Astella Pharma filed Israel Patent Application No. 178249 titled “Pharmaceutical Composition for use in Solid Formulation Crystalline Solifenacin or Salt Thereof and a Process for its Preparation”. The Application was the national phase of PCT/JP/2005/005377 which was filed on 24 March 2005 and claimed priority from a couple of earlier US provisional applications.
The Application relates to a solid pharmaceutical containing Solifenacin or Solifenacin Succinate that is up to 77% amorphous as determined using NMR.
The Application was allowed, and on 27 February 2002 Teva Pharmaceuticals submitted an Opposition. On 26 June 2013, Astella requested permission to amend the specification. Teva opposed some of the amendments and in an interim ruling of 19 May 2014 Ms Jacqueline Bracha approved some of the amendments, which were then published for Opposition purposes, and since no oppositions were submitted, were then allowed. This ruling relates to the amended specification.
On 29 July 2015, instead of submitting an amended statement of case, Teva abandoned the Opposition. Nevertheless, on 27 March 2016, in a detailed ruling, Ms Bracha explained to Astella that under the Authority granted by Section 34 of the Law, she was refusing to grant the patent. The ruling was based on two publications that Teva had submitted in the Original statement of case that showed that persons of the art would expect the rate and degree of solubility to increase with increased amorphousness of a tablet. On 22 May 2016 the Applicant requested an oral hearing which was held on 4 January 2017 and this ruling follows that hearing.
Astella, represented by Gilat Bareket, claimed that in a Section 34 proceeding, the burden of proof is on the Commissioner. The claim that since the Opposition was abandoned and following allowance by the Examiner, there is an assumption of validity. Therefore, the Commissioner has to overcome this rebuttable assumption.
The Applicant claims that the prior art describes a process for fabricating Solifenacin hydrochloride crystals. It did not relate to amorphous Solifenacin or to degradation of the amorphous Solifenacin or to medical formulations comprising Solifenacin Succinate.
The Applicant claims that there is a continuous decrease of the active ingredient due to degradation which they determined to be due to the amorphous Solifenacin that is produced in when preparing the tablets.
The Applicant clarified that restricting the amount of the amorphous Solifenacin to no more than 77% increases the stability and reduces degradation to rates tolerable in Japan. Furthermore, the Applicant found that when the fabrication process is wet granulation they can control the amount of amorphous material by controlling the moisture levels. They also claim that using PEG as a binder also lowers the degradation, however the Deputy Commissioner notes that this was not claimed and is thus not part of the invention.
As stated, the invention is intended to provide a stable formulation with less than 0.4% degradation of Solifenacin Succinate in the total amount.
The discussion related to the following publications:
- Ahlneck and G. Zografi., The Molecular Basis of Moisture Effects on the Physical and Chemical Stability of Drugs in the Solid State,Int. J. PHARM., vol. 62(2-3) (1990) – “Appendix 10”;
- Y.Shalaev and G. Zografi., How Does Residual Water Affect the Solid-State Degradation of Drugs in the Amorphous State?, J. PHARM. SCI., vol. 85(11) (1996) – “Appendix 9”;
- C. Hancock and G. Zografi., Characteristics and Significance of the Amorphous State in Pharmaceutical Systems, J. PHARM. SCI., vol. 86(1)(1997) – “Appendix 11”.
The Burden of Proof
The Applicant alleges that the burden of proof resides with the Commissioner. In Y Kedmi “On Evidence”, 4th Edition 2009, it is stated that the burden of evidence depends on the substantive law:
The determination regarding which side bears the burden of proof depends on two basic principles:
- “The one seeking redress has the burden of proof” [Baba Kama 46a] and this may be plaintiff or the defendant, depending on circumstances.
- “Evidence follows the Substantive Law” – both when establishing the basis of the legal claim / defense, and when overcoming presumptions.
As a general rule, the burden of proof that a patent application is registerable is on the Applicant see 665/84 Sanofi ltd. vs Unipharm ltd. p.d. 41(4) 729 and Appeal 645-06-13 Unipharm vs. Lilly Icos, 26 January 2014.
The Opposition is considered as a completion of the Examination, and the allowability is reconsidered. It serves to protect the integrity of the register and the executive examination, see Opposition of IL 136482 Bromium Compounds ltd vs. Albermarle Corporation USA, 7 November 2010:
It appears that the attitude of the court has changed since then. Now the Supreme Court sees the Opposition process as a completion of the executive examination that is designed to ensure the public interest and the integrity of the register.
