PERSPECTIVE mAbs 7:6, 989--1009; November/December 2015; © 2015 Taylor & Francis Group, LLC

Antibody-drug conjugates: Intellectual property considerations

Ulrich Storz* Michalski Huttermann€ Patent Attorneys; Dusseldorf,€ Germany

ntibody-drug conjugates are highly to develop and sell new ADCs or protect Acomplex entities that combine an the compounds and technologies from antibody, a linker and a toxin. This com- which they are derived are faced with chal- plexity makes them demanding both lenges when making business decisions. In technically and from a regulatory point addition, the numerous players active in of view, and difficult to deal with in their this field have created a maze of third- patent aspects. This article discusses dif- party IP rights that is difficult to navigate. ferent issues of patent protection and Further, because ADCs combine biotech- freedom to operate with regard to this nology and organic chemistry, IP counsels promising new class of drugs. working in this area need a thorough tech- nical background in both disciplines. This article discusses some of these Introduction aspects in more detail, and discloses IP rights that stand exemplarily for a given Antibody-drug conjugates (ADCs) are technology or concept. It can, however, one of the most promising classes of new not replace a case-specific FTO analysis or drugs, although the idea is not new.1 novelty search. Some of the IP rights dis- ADCs embody the oft-cited concept of cussed herein may not have been granted “magic bullets,” which was described by yet, or they may have already expired or Paul Ehrlich over 100 y ago. As of 2015, been revoked. The latter, which are 3 ADCs have been approved by the marked with an asterisk in the respective US Food and Drug Administration tables, may thus constitute free prior art, (FDA), namely gemtuzumab ozogamacin and, as such, provide a valuable source of (MylotargÒ), ado-trastuzumab emtansine information for competitors. Keywords: ADC, antibody-drug conju- (KadcylaÒ) and brentuximab vedotin gates, antibody, freedom to operate, (AdcetrisÒ). Their characteristics are Freedom to operate immunotoxin, Kadcyla, patent shown in Table 1. More than 40 other The term “Freedom to Operate” refers 2 Abbreviations: FDA, Food and Drug ADCs are in clinical studies today. to a determination that the commerciali- Administration; FTO, Freedom to Oper- ADCs combine an antibody, a linker zation of a product does not infringe ate; IP, Intellectual property; ADC, Anti- and a toxin (often called “payload” or, third-party IP rights, in particular patents. body-Drug Conjugates; EPO, European more martial, “warhead”), and, for that Establishing FTO requires that all compo- Patent Office; USPTO, United States Pat- reason, they are technically demanding to nents of the respective technology, encom- ent And Trademark Office; CDR, Com- develop and pose challenges in passing methods as well as compounds 3 plementarity Determining Region; HC/ manufacturing. They can also raise regu- and intermediates, are analyzed with 4 LC, Heavy Chain/Light Chain; DAR, latory issues. because ADCs can be con- respect to whether they are the subject of Drug-Antibody Ratio; IPR, Inter Partes sidered prodrugs that release their active valid and enforceable third-party IP rights. Review; PTAB, Patent Trial and Appeal compound–the toxin–at the site of action. Because IP rights have a territorial Board While their complexity has been called effect and a restricted lifetime only, an „ 5 *Correspondence to: Ulrich Storz; Email: an invitation to innovation,” ADCs are FTO analysis does not only focus on the [email protected] difficult to deal with in their intellectual technologies as such, but also considers Submitted: 05/28/2015 property (IP) aspects. Both Freedom to where IP rights are in force and when they Operate (FTO), as well as the protection expire. In this context, the estimated time Revised: 08/03/2015 of ADCs and technologies to generate to market of the product that is to be com- Accepted: 08/05/2015 them, are affected by the complexity of mercialized should be weighed against the http://dx.doi.org/10.1080/19420862.2015.1082019 the molecules, and thus those who want lifetime of a given IP right. Further www.tandfonline.com mAbs 989 Table 1. Characteristics of the 3 ADCs approved to date by the US Food and Drug Administration Target also used in conventional Drug Antibody Key IP right mAb Linker Site specific Antibody ADC name target US/EP therapy? Linker cleavable? Toxin conjugation? Ratio

Gemtuzumab CD33 US5773001/ no hydrazone yes calicheamicin no Only 50% of the ozogamicin** EP0689845B1* antibody is loaded at all (avg 4 – 6) Trastuzumab HER-2/neu US8337856/ yes SMCC (maleimide) no DM1 (maytansinoid) no 0–8 (avg 3,5) emtansine EP2283867B1 Brentuximab CD30 US7829531/ no maleimidocaproyl yes MMAE (auristatin) no 3–5 vedotin EP2353611B1 spacer, valine– (cathepsin) citrulline linker, and PABC spacer

*expired; **product voluntarily withdrawn from the market in 2010. considerations should focus on potential linker. The existing IP landscape thus times in biologics are slightly longer than research exemptions as well as on ques- appears more complicated than for naked those reported for small molecular drugs.8 tions of exhaustion, or process patents antibodies, with overlapping patent estates Because of the higher complexity and that might extend their protection on assigned to different owners. Navigating the higher regulatory burden, it can be products obtained therewith. These non- this landscape can become a laborious assumed that, generally, these figures will ADC specific regulations are subject to challenge, and again requires a thorough be even higher in ADCs. A meaningful large variations between different jurisdic- understanding of the technical back- patent strategy is thus indispensable to tions, and thus are outside the scope of ground, including biotechnology and ensure that these investments can be recu- this article. organic chemistry, and the filing strategies perated over at least a given period of If, in the course of an FTO analysis, IP used by competitors. time. ADC-related embodiments that can rights that are likely to be infringed by the Further, inventors often believe that, become subject of patent protection will commercialization of a given product are once a patent has been granted on a given also be discussed in the following. detected, one should consider whether or invention, FTO would be automatically not they are valid and enforceable. If not, warranted. This thinking relies on a mis- The antibody component respective countermeasures should be con- conception. The truth is that even if a pat- An antibody as such can be subject of sidered, like invalidity opinions, opposi- ent has been awarded on a structurally third-party patents. This may encompass tions, nullity actions, or post grant review/ improved second-generation antibody, it 4 categories: 1) patents that protect any inter partes review. can still be the subject of earlier third- kind of antibody binding a particular tar- As an alternative, in-licensing of the party patents protecting the starting anti- get, which at the filing date was novel respective IP rights could be a solution. body, if these are still in force. In the fol- (and specified by the applicant in a suffi- This approach is frequently used in cases lowing sections, the methods and cient way as to enable skilled persons to where the patent protected technology is compounds that are relevant in an ADC make an antibody thereagainst); 2) patents an enabling technology, or refers only to a FTO analysis will be briefly addressed. that protect all antibodies against a given part of the molecule, like a linker. These epitope of such target (if binding said epi- technologies have often been developed by Active IP strategies tope has unprecedented effect); 3) patents technology companies who use out-licens- ADCs do also offer new possibilities to that protect all antibodies against a given ing as their business model. Large bio- obtain patent protection. ADCs can, in target that have a particular functionality pharmaceutical companies are generally some way, be considered as an advance- (e.g., minimum affinity, inhibition of a less inclined to grant a license, in particu- ment of conventional therapeutic antibod- given effect); or 4) patents that protect a lar on a compound-related patent, because ies, and, according to a general principle, specific antibody (either defined by the they seek exclusivity rather than royalties. each bit of advancement can be made sub- respective expressor cell, or by a particular For ADCs, an FTO analysis encom- ject of a patent application. sequence, e.g., of the CDRs, the variable passes all components, i.e., the antibody, According to a study performed at domains or the HC/LC sequences). the toxin and the linker. Numerous play- Tufts University in 2007, the estimated It needs to be added, in this context, ers have already staked their claims, and average costs of developing a new biologic that new targets for ADC therapy are hard many patents and patent applications refer was 1.2 billion USD.6 This figure has to find,9 thus making patents of categories to a combination of 2 of the components, been adjusted upwards in 2014 to even 1 and 2 less frequent nowadays. Further, very often a combination of a toxin and a 2.6 billion USD.7 Further, development it appears that the US Patent and

