PATENTABILITY OF ANTIBODIES IN MEXICO

An antibody is a protein produced by B lymphocyte cells that recognizes a particular foreign antigen, and thus triggers the immune response. Recognition requires the antibody to bind to a small region or structure on the antigen.

Antibodies have long been used in a wide range of technologies, such:

–diagnostics (immunoenzymatic assays) and other biochemical analyses, including the detection of specific markers for cancer and other diseases to diagnose tumors, bacterial infections or hormonal disorders; pregnancy tests; assessments of cancer immunohistopathology; and other uses;

–protein purification (e.g., of hormones or cytokines) through approaches such as immunoaffinity chromatography; in forensic medicine to assess autoantibodies in cases that require the identification of specific individuals;

–genetic manipulation of hybrid antibodies, which combine different antibodies and func¬tions to form ‘abzymes’ that have enzymatic and immunological activity. Both enzymes and anti¬bodies are proteins, and abzymes have the advantage of combining the specificity of an antibody with the catalytic capacity of an enzyme;

–therapeutic uses to treat autoimmune diseases (rheumatoid arthritis), cancer and immune deficiencies; to destroy pathogens; in anti-rejection therapy; and to enhance the immune defense system. They are also used as a means of interfering with the complicated mechanisms of stimu¬lation or repression of the body’s immune response, and as carriers in drug delivery and drug-targeting strategies. They can be used in radio-immunotherapy or as carriers to trans¬port drugs to specific target tissues or organs; conjugated with toxins to form immunotoxins for cancer and viral therapy, or with enzymes to convert a pro-drug into a drug, as in the conjugation of tissue plasminogen activator with an antibody and a fibrin, which helps dis¬solve thrombi; and attached to the surface of liposomes

The antibodies may be eligible for patent protection if and when they comply with the requirements of patentability of novelty, inventive step, and industrial applicability.

An antibody is not guaranteed to receive patent protection simply because it is an isolated antibody or monoclonal antibody, and if the process for obtaining the antibody in question is the conventional one, the claimed invention is not necessarily considered as involving an ‘inventive step’.

In view of the fact that sequencing of genomes is usually considered straightforward, patent offices around the world in many cases consider the identification of a new protein as obvious and non-patentable. Furthermore, and even more important, most of the therapeutically interesting proteins are now known. Only in exceptional cases where the identification of the protein has faced considerable difficulties may it still be possible to obtain patent protection for a naturally occurring protein (or at least for a specific epitope). In the United States, it was easier to obtain patent protection for proteins defined by their structure. However, the situation has become even more complicated in view of recent Supreme Court decisions (e.g., the Myriad or the Prometheus decision), putting the whole concept of the patentability of naturally occurring substances in question.

However, a monoclonal antibody (mAb) may be patented if, for example, it proves useful for producing a therapeutic response, provided the effect produced is not obvious (for the purposes of patentability). Moreover, unlike a polyclonal antibody, if the mAb normally exhibits a therapeutic effect that is most reproducible in a particular type of patient, this characteristic of the mAb may contribute to the patentability of the invention.

Furthermore, if the mAb is used for therapeutic purposes, the patent application must include experimental results that pro¬vide plausible evidence that the antibody is able to produce the claimed pharmacological effect.

All antibody applications, especially those that use monoclonal antibodies (mAbs), depend on antibodies’ ability to form specific and selective bonds with a given epitope on the surface of an antigen. This selective specificity is also key in determining the patentability of an invention involving antibodies.

An antibody may also be eligible for patent protection if, during the research phase, there was no reasonable expectation of success in obtaining mAbs with the desired specific characteristics pre¬sented by that antibody.

Since the new and surprising properties are considered linked to the specific sequence of the antibody, often the patent protection obtained is restricted to the specific antibody identified during the research project. The antibody is then characterized structurally both in the claims and in the patent specification either by specifically naming and claiming the sequence of the antibody or at least the sequence of the six complementarity determining regions (CDRs) of the antibody. Alternatively, it is also possible to deposit the hybridoma producing the antibody at specific depositary institutions, and directing the patent claims to an antibody produced by said hybridoma. The latter option has been used less frequently in the past years because today it is common knowledge how to produce a given antibody once its sequence or the sequences of its CDRs are known.

