• Dr. Mohan Dewan

 An Antibody-drug conjugate (ADC) may be defined as a man-made chimera comprising essentially of a therapeutically active chemical component selected from a drug or a toxin, and a biological component, maybe a monoclonal antibody (mAb), useful for treating certain disease(s) or disorder(s) like cancer. The monoclonal antibody conjugates the drug naturally has a monovalent affinity for binding to specific targets i.e. specific surface antigens, or receptors of the cells. The conjugation in ADC is facilitated by linkers, usually amino acids, enzymes, or chemical functionality, which shows stability in blood circulation. The first revolutionary ADC was Gemtuzumab ozogamicin, and was approved for use by the US FDA in the year 2000. 

Before the USPTO (United States Patent and Trademark Office), the patenting of a target-specific ADC is arduous to achieve, unless the possession of the naked mAb is clear. Before the EPO (European Patent Office) and IPO (Indian Patent Office), an even more complicated patentability standard is applied, therefore, requiring the antibody to either have a new sequence or an alternative target or at least a new conjugation moiety for ADC over the disclosure in the prior art. 

ADCs are the structures, likely to fall under the scope of a known naked mAb in the prior art.  So, an applicant’s focus is to develop an ADC consisting of a novel antibody (i.e. antibody having a new sequence) or a known antibody with a little modification of sequence(s) of interest that allows it to fit the linker to be further conjugated with a chemical substance. Therefore, the scope of patenting an ADC is broadened.

For the purpose of this article, only the Indian prosecution before the IPO is focussed. For instance, the Indian patent (IN360407) claimed “A transglutaminase-mediated site-specific antibody-drug conjugate comprising the formula: antibody-(T-(X-Y-Za) b) c, wherein: T is

1) a glutamine-containing tag engineered at a specific site,

2) an endogenous glutamine, and/or

3) an endogenous glutamine made reactive by antibody engineering or an engineered transglutaminase;

X is an amine donor unit;

Y is a linker; and Z is an agent moiety;

X-Y-Z is an amine donor agent site-specifically conjugated to a glutamine of T via gamma-carboxamide; a is an integer from 1 to 6; b is an integer from 1 to 6; c is an integer from 1 to 20; and wherein the product (drug-antibody ratio) of a, b, and c is at least 5 comprising a) amino acid substitution at positions N297Q and K222R, wherein the amine donor agent is site-specifically conjugated to the endogenous glutamine at position 295 and the substituted glutamine at position 297; and b) one or more glutamine-containing tags, wherein the amine donor agent is site specifically conjugated to the glutamine-containing tag(s) at a carboxyl terminus of a light chain of the antibody, wherein the drug-antibody ratio is 5-7”.

This claim along with the dependent claims were objected u/s 3(d) allegedly due to “a new form of a known substance which does not result in the enhancement of the known efficacy of that substance”, however, the agent defended the same by submitting that “EC50 (nM) to indicate that the antibody-drug conjugates of claim 1 provide the advantage of significantly lower cytotoxicity to cells not expressing the targeted cancer marker (Trop-2) in comparison to the conventional produced maleimide based conjugates which lack K222R (a kinase-impaired lysine-to-arginine mutant) protein but have equivalent drug antibody ratio. Furthermore, as disclosed at page 60 of the corresponding international publication, lines 3-6, it was surprisingly found that the claimed antibody-drug conjugate have the effect of resulting in more homogenous antibody and payload conjugate composition, and/ or significant decrease in interchain crosslinking with the glutamine tag on the C terminus of the antibody light chain” i.e. in simpler words, a surprising effect of the conjugates referred from the corresponding specification was submitted.

The composition claims 23 to 25 were also objected u/s 3(e) for “mere admixture resulting only in the aggregation of the properties of the components thereof or a process for producing such substance”, however, the agent also defended the same by submitting that the ADC conjugate should be considered as a single entity and not a mere admixture.

Further, an Indian patent application (IN201727040436) claimed “A conjugate of formula:

L - (DL) p,

where DL is of formula I or II:

wherein: L is an antibody (Ab) which binds CD22, and

which comprises: heavy chains comprising an amino acid substitution of each of HC226 and HC229 according to the EU index as set forth in Kabat, light chains each having an amino acid substitution of the interchain cysteine residue κLC214 or λLC213 according to the EU index as set forth in Kabat, and heavy chains each retaining the unsubstituted interchain cysteine HC220 according to the EU index as set forth in Kabat……..”