The public interest that the Opposition proceedings serves is detailed in 2826/04 Commissioner of Patents vs. Recordati Ireland Ltd. p.d. 59(2) 85.
The purpose of the Section 34 proceeding is identical to that of Oppositions, i.e. to maintain the integrity of the register, see the Section 34 ruling concerning IL 156034 Serguei Borisovish Sivolovenko vs. Diamcad NV, 25 January 2015:
The Section 34 proceeding is another hurdle that the Applicant may have to negotiate before receiving a patent. During this proceeding, the Commissioner is allowed to consider all the material before him from the Opposition proceeding, and to decide whether to uphold the Examiner’s decision or to change it. The purpose is no different from that of Examination or Oppositions, and is to protect the integrity of the register and the public interest to not issue patents contrary to Section 3 of the Law. Successful negotiation of the Examination stage does not bestow a right to a patent.
The patentee’s right to a monopoly for the patented invention is in rem. Consequently he has to show that the invention fulfils all the requirements of patentability under the Law. The burden of proof only changes once a patent issues. This was clarified by Commissioner Kling in IL 142896 and IL 179379 Medice Arzneimittel GmbH & Co.KG Alkermes Pharma Ireland Ltd, 4 April 2017.
In a cancellation proceeding, the burden of proof that a patent is invalid is on the Requester for cancellation. For example, this was established in Appeal 8802/06 Unipharm ltd. vs. Smithkline Beecham PLC, 18 May 2011:
Section 37 of the Law completes this idea by establishing that Examination and granting of a patent do not guarantee it has validity. So the issuance of a patent by the Commissioner does not create a non-rebuttable assumption of validity. It merely establishes that the Commissioner considered it issuable. (appeal 47/87 Hasam Systems for Defence of Trustworthiness ltd. vs. Bahari, p.d. 45(5) 194, 201-202 (1991). However, the burden of proof that an issued patent is invalid is on the party claiming invalidity (See Appeal 665/84 Sanofi vs. Unipharm ltd. p.d. 41(4) 729, 736 (1987), Appeal 700/78 Isisco International Company for Solar Energy Systems ltd. vs. Banit, p.d. 34(1) 757, 763 (1979).
Thus, before a patent issues, the burden of proof is on the Applicant.
Validity of Patent Application
On page 2 of the Application, the Applicant notes that solifenacin was known as was its efficacy for treating diseases of the urinary tract, salts of solifenacin and the crystalline state of solifenacin hydrochloride and methods of manufacture.
Solifenacin Succinate was used in Vesicare, see accompanying flyer which was published in December 2004, before the priority date of the present application. The synthesis of Solifenacin Succinate is also described in the prior art (Appendix 3 of the Opposer’s Statement).
The Applicant claims that during development of the formulation they discovered that there is degradation where the amorphous state is present. The Applicant claims that the prior art was unaware of this phenomenon and thus did not address it.
Appendix 9 page 1137 teaches that exposure of solid pharmaceuticals to high moisture results in degradation:
“It is widely recognized in the pharmaceutical field that exposure of solid drugs (small molecules or proteins) to high relative humidity and the resulting association of water vapor with the solid generally accelerate the rate of chemical degradation.”
Further on it is mentioned that the instability typically occurs in the amorphous part of the formulation:
“…most instabilities observed for drugs occur in solution much more readily than in the solid state; when they do occur over practical time scales in the solid state, it is very likely that the reaction is taking place in the more disordered amorphous regions of the solid. Indeed, it has been shown in a number of cases that under otherwise identical conditions reactivity of a particular substance in the amorphous state is greater than that in the crystalline state.”
Appendix 11 teaches that in cases where the active ingredient is found in an amorphous form, this is likely to accelerate the degradation. However, sometimes, the amorphous form spontaneously crystallizes:
“The high internal energy and specific volume of the amorphous state relative to the crystalline state can lead to enhanced dissolution and bioavailability, but can also create the possibility that during processing or storage the amorphous state may spontaneously convert back to the crystalline state.
