Antibody-drug conjugates: Intellectual property considerations · Antibody-drug conjugates:...
Transcript of Antibody-drug conjugates: Intellectual property considerations · Antibody-drug conjugates:...
Antibody-drug conjugates: Intellectual property considerations
Ulrich Storz*Michalski H€uttermann Patent Attorneys; D€usseldorf, Germany
Antibody-drug conjugates are highlycomplex entities that combine an
antibody, a linker and a toxin. This com-plexity makes them demanding bothtechnically and from a regulatory pointof view, and difficult to deal with in theirpatent aspects. This article discusses dif-ferent issues of patent protection andfreedom to operate with regard to thispromising new class of drugs.
Introduction
Antibody-drug conjugates (ADCs) areone of the most promising classes of newdrugs, although the idea is not new.1
ADCs embody the oft-cited concept of“magic bullets,” which was described byPaul Ehrlich over 100 y ago. As of 2015,3 ADCs have been approved by theUS Food and Drug Administration(FDA), namely gemtuzumab ozogamacin(Mylotarg�), ado-trastuzumab emtansine(Kadcyla�) and brentuximab vedotin(Adcetris�). Their characteristics areshown in Table 1. More than 40 otherADCs are in clinical studies today.2
ADCs combine an antibody, a linkerand a toxin (often called “payload” or,more martial, “warhead”), and, for thatreason, they are technically demanding todevelop and pose challenges inmanufacturing.3 They can also raise regu-latory issues.4 because ADCs can be con-sidered prodrugs that release their activecompound–the toxin–at the site of action.
While their complexity has been calledan„invitation to innovation,”5 ADCs aredifficult to deal with in their intellectualproperty (IP) aspects. Both Freedom toOperate (FTO), as well as the protectionof ADCs and technologies to generatethem, are affected by the complexity ofthe molecules, and thus those who want
to develop and sell new ADCs or protectthe compounds and technologies fromwhich they are derived are faced with chal-lenges when making business decisions. Inaddition, the numerous players active inthis field have created a maze of third-party IP rights that is difficult to navigate.Further, because ADCs combine biotech-nology and organic chemistry, IP counselsworking in this area need a thorough tech-nical background in both disciplines.
This article discusses some of theseaspects in more detail, and discloses IPrights that stand exemplarily for a giventechnology or concept. It can, however,not replace a case-specific FTO analysis ornovelty search. Some of the IP rights dis-cussed herein may not have been grantedyet, or they may have already expired orbeen revoked. The latter, which aremarked with an asterisk in the respectivetables, may thus constitute free prior art,and, as such, provide a valuable source ofinformation for competitors.
Freedom to operateThe term “Freedom to Operate” refers
to a determination that the commerciali-zation of a product does not infringethird-party IP rights, in particular patents.Establishing FTO requires that all compo-nents of the respective technology, encom-passing methods as well as compoundsand intermediates, are analyzed withrespect to whether they are the subject ofvalid and enforceable third-party IP rights.
Because IP rights have a territorialeffect and a restricted lifetime only, anFTO analysis does not only focus on thetechnologies as such, but also considerswhere IP rights are in force and when theyexpire. In this context, the estimated timeto market of the product that is to be com-mercialized should be weighed against thelifetime of a given IP right. Further
Keywords: ADC, antibody-drug conju-gates, antibody, freedom to operate,immunotoxin, Kadcyla, patent
Abbreviations: FDA, Food and DrugAdministration; FTO, Freedom to Oper-ate; IP, Intellectual property; ADC, Anti-body-Drug Conjugates; EPO, EuropeanPatent Office; USPTO, United States Pat-ent And Trademark Office; CDR, Com-plementarity Determining Region; HC/LC, Heavy Chain/Light Chain; DAR,Drug-Antibody Ratio; IPR, Inter PartesReview; PTAB, Patent Trial and AppealBoard
*Correspondence to: Ulrich Storz; Email:[email protected]
Submitted: 05/28/2015
Revised: 08/03/2015
Accepted: 08/05/2015
http://dx.doi.org/10.1080/19420862.2015.1082019
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mAbs 7:6, 989--1009; November/December 2015; © 2015 Taylor & Francis Group, LLCPERSPECTIVE
considerations should focus on potentialresearch exemptions as well as on ques-tions of exhaustion, or process patentsthat might extend their protection onproducts obtained therewith. These non-ADC specific regulations are subject tolarge variations between different jurisdic-tions, and thus are outside the scope ofthis article.
If, in the course of an FTO analysis, IPrights that are likely to be infringed by thecommercialization of a given product aredetected, one should consider whether ornot they are valid and enforceable. If not,respective countermeasures should be con-sidered, like invalidity opinions, opposi-tions, nullity actions, or post grant review/inter partes review.
As an alternative, in-licensing of therespective IP rights could be a solution.This approach is frequently used in caseswhere the patent protected technology isan enabling technology, or refers only to apart of the molecule, like a linker. Thesetechnologies have often been developed bytechnology companies who use out-licens-ing as their business model. Large bio-pharmaceutical companies are generallyless inclined to grant a license, in particu-lar on a compound-related patent, becausethey seek exclusivity rather than royalties.
For ADCs, an FTO analysis encom-passes all components, i.e., the antibody,the toxin and the linker. Numerous play-ers have already staked their claims, andmany patents and patent applications referto a combination of 2 of the components,very often a combination of a toxin and a
linker. The existing IP landscape thusappears more complicated than for nakedantibodies, with overlapping patent estatesassigned to different owners. Navigatingthis landscape can become a laboriouschallenge, and again requires a thoroughunderstanding of the technical back-ground, including biotechnology andorganic chemistry, and the filing strategiesused by competitors.
Further, inventors often believe that,once a patent has been granted on a giveninvention, FTO would be automaticallywarranted. This thinking relies on a mis-conception. The truth is that even if a pat-ent has been awarded on a structurallyimproved second-generation antibody, itcan still be the subject of earlier third-party patents protecting the starting anti-body, if these are still in force. In the fol-lowing sections, the methods andcompounds that are relevant in an ADCFTO analysis will be briefly addressed.
Active IP strategiesADCs do also offer new possibilities to
obtain patent protection. ADCs can, insome way, be considered as an advance-ment of conventional therapeutic antibod-ies, and, according to a general principle,each bit of advancement can be made sub-ject of a patent application.
According to a study performed atTufts University in 2007, the estimatedaverage costs of developing a new biologicwas 1.2 billion USD.6 This figure hasbeen adjusted upwards in 2014 to even2.6 billion USD.7 Further, development
times in biologics are slightly longer thanthose reported for small molecular drugs.8
Because of the higher complexity andthe higher regulatory burden, it can beassumed that, generally, these figures willbe even higher in ADCs. A meaningfulpatent strategy is thus indispensable toensure that these investments can be recu-perated over at least a given period oftime. ADC-related embodiments that canbecome subject of patent protection willalso be discussed in the following.
The antibody componentAn antibody as such can be subject of
third-party patents. This may encompass4 categories: 1) patents that protect anykind of antibody binding a particular tar-get, which at the filing date was novel(and specified by the applicant in a suffi-cient way as to enable skilled persons tomake an antibody thereagainst); 2) patentsthat protect all antibodies against a givenepitope of such target (if binding said epi-tope has unprecedented effect); 3) patentsthat protect all antibodies against a giventarget that have a particular functionality(e.g., minimum affinity, inhibition of agiven effect); or 4) patents that protect aspecific antibody (either defined by therespective expressor cell, or by a particularsequence, e.g., of the CDRs, the variabledomains or the HC/LC sequences).
