Intervet parries a challenge to its combination injectable anthelmintic formulation patent application

Boehringer Ingelheim Animal Health USA Inc. v Intervet International B.V. [2020] FCA 1333

Key takeaways:

  • For novelty purposes, expert evidence does not make up for a lack of sufficiently clear and unambiguous directions in the prior art or for a lack of teaching that would inevitably result in the invention

  • Invention was a “substantial departure” from known formulations, particularly in the face of a long-standing need for combination anthelmintic treatments and was thus not obvious

  • Lack of utility was not established in the circumstances

 

Background

Merial Inc (now Boehringer Ingelheim Animal Health USA Inc (Boehringer)) appealed from an opposition decision in respect of Australian patent application AU 2011268899 (the application).

The invention described in the application relates to injectable formulations comprising a macrocyclic lactone and levamisole for controlling parasites in animals, and the use of such formulations in the preparation of a medicament for controlling parasites.

The problem addressed by the application was that some parasites develop a resistance to anti-parasitic drugs. Combinations of known drugs had been used in the art to overcome this resistance, but it was desirable to develop an injectable formulation for a combination of a macrocyclic lactone and levamisole, two of the most widely used and effective antiparasitic (anthelmintic) drugs.

However, such combinations have been difficult to formulate, for three main reasons:

First, levamisole and macrocyclic lactones are chemically incompatible and tend to react with each other when combined.  Secondly, levamisole and macrocyclic lactones are stable under different pH conditions (levamisole requires a pH of about 3.0-4.0 to be stable, while macrocyclic lactones require a pH of around 6.0-7.0).  Finally, levamisole salts are soluble in water, whereas macrocyclic lactones are not water soluble but are soluble in organic solvents, and are commonly formulated in oils and organic solvents.

The invention in the application addressed these issues by adopting a non-aqueous solvent system comprising oil and an organic solvent, in which the macrocyclic lactone is in solution, and the levamisole is a salt in particulate form (that is, in suspension).  This type of formulation achieves a separation of the macrocyclic lactone and the levamisole, thus addressing the issue of chemical incompatibility.

Claim 1 of the application is as follows:

  1. An injectable formulation of a macrocyclic lactone and levamisole in a non-aqueous solvent system comprising oil and an organic solvent, wherein the macrocyclic lactone is in solution and the levamisole is a salt in a particulate form, and wherein the levamisole salt is present in the range of between 10-35% w/v.

The Appeal

Boehringer was unsuccessful in its opposition in the Patent Office and appealed on various grounds:

(a)          Lack of novelty.  Boehringer contended that various claims were not novel in light of Chinese patent application CN 1375291A (CN 291).

(b)          Lack of inventive step.  Boehringer contended that the claims did not involve an inventive step because they were obvious in the light of the common general knowledge considered alone, or the common general knowledge combined with CN 291.

(c)           Lack of utility.  Boehringer contended that the invention claimed in each of the claims was not useful, in that the claims of the application include embodiments that do not achieve the promise of a physically and chemically stable suspension formulation of a macrocyclic lactone and levamisole.

Novelty

CN 291 was a patent application published on 23 October 2002 for an invention titled “Veterinary Compound Injection Containing Levamisole or Salts thereof”.

Example 3 of CN291 set out an oil injection containing a combination of ivermectin (a macrocyclic lactone) and levamisole hydrochloride.  However, it was clear that the concentration of levamisole HCl in Example 3 at 5% w/v did not fall within the scope of claim 1 of the application, which specified 10-35% w/v.  Further, Example 3 did not set out any manufacturing steps, or any description of what was intended to be made.  Moreover, it did not describe the levamisole HCl as being in particulate form (or in a suspension).

Boehringer submitted that Example 3 of CN 291 was to be read in conjunction with claim 3 of CN 291, which discloses levamisole HCl in the amount of 10-20% w/v, and with page 3 of the specification, which discloses that preferably the levamisole HCl is present in the amount of 10-20% w/v.  Further, Boehringer submitted that a skilled person reading CN 291 as a whole would understand that CN 291 contained a direction, recommendation or suggestion to make the Example 3 formulation using 10-20% w/v levamisole HCl, because they would consider the 5% w/v concentration of levamisole HCl stated in Example 3 to be far too low for cattle, particularly in light of the other teaching in CN 291.

