Rosuvastatin is a member of the statin class of drugs that is used in combination with exercise, diet, and weight-loss to treat high cholesterol and related conditions, and to prevent cardiovascular disease.
Israel Patent IL 166626 to Astrazeneca is the National Phase of PCT/GB2003/003463 filed in August 2003 and titled ” Process for preparing the calcium salt of rosuvastatin ”
The Application was allowed and published for opposition in September 20011 and Teva filed an Opposition. A hearing was held in July 2015, and by June 2016 both sides had finished submitting their summaries and counter summaries.
The patent covers a process for obtaining (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt. The application included 27 claims of which the first, independent claim is as follows:
“A process for the manufacture of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt, which process comprises mixing of an aqueous or substantially aqueous solution of calcium chloride with a solution of a water-soluble salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino|pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6- enoic acid, wherein the solution of calcium chloride is added to the solution of a water-soluble salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, at a temperature of 30-45°C.”
Dependent claim 2 gives the time window for adding the CaCl2 as between 5 and 60 minutes. Claim 3 requires adding slowly and stirring over 10 minutes. Claim 4 requires holding the mixture for at least 10 minutes at 30-45°C, filtering, washing (optional) and drying. Claims 5 and 11 give different temperature and time parameters for mixing and stirring.
Claims 12-14 relate to the temperature –time regime to create crystals with high surface area to volume ratio, claims 15-17 relate to various paste strengths and claims 18-27 relate to applying the process to different rosuvastatin salts.
Essentially Teva presented affidavits of various professors with appended patents and references to Analytically Chemistry text books to claim that there was nothing inventive and that the claims were not fairly supported by the specification. Astrazenica countered with Professorial opinion to the contrary.
Teva considers that the point of the Application is to relate to the issue of scaling from lab preparation to commercialization which is difficult due to the need to filter extremely small particles. The precipitation is achieved by adding calcium chloride and making a supersaturated solution. There is always competition between nucleation of new crystals and growth of already nucleated crystals and the greater the nucleation rate, the smaller the resultant crystals. By favouring growth over nucleation, large crystals which are easier to filter are obtained. Supersaturation favours nucleation, so by suppressing the degree of supersaturation nucleation is favoured. This is well established and known as the Von-Weiman ratio.
Teva argued that for 99.99% of normal salts, including rosuvastatin calcium salt, increasing the temperature increases the saturation, lowers the supersaturation and results in precipitation of larger crystals.
EP 0521471, WO/00/49014 and WO/01/60804 all deal with preparation of the rosuvastatin sodium salt and its conversion into rosuvastatin calcium salt. The novelty of the present invention is that the temperature is raised from 25ºC to 3—45ºC and this, the Opposer claims, is simply optimization of the process and lacks an inventive step. In addition, the claimed temperature range is alleged to be random and unexplained. The effect of the degree of supersaturation is allegedly the same for both crystalline and amorphous precipitates.
Teva claims that their publication WO/2005/023778 “Process of the preparation of Rosuvastatin Calcium” although not prior art, since it was filed afterwards, nevertheless describes real improvements to the multi-stage process for making the rosuvastatin sodium salt.
Finally, Teva claims that claim 1 and its dependencies are ‘greedy’ in that their scope is much wider than that disclosed and supported by the evidence. In particular, there is no explanation for the 30-45 C temperature range. The alleged improvement is not shown for this range. The parameter used to demonstrate the alleged improvement is the ‘paste strength’ which is a function of the water to solid ratio and over part of the claimed range, this is no better than that previously known.
Asrazeneca’s Statement of Case
Astrazeneca claims that the invention relates to a small improvement having industrial significance. The basic process of obtaining the calcium salt is known but the parameters are different and these are more easily filtered. Since the prior art describes crystals with a surface area of 2 m2/g (square meters per gram) whereas their crystals have a surface area of 1 m2/g, their product is both novel and inventive.
