SSRN Id2154396

SOWING THE SEEDS OF CHANGE?
PATENT POLICY AND SECTION 3(D) OF THE INDIAN PATENT ACT, 1970 Adarsh Ramanujan and Rajarshi Sen
INTRODUCTION The originator pharmaceutical industry has always been the poster child for stronger intellectual property regimes.1 It should come as no surprise, therefore, that multinational pharmaceutical companies have expressed grave reservations against Section 3(d) of the Indian Patents Act, 1970 (the Act), claiming that it is bad patent policy, establishing new criteria for patentability which are both unconstitutional and violative of the World Trade Organization Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPs).2
Adarsh Ramanujan, Advocate, Lakshmikumaran & Sridharan, New Delhi; LL.M graduate 2010, University of California, Berkeley; B.Sc. LL.B. (IPR Hons.) graduate of National Law University, Jodhpur (India). He may be contacted at <adarshramanujan@gmail.com>. Rajarshi Sen, Manager, Corporate Legal Department, Siemens Ltd., is a B.Sc. LL.B. (WTO and Trade-related Laws Hons.) graduate of National Law University, Jodhpur (India). He may be contacted at <rajarshisen1@gmail.com>. The views expressed in this article are personal and do not represent the views of Siemens Ltd. or Lakshmikumaran & Sridharan. It has been provided only to provide general information and to communicate the authors personal comments on the topic. They are neither legal advice nor legal opinion. Reading this article does not create an attorney-client relationship. We specifically disclaim any liability resulting from use of any information contained in this article.
See, International Federation of Pharmaceuticals Manufacturers and Associations (IFPMA), Issues: Intellectual Property and Patents, as available at <http://www.ifpma.org/Issues/index.php?id=418> (last visited on 1st April, 2010); European Federation of Pharmaceutical Industries and Associations, Intellectual Property Rights, as available at <http://www.efpia.eu/Content/Default.asp?PageID=538> (last visited 1st April, 2010); IFPMA, THE PHARMACEUTICAL INNOVATION PLATFORM (IFPMA, Geneva, 2004). 2 See, IFPMA, News Release: Chennai Court Ruling: Indias Innovative Potential Continues to be Stifled by Its Poor Patent Law, as available at <www.ifpma.org/News/NewsReleases.aspx?nID=7860> (last visited on 1st April, 2010) citing Professor Trevor M. Jones, India: Innovation at the Crossroads, Creative & Innovative Economy Center Working Paper, (Creative & Innovative Economy Center, George Washington University Law School, Washington DC, May 2007) as available at <http://www.law.gwu.edu/Academics/research_centers/ciec/Documents/Notes%20on%20Cr eativity/InnovationattheCrossroads.pdf> (last visited 1st April, 2010) (arguing that Section 3(d) severely restricts innovation through incremental steps by imposing a test which was almost impossible to perform at a time when patents are filed). See also, Writ Petition filed by Novartis AG, in the High Court of Judicature of Madras (Writ Petition No.24759 of 2006) (hereinafter Novartis - Writ Petition) (on file with the authors).
Adarsh Ramanujan, Rajarshi Sen 1
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Drawing on the decision of the Madras High Court regarding the constitutionality of Section 3(d),3 we have previously discussed the scope and application of this controversial provision.4 In that article, we expressed the opinion that rather than establishing new grounds for patentability over and above the existing criteria, the provision is merely a re-formulation of the fundamental patentability requirements of novelty and non-obviousness in an attempt to curb the evergreening of patents. On this basis, we have also previously argued that Section 3(d) is not a de jure violation of Indias obligations under TRIPs, while warning that a reasonable and rigorous application of the provision will be necessary to achieve its objective while avoiding potential de facto TRIPs violations.5 In what is widely regarded in the industry as the test-case on Section 3(d), the Patent Controller,6 and on appeal, the Intellectual Property Appellate Board (IPAB),7 have rejected Novartiss patent application for Glivec/Gleevec on the grounds that it was a mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance, and hence, barred by the first part of Section 3(d). These decisions provide a preliminary insight into how the Indian legal system is likely to interpret, apply and enforce this unique and controversial provision in the future. The decision of the IPAB was appealed almost immediately before the Honble Supreme Court of India in 2009. However, hearings on the matter in the Supreme Court of India were delayed due to the recusal of two different Honble Judges of the Supreme Court of India with one Honble Judge actually recusing himself after partly hearing the matter. As on date, the matter is presently being argued before the Supreme Court of India. Therefore, with the momentum building-up, it is important to visit the implications of the impugned IPAB decision and the factors that the Honble Supreme Court of India may take into consideration in deciding the matter.
Novartis AG represented by its Power of Attorney Ranjna Mehta Dutt v. Union of India through the Secretary, Department of Industry, Ministry of Industry and Commerce and Others, (2007) 4 MLJ 1153: MANU/TN/1263/2007 (hereinafter Novartis High Court). 4 Adarsh Ramanujan and Rajarshi Sen, Pruning the Evergreen Tree: Section 3(d) of the Indian Patents Act, 1970, 31(3) E.I.P.R. 135-146 (2009) (hereinafter Ramanujan/Sen). 5 Rajarshi Sen and Adarsh Ramanujan, Pruning the Evergreen Tree or Tripping Up Over TRIPs? Section 3(d) of the Indian Patents Act, 1970, 41 (2) I.I.C. 170-186 (2010) (hereinafter Sen/Ramanujan). 6 Decision of the Assistant Controller of Patents & Designs, In the matter of an Application for Patent No. 1602/MAS/98 filed on July 17, 1998 AND In the matter of a Representation under Section 25(1) of the Patents Act, 1970 AND In the matter of Rule 55 of the Patents Rules, 2003 (hereinafter Novartis PC) (on file with the authors). 7 Novartis AG represented by its Power of Attorney Ranjna Mehta Dutt v. Union of India through the Secretary, Department of Industry, Ministry of Industry and Commerce and Others, MIPR 2009 (2) 345: MANU/IC/0034/2009 (hereinafter Novartis IPAB).
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This article makes an attempt to view the interpretation of Section 3(d) by the IPAB from a policy perspective. We should clarify that this article does not deal with the public policy objective of Section 3(d); to the extent that Section 3(d) was intended to curb certain illegitimate patent practices which, among others, have been termed as evergreening of patents, this issue has been briefly addressed in our previous articles. Rather, we will consider the practical and policy implications of the manner in which Section 3(d) has been interpreted by the IPAB and how it is likely to be applied in future cases as a result. While there are, of course, a number of issues and questions which are to be decided by the Honble Supreme Court of India, the scope of our policy analysis is limited to the question of the evidentiary basis for the rejection of Novartiss patent application and its possible implications on how the efficacy requirement may be met in future cases. What, for example, is the standard of proof required to fulfill the efficacy requirement? On whom does the burden of proof lie and at what stage must it be discharged? More importantly, how may the burden of proof be discharged? Most significantly, how would this affect the incentives of applicants to innovate and to patent their innovations? None of these questions have been deliberated, even in passing, in the various decisions by the Madras High Court, the IPAB and the Patent Controller, nor has it been considered in the limited literature that has been generated on the issue of Section 3(d). These are important questions that face the Indian intellectual property regime. Indeed, these questions must be faced, and answered, by any jurisdiction which hopes to attempt to curb the illegitimate evergreening of patents whilst also encouraging legitimate incremental innovation in all fields of science and technology. This, therefore, is our attempt at providing answers to some of these questions facing jurisdictions hoping to implement a provision similar in effect to Section 3(d). It must be understood, of course, that none of the answers we hope to provide can be definitive; indeed, we would not wish them to be controversial questions of policy are not, and should never be, susceptible to rigidly definitive answers. Instead, our attempt is as much to provide answers as it is to provoke thought and stimulate further debate and discussion on these contentious issues. Our self-imposed limitation will not limit the scope of our analysis, since we hope to show that such an analysis of the policy aspects and practical implications of implementing and enforcing a provision such as Section 3(d) is an important one. For one thing, such an analysis will serve to inform decision makers within the Indian legal system, especially the judiciary and the executive, as to how best one might approach the task of interpreting and applying Section 3(d). More importantly, if at all a unique provision such as Section 3(d) is to be considered a successful legislative achievement which ought to be implemented elsewhere, the
policy aspects as well as the practical implications (including, but not limited to evidentiary requirements) of Section 3(d) can and should be given due consideration and regard. Therefore, our policy analysis will not limit us; it will take us even further afield: it will allow us to analyse whether, and if so, how other jurisdictions might want to consider adopting provisions similar to Section 3(d) for the purposes of preventing certain illegitimate patent practices which, among others, have been termed as evergreening of patents. India is not the only country faced with the various problems caused due to such practices, which, it has been argued, undermine intellectual property regimes,8 impede competition,9 create market distortions,10 distort international trade,11 and hamper public welfare by hindering the protection of public health.12 This makes it imperative for all countries, not just India, to consider measures for dealing with this menace. But how do countries decide how to manage the delicate balancing act between preventing illegitimate evergreening and encouraging legitimate incremental innovation? While each country must decide how to approach this question for itself, in light of their own socio-economic policy considerations, this article attempts to highlight the significance of these considerations in arriving at exactly such a decision. It is only for the sake of convenience that the hypothetical scenarios and other illustrations used here are all based on the explicit assumption that Section 3(d) (on the basis of its current interpretation) has been transposed and integrated into the American legal system; any other standard of comparison with any other developed legal jurisdiction would have served just as well. Therefore, although the policy analysis contained in this article analyses the policy implications of the Novartis - IPAB decision from within the current state of the institutional and developmental pipeline for drugs in the United States of America, it should be noted that similar (if not exactly the same) considerations will apply for almost all legal systems. Therefore, the general concerns and considerations highlighted in our policy analysis would apply with equal force in any and every patent system when considering whether importing and implementing a provision like Section 3(d) would be capable of spreading the seeds of change in patent policy within that particular national system.
Graham M. Dutfield, The Innovation Dilemma: Intellectual Property and the Historical Legacy of Cumulative Creativity, 4 I.P.Q. 379, at 381 (2004). 9 John Barton, Reforming the Patent System, 287 Science 1933-1934 (2000). 10 RESOURCE BOOK ON TRIPS AND DEVELOPMENT: UNCTAD-ICTSD PROJECT ON INTELLECTUAL PROPERTY RIGHTS AND SUSTAINABLE DEVELOPMENT 360 (Cambridge University Press, New York, 2005). 11 Paul Crampton and Milos Barutciski, Trade Distorting Private Restraints: A Practical Agenda for Future Action, 6 Sw. J.L. & Trade Am. 3, 8-11 (1999). 12 Sen/Ramanujan, supra note 5, at 180-181.
Our discussion starts in Part-I, where we attempt to provide the necessary background to the present debate by briefly explaining the current interpretation accorded to Section 3(d). Beginning in Part-I (A), we revisit the conclusions we reached in our previous works, updating them in Part-I (B), in light of the Novartis IPAB decision. In Part-I (B), we discuss the most reasonable manner of reading the Novartis IPAB decision, as it regards the question of the evidentiary requirements of Section 3(d). This reading will show that the Novartis IPAB decision leaves open multiple possibilities by which the evidentiary requirements of Section 3(d) may be established. Based on these possibilities, we develop, in Part-II (B), the various likely scenarios whereby one may attempt to prove that a particular drug has fulfilled the requirements of Section 3(d). These scenarios are developed in the scientific background of the drug development process provided in Part-II (A) and Part-II (B). In Part-III, we use the scenarios developed in Part-II and analyse the likely impact of the Novartis - IPAB decision on drug innovation policy and the manufacture of new forms of beneficial drugs. PART-I REVISTING SECTION 3(D) A. What Section 3(d) says (and What Section 3(d) Does Not Say) As it now stands, Section 3(d) provides: The mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs atleast one new reactant. Explanation: For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy. (Emphasis supplied)13 This article concerns itself only with the first part of Section 3(d), which excludes patents on the mere discovery of a new form of a known substance, where such a discovery does not result in the enhancement of the known efficacy of that substance. In Novartis - High Court, the Madras High Court used Dorlands Medical Dictionary to define the term efficacy to mean the ability of a drug to produce the desired therapeutic effect - healing of
13
It may be noted that the emphasized portion, the first part of Section 3(d) (which is, in effect, the controversial part) and the Explanation to this part were added to the original provision by amendment in 2005.
disease.14 However, the High Courts decision was quite cryptic when it came to defining the phrase enhancement of the known efficacy. The High Court stated, without any explanation, that scientific parameters for comparing the respective efficacies of two different forms of a substance existed.15 The High Court neglected to answer the question of what would amount to enhancement for the purposes of Section 3(d).16 In our previous work, we have argued that not every enhancement in efficacy (however miniscule) could be considered as being sufficient to escape the bar under Section 3(d), as this would defeat the very purpose of the provision.17 We concluded that, to achieve the object intended by the drafters, the word enhancement would have to be construed to mean a substantial or significant enhancement, as determined from the technical and scientific basis of a person skilled in the art.18 This conclusion is buttressed by the wording of the Explanation, which clarifies that certain known forms of known substances shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy.19 In an effort to prevent potential arbitrary exercise of power by the Patent Controller of India while deciding the matter of significant enhancement, we suggested a balancing approach based on the allocation of the burden of proof on this issue: so long as the applicant could produce evidence to prove enhancement, the Patent Controller could not reject the application unless there was evidence, produced either by the examiner or oppositionists, that such an enhancement would be considered insignificant by persons skilled in the art.20 Therefore, while the onus of proving enhancement of efficacy rests solely upon the applicant;21 our suggestion allocates the burden of proof on the degree of increase in efficacy sufficient to cross the bar under Section 3(d). As yet another check on potential arbitrary exercise of power, we argued that once an invention crosses the bar under Section 3(d), the Patent Controller should not impose a higher standard for scrutinising the application for patentability. That is, an invention that has been held to have crossed the bar under Section 3(d) should not be denied a patent on the ground that the enhancement of efficacy is not sufficient for it to qualify for the novelty or the non-obviousness
14 15
Novartis High Court, supra note 3, at paragraph 13. Novartis High Court, supra note 3, at paragraph 13. 16 Ramanujan/Sen, supra note 4, at 143-144. 17 Ramanujan/Sen, supra note 4, at 144. 18 Ramanujan/Sen, supra note 4, at 144. 19 See, Novartis IPAB, supra note 7, at paragraph 9(xvii). 20 Ramanujan/Sen, supra note 4, at 145. 21 See, Novartis IPAB, supra note 7, at paragraphs 9(xiii)-9(xvi).