990 mAbs Volume 7 Issue 6 Trademark Office (USPTO) and the established, and in which markets. The The use of an approved naked antibody European Patent Office (EPO) have same applies in cases where the target of for making an ADC has its merits. For become more critical toward patents of the planned ADC is the subject of third- example, it may appear useless to category 3 because a functional claim fea- party patents. Patents of such type are on “reinvent the wheel,” i.e., to develop a ture is quite often considered to be a mere the decline (simply because quite a few new antibody when ones that bind rele- desideratum only, putting into question targets have already been described 10 y vant targets with high specificity and affin- the true possession of the entire invention ago or earlier), but still exist and provide ity are already on the market, and have by the applicant at the filing date, as well meaningful patent protection. Table 2 proven sufficiently safe and efficient to be as the inventive character involved. shows typical examples of different types approved. However, not all therapeutic Regarding category 4, it seems that the of naked antibody compound patents, as antibodies on the market are suitable as EPO applies a higher standard than the granted by the EPO. ADCs. USPTO by requiring that the applicant As shown above, some ADC For ADCs, internalization of the anti- disclose some kind of surprising effect of approaches use existing antibodies that body may be necessary, whereas, for the new sequence-wise specified antibody have already proven useful either in the naked antibodies that evoke antibody- over prior art antibodies addressing the clinic or in preclinical research, and may dependent cell-mediated cytotoxicity or same target.10 have a substantial global market. For complement-dependent cytotoxicity (e.g., As a general rule, all therapeutic anti- example, trastuzumab, which as a solo anti-CD20 rituximab), quick internaliza- bodies on the market are, or were, pro- product, generated global sales of 6.5 bn tion would be counterproductive. Fur- tected by such compound patents. The USD in 2013. ther, antibodies that bind cytokines (e.g., use of an approved antibody to generate As can be seen in Table 2, Claim 3 of anti-TNF adalimumab, anti-VEGF-A an ADC is thus likely to fall under the EP0590058 (which has expired June bevacizumab) instead of cell surface anti- scope of the respective naked antibody 2012) protected Genentech’s anti-HER2 gens are unlikely to be useful for ADC patent, provided it is still in force. The antibody trastuzumab by its VL and VH therapy because they would not deliver fact that the antibody is conjugated to a sequence. ADCs comprising trastuzumab, their toxin to a suitable target cell. An toxin does not per se change this situation. such as Genentech’s ado-trastuzumab ideal ADC target should therefore: 1) In case the planned ADC comprises an emtansine, would therefore fall under reliably differentiate cancer cells from existing antibody that is already on the claim 3 of EP0590058B1. Interestingly, healthy cells; 2) occur in sufficient market, or will enter the market, a thor- claim 11 explicitly specified, as a preferred abundancy on the cell surface; 3) inter- ough FTO analysis should be carried out embodiment, an immunotoxin compris- nalize the bound ADC with sufficient in order to define when FTO can be ing trastuzumab plus a cytotoxin. speed 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 or EP1587837B1 Proscan RX PSMA An antigen comprising an immunogenic moiety or target epitope carrier and an epitope of the extracellular region of PSMA consisting of SEQ ID NO:8, wherein the N- terminal cysteine residue on SEQ ID NO:8 is optional. An isolated antibody or antigen binding fragment thereof, which binds to the antigen wherein the antibody and/or antigen binding fragment thereof also binds to PSMA. Antibody claimed by functional EP1347730B2 Seattle Genetics CD30 An antibody that immunospecifically binds CD30 and properties exerts a cytostatic or cytotoxic effect on a Hodgkin’s disease cell line in the absence of conjugation to a cytostatic or cytotoxic agent. Antibody claimed by expressor cell EP0660721B1* Dana Farber CD22 A monoclonal antibody that: is produced by a hybridoma cell line selected from the group consisting 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 domain comprising the polypeptide sequence X and a VH domain comprising the polypeptide sequence Y. Antibody claimed by sequence EP1951757B1 Xencor CD30 An anti-CD30 antibody, comprising a variable heavy chain sequence 1 and a variable light chain sequence 2

*expired; the symbol [...] indicates that claim language has been truncated.

www.tandfonline.com mAbs 991 Concerns have already been raised that The linker technology efficacy of the ADC. Table 6 shows some all acceptable targets meeting these In principle, a large variety of linker new approaches related to ADC linker requirements have been discovered technologies exists to bind small molecules technology, and exemplary IP rights. already, and that it is unlikely new ones to proteins. A well-established technique is will be found. 11 Regardless, in the event a the maleimide-based conjugation of thiol- novel and suitable target for ADC therapy comprising molecules to proteins. This The toxin is found, it is definitely worth seeking pat- approach has often been used in first-gen- Before the toxin component of a pro- ent protection for antibodies against said eration ADCs. Other linkers frequently jected ADC is selected, consideration target on the basis of the classical catego- used rely on hydrazone, disulfide or amide should be given to whether the respective ries of antibody compound protection bonds. toxin is subject to third-party IP, and, if (see above). If the target is already known Early attempts to improve linker tech- so, where, and until when, and whether or but has not yet been described as a target nology focused mainly on increasing not it can be in-licensed. Today, 3 classes for ADC therapy, patent protection may linker stability, to avoid cleavage thereof of toxins are typically used in ADCs, focus on an ADC binding to said target. when the ADC is still in the bloodstream. namely maytansinoids, auristatins, and An example of the latter category is shown These demands were met, e.g., by linkers calcheamicins, but others are under inves- in Table 3. developed by Seattle Genetics or Immu- tigation. Table 7 shows some selected tox- In addition thereto, further develop- noGen. See Table 5 for some exemplary ins and exemplary IP rights, some of ments regarding the antibody concept as IP rights. However, there was, and still is, which refer to the combination of a toxin such can be made the subject of patent further potential for innovation and, and a given linker or antibody. protection. This could involve, for accordingly, new IP, in the field of ADC Interestingly, of 47 ADC candidates in example, the use of new antibody for- linker technology for various reasons, clinical studies as of 2014,14 16 candidates mats or protein binders derived from including insufficient linker stability, use maytansinoids, while 22 candidates alternative scaffolds. Another approach insufficient site specificity of the conjuga- use auristatins. In most cases, a license, or is to modify antibodies in such way that tion or insufficient stoichiometry. These a purchase of the respective toxin, from they become active only at the tumor problems affect the efficacy and safety of ImmunoGen, or Seattle Genetics, respec- site,eveniftheytargetanantigenthatis an ADC and, as such, may pose challenges tively, would be necessary, because these 2 expressed both on healthy cells and during regulatory agency reviews. New companies are the major IP holders tumor cells.12 This approach relies on linker technologies therefore strive to: 1) regarding these toxins, or toxin-linker specific environmental conditions at the increase linker stability (and thus avoid combinations (see Table 7). tumor site (e.g., abundance of proteases) cleavage thereof in the extracellular space); With respect to ado-trastuzumab to activate the antibody, thus avoiding 2) modulate cleavability after internaliza- emtansine, which carries ImmunoGen’s damage to healthy cells are bound. In tion (cleavage by plasma enzymes or maytansinoid DM1, the original deal suchway,targetsthatarenotdruggable medium conditions, e.g., pH, allows the forged between Genentech and Immuno- due to insufficient discrimination drug to leak into neighboring cells; non- Gen provided 2 mn USD upfront pay- between cancer cells and healthy cells cleavable linkers release the toxin only ments, plus 44 mn USD in milestone and can be used. Still other approaches have after degradation of the antibody); 3) royalty payments.15 This is quite modest identified targets that do not require increase site specificity of the conjugation in view of the commercial power of ado- internalization of the ADC. Accumula- site to establish homogenicity of the ADC trastuzumab emtansine, which was tion of the ADC in the sub-endothelial and avoid steric hindrance of the binding launched in February 2013, achieved sales extracellular matrix of tumors was found domains; or 4) increase stoichiometry of 91 mn USD in the first half of 2013, efficient at very low side effects.13 (also called „drug-antibody ratio,” DAR) and may achieve sales of 2.55 bn USD in Table 4 shows some of these approaches to yield sufficient efficacy of the ADC, 2018 according to analysis by Fierce where the antibody concept has been e.g., by avoiding antibodies that carry no Pharma. It appears, however, that in more further developed, plus exemplary IP toxin, which would compete with the recent deals, ImmunoGen has negotiated rights. ADC for target binding and thus affect more 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 thereagainst cKIt US20140271688 Novartis ADC of the formula Ab-(L-(D)n)n or a pharmaceutically are known, but not in an ADC acceptable salt thereof; wherein Ab is an antibody or antigen binding fragment thereof that specifically binds to an epitope of human cKIT; L is a linker; D is a drug moiety; m is an integer from 1 to 8; and n is an integer from 1 to 10.

