Patentability of polymorphs in Argentina: some thoughts in the light of recent rulings
On December 16, 2021, and May 3, 2022, Division I of the Argentine Federal Court in Civil and Commercial matters rendered two separate rulings – PFIZER PRODUCTS INC v. INPI, Case No. 3753/2016, and BAYER CROPSCIENCE AG v. INPI, Case No. 5631/2015, respectively – which are thematically associated, since both refer to the patentability of polymorphs. Both rulings are the result of different lawsuits filed by the applicants of two patent applications that were rejected by the Argentina’s National Institute of Industrial Property (INPI), seeking to reverse the corresponding rejection decisions. Even though the rulings at issue rule that the controverted decision must be upheld, it is interesting to analyze the arguments set forth therein.
In both rulings, even though the arguments raised differ in certain aspects, the courts essentially held that the arguments set out by the appellant, just as the technical expert evidence produced ex officio, fail to undermine the conclusions of the INPI’s Examiner appointed for each application, which in both cases can be summarized in: (i) a lack of novelty (and inventive activity in the case of Case No. 5631/2015) of the claimed matter in view of a document of the previous art that discloses the “base” chemical compound (that is, the compound as it was initially synthesized, without having the crystalline form of the polymorph claimed in each application); and (ii) the characterization of the polymorphs as a discovery, a matter that is not patentable pursuant to Article 6 of Law No. 24481.
In the first place, it is worth reviewing briefly what a polymorph is. The molecules of a solid chemical compound can adopt one or more stable and organized spatial dispositions that result in structures known as “crystalline”. When a crystalline compound can adopt more than one distinctive crystalline structure, these are known as polymorphs.
When a new chemical compound is synthesized, it is common to obtain that compound with a certain crystalline structure. However, what cannot be predicted beforehand is whether the new compound will show polymorphism. The obtention of new crystalline forms of an already known compound will often involve laborious research programs, since finding the specific conditions for the generation of a new crystalline form may be a difficult task.
The different polymorphs of a chemical compound usually have different physicochemical properties, which could make a particular polymorph preferable over another, for instance, when formulating a medication comprising the chemical compound at issue. As a result of such advantageous properties, it may be convenient to obtain protection for a new polymorph by means of a patent.
The Patentability Guidelines used by the INPI’s Examiners to examine patent applications clearly set a negative criterion with regards to the patentability of polymorphs. In this sense, in the section known as “GUIDELINES FOR THE PATENTABILITY EXAMINATION OF PATENT APPLICATIONS ABOUT CHEMICAL-PHARMACEUTICAL INVENTIONS” (from now on, “the Guidelines”), in the subsection associated specifically to polymorphs, the following is mentioned:
“Polymorphism is a property inherent to the solid form exhibited by drugs used in the pharmaceutical industry (active principles and excipients).
That is, it is not a man-made invention but a property of the substance instead.”
Said subsection concludes that:
“1. As long as claims about polymorphs stem from the mere identification and/or characterization of a new crystalline form of a substance that is already known in the state of the art, even when they show pharmacokinetic or stability differences with regards to the already known solid forms (amorphous and/or crystalline) of the same substance, such claims are not admissible.
2. The processes used to obtain polymorphs constitute a routine experimentation in the preparation of drugs; they are not patentable because trying to obtain the pharmaceutically most adequate polymorph by means of conventional methods is evident.”
That is, according to what is described in the Guidelines, a polymorph would not be an invention, instead, it would be the discovery of an inherent property of a substance that was previously known and, consequently, not patentable. Furthermore, the processes used to obtain polymorphs would lack inventive activity in a general manner, a reason for which they would not be patentable either.
Considering what was analyzed in the previous paragraphs, two aspects of the rulings at issue are particularly remarkable.
On the one hand, it is worth noticing that in both administrative procedures the Examiner of each application has raised not only an objection of exclusion from patentability of the discoveries, which, while being debatable, turns out to be consistent with what is established in the Guidelines, but also an objection of lack of novelty, when the documents of the previous art already mentioned do not disclose the claimed polymorph in each case (it is worth highlighting that in both cases the cited document belongs to the same applicant as that of the application in controversy, therefore, it is to be expected for said applicant to perfectly know that they have actually obtained a previously unknown polymorph). The INPI seems to construe that the disclosure of a chemical compound leads to, implicitly, the disclosure of any crystalline form thereof.
On the other hand, we consider it relevant that in both cases the court sets out the inability of the arguments set forth and, in particular, of the court’s technical expert evidence produced ex officio, to disqualify the technical opinion of the Examiner of each application, mentioning that a mere contrary opinion is not sufficient, and that, instead, it must be shown that the Examiner incurred in an error in the assessment of the claimed matter. Thus, when posing questions to a court appointed expert in a litigation that seeks to reverse a rejection decision from the INPI, such questions must be posed in such a way that the alleged errors identified in the manner in which the Examiner examined the application come to light. In this sense, it is of great importance to develop an appropriate strategy.
Our experts are available to debate protection and litigation strategies in line with the needs of each inventor or patent applicant.
