Why Protecting Patents in India is Giving Hard Time to Drug Patent Holders

Introduction

A lot has been discussed on the Novartis ruling indicating much higher standards of patentability under Indian law under section 3d. The ruling decided that any new form of known compound (in medicine) would be patentable only if there is enhanced ‘therapeutic efficacy’ over the known compound. Post Novartis ruling, a couple of patent revocation decisions at Intellectual Property Appellate Board (IPAB) ruled on section 3d giving precedent of Novartis. In addition, these decisions also seem to be setting higher standards of non-obviousness as compared to countries such as United States.

Case I: Fresenius Kabi Oncology Limited v. Glaxo Group Limited, decided in July 2013

a)     Case Facts:

Fresenius Kabi filed a revocation petition against Glaxo’s patent IN221171 (referred to us ‘171 hereinafter) claiming di-tosylate salts of Lapatinib on grounds of obviousness, section 3d and section 8. Fresenius alleged that the ‘171 patent was obvious to a person skilled in the art with reasonable expectation of success in view of the combined teachings of  D1  read along with D2 to D4.  D1 was a basic product patent of Glaxo (IN221017) disclosing Lapatinib free base and its various salts. Amongst salts, hydrochloride (HCl) salts were the ones selected and exemplified, however D1 also disclosed ditosylate salts as one example. Furthermore, background section of D1 discussed problems of hygroscopicity and instabity of HCl salts.  D2 was a prior patent disclosing ditosylate salts of different compounds disclosing the problems solved by the ditosylate salts such as better moisture sorption and better stability. D3 and D4 were general prior art literature articles disclosing pharmaceutical salts and selection of salts for basic drugs. Fresenius also alleged that the ditosylate salts of the said patent are new forms of known HCl salts of Lapatinib showing no enhancement in therapeutic efficacy and hence not patentable under section 3d as well. b)     Decision:  i. On Obviousness: IPAB, first of all, reinforced that under Indian law, it is the “person skilled in the art” (referred to as Ms. P. SITA) who would decide obviousness of the invention, rather than person having ordinary skill in the art as in United States and other geographies. It was held that Ms. P.SITA was not a dumb person who was ignorant of happenings in her field of art, but had skill to perform experiments with the knowledge of state of the art. It would be obvious for Ms. SITA to solve the problem of hygroscopicity and instability by combined teachings of D1 to D4. She already knew the problems being faced with HCl salts and the said prior art would give her motivation to prepare the ditosylate salts to arrive at the invention of the ‘171 patent with reasonable expectation of success. ii. On Section 3d: Citing precedent of Novartis ruling, it was held that the salts were shown not to have enhanced ‘therapeutic efficacy’. Better stability, better moisture sorption properties and other physicochemical properties exhibited by di-tosylate salts were rejected as proof of better ‘therapeutic efficacy’ over known HCl salts. Note: Fresenius also filed another patent revocation application against the basic product patent IN221017 claiming Lapatinib, which was dismissed by IPAB. Case II: Ajanta Pharma Limited v. Allergan Inc., Allergan India Private Limited and The Controller of Patents and Designs, decided in August 2013  a) Case Facts: Two Revocation Petitions were filed by Ajanta Pharma against Allegan’s two patents, one claiming fixed dose combination of Timolol and Bimatoprost (IN212695, referred to as IN‘695 hereinafter) marketed as Ganfort® and the other claiming fixed dose combination of Brimonidine and Timolol (IN219504, referred to as IN‘504 hereinafter) marketed as Combigan®. Both drug combinations are for treatment of ocular hypertension. Both patents were revoked by IPAB on ground of obviousness and section 8.

b)Decision:

i.On obviousness:

· IN‘695 Patent:

IPAB held that it was obvious for Ms SITA to arrive at the fixed dose combination of Timolo and Bimatoprost for the treatment of ocular hypertension in view of the combined teachings of known serial (five minute gap) administration of these two drugs further in view of Diestelhorst M. et al disclosing fixed dose combination of Latanoprost and TImolol for treatment of glaucoma, and two other prior art documents teaching better efficacy and potency of Bimatoprost over Latanoprost. Latanoprost was a predecessor of Bimatoprost, both belonging to the same class of Prostaglandin Analogs. The fixed dose combination of Latanoprost and TImolol was known to reduce side effects and increase potency to treat glaucoma as compared to individual drugs. IPAB rejected Allergan’s contentions that both drugs were structurally different or acted on different receptors. IPAB further rejected Allergan’s contentions of achieving unexpected effects of reduced side-effects and increased potency. Secondary considerations were not considered relevant in determining obviousness. IPAB held that Ms. P. SITA would find the drugs closely related and be motivated by teachings of Diestelhorst M. et al to produce fixed dose combination of Timolol and Bimatoprost with reasonable expectation of reduced side-effects and increased potency. She would know the trend going from monotherapy to adjunct therapy to fixed dose combination in order to optimize the convenience and the patient compliance. ·IN ‘504 Patent IPAB held that it was obvious for Ms. P.SITA to arrive at the fixed dose combination of Brimonidine and Timolol in view of the combined teachings of known topical administration of Brimonidine in combination with Timolol spaced 5 minutes further in view of Desantis disclosing fixed dose combination of Timolol and alpha 2 agonists. It was held that both Timolol and Brimonidine were commercially available. It was known that serial administration of Brimonidine and Timolol reduced intraocular pressure better than TImolol and Brimonidine alone. It was held that DeSantis expressly provided motivation for fixed combination to increase patience compliance.  It was held that when viewed under a proper standard, the evidence establishes a motivation to combine since it was common at that time to provide Brimonidine and Timolol sequentially and DeSantis taught fixed combination. IPAB also cited the US Court of Appeals judgement in respect of the US equivalent patent in Allergan Inc vs. Sandoz wherein the US equivalent patent was held invalid as obvious. Key take-aways:

