icic 2016: 20 years is not enough

20 years is not enough

Ch. Hoock – PATON

18.10.2016

2

20yrs// ICIC

Heidelberg 2016

Agenda

PATON

Patent strategy

Life cycle management of pharmaceutical patents

3

20yrs// ICIC

Heidelberg 2016

Hoock-PATON

• Thuringia Patent Centre PATON, founded 1895,

since 1957 located at the Technical University Ilmenau

• Dedicated to support you regarding all aspects of

industrial intellectual property (IP)

• From idea to innovation

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20yrs// ICIC

Heidelberg 2016

PATONINFORM

About us

PIZNET (PATLIBS)

PATON – State patent centre at Technical University Ilmenau (Landespatentzentrum Thüringen)

Public reading/searching roomReceiving of patent filings, utility models, designs, and trademarks on behalf of DPMA (German Patent office)

Search & Analysis Services

PATON-Academy:University curricula, seminars, training on scientific and patent information

Technology transfer:assessment of the economic potential of an invention; selling/out-licensing of IP

PATINFO (31.05.-02. 06.2017)

Patent Information Technology:software developmentfull text servicesstatistical analyses of patent data

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20yrs// ICIC

Heidelberg 2016

PATONINFORM

About us

Receiving of patent

/trademark

filings

Patent marketing/

technology transfer

PatentIdea Innovation

Customized in-

house databases

Custom Online

searches

Trend analysis in

Science & business,

competitive

intelligence

Full text delivery

Patent library:

assisted online

searchesConsulting

Support

Training

One Stop Shop for all Patent Services

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20yrs// ICIC

Heidelberg 2016

Hoock-PATON

patent strategy general

To file or not to file

When

Where

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Hoock-PATON


SMEs

SME strategies of IP protection:

source: Inno-Tec Study 2010 LMU

Patents Secrecy Copyright complex design head start

suitable very suitable OKNot suitableTotally unsuitable

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Hoock-PATON


As soon as possible:

• How likely is competition? Danger of patent filing by competitors or publication

• Observe patent strategy of competitors

As soon as necessary:

• estimate development time (<20yrs?)

• Development projection:satisfy 18m to disclosure?

• Is the market ready?

when

R & DFirst

effectsTesting

secure knowledge

Date of filing

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20yrs// ICIC

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Hoock-PATON


Advantages:

- Flexibility

- Competitors long in the dark

- Developments of the invention can be used for drafting more precise claims

- Diversion divisional applications

- DE: “Branch off” of utility model from pending application

- …

Disadvantages:-Filed vs. granted patents in patent statistics (portfolio value, stakeholder)-Poorer legal position in case of infringement-Utility patents not for procedures, methods

when

Late Granting

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Hoock-PATON

Economic relevance of the designated state

• Market size in the range of the invention• Own position in the market• Licensing potential

Legal framework

• Patentability• grant procedure (length, costs, examination?)• Enforceability in case of infringement• Licensability to third parties


where

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Hoock-PATON

patent strategy Pharma

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Hoock-PATON


general

Differences to technical patents:

- Long development time (10 – 20 yrs.)

- Long product cycle (30 yrs. or more)

- High costs of development (NCE 500- 1000 Mio. €)

- High value of single invention

- High risk

- Special IPR for use („medical use“)

- Registration procedure necessary

- SPCs / term extensions

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general

Differences determine procedures for:

• Filing – Strategy

• Litigation - Strategy

• Market Strategy (launch)

• R & D - strategy

• Registration strategy (market authorisation)

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* Patent expiry: Lipitor: November 2011 Seroquel: April 2012 Plavix: May 2012 Diovan: September 2012 Zyprexa: October 2011

Sales of blockbuster drugs before and after the patent expiration * in 2011 and 2012 (in bill. $)

7.087

9.580

5.665

4.6224.338

2.547

3.900

4.417

1.701

1.294

0

2.000

4.000

6.000

8.000

10.000

12.000

Plavix (Sanofi/ BMS) Lipitor (Pfizer) Diovan (Novartis) Zyprexa (Eli Lilly) Seroquel IR (AstraZeneca)

Sale

sin

Mio

US

D

Drug (Originator)

Sales 2011 Sales 2012

Source: Thomson Reuters

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Hoock-PATON


Source: IMS health /GPhA 2015

Development of the price reduction of medicines after patent expiry in the US in 2015

