best practices: ip strategies for diagnostics

MaRS Best PracticesSeries:IP Strategies forDiagnostics

Cynthia TapeAnna Wilkinson

MaRS, TorontoFebruary 28, 2008

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1. Brief review of patent basics2. Scope of patent protection for diagnostics3. Types of claims4. Support5. Enforcement and exploitation

Outline

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1. Brief review of patent basics

What is a patent• Patent is a bargain/contract between an inventor and the

state: the inventor discloses his/her know-how so that others can

practice the invention; in return for a time limited monopoly

• Restrictions on the type and quality of information that ispatentable categories of patentable subject matter information must be new, useful, unobvious

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What is a patent (continued)• Bargain is reflected in the format of a patent:

a description (text and maybe drawings), wherein inventorteaches how to practice the invention

a set of claims, which define the monopoly

• Bargain assessed during examination of a patent application:detailed examination procedure before the patent officemeant to ensure scope of monopoly reflects new subject matter

that the inventor actually invented and taught to the public

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The patent monopoly

•Patent monopolies are territorially limited• generally, must apply for a patent and application must be

examined in each country in which a monopoly is desired

•Patent monopolies are time limited• generally, 20 years from filing application

•Patent monopolies are exclusionary• a patent does not give the patentee the right to practice the

invention, only the right to sue someone else who practicesit without permission

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The monopoly (continued)

•Patent excludes others from making, using or sellingyour invention without permission

•Your patent may not allow you to practice the invention:No guarantee of Freedom to Operate

•Filing preserves your place in line: right to enforce onlywhen patent issues, which can take many years

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2. Scope of patent protection for diagnostics

What can be patented?• An “invention”: defined very broadly, with exceptions carved

out either through legislation or by case law:

In the United States: “anything new and useful made by man”

In Canada: any new and useful art, process, machine,manufacture or composition of matter, or any new and usefulimprovement thereon

In Europe: any inventions, in all fields of technology, providedthat they are new, involve an inventive step and are susceptibleof industrial application…followed by a list of specific exclusions

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What can be patented? (continued)• Selection patents:

permit a species of a previously patented genus to be patentedbased on a special advantage

• requirements: no prior specific disclosure; unpredictable,unexpected advantage

arise in context of chemical patents; could be relevant todiagnostics

hot issue in Canadian patent law:• long recognized in UK and US law; also here• SCC case being heard in April – whether

they should be recognized in Canada

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What can be patented? (continued)• Subject-matter restrictions relevant to diagnostics:

no patents for scientific principles or abstract theorems (PatentAct, section 27(8))

• E=mc2, Newton’s laws not patentable

• restriction relevant to diagnostics, but distinction may not beclear: LabCorp v. Metabolite Laboratories, Inc. USSC 2006

be aware of limitations on methods of medical treatment, higherlife forms, biotech

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What can be patented? (continued)• LabCorp v. Metabolite Laboratories

Patent for a test for detecting vitamin B deficiencies by measuring amino acidhomocysteine in a patient’s blood; method claim: assaying levels of homocysteineand correlating level with vitamin deficiency

LabCorp, licensee of Metabolite, began using a different method for measuringhomocysteine; stopped paying royalties

Metabolite sued and was successful at trial: LabCorp enjoined from using anyhomocysteine test

US Supreme Court dismissed appeal by LabCorp without explanation; dissent wouldhave held that broad method claim was unpatentable for being a basic scientific fact

value in having a variety of different types of claims

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Medical methods•Medical methods are not patentable in Canada and Europe

• may be able to claim “method” as a new usee.g. use of drug X for treating Y

• diagnostic methods are not patentable in Europe

• patentability of diagnostics in Canada may depend on whetherinvention includes an invasive step and if what you are doingcould also have a therapeutic effect

• Canadian example: diagnostic method that involved injection ofradiolabelled antibodies as tumour markers was permitted onbasis that would not have a therapeutic effect

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Medical methods (continued)•Medical and diagnostic methods are patentable in the United

States, but medical methods are not enforceable against adoctor can’t sue a doctor for infringement, but can sue a lab technician

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Higher life forms

•Not patentable in Canada per se• Harvard College v. Commissioner of Patents, SCC 2002

• 5:4 split decision: Harvard Mouse not patentable subjectmatter (not a composition of matter)

• But note Schmeiser v. Monsanto, SCC 2004• 5:4 split decision: claims for genes and cells of genetically

modified canola could be enforced against grower of canolaplants

•Patentable in the U.S. and Europe

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Biotechnological inventions

•Patent Offices and Courts have had to wrestle withvarious issues in determining what biotechnologicalmatter is patentable:

• Basic scientific facts are not patentable• Novelty: i.e. if sequence is present in nature, can it be

patented as new once isolated and sequenced?• Utility: what is required to show that a gene sequence is

useful?

