In 2016 Apotex Pty Ltd brought invalidity proceedings in the Federal Court against two Eli Lilly and Company tadalafil patents. No grounds of invalidity submitted by Apotex in relation to either patent were successful. The judge also held that Apotex threatened to infringe the relevant claims in both patents. Notably, the exploitation in Australia of the Apotex products was found to infringe Swiss-style claims irrespective of where the products were manufactured.
Eli Lilly and Company (Lilly) is the holding company of ICOS Corporation (ICOS) and holds a number of patents relating to a compound known as tadalafil (a PDE5 inhibitor). Lilly markets in Australia pharmaceutical compositions comprising doses of tadalfil under the brand name CIALIS indicated for (i) erectile dysfunction in adult males and (ii) moderate to severe lower urinary tract symptoms associated with benign prostatic hyperplasia in adult males.
The patents in suit were Australian Patent No. 773666 (the 666 Patent) and Australian Patent No. 769946 (the 946 Patent). Following commencement of the proceedings, but before trial, ICOS made an application to amend the two patents. The amendments were allowed and were the subject of the main proceedings.
The lengthy decision was originally made on 14 August 2018, but was not published until confidential material had been removed. The decision was finally handed down on 27 August 2018 .
The 666 Patent
The 666 Patent relates to compositions containing tadalafil, including in micronised particle sizes, and methods of treatment using such compositions. The amendments to the 666 Patent, made before trial, did not include amendments to the specification, but the addition of 15 claims to the existing 23 claims. The 666 Patent is due to expire on 26 April 2020.
Lack of inventive step
Apotex argued that the claims of the 666 Patent lacked an inventive step in light of common general knowledge and the information contained in WO97/03675 (Daugan 1997), either alone or in combination with one or both of WO95/19978 (Daugan 1995) and GB9514464.8 (GB 464).
Daugan 1997 teaches the use of cGMP-phosphodiesterase inhibitors, including tadalafil, for the treatment of erectile dysfunction. The examples within this document describe a unit dosage form containing 50 mg of tadalafil. It was argued by Apotex that it was well known that particle size improves bioavailability and that micronisation of tadalafil to improve rate and extent of absorption would have been the most obvious solution to try with the required expectation of success.
ICOS submitted that Daugan 1997 reveals a clear solubility problem which the team would address as a priority. However, there were several solutions to the problem, such as formation of a salt of tadalafil, different polymorphs and amorphous forms, and solid dispersions, including co-precipitates. Micronisation was not a solution that would be tried. And even if it would, it would not be tried with the required expectation of success.
The trial judge, Besanko J, held in favour of ICOS’s submissions. His honour gave more weight to the evidence provided by ICOS on the basis that Apotex’s expert formulator did not have the required experience. Therefore, his honour was not satisfied that the development team would be directly led as a matter of course to try micronisation with the required expectation of success. As a result, Apotex’s inventive step challenge to the claims in suit in the 666 Patent was rejected.
Lack of novelty
Apotex argued that certain claims to a tadalafil composition exhibiting “a Cmax of about 180 to about 280 micrograms/litre or an AUC (0-24) of about 2280 to about 3560 microgram.hour/litre, measured using a 10 mg dose of the compound” lacked novelty in light of WO 01/08686 (Oren).
These claims (claims 10-12 and 18) were added during the filing of the international application on 1 August 2000. The priority document, US provisional 60/147,048, filed 3 August 1999, only discusses particulate preparation of free drug forms of tadalafil, having specific and defined particle size characteristics.
Oren also claims a priority date of 3 August 1999 and was published on 8 February 2001. Oren teaches in Example 1 a formulation and method of preparing a tablet providing 10mg of Tadalafil . Oren does not specifically mention the pharmacokinetic values on the composition. Example 1 of Oren is identical to Example 4 in the 666 Patent.
Apotex argued that the relevant claims were not entitled to the priority and thus were anticipated by Oren. Apotex submitted that the fact that while neither the priority document discloses the pharmacokinetic parameters, it has proved that following Example 1 of Oren will have the inevitable result of achieving the pharmacokinetic parameters of claims 10-12 and 18 of the 666 Patent, and therefore these claims lack novelty. However, Apotex submitted that an inevitable result cannot be a “real and reasonably clear disclosure” for the purposes of concluding that the 666 Patent is fairly based on the 666 Priority document and, therefore, the priority date is 1 August 2000.
