In a surprising move,DIPP has taken a decision to refuse grant of CL for anticancer biologic Trastuzumab/Herceptin as reported by Sidhartha of Times of India.
Background:
Earlier in Nov 2012 and again in March 2013 campaign for affordable trastuzumab (an association of patients and NGO’s) had urged the Govt to take appropriate measures to ensure affordability of Herceptin. Subsequently Trastuzumab was recommended for CL by the health ministry. Read our previous posts (here and here).
However after several months of deliberation and debates, the DIPP has refused a plea for CL for Trastuzumab. India, in the recent past has attracted strong criticism from several quarters for taking a pro-patient stand in its patent disputes involving Pharma MNC’s. International scrutiny on India’s IP policies, heightened when India granted its first ever CL against Bayer’s anti-cancer drug Nexavar (read Shamnad’s post here). Ergo, I believe the DIPP must have decided to take it easy with grant of compulsory license.
Prashant makes a very interesting point here; does the DIPP have the right to turn down the recommendations of the health ministry? If the DIPP and health ministry disagree on the grant of CL for Herceptin, the matter should ideally have been directed to the Prime Minister’s office or Cabinet.
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| Image from here |
Herceptin patent status:
Apart from platform technology patents, Herceptin is protected by three patents in the US viz. US6339142, US6407213 and US7074404, all of which expire in 2019. In India however, I am aware of only one granted patent relevant to Herceptin IN205534. This patent broadly covers a method of purification where a product molecule must be separated from a very closely related contaminant molecule (acidic variant). I have covered this in detail in this post here.
What next?
Now after refusal of plea for CL, the health ministry has suggested that the government use powers vested with it under section 66 of the Indian Patents Act to revoke the patent in public interest.
Revocation of patent in public interest: Where the Central Government is of opinion that a patent or the mode in which it is exercised is mischievous to the State or generally prejudicial to the public, it may, after giving the patentee an opportunity to be heard, make a declaration to that effect in the Official Gazette and thereupon the patent shall be deemed to be revoked.
History of Section 66 shows that it has been used only a couple of times to revoke patents. The first instance was when a process patent was granted to Agracetus, a U.S. company, for genetically engineered cotton cell lines. Around the year 1997, this patent was revoked in public interest because it was viewed as being prejudicial to farmers’ rights. The Govt was of the view that Cotton is an important crop essential to national economy and should not be the subject matter of patents.
The other instance was when Indian patent 252093 was granted to Avesthagen for “synergistic ayurvedic/functional food bioactive composition”. The patent covered the composition consisting of jamun, lavangpatti and chandan to be used for treatment of diabetes, which is in effect traditional knowledge (section 3(p) of Indian patent act precludes patenting of traditional knowledge). Thus the patent was revoked as it was deemed to be generally prejudicial to public. Prashant has covered this development extensively in his blog posts here, here and here.
In both instances the patents were revoked either because their working was detrimental to public interest or because they contravened provisions of the Indian patent act. As I see it, Section 66 is a safeguard against patents (detrimental to public interest), which have been inadvertently granted by the patent office. However in this case, the fact that Trastuzumab/Herceptin is exorbitantly priced; can it be construed as being generally prejudicial to public?
CL u/s 92 versus Patent revocation in public interest
Provisions relating to grant of CL u/s 92 require that an interested person should make an application after weighing the benefits conferred by the CL against other costs like payment of reasonable royalties to the patentee, manufacturing costs etc. However these factors need not be considered by a potential biosimilar manufacturer if a patent is revoked u/s 66.I believe that high price of Herceptin alone is not reason enough for the Govt. to invoke Section 66. It would be unfair to the patentee. Compulsory license would have been a better option in my opinion. Also if DIPP has refused a plea for CL; we wonder whether it will accept a plea for revocation of patent in public interest. It remains to be seen, what stance will be adopted by DIPP regarding this. Interesting times ahead!
Madhulika – homework!!
