Australia: Patenting Of Polymorphs In Australia And New Zealand – Obviously Not Obvious

Polymorphism is the ability of a substance to exist as two or more crystalline forms, which have an identical chemical content but different arrangement of the constituents in the solid state. The identification of one or more polymorphs of a compound with advantageous properties is an important step in the development of many products, including pharmaceuticals and agrochemicals, such as new drug compounds, pesticides and herbicides. It has been recognised that differences in the physical characteristics of a particular polymorph relative to the amorphous form of the compound may translate to improvements in properties such as stability, compactibility and flowability (which affect bulk processing and formulation), dissolution rates, solubility and bioavailability. Those skilled in the art are aware that identifying and obtaining polymorphs is a significant experimental undertaking. Despite this, patenting polymorphs in Australia and New Zealand is not without its challenges. The mere fact that polymorphic screens are routinely conducted can give way to the misconception that the results of such screens would be obvious.

Obviousness/Lack of Inventive Step

The primary test for determining obviousness in Australia (often referred to as the reformulated Cripps Question) was approved by the High Court in Aktiebolaget Hässle v Alphapharm Pty Ltd (2002) 212 CLR 411; [2002] HCA 59 at [53], as follows:

Would the notional research group at the relevant date in all the circumstances ... directly be led as a matter of course to try the [claimed invention] in the expectation that it might well produce a useful [product or process]?

The test applied in New Zealand mimics the UK Windsurfing/Pozzoli four-step approach in which the last step requires one to consider, without any knowledge of the alleged invention as claimed, if the differences from the prior art constitute steps which would have been obvious to the person skilled in the art, or whether they require any degree of invention. In assessing the inventive step, New Zealand examiners are taught to consider the weight to be attached to any particular factor in light of all the relevant circumstances, including the motivations to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, and the effort involved in pursuing these possibilities and the expectation of success.

For both the Australian and New Zealand inventive step assessments, significant weight is given to whether there would have been a reasonable expectation of success of arriving at the claimed invention, at the priority date of the patent or application.

The argument often presented against patentability of polymorphs with advantageous properties is that it would have been obvious to obtain such polymorphs. The basis of this argument is commonly that polymorphic screens are routinely conducted in the field, and a skilled person, such as a chemist, would inevitably have arrived at the claimed polymorph(s) after conducting a polymorphic screen and would reasonably have expected such new crystalline form(s) to provide particular advantages.

Polymorphic Screens Being “Routine”

While it may be the case that a polymorphic screen is routinely performed, like a salt screen or certain medicinal chemistry screening practices to identify lead compounds or new salts, the process of designing and conducting the screen is not straightforward and the outcome is rarely predictable. As stated by Braga et al.¹:

“polymorphism as a phenomenon still represents a substantial scientific challenge. Indeed, it is hard to predict whether a given molecule will crystallize in one or several crystal forms, whether it will form solvates with different stoichiometries or will ever be ‘happy' to link up with other molecules and form stable co-crystals.”

It should be kept in mind that not all compounds will exhibit polymorphism.

The experiments performed in a polymorphic screen first require setting particular parameters, the selection of which varies considerably. These include:

• solvent(s);
• time;
• temperature;
• rate and temperature of cooling;
• concentration;
• use of stirring and stirring rate;
• pressure;
• purity; and
• method of solvent removal.

The selection and determination of these parameters will influence the polymorphs that may (or may not) be identified. However, the effect that a certain parameter would have on whether a polymorphic form is obtained is largely unpredictable. It is well known in the art that even a minor variation can have a significant effect on the outcome, leading to the particular parameters being carefully selected and the impact of each monitored throughout the screen. As noted by Hilfiker et al.²:

“typically, many attempts to crystallise an amorphous drug substance fail until, suddenly, a stable crystalline form is obtained. Once seed crystals are available, the crystallization becomes the simple last step of a production process.”

It can be seen that irrespective of the comprehensiveness of the polymorphic screen conducted, there is no guarantee that any polymorphs or all polymorphs will be obtained. There is no standard, exhaustive screen in the art that will guarantee all possible polymorphs of a compound being identified, as confirmed by Braga et al. and Henck et al.³ It is only through the considered and somewhat fortuitous selection of the particular compound and parameters used that polymorphs will be identified.

Expectation During Polymorph Identification

When conducting a polymorphic screen, there is no expectation that the screen would result in the identification of one or more polymorphs, let alone one with advantageous properties.