It needs to be added, in this context,that new targets for ADC therapy are hardto find,9 thus making patents of categories1 and 2 less frequent nowadays. Further,it appears that the US Patent and
Table 1. Characteristics of the 3 ADCs approved to date by the US Food and Drug Administration
ADC nameAntibodytarget
Key IP rightUS/EP
Target alsoused in
conventionalmAb
therapy? LinkerLinker
cleavable? ToxinSite specificconjugation?
DrugAntibodyRatio
Gemtuzumabozogamicin**
CD33 US5773001/EP0689845B1*
no hydrazone yes calicheamicin no Only 50% of theantibody isloaded at all(avg 4 – 6)
Trastuzumabemtansine
HER-2/neu US8337856/EP2283867B1
yes SMCC (maleimide) no DM1 (maytansinoid) no 0–8 (avg 3,5)
Brentuximabvedotin
CD30 US7829531/EP2353611B1
no maleimidocaproylspacer, valine–citrulline linker,and PABC spacer
yes(cathepsin)
MMAE (auristatin) no 3–5
*expired; **product voluntarily withdrawn from the market in 2010.
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Trademark Office (USPTO) and theEuropean Patent Office (EPO) havebecome more critical toward patents ofcategory 3 because a functional claim fea-ture is quite often considered to be a meredesideratum only, putting into questionthe true possession of the entire inventionby the applicant at the filing date, as wellas the inventive character involved.Regarding category 4, it seems that theEPO applies a higher standard than theUSPTO by requiring that the applicantdisclose some kind of surprising effect ofthe new sequence-wise specified antibodyover prior art antibodies addressing thesame target.10
As a general rule, all therapeutic anti-bodies on the market are, or were, pro-tected by such compound patents. Theuse of an approved antibody to generatean ADC is thus likely to fall under thescope of the respective naked antibodypatent, provided it is still in force. Thefact that the antibody is conjugated to atoxin does not per se change this situation.
In case the planned ADC comprises anexisting antibody that is already on themarket, or will enter the market, a thor-ough FTO analysis should be carried outin order to define when FTO can be
established, and in which markets. Thesame applies in cases where the target ofthe planned ADC is the subject of third-party patents. Patents of such type are onthe decline (simply because quite a fewtargets have already been described 10 yago or earlier), but still exist and providemeaningful patent protection. Table 2shows typical examples of different typesof naked antibody compound patents, asgranted by the EPO.
As shown above, some ADCapproaches use existing antibodies thathave already proven useful either in theclinic or in preclinical research, and mayhave a substantial global market. Forexample, trastuzumab, which as a soloproduct, generated global sales of 6.5 bnUSD in 2013.
As can be seen in Table 2, Claim 3 ofEP0590058 (which has expired June2012) protected Genentech’s anti-HER2antibody trastuzumab by its VL and VHsequence. ADCs comprising trastuzumab,such as Genentech’s ado-trastuzumabemtansine, would therefore fall underclaim 3 of EP0590058B1. Interestingly,claim 11 explicitly specified, as a preferredembodiment, an immunotoxin compris-ing trastuzumab plus a cytotoxin.
The use of an approved naked antibodyfor making an ADC has its merits. Forexample, it may appear useless to“reinvent the wheel,” i.e., to develop anew antibody when ones that bind rele-vant targets with high specificity and affin-ity are already on the market, and haveproven sufficiently safe and efficient to beapproved. However, not all therapeuticantibodies on the market are suitable asADCs.
For ADCs, internalization of the anti-body may be necessary, whereas, fornaked antibodies that evoke antibody-dependent cell-mediated cytotoxicity orcomplement-dependent cytotoxicity (e.g.,anti-CD20 rituximab), quick internaliza-tion would be counterproductive. Fur-ther, antibodies that bind cytokines (e.g.,anti-TNF adalimumab, anti-VEGF-Abevacizumab) instead of cell surface anti-gens are unlikely to be useful for ADCtherapy because they would not delivertheir toxin to a suitable target cell. Anideal ADC target should therefore: 1)reliably differentiate cancer cells fromhealthy cells; 2) occur in sufficientabundancy on the cell surface; 3) inter-nalize the bound ADC with sufficientspeed and efficacy.
Table 2. Examples of different types of naked antibody compound patents
Category Example IP right Assignee Target Claim language
Antibody claimed by its target ortarget epitope
EP1587837B1 Proscan RX PSMA An antigen comprising an immunogenic moiety orcarrier and an epitope of the extracellular region ofPSMA consisting of SEQ ID NO:8, wherein the N-terminal cysteine residue on SEQ ID NO:8 isoptional.
An isolated antibody or antigen binding fragmentthereof, which binds to the antigen wherein theantibody and/or antigen binding fragment thereofalso binds to PSMA.
Antibody claimed by functionalproperties
EP1347730B2 Seattle Genetics CD30 An antibody that immunospecifically binds CD30 andexerts a cytostatic or cytotoxic effect on aHodgkin’s disease cell line in the absence ofconjugation to a cytostatic or cytotoxic agent.
Antibody claimed by expressor cell EP0660721B1* Dana Farber CD22 A monoclonal antibody that: is produced by ahybridoma cell line selected from the groupconsisting of HB22–7 (ATCC No. HB 11347), HB22–22 (ATCC No. HB 11348) and HB22–23 (ATCC No.HB11349) [. . .]
Antibody claimed by sequence EP0590058B1* Genentech HER2 A humanized Antibody which comprises a VL domaincomprising the polypeptide sequence X and a VHdomain comprising the polypeptide sequence Y.
Antibody claimed by sequence EP1951757B1 Xencor CD30 An anti-CD30 antibody, comprising a variable heavychain sequence 1 and a variable light chainsequence 2
*expired; the symbol [. . .] indicates that claim language has been truncated.
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Concerns have already been raised thatall acceptable targets meeting theserequirements have been discoveredalready, and that it is unlikely new oneswill be found. 11 Regardless, in the event anovel and suitable target for ADC therapyis found, it is definitely worth seeking pat-ent protection for antibodies against saidtarget on the basis of the classical catego-ries of antibody compound protection(see above). If the target is already knownbut has not yet been described as a targetfor ADC therapy, patent protection mayfocus on an ADC binding to said target.An example of the latter category is shownin Table 3.
In addition thereto, further develop-ments regarding the antibody concept assuch can be made the subject of patentprotection. This could involve, forexample, the use of new antibody for-mats or protein binders derived fromalternative scaffolds. Another approachis to modify antibodies in such way thatthey become active only at the tumorsite, even if they target an antigen that isexpressed both on healthy cells andtumor cells.12 This approach relies onspecific environmental conditions at thetumor site (e.g., abundance of proteases)to activate the antibody, thus avoidingdamage to healthy cells are bound. Insuch way, targets that are not druggabledue to insufficient discriminationbetween cancer cells and healthy cellscan be used. Still other approaches haveidentified targets that do not requireinternalization of the ADC. Accumula-tion of the ADC in the sub-endothelialextracellular matrix of tumors was foundefficient at very low side effects.13
Table 4 shows some of these approacheswhere the antibody concept has beenfurther developed, plus exemplary IPrights.
The linker technologyIn principle, a large variety of linker
technologies exists to bind small moleculesto proteins. A well-established technique isthe maleimide-based conjugation of thiol-comprising molecules to proteins. Thisapproach has often been used in first-gen-eration ADCs. Other linkers frequentlyused rely on hydrazone, disulfide or amidebonds.