992 mAbs Volume 7 Issue 6 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 immunoglobulin variable region comprising: (i) at least 2 cysteine residues positioned within framework region (FR) 2, wherein if at least 2 of the cysteine residues in FR2 are not conjugated to a compound then a disulfide bond is capable of forming between the cysteine residues in FR2; and/or (ii) at least 2 cysteine residues positioned within framework region (FR) 3, wherein if at least 2 of the cysteine residues in FR3 are not conjugated to a compound then a disulfide bond is capable of forming between the cysteine residues in FR3. Conditionally Antibodies are activated US8709755 BioAtla A method of preparing a conditionally active antibody, active and/or inactivated at defined the method comprising the steps of: Biologics physiological conditions. i. selecting a wild-type antibody against an antigen; ii. evolving the DNA which encodes the wild-type antibody using one or more evolutionary techniques to create mutant DNAs; iii. expressing the mutant DNAs to obtain at least one mutant antibody; iv. subjecting the at least one mutant antibody and the wild-type antibody to an assay under a normal physiological condition selected from the group consisting of temperature, pH, osmotic pressure, osmolality, oxidation and electrolyte concentration, and to an assay under an aberrant condition selected from the group consisting of temperature, pH, osmotic pressure, osmolality, oxidation and electrolyte concentration; and v. selecting the conditionally active antibody from the at least one mutant antibody [...] Cleavable Masking peptides are released, US20100189651 CytomX A modified antibody comprising: an antibody or antibody masking e.g., by proteases secreted fragment (AB), capable of specifically binding its peptides by the tumor target, coupled to a masking moiety (MM), wherein the coupling of the MM reduces the ability of the AB to bind its target such that that the dissociation constant

(Kd) of the AB when coupled to the MM toward the target is at least 100 times greater than the Kd of the AB when not coupled to the MM toward the target Target which does not Extra domains A and B of US20150030536 Philogen A method of treating lung cancer or lymphoma in an require toxin fibronectin individual, comprising administering to the individual internalization a therapeutically effective amount of an antibody, or antigen-binding fragment thereof, which binds Extra Domain-A (ED-A) of fibronectin comprising a VH domain and a VL domain with given CDR sequences and wherein the antibody is conjugated to a molecule that has biocidal or cytotoxic activity or is conjugated to a radioisotope. the symbol [...] indicates that claim language has been truncated.

Novartis in 2010 provided an upfront milestones per target),16 demonstrating specificity. For this reason, this approach payment of 45 mn USD, and milestone that there is substantial value even in just opens the possibility to reduce non-specific payments totaling »200 mn USD per the toxin technology used in ADCs. side effects common to chemotherapy, thus target, plus royalties on the sales. The first experimental ADCs used cyto- broadening the therapeutic window. This ImmunoGen’s other deals include, among toxic payloads that were already established again allows the use of toxic payloads that others, Eli Lilly (2011, 20 mn USD in conventional chemotherapy, e.g., meth- otherwise would be too toxic for systemic upfront and approximately 200 mn USD otrexate,17 vinblastine.18 However, ADCs administration, or have a too short half-life per target in milestones), Takeda (2015, have a distinct advantage over conventional in the human plasma. 440 mn USD upfront and milestones), or chemotherapy because they can direct their On the other hand, antibodies are rela- Sanofi (2006, 32 mn USD upfront and toxic payload to the target tissue with high tively large molecules (the molecular

www.tandfonline.com mAbs 993 Table 5. Early ADC linker technology patents Technology Example IP right Assignee Claim language

Maleimidocaproyl-val-cit- US7745394 Seattle Genetics 1. A method for treating cancer comprising administering to a patient in need thereof PAB (combination with an effective amount of an antibody-drug conjugate compound having formula Ic: auristatins)

Ab Aa-Ww-Yy-D)p Ic

wherein Ab is an antibody which binds to one or more tumor-associated antigens

D is a drug moiety selected of Formula DE:

[]

Maytansinoids plus SMCC US5208020* ImmunoGen A cytotoxic agent comprising one or more maytansinoids linked to a monoclonal linker antibody or fragment thereof via a disulfide bridge at the C-3, ¡14, ¡15, or ¡20 position of said maytansinoids and wherein said monoclonal antibody or fragment thereof is selective for tumor cell antigens.

*expired; the symbol [...] indicates that claim language has been truncated. weight of an IgG is »150 KDa), compared Second medical use patents and other with naked antibodies, and similar second to which the toxin, which is commonly an higher generation patents generation claim categories can hence be organic molecule, is small (molecular Second medical use claims strive to generated. Table 10 shows some examples weight usually in the range of 0.3 to protect the use of a given drug for a new of higher generation ADC patents. 1 KDa). Therefore, the total amount of indication discovered after the drug (and toxin that can be administered with ADC at least one medical indication) was Specific combination of antibody therapy is relatively small. Accordingly, an already known. They usually specify the and toxin ADC carrying 4 toxin molecules comprises drug and its new use in a language such as The specific combination of an anti- only 0.8–2.67% w/w toxin. Further, it has “antibody X for the treatment of disease body and a toxin can be also patent eligi- been reported that, despite the target speci- Y.” ble. A given tumor cell type characterized ficity an ADC has due to its antibody com- If an ADC comprising a given anti- by a specific antigen can, for example, be ponent, only 1.56% of the administered body is used for the treatment of a disease particularly susceptible to a given toxin dose of the toxin will reach the intracellular that is the subject of a third-party patent conjugated to an antibody against said tar- target.19 This in turn means that a toxin claiming a second medical use of that get. In such case, patent claims providing candidate must show high potency to be naked antibody, it should be thoroughly the broadest protection would merely useful in ADC therapy. checked as to whether or not said use for recite the antibody target and the toxin As discussed already, 3 classes of toxins the ADC falls under the scope of said sec- class. have been typically used in ADCs, namely ond medical use patent. The fact alone If such a broad concept is already antic- maytansinoids, auristatins and calcheami- that the antibody has been structurally ipated, or does not meet the non-obvious- cins. Other classes are in clinical or preclinical modified by conjugating a toxin thereto ness/inventive step criterion, fallback trials,20 including pyrrolobenzodiazepines does not automatically mean that it would positions for the antibody component and other benzodiazepine derivatives, no longer fall under the scope of such pat- could focus on a target epitope, a specific duocarmycins, tubulysins, a-amanitin or ent, at least as long as the claim language binding behavior or a structurally defined bouganin protein toxin (see Table 7). does not exclude such modification explic- antibody. For the toxin component, fall- Most of these toxins are significantly itly. Similar logic applies to other higher back positions lie in a more restricted defi- more potent than toxins used for conven- generation patents, like dosage patents or nition of the specific toxin. Even though tional chemotherapy. In any case, the dis- formulation patents, in which the claims narrow on paper, such restricted claims covery of a new toxin (either a derivative refer to a naked antibody. However, it can still provide meaningful patent protec- from an existing class or a whole new appears unlikely that an ADC using a tion when backed by a respective market- class) that can be used in ADCs can give given naked antibody would use the same ing authorization. rise to specific patent protection. The dosage or formulation. So far, the legal framework for ADC same applies for the transfer of an existing Table 9 shows typical claim categories biosimilar products is far from clear, and toxin into the ADC context. Typical pat- for second medical use antibody patents the US and European Union regulatory ent categories that cover such types of and other higher generation antibody pat- agencies have only recently begun evalua- innovations are shown in Table 8. ents. With ADCs, the same rules exist as tions of biosimilar antibodies. However,

994 mAbs Volume 7 Issue 6 www.tandfonline.com Table 6. Patents protecting new approaches related to ADC linker technology Technology Example IP right Assignee Claim language

Non-natural amino acids EP1968635B1 Ambrx A polypeptide, or salt thereof, containing at least one compound selected from the group consisting of:

wherein each Ra is independently selected from the group consisting of [...] Cysteine-engineered US20070092940 Genentech A cysteine engineered antibody comprising one or more free cysteine amino acids having a thiol reactivity value in the range antibodies (THIOMAB) of 0.6 to 1.0, wherein the cysteine engineered antibody is prepared by a process comprising replacing one or more amino acid residues of a parent antibody by cysteine. SMAC (sortase- mediated WO2014140317 NBE therapeutics A method of producing an immunoligand/payload conjugate, which method encompasses conjugating a payload to an antibody conjugation) immunoligand by means of a sequence- specific transpeptidase, or a catalytic domain thereof. with N-terminal LPTXG tag/linker SpaceLink Technology EP1370298B1 Syntarga A compound of the formula V-(W)k-(X)l-A-Z wherein: V is a specifier which is removed by an enzyme, optionally after prior binding to a receptor; mAbs (W)k-(X)l-A is an elongated self-eliminating spacer system; W and X are each a 1,(4C2n) electronic cascade spacer, being the same or different; A is either a spacer group of formula (Y)m, wherein Y is a 1,(4C2n) electronic cascade spacer, or a group of formula U being a cyclisation elimination spacer; Z is a therapeutic or diagnostic moiety; k and l are independently an integer from 0 (included) to 5 (included); m is an integer from 1 (included) to 5 (included); n is an integer of 0 (included) to 10 (included), andkC1>0. Microbial transglutaminase WO2014202775 Innate A method for conjugating a hydrophobic, high molecular weight or charged organic compound to an antibody, comprising (MTGase) the steps of: a) providing an antibody or antibody fragment comprising an acceptor glutamine residue; b) reacting said antibody with a linking reagent comprising a primary amine and a moiety of interest (Z), wherein (Z) is a hydrophobic compound, a charged organic compound and/or organic compound having a molecular weight of at least 500, 700 or 800 g/mol, in the presence of a TGase, under conditions sufficient to obtain an antibody comprising an acceptor glutamine linked to said moiety of interest (Z), via the linking reagent [...] SMARTag US20120183566 Redwood An isolated aldehyde-tagged immunoglobulin (Ig) polypeptide comprising an Ig constant region amino acid sequence comprising an amino acid sequence of a sulfatase motif, wherein the sulfatase motif is positioned within or adjacent a solvent-accessible loop region of the Ig polypeptide constant region, and wherein the sulfatase motif is not at the C-terminus of the Ig polypeptide chain. Transglutaminase C US provisional 62/011,534, Dophen Not published yet “endosome escaping non not published yet cleavable” (EENC) linkers