criteria. However, we noted that the application for patent could still be rejected for failing to fulfil the standards of patentability on other grounds.22 The Explanation to Section 3(d) creates a legal fiction to the effect that certain forms of a substance shall be considered one and the same unless it can be proved that the forms differ significantly in their properties with regard to efficacy. We have previously argued that although the explanation, coupled with the operative portion of Section 3(d) was intended to create a twostep process to complete a Section 3(d) analysis; in effect, they merely reinforced each other. This is because only when one form of a substance differs significantly in its properties with regard to efficacy, can that form result in an enhancement of efficacy.23 B. The Glivec Dispute: Novartis, the Patent Controller and the Intellectual Property Appellate Board The Novartis dispute arose from a patent application consisting of 17 claims relating to the beta crystalline form of imatinib mesylate for an invention titled Crystal Modification of a N-Phenyl-2-Pyrimidineamine derivative, processes for its manufacture and its use filed by Novartis.24 The Patent Controller rejected the patent application on four different grounds,25 including Section 3(d).26 Unfortunately, the judgement just concludes that enhancement of efficacy has not been proved; it provides no reasoning for this conclusion. Aggrieved by the decision, Novartis filed two separate Writ Petitions challenging the constitutional validity of Section 3(d) and the validity of this order on merits, respectively.27 The first Writ Petition, challenging the constitutional validity of Section 3(d) was rejected by the Madras High Court.28 The second Writ Petition, challenging the legality of the order on merits was withdrawn pursuant to a notification which transferred all such cases to the newly created IPAB.29 On appeal, the IPAB reversed the findings of the Patent Controller relating to the
22 23
Ramanujan/Sen, supra note 4, at 145. Ramanujan/Sen, supra note 4, at 146. 24 See, Novartis IPAB, supra note 7, at paragraph 2; Novartis - Writ Petition, supra note 2, at paragraphs 9.12 9.14. This formulation and all previous variants thereof (including the imatinib free base) are sold under the brand name Glivec or Gleevec. For the scientific background leading to the invention of Glivec, see, Ramanujan/Sen, supra note 4, at 138-139. 25 See, Decision of the Patent Controller, supra note 6, at 4-5. The application was rejected on grounds of incorrect priority date, anticipation by prior art, non-obviousness over prior art and for failing to cross the bar under Section 3(d). 26 See, Decision of the Patent Controller, supra note 6, at 3-4. 27 See, Novartis - Writ Petition, supra note 2, at paragraph 4. 28 See, Novartis High Court, supra note 3, at paragraphs 15-17. 29 See, Novartis IPAB, supra note 7, at paragraph 2. See also, Ministry of Commerce & Industry, Notification No.12/15/2006-IPR-III (Regd. No. D.L. 33004/99), at S.O.514(E), (3rd April,
inventions priority date,30 novelty,31 and non-obviousness,32 but held that the subject matter is not patentable under Section 3(d).33 In its decision, the IPAB dealt with four different types of claims:34 1.Claims 1-10 and 14, product claims for the beta crystalline form of imatinib mesylate, which were rejected under Section 3(d).35 2.Claims 11 and 15, pharmaceutical compositions containing the claimed form, which were rejected under Section 3(d) and Section 3(e).36 3.Claims 12 and 16, use claims for the claimed forms and compositions, which were rejected under Section 3(d) and 3(i).37 4.Claims 13 and 17, process claims for consideration of grant, which were remanded to the Controller of Patents with certain observations.38 For this article, only the IPABs discussion on the first part of Section 3(d) is relevant (Claims 1-10, 11, 14-15). The IPAB concluded that the applicant failed to demonstrate a significant enhancement of efficacy of the claimed form over the prior art, and therefore, the product claims for the beta form of imatinib mesylate and pharmaceutical formulations containing the claimed form failed to cross the bar under Section 3(d).39 The essential argument of the patent applicant, Novartis, was that the beta crystalline form of imatinib mesylate (the claimed product) demonstrates enhanced efficacy compared to the known substance, i.e., imatinib free base, which was disclosed and claimed in Novartiss earlier patent (US 5521184)40 since the beta crystalline form shows 30% increased bioavailability (BA) and was more suitable for the preparation and formation of drugs due to decreased hygroscopicity and 2007), as available at <http://ipindia.nic.in/ipr/patent/gazetteofindia_apr2007.pdf> (last visited 1st April, 2010). 30 See, Novartis IPAB, supra note 7, at paragraphs 10(I), 11. 31 See, Novartis IPAB, supra note 7, at paragraphs 10(II), 11. 32 See, Novartis IPAB, supra note 7, at paragraphs 10(III), 11. 33 See, Novartis IPAB, supra note 7, at paragraphs 10(V), 11. 34 See, Novartis IPAB, supra note 7, at paragraph 11. 35 See, Novartis IPAB, supra note 7, at paragraphs 10(V), 11. 36 See, Novartis IPAB, supra note 7, at paragraphs 10(V), 11. 37 See, Novartis IPAB, supra note 7, at paragraphs 10(V), 11. 38 See, Novartis IPAB, supra note 7, at paragraph 11. 39 See, Novartis IPAB, supra note 7, at paragraph 10(V). 40 One definite issue that was contested in the Novartis IPAB case was whether the known compound was the imatinib free base or the imatinib mesylate salt itself. For instance, claim 1 of the prior art patent US 5521164 specifically claimed salt forms of the imatinib free base and the description stated that the salt could be formed using methane-sulphonic acid. However, it is not necessary go further into this issue, for the purposes of the present article.
improved thermodynamic stability, flow properties and processability, and was, therefore, far more suitable for the formulation and preparation of drugs.41 To this, the IPAB held that whether the claimed new form has a significantly enhanced efficacy or not, has to be decided on the basis of the disclosures made in the application.42 That is, the applicant must demonstrate enhanced efficacy in its patent application itself, and not by adducing further evidence at a later date.43 Although this has only been briefly stated and discussed in the judgment itself, this requirement imposed by the IPAB is highly significant, as will be seen in Part-III of this paper. Following the Madras High Court, the IPAB defined efficacy, for the purposes of Section 3(d), to mean therapeutic effect in healing a disease or having a good effect on the body.44 Based on this, the IPAB held that none of the alleged advantageous properties of the claimed form over the prior art, namely, better thermodynamic stability (facilitating storage), lower hygroscopicity (increasing shelf life), better flow properties (more processable) had any relationship with the curative properties of the claimed form, and were therefore irrelevant to the efficacy analysis.45 With regard to Novartis argument based on increased BA, the IPAB first referred to Dorlands Illustrated Medical Dictionary to define BA to mean the degree to which a drug or other substance becomes available to the target tissue after administration.46 Placing its reliance on various pharmacology books, the IPAB noted that increased BA of a drug leads only to more of the drug being absorbed by the body; but healing takes place only when the drug binds with an intended receptor within the body, occasioning the intended therapeutic response.47 In the words of the IPAB:48 Absorption relates to the amount of active ingredient that has been absorbed by the body. After the active ingredient is absorbed by the body for it to act, it must bind with the relevant reception of the target cell. This binding is the crucial step that determines effect. Where there are less number of receptor sites, increased availability of the active ingredient does not produce any therapeutic response. Therefore, binding and not absorption, is the key to healing the disease. Subsequently, after the receptor-drug binding occurs, the subsequent response can be measured. This response is typically in the form of increase or decrease of some parameters (in this case white blood cell count). Bioavailability relates to the absorption and not the binding stage of drug action and therefore is not a measure of efficacy of a drug. [see paragraph 7(3)
41 42
See, Novartis IPAB, supra note 7, at paragraphs 6, 7(1), 7(7)-7(11). See, Novartis IPAB, supra note 7, at paragraph 9(xvii). 43 Ibid. 44 See, Novartis IPAB, supra note 7, at paragraphs 9(xxi), 10(V). 45 See, Novartis IPAB, supra note 7, at paragraph 9(xxi). 46 See, Novartis IPAB, supra note 7, at paragraph 9(xviii). 47 See, Novartis IPAB, supra note 7, at paragraph 9(xviii). 48 Novartis IPAB, supra note 7, at paragraph 9(xviii)
supra]. Appellant has neither responded to this argument nor contradicted. The cited text book references relied upon by the Appellant also establish that bio-availability and efficacy are not the same.... On this basis, the IPAB concluded that bio-availability is concerned solely with the onset, intensity and duration of therapeutic response of the drug (that is, how quickly and how much of a drug appears in the blood after a specific dose is administered); the actual healing effect is caused by the binding of the drugs active ingredient with the appropriate receptors in the target cells.49 Therefore, the IPAB was convinced that bio-availability is not the same as therapeutic efficacy50 and hence, bio-availability and efficacy are generally not one and the same.51 This is a very significant statement as well as a highly confusing one, which requires further clarification. At first glance, it may seem that the IPAB has laid down two absolute per se rules; namely, that for the purposes of Section 3(d): (1) efficacy is to be understood as referring only to therapeutic efficacy;52 and that (2) bio-availability and therapeutic efficacy are not the same.53 While the first merely reiterates what the Madras High Court held, the second alleged per se rule is not really absolute, nor, in fact is it really a per se rule at all. Stating that bio-availability and efficacy are generally not one and the same54 is far less definitive and absolute than bioavailability and efficacy are never the same. The wording of the IPAB decision seems to suggest that the IPAB did not intend for statement (2) to be considered as gospel truth de hors an analysis of the relevant facts. Indeed, the IPAB pointed out that the reason it decided that bio-availability is not the same as therapeutic efficacy was that this was not responded to nor contradicted by the applicants.55 This suggests that, far from being a per se rule, the statement bio-availability is not the same as therapeutic efficacy, is a principle that is, at the very least, capable of being contradicted. This further suggests that the decision of the IPAB in this regard was specific to the particular factual circumstances of this particular case, and was not intended for general application. Since the IPAB seems to have treated the issue as a question of fact, we should not discount the distinct and very real possibility there may well be certain instances where an increase in BA causes an increase in therapeutic efficacy. However, the IPABs decision does provide support to the
49 50
Ibid. Ibid. This has been subsequently followed by the Patent Controller in its order on 30 April 2010, in the post-grant opposition matter of Hoffman-La Roche v. Ranbaxy, as available at <http://124.124.220.67/decision/959-MAS-1995-185/959-mas-1995.pdf> (last visited 22nd May, 2010). 51 See, Novartis IPAB, supra note 7, at paragraph 9(xviii). 52 See, Novartis IPAB, supra note 7, at paragraphs 9(xxi), 10(V). 53 Ibid. 54 See, Novartis IPAB, supra note 7, at paragraph 9(xviii). 55 Ibid.
argument that it is fallacious to presume that merely because there is an increase in BA, one can automatically conclude that there will also be an increase in therapeutic efficacy in all cases. The judgement does not further enumerate situations when this would or would not be the case, nor does it definitively address the question of what further tests are to be conducted and what evidence is to be submitted to prove increased therapeutic effect in such cases. However, the IPAB does note that experts in the pharmaceutical and pharmacological fields can measure the degree of therapeutic response by various well-known parameters (citing white blood cell count as an example),56 and thereby determine the therapeutic efficacy of a pharmaceutically active substance.57 C. The Final Status Before proceeding further with the analysis, it would be beneficial to summarize the conclusions of this part in the following question-answer format: Q.1: A.1: Q.2: A.2: What, for the purposes of Section 3(d), is efficacy? efficacy=therapeutic effect Given that efficacy=therapeutic effect, is increased BA suffice to The Madras High Court did not answer this question. The IPAB held that in the
demonstrate an enhancement of therapeutic effect? facts of the case, increased BA was insufficient. However, this is not a per se or general rule. The IPAB clearly considers this to be a question of fact and therefore leaves open the possibility that in a given case, increased BA may be sufficient. Q.3: efficacy? A.3: The Madras High Court did not answer this question. Although the IPAB did not definitely answer the question, it makes a reference to tests that study the degree of therapeutic response by various parameters. What exactly the IPAB meant by this is unclear. Given that in certain circumstances, increased BA alone may be insufficient to
establish increased therapeutic effect, what else is necessary to establish enhancement of
56 57
Ibid. See, Novartis IPAB, supra note 7, at paragraph 10(V).
Therefore, the second and the third questions have not been satisfactorily answered. The next part of this article will attempt to do so. This would be the scope of the policy analysis involved in this paper. Issues relating to Question 1 are not within the scope of this paper. PART-II PREPARING THE GROUND A. What, Beyond Increased BA, May Be Necessary to Establish Increase in Therapeutic Effect? The IPABs decision holds that, in certain cases, it may require something more than increased BA to conclude that the new form has increased therapeutic effect. It indicates the need for evidence that studies actual therapeutic response using well-known parameters. However, to even attempt to provide any sort of answer to this issue, one must necessarily understand the scientific framework involved. For this purpose, we turn to regulations of the Food and Drug Administration (FDA) and other scientific literature. As stated previously, the use of literature associated with the FDA is an attempt to analyse the Novartis - IPAB decision in the US setting. According to the FDA regulations, BA refers to the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.58 This is similar to the definition used by the IPAB in its decision. Neither efficacy nor therapeutic effect are clearly defined in the FDA regulations. However, it is relevant to this discussion to note the manner in which the FDA defines the relationship between BA and therapeutic effect. To understand this relationship, one has to look at another term bioequivalence (BE): Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Where there is an intentional difference in rate (e.g., in certain extended release dosage forms), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no significant difference in the extent to which the active ingredient or moiety from each product becomes available at the site of drug action. This applies only if the difference in the rate at which the active ingredient or moiety becomes available at the site of drug action is intentional and is reflected in the proposed labeling, is not essential to the attainment of effective body drug
58
21 C.F.R. 320.1(a).
concentrations on chronic use, and is considered medically insignificant for the drug.59 (Emphasis supplied) Technically, this is nothing but an absence of significant difference in the bioavailability (BA) of the two drugs. Two drugs without a significant difference in BA would, therefore, be considered bioequivalent. So how does BE connect BA and therapeutic effect? As the FDA states in its Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book),60 BE is taken as a proxy/surrogate for therapeutic equivalence:61 A major premiseis that bioequivalent drug products are therapeutically equivalent, and therefore, interchangeable. Underlying the concept of bioequivalence is the thesis that, if a drug product contains a drug substance that is chemically identical and is delivered to the site of action at the same rate and extent as another drug product, then it is equivalent and can be substituted for that drug product. (Emphasis supplied) It should be noted that the Orange Book, originally intended as a supplement towards fulfilling the goals of public health and economic efficiency,62 represents the FDAs judgement that when two drugs are declared to be therapeutically equivalent, they can be expected to have equivalent therapeutic effect and equivalent potential for adverse effects when used under the same conditions.63 That is, for the purposes of the Orange Book listing of therapeutically equivalent drugs, the FDA uses a one-to-one correspondence between BA and therapeutic effect. This raises an important question: can this one-to-one correspondence between BA and therapeutic effect be extrapolated to cases of increase in BA as well? In other words, if two bioequivalent drugs are considered therapeutically equivalent and if BE is based on comparing the BA of the two drugs, does it not automatically imply that an increased BA in one drug automatically means an increased therapeutic effect of that drug? An affirmative answer would contradict the decision of the IPAB. Although there may often be a correlation between an increase in BA and a consequential increase in the therapeutic effect of a drug, it may not
59 60
21 C.F.R. 320.1(e). APPROVED DRUG PRODUCTS WITH THERAPEUTIC EQUIVALENCE EVALUATIONS vii (Food and Drug Administration, Center for Drug Evaluation and Research, Approved Drug Products with Therapeutic Equivalence Evaluations29th edn., 2009), as available at <http://www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm> (last visited March 10, 2010) [hereinafter Orange Book]. 61 Orange Book, at viii. 62 See generally Department of Health, Education and Welfare, FDA, Proposed Rules Therapeutically Equivalent Drugs, 44 FR 2932, 2932-2934 (1979). [hereinafter Proposed Rules] 63 Id.