Whilst the 666 Patent does not disclose the specific pharmacokinetic values, Besanko J found that the statements in the 666 Priority Document about rapid achievement of maximum blood concentration and Examples 2 and 3 are a real and reasonably clear disclosure of the claimed pharmacokinetic values . “To adapt the words of Yates J in Vehicle Monitory Systems, if Oren anticipates the claims then it must also be the case that the 666 Priority Document is a real and reasonably clear disclosure of the claims. In addition, […], the case is even stronger here because the novelty document is a ‘whole of contents’ citation which requires the information contained therein to be capable of being made the subject of an actual or notional claim that is, itself, fairly based, before the information can form part of the prior art base. Another way of putting this argument is that first there is no reference to pharmacokinetic parameter in Oren and it does not anticipate the pharmacokinetic claims of 666 Patent. Alternatively, if the inevitable result of Example 1 is the pharmacokinetic parameters in the 666 Patent, then the inevitable result of Example 3 in the 666 Priority Document is the same and the pharmacokinetic claims 10-12, 18 in the 666 Patent are fairly based on the 666 Priority document.”
Besanko J concluded that Oren does not anticipate claims 10-12 and 18 (any dependent claims) in the 666 Patent.
The 946 Patent
The 946 Patent relates to compositions containing particular daily dosages of tadalafil for oral administration and methods of treatment using such dosages. The dosage unit form is suitable for “oral administration up to a maximum total dose of 20 mg per day”.
The amendments made before trial involved various deletions from, and amendment to, statements which appeared in the body of the specification; there was no application to amend the claims. The 946 Patent is due to expire on 1 August 2020.
Lack of inventive step
Apotex argued that the claims lacked an inventive step in light of common general knowledge and the information contained in WO97/03675 (Daugan 1997) either alone or in combination with one or both of WO95/19978 (Daugan 1995) and GB9514464.8 (GB 464).
Daugan 1997 teaches the use of cGMP-phosphodiesterase inhibitors, including tadalafil for the treatment of erectile dysfunction. The examples within describe a unit dosage form containing 50 mg of tadalafil. It was argued by Apotex that, although Daugan 1997 does not predict the maximum total dose of 20mg per day, the relevant drug development team would perform dose ranging studies to arrive at the relevant dose. Such studies, it was argued, were no more than mere routine steps.
Besanko J found that “ although I am satisfied that the development team would, as a matter of course, be directly led to try tadalafil with the required expectation of success, I am not satisfied that the team would, as a matter of course, be directly led to the claimed doses with an expectation of success. Certainly at the start of the drug development process, there would be no expectation as to the dose or range of doses [….] The nature of the condition, the nature of measurement tools available and the limits on the information available lead me to conclude that a dose ranging study at the claimed doses would not be undertaken as a matter of course and, even if a decision was made to carry out a study at the claimed doses, it would not be a decision with the required expectation of success.”
Lack of novelty
Apotex also argued that the claims lacked whole of contents novelty in light of WO00/53148 (Stoner).
Stoner describes a drug combination useful in the treatment of erectile disfunction. The drug combination involves two compounds, namely, a drug acting as an agonist of the melanocortin receptor and either a PDE inhibitor or an alpha-adrenergic receptor antagonist. The PDE inhibitor is a PDE5 inhibitor, including inter alia, sidalafil. Tadalafil is mentioned. A broad range of doses of the drug combination are described, from 0.01 up to 500mg.
As part of the argument by Apotex, it was submitted the 946 Patent included within its scope a combination therapy, because of the co-administration with nitrates and the inclusion of the term “comprises” in the claim. Besanko J found that the 946 Patent does not describe a combination therapy in which tadalafil is co-administered with another drug, such that a synergistic effect is observed, i.e. the 946 Patent describes a monotherapy. In contradistinction, Stoner describes a combination therapy in which the drug combination has a synergistic effect [at 578]. Besanko J agreed with ICOS submission that “to construe the 946 Patent as extending beyond monotherapy by reason of the definition of the word “comprising” would be to impermissibly change the nature of the invention.” [at 577]
Besanko J found that Stoner could be further distinguished from the 946 Patent on the basis that it does not teach the maximum daily dosage of tadalafil.
