Chris’ post had me thinking that very often, when discussing pharmaceutical patents and the “access” issue in India, we tend to forget that pharma patent monopolies are restricted to what is “claimed” by the patentee. Depending on the pharma product and the technology in question, generic manufacturers may be able to cleverly work around a patent claim and thereby avoid infringement. As Mylan did in this case, by deploying “Talc” in its product and arguing that it wasn’t an “ARC” (an essential element of the patent claim by Astra Zeneca).
To this extent, the “access” issue (i.e. that a patent over a pharma product always results in excessively priced products and a market without competition) may not turn out to be as extreme as we expect. Let me illustrate this point with the help of the pending Novartis litigation in India. As our readers know from the several posts around this controversy, the facts are as below (copied from a recent article that we have written):
Glivec (Novartis) Patent Case
“Imatinib,” a free base, discovered in the early ’90’s was seen to have anti-cancer properties. In 1993, Novartis filed a patent covering this free base and all pharmaceutically acceptable salts. Imatinib was then further researched upon and improved – first, by converting it to a particular salt form, namely imatinib mesylate. From this salt, Novartis found that the most stable version was a particular polymorphic form, namely the beta crystalline form.
Novartis then formulated the beta crystalline form of imatinib mesylate into a pharmaceutically useful drug, Glivec, which was approved by the FDA in 2001.
In short, the various steps in this alleged invention can be encapsulated as under:
i) Synthesizing imatinib as its free base, a compound that was patented in the US, EU and several other countries. However, this could not be patented in India, owing to the fact that in 1993, India did not provide product patents for pharmaceutical substances.
ii) Converting the free base to a particular salt form, imatinib mesylate, by adding methanesulfonic acid.
iii) Crystallising the imatinib mesylate to obtain the beta crystalline form, which is allegedly the most stable polymorphic form of the salt. A patent application was filed for this and it is this application that is the subject matter of dispute.
iv) Formulating the beta crystalline form of imatinib mesylate into a pharmaceutically useful drug, Glivec.
Novartis claimed that the active ingredient in Glivec (beta crystalline form of imatinib mesylate) is more effective than the imatinib free base, since it displays better bio-availability properties, i.e. it is absorbed more easily into the blood. To this effect, it submitted evidence before the Assistant Controller demonstrating an increase in bio-availability of up to 30%. It also claimed that the beta form “stores better, is less hygroscopic, is easier to process and guarantees a constant quality of the final drug product.” (See Novartis AG v Union of India, writ petition filed by Novartis para 4).
The Indian patent office however did not agree with Novartis and rejected the patent application on a variety of grounds, including section 3(d). It held that Glivec was not significantly more efficacious than previously existing pharmaceutical substances and did not therefore meet with the requirements of section 3(d).
As SpicyIP has been reiterating, as to whether or not Glivec is patentable is a technical patentable issue that ought to be decided by the Indian courts. And the case should be permitted to run its course. Not least because the contours of section 3(d) are still far from certain and we need more clarity on it.
Let us assume (for the sake of this discussion) that the IPAB/courts overturn the patent office ruling and grant a patent in favour of Novartis. The question then arises:
How is this patent covering the “beta crystalline form of Imatinib Mesylate” likely to impact “access’ to this drug in India? Does the issue of the patent necessarily mean that there will no competitors in the market at all? And that the prices would therefore be exorbitant and unaffordable.
Cipla and Alpha Form of Imatinib Mesylate
What if a generic manufacturer such as Cipla “invents around” Novartis’ patent? In fact, a Mint report suggests that this might be the case i.e. Cipla has a drug that corresponds to the alpha crystalline form of Imatinib Mesylate. Note that the Novartis patent in issue is restricted to the “beta crystalline form” (both alpha and beta are different polymorphic forms of the same salt, Imatinib Mesylate). In particular, the news item notes:
“Although Novartis is yet to launch a brand of the alfa crystal form of this cancer drug in India, a local drug maker, Cipla Ltd, has been selling a generic version of the drug here the last couple of years.” The news item goes on to report that Cipla owns a process patent covering the alpha crystalline form.
Do any of our readers have more news of this alleged drug by Cipla that is based on the alpha crystalline form? I’m a little skeptical of this news, since Cipla could have introduced this drug at the time that it was injuncted by the Madras High Court in the EMR matter (prior to the Glivec patent rejection by the patent office, Novartis held a valid Exclusive Marketing Right over Glivec and injuncted several companies based on this). Cipla could have easily escaped the injunction order by relying on the non infringing alpah form (or perhaps it hadn’t come up with the alpha form at that stage?).
The same Mint piece also reports that Novartis itself has a pending patent application covering the alpha form in India and that this is currently being opposed by Okasa. If this patent issues, then (depending on the claims), Cipla may not be able to sell its alpha form. But if Novartis fails to procure a patent for the alpha version, then Cipla is free to manufacture a Glivec equivalent based on the alpha form.