Early attempts to improve linker tech-nology focused mainly on increasinglinker stability, to avoid cleavage thereofwhen the ADC is still in the bloodstream.These demands were met, e.g., by linkersdeveloped by Seattle Genetics or Immu-noGen. See Table 5 for some exemplaryIP rights. However, there was, and still is,further potential for innovation and,accordingly, new IP, in the field of ADClinker technology for various reasons,including insufficient linker stability,insufficient site specificity of the conjuga-tion or insufficient stoichiometry. Theseproblems affect the efficacy and safety ofan ADC and, as such, may pose challengesduring regulatory agency reviews. Newlinker technologies therefore strive to: 1)increase linker stability (and thus avoidcleavage thereof in the extracellular space);2) modulate cleavability after internaliza-tion (cleavage by plasma enzymes ormedium conditions, e.g., pH, allows thedrug to leak into neighboring cells; non-cleavable linkers release the toxin onlyafter degradation of the antibody); 3)increase site specificity of the conjugationsite to establish homogenicity of the ADCand avoid steric hindrance of the bindingdomains; or 4) increase stoichiometry(also called „drug-antibody ratio,” DAR)to yield sufficient efficacy of the ADC,e.g., by avoiding antibodies that carry notoxin, which would compete with theADC for target binding and thus affect
efficacy of the ADC. Table 6 shows somenew approaches related to ADC linkertechnology, and exemplary IP rights.
The toxinBefore the toxin component of a pro-
jected ADC is selected, considerationshould be given to whether the respectivetoxin is subject to third-party IP, and, ifso, where, and until when, and whether ornot it can be in-licensed. Today, 3 classesof toxins are typically used in ADCs,namely maytansinoids, auristatins, andcalcheamicins, but others are under inves-tigation. Table 7 shows some selected tox-ins and exemplary IP rights, some ofwhich refer to the combination of a toxinand a given linker or antibody.
Interestingly, of 47 ADC candidates inclinical studies as of 2014,14 16 candidatesuse maytansinoids, while 22 candidatesuse auristatins. In most cases, a license, ora purchase of the respective toxin, fromImmunoGen, or Seattle Genetics, respec-tively, would be necessary, because these 2companies are the major IP holdersregarding these toxins, or toxin-linkercombinations (see Table 7).
With respect to ado-trastuzumabemtansine, which carries ImmunoGen’smaytansinoid DM1, the original dealforged between Genentech and Immuno-Gen provided 2 mn USD upfront pay-ments, plus 44 mn USD in milestone androyalty payments.15 This is quite modestin view of the commercial power of ado-trastuzumab emtansine, which waslaunched in February 2013, achieved salesof 91 mn USD in the first half of 2013,and may achieve sales of 2.55 bn USD in2018 according to analysis by FiercePharma. It appears, however, that in morerecent deals, ImmunoGen has negotiatedmore favorable terms. A deal signed with
Table 3. Suitable patent category if target and antibody are known, but not in an ADC
Embodiment Target Example IP right Assignee Claim language
Target and antibody thereagainstare known, but not in an ADC
cKIt US20140271688 Novartis ADC of the formula Ab-(L-(D)n)n or a pharmaceuticallyacceptable salt thereof; wherein Ab is an antibodyor antigen binding fragment thereof thatspecifically binds to an epitope of human cKIT; L isa linker; D is a drug moiety; m is an integer from 1to 8; and n is an integer from 1 to 10.
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Novartis in 2010 provided an upfrontpayment of 45 mn USD, and milestonepayments totaling »200 mn USD pertarget, plus royalties on the sales.ImmunoGen’s other deals include, amongothers, Eli Lilly (2011, 20 mn USDupfront and approximately 200 mn USDper target in milestones), Takeda (2015,440 mn USD upfront and milestones), orSanofi (2006, 32 mn USD upfront and
milestones per target),16 demonstratingthat there is substantial value even in justthe toxin technology used in ADCs.
The first experimental ADCs used cyto-toxic payloads that were already establishedin conventional chemotherapy, e.g., meth-otrexate,17 vinblastine.18 However, ADCshave a distinct advantage over conventionalchemotherapy because they can direct theirtoxic payload to the target tissue with high
specificity. For this reason, this approachopens the possibility to reduce non-specificside effects common to chemotherapy, thusbroadening the therapeutic window. Thisagain allows the use of toxic payloads thatotherwise would be too toxic for systemicadministration, or have a too short half-lifein the human plasma.
On the other hand, antibodies are rela-tively large molecules (the molecular
Table 4. Patents protecting new antibody concepts that can be used in ADCs
Technology Embodiment Example IP right Assignee Claim language
New antibody format Diabody EP2516462B1 Avipep An isolated protein comprising an immunoglobulinvariable region comprising:
(i) at least 2 cysteine residues positioned withinframework region (FR) 2, wherein if at least 2 of thecysteine residues in FR2 are not conjugated to acompound then a disulfide bond is capable of formingbetween the cysteine residues in FR2; and/or
(ii) at least 2 cysteine residues positioned withinframework region (FR) 3, wherein if at least 2 of thecysteine residues in FR3 are not conjugated to acompound then a disulfide bond is capable of formingbetween the cysteine residues in FR3.
ConditionallyactiveBiologics
Antibodies are activatedand/or inactivated at definedphysiological conditions.
US8709755 BioAtla A method of preparing a conditionally active antibody,the method comprising the steps of:
i. selecting a wild-type antibody against an antigen;ii. evolving the DNA which encodes the wild-type
antibody using one or more evolutionary techniquesto create mutant DNAs;
iii. expressing the mutant DNAs to obtain at least onemutant antibody;
iv. subjecting the at least one mutant antibody and thewild-type antibody to an assay under a normalphysiological condition selected from the groupconsisting of temperature, pH, osmotic pressure,osmolality, oxidation and electrolyte concentration,and to an assay under an aberrant condition selectedfrom the group consisting of temperature, pH, osmoticpressure, osmolality, oxidation and electrolyteconcentration; and
v. selecting the conditionally active antibody from the atleast one mutant antibody [. . .]
Cleavablemaskingpeptides
Masking peptides are released,e.g., by proteases secretedby the tumor
US20100189651 CytomX A modified antibody comprising: an antibody or antibodyfragment (AB), capable of specifically binding itstarget, coupled to a masking moiety (MM), wherein thecoupling of the MM reduces the ability of the AB tobind its target such that that the dissociation constant(Kd) of the AB when coupled to the MM toward thetarget is at least 100 times greater than the Kd of theAB when not coupled to the MM toward the target
Target which does notrequire toxininternalization
Extra domains A and B offibronectin
US20150030536 Philogen A method of treating lung cancer or lymphoma in anindividual, comprising administering to the individuala therapeutically effective amount of an antibody, orantigen-binding fragment thereof, which binds ExtraDomain-A (ED-A) of fibronectin comprising a VHdomain and a VL domain with given CDR sequencesand wherein the antibody is conjugated to a moleculethat has biocidal or cytotoxic activity or is conjugatedto a radioisotope.
the symbol [. . .] indicates that claim language has been truncated.
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weight of an IgG is »150 KDa), comparedto which the toxin, which is commonly anorganic molecule, is small (molecularweight usually in the range of 0.3 to1 KDa). Therefore, the total amount oftoxin that can be administered with ADCtherapy is relatively small. Accordingly, anADC carrying 4 toxin molecules comprisesonly 0.8–2.67% w/w toxin. Further, it hasbeen reported that, despite the target speci-ficity an ADC has due to its antibody com-ponent, only 1.56% of the administereddose of the toxin will reach the intracellulartarget.19 This in turn means that a toxincandidate must show high potency to beuseful in ADC therapy.
As discussed already, 3 classes of toxinshave been typically used in ADCs, namelymaytansinoids, auristatins and calcheami-cins. Other classes are in clinical or preclinicaltrials,20 including pyrrolobenzodiazepinesand other benzodiazepine derivatives,duocarmycins, tubulysins, a-amanitin orbouganin protein toxin (see Table 7).
Most of these toxins are significantlymore potent than toxins used for conven-tional chemotherapy. In any case, the dis-covery of a new toxin (either a derivativefrom an existing class or a whole newclass) that can be used in ADCs can giverise to specific patent protection. Thesame applies for the transfer of an existingtoxin into the ADC context. Typical pat-ent categories that cover such types ofinnovations are shown in Table 8.