-90,0%

-80,0%

-70,0%

-60,0%

-50,0%

-40,0%

-30,0%

-20,0%

-10,0%

0,0%

0 12 24 36 48 60 72 84 96 108 120

Pric

e d

eclin

e

Months after patent expiry

Oral drugs all drug forms

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Hoock-PATON

Active Ingredient

Indication

Process

Formulation

Dosage


general

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Active Ingredient

Indication

Process

Formulation

Dosage

Indication II, III

Intermediates

Analysis methods

Test systems for identification of mode of action

process II, III…

Packaging

Routes of administration

SPC


general

Dosage form

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Hoock-PATON


what

source: VFA, “Forschung für das Leben 2015”

Drug developments of VFA members with est. MA by 2017 (NMEs)

Bio-tech

Vaccines

Natural products

Cells

Chem. Synthesis

Size of drug molecules

a) Chem. Synth.:

ASA (aspirin) 21 atoms

b) Chem. Synth.: Ramipril 62 atoms

c) Natural product:

Ciclosporin 196 atoms

d) Biotech: Insuline 790 atoms

e) Biotech: mABs 20.000 atoms

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Pre-clin.

Lab

0 Pers.

Months to yrs

clin. ph. I

Pharmacokinetics, pharmacodynamics,

safety and tolerability of the

drug10-50 Pers.

Weeks/months

clin. ph. II

a) Proof of concept

b) Dose finding

50 – 200 Pers.

months

clin. ph III

Proof of effectiveness in studies, often

against standard placebo

Often> 1000 pers.

Months to years

clin. ph. IV

Observations on the market,

Often the basis for further

development

Filing date

Marketing authorisation,launch

Phases of clinical development


general -when

5y

10 y 15 y 20 y

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Pre-clin.

Lab

5.000-10.000

clin. ph. I

6.7

clin. ph. II

4.3

clin. ph III

3.3

clin. ph. IV

1

Marketing authorisation,launch


general -when

Success rates for market entry are low – selection from 5.000-10.000:

source: Paul, S.M., et al.: Nature Reviews Drug Discovery 9, 203–214 (2010)

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general -when

First filing without exact definition of structure: Markush- formula Publication of drug effect of pre-clinic or early clin. phases as long possible linked to „Lab-Codes“

Lab-Codes not clearly defined: not for 1 substance, but for project or for group of substances

1 Lab code more substances or1 substance more Lab Codes: „Losartan“ (DuPont):

MK 954, DuP 753, L-158086, MK-0954, E-3340

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where

Due to high investment: broad protection necessary

First filing national (to win priority year), PCT focussed to:

• Developed countries (potential production sites)

• Market (with premium price!)

• Countries where patent protection influences sales price (e.g. EU, CN)

Costs for filing + prosecution often of secondary interest

Often > 20 countries

Reason:

• competitors will use regional patent gaps as high profit margins give good opportunities, even if the market is limited to small countries.

• Reduce development/production in "patent-free countries“ –changed situation in China, India (Israel)

• Expensive development + authorization procedure must be recouped through worldwide revenues.

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SPC

Definitions

SPC = Supplementary Protection Certificate

PTE = patent term extension

SPCs can extend the protection (exclusivity period) for DRUGS and Plant protection products up to 5 years.

PIP = Paediatric Investigation Plan

Paediatric studies can extend the SPC term by 6 months

Art. 63 EPC (DE Art 49a PatG)

EEC1992 no 1768/92 products for human or veterinary use

EC 1996 no 1610/96 products for plant protection

EC 2006 no 1901,1902/2006 medicinal products for pediatric use

EC 2009 no 469/2009 medicinal products

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- Market success depends on patent protection +

marketing authorisation

Extension of the exclusivity 1: SPC

Extension of the SPC 2: PIP (ZLV) Zertifikatslaufzeitverlängerung

Patent Marketing Auth.

SPC/PIP

0 J.20J. 25J.

SPC PIP (ZLV)Patent

M.A.