necessarily apply in any and all circumstances. Although explaining these reasons will be a slight deviation from the topic at hand, it is necessary to clarify the relationship between the various scientific terms this will be helpful in weeding out certain scientific misconceptions. These reasons are presented below in increasing order of complexity. Firstly, concluding that two drugs are therapeutically equivalent based solely on their BE, and consequently their respective BA, is allowed only when the two drugs have the identical active ingredient(s) and does not encompass a comparison of different therapeutic agents used for the same condition.64 For a drug to be considered therapeutically equivalent to another, it must be established, among other things, that the two drugs are both bioequivalent and are pharmaceutical equivalents (PE).65 PE has been defined by the FDA as follows: Pharmaceutical equivalents means drug products in identical dosage forms that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of modified release dosage forms that require a reservoir or overage or such forms as prefilled syringes where residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing period; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates.66 (Emphasis supplied) On the other side of the spectrum, are Pharmaceutical Alternatives (PA): Pharmaceutical alternatives mean drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates.67 (Emphasis supplied) According to the FDA, different salts or esters are considered as pharmaceutical alternatives and not equivalents.68 Therefore, automatically, such products are not considered to be therapeutically equivalent.69 At the same time, the FDA makes a clear distinction between pharmaceutical alternatives such as salts and esters, and polymorphs. Polymorphs are defined as substances that have the same active ingredient, but exist in different physical forms
64 65
Orange Book, at vii. Id. 66 21 C.F.R. 320.1(c). 67 21 C.F.R. 320.1(d). 68 Proposed Rules, at 2938. 69 Orange Book, at xiv.
different crystalline structures, different waters of hydration, solvates, and amorphous forms.70 The drug in the Novartis case fits squarely within this profile.71 Polymorphs are considered pharmaceutical equivalents and must meet the same standards of therapeutic equivalence (such as BE etc.):72 Anhydrous and hydrated entities, as well as different polymorphs, are considered pharmaceutical equivalents and must meet the same standards... Essentially, a one-to-one correspondence between BA and therapeutic effect is not allowed by the FDA when the two drugs do not have identical chemical formulae; i.e. they are not PEs. Where the two drugs have mostly identical chemical formulae, difference in the physical forms or structures does not prevent them from being considered PEs and one-to-one correspondence between BA and therapeutic effect is allowed. Therefore, in cases of new derivatives of known substances that do not have identical chemical formula, the FDA does not consider it legitimate to derive a one-to-one relationship between BA and therapeutic effect. As for the second reason, let us consider the following scenario Drug B has a BA less than that of Drug A and both are meant to treat the same condition. Does this necessarily mean that Drug B is less effective in treating the condition than drug A? Evidence indicates that this is not the case. The fact that the definition of BE is negatively worded becomes crucially important at this juncture; BE refers to the absence of a significant difference in the BA of the two drugs. That is, two drugs with different BA may still be considered as having the same therapeutic effect so long as the difference in their BA is not significant. Usually, if BA of one product is within the range of 80-125% of the BA of the other product, both being measured using well-accepted pharmacokinetic parameters and analysed using well-accepted statistical models, then they are considered bioequivalent.73 This is not always true since what amounts to a significant difference depends on the nature of the drug, targeted patient population, and clinical endpoints.74 For instance, the range of 80-125% may be narrowed in case the parent drug
70 71
See 68 Fed. Reg. at 36676, at 36678. See supra note 24. 72 Orange Book, at xiv. 73 FDA-CENTER FOR DRUG EVALUATION AND RESEARCH, GUIDANCE FOR INDUSTRY: STATISTICAL APPROACHES TO ESTABLISHING BIOEQUIVALENCE 2 (2001), as available at <http://www.fda.gov/cder/guidance/index.htm> (last visited May 3, 2010). 74 SHEIN-CHUNG CHOW, JEN-PEI LIU, DESIGN AND ANALYSIS OF BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES 15 (3rd edn., 2009).
has a narrow therapeutic range.75 Therefore, an increase in the BA for the new form does not translate into a significant increase in therapeutic effect in all cases. The third and most complex reason revolves around the manner in which drugs produce the desired response in a biological system. To illustrate, this paper assumes (at the risk of oversimplification) a highly simplistic model of drug action. At the most basic level, according to the classical Receptor Occupancy theory, a drug (an agonist, in chemical terms) interacts with receptors in the body in order to induce a physiological response.76 This occupancy theory, as originally proposed by Clark, states that a ligand, akin to normal enzymatic reactions, binds with the receptor forming the receptor-ligand complex and this complex elicits the physiological response.77 It was assumed that the physiological response generated is linearly proportional to the number of receptors occupied by the drug/ligand and maximum response is obtained when all the receptors are occupied.78 Due to this, mathematically and graphically, the response generated increases linearly with the increase in the concentration of the ligand, and once 100% occupancy is reached, the curve flattens out; that is, after a particular concentration level, the response tends towards becoming constant despite any further increase in the concentration of the drug.79 Therefore, once all the receptors are occupied (i.e. maximum response is elicited), presence of additional ligand/drug molecules will not result in an increase in the response. However, this did not show how, in certain cases, less-than-maximal responses were elicited even after 100% occupancy, which led Arins to add an additional factor in the equation known as intrinsic activity of the ligand, which could take values between 0 and 1.80 Since even this modified equation did not account for the ability of certain ligands to elicit maximal response despite occupying less than 100% of the receptor, Stephenson introduced the concept of receptor stimulus, which was proportional to what he termed as efficacy the ability of a
75
COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS, NOTE FOR GUIDANCE ON THE INVESTIGATION OF BIOAVAILABILITY AND BIOEQUIVALENCE, at 3.6.2 (2000), as available at <www.ema.europa.eu/pdfs/human/ewp/056095en.pdf> (last visited May 3. 2010). 76 R.R Ruffolo Jr., Important Concepts of Receptor Theory, 2 J. Auton. Pharmac. 277, 278 (1982), as available at <http://www3.interscience.wiley.com/journal/119567149/abstract> (last visited May 22, 2010). 77 Id. 78 Id. at 278. 79 See Terry Kenakin, Receptor Theory, 1.2.2-1.2.4 (Figures 1.2.1 & 1.2.2), in CURRENT PROTOCOLS IN PHARMACOLOGY 1.2 (S.J. Enna & Michael Williams et. al. (eds.), 2008), as available at <http://mrw.interscience.wiley.com/emrw/9780471141754/cp/cpph/article/ph0102/current/ abstract> (last visited May 22, 2010). 80 William P. Clarke and Richard A. Bond, The Elusive Nature of Intrinsic Efficacy, 19(7) Trends Pharmacol. Sci. 270, 270-271 (1998)
drug to produce an effect.81 This equation was finally modified by Furchgott, who theorized that the effect produced by a ligand (drug) is a function, inter alia, of: (i) intrinsic efficacy of the ligand, which is the ability of a drug to produce a stimulus from a single receptor; (ii) the affinity of the ligand to the receptor, and (iii) the concentration/density of the receptor and (iv) the efficiency of the stimulus-response coupling.82 While the original theory proposed a linear relationship, the modified theory projects a hyperbolic (non-linear) relationship between receptor occupancy and response, as well as between response and drug concentration.83 It represents the same principle: at a certain drug concentration, the tissue response peaks and further increases in concentration of the drug will not result in any increase in the response.84 Later, in 1983, the Operational Model of Agonism was developed and used to explain drug action and even this furnishes a hyperbolic relationship.85 While this represents the basic model of drug action, these equations do not and cannot fully quantify the efficiency of the post-receptor/ligand interaction that results in the cellular response. Current knowledge in the field indicates that a complex set of intra-cellular and intercellular signalling is involved in the functioning of a human body at a cellular level, whether under normal, diseased, or drug-induced conditions. The mechanism of signal transduction is involved in converting a chemical stimulus (in the form of a drug) into a specific cellular response:86 at a basic level, a ligand binds to a chemical receptor at the cells surface, which in turn triggers a cascade of bio-chemical reactions within the cell, and cross-talk between such cascades, which may vary in quantity and complexity depending on the condition involved. These reactions ultimately result in a response at the cellular level that may affect the functioning of a tissue or an organ thereby translating to a physiological response at the macro level. These molecular signalling pathways involve multiple cascades of biochemical reactions and therefore the signalling at each step may be amplified87 or retarded.88 Adding to the complexity is the
81 82
Id. Ruffolo Jr., Important Concepts of Receptor Theory, supra note 76, at 279-280. For a good summary of the historical development of the occupancy theory, see William P. Clarke and Richard A. Bond, The Elusive Nature of Intrinsic Efficacy, supra note 80, at 271 (Box 1). 83 See Terry Kenakin, Receptor Theory, supra note 79, at 1.2.3 (Figures 1.2.1). 84 See RICHARD FINKEL ET AL., LIPPINCOTT'S ILLUSTRATED REVIEWS: PHARMACOLOGY 30-31 th (4 edn., 2008). 85 See Terry Kenakin, Receptor Theory, supra note 79, at 1.2.13 (Figure 1.2.8). 86 See C. B. Brink et al., Recent Advances in Drug Action and Therapeutics: Relevance of Novel Concepts in G-Protein-Coupled Receptor And Signal Transduction Pharmacology, 57:4 Br. J. Clin. Pharmacol. 373, 374-375 (2003). 87 See Julio Vera et al., A Systems Biology Approach to Analyse Amplification in the JAK2-STAT5 Signalling Pathway, 2:38 BMC Systems Biology (2008), text accompanying n.1-10, available at http://www.biomedcentral.com/1752-0509/2/38 (last visited September 18, 2010).
presence of homeostatic feedback mechanisms within the human body. For instance, the chemical noradrenaline induces contraction in isolated vascular preparations and an increase in heart rate in isolated cardiac preparations; but when administered as a drug (in vivo) there is an increase in blood pressure, which is accompanied by a decrease, and not an increase, of heart rate. This reversal when administered in vivo, is due to the activation of homeostatic feedback mechanism that triggers a parasympathetic discharge (a nervous discharge to reduce the heart rate), which overrides the direct effect of noradrenaline on the heart.89 Accordingly, research indicates that different levels of non-linearity may exist depending on the nature of the signalling pathways involved in a disease and hence one cannot generalize to automatically classify drug action as linear.90 Hence, for a given condition and mechanisms of drug actions, even significant increases in the BA of one drug does not mean that there is a corresponding significant increase in the physiological response produced. Let us take the real-world example of two drugs which would obviously fall within the scope of Section 3(d) Omeprazole and its S-enantiomer (which was developed later) Esomeprazole. For our purposes, it is sufficient to note that Esomeprazole (S-O) is a new form of the known substance, Omeprazole (O). Both these drugs fall within the therapeutic class of proton pump inhibitors and have a very similar mechanism of action.91 They can be used to treat a variety of conditions, all associated with acid secretion, including duodenal ulcer, erosive oesophagitis and gastric ulcer.92 Comparative in-vivo studies of 20mg of the two drugs in human volunteers shows that the amount of S-O that that reaches systemic circulation and becomes available for action is 80% higher than that of O.93 Therefore, this shows that the BA of S-O, the new form, is definitely significantly higher than that of O, the known substance.
88
Interview with Mr. K.S. Ramanujan, Consultant-Computational, Cell Works Group Inc. (on file with Authors) 89 G. Castaeda-Hernndez and V. Granados-Soto, Considerations on Pharmacodynamics and Pharmacokinetics: Can Everything Be Explained By The Extent of Drug Binding to its Receptor?, 78 Can. J. Physiol. Pharmacol. 199, 201 (2000). 90 Interview with Mr. K.S. Ramanujan, Consultant-Computational, Cell Works Group Inc. (on file with Authors) 91 For a more detailed and scientific explanation of their mechanism of action, see G. Sachs et al., Review Article: The Clinical Pharmacology of Proton Pump Inhibitors, 23 (Suppl. 2) Aliment Pharmacol. Ther. 2, 3-4 (2006), available from http://www3.interscience.wiley.com/journal/118572328/abstract (last visited on July 8, 2010) (On file with authors). 92 Id. at 6. 93 T. Lind et al., Esomeprazole Provides Improved Acid Control vs. Omeprazole in Patients With Symptoms of Gastro-oesophageal Reflux Disease, 14 Aliment Pharmacol. Ther. 861, 864-865 (2000), available from http://www3.interscience.wiley.com/journal/120708914/abstract (last visited on July 8, 2010) (On file with authors).
What, however, about their efficacy? In the context of using any of these drugs to treat erosive oesophagitis, the relevant scientifically accepted benchmark (the therapeutic target to achieving the clinical end-point of treating erosive oesophagitis) is that the drug has to maintain the pH of the gastric content above 4.94 When the action of these two drugs are measured in the context of this parameter, pH > 4 was maintained for more than 12 hours in 54% and 44% of patients receiving S-O (20 mg) and O (20 mg), respectively, and pH > 4 was maintained for more than 16 hours in 24% and 14% of patients, respectively.95 Essentially, this constitutes approximately 9-10% enhancement of efficacy, compared to the 80% increase in bioavailability. On a similar note, another study (double-blind, randomized, multicentre, parallel-group trial) concluded that the difference in efficacy between S-O (20mg) and O (20mg) was statistically insignificant.96 At the same time, most of these studies concluded that S-O (40mg) has a significant increase in efficacy compared to the standard dose of O (20mg).97 That is, when comparing clinically accepted doses, S-O has significantly higher efficacy compared to O; but when comparing pharmacologically equivalent doses, the difference in efficacy is not considered significant enough. To this extent, evidence indicates that any clinical improvement noted on SO is more likely due to the dose increase than to any molecular advantage;98 that is, both S-O and O seem to have equivalent acid-suppressing capabilities on a milligram per milligram basis. The New Drug Application for Nexium (the brand product name for S-O), as submitted to the FDA,99 includes data on the healing rates of S-O (40 mg, 20mg) and O (20mg).100 From the data presented on the said document, it is apparent that pharmaceutically equivalent doses of S94 95
Id. at 864-865. Id. at 864. 96 P. J. Kahrilas et al., Esomeprazole Improves Healing and Symptom Resolution as Compared with Omeprazole in Reflux Oesophagitis Patients: A randomized Controlled Trial, 14 Aliment Pharmacol. Ther. 1249, 1253 (2000), available from http://www3.interscience.wiley.com/journal/120708765/abstract (last visited on July 8, 2010) (On file with authors). 97 See id.; see also supra note 3 at 864; see also Kwong Ming Fock et al., Proton Pump Inhibitors: Do Differences in Pharmacokinetics Translate into Differences in Clinical Outcomes?, 47 (1) Clin. Pharmacokinet 1, 4 (2008), as available at http://adisonline.com/pharmacokinetics/Fulltext/2008/47010/Proton_Pump_Inhibitors__Do _Differences_in.1.aspx (last visited on July 8, 2010). 98 B. R. Yacyshyn & A. B. Thomson, The Clinical Importance of Proton Pump Inhibitor Pharmacokinetics, 66 Digestion 67, 69 (2002), available from http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowFulltext&ArtikelNr=6558 8&ProduktNr=223838 (last visited July 8, 2010) (On file with authors). 99 NEXIUM (esomeprazole magnesium) DELAYED-RELEASE CAPSULES, NDA 21153/S-022, as available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021153s022lbl.pdf (last visited July 8, 2010). 100 Id. at 10.
