Patent Sem inar Barcelona, Sept. 29, 2003

Screening Methods andResearch Tool Patents

- selected topics - 

Dr. Leo Polz

Patent Sem inar Barcelona – 29.09.2003

Talk OutlinePatentability of Screening Method / Research ToolPatents

EPO Practice – Case Study EP 0 624 100 B1Claim DraftingSufficiency of Disclosure

Enforcement of Screening Method / Research Toolpatents

Housey vs. Bayer - EP 0 403 506Research ExemptionScope of Protection

Patent Sem inar Barcelona – 29.09.2003

Quantum Leaps in Synthesis

Miniaturization and AutomatizationMiniaturization and AutomatizationCombinatorial ChemistryHigh Throughput ScreeningParallel Analysis/Sequencing

Patent Sem inar Barcelona – 29.09.2003

Research Tools

Eukaryotic TranscriptionFactorsNuclear ReceptorsLigands of OrphanReceptorsDevelopment of Cell CycleControl of MetabolicPathwaysActivity is ligand-dependent

PO4

Target/Receptor

Ligands Pharmaceuticals

Assays BiologicalPathway

Research Tools aim at Biochemical TargetsResearch Tools aim at Biochemical Targets

Patent Sem inar Barcelona – 29.09.2003

Screening Method Patent

Selection and Characterization of ReceptorModulatorsHigh-Throughput ScreeningStructure-based Drug DesignVirtual / in in silicosilico ScreeningReach-Through to Active Ingredients

Patent Sem inar Barcelona – 29.09.2003

EPO Case StudyEPO Case Study: EP 0 624 100 B1

“DNA Encoding a Human Serotonin Receptor“DNA Encoding a Human Serotonin Receptor(5-HT 4B) And Uses Thereof”(5-HT 4B) And Uses Thereof”

Applicant: Synaptic Pharmaceutical Corp.Paramus, N.J., USA

Date of Filing: 29.10.1993Grant of Patent: 03.05.2000No Opposition Filed !No Opposition Filed !

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 – Claims (i)

47. A process for identifyingidentifying a chemicalcompound which specificallyspecifically bindsbinds to a 5-HT4B receptor, […] which comprisescontacting non-neuronal cells expressingon their cell surface the 5-HT4B receptor[…] with the chemical compound underconditions suitablesuitable for binding, anddetectingdetecting specific binding of the chemicalcompound to the 5-HT4B receptor.

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 – Claims (ii)

48. A process involving competitive binding foridentifying a chemical compound whichspecifically bindsspecifically binds to a 5-HT4B receptor, […] whichcomprises separately contacting non-neuronalcells […] with the chemical compound and asecond chemical compound known to bindknown to bind to the5-HT4B receptor, […], and detectingdetecting […] thedecrease in the binding of the second chemicalcompound […] in the presence of the chemicalcompound indicatingindicating that the chemical compoundbinds to the 5-HT4B receptor.

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 – Claims (iii)

49. A process for determiningdetermining whether achemical compound specifically binds toand activatesactivates a 5-HT4B receptor, […] whichcomprises […] measuring the secondmessenger response in the presence and inthe absence of the chemical compound, achange in the second messenger response[…] indicatingindicating that the chemical compoundactivatesactivates the 5-HT4B receptor.

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 – Claims (iv)

50. A process for determiningdetermining whether achemical compound specifically binds toand inhibitsinhibits a 5-HT4B receptor, […] whichcomprises […] measuring the secondmessenger response […], a smaller changein the second messenger response […]indicatingindicating that the chemical compoundinhibits activation inhibits activation of the 5-HT4B receptor.

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 - Screening Method (i)Screening Method (i)

What is the screening aimed at?What is the screening aimed at?IdentifyingIdentifying a chemical substance thatspecifically bindsbinds to the receptorDeterminingDetermining a substance that activatesactivates thereceptorDeterminingDetermining a substance that inhibitsinhibits thereceptor

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 - Screening Method (ii)Screening Method (ii)

Identifying a binding substanceIdentifying a binding substance:Functional language (under conditionssuitable for binding chemical compound)Involving competitive bindingComparison of measured results (secondmessenger response)Specific result (decrease in second messengerresponse) indicates that compound bindsspecifically to receptor

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 - Screening Method (iii)Screening Method (iii)

Determining a modulatorDetermining a modulator:Comparison of measured results (secondmessenger response)Specific result (change in second messengerresponse) indicates that compound is anactivatoractivator of receptorSpecific result (smaller change in secondmessenger response) indicates thatcompound is an inhibitorinhibitor of receptor

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 – Claims (v)

65. A method of preparing a pharmaceuticalpharmaceuticalcompositioncomposition which comprises obtainingobtaining achemical compound, identifyingidentifying a chemicalcompound as one which specifically bindsto a 5-HT4B receptor according to themethod of any of claims 47, 48, 49 or 50, andadmixingadmixing the compound with apharmaceutically acceptable carrier.

