The Manufacturers Association of Israel opposed an ex-partes decision to allow a patent term extension for Dexlansoprazole, and New Commissioner Ofer Alon has disallowed the extension accepted by his predecessor.
Dexlansoprazole is used for treating gastro-reflux and for treating or preventing digestive ulcers.
IL 145996 to Takeda is a patent for Dexlansoprazole that claims various crystalline forms of the salt, a pharmaceutical preparation including the forms, and methods of treatment or prevention of digestive ulcers.
After Takeda successfully obtained regulatory approval for Dexilant™. (Dexlansoprazole) which is the R enantiomer of Lansoprazole, they applied for a patent term extension, which was refused by the Deputy Chief Examiner on 30 June 2016 on the grounds that the registration of Dexlansoprazole is not the first approved medical usage of the active ingredient in Israel, as the racemic mixture of the same active ingredient (Lansoprazole) is already registered.
In a response filed on 28 August 2016, the Applicant acknowledged that the racemic mixture Lansoprazole includes the R-enantiomer Dexlansoprazole, but the R-enantiomer cannot be separated from the racemic mixture since the crystals themselves contain both the right and the left enantiomers within the same lattice, creating a new complex that is different from the separate enantiomers.
The Applicant submitted that previously registered Lansoprazole is thus not a racemic mixture but rather a racemic compound and consequently the Dexlansoprazole crystals are substantially different from those of Lansoprazole and should, therefore, be registerable.
The Applicant distinguishes between racemic mixtures and racemic compounds with reference to Mitchell AG, Racemic drugs: Racemic Mixture, Racemic Compound, or Pseudoracemate? J. Pharm Pharmaceut Sci 1(1):8-12, 1998).
On 27 October 2016, the Deputy Chief Examiner understood the argument as stressing that the enantiomer is more efficacious than the racemic mixture and rejected the request for the patent term extension citing former Commissioner Meir Noam’s ruling concerning Unipharm’s opposition to IL 90465 to A/S Lundbeck (3 February 2009), which ruled that the higher efficacy of enantiomer with respect to the racemic mixture was patent worthy, but did not provide a new material in the sense required for a basic patent that is eligible for patent term extensions.
On 24 November 2016, the Applicant appealed this decision to the Commissioner of Patents, reiterating the arguments that were rejected. Then Commissioner Asa Kling accepted that the enantiomer was not found in the racemic compound and agreed to a patent term extension of 959 days until 30 January 2023 (see ruling re IL 145996 to Takeda from 12 Feb 2017:
In paragraphs 24 to 26 of his decision, then Commissioner Kling stated:
I have been convinced that Lansoprazole is a compound of the enantiomers and it is not possible to isolate Dexlansoprazole from the racemic compound, in contradistinction to the state of affairs in Unipharm vs. Lundbeck where the racemic mixture could be separated into the enantiomers.
Where the relative efficacy is different, Applicants assertion that Lansoprazole is NOT a racemic mixture but rather that the enantiomers share the crystalline structure, one cannot isolate the R enantiomer.
On 25 May 2017, the Association of Israeli Industrialists opposed the ex-partes decision to issue a patent term extension, based on Section 64g(a) of the Israel Patent Law 1967 for the following reasons:
- the registration in the register of medical formulations which was the basis for the patent term extension was not the first registration for the active ingredient, contrary to Section 6d(3) of the Law.
- The Applicant concealed significant relevant facts from the Patent Office. So the Application for a Patent Term Extension is contaminated with inequitable behaviour and is contrary to Section 64b(1) of the Law.
These claims were supported by an expert opinion from Professor Menachem Kaftori dated 24 May 2017.
The Opposer relies on the Lundbeck ruling (Appeal 223/09 Lundbeck vs. Unipharm ltd from 25 May 2009 which asserted that the various terms for material in Section 64a include enantiomers, and wherever the material is an active ingredient or form of the active ingredient that is found in a prior medical formulation that is listed in the register, it cannot be considered as being a first registration under Section 64d(3) of the Law.
The Opposer further alleged that the applicant had already acknowledged that the active ingredient Dexlanoprazole is included in the racemic Lansoprazole in the pharmacology report for Kapidex in a request to market a formulation including Dexlansoprazole in the US (NDA 22,287) which was appended to the ex-partes submission.
Based on Professor Kaftori’s opinion, the Opposer further alleged that coupling between the different molecules in the crystal were inter-molecular bonds and not intra-molecular bonds, so that on dissolution into water a racemic mixture of the enantiomers results.
