Wednesday, January 19, 2011

Application 4015/DELNP/2006 refused under S.15

In an order dated January 10, 2011, the Delhi Patent Office refused the Application No. 4015/DELNP/2006 filed by Warner-Lambert claiming topical formulation of Pfizer’s potential potassium channel opener UK-157147 for the treatment of alopecia but got discontinued in phase II trials. The Assistant Controller, Dr. Rajesh Dixit, refused the Application after Warner failed to overcome the substantive objections raised in the First and Subsequent examination reports concerning lack of inventive step and not patentable subject-matter under S.3 (d) and (e).

While replying to the examination reports, the Applicant tried to substantiate the inventive step in terms of selection of UK-157147 from thousands of potassium channel openers disclosed in the closest prior art document, and selection of alopecia treatment from the list of twenty different diseases (reach through clause) mentioned in the closest prior document. Over S.3 (d) and (e) objections, the Applicant argued that the claims relate to pharmaceutical formulation and is neither a mere new form of a known substance under S.3 (d) nor a mere admixture under S.3 (e). The Controller was nowhere satisfied with the Applicant’s arguments and concluded that the claims lack inventive step over the closed prior art document and the formulation are merely a new form of the known substance and lack synergy.

It is quite unforunate that the pharmaceutical formulations are often refused under S.3 (d) and (e), considering use of pharmaceutically acceptable ingredients as combination and admixture with active ingredients. Formulations facilitate delivery of therapeutic agents and are responsible for achieving proper therapeutic effects that cannot be obtained from its component when used individually. Equating formulations with new form of known substance (putting in category of polymorph, salt, complex etc.) seems to be improper and unfair.

Monday, January 17, 2011

Application 924/DELNP/2006 refused under S.15

In an order dated January 12, 2011, the Delhi Patent Office refused the Application Number 924/DELNP/2006 filed by Boehringer Ingelheim claiming polymorphic form II of anticoagulant drug Dabigatran etexilate mesylate. The Assistant Controller, Dr. Rajesh Dixit, refused the Application after Boehringer failed to overcome the substantive objections raised in the First and Subsequent Examination Reports concerning lack of inventive step under S.2 (1) (j) and not patentable under S.3 (d).

While replying to the examination reports, the Applicant tried to substantiate the inventive step in terms of better solubility and argued that the cited prior art documents provide no hint that mesylate salt have better solubility and exists in different polymorphic modifications. The Applicant further argued that better the solubility of the compound the higher is its bioavailability, which, as direct consequence, translates to a higher efficacy as required by S.3 (d). However, the Applicant failed to submit to validate its bioavailability presumption. Moreover, in its post hearing reply the Applicant argued that to prove enhanced efficacy a clinical trial in human beings would be required and for which regulatory approval is needed. The Applicant further argued that such a regulatory permission would hardly be granted just to prove efficacy under S.3 (d). The Controller was nowhere persuaded by the Applicant’s arguments and concluded that the claims lack inventive step and fail to meet efficacy requirement under S.3 (d).

Wednesday, January 12, 2011

Application 925/CHE/2003 refused under S.15

In an order dated January 10, 2011, the Chennai Patent Office refused the Application Number 925/CHE/2003 filed by Novartis claiming mixture of anti-oxidant with oxidation sensitive macrolide everolimus. The Application is divisional of the parent application number IN/PCT/2001/783/CHE which matured into issued Patent Number IN202379. The Assistant Controller, Dr. S.P. Subramaniyan, refused the Application after Novartis failed to overcome the substantive objections raised in the First Examination Report (FER) particularly concerning prior claiming and conflict with claims of the ‘379 patent.

While replying to the FER, Novartis deleted all claims of the Application and filed a single amended claim which the Controller found to be conflicting with the claims of the ‘379 patent and hence concluded not allowable under S.10 (5) of the Act. The Controller also held that the subject-matter of the Application and the ‘379 patent are one and the same and thus, divisional status not allowable under S.16 of the Act.