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Biotechnological inventions (continued)

• In Europe biological material (including sequence orpartial sequence of a gene) which is isolated from itsnatural environment or produced by means of a technicalprocess even if it previously occurred in nature

• In US novelty is also based on isolation from nature

•Will also need to demonstrate utility of what you haveisolated/sequenced

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3. Types of claims

Common claim types

•Product• Structure• Process by which it is made (product-by-process)• Physical or chemical properties

•Machine or apparatus•System•Method or process•New use (of a new or known product)•Kit

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3. Types of claims

Subject matter

•Subject matter of claims dictated by technologicaldevelopments• In-vitro diagnostic testing (IVD): analyzingblood/urine/other specimens to screen for or monitordiseases or other medical conditions•Molecular diagnostics: determining the function of genesand gene products•Pharmacogenomics: functional genomics + molecularpharmacology•Personalized medicine

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3. Types of claims

Subject matter (continued)

•Diagnostic tests can be:• Predictive• Screening• Prognostic• Monitoring• Pharmacogenomic

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3. Types of claims

Participants in field

•When formulating claims, should consider differentparticipants:

• Innovators• Manufacturers• Users:

• Commercial labs• Hospital labs• Physician office labs• Patients

• Supervised• Over the counter

• Payers

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3. Types of claims

Structure of a claim

•Preamble (green)•Transition language (red)

open: “comprising”, “including”closed: “consisting of”

•Body (blue)•Claims are numbered• Independent claim (claim 1) does not make reference toanother claim and is broadest in scope; a dependentclaim incorporates the limitations of a preceding claimand so is narrower

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3. Types of claims

Examples of subject matter

•Amplification•Fluorescent in situ hybridization•DNA probes•Molecular labels•Biochips•Microfluidics•Signal detection•Biosensors•Medical imaging

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3. Types of claims

Example: Method (US 5314809)1. A method for nested amplification of a sequence within a target nucleic acid in a sample, the

method comprises:(a) simultaneously mixing said sample in an amplification reaction mixture containing an outer

primer pair and an inner primer pair, wherein said outer primer pair is capable of amplifying atarget nucleic acid to provide an amplified target sequence, and said inner primer pair iscapable of amplifying a subsequence within said target sequence;

(b) treating the amplification reaction mixture of step (a) in an amplification reaction at atemperature for annealing and extending said outer primer pair on said target nucleic acidand at a temperature for denaturing the extension products of said outer primer pair toprovide an amplified target sequence, wherein said temperature for annealing and extendingsaid outer primer pair is higher than the temperature for annealing and extending said innerprimer pair to said target nucleic acid and said temperature does not allow efficient extensionof at least one member of said inner primer pair; and

(c) treating the mixture of step (b) in an amplification reaction at said temperature for annealingand extending said inner primer pair on said amplified target sequence, and at antemperature for denaturing the extension products of said inner primer pair to provide anamplified subsequence.

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3. Types of claims

Example: Product (US 6576424)

1. An array comprising a solid substrate and a plurality ofpositionally distinguishable sequence specificpolynucleotides attached to the solid substrate of at least100 polynucleotides per cm2, at least a plurality of saidpolynucleotides comprising at least 25 nucleotides.

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3. Types of claims

Example: Apparatus (US 7238323)

1. A sequencing apparatus comprising: a body having a top portion, a bottom portion and aninterior portion;the interior portion comprising at least two intersecting channels, wherein at least one of thetwo intersecting channels has at least one cross sectional dimension between about 0.1 µmand 500 µm;an electrokinetic fluid direction system for moving a first sequencing reagent through at leastone of the two intersecting channels;a source of sequencing primers;an electropipettor for introducing sequencing primers from the source of sequencing primersto the at least two intersecting channels;a mixing zone fluidly connected to the at least two intersecting channels for mixing the firstsequencing reagent with a second sequencing reagent;a size separation zone fluidly connected to the mixing zone for separating sequencingproducts by size, thereby providing the sequence of a target nucleic acid; anda computer having computer-readable code for selecting a sequencing primer.

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3. Types of claims

Example: System (US 6816742)1. A sampling system for monitoring the concentration of an analyte present in asubject, said sampling system comprising:a sensing device comprising a collection reservoir comprising an enzyme capableof reacting with the analyte to produce hydrogen peroxide and a sensor element inoperative contact with the reservoir, wherein said sensor element reactselectrochemically with the hydrogen peroxide produced in the reservoir to provide adetectable signal, and said sensor element comprises an electrode having ageometric surface area which ranges from about 0.1 to 3 cm2, a backgroundcurrent which ranges from about 2 to 60 nA or less when measured in a buffersolution at 0.6V, and a sensitivity which ranges from about 6 to 180 nA/µM ofhydrogen peroxide when measured in a buffer solution at 0.6V, andone or more microprocessors in operative communication with the sensing devicecomprising programming to control operation of the sensing device.