SPC

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Hoock-PATON

Patent filing

Max 25,5 yrs

protection

20 yrs (PatG §16,

Art. 63 EPC)

1. EEC-M.A.

max. 15,5 yrs

max. 5,5 yrs

Patent/SPC-expiry

Launch generics

SPC

dossier protection 8+2+1 yrs

(Art. 10 Dir. 2004/27/EC)

1-2 y. generics

developmentM.A.

generics

current model of generic drug approval in EU


Calculation of SPC expiry

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Hoock-PATON

patent strategy PharmaSPC

1986 launch of Prozac® (Fluoxetine - antidepressant ) in UK,

Patent expiry 1995. About 80% of Prozac sales during SPC term source: IMS health

„SPCs worth millions to Pharma Companies in Europe”

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patent strategy PharmaSPC

SPC-Impact

INN EU_MA SPC PAT_EXP SPC-yrs

Carvedilol 18.04.1990 07.04.2004 07.04.1999 5

Enalapril HCT 15.11.1993 10.12.2004 10.12.1999 5

Ciclosporin 01.04.1992 26.02.2004 26.02.1999 5

Lamotrigin 05.11.1990 30.05.2005 30.05.2000 5

Terbinafin 03.10.1990 07.08.2005 07.08.2000 5

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SPC

0

10.000.000

20.000.000

30.000.000

40.000.000

50.000.000

60.000.000

70.000.000

80.000.000

90.000.000

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

CARVEDILOL

7.4.1999

Ca 150 Mio € Ca 350 Mio €

7.4.2004

Sales for Carvedilol in DE (per yr, originator). 30% during patent term( to 07.04.99), 70% during SPC (to 7.4.2004)

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SPC

LAMOTRIGIN

0

10.000.000

20.000.000

30.000.000

40.000.000

50.000.000

60.000.000

70.000.000

80.000.000

90.000.000

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Ca 100 Mio € Ca 250 Mio €

30.5.2000 30.5.2005

Sales for Lamotrigine in DE (per yr, originator). 35% during patent term( to 30.05.00), 65% during SPC (to 30.5.2005)

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Hoock-PATON


SPC/PTE where

Introduction varies nationally:

US 1984 Hatch-Waxman ActJP 1988

In Europe in 27 EU countries + NO, IS, CH1993: Belgium, Denmark, France, Germany, Ireland, Italy,

Luxembourg, Netherlands, UK

1994 EFTA - Austria, Finland, Iceland, Norway, Sweden(+ Liechtenstein / Switzerland from 03.02.1995)

1998: Greece, Spain, PortugalNew EU Countries: From May 2004, Croatia (07/2013), different transition periods

PTE / SPC also available in: Australia, Israel, Japan, Morocco, Russia, Singapore, South Korea, Taiwan, Ukraine, Belarus, Serbia (2013..)

Not in: China, India, Canada, South America, South Africa, …

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„Me too“

"Me too" strategy

First member of a new class of agents (NCE = "new chemical entity") often is not perfectly protected.

Other originators use gaps in the scope of the patent protection

"Me too" versions may not be covered by general Markush structure and / or show a selection, special, unexpected benefits, … in

Pharmacokinetics, efficacy, tolerance etc.

NDA (complete new MA) needed

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Hoock-PATON

Agopton®, Takedapatented : 1985authorized:1990

Losec®, Haessle/AZ, patented:1979authorized: 1987

Pantozol®, Byk Gulden/Altana, patented: 1985authorized:1994

Pariet®, Eisai,patented: 1987authorized:1998


„Me too“

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1960 1963 1965

1963 1980 CH 1978


„Me too“

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Life Cycle Management usually begins shortly after 1. M.A.Reason: term of basic patent after M.A. often only 5-10 y. protection, with SPC up to 15 years (+ possibly. 6m)

Possibilities:Formulation patents (for example, 3 * times/d 1 * daily,

capsule effervescent tablet)New routes of administration: tablet, injection, suppositories

Identification of additional effects

Structural variants: Salts

Hydrates /Solvates

Pure enantiomers instead of racemates

Polymorphs

Prodrugs

combination productsE.g.: Antihypertensives + diuretics, aspirin complex (aspirin + pseudoephedrine HCl)


„Life Cycle“

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Basic patent is often "only" protection of the active substance, if necessary with reference to a possible pharmaceutical application, for example alendronate

For substance X effect E1 is detected first medical indication

Art. 54(4) EPC = 1st Medical Use


1st medical use

Broadest claim is functional:"Use of effectors of dipeptidyl peptidase for lowering blood sugar levels"

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1st medical use

Examples:Alendronate, Henkel 1981 (EP39033):Markush structure

use for water softening …

also suitable for production of cosmetic or pharmaceutical preparations

MSD (Inst Gentili.) 1983:

Patent claim:(US04621077A)

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For substance X effects are E2, E3 discovered second and further medical use

The second indication is defined as a new and not obvious therapeutic use of an already known substance in another field of medicine