Second medical use patents and otherhigher generation patents
Second medical use claims strive toprotect the use of a given drug for a newindication discovered after the drug (andat least one medical indication) wasalready known. They usually specify thedrug and its new use in a language such as“antibody X for the treatment of diseaseY.”
If an ADC comprising a given anti-body is used for the treatment of a diseasethat is the subject of a third-party patentclaiming a second medical use of thatnaked antibody, it should be thoroughlychecked as to whether or not said use forthe ADC falls under the scope of said sec-ond medical use patent. The fact alonethat the antibody has been structurallymodified by conjugating a toxin theretodoes not automatically mean that it wouldno longer fall under the scope of such pat-ent, at least as long as the claim languagedoes not exclude such modification explic-itly. Similar logic applies to other highergeneration patents, like dosage patents orformulation patents, in which the claimsrefer to a naked antibody. However, itappears unlikely that an ADC using agiven naked antibody would use the samedosage or formulation.
Table 9 shows typical claim categoriesfor second medical use antibody patentsand other higher generation antibody pat-ents. With ADCs, the same rules exist as
with naked antibodies, and similar secondgeneration claim categories can hence begenerated. Table 10 shows some examplesof higher generation ADC patents.
Specific combination of antibodyand toxin
The specific combination of an anti-body and a toxin can be also patent eligi-ble. A given tumor cell type characterizedby a specific antigen can, for example, beparticularly susceptible to a given toxinconjugated to an antibody against said tar-get. In such case, patent claims providingthe broadest protection would merelyrecite the antibody target and the toxinclass.
If such a broad concept is already antic-ipated, or does not meet the non-obvious-ness/inventive step criterion, fallbackpositions for the antibody componentcould focus on a target epitope, a specificbinding behavior or a structurally definedantibody. For the toxin component, fall-back positions lie in a more restricted defi-nition of the specific toxin. Even thoughnarrow on paper, such restricted claimscan still provide meaningful patent protec-tion when backed by a respective market-ing authorization.
So far, the legal framework for ADCbiosimilar products is far from clear, andthe US and European Union regulatoryagencies have only recently begun evalua-tions of biosimilar antibodies. However,
Table 5. Early ADC linker technology patents
Technology Example IP right Assignee Claim language
Maleimidocaproyl-val-cit-PAB (combination withauristatins)
US7745394 Seattle Genetics 1. A method for treating cancer comprising administering to a patient in need thereofan effective amount of an antibody-drug conjugate compound having formula Ic:
Ab Aa-Ww-Yy-D)p Ic
wherein Ab is an antibody which binds to one or more tumor-associated antigensD is a drug moiety selected of Formula DE:
[ ]
Maytansinoids plus SMCClinker
US5208020* ImmunoGen A cytotoxic agent comprising one or more maytansinoids linked to a monoclonalantibody or fragment thereof via a disulfide bridge at the C-3,¡14,¡15, or¡20position of said maytansinoids and wherein said monoclonal antibody or fragmentthereof is selective for tumor cell antigens.
*expired; the symbol [. . .] indicates that claim language has been truncated.
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Table
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tentsprotectin
gne
wap
proa
ches
relatedto
ADClin
kertechn
olog
y
Tech
nolog
yEx
ample
IPright
Assignee
Claim
langua
ge
Non
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6863
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lype
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f,containing
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necompo
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gof:
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rein
each
R aisinde
pend
ently
selected
from
thegrou
pconsistin
gof
[...]
Cysteine-en
gine
ered
antib
odies(THIOMAB)
US200
7009
2940
Gen
entech
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ered
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odycomprisingon
eor
morefree
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ving
athiolreactivity
valuein
therang
eof
0.6to
1.0,
whe
rein
thecysteine
engine
ered
antib
odyisprep
ared
byaprocesscomprisingreplacingon
eor
moream
inoacid
residu
esof
apa
rent
antib
odyby
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ediated
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ker
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euticsAmetho
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oligan
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ence-spe
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tidase,or
acatalytic
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f.
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logy
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7029
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Acompo
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edby
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zyme,op
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998 Volume 7 Issue 6mAbs
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www.tandfonline.com 999mAbs
experience with regulations for genericsand biosimilars teaches that, once estab-lished, respective approval pathways donot allow any chemical modifications ofthe toxin or sequence modifications of theantibody. Therefore, although the scopeof such claims could theoretically bebypassed by even minor modification ofeither the toxin or the antibody, suchstrategy would necessitate an entirely newapproval, because the product would nolonger be a biosimilar. Table 11 showsexamples of patents claiming specific anti-body/toxin combinations.
Non-obviousness / inventive stepPatent claims relating to ADCs or their
components must pass the test on non-obviousness, as codified on 35 USC. x103, or its European counterpart, inven-tive step, as codified in Art. 56 of theEuropean Patent Convention. Both testsdecline patentability to an alleged inven-tion, even if it is novel, in case it was obvi-ous for a person of skill in the art in viewof existing prior art. In the US, differenttests have been applied in the past.
In the decision KSR v. Teleflex,21 theUS. Supreme Court set forth that the truetest of nonobviousness is the so called“Graham analysis,” thus denouncing a dif-ferent type of test that was used by thelower instance courts, which the SupremeCourt deemed too liberal. The SupremeCourt declared that the bar on patentsclaiming obvious subject matter shouldnot be confined within a test „too con-strained to serve its purpose.“ In the Gra-ham analysis, the courts examine thescope and content of the prior art, thelevel of ordinary skill in the art; the differ-ences between the claimed invention andthe prior art; and objective evidence ofnon-obviousness. Examples for the latterare, e.g., commercial success, long-felt butunsolved needs, and failure of others.
The EPO applies the so-called“problem solution approach.” In this test,the closest prior art is defined first. Sec-ond, the difference between the claimedinvention and the prior art is determined,and its technical effect is established.Accordingly, it is stipulated that it wouldbe the objective technical object of thealleged invention to obtain such effectstarted from the closest prior art. Eventu-ally, it is considered whether it was obvi-ous for the person of skill to solve thisobjective technical problem.
Despite all attempts to make the afore-mentioned tests as reproducible as possi-ble, large uncertainties still exist. Thepractical implementations differ not onlybetween the US and European Union orother jurisdictions, but also between dif-ferent technical disciplines, and evenbetween different examination divisions inthe same jurisdiction.
Table 12 gives an overview of theEuropean patents protecting gemtuzumabozogamicin, ado-trastuzumab emtansineand brentuximab vedotin (see alsoTable 1), and the reasons why the respec-tive examiner found the claimed subjectmatter inventive over the prior art. It canbe seen that in each case, the respectiveexaminer’s motif to allow the patent wasdifferent.
A look into the board of appeal deci-sions database of the EPO does not pro-vide better guidance either. In June 2015,only 2 decisions existed that relate to pat-entability issues of ADC patents, one ofwhich is referring to sufficiency of disclo-sure, while the other one refers to inven-tive step. Table 13 shows these 2decisions. Again, no true guidance can bederived from these decisions. Thus, unlikein naked antibody patent claims that spec-ify the antibody by a particular sequence,and where a clear guidance as to howinventive step is to be assessed exists,22 no
such guidance has so far been establishedwith respect to inventive step questions ofpatent claims for ADCs.
It needs to be recalled, in this context,that combining a particular toxin withsuperior potency and an antibody withexcellent target affinity does not necessar-ily yield a clinically effective ADC. Thebinding process, or the linker as such, canaffect either the toxin, or the antibody, orboth. Likewise, the toxin may not be ade-quate for the target bound by the anti-body. As can be seen in Table 12,Genentech has successfully used this lineof argumentation when defending theirpatent application EP2283867, protectingado-trastuzumab emtansine, over theirown prior art, which disclosed trastuzu-mab, plus generally mentioned the combi-nation thereof with maytansinoids.