IN 205534 covers a composition containing Her2 antibody with less than 25% acidic variants. This effectively ensures that all methods (even if developed post grant) are covered – unless of course Roche/Genentech decides not to read Sec. 48 in the same manner that MSD did for Januvia.
Secondly, there is no precedent for what exactly constitutes generally prejudicial to the public. It is arguable that the 25000+ patients added to the NCR annually with Her2 variant of breast cancer may well be prejudiced by the manner of working of this patent. There is an interesting piece by Vikas Dandekar and Joshua Berlin on pricing strategies with respect to biologics on Elsevier. It is again arguable that Roche’s strategy of introducing PAP’s in China and not in India is again prejudicial to the public.
Finally, has anyone ever given thought to the composition claims of IN205534 vis a vis Section 3(e)? This should make for an interesting analysis!!
Regards,
oncopat
Oncopat:
If only you had read the post and patent carefully..!!
The claim language is misleading, you have to read the whole patent (with definitions) to get a better picture. So what the claim actually means is “A composition comprising anti HER-2 antibody; with less than 25% contaminants/impurities”
Yes there are no precedents for interpretation of the term “prejudicial to public interest.” It is my opinion that high price of a drug alone cannot be construed as being prejudicial to public.
You may differ!
The composition as described in this patent is actually a partially purified protein directly obtained from host cell/organism producing the polypeptide. What they are essentially claiming is the unpurified version of Herceptin antibody. So it is not a composition patent in that sense of the term. No, it doesn’t fall under the purview of Section 3(e).
Madhulika… sorry, but the patentee seems to think it is a composition. See their responses on file. I quote “The cited reference does not disclose a mixture of anti-HER2 antibody and one or more acidic variants wherein the amount of acidic variant(s) is less than 25%…..On the other hand the present invention discloses a composition comprising acidic variant(s)…”
The thing is that the nature and scope of monopoly are determined by the language of a claim. the specification is a guide towards interpreting terms in a claim are that unclear. Where the claim unambiguously states ‘A composition…’ and the patentee affirms this in responses, there is no doubt as to teh fact that they are claiming a composition. This then brings Sec. 3(e) into the picture.
Genentech will find it hard to defend an argument now that they are not claiming a composition. if that is the case, then the question of isolation kicks in. If it is a composition Sec. 3(e) kicks in. They are not exactly beign hoist on thier petard – they are raising the petard and jumping on it!!!
Am looking forward to literature on this particular patent battle.
On the question of high pricing and public interest, I wish someone would do an analysis of teh bogey of high R&D costs, the extent and number of years for which a patent has been in force, differential pricing strategies in developing markets, with a focus on Sec. 83. This should make for interesting reading for people like us who wish to enlarge our knowledge base.
Kind regards,
Oncopat
Oncopat, please read the definition of composition in the patent.
In order to understand the claims of the patent, one needs to be versed with biotechnological drugs. Every recombinantly produced biotech drug has “impurities” i.e. proteins in unfolded form, or some variant of correctly folded forms. These are characterised and also injected along with the correctly folded proteins through the formulations. “Impurities” may not have therapeutic benefits but they may have a plenty of non-therapeutic ones like stability of drug substance.
So, as Madhulika pointed out, it does not fall under purview of Section 3e- because it is not “mere” admixture. They are result of the process – upstream plus downstream – they have not brought together impurities and purities to make this mixture. The process generated this “mixture” itself and they have regulated the percentage of contaminants because they may be providing one or the other benefit or may be it is not possible to obtain pure trastuzumab and therefore claimed in such a manner and therefore perfectly fine.
Rahul
Oncopat
Please get your facts straight before commenting.
It is important to note that you should have understanding of the subject in full before placing allegations
Just an FYI
Anon.. at 1.52. Tsk, Tsk.. Getting touchy?
Madhulika.. The spec also defines a mixture a little after it defines a composition. The definitions are pari materia (For Anon @ 1.52..similar in nature and substance).