the symbol [...] indicates that claim language has been truncated. 995 996 Table 7. Patents protecting selected toxins Technology Example IP right Assignee Claim language

Auristatins (MMAE, US6884869 Seattle Genetics A compound of the formula MMAF)

and pharmaceutically acceptable salts and solvates there of wherein [...] Maytansinoids plus US5208020* ImmunoGen A cytotoxic agent comprising one or more maytansinoids linked to a monoclonal antibody or fragment thereof via a SMCC linker disulfide bridge at the C-3, ¡14, ¡15, or ¡20 position of said maytansinoids and wherein said monoclonal antibody or fragment thereof is selective for tumor cell antigens. New anthracyclin US8900589 Genentech An antibody-drug conjugate compound comprising an antibody covalently attached by a linker L and an optional spacer derivatives Z to one or more anthracycline derivative drug moieties D, the compound having the formula (D-L-(Z)m)p-Ab or a pharmaceutically acceptable salt thereof, wherein: Ab is an antibody; D is an anthracycline derivative selected from the structures A and B: mAbs

[...]

Calicheamicins US5714586 American Cyanamid A method for preparing monomeric calicheamicin derivative/carrier conjugates with higher drug loading/yield and Company decreased aggregation having the formula,

Pr(–X–S–S–W)m

wherein: Pr is a proteinaceous carrier, X is a linker that comprises a product of any reactive group that can react with a proteinaceous carrier, W is the calicheamicin radical formed by removal of the naturally occurring methyl trisulfide group [...] Duocarmycins EP2560645A2 Syntarga 1. A compound of formula (III): oue7Ise6 Issue 7 Volume

(Continued on next page) www.tandfonline.com

wherein [...] each Z is independently a compound of formula (I), (II), (I’), or (IG):

[...] Novel taxanes US7390898 ImmunoGen A compound represented by formula (I): mAbs

wherein [...] Pyrrolobenzodiazepine EP2766048B1 ADC Therapeutic & A conjugate of formula ConjB:: Spirogen Limited

where CBA represents a cell binding agent.

(Continued on next page) 997 998 Table 7. Patents protecting selected toxins (Continued) Technology Example IP right Assignee Claim language a-amanitin EP2436398B1 Heidelberg Pharma A conjugate comprising a target-binding moiety linked via a linker L to an amatoxin, wherein the linker L is connected to the amatoxin via (i) the g C-atom of amatoxin amino acid 1, particularly via an amide linkage; (ii) an oxygen atom bound to the d C-atom of amatoxin amino acid 3, particularly via an ester linkage, an ether linkage or a urethane linkage; or (iii) the 60 C-atom of amatoxin amino acid 4, particularly via an oxygen atom bound to the 60 C-atom of amatoxin amino acid 4; in each case wherein the linker L is connected to the target-binding moiety via a urea moiety. CC-1065 (duocarmycin) US5475092* ImmunoGen A cytotoxic agent comprising a cell binding agent linked via a disulfide bond to one or more analogs or derivatives of a US5585499* cyclopropylbenzindole-containing cytotoxic drug, wherein said cell binding agent is a monoclonal antibody or an antigen-binding fragment of a monoclonal antibody having at least one binding site thereof, and wherein prior to linking said analogs or derivatives to said cell binding agent said analogs or derivatives are selected from the group consisting of analogs or derivatives formed from an A subunit of the formulae (A-3) or (A-4) and a B-C subunit of the formulae (F-3), (F-4), (F-5) or (F-6), said B-C subunit having a B moiety shown on the left-hand side of the formulae and a C moiety shown on the right-hand side of the formulae and wherein said A subunit is covalently linked to said B-C subunit via an amide bond from the secondary amino group of the pyrrole moiety of the A subunit to the C-2 carboxyl group of the B moiety of the B-C subunit, wherein the formulae (A-3) and (A-4) are as follows mAbs

[...] wherein the formulae (F-3) to (F-6) are as follows:

[...]

De-immunized US8716234 Merck A method of inhibiting or destroying a lymphoma cancer cell comprising administering a cytotoxin to an animal having bouganin protein lymphoma, wherein said cytotoxin comprises a targeting moiety that binds to the lymphoma cancer cell and is linked toxin to a modified bouganin protein, wherein said modified bouganin protein comprises AA sequence SEQ ID NO: 11, [...] Tubulysins US2015141646 Concortis 1. A compound having the structure of Formula I: oue7Ise6 Issue 7 Volume

or a pharmaceutically acceptable salt thereof, wherein: A is a tubulin binding moiety; B is a functional moiety; [...]

(Continued on next page) Benzodiazepine US8765740 ImmunoGen 1. A compound represented by the following formula: www.tandfonline.com derivatives

or a pharmaceutically acceptable salt thereof, wherein: the double line – between N and C represents a single bond or a double bond, [...] Pyrrolobenzodiazepine US2013028919 Seattle/Spirogen A Conjugate having formula L-(LU-D)p or a pharmaceutically acceptable salt or solvate thereof; wherein L is a Ligand unit, LU is a Linker unit, p is 1 to 20; and D is a Drug unit comprising a PBD dimer having the following formula II mAbs

wherein: R2 is 2’X[...] Pyrrolobenzodiazepines US20110256157 Spirogen A conjugate of formula (A)

and salts and solvates thereof, wherein: the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; [...] or the compound is a dimer with each monomer being of formula (A), or with one monomer being of formula (A) and the other being of formula (B):

999 wherein [...]