For these reasons, the mere provisionof a functional ADC comprising a knowntoxin and antibody can already meet theinventive step criterion, at least in therecent past. However, with technical prog-ress, the likelihood that a prior art bench-mark exists already (e.g., an ADC using,for example, the same antibody, or at leastan antibody against the same target),increases. The patentee may in such casebe required to provide further arguments,or restrict the claim scope, to meet thenon-obviousness/inventive step criterion.
This criterion is thus a moving target,where, with technical progress of therespective discipline, requirements arechanged accordingly. Predictions of therequirements the offices will set withrespect to a given ADC patent applicationare thus educated guesses that take intoaccount the applicable state of the art, notonly with respect to the target, but alsowith respect to the toxin and the linkertechnology.
One objective evidence for inventivestep commonly accepted by EPO
Table 8. Claim categories for different types of toxin inventions
Subject matter Claim category Claim language
New class of toxin Compound protection Compound according to the general structural formula X, with R1 –Rx being [.]
Class is known, but specific toxin is novel Compound protection Compound of class X, having the following structural formula YClass or specific toxin is known, but
transfer to ADC is novel(i) Use/process protection or (ii) purpose
bound compound protection(i) Use of toxin x for the manufacture of an ADC(ii) Toxin x for use in an ADC for the treatment of cancer
the symbol [. . .] indicates that claim language has been truncated.
1000 Volume 7 Issue 6mAbs
examiners is if the novel embodiment hassurprising properties. In the ADC world,and in particular regarding specific anti-body-toxin combinations, this wouldmean that a specific characteristic of aclaimed ADC would be unprecedentedeven in view of the prior art benchmark.Such characteristic would not necessarilymean efficacy or potency. It could also bereduced side effects or, at least in the USand European Union, even non-clinicaladvantages, e.g., shelf life, ease ofmanufacture.
The problem of trade secretsThe term “trade secret” relates to a
product, process or know how thatprovides a commercial advantage to itsowner or creator, who, however, prefers tonot make it the subject of a patent
application. In some cases, creators orowners of such embodiments see it as aproblem that the content of a patentapplication is published after 18 months,while it is not yet clear at that timewhether a patent will be awarded on therespective subject matter or not. Further,if eventually granted, a patent expiresroughly after 20 years, after which thecontent of the patent becomes publicdomain. As a consequence, an inventionmay not be a subject of a patent applica-tion, but rather it may be kept a tradesecret. While this strategy does not workwith products that are to be sold (becauseputting them to the market without pat-ent protection makes such products publicdomain), it may have its merits withrespect to technologies, in particularmethods, that are practiced in-house, at
least in cases where a marketed productdoes not carry any traceable marks thatenable competitors to reverse-engineersaid technology.
A trade secret, however, is not an exclu-sive right. If the secret is disclosed, unin-tentionally, intentionally or even in badfaith, its content becomes public domainimmediately, and can be practiced bycompetitors. Therefore, in a strategy thatrelies on trade secrets, measures must betaken that ensure these secrets cannot bedisclosed, e.g., by former employees, norbe discovered by reverse-engineering. Incases when the owner of a trade secret col-laborates with third parties to whom saidtrade secret needs to be disclosed, non-dis-closure agreements should be signed. Incase such agreement is violated by thethird party, the latter will be liable for
Table 9. Claim categories for higher generation antibody patents
CategoryExample IPrights Assignee Target Claim language
2nd medical use EP1734996B1 University of California a vbeta 5 integrin Use of an antibody that specifically binds to a vbeta 5 integrin, wherein theantibody is a humanized form of the antibody produced by thehybridoma deposited as ATCC Deposit No. PTA-5817, for themanufacture of a medicament for treating pulmonary edema.
Dosage patent EP1210115B1* Genentech HER2 Use of the anti-ErbB2 antibody huMab 4D5 for treating a human patientdiagnosed with a breast cancer characterized by overexpression ofErbB2, said method comprising the steps of administering to the patientan initial dose of 8mg/kg of the anti-ErbB2 antibody; and administeringto the patient a plurality of subsequent doses of the antibody in anamount that is 6 mg/kg, wherein the doses are separated in time fromeach other by 3 weeks.
Formulation EP2459167B1 Roche HER2 A highly concentrated, stable pharmaceutical formulation of apharmaceutically active anti-HER2 antibody for subcutaneous injectioncomprising:
a. about 50 to 350 mg/ml anti-HER2 antibody;b. about 1 to 100 mM of a buffering agent providing a pH of 5.5 § 2.0;c. about 1 to 500 mM of a stabilizer or a mixture of 2 or more stabilizers;d. about 0.01 to 0.08 % of a nonionic surfactant; ande. more than 150 to about 160000 U/ml, about 20000 U/ml, or about
120000 U/ml, respectively of a hyaluronidase enzyme.
*EP Patent revoked in opposition, appeal pending. In UK finally revoked.
Table 10. Higher generation ADC patents
Category Example IP rights Assignee Target Claim language
2nd medical use US20110165155 Genentech HER2 A method for the treatment of metastatic or unresectable locallyadvanced HER2 positive cancer in a patient comprisingadministering a therapeutically effective amount of trastuzumab-MCC-DM1 wherein the patient has been previously treated with atleast 2 anti-HER2 agents.
Formulation WO2014143765 Abbvie EGFR A formulation comprising an anti-Epidermal Growth Factor Receptor(EGFR) antibody drug conjugate (ADC), a sugar, histidine, and asurfactant, wherein said formulation has a pH of about 5 - 7, andwherein said anti-EGFR ADC comprises an anti-EGFR antibody, orantigen-binding portion thereof, conjugated to an auristatin.
www.tandfonline.com 1001mAbs
damages; however, the disclosure as suchinvolving the loss of the trade secret can-not be undone.
For ADCs, the supply chain can bevery long. While an innovator can beresponsible for a series of innovative tech-nologies covering the entire supply chainof an ADC (encompassing, antibodies,linker technology, toxins, methods ofproduction and so forth), reality showsthat, at least when commercializationstarts, different steps of the supply chain
are taken over by contract manufac-turers.23 In such an environment, wheredifferent steps are outsourced to differentpartners, a trade secret strategy bears par-ticular risks, which may result in the lossof a given trade secret and, accordingly,availability of the respective technologyto competitors. Therefore, ADC innova-tors should use trade secrets with utmostcare, and consider relying on patentapplications to protect their intellectualproperty.
Immunotoxins and radiolabelledantibodies
Although not specifically discussedherein, most of the principles set forthabove do also apply to immunotoxins andradiolabelled antibodies. Immunotoxinsare fusion proteins that consist of a target-ing protein, ideally an antibody, fused to atoxic protein. Immunotoxins offer advan-tages over ADCs in manufacture (becausethey can be produced by recombinantprotein expression in one step) as well as
Table 11. Examples of patents claiming specific antibody/toxin combinations
Category Example IP right Assignee Claim language
Combination of target and toxin class US8337856 ImmunoGen An immunoconjugate comprising an anti-ErbB2 antibody conjugatedto a maytansinoid, wherein the antibody is huMAb4D5–8
Combination of specific antibody and toxin US8153768 Wyeth HoldingsCorporation
A composition comprising a drug conjugate, wherein said drugconjugate comprises calicheamicin derivatives and an anti-CD22antibody and has the formula:
[b]wherein the antibody comprises SEQ ID NO. [. . .]
the symbol [. . .] indicates that claim language has been truncated.
Table 12. European patents protecting gemtuzumab ozogamicin, ado-trastuzumab emtansine and brentuximab vedotin
EP Patent Claimed subject matter Closest prior art Why inventive?
