Sunday, January 9, 2011

Application IN/PCT/2002/410/CHE refused under S.25 (1)

In a decision dated December 02, 2010, the Chennai Patent Office refused issuance of patent against the Application Number IN/PCT/2002/410/CHE filed by Bayer Schering Pharma AG claiming contraceptive combination formulation of drosperinone and ethinylestradiol (EE) marketed as Yasmin and Yaz/Yasminelle in Europe and the US. The Assistant Controller, Dr. S.P. Subramaniyan refused the Application after Bayer failed to defend the Application in pre-grant oppositions filed by generic manufacturers Cipla Ltd. and Natco Pharma Ltd.

This is one of the rare decisions by the Patent Office that have heavy reliance on strong technical arguments though most of the arguments and counter-arguments got merely borrowed from the CAFC decision in Bayer Schering Pharma, AG v. Barr Laboratories, Inc. The decision seems to be silent affirmation to KSR ‘obvious-to-try’ test of ‘choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success’ that will significantly raise the bar of patentability in India. The impact of the decision may be more far-reaching and will allow patent examiners to have more freedom to reject claims on the grounds of obviousness. Although the full ramifications of this decision cannot be gauged at this moment but patent practitioners should be aware of challenges lying ahead.

Drospirenone is a contraceptive agent susceptible to isomerization upon exposure to an acidic environment and exhibit poor solubility. The Application at issue is directed to overcome isomerization and solubility problems by adopting two commonly employed formulation techniques to increase the bioavailability of drosperinone in vivo: “enteric coating” and “micronization”. Customarily, an enteric coating protects a drug agent from being isomerized by stomach acid, and releases the compound when it has passed into the less acidic duodenum and small intestine whereas micronization decreases the particle size of a compound, thereby increasing the bioavailability of the compound in vivo. Nevertheless, the formulation of drospirenone continued to remain a problem because use of enteric coating reduced drospirenone’s exhibited bioavailability, which was not desirable for a single dose concentration. As a result, Bayer from 1983-88 continued to study enteric-coated formulations of drosperinone.

At the same time, Bayer had been working with structurally related compound, spirorenone, technically a metabolic precursor of drospirenone. Dr. Werner Krause, a scientist working at Bayer, performed in vivo studies with spirorenone which he published in three articles. These studies, Krause I, II and III, confirmed two key findings: (1) spirorenone absorbed in vivo before it becomes isomerized, and (2) drospirenone is a metabolite of spirorenone. However, Dr. Johannes Tack, a Bayer scientist working on drospirenone decided that Krause in vivo studies gathered little information on the practice of drospirenone in vivo. Tack tested the stability of drospirenone in vitro and found that after 10 minutes, 21% of the drosperinone had isomerized in the acid, and after 45 minutes, half had isomerized. He concluded that

“if the in vitro results are applied to in vivo conditions, it can be presumed that, with an assumed gastric juice volume of 100ml, the majority of dose (solubility of drospirenone 5-10 mg/l) passes into solution during passage through the stomach and consequently undergoes rapid isomerization. A clear reduction in the bioavailability of the unchanged active substance is to be expected as a result.

The planned studies on the progestogenic efficacy of [drospirenone] should therefore be performed with an enteric-coated formulation.”
Following above conclusion, Tack began clinical studies with an enteric-coated formulation of drospirenone and even after 5 years of extensive studies reconfirmed that drospirenone needed an enteric coating because it isomerized quickly in vitro. In 1998, Bayer conducted a study to compared the effectiveness of enteric-coated tablet to an intravenous injection of same formulation and added a “non-routine” element i.e., unprotected (normal) drospirenone tablet – and fully expected to find that the enteric-coated tablet would produce a lower bioavailability than an intravenous injection, while the normal tablet would produce an even lower bioavailability than the enteric-coated tablet. Unexpectedly, they found that the normal tablet and the enteric-coated tablet resulted in the same bioavailability. The finding led Bayer to develop drospirenone in a normal tablet rather than an enteric-coated tablet, upon which the Application at issue is based.