O and O do not show any significant difference in the healing rates. Indeed, even as regards S-O (40mg) and O (20mg), whereas few studies showed a statistically significant increase in the healing rate, other studies have concluded that this was not the case.101 This brief case study demonstrates that there can be no basis for the argument that a statistically significant increase in the BA of the new form over the known form is bound to lead to a statistically significant increase in the efficacy of the new form over the known form as well. Getting back on track, as seen above, BA and BE studies indicates how fast the drug enters the systemic circulation (rate of absorption) and how much of the nominal strength enters the body (extent of absorption). In pharmacological terms, such studies fall under the branch of pharmacokinetics (PK), which deals with the way a chemical is absorbed, transported through the bloodstream to the target organ, metabolized, and excreted.102 Pharmacodynamics (PD), on the other hand, deals with the related field of the study of biochemical and physiological effects of the drug on the body.103 In other words, PD deals with what the drug does to the body, which is exactly what the IPAB seems to be referring to. PD studies involve the measurement of the pharmacological effects of a drug on the body, which is defined as any physiological action or effect attributable to the presence of the drug.104 Any effect that is desired is taken as the surrogate for the therapeutic effectiveness of the drug.105 Every drug is used to treat a condition using a particular mechanism, depending on the class of drugs it belongs to. Depending on these, each drug would be intended to product a particular effect on the body, which has a clinical meaning, and this effect should be such that it can be measured reasonably and reliably.106 For instance, antihyperintensives are a class of drugs that are used to treat hypertension by lowering blood pressure. A study on the decrease in the blood pressure achieved by the drug would be a measure of its therapeutic effect. This can be understood intuitively as well as logically. What is measured in such PD studies is the concentration-effect relationship, where concentration refers to the concentration of the drug in
101 102
Id. Erica Beecher-Monas, The Heuristics Of Intellectual Due Process: A Primer For Triers Of Science, 75 N.Y.U. L. Rev. 1563, n.310 (2000); see also THOMAS N. TOZER & MALCOLM ROWLAND, INTRODUCTION TO PHARMACOKINETICS AND PHARMACODYNAMICS: THE QUANTITATIVE BASIS OF DRUG THERAPY 2-3 (2006). 103 Lieutenant Commander David A. Berger & Captain John E. Deaton, Campbell And Its Progeny: The Death Of The Urinalysis Case, 47 Naval L. Rev. 1, n.155 (2000); THOMAS N. TOZER & MALCOLM ROWLAND, id. 104 Robert J. Wills, Basic Pharmacodynamic Concepts and Models, at 3, in, PHARMACODYNAMICS AND DRUG DEVELOPMENT: PERSPECTIVES IN CLINICAL PHARMACOLOGY 3 (NEAL R. CUTLER ET AL. EDS., 1994). 105 Id. 106 Id. at 4.
the blood plasma and not the dosage of the drug.107 Various models, such as the Linear Model, the Emax model and the Link model may be used to conduct PD studies.108 The most common method seems to be the Emax model, which involves finding out the maximum effect that can be reached (Emax) and the E50, or concentration in plasma or blood capable of producing 50% of the maximum effect, known as potency in in vivo studies.109 There seems to be sufficient literature on how to conduct such PD studies to measure therapeutic effect and even compare them. B. What Type of PD Studies May be Required? Clearly, methods and models exist to measure and compare therapeutic effect of drugs and with such PD studies, a patent applicant can prove that the new form is more therapeutically effective than the already known form. From this follows the next crucial question: what type of PD studies will be required as proof of increased therapeutic effect? The significance of this question will become apparent once we analyse the various stages of drug development and approval. Here again, we turn to the institutional and regulatory process in the USA for drug development. The general process for the development and approval of a new drug involves the following steps:110 Pre-clinical investigations that involve PK/PD studies conducted in vitro and on live animals for basic safety and efficacy data. This is to prove that further testing on humans is safe and justified. This is followed by filing an Investigational New Drug (IND) application with the FDA. The FDA must evaluate the IND and grant permission before the company can begin clinical studies on humans; the FDA decides whether the drug poses an unreasonable risk to humans in a proposed clinical trial. If the FDA approves the drug, the IND applicant may proceed to the clinical trials. Unless the FDA raises an objection within 30 days, the IND applicant may proceed with the clinical trials.111
107 108
Id. at 3-4. See id. at 6-11. 109 Rosario Calvo et al., Assessment of Endpoints: Kinetics and/or Dynamics, at 23, in THE IUPHAR COMPENDIUM OF BASIC PRINCIPLES FOR PHARMACOLOGICAL RESEARCH IN HUMANS 16 (Patrick du Souich, Michael Orme and Sergio Erill, eds., 2004), as available at <www.iuphar.org/pdf/hum_366.pdf> (last visited on April 1, 2010) 110 21 C.F.R. 312.21; THOMAS, PHARMACEUTICAL PATENT LAW 303-307 (2005). 111 21 C.F.R. 312.40(b)(1).
Phase-I investigation tests for safety and tolerability of the drug in humans. It involves about twenty to one hundred healthy, nominally paid volunteers; and generally lasts between one to three months.112
Phase II clinical trials continue testing for safety and tolerability and assess the preliminary efficacy of the drug. It often involves several hundred unpaid volunteers diagnosed with a particular condition and generally last about six months to two years.113
Phase III clinical trials constitute the most costly stage of drug development since they involve hundreds to several thousands of patients and last an average of four years.114 They are designed to evaluate the safety and efficacy of the drug within a larger and typically more diverse population. By the very objective and nature of each of these phases, each phase involves different
studies. In pre-clinical testing, prior to filing an IND, PK and PD studies are conducted on live animal subjects.115 Such studies assist in the identification of the parameters that act as a proxy for the clinical end-point of the drug, which necessarily produces evidence that show the efficacy of the drug, albeit in animals. The objective of a Phase-I trial which involves PK studies is to define the maximum tolerated dose (including the BA associated with each dose) in the system and identify specific adverse affects.116 Although there may be a trend towards studying the PD component of the drug action even in Phase-I,117 it should be remembered that Phase-I studies involve few volunteers, who are generally healthy;118 the focus is on deciding candidate dosage regimens.119 However, according to the guidance document prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of
112
Cf. Donna M. Gitter, Innovators and Imitators: An Analysis of Proposed Legislation Implementing an Abbreviated Approval Pathway for Follow-on Biologics in the United States, 35 Fla. St. U. L. Rev. 555, 566 (2008). 113 Id. 114 Id. 115 THOMAS N. TOZER & MALCOLM ROWLAND, supra note 84, at 11. 116 Lawrence Lesko & Roger L. Williams, Regulatory Perspective: The Role of Pharmacokinetics and Pharmacodynamics, at 123, in, PHARMACODYNAMICS AND DRUG DEVELOPMENT: PERSPECTIVES IN CLINICAL PHARMACOLOGY 115 (NEAL R. CUTLER ET AL. EDS., 1994). 117 Id. at 125. 118 Supra note 94. 119 THOMAS N. TOZER & MALCOLM ROWLAND, supra note 84, at 10; Joseph C. Fleishaker & James J. Ferry, Pharmacokinetic-Pharmacodynamic Modeling in Drug Development: Comments and Application, at 62 & 68, in HANDBOOK OF PHARMACOKINETIC/PHARMACODYNAMIC CORRELATION 57(Hartmut Derendorf & Gnther Hochhaus (eds.), 1995)
Pharmaceuticals for Human Use (ICH), during Phase-I trails:120 pharmacodynamic studies and studies relating drug blood levels to response (PK/PD studies) may be conducted in issued under the healthy volunteer subjects or in patients with the target disease. In patients, if there is an appropriate measure, pharmacodynamic data can provide early estimates of activity and potential efficacy and may guide the dosage and dose regimen in later studies....Preliminary studies of activity or potential therapeutic benefit may be conducted in Phase I as a secondary objective. Such studies are generally performed in later phases but may be appropriate when drug activity is readily measurable with a short duration of drug exposure in patients at this early stage.121 (Emphasis Supplied) In Phase-II, more thorough and statistically significant PD studies or concentrationeffect/response studies are undertaken.122 With the candidate dose regimens collected from Phase-I, these are tested on patients with the disease or condition of interest in Phase-II. It is generally the first time a drug is tested on humans with the disease or condition of interest, and hence the first opportunity to obtain statistically valuable data on its efficacy. More obviously, Phase-III involves PD studies on a wider scale. Simply put, PD studies, in form of another, are conducted in almost every stage of a drugs development: (a) pre-clinical testing involves PD studies on animals; and (b) PD studies are conducted in vivo in humans in all three phases of clinical trials, with the quantity and accuracy increasing with each phase. This explains the question presented earlier: which of these PD studies are required, according to the IPAB? Unfortunately, beyond just hinting at the need for PD studies, albeit impliedly, the IPAB decision does not provide any definitive answers. The first possibility is the use of PD studies in animal models. In the context of the utility doctrine in patent law, cases have held that, generally, animal testing evincing some sort of phamacological activity is sufficient to establish utility; certainty that the drug will have the intended phamacological effect in humans (through clinical trials) is not essential.123 If animal studies are, without question, sufficient to prove utility, why should they also not be sufficient to prove increased therapeutic effect? To apply a per se rule that PD studies in animal models are sufficient to prove increased therapeutic effect may work against the object and purpose of Section 3(d). The apparent purpose of Section 3(d) is to prevent the patenting of drugs that do not have a significant
120
INTERNATIONAL CONFERENCE ON HARMONISATION: GUIDANCE ON GENERAL CONSIDERATIONS FOR CLINICAL TRIALS (July 1997), as available at <http://www.ich.org/cache/compo/475-272-1.html#E8> (last visited 1 May 2010) 121 Id. at 6-7. 122 THOMAS N. TOZER & MALCOLM ROWLAND, supra note 84, at 11. 123 See generally, Jansen v. Teva, 583 F.3d 1317, 1327-1328 (Fed.Cir. 2009)
increase in efficacy.124 When applied to drugs that are meant for use in humans, this would translate into preventing the patenting of drugs that lack a significant increase in therapeutic effect in humans. Consider the hypothetical situation where a new form of a drug intended to be used as medication in humans shows significant increase in therapeutic effect in animal PD studies and is allowed to be patented,125 although later clinical trials in humans may indicate that the therapeutic effect in humans is actually quite similar to that of the already known form. This would result in a situation where a new form of a known substance, which is meant for use as medication for humans, and which does not have a significant increase in therapeutic effect, has been granted a patent. This completely undermines the enactment of Section 3(d) itself. The question, therefore, is whether there are possible models for scaling PD data from animals to predict effect in humans. For instance, an existing model for scaling PD data from animals to humans is called the empirical efficacy scaling model, which assumes that the relative potency and maximum efficacy in humans is equal to the relative potency and maximum efficacy in an animal model.126 This method can only be applied when there are comparative molecules of the same class, and preclinical and clinical PK/PD properties of a comparator drug are known.127 By comparing the preclinical data for the new chemical entity (NCE) with that of comparator molecules and based on the existing clinical data on the comparative molecules, this model allows one to predict the PK/PD properties of the NCE on humans. While applying this model, data on the difference in protein binding and difference in receptor binding affinity between the NCE and a comparative drug will be needed since the ratio of human-toanimal binding affinity of the new chemical NCE may not be the same as that for the comparative drug.128 It is these factors that make the model scientifically sound. While it is accepted in the art that interspecies differences (rats and humans, for instance) in relative receptor affinity and plasma protein binding occur, several examples have shown that these factors are similar between rats and humans for certain chemically-related series of drugs.129 It has been stated that the scaling of PD data from in vitro and animal studies relies heavily on the
124 125
Ramanujan/Sen, supra note 4, at 137-138. Assuming it fulfills all other criteria for patentability. 126 Chien, J. Y. et al., Pharmacokinetics/pharmacodynamics and the stages of drug development: Role of modeling and simulation, (2005), as available at <http://www.aapsj.org/view.asp?art=aapsj070355> (last visited May 7, 2010) (illustrating the application of this model for a new chemical entity for treating hypertension). 127 Id. 128 Id. 129 Donald E. Mager et al., Scaling Pharmacodynamics from in vitro and Preclinical Animal Studies to Humans, Vol.24 (No.1) Drug Metabolism and Pharmacokinetics 16, at 20 (2009), as available at <http://www.jstage.jst.go.jp/article/dmpk/24/1/24_16/_article> (last visited May 10, 2010).
ability to predict and integrate the fundamental processes controlling drug exposure (pharmacokinetics), drug action (pharmacology), and interactions with physiological systems.130 On the other hand, there is literature to the contrary stating that while there are accepted methods of extrapolating PK studies conducted on animal models to humans,131 there are no accepted robust methods for scaling of PD studies from animal models to humans,132 since enzymes of drug metabolism differ across species, the selectivities and affinities for different ligands and receptors are also different across species.133 Not being experts in this field, we can at best surmise that while scaling of PD studies from animals and humans is possible using certain models, much more work needs to be done on the development of these models before they are accepted as being authoritative. Further, such scaling is highly dependent on several factors, including the class of drugs at issue, availability of information on the parent substance, and the mechanism followed by the drugs to induce the desired pharmacological effect in the human body, as well as the similarities and differences between the parent substance and the new form. Therefore, just as there is no per se rule that PD studies in animal models would be sufficient to prove increased therapeutic effect in humans, there can be no per se rule against the use of PD studies from animals to prove significant enhancement of therapeutic effect in humans, so long as the same can be supported by a scientifically sound model to scale the data from animals to humans. Furthermore, as previously stated, drug action within a human body is a complex process involving chemical signalling pathway(s) at the cellular level that may involve homeostatic feedbacks. Therefore predicting drug action in humans based on animal studies may not be feasible in certain cases. To reiterate an earlier conclusion, this is a question of fact and has to be accordingly dealt with on a case-to-case basis and we believe that the IPAB decision in the Novartis case leaves this possibility open. Therefore, in some cases, it may not be sufficient to submit PD studies from animal models. The PTO may require PD studies in humans. Even when this is the case, as stated earlier, PD studies in humans are conducted in all three phases of clinical trial. From the scientific literature presented earlier, Phase-III trials seem definitive enough to establish an increase in therapeutic effect and it can be reasonably presumed that the
130 131
Id. at 22. These include Scaling based on Allometric principles, Physiologically Based PK Model Scaling, Population Compartmental Model Scaling. Cf. Joy C. Hsu, Animal to Human Scaling and Pharmacokinetic and Pharmacodynamic Modeling of Anticancer Drugs, at 2-18 (Dissertation, May 2009), as available at <http://www.digitallibrary.usc.edu/assetserver/controller/item/etd-Hsu2618.pdf> (last visited May 1, 2010). 132 Id. at 20-21 ( 1.1.5). 133 Id. at 19.
PTO or the courts will not require a Phase-III clinical trial. This leaves Phase-I134 and Phase-II clinical trials.135 This concludes the background and review of the implications of the IPABs decision in the Novartis case. Depending on the factual context, the IPABs decision leaves open the possibility that evidence from Phase-I trials or Phase-II trials or simple animal studies (coupled with scaling models) may be needed to prove increased therapeutic effect. The consequences of each of these possibilities will be discussed in the next part. However, prior to proceeding to the policy implications, it is important to take note of one particular consequence - whether any of these possibilities create any sort of practical impediments, in the form of additional tests/trials and costs, for pharmaceutical companies to engage in the R&D of new forms of known substances? This issue is dealt with at this juncture, only so as to dismiss it, thereby giving more clarity to the scope of the policy analysis in Part-III.
C.
Do the various Possible Evidentiary Requirements of Section 3(d) result in additional responsibilities and costs to a Pharmaceutical Company? Under the existing regulatory set-up in America, approval for any drug, including a new