EP0689845B1* ADC with calicheamicin andhydrazine linker
EP0392384 discloses Calicheamicinsuccinimidyl derivativesconjugated to an antibody
Examiner accepted that “nothing in the prior art suggeststhat the use of the current linker system to bindcalicheamicin to an antibody would yield conjugateshaving high immunoaffinity to the target, low toxicityand high antitumour activity.” (EP office action of May 11,2001)
EP2283867B1 Trastuzumab maytansinoidconjugate for treatment ofcancer over-expressingErbB2
WO0069460 discloses trastuzumab,plus generally mentionscombination therof withmaytansine
Examiner accepted applicant’s arguments of Nov 18, 2013,that (i) the specific selection of trastuzumab andmaytansine would be novel over WO’460. In support ofinventive step, applicant argued (ii) against Chari et al(1992), which discloses a murine anti-cancer ADCcomprising a maytansinoid and an anti ErbB2 antibodyas not being the closest prior art, and (ii) that it wassurprising that trastuzumab retained its cytostatic activityin an ADC, and would not be degraded to a meretargeting device, thus leading to an ADC where theantibody and the toxin act in concert. Applicant had alsoargued that at the priority date, there was uncertaintyregarding the therapeutic potential ofimmunoconjugates.
EP2353611B1 ADC with Pentapeptide linkerplus auristatin
WO02088172 disclosespentapeptide linkers, and ADCsusing them, but not auristatin
WO0208817 was the only prior art document, but althoughpre-filed, published after the priority date, and did thusnot affect inventive step
*expired
1002 Volume 7 Issue 6mAbs
to site specificity and stoichiometry of theconjugation. Disadvantages may lie in anincreased immunogenicity. So far onlyone immunotoxin has received approvalin the US, namely denileukin diftitox(Ontak�), which consists of an interleu-kin-2 protein fused to a diphtheria toxin.
Radiolabelled antibodies are antibodiesthat carry a radioactive isotope. Theseconjugates do not have to be internalizedinto the cells to become effective, and canthus also be used to attack cellular targetsthat do not involve internalization, justlike the CD20 receptor. Two radiolabelledantibodies have been approved, Gen-entech’s 90Y ibritumomab tiuxetan(Zevalin�; Key IP right: EP1112084B1)and 131I tositumomab (Bexxar�; Key IPright: US6090365; marketing discontin-ued in 2014), which both include an anti-CD20 antibody component. Both havebeen the subject of litigation betweenGenentech and GlaxoSmithKline.24
Case study 1Because of their commercial potential,
ADC patents will inevitably become thesubject of IP litigation. One very recentdispute is evolving between Phigenix,based in Atlanta, Georgia, and Genentechof South San Francisco. Phigenix, who ontheir website claim that they “will leveragelicensed patented technology to establish astrong first-mover advantage in Personal-ized Medicine and forge a lasting leader-ship position in the rapidly evolving
cancer diagnostic and therapeuticsindustry,” has in 2014 filed requests forinter partes review (IPR) against Gen-entech’s US Patent 7575748 (IPR2014–00842) and ImmunoGen’s US patent8337856 (IPR2014–00676), which bothprotect Genentech’s ADC ado-trastuzu-mab emtansine. Further, Phigenix suedGenentech on Jan 31, 2014 for patentinfringement of their own US patent8080534 in the Georgia Northern DistrictCourt (1:14-cv-00287). Table 14 showsthe respective patents and selected claimlanguage. As discussed above, Genentechhas acquired a license from ImmunoGenfor use of the SMCC linker and the DM1toxin conjugated to trastuzumab. A conju-gate of said toxin-linker combination withan antibody was protected, among others,by ImmunoGen’s patent US5208020(now expired; see Table 5).
On December 9, 2014, the PatentTrial and Appeal Board (PTAB) of theUSPTO denied institution of IPR2014–00842 against US7575748, on thegrounds that Phigenix did not establish areasonable likelihood of prevailing withrespect to any challenged claim. Phigenix’attacks were based on alleged obviousnessin view of the trastuzumab (Herceptin�)1998 label and several prior art docu-ments. According to the Board, whichapplied the “broadest reasonable construc-tion in light of the specification of the pat-ent,” Phigenix failed to explain adequatelyhow, nor provided sufficient evidence
indicating that, the teaching in the trastu-zumab label that certain patients failed torespond to the product would have moti-vated an ordinary artisan to treat suchpatients using a trastuzumab (huMab4D5–8) conjugate.
In contrast thereto, IPR2014–00676against US8337856 was instituted onOctober 29, 2014. The PTAB found thatPhigenix has demonstrated that there is areasonable likelihood that it would prevailon the ground that claims 1–8 of the pat-ent would have been obvious over some ofthe prior art documents in view of thetrastuzumab label. This, however, is not afinal determination on the patentability ofthe challenged claims. IPR proceedingswere thus instituted. The case is ongoingas of mid-2015.
Regarding the litigation at the GeorgiaNorthern District Court, Phigenixasserted that Genentech would infringetheir patent US8080534 via certain acts,“directly and/or indirectly, of making,using, selling, or offering for sale the drugado-trastuzumab emtansine under thetrade name Kadcyla�, and inducinghealthcare professionals to prescribe andadminister Kadcyla�,” among others bydistribution of the respective prescribinginformation.
The infringement contentions wereserved to Genentech’s attorneys in Sep-tember 2014, but are so far not public yet.As of mid-2015, Phigenix has not publiclydisclosed which part of ado-trastuzumab
Table 13. Abstract of the 2 EPO Appeal decisions that relate to ADC patents
Decision Date Patent/ application Claimed subject matter Outcome
T 0619/01 August 2004 EP0634938A1* conjugate of SMPT linked-humanizedM195 antibody and 2-iminothiolanemodified gelonin or recombinantgelonin for the treatment of leukemia
Claims found unallowable for insufficient disclosure,because the term “term “recombinant gelonin” wasnot properly defined. The only vague definition(JM105 E. coli expressing optimized gelonin”)would leave the burden of finding out how toarrive at recombinant gelonin entirely upon theskilled reader.
T 1014/01 Nov 2003 EP0439095B1** Antibody-based fusion proteincomprising an Ig portion capable ofdirecting the fusion protein to a tumor,an IL2 molecule capable of promotinglymphocyte proliferation, and amodified IgG1 hinge region with the 2Cys residues replaced by Pro andSerine to permit greater flexibility inthe fused molecule.
Claim 1 (3rd request) was found inventive becauseprior art suggested that the hinge feature wouldavoid the reactive side groups in the AA sequence,not for increasing the flexibility. Further, prior artwould contains no pointer to replace Cys with Pro,while prejudice against the use of Pro (“helix-killer”)would exist.2nd request, which recited, as an alternative, also anatural hinge region, was not deemed inventive.
*rejected; **expired
www.tandfonline.com 1003mAbs
emtansine they believe to inhibit PAX2expression or PAX2 activity and/or expressDEFB1, as set forth in claim 1 ofPhigenix’s patent. However, dependentclaim 15 stipulates that the therapy canalso comprise administration of an anti-Her-2 agent. This suggests that Phigenixconsiders the DM1 toxin as the part ofado-trastuzumab emtansine that inhibitsPAX2 expression or PAX2 activity and/orexpresses DEFB1, as set forth in claim 1,while the trastuzumab part would bedefined in said dependent claim 15.
Furthermore, claim 19 claims adminis-tering the composition to a patient afterdetermining the PAX2-DEFB1 expressionratio and the ER/PR status in a breast can-cer tissue isolated from the patient. How-ever, the prescribing information,25 ofado-trastuzumab emtansine does not men-tion either PAX2 or DEFB1. Therefore, itremains unclear so far what exactly theinfringement contentions refer to. Uponmotion of Genentech, the infringementaction was transferred to the NorthernDistrict of California Court on March 17,
2015 (3:2015cv01238), where it is stillpending.