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 – Pharmaceutical Composition (i)Pharmaceutical Composition (i)

Process of Process of ManufacturingManufacturing a Product: a Product:Scope of Protection extends to productimmediately obtained by manufacturingprocessActual process steps (obtaining compound;admixing carrier) are not definedActive ingredient (chemical compound)identified by screening method

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 – Claims (vi)

66. A process of obtainingobtaining a chemicalcompound which comprises identifyingidentifying achemical compound which specificallybinds to a 5-HT4B receptor according to themethod of any of claims 47, 48, 49 or 50, andpreparingpreparing the chemical compound.

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 – Chemical CompoundChemical Compound

Legal Validity - Sufficiency of DisclosureLegal Validity - Sufficiency of DisclosureSkilled person must be in a position tomanufacture chemical compound that hasbeen identified by screening method justrelying on his common general knowledgeNOTE:NOTE: Identification of compound does notnecessarily provide sufficient information tomanufacture it (e.g. structural formula)!

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 – Claims (vii)

38. A pharmaceutical compositionpharmaceutical composition comprisingan amount of a substancesubstance effective toalleviate the abnormalities resulting fromover-expressionover-expression of a human 5-HT4Breceptor, wherein the […] receptor has anamino acid sequence […] encoded by thenucleic acid of claim 1 to 3 […].

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 – Claims (viii)

39. A pharmaceutical compositionpharmaceutical composition comprisingan amount of a substancesubstance effective toalleviate the abnormalities resulting fromunder-expressionunder-expression of a human 5-HT4Breceptor, wherein the […] receptor has anamino acid sequence […] encoded by thenucleic acid of claim 1 to 3 […].

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 – Pharmaceutical Composition (ii)Pharmaceutical Composition (ii)

Disease to be treated characterized byDisease to be treated characterized byfunctional features relating to underlyingfunctional features relating to underlyingbiochemical mechanism:biochemical mechanism:Over / Under-Expression of receptorPatentable in the view of T241/95„Serotonin Receptor / ELI LILLY“?

Decision issued (14.07.2000) after grantMedical condition must be a “real life disease”

Patent Sem inar Barcelona – 29.09.2003

EP 0 624 100 B1 – Pharmaceutical Composition (iii)Pharmaceutical Composition (iii)

Support in the description:Support in the description:Patent discloses receptor and manufacture thereofPatent discloses method of detecting expression ofreceptor in tissuePatent discloses method of determining thephysiological effects of expression varying levels ofreceptor (by creating a non-human transgeneticanimal)Patent gives concrete examples of compounds anddiseases

Sufficient to comply with Art. 83 EPC?Sufficient to comply with Art. 83 EPC?

Patent Sem inar Barcelona – 29.09.2003

Legal Questions resulting from EP 0 624 100 (i)

What is the What is the resultresult of a screening method of a screening method:product product oror information? information?

If it is a product, does scope of protection alsoextend to products identifiableidentifiable by saidscreening method (“Reach-Through ClaimReach-Through Claim”)?If it is information, does including trivialprocess steps turn the claim into a true processprocessof manufactureof manufacture claim?

Patent Sem inar Barcelona – 29.09.2003

Legal Questions resulting from EP 0 624 100 (ii)

If the claim is directed to a cell-based methodof identifying a modulator of a target:

Is claim infringed if activity of substance wasknownknown before testing?Is claim infringed if activity was known only invitro and is now verified in vivo?Is claim infringed by activity verification duringdrug optimizationdrug optimization?

Patent Sem inar Barcelona – 29.09.2003

Legal Questions resulting from EP 0 624 100 (iii)

If the claim is directed to a cell-based method ofidentifying a modulator of a target:

Is claim infringed by determination of degree ofdegree ofpurificationpurification of mixtures of many substances (vs.screening of many individual substances)?Is claim infringed if screening method itself isestablishedestablished (e.g. verification that cloning ofrecombinant cell line was successful using knownmodulator)?

Patent Sem inar Barcelona – 29.09.2003

Legal Questions resulting from EP 0 624 100 (iv)

If the claim is directed to a cell-based methodof identifying a modulator of a target:

Can alleged infringer use the defense thatscreening method was not enablednot enabled?Method not able to distinguish between

an activatoractivator or inhibitorinhibitora specificspecific or non-specificnon-specific modulator

Patent Sem inar Barcelona – 29.09.2003

EP 0 403 506 B1 – Claim 3 (i)

3. Method of determiningdetermining whether a substanceis an inhibitor or activator of a proteinwhose presence in a cell line evokes aphenotypic characteristic other than thelevel of said protein in said cell per se,which comprises:[…]

Patent Sem inar Barcelona – 29.09.2003

EP 0 403 506 B1 – Claim 3 (ii)

[…] which comprises:(a) providing a first cell line which overproduces

said protein and exhibits said phenotypic response to the protein;

(b) providing a second cell line which produces theprotein at a lower level than the first cell line, ordoes not produce the protein at all, and whichexhibits said phenotypic response to the protein to a lesser degree or not at all;

Patent Sem inar Barcelona – 29.09.2003

EP 0 403 506 B1 – Claim 3 (iii)

[…](c) incubating the first and second cell line

with the substance; and(d) comparing the phenotypic response of

the first cell line to the substance with thephenotypic response of the second all line to the substance.

