platform patents and antibodies...#acibiosimilars aci’s 5thannual summit on biosimilars michael j....
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#ACIBiosimilars
ACI’s5th AnnualSummitonBiosimilars
MichaelJ.BrignatiAssociateGeneralCounselThePennsylvaniaStateUniversity
Platform Patents and Antibodies: Specific Action Plans for Patents Most Ripe
for a Biosimilars First Wave Challenge
GregoryA.MorrisOfCounselPaulHastings(Chicago,IL)
June 4‐6, 2014
Tweetingaboutthisconference?
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#ACIBiosimilars
Topics
•Action plan in preparation for antibody biosimilars litigation
• Strategies for developing and commercializing antibodies
• Strengthening your portfolio with licensing agreements
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ActionPlaninPreparationforAntibodyBiosimilars Litigation
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#ACIBiosimilars
Celltrion’sBidtoMakeaBiosimilarofInfliximab(Remicade®)
• Filed DJ suit in D. Mass. Alleging invalidity and unenforceability of 3 Jansen patents on March 31, 2014
•Desires to be the first biosimilar mAB approved for the US market
•DJ complaint provides a peek in to the details of biosimilar development 4
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DevelopmentofRemsima®AccordingtoCelltrion
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2008 2009 2010 2011 2012 2013 2014 2015
BeganR&D CompletedPD,PKandtoxicokineticstudies
MetwithFDAtoreviewclinicaldata
CompletedPhaseIclinicaltrials
SubmittedIND
EMAapproval
INDaccepted
CompletedPhaseIIIclinicaltrials
CompletedbridgingstudycomparingRemsima® withEU‐sourcedandUS‐sourcedRemicade®
FDAapproval?
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Celltrion’sBidtoMakeaBiosimilarofInfliximab(Remicade®)
• Invested more than $112M in out‐of‐pocket external costs in addition to internal manpower
•Developed platform IP related to cell lines and mAB purification methods
•Anticipates that FDA will approve Remsima® in Q1 2015 6
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Biosimilar Applicant (BA) Provides Confidential Access to Application
Biosimilar Application Accepted
w/in 20 days
BLA holder provides list of patents infringed and whether any are available for license
w/in 60 days
w/in 60 days
BA provides list of additional patents infringed and non‐infringement, invalidity contentions
w/in 60 days
BLA holder provides patent infringement and validity contentions
w/in 15 daysParties agree on patents to be litigated
w/in 30 days
BA gives BLA holder 180‐day notice of first commercial marketing
Complaint served
? w/in 180 days BLA holder files for preliminary injunction
Phase I Phase II
BiosimilarsPatentLitigation:TwoPhases
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DeterminingthePatentsLitigatedinPhaseI• Parties must engage in good faith negotiations to determine which patents listed by each party (in their “first lists”) will be the subject of Phase I litigation
• If agreement cannot be reached, parties enter a resolution phase• BA notifies RFP of the number of patents to be exchanged in a “second list” exchange
• Within 15 days, the parties exchange “second patent lists”
• Patents in parties’ combined “second lists” are litigated
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TypesofPatentsPotentiallyAsserted•Compound
• Binding a specific target• Binding to a conformational epitope• CDR or VL/VH sequence• Target affinity• Deposited cell• Product by process
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TypesofPatentsPotentiallyAssertedCont.•Methods of treatment
• Patient stratification with biomarkers
•Combination therapy• Formulation / Dosage Form•Dosage regimen•Methods of manufacture
• (i.e., DNA encoding protein, vectors, host cells, regulatory elements, expression systems, protein engineering platforms, purification) 10
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WhichPatentsShouldtheBLAHolderAssertinPhaseI?Factors to consider:
• Litigate the strongest patent(s) (i.e., compound patents)
• Which patents expire the latest beyond the 12 year exclusivity period (i.e., formulation, method of manufacture, dosing regimen)?
• Avoid litigating platform patents?
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RelevantProteinEngineeringPlatforms
• Discovery Platforms (e.g., Medarex)• Bispecific Platforms (e.g., GenMab)• Humanization (e.g., Queen patents)• Antibody Production (e.g., Cabilly II)• Vector component (e.g., U. Iowa)• Cell lines (e.g., Crucell)• Expression Systems (e.g., Lonza)
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ImportanceofPlatformPatents
• Biosimilar defined• the biological product is highly similar to the reference product
notwithstanding minor differences in clinically inactive components; and• there are no clinically meaningful differences between the biological product
and the reference product in terms of the safety, purity, and potency of the product.
