responsible for thinning and loosing of hair.

Functions of Sebum Production Inhibitor

[[25]]

Functions of Sebum Production Inhibitor

IP map for Sebum Production Inhibitor

Pat/Pub#	Nature	Composition	Composition action
US20050277699 Unilever(2005) [26]	Natural extract and organic compound	Polyamine (putrescine, spermine or spermidine) analogs and/or derivatives; DFMO; N-acetyl cysteines; neutralized salts of a non-hydroxy C2-C40 dicarboxylic acids, preferably malonate salts; and mixtures thereof.	Decreasing sebum production and/or pore size
US20050244362 KAO COPR.(2004) [27]	Natural extract and organic compound	Avocado oil (Butyl esters of fatty acids)	Reduce sebum of the hair and scalp
US4529587 Unilever(1982) [28]	organic compound	Biotin antagonist or a salt thereof	Decrease activity of the enzyme acetyl-SCoA-carboxylase and hence reduce lipid synthesis in sebaceous glands so that less sebum is produced

Composition nature matrix

IP map for Composition nature matrix

Year	Organic Compound	Natural extracts	Peptides	Nucleotides	Natural extract + Organic comp
2005	....	....	....	....	UNILEVER (1)
2004	WARNER (1)	BLOTECH (1)	....	....	KAO (1)
2003	WARNER (1)	APHIOS (1)	....	FUNDIACION (1)	....
2002	WARNER (1)	....	....	....	....
2001	PFIZER (1)	LG HEALTH-CARE (1)	....	....	....
2000	....	....	L’OREAL (1) / N/A (1)	....	....
1999	SHISEDIO (1)	COLOMER (1)	....	....	....
1998	....	....	L’OREAL (1)	....	....
1995	....	....	N/A (1)	....	....
1987	....	KAO (1)	....	....	....
1982	UNILEVER (1)	....	....	....	....

Focus on different aspects

Focus on patents

Focus of patents	Patent no.	Rec. no.
2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.	US20020052498 [29]	1
Thyromimetic compounds, and its role in treating hair loss	US20030007941 [30]	2
Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT	US20060009430 [31]	3
4-cycloalkoxy benzonitriles and its use as androgen receptor modulators	US20060009427 [32]	4
Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity	US20050118282 [33]	5
New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists	US20050085467 [34]	6
Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders	US20060009429 [35]	7
Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss	US20030073616 [36]	8
Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor	EP0279010 [37]	9
Stimulating hair growth using benzopyrans	US20040157856 [38]	10
Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.	US20050053572 [39]	11
Compositions to prevent or reduce hair loss	US20060052405 [40]	12
Prostaglandin EP-3 receptor antagonists for reducing hair loss	US20050123577 [41]	13
Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth	US6447762 [42]	14
Metalloprotease inhibitors to induce and/or stimulate the growth	US20040071647 [43]	15
Method of decreasing sebum production and pore size	US20050277699 [44]	16
Method for reducing sebum on the hair and skin	US4529587 [45]	17

Focus on Technology

Technology focus

Distribution on different aspects

Distribution based on patent types

Distribution based on patent types

Distribution of key ingredients

Distribution of key ingredients

Other attributes of the key ingredients

Other attributes of the key ingredients

Distribution based on target diseases

Distribution based on target diseases

Key ingredients vs. Target disease/disorder

Key ingredients vs. Target disease

Target species

Target species

Mode of administration

Mode of administration

Product type vs. Product form

Product type vs. Product form

Distribution of patents based on different aspects

List of patents

List of patents

Distribution of patents based on target diseases

Distribution of patents based on target diseases

Distribution of patents based on application

Distribution of patents based on application

Questions Dolcera Answers

What’s hot?

• What compositions/ approaches are the most promising?
• What can I license?
• Can you map blockbuster products to their patents?

Can you save me some time?

• What combinations/ compounds have already been tried?
• Is any empirical data available?
• Can you tell me the side effects?

Where should I focus my R&D investment?

• What are the most promising approaches?
• Where’s the ‘white space’ for me to play in?

Any hints for research?

• Are there any combinations I could develop?

What should I do in this geography?

• What are my competitors up to in this geography?
• What are my strengths/ weaknesses here?

What’s my competition up to?

• What’s my top competitor investing in?
• Are there any loopholes in their patents?
• When are their patents expiring?
• Will a competitor emerge from nowhere and surprise me?
• What are the crowded areas?

How do I play defense?

• What should my blocking/reactive strategies be?

New Combinations based on IP study?

Yes, new Combinations can be made with natural products based on IP study

• Walnut extract containing inhibitor (as anti-androgen) and Flavnones (for vasodilation).
• Sophora Flavnones (for vasodilation) in combination with Saw Palmetto berry (as anti-androgen).

Note: The above combinations are based on limited study and are only possible examples

IP studies provides

Technology trends

• Use of saw palmetto berry for treating alopecia was first patented in 1996.
• Since then, 144 patents (including family patents) have been filed till 2006.
• Most patents use saw palmetto berry in combination with other products.

Technology trends

New opportunities

Yes, the IP studies provide new opportunities in the following area.

• Sophora Flavescens contain flavnoids.
• Natural extract Sophora Flavescens cited in LG patent of 2001.
• Research shows fewer than 7 patents based on Sophora Flavescens for hair loss or alopecia.

Conclusions

• Hair loss medication is a very active area of research and intellectual property development.
• One of the most promising areas of development is the area of Anti-androgens.
• The top companies are Merck, L’Oreal and Smithkline.

Useful links

• Pathways example
• Signaling Pathways