Patenting antibodies in Europe and Argentina
On March 1, 2021, the new Guidelines for Examination of the European Patent Office (EPO) came into force. These Guidelines set the rules by which Examiners at the EPO analyze the patent applications prosecuted therein to evaluate whether they are in conditions to be granted as European patents, thus providing more homogeneity and transparency to said prosecutions.
The new Guidelines include a section devoted to the patentability of antibodies, inexistent thus far, which essentially sets in stone the criteria by which the Examiners at the EPO have been conducting their examinations on applications related to antibodies lately. Said criteria are based in decisions issued in the last few years by the Technical Board of Appeals of the EPO on antibodies-related issues, used so far by the Examiners to carry out their analyses in lieu of specific indications in the Guidelines.
The new section of the Guidelines (section G-II-5.6), on one hand, establishes requisites for the proper definition of antibodies in claims, and on the other, provides considerations on how to demonstrate the inventive step involved in the development of novel antibodies.
Antibodies are proteins (i.e., polypeptides) and, as such, they structurally consist of a series of linear amino acids chains. They are part of the immune system of many living organisms, and every antibody is adapted to bind to a particular antigen (i.e., a substance which generates an immune response in the organism) by specific regions in its amino acids sequence named complementarity-determining regions (CDRs). Each antibody has 6 CDRs, which define to which antigen they will bind.
According to the new Guidelines, the EPO accepts defining a claimed antibody by either structural or functional features, as well as by its production process.
- Structural features The essential structural feature of antibodies is their amino acid sequence. Since the CDRs are the parts of an antibody which determine their ability to bind to a certain antigen, the EPO establishes that the structural definition of an antibody must include, at least, the amino acid sequences of the 6 CDRs thereof. The EPO will only accept a structural definition of an antibody including less than all 6 CDRs if it is unequivocally proven that not all CDRs are involve in the binding to the antigen. Another way to define an antibody structurally would be by means of the nucleotide sequence codifying it (i.e., the specific portion of a nucleic acid molecule, for instance DNA, which may be used by a cell to generate the corresponding antibody).
- Functional features The EPO contemplates the possibility of defining an antibody by several types of functional features, such as the antigen to which it binds, the affinity therefor it exhibits, the specific regions of the antigen to which it binds (named epitopes), etc., as well as combinations thereof. Even though this kind of definitions may be desirable because they are usually of a broader scope than structural definitions, it is important to note the new EPO Guidelines clearly establish that in these cases it is especially important for the Examiner to verify whether the specification of the patent application under analysis provides a sufficient description of the invention, so that it may by reproduced by a person of skill in the art (i.e., that the description of the invention allows for it to be reproduced without any ambiguity). On the other hand, the Guidelines clarify that, if there is any prior art disclosing an antibody directed to the same antigen as the one being claimed, which is also obtained by a process as the one used for the claimed antibody, it will be assumed that the prior art inherently disclosed the functional features by means of which the same is defined, which would deny its novelty.
- Production process The EPO allows defining an antibody by means of the process by which it is obtained. For instance, the antibody could be defined by the immunization protocol used to generate it. However, it should be noted that in these cases the antigen used for the generation of the antibody should be defined by its sequence without any ambiguity whatsoever.
Regarding inventive step, the new section of the EPO Guidelines establishes that a novel antibody which binds to a known antigen must exhibit an unexpected property over antibodies known in the prior art for the same antigen. Examples of such properties might be a greater affinity, a higher therapeutic efficacy, reduced toxicity or secondary effects, etc. A mere structural difference with the antibodies of the prior art would not be considered enough in this case to provide an inventive step, since such a difference would be considered an “alternative solution” to a technical problem previously solved, which the EPO considers obvious in view of the prior art as a general rule in this technical field.
Situation in Argentina
Even though the Argentinean PTO (INPI, National Institute of Industrial Property) included in its Patentability Guidelines a section directed to biotechnological inventions by means of Resolution INPI N° P-283 of September 25, 2015, they do not provide specific indications regarding inventions related to antibodies. However, there are some tendencies which Examiners at the INPI usually follow when analyzing this kind of applications.
Regarding the definition of claimed antibodies, the INPI only accepts a structural definition thereof. Unlike the EPO, neither a functional definition nor a definition by means of the production process for the claimed antibody are acceptable. This means that some inventions which would be potentially patentable in Europe would not be accepted in Argentina, or at least they would be accepted with a much more limited scope (for instance, having to limit a broad functional claim to a narrower one defined by the specific sequences of the claimed antibody).
For a proper structural definition of a claimed antibody, Examiners at the INPI usually require that all 6 CDRs of the antibody to be defined. On the other hand, defining an antibody solely by means of the nucleotide sequence which codifies it is generally not accepted, as it should be complemented specifying as well the codified amino acid sequence (as mentioned, al least the 6 CDRs).
Regarding the evaluation of inventive step, the INPI does not have a criterion as clear as the EPO in this aspect. However, as a general rule, Examiners at the INPI tend to expect a patent application to include comparative results to the closest prior art, showing any surprising effect. In the specific case of antibodies, this would imply a similar criterion to that of the EPO, which is why it would be appropriate to include results in the specification showing some unexpected advantageous property of the claimed antibody in comparison to those of the prior art directed to the same antigen.