The substances for medical use are also new, if this application is not part of the prior art. (Art. 54 (5) EPC) = 2. Medical Indication

Example: Pfizer SildenafilE1) EP 0463756, 1991, Pyrazolopyrimidone as agents against anginaE2) EP 0702555, 1994, for the treatment of erect. Dysfunction (Viagra®)E3) EP 1097711, 2000, treatment of pulmonary hypertension (Revatio®)

SPC for E1 to 2013


2nd medical use

http://upload.wikimedia.org/wikipedia/commons/0/08/Sildenafil_Structural_Formulae.png

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2nd + further medical use

Source: Thomson-Reuters White Paper Sept. 2012 KNOWLEDGE-BASED DRUG REPOSITIONING TO DRIVE R&D PRODUCTIVITY

DRUGS THAT HAVE BEEN SUCCESSFULLY REPOSITIONED

DRUG ORIGINAL INDICATION NEW INDICATION

Amphotericin B Fungal infections Leishmaniasis

Aspirin Inflammation, pain Antiplatelet

Bromocriptine Parkinson’s disease Diabetes mellitus

Finasteride Prostate hyperplasia Hair loss

Gemcitabine Viral infections Cancer

Methotrexate Cancer Psoriasis, rheumatoid arthritis

Minoxidil Hypertension Hair loss

Raloxifene Cancer Osteoporosis

Thalidomide Morning sickness Leprosy, multiple myeloma

Sildenafil Angina Erectile dysfunction,

pulmonary hypertension

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In good time before expiry of the patent for a racemate of active ingredient file a new patent protecting on pure enantiomer, usually in combination with manufacturing processes.

Example 1: Haessle / AstraZeneca omeprazole esomeprazole

Omeprazole EP 05129 filed 1979, 1st MA 1987 Esomeprazole EP124495 fil.1984, 1st MA 2000 SPC to 2009


„Chiral switch“

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Example 2: Lundbeck citalopram escitalopram (antidepressants)

Citalopram Pat 1976 - 1994 M.A. Jan. 1989Escitalopram Pat 1989 -2009 to 2014 SPC 2014

Escitalopram (S Enantiomer)

Citalopram: (R)-Isomer

+ (S)-Isomer

As a drug initially was the racemate [1: 1 mixture of the (S) - form and (R) -form] used. However, the effect is due to the (S) - (+) - enantiomer (escitalopram) of citalopram


„Chiral switch“

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First development must be launched quickly, but is often not "ideal" form of the active ingredient.

Salt form:Active compounds usually „large“ organic molecules which are sufficiently soluble only as a salt. Salt partners crucial for stability, solubility, pharmaceutical workability

Examples:Pfizer -Amlodipine maleate pat. 1983 2003, M.A. 1989 SPC 2004Amlodipine besilate fil. 1987 2007 Norvasc®

Sanofi -Clopidogrel (fil. 1983 2003)Clopidogrel bisulphate (fil. 1988 1998 SPC 2013, Plavix®)Generic "non-hydrogen sulphates"


„Salts, Hydrates, Polymorphes“

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Hydrates:Azithromycin Pfizer / PLIVABasic formula, with Markush structure PLIVA, 1981 20011. EU approval: 04/1991, SPC 2006Azithromycin - dihydrate (A * 2 H2O), Pfizer, filing 1988 2008

and- Sesquihydrate (A * 1.5 H2O) vs. Azithromycin monohydrate and

dihydrate (EP 1390377 revoked 2009)



EP298650B

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Polymorphism, that is, arrangement of the molecules in the crystal lattice, influences:

Macroscopic crystalline form (cubes, columns, needles)melting pointsolubilitywettabilitystability ("best before ...")dissolution rate, …

Determinable by DSC and XRPD or sNMR

Examples:Flupirtine maleate (Katadolon®), torasemide (UNAT®), ranitidine (Zantac®), paroxetine (Seroxat®), azithromycin (Zithromax®)

Affected by the crystallization process: temperature, speed, solvents or by heat treatment after crystallization or even mechanically!