a)Prepare to clear a higher bar: Ms. P Sita has more than ordinary skill

Obviousness standards in India are higher as compared to countries such as US, in such a manner that the skilled person in US is a “person having ordinary skill in the art”, called as PHOSITA whereas in India she is a “person skilled in the art” called as Ms. P.SITA. The level of skill of Ms. SITA looks to be higher than PHOSITA. IPAB, in above cases, cited Roche v Cipla wherein the judge highlighted in context of obviousness that Ms. P.SITA is a not a dumb person who is ignorant of happenings in her field of art, but has skill to perform experiments with the knowledge of state of the art.  Glaxo (the respondent in the above first case) cited various foreign decisions to show how obviousness is decided, who is the person Skilled in the Art, what is the Common General Knowledge and so on, however, IPAB citing Roche v. Cipla highlighted that observations made in foreign judgements would not be guiding factors. May be that is a reason that the US counterpart of the IN‘171 patent is a granted and unopposed patent whereas its Indian equivalent patent is held to be obvious and revoked. Not only US, even the corresponding EP granted patent passed EPO’s obviousness standards. Again for the combination therapy patents in India, as seen in the above Ajanta v. Allergan IPAB decision, standards of obviousness seem to be stricter. Both the patents of Allergan covering ophthalmic compositions were revoked. Ganfront®, for example, in US and EP is protected as EP and US patents, but here in India the patent is revoked. For combination therapy of A and B, if serial administration of A and B is known to alleviate the condition better than monotherapy and a fixed dose combination of A or B with C is known for alleviating the same condition, it seems that it will be difficult to pass the obviousness challenge in India, owing to Ms. P. SITA who would be knowing the happenings in her field and would know the trend going from monotherapy to adjunct therapy to fixed dose combination in order to optimize the convenience and the patient compliance. Furthermore, it seems that secondary considerations in India have not been considered relevant in India in determining non-obviousness. Unexpected effects are generally accepted in US as a means to rebut obviousness rejection. Thus, person skilled in the art in India is considered to be having more skill, more creative imagination as compared to the person having ordinary skill in the art in other important geographies such as US, and hence clearing obviousness challenge is tougher. For patent holders around the globe, to clear these higher standards of obviousness is becoming problematic. b)3d after Novartis: Physico-chemical properties are not enough This is clear that after Novartis case, salts (or other new forms) of known compounds would always be hit by section 3d unless enhancement of therapeutic efficacy is not proven. Physico-chemical properties would not be considered to impart therapeutic efficacy. The “therapeutic efficacy” test as laid down by Supreme Court (SC) in Novartis will be cited as precedent in all such cases. Again, patent holders around the globe would have hard time pursuing their salts (or other new forms) patent applications in India unless enhancement in therapeutic efficacy is proven. Considering that the pharmacophore remains the same in developing these new forms, proving enhancement in therapeutic efficacy would be very difficult. The enhancement in physico-chemical properties, which impart inventive step over the known compounds, would not generally be able to comply with “enhancement in efficacy” clause in section 3d till Novartis precedent prevails. Even though SC clearly laid down that physico-chemical properties such as increased stability, absorption, lower hygroscopicity etc. could not be said to enhanced therapeutic efficacy, regarding bioavailability, SC pointed that increased bioavailability may or may not lead to enhanced therapeutic properties and would be dependent on case to case basis. But again, proving enhanced bioavailability leading to enhanced therapeutic efficacy would be difficult. No matter how enhanced bioavailablity has helped the drug to perform better, the test relied by India is to prove therapeutic efficacy enhancement over the known compound.

The law of the land

The Indian Patent Office has been receiving criticism from the US and other developed countries for following such stricter standards of patentability in refusing applications and revoking patents. The intention behind section 3(d) and setting higher standards of obviousness is to prevent evergreening and frivolous pharmaceutical patents in India, so that the public access to medicines is ensured. Such provisions are necessary for protecting public interest and ensuring public access to medicines in developing countries like India. However, steps should be taken to ensure that genuine innovative inventions should not be rejected so that the right balance between patent protection and public access is maintained to further research and development of newer medicines.