This is a classic example of a claim regarding ADC, the said claim is not from a granted patent; wherein, neither the antibody nor the drug is novel. The prosecution of this case may further add to the justification of the nature of the prosecution, however, in the absence of set case law, a definitive comment is difficult.

Coming to the probable objection from the IPO, first of all, it may be noted that the subject matter is patenteligible i.e. subjected to the satisfaction of Novelty, Inventive Step and Industrial Application, although the patentability further would depend on bypassing the non-patentability section. In India, the situation is challenging as the biological activity of a known active chemical substance is not sufficiently substantial evidence of the efficacy of the ADC. Further, to claim an ADC comprising of chemically active and the active biomolecule, a synergy over their individual biological effects is also to be established. It was put forth by various examiners during prosecution that an ADC to be patentable, it requires an antibody having a new sequence or at least a new bio conjugation moiety i.e. a linker that supports considerably to the overall activity of the ADC.    

Regarding any application claiming an ADC, the general perception is that the components of the ADC outght not be novel, but rather well-known. Engineering could be done in the protein structure of the antibody to facilitate the addition of a linker to be conjugated with a known drug; however, the chances are remote that either the corresponding antibody or the drug, would be novel. Novelty in antibodies or the drug should result in at least a separate patent application for each of the drug and antibody. Therefore, the Novelty, as well as Inventive Step, is to be judged corresponding to the ADC, not to the individual components of the ADC.

Further, coming to the relevant provisions of the Non-patentable sections of the Indian Patent Act:

Section 3(d) of the Indian Patent Act bars-

the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant”, from patentability”.

Section 3(d) is applied when the ADC is considered as a separate entity from the components i.e. when it is established that there is no mere admixture. While defending against the tentative objection u/s 3(d), enhancement of efficacy data should be submitted. However, it is common knowledge of a researcher that finding such “significantly” enhanced efficacy is remote. The data that may be easier to generate is the data regarding selectivity, however, which is also owing to the use of the mAb component. A mAb would always be selective, therefore, the attached drug would also be working specifically on the target, thereby, a significantly improved potency, as well as bioavailability, is expected.

Regarding this, although a valid defense against such objection, it may be noted that even 30% more bioavailability was not considered as a valid defense against section 3(d) by the Apex court of India in the Novartis case decided back in 2013-14. Thus, the rebuttal to such objection should always be centered on “selectivity”, however, as the selectivity is imposed automatically because of the use of a known mAb, it may be difficult to predict whether such selectivity would be equated with “enhance of therapeutic efficacy” or not, in absence of set case law in like matters.

Frthermore, in case, the ADC is considered as a conjugate, and not a single unitary entity, then scope u/s 3(e) may be relevant.

Section 3(e) of the Indian Patent Act bars-

a substance obtained by a mere admixture resulting only in the aggregation of the properties of the components thereof or a process for producing such substance” from patentability. 

An understanding of the ADCs suggests that this may also be a relevant section. However, in this case, especially, the scope u/s 3(d) and 3(e) are mutually exclusive i.e. in case an objection u/s 3(d) is raised, then the understanding is that the examiner considered ADC as a single unitary entity, not a formulation. Similarly, if the ADC is considered as a formulation, then there is no question of unitary entity, and correspondingly, scope u/s 3(d) should automatically be nullified.

In case there is objection u/s 3(e), the rebuttal should be enhanced efficacy than that of standalone components used. In case such data is not available, “enhanced selectivity” may be the solution; however, the said “selectivity” is a direct result of the use of a monoclonal antibody. There is yet another way to defend against such objection i.e. by submitting anyone of the components is novel. In ADC-related cases, there may be a little modification of the known mAb used, said modification may provide the required Novelty to the mAb component, subject to argument. In case the novelty of the mAb is accepted by the IPO, any alleged scope u/s 3(e) would stand null and void as this section only concerns about known digits in a composition. formulation.

In sum, ADC as a subject matter is new, and it may take a while for the court to receive some appeal against any decision of the IPO. Once that happens, through a set case law, a strategy may be made. As of now, it is at the discretion of the concerned controllers of the IPO, whether ADC(s) is to be considered a standalone molecule or a conjugate. Depending on such consideration, a rebuttal should be formulated by the agent during prosecution. 



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