• Exact structural identity is not required under the BPCIA
• Platform patents may provide greater scope of protection around a reference product than composition patents• Increased likelihood of securing a claim to a genus• More likely to have a term that extends beyond the 12 year market
exclusivity 13
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WhichPatentsShouldtheBiosimilarApplicantLitigateinPhaseI?Factors to consider:
• Achieve greater clarity by litigating strongest patents upfront in Phase I ?
• Delay litigation of certain patents until Phase II (and reduce up front litigation costs)?
• Target weak patents in Phase I to gain momentum?
• Force litigation of key platform or research tool patents?
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ConsiderationsforBLAHolderPriortoLitigation
•60‐day window to provide patent list to BA holder is short – plan ahead
•Conduct pre‐suit investigation well in advance of potential litigation
•Plan for possibility of IPRs in parallel with litigation
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EarlyCaseEvaluationTasks• Create internal “Orange Book” list of patents to be asserted• Rank patents by type, strength, and patent term• Compound• Methods of treatment• Combination therapy• Formulation / dosage form• Methods of manufacture
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EarlyCaseEvaluationTasks
• Review critical documents for potential issues• Relevant patents, file histories and pending applications
• Selected inventor lab notebooks and other documents
• BLA documents
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EarlyCaseEvaluationTasksCont.• Interview key fact witnesses• Take action
• Double patenting issues?• Correct inventorship?• Supplemental Examination?• Reissue?
• Retain experts
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StrategiesforDevelopingandCommercializingAntibodies
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OptimizingPatentExclusivity
• Balancing considerations• Biosimilar vs. Interchangeable • Maximizing PTE while minimizing BA ability to design around• Challenge: Craft patent claims to cover products and predict biosimilar design‐arounds , while still meeting requirements for §112
• Impact of USPTO §101 Guidance • Utilization of recent FDA Guidance 20
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AntibodyPatentProtection
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Ab Sequence
VH /VL
6 CDRs
<6 CDRS
Epitope/Paratope
Functional Attribute
Novel Ag
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ScopeofAntibodyPatentProtection
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• Structural identity not a requirement for biosimilars• How much of a structural deviation is permissible to meet the requirements for biosimilarity?
• Specific sequence of heavy and light chain• Specific sequence of variable domains of the heavy and light chains
• Complete 6 CDRs of heavy and light chains• Less than 6 CDRs• Epitope/Paratope
• No clinically meaningful differences of the safety, purity, and potency of the product.• Functional attributes• Novel antigen
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Section112Dilemma•Claims to specific antibodies sequences may not be useful because of potential for design around
•Composition claiming a genus of antibodies risks invalidity under 112 (especially when antigens are not novel)• See e.g., Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011)
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UseaMulti‐TierApproachNarrow claim scope limited to specific Ab sequence, variable region sequences, and 6 CDRs of approved product • Even a minor change to variable region/CDRs of the antibody may not be permitted
• Will likely be the strongest claim from a validity perspective and logical PTE candidate
Intermediate claim scope to <6 CDRs or epitope/paratope • This may be useful to cover some design‐arounds
• Breadth of epitope/paratope claim• <6 CDRs may be difficult to overcome 112 issue in the USPTO
Broad claim scope reciting only functional attribute or percent homology• Could be vulnerable to §112 attack 24
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SatisfyingSection112
•Can claim a species of antibodies and rely on the doctrine of equivalents for protection
•Can attempt to claim structural characteristics of binding sites
•Claiming a method of use with a genus of antibodies is untested but still viable 25
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0 5 10 15 20 25
FDA Approval(Year 9)
Ped.
§156 extensionPatent Protection
Issues (Year 3)
PatentFiling
Regulatory Exclusivity IND Filing
PatentExclusivityv.BLAExclusivity
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MaximizingPatentTermExtension
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• Obtain an issued US patent prior to filing of Investigative New Drug (IND) Application• Timing for allowance of broad claims compared to narrow claims• Track One Prioritized Examination
• Goal of Track One – final disposition within twelve months of prioritized status being granted
•Does PTE reallymatter for BLAs?• 12 years of market exclusivity / 4 years data exclusivity
• Subject to pediatric exclusivity extensions
+(BLA Approval Date –BLA Filing Date)
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§101Guidance– SubjectMatterEligibility
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• Released March 2014 to address Myriad and Mayo decisions
• Three prong analysis• Question 1: Is the claimed invention directed to one of the four statutory patent‐
eligible subject matter categories: process, machine, manufacture, or composition of matter?