*expired; the symbol [...] indicates that claim language has been truncated. 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 Y Class or specific toxin is known, but (i) Use/process protection or (ii) purpose (i) Use of toxin x for the manufacture of an ADC transfer to ADC is novel bound compound protection (ii) Toxin x for use in an ADC for the treatment of cancer the symbol [...] indicates that claim language has been truncated. experience with regulations for generics The EPO applies the so-called such guidance has so far been established and biosimilars teaches that, once estab- “problem solution approach.” In this test, with respect to inventive step questions of lished, respective approval pathways do the closest prior art is defined first. Sec- patent claims for ADCs. not allow any chemical modifications of ond, the difference between the claimed It needs to be recalled, in this context, the toxin or sequence modifications of the invention and the prior art is determined, that combining a particular toxin with antibody. Therefore, although the scope and its technical effect is established. superior potency and an antibody with of such claims could theoretically be Accordingly, it is stipulated that it would excellent target affinity does not necessar- bypassed by even minor modification of be the objective technical object of the ily yield a clinically effective ADC. The either the toxin or the antibody, such alleged invention to obtain such effect binding process, or the linker as such, can strategy would necessitate an entirely new started from the closest prior art. Eventu- affect either the toxin, or the antibody, or approval, because the product would no ally, it is considered whether it was obvi- both. Likewise, the toxin may not be ade- longer be a biosimilar. Table 11 shows ous for the person of skill to solve this quate for the target bound by the anti- examples of patents claiming specific anti- objective technical problem. body. As can be seen in Table 12, body/toxin combinations. Despite all attempts to make the afore- Genentech has successfully used this line mentioned tests as reproducible as possi- of argumentation when defending their Non-obviousness / inventive step ble, large uncertainties still exist. The patent application EP2283867, protecting Patent claims relating to ADCs or their practical implementations differ not only ado-trastuzumab emtansine, over their components must pass the test on non- between the US and European Union or own prior art, which disclosed trastuzu- obviousness, as codified on 35 USC. x other jurisdictions, but also between dif- mab, plus generally mentioned the combi- 103, or its European counterpart, inven- ferent technical disciplines, and even nation thereof with maytansinoids. tive step, as codified in Art. 56 of the between different examination divisions in For these reasons, the mere provision European Patent Convention. Both tests the same jurisdiction. of a functional ADC comprising a known decline patentability to an alleged inven- Table 12 gives an overview of the toxin and antibody can already meet the tion, even if it is novel, in case it was obvi- European patents protecting gemtuzumab inventive step criterion, at least in the ous for a person of skill in the art in view ozogamicin, ado-trastuzumab emtansine recent past. However, with technical prog- of existing prior art. In the US, different and brentuximab vedotin (see also ress, the likelihood that a prior art bench- tests have been applied in the past. Table 1), and the reasons why the respec- mark exists already (e.g., an ADC using, In the decision KSR v. Teleflex,21 the tive examiner found the claimed subject for example, the same antibody, or at least US. Supreme Court set forth that the true matter inventive over the prior art. It can an antibody against the same target), test of nonobviousness is the so called be seen that in each case, the respective increases. The patentee may in such case “Graham analysis,” thus denouncing a dif- examiner’s motif to allow the patent was be required to provide further arguments, ferent type of test that was used by the different. or restrict the claim scope, to meet the lower instance courts, which the Supreme A look into the board of appeal deci- non-obviousness/inventive step criterion. Court deemed too liberal. The Supreme sions database of the EPO does not pro- This criterion is thus a moving target, Court declared that the bar on patents vide better guidance either. In June 2015, where, with technical progress of the claiming obvious subject matter should only 2 decisions existed that relate to pat- respective discipline, requirements are not be confined within a test „too con- entability issues of ADC patents, one of changed accordingly. Predictions of the strained to serve its purpose.“ In the Gra- which is referring to sufficiency of disclo- requirements the offices will set with ham analysis, the courts examine the sure, while the other one refers to inven- respect to a given ADC patent application scope and content of the prior art, the tive step. Table 13 shows these 2 are thus educated guesses that take into level of ordinary skill in the art; the differ- decisions. Again, no true guidance can be account the applicable state of the art, not ences between the claimed invention and derived from these decisions. Thus, unlike only with respect to the target, but also the prior art; and objective evidence of in naked antibody patent claims that spec- with respect to the toxin and the linker non-obviousness. Examples for the latter ify the antibody by a particular sequence, technology. are, e.g., commercial success, long-felt but and where a clear guidance as to how One objective evidence for inventive unsolved needs, and failure of others. inventive step is to be assessed exists,22 no step commonly accepted by EPO

1000 mAbs Volume 7 Issue 6 Table 9. Claim categories for higher generation antibody patents Example IP Category rights 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 the antibody is a humanized form of the antibody produced by the hybridoma deposited as ATCC Deposit No. PTA-5817, for the manufacture of a medicament for treating pulmonary edema. Dosage patent EP1210115B1* Genentech HER2 Use of the anti-ErbB2 antibody huMab 4D5 for treating a human patient diagnosed with a breast cancer characterized by overexpression of ErbB2, said method comprising the steps of administering to the patient an initial dose of 8mg/kg of the anti-ErbB2 antibody; and administering to the patient a plurality of subsequent doses of the antibody in an amount that is 6 mg/kg, wherein the doses are separated in time from each other by 3 weeks. Formulation EP2459167B1 Roche HER2 A highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody for subcutaneous injection comprising: 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; and e. 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. examiners is if the novel embodiment has application. In some cases, creators or least in cases where a marketed product surprising properties. In the ADC world, owners of such embodiments see it as a does not carry any traceable marks that and in particular regarding specific anti- problem that the content of a patent enable competitors to reverse-engineer body-toxin combinations, this would application is published after 18 months, said technology. mean that a specific characteristic of a while it is not yet clear at that time A trade secret, however, is not an exclu- claimed ADC would be unprecedented whether a patent will be awarded on the sive right. If the secret is disclosed, unin- even in view of the prior art benchmark. respective subject matter or not. Further, tentionally, intentionally or even in bad Such characteristic would not necessarily if eventually granted, a patent expires faith, its content becomes public domain mean efficacy or potency. It could also be roughly after 20 years, after which the immediately, and can be practiced by reduced side effects or, at least in the US content of the patent becomes public competitors. Therefore, in a strategy that and European Union, even non-clinical domain. As a consequence, an invention relies on trade secrets, measures must be advantages, e.g., shelf life, ease of may not be a subject of a patent applica- taken that ensure these secrets cannot be manufacture. tion, but rather it may be kept a trade disclosed, e.g., by former employees, nor secret. While this strategy does not work be discovered by reverse-engineering. In The problem of trade secrets with products that are to be sold (because cases when the owner of a trade secret col- The term “trade secret” relates to a putting them to the market without pat- laborates with third parties to whom said product, process or know how that ent protection makes such products public trade secret needs to be disclosed, non-dis- provides a commercial advantage to its domain), it may have its merits with closure agreements should be signed. In owner or creator, who, however, prefers to respect to technologies, in particular case such agreement is violated by the not make it the subject of a patent methods, that are practiced in-house, at third party, the latter will be liable for

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 locally advanced HER2 positive cancer in a patient comprising administering a therapeutically effective amount of trastuzumab- MCC-DM1 wherein the patient has been previously treated with at least 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 a surfactant, wherein said formulation has a pH of about 5 - 7, and wherein said anti-EGFR ADC comprises an anti-EGFR antibody, or antigen-binding portion thereof, conjugated to an auristatin.

www.tandfonline.com mAbs 1001 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 conjugated to a maytansinoid, wherein the antibody is huMAb4D5–8 Combination of specific antibody and toxin US8153768 Wyeth Holdings A composition comprising a drug conjugate, wherein said drug Corporation conjugate comprises calicheamicin derivatives and an anti-CD22 antibody and has the formula:

[b]wherein the antibody comprises SEQ ID NO. [...] the symbol [...] indicates that claim language has been truncated. damages; however, the disclosure as such are taken over by contract manufac- Immunotoxins and radiolabelled involving the loss of the trade secret can- turers.23 In such an environment, where antibodies not be undone. different steps are outsourced to different Although not specifically discussed For ADCs, the supply chain can be partners, a trade secret strategy bears par- herein, most of the principles set forth very long. While an innovator can be ticular risks, which may result in the loss above do also apply to immunotoxins and responsible for a series of innovative tech- of a given trade secret and, accordingly, radiolabelled antibodies. Immunotoxins nologies covering the entire supply chain availability of the respective technology are fusion proteins that consist of a target- of an ADC (encompassing, antibodies, to competitors. Therefore, ADC innova- ing protein, ideally an antibody, fused to a linker technology, toxins, methods of tors should use trade secrets with utmost toxic protein. Immunotoxins offer advan- production and so forth), reality shows care, and consider relying on patent tages over ADCs in manufacture (because that, at least when commercialization applications to protect their intellectual they can be produced by recombinant starts, different steps of the supply chain property. protein expression in one step) as well as

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 and EP0392384 discloses Calicheamicin Examiner accepted that “nothing in the prior art suggests hydrazine linker succinimidyl derivatives that the use of the current linker system to bind conjugated to an antibody calicheamicin to an antibody would yield conjugates having high immunoaffinity to the target, low toxicity and high antitumour activity.” (EP office action of May 11, 2001) EP2283867B1 Trastuzumab maytansinoid WO0069460 discloses trastuzumab, Examiner accepted applicant’s arguments of Nov 18, 2013, conjugate for treatment of plus generally mentions that (i) the specific selection of trastuzumab and cancer over-expressing combination therof with maytansine would be novel over WO’460. In support of ErbB2 maytansine inventive step, applicant argued (ii) against Chari et al (1992), which discloses a murine anti-cancer ADC comprising a maytansinoid and an anti ErbB2 antibody as not being the closest prior art, and (ii) that it was surprising that trastuzumab retained its cytostatic activity in an ADC, and would not be degraded to a mere targeting device, thus leading to an ADC where the antibody and the toxin act in concert. Applicant had also argued that at the priority date, there was uncertainty regarding the therapeutic potential of immunoconjugates. EP2353611B1 ADC with Pentapeptide linker WO02088172 discloses WO0208817 was the only prior art document, but although plus auristatin pentapeptide linkers, and ADCs pre-filed, published after the priority date, and did thus using them, but not auristatin not affect inventive step

*expired

1002 mAbs Volume 7 Issue 6 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-humanized Claims found unallowable for insufficient disclosure, M195 antibody and 2-iminothiolane because the term “term “recombinant gelonin” was modified gelonin or recombinant not properly defined. The only vague definition gelonin for the treatment of leukemia (JM105 E. coli expressing optimized gelonin”) would leave the burden of finding out how to arrive at recombinant gelonin entirely upon the skilled reader. T 1014/01 Nov 2003 EP0439095B1** Antibody-based fusion protein Claim 1 (3rd request) was found inventive because comprising an Ig portion capable of prior art suggested that the hinge feature would directing the fusion protein to a tumor, avoid the reactive side groups in the AA sequence, an IL2 molecule capable of promoting not for increasing the flexibility. Further, prior art lymphocyte proliferation, and a would contains no pointer to replace Cys with Pro, modified IgG1 hinge region with the 2 while prejudice against the use of Pro (“helix-killer”) Cys residues replaced by Pro and would exist. Serine to permit greater flexibility in 2nd request, which recited, as an alternative, also a the fused molecule. natural hinge region, was not deemed inventive.