Patent Sem inar Barcelona – 29.09.2003

Product of Screening Method (i)

BAYER AGBAYER AG vs HOUSEY PHARMACEUTICALSHOUSEY PHARMACEUTICALSInfringement under 35 U.S.C. §271(g)

Whoever without authority imports into the US […] a product whichproduct whichis made by a process patentedis made by a process patented in the US shall be liable as aninfringer […].A product which is made by a patented process will […] not beconsidered to be so made after(1) it is materially changed by subsequence processesmaterially changed by subsequence processes; or(2) it becomes a trivialtrivial and non-essential component of anothernon-essential component of another

productproduct.

Patent Sem inar Barcelona – 29.09.2003

Product of Screening Method (ii)

Decision of Fed. Circuit 02-1598 (22.08.03)Decision of Fed. Circuit 02-1598 (22.08.03)Scope of protection is limited to physical goodsphysical goods thatwere manufacturedDoes not include information generated by a patentedinformation generated by a patentedprocessprocessDoes not include importation of a productimportation of a product that hasbeen identified by the screening method outsideoutside theUSCongressCongress should expand statute if court is wrong intheir interpretation

Patent Sem inar Barcelona – 29.09.2003

Claim Construction (i)

Phenotypic CharacteristicPhenotypic Characteristic(Interpretation of US District Court):

Observable traitObservable trait of a cellDoes not include characteristics of a

temporarytemporary or transienttransient nature (e.g. levels of concentration of ions or other chemical substances)

Preferably „culturalcultural“ or „morphologicalmorphological“ characteristics as stable, non-transient traits

Patent Sem inar Barcelona – 29.09.2003

Claim Construction (ii)

US position may US position may notnot be followed by German be followed by GermanCourt:Court:

Phenotypic response may be every effectevery effect which is somehow affect by target

Efflux of ions through an ion-channel proteinLevel of product catalyzed by an enzyme, even ifof transient nature(level of second messenger cGDP)

Patent Sem inar Barcelona – 29.09.2003

Arguments in German Litigation (i)

Defendant:Defendant:Method of Identifying whether a substance isan inhibitor or activator of a POI is notinfringed if it was known before that substancehad this activity

Plaintiff:Plaintiff:Method proves whether a substance that maybe known as an inhibitor or activator in vitroshows also this activity in vivo

Patent Sem inar Barcelona – 29.09.2003

Arguments in German Litigation (ii)

Defendant:Defendant:To verify that establishment of a recombinantcell line was successful, a substance known forits activatory or inhibitory activity was used –no method of determining whether a substanceis a modulatormodulator of a POI

Plaintiff:Plaintiff:All claimed method steps are used

Patent Sem inar Barcelona – 29.09.2003

Arguments in German Litigation (iii)

Defendant:Defendant:Where an actual screening is described, nonosecond cell linesecond cell line (control cell) is used

Plaintiff:Plaintiff:Comparison with second cell line notnotobligatoryobligatory for each substance tested, onlywhen substance is tested positive with first cellline

Patent Sem inar Barcelona – 29.09.2003

Arguments in German Litigation (iv)

Defendant:Defendant:Establishment of recombinant cell line is in anycase excluded from infringement byexperimental use exemptionexperimental use exemption

Plaintiff:Plaintiff:In the actual screening assay several thousandsubstances have been tested

Patent Sem inar Barcelona – 29.09.2003

Hatch-Waxman Act 1984

Patent Term ExtensionANDA Filing (Abbreviated New DrugApplication)Research Exemption ( § 271(e)(1) of 35 U.S.C)

Designation of compound as a candidate forFDA approval is sufficient to invoke theexemption

Patent Sem inar Barcelona – 29.09.2003

US US CaseCase LawLaw: Integra vs. Merck

Decision of Fed. Circuit 2003 WL 21299492(06.06.2003):Is drug discovery reasonably related to FDAIs drug discovery reasonably related to FDAapproval processes?approval processes?

NoNo drug was identified by plaintiffsPlaintiffs activities to drug hunting only apurely speculative process of “generalgeneralbiochemical experimentationbiochemical experimentation”

Patent Sem inar Barcelona – 29.09.2003

Arguments in German Litigation (v)

Defendant:Defendant:Third party cannot evaluate whether claim isinfringed or not because claimed method is notenabled, i.e. cannot distinguish betweenspecificspecific or non specificnon specific inhibition / activation

Plaintiff:Plaintiff:Plaintiff / Opponent did only make argumentsbased on plausibility, but did not providedid not provideexperimental evidenceexperimental evidence

Patent Sem inar Barcelona – 29.09.2003

Outlook

HouseyHousey vs. BayerBayer to be decided by end ofOctober 2003 (1. instance LG Düsseldorf)Applicants will come up with moresophisticated claim language in researchtool / screening method patentsSome limited reach-through claims may begrantedAttitude of Infringement Courts remains to beseen

Patent Sem inar Barcelona – 29.09.2003

End of Talk