The active ingredient of Dexilant™ is Dexlanoprazole and not the crystal, and the morphological structure of the crystal has no relevance to the issue of patent term extensions. The racemic compound is no different to a racemic mixture as has as the difference between its components, apart from the crystal structure of the raceme. The inclusivity of the re Lundbeck decision does not relate to the isolation of the material by separating the basic cell of the crystalline structure whilst in a solid state, but to the possibility of any separation.
The Opposer further argues that the efficacy of the enantiomers when considered separately or as part of the racemic mixture is not relevant to the question of whether the application in question relates to the first formulation that allows the material to be used for medical purposes in Israel.
The Opposer further claims that the Applicant concealed the fact that the material was previously registered in the Lansoprazole registration, and the experimental evidence used to justify the registration were those using Lansoprazole which the Applicant had asked to be relied upon. Similarly, the Applicant had concealed the fact that Lansoprazole had been defined by themselves as being a racemic mixture and not, as they now claimed, a racemic compound, for example, before the Canadian Federal Court of Appeal.
Takeda reiterated the arguments submitted in the ex-partes hearing by former Commissioner Kling, his ruling of 12 February 2017, and an Opinion of Professor Avi Bino of 19 September 2017.
Furthermore, Takeda rejected the allegation of inequitable behaviour noting that the racemic material Lansoprazole was disclosed and related to in their submission for a patent term extension, and reiterated that it was a different material.
Furthermore, in their response of 28 August 2016, they clarified that Lansoprazole is racemic compound that is optically active in a different manner to that of the enantiomer. The XRay diffraction pattern of Dexlansoprazole is different, and it is a different chemical entity. The Applicant further claims that the request for a Patent Term Extension is based on a registered product and not on a material after subsequently undergoing any type of process within the human body [apparently dissolution is intended – MF].
The Applicant alleged that the Opposer did not provide support for the contradiction in Mitchell’s paper, and did not provide scientific textual support, experimental evidence or research to challenge the validity of the evidence submitted by themselves in the ex-partes proceeding.
In the pharmacology submission for Kapidex which includes Dexlansoprazole there was experimental evidence relating to pregnant women which included one test conducted with Dexlansoprazole and one test conducted with Lansoprazole. Thus contrary to Opposer’s assertion Dexlansoprazole was examined, and the testing of Lansoprazole was additional data.
Although the therapeutic results themselves are insufficient to prove that a patent term extension is justified, they do teach that there is a difference between the materials that allows a patent term extension.
Takeda referred to the definitions of racemic mixture, raceme and racemic compound in the IUPAC gold book which is the definitions used by the International Union of Pure and Applied Chemistry and which they claim accords with Mitchell’s paper.
Finally, Takeda submits that the Commissioner is not able to sit in judgment and rule on a ‘kind of appeal’ of his own decision, or that of his predecessor.
Discussion and Ruling
For sake of clarity, the Commissioner notes that the term raceme relates to racemic mixtures of S and R molecules in equal amounts, or to racemic compounds where there is a repeating arrangement of the two enantiomers in different proportions within a crystal,
The legal authority of the Commissioner to rule on the Opposition
Commissioner Alon dismisses the allegation that he cannot hear this case. Section 64f of the Law allows anybody to oppose patent term extensions or their duration. Under section 64g, ANY reason that the Commissioner should not grant a patent term extension is a valid reason for opposing the extension. The right of the Opposer is independent of whether the extension was the result of an ex-partes ruling or otherwise.
The logic is clear. In the ex-partes hearing, one side presents THEIR arguments, evidence and documentation supporting the issuance of the PTE. The opposition is an adversarial proceeding whose purpose is to allow third parties to challenge the granting of the PTE, Once an Opposition is filed, the Commissioner is obliged to consider the issues raised and to reconsider the determination that a PTE is justified in light of the claims and evidence of the parties.
Registration of Lansoprazole allowed usage of Dexlansoprazole
Section 64d of the Law sets out the conditions for obtaining a Patent Term Extension. Inter alia, it states that one can only obtain an extension for a material listed in the pharmaceutical register, and only if that registration is the first registration of the material for medical use.
It does not appear that there is any dispute between the parties regarding the following facts:
- The crystal of the Lansoprazole raceme is a racemic compound, which is difference from the enantiomer of Dexlansoprazole (Cross-examination of Professor Kaftori page 12 lines 12-18).
- When the raceme Lansoprazole is in a crystalline form, one cannot separate the enantiomers into Dexlansoprazole and Levolansoprazole.
- One can separate a solution of Lansoprazole into its enantiomers by known and established procedures for separating enantiomers. (Opinion of Professor Bino, paragraphs 13-14).
- When Lansoprazole is separated into its enantiomers one obtains the R-enantiomer Dexlansoprazole and the S enantiomer Levolansoprazole.