form of a known substance can be through one of the following possibilities: (a) an Abbreviated New Drug Application (ANDA); (b) a New Drug Application (NDA) under 505(b)(1); and (c) a 505(b)(2) application, otherwise known as a paper NDA. Let us take the hypothetical scenario that drug B, a new form of an already known drug A, shows increased BA over A, such that the FDA considers this to be a significance difference for the purposes of evaluating BE. Therefore, from the FDAs perspective, drug B will not be processed under an ANDA, leaving two other options: an NDA or a 505(b)(2) application. An NDA will require an IND application that includes PK/PD studies in animals,136 no objection from the FDA to the IND application137 and Phases I-III clinical trials prior to getting FDA approval.138 In other words, if the market approval for the drug is being pursued through a NDA, animal testing, Phase-I and Phase-II trials have to be conducted anyway. If the Patent
134
We do not have sufficient data to conclude whether one would have to fully complete a Phase-I trial to have any reliable data. For the present purpose, it is presumed that one would have to go through Phase-I completely to have any reliable data. 135 We do not have sufficient data to conclude whether one would have to fully complete a Phase-II trial to have any reliable data. For the present purpose, it is presumed that one would have to go through Phase-I completely to have any reliable data. 136 21 C.F.R. 312.23. 137 21 C.F.R. 312.20. 138 21 C.F.R. 312.21.
Office requires any of these studies for the purposes of evaluating the patent application under Section 3(d), the applicant would only be conducting studies and submitting data that it anyway would have to conduct and generate. Therefore, the evidentiary requirements of Section 3(d) do not impose any additional responsibilities or costs that the pharmaceutical company could have avoided if not for Section 3(d). But what about a 505(b)(2) application? A 505(b)(2) application is one for which one or more of the investigations relied upon by the applicant for approval were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.139 The FDA regulations surrounding the application of this provision,140 as well the FDAs draft guidance document suggests that if a proposed drug product is a modification of an existing drug product, but shows an increased BA than the listed reference drug, a 505(b)(2) application may be filed.141 The draft guidance document further indicates that in such cases, the FDA may require additional clinical studies to document safety and efficacy at the different rate and extent of delivery.142 All this is couched in largely discretionary language. In other words, in a 505(b)(2) application for a different form of a known drug with significantly higher BA, an applicant can rely on safety and efficacy studies of an already approved drug. However, to what extent it may rely on existing data and to what extent it would be required to do independent clinical trials is not clear. Elsewhere, the FDA notes that in a few instances, a significantly high absorption rate has resulted in increased toxicity.143 From all this, we can only surmise that a drug with a significant increase in BA would not be processed under a 505(b)(2) without independent clinical trials. However, it is unclear as to what type of clinical trials will be required and how long such trials may take. For instance, according to one industry source, typically, one or more PK studies, Phase-II dose finding study and confirmatory Phase-III study is required even for a 505(b)(2) application, though not to the same extent as a normal NDA.144 A case study of a neurologic product that followed the 505(b)(2) approval process shows that the company was required to
139 140
21 U.S.C. 355(b)(2). 21 CFR 314.54(a) & (b) 141 FOOD AND DRUG ADMINISTRATION (CENTER FOR DRUG EVALUATION AND RESEARCH), DRAFT GUIDANCE FOR INDUSTRY DPPLICATIONS COVERED BY SECTION 505(B)(2) 5-6 (OCTOBER 1999). 142 Id. at 6. 143 Proposed Rules, at 2941. 144 D A Prasanna, Vice Chairman, Ecron Acunova, The 505(b)(2) Alternative: An NDA that Saves Time and Money, at 3, 8, & 10 (Presented at CPHI/ICSE, Madrid, Spain, October 14, 2009), as available at <www.ecronacunova.com/pdf/whitepapers/505Alternative.pdf> (last visited 24 April, 2010).
conduct a double-blind efficacy study.145 Nonetheless, since the clinical studies that may be required for a 505(b)(2) application mirrors Phase-II and/or Phase-III studies, it can safely be assumed that this should be sufficient for the purposes of the evidentiary requirements of Section 3(d). Therefore, irrespective of whether the regulatory approval for the new form is being pursued under a 505(b)(2) application or an NDA, the evidentiary requirements of Section 3(d) do not impose any additional responsibilities or costs that the pharmaceutical company could have avoided if not for Section 3(d).146 PART -III POLICY ANALYSIS: SPREADING THE SEEDS OF CHANGE? It seems clear, therefore, that submitting acceptable evidence of increased therapeutic effect over and above evidence of increase in BA should not be an issue. The applicant has to conduct PD studies that establish the increased therapeutic effect of the new form. The issue, however, is the type of PD studies that need to be submitted. The IPAB decision seems to leave open the possibilities of proving increased therapeutic effect based on PD studies in animal models, Phase-I trial and Phase-II trial. From the IPAB decision alone, it is not possible to reach a definitive decision regarding the types of evidence that would suffice in a particular case. From a brief review of the science behind drug development and drug action, it is doubtful whether one may be able to provide or predict any watertight compartments as regards the type of evidence that may be needed vis--vis any class of drug. That being the case, for the rest of this paper, all possibilities are considered. SCENARIO 1 shall denote the situation where the necessary evidentiary basis for proof of increased therapeutic effect is PD studies in scaled animal models. SCENARIO 2 shall denote the situation where the necessary evidentiary basis for proof of increased therapeutic effect is Phase-I clinical trial. SCENARIO 3 shall denote the situation where the necessary evidentiary basis for proof of increased therapeutic effect is Phase-II clinical trial. Note that a particular drug would fit under any of these scenarios depending on the nature of the drug, its therapeutic class and other scientific parameters since, as seen earlier in Part-II of this article,
145
Harriette L. Nadler, DJA Golbal Pharmaceuticals Inc., Demystifying FDAs 505(b)(2) Drug Registration Process, as available at <www.djaglobalpharma.com/Demystifying_FDA.pdf> (last visited 24 April, 2010) 146 If no approval is anyway being sought for the new form, in which case it cannot be manufactured and sold in the market, patent protection is not necessary (both practically and theoretically as a matter of innovation policy) and hence Section 3(d) will be irrelevant.
different types of evidence may be required depends on various parameters. In Part-I of this paper, we had briefly alluded to the IPABs statement that proof of significant increase in therapeutic effect has to be part of the patent application itself. It may be pertinent to understand what exactly is meant by the following words of the IPAB:147 A patent is granted on the basis of its full disclosure of the invention in the specification furnished on the priority date of the application. Even an amendment is also not allowed in the specification which in substance is not disclosed therein (see Section 59). The patent law debars an applicant a grant of patent for belated discovery of a new thing which is not disclosed which may or may not be pivotal in determining patentability. Thus, the Appellant is not entitled to make out a case for patent in its favour by importing a new matter in the specification which was later on discovered/established. The patentability, therefore, if any, will have to be established on the basis of original disclosure contained in the specification. (Emphasis Supplied) Therefore, the facts of the Novartis case involved the specification not even alluding to any increase in BA and/or efficacy of the drug involved. For this reason, the court held that to later rely on a property or element not disclosed in the application was not allowed. However, consider, instead, the situation where the applicant does state somewhere in the specification that the new form possesses a significantly enhanced efficacy, though no data is yet to confirm this to be the case. Will this mere statement or allegation in the specification suffice for the purpose of Section 3(d) such that when the application is later examined by the patent office, the applicant may be able to amend the application to include later developed data? Or, as an alternative, can the applicant merely supplement the statement in the specification by use of later developed data showing the increase in efficacy in the form of supplementing evidence? It is a fundamental principle of patent law that patentability of an invention is to be measured at the time of filing the application (or an earlier priority date) and not by way of evidence arising later to the filing of the application. For instance, the novelty of an invention cannot be destroyed by evidence arising later to the priority or filing date of the application; similarly, publications later than the priority or filing date cannot be used to invalidate an invention as being obvious. The same holds true even for the ingredient of utility. Seen from this perspective, the enhancement of efficacy is a fundamental patentability criterion under Section 3 and hence, the examination is to proceed based on the information available as of the time of filing the application. If this be the case, the data relating to the enhancement of efficacy has to be filed at the time of the filing the application and the evidentiary basis will determine the timing of the patent application. The above-quoted language of the IPAB is broad enough to be
147
Novartis IPAB, supra note 7, at paragraph 9(xvii).
interpreted to apply to all factual situations.
Therefore, in SCENARIO 1, the patent
application can be filed immediately after pre-clinical testing, which corresponds to the general timing of patent applications today in the pharmaceutical industry. On the other hand, in SCENARIO 2 and SCENARIO 3, the patent application can be filed only after Phase-I trial and Phase-II trial, respectively. In this part of the paper, we shall analyse the policy issues that need to be considered in each of these scenarios as regards the timing of filing the patent applications for new forms of known substances and the possible policy implications for incentives to innovate that would follow from any delay in filing that may result. A. The Context of the Policy Linkage: Why Patents are important for Innovation in the Pharmaceutical Industry: To understand how and why the delay in filing a patent application for a new form may affect innovation in the industry vis--vis new forms, one must first generally comprehend the role played by patents in pharmaceutical innovation. Fortunately for us, much ink has been spilt on this point and we need merely provide a brief summary of these findings. According to estimates, a pharmaceutical company, on an average, spends at least $800 million for a new drug that reaches the market, with almost $450 million being spent on clinical trials and studies conducted to satisfy the FDA requirements of drug approval.148 On the other hand, due to the ANDA process, where generic companies may rely on the clinical data developed by the innovator company, the cost of getting approval for a generic imitation of that drug is estimated to be around $2 million only.149 Once this approval has been granted, reverseengineering of the contents of the drug by competitors is not difficult and the cost of actually manufacturing such drugs is low.150 This is especially because the reverse-engineering process is fairly straightforward once the drug is available in the market. Simply put, the ratio of innovation cost/imitation cost in the pharmaceutical industry is very high - it is highly expensive to innovate, but very inexpensive to imitate. And this high cost of innovation is spread out over an average of eight to eleven years from initial identification through FDA approval.151 This
148
Ben Roin, Unpatentable Drugs and the Standards of Patentability, 87 Texas L. Rev. 503, 510-511 (2009) (citing the most acknowledged estimates on this topic at n.21 and n.22). [hereinafter Roin] 149 Id. at 511. 150 Cf. William Fisher, Intellectual Property and Innovation: Theoretical, Empirical and Historical Perspectives, at 11 (2001), as available at <http://cyber.law.harvard.edu/people/tfisher/Innovation.pdf> (last visited May 7, 2010). 151 WILLIAM W. FISHER III & TALHA SYED, DRUGS, LAW AND THE GLOBAL HEALTH CRISIS 2, p.4 (Draft - On file with the author). [hereinafter WILLIAM W. FISHER III & TALHA SYED]
investment is also risky, considering that, on an average, out of every 5000 compounds initially chosen for screening, 250 on average are selected for pre-clinical testing, five are selected for clinical testing, and one receives FDA approval and finds its way onto the market.152 As a result, whereas the innovator company has to price its drug to recover its R&D and approval costs, the generic company can price its drug 30-80% lower than the innovator.153 The resulting loss of market share to the innovator company can be swift and severe. For instance, Eli Lilys Prozac lost 80% of its market share within just 2 months after generic entry (after patent expiry).154 Therefore, without exclusivity, the innovator company cannot recover its huge innovation costs and without the possibility of such cost-recovery, pharmaceutical companies will not engage in innovation. Patent exclusivity, therefore, provides an incentive to pharmaceutical companies to invest in drug innovation.155 Having briefly summarized the significance of patents for pharmaceutical innovation, the topic that needs to be addressed is the impact the delay in filing of a patent application for a new form of a known substance might have, on innovation in this field. The potential issues, as we see it, are dealt with below.156
152 153
Id. at 2, p.5. Richard G. Frank & Erica Seiguer, Generic Drug Competition in the U.S., in BUSINESS BRIEFING: PHARMATECH 56, at 56 (2003), as available at <http://www.touchbriefings.com/download.cfm?fileID=493> (last visited 24 April 2010). 154 Id. 155 Without risking further digressions, it is assumed for the purposes of this paper that a patent is the most effective way to incentivize such innovation compared to other methods in isolation. 156 For the purposes of analysis, we have also assumed that the position of law is certain, and that the courts as well the PTO apply the same standard for any relevant doctrine. If, however, there is inconsistency between the standard applied by the PTO and the courts, this may result in an incentive problem. Take for instance, the case of Jansen v. Teva. 583 F.3d 1317 (Fed.Cir. 2009). Although the case was on the doctrine of utility, the underlying issue is analogous. In that case, the PTO approved and granted a patent on a method to treat Alzheimers disease with a particular drug and accepted as evidence of utility, the inventors analytical reasoning in the specification; no in vitro or animal testing was done at the time of the patent application. Id. at 1325-1326. Subsequent testing proved the methods effectiveness and even the FDA approved the treatment. Id. at 1322, 1325, 1327; id. at 1328 (Gajarsa J., dissenting). However, after the company spent time, money and resources in getting the FDA approval for the treatment, the patent was invalidated by the court on the basis that analytical reasoning alone, without in vitro and animal testing, was insufficient to establish utility. Id. at 1327-1328. Similarly, if the PTO uses a particular standard to approve a patent application on a new form of a drug, which is later invalidated by the courts using a higher standard, this inconsistency and uncertainty may act as a severe disincentive to engage the R&D and development of such drugs. Although the damage may have already been done with respect to a given drug, the incentive problem arises based on the fact that while planning on such R&D in the future, the uncertainty in the position of law would definitely be a major factor that companies would consider.
C.
The Issue of Duplicative Research:157 One issue associated with the filing of patent application is whether it leads to greater
inefficiency and social waste. This directly bears on the point at which drug innovation shifts from the many minds phase to the single mind phase. One of the most basic economic models on IPR and innovation is that rival firms competing with each other for a patent (or any other IPR) will tend towards accelerated innovation.158 A necessary by-product of this system is that, for a given innovation, rival firms may compete for the same prize of exclusivity (through patent and other methods) and associated supra-normal profits or rents. The patent system represents a winner takes it all scenario since it only allows for one patent holder on a particular invention the company which is the first to win the R&D race. This results in the race to patent the new drug.159 Once one of the players files a patent on a particular drug, the patent incentive for the other players to engage or continue with the same research is removed.160 This patent race will tend to result in over-investment in R&D and duplicative R&D.161 During this race to patent many minds in the form of rival firms will work on the same invention; but after the race is over, the further development of the innovation will be in the hands of a single mind - the patent applicant/holder. The pharmaceutical industry is no exception; there is strong evidence indicating parallel R&D and clinical testing paths.162 Whether this duplication is wasteful or optimal is a different question all together. A few scholars opine that this duplicative R&D is wasteful and causes inefficiency, while others emphasize on the fact that this encourages higher aggregate