Apotex argued that the patent was obtained by false suggestion, relying on arguments submitted by the applicant’s attorneys during examination, which in turn relied on statements made in the specification, some of which were later deleted from the description. These included statements that the invention “eliminates or reduces” side effects in comparison with the first generation drug, sildenafil (marketed as VIAGRA®), and the unexpected nature of the benefits of low doses of tadalafil. Apotex submitted that the representations made by the attorneys during examination contributed in a material way to the decision to grant the 946 Patent.
Besanko J outlined the principles for establishing the ground for false suggestion: “First, a false suggestion can be made by statement in the specification about the nature or utility of the invention. Secondly, it is not necessary in order to make out a false suggestion case to establish that the person making the suggestion had an intention to deceive.[…] Thirdly, it is not necessary […] to establish that the patent would not have been granted but for the conduct constituting the false suggestion or misrepresentation. It is sufficient if the conduct which constitutes the false suggestion or misrepresentation materially contributed to the decision to grant the patent. Fourthly, where the Commission (or delegate) does not complain about the patentee’s conduct and does not give evidence, the question becomes one of whether the Court should infer that the representation played a part in the decision. Nevertheless, in deciding whether to draw inference, it is relevant that the Commissioner has not complained about being misled or deceived.”
Therefore, in order for this ground to be successful, it needs to be established that the patent would not be granted “but for” the false suggestion.
Besanko J determined, having regard to expert evidence from the clinicians, that the statements made in the specification relating to the claimed benefits were applicable to most patients – not some patients and not all patients.
Therefore, it was held that the representation that one of the side effects, facial flushing, occurs less frequently with tadalafil administered in accordance with the claimed invention than with sildenafil, was not shown to be false. Additionally, there was no evidence that the administration of tadalafil alone caused a decrease in blood pressure, which in turn caused clinically significant symptoms. To the extent that ICOS suggested or represented that tadalfil could be administered without clinically significant side effects, that representation was found to be true, or at not shown to be false.
Conclusion on validity
At the conclusion of his decision, Justice Besanko found that “Apotex’s challenge to the validity of the 946 Patent and the 666 Patent must be rejected.”
Besanko J held that Apotex threatened to infringe the relevant claims in both patents. More specifically, Besanko J found that Apotex had threatened to infringe each of claims 1-6, 8-17, 19-29 and 31-35 of the 946 Patent and each of claims 1-3, 5-8, 10-12, 14-18 and 24-38 of the 666 Patent.
Notably, following the recent the recent Full Federal Court decision in an appeal from the decision of Nicholas J in Warner-Lambert Co LLC v Apotex Pty Ltd (No 2)  FCAFC 26, the exploitation in Australia of the Apotex products was found to infringe Swiss-style claims irrespective of where the products were manufactured.
Apotex Pty Ltd v ICOS  FCA 466
1. Apotex Pty Ltd v ICOS Corporation (No 3)  FCA 1204
2. Apotex Pty Ltd v ICOS  FCA 466
3. Apotex Pty Ltd v ICOS Corporation (No 3)  FCA 1204 at 531-532
4. Apotex Pty Ltd v ICOS Corporation (No 3)  FCA 1204 at 598
5. Apotex Pty Ltd v ICOS Corporation (No 3)  FCA 1204 at 612
6. Apotex Pty Ltd v ICOS Corporation (No 3)  FCA 1204 at 627
7. Apotex Pty Ltd v ICOS Corporation (No 3)  FCA 1204 at 627
8. Apotex Pty Ltd v ICOS  FCA 466
9. Apotex Pty Ltd v ICOS Corporation (No 3)  FCA 1204 at 465
10.Apotex Pty Ltd v ICOS Corporation (No 3)  FCA 1204 at 577
11.Apotex Pty Ltd v ICOS Corporation (No 3)  FCA 1204 at 653
This article was written by Dr Sarah Couper.
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