The paste strength resulting from the increased processing temperature is 50% higher and this is surprising. The rule-of-thumb that changing temperature changes the solubility of a material is not universally true. Teva’s witness, Dr Genak’s cited text books are not relevant to rosuvastatin. The chemical properties of molecules are influenced by their construction and not by their therapeutical properties and so Dr Genak’s references to other statins is simply not relevant. The Physical Chemistry texts by Harvey, Christian and Kellner are not relevant as they relate to analytical techniques and not to industrial manufacturing. Furthermore, the citations all relate to the amorphous material and not to crystals.
Astrazeneca allege that the later ‘778 patent describes essentially the same process but at a temperature of 5-25 C which shows that the Opposer themselves thought that they should operate contrary to that taught and this shows that the claimed invention was not obvious to persons of the art.
During Oppositions, the onus is on the Applicant to demonstrate an inventive step. See 665/84 Sanofi vs. Unipharm LTD p.d. 41(4) 729, Appeal 645-06-13 Lilly Icos vs. Unipharm 16 Jan 2014.
The Opposer does have to bring some evidence – see Opposition IL 143977 Unipharm vs. Astrozeneca 29 July 2007, but once the Opposer succeeds in raising doubts, the burden of proof is on the Applicant to show that the claimed invention is inventive.
The Opposer alleges that the claimed invention lacks inventive step and is not sufficiently supported:
Section 5 defines inventive Step (Non-Obviousness) as follows:
An inventive step is a step which does not, to an average skilled person, appear obvious in the light of information published before the application date in ways stated in section 4.
In Hughes Aircraft it is established that to destroy inventiveness it is legitimate to cobble together a number of publications to create a general picture when considering whether or not there is an inventive step:
The basic question of inventive step is determined by considering the total professional knowledge in the relevant field, and to do so it is legitimate to join different publications into a general picture Appeal 3314/77  page 209. However, one must always bear in mind that the joining together of the disparate documents must be obvious to persons of the art at the date in question; for if it requires an inventiveness to do so, particularly where scattered crumbs of knowledge are gathered together – the general picture obtained is not obvious and one cannot say that the patent has no inventive step.” –page 111.
See also Sanitovsky pages 515-516 and Appeal 793/86 Michael Porat vs. Tzamal Modern Medical Equipment, p.d. 44(4) 578, 585.
The present application relates to a process for fabricating a chemical species. It has already been established that chemistry is an experimental science and one cannot be certain of the outcome of an experiment. See Oppositions to IL 166550, 166189 , 135898 131392 Unpiharm vs. SmithKline Beecham Co. from 2009:
This patent is essentially one for a chemistry process. This is an empirical science whose results cannot be anticipated with full certainty, but results can often be expected with high probability.
“Moy`s Walker on Patents”, 4th ed. (2007) establishes that optimizing a known parameter does not have an inventive step even if the process involves trial and error, particularly if the optimization is over a relatively narrow range:
“A common set of circumstances that present these concerns is where the prior art discloses a general configuration, and the claimed represents a specific form in which one or more variables has been optimized. Cases generally hold that modifications that optimizing a known variable are obvious, even if the process of optimization required some amount of trial and error. This is particularly true where the range over which the investigation takes place is relatively narrow. The modification is more likely to be unobvious if the improvement obtained by optimization is usually large, the range of the variable is wide, or if the property being optimized was not itself recognized previously in the art.”
Then Commissioner Dr Meir Noam ruled in IL 136482 Bromium LTD vs. Albermarle Corporation USA from 7 November 2010:
From that stated previously I conclude that the changes between the basic patent and that before me are relatively minor that a person of the art, including a technician would be expected to make – see 259/71 Rothschild vs. Miceliborsky, p.d. 26(2) 317 – and do not include an inventive step.
The parties concur that the ‘471, ‘014 and ‘804 patents describe a process for making the calcium salt of rosuvastatin and that the invention is intended for industrial scale manufacturing.
