With the recent recusal in the Novartis patent dispute, one is not sure as to when a new bench is likely to be constituted. Will it take a month? Several months? A year? Will there be more recusals along the way, given that the threshold for recusals has sunk really low?The intervention begins by focussing on the key issues raised by the dispute:
A. Whether or not the petitioners’ patent application covering the beta crystalline version complies with section 3(d)?
B. Whether or not the said version is novel and inventive?
C. Whether or not it violates public order?
The key submissions on the above issues are highlighted below:
A. Section 3(d) Standard
1. Interpreting the term “Efficacy”
The intervention asks that the court interpret “efficacy” in section 3(d) as “therapeutic advantage”. It also asks the court to draw from the Orphan Drugs Act (ODA) to help determine the contours of the term “therapeutic advantage”. The ODA/FDA regulations on this count stipulate that therapeutic advantage can be shown in one of three ways:
(1) greater effectiveness; (2) greater safety; or, (3) demonstration that the drug makes a major contribution to patient care in “unusual cases.”
The ODA angle is one that I’ve been thinking through a while now and we had raised this on the blog earlier. So am particularly interested in comments on this aspect.
The key reason for arguing that section 3(d) admits of only “therapeutic” properties and not any “property” is that:
“The Explanation to section 3(d) clearly states that all pharmaceutical derivatives would be considered the same “substance”, unless “they differ significantly in properties with regard to efficacy.”
The above clause refers to only those “properties” that have some bearing on “efficacy” and not all properties. If “all properties” were to qualify, it would effectively render the term “efficacy” redundant. Principles of statutory interpretation followed by Indian courts suggest that one cannot interpret a statute in a manner as to render a term in the statute redundant. Had Parliament intended any property to qualify, the Explanation would simply have stated “unless they differ significantly in properties”. And the main section would have stated “the mere discovery of a new form of a known substance which does not result in the enhancement of the known “properties” of that substance.”
Therefore, not all advantageous properties (such as improved processability or flow characteristics, storage potential etc) of a new form ought to qualify under section 3(d), but only those properties that have some bearing on efficacy.
Although this precise line of argument pointing to the phrase “properties with regard to efficacy” does not appear to have been explicitly articulated by either the Madras High Court or the IPAB, it is one that compellingly supports a restrictive interpretation of the term “efficacy”. This interpretation in favour of a stricter efficacy reading is further buttressed by the objectives of the Act, which suggest that section 3(d) was introduced to prevent ever-greening.”
2. Evidentiary Requirements For Section 3(d)
The intervention submits that the evidentiary requirements for efficacy ought not be as onerous as that required for by drug regulatory regimes. It argues:
“Therefore, in many cases, it is unlikely that at the patenting (drug discovery) stage, the applicant would possess any clinical trial data at all. It would therefore be irrational and unethical even to insist on clinical trial evidence only for the purpose of satisfying patentability requirements under section 3(d).”
3. Does Bioavailability Amount to Increased Efficacy?
The intervention argues that bio-availability by itself cannot amount to enhanced efficacy. Rather, this has to be independently established. Bioavailability means “the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of drug action”
In some cases, a new form with increased bio-availability might confer significant benefits in terms of reduced toxicity. Assume that the earlier known substance had to be administered at 10gm to be therapeutically effective, but that this 10 gm was significantly toxic to the patient. If the new form now enables 5 gm to deliver the same therapeutic impact with greatly reduced or no toxicity at all, this is a significant clinical advantage in so far as the patient is concerned.
In the specific facts of the case under dispute before this Hon’ble Court, the Petitioner sought to establish that when compared with the Imatinib free base, the beta crystalline form demonstrates a 30% increase in bio-availability. However, this by itself does not demonstrate any therapeutic advantage in relation to the patient.
Such advantage has to be independently established. The intervenor refers the Hon’ble Court to a drug regulatory norms which state that “it is not the intent of a bio-availability study to demonstrate effectiveness, but to determine the rate and extent of absorption. If a drug product is not bio-available, it cannot be regarded as effective. However a determination that a drug product is bio-available is not in itself a determination of effectiveness.”
4. What is the known substance for the purpose of section 3(d)?
One of the key issues under section 3(d) is: what is the “known substance” against which the enhanced “efficacy” comparison ought to be made?
This would in turn turn upon the question below:
Could a person skilled in the art have produced imatinib mesylate from the teaching of the 1993 patent and other prior art existing up to 18 July, 1997 (the priority date of the patent application covering the beta crystalline form) without undue experimentation? And if yes, in what form would such imatinib mesylate be obtained?