Additionally, it could be possible to obtain a patent of antibody by its functional properties. Such functional parameters include the affinity, specificity, or therapeutic activity of the antibody. Furthermore, it may be possible to direct the claims to antibodies recognizing the same epitope as the identified antibody.

Developing new generations of antibodies specific for the same antigens but targeting other epitopes and/or triggering different mechanisms of action (second- or third-generation antibodies), or even specific for the same epitopes but with only one improved property, also can be protected.

Identification of new or less well studied target proteins, called “second functional approach”, that confer particular functions to cells that might be involved in pathogenic disorders are associated with greater potential for innovation and intellectual property rights.

Second-generation antibodies directed against the same antigens have alterations such as improved variable domains to decrease immunogenicity and/or to target distinct epitopes with higher or lower affinity for their antigens, and/or have different antibody formats (such as conjugating the Fab domain to polyethylene glycol (PeGylation) and Fc-fusion proteins). These antibodies have been researched clinically and recently approved for use in several diseases.

In addition, third-generation antibodies, which target different epitopes, trigger other mechanisms of action and are often engineered for improved Fc-associated immune functions or half-life, are also susceptible to be protected.

Another interesting concept to be protected is designed recombinant polyclonal or oligoclonal antibodies directed against the same or different targets. These recombinant mixtures are produced by a single cell type and are co-purified, which should result in a less expensive drug product than the use of two or more separately produced monoclonal antibodies

Now then, unfortunately, the Mexican Legislation does not specify all the requirements that the patent applications related with antibodies must comply, but in a generality, it stablished on Articles 15, 16, and 19 of the Mexican Patent Law the fundaments that allow to protect this kind of matter.

Basically, Articles 15, 16, and 19 of the Mexican Patent Law, included herein below, state that all human creations, that are new and not obvious, that allow to transform the matter or the energy that exists in the nature, for its use by the human and to satisfy its concrete needs are susceptible to be patentable. Additionally, it is stated therein, which matter is not considered to be patentable in Mexico.

Article 15. All human creation is considered an invention that allows to transform the matter or the energy that exists in the nature, for its use by human to satisfy its concrete needs.

Article 16. Inventions that are new, the result of an inventive step and susceptible of industrial application within the meaning of this Law shall be patentable, with the exception of:

I essentially biological processes for obtaining, reproducing and propagating plants and animals;
II. biological and genetic material as found in nature;
III. animal breeds;
IV. the human body and the living parts constituting it; and
V. plant varieties.

Article 19 states that the following shall not be considered inventions for the purposes of this Law:

I.theoretical or scientific principles,
II.discoveries that consist in making known or disclosing something that already existed in nature, even though it was previously unknown to man;
III.schemes, plans, rules and methods for carrying out mental processes, playing games or doing business, and mathematical methods;
IV.computer programs;
V.methods of presenting information;
VI.esthetic creations and artistic or literary works;
VII.methods of surgical, therapeutic or diagnostic treatment applicable to the human body and to animals;
VIII.the juxtaposition of known inventions or mixtures of known products, or alteration of the use, form, dimensions or materials thereof, except where in reality they are so combined or merged that they cannot function separately, or where their characteristic qualities or functions have been so modified as to produce an industrial result or use not obvious to a person skilled in the art.

So, based on what is allowed and prohibited by the Mexican Legislation, it is possible to obtain patent protection for the following matter related with antibodies:

1.Antigen specificity;
2.Structural features;
3.Functional features;
4.Hybridoma accession number;
5.Production process; and
6.Target epitope.