157
Although, it would be reasonable to state that the clinical trials required for a 505(b)(2) application would not be as long and costly as those required for NDA, due to the uncertainty as to what kind of clinical trials will be needed, developing a policy analysis for based on a 505(b)(2) application would not be possible. Under any circumstance, the NDA process represents the more rigorous, costlier and lengthier approval process and consequently the worst-case scenario for the drug company. Since there is not much guidance, a pharmaceutical company would have to consider the very real possibility that it would be required by the FDA to file a NDA for the new form. Hence, for the purposes of the paper, it is assumed that the patent applicant, in hypothetical scenarios presented from here on in, has to go through a complete clinical trial process just as in a NDA. 158 See generally Yoram Barzel, Optimal Timing of Innovations, 50 Rev. Econ. & Stat. 348 (1968). 159 Roin, supra note 129, at 513. 160 The position remains the same, irrespective of whether the patent is ultimately granted or not since either way, the application becomes a public document and will be considered as anticipatory prior art under 35 USC 102. 161 See e.g. Pankaj Tandon, Rivalry and the Excessive Allocation of Resources to Research, 14 The Bell Journal of Economics 152, 152-153 & 164 (Spring, 1983). Due to this competing environment, and the otherwise non-excludable nature of the results of research processes, research processes by each player in the marker would take place in secrecy from one another. 162 F.M Scherer, Markets and Uncertainty in Pharmaceutical Development, at 13 (2007), as available at <http:// web.hks.harvard.edu/publications/getFile.aspx?Id=267> (last visited May 7, 2010).
investment.163 However, firstly, as stated earlier, the patent race that is causing this duplication advances the date at which a successful solution is available.164 In the field of medicines, this could mean life or death to many people. Second, the wastefulness of such duplicative research may be ameliorated by the fact that there is a distinct likelihood that a significant amount of the R&D invested in developing the main pioneer drug by those companies that lose the patent race gets channelled into developing me-too165 drugs.166 Given that the same patient may react differently to even two therapeutically equivalent drugs, me-too drugs result in larger number of therapeutic equivalents, which may enable relief, and with fewer side effects, for a broader range of people.167 For now, it is believed that these costs are acceptable sacrifices since the social benefits outweigh these costs.168 In any case, it is ultimately a question of how much duplicative research is valuable and optimal, and at what point it becomes excessive enough for it to not be justified by a cost-benefit evaluation. This is a much more complex question, the answer to which is not easily decipherable.169 It is not possible, on the basis of the existing literature, to come to any conclusion on this point. Nonetheless, there seems to be sufficient literature to indicate that this is potentially a problematic area that needs further analysis. Given the relevance of this debate surrounding duplicative research, it is crucial to understand the implications of the evidentiary requirements of Section 3(d) to the debate. This race to patent need not necessarily end at the time of filing of the patent application; it occurs only when the other players in the market gain access to this information, which may be different from the filing date. Under 35 USC 122(b)(1)(A), a patent application shall promptly be published 18 months after the earliest filing date claimed by the application, unless the applicant requests earlier publication. Therefore, at best, the shift in phase for a particular drug from many minds to a single mind will occur immediately after filing the
163
Peter Menell, Intellectual Property: General Theories, at 138, in 2 ENCYCLOPEDIA OF LAW & ECONOMICS 129 (Boudewijn Bouckaert and Gerrit de Geest (eds.), 2000), as available at <http://encyclo.findlaw.com/1600book.pdf> (last visited May 7, 2010). It has been suggested that certain amount of duplicative R&D is socially desirable since research outcomes are uncertain and ex ante probability of overall success is increased by duplication. Pankaj Tandon, id. at 153 & 157. 164 F.M Scherer, supra note 143, at 14-15. 165 Me-too drugs those drugs that are therapeutically equivalent enough to compete in the same product market with the pioneer drug, but bio-chemically different enough to obtain a new patent without infringing the prior drugs claims was spent by companies. WILLIAM W. FISHER III & TALHA SYED, supra note 132, at 4. 166 WILLIAM W. FISHER III & TALHA SYED, supra note 132, at 4, p.50. 167 WILLIAM W. FISHER III & TALHA SYED, supra note 132, 4, p.54. 168 Roin, supra note 129, at 514. 169 F.M Scherer, supra note 143, at 13.
patent application, and at the very latest, 18 months after filing the patent application.170 The earlier this shift in phase, the less inefficient the system becomes due to the reduction in duplicative research. In SCENARIO 1, the patent application is filed after pre-clinical testing/during IND phase. This is the earliest phase of the FDA approval process and assuming that the FDA has no objection, the company can go ahead with Phase-I trial. One possibility is that the patent application is published immediately after filing and therefore, the shift to the single mind phase for a new chemical entity occurs before Phase-I trials. Hence, duplicative efforts are limited to the basic research level and pre-clinical testing stage. This represents the best-case version of SCENARIO 1. On the other hand, assuming that the applicant has not requested for immediate publication, the default publication time for a patent application would be 18 months.171 Hence, in this case, by the time the other players are made aware of the patent filing, they would be 18 months further into the drug development stage. According to one estimate (First Estimate), on an average, a Phase-I trial takes 18 months172 and according to another (Second Estimate), a Phase-I trial takes 21 months.173 Therefore, in this case, according to the First Estimate, the duplicative research will include the whole Phase-I trial, which costs an average of $10 million.174 According to the second estimate, this additional 18 months corresponds to approximately 85% of the time-length of Phase-I trial and assuming a linear relationship between the time and cost of Phase-I trial, the duplicative research would correspond to 85% of the average costs of a Phase-I trial: $25 million.175 This represents the worst-case version of SCENARIO 1. However, it is to be remembered that SCENARIO 1 also represents the general filing time for most drugs, irrespective of the requirements of Section 3(d). Therefore, duplicative research in SCENARIO 1 represents the current situation. This will be used as a reference for the other scenarios.
170
A patent applicant can choose to have his or her patent application held in secrecy until it issues as a patent, by submitting a written request for non-publication and swear that he or she will not file any corresponding foreign patent applications. 35 USC 122(b)(2)(B) In todays world, it is doubtful that any pharmaceutical company would wish to forego the opportunity to file patent applications in other countries, though the author has not done any such independent study. 171 35 USC 122(b)(1)(A). 172 Cf. Sikora, James P., Providing hope: developing a viable regulatory framework for providing terminally ill patients with adequate access to investigational drugs, 70 U. Pitt. L. Rev. 191, 196 (2008). [hereinafter Sikora] 173 Joseph A. DiMasi et al., The Price of Innovation: New Estimates of Drug Development Costs, 22 J. Health Econ. 151, 165 (Table 3) (2003), as available at <http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.128.4362&rep=rep1&type=pdf> (last visited May 1, 2010). [hereinafter DiMasi et al.] 174 Sikora, supra note 152, at 196. 175 DiMasi et al., supra note 153, at 165 (Table 3).
In SCENARIO 2, the best-case version would mean that the additional time and resources wasted in duplicative research would correspond to the average length and costs of Phase-I trial. Compared to the best-case version of SCENARIO 1, going by the First Estimate, this adds 18 months and $10 million176 of duplicative research, and going by the Second Estimate, this adds an average of 21 months and $30 million177 of duplicative research. In the worst-case version of SCENARIO 2 where publication takes place 18 months after applying for the patent, the drug would have proceeded into its Phase-II trial. Based on the First Estimate, this corresponds to 75% of the average time of Phase-II testing,178 and according to the Second Estimate, approximately 72% of average time of Phase-II testing.179 Assuming a linear relationship between the time and the cost in Phase-II testing, this corresponds to an average of approximately $15 million180 and $21 million,181 respectively. This would be the additional duplicative research as compared to the worst-case version of SCENARIO 1. Similarly, in the best-case version of SCENARIO 3, where the patent application is published immediately after filing, the additional time and resources wasted in duplicative research would correspond to the average length and costs of Phase-I and Phase-II trial. Going by the First Estimate, compared to best-case version of SCENARIO 1, this would result in an additional 42 months and $30 million in duplicative research. In the worst-case scenario, the drug would be in its Phase-III testing. The First Estimate suggests that the additional 18 months is approximately 50-37.5% of the average time of Phase-III testing,182 and the Second Estimate suggests that this additional 18 months is approximately 60% of the average time of Phase-III testing.183 Again, assuming a linear relationship between the time and the cost in Phase-III testing stage as well, this corresponds to approximately $22-$17 million according to the First Estimate,184 and $22 million according to the Second Estimate, of duplicative research.185 Understandably, one may be highly skeptical regarding the numbers mentioned herein. For one, we are assuming the accuracy of the data being used. Secondly, we have highlighted the assumptions made to arrive at these numbers. Admittedly, both these factors may tend to make the calculations questionable. However, these calculations are only to provide an idea of
176 177
Sikora, supra note 152, at 196. DiMasi et al., supra note 153, at 165 (Table 3). 178 Sikora, supra note 152, at 196. 179 DiMasi et al., supra note 153, at 165 (Table 3). 180 Sikora, supra note 152, at 196. 181 DiMasi et al., supra note 153, at 165 (Table 3). 182 Sikora, supra note 152, at 197. 183 DiMasi et al., supra note 153, at 165 (Table 3). 184 Sikora, supra note 152, at 197. 185 DiMasi et al., supra note 153, at 165 (Table 3).
duplicative research that may potentially occur. Even if one disagrees with the data or the calculations, the underlying analysis as to increase in the time-length of and the resources spent on duplicative research is logically sound. At this juncture, it is important to consider an important objection one may raise to the analysis presented above. One may question whether the same scenario of duplicative research used for drugs in general, fits with new forms of known substances based on the following intuitive reasoning: if the making and using the new form is not possible without the use or manipulation of the know drug, there would be no duplicative effort since the patent applicant (assuming that the applicant holds the patent for the known drug) is anyway the only one who could use or manipulate the known drug; on the other hand, if this new form is otherwise patentable and can be made or used without the use or manipulation of the older patented drug, then the above scenario fits perfectly since there is a distinct possibility that other players will be engaged in such duplicative research. However, as intuitive as this may seem, it is also incorrect due to the controversial interpretation accorded to the Bolar Exemption186 by a recent US Supreme Court decision.187 The Bolar Exemption holds that it shall not be an act of infringement to make, use, offer to sell, or sell a patented invention solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs.188 The Supreme Court concluded that this exemption covers use of a patented drug during pre-clinical testing of another drug.189 In doing so the court laid out a few ground rules in applying the Bolar Exemption: basic scientific research using the patented compound performed without the intent or a reasonable belief to develop a particular drug (cause the sort of physiological effect the researcher intends to induce) is not covered by the exemption.190 it will cover other experiments using patented drugs during preclinical or clinical research so long as this reasonably generates information relevant to FDA premarket approval process, even if the experiments are not ultimately submitted to the FDA or the new drug was not ultimately the subject of an FDA submission.191 This means that even if the making or using of the new form requires the use or manipulation of older patented drug, it can still be performed under the Bolar Exemption
186 187
35 USC 271(e)(1). Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005). [hereinafter Merck case] 188 35 USC 271(e)(1). 189 Merck case, at 202 & 204. 190 Merck case, at 205-206. 191 Merck case, at 206.
without any fear of infringement since such use is with the intent of generating information for gaining FDA approval on the new form. Therefore, the estimates and analysis developed above for SCENARIO 1, SCENARIO 2 and SCENARIO 3 applies with equal force even for new forms of known substances. All this proves that in both SCENARIO 2 and SCENARIO 3, which, generally, differs from the current set-up, the evidentiary requirements for Section 3(d) would add more duplicative research. However, whether this is truly wasteful or not, depends first on what is the optimal level of duplicative or parallel research. As stated earlier, the answer to this question is not known. Further, the potential increase in duplicative research due to Section 3(d) has to be balanced by the alleged benefits of Section 3(d). It remains to be seen as to how this can be done and what results can be discerned from such an analysis. B. The Interplay of the Novelty doctrine in Patent Law: Could the Evidentiary Requirements of Section 3(d) create an incentive problem? The second potential problem that arises from the timing of filing the patent application is the doctrine of anticipation under 35 USC 102, which in turn affects the incentives for pharmaceutical companies to engage in such research. If at the time the patent application for a new form is being applied for, the applicant has robust reasons to believe that no patent will be granted due to the invention becoming anticipated, this would act as a huge dis-incentive to that applicant to proceed with further trials and the development of that drug.192 Under 102(b), a person shall not be entitled to a patent if the invention was described in a printed publication or was in public use more than one year prior to the date of the application for patent in the United States. The novelty issue arises because, in SCENARIO 2, by the time the patent application is filed, an IND has been filed and Phase-I testing is already complete. Similarly, in SCENARIO 3, an IND would have been filed, and both Phase-I and Phase-II testing would already be complete. This means that the new form has actually already been used on humans and all data relating to these tests is present in some tangible material in the form of documents and data, maintained by the company and submitted to the FDA. If the latter amounts to a printed publication and/or the former amounts to public use, then in SCENARIO 2 and SCENARIO 3, the IPABs decision has very serious implications on the incentives companies have to engage in the R&D of new forms of drugs.
192
See supra Part-III(A) of this paper.
B.1.
Is the Printed Publication Doctrine a Cause for Concern? Taking up the question of possible anticipation by printed publication first, case law
establishes that to prove a reference to be a printed publication under 102(b), it has to be: publicly accessible any person interested and ordinarily skilled in the subject matter or art, exercising reasonable diligence, can locate it.193 printed all material accessible to the public in tangible form a description, drawing, or photograph.194 It could be printed, handwritten, or on microfilm or magnetic disc or tape, etc.195 The FDA regulations clearly state that the FDA shall not disclose the existence of an IND nor any data/information in an IND,196 nor even any data relating to safety-and-efficacy studies,197 unless it has previously been otherwise publicly disclosed or acknowledged. Obviously, pharmaceutical companies have all the more reason to maintain them as confidential. Any access to these data would occur only under obligations of confidentiality. As such, therefore, they are not accessible for a reasonable person having ordinary skills in the art (pharmacology, chemistry, medicine etc.) and would, therefore, not qualify as a printed publication.198 B.2. Is the Public Use Doctrine a Cause for Concern? The second potential issue arising from the novelty doctrine is the public use bar. Under 35 USC 102(b), an inventor must file a patent application within one year after placing the invention in public use in the United States. Coming directly to the point, the question is whether clinical trials would be considered as public use for the purposes of 35 USC 102(b)? This becomes relevant in SCENARIO 2 and SCENARIO 3 since both circumstances involve the filing of the patent application after some form of clinical trials. This is because, in both SCENARIO 2 and SCENARIO 3, based on the average time that Phase-I and PhaseII trials take, it is a definite possibility that the clinical trials would have been conducted one year prior to the filing date.199 In one of the earliest landmark cases on this public use bar, the Supreme Court laid