Assume that the skilled person would get to Imatinib Mesyalte in Form X by following the teachings of the prior art. If so, then Imatinib Meslate in Form X is the known substance against which to compare under section 3(d).
The IPAB fails to see the distinction between the alleged disclosure of a substance and an enabling disclosure. It must be borne in mind that the imatinib mesylate salt, mentioned in the 1993 patent and the 1996 Cancer Research’ Article was known only to Ciba Corporation and its scientists (the predecessor of Novartis). Therefore, the mere fact that imatinib mesylate finds mention in this article written by insiders cannot be taken to mean that it is indeed now known to the public. Even assuming the skilled person could have arrived at imatinib mesylate from the teachings of the prior art, the decision of the IPAB does not indicate as to what form such imatinib mesylate would be obtained in.
The intervenor therefore requests the court to appoint an independent scientific expert under section 115 of the patents act to aid it in making this determination.
B. Novelty and Inventive Step:
Since the IPAB ruling on this count does not appear well reasoned and is not based on expert evidence testifying to the appropriate capabilities of a skilled person in the art at that given point in time, the intervention asks that the court appoint an independent scientific expert under section 115 to help determine this issue.
In particular, the intervention notes that if the person skilled in the art could have produced the beta crystalline versions (knowingly or unknowingly) from the teaching of the prior art, then the said beta crystalline version is anticipated.
C. Can Patents Be Denied on Grounds of Excessive Pricing?
The intervention submits that this is a ludicrous legal proposition. Under current Indian patent law, the excessive price of a drug cannot be a ground for denying a patent to an invention underlying the said drug. The key issue at the time of granting a patent is whether the invention represents a good enough technical/scientific advance to merit a twenty year monopoly. Any potential abuse of a patent after its grant is redressable through ex post measures such as compulsory licenses and price controls.
Such an additional patentability criterion based on price will most likely fall foul of TRIPS.
Dr Basheer
Your intervention is well intended but seem to be limiting and could result in presetting judicial discussion in this case.
The limiting interpretation of efficacy to therapeutic efficacy is contrarian to your views in your paper published jointly with Mr. Reddy in 2008. You must raise the issue as you have done in the paper. If you are going to insist on therapeutic interpretation only the court may be prejudiced in coming out with a view point on this interpretation. Your job as an intervener will be better served if you motivate the court to interpret the statute in accordance with what it decides was the will of legislatures.
Further the ODA and FDA parameters on efficacy bring in more subjectivity. How are we to define ‘greater’ and even if a numerical value is associated what will be the criterion.
The next point you have highlighted it is that only those properties which have a bearing on efficacy will have a bearing. This is a self limiting argument and I doubt whether it will sustain judicial scrutiny.
I cannot agree that insistence on the clinical data will be irrational and unethical at the stage of conforming the satisfaction of an invention for S3(d). While this is a charitable argument and well meant for prospective inventors, but pragmatically it is the well resourced multinational who are applying for patents in pharma sector. They should not be allowed to have all things easy. And also the appointment of an expert to define the skill levels in this case. Such an expert may articulate the skill level required in this case, but can such recommendations be generalized. Also having an expert to determine the obviousness would be akin to establishing another decision taking authority in this myriad structure.
Sir, respectfully it is submitted that the bigger picture is being missed. The real issue is the interpretation of statute in line with the legislatures thinking of avoiding evergreening. And it must also be kept in mind that one of the unstated purpose of the act is to make available the important drugs at prices which are beyond the abuse of the MNCs. Note this does not mean affordable.
With MNC and a generic manufacturer fighting for their own turf , your intervention must explore the possibility of getting a getting a true judicial interpretation and not be pre emptive.
R.K.Jain
Patent Agent
Dear Mr Jain:
Thanks for your detailed comments. Appreciate it. You’re right that I left the issue open ended (therapeutic efficacy vs all forms of advantages) when i wrote the article some years back.
Since then however, i’ve perused most of the decisions by the patent office on 3.d and have thought through this issue in greater detail and have arrived at the conclusion that the best reading of section 3(d) is to interpret the term as therapeutic advantage (note that I do not use “therapeutic efficacy” but therapeutic advantage: since therapeutic advantage even forecloses the possibility of using reduced toxicity as a ground for claiming enhanced efficacy. In order to take reduced toxicity also within its fold, i’ve recommended therapeutic advantage. Also, you’ll notice that the section reads as “properties with regard to efficacy”. If all properties were meant to be included, then the term “efficacy” effectively becomes redundant. Which is why I opted against a reading in of all kinds of “advantageous properties”. Quite apart from the legislative history which endorses a more restrictive reading of the term.
