Taking a new drug candidate from the initial discovery phase, through clinical trials, and then to market can be a lengthy process. In some cases, the maximum 20-year term of a patent for a new chemical entity (NCE) may not be enough to provide innovators with adequate protection at the later stages of the drug development process. This issue can be addressed somewhat by pursuing patent term extensions (e.g. supplementary protection certificates (SPCs) in Europe) – however, the availability of patent term extensions can be subject to certain restrictions.
As such, it may be desirable to extend exclusivity for a drug candidate in other ways, even if a patent filing has already been made for the NCE (or Markush structure thereof) per se. For example, further patent filings can be directed to new medical uses, drug combinations, specific enantiomers, dosage regimens and polymorphs, for instance.
We discuss the patentability of polymorphs in Europe in greater detail below.
Novelty
To be novel, a new polymorph must be distinguishable from previously known polymorphs. Typically, comparative data is used to distinguish polymorphs from each other, e.g. by comparing the positions of signals in X-ray powder diffraction (XRPD) spectra. Generally, it is best practice for claims to new polymorphs to define the polymorph by reference to its characteristic XRPD peaks, specifying the source/wavelength of radiation used, and the temperature at which the XRPD spectrum is obtained.
During prosecution of polymorph applications, lack of novelty objections may be raised based on implicit disclosure of the polymorph in the prior art. For example, where a prior art document discloses that crystals of a particular compound have been obtained, but has not explicitly disclosed what type of polymorph it is, European Examiners can (and usually will) raise novelty objections on grounds of implicit disclosure. Under European practice:
"It may happen that in the relevant prior art a different parameter, or no parameter at all, is mentioned. If the known and the claimed products are identical in all other respects (which is to be expected if, for example, the starting products and the manufacturing processes are identical), then in the first place an objection of lack of novelty arises. The burden of proof for an alleged distinguishing feature lies with the applicant. No benefit of doubt can be accorded if the applicant does not provide evidence in support of the allegations (see T 1764/06)."
(see Guidelines for Examination, G-VI: 6 – Implicit disclosure and parameters; emphasis added)
Where such objections arise, it is the responsibility of the patentee to provide evidence (e.g. comparative tests) to distinguish the new polymorph from the material described in the prior art. Arguments framed around the point that the prior art does not explicitly disclose the form of the polymorph are generally less convincing to European Examiners.
As such, where the patentee is aware of prior art disclosures of crystalline compounds, it is best practice to take a pro-active approach and explicitly demonstrate that the claimed polymorph(s) are different (e.g. obtaining XRPD spectra of the prior art crystals and showing that they are different to the claimed polymorph(s)).
It can also be useful to characterise a polymorph by the method used to produce it, using a product-by-process claim (e.g. if it is not possible to refer to XRPD peaks of the polymorph).
However, under European practice, the product of a known process is not rendered new merely by virtue of a modification to the process (T 205/83). For example, if a product cannot be defined by structural characteristics but only by its method of manufacture, novelty can be established only if evidence is provided that the process results in other products.
Examples of cases where the patentee was unsuccessful in arguing for novelty of product-by-process claims to a polymorph are shown below:
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Case |
Claim in question |
Novelty |
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A morphologically homogeneous polymorph, designated Form "B", of famotidine which has an endotherma maximum of melting at a heating rate of 1°C/min of 159°C on the DSC; its characteristic absorption bands in its infrared spectrum are at...; its melting point is 159-162°C; and it has a needle-like crystal structure, obtainable by dissolving... |
It was considered that "the product disclosed in document (3) [the prior art] is the same as that claimed. This conclusion cannot be altered by the indication of its process of preparation even if this process is new." (Reasons 12.10) |
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A Polymorph I of Dasatinib monohydrate, characterized by diffraction peaks at..., obtainable ... by the method according to claim 5. |
It was considered that "none of the data referred to by the appellant demonstrates that the method of preparation in claim 1 of the main request allows the preparation of a polymorph different from the polymorph of example 8 of D1 or H1-7 of D7 [the prior art]... Therefore, the subject-matter of claim 1 lacks novelty in view of D1 or D7 [the prior art]." (Reasons 3.5 and 3.6) |
As such, where product-by-process features are relied upon to establish novelty, it is best practice to provide experimental data explicitly showing that the process(es) used in the application results in different polymorph form compared to the process(es) used in the prior art.
Inventive Step
Perhaps the most significant hurdle to overcome during prosecution of a polymorph patent is successfully arguing in support of an inventive step.
In Europe, a key piece of case law (T 0777/08) established that "in the absence of any technical prejudice and in the absence of any unexpected property, the mere provision of a crystalline form of a known pharmaceutically active compound cannot be regarded as involving an inventive step". In addition, starting from an amorphous form of the compound, the "arbitrary selection of a specific polymorph from a group of equally suitable candidates cannot be viewed as involving an inventive step".
In other words, under European practice, a claim to a particular polymorph is assumed at first instance to be non-inventive. The onus is on the patentee to demonstrate otherwise that the particular polymorph has an unexpected property. This unexpected property must also be supported by evidence, such as experimental data (see e.g. T 2007/11).