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Polymorphs:DSC famotidine (Pepsid®) sNMR CRYSTAL FORMS OF AZITHROMYCIN



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Polymorphs A and B of Flupirtine Maleate

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Polymorphs of Torasemide (UNAT®, Diuretic)

Az. COMPANY EXP. REMARK PAT_FIL

P 25 16 025.2 Christiaens

Pharma

12.04.1993 Torsemide 12.04.1975

P 35 29 529.5

(Prio f. 36 67 970)

Boehringer

Mannheim

GmbH

01.05.1991 (ZRN4) 17.08.1985

P 36 67 970.4 Roche 12.08.2006 Torasemide Form I (UNAT®) 12.08.1986

P 699 22 977 Pliva 01.10.2019 18.01.08 (NIT0) Nichtigkeitsklage

zurückgenommen

01.10.1999

U 299 24 789 Pliva 02.11.2009 Toracard®; Torasemide N 01.10.1999

P 601 03 276 Teva STABILE PHARMAZEUTISCHE

Formulation DIE TORSEMID

MODIFIKATION II ENTHÄLT

21.02.2001

U 201 22 564 Teva 01.09.09 STABILE PHARMAZEUTISCHE

Formulation DIE TORSEMID

MODIFIKATION II ENTHÄLT

21.02.2001



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Patenting of new galenic formulation

Pharmaceutical formulation affects:Compatibility (as altered side effect profile with a slower rise in level)Duration (1 * daily instead of 3 * day)Potency (better bioavailability - 300mg instead of 1000 mg)Durability (3 years instead of two years)Administration (tablet instead syringe)

New formulations often have therapeutic benefits and higher patient complianceTo block generics, old formulations are taken off the market, dropping the original marketing authorisation.


„Formulation“

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Example Omeprazole Prilosec vs. Antra MUPS®

MUPS = Multiple Unit Pellet System. Antra MUPS® tablets are compressed from small enteric coated pellets that disintegrate rapidly on contact with fluid better bioavailability.

Omeprazole MUPS® EP1078628 (filed 1995, rev. 2014), launched 1998,generic competition for old formulation starting ‘99 (Hexal, Ratiopharm)


„Formulation“

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Drug is chemically modified (covalent bond).

Derivative is cleaved before / during / after absorption releasing the active substance.

Benefits in bioavailability and pharmacodynamics and pharmacokinetics

Is usually regarded as NCEs

Examples: EPO vs. PEG-EPO, PPIs (Sulfinylbenzimidazole), valacyclovir, fosamprenavir, esters of steroids, insulin derivatives,…


„Pro-Drugs“

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Timing Life Cycle Management

First mention basic structureS1: Defined structureE1: structure S1 with effect E1Marketing authorizationsubmit SPC for E1F1: Formulation to structure S1 with effect E1F2: Formulation to structure S1 with effect E1...E2: structure S1 with effect E2S2: Combination product with S1 to effect E1

D1: derivative of S1, e.g. new saltD2: derivative of S1, e.g. hydrateD2: derivative of S1, e.g. polymorph

S3: pro-drug to S1

By combining: many products + patents possible

Omeprazole from AZ> 80 patent families


„Life Cycle“

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„Life Cycle“

Lifecycle-Management can lead to patent thickets (fencing)

lifecycle stage early late

imitation blocking imitation blocking

patent category

Comple-mentary

Substi-tutive

comple-mentary

Substi-tutive

Comple-mentary

substi-tutive

comple-mentary

substi-tutive

substance •crystals, isomers…

• • • • • •process • • • •formulation/ dosing

• • • • • •fixed dose combination

• •indication/ use • •

Source: Christian Sternitzke Research Policy, 2013, 42(2), 542-551

http://econpapers.repec.org/article/eeerespol/

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Example Degussa / AstaMedicaP1 First mention of the basic structure "AM" as part of a substance class -Markush structure, disclosure preparation, no effect or impact rather unspecific as another list of possible applications, especially interesting compounds only in large list or combination of listsRegistration abroad eg. FR / BE / ZAProtection: 1967-1987 (1984)

P2 patent of addition, divisional application,Diversion from P1 with disclosure ofStructure "AM" explicitly, but as oneof many examples, mentioningpossible uses (FR / BE / ZA) protection as above


life cycle-ex.