I meant: “note that I do not use “therapeutic efficacy” but therapeutic advantage: since therapeutic “efficacy” even forecloses the possibility of using reduced toxicity as a ground for claiming enhanced efficacy.”
Dr Basheer
Thanks for your response. But I still feel that you must visualize your role as an intervener more as an active evangelist rather than simply getting the courts to give judicial interpretation on points of your concern.
A few points for you to ponder:
1. You have mentioned that the intentional use of term therapeutic advantage instead of therapeutic efficacy is to take reduced toxicity within its fold. From the reading of your response it seems that therapeutic advantage narrows the likely interpretation to even foreclose of possibility of reduced toxicity within its fold. Same will be the case with bio-availability. As has been rightly discussed earlier increased bio-availability is no precursor to increased efficacy.
2. Sir, while it will be prudent to have judicial clarifications on all the issues and limiting to considerations of IPAB decisions, it will be akin to be using a computer as a typewriter.
3. To me the issues more pertinent to the intervener is to broaden the ongoing discussion and force the court to frame issues which uplift the raison dtre’ of the Act. One of the points could be that the incremental invention be interpreted to bring about the correlation between characteristics of the invention (both physical & chemical) and advantage (both therapeutic and non therapeutic). You must not be limited by the considerations of IAPB in its judgments. For example a salt which is not stable at room temperature is offered in form of pill with no loss of efficacy, or added toxicity is to considered as another product or not. Just because the name of salt is same does not mean that the inventive step would be made inconsequential. You have an opportunity to intervene at the highest level and what comes out of your efforts will be final and non challengeable. Hence you must be taking up issues which enhance the overall intellect interpretation of the ACT. Some of the points I have highlighted in my earlier blog.
4. We must be guarded in recognizing that we do not develop unhealthy bias against the MNCs while being in pursuit of welfare of the general public interest. It is a hard fact that these MNCs are the sources of new drugs and technology and have resources to engage in never ending litigation. It is therefore important that we must leverage our skills in challenging them with dexterity such that a balance is created in their interests and also that of our generic manufacturers and general public.
R.K.Jain
Patent Agent
The term efficacy as defined by Oxford Dic. Is ‘the ability to produce a desired or intended result” whereas Dorland defines it as “the ability of a drug to produce the desired therapeutic effect”. Therapeutic means “tending to overcome disease and promote recovery”. Elsevier’s Mosby defines it as “beneficial, pertaining to a treatment”
If all these definitions are taken into consideration, “bioavailability” should come under “efficacy”. Efficacy is a broad term which will include the potency of drug (with dosage and frequency), bioavailability (with drug delivery characteristics), side effects, toxicity and formulation related things like heat stability, humidity control, form of drug, binders, etc . So is the bioavailability sufficient to prove the efficacy?
I guess “therapeutic advantage” is a proper term.
Besides, in early 2010, Novartis was granted an Indian patent for nilotinib. It was reported that nilotinib has better efficacy than imatinib. So is there any data of imatinib for comparison like cytogenetic response, molecular response, etc?
Thirdly, where would one get to see the evidences by technical experts (if asked by the court) in this case right from the Hon’ Madras High court till IPAB?
tahnks
S
Dear Mr Jain:
I’m a bit confused here. If the statutory framework is such that it calls for a restrictive interpretation of efficacy, why should I not express my view so to the court? I have argued this point with several colleagues, and none have, as yet proferred a credible enough reason as to why all advantageous properties can satisfy the requirements of section 3(d). As I argue, if all advantageous properties suffice, then the term “efficacy” becomes redundant. And a cardinal principle of statutory interpretation is that you cannot interpret in such a way as to render something redundant. Surprisingly, this interpretative angle was never taken up at the patent office or the IPAB to restrict the scope of term efficacy. And even I’d missed it for a long time. To me, this interpretative line is dispositive of the issue.
Tks for comments S,
how do you arrive at the conclusion based on the definitions that you cite that “If all these definitions are taken into consideration, “bioavailability” should come under “efficacy”.” if increase in bio-avialability has no further impact on the curative impact of drug (including reduction of toxicity), why should it qualify?