… In the first, a material may exist intrinsically in the main amorphous state or it may be purposefully rendered amorphous and we would like to take advantage of its unique physical chemical properties. Under these circumstances we usually want to develop strategies to prevent physical and chemical instability of the amorphous sample. In the second case, we may be dealing with a crystalline material that has been inadvertently rendered amorphous during processing. This type of amorphous character usually exists predominantly at surfaces at levels not easily detected and has the potential to produce unwanted changes in the physical and chemical properties of the system. In this situation we usually want to process the system so that the amorphous portions of the solid are converted back to the most thermodynamically stable crystalline state.”
The Application describes attempts by the applicant to prove that there is a connection between the amorphous state and the results of degradation F1 (table 2 on page 38 of the Application.
The Applicant compared the stabilities of samples 1-4 that included 63%, 73%, 715 and 7% amorphous material, with samples 1-3 that contained 92%, 90% and 92% amorphous material. However, the results of table 2 do not show a clear correlation between the amount of amorphous material and the F1 decomposition product. For example, example 1 had 63% amorphous material but only 0.31% F1, whereas example 2 had 73% amorphous material but only 0.29% F1, and in comparative sample 1 with 92% amorphous material there was 0.48% F1, and in comparative sample 3 with 92% amorphous material there was 0.4% F1.
Furthermore, as can be seen from table 2, the moisture of the granulate influences the F1 breakdown product, and can at least partially explain the difference between the results of comparison samples 1 and 3. The Applicant claims that there is some correlation between the water content of the granulate and the amount of amorphous material but it is not certain that the amorphous material content influences the amount of F1 degradation product.
Furthermore, it appears that the 0.4% limit that the Applicant set was based on the Japanese Health Ministry requirements and was not empirically determined. The Applicant admits that the Japanese acceptable limit was 0.5% and 0.4% is preferable. Table 2 shows that even where the amorphous quantity exceeded 77%, less than 0.5% of F1 was obtained.
Even if we assume that the Japanese Ministry of Health limits are desirable, the applicant has not established that there is a problem attaining these limits that the invention overcomes, due to the stability of the salt. The 77% amorphous material limit is also not empirically established. The Applicant was not able to produce Solifenacin Succinate with more than 0.5% F1 degradation product, and there is no linear connection between moisture content and amorphous material content.
Applicant does not deny that amorphous Solifenacin Succinate can spontaneously crystallize (see Appendix 2 and letter of 5 December 2012 and “Analysis of Appeal in European examination file from 17 April 2012 that the Applicant submitted in the corresponding European application. The slight differences in F1 product are even less significant due to this spontaneous crystallization.
There are a few more paragraphs regarding the various compositions and the binder (that wasn’t claimed and then, the Deputy Commissioner states that) from another angle, Appendix 9 teaches that there is a close connection between moisture and the amount of amorphous material present – page 113:
“Generally, for reactions occurring in the amorphous solid state, the rate of reactivity increases with increasing water content, and this can be attributed to the ability of the amorphous solid to absorb water vapor into its bulk structure, forming an amorphous solution. In a few cases it has been reported that a certain amount of water must be present to ensure chemical stability, e.g., lipid peroxidation rates decrease with the addition of small amounts of water; however, a destabilizing effect of absorbed water is more generally the case for the major types of drug degradations, e.g., hydrolysis, oxidation, or deamidation.”
So it seems that average persons of the art at the time in question would conclude that limiting moisture would limit the amorphous material in the formulation and this would, in turn, limit degradation. Consequently, this has no inventive step whatsoever.
The invention is wholly lacking in inventive step and so the IL 178249 Application is rejected.
I am not a pharmacist, but have a fairly strong background in chemistry. It seems to me to be fairly obvious how to control the crystallization rate and extent, and how this will affect solubility. Possibly high school thermodynamics in inadequate, but a basic undergraduate course of chemical thermodynamics is more than adequate to predict this invention, so it seems to me that the Deputy Commissioner was correct to refuse the patent.
Formally, the Opposer is wrong to claim that the onus of proof is on the Commissioner. The case-law considers the Opposition proceeding as part of Examination and does not assume that the Examiner concluding that an invention is patentable establishes a presumption of validity. TEVA’s withdrawal of their Opposition may have been a commercial decision. In practice, although formally Israel requires an inventive step, an Examiner has to show anticipation or obviousness not to grant a patent. TEVA made some of the scientific literature of record, and the Deputy Commissioner was correct to relate to it.
This decision seems to be correct. However Astella, may appeal it to the courts.