About the Author: Meenakshi Khurana, Partner at Khurana and Khurana and can be reached at: meenakshi@khuranaandkhurana.com

Note: This Article was first published in a premier Managing IP magazine in March 2014 here

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Comments

  • Anil  On November 19, 2016 at 8:11 am

    suppose a known compound never gain the status of being drug (like it failed in pre clinical study and was scrapped ) in this case will new salt be patentable for new disease indication or same indication if there is therapeutic enhancement of efficacy . How the therapeutic efficacy will be determined as there was no efficacy established for known compound .

    • IIPRD  On November 22, 2016 at 7:10 am

      Dear Anil,

      Before answering your question(s), lets break-down the instant case into following scenarios and then look into each of them in agreement with various decisions provided in recent cases[1] –

      Premise: A known compound (say a compound named “XYZ”) never gained the status of being a drug as it failed in pre-clinical study and was scrapped. If inventor(s) (same or others) comes up with a new form of the drug “XYZ”, will it be patentable?

      For the present situation, we have assumed that when you refer to “a new salt form”, you would mean “a new form of a compound” as otherwise, in most cases, therapeutic efficacy for a compound and its salt form remains more or less constant except for changes in the physicochemical properties viz. solubility, hygroscopic nature, lipophilicity and the like and/or toxicological profile. With respect to current Indian Patent Regime, improvements in the physicochemical properties and/or toxicological profile are not considered within the meaning of “enhancement in therapeutic efficacy” (See decision in case of Gilead Pharmaset LLC (6087/DELNP/2005) – Sofosbuvir – Revoked on Jan 2015).

      The compound “XYZ” may have been scrapped due to either of the following reasons – (a) the compound “XYZ” lacks efficacy to elicit desired pharmacological effect or (b) the compound “XYZ” exhibits unacceptable side-effects despite exhibiting desired pharmacological effect.

      (1) Now let us first consider a situation as delineated in point (a) above viz. compound “XYZ” lacks desired therapeutic efficacy –

      Situation 1: The new form of compound “XYZ” exhibits utility in the same disease indication as that of compound “XYZ”, wherein the new form exhibits significant enhancement in the therapeutic efficacy – In this case, the new form of compound “XYZ” will be patentable over the compound “XYZ” as new form exhibits significant enhancement in the therapeutic efficacy, provided that such enhancement in therapeutic efficacy is shown by way of comparative studies in the patent application.

      Situation 2: The new form of compound “XYZ” exhibits utility in a different disease indication as compared to that of compound “XYZ” – In this case, the question on patentability of new form of the compound “XYZ” will be more complex as it hinges on the critical question – whether the new form of compound “XYZ” falls within the purview of “known compound”. In case applicant/patentee establishes that “new form of compound XYZ” is not an “already known compound”, new form of compound “XYZ” will be patentable. However, in case the new form of compound “XYZ” falls within the purview of “known compound”, it renders the new form unpatentable over the known compound “XYZ” as it comes under the ambit of section 3(d) which states that new indication or new use of an already known compound is not patentable (emphasis added, it does not matter if a compound has acquired the status of “a drug” or not).

      (2) In case of the latter situation, as delineated in point (b) above, viz. the compound “XYZ” exhibits unacceptable side-effects despite retaining desired pharmacological effect as that of the parent compound –

      Situation 1: The new form of compound “XYZ” exhibits utility in the same disease indication as that of compound “XYZ”, wherein the new form exhibits significant reduction in the side-effect while retaining desired therapeutic efficacy – In this case, the new form of compound “XYZ” will not be patentable over the compound “XYZ”, as improvement in toxicological profile is not considered within the meaning of “enhancement in therapeutic efficacy” according to current Indian Patent Regime.

      (3) How the therapeutic efficacy will be determined as there was no efficacy established for known compound?

      A comparative study depicting pharmacological activity (therapeutic efficacy) of the known compound vis-à-vis new form of the compound would be of paramount importance in establishing a prima facie case for patentability of the new form of compound.

      Please note that although the above discussion holds true in generality, the same should not be construed as a rule of thumb as each case is decided on its merits.

      Please refer to following decisions –

      Novartis AG (1602/MAS/1998) – Imatinib mesylate (Glivec) – Revoked on April 2013

      Abraxis Biosciences (4572/CHENP/2006) – Abraxane – Revoked on June 2015

      Boehringer Ingleheim (558/DELNP/2003, granted patent No. IN254813) – Crystalline tiotropium bromide monohydrate salt (Spiriva) – Revoked on March 2015

      Hoffmann La Roche (959/MAS/1995, granted patent No. IN207232) – Valganciclovir – Revoked on Jan 2014

      Gilead Pharmaset LLC (6087/DELNP/2005) – Sofosbuvir (sovaldi) – Revoked on Jan 2015

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