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P3 DE before publication of P1 new application with selected content from P1 and P3 disclosing selected compounds. Effect not related to specific structures but LAB codes.Protection: 1968-1986

P4 1980 In DE Priority filing- new salt form with improved pharmacological properties as a mixture of different crystal forms, processes for preparing + application as medicines, publication withdrawnP4N 1981 DE subsequent application to P4 (internal priority), 2001


life cycle-ex

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P5 1985: New method of synthesis of active ingredient

P6 1985: A process for preparing an important precursor

P7 1990: Priority filing: new indication

P8 1992: Priority filing combination product with active X

P9 1993: 1st Sustained-Release formulation

P10 1994: New indication (CNS)

P11 1998: Synthesis of pure polymorph A

P12 2000: New Indication - veterinary pharmaceuticals, transdermalFormulation


life cycle-ex

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P13, 2003: Other salt form for new formulation-new application form: injection

P14 2005: New formulation - once daily

P15, P16, 2008: New salt forms of active ingredient –improve the solubility / hedging of the main product / protection against workarounds

P17 -P19, 2009-2013:new polymorphs of the drug better pharmaceutical processing / stability


life cycle-ex

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patent strategy Pharmalife cycle-ex

P1 Markush-Formel, FR/BE/ZA

P3 DE-Anmeldungdef. Strukturen + allg.

Wirkung

P2 Ausl. Zusatzanmeldungdefinierte Strukturen

BE-Zusatzanmeldung zu P1

P4 DE Prioanm.neue Salzform Mischung v. Polymorphen, Arzneimittel

P4N DE-Nachanmeldung

P5 DE-Prio NeuesVerfahren Herstell-

ung reineres Produkt, PbP

P6 Herstellung-2Zwischenstufe PbP

P5N EP Nachanmeldung

P7 DE-PrioMed. Indikation II

P7N EP-Nachanmeldung

P8 DE-Prio: Kombinationsprodukt 1

P9 Formulierung I

P8N

P9N

P10 Indikation II (ZNS)

P11 reines Polymorph + Herstellung + PbP

P11N-EP

P12 Indikation Tierarznei + transdermal Formulierung

P13 Injektformulierung

P13N

P14 Orale Formulierung 1/d

P14N

P15 neue Salzformen, Formulierungen

P16 spez. Salz, Formulierung

P17-P19 neue polymorphe Formen

15

.09

.19

65

16

.08

.19

67

16

.07

.19

69

16

.06

.19

71

16

.05

.19

73

16

.04

.19

75

16

.03

.19

77

14

.02

.19

79

14

.01

.19

81

15

.12

.19

82

14

.11

.19

84

15

.10

.19

86

14

.09

.19

88

15

.08

.19

90

15

.07

.19

92

15

.06

.19

94

15

.05

.19

96

15

.04

.19

98

15

.03

.20

00

13

.02

.20

02

14

.01

.20

04

14

.12

.20

05

14

.11

.20

07

14

.10

.20

09

14

.09

.20

11

14

.08

.20

13

15

.07

.20

15

14

.06

.20

17

patent strategy Pharmalife cycle-ex

P1 Markush-Formel, FR/BE/ZA

P3 DE-Anmeldungdef. Strukturen + allg.

Wirkung

P2 Ausl. Zusatzanmeldungdefinierte Strukturen

BE-Zusatzanmeldung zu P1

P4 DE Prioanm.neue Salzform Mischung v. Polymorphen, Arzneimittel

P4N DE-Nachanmeldung

P5 DE-Prio NeuesVerfahren Herstell-

ung reineres Produkt, PbP

P6 Herstellung-2Zwischenstufe PbP

P5N EP Nachanmeldung

P7 DE-PrioMed. Indikation II

P7N EP-Nachanmeldung

P8 DE-Prio: Kombinationsprodukt 1

P9 Formulierung I

P8N

P9N

P10 Indikation II (ZNS)

P11 reines Polymorph + Herstellung + PbP

P11N-EP

P12 Indikation Tierarznei + transdermal Formulierung

P13 Injektformulierung

P13N

P14 Orale Formulierung 1/d

P14N

P15 neue Salzformen, Formulierungen

P16 spez. Salz, Formulierung

P17-P19 neue polymorphe Formen

15

.09

.19

65

16

.08

.19

67

16

.07

.19

69

16

.06

.19

71

16

.05

.19

73

16

.04

.19

75

16

.03

.19

77

14

.02

.19

79

14

.01

.19

81

15

.12

.19

82

14

.11

.19

84

15

.10

.19

86

14

.09

.19

88

15

.08

.19

90

15

.07

.19

92

15

.06

.19

94

15

.05

.19

96

15

.04

.19

98

15

.03

.20

00

13

.02

.20

02

14

.01

.20

04

14

.12

.20

05

14

.11

.20

07

14

.10

.20

09

14

.09

.20

11

14

.08

.20

13

15

.07

.20

15

14

.06

.20

17

0

10

20

30

40

50

60

70

80

90

100

1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013

year

Sales (Mio €) KATADOLON

icic 2016: 20 years is not enough

Healthcare