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Part II: Novartis feels the heat of the Indian Summer. What is the fate of similar applications filed by Indian Manufacturers?


Following the concerns raised over allegations of lack of uniform standards of the Indian Patent Office in part I of this post series, this post attempts to put forth details of the various patent applications made by Indian companies (claiming patent for variants of imatinib mesylate). The aim is to get readers familiar with this area to comment on the possible outcome of these applications given the rigorous Section 3(d) standards as introduced applied in the Novartis case.



To reiterate, there are several patent applications by domestic pharmaceutical companies relating to different forms of imatinib mesylate pending before the Indian Patent Office. The concern is whether the Patent Office will apply the rigorous standards it applied in Novartis’s case to the applications made by the Indian companies.

A blog post on the IAM blog puts forth the concerns which arise from differential treatment are clearly outlined as follows:

“The Indian authorities need to make sure that they act and, crucially, that they are seen to act, as disinterested participants in the patenting process. Any reputation for partiality would cause a lot of potential inward investors a lot of trouble.”

The list of the Indian applications and brief details of the same is provided below, please note that the italicized text relates to specific definitions or improvements that are claimed by the applicant in the patent application. As stated in the earlier post, the fate of none of these applications is traceable. It would be interesting if our readers could comment on the possible outcome of these applications against the ‘efficacy’ requirement of Section 3(d) of the Indian Patent Act as interpreted by the Madras High Court and the Indian Patent Office in Novartis’s case.

1. Application no. 500/CHE/2004 (dated 02/06/2004) filed by Hetero Drugs Ltd. for novel polymorphs of imatinib mesylate.

The claimed invention is defined as follows:

The invention relates to novel polymorphs of imatinib mesylate, to processes for their preparation and to pharmaceutical compositions containing them.

The background of the invention is as follows:

“Imatinib and its salts are anti-tumor agents, which were disclosed in US 5,521, 184. Two crystalline modifications (a-form and (3-form) of imatinib mesylate were mentioned in WO 99/03854. WO 99/03854 mentioned amorphous imatinib mesylate, but it did not make any reference to hydrate of imatinib mesylate….

We have discovered a stable novel crystalline form of imatinib mesylate. The novel form is at least as stable as the reported forms, a-and p-forms. The novel crystalline form is stable over the time and has good flow properties and so, the novel crystalline form is suitable for formulating imatinib mesylate…

Amorphous forms of pharmaceutical products are usually known to have better dissolution properties than their crystalline forms. If amorphous form of a pharmaceutical product is stable enough, it can be formulated to a pharmaceutical composition having good dissolution properties.

We have discovered hydrate of imatinib mesylate. We have also discovered a sufficiently stable non-hygroscopic amorphous form of imatinib mesylate hydrate. So, amorphous form of imatinib mesylate hydrate can be utilized to prepare stable pharmaceutical dosage forms having good dissolution properties.”

Spicy IP dealt with Hetero’s patent application in an earlier post relating to analyzing the possibility of solving the problem of ‘access’ to medicines by inventing around granted patents.

2. Application no. 105/CHE/2004 (dated 11/02/2004) filed by Natco Pharma Ltd. for a polymorphic form of imatinib mesylate.

The claimed invention is defined as follows:

“The invention relates to improved processes for the preparation of imatinib mesylagte, beta form suitable for industrial operations. This stable a2 form of imatinib Mesylate is not hither to known and is a novel polymorphic form. This form prepared by us now is also suitable for developing a pharmaceutical composition. Such a pharmaceutical composition containing a2 form is also not known and is novel.

The main objective of the present invention is to provide a novel au crystalline form of Imatinib Mesylate which is stable at room temperature and even at higher temperatures like 120°C and accelerated stress conditions, freely soluble in water… Another objective of the present invention is to provide a process for the preparation of novel a2 form of Imatinib Mesylate which is stable and less hygroscopic and water soluble… Yet another objective of the present invention is to provide a pharmaceutical composition useful for the treatment of Chronic Myeloid Leukemia containing the novel aa form of Imatinib Mesylate which is stable and less hygroscopic and water soluble …. Still another objective of the present invention is to provide an improved process for the preparation of P-polymorphic Imatinib mesylate.