Hetero and New Form of Imatinib Mesylate
Interestingly, Hetero has a patent application covering “novel polymorphic forms of Imatinib Mesylate” (not sure if this has issued as yet). In particular, the portion in their application covering the “background to their invention” states as below:
“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.”
Conclusion
In short, if a drug can be developed based on alternative forms of Imatinib Mesylate (forms other than the beta crystalline form), wouldn’t this temper the perceived “access’ issue that we all keep speaking about? Of course, this is not to say that the patent over the beta crystalline form ought to be granted (if it otherwise doesn’t deserve a patent). But only to demonstrate that even if granted, the possibility of “inventing around”/”working around” and generic substitutes may help buffer the “access” issue a bit.
What do our readers think?
One challenge in an invent-around case will be the drug registration requirement. I believe that in Chile Novartis attempted to block use of the un-patented version of imatinib mesylate by claiming it would require different safety and efficacy registration data.
I suppose the first hurdle in the event of an infringement suit would be overcoming doctrine of equivalence? if it is an attempt to invent around. if you do manage to show no equivalence, drug approval would definitely be an issue.
Besides, I think this might have implication on access, but its not something that would affirmatively facilitate access. it seems to be an argument a generic will put his head to only if there is litigation.
Hey Shamnad,
a) Novartis is going ahead with its application of the alpha form;
b) Sun has a polymorph application of its own.
c) I agree that a generic company could by-pass the beta form by using their own alternative forms.
But, being an industry insider, I can tell you that most companies merely use the technology and process disclosed in 1st US / EP filing for launching products in India.
Hence for them to change course mid-way and create a new formulation/ polymorph for India is not easily possible.
That is the reason that the companies fight polymorph patents – because they use the same polymorph and for them, the issue is to spend time/ efforts on developing alternative forms + no sale v/s legal challenges!
Such design-around strategies are very common knowledge in pharmaceutical industry and often thought about in strategizing non-infringing formulation. Over the years, newspaper media significantly twisted the facts around imatinib case and keep alarming that patent on imatinib mesylate will prevent Indian companies from manufacturing generic copy.
We all know that Novartis application was specifically about beta-crystalline form of imatinib mesylate, not imatinib base or mesylate salt per se. The genus patent particularly exemplified imatinib base and though not exemplified but suggested various salts including mesylate. Novartis application for beta crystalline form explicitly mentioned this fact and went on to claim beta-crystalline form of imatinib mesylate referring its advantageous flow properties, thermodynamic stability and less hygroscopic over alpha crystalline form. Although it is quite surprising that Novartis also filed application for alpha-crystalline form which is also opposed by an Indian company.
It was well-clear that the issue was beta-crystalline form of imatinib mesylate not imatinib mesylate per se but still most of the newspapers stories misrepresented quoting patenting of imatinib mesylate. Any Indian company would easily circumvent the patent application by using another crystal variant of imatinib mesylate and market without any patent issue. Novartis received EMR for beta-crystalline form in November 2003 which was subsequently challenged by Natco. Incidentally during 2003-04 Indian companies Hetero, Sun Pharma and Natco filed patent applications for different crystal variants of imatinib mesylate which are still pending with Indian patent office.
Following EMR, in January 2004 Novartis obtained injunction against the Indian generic companies from manufacturing and selling the generic version. Companies such as Ranbaxy, Cipla and Sun Pharma halted distribution of their generic versions which is more than enough to acknowledge the fact that their generic version contains beta-crystalline form of imatinib mesylate or otherwise they would go on litigating that their form is other than beta-crystalline form.
What is important to find out why Indian companies preferred only beta-crystalline form knowing that the application for beta-crystalline is pending with Indian patent office and even when they have filed their own patent applications for new crystalline forms. Is beta-crystalline form that significant in formulation development or is there bioavailability problem with other crystal variants?
This is not uncommon that generic companies circumvent polymorph patents using different crystal forms. Even in the US, generic companies successfully launched generic products having different polymorphic forms from the drug substances in the respective RLD (e.g., ranitidine, cefadroxil, terazosin etc.). As far as my understanding is concern, use of different polymorphic form does not result in 505 (b) (2) submissions.
I believe that Indian drug regulatory would not have any objection if any generic company uses different crystal form other than beta-crystalline form of imatinib mesylate and provide required regulatory information for marketing. What really puzzling me why most generic companies preferred zeroing down on beta-crystalline form? What really stopping them from using different form? If it is some technical problem that is preventing generic companies from using different crystalline forms then does this fact not sufficient to prove that beta-crystalline form is not a mere improvement.
Dear Jamie,
Thanks for the comment. You’re absolutely right–regulatory requirements could prove a hurdle for such strategies.
Though, my understanding is that in a number of cases in India, you don’t need to really submit fresh data if the drug is a polymorphic variant of an existing one for which approval has already been granted. I’m guessing a somewhat similar situation prevails in the EU and US as well–and it is only in select cases that the FDA will insist on comprehensive fresh safety and efficacy data. Am I correct in assuming this?