As such matter must comply with the requirements of patentability: novelty, inventive step and industrial applicability, it is highly recommendable that the description of the invention of the Mexican application contains the following information, among others:

–Description of the unexpected effect;
–Sufficiency of disclosure and clarity;
–Experimental evidence and comparative data to emphasize the unexpected properties;
–Experimental data should be commensurate to the claimed scope;
–In vivo experimental data supporting the claimed therapeutic/protective effect which shall be present in the application as filed
–Claims directed to product for use in therapy shall be accompanied as often as possible by in vivo experimental data supporting the claimed therapeutic/protective effect;
–Functional feature in 6 CDR claim (make sure specific method of CDR numbering, e.g., Kabat, is disclosed in the application if needed to overcome clarity objection);
–Percent identity;
–Claiming of complete amino acid sequence of VH and VL regions;
–Binding affinity (e.g. KD of ≤ 5×10-12 M). (Make sure specific method of measuring KD is clearly disclosed in the application if needed to overcome clarity objection);
–Activity, e.g. inhibitory activity, effect on specific cells;
–Competition for binding with a specific Ab, binding to specific epitopes on an antigen, specific binding characteristics (e.g. target X vs. target Y);
–Information of suitable assay in the specification, if a functional definition is claimed;
–Details of how affinity is measured, if a claim includes a reference to the affinity of the antibody
–Preferably identify a single assay to be used to assess functional characteristic/affinity;
–Details of how epitope is determined in the claim;
–Including as much sequence information as possible, including isotype and full-length sequences where available;
–Layered approach to fall-back positions –one CDR, combination of CDRs, VH and VL and full length;
–Information on assays used to determine properties or any functional properties of the antibodies (affinity, epitope, functional characteristics),
–Identify a preferred assay that can be used to determine the relevant property;
–Data relating to a preferred antibody in a number of different assays;
–Including basis for improved property during prosecution, even if not identified as improved in the specification;
–Data available for comparison with other antibodies;
–Etc.

Example Claims

An isolated antibody capable of binding antigen X.

A humanized antibody that binds to at least one of residues. of antigen X.

Antibody against protein X, being capable of inhibiting the Y with an IC50 lower than 10−9 M

Anti-X antibody which prevents interaction with Y but not Z

Other routes for patentability

–New indication
–New dosage regime
–New patient population
–Combination therapies (including bispecifics and conjugates)

It is important to mention that the Mexican Legislation is not too specific for most of the requirement. However, the Mexican practice is highly based in the European practice. Therefore, it is usual that for controversial or unusual cases, the Mexican examiner follows the same practice of the European Patent Office.

Conclusions

The criteria of the Mexican Examiner are not completely clear due to fact that the Mexican Legislation has been drafted in a very general manner and due to the lack of an Examiner´s Manual. Due to these inconveniences, for years, the Mexican Patent Office has followed the same practice of the European Patent Office for most of the cases with controversial matter. Therefore, it is recommendable to follow the same course of action of the patent applications filed in Europe since it will be highly probable that the objections issue by the Mexican Examiner are addressed in the same way.

Additionally, it should be considered that monoclonal antibodies and their therapeutic potential have been well known for decades, thus the mere production of another therapeutic antibody is not considered as patentable matter in Mexico. In contrast, antibodies with novel structural features and/or improved properties may be patentable. When drafting the claims, it is recommendable to encompass a broad patent scope that protects the antibody of interest and related antibodies having the same functional features. Furthermore, if the application contains experimental evidence showing the improved properties of the claimed antibody, it will make for a strong patent application with more probability of being granted. Subsequent inventions relating to novel uses, formulations, dosage regimens, and combinations with other treatment modalities could be also protected by further patent applications.


REFERENCES

–Beck, A.; Wurch, T.; Bailly, C.; et al. Strategies and Challenges for the Next Generation of Therapeutic Antibodies. Nat. Rev. Immunol. 2010, Vol. 10, 345–352.
–Fritz Lahrtz. How to Successfully Patent Therapeutic Antibodies. Journal of Biomolecular Screening. 2015, Vol. 20(4) 484–491.
–Claudio Germinario, Sara Bertoli, Patrizia Rampinelli & Maurizio Cini. Patentability of antibodies for therapeutic use in Europe. Nature Biotechnology. 2018, Vol. 36, Num. 5.
–https://immunologynotes.com/antibody-introduction-structure-and-classes/
–Benjamin Lewis. Genes VII. Oxford University Press. 2000.
–European Patent Convention, 15th ed (European Patent Office, 2013).
–Guidelines for Examination in the European Patent Office (European Patent Office, 2017).