Accordingly, the present invention provides a novel a2 crystalline form of Imatinib Mesylate which is stable at room temperature and even at higher temperatures upto 120°C and accelerated stress conditions, freely soluble in water having the XRD characteristics ….”

3. Application no. 1188/MUM/2004 (dated 04/11/2004) filed by Sun Pharmaceutical Industries Ltd. for a crystal form of imatinib mesylate and process for preparation thereof.

The abstract of the claimed invention reads as follows:

“The present invention provides crystalline imatinib mesylate in a non-needle shaped a-crystalline form. In one aspect the present invention provides crystalline form of imatinib mesylate, characterized in that the difference between the tapped and untapped density is less than 0.15 gm/ml. The present invention also provides a novel, simple viable process for preparation of crystalline imatinib mesylate.”

The background of the invention reads as follows:

“United States Patent No. 5521184 discloses N-phenyl-2-pyrimidine amine compounds including the compound of formula 1.

United States Patent No. 6894051 (equivalent of WO 99/03854) discloses that the methanesulfonic acid addition salt of imatinib (imatinib mesylate) can exist in needle – shaped α-crystalline form or non-needle-shaped β-crystalline form. It is reported that the α-crystalline form of imatinib mesylate is characterized by needle-shaped crystals, is hygroscopic and not particularly well suited to pharmaceutical formulation as solid dosage forms because of its physical properties, for example its flow characteristics are unfavourable. The patent application discloses a method for preparation of the α-crystalline form of imatinib mesylate wherein a hot solution of imatinib mesylate in aqueous ethanol is cooled. However, we have found that this process for preparation of the α-crystalline form is inconsistent, non-reproducible…

We have found surprising results when we prepared crystalline imatinib mesylate by the process of thin film drying. We found that the process resulted in a crystalline imatinib mesylate in a non-needle shaped form. The process resulted in a crystalline form that has a bulk density, which is relatively insensitive to tapping and which is non-hygroscopic. This crystalline imatinib mesylate is easy to handle and convenient to process into a dosage forms, for example it can be conveniently formulated and processed into tablets by dry granulation and direct compression methods.

We have also found a process for preparation of imatinib mesyalte in α-crystalline form in a reproducible manner, which is convenient for industrial use to provide α-crystalline form of imatinib mesylate reproducibly.”

4. Application no. 1209/MUM/2003 (dated 24/11/2003) filed by Sun Pharmaceutical Industries Ltd. for a substantially amorphous form of an anticancer agent, commonly known as imatinib mesylate and process for preparation thereof.



5. Application no. 4745/KOLNP/2007 (dated 06/12/2007) filed by Elan Pharma International Ltd. for nanoparticulate imatinib mesylate formulations, or a salt or derivative thereof, having improved pharmacokinetic profiles and reduced fed/fasted variability.

In the application, the claimed invention is defined as follows:

“The present invention is directed to a nanoparticulate compositions of imatinib mesylate, or a salt or derivative thereof, having improved pharmacokinetic profiles and reduced fed/fasted variability. The nanoparticulate imatinib mesylate particles of the composition have an effective average particle size of less than about 2000 nm and are useful in the treatment of chronic myeloid leukemia, gastrointestinal stromal tumors and related diseases.”

In brief the benefit of this form of imatinib mesylate formulations is that, “Imatinib mesylate has high therapeutic value in the treatment of chronic myeloid leukemia, gastrointestinal stromal tumors, and related diseases. However, because conventional, non-nanoparticulate imatinib mesylate tablets are only very slightly soluble in water at 370C, the dissolution of conventional imatinib mesylate tablets is reduced in the fasting state as compared to the fed state. Thus, imatinib mesylate has limited bioavailability in the fasting state as compared to the fed state, which limits the therapeutic outcome for all treatments requiring imatinib mesylate. There is a need in the art for imatinib mesylate formulations which overcome the fed/fasted absorption variability, along with other problems, observed with conventional imatinib mesylate dosage forms. The present invention, which overcomes such problems, relates to a nanoparticulate composition comprising imatinib mesylate, or a salt or derivative thereof for the treatment of chronic myeloid leukemia, gastrointestinal stromal tumors and related diseases.”