What is considered an "unexpected property"? This can vary on a case-by-case basis depending on the nature of the prior art cited. However, examples of where patentees have been successful (and where they have not) are detailed below.
Cases where the patentee was successful in arguing for inventive step:
|
Case |
Technical effect |
Obviousness |
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Improved stability with respect to epimerisation of tigecycline polymorph vs. amorphous tigecycline |
It was considered that there was "no prior art teaching that the problem of epimerisation of tetracyclines may be solved by crystalline forms thereof, such that this property may be regarded as unexpected, the problem of epimerisation being very specific to tetracyclines" (Reasons 2.6.2 – c.f. T 1894/15 below) |
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Improved solubility under acidic conditions of amorphous hemipentahydrate sodium risedronate vs. prior art polymorph |
It was considered that there was "no hint in the cited prior art that the solubility problems under acidic conditions of the known crystalline hemipentahydrate of sodium risedronate could be solved by means of an amorphous form" (Reasons 6.4.3) |
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Lower hygroscopicity and improved stability to polymorphic conversion of lenvatinib mesylate polymorphs vs. prior art polymorph |
It was considered that "the specific polymorphs of the mesylate salt claimed would not have been expected to deliver the desired combination of properties" and that "the skilled person would not have had a reasonable expectation that any arbitrary crystalline salt form of lenvatinib would be equally suitable in this respect" (Reasons 5.4.3) |
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Improved solubility, bioavailability, stability to polymorphic interconversion, and lower hygroscopicity of O-desmethyl venlafaxine succinate hydrate polymorphs vs. general disclosure of O-desmethyl venlafaxine salts |
It was considered that "it could not have been expected that crystalline hydrates of ODV succinate would possess the exceptional stability under heat, mechanical stress and humidity, as well as good solubility, permeability and bioavailability demonstrated, and thus be capable of solving the ambitious technical problem underlying the patent in suit" (Reasons 3.5.1) |
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Improved stability to polymorphic conversion of ibandronate sodium polymorph vs. prior art polymorph |
It was considered that "in following the avenue presented by the combined teachings of documents (44) and (1), the skilled person would identify a crystalline form of ibandronate sodium that solves the problem posed, but is different from that now claimed" and that "the skilled person would have no cause to expect to be able to obtain a further crystalline form with similarly favourable properties, nor is a method suggested in the prior art as to how this was to be achieved" (Reasons 5.5.4 – c.f. T 0205/14 below) |
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Improved stability to polymorphic conversion of aripiprazole polymorph vs. prior art polymorph |
It was considered that "it was not obvious for the skilled person that Type 1 crystals according to document (3) could be transformed into a crystalline form that, unlike Type 2 crystals, is thermally stable and can therefore be obtained in constant quality (or high purity as the appellant characterised it) in a reliable manner" (Reasons 9.5) |
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Improved stability to polymorphic conversion of febuxostat polymorph vs. prior art polymorph mixture |
It was considered that "not all crystalline forms of febuxostat are equally suitable candidates to solve the problem of providing a crystalline form with improved polymorphic stability" (Reasons 5.7.4) |
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Improved stability in terms of appearance, purity, water content and crystallinity of bosutinib monohydrate polymorph vs. prior art polymorphs |
It was considered that the case was "NOT about the selection of any crystalline form but about the selection of one specific crystalline form, namely Form I of bosutinib monohydrate" and that "the selection of this specific crystalline form is not arbitrary, but rather this form has unexpected properties, namely an improved stability when compared with the other crystalline forms in D1, D2 and D3" (Reasons 4.3.4) |
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Lower hygroscopicity of dapagliflozin vs. amorphous dapagliflozin |
It was considered that the skilled person "would not have had a reasonable expectation of obtaining a form of dapagliflozin which is less hygroscopic than amorphous dapagliflozin" (Reasons 5.5.6) |
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Higher solubility and sufficient polymorphic stability of imatinib mesylate polymorph vs. prior art imatinib mesylate polymorph |
It was considered that "passages in D1 provide teaching that leads away from considering the alpha crystalline form as a candidate for solving the problem posed" (Reasons 17.5). |
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Lower hygroscopicity of afatinib dimaleate polymorph vs. other afatinib dimaleate polymorphs |
It was considered that "neither D1 nor any other prior art suggests the production of form A mentioned in claim 4, let alone that such a production in connection with a low hygroscopicity. The person skilled in the art dealing with the task formulated above and starting from D1 would therefore have had no reason whatsoever to produce this form" (Reasons 19) |
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Improved stability to polymorphic conversion of CNDAC-HCl polymorphs vs. prior art CNDAC-HCl polymorph |
It was considered "the closest prior art discloses a crystalline rather than an amorphous API" and that "the skilled person would not have gleaned from it a reasonable expectation of success in solving the problem of providing crystal forms of CNDAC-HCl that are more stable than others" (Reasons 16.6) |
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Improved dissolution profile under physiological conditions of cabozantinib (L)-malate polymorph vs. amorphous cabozantinib (L)-malate |