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3. Types of claims

Example: Use (EP 0241106) 1. The use of detectably labeled immunoglobulin or a fragment thereof,

wherein said immunoglobulin or fragment(a) substantially accumulates at an inflammation site when said site is

inflamed,(b) has no substantial epitopic specificity for said inflamed site, and(c) comprises one or more of:

(i) pooled, human, polyclonal immunoglobulin;(ii) Fc fragment of pooled, human immunoglobulin;(iii) monoclonal antibody;(iv) Fc fragment of monoclonal antibody;

in the preparation of an agent for the detection of an inflammation sitein vivo.

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3. Types of claims

Example: Use (US 785 216)

1. Use of an isolated nucleic acid which comprises thecoding sequence set forth in SEQ ID NO: 1 fromnucleotide position 229 to nucleotide position 10482 andfurther comprising the mutation associated with apredisposition to breast cancer, wherein T at nucleotideposition 6174 is deleted, for diagnosing a predispositionto breast cancer in Ashkenazi-Jewish women in vitro.

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3. Types of claims

Example: Kit (US 7122324) 1. A diagnostic test kit for assaying for the presence of C-

terminal human glycoprotein IIb (hGPIIb) fragments in a bodyfluid sample, comprising a package containing an antibodycomposition comprising antibody molecules that:a) immunoreact with a polypeptide having an amino acidresidue sequence as shown in SEQ ID NO: 3 from residues173 to 193, 173 to 181, residues 179 to 189, residues 187 to200, or residues 194 to 200;b) do not immunoreact with a second polypeptide having theamino acid residue sequence REQNSLDSWGPK, as shownin SEQ ID NO: 3 from residue 113 to residue 124.

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4. Support

The Examination Procedure: Key Criteria

• Subject matter: is it a patentable invention?• Novelty: is it new?• Inventiveness: is it obvious?• Utility: is it useful?• Enablement or sufficiency: do the teachings you have

provided entitle you to the scope of the monopoly you areseeking?

• Specifics vary among jurisdictions

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4. Support

Enablement

•Description must enable a person skilled in the art topractice the invention without undue experimentation•How much disclosure is necessary to support broadclaims?

Fact dependent

•May involve sequence listing for amino acid or nucleicacid sequences•May involve deposit of biological material

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4. Support

Enablement: Factors to consider• Breadth of claims• Nature of invention• Predictability of art• State of prior art• Relative skill of those in art• Quantity of experimentation necessary• Presence of working examples

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4. Support

Utility

•What is the use or function?•Credible, specific, substantial (i.e. real world use)•Unpredictable factors associated with chemical reactionsand physiological activity may make standard harder tomeet than in some other art fields

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4. Support

Sound prediction• Do not have to test every species in a genus – may be able to

rely on the Doctrine of Sound Prediction

Apotex v. Wellcome Foundation, SCC 2002

• AZT – new use for an old compound• issue: Could the data in the patent support claims to the

treatment and prevention of HIV?• test for establishing a sound prediction:

1.Factual basis2.Sound line of reasoning3.Proper disclosure

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4. Support

Sound prediction (continued)• Patent can be defeated if challenger can show that the

prediction was not sound (i.e., if any element of 3-part test notmet):Eli Lilly v. Apotex, Federal Court 2008: factual basis and sound

line of reasoning, but lack of proper disclosure patent invalid interesting because SCC gave little guidance on this issue in

Apotex v. Wellcome casenote: proper disclosure a hot button issue generally

• Patent can also be defeated if, despite soundness ofprediction, invention in fact does not work

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4. Support

Description requirements: diagnostics

•Generally molecular diagnostic applications will requireworking examples•Prophetic examples have been sanctioned by court, butmust not be written in past tense•For utility:

• With genetic sequences, “research tool” not enough• Gene probe will require disclosure of specific target• Claim to receptor will only be granted with disclosure of

disease or condition

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5. Enforcement and exploitation

Developing a patent portfolio

•Patent as a commercial tool: • To develop or insure market position• To find an investment partner• To license

• May enable access to other technologies

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Decision to obtain patent protection• Importance of invention• Scope of likely patent protection• Potential commercial life of invention• Simple or complex technology• Ability to keep secret• Ability to police patent• Role in larger portfolio/strategy• Financing/licensing• Defensive reasons

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When to seek patent protection