Snippets of the summary of the application are as follows:

“The compositions disclosed herein typically include nanoparticulate imatinib mesylate, or a salt or derivative thereof, having an effective average particle size of less than about 2000 nm and at least one surface stabilizer. The surface stabilizer is typically adsorbed on or associated with the surface of the nanoparticulate imatinib mesylate particles. Optionally, the compositions may include a pharmaceutically acceptable carrier and any suitable excipients….

..One embodiment of the invention encompasses a nanoparticulate imatinib mesylate composition, wherein the pharmacokinetic profile of the nanoparticulate imatinib mesylate is not affected by the fed or fasted state of a subject ingesting the composition.

In yet another embodiment, the invention encompasses a nanoparticulate imatinib mesylate composition, wherein administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state….”

6. Application no. 951/MUM/2004 (dated 02/09/2004) filed by M/S. Cipla Ltd. for a stable crystal form of imatinib mesylate and process for the preparation thereof.

In the application, the abstract reads as follows:

“The invention relates to a stable, non hygroscopic alpha crystalline form of methane sulfonic acid addition salt of 4-(4-methyl piperazin-lyl methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidin-2-yl amino) phenyl]-benzamide (imatinib mesylate). A process for the preparation of the crystalline form is also described.”

The background of the invention is as follows:

“Imatinib is the international non-proprietary name of 4-(4-methylpiperazin-l-yl methyl)-N-[4- methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide. Imatinib is currently used for the treatment of patients with certain types of leukaemia (most commonly chronic myeloid leukaemia) and a rare type of cancer known as gastro-intestinal stromal tumour (GIST).

EP564409 and US5521 184 first reported a process for preparation of 4-(4-methylpiperazin-l-yl methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidin-2-yl amino) phenyl] benzamide of formula I and the use thereof, especially as an anti-tumor agent. However, it does not specify any crystal modifications. Patent Application WO 99/03854 disclosed two polymorphic forms of Methane sulfonic acid addition salt of imatinib (Imatinib Mesylate) viz: an (α) Alpha crystal form and a (β) Beta crystal form and the processes for their preparation. The process for the preparation of the alpha crystalline form comprises suspending imatinib base in ethanol, adding methane sulfonic acid dropwise to the said solution, heating the solution to reflux and filtering; evaporating the filtrate to 50 %, filtering off the residue; evaporating the mother liquor to dryness; suspending the residue and filtered material in ethanol; dissolving under reflux conditions by simultaneously adding water; cooling overnight, filtering and drying to obtain alpha crystalline form. The obtained alpha-crystalline form is not stable, is highly hygroscopic, is amorphous in nature and not useful for the preparation of pharmaceutical preparations.

The previously known method for producing the alpha-crystal form of methane sulfonic acid addition salt of the compound of formula (I) involves the precipitation of the salt from its solution in non-alcoholic solvents. It has also been acknowledged in the prior art that the α-crystal form obtained by such a process was inconsistent and hence had an undesirable property such as hygroscopic nature and unfavourable flow characteristics. It was thus an unstable crystal form and unsuited for pharmaceutical preparations.

The known process for preparing the beta-crystal form involves use of an alcoholic solvent such as methanol or ethanol, or a mixture of acetone and water or dimethyl formamide and crystallization is induced by seeding.

The summary of the invention is produced below:

“The present invention relates to a crystalline form of methanesulfonic acid addition salt of 4-(4- methylpiperazin-lylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)-pyrimidin-2-ylaminophenyl]- benzamide (imatinib mesylate). More specifically, the invention relates to the alpha crystalline form of imatinib mesylate. It is important to understand that the crystalline polymorphic form of imatinib mesylate according to the invention not the same material as is described in WO 99/03854. The alpha imatinib mesylate described in WO 99/03854 is not a stable compound, whereas the alpha imatinib mesylate according to the invention is stable.