*rejected; **expired to site specificity and stoichiometry of the cancer diagnostic and therapeutics indicating that, the teaching in the trastu- conjugation. Disadvantages may lie in an industry,” has in 2014 filed requests for zumab label that certain patients failed to increased immunogenicity. So far only inter partes review (IPR) against Gen- respond to the product would have moti- one immunotoxin has received approval entech’s US Patent 7575748 (IPR2014– vated an ordinary artisan to treat such in the US, namely denileukin diftitox 00842) and ImmunoGen’s US patent patients using a trastuzumab (huMab (OntakÒ), which consists of an interleu- 8337856 (IPR2014–00676), which both 4D5–8) conjugate. kin-2 protein fused to a diphtheria toxin. protect Genentech’s ADC ado-trastuzu- In contrast thereto, IPR2014–00676 Radiolabelled antibodies are antibodies mab emtansine. Further, Phigenix sued against US8337856 was instituted on that carry a radioactive isotope. These Genentech on Jan 31, 2014 for patent October 29, 2014. The PTAB found that conjugates do not have to be internalized infringement of their own US patent Phigenix has demonstrated that there is a into the cells to become effective, and can 8080534 in the Georgia Northern District reasonable likelihood that it would prevail thus also be used to attack cellular targets Court (1:14-cv-00287). Table 14 shows on the ground that claims 1–8 of the pat- that do not involve internalization, just the respective patents and selected claim ent would have been obvious over some of like the CD20 receptor. Two radiolabelled language. As discussed above, Genentech the prior art documents in view of the antibodies have been approved, Gen- has acquired a license from ImmunoGen trastuzumab label. This, however, is not a entech’s 90Y ibritumomab tiuxetan for use of the SMCC linker and the DM1 final determination on the patentability of (ZevalinÒ; Key IP right: EP1112084B1) toxin conjugated to trastuzumab. A conju- the challenged claims. IPR proceedings and 131I tositumomab (BexxarÒ; Key IP gate of said toxin-linker combination with were thus instituted. The case is ongoing right: US6090365; marketing discontin- an antibody was protected, among others, as of mid-2015. ued in 2014), which both include an anti- by ImmunoGen’s patent US5208020 Regarding the litigation at the Georgia CD20 antibody component. Both have (now expired; see Table 5). Northern District Court, Phigenix been the subject of litigation between On December 9, 2014, the Patent asserted that Genentech would infringe Genentech and GlaxoSmithKline.24 Trial and Appeal Board (PTAB) of the their patent US8080534 via certain acts, USPTO denied institution of IPR2014– “directly and/or indirectly, of making, Case study 1 00842 against US7575748, on the using, selling, or offering for sale the drug Because of their commercial potential, grounds that Phigenix did not establish a ado-trastuzumab emtansine under the ADC patents will inevitably become the reasonable likelihood of prevailing with trade name KadcylaÒ, and inducing subject of IP litigation. One very recent respect to any challenged claim. Phigenix’ healthcare professionals to prescribe and dispute is evolving between Phigenix, attacks were based on alleged obviousness administer KadcylaÒ,” among others by based in Atlanta, Georgia, and Genentech in view of the trastuzumab (HerceptinÒ) distribution of the respective prescribing of South San Francisco. Phigenix, who on 1998 label and several prior art docu- information. their website claim that they “will leverage ments. According to the Board, which The infringement contentions were licensed patented technology to establish a applied the “broadest reasonable construc- served to Genentech’s attorneys in Sep- strong first-mover advantage in Personal- tion in light of the specification of the pat- tember 2014, but are so far not public yet. ized Medicine and forge a lasting leader- ent,” Phigenix failed to explain adequately As of mid-2015, Phigenix has not publicly ship position in the rapidly evolving how, nor provided sufficient evidence disclosed which part of ado-trastuzumab

www.tandfonline.com mAbs 1003 emtansine they believe to inhibit PAX2 Furthermore, claim 19 claims adminis- 2015 (3:2015cv01238), where it is still expression or PAX2 activity and/or express tering the composition to a patient after pending. DEFB1, as set forth in claim 1 of determining the PAX2-DEFB1 expression This case impressively demonstrates Phigenix’s patent. However, dependent ratio and the ER/PR status in a breast can- how even originators of a naked antibody claim 15 stipulates that the therapy can cer tissue isolated from the patient. How- can run into patent litigation when mar- also comprise administration of an anti- ever, the prescribing information,25 of keting an ADC, even if said ADC com- Her-2 agent. This suggests that Phigenix ado-trastuzumab emtansine does not men- prises their established antibody, and even considers the DM1 toxin as the part of tion either PAX2 or DEFB1. Therefore, it if the respective toxin and linker technol- ado-trastuzumab emtansine that inhibits remains unclear so far what exactly the ogy have been in-licensed. Further, this PAX2 expression or PAX2 activity and/or infringement contentions refer to. Upon case shows that even having obtained a expresses DEFB1, as set forth in claim 1, motion of Genentech, the infringement lege artis FTO opinion – an exercise Gen- while the trastuzumab part would be action was transferred to the Northern entech has undoubtedly gone through defined in said dependent claim 15. District of California Court on March 17, before 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 receptor and as being a tumor that does not respond, or responds poorly, to treatment with an anti-ErbB antibody, and (ii) intravenously administering to the mammal a therapeutically effective amount of a conjugate of a humanized antibody huMab 4D5–8 covalently linked via a thioether linking group with a maytansinoid DM1 having the structure

at a dose of between about 0.2 mg/kg and about 10 mg/kg (antibody-maytansinoid conjugate weight/body weight) and at a frequency of dosing selected from the group of dosing frequencies consisting of bolus, less than about 1 time per week, one time per week, 2 times per week, more than 2 times per week, and continuous infusion, whereby said tumor characterized by overexpression of an ErbB2 receptor and that does not respond, or responds poorly, to treatment with an anti-ErbB antibody, is treated. 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 a breast 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 subject an 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 from said 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, a first composition that (1) inhibits PAX2 expression or PAX2 activity, (2) expresses DEFB1 or (3) inhibits PAX2 expression or PAX2 activity and expresses DEFB1.