Monday, January 10, 2011

IN212199 revoked under S.25 (2)

In a decision dated December 15, 2010, the Indian Patent Office revoked the Patent Number IN212199 issued to Novartis claiming single-pill combination of aliskiren and valsartan, marketed as Valturna. The Assistant Controller, B. Ahilan, revoked the patent after Novartis failed to defend the patent in a post-grant opposition filed by Sun Pharmaceuticals Ltd. The patent was issued on November 26, 2007 against the Application Number 724/CHENP/2003.

Aliskiren is the first in the class of orally effective direct renin inhibitors approved for the treatment of primary hypertension and marketed by Novartis under the brand name Tektuma. In contrast to conventional RAS blockers (ACE inhibitor and ARB), aliskiren blocks renin system by directly inhibiting plasma renin activity and preventing the formation of both angiotensin I and angiotensin II. Since aliskiren promising clinical results, Novartis began clinical studies on aliskiren combination with other hypertensive agents that included ACE inhibitors (enalapril, amlodipine and ramipril) and ARBs (valsartan and losartan) and HCTZ. The aliskiren-valsartan combination study yielded greater blood pressure reductions than either monotherapy or placebo, upon which the patent at issue is based.

Sun Pharmaceuticals filed the post-grant opposition appealing revocation of the patent under S.25 (2), particularly on the grounds of lack of inventive step, insufficient disclosure/lack of best method, not an invention and non-patentable under the Act.

During the post-grant opposition, Novartis proposed to amend the claims having narrowed scope than the issued claims which the Controller agreed and instructed that arguments will be made on the proposed claims. Sun argued that the specification disclosure lack enablement and best method requirements because none of examples exemplified the compositions of amended claims. Sun further argued that use of generic name ‘aliskiren’ in amended claim is not supported by the description. The Controller agreed with Sun’s arguments that amended claims lack enablement and best method requirements under S.10 (4) (a) and (b), also agreed that despite the compound represent by formula I of amended claim is aliskiren but use of generic name ‘aliskiren’ is not explicitly mentioned in the specification disclosure. He therefore concluded that the specification lack sufficiency of disclosure and best method requirements.

Sun further argued that amended claims are obvious because prior art documents described aliskiren a highly specific and potent for human renin (referred as D5) and also provided synergetic compositions comprising at least two therapeutic agents selected from the group consisting of a renin inhibitor, an ACE inhibitor and an angiotensin II antagonist (referred as D2). Responding to Sun’s obviousness arguments, Novartis tried to distinguish amended claims over the prior art documents and argued that renin inhibitor described in D2 is terlakiren and not relevant to amended claims. Considering D2 (combination of renin inhibitor with ACE inhibitor or AT1 antagonist) and D5 (aliskiren a highly potent renin inhibitor), the Controller held that the amended claims was obvious to try and lack inventive step.

Sun also argued that amended claims are not patentable under S.3 (d) because enhanced efficacy is not demonstrated over the prior art document D2. Agreeing with Sun’s arguments, the Controller concluded that amended claims are not patentable under S.3 (d).

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).

Thursday, January 6, 2011

Application No.1770/DELNP/2006 rejected under S.15

In an order dated Dec. 24, 2010, the Delhi Patent Office rejected National Phase Application No. 1770/DELNP/2006 filed by US-based Biopharmaceutical Company Theravnce, Inc. claiming hydrochloride salt of Telavancin, a lipoglycopeptide antibacterial drug marketed as Vibativ for the treatment of adult patients with complicated skin and skin structure infections caused by susceptible Gram-positive bacteria. The Assistant Controller, Shah Alam, refused the Application after Theravnce failed to overcome the substantive objections raised in the First Examination Report (FER) concerning lack of novelty and inventive step under S.2 (1) (j) and non-patentable subject-matter under S.3 (d).

While replying to the FER, the Applicant tried to substantiate the novelty over the prior art in terms of chloride ion content and inventive step in terms of improved storage stability an ambient temperature but failed to provide any supporting data to validate stability argument. During the hearing under S.15, the Applicant further requested additional time to submit written arguments to support the inventive-step and validate efficacious arguments. However, the Applicant failed to submit any material data that can either support the inventive-step or validate efficacious arguments. Notably, the Applicant made very ridiculous argument against the applicability of S.3 (d) rejection. The Applicant stated that claimed substance (i.e., hydrochloride salt of known antibiotic Telavancin) is not a ‘known substance’ and hence does not fall under S.3 (d).