193
Bruckelmyer v. Ground Heaters, Inc., 445 F.3d 1374, 1378 (Fed. Cir. 2006); see also In re Klopfenstein, 380 F.3d 1345, 1348 (Fed. Cir. 2004). 194 Baron v. Bausch & Lomb Inc., 25 U.S.P.Q.2d 1641, 1662 (W.D.N.Y., 1992). 195 In re Wyer, 655 F.2d 221, 227 (C.C.P.A. 1981). 196 21 CFR 312.130 197 21 CFR 314.430 198 General Tire & Rubber Co. v. Firestone Tire & Rubber Co., 349 F. Supp. 345, 355 (N.D. Ohio 1972); Vetco Offshore Industries, Inc. v. Rucker Co., 448 F. Supp. 1203 (N.D. Cal. 1978) (holding that information disseminated under confidential conditions may not amount to printed publication) 199 For an estimate of the general time-period Phase-I and Phase-II testings take, refer to supra notes 1521-152 153 and associated text.
down three guidelines to determine whether a use amounted to public use:200 (a) use of a single patented article in public is sufficient to constitute public use; (b) the use or knowledge of a single person, other than the inventor, is sufficient; (c) a use may be public although it is not observable by the public eye. At the same time, there exists a judicially created doctrine of experimental use (activity in order to ascertain whether the invention works for its intended purpose) that acts an exception to the public use bar.201 Generally, it was held that two requirements are needed for a finding of experimental use:202 first, the invention cannot have previously been perfected; and, second, the activity must have been for the purpose of experimentation; that is, bringing the invention to perfection. In SmithKline Beecham Corp. v. Apotex Corp.,203 the Federal Circuit ruled that the patent was invalid because clinical trials of the drug more than one year before filing was a public use under 102(b).204 However, the Court of Appeal for the Federal Circuit (en banc) vacated the original Federal Circuit opinion, without offering a replacing opinion.205 This left the question open as to whether clinical trials would amount to public use. In 2006, in Eli Lilly & Co. v. Zenith Goldline Pharmaceuticals, Inc.,206 the court considered whether a drug, olanzapine, used in clinical trials for over one year was subject to the public use bar. The court held that this was experimental use and therefore not subject to the public use bar. The court listed six indicia as relevant: (1) the length of the test period, (2) any confidentiality agreement, (3) any records of testing, (4) any monitoring and control of the test results, (5) the number of tests, and (6) the length of the test period in relation to tests of similar inventions.207 Applying these indicia to the facts of the case, the court noted:208 Lilly restricted access to the facility and provided full-time security. Lilly closely monitored and confined the movements of the volunteers, who were healthy and not suffering from schizophrenia, for the duration of the study. Visitors to the volunteers did not interrupt the control or confidentiality of the study. Moreover, as the trial court noted, the clinical trials did not use the drugs to treat schizophrenic patients, but merely to test the safety and efficacy of the drug.... In this case, Lilly tailored its tests to their experimental drug safety and efficacy purpose, adequately monitored for results, and maintained confidentiality throughout the duration of the study. The trial court did not err in finding
200 201
Egbert v. Lippmann, 104 U.S. 333, 336 (1881), City of Elizabeth v. American Nicholson Pavement Co., 97 U.S. 126, 135-136 (1877) 202 See generally Michele M. Glessner, One Size Fits All: Keeping the Totality of the Circumstances Test for Public Use Cases After Pfaff and Smithkline, 81 Notre Dame L. Rev. 387, 396-398 (2005). 203 365 F.3d 1306 (Fed. Cir. 2004). 204 Id. at 1318, 1320. 205 403 F.3d 1328, 1329 (Fed. Cir. 2005). 206 471 F.3d 1369 (Fed. Cir. 2006). 207 Id. at 1381. 208 Id.
no public use. (Emphasis Supplied) While this case only dealt with Phase-I trials, most of the criteria that applied to Phase-I trials (monitoring test results, maintaining confidentiality etc.) apply equally to Phase-II trials; logically the same conclusion will apply to Phase-II trials as well. However, as is clear from the above quote, there were two particular facts noted by the court: the trials were merely to test the safety and efficacy of the drug, and in those trials the drug was used on healthy volunteers. These were not mentioned as factors in the general criteria laid down by the court. It is unclear as to whether the court considered these two factors as disjunctive. That is, when the court states ...the clinical trials did not use the drugs to treat schizophrenic patients, but merely to test the safety and efficacy of the drug, is this based on the fact that the trial involved only healthy volunteers? Or is the court suggesting that they are separate factors in that the statement ...the clinical trials did not use the drugs to treat schizophrenic patients, but merely to test the safety and efficacy of the drug refers to the purpose and intent of the trials, rather than the volunteers being healthy? To the extent of this lack of clarity, the decision is unclear as to whether use of non-healthy volunteers in later parts of Phase-I and Phase-II trials, in toto, would result in a public use bar. Therefore, the decision in the Eli Lilly case alone does not provide a satisfactory and complete answer to the earlier question. This necessitates reference to another case: In re Omeprazole Patent Litigation.209 That case involved four large clinical trials, including Phases I-III, on the claimed drug.210 The court ultimately held that the clinical studies investigating the claimed drug formulation did not qualify as invalidating public use, on the grounds that the drug was not reduced to practice at the time of the clinical trials.211 The court noted that reduction to practice involves constructing an embodiment that meets all claimed limitations and a determination that the invention would work for its intended purpose.212 The court noted that though the actual formulation ultimately patented was produced prior to the Phase-III clinical trial,213 this did not amount to proving that the patentee has determined the intended purpose of increasing in vivo drug stability without significantly compromising long-term storage stability.214 Similarly, though not in the context of clinical trials, in Manville Sales Corp. v. Paramount Sys., Inc.,215
209 210
536 F.3d 1361 (Fed. Cir. 2008). Id. at 1371-1373. 211 Id. at 1373-1375. 212 Id. at 1373. 213 Id. at 1374. 214 Id. at 1373-1375. 215 917 F.2d 544 (Fed. Cir. 1990); see also Seal-Flex, Inc. v. Athletic Track and Court Constr., 98 F.3d 1318, 1320 & 1323 (Fed. Cir. 1996). Importantly, the inherent feature that was tested was not part of the claim itself.
the court held that outdoor testing of the claimed light pole to test the durability of the invention was not public use since the testing was done to determine whether the invention possessed a feature that is inherently necessary for that invention.216 Following this logic, irrespective of whether the patent applicant files the patent application after Phase-I or Phase-II trials, this delay in filing the application would solely be the result of testing done to establish an enhancement in the therapeutic effect of that new form. Where establishing this increase in therapeutic effect is a necessary criteria to patent that drug and is therefore an inherent feature of the invention (irrespective of the claim language), the Phase-I and the Phase-II trials will not be considered as public use for the purposes of 102(b). B.3. International Applications: Potential Problems under the Patent Cooperation Treaty: The Patent Cooperation Treaty (PCT) is a treaty that is administered by the WIPO, which came into force in 1978.217 Much has been written about the PCT system and we need only provide the relevant provision of the PCT that are necessary for our discussion. The PCT system was created to facilitate the process of pursuing the patenting of an invention in several countries and basically consists of a two-phase process an international phase and a national phase. The international phase starts with the filing of an international application.218 Typically, an international application claims benefit from the filing date of an earlier application which was filed less than twelve months ago (as provided under the Paris Convention).219 A national phase follows the international phase during which applicants pursue their applications in the national patent offices of countries in which protection is desired. The time limit by which the applicant must undertake the necessary steps for entry into the national phase is thirty months from the priority date, with a few exceptions.220 The PCT allows countries to fix the time limit at thirty-one months.221 This window of thirty/thirty one months is extremely crucial herein. An international application will be promptly published within 18 months from the international filing date.222 When the national phase in the respective countries is initiated, the respective authority in those
216 217
Id. at 551. Patent Cooperation Treaty, June 19, 1970, 28 U.S.T. 7645, 1160 U.N.T.S. 231, as available at <http://www.wipo.int/pct/en/texts/articles/atoc.htm> (last visited May 10, 2010). 218 Id., Article 3. 219 Id., Article 8. 220 Id., Article 39(1). 221 Id., Article 22(3) & 39(1)(b). 222 Id., Article 21.
countries will have to consider the date of filing of an international application as the relevant filing date for the national law purposes.223 Therefore the publication of the international application (and that of an earlier application, in case the international application claims priority from an earlier application) will not act as anticipatory documents. However, after this thirty/thirty one month period expires, the national filing in any of the PCT countries cannot claim the benefit of priority of the international application. This will make the international application (and that of an earlier application, in case the international application claims priory from an earlier application) anticipatory for any further national filings. Presently, India is the only country that has implemented Section 3(d). While, this article is written to analyse the potential implications of incorporating a provision such as Section 3(d) into the American legal system, let us, for a limited purpose, discard this structure and limit the presence of Section 3(d) to India. Let us now consider the case of a company, COMPANY 1, that is engaged in the R&D of a new form of a new substance and which intends to file an application in all PCT countries, including India.224 In SCENARIO 2, for the purpose of India, it would seem that the company would need to have completed Phase-I trials prior to filing the application. Since the date considered by the national authority as the filing date for the purposes of the national phase is the international filing date, it would seem that Phase-I evidence needs to be present in the international application itself.225 Similarly, in SCENARIO 3, it would seem that Phase-II evidence needs to be present in the international application itself. Therefore, it would seem that to even initiate the PCT process, COMPANY 1 would have to have completed the necessary Phase-I or Phase-II trials. Every entity interested to obtain a patent in India would have to follow such a strategy. But what if, another company (COMPANY 2) engaged in the same research, is willing to forego patent protection in India? Unlike COMPANY 1, COMPANY 2 need not worry about either Phase-I or Phase-II trial evidence to establish patentability in any other jurisdictions. Without this requirement, therefore, COMPANY 2 will be able to file a patent earlier and thereby preclude COMPANY 1 from obtaining patent protection anywhere in the world, even though COMPANY 1 may have arrived at the invention first. Assuming that both companies have kept their research confidential, neither company would be aware that they were engaged in parallel research, nor will COMPANY 1 be aware
223 224
Id., Article 11(3)&(4). It should be noted that SCENARIO 1 does not raise much of an issue since it mirrors the existing situation. 225 Later evidence as to increased therapeutic effect cannot be incorporated into the application since that would constitute new matter.
that COMPANY 2 is willing to forego patent protection in India. Of course, for the above hypothetical, the existence of a company such as COMPANY 2 (which is willing to forego patent protection in India) must be realistically possible. At the very least, companies would be alive to such a possibility, especially given the competitive nature of the pharmaceutical industry. As a result of the secrecy and uncertainty surrounding the R&D and patenting decisions within pharmaceutical companies, it would be an extremely risky decision for COMPANY 1 to not consider the possibility that a competitor may be willing to forego patent protection in India. How far will this affect the incentives to COMPANY 1 to engage in the R&D of new forms of known substances? Note that the hypothetical till now was based on the fact that the evidentiary burden imposed by Section 3(d) is present only in India. Let us change this hypothetical a little. Reapplying the original structure of this article, i.e., assuming Section 3(d) as been implemented in the American legal system, would result in two countries (India and America) requiring the additional evidentiary burden of Section 3(d). Would COMPANY 2 in order to definitely beat COMPANY 1 in the PCT race, be willing to forego patent protection in the USA and India? As a corollary, would COMPANY 1 even consider the possibility that a rival, such as COMPANY 2 would decide to forego patent protection in both countries? Compared to the earlier hypothetical involving just India, the stakes are much higher in the present hypothetical and is consequently much more risky. To what extent the incentives to engage in the R&D new forms are affected in either hypothetical, is extremely difficult to gauge. It not possible to state, without any conclusive empirical studies, how far the operation of just such a dis-incentive in one country (such as India) or two countries (especially countries such as America and India) might affect the incentives for a pharmaceutical company to engage in the R&D of new forms altogether. This is even more especially true when the question is not one of patent protection per se but of the process that must be completed for acquiring such protection. Therefore, it would be even more difficult to determine (due to the increasing complexity of such a determination) how far the incentive to innovate would be affected if more countries start implementing Section 3(d). Such issues cannot be easily answered and we shall make no attempt to answer them. It should be noted, however, that this dilemma arises due to the fact that Section 3(d) is enacted only in two countries (at least, so we have assumed); in a world where such a requirement is present everywhere, this would not occur. Nonetheless, it is doubtful whether such a level of harmonisation will occur in the near future, if at all it does. In such a situation, it is extremely important to consider that the hypothetical situations
mentioned above turn out in the worst possible way, i.e., there exists a COMPANY 2, which is willing to forego patent protection in Section 3(d) countries and gets away with a patent on a new form though it came up with the same invention later than COMPANY 1, only because COMPANY 1 was forced to apply for patents in Section 3(d) countries. This would indeed be a huge blow for companies to engage in the R&D of new forms, unless the dilemma can be resolved. The logical way to resolve this dilemma would be allow companies to file the international patent application as they do currently, and at the same time not be subject to a Section 3(d) rejection at the national stage. PCT Article 28 provides applicants the opportunity to amend the claims, the description, and the drawings of their application during the national stage before the Designated Offices, so long as such amendments do not go beyond the disclosure in the international application as filed. As long as the amendments are in accordance with national law and the PCT, it would seem that it might be permissible to furnish further evidence which would help make the substantive determination of whether the patent should be granted or the application rejected.226 It should be noted that PCT Article 27(2)(ii) provides that it shall not be inconsistent with the provisions of the PCT for national law to require applicants to furnish documents not part of the international application but which constitute proof of allegations or statements made, while PCT Article 27(6) further clarifies that national law may require that the applicant furnish evidence in respect of any substantive condition of patentability prescribed by such law. Presumably, therefore, PCT Article 28 was intended for just such a purpose as we have envisaged allowing applicants to ensure that they complied with the minutiae of requirements of national patent laws (where such requirements are present only in certain countries but not in others) without having to wait for such compliance before they could file their international application. The relevant question is whether Article 28 will allow an applicant to amend the appication to add evidence supporting enhanced efficacy later? If yes, then international applications for new forms can be filed at an earlier stage rather than waiting till end of Phase-I or Phase-II trials. This is possible when the added material to the application (proof of enhanced efficacy) does not go beyond the disclosure in the international application as filed. To state more plainly, it would seem that, so long as the international application discloses the fact that the claimed new form demonstrates enhanced efficacy over the known form by some form of acceptable evidence, it may be permissible to introduce further evidence of enhanced efficacy of the new form over the known form during the national phase.