As to the possibility of separating the enantiomers. Under cross-examination, Opposer’s expert Professor Bino agreed:
Attorney Tal Band: Take, let’s repeat this, take a crystal of Lansoprazole, dissolve it in water and what do you get? I suppose you will allow me…
Professor Avi Bino: With pleasure
Adv. Band: You will obtain a solution that includes the R-enantiomer
Prof Bino: the R-enantiomer and the S enantiomer
Adv. Band: and the S enantiomer, which is the active ingredient if we now know that the active ingredient is the R enantiomer? It is the R enantiomer, right?
Prof Bino: the R-enantiomer in solution
Adv. Band: the R enantiomer I solution is the active ingredient?
Prof Bino: Correct.
Protocol of 9 January 2018, page 53 lines 17-26.
In a different stage of the cross-examination, 9 January 2018, page 46 line 6:
Attorney Tal Band: It can, that means to say, it can dissolve into the solution…
Professor Avi Bino: Yes
Adv. Band: And this change from crystalline to solution is not a chemical change but a physical one, correct?
Prof Bino: True.
Adv. Band: Good. So in the two states the chemical compound maintains its identity, correct?
Prof Bino: Correct.
See also paragraph 60 of the Applicant’s claims from 19 September 2017 and paragraphs 9-15 of Professor Bino’s Opinion.
Thus there is no argument that the R-enantiomer included in Dexilant™ is the same R-enantiomer included in Lansoprazole.
In the Lundbeck ruling, the District Court ruled that registration of a raceme would be considered the first registration for the enantiomers.
The Applicant considers that the Lundbeck case is different since there one could separate the enantiomers as the patent covered a racemic mixture. However, in the present instance, one cannot separate the enantiomers whilst solid, but have to dissolve them in water first, and only then can the enantiomers be separated.
To clarify the point, the Applicant submitted the following schematic illustration on 28 August 2016 to the Deputy Chief Examiner:
The Applicant claims that the law relates to the active ingredient of the medical formulation, which is crystalline and so should be considered in this form.
In re Lundbeck, a mixture was considered, and the unit cell of r-enantiomer structure is found in the mixture (right side) and in the enantiomer (center top), whereas in the present case, (illustrated on the left), there is no r-enantiomer unit cell so one has to dissolve the crystal and then separate and recrystallize to obtain the separate enantiomers in crystalline form.
Applicant claims that the Law relates to the active ingredient of the medical formulation. The medical formulation includes the crystalline structure, and so it should be [examined for patent term extension purposes] in this manner.
The Examiner considers that the fact that one cannot separate the R and L enantiomers whilst crystalline is irrelevant. In paragraph 17 of the District Court ruling in re Lundbeck the court differentiates between inter- molecule bonds and intra-molecular bonds.
Even if we were to accept the Applicant’s claim that the Lansoprazole is a racemic molecule, there are no intra-molecular bonds, but only bonds connecting the molecules to each other, and each enantiomer molecule maintains its identity within the crystal. The attractive forces between the S and R molecules creates the crystal by inter molecular bonds (see paragraph 18 of Professor Kaftori’s opinion and Professor Bino’s remarks on page 48 lines 6-12 of the protocol. As Commissioner Alon clarifies below, it is incorrect to consider the material at the crystalline layer, and so the R-enantiomer is NOT to be considered a new material as far as Patent Term Extensions are concerned.
If one were to consider the crystalline form of the pharmaceutical formulation as being a new material as far as Patent Term Extensions are concerned, the consequence would be that one could dissolve Lansoprazole and consider the solution as being a pharmaceutical formulation, the solution contains both enantiomers in solution would be considered as a different formulation and thus subject to a Patent Term Extension, and it is difficult to accept this result.
Furthermore, the definition of material in Section 64a of the Law is:
“Material” – the active ingredient of the medical formulation or its salt, ester, hydrate or other crystalline structures of the same component.
Commissioner Alon considers that one should read Section 64a as all the forms of the active ingredient being considered the same material. This definition implies that the identity of the material is NOT considered in terms of its form in the formulation. The case-law has ruled that the fact that different enantiomers and crystalline structures have different physical properties does not make them considered as being different materials as far as patent term extensions (PTEs) are concerned – see District Court ruling in re Lundbeck, section 20.
This interpretation sits well with the rationale of the Law as stated in the Patent Term Extension ruling concerning IL 124123 to Bayer Healthcare LLC, 16 April 2018:
With regards to active chemical ingredients, one can claim that the legislator defined enantiomers that, although not structurally identical, can be considered as being the same active ingredient, since the experiments on the active ingredient will shorten the way or help develop drugs based on the same active ingredient. So different salts of the same active ingredient are defined as being the same active ingredient with respect to Section 64D(3) of the Law (it is noted that in other jurisdictions, a different conclusion was reached).