The term “stable” as used in this specification preferably means that the imatinib mesylate retains polymorphic or chemical stability for at least three months, more preferably for at least six months, and most preferably for at least twelve months. More preferably, the term “stable” as used in this specification preferably means that the imatinib mesylate retains polymorphic and chemical stability for at least three months, more preferably for at least six months, and most preferably for at least twelve months.

The invention also relates to a process for the preparation of said crystalline form of imatinib mesylate. The process according to the invention makes it possible to produce a crystalline form of methanesulfonic acid addition salt of imatinib in a form which is stable and non-hygroscopic. We have found that the stable, non-hygroscopic crystalline form of methanesulfonic acid addition salt of imatinib has needle shaped crystals. The stable, non-hygroscopic crystalline form of methanesulfonic acid addition salt of imatinib can be produced in an essentially pure crystal form.

Thus, the invention relates to a process for preparing the alpha-crystalline form of methanesulfonic acid addition salt of imatinib and also to a stable, non-hygroscopic form of the salt itself. This salt is very suitable for the preparation of pharmaceutical formulations.”

It would be great if our readers could get back with their feedback on the possible fate of these applications in light of the Novartis standards.

4 comments.

  1. AvatarHarry

    Wow. In a purely hypothetical scenario, if all these patents were granted and co-existed simultaneously with a granted Novartis patent there would potentially be no monopoly on imatinib mesylate and consequently no controversy about access.

    On the assumption that all these variants of imatinib mesylate are novel and “inventive” then it suggests that Indian companies still have a lot of scope for “inventing around” both product and process patents – supporting Shamnad’s view in an earlier post.

    Harry Thangaraj

    Reply
  2. Avatarmnbvcxzaq1

    harry,
    without adverting to other issues, let me address one issue i feel strongly about. i would totally disagree with you where you observe that “Indian companies still have a lot of scope for “inventing around” both product and process patents”. there lies a great indian fallacy in the mindset of the indian pharma companies. most of them have become primarily “inventing around” comapnies, in quite contrast to “inventing” companies. this relative lack of original r&d (esp. in NME/NCE) will always keep indians on the margins of the world pharma scene. we’ll never be big players. that is why, i am strongly opposed to the “inventing around” as the primary strategy; at the most, it should be a secondary focus-area. i just wish, indian companies heeded to this advice regarding re-focussing of their vision!

    Reply
  3. AvatarHarry

    Dear mnbvcxzaq1

    I am eyeing this from a different angle. I hope that a lot of “inventing around” will give patients in India and the rest of the developing world affordable access to key pharmaceuticals.

    Please allow me to also put forward some personal views. Inventing around is a highly innovative activity on its own. However I agree with you that merely focusing on “inventing around” as a primary strategy will not allow India to enter into the world pharma championship league.

    I do however see a fair number of patents by Indian pharmaceutical companies for new chemical entities filed via the PCT route. I suspect there are many more such patents filed initially or solely at the Indian Patent Office. But as you know IP researchers such as myself based outside India cannot easily access such information to comment further. Let us hope Shamnad’s recent petition will help address this.

    Secondly the product patent regime in India is still fairly recent in historical terms. It may be too early to evaluate whether India is making, or will make, full use of its R&D potential.

    Cheers

    Harry Thangaraj

    Reply
  4. Avatarmnbvcxzaq1

    dear harry,
    i agree with ur latest comments. i had put in my last comment only to highlight a thing about which i am really concerned/pained – that India is ‘not innovating enough’, primarily because indian companies’ primary focus seems to be on peripheral inventions, i.e. ‘inventing around’. i am not denying the importance of ‘inventing around’, but indian companies are according unduly high weightage to ‘inventing around’ r&d, instead of the ‘inventing’ r&d. no doubt that indian companies have a resource crunch (compared to MNCs), but still, that is not sufficient ground for not making the ‘original innovation’ the primary focus. if we are ‘inventing’ new products, then the ‘inventing around’ products will automatically follow as by-products/offshoots thereof.
    tc

    Reply

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