This case impressively demonstrateshow even originators of a naked antibodycan run into patent litigation when mar-keting an ADC, even if said ADC com-prises their established antibody, and evenif the respective toxin and linker technol-ogy have been in-licensed. Further, thiscase shows that even having obtained alege artis FTO opinion – an exercise Gen-entech has undoubtedly gone throughbefore marketing ado-trastuzumab
Table 14. Patents that play a role in the Phigenix-Genentech dispute
Novel embodiment Assignee Case No Claim language
US7575748 Genentech IPR2014–00842 1. A method for the treatment of a tumor in a mammal, comprising the steps of (i)identifying said tumor as being characterized by overexpression of an ErbB2 receptorand as being a tumor that does not respond, or responds poorly, to treatment with ananti-ErbB antibody, and (ii) intravenously administering to the mammal atherapeutically effective amount of a conjugate of a humanized antibody huMab 4D5–8covalently linked via a thioether linking group with a maytansinoid DM1 having thestructure
at a dose of between about 0.2 mg/kg and about 10 mg/kg (antibody-maytansinoidconjugate weight/body weight) and at a frequency of dosing selected from the groupof dosing frequencies consisting of bolus, less than about 1 time per week, one time perweek, 2 times per week, more than 2 times per week, and continuous infusion,whereby said tumor characterized by overexpression of an ErbB2 receptor and thatdoes not respond, or responds poorly, to treatment with an anti-ErbB antibody, istreated.
US8337856 ImmunoGen IPR2014–00676 1. An immunoconjugate comprising an anti-ErbB2 antibody conjugated to a maytansinoid,wherein the antibody is huMAb4D5–8
US8080534 Phigenix 1:14-cv-00287 1. A method for treating a breast condition in a subject, comprising administering to abreast tissue of the subject, a composition that(1) inhibits PAX2 expression or PAX2 activity,(2) expresses DEFB1 or(3) inhibits PAX2 expression or PAX2 activity and expresses DEFB1.15. The method of claim 1, further comprising the step of: administering to the subjectan effective amount of an anti-HER-2 agent.16. The method of claim 15, wherein the anti-HER-2 agent is trastuzumab.19. A method for treating a breast condition in a subject, comprising:(a) determining the PAX2-to-DEFB1 expression ratio in a diseased breast tissue fromsaid subject;(b) determining the ER/PR status of said diseased breast tissue from said subject; and(c) based on the results of (a) and (b), administering to a breast tissue of said subject, afirst composition that (1) inhibits PAX2 expression or PAX2 activity, (2) expresses DEFB1or (3) inhibits PAX2 expression or PAX2 activity and expresses DEFB1.
1004 Volume 7 Issue 6mAbs
emtansine – does not provide a guaranteeagainst IP attacks from unforeseen cor-ners. This again demonstrates the com-plexity of the IP landscape in the ADCfield, and the residual risk players mustdeal with even with a proper FTO opinionin their hands.
Phigenix also filed an oppositionagainst ImmunoGen’s EP counterpart ofUS patent 8337856, EP2283867 (seeTables 1 and 12) on February 19, 2015.In the opposition, Phigenix alleges thatthe patent claims would lack novelty overWO0069460, and lack inventive stepover, among others, a journal article auth-ored by Chari et al.,26 and the trastuzu-mab label, in combination with otherdocuments disclosing maytansinoid tox-ins. While Phigenix thus largely relies onprior art that has already been consideredby the office (see Table 12), their mainline of argumentation is that the selectionof trastuzumab and a maytansinoid wouldnot be a specific selection that would pro-vide novelty over WO0069460. Further,they argue that Chari et al. would indeedbe the closest prior art, as it relates to afunctional anti-cancer ADC comprising amaytansinoid and a murine anti-ErbB2antibody, thus rebutting Genentech’sarguments according to which it was sur-prising that trastuzumab retained its cyto-static activity in an ADC, and would notbe degraded to a mere targeting device.
A first decision in this case cannot beexpected prior to mid-2016. Interestingly,on February 2015, Genentech receivedthe allowance for another EP applicationof the same family, EP2283866, with analmost identical claim scope. The opposi-tion term of this patent will be open untilNovember 2015.
Case study 2HER2 seems to be an attractive target
for ADC therapy, not only because it hasproven safe and efficacious in antibodytherapy, but also because it meets theother requirements set forth above,including rapid internalization.27 Unsur-prisingly, Genentech is not the only com-pany that has an anti-HER2 ADC intheir portfolio. In some way, ado-trastu-zumab emtansine can be considered afirst-generation ADC, while second-
generation anti-HER2 ADCs are alreadyunder development.
Based in Nijmegen, The Netherlands,Synthon has developed SYD985, whichcomprises trastuzumab conjugated to acleavable linker and duocarmycin pay-load. According to Synthon, SYD985 isalso active against tumors that exhibitlow expression of HER2, and does thusallow extension of the target populationof cancer patients who may respond tothis treatment to include FISH (fluores-cence in situ hybridization)-negative/immunohistochemistry (IHC)-HER2 1Cand 2C patients.28 According to theFDA label, ado-trastuzumab emtansineis, however, only indicated for the treat-ment of patients with HER2-positivebreast cancer in which the tumors showHER2 overexpression defined as 3CIHC. While trastuzumab is beginning tocome off patent (EP0590058 has expiredJune 15, 2012), the linker technologyand the duocarmycin used in SYD985are being pursued in pending applicationEP2560645 (see Table 12), assigned toSyntarga, which is a subsidiary of Syn-thon. Although SYD985 addresses a simi-lar market as ado-trastuzumab emtansine,and clinical trials are currently underway,29 it has, so far, not been subject of apatent litigation by third parties. Itappears that SYD985 would at least notfall under the scope of US8337856 pro-tecting ado-trastuzumab emtansine (seeTable 15) because SYD985 does notcomprise a maytansinoid.
The same circumstances apply to theanti-HER2 ADC ARX788 developed byAmbrx. ARX788 comprises an anti-HER2antibody coupled site specifically to a toxincalled Amberstatin (AS269) by means ofAmbrx’ technology using non-naturalamino acids (EP1968635B1, see Table 6).Like Synthon, Ambrx claims that ARX788serves a broader spectrum of HER2C can-cer patients than ado-trastuzumab emtan-sine. Similarly, it appears that ARX788has so far not been the subject of a patentlitigation by third parties. ARX788 is cov-ered by Ambrx’s international patentapplication WO2013192360. The linker,toxin and antibody are not chemicallyspecified, but according to a report pub-lished in 2012,30 it appears that the anti-body could be a modified trastuzumab
that carries a p-acetylphenylalanine (pAc-Phe) residue instead of a naturally occur-ring amino acid reside, to which analkoxy-amine derivatized auristatin F(MMAF) is conjugated by oxime ligation.
Another anti-HER2-toxin construct inclinical development is MM-302 devel-oped by Merrimack Pharmaceuticals Inc.MM-302 is not a conjugate in strictusensu because it consists of a liposome75–110 nm in diameter that encapsulatesdoxorubicin. The lipid membrane is com-posed of phosphatidylcholine, cholesterol,and PEGylated phosphatidylethanolamine(1 PEG molecule for 200 phospholipidmolecules), wherein one PEG moleculefor each 1780 phospholipid moleculesbears at its end an anti-HER2 scFv anti-body fragment called F5.31
Exact targeting is critical in this ADCbecause cardiomyocytes, which are affectedby the highly cardiotoxic doxorubicin,must be avoided. The fact that doxorubicnis encapsulated by liposomes further pro-tects the cardiomyocytes. As with SYD985and ARX788, it appears that MM-302,which is covered by international patentapplication WO2012078695, has so farnot been subject of a patent litigation bythird parties.