Cipla and Natco separately filed the pre-grant oppositions appealing refusal of the Application under S.25 (1), particularly on the grounds of lack of novelty and inventive-step and not patentable subject-matter under S.3 (d). The Application is equivalent of US6787531 which got invalidated by Barr Laboratories in the District Court and later affirmed by the CAFC.

During the pre-grant opposition proceedings, Cipla argued that the claims at issue are not novel because the prior art documents suggest combination of EE and micronized drospirenone. Responding to Cipla’s not novel argument, Bayer tried to distinguish the claims at issue over the prior art documents and argued that none of the prior art documents suggest drospirenone in micronized form, hence is novel. The Controller though agreed with Bayer’s argument that micronized drospirenone distinguish over the prior art but held that
“Physical form cannot be considered for assessing novelty of any given substance, because there is improvement only in physical properties such as solubility, particle surface area etc., but the activity of said substance remains the same.”
Finding the use of micronized drospirenone not novel, he held that
“It may be convenient to manufacture the composition as a medicament in dosage form and improved dissolution with such a physical form i.e., micronized (smaller particle size), but it cannot be considered as novel since the substance is already known in other form i.e., large particle size. Making smaller particle size from larger particle or any other such form may give many advantages, which are considered as discovery but not considered to be a novel substance, because the active substance remains same whereas the change is only in the nature/appearance of the substance.”
He further held that
“Novelty should reside in the compound itself but not in the physical form of the compound.”
Substantiating his above findings, the Controller stated
“sea salt and powdered sea salt are one and the same but there is a difference in the crystalline size. The powder salt is convenient in many ways but it is not a different matter with respect to sea salt and it is considered to be other form of the matter. In both cases chemical substance is same.”
Satisfied with his finding, the Controller concluded that changing the particle size for better physical property is mere change in the physical form, and hence claims at issue is not novel. Generally all across the globe, the novelty of a claim is judged by the fact that all recited (essential) elements of an independent claim must not be anticipated by the cited prior art. Going by the Controller’s judgment no polymorph would be considered novel as it is mere change of the physical form.

Cipla and Natco further argued that the claims at issue are not inventive because use of micronization technique for improving bioavailability is obvious to a person skilled in the art. Cipla’s obviousness arguments were based on studies published by Krause I, II and III and more or less similar to that of arguments made by Barr in Bayer Schering Pharma AG v. Barr Laboratories LtdMajorily borrowing from Barr arguments, Cipla too argued that drospirenone and spirorenone are structurally similar compounds, and spirorenone is absorbed in vivo before it becomes isomerized from which one can foresee that there is no problem of isomerization of drospirenone under acidic conditions as the process of absorption is much faster than isomerization. Responding to Cipla’s obviousness argument, Bayer argued that the Krause papers only described the behavior of spirorenone in the gastrointestinal tract not of drospirenone and also argued the problems faced with drospirenone formulation because of which one of ordinary skill in the art would not expect the normal drospirenone tablet would be absorbed in vivo without being isomerized. Bayer submitted documents supporting its position that the formulation taught in the Application was surprising and unexpected. Bayer claimed that it was not obvious for drospirenone to be micronized to increase its bioavailability without the need of enteric coating to protect drospirenone from acid isomerization. The Controller though agreed with Bayer’s argument that the Krause study was related to spirorenone but still held the claims at issue obvious over Krause I and III which again was more and less influenced from the decision of the CAFC.

Cipla also argued that claims at issue are not patentable under S.3 (d) because drospirenone is metabolite of spirorenone and micronization of drospirenone should be considered as the same substance. Cipla further argued that the combination of EE and drospirenone is mere admixture and not patentable under S.3 (e). Agreeing with Cipla’s argument, the Controller concluded that the micronized form a known metabolite is not patentable under S.3 (d) and combination of EE and drospirenone is a mere admixture and not patentable under S.3 (e). Going by the Controller's judgment all pharmaceutical compositions are likely not patentable under S.3 (d) and would be taken as mere admixture under S.3 (e).

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