1004 mAbs Volume 7 Issue 6 emtansine – does not provide a guarantee generation anti-HER2 ADCs are already that carries a p-acetylphenylalanine (pAc- against IP attacks from unforeseen cor- under development. Phe) residue instead of a naturally occur- ners. This again demonstrates the com- Based in Nijmegen, The Netherlands, ring amino acid reside, to which an plexity of the IP landscape in the ADC Synthon has developed SYD985, which alkoxy-amine derivatized auristatin F field, and the residual risk players must comprises trastuzumab conjugated to a (MMAF) is conjugated by oxime ligation. deal with even with a proper FTO opinion cleavable linker and duocarmycin pay- Another anti-HER2-toxin construct in in their hands. load. According to Synthon, SYD985 is clinical development is MM-302 devel- Phigenix also filed an opposition also active against tumors that exhibit oped by Merrimack Pharmaceuticals Inc. against ImmunoGen’s EP counterpart of low expression of HER2, and does thus MM-302 is not a conjugate in strictu US patent 8337856, EP2283867 (see allow extension of the target population sensu because it consists of a liposome Tables 1 and 12) on February 19, 2015. of cancer patients who may respond to 75–110 nm in diameter that encapsulates In the opposition, Phigenix alleges that this treatment to include FISH (fluores- doxorubicin. The lipid membrane is com- the patent claims would lack novelty over cence in situ hybridization)-negative/ posed of phosphatidylcholine, cholesterol, WO0069460, and lack inventive step immunohistochemistry (IHC)-HER2 1C and PEGylated phosphatidylethanolamine over, among others, a journal article auth- and 2C patients.28 According to the (1 PEG molecule for 200 phospholipid ored by Chari et al.,26 and the trastuzu- FDA label, ado-trastuzumab emtansine molecules), wherein one PEG molecule mab label, in combination with other is, however, only indicated for the treat- for each 1780 phospholipid molecules documents disclosing maytansinoid tox- ment of patients with HER2-positive bears at its end an anti-HER2 scFv anti- ins. While Phigenix thus largely relies on breast cancer in which the tumors show body fragment called F5.31 prior art that has already been considered HER2 overexpression defined as 3C Exact targeting is critical in this ADC by the office (see Table 12), their main IHC. While trastuzumab is beginning to because cardiomyocytes, which are affected line of argumentation is that the selection come off patent (EP0590058 has expired by the highly cardiotoxic doxorubicin, of trastuzumab and a maytansinoid would June 15, 2012), the linker technology must be avoided. The fact that doxorubicn not be a specific selection that would pro- and the duocarmycin used in SYD985 is encapsulated by liposomes further pro- vide novelty over WO0069460. Further, are being pursued in pending application tects the cardiomyocytes. As with SYD985 they argue that Chari et al. would indeed EP2560645 (see Table 12), assigned to and ARX788, it appears that MM-302, be the closest prior art, as it relates to a Syntarga, which is a subsidiary of Syn- which is covered by international patent functional anti-cancer ADC comprising a thon. Although SYD985 addresses a simi- application WO2012078695, has so far maytansinoid and a murine anti-ErbB2 lar market as ado-trastuzumab emtansine, not been subject of a patent litigation by antibody, thus rebutting Genentech’s and clinical trials are currently under third parties. arguments according to which it was sur- way,29 it has, so far, not been subject of a Dophen Biomed of Sacramento, USA, prising that trastuzumab retained its cyto- patent litigation by third parties. It has recently presented results32 on an anti- static activity in an ADC, and would not appears that SYD985 would at least not HER2 ADC consisting of trastuzumab be degraded to a mere targeting device. fall under the scope of US8337856 pro- and MMAE, conjugated to one another A first decision in this case cannot be tecting ado-trastuzumab emtansine (see by Dophen’s transglutaminase using expected prior to mid-2016. Interestingly, Table 15) because SYD985 does not Dophen’s endosome escaping non- on February 2015, Genentech received comprise a maytansinoid. cleavable” (EENC) linkers (see Table 6). the allowance for another EP application The same circumstances apply to the The company claims that this ADC has of the same family, EP2283866, with an anti-HER2 ADC ARX788 developed by 100% stability and higher potency than a almost identical claim scope. The opposi- Ambrx. ARX788 comprises an anti-HER2 comparable ADC with a cleavable linker. tion term of this patent will be open until antibody coupled site specifically to a toxin Further, Dophen uses this technology to November 2015. called Amberstatin (AS269) by means of generate anti-HER2 ADC comprising Ambrx’ technology using non-natural trastuzumab and 2 different toxins of amino acids (EP1968635B1, see Table 6). undisclosed nature. Quite apparently, at Case study 2 Like Synthon, Ambrx claims that ARX788 least one of these toxins is a tubulysin HER2 seems to be an attractive target serves a broader spectrum of HER2C can- because of a collaboration with Austrian for ADC therapy, not only because it has cer patients than ado-trastuzumab emtan- tubulysin specialist Tubepharma.33 It has proven safe and efficacious in antibody sine. Similarly, it appears that ARX788 been reported that such a hybrid ADC has therapy, but also because it meets the has so far not been the subject of a patent better potency than the respective homo- other requirements set forth above, litigation by third parties. ARX788 is cov- geneous ADCs of the same toxins, and including rapid internalization.27 Unsur- ered by Ambrx’s international patent also better potency than a 1:1 mixture of prisingly, Genentech is not the only com- application WO2013192360. The linker, the 2 homogeneous ADCs. No patent pany that has an anti-HER2 ADC in toxin and antibody are not chemically information is available for Dophen’s their portfolio. In some way, ado-trastu- specified, but according to a report pub- technologies. zumab emtansine can be considered a lished in 2012,30 it appears that the anti- NBE Therapeutics of Basel, Switzer- first-generation ADC, while second- body could be a modified trastuzumab land, has created different anti-HER2

www.tandfonline.com mAbs 1005 1006

Table 15. Details of different anti-HER2 ADCs in development ADC name Antibody Linker Toxin Key IP right Company Status Claim language

Trastuzumab Trastuzumab SMCC DM1 US8337856 Genentech Approved in An immunoconjugate comprising an anti-ErbB2 antibody conjugated emtansine US and EU to a maytansinoid, wherein the antibody is huMAb4D5–8. MM-302 scFv anti-HER2 PEG-DSPE Liposome- US2014023698 Merrimack Phase 2/3 A method of treating a human cancer patient by administration of encapsulateddoxorubicin anthracycline - comprising anti-HER2 immunoliposomes, the method comprising determining a first dosage, such a dosage indicating a dose magnitude and frequency of dosing, for a patient diagnosed with a cancer characterized by expression of HER2 receptor, the first dosage being for a liposomal anthracycline chemotherapeutic agent that does not comprise an immunoliposome, which dosage is determined to provide to the patient a safe and effective amount of the liposomal formulation, and administering anthracycline-comprising anti-HER2 immunoliposomes, a plurality of which immunoliposomes is each bearing a plurality of anti-HER2 antibody molecules on its surface and each containing the anthracycline chemotherapeutic agent, mAbs wherein the anthracycline-comprising anti-HER2 immunoliposomes are administered to the patient at the first dosage.

SYD985 Trastuzumab SpaceLink Duocarmycin EP2560645A2 Syntarga Phase 1 A compound of formula (III):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein [...] oue7Ise6 Issue 7 Volume (Continued on next page) www.tandfonline.com

ARX788 Undisclosed Undisclosed Amberstatin AS269 US2015141624 AmbrX Preclinical* mAbs wherein [...] Not available Trastuzumab Transglutaminase MMAE, hybrid ADCs with Not available Dophen R&D Not available C EENC linker different toxins Not available Trastuzumab SMAC with N-terminal (i) DM1 (mertansine), (i) – (iv) NBE R&D 1. A method of producing an immunoligand/payload conjugate, LPTXG tag/linker (ii) maytansine, WO2014140317 Therapeutics which method encompasses conjugating a payload to an (iii) MMAE/MMAF (v) not disclosed immunoligand by means of a sequence- specific transpeptidase, (iv) a-amanitin or a catalytic domain thereof. (v) undisclosed new toxin, 6. The method according to any of the aforementioned claims, respectively wherein the sequence-specific transpepeptidase is at least one selected from the group consisting of a sortase enzyme, or one or more fragments or derivatives thereof a split-intein, or one or more fragments or derivatives thereof Not available Trastuzumab N-Hydroxysuccinimide Tubulysin Not available VUMC R&D Not available ester Amsterdam