Even if a polymorph is obtained, whether it will have improved properties is unknown, let alone which specific property or properties will be improved. At the outset of a polymorphic screen, there is no expectation that a polymorph with improved properties will be identified. This is only determined after substantial experimentation to identify any polymorphs and further experimentation to assess the properties of each individual polymorph (such as thermal and/or shelf life stability, solubility, hygroscopicity, bioavailability, flowability, etc.). As acknowledged in the literature, this is a significant experimental undertaking.⁴

To identify a specific polymorph with improved properties, the skilled person must:

• select a compound which may or may not exhibit polymorphism;
• decide to perform a polymorphic screen;
• select the correct combination of parameters to identify the specific polymorph(s) out of all possible parameters and combinations thereof;
• conduct the polymorphic screen using such parameters;
• select the specific polymorph out of all polymorphs identified for further experimentation/testing; and
• test the particular property or properties of the polymorph out of all possible properties and make comparisons in order to determine if there are any advantages over any other forms (including the amorphous form).

All of these steps are performed by a chemist with no enabling guidance to any specific methodology to ensure a resultant new form, or any expectation that they will be successful in identifying a polymorph with improved properties. Thus, the process cannot be said to be routine and predictable, and it is clearly not the case that the skilled person would, from the outset of the task, inevitably arrive at the identification of a new polymorph with improved properties.

The above rationale is not foreign to our US audience, especially in light of the Federal Circuit decision in Grunenthal GMBH v. Alkem Laboratories Limited, Appeal No. 2017-1153 (Fed. Cir. March 28, 2019). This case involved a claimed new polymorph (Form A) of tapentadol hydrochloride and its use for treating pain. The defendant (Alkem) asserted a case for obviousness based on, inter alia, reference to Byrn et al., (1995).⁵ This document, like many of the documents referenced above, provides the reader with information and flow charts to instruct on the general considerations one is required to make when carrying out a polymorphic screen (solvents, temperature considerations, stirring conditions, pH, etc.). Under the heading "Reasonable Expectation of Success", the Court considered that these types of documents only identify that these parameters should be varied and considered when undergoing a polymorphic screen. The Court ultimately sided with the Plaintiff's (Grunenthal) expert in that:

"[T]his lack of disclosure supports Dr. Bernstein's testimony that a POSA [person of skill in the art] would have to manipulate the variables to ‘determine what the crystal form landscape looks like' because ‘you don't know what the result's going to be.'... Indeed, a POSA could alter any number of variables and still fail to find a polymorph of a particular compound."

Tips to Facilitate Allowance of Claims

Both Australian and New Zealand examiners, while being technically very competent, generally approach the inventive step assessment by trying to place themselves in the shoes of the person skilled in the art as of the priority date. Many of the examiners have not actually been involved in a polymorphic screening program during their scientific careers. Accordingly, any information that can be provided to assist in a better understanding is often persuasive. Such information may include:

• documents demonstrating what the skilled person would have had to consider when facing the problem posed in the patent specification and the mindset and expectation of this person at the outset of the investigation (for example, the Braga, Hilfiker, and Byrn articles mentioned above).
• inventor declarations, which are often persuasive. It is also often the case that we can simply file an inventor declaration intended for the prosecution of a corresponding foreign application (e.g. an inventor declaration filed at the US PTO to overcome a similar 35 U.S.C. 103 rejection).
• post-filing data, which will be considered by both Australian and New Zealand examiners. This data can be extremely persuasive, especially if it highlights the non-obvious nature of the advantage(s) of the polymorph by comparison with other polymorphic forms or even the amorphous form.

Footnotes

1. Braga, D., et al. (2009) Struct Bond, 132: 25-50.

2. Hilfiker, R., et al. (2006) Relevance of Solid-state Properties for Pharmaceutical Products. In Hilfiker, R. (Ed.), Polymorphism: in the Pharmaceutical Industry (pp. 1-19). Wiley-VCH Verlag GmbH & Co. KGaA.

3. Braga, D., et al. (2009) Struct Bond, 132: 25-50; Henck, J., et al. (1997) Pharm Ind, 59: 165-169.

4. Braga, D., et al. (2009) Struct Bond, 132: 25-50; Hilfiker, R., et al. (2006) Relevance of Solid-state Properties for Pharmaceutical Products. In Hilfiker, R. (Ed.), Polymorphism: in the Pharmaceutical Industry (pp. 1-19). Wiley-VCH Verlag GmbH & Co. KGaA.

5. Byrn, S., et al. (1995) Pharmaceutical Res, 12: 945-954.

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.