Perhaps some of the regulatory experts on this list can tell us if Cipla needs to submit fresh regulatory safety and efficacy data, if it needs to market the alpha crystalline version–in the US, EU and India.
Dear Varun,
Thanks very much for the extensive comments. I couldn’t agree more with the key thrust of your argument–that we need to examine more closely as to why alternate forms to beta crystalline are not being used (and in particular, I am curious as to why they weren’t used post the EMR injunction–which would have been the best test case for whether these were effective alternatives).
However, I wouldn’t go so far as to assume that just because alternative forms are not used, it immediately confers patentability on the one form that is being used. As you know better than me, I might have a better product on the market that my competitors wish to use–but that does not necessarily mean that my product is “patentable” automatically.
Dear Anon*2 (since there are 2 anon comments),
Thanks for comments and information re: Sun’s application which had blogged on in part earlier.
As for the doctrine of equivalents, is this US concept applicable in India? Have we had cases yet that have applied this? Or as with most other IP case law, will our judges be more inclined to follow UK case law and the doctrine of “purposive construction”.
Lastly, you’re absolutely right–inventing around is not something that one positively asserts as a factor enabling access–BUT conversely, is a factor that one takes into account when gauging the severity of access. And I think this has important policy implications. If claims are read tightly (without necessarily buying into expansive US concepts like doctrine of equivalents), we give protection strictly to only what is claimed and leave more scope for inventing around.
Dear Jamie/Shamnad
I agree that there might be a regulatory hurdle when you design-around an active ingredient in a drug formulation. From what i have known, a second regulatory approval is given for the same drug in the same form as that of the first approval. If the applicant changes the polymorphic form of an active ingredient, he may have to file an IND (instaed of NDA) which would require extensive clinical trials. I think the only exception to this may lie if the first applicant has not stated in his application that the molecule exhibits polymorphism or that a particular form is active. This seems to have a scientific rational because a change in the form may effect the safety of the drug. The Mylan case is different because a change in the inactive ingredient or excipients may only effect the bioavailability which is established by Bioavailability/bioequivalence studies for generic approval. Drugs like Amlodipine and (S)-amlodipine ; citalopram and escitalopram etc. have different approvals for different forms. Although these are enatiomers; i feel polymorphs may have a similar treatment.
Dear Vandana,
Just wanted to correct that change in polymorphic form of an active substance do not require IND (or even NDA). Yes you are correct that substituting racemic form with enantiomeric form do require fresh IND but same rule is not at all applicable to polymorphic forms. In past, USFDA has approved generic equivalents having different polymorphs from the drug substance in the respective RLD including famous rantidine and cefadroxil case. Even change of polymorphic form do not necessary requires submission under 505 (b) (2). Often NDA applicants do file petitions (like Pfizer made with respect to amorphous atorvastatin in the US) against the use of different polymorphic form in generic product on the grounds of impurity and stability.
Dr Gopakumar Nair (Director, Patent Gurukul) writes:
“Dear Shamnadji,
I may respond to your invitation to “think”.
As regards the latest on Imatinib mesylate and its Alpha and Beta crystalline forms are concerned, I may throw some light on existing information/documents.
The US 5, 521,184 patent describes a process for making alpha crystalline and another for beta crystalline.
The alpha crystalline users, makers or claimers were relying on the process as disclosed in patent to obtain alpha crystalline when the beta crystalline was under dispute post-EMR. The Alpha crystalline was not earlier claimed in the original parent application.
However, tests carried out at reputed laboratories at IICT, Hyderabad and CDRI, Lucknow have indicated that the process described for making Alpha crystalline form actually yields only beta crystalline form (copies of the certificates are attached). Oflate, there is an argument put forward in more than one litigation, including that for Gleevec, that once the “air gets seeded” with a more stable version of a molecule, any process which earlier would have been leading to an unstable or “metastable” version of the drug, would thereafter “get seeded automatically” and will lead to only the more stable form and not to the less stable form anymore.
I do agree with you that the “inventing around” option is open and “available”. However, whether the “invented around” form or new salt or hydrate will be treated as (ANDA) “bioequivalent” and will not be needed to go for full clinical evaluations (NDA) will be the crucial issue.
S. 3(d) having been held valid, the fate of both Beta crystalline and Alpha crystalline forms in India appears worth the wait.
With best regards,
Dr. Gopakumar G. Nair”
Good i am happy to know some interesting things happening between alpha and beta form of Imatinib
As a small trader i was confusing myself between the two beta and alpha form. exactly wanted to know what is the genuine form of Imatinib, either by patent or without
i was dealing with some intermediates for present alpha form Imatinib, does my intermediates business effect with this patent fight?.
apart from Indian is there any other country / countries which produce the alpha form imatinib.