•Key considerations:Timing of your own disclosureState of development of technology: ability to satisfy

description requirements•Want sufficient disclosure, but do not want to wait toolong and be blocked by somebody else•Filing patent at the time of genetic discovery increasesprobability that funding can be found to develop actualclinical test

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Diagnostics field

• Includes large entrenched participants•Stand alone IVD companies•Companies affiliated with pharmaceutical or medicaldevice companies• Large diagnostic laboratories

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Business models

•Different models:Build a businessLicense outSomething in between, e.g. a partnering model

•Appropriate model can depend on a number of factors:• Who funded the research?• How much funding is available for ongoing R&D, testing, regulatory processes?• What is the scope of your patent protection?• Are there roadblock patents? Can you obtain licenses or work around them?• What jurisdictions will you be working? e.g. socialized versus private healthcare• What is likelihood/timeline of regulatory approval?

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Motivation to partner

•Well-established companies looking for new molecularmarkers; junior partner gets access to other necessities,including funding and regulatory expertise• Likely to involve a cross-licensing arrangement•Technology in field rapidly progressing, requiressignificant R & D investments to remain competitive•Diagnostic tests require regulatory approval: requiresfunding and expertise

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Freedom to operate• Something to consider from the outset•Other market participants may control roadblock (e.g. a

patented process that must be practised in order to use yourkit) or complementary technologies (e.g. reagents, devicesbeneficially used in conjunction with your invention)• Early investigation might stop wasted outlay on

research/patents/regulatory approval• FTO opinion a search of current patents (pending

applications) and an analysis of the scope (likely scope) oftheir claims

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Freedom to operate (continued)

•Steps taken at the outset to ensure proper IP protectionis obtained increase the chance of a partneringopportunity in the future• If going to “build a business” rather than licensing out,then will be important to ensure from the outset access tothe necessary technologies•Even if plan is only to license out technology, can be acovenant to hold licensee harmless

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Licensing

•Open license i.e. available to all for payment of a “toll”• Results in more extensive use• May be better for a test with broad applicability• May insulate the patent from challenge

•Exclusive license i.e. single vendor• May yield more money at the outset• May be better for a test with more specific applicability

•Something in between these two extremes e.g. license tospecifically selected class of licensees

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Licensing (continued)• Issues to consider:

“patent thickets” and “royalty stacking”:

• overlapping rights can lead to complicated scenarios

• for a single test, licenses may be necessary from a number ofparties

large payers may have significant influence

public and private cost v. return on investment: one size fits all?

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Example: Cancer susceptibility genes BRCA1 and BRCA2•Myriad Genetics – patents for genes, mutation detection

• Built business around performing the tests itself:

BRACAnalysis® assesses a woman's risk of developing breastor ovarian cancer based on detection of mutations in the BRCA1and BRCA2 genes

blood sent to Myriad’s laboratories (or very small group oflicensed laboratories), then results sent to doctor who discussesthem with the patient

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Example: Cancer susceptibility genes BRCA1 and BRCA2• United States:

• Myriad licensed the rights to perform these tests to about adozen laboratories in exchange for high royalties on each testperformed

• federal government brokered deal to pay lower royalties whenthe genes are used by NCI and NIH-sponsored researchinstitutions and investigators

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Example: Cancer susceptibility genes BRCA1 and BRCA2• Canada:

provinces performing genetic testing using BRCA genes but adifferent method

• in 2001, Myriad sent cease and desist letters:• provincial governments infringing Myriad gene patents• stop using any tests to detect the BRCA1 and 2 genes other

than BRACAnalysis®• use Myriad testing at higher cost

• BC stopped testing for a time; Ontario continued testing(now using a different system)

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Example: Cancer susceptibility genes BRCA1 and BRCA2• Europe:

opposition from research institutes, ministries of health and politicalparties

October 2007, Board of Appeal of EPO upheld revocation of oneMyriad patent (EP 705 902) regarding the BRCA1 gene and itsapplications (other opposition proceedings ongoing)

patent claimed isolated gene, corresponding protein, therapeuticapplications and diagnostic kits (use of probes or primers specific tocertain mutations)

revoked on basis of lack of novelty (i.e. sequence had already beenisolated and determined)

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Example: Cancer susceptibility genes BRCA1 and BRCA2•Diagnostic patents can raise highly politicized issuesrelated to access and publicly funded research andtreatment

•But, this time limited monopoly has been put in place totry to provide an appropriate reward for inventordisclosure of useful inventions

Thank You!

Any Questions?

Ogilvy Renault LLP200 Bay Street, Suite 3800P.O. Box 84Royal Bank Plaza, South TowerToronto, CanadaM5J 2Z4

Cynthia TapeT [email protected]

Anna WilkinsonT [email protected]