It was considered that none of the prior art documents "includes any teaching on how to improve the dissolution profile under physiological conditions of the cabozantinib malate salt" (Reasons 5.4) |
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Improved dissolution rate in aqueous solution of febuxostat polymorph vs. prior art febuxostat polymorph |
It was considered that there was "no teaching in the prior art on the basis of which a crystalline form of febuxostat with an improved dissolution rate in aqueous solution could be expected to exist" (Reasons 3.2.3) |
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Improved stability to polymorphic conversion of febuxostat polymorph vs. prior art febuxostat polymorph |
It was considered that there was "no teaching in the prior art providing the skilled person with a reasonable expectation of success that a certain measure will provide a solution to the objective technical problem" (Reasons 3.2.5) |
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Improved processability (flowability and compactability) of febuxostat polymorph vs. prior art febuxostat polymorph |
It was considered that there was "no teaching in the prior art providing the skilled person with a reasonable expectation of success that a certain measure will provide a solution to the objective technical problem" (Reasons 4.2.1) |
Cases where the patentee was unsuccessful in arguing for inventive step:
|
Case |
Technical effect |
Obviousness |
|
Improved filterability and drying characteristics of atorvastatin vs. amorphous atorvastatin |
It was considered that "the skilled person, starting from the amorphous form of a pharmaceutically active compound as closest prior art, would have a clear expectation that a crystalline form thereof would provide a solution to the problem" (Reasons 5.2) |
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Improved stability to polymorphic conversion of ibandronate sodium polymorph vs. prior art polymorph |
It was considered that "consistent and convincing evidence has been provided that, by performing routine experimentation within the teaching of document (2), the skilled person would directly arrive at ibandronate sodium monohydrate in the crystalline form QQ, falling within the scope of claims 1 to 3, without the exercise of inventive skill" (Reasons 5.5.6 – c.f. T 0517/14 above) |
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Improved stability with respect to epimerisation of tigecycline polymorph vs. amorphous tigecycline |
It was considered that "the skilled person, would have known that: [w]ater enhances epimerisation of tetracyclines (D12), including tigecycline (D1); [c]rystalline forms of tetracycline are known to be less hygroscopic and chemically more stable than the corresponding amorphous solid (D21)" and that "the skilled person would have tried to crystallise tigecycline, with the expectation of solving that problem" (Reasons 7.4 – c.f. T 1422/12 above) |
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Improved thermodynamic stability of sorafenib tosylate vs. prior art polymorphs |
It was considered that "the skilled person would therefore have performed a screening of the different polymorphs of sorafenib tosylate which could exist in order to isolate and identify the thermodynamically most stable form thereof" and that they "would have arrived at polymorph I of sorafenib tosylate, which is the thermodynamically most stable form and which is, for this reason, expected not to convert to other forms under mechanical stress" (Reasons 1.3) |
In sum, a number of effects have been successfully relied on as "unexpected properties":
- Polymorphic stability (T 0643/12, T 0094/11, T 0517/14, T 1555/12, T 2114/13, T 1326/18, T 0325/16, T 1667/15; dissenting opinion in T 0205/14 due to specific prior art documents)
- Chemical stability, e.g. epimerisation (T 1422/12; dissenting opinion in T 1894/15 due to specific prior art documents)
- Physical stability, e.g. appearance, purity, water content, crystallinity (T 1684/16)
- Solubility (T 1723/10, T 0094/11, T 1326/18, T 0500/16, T 1667/15)
- Bioavailability (T 0094/11)
- Hygroscopicity (T 0643/12, T 0094/11, T 2730/16, T 1442/18)
- Processability, e.g. flowability and compactability (T 1667/15)
Effects to avoid when considering patentability of polymorphs include:
- Thermodynamic stability (T 0041/17)
- Filterability and drying characteristics with respect to amorphous form (T 0777/08)
Patentees may therefore wish to consider relying on properties that have been successful in the past for supporting inventive step arguments.
Summary
Obtaining patent protection for polymorphs can be a challenge. However, with good preparation during drafting of the application, the odds can certainly be stacked in favour of the patentee. Experimental data is crucial in polymorph patents and a pro-active approach to gathering relevant experimental data is helpful.
Some key take-home points include the following:
- Consider obtaining experimental data (e.g. X-ray powder diffraction data) showing that the claimed polymorph is different from known prior art polymorphs to overcome implicit disclosure objections.
- If it is necessary to rely on product-by-process features, consider obtaining experimental data explicitly showing that the process disclosed in the application results in a polymorph that is different from prior art methods.
- When drafting, consider focussing on "unexpected properties" such as polymorphic stability, chemical stability, physical stability, solubility, bioavailability, hygroscopicity and processability.
- If it is necessary to rely on stability as an "unexpected property", be specific about what type of stability it is – and avoid thermodynamic stability at all costs!
- Experimental data as evidence of the "unexpected property" is essential to success, and in particular a comparison with the closest known polymorph (or amorphous form).
- When the amorphous form is the closest prior art, consider providing further comparative data with other polymorphs – this can help prove that the specific polymorph has special properties amongst all polymorphs, and is therefore not an arbitrary selection.
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.