• Question 2: Does the claim recite or involve a judicial exception?• Judicial Exceptions: abstract ideas, laws of nature/natural principles, natural
phenomena and natural products• Per Guidance, natural products include nucleic acids; organisms; proteins
and peptides; and other substances found in or derived from nature• Question 3: Does the claims as a whole recite something significantly different
than the judicial exceptions?• Significantly different is determined by a balance of multiple factors
• For example, markedly different structure from naturally occurring products or adds a feature that is more than well‐understood, purely conventional or routine in the relevant field
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SubjectMatterEligibilityforBiologics
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• Biologics are inherently natural products or products derived from natural products• Issue – Is your biologic significantly different than that which occurs in nature?
• Amazonic Acid Hypothetical • Claim 1. Purified amazonic acid.
• Unpatentable natural product• Claim 2. Purified 5‐methyl amazonic acid.
• Patentable ‐ Structural Difference and Function Difference• USPTO – “a functional difference resulting from the structural difference
makes a stronger case that the structural difference is a marked difference”
• Claim 3. A method of treating colon cancer, comprising: administering a daily dose of purified amazonic acid to a patient suffering from colon cancer for a period of time from 10 days to 20 days, wherein said daily dose comprises about 0.75 to about 1.25 teaspoons of amazonic acid.
• Patentable – meaningful limits on claim scope that do not substantially foreclose others
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Post‐KSRObviousnessAnalysis• An invention is obvious is if it is a combination of familiar element according to known methods that does no more than yield predictable results • “Obvious to try” is an acceptable to rationale to defeat patentability
• Antibody Dilemma: many pioneering antibody technologies have become mainstream• Antibody discovery and production
• Novel antigens are becoming increasing rare • Humanization• Vector components/Expression Systems• Fc engineering 30
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Post‐KSRPracticeTips
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• Anticipate the Rejection (Filing Strategies)• AVOID identifying a known problem for which there may be obvious solutions
• Focus on the interdependency of features in a claim• Counsel and scientists must work together to characterize Abs as much as possible before filing• Epitope mapping• Functional properties
• Include in vivo data as early as possible• Include unexpected results• Benchmark your Ab against prior art Abs to identify superior features
• Follow up with clinical observations (often unpredictable)
#ACIBiosimilars
ProvidinganInventiveStep
• Patenting of antibodies in EP has become increasingly difficult• In EP, it is considered uninventive (i.e., obvious) to generate an antibody to a known antigen using standard techniques.
• EP Inventive step requires that the antibody can be shown to have an unexpected advantage over known antibodies to the same target• Exemplary advantages – increased binding affinity, cross‐reactivity, increased selectivity, improved stability• Implementation of functional claim language 32
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FunctionalClaimLanguage
• Generally, functional claim language can create complexities in patent infringement cases
• Is this necessarily the case for biosimilars?• No clinically meaningful difference in potency • FDA Guidance on Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (May 2014)• “Clinical pharmacology studies are normally a critical part of demonstrating biosimilarity”• Pharmacokinetic (PK) and pharmacodynamic (PD) properties
• Utilize functional attributes to maintain claim breadth while minimizing the ability of a biosimilar to design around?
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StrengtheningYourPortfolioWithLicensingAgreements
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PatentLicensingandBiologics• Generally, BLA holder is an exclusive licensee of IP developed at university, research institution, or small biotech company• Exclusivity is usually field‐restricted
• Licensor may have additional revenue streams from other licensees
• Disparate litigation tolerance between Licensor and Licensee
• Issue of control of litigation by licensee and involvement of licensor in proceedings 35
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PerspectiveMatters• Licensee is interested in securing an exclusive license and controlling patents covering the biologic • Ability to assert a licensed patent provides another barrier to a biosimilar applicant
• Licensee will want the ability to assert the patent, settle the litigation, and the right to sublicense the patent
• Licensor is interested in protecting revenue stream(s) from out‐licensed patents• Ability to control any potential litigation to avoid jeopardizing the revenue stream
• Licensor will want the final decision as to whether a patent is included in the RPS’s list in biosimilar litigation
• Forfeiture of rights against biosimilar applicant vs. risk of invalidity• Licensor will want to retain control over sublicensing 36
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SelectingtheRightLicense
•Consider scope of license• Exclusive v. non‐exclusive• Option for exclusivity• Right to sublicense
•Carefully craft definitions • E.g., “Antibody”, “Licensed Product”, etc.
•Royalty structure• Sublicensing royalties should a biosimilar become a sublicensee• Differential royalty rates depending on presence of biosimilar
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SelectingtheRightLicense
•Consider enforcement provisions• Right to list / right to assert / obligation to enforce licensed patents?
• Notice requirements• Participation in ligation by licensor?• Right to settle?
• Indemnification provisions•Dispute resolution provisions
• Provide for quick resolution in event of dispute to list patent38