Based upon expert evidence, Boehringer further argued that the skilled person would expect the levamisole HCl in Example 3 to be suspended in the solvent system and to be present in particulate form, because the skilled person would expect that levamisole HCl will not dissolve in the solvent system of Example 3.  To support this view, Boehringer provided details of two formulations prepared by its expert witnesses following the guidance of CN 291 that fell within the scope of claim 1 of the application.

However, Moshinsky J was not convinced, finding that there was no sufficiently clear and unambiguous direction to modify Example 3 by applying the higher concentration level described elsewhere.  Further, the Court emphasised that Example 3 did not describe the intended formulation as one in which the levamisole HCl is in particulate form.

In addition, the appellant’s expert formulator conceded under cross-examination that the formulation in Example 3 could be a suspension or a solution.

The Court was not swayed by the experiments conducted by the appellant as they involved a number of departures from the teaching of Example 3, and did not establish that any steps used to manufacture a formulation having the composition of Example 3 would inevitably contain levamisole HCl in particulate form.

Inventive Step

Boehringer contended that that it would have been obvious to the notional skilled person or team, based on the common general knowledge alone, or in light of the common general knowledge together with CN 291, to make a suspension formulation using an oil or organic carrier as a base and a co-solvent such as benzyl alcohol (an organic solvent), in which the macrocyclic lactone was in solution and the levamisole salt was in suspension.  It submitted that the skilled person would appreciate that, in such a composition, the levamisole salt would be in particulate form, and that they would know to use a concentration of levamisole salt sufficient to achieve the desired dose in a product for cattle having a dose volume rate of 1 mL/25 kg, which results in a formulation in accordance with claim 1 of the application.

However, the Court found that an oily formulation with levamisole present as a particulate was a substantial departure from known formulations, particularly (and most significantly) in respect of levamisole.  The expert evidence had also shown that, in order to be effective, levamisole needed to reach a high peak concentration in the animal’s gut rapidly, and preferably underwent similarly rapid clearance from the animal to meet regulatory requirements.  As there were no existing formulations of levamisole as a particulate in oil, a carrier often used to slow down absorption of a drug, it was not clear in the common general knowledge whether an effective peak concentration of levamisole could be reached in the animal using such a formulation.  Further, the evidence showed that there is a risk that an active ingredient formulated as a suspension will not be dispersed evenly throughout the formulation, or may result in agglomeration of the particles.

Based upon the evidence, it was held that a solution appeared to be preferable to a suspension for an injectable formulation, and that the above uncertainties as to efficacy, as well as others, would point away from the adoption of such an approach.

Secondary evidence such as the long-standing need for combination treatments of levamisole and a macrocyclic lactone and the desirability of having such a combination in injectable form were also held to support the existence of an inventive step.

Moreover, it was held that CN 291 would not provide any direct assistance to the notional skilled team in addressing the known chemical incompatibility of levamisole and macrocyclic lactones, a finding that was conceded by experts for Boehringer during cross-examination.

Lack of Utility

Boehringer submitted that the stability data in Intervet’s patent application WO 2017/108954 A1 (WO 954) (which Intervet accepted disclosed formulations falling within the scope of claim 1 of the application in suit) demonstrates that not all formulations falling within the scope of the claims of the application achieve the promise of being physically and chemically stable.  In particular, Boehringer relied on data in Table 4 of WO 954 for 2 months, at which point a loss of stability was shown.

However, the figures in Table 4 for 3 months – this being the relevant period for the purposes of the promise – did not show such a loss of stability.  Accordingly, it was held that the data in Table 4 did not establish that the invention failed to meet the promise of stability (that is, stability for 3 months under accelerated conditions).  Moreover, it was found that the data in Table 4 was inherently unreliable, and, even if it had shown a loss of stability as at 3 months, the Court would not have been satisfied that the invention failed the promise of stability.

Costs of amendment applications

In a subsequent judgment (Boehringer Ingelheim Animal Health USA Inc. v Intervet International B.V. (No 2) [2020] FCA 1433, The Court dealt with the costs of two interlocutory amendment applications.

In respect of each interlocutory application to amend, the Court found that “Intervet sought something in the nature of an indulgence.”  Referring to Les Laboratoires Servier v Apotex Pty Ltd (2010) 273 ALR 630 at [59]; cf Eli Lilly and Co v Pfizer Research and Development Co NV/SA (2003) 59 IPR 234, the Court held that in such cases, the patentee may be ordered to pay the costs of the amendment application, regardless of the outcome.

Accordingly, Boehringer’s request that each party bear its own costs was appropriate, particularly in circumstances where there was no adjudication on the merits of either application because Boehringer had ultimately consented to the amendments.