*Phase 1 study (NCT02512237) scheduled to start in September 2015; the symbol [...] indicates that claim language has been truncated. 1007 ADCs with trastuzumab using their sor- thorough technical understanding of both 16. ImmunoGen press releases of October 11, 2013 tase-mediated antibody conjugation tech- biotechnology and organic chemistry. (http://investor.immunogen.com/releasedetail.cfm? ReleaseIDD796395); December 20, 2011 (http:// nology (SMAC) with N-terminal LPTXG investor.immunogen.com/releasedetail.cfm?ReleaseIDD tag/linker (see Table 6, WO2014140317) 634459); March 23, 2015 (http://investor.immunogen. Disclosure of Potential Conflicts of Interest com/releasedetail.cfm?ReleaseIDD902766) and December to couple trastuzumab to DM1 (mertan- 26, 2006 (http://www.biospace.com/News/immunogen- sine), maytansine, MMAE, MMAF and The author is involved in the prosecu- inc-announces-that-sanofi-aventis-has/41104). a-amanitin, and thus create ADCs with tion of some of the patent applications 17. Endo N, Takeda Y, Umemoto N, Kishida K, Watanabe K, Saito M, Hara T. Nature of linkage and mode of site-specifically conjugated toxins of mentioned herein. action of methotrexate conjugated with antitumor anti- homogeneous DAR. The first 2 have been The information provided herein bodies: implications for future preparation of conju- gates. Cancer Res 1988; 48(12):3330-5; Retrieved from reported to be equally potent as ado-tras- reflect the personal views and considera- http://cancerres.aacrjournals.org/content/48/12/3330. tuzumab emtansine. Another ADC com- tions of the author. They do not represent short; PMID:3259466 legal counsel and should not be attributed 18. Starling JJ, Maciak RS, Hinson NA, Nichols CL, Briggs prises an undisclosed new toxin, which SL, Laguzza BC. In vivo efficacy of monoclonal anti- has demonstrated significantly better to Michalski ¢ Huttermann€ and Partner body-drug conjugates of three different subisotypes potency in cells expressing only low Patent Attorneys or to any of its clients. which bind the human tumor-associated antigen defined by the KS1/4 monoclonal antibody. Cancer amounts of HER2 than ado-trastuzumab Patent numbers and patent lifetimes have Immunol Immunother 1989; 28(3):171-8; Retrieved emtansine.34 been verified with utmost care, but no lia- from http://www.ncbi.nlm.nih.gov/pubmed/2784353; PMID:2784353 Still another anti-HER2 ADC has been bility is taken for their correctness. 19. Teicher BA, Chari RVJ. Antibody conjugate therapeu- developed by researchers of the VU Uni- tics: challenges and potential. Clin Cancer Res 2011; versity Medical Center Amsterdam, who 17(20):6389-97; PMID:22003066; http://dx.doi.org/ Supplemental Material 10.1158/1078-0432.CCR-11-1417 used a moderately toxic tubulysin analog 20. Rostami S, Qazi I, Sikorski R. The Clinical Landscape (TUB-OMOM). Tubulysins have a nar- Supplemental data for this article can of Antibody-drug Conjugates. ADCReview 2014 be accessed on the publisher’s website. August 1; 2014. row therapeutic window and are thus 21. Decision KSR Int’l Co. v. Teleflex, Inc., 550 US 398, interesting for ADC use. For this purpose, US Supreme Court 2007. tubulysin-NHS-esters were coupled to 22. Stewart M, Kent L, Smith A, Bassinder E. The special References inventive step standard for antibodies. epi information trastuzumab, while for control purposes, 1. Beck A, Reichert JM. Antibody-drug conjugates: pres- 2011; 2/2011; 72-76. 131 89 I-tubulysin and Zr-trastuzumab were ent and future. MAbs 2014; 6(1):15-17; 23. Wooge C, Swamy J. Next-Gen ADCs: collaborating to improve supply chains for development and technology used. The conjugation reaction was 45– PMID:24423577 2. Rostami S, Qazi I, Sikorski R. The Clinical Landscape transfer with novel technology platforms. Contract 55% efficient, resulting in ADCs with of Antibody-drug Conjugates. ADC Review 2014; Pharma 2014; Nov/Dec 2014; 16(9):50. 96–98% radiochemical purity and an August 1, 2014. 24. Storz U. Rituximab: how approval history is reflected 3. Rohrer T. Consideration for the safe and effective by a corresponding patent filing strategy. MAbs 2014; average DAR of between 2 and 4. The manufacturing of antibody drug conjugates. Chemistry 6(4):820-37; PMID:24866199; http://dx.doi.org/ researchers report a potency comparable Today 2012; 30(5):76-79. 10.4161/mabs.29105 25. Prescribing information for KadcylaÒ (Ado-trastuzu- to that of ado-trastuzumab emtansine, 4. Wu WJ. Regulatory Perspective on Challenges in ADC Development (Keynote presentation) PepTalk 2015; mab emtasine); http://www.accessdata.fda.gov/drug while the availability of synthetic tubuly- January 19–23; 2015, San Diego, CA. satfda_docs/label/2013/125427lbl.pdf 5. Lash A. Antibody-drug conjugates: the next generation 26. Chari RV, Martell BA, Gross JL, Cook SB, Shah SA, sins that are more potent than TUB- € of moving parts. START-UP 2001; 27 Dec 2011. Blattler WA, Goldmacher VS. Immunoconjugates con- OMOM offers additional options to 6. DiMasi JA, Grabowski HG. The cost of biopharmaceu- taining novel maytansinoids: promising anticancer make more potent ADCs.35 No patent tical R&D: is biotech different? Manag Decis Econ drugs. Cancer Res 1992; 52(1):127-31; Retrieved 2007; 28:469-479. from http://www.ncbi.nlm.nih.gov/pubmed/1727373; information is available for this approach. 7. Mullard A. New drugs cost US$2.6 billion to develop. PMID:1727373 Table 15 shows some details of the anti- Nature Reviews Drug Discovery 2014; 13(12):877-877 27. Minami T, Kijima T, Kohmo S, Arase H, Otani Y, HER2 ADCs discussed above. 8. Grabowski H, Cockburn I, Long G. The market for fol- Nagatomo I, Kumanogoh A. Overcoming chemoresist- low-on biologics: how will it evolve? Health Affairs ance of small-cell lung cancer through stepwise HER2- (Project Hope) 2006; 25(5):1291-301; targeted antibody-dependent cell-mediated cytotoxicity PMID:16966725 and VEGF-targeted antiangiogenesis. Sci Rep 2013; 9. Lash A. Antibody-drug conjugates: the next generation 3:2669; PMID:24036898; http://dx.doi.org/10.1038/ of moving parts. START-UP 2001; 27 Dec 2011. srep02669 Summary 10. Stewart M, Kent L, Smith A, Bassinder E. The special 28. Synthon press release of April 02, 2014; http://www. inventive step standard for antibodies. epi information synthon.com/en/Corporate/News/PressReleases/Synthons- Anti-HER2-ADC-Frontrunner-SYD985-Outperforms- Regarding IP aspects, ADCs pose 2011; 2/2011:72-76. 11. Bander NH. Antibody-drug conjugate target selection: Only-Available-HER2-targeting-ADC.aspx severe challenges, but also tremendous critical factors. Methods Mol Biol 2013; 1045:29-40; 29. https://clinicaltrials.gov/ct2/show/NCT02277717 possibilities. ADCs comprise a field of PMID:23913139 30. Axup JY, Bajjuri KM, Ritland M, Hutchins BM, Kim 12. Erster O, Thomas JM, Hamzah J, Jabaiah AM, Getz CH, Kazane SA, Schultz PG. Synthesis of site-specific their own, in which only part of the rules JA, Schoep TD, Daugherty PS. Site-specific targeting antibody-drug conjugates using unnatural amino acids. can be translated from antibody IP. Fur- of antibody activity in vivo mediated by disease-associ- Proc Natl Acad Sci USA 2012; 109(40):16101-6; ated proteases. J Control Release 2012; 161(3):804-12 PMID:22988081; http://dx.doi.org/10.1073/pnas. ther, because many players are active in 13. List T, Neri D. Biodistribution studies with tumor-tar- 1211023109 this field, the third-party IP situation is geting bispecific antibodies reveal selective accumula- 31. International Patent Application WO2014089127A1, complicated, with many overlapping pat- tion at the tumor site. mAbs 2012; 4(6):775-83; assigned to Merrimack. 12 June 2014; Available at PMID:23032949 http://worldwide.espacenet.com/publicationDetails/ ent estates. A meaningful IP strategy for 14. Rostami S, Qazi I, Sikorski R. The clinical landscape of originalDocument? D D D D antibody-drug conjugates. ADCReview 2014; August CC WO&NR 2014089127A1&KC A1&FT D& protecting ADC inventions and establish- D D D D 1, 2014. ND &date 20140612&DB &&locale en_EP ing FTO requires specific expertise in this 15. Lash A. Antibody-drug conjugates: the next generation 32. Hu S. Homogeneous ADCs of Herceptin-MMAE with challenging IP discipline, as well as a of moving parts. START-UP 2001; 27 Dec 2011. Non-cleavable Linker is more Potent than that with a

1008 mAbs Volume 7 Issue 6 Cleavable Linker. Oral presentation at ICA 7th Annual 0&Link=http://www.eposters.net/pdfs/homogeneous- 35. Cohen R, Vugts DJ, Visser GWM, Stigter-van Walsum Internatl Congress on Antibodies; Nanjing, CN; April adcs-bearing-two-different-payloads-show-strong-syn- M, Bolijn M, Spiga M, van Dongen GAMS. Develop- 27, 2015 ergy-in-tumor-killing.pdf ment of novel ADCs: conjugation of tubulysin ana- 33. Allen L, Mi Y, Abbas M, Richter W, Hu S. Homoge- 34. Grawunder U. Sortase-mediated generation of site-spe- logues to trastuzumab monitored by dual radiolabeling. neous ADCs bearing two different payloads show cifically conjugated next-generation ADCs for treat- Cancer Res 2014; 74(20):5700-10; PMID:25145670; strong synergy in tumor killing. Poster presented at ment of cancer. Oral Presentation at PEGS conference, http://dx.doi.org/10.1158/0008-5472.CAN-14-1141 World ADC Summit; 2014; San Diego, CA. Available Boston, USA, on May 06 2015; 2015. at http://www.eposters.net/redirect/?IDD2456&UIDD

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