Dophen Biomed of Sacramento, USA,has recently presented results32 on an anti-HER2 ADC consisting of trastuzumaband MMAE, conjugated to one anotherby Dophen’s transglutaminase usingDophen’s endosome escaping non-cleavable” (EENC) linkers (see Table 6).The company claims that this ADC has100% stability and higher potency than acomparable ADC with a cleavable linker.Further, Dophen uses this technology togenerate anti-HER2 ADC comprisingtrastuzumab and 2 different toxins ofundisclosed nature. Quite apparently, atleast one of these toxins is a tubulysinbecause of a collaboration with Austriantubulysin specialist Tubepharma.33 It hasbeen reported that such a hybrid ADC hasbetter potency than the respective homo-geneous ADCs of the same toxins, andalso better potency than a 1:1 mixture ofthe 2 homogeneous ADCs. No patentinformation is available for Dophen’stechnologies.
NBE Therapeutics of Basel, Switzer-land, has created different anti-HER2
www.tandfonline.com 1005mAbs
Table
15.D
etailsof
differen
tan
ti-HER
2ADCsin
developm
ent
ADCnam
eAntibod
yLinke
rTo
xin
Key
IPright
Com
pan
yStatus
Claim
langua
ge
Trastuzumab
emtansineTrastuzumab
SMCC
DM1
US833
7856
Gen
entech
App
rovedin
USan
dEU
Anim
mun
ocon
juga
tecomprisingan
anti-ErbB
2an
tibod
yconjug
ated
toamaytansinoid,
whe
rein
thean
tibod
yishu
MAb4
D5–
8.MM-302
scFv
anti-HER
2PE
G-DSP
ELipo
some-
encapsulated
doxorubicin
US201
4023
698
Merrim
ack
Phase2/3
Ametho
dof
treatin
gahu
man
cancer
patie
ntby
administrationof
anthracycline-com
prisingan
ti-HER
2im
mun
oliposom
es,the
metho
dcomprisingde
term
iningafirstd
osag
e,such
ado
sage
indicatin
gado
semag
nitude
andfreq
uencyof
dosing
,for
apa
tient
diag
nosedwith
acancer
characterized
byexpression
ofHER
2receptor,the
firstd
osag
ebe
ingfora
liposom
alan
thracycline
chem
othe
rape
uticag
enttha
tdoe
sno
tcom
prisean
immun
oliposom
e,which
dosage
isde
term
ined
toprov
ideto
the
patie
ntasafe
andeffectiveam
ount
ofthelip
osom
alform
ulation,
andad
ministerin
gan
thracycline-comprisingan
ti-HER
2im
mun
oliposom
es,a
plurality
ofwhich
immun
oliposom
esiseach
bearingaplurality
ofan
ti-HER
2an
tibod
ymolecules
onits
surface
andeach
containing
thean
thracyclinechem
othe
rape
uticag
ent,
whe
rein
thean
thracycline-comprisingan
ti-HER
2im
mun
oliposom
esaread
ministeredto
thepa
tient
atthefirst
dosage
.
SYD98
5Trastuzumab
SpaceLink
Duo
carm
ycin
EP25
6064
5A2
Syntarga
Phase1
Acompo
undof
form
ula(III):
oraph
armaceu
ticallyacceptab
lesalt,hy
drate,or
solvatethereo
f,whe
rein
[...]
(Con
tinuedon
nextpa
ge)
1006 Volume 7 Issue 6mAbs
ARX
788
Und
isclosed
Und
isclosed
Ambe
rstatin
AS269
US201
5141
624
AmbrX
Preclin
ical*
whe
rein
[...]
Not
available
Trastuzumab
Tran
sglutaminase
CEENClin
ker
MMAE,hy
brid
ADCswith
differen
ttoxins
Not
available
Dop
hen
R&D
Not
available
Not
available
Trastuzumab
SMACwith
N-terminal
LPTX
Gtag/lin
ker
(i)DM1(m
ertansine),
(ii)m
aytansine,
(iii)MMAE/MMAF
(iv)a
-aman
itin
(v)u
ndisclosed
newtoxin,
respectiv
ely
(i)–(iv)
WO20
1414
0317
(v)n
otdisclosed
NBETh
erap
euticsR&
D1.Ametho
dof
prod
ucingan
immun
oligan
d/pa
yloa
dconjug
ate,
which
metho
den
compa
sses
conjug
atingapa
yloa
dto
anim
mun
oligan
dby
means
ofasequ
ence-spe
cifictran
spep
tidase,
oracatalytic
domainthereo
f.6.Th
emetho
daccordingto
anyof
theaforem
entio
nedclaims,
whe
rein
thesequ
ence-spe
cifictran
spep
eptid
aseisat
leasto
neselected
from
thegrou
pconsistin
gof
�asortaseen
zyme,or
oneor
morefrag
men
tsor
deriv
atives
thereo
f�a
split-in
tein,oro
neor
morefrag
men
tsor
deriv
atives
thereo
fNot
available
Trastuzumab
N-Hyd
roxysuccinim
ide
ester
Tubu
lysin
Not
available
VUMC
Amsterda
mR&
DNot
available
*Pha
se1stud
y(NCT025
1223
7)sche
duledto
startin
Septem
ber2
015;thesymbo
l[...]indicatesthat
claim
lang
uage
hasbe
entrun
cated.
www.tandfonline.com 1007mAbs
ADCs with trastuzumab using their sor-tase-mediated antibody conjugation tech-nology (SMAC) with N-terminal LPTXGtag/linker (see Table 6, WO2014140317)to couple trastuzumab to DM1 (mertan-sine), maytansine, MMAE, MMAF anda-amanitin, and thus create ADCs withsite-specifically conjugated toxins ofhomogeneous DAR. The first 2 have beenreported to be equally potent as ado-tras-tuzumab emtansine. Another ADC com-prises an undisclosed new toxin, whichhas demonstrated significantly betterpotency in cells expressing only lowamounts of HER2 than ado-trastuzumabemtansine.34
Still another anti-HER2 ADC has beendeveloped by researchers of the VU Uni-versity Medical Center Amsterdam, whoused a moderately toxic tubulysin analog(TUB-OMOM). Tubulysins have a nar-row therapeutic window and are thusinteresting for ADC use. For this purpose,tubulysin-NHS-esters were coupled totrastuzumab, while for control purposes,131I-tubulysin and 89Zr-trastuzumab wereused. The conjugation reaction was 45–55% efficient, resulting in ADCs with96–98% radiochemical purity and anaverage DAR of between 2 and 4. Theresearchers report a potency comparableto that of ado-trastuzumab emtansine,while the availability of synthetic tubuly-sins that are more potent than TUB-OMOM offers additional options tomake more potent ADCs.35 No patentinformation is available for this approach.Table 15 shows some details of the anti-HER2 ADCs discussed above.
Summary
Regarding IP aspects, ADCs posesevere challenges, but also tremendouspossibilities. ADCs comprise a field oftheir own, in which only part of the rulescan be translated from antibody IP. Fur-ther, because many players are active inthis field, the third-party IP situation iscomplicated, with many overlapping pat-ent estates. A meaningful IP strategy forprotecting ADC inventions and establish-ing FTO requires specific expertise in thischallenging IP discipline, as well as a
thorough technical understanding of bothbiotechnology and organic chemistry.
Disclosure of Potential Conflicts of Interest
The author is involved in the prosecu-tion of some of the patent applicationsmentioned herein.
The information provided hereinreflect the personal views and considera-tions of the author. They do not representlegal counsel and should not be attributedto Michalski ¢ H€uttermann and PartnerPatent Attorneys or to any of its clients.Patent numbers and patent lifetimes havebeen verified with utmost care, but no lia-bility is taken for their correctness.
Supplemental Material
Supplemental data for this article canbe accessed on the publisher’s website.
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