The Applicant claims that a number of variables including the temperature bring the material into a state for optimal filtration. They claim that the table on page 20 of the Application describes the effect of the changes on the paste strength. The Opposer claims that the only change claimed is to the temperature and this is clear from page 20 of the specification:
“Precipitation at 20°C according to the process described in these applications produces a product which has a physical form such that it is difficult and slow (i.e. inefficient) to filter, and retains a substantial quantity of water after filtration. This necessitates extensive drying in order to obtain a final product suitable for use as a pharmaceutical. Although manageable on a small (laboratory) or medium scale, on a manufacturing scale, handling a product requiring such treatment is highly problematic and is undesirable in terms of manufacturing output and, potentially, product quality.”
Consequently, the Opposer considers that the application only claims the change in the temperature as being inventive, with the other changes not even being allegedly inventive. The Applicant does not deny this, and the change in temperature simply increases the solubility and leads to larger crystals being precipitated.
The Opposer claimed that this would be expected by persons of the art:
Kellener, page 274:
“As a general rule, hot solutions should be used to form precipitates with the appropriate features necessary for the filtration.”
Christian pages 157-158:
“Several steps are commonly taken to maintain favorable conditions for precipitation:
- Precipitate from hot solution.”
Harvey page 241:
“A precipitate’s solubility usually increases at higher temperatures”
The cross-examination of the various witnesses establishes that these general principles show what is to be expected and though the Applicant objected to Prof. Lamkoff’s assertion that the solution phase diagram for calcium salt of rosuvastatin is totally normal, they did not justify why it would be expected to behave differently.
The Commissioner accepts the argument that a rule-of-thumb is inconclusive but rejects that there is an inventive step is trying something predicted by the rule of thumb.
The Commissioner notes that the Applicant has to provide evidence that there is an inventive step, and that persons of the art would not optimize in accordance with such general rules-of-thumb.
The increase in paste strength appears to be a consequence of the predictable and obvious change in temperature and thus even if the increase in paste strength is surprising, it does not negate the obviousness of changing the temperature regime.
Citing the recent Unipharm vs. Novartis Panobinostat decision the commissioner rules that a surprising discovery does not, in and of itself constitute an inventive step.
The paste strength shown in the table on page 20 drops below the 45% that the Applicant considers optimal. Now the Applicant explains this as being due to changes in parameters other than temperature, but this undermines their contention that the change in temperature is inventive since it enables optimization of this variable.
The ‘778 patent to Teva is indicative of the state of the art but does not define the state of the art. True it processes at a lower temperature but the Commissioner does not think that this fact alone is sufficient to justify that the present invention is inventive over the prior art.
The Opposer alleges that the temperature range of 30-45°C is not sufficiently supported to fulfill the requirements of Section 13(a). The Applicant did not successfully undermine this allegation. Their witness did not provide sufficient explanation for this and it seems that the patent is also invalid on the grounds of adequate support.
The Opposition is accepted and the patent is refused.
Back in 2015 the Commissioner invited the parties to submit their costs together with their summations.
Teva claimed expenses of 1,980,822 Shekels and backed this with an affidavit of oneof their in-house lawyers but no further evidence. Citing the cost request in IL 153109 Unipharm vs, Merck Sharp & Dohme from 2011, the Commissioner noted that where extraordinarily large costs are required, additional evidence is likewise required to substantiate the claim. He felt that in the circumstances he could only estimate costs by the principles laid out in IL 199389 Unipharm vs. Pfizer Products Inc. based on complexity, longevity, weight of evidence, etc. and decided that 300,000 shekels were appropriate.
The Opposer’s basic claims were that the effect of raising temperature of a saturated solution is to favour crystal growth over nucleation. This is indeed obvious, or at least it is obvious for someone wishing to achieve the precipitation of larger crystals to try raising the temperature – which is the standard that Dr Noam established for this type of thing.
We note that Opposers accused Applicants of being greedy. Pot? Kettle here…Two million shekels is a hell of a lot of money for what seems to be a fairly straightforward opposition. In this instance, the costs included outside legal counsel – Adin Liss, and also expert witness fees. TEVA could probably have handled both legal and technical expertise in-house, but despite that, it does seem a lot of money.