Additionally, there is an explicit connection between the breadth of patent protection under Section 64h(d) of the Law and the interpretation of the term ‘material’. Section 64h(d) states:
- d) If the Registrar granted an extension order, then the holder of the basic patent may – during the period in which the extension order is in effect – prevent any person from marketing or from producing in order to market without his permission the medical equipment or the medical preparation that incorporates the material, as far as the material, the process of its production, its use or the medical preparation or the process for its production were claimed in the claims for the basic patent.
Recognizing all forms of the active ingredient as being a new material as far as Patent Term Extensions are concerned would result in Patent Term Extensions being granted, not for all forms but only for the form of the active ingredient in the medical formulation. Commissioner Alon considers that proper policy is to provide wide protection for the party developing a new drug, and recognizing the physical form of the material as being different would result in narrowing the breadth of the patent term extension.
The Applicant argues that from the ruling of former Commissioner Noam regarding the Patent Term Extension for IL 97219 Novartis AG (26 December 2005) one can conclude that two active ingredients acting together could be considered as being a new material that is different from the two ingredients considered separately.
Commissioner Kling does not agree. In re Novartis, Commissioner Noam considered the eligibility for a Patent Term Extension for a formulation including two active ingredients that were previously separately recorded in the pharmaceutical register, and concluded that even were there to be a synergetic effect and not merely an additive effect (aggregation), this is only relevant for the question of patentability but not for the question of eligibility of Patent Term Extension, nothing further is stated.
It appears that Commissioner Kling’s ruling of 12 February 2017 was largely based on the conclusion that one cannot separate the enantiomers of the racemic compound. As shown in the Opposition by the statements of case and evidence, is that the compound can be separated into its enantiomers, and that the form is not significant. In other words, the factual basis for Commissioner Kling’s ruling has been eroded and we can thus change the decision.
In light of above, Commissioner Alon rules that the R enantiomer is found in Lansoprazole and the registration of Lansoprazole is the first registration of the R-enantiomer Dexlansoprazole which is the active ingredient of Dexilant™.
The Allegation of Inequitable Behaviour
The Opposer’s allegation that Takeda’s behavior was inequitable, contrary to Section 64b(1) of the Law, is supported by two props. One is the statement appended to the request for a patent term extension that was written by Miyuki Hora which states that Dexlansoprazole is the first registration that allows the use of the product for medical purposes in Israel, without going into details, which comes later.
In addition, the Oppose claims that the Applicant concealed the fact that the examination of the request for registration in the pharmaceutical formulation register relied on tests performed on Lansoprazole, and that the Applicant itself relates to Lansoprazole as being the racemic mixture in a proceeding before the Federal Court of Appeal in Canada, and regarding the date of the claim that Lansoprazole is a racemic compound.
The Applicant’s response to these claims was that the experiments were clearly indicated in the pharmacology report mentioned above, and Commissioner Kling even related to it in his ruling of 12 February 2017. As to the Canada decision, the Applicant acknowledges that they were inaccurate in their terminology regarding mixtures and compounds, but this was due to the fact that case related to a different issue and not to something relevant to the issue of whether the Lansoprazole raceme is a compound or mixture. The same inaccuracy is found in the FDA regulatory approval in the US.
When considering Miyuki Hora’s affidavit, it is true that it relates to the Lansoprazole raceme:
“… Although racemic Lansoprazole was previously approved for medical use, enantiomerically pure Dexlansoprazole has never been approved …”.
Additionally, it seems that the Applicant themselves muddled up the terms in the definition of the raceme, and sometimes referred to it as a mixture and sometimes as a compound, however the Commissioner does not consider that this is indicative of inequitable behaviour. Furthermore, in light of the above ruling, it is irrelevant whether we refer to the raceme as a mixture or a compound, since the question of whether the molecule were previously registered exists in the raceme, which we have established to be the case.
In light of the above, the Commissioner accepts the Opposition and cancels the patent term extension. The Applicant will pay 15000 Shekels costs and 100,000 Shekels legal fees to the Manufacturers Association of Israel.
Opposition by the Manufacturers Association of Israel to Patent Term Extension for IL 145996 to Takeda, ruling by Commissioner Ofir Alon, 24 May 2018
I think this decision is completely correct and is also well written and whilst comprehensively addressing the issues raised, is relatively concise.
Since the racemic compound dissolves into the free molecules, the discovery that the R-enantiomer is active may be inventive, but the clam that this is a new material that warrants a patent term extension is ludicrous in light of the previous cases related to by the Commissioner and linked to above.