226
Jay Erstling and Isabelle Boutillon, The Patent Cooperation Treaty: At the Center of the International Patent System, 32 Wm. Mitchell L. Rev. 1583, 1598 (2006).
The restriction under Article 28, therefore, is similar to the restriction under American law which states that amendments to a patent application, though freely allowed,227 can only be allowed if they do not introduce new matter into the disclosure of the invention.228 Since the PCT regime itself does not provide for any treaty body that provides authoritative interpretrations of the PCT, the interpretation of the text will be done by the relevant national authority. In our hypothetical structure, this is the USPTO. In our opinion, the rationale behind this prohibition against adding new matter in an amendment in the USA, as in any other country, (as opposed to a new matter rejection for a re-issue patent) is straight-forward it is to ensure that the patent applicant, as of the filing date, files an application that is complete in all respects for the purposes of its examination. As stated earlier in this article, the filing of the patent application serves an imporant function of ending the patent-race, which, arguably, has its own economic merits. If any and every amendment is allowed, an abusive applicant may end the patent-race very early by using an incomplete disclosure and later amend this disclosure to satisfy the requirements of law, including 112. A second consequence of allowing any and all amendments is that the examination of patent applications becomes impossible since the PTO will never have a finalized discloure to examine! As a matter of policy, therefore, not every amendment can be allowed. At the same time, none would dispute the unfair results of prohibiting every amendment. The doctrine of new matter is meant to be the balancing point. From the above analysis, one may provide an approximate meaning of the term new matter matter that would tend to affect the substance of the patent (i.e., the invention); matter that would affect the patentability of the invention covered by the patent. In general terms, courts have noted that new matter means substantive matter which would have the effect of changing the invention or of introducing what might be the subject of a separate patent application;229 new matter is any substantive matter which is not found in the specifications as originally filed, and which involves a departure from the original invention.230 Does this definition mean that any matter that is being added to a patent application is new matter simply because it is not present in the originial application?
227
U.S.Application of Saunders, 444 F.2d 599, 607 (1971); Technicon Instruments Corp. v. Coleman Instruments Corp., 385 F.2d 391, 393 (1967) (amendments to further explain or claim what is disclosed in an earlier application are permissible). 228 35 U.S.C.A. 132; 37 C.F.R. 1.121(f). 229 Topliff v. Topliff, 145 U.S. 156, 166 (1892). 230 U.S.Westinghouse Electric & Mfg. Co. v. Radio Corporation of America, 24 F. Supp. 933, 940, (1938).
The answer is no.231 Even in the case where the amendment adds matter to the original application, this addition will not be new matter if what has been added was inherently contained in the original application.232 For instance, clarifications and explanations of details already contained in the original application are permissible.233 What is the test for determining whether something added by way of an amendment is inherently present in the original appication? The Federal Circuir notes that to avoid the new matter prohibition, an applicant must show that its original application supports the amended matter, (emphasis supplied)234 without explaining further as to what is meant by the original application supporting the amended matter. Another Federal Ciruit decision holds that the the test for sufficiency of support in a parent application is whether the disclosure of the application relied upon reasonably conveys to the artisan that the inventor had possession at that time of the later claimed subject matter.235 In other words, an amendment adding matter to the specification is said to be sufficently supported by the original application if a person skilled in the art would have thought so. The above language may still seem vague and unclear, which is inevitable since the issue involves questions of fact. One manner of crystallizing this requirement for support is to state that if a person skilled in the relevant art would not have to undertake any independent experimentation in order to decipher the amended matter from the original application, then the added matter is not new matter.236 With this test in mind, let us proceed to analyse its implications in terms of Section 3(d). Consider an original application that merely contains a statement that the new form has a siginifcant enhancement in efficacy, without evidence of scaled animal studies (in cases falling under SCENARIO 1), Phase-I trial (in cases falling under SCENARIO 2) and Phase-II trial (in cases falling under SCENARIO 3). The direct question is whether any of this evidence can be added later by way of an amendment without being rejected as new matter. To remind our readers, the three scnearios created in this article are on the basis of the minimal evidence required to establish increased efficacy, based on the nature of the drug
231
Application of Oda, 443 F.2d 1200, 1203 (1971) (In a sense, anything inserted in a specification that was not there before is new to the specification but that does not necessarily mean it is prohibited as new matter.) 232 Schering Corp. v. Amgen Inc., 222 F.3d 1347, 1352 (Fed. Cir. 2000). 233 Triax Co. v. Hartman Metal Fabricators, Inc., 479 F.2d 951, 956-957 (2d Cir. 1973); . 234 Schering Corp. v. Amgen Inc., 222 F.3d 1347, 1352 (Fed. Cir. 2000). 235 TurboCare Div. of Demag Delaval Turbomachinery Corp. v. General Elec. Co., 264 F.3d 1111, 1118 (Fed. Cir. 2001) (quoting Ralston Purina Co. v. Far-Mar-Co, Inc., 772 F.2d 1570, 1575 (Fed.Cir.1985)). 236 Acme Highway Products Corp. v. D. S. Brown Co., 431 F.2d 1074, 1081 (6th Cir. 1970), cert. denied, 401 U.S. 956, 91 S.Ct. 977, 28 L.Ed.2d 239 (1971); cited approvingly in Stearn v. Superior Distributing Co., 674 F.2d 539, 544 (6th Cir. 1982).
involved and other scientific factors. In other words, for a drug that fits within SCENARIO 1, a person skilled in the art can conclude increased efficacy based on scaled animal studies, at a minimum. Similarly for a drug that fits within SCENARIO 2 and SCENARIO 3, a person skilled in the art can conclude increased efficacy based on Phase-I trials or Phase-II trials, at a minimum, respectively. Therefore, in the specific hypothetical stated above, in SCENARIO 1, a skilled person can reasonably conclude (without independent expermination) that the original patent application for the new form has increased efficacy only if scaled animal studies are disclosed in the original application itself. Similarly, in SCENARIO 2 and SCENARIO 3, a skilled person can reasonably believe (without independent expermination) that the original patent application for the new form has increased efficacy only if Phase-I trials or Phase-II trials, are disclosed in the original application itself. Therefore, regardless of the provisions for amendment that may allow applicants a limited amount of discretion as regards the amount of evidence of enhanced efficacy with which to proceed with their international application, all the concerns and considerations discussed above with regard to Section 3(d)s evidentiary requirements remains equally true. CONCLUSION: SPREADING THE SEEDS OF CHANGE The IPAB decision in the Novartis case seems to consider the question of proving enhancement of efficacy as a question of fact. In the opinion of the authors, the case establishes no per se rule that increase in BA alone will never suffice to prove an enhancement of efficacy. However, the IPAB was quite clear that proof of significant enhancement of efficacy has to be available at the time of filing the patent application. In those subset of cases where an increase in BA alone will not suffice, the IPAB decision seems to incline towards requiring PD studies as proof of increased efficacy, though the language in the decision is the least bit definitive. Looking into the institutional and regulatory pipeline of drug development, PD studies are conducted at various stages, with increasing level of scientific certainty. This article developed them as three different scenarios - PD studies from animal models, PD studies from Phase-I testing and PD studies from Phase-II testing. Each of these scenarios results in a temporal difference in the filing of the patent application. This article then delved into the policy implications of the temporal differences each of these scenarios. The article noted that any potential impact on the incentives to engage in the R&D of new forms of known substances may result from whether the temporal differences affected the patentability of new form. After analysing the current position of law on the most probable anticipation issues that may arise from the temporal differences, the article concluded that patentability of the new form will not
be affected. However, in the context of international applications pursed under the PCT route, it was seen that the evidentiary requirements under Section 3(d) leads to an interesting result. The Novartis - IPAB decision requires evidence of significant enhancement of efficacy as part of the initial disclosures at the filing date of application, which translates into the international filing date in the PCT context. This may unnecessarily delay the initiation of the PCT process itself, unless pharmaceutical companies would be willing to forego patent protection in countries with requirements such as Section 3(d) - presently, only India. Even if one firm is willing to forego this protection by ignoring the evidentiary requirements of Section 3(d) in the international application, there is a significant likelihood that this would force other firms to do the same. Will any one firm would be willing to take this decision and if so, whether this firm would do the same in case more countries started implementing provisions and evidentiary requirements similar to Indian Section 3(d)? Will this lack of patent protection in one country for a new form dis-incentivize a firm from engaging in the R&D of such new forms when it can gain protection in other parts of the world? Will the incentives change if, and when, more countries implement provisions and evidentiary requirements similar to Indian Section 3(d)? Irrespective of any incentive problem, does this amount to a de facto violation of TRIPs? Admittedly, these are questions raised and left un-answered as being beyond the scope of this paper. However, these are interesting and important questions that deserve special significant attention. The article proceeded further and analysed another consequence of these temporal differences - duplicative research. Since filing the patent application / publishing the application puts an end to the race to patent and duplicative research, the postponement of the filing date of the patent in each of the scenarios, would result in increasingly additional time being spent on, and resources wasted in, duplicative research. The IPAB decision is completely silent as to the standard of proof and hence the evidentiary basis to prove significant enhancement of efficacy is unclear. Only more instances of application of Section 3(d) will give a clearer picture. From a rudimentary understanding of the science involved, it seems a far stretch to imagine that the IPAB or the courts will be in a position to provide any sort of guidance as to what type of evidence may be needed for a given class of drug. That being said, pharmaceutical companies would have trouble in deciding ex ante when to file the patent application and most logically, they would err on the side of caution, thereby postponing the patent application filing date. As a consequence, the evidentiary requirements would result in greater social waste and economic inefficiency. Whether, this is an additional cost that can be ignored in light of the overall increased social benefit due to Section
3(d) needs further detailed analysis. Any action, including the passing of Section 3(d) and any decision dealing with the evidentiary requirement of Section 3(d), has its pros and cons and to reach a sound final decision, one must: (a) decipher the pros and cons, or in the eyes of the economists, costs and benefits; and (b) weigh these costs and benefits to make a reasonable decision as to whether the benefits are higher than the costs or vice-versa. However, neither the IPAB, nor the Patent Controller nor the legislature, seems to have paid any attention to the issues highlighted in this paper. This paper provides the basic analytical framework to these potential issues. In doing so, it shows the way towards deciphering how Section 3(d) may serve as a blueprint for spreading the seeds of change as regards patent policy with specific reference to the delicate balance to be achieved between the necessity of discouraging illegitimate evergreening of patents on the one hand and encouraging legitimate incremental innovation on the other. At the beginning of this article, the authors had noted that the article would not deal in any level of detail with the public policy debate surrounding the existence of Section 3(d) itself, that is, to curb certain alleged illegitimate patent practices. However, as a concluding thought, the authors wish to point out only one thing the Novartis / Gleevec case, in our opinion, may not be the most appropriate set of facts for innovator companies to argue that protecting new forms of known substances is important. The marketing approval obtained by Novartis for its drug Gleevec, permits the marketing of the imatinib mesylate salt form, without this approval being limited to any particular crystalline form, let alone the beta crystalline form.237 The Orange Book listing for the drug Gleevec, among others, lists both US 5521164 and US 6894051, the latter being the US patent corresponding to the patent application rejected by the IPAB under Section 3(d), i.e., claiming the beta crystalline form of imatinib mesylate.238 US 5521164 was the admitted prior art before the IPAB and specifically claimed salt forms of the imatinib free base and the description stated239 that the salt could be formed using methane-sulphonic acid. The interesting point to be noted is that as per the FDA regulations governing the listing of patents in the Orange Book,240 polymorph patents, such as the one covering the beta crystalline form of
237
See Chemistry Review - Gleevec (imatinib mesylate) Tablets 100 mg and 400 mg, Application No. NDA 21-588, as available at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/021588s000_GleevecTOC.cfm, (last visited on 10th March, 2012) 238 See Orange Book, as available from http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021588&Pro duct_No=001&table1=OB_Rx (last visited on 10th March, 2012) 239 One argument that was heavily contested before the IPAB was whether the prior art patent actually enabled a skilled person to derive the imatinib mesylate salt 240 21 CFR 314.53.
imatinib mesylate salt, can be listed in the Orange Book for a given drug only if they are bioequivalent. In other words, the beta crystalline form of imatinib mesylate salt appears to be considered as bio-equivalent / a therapeutic substitute for imatinib mesylate salt as such. Logically, therefore, the clinical trials for Gleevec and the corresponding approval from the FDA are not specifically limited to the beta crystalline form of the imatinib mesylate salt. However, by the claim language and the description in the prior art patent US 5521164, the patentee appears to have ended the patent race / R&D race, so to speak, with regard to the various salts of the imatinib free base, including imatinib mesylate. The question, therefore, is this: did the patentee in this case, really require an incentive (in the form of a patent) just for the beta crystalline form? This is a question, cannot, of course, be answered within the scope of this paper. However, in the opinion of the authors, this question may definitely be of importance in adjudging the validity of Novartiss patent application for Gleevec, before the Supreme Court of India.

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SOWING THE SEEDS OF CHANGE?

Electronic copy available at: http://ssrn.com/abstract=2154396

Electronic copy available at: http://ssrn.com/abstract=2154396

Adarsh Ramanujan, Rajarshi Sen 3

establish increased therapeutic effect, what else is necessary to establish enhancement of

Ibid. See, Novartis IPAB, supra note 7, at paragraph 10(V).

Adarsh Ramanujan, Rajarshi Sen 11

Adarsh Ramanujan, Rajarshi Sen 12

Novartis IPAB, supra note 7, at paragraph 9(xvii).

Adarsh Ramanujan, Rajarshi Sen 29

interpreted to apply to all factual situations.

Therefore, in SCENARIO 1, the patent

See supra Part-III(A) of this paper.

Adarsh Ramanujan, Rajarshi Sen 37

Adarsh Ramanujan, Rajarshi Sen 50

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