I see Rahul’s point that Sec. 3(e) can be avoided by arguing that the prohibition there requires a physical act of admixing of two discrete ingredients, which is not the case here and would not apply to biologics. Am more interested in this debate – does Sec. 3(e) require actual physical admixing of two discrete ingredients or would it cover any composition/mixture, no matter how they are formed. I suspect that this principle has not been tested as yet. The issue really is that the spec also does not appear to provide any stated advantages of the presence of the contaminant variant (except to identify it as an impurity).
There are at least a few decisions of the IPO which in the context of biologics/bioetch inventions say that if the essence of the invention is ‘purification’, then the claim cannot be allowed. Wonder how this post-grant on Trastuzumab will be argued.
And for Anon @1.52. contrary to perception, this debate can actually be motivated by a desire to learn about different perceptions w.r.t. this issue.
Oncopat
does Sec. 3(e) require actual physical admixing of two discrete ingredients or would it cover any composition/mixture, no matter how they are formed.
===
Oncopat, I will here have my views only on the letters and not on the spirit of law. The “mere admixture” – Admixture is noun – so law is about the noun mixture and not the verb(or the process) mixture. But the saving grace is “mere”. And mere admixture might be read as you stated – independent of the process of formation of mixture – and therefore it may fall under Section 3e. Thanks for making me think in this regard. But then it is not “mere” admixture — I happen to read mere as “obvious” – but non-mere or non-trivial or non-obvious admixture is allowed – and this trastuzumab composition is non-trivial admixture for the reasons I stated before. I welcome more debate on this and will love to stand corrected in case I have wrongly interpreted words and their meanings ! Cheers !
Rahul
And yes even if patent is revoked – there is NO company in India which can manufacture trastuzumab.Dr Reddy’s Reditux is not equal in quality to Rituximab and it is in market since 2003. They developed it by importing cell lines/clones from abroad from a startup – and the cells might have not worked well Biologics are not pharmaceutics and India needs to understand that in order for Indians to have access to these superior drugs, they need to negotiate and force these companies to reduce prices, offer differential pricing etc.
Rahul
Thanks Rahul.. that is an interesting perspective – that we should (and always should) begin at the beginning. the focus on ‘mere’ is quite often lost when Sec. 3(e) is applied. I would tend to agree that the term ‘mere’ should be interpreted in the light of obviousness/inventive step or to put it slightly differently ‘workshop modification’. I wonder how the Trastuzumab patent will be interpreted by the courts. This is something that should actually end up laying down guidelines on application of Sec. 3(e) for biologic and pharmaceutical formulations.
Cheers,
Oncopat
Thanks oncopat for this interesting debate 🙂
I couldn’t agree more with Rahul!
Section 3(e): A substance obtained by a mere admixture resulting only in the aggregation of the properties of the components thereof or a process for producing such substance is not an invention.
There is no admixture here; this is a product patent of unpurified version of Herceptin antibody plain and simple.
Look at it this way; consider a new chemical entity X which has two enatiomeric forms. One of the enantiomeric forms has more activity, so the patent claims the drug as “a drug X, which has less than 25% of R enantiomer.” In this case would you construe the drug X as being a mere admixture?
The terms stereoisomers, diastreomers, enantiomers each have different meanings,and only an organic chemist with strong background and understanding of stereochemistry, and particularly Ingold-Prelog’s absolute method of configuration can say whether the optical isomer is of the R or S configuration, Thus Madhulika Vishwanathan’s comments, “Look at it this way; consider a new chemical entity X which has two enatiomeric forms. One of the enantiomeric forms has more activity, so the patent claims the drug as “a drug X, which has less than 25% of R enantiomer.” in which she uses the term ENANTIOMER to refer to a molecule of R configuration, strictly speaking, is not incorrect. DIASTREOMER is the correct term. Thus glucose has at least 16 enantiomers ( d + or l – ) forms whereas it has fewer number of R and S isomers