Dear Mr Jain:
Thanks again for your insightful comments: A quick clarification. You state as below:
“You have mentioned that the intentional use of term therapeutic advantage instead of therapeutic efficacy is to take reduced toxicity within its fold. From the reading of your response it seems that therapeutic advantage narrows the likely interpretation to even foreclose of possibility of reduced toxicity within its fold.”
I think you’ve misunderstood my point. I’m arguing in favour of adopting a “therapeutic advantage” standard, and asking that guidelines be derived from the ODA use of this term. The ODA clearly interprets “therapeutic advantage” to include reduced toxicity. So why would this “foreclose the possib of reduced toxicity” as you suggest?
Also, you state:
“I cannot agree that insistence on the clinical data will be irrational and unethical at the stage of conforming the satisfaction of an invention for S3(d). “
as you will appreciate, 3(d) goes beyond classic evergreening—since evergreening normally requires an earlier drug product. with section 3(d), you dont need an earlier drug –you simply need an earlier known substance, whether or not that substance is capable of being converted to drug. Subjecting human patients to this substance (which may not be druggable and which may have toxicity etc) merely for the purpose of satisfying section 3(d) is highly unethical.
I am not sure if I understand what you want to say in your last sentence. However, I will try to explain once again.
see, for any non-IV drug, its important to look at the ability of the “active ingredient’ to deliver to the blood stream. the rate of absorption and to what extent it is absorbed, both the criteria are important when it comes to bioavailablity. The efficacy depends upon the bioavailability but there are certain other factors too which impact the efficacy. Thus my concern is if bioavailability alone is sufficient to prove ‘enhanced efficacy”?
tks
S
Dear Dr Basheer,
Thanks for your detailed explanations. I guess my thinking on the issues seem to be a bit different from your interpretations. But I think this is good as you will be faced with wholly different interpretations in the court. And perhaps my submissions would have been helpful in this.
Now to the point that, Novartis was granted an Indian patent for nilotinib. It was reported that nilotinib has better efficacy than imatinib. So is there any data of imatinib for comparison like cytogenetic response, molecular response, etc?
Sir, if nilotib has been granted patent with the claim that it has better efficacy than imatinib, then it ought to be brought to the attention of the court on how and what criterion for efficacy has been taken. Further the data for other characteristics of imatinib is a matter of later concern (And producing such data will be more of Novartis concern). Firstly it has to decided what constitutes efficacy. If IAPB has limited itself to therapeutic efficacy that does not make a convention. Similar to new judgments which is based on price factor to trample the validity of patents. These are challengeable and will be under judicial review soon.
Your point of cardinal interpretation in not making anything redundant begets different interpretation. You are not making efficacy redundant by calling for expanding the definition through inclusion of factors which are caused by an inventive step. In the criterion for patenetibility the inventive step precedes the industrial applicability criterion. There is no need to be confused on this.
Regarding the third point that for salts which are not druggable should not be tested on ethical grounds. Sir it is the MNCs who have to decide on this for they are the ones who are running after patents. And their yard stick of public morality is vastly different from yours. As I said earlier your role is get the judiciary to give interpretations on the issues you have raised. And they can give a proper review only if they are forced to see the bare facts devoid of morality issues. Morality should follow from the final interpretation and not be camouflaged by wrong or intentional misinterpretations.
I will end my blogging on this issue here as I have conveyed to you what I had to say. I will appreciate if I can get a response on the question I raised viz.
To me the issues more pertinent to the intervener is to broaden the ongoing discussion and force the court to frame issues which uplift the raison dtre’ of the Act. One of the points could be that the incremental invention be interpreted to bring about the correlation between characteristics of the invention (both physical & chemical) and advantage (both therapeutic and non therapeutic). You must not be limited by the considerations of IAPB in its judgments. For example a salt which is not stable at room temperature is offered in form of pill with no loss of efficacy, or added toxicity is to considered as another product or not. Just because the name of salt is same does not mean that the inventive step would be made inconsequential.
I look forward to your comments on this.
R.K.Jain
Patent Agent
Dear S:
I thought this was clear from the petition. Bio-availab (BA for short) will not by itself do. one has to make the extra linkage to therap efficacy–either in terms of the enhanced BA contributing to the cure of the disease or to reduced toxicity….
Dear Mr Jain:
Thanks again for your insightful comments. Lets keep the discussion going.